Pyrimidine-2-amine compounds and their use as inhibitors of jak kinases

This invention relates to compounds, or a pharmaceutically acceptable salt thereof, and to pharmaceutical compositions containing these compounds or salts that are useful as modulators of the JAK pathway or as inhibitors of JAK kinases, especially JAK2. Also described are methods of using these compounds or their pharmaceutically acceptable salts and pharmaceutical compositions in the treatment of diseases and conditions associated with JAK activity.

BACKGROUND OF THE INVENTION [0002] Protein kinases represent a large family of structurally related enzymes that are responsible for the control of many signal transduction processes in cells (see, e.g., Hardie and Hanks, The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA, 1995). It is believed that protein kinases have evolved from a common inherited gene by maintaining their catalytic structure and function. Almost all kinases contain a similar catalytic domain of 250-300 amino acids. Kinases can be classified into families for their phosphorylated substrates (e.g., protein-tyrosine, proteinserine / threonine, lipid, etc.). Sequence motifs that normally correspond to each of these families have been identified (see, e.g., Hanks and Hunter, (1995), FASEB J. 9: 576-596, Knighton et al., (1991), Science 253: 407-414; Hiles et al. (1992), Cell 70: 419-429; Kunz et al. (1993), Cell 73: 585-596; Garcia-Bustos et al. (1994), EMBO J. 13: 2352-2361).

[0003] JAK kinases (called JAnus Kinases, Janus kinases) are a family of cytoplasmic protein tyrosine kinases including JAK1, JAK2, JAK3 and TYK2. Each of the JAK kinases is selective for the receptors of specific cytokines, although many JAK kinases may depend on a particular cytokine or signaling pathways. Research suggests that JAK3 associates with the common gamma chain (yc) of various cytokine receptors. JAK3, in particular, selectively binds to receptors and is part of the cytokine signaling pathway for IL-2, IL4, IL-7, IL-9, IL-15 and IL-21. JAK1 interacts with, inter alia, cytokine receptors IL-2, IL-4, IL-7, IL-9 and IL-21, while JAK2 interacts with, inter alia, receptors for IL-9 and TNF-α. After binding of specific cytokines to their receptors (eg IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), this leads to oligomerization of the receptor, resulting in the cytoplasmic tails of associated JAK kinases brought to the approximation and facilitating the transphosphorylation of tyrosine residues on the JAK kinase. This transphosphorylation leads to activation of the JAK kinase.

[0004] Phosphorylated JAK kinases bind different STAT (Signal Transducer and Activator of Transcription) proteins. STAT proteins, which are DNA-binding proteins activated by phosphorylation of tyrosine residues, function as both signal molecules and transcription factors, and ultimately bind to specific DNA sequences occurring within the cytokine-responsive gene promoters (Leonard et al., (2000), J Allergy Clin. Immunol. 105: 877-888). JAK / STAT signaling plays a role in mediating many abnormal immune responses such as allergies, asthma, autoimmune diseases

Such as transplant rejection (allograft), rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis as well as in solid and hematological cancers such as leukemia and lymphomas. For a review of the pharmaceutical interventions of the JAK / STAT pathway, see Frank, (1999), Mol. Med. 5: 432: 456 and Seidel et al. (2000), Oncogene

19: 2645-2656.

[0005] As described above, JAKs are the basic components of a variety of signal transduction pathways that regulate important cellular functions, including cell survival, proliferation, differentiation and apoptosis. Interfering with JAK activity may lead to the loss of a significant signal transduction pathway, thereby interfering with the normal cellular processes needed for cell survival. Therefore, it is important to selectively inhibit specific JAKs that are involved in various disease states.

[0006] JAK2 associates with cytokine receptors and is necessary for signal transduction by mediating tyrosine phosphorylation. JAK2 activity is regulated by a series of interactions, beginning with binding to specific domains at the receptors, suppression of activation by the pseudokhase domain, and the need for phosphorylation in the activation loop. Recent studies indicate the role of dysregulation of JAK2 kinase activity by chromosomal translocations in hematopoietic tumors and mutations in the pseudokinase domain in the spectrum of myeloproliferative diseases (Ihle, JN et al., Current Opinion in Genetics and Development (2007) 17: 1, 8-14.

[0007] Furthermore, JAK2 has been implicated in the upregulation of the angiotensinogen promoter activity in hypertrophy and ischemia (Mascareno E, et al (2000) Mol. Cell. Biochem., 212: 171-175; and Mascareno E, and et al. (2001) Circulation, 104: 1). One particular tyrphostin, AG490, selectively inhibits JAK2 and has been proposed for the treatment of cancer (Meydan N, et al. (1996) Nature, 379: 645). The administration of tyspfostin AG490 has been suggested in achieving cardioprotection on ischemia / reperfusion hearts (Mascareno E, et al. (2000) Mol. Cell. Biochem., 212: 171 and Mascareno E, et al. (2001) Circulation, 104: 1). TG101209, a JAK2-selective compound has recently been shown to be effective in suppressing mutations in myeloproliferative disorders (Pardanani A, et al. (2007) Leukemia, 1-11).

[0008] JAK3, in particular, plays a role in a variety of biological processes. For example, the proliferation and survival of mouse mast cells induced by IL-4 and IL-9 has been shown to depend on JAK3 signaling and the gamma chain (Suzuki et al., (2000), Blood 96: 2172-2180). JAK3 also plays a key role in IgE receptor-dependent mast cell degranulation responses (Malaviya et al., (1999), Biochem. Biophys. Res. Commun. 257: 807-813), and inhibition of JAK3 kinase has been shown to prevent Type I hypersensitivity reactions , including anaphylaxis (Malaviya et al., (1999), J. Biol. Chem. 274: 2702827038). JAK3 inhibition also appeared to lead to suppression of the immune system in allograft rejection (Kirken, (2001), Transpl. Proc. 33: 32683270). JAK3 also play a role in the mechanism involved in the early and late stages of rheumatoid arthritis (Muller-Ladner et al. (2000), J. Immunol. 164: 3894-3901); familial amyotrophic lateral sclerosis (Trieu et al., (2000),

-3 Biochem. Biophys. Res. Commun. 267: 22-25); leukemia (Sudbeck et al., (1999), Clin. Cancer

Res. 5: 1569-1582); mycosis fungoides, a form of T-cell lymphoma (Nielsen et al. (1997), Prac. Natl Acad. Sci. USA 94: 6764-6769); and abnormal cell growth (Yu et al., (1997), J. Immunol. 159: 5206-5210; Catlett-Falcone et al., (1999), Immunity 10: 105-115).

[0009] JAK kinases, including JAK3, are expressed in large amounts in primary leukemic cells in children with acute lymphoblastic leukemia, the most common form of cancer in children, and studies show the relationship between STAT activation in some cells and apoptosis regulating signals (Demoulin and al., (1996), Mol. Cell Biol. 16: 4710-6; Jurlander et al., (1997), Blood. 89: 4146-52; Kaneko et al. (1997), Clin. Exp. Immun 109: 185-193, and Nakamura et al. (1996), J. Biol. Chem. 271: 19483-8). It is known that they are also important for the differentiation, function and survival of lymphocytes. JAK-3, in particular, plays a key role in the function of lymphocytes, macrophages and mast cells. Considering the importance of this JAK kinase, compounds that modulate the JAK pathway, including those selective for JAK3, may be useful for treating diseases or conditions mediated by lymphocyte, macrophage or mast cell function (Kudlacz et al., (2004) Am. J. Transplant 4: 51-57; Changelian (2003) Science 302: 875-878 ). Conditions in which targeting the JAK pathway or modulating JAK kinases, especially JAK3, is considered as therapeutically useful, include leukemia, lymphoma, graft rejection (e.g., rejection of pancreatic adipose grafts), bone marrow transplantation (e.g., graft versus host disease). ), autoimmune diseases (e.g., RA, type I diabetes) and inflammation (e.g., asthma, allergic reactions). Conditions that can benefit from JAK2 inhibition are discussed in more detail below. Transplant 4: 51-57; Changelian (2003) Science 302: 875-878). Conditions in which targeting the JAK pathway or modulating JAK kinases, especially JAK3, is considered as therapeutically useful, include leukemia, lymphoma, graft rejection (e.g., rejection of pancreatic adipose grafts), bone marrow transplantation (e.g., graft versus host disease). ), autoimmune diseases (e.g., RA, type I diabetes) and inflammation (e.g., asthma, allergic reactions). Conditions that can benefit from JAK2 inhibition are discussed in more detail below. Transplant 4: 51-57; Changelian (2003) Science 302: 875-878). Conditions in which targeting the JAK pathway or modulating JAK kinases, especially JAK3, is considered as therapeutically useful, include leukemia, lymphoma, graft rejection (e.g., rejection of pancreatic adipose grafts), bone marrow transplantation (e.g., graft versus host disease). ), autoimmune diseases (e.g., RA, type I diabetes) and inflammation (e.g., asthma, allergic reactions). Conditions that can benefit from JAK2 inhibition are discussed in more detail below. rejection of pancreatic fistulas), use in bone marrow transplantation (e.g., graft versus host disease), autoimmune diseases (e.g., RA, type I diabetes) and inflammation (e.g., asthma, allergic reactions). Conditions that can benefit from JAK2 inhibition are discussed in more detail below. rejection of pancreatic fistulas), use in bone marrow transplantation (e.g., graft versus host disease), autoimmune diseases (e.g., RA, type I diabetes) and inflammation (e.g., asthma, allergic reactions). Conditions that can benefit from JAK2 inhibition are discussed in more detail below.

[0010] In the light of the numerous conditions that are contemplated as being able to benefit from treatment involving modulation of the JAK pathway, it immediately becomes apparent that novel compounds that modulate JAK pathways and methods of using these compounds should provide significant therapeutic benefits to a wide range of patients.

Related Disclosures [0011] Patents and patent applications related to the modulation of the JAK pathway include: Pat. US Names 5728536; 6080747; 6080748; 6133305; 6177433; 6210654; 6313130; 6316635; 6433018; 6486185; 6506763; 6528509; 6593357; 6608048; 6610688; 6635651; 6677368; 6683082; 6696448; 6699865; 6777417; 6784195; 6825190; 6506763; 6784195; 6528509; 6608048; 7105529; 6699865; 6825190; 6815439; 6949580; 7056944; 6998391; 7074793; 6969760; Pub. Appl. Stalemate. US Names 2001/0007033 A1; 2002/0115173 A1; 2002/0137141 A1;

2003/0236244 A1; 2004/0102455 A1; 2004/0142404 A1; 2004/0147507 A1; and 2004/0214817 A1; and Publication of the International Patent Application No. WO 95/03701 A1; WO 99 / 15500A1; WO 00/00202A1; WO 00/10981A1; WO 00/ 47583A1; WO 00 / 51587A2; WO 00/55159A2; WO 01 / 42246A2; WO 01 / 45641A2; WO 01 / 52892A2; WO 01 / 56993A2; WO 01 / 57022A2; WO 01 / 72758A1; WO 02 / 00661A1; WO 02 / 43735A1; WO 02 / 48336A2; WO 02 / 060492A1; WO 02 / 060927A1; WO 02 / 096909A1; WO 021102800A1; WO 03 / 020698A2; WO 03 / 048162A1; WO 03 / 101989A1; WO 2004 / 016597A2; WO 2004 / 041789A1; WO

-42004 / 041810A1; WO 2004 / 041814A1; WO 2004 / 046112A2; WO 2004 / 046120A2; WO

2004 / 047843A1; WO 2004 / 058749A1; WO 2004 / 058753A1; WO 2004 / 085388A2; WO

2004 / 092154A1; WO 2005 / 009957A1; WO 2005 / 016344A1; WO 2005 / 028475A2; WO

2005 / 033107A1; WO 2007/089768; and WO2004 / 041810.

[0012] WO 2008/003766, WO 2007/053776, and WO 2007/042786 disclose pyrimidine derivatives for use in the treatment of kinase mediated diseases; WO 2004/005282 describes pyrimidine derivatives for the treatment of proliferative diseases; Paul et al., J. Med. Chem. 1993, 36, 2716 to 2725 describe pyrimidinamines as Mediators Release Inhibitors.

SUMMARY OF THE INVENTION This invention is devoted to compounds 2-pyrimidinamines, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these compounds, or pharmaceutically acceptable salts thereof, for use in treating conditions in which modulation of the JAK pathway or inhibition of JAK kinases, in in particular JAK2, may be therapeutically useful.

[0014] Accordingly, in one aspect, the invention is directed to compounds of formula (Ia):

<img file="PL2265607T3_D0001.tif" />

or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1 or 2; m is 0, 1 or 2;

Y is selected from the group consisting of = C (R.⁶) - i = N-;

R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷ and -R⁹-OR⁶;

every R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

every R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents

Selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, nheterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a (where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, -R⁸N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted aralkyl, and wherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted by one. or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R⁵ is N-heterocyclyl, wherein the N-heterocyclyl nitrogen is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl,optionally substituted heteroarylalkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2); and the N-heterocyclyl carbon atom is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl,⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸-S (O) pR⁶ (where p is 0, 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted

-6 -aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; and every R⁹ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; with the proviso that at least the substituent on R⁴ is a bridged N-heterocyclyl;

as an isolated stereoisomer or a mixture thereof.

[0015] In another aspect, the invention is directed to compounds of formula (Ia):

<img file="PL2265607T3_D0002.tif" />

or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1 or 2; m is 0, 1 or 2;

Y is selected from the group consisting of = C (R.⁶) - i = N-;

R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷ and -R⁹-OR⁶;

every R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

every R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

-7R⁴ is selected from the group consisting of heteroaryl, wherein the heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a (where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) R⁹-N (R^6a) S (O) 2 R^7awhere every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted aralkyl, and wherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted by one. or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl; or

R⁴ is selected from the group consisting of aryl, wherein the aryl is independently optionally substituted with one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁶-S (O) pR^6a (where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁶C (O) N (R^6a) R^7a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹N (R^6a) S (O) 2 R^7awhere every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted aralkyl, and wherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted by one. or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R⁵ is N-heterocyclyl, wherein the N-heterocyclyl nitrogen is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl,optionally substituted heteroarylalkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2); and the N-heterocyclyl carbon atom is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, optionally substituted

-8-olary, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl , optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸-S (O) pR⁶ (where p is 0, 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; and every R⁹ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain;

provided that R⁵ is a bridged N-heterocyclyl; as an isolated stereoisomer or a mixture thereof.

[0016] Preferred embodiments are set forth in dependent claims 2 to 22.

[0017] In another aspect, the invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound of the invention as described herein as an isolated stereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, the invention is directed to a compound for use in methods of treating a disease or condition associated with JAK activity in a mammal, in particular

JAK2, the methods comprising administering to the mammal a therapeutically effective amount of a compound of the invention as described above as an isolated stereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the invention as described above as an isolated stereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, this invention provides assays to determine the efficacy of the compounds of the invention in inhibiting JAK activity, in particular JAK2 activity in a cell based assay.

[0020] In another aspect, this invention provides a method of inhibiting JAK kinase activity comprising contacting in vitro JAK2 kinase with an amount of a compound effective to inhibit JAK kinase activity, wherein the compound is selected from the compounds of this invention, or pharmaceutically acceptable salts thereof, as herein described.

In another aspect, this invention provides a compound for use in a method of inhibiting JAK kinase activity comprising contacting a JAK2 kinase in a cell with an amount of a compound effective to inhibit JAK2 kinase activity, wherein the compound is selected from compounds of the invention, or a pharmaceutically acceptable salt thereof. as described here.

[0022] In another aspect, the present invention provides a compound for use in a method of treating a T-cell mediated autoimmune disease comprising administering to a patient suffering from such an autoimmune disease an amount of a compound effective to treat an autoimmune disease wherein the compound is selected from the compounds of the invention. , or a pharmaceutically acceptable salt thereof, as described herein.

In another aspect, this invention provides a compound for use in a method of treating allograft rejection in a mammal, preferably a transplant recipient, comprising administering to the mammal a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, as described herein.

[0024] In another aspect, the present invention provides a compound for use in a method of treating type IV hypersensitivity reactions in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, as described herein.

[0025] In another aspect, the present invention provides a compound for use in a method of inhibiting a signal transduction cascade in which the JAK2 kinase plays a role, comprising contacting the cell with the expression of the receptor involved in such signaling cascade with an inhibitory amount of a compound of the invention, or a pharmaceutically acceptable amount thereof. salt, as described here.

[0026] In another aspect, the present invention provides a compound for use in a JAK kinase-mediated disease or condition in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof as described herein. .

[0027] In another aspect, the present invention provides a compound for use in the treatment of a JAK2 kinase-mediated myeloproliferative disorder (MPD) such as polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) or tumors. malignancies mediated by JAK in a mammal, comprising administering to a mammal in need of a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, as described herein. DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS [0028] The following terms used in the present description and appended claims, unless otherwise indicated, have the indicated meanings:

"Amino" refers to the radical -NH2.

"Carboxy" refers to the radical -C (O) OH.

"Cyano" refers to the radical -CN.

"Nitro" refers to the -NO2 radical.

"Oxa" refers to the radical -O-.

"Okso" refers to the radical = O.

"Tioco" refers to the radical = S.

"Alkyl" refers to a fully saturated, straight or branched chain hydrocarbon radical consisting only of carbon atoms and hydrogen atoms having from one to twelve carbon atoms, one to eight carbon atoms or one to six carbon atoms and which is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2 -metyloheksyl. For purposes of the present invention, the term "lower alkyl" refers to an alkyl radical having one to six carbon atoms.

[0029] "Optionally substituted alkyl" refers to an alkyl radical as defined above that is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) R²⁰, -N (R.²⁰) 2, -C (O) R²⁰, -C (O) OR²⁰ -C (O) N (R²⁰) 2, -N (R.²⁰) C (O) OR²⁰, -N (R.²⁰) C (O) R²⁰, N (R.²⁰) S (O) 2 R²⁰, -S (O) tOR²⁰ (where t is 1 or 2), -S (O) pR²⁰ (where p is 0, 1 or 2), and -S (O) 2N (R.²⁰) 2, where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl,

-He optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or two R²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl.

[0030] "Alkenyl" refers to a straight or branched hydrocarbon radical consisting only of carbon atoms and hydrogen atoms containing at least one double bond having from one to twelve carbon atoms, or one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, for example, ethenyl, prop-1-enyl, but-1-enyl, pent-1enyl, penta-1,4-dienyl.

[0031] "Optionally substituted alkenyl" refers to an alkenyl radical as defined above, which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) -R²⁰, -N (R.²⁰) - C (O) R²⁰, -C (O) OR²⁰ -C (O) N (R²⁰) 2, N (R.²⁰) C (O) OR²⁰, -N (R.²⁰) C (O) R²⁰, -N (R.²⁰) S (O) 2 R²⁰, -S (O) tOR²⁰ (where t is 1 or 2), S (O) pR²⁰ (where p is 0, 1 or 2), and -S (O) 2N (R.²⁰) 2 where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or two Rs.²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted Nteroaryl.

[0032] "Alkynyl" refers to a straight or branched hydrocarbon radical consisting only of carbon atoms and hydrogen atoms containing at least one triple bond, optionally containing at least one double bond, having from two to twelve carbon atoms, or two to eight carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl.

[0033] "Optionally substituted alkynyl" refers to an alkynyl radical as defined above, which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) -R²⁰, -N (R.²⁰) 2, -C (O) R²⁰, -C (O) OR²⁰, -C (O) N (R.²⁰) 2, N (R.²⁰) C (O) R²⁰, -N (R.²⁰) C (O) R²⁰, -N (R.²⁰) S (O) 2 R²⁰, -S (O) tOR²⁰ (where t is 1 or 2), S (O) pR²⁰ (where p is 0, 1 or 2), and -S (O) 2N (R.²⁰) 2 where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or two Rs.²⁰, together with the common nitrogen atom to which they are both

When attached, form an optionally substituted N-heterocyclyl or an optionally substituted Nteroaryl.

[0034] "Straight or branched alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group consisting solely of carbon and hydrogen, not containing unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene. The alkylene chain is attached to the rest of the molecule via a single bond and to the radical group via a single bond. The point of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through one carbon in the alkylene chain or through any two carbon atoms in the chain.

[0035] "Optionally substituted straight or branched alkylene chain" refers to an alkylene chain as defined above, which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl , oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) -R²⁰, N (R.²⁰) 2, -C (O) R²⁰, -C (O) OR²⁰, -C (O) N (R.²⁰) 2, -N (R.²⁰) C (O) OR²⁰, -N (R.²⁰) C (O) R²⁰, N (R.²⁰) S (O) 2 R²⁰, -S (O) tOR²⁰ (where t is 1 or 2), -S (O) pR²⁰ (where p is 0, 1 or 2), and -S (O) 2N (R.²⁰) 2 where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or two Rs.²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl.

[0036] "Straight or branched alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the remainder of the molecule to a radical group consisting solely of carbon and hydrogen containing at least one double bond and having from one to twelve carbon atoms, for example, ethenylene, propenylene, n-butenylene. The alkenylene chain is attached to the rest of the molecule via a double bond or a single bond and to the radical group via a double bond or a single bond. The point of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbon atoms contained in the chain.

[0037] "Optionally substituted straight or branched alkenylene chain" refers to an alkenylene chain as defined above, which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl , oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) R²⁰, -N (R.²⁰) 2, -C (O) R²⁰, -C (O) OR²⁰, -C (O) N (R.²⁰) 2, -N (R.²⁰) C (O) OR²⁰, -N (R.²⁰) C (O) R²⁰, N (R.²⁰) S (O) 2 R²⁰, -S (O) tOR²⁰ (where t is 1 or 2), -S (O) pR²⁰ (where p is 0, 1 or 2), and -S (O) 2N (R.²⁰) 2 where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl,

- optionally a substituted heterocyclyl, an optionally substituted heterocyclylalkyl, an optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl.

[0038] "Straight or branched alkynylene chain" refers to a straight or branched divalent hydrocarbon chain combining the rest of the molecule with a radical group consisting only of carbon and hydrogen, containing at least one triple bond and having from two to twelve carbon atoms, example, propynylene, n-butynylen. The alkynylene chain is attached to the rest of the molecule via a single bond and to the radical group via a double bond or a single bond. The point of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbon atoms contained in the chain.

[0039] "Optionally substituted straight or branched alkynylene chain" refers to an alkynylene chain as defined above, which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl , cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR²⁰, -OC (O) -R²⁰, -N (R.²⁰) 2, -C (O) R²⁰, -C (O) OR²⁰, -C (O) N (R.²⁰) 2, N (R.²⁰) C (O) OR²⁰, -N (R.²⁰) C (O) R²⁰, -N (R.²⁰) S (O) 2 R²⁰, -S (O) tOR²⁰ (where t is 1 or 2), S (O) pR²⁰ (where p is 0, 1 or 2), and -S (O) 2N (R.²⁰) 2 where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or two Rs.²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted Nteroaryl.

[0040] "Aryl" means a hydrocarbon radical of a ring system containing hydrogen, 6 to 14 carbon atoms and at least one aromatic ring. For the purposes of the present invention, the aryl radical may be a monocyclic, bicyclic or tricyclic system and which may include spiro ring systems. The aryl radical is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the aryl radical. The aryl radicals include aryl radicals derived from acenaphthylene, anthracene, azulene, benzene, 6,7,8,9-tetrahydro-5H-benzo [7] annulene, fluoren, as-indacene, s-indacene, indane, indene, naphthalene, phenol and phenanthrene.

[0041] "Optionally substituted aryl" refers to an aryl radical as defined above, which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro. optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,

- optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R²¹-OR²⁰, -R²¹-OC (O) -R²⁰, -R²¹-N (R²⁰) 2, -R²¹-C (O) R²⁰, R²¹-C (O) OR²⁰, -R²¹-C (O) N (R²⁰) 2, -R²¹-OR²²-C (O) N (R²⁰) 2, -R²¹-N (R²⁰) C (O) OR²⁰, -R²¹N (R²⁰) C (O) R²⁰, -R²¹-N (R²⁰) S (O) 2 R²⁰, -R²¹-C (= NR²⁰) N (R²⁰) 2, -R²¹-S (O) t²⁰ (where t is 1 or 2), -R²¹-S (O) pR²⁰ (where p is 0, 1 or 2), and -R²¹-S (O) 2 N (R²⁰) 2, where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or two Rs.²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted Nterhodyclyl or optionally substituted N-heteroaryl, each R²¹ is independently a direct bond or a straight or branched alkylene or alkenylene chain, and _R22 is a straight or branched alkylene or alkenylene chain.

[0042] "Aralkyl" refers to a radical of the formula -Rb-Rc, wherein Rb is an alkylene chain as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl.

[0043] "Optionally substituted aralkyl" refers to an aralkyl radical as defined above in which the alkylene chain of the aralkyl radical is an optionally substituted alkylene chain as defined above, and each aryl radical of the aralkyl radical is an optionally substituted aryl radical as defined above.

[0044] "Aralkenyl" refers to a radical of the formula -Rd-Rc, wherein Rd is an alkenylene chain as defined above and Rc is one or more aryl radicals as defined above.

[0045] "Optionally substituted aralkenyl" refers to an aralkenyl radical as defined above, wherein the alkenyl alkene chain is an optionally substituted alkenylene chain as defined above, and each aralkenyl radical of the aryl is an optionally substituted aryl radical as defined above.

[0046] "Aralkynyl" refers to a radical of the formula -ReRc, wherein Re is an alkynylene chain as defined above and Rc is one or more aryl radicals as defined above.

[0047] "Optionally substituted aralkynyl" refers to an aralkynyl radical as defined above, wherein the alkynylene chain of the aralkynyl radical is an optionally substituted alkynylene chain as defined above, and each aryl radical of the aralkynyl radical is an optionally substituted aryl radical as defined above.

[0048] "Cycloalkyl" refers to a stable non-aromatic, monocyclic or polycyclic hydrocarbon radical consisting solely of carbon atoms and hydrogen atoms that includes fused, spiro or bridged ring systems having from three to fifteen carbon atoms, or having from three to ten carbon atoms, or from five to seven carbon atoms, and which is saturated or unsaturated and is attached to the rest of the molecule by a single bond. For purposes of the present invention, a bridged ring system is a system in which its two non-adjacent ring atoms are connected by an atom or group of atoms, the atom or group of atoms being a bridging element. An example of a bridged (monovalent) cycloalkyl radical is norbornanyl (also called bicyclo [2.2.1] heptanyl). For purposes of the present invention, the non-bridged ring system is a system that does not contain any bridging element as described above. For purposes of the present invention, a fused ring system is a system in which two adjacent ring atoms are connected by an atom or group of atoms. An example of a condensed (monovalent) cycloalkyl radical is decahydronaphthalenyl (also called decalinyl). For purposes of the present invention, a spiro ring system is a system in which two rings are connected by means of a single carbon (quaternary) atom. An example of a (monovalent) spiro cycloalkyl radical is spiro [5.5] undecanyl. Monocyclic cycloalkyl radicals do not include cycloalkyl spiro, fused or bridged radicals, but include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include condensed, spiro or bridged cycloalkyl radicals, for example C10 radicals such as adamantanyl (bridged) and decalinyl (condensed), and C7 radicals such as bicyclo [3.2.0] heptanyl (fused), norbornanyl and norbornenyl (bridged) ), as well as substituted polycyclic radicals, for example, substituted C7 radicals such as 7.7-dimethyl-bicyclo [2.2.1] heptanyl (bridged).

[0049] "Optionally substituted cycloalkyl" refers to a cycloalkyl radical as defined above, which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo , cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl optionally substituted heteroaryl,optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R²¹-OR²⁰, -R²¹-OC (O) -R²⁰, -R²¹-N (R²⁰) 2, R²¹-C (O) R²⁰, -R²¹-C (O) OR²⁰, -R²¹-C (O) N (R²⁰) 2, -R²¹-N (R²⁰) C (O) OR²⁰, -R²¹-N (R²⁰) C (O) R²⁰, -R²¹-N (R²⁰) S (O) 2 R²⁰, -R²¹-C (= NR²⁰) N (R²⁰) 2, -R²¹-S (O) t²⁰ (where t is 1 or 2), -R²¹S (O) pR²⁰ (where p is 0, 1 or 2), and -R²¹-S (O) 2 N (R²⁰) 2, where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted

-16 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two Rs²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹ is independently a direct bond or a straight or branched alkylene or alkenylene chain.

[0050] "Cycloalkylalkyl" refers to a radical of the formula -RbR9 where Rb is an alkylene chain as defined above and Rg is a cycloalkyl radical as defined above.

[0051] "Optionally substituted cycloalkylalkyl" refers to a cycloalkylalkyl radical as defined above, wherein the alkylene chain of the cycloalkylalkyl radical is an optionally substituted alkylene chain as defined above, and the cycloalkyl radical of the cycloalkylalkyl radical is an optionally substituted cycloalkyl radical as defined above.

[0052] "Cycloalkylalkenyl" refers to a radical of the formula -RdR9 where Rd is an alkenylene chain as defined above and Rg is a cycloalkyl radical as defined above.

[0053] "Optionally substituted cycloalkylalkenyl" refers to a cycloalkylalkenyl radical as defined above, wherein the alkenylene chain of a cycloalkylalkenyl radical is an optionally substituted alkenylene chain as defined above, and the cycloalkyl radical of the cycloalkylalkenyl is an optionally substituted cycloalkyl radical as defined above.

[0054] "Cycloalkylalkynyl" refers to a radical of the formula -ReR6 where Re is an alkynylene radical as defined above and Rg is a cycloalkyl radical as defined above.

[0055] "Optionally substituted cycloalkylalkynyl" refers to a cycloalkylalkynyl radical as defined above, wherein the alkynylene chain of the cycloalkylalkynyl radical is an optionally substituted alkynylene chain as defined above, and the cycloalkyl radical of the cycloalkylalkynyl radical is an optionally substituted cycloalkyl radical as defined above.

[0056] "Halo" refers to bromine, chlorine, fluorine or iodine.

[0057] "Haloalkyl" refers to an alkyl radical as defined above that is substituted with one or more halo radicals as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl -2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl.

[0058] "Haloalkenyl" refers to an alkenyl radical as defined above that is substituted with one or more halo radicals as defined above.

[0059] "Haloalkynyl" refers to an alkynyl radical as defined above that is substituted with one or more halo radicals as defined above.

[0060] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic radical of a ring system that contains one to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless otherwise specifically provided herein, a heterocyclyl radical may optionally be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include bridged or spiro-ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of bridged heterocyclyl include, but are not limited to, azabicyclo [2.2.1] heptanyl, diazabicyclo [2.2.2] octanyl, azabicyclo [3.3.1] nonanyl,

6,9-methano-octahydropyrido [1,2-a] pyrazinyl, diazabicyclo [3.3.2] decanyl. A "bridged N-heterocyclyl" is a bridged heterocyclyl containing at least one nitrogen, but which optionally contains up to four additional heteroatoms selected from O, N and S. For the purposes of the present invention, an un-bridged ring system is a system in which no two non-adjacent each other, ring atoms are connected by an atom or group of atoms. Examples of heterocyclyl radicals include, but are not limited to, dioxolanyl, 1,4-diazepanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, octahydro-1H-pyrrolo [3,2-c] pyridinyl, octahydro-1H-pyrrolo [2] , 3-c] pyridinyl, octahydro-1H-pyrrolo [2,3-b] pyridinyl, octahydro-1H-pyrrolo [3,4-b] pyridinyl, octahydropyrrolo [3,4-c] pyrrolyl,

[0061] "Optionally substituted heterocyclyl" refers to a heterocyclyl radical as defined above which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo , cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R²¹-18OR²⁰, -R²¹-OC (O) -R²⁰, -R²¹-N (R²⁰) 2, -R²¹-C (O) R²⁰, -R²¹-C (O) OR²⁰, -R²¹-C (O) N (R²⁰) 2, -R²¹N (R²⁰) C (O) OR²⁰, -R²¹-N (R²⁰) C (O) R²⁰, -R²¹-N (R²⁰) S (O) 2 R²⁰, -R²¹-C (= NR²⁰) N (R²⁰) 2, -r²¹S (O) t²⁰ (where t is 1 or 2), -R²¹-S (O) pR²⁰ (where p is 0, 1 or 2), and -R²¹S (O) 2 N (R²⁰) 2, where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or two Rs.²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹ is independently a direct bond or a straight or branched alkylene or alkenylene chain.

[0062] "N-heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and wherein the point of attachment of the N-heterocyclyl radical to the remainder of the molecule may be via a nitrogen atom in the N-heterocyclyl radical or via a carbon in the radical N- heterocyclyl.

[0063] "Optionally substituted N-heterocyclyl" refers to an N-heterocyclyl as defined above, which is optionally substituted with one or more substituents as defined above for optionally substituted heterocyclyl.

[0064] "Heterocyclylalkyl" refers to a radical of the formula -RbRh where Rb is an alkylene chain as defined above and Rh is a heterocyclyl radical as defined above, and when heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl can be attached to an alkylene chain on an atom nitrogen.

[0065] "Optionally substituted heterocyclylalkyl" refers to a heterocyclylalkyl radical as defined above, wherein the alkylene chain of the heterocyclylalkyl radical is an optionally substituted alkylene chain as defined above, and the heterocyclyl radical of the heterocyclylalkyl radical is an optionally substituted heterocyclyl radical as defined above.

[0066] "Heterocyclylalkenyl" refers to a radical of the formula -RdRh where Rd is an alkenylene chain as defined above and Rh is a heterocyclyl radical as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl can be attached to the alkenylene chain at Nitrogen.

[0067] "Optionally substituted heterocyclylalkenyl" refers to a heterocyclylalkenyl radical as defined above, wherein the alkenylene chain of the heterocyclylalkenyl is an optionally substituted alkenylene chain as defined above, and the heterocyclyl radical of the heterocyclylalkenyl is an optionally substituted heterocyclyl radical as defined above.

[0068] "Heterocyclylalkynyl" refers to a radical of the formula -ReRh where Re is an alkynylene chain as defined above and Rh is a heterocyclyl radical as defined

Above, and when heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkynylene chain on the nitrogen.

[0069] "Optionally substituted heterocyclylalkynyl" refers to a heterocyclyl alkynyl radical as defined above, wherein the alkynylene chain of the heterocyclyl alkynyl radical is an optionally substituted alkynylene chain as defined above, and the heterocyclyl radical of the heterocyclyl alkynyl is an optionally substituted heterocyclyl radical as defined above.

[0070] "Heteroaryl" refers to a radical of a 5- to 14-membered ring system containing hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring . The heteroaryl radical is typically, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl radical. For purposes of the present invention, the heteroaryl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include bridged or spiro-ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. For the purposes of the present invention, the aromatic ring of a heteroaryl radical need not contain a heteroatom if one ring of the heteroaryl radical contains a heteroatom. For example, benzo-fused heterocyclyls, such as 1,2,3,4-tetrahydroisoquinolin-7-yl, are considered "heteroaryl" for the purposes of this invention. Examples of heteroaryl radicals include, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1,4] dioxepinyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1H-benzo [b] azepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothienoate [ 3,2-d] pyrimidinyl, benzotriazolyl, benzo [4,6] imidazo [1,2-a] pyridinyl, carbazolyl, cinnolinyl,

-20-pyrazolyl, pyrazolo [3,4-d] pyrimidinyl, pyridinyl (pyridyl), pyrido [3,2-d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl (pyridazinyl), pyrrolyl, pyrrolopyrimidinyl , pyrrolopyridazinyl, pyrrolopyrazinyl, 2H-pyrido [3,2-b] [1,4] oxazinonyl, 1H-pyrido [2,3-b] [1,4] oxazinonyl, pyrrolopyridinyl such as 1H-pyrrole [2,3 -b] pyridinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 2,3,4,5-tetrahydrobenzo [b] oxepinyl, 6,7,8,9-tetrahydro-5H pyrido [2] , 3-b] indolyl, 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridinyl, 6,7,8,9-tetrahydro-5H pyrido [3,2-c] azepinyl, 5,6,7 , 8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta [4,5] thieno [2,3-d] pyrimidinyl, 5,6,7 , 8-tetrahydropyrido [4,5-c] pyridazinyl, 7,8,9,9a-tetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine-10 (11H) -onyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, 1,2,3,4-tetrahydroisoquinolin-7-yl, triazinyl, thieno [2,3d] pyrimidinyl, thienopyrimidinyl (e.g., thieno [3 , 2-d] pyrimidinyl), thieno [2,3-c] pyridinyl, thienopyridazinyl, thienopyrazinyl, and thiophenyl (thienyl).

[0071] "Optionally substituted heteroaryl" refers to a heteroaryl radical as defined above that is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo , cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R²¹OR²⁰, -R²¹-OC (O) -R²⁰, -R²¹-N (R²⁰) 2, -R²¹-C (O) R²⁰, -R²¹-C (O) OR²⁰, -R²¹-C (O) N (R²⁰) 2, -R²¹N (R²⁰) C (O) OR²⁰, -R²¹-N (R²⁰) C (O) R²⁰, -R²¹-N (R²⁰) S (O) 2 R²⁰2, -R²¹-C (= NR²⁰) N (R²⁰) 2, -R²¹S (O) t²⁰ (where t is 1 or 2), -R²¹-S (O) pR²⁰ (where p is 0, 1 or 2), and -R²¹S (O) 2 N (R²⁰) 2, where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or two Rs.²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹ is independently a direct bond or a straight or branched alkylene or alkenylene chain.

[0072] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the N-heteroaryl radical to the rest of the molecule may be through a nitrogen atom in the N-heteroaryl radical or via a carbon atom in the N- radical. heteroaryl.

[0073] "Optionally substituted N-heteroaryl" refers to N-heteroaryl as defined above, which is optionally substituted with one or more substituents as defined above for an optionally substituted heteroaryl.

[0074] "Heteroarylalkyl" refers to a radical of the formula -RbRi where Rb is an alkylene chain as defined above and R1 is a heteroaryl radical as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkylene chain on the atom nitrogen.

[0075] "Optionally substituted heteroarylalkyl" refers to a heteroarylalkyl radical as defined above, wherein the alkylene chain of the heteroarylalkyl radical is an optionally substituted alkylene chain as defined above, and the heteroaryl radical of the heteroarylalkyl radical is an optionally substituted heteroaryl radical as defined above.

[0076] "Heteroaralkenyl" refers to a radical of the formula -RdRi where Rd is an alkenylene chain as defined above and R1 is a heteroaryl radical as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkenylene chain on the atom nitrogen.

[0077] "Optionally substituted heteroarylalkenyl" refers to a heteroarylalkenyl radical as defined above, wherein the alkenylene chain of the heteroarylalkenyl radical is an optionally substituted alkenylene chain as defined above, and the heteroaryl radical of the heteroarylalkeyl radical is an optionally substituted heteroaryl radical as defined above.

[0078] "Heteroarylalkynyl" refers to a radical of the formula -ReRi where Re is an alkynylene chain as defined above and R1 is a heteroaryl radical as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be attached to the alkynylene chain on an atom nitrogen.

[0079] "Optionally substituted heteroarylalkynyl" refers to a heteroarylalkynyl radical as defined above, wherein the alkynylene chain of a heteroarylalkynyl is an optionally substituted alkynyl chain as defined above, and the heteroaryl radical of the heteroarylalkeic radical is an optionally substituted heteroaryl radical as defined above.

[0080] "Hydroxyalkyl" refers to an alkyl radical as defined above that is substituted with one or more hydroxy radicals (-OH).

[0081] "Hydroxyalkenyl" refers to an alkenyl radical as defined above that is substituted with one or more hydroxy (-OH) radicals.

[0082] "Hydroxyalkenyl" refers to an alkynyl radical as defined above that is substituted with one or more hydroxy (-OH) radicals.

[0083] Some of the chemical groups mentioned herein may be preceded by a shorthand notation indicating the total number of carbon atoms to be included in a given chemical group. E.g; C7-C12alkyl describes an alkyl group as defined above, having w

The amount of 7 to 12 carbon atoms and the C4-C12cycloalkylalkyl describe a cycloalkylalkyl group as defined above having a total of 4 to 12 carbon atoms. The total number of carbon atoms in the abbreviated notation does not include carbon atoms that may be in the substituents of the groups described.

[0084] A "stable compound" and "stable structure" are intended to indicate a compound that is sufficiently stable to survive secretion to a usable degree of purity from the reaction mixture, and formulation into an effective therapeutic agent.

[0085] "Mammal" means any vertebrate of the Mammalia class. People and domestic animals such as dogs, cats, pigs, cattle, sheep, goats, horses, rabbits are a special goal. Often, for the purposes of the present invention, the mammal is a human.

[0086] "Possible" or "optionally" means that the event or circumstances described below may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not exist. For example, "optionally substituted aryl" means that the aryl radical may be substituted or not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution. However, when the first functional group is described as "optionally substituted" and in turn, the substituents on the first functional group are also "optionally substituted" and so on, for the purposes of the invention, such iterations for the radicals to be optionally substituted are limited to three . Therefore, the groups described as substituents on the third iteration are not themselves optionally substituted. For example, if the R group is referred to herein as "optionally substituted aryl" (first iteration) and optional for "optionally substituted aryl" substituents include "optionally substituted heteroaryl" (second iteration) and optional substituents for "optionally substituted heteroaryl" include "optionally substituted cycloalkyl "(third iteration), optional substituents on the cycloalkyl may not be optionally substituted.

[0087] "Para" for the purposes of this invention refers to the position of a phenyl substituent or a six-membered heteroaryl ring with respect to another substituent on the ring; wherein said relative position is 1,4-substitution. That is, starting from one substituent attached to the first phenyl atom or six-membered heteroaryl ring and counting the atoms in the ring from the first atom, another substituent is on the 4-phenyl or heteroaryl six-membered ring, the relative orientation of the substituents around the phenyl or six-membered heteroaryl ring is "couple". For example, a compound of formula (Ia), as described above in the Summary of the Invention, is shown below as a compound of formula (Ia-1), wherein R⁵ is on the first atom of the phenyl ring, and nitrogen having R¹ is the fourth atom, then R⁵ and nitrogen having R¹ there are "pair" in relative orientation.

<img file="PL2265607T3_D0003.tif" />

[0088] "Meta" for the purposes of this invention refers to the position of a substituent on a phenyl or heteroaryl ring of a six-membered relationship to another substituent on the ring; wherein the relative position is 1,3-substitution. That is, starting from one substituent attached to the first phenyl atom or six-membered heteroaryl ring and counting the atoms in the ring from the first atom, another substituent is on the third phenyl or hexaryl heteroaryl ring, the relative orientation around the phenyl or six-membered heteroaryl ring is "meta". For example, a compound of formula (Ia), as described above in the Summary of the Invention, is shown below as a compound of formula (Ia-1c), wherein R² is on the first atom of the phenyl ring, and nitrogen having hydrogen on the third atom, then R² and nitrogen having hydrogen are a "pair" in relative orientation.

<img file="PL2265607T3_D0004.tif" />

[0089] A "pharmaceutically acceptable excipient" includes an adjuvant, carrier, excipient, lubricant, sweetener, diluting agent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, agent a stabilizing, isotonic agent, solvent or emulsifier that has been approved by the US Food and Drug Administration as being acceptable for use in humans or pets.

[0090] A "pharmaceutically acceptable salt" includes both acid and base addition salts.

[0091] A "pharmaceutically acceptable acid addition salt" refers to those salts that retain the efficacy and biological properties of free bases that are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and organic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulphonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid , fumaric acid, galactaric acid,gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hypuric acid, isobutyric acid, lactic acid, acid

-Lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, acid nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoeic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, acid Ptoluenesulphonic acid, trifluoroacetic acid, undecylenic acid.

[0092] A "pharmaceutically acceptable base addition salt" refers to those salts that retain the efficacy and biological properties of free acids that are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or organic base to the free acid. Salts derived from inorganic bases include the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts. Preferred inorganic salts are the salts of ammonium, sodium, potassium, calcium and magnesium. Salts derived from organic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethanolamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0093] "Pharmaceutical composition" refers to a formulation of a compound of the invention and a medium normally acceptable in the art for delivering a biologically active compound to mammals, e.g. humans. Such medium includes any pharmaceutically acceptable carriers, diluents or excipients.

[0094] A "therapeutically effective amount" refers to that amount of a compound of the invention which when administered to a mammal, e.g. a human, is sufficient for effective treatment, as defined below, of a disease or condition of interest in a mammal, preferably a human. The amount of a compound of the invention which is a "therapeutically effective amount" will vary depending on the compound, disease or condition and severity thereof, and the age of the mammal to be treated, but may be routinely determined by a person skilled in the art having regard to its own knowledge and this description.

[0095] "Treating" or "treating" as used herein refers to treating a disease or condition of interest in a mammal, e.g. a human, having a disease or condition of interest, and includes:

(i) preventing the disease or condition, or one of their manifestations or symptoms from occurring in a mammal, in particular if such a mammal is predisposed to a given condition but has not yet been diagnosed with it;

(Ii) inhibiting the disease or condition, i.e. arresting its development or one or more of its manifestations or symptoms;

(iii) relieving the disease or condition, i.e. causing regression of the disease or condition or one of its manifestations or symptoms; or (iv) stabilizing the disease or condition, or one of its manifestations or symptoms.

[0096] The terms "disease" and "condition" as used herein may be used interchangeably or may differ in that the particular condition or condition may not have a known causative agent (such that etiology has not yet been developed) and are therefore not yet recognized for the disease, and only for an undesirable condition or syndrome in which a more or less specific set of symptoms has been identified by doctors.

The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and may thus be enantiomers, diastereoisomers and other stereoisomeric forms that can be determined for absolute stereochemistry as (R) - or (S) - or, as (D) - or (L) - for amino acids. The present invention is intended to cover all such possible isomers as well as their racemic and optically pure forms. Similarly, all tautomeric forms of the structures described in detail are also intended to be included. Optically active (+) and (-), (R) - and (S) -, or (D) - and (L) -isomers can be prepared using chiral synthons or chiral reagents, or separated by conventional techniques, such as HPLC, using chiral column. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is assumed that these compounds include both the E and Z geometric isomers. Similarly, with respect to the bicyclic ring systems present in individual embodiments, such moieties often they may have substituents attached in a relative "endo" or "exo" configuration. The stereochemical descriptor "endo" refers to a bridging substituent that points towards the larger of the two remaining bridges. If the substituent points towards the smaller remaining bridge, it is referred to as the "exo" substituent. with respect to the bicyclic ring systems present in individual embodiments, such moieties may often have substituents attached in a relative "endo" or "exo" configuration. The stereochemical descriptor "endo" refers to a bridging substituent that points towards the larger of the two remaining bridges. If the substituent points towards the smaller remaining bridge, it is referred to as the "exo" substituent. with respect to the bicyclic ring systems present in individual embodiments, such moieties may often have substituents attached in a relative "endo" or "exo" configuration. The stereochemical descriptor "endo" refers to a bridging substituent that points towards the larger of the two remaining bridges. If the substituent points towards the smaller remaining bridge, it is referred to as the "exo" substituent.

[0098] When used in a formula to indicate a chemical bond rather than an indication of the point of attachment of a substituent to the rest of the molecule (as shown in Tables 2 and 3 below), the binding symbol indicates that the chemical bond may be attached in any relative or absolute configuration for example, the chemical bond may be in a relative endo or exo configuration. Similarly, the chemical bond may be attached in the absolute R or S configuration.

[0099] A "stereoisomer" refers to a compound made up of the same atoms connected by the same bonds but having different three-dimensional structures that are not interchangeable. The present invention includes various stereoisomers and mixtures thereof, and includes "enantiomers" which refers to two stereoisomers whose molecules are non-overlapping images of mirror reflection.

[0099] "Tautomer" refers to the shift of a proton from one atom of a molecule to another atom of the same molecule. The invention includes tautomers of all named compounds.

[0101] "Atropisomers" are stereoisomers resulting from blocked rotation around single bonds, where the rotation barrier is high enough to allow the isolation of conformers (Eliel, EL; Wilen, SH Stereochemistry of Organic Compounds; Wiley &amp; Sons: New York, 1994; Chapter 14). Atropisomerism is important because an element of chirality is introduced in the absence of stereogenic atoms. The invention is intended to include atropisomers, for example in the case of limited rotation around single bonds derived from the pyrimidine core structure, atropisomers are also possible and are also specifically included in the compounds of the invention.

[0102] The chemical naming protocols and structural schemes used herein are a modified form of the IUPAC nomenclature system wherein the compounds of the invention are referred to as the main core structure, i.e. the pyrimidine-2-amine structure. In the case of complex chemical names used herein, the substituent group is mentioned before the group to which it is bound. For example, cyclopropylethyl contains an ethyl backbone with a cyclopropyl substituent. In the chemical structure schemes, all bonds have been determined, with the exception of some carbon atoms, which are considered to be associated with a sufficient number of hydrogen atoms to saturate with valency.

For example, a compound of formula (Ia), as described above in the Summary of the Invention wherein n is 0, m is 1, R¹ is hydrogen, R² means fluorine in the meta-position, R⁴ is 6- (4-acetylpiperazin-1-yl) pyridin-3-yl and R⁵ is (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl at the para position relative to a nitrogen having hydrogen, i.e. a compound of the following formula (wherein the positions of the pyrimidine ring are indicated):

<img file="PL2265607T3_D0005.tif" />

is referred to herein as 4- (6- (4-acetylpiperazin-1-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine.

EXAMPLES FOR CARRYING OUT THE INVENTION [0104] One aspect of the invention are the compounds of formula (Ia), as described above in the Summary of the Invention, as an isolated stereoisomer or a mixture thereof, or as a pharmaceutically acceptable salt thereof. From this aspect, certain embodiments are preferred for compounds of formula (Ia).

[0105] In one embodiment, R⁵ is a bridged N-heterocyclyl. From this embodiment, a preferred embodiment is one in which the bridged Nterhodycyl is selected from the group consisting of:

<img file="PL2265607T3_D0006.tif" />

<img file="PL2265607T3_D0007.tif" />

where every R^5a is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶)) R⁷ -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ where t is 1 or 2 and each R⁶, R⁷ , R⁸ and R⁹ is as defined above in the Summary of the Invention for compounds of formula (I), and where each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or two Rs.²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted Nteroaryl.

[0106] Another embodiment of the compounds of formula (Ia) as described above in the Summary of the Invention are compounds in which R⁵ is a bridged N-heterocyclyl, or a R substituent⁴ is a bridged N-heterocyclyl or R⁵ and

-Regument R⁴ they are both bridged N-heterocyclyls. In certain example embodiments of this invention, R⁵ is a bridged N-heterocyclyl.

[0107] In the compounds of formula (Ia), wherein R⁵ is a bridged N-heterocyclyl or R substituent⁴ is N-heterocyclyl, R⁵ and R substituent⁴ it does not have to be attached through the annular nitrogen of the bridged N-heterocyclyl but can be attached via a ring carbon, for example. In some embodiments, the bridged N-heterocyclyl is R⁵ or as a substituent of R⁴ it is condensed with another ring, part of the spiro ring system or both. In some embodiments, the bridged heterocyclyl is R⁵ or as a substituent of R⁴, alone or as part of a larger condensed, spiro or connected ring system, contains the geometry of substructures selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3. 0], [3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2] and [2.2.1].

[0108] In one embodiment, bridged N-heterocyclyl as R⁵ or as a substituent of R⁴, independently, if more than one is selected from the group consisting of:

<img file="PL2265607T3_D0008.tif" />

<img file="PL2265607T3_D0009.tif" />

where every R^5a is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally

-Substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ where t is 1 or 2 and each R⁶, R⁷, R⁸ and R⁹ is as defined above in the Summary of the Invention for compounds of formula (Ia) and wherein each R²⁰ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or two Rs.²⁰, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted Nteroaryl.

[0109] In a particular embodiment, R⁵ is bridged N-heterocyclyl and R⁴is heteroaryl optionally substituted with bridged N-heterocyclyl. In the exemplified compounds of the invention for this embodiment, R⁵ is a bridged N-heterocyclyl containing an additional nitrogen atom, R⁴ is 5 or 6 membered heteroaryl and n is 0. In a specific embodiment, R⁵ and nitrogen having R¹they are in the relationship of the regiochemical couple with each other and R⁴ is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, tetrazinyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl and pyrazolyl. In some embodiments, R⁴ it is substituted with a group containing an amino group, e.g. -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a or -R⁸-N (R^6a) -R⁹OR^7awhere every R^6a, R^7a, R⁸ and R⁹ are as described above in the Summary of the Invention for compounds of formula (Ia), or R⁴ is substituted with optionally substituted heterocyclyl, e.g. optionally substituted with piperidinyl, optionally substituted with piperazinyl, optionally substituted with morpholinyl, and optionally substituted with thiomorpholinyl. In some examples of this embodiment, R⁴ it is substituted with bridged N-heterocyclyl. In further examples, ring A and / or R⁴ are substituted with up to three additional substituents selected from the group consisting of halo, alkyl, haloalkyl, cyano, nitro, hydroxy, -OR²⁵, -N (R.²⁵) 2, -C (O) OR 2⁵, -C (O) N (R2⁵) 2 and their combinations; where every R²⁵ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and cycloalkylalkyl.

[0110] One embodiment of the compounds of formula (Ia) is a compound of formula (Ia) as set out above in which:

m is 0 or 1;

R²when present, is in the meta position relative to the nitrogen having R¹; and

R⁵ is in the para position relative to the nitrogen having R¹.

[0111] One embodiment of the compounds of formula (Ia) is a compound of formula (Ia) as set out above in which:

-30n is 0 or 1; and

R³when present, it is in the 5-position of the pyrimidine ring.

[0112] One embodiment of the compounds of formula (Ia) is a compound of formula (Ia) as set out above in which:

m is 0 or 1; n is 0 or 1;

R²when present, is in the meta position relative to the nitrogen having R¹;

R³when present, it is in the 5-position of the pyrimidine ring; and

R⁵ is in the para position relative to the nitrogen having R¹.

[0113] One embodiment of the invention is a compound of formula (I) as described above in the Summary of the Invention of formula (Ia-1):

(Ia-1)

R 'where:

n is 0, 1 or 2;

m is 0, 1 or 2;

R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷ and -R⁹-OR⁶; every R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

every R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, nheterocyclyl, N-heteroaryl, aryl, R⁸-OR^6a, -R⁸-S (O) pR^6a (where p is 0, 1 or

<img file="PL2265607T3_D0010.tif" />

N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally

-Substituted cycloalkyl, optionally substituted heterocyclyl, an optionally substituted heterocyclylalkyl, an optionally substituted heteroaryl and optionally substituted aralkyl, and wherein the N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C ( O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl, and where any R^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted Nterhodyclyl;

R⁵ is N-heterocyclyl, wherein the N-heterocyclyl nitrogen is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl,optionally substituted heteroarylalkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶.

-R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2); and the N-heterocyclyl carbon atom is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl,⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷.

-R⁸-C (O) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸-S (O) pR⁶ (where p is 0, 1 or 2); every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted

-Heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; and every R⁹ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain;

provided that at least one of R⁵ and substituent on R⁴ is a bridged Ntero-cyclic group.

[0114] From the compounds of formula (Ia-1), shown above, one embodiment is a compound selected from the following formulas:

<img file="PL2265607T3_D0011.tif" />

<img file="PL2265607T3_D0012.tif" />

wherein:

each n is 0, 1 or 2;

every R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

every R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

every R⁴ is independently selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a (where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, (O) R^7a, -R⁸-N (R^6a) R^7a, R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a and

-R⁸-N (R6^and) -R⁹-N (R^6a) S (O) 2 R^7awhere every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted aralkyl, and wherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted by one. or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl, and where any R^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R^5a is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl,

- optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, optionally substituted substituted heteroarylalkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; and every R⁹ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain.

[0115] With this embodiment, one embodiment is a compound selected from the above formulas, wherein:

each n is 0 or 1;

every R⁴ is independently selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro -2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1, 2-a] pyridinyl, 6.7 , 8.9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepin-10 (11H) -onyl, indolyl,

-Indindinylyl, naphthyrinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from the group consisting of oxo, alkyl, halo , haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R6^and) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R6^and) S (O) 2R7^and, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0116] One embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1a):

<img file="PL2265607T3_D0013.tif" />

-36with what:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from a group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R⁶a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere

N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl,

- optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0117] From this embodiment, one embodiment is a compound of the formula (Ia1a), shown above, in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, cyano, -R⁸-OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) R⁹-N (R^6a) R^7a and -R⁸-N (R^6a) -R⁹-OR^7a;

R^5a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, -R⁸-C (O) R⁶ and -R⁸-S (O) t R⁶ (where t is 1 or 2); every R⁶ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted

-Substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkynyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0118] A particular embodiment of this embodiment is a compound of formula (Ia-1a) as set forth above, selected from the group consisting of:

4- (6- (N, N-dimethylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-methyl-N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-trifluoromethyl-N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-fluoro-N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-fluoro-N- (3-fluoro-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-methyl-N- (3-fluoro-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (dimethylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

-394- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (benzylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (benzylamino) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-tifluoromethyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (dimethylamino) pyridin-3-yl) -N- (3-tifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6-Cyano-pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (5-cyano-pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine;

4- (6-aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (6-aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (6-ethoxypyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (6-ethoxypyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (6- (dimethylamino) pyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine;

4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5etylokarbonylo-2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (3-methylbutyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (3,3-dimethylbutyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

-404- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidin-2-amine;

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (2- (trifluoromethyl) pyridin-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5-Acetyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine; and

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5cyklopentylo-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine.

[0119] With this embodiment, another embodiment is a compound of the formula (Ia1a), shown above, wherein:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from a group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷ and -R⁸-S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted

-Heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0120] A particular embodiment of this embodiment is a compound of formula (Ia-1a) as set forth above, selected from the group consisting of:

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5- ((ethylamino) carbonyl) -2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (2,2,2-trifluoroethyl) 2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (cyclopropyl) metylo2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3-fluoro-2- (morpholin-4-yl) pyridin-4-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

5-methyl-4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

5-methyl-4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

-424- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-tifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-Acetyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-cyclopentyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (cis-2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (2- (dimethylamino) methylmorpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (piperidin-1-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (3- (aminocarbonyl) piperidin-1-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-amidino-2,5- diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-isobutyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (1,4-oxazepan-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4- ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (tiamorfolin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine; and

-434- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-cyclopropylo-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5-Acetyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5- (1-methylethyl) -2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4- ((1S, 4S ) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine; and

4- (6 - ((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4- ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine.

[0121] Another embodiment is a compound of formula (Ia-1a) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R⁶a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a and tetrazolyl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷ and -R⁸-S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl,

- optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and_R9 is an optionally substituted straight or branched alkylene chain.

[0122] A particular embodiment of this embodiment is a compound of formula (Ia-1a) as set forth above, selected from the group consisting of:

4- (6- (methylaminocarbonyl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (5 - ((morpholin-4-yl) carbonyl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine. TFA salt;

4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6 - ((2- (cyclopropylsulfonyl) aminoethyl) -amino) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (1H-tetrazol-5-yl) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine

4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidin-2-amine;

-454- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (2- (dimethylamino) acetamido) -pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidin-2-amine; and

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine; and

4- (5- (1-methylethoxy) karbonylopropylo-6-amino-pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine.

[0123] Another embodiment is a compound of formula (Ia-1a) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of naphthyridinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1H-benzo [b] azepinyl, benzo [b] [1,4] oxazinyl, 3,4-dihydro-2Hbenzo [ b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3.2] -b] [1,4] thiazinyl, 6,7,8,9-tetrahydro5H-pyrido [2,3-b] indolyl, 7,8,9,9a-tetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2a] [1,4] diazepin-10 (11H) -enyl, and 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazinyl, each optionally substituted with one or more more substituents independently selected from the group consisting of alkyl and oxo;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) t R⁶ (where t is 1 or 2), and -R⁸-S (O) 2 N (R⁶) R⁷;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl;

-46 or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0124] A particular embodiment of this embodiment is a compound of the formula (Ia-1a), set forth above, selected from the group consisting of:

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S) - 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4 - ((1S, 4S) 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5- (ethylcarbonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3'-oxo-3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazine] -7'-yl) -N- (3-methyl -4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3'-oxo-3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazine] -7'-yl) -N- (3-methyl -4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5- (aminosulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (7-oxo-5,6,7,8-tetahydro-1,8-naphthyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

-474- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-cyano-4- ( (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4 - (( 1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-tifluoromethyl-4 - ((1S, 4S) -5-methyl- 2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2H-benzo [b] [1,4] oxazin-3 (4H) -one-6-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2 5diazabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

4- (2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-trifluoromethyl-4 - (( 1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4 - ((1S, 4S) -5-methyl-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S) - 5-methylsulfonyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

-484- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (7-oxo-5,6,7,8-tetahydro-1,8-naphthyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) 2,5--5metylosulfonylo diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S ) -5-methylsulfonyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5metylosulfonylo-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-chloro-4 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-chloro-4 - (( 1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-cyclopentyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-acetyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

4- (6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

-494- (7,8,9,9a-tetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepin-10 (11H) -one-3-yl) N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-cyano-4 ((1 S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-cyano-4 - ((1S, 4S) -5-methyl-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-cyano-4 - ((1S, 4S) -5-methyl-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine; and

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine.

[0125] Another embodiment is a compound of formula (Ia-1a) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is phenyl substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, -R⁸-OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, N-heteroaryl and Ntero-cyclicyl, wherein the N-heterocyclyl and N-heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, -R⁸-C (O) R⁶ and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both

Coupled, form an optionally substituted N-heteroaryl or optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0126] A particular embodiment of this embodiment is a compound of formula (Ia-1a) as set forth above, selected from the group consisting of:

4- (4- (N, N-dimethylamino) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (4- (N, N-dimethylamino) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (4- (4,5-dihydro-thiazol-2-ylcarbamoyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (4- (1,1-dimethylethyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (4- (morpholin-4-yl) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine. TFA salt;

4- (4 - ((methyl) aminocarbonylmethyl ) -phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine. TFA salt;

4- (4 - ((cyclopropyl) aminocarbonyl-methyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4- (5- (4-dimethylaminophenyl) oxazol-2-yl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine;

4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine;

4- (4- (methylsulfonylamino) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine;

4- (4- (methylsulfonylamino) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine;

-514- (4- (3-cyklopropyloureido) phenyl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2- amine;

4- (4- (1-ethoxyethyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (4- (1-ethoxyethyl) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine; and

4- (4- (trifluoromethyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine.

[0127] Another embodiment is a compound of formula (Ia-1a) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of benzimidazolyl, imidazo [1,2-a] pyridinyl, indolyl, indolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl and thiazolyl, each independently substituted with one or more substituents selected from the group consisting of alkyl, cyano, oxo, -R⁸-OR^6a, -R⁸N (R^6a) R^7a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, -R⁸N (R^6a) C (O) -R⁸-N (R^6a) R^7a, aryl, N-heteroaryl and N-heterocyclyl, where the aryl, nheterocyclyl and N-heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, -R⁸-C (O) R⁶ and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

-52R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0128] A particular embodiment of this embodiment is a compound of the formula (Ia-1a), set forth above, selected from the group consisting of:

4- (1H-indol-6-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (2,2,2-trifluoroethyl) 2.5 diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (cyclopropyl) metylo2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (2 - ((cyclopropyl) carbonylamino) -pyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (2- (propyl) aminopyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (2- (propyl) aminopyrimidin-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (imidazo [1,2-a] pyridin-6-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine;

4- (6-methoxy-1H-indol-2-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

-534- (1- (3-chlorophenyl) -1H-pyrazol-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidin-2-amine;

4- (1-methylbenzimidazol-6-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (5-cyano-1H-indol-2-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine;

4- (2-oksoindolin-5-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine;

4- (5- (3-methyl-piperidin-1-yl) pyrazin-2-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidin-2-amine;

4- (2- (diethylamino) thiazol-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (2- (diethylamino) thiazol-4-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (1H-pyrrol-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (1H-pyrrol-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1H-pyrrol-3-yl) -N- (3-trifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (2- (dimethylamino) thiazol-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (2- (dimethylamino) thiazol-4-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine; and

-544- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-isobutyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine.

[0129] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1b):

<img file="PL2265607T3_D0014.tif" />

wherein: n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from a group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R 8^-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted

-Substituted heteroarylalkenyl, and optionally substituted heteroaralkynyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0130] From this embodiment, one embodiment is a compound of formula (I1b) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of alkyl, cyano, -R⁸-OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹N (R^6a) R^7a and -R⁸-N (R^6a) -R⁹-OR^7a;

R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are

Bonded, may form optionally substituted N-heteroaryl or optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0131] A particular embodiment of this embodiment is a compound of the formula (Ia-1b) as set forth above, selected from the group consisting of:

4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oksa2-azabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine; and

4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2- yl) phenyl) pyrimidine-2-amine.

[0132] Another embodiment is a compound of formula (I-1b) wherein: n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl;

-57 or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0133] A particular embodiment of this embodiment is a compound of formula (Ia-1b) as set forth above, selected from the group consisting of:

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6-cis-2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (1,4-oxazepan-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptane -2-yl) phenyl) pyrimidin-2-amine; and

4- (6 - ((1S, 4S) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -N- (3-methyl-4- ((1S, 4S ) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine.

[0134] Another embodiment is a compound of formula (Ia-1b) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of -R⁸-C (O) R^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-S (O) pR^6a (where p is 0, 1 or 2), -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and tetrazolyl;

R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl,

- optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and_R9 is an optionally substituted straight or branched alkylene chain. [0135] A particular embodiment of this embodiment is a compound of formula (Ia-1b) as set forth above, selected from the group consisting of:

4- (6 - ((2- (cyclopropylsulfonyl) aminoethyl) -amino) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-oxa-2-azabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-tifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine; and

4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine.

[0136] Another embodiment is a compound of formula (Ia-1b) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of naphthyridinyl, benzo [b] azepinyl, benzo [b] [1,4] oxazinyl, 3,4-dihydro-2H-benzo [b] [1,4] thiazinyl, 3 ', 4' dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [3,2-b] [1,4] thiazinyl and 3,4-dihydro -2H-pyrido [3,2-b] [1,4] oxazinyl, each optionally substituted with one or more substituents independently selected from the group consisting of alkyl and oxo; and

R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl,

- optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl;

[0137] A particular embodiment of this embodiment is a compound of formula (Ia-1b) as set forth above, selected from the group consisting of:

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S) - 5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine; and 4- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) - 5oksa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine.

[0138] Another embodiment is a compound of formula (Ia-1b) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of benzimidazolyl, imidazo [1,2-a] pyridinyl, indolyl, indolinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H pyrrole [2,3-b] pyridinyl and thiazolyl, each independently substituted by one or more substituents selected from the group consisting of alkyl, cyano, oxo, -R⁸OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, aryl, N-heteroaryl and N-heterocyclyl, where the aryl, nheterocyclyl and N-heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both

When combined, form an optionally substituted N-heteroaryl or optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0139] A particular embodiment of this embodiment is a compound of formula (Ia-1b) as set forth above, selected from the group consisting of:

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine; and

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine.

[0140] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1c):

<img file="PL2265607T3_D0015.tif" />

wherein: n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl,

-611H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl , -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R⁶a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere

N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and

- every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0141] From this embodiment, one embodiment is a compound of the formula (Ia1c) set forth above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of alkyl, cyano, -R⁸-OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹N (R^6a) R^7a and -R⁸-N (R^6a) -R⁹-OR^7a;

R^5a is independently selected from the group consisting of hydrogen, alkyl, -R⁸-C (O) R⁶ and -R⁸S (O) t R⁶ (where t is 1 or 2);

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁶ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and_R9 is an optionally substituted straight or branched alkylene chain.

[0142] A particular embodiment of this embodiment is a compound of formula (Ia-1c), set forth above, selected from the group consisting of:

-634- (6- (dimethylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine;

4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine;

4- (6- (dimethylamino) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine;

4- (4- (dimethylamino) phenyl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine ;

4- (6- (benzyl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine;

4- (6- (benzyl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine;

4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl ) pyrimidin-2-amine;

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine;

4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N- (3-methyl-4- (1,5,7-trimetylo3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl ) pyrimidin-2-amine; and

4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimetylo3,7-diazabicyclo [3.3.1] nonane-3- yl) phenyl) pyrimidine-2-amine.

[0143] Another embodiment is a compound of formula (Ia-1c) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from a group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷ and -R⁸-S (O) t R⁶ (where t is 1 or 2);

- every time R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0144] A particular embodiment of this embodiment is a compound of formula (Ia-1c), set forth above, selected from the group consisting of:

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl ) phenyl) pyrimidin-2-amine;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonane -3-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl ) phenyl) pyrimidin-2-amine; and

4- (6 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7trimetylo-3,7-diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidine-2-amine.

[0145] Another embodiment is a compound of formula (Ia-1c) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of naphthyridinyl, benzo [b] azepinyl, benzo [b] [1,4] oxazinyl, 3,4-dihydro-2H-benzo [b] [1,4] thiazinyl, 3 ', 4' dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [3,2-b] [1,4] thiazinyl and 3,4-dihydro -2H-pyrido [3,2-b] [1,4] oxazinyl, each

Being optionally substituted with one or more substituents independently selected from the group consisting of alkyl and oxo;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) t R⁶ (where t is 1 or 2), and -R⁸-S (O) 2 N (R⁶) R⁷;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0146] A particular embodiment of this embodiment is a compound of formula (Ia-1c) as set forth above selected from the group consisting of:

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1,5,7-trimetylo3,7 diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine;

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (1,5,7-trimetylo3,7 diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine; and

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1 , 5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine.

[0147] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1d):

<img file="PL2265607T3_D0016.tif" />

wherein:

n is 0 or 1;

-66R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from a group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere

N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted

-Substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkynyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0148] From this embodiment, one embodiment is a compound of formula (Ia1d), shown above, wherein:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of alkyl, cyano, -R⁸-OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹N (R^6a) R^7a and -R⁸-N (R^6a) -R⁹-OR^7a;

R^5a is independently selected from the group consisting of hydrogen, alkyl, -R⁸-C (O) R⁶ and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl;

-68R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0149] A particular embodiment of this embodiment is a compound of formula (Ia-1d) as set out above which is 4- (6-aminopyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo) [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine.

[0150] Another embodiment is a compound of formula (Ia-1d) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from a group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷ and -R⁸-S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocykliloalkenylu, optionally substituted heterocykliloalkinylu, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, any potential e

Unsubstituted heteroarylalkenyl, and optionally substituted heteroaralkynyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0151] A particular embodiment of this embodiment is a compound of formula (Ia-1d) as set forth above, selected from the group consisting of:

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine ; and

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine -2-amine.

[0152] Another embodiment is a compound of formula (Ia-1d) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of -R⁸-C (O) R^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-S (O) pR^6a (where p is 0, 1 or 2), -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and tetrazolyl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷ and -R⁸-S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both

When attached, form an optionally substituted N-heteroaryl or optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and_R9 is an optionally substituted straight or branched alkylene chain.

[0153] A particular embodiment of this embodiment is a compound of formula (Ia-1d) as set forth above, selected from the group consisting of:

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine;

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine ; and [0154] Another embodiment is a compound of formula (Ia-1d) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of naphthyridinyl, benzo [b] azepinyl, benzo [b] [1,4] oxazinyl, 3,4-dihydro-2H-benzo [b] [1,4] thiazinyl, 3 ', 4' dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [3,2-b] [1,4] thiazinyl and 3,4-dihydro -2H-pyrido [3,2-b] [1,4] oxazinyl, each optionally substituted with one or more substituents independently selected from the group consisting of alkyl and oxo;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) t R⁶ (where t is 1 or 2), and -R⁸-S (O) 2 N (R⁶) R⁷;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted

-7-cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl , and optionally substituted heteroarylalkynyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0155] A particular embodiment of this embodiment is a compound of formula (Ia-1d), set forth above, selected from the group consisting of:

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (8-methyl-3 8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine; and

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (8 methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine.

[0156] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1e):

<img file="PL2265607T3_D0017.tif" />

wherein: n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl,

-721H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl , -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere

N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0157] From this embodiment, one embodiment is a compound of the formula (Ia1e), wherein:

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of alkyl, cyano, -R⁸-OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹N (R^6a) R^7a and -R⁸-N (R^6a) -R⁹-OR^7a; and

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted

-Heteroaryl, and optionally substituted aralkyl, and when any R^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl.

A particular embodiment of this embodiment is a compound of the formula (Ia-1e), supra, which is 4- (6-cyanopyridin-3-yl) -N- (3-methyl-4- (7-azabicyclo [2.2 .1] heptan-7-yl) phenyl) pyrimidin-2-amine.

[0159] Another embodiment is a compound of formula (Ia-1e) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from a group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

A particular embodiment of this embodiment is a compound of the formula (Ia-1e), shown above, which is 4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl4 - (7-azabicyclo [2.2.1] heptan-7-yl) phenyl) pyrimidin-2-amine.

[0161] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1f):

<img file="PL2265607T3_D0018.tif" />

wherein: n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from a group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R8 -C (O) N (R.^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R⁶a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

-75R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0162] From this embodiment, one embodiment is a compound of formula (Ia1f), shown above, wherein:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with -R⁸-OR^6a;

or R⁴ is N-heterocyclyl substituted pyridinyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with -C (O) R⁶; and every R⁶ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a is selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl; and

-76R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0163] A particular embodiment of this embodiment is a compound of formula (Ia-1f), set forth above, selected from the group consisting of:

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine ;

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine ;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((R) -1,4diazabicyklo [3.2.1] octan-4-yl) phenyl) pyrimidine -2-amine; and

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((S) -1,4-diazabicyclo [3.2.1] oktan4-yl) phenyl) pyrimidine -2-amine.

[0164] Another embodiment is a compound of formula (Ia-1f) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of benzimidazolyl, imidazo [1,2-a] pyridinyl, indolyl, indolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazinyl and thiazolyl, each independently substituted with one or more substituents selected from the group consisting of alkyl, cyano, oxo, -R⁸-OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-C (O) N (R^6a) R^7a, R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, aryl, nteroaryl and N-heterocyclyl, where the aryl, N-heterocyclyl and N-heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, -R⁸-C (O) R⁶ and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted

-Substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0165] A particular embodiment of this embodiment is a compound of formula (Ia-1f), set forth above, selected from the group consisting of:

4- (2-oksoindolin-5-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine;

(1-methylbenzimidazol-6-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine;

4- (imidazo [1,2-a] pyridin-6-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine; and

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1 4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine.

[0166] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1g):

<img file="PL2265607T3_D0019.tif" />

wherein: n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

-78R⁴ is selected from benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, the group consisting of phenyl, benzimidazolyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1H3, 3-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from a group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere

N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0167] In one embodiment, the compound has the formula (Ia-1g) set forth above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from a group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0168] A particular embodiment of this embodiment is a compound of the formula (Ia-1g), supra, selected from the group consisting of:

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.2] nonane-4-yl) phenyl) pyrimidin-2-amine ; and

4- (6 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4 (1,4- diazabicyclo [3.2.2] nonan-4-yl) phenyl) pyrimidin-2-amine.

[0169] Another embodiment is a compound of the formula (Ia-Ig) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

-80R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of -R⁸-C (O) R^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-S (O) pR^6a (where p is 0, 1 or 2), -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and tetrazolyl;

R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and_R9 is an optionally substituted straight or branched alkylene chain.

A particular embodiment of this embodiment is a compound of formula (Ia-1g), as set out above, which is 4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N (3-methyl-4 - (1,4-diazabicyclo [3.2.2] nonan-4-yl) phenyl) pyrimidin-2-amine.

[0171] Another embodiment is a compound of formula (Ia-1g) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of naphthyridinyl, benzo [b] azepinyl, benzo [b] [1,4] oxazinyl, 3,4-dihydro-2H-benzo [b] [1,4] thiazinyl, 3 ', 4' dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-81pyrido [3,2-b] [1,4] thiazinyl and 3,4 -dihydro-2H-pyrido [3,2-b] [1,4] oxazinyl, each optionally substituted with one or more substituents independently selected from the group consisting of alkyl and oxo; and

R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl.

A particular embodiment of this embodiment is a compound of the formula (Ia-1g), supra, which is 4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H pyrido [3,2-] b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.2] nonane-4-yl) phenyl) pyrimidin-2-amine.

[0173] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1h):

<img file="PL2265607T3_D0020.tif" />

wherein: n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from a group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a

-82 (where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere

N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0174] In one embodiment, the compound has the formula (Ia-1h) set forth above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally

-Substituted by one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

A specific embodiment of this embodiment is a compound of formula (Ia-1h) as set out above, which is 4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4R) -2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine.

[0176] Another embodiment is a compound of formula (Ia-1h) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of naphthyridinyl, benzo [b] azepinyl, benzo [b] [1,4] oxazinyl, 3,4-dihydro-2H-benzo [b] [1,4] thiazinyl, 3 ', 4' dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [3,2-b] [1,4] thiazinyl and 3,4-dihydro -2H-pyrido [3,2-b] [1,4] oxazinyl, each optionally substituted with one or more substituents independently selected from the group consisting of alkyl and oxo; and

R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl,

- optionally a substituted heterocyclylalkynyl, an optionally substituted heteroaryl, an optionally substituted heteroarylalkyl, an optionally substituted heteroaralkenyl, and an optionally substituted heteroaralkenyl.

[0177] A particular embodiment of this embodiment is a compound of formula (Ia-1h) which is 4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] ] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4R) -2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine.

[0178] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1i):

<img file="PL2265607T3_D0021.tif" />

wherein: n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from a group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally

-Substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0179] From this embodiment, one embodiment is a compound of the formula (Ia1i) set forth above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

-86_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from a group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷ and -R⁸-S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0180] A particular embodiment of this embodiment is a compound of the formula (Ia-1i), set forth above, selected from the group consisting of:

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (2-methylsulfonyl-2azabicyklo [2.2.1] heptan-5-yl) phenyl) pyrimidine-2 -amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (2-methylsulfonyl-2azabicyklo [2.2.1] heptan-6-yl) phenyl) pyrimidine-2 -amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (2-methylsulfonyl-2azabicyklo [2.2.1] heptan-5-yl) phenyl) pyrimidin-2-amine; and

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (2-methylsulfonyl-2azabicyklo [2.2.1] heptan-6-yl) phenyl) pyrimidin-2-amine.

[0181] Another embodiment is a compound of formula (Ia-1i) as set out above in which:

n is 0 or 1;

-87R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³ when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of naphthyridinyl, benzo [b] azepinyl, benzo [b] [1,4] oxazinyl, 3,4-dihydro-2H-benzo [b] [1,4] thiazinyl, 3 ', 4' dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [3,2-b] [1,4] thiazinyl and 3,4-dihydro -2H-pyrido [3,2-b] [1,4] oxazinyl, each optionally substituted with one or more substituents independently selected from the group consisting of alkyl and oxo;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) t R⁶ (where t is 1 or 2), and -R⁸-S (O) 2 N (R⁶) R⁷;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0182] A particular embodiment of this embodiment is a compound of the formula (Ia-1i), set forth above, selected from the group consisting of:

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (2 -metylosulfonylo-2-azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (2 -metylosulfonylo-2-azabicyclo [2.2.1] heptan-6-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (2-2metylosulfonylo azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidin-2-amine; and

-884- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (2metylosulfonylo- 2-azabicyclo [2.2.1] heptan-6-yl) phenyl) pyrimidin-2-amine.

[0183] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1j):

<img file="PL2265607T3_D0022.tif" />

wherein n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from a group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted

-Substituted heteroarylalkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0184] From this embodiment, one embodiment is a compound of the formula (Ia1j) set forth above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from a group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both

Coupled, form an optionally substituted N-heteroaryl or optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0185] A particular embodiment of this embodiment is a compound of formula (Ia-1j) as shown above which is 4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl4 - ((6R, 9S) -6,9-metanooktahydro-1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidin-2-amine.

[0186] Another embodiment is a compound of formula (Ia-1j) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of naphthyridinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1H-benzo [b] azepinyl, benzo [b] [1,4] oxazinyl, 3,4-dihydro-2Hbenzo [ b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3.2] -b] [1,4] thiazinyl and 3,4-dihydro-2H pyrido [3,2-b] [1,4] oxazinyl, each optionally substituted with one or more substituents independently selected from the group consisting of alkyl and oxo; and

R⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl.

[0187] A particular embodiment of this embodiment is a compound of formula (Ia-1j) selected from the group consisting of:

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((6R, 9S ) -6,9-metanooktahydro-1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidin-2-amine;

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-methyl-4 - ((6R, 9S) -6,9metanooktahydro- 1 H-pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidin-2-amine;

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-methyl-4 - ((6R, 9S) -6,9metanooktahydro -1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidin-2-amine.

[0188] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1k):

<img file="PL2265607T3_D0023.tif" />

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from a group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶.

-92-R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0189] From this embodiment, one embodiment is a compound of formula (Ia1k) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from a group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

-93R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷ and -R⁸-S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

A particular embodiment of this embodiment is a compound of formula (Ia-1k) which is 4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4- (3,9diazabicyklo [3.3.2] decan-10-one-3-yl) phenyl) pyrimidin-2-amine.

[0191] Another embodiment is a compound of formula (Ia-1k) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of naphthyridinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1H-benzo [b] azepinyl, benzo [b] [1,4] oxazinyl, 3,4-dihydro-2Hbenzo [ b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3.2] -b] [1,4] thiazinyl, 6,7,8,9-tetrahydro-5H pyrido [2,3-b] indolyl, 7,8,9,9a-tetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine-10 (11H) -onyl, and 3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazinyl, each optionally substituted with one or more more substituents independently selected from the group consisting of alkyl and oxo;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl,

-94-R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷ and -R⁸-S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0192] A particular embodiment of this embodiment is a compound of formula (Ia-1k) which is 4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] ] [1,4] oxazin-7-yl) -N- (3-cyano-4- (3,9-diazabicyclo [3.3.2] decan-10-one-3-yl) phenyl) pyrimidin-2-amine.

[0193] Another embodiment of the compounds of formula (Ia-1), shown above, is a compound of formula (Ia-1l):

<img file="PL2265607T3_D0024.tif" />

wherein n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³ when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more

-Moremore substituents independently selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere

N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and

- every R⁹ is an optionally substituted straight or branched alkylene chain.

[0194] From this embodiment, one embodiment is a compound of the formula (Ia1l) as set out above in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, cyano, -R⁸-OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) R⁹-N (R^6a) R^7a and -R⁸-N (R^6a) -R⁹-OR⁷and;

R^5a is independently selected from the group consisting of hydrogen, alkyl, -R⁹-N (R⁶) R⁷ and optionally substituted heterocyclyl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl, and wherein any^6a and R^7a are associated with common nitrogen, R^6a and R^7a together with the common nitrogen atom to which they are both attached, they may form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0195] A particular embodiment of this embodiment is a compound of the formula (Ia-1) selected from the group consisting of:

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (3- (dimethylamino) -8- azabicyclo [3.2.1] octan-8-yl) phenyl) pyrimidine -2-amine; and

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (3- (morpholin-4-yl) -8-azabicyclo [3.2.1] octan-8-yl ) phenyl) pyrimidin-2-amine.

[0196] Another embodiment is a compound of formula (Ia-1), as depicted above, in which:

n is 0 or 1;

R^2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally substituted with one or more substituents selected from a group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, -R⁹-N (R⁶) R⁷ and optionally substituted heterocyclyl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0197] A particular embodiment of this embodiment is a compound of formula (Ia-1) selected from the group consisting of:

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (3- (morpholin-4-yl) -8-azabicyclo [3.2.1] octan-8-yl ) phenyl) pyrimidin-2-amine; and

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (3- (dimethylamino) -8- azabicyclo [3.2.1] octan-8-yl) phenyl) pyrimidine -2-amine.

[0198] From the compounds of formula (Ia-1), shown above, another embodiment is a compound, wherein:

n is 0 or 1; m is 0 or 1;

R¹ is selected from the group consisting of hydrogen or alkyl;

R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_RIs heteroaryl optionally substituted with a bridged N-heterocyclyl, wherein the bridged N-heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of alkyl, halo and optionally substituted aryl;

R⁵ means a non-trimmed N-heterocyclyl wherein the nitrogen atom in the non-blended N-heterocyclyl is optionally substituted with a substituent selected from the group consisting of alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸-S (O) t R⁶ (where t is 1 or 2); and wherein the carbon atom in the non-blended N-heterocyclyl is optionally substituted with a substituent selected from the group consisting of alkyl, halo, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, an optionally substituted heterocyclylalkyl. , optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, R⁸-C (O) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸-S (O) pR⁶ (where p is 0, 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted

-99aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted Nteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0199] From this embodiment, one embodiment is a compound of formula (Ia1), wherein:

n is 0 or 1; m is 1;

R¹ is selected from the group consisting of hydrogen or alkyl;

R² is alkyl;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is pyridinyl substituted with a bridged N-heterocyclyl, wherein the bridged N-heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of alkyl, halo and optionally substituted aryl; and

R⁵ is a non-bridged N-heterocyclyl selected from the group consisting of piperazinyl, piperidinyl and morpholinyl.

[0200] A particular embodiment of this embodiment is a compound of the formula (Ia-1) selected from the group consisting of:

4- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -N- (3-methyl-4- (4-methylpiperazin -1-yl) phenyl) pyrimidin-2-amine; and

4- (6 - ((1S, 4S) -5- (4-fluorophenyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) N- (3-methyl-4 - (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine.

[0201] Another embodiment of the invention is a compound of formula (Ia), as described above in the Summary of the Invention of formula (Ia-2):

<img file="PL2265607T3_D0025.tif" />

wherein:

-100n means 0, 1 or 2;

m is 0, 1 or 2;

R¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷ and -R⁹-OR⁶;

every R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

every R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of aryl and heteroaryl, where aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, nheterocyclyl, N-heteroaryl, aryl, R⁸-OR^6a, -R⁸-S (O) pR^6a (where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, -R⁸N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted aralkyl, and wherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted by one. or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R⁵ is N-heterocyclyl, wherein the nitrogen atom in the N-heterocyclyl is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl , optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2); and the carbon atom in the N-heterocyclyl is optionally

Is substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸-S (O) pR⁶ (where p is 0, 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; and every R⁹ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain;

provided that at least one of R⁵ and substituent on R⁴ is bridged Nterhodycyl;

[0202] From compounds of formula (Ia-2), as set out above, one embodiment is a compound selected from the following:

-102-

<img file="PL2265607T3_D0026.tif" />

wherein:

each n is 0, 1 or 2; each m is 0, 1 or 2;

every R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

every R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

every R⁴ is independently selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a (where p means

-1030, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-N (R^6a) R^7a, -R⁸N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere every R^6a and R^7ais independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted aralkyl, and wherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted by one. or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R^5a is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R⁸ is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; and every R⁹ is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, optionally substituted

Straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain.

[0203] From this embodiment, one embodiment is a compound selected from the above formulas, wherein:

each n is 0 or 1;

each m is 0 or 1;

every R⁴ is independently selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro -2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1, 2-a] pyridinyl, 6.7 , 8.9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepin-10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from the group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awhere

N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl;

-105 each R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0204] One embodiment of the compounds of formula (Ia-2), described above, is a compound of formula (Ia-2a):

<img file="PL2265607T3_D0027.tif" />

n is 0 or 1;

m is 0 or 1;

R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of phenyl, benzimidazolyl, benzo [b] [1,4] oxazinyl, benzo [b] azepinyl, 2,3,4,5-tetrahydro-1Hbenzo [b] azepinyl, 3,4-dihydro- 2H-benzo [b] [1,4] thiazinyl, 3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [ 3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazinyl, imidazo [1,2-a] pyridinyl, 6.7, 8,9-tetrahydro-5H-pyrido [2,3-b] indolyl, 7,8,9,9atetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepine -10 (11H) -onyl, indolyl, indolinyl, naphthyridinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H-pyrrolo [2,3-b] pyridinyl, and thiazolyl, each optionally substituted with one or more substituents independently selected from a group consisting of oxo, alkyl, halo, haloalkyl, cyano, N-heterocyclyl, N-heteroaryl, aryl, -R⁸-OR^6a, -R⁸-S (O) pR^6a(where p is 0, 1 or 2), -R⁸-C (O) R^6a, -R⁸-C (O) OR^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹-OR^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7awherein N-heterocyclyl, N-heteroaryl and aryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkyl, optionally substituted

-106heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, optionally substituted heteroaralkynyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0205] From this embodiment, one embodiment is a compound of formula (Ia2a), wherein:

n is 0 or 1; m is 0 or 1;

R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of alkyl, cyano, -R⁸-OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-N (R^6a) -R⁹N (R^6a) R^7a and -R⁸-N (R^6a) -R⁹-OR^7a;

-107R^5a is independently selected from the group consisting of hydrogen, alkyl, -R⁸-C (O) R⁶ and -R⁸S (O) t R⁶ (where t is 1 or 2); and every R⁶ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl;

R^6a and R^7a are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0206] A particular embodiment of this embodiment is a compound of formula (Ia-2a) selected from the group consisting of:

4- (6- (dimethylamino) pyridin-3-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl ) pyrimidin-2-amine;

4- (6- (dimethylamino) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridine -3-yl) pyrimidine-2-amine; and

4- (6-aminopyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3- yl) pyrimidine-2-amine.

[0207] Another embodiment is a compound of formula (Ia-2a) wherein: n is 0 or 1; m is 0 or 1;

R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with N-heterocyclyl selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, oxazepanyl, 5-oxa-2azabicyclo [2.2.1] heptanyl and thiamorpholinyl, wherein the N-heterocyclyl is optionally

Is substituted with one or more substituents selected from the group consisting of -C (O) R ⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷ and -R⁸-S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0208] A particular embodiment of this embodiment is a compound of formula (Ia-2a) selected from the group consisting of:

4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) pyridin-3-yl) pyrimidine-2-amine;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) pyridin-3-yl) pyrimidine-2-amine;

4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2-yl) pyridin-3-yl) pyrimidine-2-amine;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) pyridin-3-yl) pyrimidine-2-amine;

4- (6 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (5-methyl-6 ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine.

[0209] Another embodiment is a compound of formula (Ia-2a) wherein: n is 0 or 1;

-109m means 0 or 1;

R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is pyridinyl substituted with one or more substituents selected from the group consisting of -R⁸-C (O) R^6a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-S (O) pR^6a (where p is 0, 1 or 2), -R⁸-N (R^6a) -R⁹-N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, and tetrazolyl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷ and -R⁸-S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl;

every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain; and every R⁹ is an optionally substituted straight or branched alkylene chain.

[0210] A particular embodiment of this embodiment is a compound of formula (Ia-2a) selected from the group consisting of:

4- (6- (methylcarbonylamino) pyridin-3-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl ) pyrimidin-2-amine;

-1104- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2 .1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine;

4- (6- (acetamido) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridine -3-yl) pyrimidine-2-amine; and

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridine -3-yl) pyrimidine-2-amine.

[0211] Another embodiment is a compound of formula (Ia-2a), wherein: n is 0 or 1; m is 0 or 1;

R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of naphthyridinyl, benzo [b] azepinyl, benzo [b] [1,4] oxazinyl, 3,4-dihydro-2H-benzo [b] [1,4] thiazinyl, 3 ', 4' dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazinyl, 3,4-dihydro-2H pyrido [3,2-b] [1,4] thiazinyl and 3,4-dihydro -2H-pyrido [3,2-b] [1,4] oxazinyl, each optionally substituted with one or more substituents independently selected from the group consisting of alkyl and oxo;

R^5a is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R⁸-C (O) R⁶, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) t R⁶ (where t is 1 or 2), and -R⁸-S (O) 2 N (R⁶) R⁷;

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0212] A particular embodiment of this embodiment is a compound of formula (Ia-2a) selected from the group consisting of:

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (5-methyl-6 ((1S, 4S) - 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine; and

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (5-methyl-6 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidin-2-amine.

[0213] Another embodiment is a compound of formula (Ia-2a), wherein: n is 0 or 1; m is 0 or 1;

R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

_R4 is phenyl substituted with one or more substituents selected from the group consisting of alkyl, -R⁸-OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-C (O) N (R^6a) R^7a, -R⁸N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, -R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, N-heteroaryl and Ntero-cyclicyl, wherein the N-heterocyclyl and N-heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, -R⁸-C (O) R⁶ and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkenyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl,

- optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0214] A particular embodiment of this embodiment is a compound of formula (Ia-2a) selected from the group consisting of:

4- (4- (dimethylamino) phenyl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2 -amine;

4- (4- (dimethylamino) phenyl) -N- (5-methyl-6 - ((1S, 4S) - (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3- ylo) pyrimidine-2-amine;

4- (4- (3-cyklopropyloureido) phenyl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3 yl) pyrimidin-2-amine.

[0215] Another embodiment is a compound of formula (Ia-2a) wherein: n is 0 or 1; m is 0 or 1;

R²when present, is independently selected from the group consisting of optionally substituted alkyl, halo, cyano and -OR⁶;

R³when present, is independently selected from the group consisting of alkyl, halo and haloalkyl;

R⁴ is selected from the group consisting of benzimidazolyl, imidazo [1,2-a] pyridinyl, indolyl, indolinyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, 1H pyrrole [2,3-b] pyridinyl and thiazolyl, each independently substituted by one or more substituents selected from the group consisting of alkyl, cyano, oxo, -R⁸OR^6a, -R⁸-N (R^6a) R^7a, -R⁸-C (O) N (R^6a) R^7a, -R⁸-N (R^6a) C (O) R^7a, -R⁸-N (R^6a) S (O) 2 R^7a, R⁸-N (R^6a) C (O) -R⁸-N (R^6a) R^7a, aryl, N-heteroaryl and N-heterocyclyl, where the aryl, nheterocyclyl and N-heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of -C (O) R⁶, -R⁸-N (R⁶) R⁷, R⁸-C (O) N (R⁶) R⁷, alkyl, halo and optionally substituted aryl;

R^5a is independently selected from the group consisting of hydrogen, alkyl, -R⁸-C (O) R⁶ and -R⁸S (O) t R⁶ (where t is 1 or 2);

every R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkyl, optionally substituted

Unsubstituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaralkenyl, and optionally substituted heteroaralkynyl; or any R⁶ and R⁷, together with the common nitrogen atom to which they are both attached, form an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;

every R^6a and R^7a is independently selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted aralkyl; and every R⁸ is independently selected from the group consisting of a direct bond and an optionally substituted straight or branched alkylene chain.

[0216] A particular embodiment of this embodiment is a compound of formula (Ia-2a) selected from the group consisting of:

4- (2- (dimethylamino) thiazol-4-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl ) pyrimidin-2-amine;

4- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridine -3-yl) pyrimidine-2-amine; and

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine.

[0217] In some embodiments of the compounds of the invention, n is 0 or 1.

[0218] In certain embodiments of the compounds of the invention, m is 0 or 1.

[0219] In certain embodiments of the compounds of the invention, Y is = C (R.⁶) [0220] In some embodiments of the compounds of the invention, Y is = N-.

[0221] In some embodiments of the compounds of the invention, R¹ is selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, -R⁸-C (O) OR⁶, -R⁹-N (R⁶) R⁷ and -R⁹-OR⁶;

[0222] In some embodiments of the compounds of the invention, R⁵ is Nterhodocyclyl, wherein the nitrogen atom in the N-heterocyclyl is optionally substituted with a substituent selected from the group consisting of alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, an optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸-C (O) OR⁶, -R⁹N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-C (N = R⁶) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸-S (O) t R⁶ (where t is 1 or 2); and the carbon atom in the N-heterocyclyl is optionally substituted by

A substituent selected from the group consisting of alkyl, halo, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -R⁸-OR⁶, -R⁸-C (O) R⁶, -R⁸C (O) OR⁶, -R⁹-N (R⁶) R⁷, -R⁸-C (O) N (R⁶) R⁷, -R⁸-S (O) 2 N (R⁶) R⁷, and -R⁸-S (O) pR⁶ (where p is 0, 1 or 2).

[0223] In some embodiments of the compounds of the invention, each R⁶ and every R⁷ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl.

[0224] In one embodiment, the compounds of formula (Ia) are selected from the group consisting of:

4- (6- (N, N-dimethylamino) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-methyl-N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-trifluoromethyl-N- (3-methyl-4- (5-metylo2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-fluoro-N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-fluoro-N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-methyl-N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (N, N-dimethylamino) pyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5-methyl-2,5 diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (5-methyl-2,5 diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

-1154- (6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -N- (3-methyl-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;

4- (6- (5- (4-fluorophenyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -N- (3-methyl-4- (4-methylpiperazin-1 yl) phenyl) pyrimidin-2-amine;

4- (4- (N, N-dimethylamino) phenyl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4- (N, N-dimethylamino) phenyl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (5 methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1H-indol-6-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (dimethylamino) pyridin-3-yl) -N- (3-methyl-4- (5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5 - ((ethylamino) carbonyl) -2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 - (ethylcarbonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 - (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 -ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

-1164- (3'-oxo-3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazine] -7'-yl) -N- (3- methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3'-oxo-3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazine] -7'-yl) -N- (3-methyl -4- (5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4- (5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4- (5- (2,2,2-trifluoroethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4- (5- (cyclopropyl) methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5- (2,2,2-trifluoroethyl) -2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5- (cyclopropyl) methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 - (aminosulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3-fluoro-2- (morpholin-4-yl) pyridin-4-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine ;

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-methyl-4- (5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine;

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (2 - ((cyclopropyl) carbonylamino) -pyrimidin-5-yl) -N- (3-methyl-4- (5-metylo2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (4- (4,5-dihydro-thiazol-2-ylcarbamoyl) phenyl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (4- (1,1-dimethylethyl) phenyl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

-1174- (4- (morpholin-4-yl) phenyl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2- amine. TFA salt;

4- (4 - ((methyl) aminocarbonylmethyl) -phenyl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine TFA salt;

4- (4 - ((cyclopropyl) aminocarbonyl-methyl) phenyl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2- amine;

4- (6- (methylaminocarbonyl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) phenyl) pyrimidine-2-amine. TFA salt;

4- (5 - ((morpholin-4-yl) carbonyl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine. Sodium bis TFA;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-cyano-4- (5 methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

5-methyl-4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

5-methyl-4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (5 methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl ) phenyl) pyrimidin-2-amine;

-1184- (6- (dimethylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine;

4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine;

4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (benzyl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (benzyl) pyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine ;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonane -3-yl) phenyl) pyrimidin-2-amine;

4- (6- (dimethylamino) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine;

4- (4- (dimethylamino) phenyl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine ;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl ) phenyl) pyrimidin-2-amine;

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1,5,7-trimetylo3,7 diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine;

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (1,5,7-trimetylo3,7 diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine;

4- (6- (benzyl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine;

4- (6- (benzyl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine;

4- (2- (propyl) aminopyrimidin-5-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (2- (propyl) aminopyrimidin-5-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

-1194- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-trifluoromethyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2- amine;

4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (dimethylamino) pyridin-3-yl) -N- (3-trifluoromethyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-trifluoromethyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-trifluoromethyl-4- (5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6 - ((2- (cyclopropylsulfonyl) aminoethyl) -amino) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine;

4- (6 - ((2- (cyclopropylsulfonyl) aminoethyl) -amino) pyridin-3-yl) -N- (3-methyl-4- (5oksa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-trifluoromethyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (imidazo [1,2-a] pyridin-6-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (4- (5- (4-dimethylaminophenyl) oxazol-2-yl) phenyl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6-methoxy-1H-indol-2-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2- amine;

4- (1- (3-chlorophenyl) -1H-pyrazol-4-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1-methylbenzimidazol-6-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (5-cyano-1H-indol-2-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2- amine;

4- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (7-azabicyclo [2.2.1] heptan-7-yl) phenyl) pyrimidin-2-amine;

4- (6-Cyano-pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

-1204- (6-cyanopyridin-3-yl) -N- (3-methyl-4- (7-azabicyclo [2.2.1] heptan-7-yl) phenyl) pyrimidin-2-amine;

4- (2-oksoindolin-5-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (5-cyanopyridin-3- yl) -N- (3-methyl-4 (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (1H-tetrazol-5-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4- (5-acetyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4- (5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4- (5-cyclopentyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine ;

4- (2-oksoindolin-5-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine;

(1-methylbenzimidazol-6-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine;

4- (imidazo [1,2-a] pyridin-6-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine;

4- (2H-benzo [b] [1,4] oxazin-3 (4H) -one-6-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (5- (3-methyl-piperidin-1-yl) pyrazin-2-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2,1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

-1214- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (4- (methylsulfonylamino) phenyl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4- (methylsulfonylamino) phenyl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (5-methyl-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4- (3-cyklopropyloureido) phenyl) -N- (4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine;

4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4- (5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6-aminopyridin-3-yl) -N- (3-methyl-4- (5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4- (5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6-aminopyridin-3-yl) -N- (3-methyl-4- (5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (2- (dimethylamino) acetamido) -pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine ;

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine;

-1224- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (8metylo- 3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine;

4- (6-aminopyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.2] nonane-4-yl) phenyl) pyrimidin-2-amine ;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1 4-diazabicyclo [3.2.2] nonan-4-yl) phenyl) pyrimidin-2-amine;

4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.2] nonan-4-yl) phenyl) pyrimidin-2-amine;

4- (2- (diethylamino) thiazol-4-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (2- (diethylamino) thiazol-4-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (8 methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine -2-amine;

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine ;

4- (1H-pyrrol-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1H-pyrrol-3-yl) -N- (4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1H-pyrrol-3-yl) -N- (3-trifluoromethyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-trifluoromethyl-4- (2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6-ethoxypyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6-ethoxypyridin-3-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2- (dimethylamino) thiazol-4-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (2- (dimethylamino) thiazol-4-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

-1234- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (4- (1-ethoxyethyl) phenyl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4- (1-ethoxyethyl) phenyl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (dimethylamino) pyridin-3-yl) -N- (4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine;

4- (6- (cis-2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (2- (dimethylamino) methylmorpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine;

4- (6- (piperidin-1-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (3- (aminocarbonyl) piperidin-1-yl) pyridin-3-yl) -N- (3-methyl-4- (5-metylo2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5-methylsulfonylbenzoic 2.5 diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine;

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5oksa-2-aza- [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

-1244- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (3-methyl-4- (5-etylokarbonylo2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine;

4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-amidino-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine. TFA salt;

4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4- (5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6-cis-2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4- (5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N- (3-methyl-4- (5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (1,4-oxazepan-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-isobutyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (1,4-oxazepan-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1 , 5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (1 , 5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine;

4- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5-methyl-2,5 diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl ) pyrimidin-2-amine;

4- (6 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7trimetylo-3,7-diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidin-2-amine;

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine;

-1254- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N- (3-methyl-4- (1,5,7-trimetylo3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine;

4- (6- (2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (5-oksa2-azabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -N- (3-methyl-4- (5-oksa2-azabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (3-methylbutyl) aminopyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine;

4- (6- (3,3-dimethylbutyl) aminopyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4- (5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine;

4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimetylo3,7-diazabicyclo [3.3.1] nonane-3- yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (2 azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (2 -methylsulfonyl-2-azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidine-2-amine and 4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-] b] [1,4] oxazin-7-yl) -N (3-methyl-4- (2-methylsulfonyl-2-aza-bicyclo [2.2.1] heptan-6-yl) -phenyl) pyrimidine-2-amine (68:31 );

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (2-methylsulfonyl-2azabicyklo [2.2.1] heptan-5-yl) phenyl) pyrimidine-2 -amin and 4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (2-methylsulfonyl-2-aza-bicyclo [2.2.1] heptan-6-yl) phenyl) pyrimidine 2-amine (85:15);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (2-2metylosulfonylo azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (2-methylsulfonyl-2azabicyklo [2.2.1] heptan-5-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (2-2metylosulfonylo azabicyclo [2.2.1] heptan-6-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (2-methylsulfonyl-2azabicyklo [2.2.1] heptan-6-yl) phenyl) pyrimidin-2-amine;

-1264- (6- (tiamorfolin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-fluoro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4- (5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4- (5-isobutyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) -N- (3-methyl-4- (5-methylsulfonylbenzoic 2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4- (5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (4- (5-methyl-2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5-methyl- 2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5-metylosulfonylo- 2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-methyl-4- (5-methylsulfonylbenzoic 2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4 (6,9- metanooktahydro-1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (6,9-metanooktahydro-1Hpirydo [1,2-a] pyrazin-2-yl) phenyl ) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 - (1-methylethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

-1274- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-chloro-4- ( 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-chloro-4- (5 - (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 -cyclopentyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (5 -acetyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1 4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine;

4- (5- (1-methylethoxy) karbonylopropylo-6-amino-pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine ;;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (2- (trifluoromethyl) pyridin-4-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine ;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4- (5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine;

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-chloro-4- (5- (methylsulfonyl) 2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4- (5-acetyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-chloro-4- (5-acetyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (5-cyclopentyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;

4- (6- (2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4- (5- (methylsulfonyl) -2,5 diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

-1284- (6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-3-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-3-yl) -N- (3-methyl-4- (5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (4- (trifluoromethyl) phenyl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (7,8,9,9a-tetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepin-10 (11H) -one-3-yl) -N - (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-cyano-4- (5-methyl- 2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-cyano-4- (5-methyl-2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-cyano-4- (5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-methyl-4- (5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine ;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine ;

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-methyl-4- (6,9metanooktahydro-1 H-pyrido [1, 2-a] pyrazin-2-yl) phenyl) pyrimidin-2-amine;

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-methyl-4- (6,9metanooktahydro-1 H-pyrido [1 , 2-a] pyrazin-2-yl) phenyl) pyrimidin-2-amine;

4- (6- (2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.2] nonane -4-yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4- (3,9-diazabicyclo [3.3.2] decan-10on-3-yl) phenyl) pyrimidine -2-amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-cyano-4- (3 9-diazabicyclo [3.3.2] decan-10-one-3-yl) phenyl) pyrimidin-2-amine;

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (3- (dimethylamino) -8- azabicyclo [3.2.1] octan-8-yl) phenyl) pyrimidine -2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (3- (morpholin-4-yl) -8-azabicyclo [3.2.1] octan-8-yl ) phenyl) pyrimidin-2-amine;

-1294- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (3- (morpholin-4-yl) -8-azabicyclo [3.2.1] octan-8- yl) phenyl) pyrimidin-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (3- (dimethylamino) -8- azabicyclo [3.2.1] octan-8-yl) phenyl) pyrimidine -2-amine;

4- (6- (dimethylamino) pyridin-3-yl) -N- (6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine ;

4- (6- (methylcarbonylamino) pyridin-3-yl) -N- (4- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine ;

4- (4- (dimethylamino) phenyl) -N- (6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine;

4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl ) pyrimidin-2-amine;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3 yl) pyrimidin-2-amine;

4- (6- (dimethylamino) pyridin-3-yl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine -2-amine;

4- (4- (dimethylamino) phenyl) -N- (5-methyl-6 - ((5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2- amine;

4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridine -3-yl) pyrimidine-2-amine;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) pyridin-3-yl) pyrimidine-2-amine;

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (5-methyl-6- (5-methyl-2,5 diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3 yl) pyrimidin-2-amine;

4- (4- (t-butylcarbonylamino) phenyl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2 -amine;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (5-methyl-6- (5 methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine;

4- (4- (3-cyklopropyloureido) phenyl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2 -amine;

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) pyridin-3-yl) pyrimidine-2-amine;

-1304- (6-aminopyridin-3-yl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2 -amine;

4- (6- (acetamido) pyridin-3-yl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine -2-amine;

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine -2-amine;

4- (2- (dimethylamino) thiazol-4-yl) -N- (6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine ;

4- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine -2-amine;

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine; and

4- (6- (2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (5-methyl-6- (5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine.

[0225] It is understood that various embodiments of the compounds of the invention as set forth above do not include compounds that are specifically disclosed in previous publications, including scientific journals, patents and published patent applications.

[0226] Another aspect of the present invention is pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of the invention as described above in the Summary of the Invention as an isolated stereoisomer or a mixture thereof, or as a pharmaceutically acceptable salt thereof. In particular, some embodiments of the pharmaceutical compositions of the invention comprise a pharmaceutically acceptable excipient and a therapeutically effective amount of an embodiment of the compound of formula (Ia) as set out above.

[0227] Another aspect of the invention are compounds for use in a method of treating diseases or conditions associated with JAK2 activity in a mammal using the compounds and pharmaceutical compositions of the invention. One embodiment of the compounds for use in the methods of the invention disclosed herein is the administration of a therapeutically effective amount of a compound of formula (Ia) as set forth above to a mammal, preferably a human, in need thereof. Another embodiment of the compounds for use in the methods of the invention disclosed herein are methods of treating diseases or conditions associated with JAK2 activity in a mammal, wherein the disease or conditions is leukemia, lymphoma, multiple myeloma, transplant rejection, bone marrow transplantation, autoimmune diseases, inflammatory, myeloproliferative disorders, disorder,

[0228] It will be understood that any one of the embodiments of the compounds of the invention set forth above and each specific substituent as defined herein for a particular n,

-131m, R¹, R², R³, R⁴, R⁵ or Y in the compounds of the invention, presented above, may be independently combined with other embodiments and / or substituents of the compounds of the invention to form embodiments of the inventions not specifically mentioned above. Furthermore, in the case where a list of substituents is mentioned for a particular R or Y group in a particular embodiment and / or claim, it is understood that each particular substituent can be removed from a particular embodiment and / or claim and the rest of the substituent list will be considered falling within the scope of the invention.

[0229] Specific embodiments of the invention are described in more detail below in the following sections.

USEFULNESS AND TESTING OF THE COMPOUNDS OF THE INVENTION [0230] The present invention provides pyrimidine-2-amine compounds or pharmaceutically acceptable salts thereof, as described above in the Summary of the Invention, for use in the treatment of the diseases or conditions described herein. The present invention further provides the use of the compounds of the present invention in the manufacture of a medicament for the treatment of diseases or conditions in which targeting the JAK pathway or inhibiting JAK kinases, in particular JAK2, may be therapeutically useful. These include diseases or conditions that involve the function of lymphocytes, macrophages or mast cells. Accordingly, diseases or conditions associated with JAK2 activity are in particular diseases or conditions in which targeting the JAK pathway or inhibiting JAK kinases, in particular JAK2, may be therapeutically useful,

[0231] As noted above, numerous diseases or conditions can be treated using the compounds of the invention, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof. As well known in the art, "treatment" is an approach to obtaining beneficial or desired results, including clinical results. For purposes of this invention, the beneficial or desirable results may include one or more: alleviating or ameliorating one or more than one symptom; reducing the degree of the condition, including illness; stabilization (ie no deterioration) of condition for the condition, including diseases; preventing the spread of the disease; delaying or slowing down the condition, including disease progression; ameliorating or ameliorating the condition, including the medical condition; and remission (partial or total); in each case, whether it is detectable or undetectable. Compounds that are highly potent and can be administered topically at very low doses are preferred, thereby minimizing systemic side effects.

[0232] The compounds of the invention described herein, or their pharmaceutically acceptable salts, are potent and selective inhibitors of JAK kinases, and in particular selective for JAK2-containing cytokine signaling pathways. As a result of this effect, the compounds can be used in a variety of in vitro, in vivo and ex vivo contexts in regulating or inhibiting JAK kinase activity, signaling cascades in which JAK kinases play a role, and biological responses performed using such signaling cascades. For example, in one embodiment, these compounds can be used to inhibit JAK kinase, either in vitro or in vivo, in practically any type of cells expressing JAK kinase.

[0233] In hematopoietic cells expressing JAK kinases, compounds of the invention can be used to regulate signal transduction cascades in which the JAK kinase, in particular JAK2, plays an important role. Such JAK-dependent signal transduction cascades include, but are not limited to, those signaling cascades having a wide range of cytokine receptors, including those activated by growth hormone, erythropoietin, prolactin, granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor, Ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M, interferon-γ, thrombopoetin, leptin, IL-3, IL-5, IL-6, IL11, IL-12 and part of the G protein-coupled receptor signaling cascades (GPCR) (angiotensin II, bradykinin, endothelin, platelet activating factor, stimulating hormone α-melanocytes, isoproterenol and phenylephrine). These compounds may also be used in vitro or in vivo to regulate, and in particular inhibit, cellular or biological responses affected by such JAK-dependent signal transduction cascades. Such cellular or biological responses include activation of the MAPK and AKT pathway, IL-3 mediated cell proliferation, etc.

[0234] It is important that the compounds can be used to inhibit JAK kinase in vivo as a therapeutic approach for treating or preventing diseases or conditions mediated, in whole or in part, by JAK kinase activity (referred to herein as "kinase-mediated diseases or conditions"). HOW"). Non-limiting examples of JAK kinase mediated diseases or conditions that can be treated or preventable with the compounds of the invention, or pharmaceutically acceptable salts thereof, include allergies; asthma; autoimmune diseases such as transplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin, host versus transplantation (HVGR), graft versus host reaction (GVHR) etc.), rheumatoid arthritis, and amyotrophic lateral sclerosis; autoimmune diseases mediated by T cells such like multiple sclerosis, psoriasis and Sjogren's syndrome; type II inflammatory diseases such as vasculitis (including vasculitis, atherosclerosis and coronary artery disease); diseases of the central nervous system, such as stroke; lung diseases such as obliterative bronchitis, primary pulmonary hypertension and pulmonary arterial hypertension, and persistent, delayed type IV hypersensitivity reactions; and haematopoietic tumors such as leukemia and lymphomas. The compounds of the invention may also be used in the treatment of obesity, because in obese animals, JAK2 / STAT and MAP kinase pathways are hyperactive in response to insulin. lung diseases such as obliterative bronchitis, primary pulmonary hypertension and pulmonary arterial hypertension, and persistent, delayed type IV hypersensitivity reactions; and haematopoietic tumors such as leukemia and lymphomas. The compounds of the invention may also be used in the treatment of obesity, because in obese animals, JAK2 / STAT and MAP kinase pathways are hyperactive in response to insulin. lung diseases such as obliterative bronchitis, primary pulmonary hypertension and pulmonary arterial hypertension, and persistent, delayed type IV hypersensitivity reactions; and haematopoietic tumors such as leukemia and lymphomas. The compounds of the invention may also be used in the treatment of obesity, because in obese animals, JAK2 / STAT and MAP kinase pathways are hyperactive in response to insulin.

[0235] Also described is a method of inhibiting JAK kinase activity, comprising contacting JAK kinase in an amount of a compound effective to inhibit JAK kinase activity, wherein the compound is selected from the compounds of this invention or their pharmaceutically acceptable salts. In certain embodiments of the methods described herein, the method is carried out in vivo. In certain embodiments of the methods described herein, the method is carried out in vitro.

[0236] In some embodiments of the methods, the compound is administered to a subject suffering from an autoimmune disease mediated by T cells. In certain other embodiments, the subject is a transplant recipient suffering from or predisposed to reject allograft transplantation. In certain other embodiments, the compound is administered to a subject suffering from or predisposed to developing type IV hypersensitivity reactions.

[0237] Also described is a method of inhibiting JAK kinase activity, comprising contacting in vitro a JAK2 kinase with an amount of a compound effective to inhibit JAK kinase activity, wherein the compound is selected from the compounds of this invention, or a pharmaceutically acceptable salt thereof.

[0238] In a specific embodiment, the compounds of the invention, or a pharmaceutically acceptable salt thereof, can be used to treat and / or prevent rejection of organ transplants and / or tissues of recipients (i.e., treatment and / or prevention of transplant rejection). Allografts can be rejected by the immune reaction either of a cellular or humoral recipient against the graft antigens (tissue compatibility system) present on the membranes of the donor cells. The strongest antigens are regulated by a complex of genetic loci called Human Leukocyte Group A (HLA) antigens. Together with ABO blood group antigens, they are the main human-detectable antigens.

[0239] Rejection after transplantation can generally be divided into three categories: hyperstrepe, occurring hours to several days after transplantation; acute, occurring days to a few months after transplantation; and chronic, occurring months or years after transplantation.

[0240] Hyperostrejection is mainly caused by the production of host antibodies that attack the graft tissue. In the hyper-rejection reaction, antibodies are observed in the vascularization of the graft shortly after transplantation. Soon there is vascular clotting, which leads to ischemia, necrosis and possible death. The transplantation graft does not respond to known immunosuppressive therapies. Because HLA antigens can be identified in in vitro studies, screening before transplantation is used to significantly reduce hyper-rejection. As a consequence of this screening, hyper-rejection is relatively rare today.

[0241] It is believed that acute rejection is mediated by the accumulation of antigen-specific cells in the graft tissue. The T-cell immune response to these antigens (i.e., HVGR or GVHR) is the main mechanism of acute rejection.

The accumulation of these cells causes damage to the graft tissue. It is considered that

Both CD4 + T helper cells and CD8 + cytotoxic T cells are involved in this process, and that this antigen is presented by the donor and dendritic cells of the host. CD4 + helper T cells help recruit other effector cells such as macrophages and eosinophils for transplantation. The participation also takes access to the cascades of T cell activation signal transduction (e.g., CD28, CD40L and CD2 cascades).

[0242] Acute cellular rejection can be reversed in many cases by intensifying immunotherapy. After successful reversal, the severely damaged graft elements are healed by fibrosis and the transplant residue looks normal. After acute rejection, the dose of immunosuppressive drugs can be reduced to a very low level.

[0243] Chronic rejection, which is a particular problem in kidney transplants, often develops insidiously despite increased immunosuppressive therapy. It is believed that it is caused largely by the type IV hypersensitivity cell. The pathological profile differs from acute rejection. The participation primarily involves arterial endothelium, with extensive proliferation, which can gradually close the lumen of the vessel, which leads to ischemia, fibrosis, densities of the intimal membrane and atherosclerotic lesions. Chronic rejection is mainly caused by progressive obliteration of the vascular graft, and recalls the slow process of vasculitis.

[0244] In type IV hypersensitivity, CD8 cytotoxic T cells and CD4 helper T cells recognize both intracellular or extracellular synthesized antigen when complexed with MHC Class I or Class II molecules respectively. The function of macrophages as antigen presenting cells and release IL-1, which promotes the proliferation of T helper cells. T helper cells release interferon gamma and IL-2, which together regulate delayed hypersensitivity reactions mediated by macrophage-mediated activation and T-cell mediated immunity. In the case of organ transplants, cytotoxic T-cells destroy cell transplants on contact.

[0245] Since JAK kinases play a critical role in T-cell activation, the pyrimidin-2-amino compounds described herein or their pharmaceutically acceptable salts can be used to treat and / or prevent many aspects of transplant rejection, and are particularly useful in treatment and / or to prevent rejection reactions mediated, at least in part, by T cells, such as HVGR or GVHR. The pyrimidine-2-amine compounds can also be used to treat and / or prevent chronic rejection in transplant recipients, in particular kidney transplant recipients.

[0246] This invention also provides a compound for use in a method of treating a T-cell mediated autoimmune disease comprising administering to a patient suffering from such an autoimmune disease an amount of a compound effective to treat an autoimmune disease, wherein the compound is selected from compounds of the invention or their pharmaceutically acceptable salts. In some

For examples of the methods of autoimmune disease is MS (MS), psoriasis, or Sjogren's syndrome.

monoclonal antibodies against T cells (OKT3)) and irradiation. These various agents can be used in accordance with their standard and typical doses as outlined in the information accompanying the prescribing of commercially available dosage forms (see also the Prescription in the 2006 Edition of The Physician's Desk Reference). Azathioprine is currently available from Salix Pharmaceuticals, Inc. . under the trade name AZASAN; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name PURINETHOL; prednisone and prednisolone are currently available from Roksane Laboratories, Inc .; Methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name RAPAMUNE; tacrolimus is currently available from Fujisawa under the trade name PROGRAF; cyclosporine is currently available from Novartis under the trade name SANDIMMUNE and Abbott under the trade name GENGRAF; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the trade name CELLCEPT and Novartis under the trade name MYFORTIC; Azathioprine is currently available from Glaxo Smith Kline under the trade name IMURAN; and antibodies are currently available from Ortho Biotech under the trade name ORTHOCLONE, Novartis under the trade name SIMULECT (basiliximab) and Roche under the tradename ZENAPAX (daclizumab). Azathioprine is currently available from Glaxo Smith Kline under the trade name IMURAN; and antibodies are currently available from Ortho Biotech under the trade name ORTHOCLONE, Novartis under the trade name SIMULECT (basiliximab) and Roche under the tradename ZENAPAX (daclizumab). Azathioprine is currently available from Glaxo Smith Kline under the trade name IMURAN; and antibodies are currently available from Ortho Biotech under the trade name ORTHOCLONE, Novartis under the trade name SIMULECT (basiliximab) and Roche under the tradename ZENAPAX (daclizumab).

[0248] Furthermore, the pyrimidine-2-amine compounds of the invention may be co-administered with or adjuvantly with a Syk kinase inhibitor. Syk kinase is a known tyrosine kinase that plays a key role in Fc signaling as well as other signaling cascades such as those that involve B cell receptor signaling (Turner et al., (2000), Immunology Today 21: 148-154 ) and beta (1), beta (2) and beta (3) integrins in neutrophils (Mocsavi et al., (2002), Immunity 16: 547-558). For example, Syk kinase plays a decisive role in signaling a high affinity IgE receptor in mast cells that leads to the activation and subsequent release of many chemical mediators that cause allergic attacks. However, unlike JAK kinases, which help regulate the pathways involved in delayed or cell-mediated type IV hypersensitivity reactions, the Syk kinase helps regulate the pathways involved in IgE-mediated direct type I hypersensitivity reactions. Some compounds that affect the Syk pathway may or may not affect the JAK pathways.

-136 [0249] Suitable Syk-inhibiting compounds are described, for example, in U.S. Patent Application Serial No. 10 / 355.543, filed January 31, 2003 (Publication No. 2004/0029902); Published PCT Patent Application No. WO 03/063794; U.S. Patent Application Serial No. 10 / 631,029, filed July 29, 2003; Published PCT Patent Application No. WO 2004/014382; U.S. Patent Application Serial No. 10 / 903,263 filed on July 30, 2004; Published PCT Patent Application No. WO 2005/016893; U.S. Patent Application Serial No. 10 / 903,870 filed on July 30, 2004; Patent Application PCT No. PCT / US2004 / 24920, filed on July 30, 2004; Patent Application US, Serial No. 60 / 630,808, filed on November 24, 2004; Patent Application US, Serial No. 60 / 64,424, filed January 19, 2005; and Patent Application US, Serial No. 60 / 654,620, filed February 18, 2005.

[0250] Furthermore, the pyrimidine-2-amino compounds of the invention, or pharmaceutically acceptable salts thereof, can be used to treat or prevent these diseases or conditions in patients who either pre-react (refractively) to or become non-responsive to treatment with a Syk-inhibiting compound, or one of the other current therapies for a given disease. The pyrimidine-2-amine compounds of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with Syk inhibitory compounds in patients who are immune or unresponsive to the Syk compound. Suitable Syk inhibitory compounds with which the pyrimidine-2-amino compounds of the invention, or pharmaceutically acceptable salts thereof, can be administered are provided supra.

[0251] This invention also provides a compound for use in a method of treating a T-cell mediated autoimmune disease comprising administering to a patient suffering from such an autoimmune disease an amount of a compound effective to treat an autoimmune disease, wherein the compound is selected from the compounds of the invention described herein. , or a pharmaceutically acceptable salt thereof, a compound or a pharmaceutically acceptable salt thereof, is administered in combination with or adjunct to a compound that inhibits Syk kinase with an IC 50 in the range of at least 10 μΜ.

[0252] This invention also provides a compound for use in a method of treating or preventing allograft transplant rejection in a transplant recipient, comprising administering to the transplant recipient an amount of the compound effective to treat or prevent rejection, wherein the compound is selected from the compounds of the invention described herein, or a pharmaceutically acceptable compound thereof. permissible salts. In a further embodiment, the compound or pharmaceutically acceptable salt is administered to the tissue or organ prior to transplantation of the tissue or organ of the recipient.

[0253] This invention also provides a compound for use in a method of treating or preventing allograft transplant rejection in a transplant recipient, wherein the rejection is an acute rejection, comprising administering to the transplant recipient an amount of the compound effective to treat or prevent rejection, wherein the compound is selected from compounds according to of the invention, or a pharmaceutically acceptable salt thereof.

This invention also provides a compound for use in a method of treating or preventing transplant allograft rejection in a transplant recipient, wherein the rejection is a chronic rejection, comprising administering to the recipient the amount of the compound effective to treat or prevent rejection, wherein the compound is selected from the compounds of the invention described herein, or their pharmaceutically acceptable salts.

[0255] This invention also provides a compound for use in a method of treating or preventing transplant allograft rejection in a transplant recipient, wherein the rejection is mediated by HVGR or GVHR, comprising administering to the transplant recipient an amount of the compound effective to treat or prevent rejection, wherein the compound is selected from the compounds of the invention, or a pharmaceutically acceptable salt thereof, as described herein.

[0256] Ten wynalazek zapewnia również związek do zastosowania w sposobie leczenia lub zapobiegania odrzucenia przeszczepu alloprzeszczepu u biorcy przeszczepu, w którym przeszczepienie alloprzeszczepu jest wybrane z przeszczepu nerki, serca, wątroby i płuca, obejmującym podawanie biorcy przeszczepu ilości związku skutecznej do leczenia lub zapobiegania odrzuceniu, przy czym związek jest wybrany ze związków według wynalazku, lub ich farmaceutycznie dopuszczalnych soli, jak tu opisanych.

[0257] This invention also provides a compound for use in a method of treating or preventing transplant allograft rejection in a transplant recipient, wherein allograft transplantation is selected from the kidney, heart, liver and lung, comprising administering to the transplant recipient an amount of the compound effective to treat or prevent rejection, wherein the compound is selected from the compounds of the invention described herein, or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt is administered in combination with or as an aid to another immunosuppressive agent.

[0258] This invention also provides a compound for use in a method of treating or preventing allograft transplant rejection in a transplant recipient, wherein allograft transplantation is selected from the kidney, heart, liver and lung, comprising administering to the transplant recipient an amount of the compound effective to treat or prevent rejection, wherein the compound is selected from the compounds of the invention described herein, or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salts are administered in combination with or as an auxiliary agent to another immunosuppressive agent in which the immunosuppressive agent is selected from cyclosporin, tacrolimus, sirolimus, an IMPDH inhibitor, mycophenolate, mycophenolate mofetil, antibodies against T cells and OKT3.

[0259] The pyrimidine-2-amine compounds described herein, or pharmaceutically acceptable salts thereof, are moderators of IL-4 cytokine signaling. Consequently, the pyrimidine-2-amino compounds of the invention, or pharmaceutically acceptable salts thereof, may have slowed down the type I hypersensitivity reaction. Thus, in a particular embodiment, the pyrimidine-2-amino compounds of the invention, or a pharmaceutically acceptable compound thereof.

The drugs may have been used to treat such reactions, i.e. diseases associated with them, in which they mediate or caused by such hypersensitivity reactions (e.g., allergies) prophylactically. For example, an individual suffering from allergy may take one or more of the JAK-selective compounds described herein before the expected exposure to allergens to delay initiation or progression, or to completely eliminate the allergic response.

[0260] When used to treat or prevent such diseases, the pyrimidine-2-amino compounds of the invention, or pharmaceutically acceptable salts thereof, can be administered singly as mixtures of one or more pyrimidine-2 amino compounds, or a pharmaceutically acceptable salt thereof, or in a mixture or combination with other agents useful for treating such diseases and / or symptoms associated with such diseases. Pyrimidine-2-amino compounds, or pharmaceutically acceptable salts thereof, may also be administered in admixture or in combination with agents useful for the treatment of other disorders or diseases such as steroids, membrane stabilizers, 5-lipoxygenase (5LO) inhibitors, leukotriene synthesis inhibitors and receptor inhibitors, IgE isotype switching inhibitors or IgE synthesis, IgG isotype switching or IgG synthesis, β-agonists, tryptase inhibitors, aspirin, cyclooxygenase inhibitors (COX), methotrexate, anti-TNF drugs, retux, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors and antihistamines to name a few. Pyrimidine-2-amino compounds, or pharmaceutically acceptable salts thereof, may be administered per se or in the form of precursors or as pharmaceutical compositions containing the active compound.

[0261] This invention also provides a compound for use in a method of treating or preventing Type IV hypersensitivity reactions comprising administering to a subject an amount of a compound effective to treat or prevent a hypersensitivity reaction, wherein the compound is selected from the compounds of the invention, or a pharmaceutically acceptable salt thereof, described here.

[0262] This invention also provides a compound for use in a method of treating or preventing type IV hypersensitivity reactions that is practically prophylactic, comprising administering to a subject an amount of a compound effective to treat or prevent a hypersensitivity reaction, wherein the compound is selected from compounds of the invention, or pharmaceutically acceptable salts as described herein, and is administered prior to exposure to the allergen.

[0263] This invention also provides an in vitro method of inhibiting signal transduction cascade in which the JAK2 kinase plays a role, comprising contacting the cell with the expression of the receptor involved in such signaling cascade with the compound, wherein the compound is selected from the compounds of the invention, or a pharmaceutically acceptable salts as described herein.

[0264] In another embodiment, the present invention provides a compound for use in a method of treating or preventing a JAK kinase mediated disease, comprising administering to the subject an amount of the compound effective to treat or prevent the disease in

Which is mediated by the JAK kinase, wherein the compound is selected from the compounds of the invention, or a pharmaceutically acceptable salt thereof, as described herein.

[0265] This invention also provides a compound for use in a JAK kinase mediated treatment or prevention method in which the JAK-mediated disease is HVGR or GVHR, comprising administering to the subject an amount of the compound effective to treat or prevent the disease in which is mediated by the JAK kinase, wherein the compound is selected from the compounds of the invention described herein, or a pharmaceutically acceptable salt thereof.

[0266] This invention also provides a compound for use in a JAK kinase-mediated treatment or prevention method wherein the JAK-mediated disease is acute allograft rejection, comprising administering to the subject an amount of the compound effective to treat or prevent the disease in which is mediated by the JAK kinase, wherein the compound is selected from the compounds of the invention described herein, or a pharmaceutically acceptable salt thereof.

[0267] This invention also provides a compound for use in a JAK kinase mediated treatment or prevention method wherein the JAK mediated disease is chronic allograft rejection, comprising administering to the subject an amount of the compound effective to treat or prevent the disease in which is mediated by the JAK kinase, wherein the compound is selected from the compounds of the invention described herein, or a pharmaceutically acceptable salt thereof.

[0268] The active compounds of the invention, or pharmaceutically acceptable salts thereof, typically inhibit the JAK / Stat pathway. The activity of a particular compound as a JAK kinase inhibitor can be assessed in vitro or in vivo. In some embodiments, the activity of a particular compound can be tested in a cellular assay. Suitable assays include assays that determine the inhibition of either the phosphorylation activity or the JAK kinase AS activity.

In this way, it is said that the compound inhibits JAK kinase activity if it inhibits the JAK kinase ATPase phosphorylation or JAK activity with an IC 50 of about 20 μΜ or less.

[0269] One way to determine such inhibition is to detect the effect of pyrimidine-2-amino compounds on up-regulation of further gene products. In the Ramos / IL4 assay, B cells are stimulated by interleukin-4 (IL-4) cytokines leading to activation of the JAK / Stat pathway by phosphorylation of the JAK, JAK1 and JAK3 kinases, which in turn phosphorylates and activates the Stat-6 transcription factor. One of the genes upregulated by activated Stat-6 is the low affinity IgE receptor, CD23. To study the effect of inhibitors (e.g. the pyrimidine-2-amine compounds described herein) on JAK1 and kinases

JAK3, human Ramos B cells are stimulated with human IL-4. Twenty to 24 hours after stimulation, the cells are stained for upregulation of CD23 and analyzed by flow cytometry (FACS). Decreasing the amount of CD23 present relative to the control conditions means that the test compound actively inhibits the JAK kinase pathway. An exemplary test of this type is described in more detail in the Biological Examples described below.

The biological activity of the compounds of the invention can be further characterized by determining the effect of pyrimidine-2-amino compounds described herein on the proliferative response of primary human T cells. In this assay, primary human T cells derived from peripheral blood and pre-activated by receptor stimulation T cells and CD28, proliferate in culture in response to cytokine, interleukin-2 (IL-2). This proliferative response is dependent on the activation of JAK1 and JAK3 tyrosine kinases, which phosphorylate and activate the Stat-5 transcription factor. Primary human T cells are incubated with pyrimidine-2-amine compounds in the presence of IL-2 for 72 hours, and at the endpoint of the assay intracellular ATP concentration is measured to assess cell viability. The reduction in cell proliferation as compared to the control of the conditions indicates inhibition of the JAK kinase pathway. An exemplary test of this type is described in more detail in the Biological Examples described below.

[0271] The biological activity of the compounds of the invention can be further characterized by determining the effect of the pyrimidine-2-amino compounds described herein on the A549 lung epithelial cells and U937 cells. A549 lung epithelial cells and U937 cells up-regulate the surface expression of ICAM-1 (CD54) in response to various stimuli. Therefore, by using ICAM-1 expression as a reading, the effects of the test compound on different signaling pathways can be assessed in the same cell type. Stimulation of IL-1β by the Π, - 1β receptor activates the TRAF6 / NFkB pathway causing upregulation of ICAM1. IFNγ induces upregulation of ICAM-1 by activation of the JAK1 / JAK2 pathway. Up regulation of ICAM-1 can be quantified by flow cytometry on a compound dose curve and the EC50 values ​​are calculated.

[0272] The biologically active compounds of the invention, or pharmaceutically acceptable salts thereof, generally inhibit the JAK kinase pathway with an IC50 in the range of about 1 mM or less as measured in the assays described herein. Obviously, it will be apparent to those skilled in the art that compounds that exhibit a lower IC 50, e.g. of the order of 100 μΜ, 75 μΜ, 50 μΜ, 40 μΜ, 30 μΜ, 20 μΜ, 15 μΜ, 10 μΜ, 5 μΜ, 1 μΜ , 500 nM, 100 nM, 10 nM, 1 nM, or even less, may be particularly useful in therapeutic applications. In cases where a cell-specific action is desired, the compound can be screened for activity with the desired cell type and anti-screened for inactivity against other cell types. Desired degree of "inactivity" in such anti-propagation,

[0273] The pyrimidine-2-amino active compounds of the invention, or pharmaceutically acceptable salts thereof, also typically inhibit IL-4 expression of CD23 in B cells with an IC50 in the range of about 20 μΜ or less, typically in the range of about 10 μΜ, 1 μΜ , 500 πΜ, 100 nM, 10 nM, 1 nM, or even lower. A suitable test that can be used is the test described in Biological Example 1 described below, entitled "Test for IinII Cells B Ramos Stimulated II-4". In some embodiments, the pyrimidine-2-amino active compounds of the invention have an IC 50 less than or equal to 5 μΜ,

- greater than 5 μΜ but less than 20 μΜ, greater than 20 μΜ or greater than 20 μΜ but less than 50 μΜ in the test described in Biological Example 1.

[0274] In addition, the pyrimidine-2-amino active compounds of the invention, or pharmaceutically acceptable salts thereof, also typically inhibit the activity of human primary T cells with an IC 50 in the range of about 20 μΜ or less, typically in the range of about 10 μΜ, 1 μΜ, 500 πΜ, 100 πΜ, 10 nM, 1 nM, or even lower. The IC50 for primary human T cells can be determined in a standard in vitro assay with isolated human primary T cells. A suitable assay that can be used is the test described in Biological Example 2 below, entitled "Proliferation Assay of Primary Human IL-2 Stimulated T Cells". In some embodiments, the pyrimidine-2-amino active compounds have an IC 50 less than or equal to 5 μΜ, greater than 5 μΜ, but less than 20 μΜ, greater than 20 μΜ, or greater than 20 μΜ,

[0275] The pyrimidine-2-amino active compounds of the invention, or pharmaceutically acceptable salts thereof, also generally inhibit the expression of ICAM1 (CD54) induced IFN? Exposure in U937 or A549 cells with an IC50 in the range of about 20 μΜ or less, typically in the range of about 10 μΜ, 1 μΜ, 500 πΜ, 100 πΜ, 10 πΜ, 1 πΜ, or even lower. The IC50 against ICAM expression (CD54) in IFNγ-stimulated cells can be determined in a functional cellular assay with an isolated cell line of A549 and U937. Suitable assays that can be used are the tests described in Biological Examples 5 and 6 below, entitled "A459 Stimulated IFNγ Line" and "FACS ICA" 11 IFNy U937 ", respectively. In some embodiments, pyrimidine-2 active compounds -amino have an IC 50 less than or equal to 20 μΜ, greater than 20 μΜ, or greater than 20μΜ, but less than 50 μΜ in the tests described in Biological Example 5 or Biological Example 6.

[0276] For the purposes of the present invention, the expression "cell proliferative disorder" refers to a disorder characterized by abnormal cell proliferation. A cell proliferative disorder does not imply any limitation with respect to cell growth rate, but only indicates a loss of control that relates to normal cell growth and division. Thus, in some embodiments, cells of cell proliferation disorder may have the same cell division rates as normal cells, but do not respond to signals that limit such growth. In the area of ​​"cell proliferation disorder" is neoplasia or a tumor that is abnormal tissue growth. Cancer refers to any of various malignant neoplasia characterized by cell proliferation,

[0277] Accordingly, cell proliferative disorders that can be treated with the compounds of the invention, or pharmaceutically acceptable salts thereof, relate to any disorder characterized by abnormal cell proliferation. These include various tumors and benign and malignant tumors, metastases or without metastases. Cell proliferative disorders include various cancers, including, but not limited to, tongue and mouth cancer,

- throat, esophagus, stomach, small intestine, colon, rectum, liver, gallbladder, pancreas, larynx, lungs and bronchi, bones and joints, including synovial sarcoma and osteosarcoma, melanomas, including basal cell carcinoma, squamous cell carcinoma, breast, cervix, endometrium, ovary, vulva, vagina, prostate, testicles, penis, bladder, kidney and pelvis, ureter, eyes, brain, including glioblastoma, glioblastoma multiforme, astrocytoma, neuroblastoma, medulloblastoma, and thyroid gland. For example, cell proliferative disorders that can be treated with the compounds of the invention, or pharmaceutically acceptable salts thereof, include, but are not limited to, the following:

a) breast proliferative disorders that include, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma, lobular carcinoma in situ and metastatic breast cancer;

b) skin proliferative disorders that include basal cell carcinoma, squamous cell carcinoma, malignant melanoma and Kaposi's sarcoma;

c) airway proliferative disorders that include small cell and non-small cell lung cancer, bronchial edema, pleural blastomy and / or lung and malignant mesothelioma;

d) brain proliferative disorders that include cerebral and hypothalamic glioblastoma, cerebellar and cerebral astrocytoma, medulloblastoma, lining tumors, oligodendroglial tumors, meningiomas and neuroectodermal and pineal tumors;

e) proliferative disorders of the male reproductive organs, which include prostate cancer, testicular cancer and penile tumor;

f) female sexual reproductive disorders, which include, uterine cancer (endometrium), cervical tumor, ovary, vagina, vulva, uterine sarcoma and ovarian tumor;

g) digestive tract disorders that include rectal, colon, colorectal, esophageal, gall bladder, stomach (gastric), pancreatic, pancreatic islet cell, anus, small intestine and salivary gland tumors;

h) liver proliferative disorders that include, hepatocellular carcinoma, cholangiocarcinoma, hepatocellular carcinoma and bile duct, primary liver cancer and metastatic liver cancer;

i) ocular proliferative disorders that include intraocular melanoma, retinal glioma, and rhabdomyosarcoma;

j) head and neck proliferative disorders that include tumors of the larynx, pharynx, nasopharyngeal cavity, mouth, and cancer of the lip and mouth, squamous carcinoma of the neck, tumor with metastases to the paranasal sinuses;

-143k) lymphocyte cell proliferative disorders, which include various T and B cell lymphomas, non-Hodgkins lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, and central nervous system lymphoma;

l) leukemia, which include acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia,

m) thyroid proliferative disorders, which include, thyroid cancer, thymoma, malignant thymoma, thyroid carcinomas, papillary thyroid carcinomas, multiple endocrine type 2A (MEN2A), pheochromocytoma, parathyroid adenomas, multiple endocrine type 2B (MEN2B), familial medullary thyroid cancer (FMTC) and carcinoids;

n) urinary tract proliferative disorders that include, bladder cancer;

o) sarcomas that include, soft tissue sarcoma, osteosarcoma, malignant fibrous sarcoma, lymphosarcoma and rhabdomyosarcoma;

p) renal proliferative disorders, which include kidney cell cancer, clear cell renal cell carcinoma; and adenocarcinoma of kidney cells;

q) lymphoblastic leukemia / lymphoma from precursor B cells (acute lymphoblastic leukemia from precursor B cells), chronic B cell lymphocytic leukemia / lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmocytic lymphoma, sphenoidal B-cell marginal zone lymphoma, hairy cell leukemia, plasma cell myeloma / plasmacytoma, extranodal marginal zone lymphoma from MALT B cells, nodular B-cell marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, large B-cell mediastinal lymphoma, primary exudative lymphoma and Burkitt's lymphoma / Burkitt's leukemia (r) leukemia / lymphoblastic lymphoma from the precursor T-line (acute lymphoblastic leukemia from precursor T-cells), prolymphocytic leukemia from T-cells,leukemia from large granular T cells, aggressive NK leukemia, adult T cell lymphoma / leukemia (HTLV-1), T / NK cell lymphoma, nasal type, intestinal enterothelial cell-associated T cell lymphoma, hepatoblastic lymphoma from gamma-delta T cells, T-cell lymphoma in subcutaneous tissue, mycosis fungoides / Sezary syndrome, large T cell / null anaplastic cell lymphoma, primary cutaneous type, peripheral T cell lymphoma, more non-characterized, angioimmunoblastic T cell lymphoma , anaplastic large T cell / null lymphoma, and a basic systemic type;hepatic spleen cell lymphoma from gamma-delta T cells, T-cell lymphoma in subcutaneous tissue, mycosis fungoides / Sezary syndrome, large T cell / null anaplastic lymphoma, primary cutaneous type, peripheral T lymphocytes, non-characterized, angioimmunoblastic T-cell lymphoma, large-cell anaplastic T-cell lymphoma, and basic systemic type;hepatic spleen cell lymphoma from gamma-delta T cells, T-cell lymphoma in subcutaneous tissue, mycosis fungoides / Sezary syndrome, large T cell / null anaplastic lymphoma, primary cutaneous type, peripheral T lymphocytes, non-characterized, angioimmunoblastic T-cell lymphoma, large-cell anaplastic T-cell lymphoma, and basic systemic type;

(s) nodular Hodgkin lymphoma with lymphocyte dominance, Hodgkin's lymphoma with nodular fibrosis (stages 1 and 2), lymphoma rich in lymphocytes

Hodgkin, Hodgkin cell type, and Hodgkin's lymphocyte lymphoma;

(t) myeloid leukemia (eg with positive Philadelphia chromosome (t (9; 22) (qq34; q11)), multiple myeloma, chronic neutrophil leukemia, chronic eosinophilic leukemia / hypereosinophilic syndrome, chronic idiopathic myelofibrosis, true polycythemia, essential thrombocythaemia , chronic myelomocytic leukemia, atypical chronic myeloid leukemia, juvenile myelocytic leukemia, refractory anemia with ringed sideroblasts and without ringed sideroblasts, resistant cytopenia (myelodysplastic syndrome) with multilinear dysplasia, refractory anemia (myelodysplastic syndrome) with excess blasts, 5q syndrome, and myelodysplastic syndrome zt (9; 12) (q22; p12);

(u) AML with t (8; 21) (q22; q22), AML1 (CBF-alpha) / ETO, acute promyelocytic leukemia (AML with t (15; 17) (q22; q11-12) and variants, PML / RAR- alpha), AML with abnormal bone marrow eosinophils (inv (16) (p13q22) or t (16; 16) (p13; q11), CBFb / MYH11X), AML with 11q23 (MLL) abnormalities, AML minimally differentiated, AML without maturation, AML with maturation, acute myelocytic leukemia, acute monocytic leukemia, acute erythroleemia, acute megakaryocytic leukemia, acute basophilic leukemia, and acute generalized myeloma with bone marrow fibrosis.

[0278] The antiproliferative effect of the combination treatment of the invention can be assessed by administering a compound of the invention to a cultured tumor cell line. In the context of an in vitro test, administration of a compound of the invention can simply be achieved by contacting the cell in culture with the compound in an amount effective to inhibit cell proliferation. Alternatively, the antiproliferative effect of a compound of the invention can be assessed by administering the compound to an animal in an approved in vivo model for cell proliferation.

[0279] Examples of tumor cell lines derived from human tumors and available for use in in vivo studies include, leukemia cell lines (e.g., CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPM1-8226, SR, P388 and P388 / ADR); cell lines of non-small cell lung cancers (e.g., A549 / ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCl-H23, NCI-H322M, NCI-H460, NCl-H522 and LXFL 529); cell lines of small-cell lung cancers (e.g., DMS 114 and SHP-77); colon cancer cell lines (e.g., COLO 205, HCC-2998, HCT-116, HCT-15, HT29, KM12, SW-620, DLD-1 and KM20L2); central nervous system (CNS) malignant cell lines (e.g., SF-268, SF-295, SF-539, SNB-19, SNB-75, U251, SNB-78 and XF 498); Melanoma cell lines (e.g. LOX and MVI, MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62, RPMI-7951 and M19-MEL) ; ovarian tumor cell lines (e.g., IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8 and SK-OV-3); tumor cell lines of the kidney (e.g., 786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, UO-31, RXF-631 and SN12K1); prostate cancer cell lines (e.g., PC-3 and DU-145); breast cancer cell lines (e.g., MCF7, NCI / ADR-RES, MDA-MB-231 / ATCC, HS

-145578T, MDA-MB-435, BT-549, T-47D and MDA-MB-468); and thyroid cancer cell lines (e.g., SK-N-SH).

[0280] In some embodiments of the invention, the cell proliferative disorder treated with the compounds of the invention, or pharmaceutically acceptable salts thereof, is hematopoietic neoplasia, which is an abnormal increase in hematopoietic cells. Malignant hematopoietic tumors may have origins in pluripotent stem cells, multipotent progenitor cells, oligopotent oriented progenitor cells, precursor cells and terminally differentiated cells involved in hematopoiesis. Some hematologic malignancies are thought to arise from hematopoietic stem cells that have the ability to self-renew. E.g, cells capable of developing specific acute myeloid leukemia subtypes (AML) after transplantation present surface markers of hematopoietic stem cells, implicating hematopoietic stem cells as a source of leukemic cells. Blast cells that do not have characteristic cell markers of haematopoietic stem cells appear to be incapable of establishing after tumor transplantation (Blaire et al., 1997, Blood 89: 3104-3112). The origin of stem cells of some malignant hematopoietic tumors is also confirmed by the observation that specific chromosomal abnormalities associated with specific types of leukemia can be found in normal haematopoietic cells and leukemic blast cells. For example, reciprocal translocation t (9q34; 22q11) associated with approximately 95% of chronic myeloid leukemia appears to be present in the myeloid, erythroid and lymphoidal cells, suggesting that chromosomal aberration is derived from hematopoietic stem cells. A subset of cells in certain types of CML presents the phenotype of a cellular marker of hematopoietic stem cells.

[0281] Although haematopoietic neoplasia is often derived from stem cells, targeted progenitor cells or more terminally differentiated developmental line cells may also be a source of some leukemias. For example, the forced expression of the Bcr / Abl fusion protein (associated with chronic myeloid leukemia) in typical myeloid progenitor or granulocyte / macrophage progenitor cells induces a leukemia-like condition. In addition, some chromosomal aberrations associated with leukemia subtypes do not occur in the cell population with the hematopoietic stem cell marker phenotype, however, they occur in a population of cells displaying markers of a more diverse hematopoietic pathway (Turhan et al., 1995, Blood 85: 2154-2161). So though,

[0282] In certain embodiments of the invention, hematopoietic neoplasia treated by the compounds of the invention, or a pharmaceutically acceptable salt thereof, is

-146neoplazja limfoidalna, gdzie nieprawidthe cells come from and / or present a characteristic cell phenotype from the lymphoid line. Lymphoid neoplasia can be divided into B cell neoplasia, T and NK cell neoplasia, and Hodgkin's lymphoma. Neoplasia from B cells can be further divided into neoplasia from precursor B cells and neoplasia from mature / peripheral B cells. Examples of B cell neoplasia are lymphoblastic leukemia / lymphoma from B precursor cells (acute lymphoblastic leukemia from precursor B cells) while exemplary neoplasia from B cells peripheral B cells are chronic lymphocytic leukemia / lymphocytic lymphoma from B cells, B-cell prolimocyte leukemia, lymphoplasmatic lymphoma, sphenoidal B cell lymphoma of marginal zone, hairy cell leukemia, plasma cell myeloma / plasmacytoma, extranodal marginal zone lymphoma from MAIT cells, nodular B-cell marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, large B-cell mediastinum, primary lymphoma, and Burkitt's lymphoma / Burkitt's leukemia . Neoplasia from T cells and Nk cells are further divided into neoplasia from precursor T cells and neoplasia from mature (peripheral) T cells. Example of neoplasia from precursor T cells is leukemia / lymphoblastic lymphoma from precursor T-line (acute lymphoblastic leukemia from precursor T-cells) , while exemplary neoplasia from mature (peripheral) T cells is T cell prolimfocytic leukemia, large granular T cell leukemia, aggressive NK cell leukemia, adult T-cell lymphoma / leukemia (HTIV-1), peripheral T / NK cell disease, nasal type, enterothelial intestinal T-cell lymphoma, hepatopoietic T gamma-delta cell lymphoma, T-cell lymphoma in subcutaneous tissue, mycosis fungoides / Sezary syndrome, anaplastic lymphoma with large T cell / null cells, primary cutaneous type, peripheral T cell lymphoma, more non-characterized, angioimmunoblastic T cell lymphoma, anaplastic large T cell / null cell lymphoma, primary systemic type. The third member of lymphoid neoplasia is Hodgkin's lymphoma, also referred to as Hodgkin's lymphoma. Exemplary recognition of this class that can be treated with the compounds of the invention includes, inter alia, Hodgkin nodular lymphoma with lymphocyte dominance, and various classical forms of the Hodgkin's dissection, examples of which are Hodgkin's lymphoma with nodular fibrosis (stages 1 and 2), lymphocyte Hodgkin's classic lymphocytes, Hodgkin's mixed cell type lymphoma, and Hodgkin's lymphocyte lymphoma. In various embodiments, any of the lymphoid neoplasia associated with abnormal JAK activity can be treated with JAK inhibitory compounds.

[0283] In some embodiments, hematopoietic neoplasia treated by the invention, or myeloid neoplasia. This group includes a characteristic phenotype of myeloid line cells. Myeloid neoplasia can be divided into myeloproliferative diseases, myelodysplastic / myeloproliferative diseases, myelodysplastic syndromes, and acute myelogenous leukemia. Exemplary myeloproliferative diseases are chronic myeloid leukemia (eg

-147 positive Philadelphia chromosome (t (9; 22) (qq34; q11)), chronic neutrophil leukemia, chronic eosinophilic leukemia / hypereosinophilic syndrome, chronic idiopathic myelofibrosis, polycythemia vera, and essential thrombocythaemia. Examples of myelodysplastic / myeloproliferative diseases are chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, and juvenile myelomocytic leukemia. Exemplary myelodysplastic syndromes with resistant blasts, myelodysplastic syndrome, and myelodysplastic syndrome. In various embodiments, each of myeloid neoplasias that are associated with abnormal JAK activity,

[0284] In the case of acute myeloid leukemias (AMLs), which are a large class of myeloid neoplasia . These subdivisions include, among others, AML with recurrent cytogenetic translocations, AML with multi-line dysplasia, and other AMLs not otherwise categorized. Exemplary AMLs with recurrent cytogenetic translocations include, but are not limited to, AML with t (8; 21) (q22; q22), AML1 (CBF-alpha) / ETO, acute promyelocytic leukemia (AML with t (15; 17) ( q22, q11-12) and variants, PML / RAR-alpha), AML with abnormal bone marrow eosinophils (inv (16) (p13q22) or t (16; 16) (p13; q11), CBFb / MYH11X), and AML with abnormalities11q23 (MLL). Exelectives AMLs with multi-line dysplasia are myelodysplastic syndrome. Other acute myeloid leukemias AML without maturation, AML with maturation, acute myelomocytic leukemia, acute monocytic leukemia, acute erythroleukemia, acute lymphocytic leukemia, acute basophilic leukemia, and acute generalized marrow with bone marrow fibrosis.

[0285] Animal models for use in the art. Suitable animal models for hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50 (21 Suppl): 6-9, discussion 34-38 and Tumas et al. (2001), J. Allergy Clin. Immunol. 107 (6): 1025-1033. Suitable animal models of allergic rhinitis are describinged in Szelenyi et al. (2000), Arzneimittelforschung 50 (11): 1037-42; Kawaguchi et al. (1994), Clin. Exp. Allergy 24 (3): 238-244 and Sugimoto et al., (2000), Immunopharmacology 48 (1): 1-7. Suitable animal models of allergic conjunctivitis are described in Carreras et al. (1993), Br. J. Ophthalmol. 77 (8): 509-514; Saiga et al. (1992), Ophthalmic Res. 24 (1): 45-50; and Kunert et al., (2001), Invest. Ophthalmol. Vis. Sci. 42 (11): 2483-2489. Suitable animal mastocytose models are described in O'Keefe et al. (1987), J. Vet. Intern. Med. 1 (2): 75-80 and Bean-Knudsen et al. (1989), Vet. Pathol. 26 (1): 90-92. Suitable animal models of the hyper IgE syndrome are described in Claman et al. (1990), Clin. Immunol. Immunopathol. 56 (1): 46-53. Suitable animal models of B-cell lymphoma are described in Hough et al. (1998), Proc. Natl. Acad. Sci. USA Suitable animal models of B-cell lymphoma are described in Hough et al. (1998), Proc. Natl. Acad. Sci. USA Suitable animal models of B-cell lymphoma are described in Hough et al. (1998), Proc. Natl. Acad. Sci. USA

-14895: 13853-13858 and Hakim et al. (1996), J. Immunol. 157 (12): 5503-5511. Suitable animal models for atopic disorders such as atopic dermatitis, atopic eczema and atopic asthma are described in Chan et al. (2001), J. Invest. Dermatol. 117 (4): 977-983 and Suto et al. (1999), Int. Arch. Allergy Immunol. 120 (Suppl 1): 70-75. Suitable animal models of transplant rejection such as HVGR models are described in O'Shea et al. (2004), Nature Reviews Drug Discovery 3: 555-564; Cetkovic-Curlje and Tibbles, (2004), Current Pharmaceutical Design 10: 1767-1784; and Chengelian et al. (2003), Science 302: 875-878. Suitable animal models for polycythemia vera, essential thrombocythemia and primary myelofibrosis are described in Shimoda, (2008) Leukemia 22 (1): 87-95; Lacout, (2006) Blood 108 (5): 1652-60; and Wernig, (2006) Blood 107 (11): 4274-81.

PHARMACEUTICAL COMPOSITIONS FOR THE INVENTION AND ADMINISTRATION [0286] Administration of the compounds of the invention, or pharmaceutically acceptable salts thereof, in a pure form or in a suitable pharmaceutical composition can be accomplished by any of the accepted modes of administration of agents that serve similar purposes. The pharmaceutical compositions of the invention may be prepared by combining a compound of the invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and may be formulated as solid, semi-solid, liquid or gas forms such as tablets, capsules, powders, granules, ointments, solutions. , suppositories, injections, inhalants, microspheres gels and aerosols. Typical routes of administration for these pharmaceutical compositions include oral, topical, transdermal, inhalative, parenteral, sublingual, buccal, rectal, vaginal and nasal. The term parenteral as used herein, includes subcutaneous injections, intravenous, intramuscular, intrasternal or infusion techniques. The pharmaceutical compositions of the invention are formulated so as to enable the active ingredients to be bioavailable upon administration of the composition to the patient. Compositions that can be administered to a subject or patient are in the form of one or more dosage units, where, for example, the tablet can be a single dosage unit, and a container of a compound of the invention in the form of an aerosol can have multiple dosage units. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will in any case contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition of interest in accordance with the teachings of this invention.

[0287] The pharmaceutical composition of the invention may be in solid or liquid form. In one aspect, the carrier (s) are in particulate form, such that the compositions are, for example, in the form of a tablet or a powder. The carrier (s) may be liquid, such compositions being, for example, an oil for oral administration, a liquid for injection, or an aerosol that is useful, for example, in inhaled administration.

[0288] For oral administration, the pharmaceutical composition is preferably in a solid or liquid form, wherein the semi-solid, semi-solid, slurry and gel forms are included in the forms herein as solid or liquid.

[0289] In a solid oral composition, the pharmaceutical composition can be formulated as a powder, a granulate, a compressed tablet, a pill, a capsule, a chewing gum, a wafer. Such a solid composition will usually contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binding agents such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, lubricants such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; lubricants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent, like peppermint, methyl salicylate or orange flavoring; and a coloring agent.

[0290] In the case where the pharmaceutical composition is in the form of a capsule, e.g. a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0291] The pharmaceutical composition may be in a liquid form, for example, an elixir, a syrup, a solution, an emulsion or a suspension. The liquid may be intended for oral administration or for administration by injection in the form of two examples. For oral administration, the preferred composition contains, in addition to the compounds of the present invention, one or more sweeteners, preservatives, dyes / colorants and flavor enhancers. One or more surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers, and isotonic agents may be included in the composition intended for administration by injection.

[0292] Liquid pharmaceutical compositions according to the invention, whether they are solutions, suspensions may contain one or more of the following adjuvants: sterile diluents, such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, non-volatile oils such as synthetic mono- or diglycerides which may serve as a solvent or suspending medium, polyethylene glycols, glycerol, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and tonicity adjusting agents such as sodium chloride or dextrose. The parenteral preparation may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The physiological saline solution is a preferred adjuvant. The pharmaceutical composition for injection is preferably sterile.

-150 [0293] The liquid pharmaceutical composition of the invention intended for both parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. In the case of oral administration, this amount may vary in the range of from 0.1 to about 70% by weight of the composition. Preferred oral pharmaceutical compositions contain between about 4% and about 75% of a compound of the invention. Preferred pharmaceutical compositions and formulations of the invention are prepared such that the parenteral dosage unit contains between 0.01 to 10% by weight of the compound prior to dilution of the invention.

[0294] The pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may conveniently comprise a solution, emulsion, ointment or gel base. The base, for example, may contain one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickeners may be present in the pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or a iontophoresis device. Topical formulations may contain a concentration of the compound of the invention from about 0.1 to about 10% w / v (mass per unit volume).

[0295] The pharmaceutical composition of the invention may be intended for rectal administration in the form of, for example, suppositories that will melt in the rectum and release the drug. The composition for rectal administration may contain an oily base as a suitable non-irritating excipient. Such bases include lanolin, cocoa butter and polyethylene glycol.

[0296] The pharmaceutical composition of the invention may contain various substances that modify the physical form of the solid or liquid unit dosage. For example, the composition may include materials that form a coating coating around the active ingredients. The materials that make up the coating coating are usually inert, and may be selected from, for example, sugar, shellac and other enteric coating agents. Alternatively, the active ingredients may be placed in gelatin capsules.

[0297] A pharmaceutical composition of the invention in solid or liquid form may contain an agent that binds to a compound of the invention and thereby helps in providing the compound. Suitable agents that can act in this capacity include monoclonal or polyclonal antibodies, a protein or a liposome.

[0298] The pharmaceutical composition of the invention may consist of dosage units that can be administered in the form of an aerosol. The term aerosol is used for the determination of various systems, ranging from those of a colloidal nature to systems consisting of pressurized packages. The delivery may take place by means of liquid or compressed gas, or by means of a suitable pump system that dispenses the active ingredients. Aerosols of the compounds of the invention may be provided in single-phase, two-phase or three-phase systems to provide the active ingredient (s). The delivery of the aerosol includes the necessary container, activator, valves, and ejections

-151 can be a set only. One skilled in the art can determine preferred aerosols without undue experimentation.

[0299] The pharmaceutical compositions of the invention can be made by a methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended for administration by injection may be prepared by combining the compound of the invention with sterile, distilled water to form a solution. The surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with a compound of the invention in such a way as to facilitate dissolution or homogeneous suspensions of the compound in the aqueous delivery system.

[0300] The compounds of the invention or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount that will vary depending on various factors, including the activity of the particular compound employed; metabolic stability and duration of action of this compound; the age, weight, general health, sex and diet of the patient; mode and time of administration; speed of excretion; combinations of drugs; the severity of a particular disorder or condition; and the subject undergoing therapy. In general, a therapeutically effective daily dose is (for 70 kg of mammal) from about 0.001 mg / kg (i.e. 0.70 mg) to about 100 mg / kg (i.e., 7.0 g); Preferably, the therapeutically effective dose is (for 70 kg mammal) from about 0.01 mg / kg (i.e. 0.7 mg) to about 50 mg / kg (i.e., 3.5 g);

[0301] The compounds of the invention, or a pharmaceutically acceptable salt thereof, may also be administered concurrently with, before or after the administration of one or more other therapeutic agents. Such combination therapy comprises administering one pharmaceutical dosage formulation containing a compound of the invention and one or more additional active agents, as well as administering a compound of the invention and each active agent in a separate pharmaceutical dosage formulation. For example, the compound of the invention and the second active agent can be administered to the patient together in one oral dosage composition such as a tablet or capsule, or each of the agents is administered in separate oral dosage formulations. Where separate dosage formulations are used, the compounds of the invention and one or more additional active agents may be administered at substantially the same time, i.e. simultaneously or separately with a time shift, i.e. sequentially; combination therapy is understood to include all these treatment regimens.

MANUFACTURE OF THE COMPOUNDS OF THE INVENTION [0302] The following Reaction Schemes illustrate methods of preparing compounds of formula (Ia), as isolated stereoisomers or mixtures, or as pharmaceutically acceptable salts thereof.

-152-

<img file="PL2265607T3_D0028.tif" />

where n, m, Y, R¹, R², R³, R⁴ and R⁵ are as described above in the section of Embodiments of the compounds of formula (Ia), as isolated stereoisomers or mixtures, or as their pharmaceutically acceptable salts. It is understood that in the following Reaction Schemes, combinations of substituents and / or variables of the formulas shown are acceptable only when stable changes are obtained with such changes. It is also understood that other compounds of formula (Ia), in particular, compounds of formula (Ia-1), (Ia-1a), (Ia-1b), (Ia-1c), (Ia1d), (Ia- 1e), (Ia-1f), (Ia-1g), (Ia-1h), (Ia-1i), (Ia-1j), (Ia-1k), (Ia-Il), (Ia-2) , (Ia-2a), (Ia-2b), (Ia2c), (Ia-2d), (Ia-2e), (Ia-2f), (Ia-2g), (Ia-2h), (Ia- 2i), (Ia-2j), (Ia-2k) and (Ia-2l), and other compounds of formula (Ia), not disclosed in detail herein,

[0303] Skilled artisans will recognize that in some cases, starting materials and intermediates in the preparation of compounds of the invention may contain functional groups that require protection during synthesis. The exact type of any protecting group (s) used will depend on the type of functional group that is protected and will be apparent to those skilled in the art. Guidance on the selection of suitable protecting groups, as well as synthetic strategies for insertion and removal can be found, for example, in Greene and Wuts, Greene's Protective Groups in Organic Synthesis, 3d Edition, John Wiley &amp; Sons, Inc., New York (1999) and literature cited therein (hereinafter 'Greene and Wuts').

[0304] In this way, the protecting group refers to a group of atoms that when bound to a reactive functional group in a molecule masks, reduces or prevents the reactivity of that functional group. Typically, the protecting group can be selectively removed as needed during the course of the synthesis. Examples of protecting groups can be found in Greene and Wuts, as mentioned above, and furthermore, in Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley &amp; Sons, NY. Representative amino-protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted groups. trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratrryloxycarbonyl ("NVOC"). Representative hydroxy protecting groups include those in which the hydroxyl group is acylated to form acetate and benzoate esters, or alkylated to form benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS groups or TIPPS) and allyl ethers.

[0305] Those skilled in the art will also recognize that, although such protected derivatives of the compounds of the present invention may not exhibit pharmacological activity as such, they may be administered to a mammal and then metabolised in the body to form compounds of the invention that are pharmacologically active. . Such derivatives may thus be referred to as "prodrugs".

[0306] In general, starting compounds can be obtained from manufacturers such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized from sources known to those skilled in the art (see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or produced as described herein. spectrum¹1 H NMR is recorded in CDCl 3, DMSO-d 6, CD 3 OD, or Acetone-d 6 with trimethylsilane (TMS) as internal standard using a Gemini 300 MHz instrument. The reagents and solvents were purchased from commercial sources and used without further purification. Flash column chromatography was carried out using silica gel (230-400 mesh) under positive nitrogen pressure. LCMS spectra for purity and mass were recorded using Waters LCMS. Deionized water was used to dilute the reaction and wash the products. The brine used was prepared by dissolving sodium chloride in deionized water until saturation.

A. Preparation of Compounds of Formula (Ia1) [0307] The compounds of formula (Ia1) are compounds of formula (Ia) as described above in Embodiments, wherein R⁴ in the compounds of the formula (Ia) has the following formula:

<img file="PL2265607T3_D0029.tif" />

[0308] The compounds of formula (Ia1) can be prepared as described below in Reaction Scheme 1, wherein n, m, Y, R¹, R² and R³ are as described above in Embodiments for compounds of Formula (Ia); q is 0, 1 or 2; Y¹ means = C (R.⁶) (where R⁶ is as described above for R⁶ in compounds of the formula (Ia) as described above in the Summary of the Invention) or = N-; each Z is chloro or bromo; R^4a means -N (R.⁶) R⁷(where R⁶ and R⁷ each is as defined above in the compounds of formula (Ia) as described above in the Summary of the Invention); and every R^4bif present, is independently selected from the group consisting of alkyl, halo and haloalkyl. Preferably, for compounds of formula (Ia1), q is 0.

-154-

<img file="PL2265607T3_D0030.tif" />

[0309] The compounds of Formula (A), Formula (B) and Formula (D) are commercially available or can be prepared according to methods known to those skilled in the art or the methods disclosed herein.

Generally, compounds of formula (Ia) can be prepared by methods known to those skilled in the art and / or by the methods set forth above in Reaction Scheme 1, wherein the compound of formula (B) is coupled to the compound of formula (A) in suitable aromatic coupling conditions such as Suzuki coupling conditions known to those skilled in the art to provide a compound of formula (C). Compounds (C) are then reacted with a compound of formula (D) under SNAr conditions (Substitution Nucleophilic Aromatic, aromatic nucleophilic substitution) known to those skilled in the art to form a compound of formula (Ia1).

A particular example of the preparation of a compound of the invention according to the method disclosed above in Scheme of Reaction 1 is the preparation of compound (1) which is a compound of formula (Ia1) as shown below in Reaction Scheme 1A.

-155-

<img file="PL2265607T3_D0031.tif" />

[0312] Details of the preparation of compound (1) are given below in the appropriate Preparation

Synthetic and / or Synthesis Examples below.

[0313] Alternatively, compounds of formula (Ia1) (where n is 0) can be produced, for example, using convergent synthesis as described below in Reaction Scheme 2. In particular, compounds of formula (Ia1-1) which are compounds of formula formula (Ia1), where n is 0 and R^4a means -N (R.^6b) R^7b (where R^6b and R^7b are independently selected from hydrogen or alkyl, or together with the common nitrogen atom to which they are attached, form an optionally substituted Nterhodocyclyl), can be prepared as described below in Scheme of Reaction 2, wherein m, Y, R¹and R² are as described above in Embodiments for compounds of Formula (Ia); q is 0, 1 or 2; Y¹ means = C (R.⁶) (where R⁶ is as described above for R⁶ in compounds of formula (Ia)) or = N-; Z is chloro or bromo; every R^4bif present, is independently selected from the group consisting of alkyl, halo and haloalkyl. Preferably, for compounds of formula (Ia1), q is 0, and R^6b and R^7b are independently selected from hydrogen or alkyl, or together with the common nitrogen atom to which they are attached, form an optionally substituted N-heterocyclyl.

[0314] The compounds of formula (D), formula (E), formula (F), formula (H) and formula (M) are commercially available or can be prepared according to methods known to those skilled in the art, or by means disclosed here are ways.

-156-

<img file="PL2265607T3_D0032.tif" />

[0315] In general, compounds of formula (Ia1-1) can be prepared by methods known to those skilled in the art and / or by the methods outlined above in Scheme

Reaction 2, wherein, for example, α, β-unsaturated enamines of formula (G) are formed from the corresponding ketones of formula (E), for example, by Wittig-type homologation using compound (F). Guanidines of formula (K) are prepared, for example, by converting anilines of formula (D) into the corresponding BOC-protected guanidines of formula (J), and then deprotecting. The guanidines of formula (K) and α, β-unsaturated enamines of formula (G) are then reacted to give pyrimidine-2-amines of formula (L), which can then be converted to further pyrimidine-2-amines of formula (Ia1) -1) by, for example, standard SNAr reaction conditions using, for example, a nucleophilic amine of formula (M).

A particular example of the preparation of a compound of the invention according to the method disclosed above in Scheme of Reaction 2 is the preparation of compound (1) as shown below in Reaction Scheme 2A.

<img file="PL2265607T3_D0033.tif" />

[0317] Details of the preparation of compound (1) according to this method are shown below in the respective Synthetic Preparations and Synthesis Examples.

[0318] Another particular example of the preparation of a compound of the invention according to the method disclosed above in Scheme of Reaction 2 is the preparation of compound (10) as shown below in Reaction Scheme 2B.

<img file="PL2265607T3_D0034.tif" />

[0319] In this example, the nucleophilic amine (Mb) was added to the pyridine (Ea) before formation of the enamine, pyrimidine, etc. According to a previous example, the ketone (Eb) is homologated to enamine (Gb). Enamine (Gb) is reacted with guanidine (Ka) to form pyrimidine-2-amine (10). Details of the preparation of compound (10) according to this method are set out below in the corresponding Synthetic Synthesis and Synthesis Examples.

[0320] Pharmaceutically acceptable salts of the compounds of the invention can be formed by conventional agents such as by reacting the free base form form with one or more equivalents of the corresponding acid in a solvent or medium in which the salt is insoluble or in a solvent such as water that it removes under reduced pressure or by lyophilization, or by exchanging the anions of the existing salt with another anion on a suitable ion exchange resin.

[0321] The following specific Synthetic Preparations (for materials and intermediates) and Synthetic Examples (for compounds of the invention) are mixed as a guide to assist in the practice of this invention. The number after each compound below refers to the number in Table 2 or Table 3, as discussed below in more detail. SYNTHETIC PREPARATION 1

Compounds of the formula (Ca)

-1582- Chloro-4- (6-dimethylaminopyridin-3-yl) pyrimidine [0322] A flask containing 2,4-dichloropyrimidine (0.5 g, 3.35 mmol), [6 (dimethylamino) pyridin-3-yl] boronic acid (0.61) g, 3.67 mmol) and DME (10 mL) was purged with N2 for 10 min. Dichloro [1,1'-bis (diphenylphosphino)] ferrocene-palladium adduct with CH2Cl2 (0.37 g, 0.50 mmol) and triethylamine (0.85 g, 1.17 mL, 8.33 mmol) was added sequentially to a N2 bubbling flask over 5 min. adding reagents. The reaction mixture was stirred and heated at 90 ° C for 5 h. The progress of the reaction was monitored by TLC (silica gel). The reaction mixture was concentrated and diluted with water to give a brownish solid. The solid was filtered off,¹H NMR (DMSO-d6): δ 8.91 (s, 1H), 8.60 (d, 1H, J = 5.3 Hz), 8.20 (dd, 1H, J = 2.3 and 9.1 Hz), 7.95 (d, 1 H, J = 5.3 Hz), 6.74 (d, 1H, J = 9.1 Hz), 3.11 (s, 3H). LCMS: purity: 98%; MS (m / e): 235 (MH⁺).

SYNTHETIC PREPARATION 2

Compounds of the formula (Da)

3- Methyl-4 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl] aniline [0323]

A. (15.45) -2-Methyl-2,5-diazabicyclo [2.2.1] heptane ^ 2HBr (6 g, 21.89 mmol) (which can be prepared by similar methods described in Braish, TF et al., J. Org Chem. (1990), Vol. 55, pp. 1684-1687), 2-fluoro-5-nitrotoluene (2.61 g, 16.82 mmol) and K2CO3 (10.57 g, 76.46 mmol) in 30 mL of NMP was heated at 110 ° C. for 14 hours while mixing. The reaction mixture was cooled to ambient temperature, poured into ice water and stirred until a precipitate formed. The resulting yellow solid was collected by filtration and washed with 15% EtOAc / hexanes to give 2 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl] -5-nitrotoluene (3.4 g). , 79%) with 98% purity;¹H NMR (DMSO-d6): δ 7.88-7.55 (m, 2H), 6.69 (d, 1H, J = 8.8 Hz), 4.37 (s, 1H), 3.64 (dd, 1H, J = 2.0 and 9.9 Hz), 3.38-3.55 (m, 2H), 2.81 (d, 1H, J = 9.9 Hz), 2.65 (d, 1H, J = 9.9 Hz), 2.33 (s, 3H), 2.23 (s, 3H), 1.87 (d, 1H, J = 9.3 Hz), 1.75 (d, 1H, J = 9.3 Hz); LCMS: purity: 98%; MS (m / e): 248 (MH⁺).

B. 2 - [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -5-nitrotoluene (3.3 g) was dissolved in EtOH (50 mL) and transferred to a flask. for hydrogenation Parr. Catalyst, Pd / C (450 mg) was added, and the mixture was hydrogenated in PSI for 2 h. The reaction mixture was filtered through celite and the filter cake on celite was washed with EtOH. Concentration of the combined filtrates afforded 3-methyl-4 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl] aniline as a tan solid (2.52 g, 86%).¹H NMR (DMSO-d6): δ 6.58 (d, 1H, J = 8.8 Hz), 6.34 (s, 1H), 6.27 (d, 1H, J = 8.8 Hz), 4.46 (s, 2H), 3.61 (s, 1H), 3.24 (s, 1H), 3.16 (d, 1H, J = 9.3 Hz), 2.93 (dd, 1H, J = 1.8 and 9.3 Hz), 2.61 (qt, 2H, J = 9.3 Hz), 2.26 (s, 3H), 2.05 (s, 3H), 1.70 (d, 1H, J = 9.1 Hz), 1.63 (d, 1H, J = 9.1 Hz). LCMS: purity: 97%; MS (m / e): 218 (MH⁺).

-159C. Alternatively, a heterogeneous mixture of (1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptane, 2HBr salt (0.544 g, 2 mmol), 2-fluoro-5-nitrotoluene (0.310 g, 2 mmol) and DIPEA (0.387 g, 6 mmol) in NMP was heated to reflux for 2 days. The obtained residue was purified by column chromatography (silica gel, hexanes then 5-10% EtOAc in hexanes to give 2 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-ol) ylo] -5-nitrotoluene, which was reduced by hydrogenation (H2, 10% Pd / C, MeOH, 40 PSI) to give 3-methyl-4 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] heptane-2-yl] aniline; ICMS: purity: 91%; MS (m / e): 218 (MH⁺).

D. Alternatively, (1S, 4S) -2-Methyl-2,5-diazabicyclo [2.2.1] heptane.2HBr (24.8 g, 90.5 mmol), 2-fluoro-5-nitrotoluene (12.0 g, 77.3 mmol) and K2CO3 (43.7 g, 316.9 mmol) in 90 mI NMP was heated at 110 ° C for 14 h with stirring. The reaction mixture was allowed to cool and quenched by pouring into water (500 mI). The contents were stirred until precipitation was observed (3-4 h). The resulting yellow solid was collected by filtration. The resulting cake was washed with water (700 m) and dried by vacuum aspiration. The filter cake was reslurried in 10% EtOAc / hexanes (100 mL) as a suspension and then filtered to give the desired 2 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane material. 2-yl] -5-nitrotoluene (14.2 g, 74% based on nitrotoluene, 63% based on diazabicycloheptane) after drying;¹H NMR (DMSO-d6): δ 7.88-7.55 (m, 2H), 6.69 (d, 1H, J = 8.8 Hz), 4.37 (s, 1H), 3.64 (dd, 1H, J = 2.0 and 9.9 Hz), 3.38-3.55 (m, 2H), 2.81 (d, 1H, J = 9.9 Hz), 2.65 (d, 1H, J = 9.9 Hz), 2.33 (s, 3H), 2.23 (s, 3H), 1.87 (d, 1H, J = 9.3 Hz), 1.75 (d, 1H, J = 9.3 Hz). ICMS: purity: 98%; MS (m / e): 248 (MH⁺).

E. 2 - [(1S, 4S) -5-Methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -5-nitrotoluene (14.2 g), prepared as in Point D above, was dissolved in EtOH. (50 mI), transferred to a Parr hydrogenation flask. Pd / C (1.5 g) was charged to the above flask and subjected to hydrogenation at 30 psi for 2 h. The reaction mixture was filtered through celite and the filter cake was further washed with EtOH (300 mI). Concentration of the filtrate afforded 3-Methyl-4 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] aniline as a brown-white solid (11.7 g, 86%);¹H NMR (DMSO-d6): δ 6.58 (d, 1H, J = 8.8 Hz), 6.34 (s, 1H), 6.27 (d, 1H, J = 8.8 Hz), 4.46 (s, 2H), 3.61 (s, 1H), 3.24 (s, 1H), 3.16 (d, 1H, J = 9.3 Hz), 2.93 (dd, 1H, J = 1.8 and 9.3 Hz), 2.61 (qt, 2H, J = 9.3 Hz), 2.26 (s, 3H), 2.05 (s, 3H), 1.70 (d, 1H, J = 9.1 Hz), 1.63 (d, 1H, J = 9.1 Hz). ICMS: purity: 97%; MS (m / e): 218 (MH⁺).

SYNTHETIC PREPARATION 3

Compounds of formula (D)

4- (1,4-Diazabicyclo [3.2.2] n-4-yl) -3-methylaniline [0324]

A. A mixture of 2-fluoro-5-nitrotoluene (1.08 g, 6.98 mmol), 1,4-diazabicyclo [3.2.2] nonane (0.8 g, 6.34 mmol) and K2CO3 (2.2 g, 15.86 mmol) in 8 mI DMF was stirred. at 100 ° C by

-16016 h. After cooling to ambient temperature, water (40 mL) was added slowly to the mixture. The obtained (yellow) solid was filtered and washed three times with water. Thin layer chromatography showed trace amounts of the starting aryl fluoride. Solid 4- (2-methyl-4-nitrophenyl) -1,4-diazabicyclo [3.2.2] nonane was suspended in 25 mL of Et2O, sonicated for 10 min, collected by filtration and washed with Et2O; 950 mg; Purity (LC-MS):&gt; 97%; MS (m / e): 262.4 (MH⁺).

B. 4- (2-Methyl-4-nitrophenyl) -1,4-diazabicyclo [3.2.2] nonane (950m) was dissolved in 30 mL of MeOH. Then catalyst, 10% Pd-C (300 mg) was added, and the mixture was hydrogenated under H2 (50 psi) for 1 h. The reaction mixture was filtered through celite and washed with MeOH. 4- (1,4-Diazabicyclo [3.2.2] 1,4-nonan-4-yl) -3-methylaniline was obtained as a dark oil in quantitative yield; Purity (LC-MS): 97.48%; MS (m / e): 231.1 (MH⁺).

SYNTHETIC PREPARATION 4

Compounds of formula (Eb)

1- [6- (Morpholin-4-yl) pyridin-3-yl)] ethanone [0325] 1- (6-Chloro-3-pyridinyl) ethanone (20 g, 128.55 mmol) and morpholine (43 mL, 43 g) , 493 mmol) in ethanol (100 mL) was heated to reflux at 95 ° C. After the consumption of 1- (6-chloro-3-pyridinyl) ethanone (18 h), the reaction mixture was cooled and concentrated to dryness. An ice cold solution of water (65 mL) was transferred to the above material, then sonicated for 10 min and stirred at 0 ° C for 2 h. The resulting solid was collected by filtration and dried by aspiration. Further work-up of the solid by resuspension in ice-water (250 mL) and filtration of the suspension gave 18.8 g (70%) of 1- [6- (morpholin-4-yl) pyridin-3-yl)] ethanone as off-whiteish brown solid body after vacuum drying;¹H NMR (DMSO-d6): δ 8.71 (d, 1H, J = 2.4 Hz), 8.00 (dd, 1H, J = 1.4 and 9.0 Hz), 6.86 (d, 1H, J = 9.0 Hz), 2.44 (s, 3H). LCMS: purity: 96%; MS (m / e): 207 (MH⁺).

SYNTHETIC PREPARATION 5

Compounds of the formula (Ga)

3- (3- (Dimethylamino) prop-2-en-1 -yl) -6-chloropyridine [0326] A homogeneous mixture of 3-acetyl-6-chloropyridine (5 mL) (which can be prepared in a similar manner according to the methods disclosed in Lee, CH. et al., J. Med. Chem. (2001), Vol. 44, pp. 2133-2138) in N, N-dimethylformamide dimethylacetal (15 mL) was heated to reflux for 4 h. After cooling, to ambient temperature, diluted with hexanes (100 mL), sonicated for 30 seconds and the resulting solid was isolated by filtration. The solid obtained was then washed with hexanes (3 x 25 mL), dried and analyzed to give 3- (3-dimethylamino) prop-2-en-1-onyl) -6-chloropyridine; LCMS: purity: 92%; MS (m / e): 212 (MH⁺).

SYNTHETIC PREPARATION 6

-161Relations of the formula (Gb)

3- [3- (Dimethylamino-2-propen-1-one) -6- (morpholin-4-yl) pyridine [0327] 1- [6- (morpholin-4-yl) pyridin-3-yl)] ethanone (18 g, 87.3 mmol) in N, N-dimethylformamide dimethylacetal (100 mL) was heated to reflux (110 ° C) until total consumption of 1- [6 (morpholin-4-yl) pyridin-3-yl)] ethanone was determined as determined by TLC on silica gel and LC / MS. After 45 h, the heterogeneous reaction mixture was cooled to ambient temperature and the crude product was collected by filtration. The filter cake was washed with Et 2 O (75 mL) and dried in vacuo to give 18.0 g (78%) of 3- [3- (dimethylamino-2-propen-1-one) -6- (morpholin-4-yl) pyridine;¹H NMR (DMSO-d6): δ 8.69 (d, 1H, J = 2.4 Hz), 8.00 (dd, 1H, J = 2.4 and 9.0 Hz), 7.62 (d, 1H, J = 12.3 Hz), 6.80 (d, 1H, J = 9.0 Hz), 5.76 (d, 1H, J = 12.3 Hz), 3.68-3.65 (m 4H), 3.61-3.59 (m, 4H), 3.30 (s, 3H), 2.87 ( s, 3H). LCMS: purity: 99%; MS (m / e): 262 (MH⁺) SYNTHETIC PREPARATION 7

Compounds of formula (I) [3-methyl-4 - ((1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptan-5-yl) phenyl] [N, N-bis (tert-butoxycarbonyl) )] guanidine [0328]

A. Compound (Da), 3-methyl-4 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl] aniline, (0.105 g, 0.6 mmol) and 1- (tert-butoxycarbonylamino (tert-butoxycarbonyonimino) methyl) pyrazole (H) (0.186 g, 0.6 mmol) was combined in DMF (2 mL) and stirred at ambient temperature for 3 days. The reaction was monitored by LCMS. The homogeneous reaction mixture was then diluted with water (20 mL), the precipitate formed was isolated by filtration, and purified by column chromatography (silica gel, CH 2 Cl 2, then 2-5% MeOH in CH 2 Cl 2) to give [3-methyl-4 - (( 1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptan-5-yl) phenyl] [N, N-bis (tert-butoxycarbonyl)] guanidine; LCMS: purity: 99%; MS (m / e): 460 (MH⁺).

B. On a large scale, 3-methyl-4 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] aniline (10.0 g, 45.8 mmol) and 1- (tert-butoxycarbonylamino (tert-butoxycarbonyonimino) methyl) pyrazole (15.0 g, 48.2 mmol) was combined in DMF (25 mL) and stirred at ambient temperature. The progress of the homogeneous reaction was monitored by LC / MS. After 36 h, the reaction mixture was added slowly to water (300 mL) in a beaker with vigorous stirring, after which a precipitate formed. The reaction flask was rinsed with DMF (2 X 5 mL) and transferred to a beaker. Vacuum filtration of the slurry followed by washing of the resulting filter cake with water (200 mL) and drying in vacuum gave 20.5 g (97%) of [3-methyl-4 - ((1S, 4S) -2-methyl-2,5-diazabicyclo [ 2.2.1] heptan-5-yl) phenyl] [N, N-bis (tert-butoxycarbonyl)] guanidine (Ja) as an off-white solid; LCMS: purity: 96%; MS (m / e): 449 (MH⁺).

SYNTHETIC PREPARATION 8

Compounds of the formula (Ka)

-162 [3-methyl-4 - ((1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptan-5-yl) phenyl] guanidine [0329]

A. A solution of [3-methyl-4 - ((1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptan-5-yl) phenyl] [N, N-bis (tert-butoxycarbonyl)] guanidine (0.100 g) in CH2Cl2 (20 mL) with TFA (5 mL) was stirred at ambient temperature for 4 h. The progress of the reaction was monitored by TLC (silica gel). The resulting mixture was concentrated and lyophilized to give [3-methyl-4 - ((1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptan-5-yl) -phenyl] guanidine as a TFA salt; LCMS: purity: 89%; MS (m / e): 260 (MH⁺).

B. Alternatively, TFA (80 mL) was added to a stirred slurry of [3-methyl-4 - ((1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptan-5-yl) phenyl] [N, N-Bis (tertbutoxycarbonyl) guanidine (20.2 g) in CH2Cl2 (80 mL) at 0 ° C for 30 min. The ice bath was removed after 1 h and the reaction contents were mixed. The progress of the reaction mixture was monitored by LC / MS. The reaction mixture was concentrated after complete conversion of the starting material [3-methyl-4 - ((1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptan-5-yl) -phenyl] guanidine, dried overnight under high pressure. vacuum and used in the next step without further purification. LCMS: purity: 96%; The crude weight: 45.4 g, back-conversion gave approximately 34 g total amount of TFA present in the crude product.

SYNTHETIC EXAMPLE 1

4- (6- (N, N-dimethylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine [0330]

<img file="PL2265607T3_D0035.tif" />

A. 2-Chloro-4- (6-dimethylaminopyridin-3-yl) pyrimidine (35 mg, 0.15 mmol) and 3-methyl4 - [(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] ] heptan-2-yl] phenylamine (55 mg, 0.25 mmol) in 1.5 mL of 2-propanol with TFA (4 drops) was heated at 100 ° C for 12 h in a sealed tube. The progress of the reaction was monitored by LC / MS. Upon completion, the reaction mixture was concentrated and purified by preparative HPLC. The pure concentrate obtained after purification was treated with aq. K 2 CO 3 solution to neutralize the remaining acid. The resulting solid was treated with aq. K2CO3 solution was collected by filtration, washed with water and dried to give 4- (6- (N, N-dimethylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2 , 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 1, as an off-white solid (35 mg, 56%).¹H NMR (DMSOd6): δ 9.13 (s, 1H), 8.81 (s, 1H), 8.31 (d, 1H, J = 5.3 Hz), 8.20 (dd, 1H, J = 2.3 and 8.8 Hz) , 7.49 (dd, 1H, J = 2.3 and 8.8 Hz), 7.43 (s, 1H), 7.17 (d, 1H, J = 5.3 Hz), 6.74 (d, 2H, J = 8.8

-163 Hz), 3.88 (s, 1H), 3.20 (apparent qt, 2H, J = 9.0 Hz), 3.09 (s, 6H), 2.71 (apparent qt, 2H, J = 9.0 Hz), 2.27 (s, 3H) ), 2.19 (s, 3H), 1.77 (d, 1H, J = 9.0 Hz), 1.69 (d, 1H, J = 9.0 Hz);

LCMS: purity: 98%; MS (m / e): 416 (MH⁺).

B. Alternatively, a non-homogeneous mixture of 3- (3- (dimethylamino) prop-2-en-1 -yl) -6-chloropyridine (0.063 g, 0.75 mmol) and TFA salt [3-methyl-4 - ((1S, 4S) - 2-methyl-2,5-diazabicyclo [2.2.1] heptan-5-yl) -phenyl] guanidine (0.110 g, 0.75 mmol) from K 2 CO 3 (0.051 g, 2.25 mmol) in isopropanol (1 mL) was shaken in a sealed tube at 100 ° C in 24h. Formation of 4- (6- (chloro) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine was confirmed by LCMS. A 40% solution of Me2NH.HCl (1 mL) was added to this reaction vial and then heated in a sealed tube for 3 h at 100 ° C. The obtained reaction mixture was purified by column chromatography (silica gel, CH2Cl2, then 1% 2N NH3 / MeOH in CH2Cl2) to give 4- (6- (N, N-dimethylamino) pyridin-3-yl) -N- (3-methyl- 4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, Compound No. 1; LCMS: purity: 99%; MS (m / e): 416 (MH⁺).

SYNTHETIC EXAMPLE 2

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-methyl-N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidine-2-amine [0331]

<img file="PL2265607T3_D0036.tif" />

[0332] According to essentially one of the procedures described in SYNTHETIC EXAMPLE 1 and without performing key modifications in experimental parameters and using appropriately substituted starting materials and reagents, 4- (6- (N, N-dimethylamino) pyridin-3-yl) was obtained. -5-methyl-N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound 2 ;

¹H NMR (DMSO-d6): δ 9.04 (s, 1H), 8.48 (d, 1H, J = 1.8Hz), 8.22 (s, 1H), 7.89 (dd, 1H, J = 2.0 and 8.8 Hz), 7.45 (apparent d, 1H, J = 8.8 Hz), 7.40 (s, 1H), 6.71 (t, 2H, J = 8.8 Hz), 3.84 (s, 1H), 3.18 (d, 1H); , J = 9.0 Hz), 3.11 (d, 1H, J = 9.0 Hz), 3.08 (s, 6H), 2.72 (d, 1H, J = 9.0 Hz), 2.64 (d, 1H, J = 9.0 Hz), 2.25 (s, 3H), 2.23 (s, 3H), 2.16 (s, 3H), 1.75 (d, 1H, J = 9.0 Hz), 1.67 (d, 1H, J = 9.0 Hz ); LCMS: purity: 99%; MS (m / e): 430 (MH⁺).

SYNTHETIC EXAMPLE 3

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-trifluoromethyl-N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine

-164 [0333]

<img file="PL2265607T3_D0037.tif" />

[0334] According to essentially one of the procedures described in SYNTHETIC EXAMPLE 1 and without performing key modifications in experimental parameters and using appropriately substituted starting materials and reagents, 4- (6- (N, N-dimethylamino) pyridin-3-yl) was obtained. -5-trifluoromethyl-N- (3-methyl-4 ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound 3;

¹H NMR (DMSO-d6): δ 9.91 (s, 1H), 8.68 (s, 1H), 8.34 (s, 1H), 7.74 (apparent d, 1H, J = 8.8Hz), 7.40-7.37 (m, 2H), 6.73 (d, 1H, J = 8.8 Hz), 6.71 (d, 1H, J = 8.8 Hz), 3.90 (s, 1H), 3.18 (s, 2H), 3.08 (s , 6H), 2.72 (d, 1H, J = 9.0 Hz), 2.65 (d, 1H, J = 9.0 Hz), 2.25 (s, 3H), 2.17 (s, 3H), 1.77 (d, 1H, J = 9.0 Hz), 1.67 (d, 1H, J = 9.0 Hz); LCMS: purity: 99%; MS (m / e): 484 (MH⁺).

SYNTHETIC EXAMPLE 4

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-fluoro-N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine [0335]

<img file="PL2265607T3_D0038.tif" />

[0336] According to essentially one of the procedures described in SYNTHETIC EXAMPLE 1 and without performing key modifications in experimental parameters and using appropriately substituted starting materials and reagents, 4- (6- (N, N-dimethylamino) pyridin-3-yl) was obtained. -5-fluoro-N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound 4 ;

¹H NMR (DMSO-d6): δ 9.23 (s, 1H), 8.80 (s, 1H), 8.40 (d, 1H, J = 4.1 Hz), 8.15 (apparent d, 1H, J = 9.1 Hz) ), 7.43-7.38 (m, 2H), 6.79 (d, 1H, J = 9.1 Hz), 6.73 (d, 1H, J = 8.8 Hz), 3.87 (s, 1H), 3.21 (d, 1H); , J = 9.0 Hz), 3.17 (d, 1H, J = 9.0 Hz), 3.10 (s, 6H), 2.72 (d, 1H, J = 9.0 Hz), 2.66 (d, 1H, J = 9.0 Hz), 2.26 9s, 3H), 2.18 (s, 3H), 1.76 (d, 1H, J = 9.0 Hz), 1.67 (d, 1H, J = 9.0 Hz); LCMS: purity: 99%; MS (m / e): 434 (MH⁺).

SYNTHETIC EXAMPLE 5

-1654- (6- (N, N-dimethylamino) pyridin-3-yl) -5-fluoro-N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidine-2-amine [0337]

<img file="PL2265607T3_D0039.tif" />

[0338] According to essentially one of the procedures described in SYNTHETIC EXAMPLE 1 and without performing key modifications in experimental parameters and using appropriately substituted starting materials and reagents, 4- (6- (N, N-dimethylamino) pyridin-3-yl) was obtained. -5-fluoro-N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound 5 ;

¹H NMR (DMSO-d6): δ 9.45 (s, 1H), 8.80 (s, 1H), 8.44 (d, 1H, J = 1.4 and 9.0 hz), 7.58 (dd, 1H, J = 9.1 and 16 Hz), 7.29 (d, 1H, J = 8.8Hz), 6.80 (d, 1H, J = 9.1H), 6.68 (apparent t, 1H, J = 9.3Hz), 4.15 (s, 1H) ), 3.39 (d, 1H, J = 9.0 Hz), 3.16 (d, 1H, J = 9.0 Hz), 3.11 (s, 6H), 2.72 (d, 1H, J = 9.1 Hz), 2.59 ( d, 1H, J = 9.0 Hz), 2.23 (s, 3H), 1.80 (d, 1H, J = 9.0 Hz), 1.69 (d, 1H, J = 9.0 Hz); LCMS: purity: 98%; MS (m / e): 438 (MH⁺).

SYNTHETIC EXAMPLE 6

4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-methyl-N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidine-2-amine [0339]

<img file="PL2265607T3_D0040.tif" />

[0340] According to essentially one of the procedures described in SYNTHETIC EXAMPLE 1 and without performing key modifications in experimental parameters and using appropriately substituted starting materials and reagents, 4- (6- (N, N-dimethylamino) pyridin-3-yl) was obtained. -5-methyl-N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, Compound No. 6 ;

¹H NMR (DMSO-d6): δ 9.27 (s, 1H), 8.49 (d, 1H, J = 2.3Hz), 8.26 (s, H), 7.88 (d, 1H, J = 2.3 and 8.8 Hz) ), 7.66 (d, 1H, J = 2.3 and 16.8 Hz), 7.31 (d, 1H, J = 8.8 Hz), 6.73 (d, 1H, J = 8.8 Hz), 6.65 (apparent t, 1H); , J = 10.0 Hz), 4.13 (s, 1H), 3.37 (apparent d, 1H, J = 9.0 Hz), 3.15 (dd, 1H, J = 2.6 and 9.0 Hz), 3.08 (s, 6H) 2.70 (d, 1H, J = 9.0 Hz), 2.59 (d, 1H, J = 9.0 Hz), 2.24 (s, 3H), 2.23 (s, 3H), 1.79 (d, 1H, J = 9.0 Hz), 1.69 (d, 1H, J = 9.0 Hz); LCMS: purity: 98%; MS (m / e): 434 (MH⁺).

-166 SYNTHETIC EXAMPLE 7

4- (6- (N, N-dimethylamino) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine [0341]

<img file="PL2265607T3_D0041.tif" />

[0342] According to essentially one of the procedures described in SYNTHETIC EXAMPLE 1 and without performing key modifications in experimental parameters and using appropriately substituted starting materials and reagents, 4- (6- (N, N-dimethylamino) pyridin-3-yl) was obtained. -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 7;

¹H NMR (DMSO-d6): δ9.36 (s, 1H), 8.88 (s, 1H), 8.35 (d, 1H, J = 5.3Hz), 8.19 (dd, 1H, J = 2.3 and 8.8 Hz), 7.64 (d, 1H, J = 2.3 and 16.8 Hz), 7.35 (d, 1H, J = 8.2 Hz), 7.22 (d, 1H, J = 5.3 Hz), 6.75 (d, 1H); , J = 9.1 Hz), 6.65 (apparent t, 1H, J = 9.0 Hz), 4.16 (s, 1H), 3.39 (apparent d, 1H, J = 9.0 Hz), 3.18 (apparent d, 1H) , J = 9.0 Hz), 3.10 (s, 6H), 2.72 (d, 1H, J = 9.1 Hz), 2.59 (d, 1H, J = 9.0 Hz), 2.23 (s, 3H), 1.79 (d , 1H, J = 9.0 Hz), 1.69 (d, 1H, J = 9.0 Hz); LCMS: purity: 98%; MS (m / e): 420 (MH⁺).

SYNTHETIC EXAMPLE 8

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine [0343]

<img file="PL2265607T3_D0042.tif" />

[0344] According to essentially one of the procedures described in SYNTHETIC EXAMPLE 1 and without performing key modifications in experimental parameters and using appropriately substituted starting materials and reagents, 4- (4-methyl-3,4-dihydro-2H-pyrido [3] was obtained. 2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidine-2-amine, compound No. 8;

¹H NMR (DMSO-d6): δ 9.13 (s, 1H), 8.49 (apparent s, 1H), 8.31 (d, 1H, J = 5.3 Hz), 7.70 (apparent s, 1H), 7.45 (apparent s, 2H), 7.16 (d, 1H, J = 5.3 Hz), 6.73 (d, 1H, J = 8.4 Hz), 4.22 (m, 2H), 3.88 (s, 1H), 3.51 (s, 2H), 3.19 ( d, 1H, J = 9.5 Hz), 3.14 (apparent d, 1H, J = 9.5 Hz),

-1673.10 (s, 6H), 2.72 (d, 1H, J = 9.5 Hz), 2.65 (d, 1H, J = 9.5 Hz), 2.26 (s, 3H), 2.18 (s, 3H), 1.76 (d, 1H, J = 9.0 Hz), 1.69 (d, 1H, J = 9.0 Hz); LCMS: purity: 98%; MS (m / e): 444 (MH⁺).

SYNTHETIC EXAMPLE 9

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine [0345]

<img file="PL2265607T3_D0043.tif" />

[0346] According to essentially one of the procedures described in SYNTHETIC EXAMPLE 1 and without performing key modifications in experimental parameters and using appropriately substituted starting materials and reagents, 4- (4-methyl-3,4-dihydro-2H-pyrido [3] was obtained. 2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- yl) phenyl) pyrimidine-2-amine, compound No. 9;

¹H NMR (DMSO-d6): δ9.34 (s, 1H), 8.51 (d, 1H, J = 0.9 Hz), 8.35 (d, 1H, J = 5.3 Hz), 7.67 (d, 1H, J = 17.4 Hz), 7.60 (d, 1H, J = 0.9 Hz), 7.31 (d, 1H, J = 8.2 Hz), 7.20 (d, 1H, J = 5.3 Hz), 6.68 (apparent t, 1 H, J = 9.5 Hz), 4.23-4.21 (m, 2H), 4.16 (s, 1H), 3.53-3.50 (m, 2H), 3.39 (d, 1H, J = 9.6 Hz), 3.17 (d , 1H, J = 9.6 Hz), 3.11 (s, 3H), 2.72 (d, 1H, J = 9.6 Hz), 2.59 (d, 1H, J = 9.6 Hz), 2.23 (s, 3H), 1.77 (d, 1H, J = 9.4 Hz), 1.69 (d, 1H, J = 9.4 Hz); LCMS: purity: 98%; MS (m / e): 448 (MH⁺).

SYNTHETIC EXAMPLE 10

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine [0347]

<img file="PL2265607T3_D0044.tif" />

A. According to essentially one of the procedures described in SYNTHETIC EXAMPLE 1 and without performing key modifications in experimental parameters and using appropriately substituted starting materials and reagents, 4- (6- (morpholin-4-yl) pyridin-3-yl) was obtained - N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 10; ¹H NMR (DMSO-d6): δ 9.19 (s, 1H), 8.91 (d, 1H, J = 0.9 Hz), 8.35 (d, 1H, J = 5.3 Hz), 8.26 (d, 1

-168H, J = 9.1 Hz), 7.48-7.44 (m, 2H), 7.20 (d, 1H, J = 5.3 Hz), 6.95 (d, 1H, J = 9.1 Hz), 3.663.63 (m, 4H), 3.55-3.53 (m, 4H), 3.19 (d, 1H, J = 8.8 Hz), 3.17 (d, 1H, J = 8.8 Hz), 2.70 (d, 1H, J = 9.1 Hz), 2.68 (d, 1H, J = 9.1 Hz), 2.27 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J = 9.1

Hz), 1.69 (d, 1H, J = 9.1 Hz); ICMS: purity: 98%; MS (m / e): 459 (MH⁺).

B. Alternatively, TFA salt [3-methyl-4 - ((1S, 4S) -2-methyl-2,5-diazabicyclo [2.2.1] heptan-5-yl) phenyl] guanidine (45.4 g) was dissolved in 2-propanol. (200 mI) and made 40 g of solid K 2 CO 3 in portions. The pH was measured by dilution with appropriate portions of water taken up after addition of the base [20g (pH 5), 25 g (pH 7), 33 g (pH 9) and 40 g (pH 10)]. 3- [3- (Dimethylamino-2-propen-1-one) -6- (morpholin-4-yl) pyridine (10.5 g, 40.1 mmol) and additional 2-propanol (100 mI) were transferred to the above white, alkaline, heterogeneous mixture guanidines and heated to reflux at 120 ° C. The progress of the reaction was monitored by IC / MS. Analysis of the reaction after 96 h gave 23%, 6% and 67% guanidine, enamine and the desired product, respectively. The resulting pale yellow heterogeneous mixture was cooled to ambient temperature and diluted with water (200 mI). A pale yellow solid, with stirring, filtered to give 10.2 g of crude product. The collected solid was suspended in water and collected by filtration to give 8.8 g (47%) of 4- (6-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) - 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine as a pale yellow powder after drying, compound No. 10,¹H NMR (DMSO-d6): δ 9.19 (s, 1H), 8.91 (d, 1H, J = 0.9 Hz), 8.35 (d, 1H, J = 5.3 Hz), 8.26 (d, 1H, J = 9.1 Hz), 7.48-7.44 (m, 2H), 7.20 (d, 1H, J = 5.3 Hz), 6.95 (d, 1H, J = 9.1 Hz), 3.66-3.63 (m, 4H), 3.55-3.53 (m, 4H), 3.19 (d, 1H, J = 8.8 Hz), 3.17 (d, 1H, J = 8.8 Hz), 2.70 (d, 1H, J = 9.1 Hz), 2.68 (d , 1H, J = 9.1 Hz), 2.27 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J = 9.1 Hz), 1.69 (d, 1H, J = 9.1 Hz); ICMS: purity: 98%; MS (m / e): 458 (MH⁺).

SYNTHETIC EXAMPLE 11

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine [0348]

<img file="PL2265607T3_D0045.tif" />

[0349] According to essentially one of the procedures described in SYNTHETIC EXAMPLE 1 and without performing key modifications in experimental parameters and using appropriately substituted starting materials and reagents, 4- (6- (morpholin-4-yl) pyridin-3-yl) was obtained. -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 11; ¹H NMR (DMSO-d6): δ 9.40 (s, 1H), 8.91 (s, 1H), 8.38 (d, 1H, J = 5.3Hz), 8.24 (d, 1H, J = 8.8Hz) .

7.67 (d, 1H, J = 16.4 Hz), 7.34 (d, 1H, J = 8.2 Hz), 7.25 (d, 1H, J = 5.3 Hz), 6.96 (d, 1H, J =

-1699.1 Hz), 6.68 (apparent t, 1H, J = 9.9 Hz), 4.16 (s, 1H), 3.69-3.67 (m, 4H), 3.58-3.57 (m, 4H), 3.41 (d, 1 H, J = 9.1 Hz), 3.17 (d, 1H, J = 9.1 Hz), 2.72 (d, 1H, J = 9.1 Hz), 2.59 (d, 1H, J = 9.1 Hz), 2.23 (s, 3H) , 1.79 (d, 1H, J = 8.8 Hz), 1.69 (d, 1H, J = 8.8 Hz); LCMS: purity: 99%; MS (m / e): 462 (MH⁺).

SYNTHETIC EXAMPLE 12 [0350] In a similar manner to that described above, using the appropriately substituted starting materials and reagents, the following compounds of formula (Ia) were prepared:

4- (4- (N, N-dimethylamino) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 14, ¹H NMR (DMSO-d6): δ 9.09 (s, 1 H), 8.28 (d, 1H, J = 5.4 Hz), 8.00 (d, 2H, J = 8.4 Hz), 7.48 (bs, 2H), 7.13 (d, 1H, J = 5.4 Hz), 6.78 (d, 2H, J = 8.7 Hz), 6.73 (d, 1H, J = 9.6 Hz), 3.87 (s, 1H), 3.17 (m, 2H); ), 2.98 (s, 6H), 2.69 (m, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.76 (d, 1H, J = 9.3 Hz), 1.68 (d, 1H, J = 9.3 Hz); LCMS: purity: 99%; MS (m / e): 415 (MH⁺);

4- (4- (N, N-dimethylamino) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 15, ¹H NMR (DMSO-d6): δ 9.33 (s, 1H), 8.32 (d, 1H, J = 5.1 Hz), 7.99 (d, 2H, J = 9.0 Hz), 7.72 (d, 1H, J = 16.5 Hz), 7.36 (d, 1H, J = 8.7 Hz), 7.18 (d, 1H, J = 5.1 Hz), 6.74 (m, 3H), 4.21 (s, 1H), 3.47 (m, 2H); ), 3.21 (m, 1H), 2.99 (s, 6H), 2.80 (bs, 2H), 2.34 (s, 3H), 1.87 (d,

H, J = 8.7 Hz), 1.77 (d, 1H, J = 8.7 Hz); LCMS: purity: 99%; MS (m / e): 419 (MH⁺);

4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidine-2-amine, compound No. 16, ¹H NMR (DMSO-d6): δ 9.40 (s, 1H), 8.91 (s, 1H), 8.37 (d, 1H, J = 5.4 Hz), 8.24 (d, 1H, J = 8.7 Hz) 7.66 (d, 1H, J = 16.2 Hz), 7.34 (d, 1H, J = 9.3 Hz), 7.25 (d, 1H, J = 5.1 Hz), 6.97 (d, 1H, J) = 9.0 Hz), 6.68 (t, 1H, J = 9.6 Hz, J = 9.8 Hz), 4.16 (s, 1H), 3.59 (m, 8H), 3.40 (m, 1H), 3.16 (m, 1H); ), 2.72 (d, 1H, J = 9.6 Hz), 2.58 (d, 1H, J = 9.6 Hz), 2.23 (s, 3H), 2.03 (s, 3H), 1.79 (d, 1H, J = 9.3 Hz), 1.69 (d, 1H, J = 9.3 Hz); LCMS: purity: 99%; MS (m / e): 503 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 19, ¹1 H NMR (CD 3 OD, 300 MHz) 8.68 (m, 1H), 8.41 (m, 2H), 7.99 (m, 1H), 7.68 (m, 1H), 7.25 (m, 2H), 6.80 (m, 1H), 4.57 (s, 1H), 4.27 (s, 1H), 3.80 (m, 2H), 4.46 (m, 1H), 3.24 (s, 1H), 2.93 (s, 3H), 2.66 (m, 3H), 2.30 (m, 2H), 1.55 (s, 6H); MS (ES) 476.19 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 20, ¹1 H NMR (CD 3 OD, 300 MHz) 8.68 (m, 1H), 8.48 (s, 1H), 8.38 (m, 1H), 8.00 (m, 1H), 7.49 (m, 2H), 7.21 (m , 1H), 6.96 (m, 1H), 4.23 (m, 2H), 3.74 (m, 1H), 3.50 (m, 2H), 3.24 (d, 1H), 2.94 (s, 3H), 2.65 (m, 1H), 2.32 (s, 3H), 2.89 (m, 2H), 1.54 (s, 6H); MS (ES) 472.22 (M + H);

-1704- (1H-indol-6-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine, compound 21, ¹H NMR (300 MHz, CDCl3): δ 10.26 (b, 1H), 8.36-8.34 (m, 1H), 8.20 (b, 1H), 7.79-7.76 (d, J = 8.8 Hz, 1H) 7.67-7.64 (d, J = 8.8 Hz, 1H), 7.79-7.41 (m, 3H), 7.31 (b, 1H), 7.13-7.12 (m, 1H), 6.81-6.79 (d, J = 9 Hz, 1H), 6.51 (b, 1H), 3.93 (s, 1H), 3.42-3.39 (m, 1H), 3.20-3.17 (d, J = 9.9Hz, 1H), 2.91 -2.82 (m, 1H), 2.69 (s, 4H), 2.41 (s, 3H), 2.31 (s, 3H); LCMS: purity: 99%; MS (m / z); 411 (M + H)⁺;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine, compound No. 22, ¹H NMR (300 MHz, CDCl3): δ9.10-9.0 (m, 2H), 8.61 (s, 1H), 8.41-8.40 (d, J = 5.2 Hz, 1H), 7.45-7.35 (m, 3H) , 7.14-7.13 (d, J = 4.1 Hz, 1H), 7.01 (s, 1H), 6.83- 6.81 (d, J = 8.8 Hz, 1H), 6.60 (b, 1H), 3.95 (b, 1H), 3.46-3.43 (m, 2H), 3.22-3.19 (d, J = 9.6 Hz, 1H), 2.96-2.84 (m, 2H), 2.44 (s, 3H), 2.33 (s, 3H). , 1.96-1.86 (m, 2H); LCMS: purity; 100%; MS (m / z); 412 (M + H)⁺;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine, compound No. 23, ¹H NMR (300 MHz, ^ -ϋΜβΟ): δ 11.86 (b, 1H), 9.55-9.46 (b, 2H), 8.97 (s, 1H), 8.64 (s, 1H), 8.44-8.42 (d , J = 5.2 Hz, 1H), 7.52-7.39 (m, 3H), 6.85 (t, J = 18.7 Hz, 1H), 6.52 (s, 1H), 4.5 (b, 1H), 4.23 ( b, 1H), 3.70-3.58 (m, 2H), 3.33-3.29 (b, 1H), 3.06-3.03 (b, 1H), 2.82 (b, 3H), 2.33-2.29 (m, 1H). ), 2.09-2.05 (m, 1H); LCMS; cleanliness; 100%; MS (m / z); 416 (M + H)⁺;

4- (6- (dimethylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 24, ¹H NMR (300 MHz, CDCl3): δ 8.86 (s, 1H), 8.30 (dd, J = 1.3 and 1.6 Hz, 1H), 8.16-8.13 (d, J = 9.0 Hz, 1H), 7.47- 7.44 (d, J = 9.0 Hz, 1H), 6.96-6.94 (m, 1H), 6.87 (s, 1H), 6.80-6.78 (d, J = 7.9 Hz, 1H), 6.58-6.55 ( d, J = 8.8 Hz, 1H), 3.95 (s, 1H), 3.53 (s, 1H), 3.423.39 (m, 1H), 3.17 (s, 6H), 3.00-2.97 (d, J = 9.6 Hz, 1H), 2.79-2.76 (d, J = 9.4 Hz, 1H), 2.63-2.51 (m, 1H), 2.30 (s, 3H), 1.93-1.85 (m, 2H), 1.59 (b, 2H), 1.11-1.06 (m, 3H); LCMS: purity; 100%; MS (m / z); 430 (M + H)⁺;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 25, ¹H NMR (300 MHz, CDCl3): δ 8.86 (s, 1H), 8.33-8.31 (d, J = 5.2 Hz, 1H), 8.19-8.17 (d, J = 8.8 Hz, 1H), 7.44- 7.41 (d, J = 8.8 Hz, 1H), 7.23 (s, 1H), 6.97-6.90 (m, 2H), 6.80- 6.77 (d, J = 8.5 Hz, 1H), 6.69-6.66 (d , J = 8.5 Hz, 1H), 3.95 (s, 1H), 3.82-3.81 (m, 4H), 3.643.61 (m, 5H), 3.43-3.40 (d, J = 9.1 Hz, 1H), 3.21-3.17 (d, J = 9.1 Hz, 1H), 3.01-2.98 (d, J = 8.8 Hz, 1H), 2.80-2.78 (d, J = 8.5 Hz, 1H), 2.64-2.57 (m , 2H), 2.30 (s, 3H), 1.91-1.89 (m, 2H), 1.12-1.07 (m, 3H); LCMS: purity; 98%; MS (m / z); 472 (M + H)⁺;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5- ((ethylamino) carbonyl) -2,5-diazabicyclo [2.2 1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 26, ¹1 H NMR (300 MHz, CDCl 3): δ 8.86 (s, 1H), 8.33 (dd, J = 1.3 and

-171I. 3 Hz, 1H), 8.19 (d, J = 9.4 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.29, (s, 1H), 6.98 (d, J = 6.6 Hz). , 1H), 6.91-6.79 (m, 2H), 6.69 (d, J = 9.1 Hz, 1H), 4.64 (s, 1H), 4.15 (s, 1H), 4.04 (s, 1H), 3.82 (d, J = 3.5 Hz, 4H), 3.64-3.61 (m, 4H), 3.52 (d, J = 7.9 Hz, 1H), 3.44-3.24 (m, 3H), 2.28 (s, 3H), 2.03 (d, J = 9.9 Hz, 1H), 1.88 (d, J = 8.8 Hz, 1H), 1.56 (b, 2H), 1.16-1.11 (m, 3H); LCMS: purity: 96%; MS (m / z); 515 (M + H)⁺;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 27, ¹H NMR (300 MHz, d6-DMSO): δ 9.22 (s, 1H), 8.64-8.62 (m, 1H), 8.36 (d, J = 5.2 Hz, 1H), 7.77 (s, 1H) 7.48-7.41 (m, 3H), 7.23 (d, J = 4.9 Hz, 1H), 6.82-6.77 (m, 1H), 4.52 (s, 1H), 4.12 (s, 1H), 3.90-3.87 (d, J = 7.1 Hz, 1H), 3.71 (d, J = 5.7 Hz, 1H), 3.07-3.02 (m, 1H), 2.18 (s, 3H), 1.88-1.73 (m, 1H); ), 1.38-1.35 (m, 8H); LCMS: purity; 99%: MS (m / z); 459 (M + H)⁺;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5- (ethylcarbonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound 28, ¹H NMR (300 MHz, d6-DMSO): δ 9.31 (s, 1H), 8.68 (s, 1H), 8.41-8.39 (m, 1H), 7.92 (s, 1H), 7.49-7.40 (m , 2H), 7.30 (d, J = 5.2 Hz, 1H), 6.83 (t, J = 15.9 Hz, 1H), 4.68 (b, 1H), 4.18 (d, J = 19.5 Hz, 1H), 3.513 .38 (m, 2H), 3.14-3.05 (m, 1H), 2.19 (s, 6H) 1.93-1.77 (m, 2H), 1.42 (s, 6H), 0.99-0.92 (m, 3H); LCMS: purity; 99%; MS (m / z); 514 (M + H)⁺;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 29, ¹H NMR (300 MHz, d6-DMSO): δ

II. 47 (s, 1H), 9.36 (s, 1H), 8.73 (t, J = 3.3 Hz, 1H), 8.45 (m, 1H), 8.01 (s, 1H), 7.51 (s, 1) H), 7.45 (d, J = 8.5 Hz, 1H), 7.34-7.32 (m, 1H), 6.88 (d, J = 6.8 Hz, 1H), 4.33 (s, 1H), 4.15 (s, 1H), 3.41-3.22 (m, 4H), 2.96 (d, J = 1.6 Hz, 3H), 2.21 (d, J = 1.9 Hz, 3H), 1.92-1.80 (m, 2H), 1.45 (s, 6H); LCMS: purity; 99%; MS (m / z); 536 (M + H)⁺;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 30, ¹H NMR (300 MHz, CDCl3): δ 8.64 (s, 1H), 8.39 (d, J = 3.8 Hz, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.46-7.38 (m, 2H), 7.00 (d, J = 4.1 Hz, 1H), 6.79 (d, J = 8.26 Hz, 1H), 3.94 (b, 1H), 3.53 (b, 1H), 3.39 ( d, J = 9.3 Hz, 1H), 3.22 (d, J = 9.0 Hz, 1H), 2.94 (b, 4H), 2.29 (s, 3H), 1.89 (d, J = 6.6 Hz, 2H), 1.54 (s, 6H), 1.09 (m, 3H); LCMS: purity; 98%; MS (m / z); 486 (M + H)⁺;

4- (3'-oxo-3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazine] -7'-yl) -N- (3-methyl -4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 31, ¹H NMR (300 MHz, CDCl3): δ 8.63 (s,

H), 8.39 (d, J = 5.2 Hz, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.45-7.36 (m, 3H), 7.00 (d,

J = 4.9 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 3.94 (s, 1H), 3.41 (d, J = 4.9 Hz, 2H), 3.22 (d, J = 8.5 Hz). , 1H), 2.93-2.82 (m, 3H), 2.67 (b, 4H), 2.41-2.26 (m, 6H), 2.01-1.84 (m,

3H); LCMS: purity; 95%; MS (m / z); 484 (M + H)⁺;

-1724- (3'-oxo-3 ', 4'-dihydrospiro [cyclobutane-1,2'-pyrido [3,2-b] [1,4] oxazine] -7'-yl) -N- (3- methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 32, ¹H NMR (300 MHz, CDCl3): δ 8.63 (s, 1H), 8.39 (d, J = 4.9

Hz, 1H), 7.96 (d, J = 13.7 Hz, 2H), 7.49-7.37 (m, 2H), 7.00 (d, J = 5.2 Hz, 1H) 6.79 (d, J = 8.2 Hz, 1H); ), 3.94 (s, 1H), 3.53 (s, 1H), 3.39 (d, J = 9.0 Hz, 1H), 3.22 (d, J = 9.0 Hz, 1H), 2.98 (d, J = 9.3 Hz, 2H), 2.80 (d, J = 9.3 Hz, 1H), 2.66-2.51 (m, 5H), 2.372.25 (m, 5H), 2.03-1.84 (m, 3H), 1.09 (t, J = 13.7 Hz, 3H); LCMS; cleanliness; 97%; MS (m / z); 498 (M + H)⁺;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2- ylo) phenyl) pyrimidine-2-amine, compound No. 33, ¹H NMR (300 MHz, d6-DMSO): δ 9.30 (s, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.67 (s, 1H), 8.43 (d,

J = 5.2 Hz, 1H), 7.55-7.50 (m, 2H), 6.84 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 3.3 Hz, 1H), 4.52 (s, 1H); ), 4.14 (s, 1H), 3.92 (d, J = 7.1 Hz, 2H), 3.73 (d, J = 5.7 Hz, 2H), 3.08 (d, J = 9.3 Hz, 1H), 2.21 (s , 3H), 1.90-1.78 (m, 2H); LCMS: 95% purity; MS (m / z); 399 (M + H)⁺;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (2,2,2-trifluoroethyl) 2.5 -diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 34, ¹H

NMR (300 MHz, d6-DMSO): δ 9.30 (s, 1H), 9.02 (t, J = 9.6 Hz, 1H), 8.68 (t, J = 9.9

Hz, 1H), 8.43 (t, J = 5.2 Hz, 1H), 7.55 (m, 4H), 7.38 (m, 1H), 6.80 (d, J = 8.8 Hz, 1 H), 6.57-6.52 (m, 1H), 3.96-2.85 (m, 7H), 2.22-2.19 (m, 4H), 1.77 (b, 2H); LCMS: purity; 96%; MS (m / z); 480 (M + H)⁺;

4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (cyclopropyl) metylo2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 35, ¹H

NMR (300 MHz, d6-DMSO): δ 9.18 (b, 1H), 8.95 (t, J = 8.2 Hz, 1H), 8.59 (d, J = 1.9

Hz, 1H), 8.33 (d, J = 5.2 Hz, 1H), 7.46-7.37 (m, 4H), 7.28 (d, J = 5.5 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.47 (d, J = 3.5 Hz, 1H), 3.82 (b, 1H), 2.81 (d, J = 7.4 Hz, 1H),

2.62 (d, J = 8.8 Hz, 1H), 2.41 (b, 2H), 2.27 (d, J = 6.3 Hz, 2H), 2.13 (s, 3H), 1.65-1.63 (m, 3H), 0.71 (b , 1H), 0.33-0.30 (m, 2H), 0.00-01 (m, 2H); LCMS: purity; 95%; MS (m / z); 452 (M + H)⁺;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (2,2,2-trifluoroethyl) 2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 36, ¹H

NMR (300 MHz, d6-DMSO): δ 9.21 (b, 1H), 8.90 (b, 1H), 8.37-8.34 (m, 1H), 8.25 (d, J = 6.6 Hz, 1H), 7.46 (b, 2H), 7.24-7.20 (m, 1H), 6.98-6.93 (m, 1H), 6.79-6.74 (m, 1H), 3.95 (b, 1H), 3.70 (b, 4H); ), 3.57 (b, 4H), 2.97 (b, 2H), 2.87-2.84 (m, 2H), 2.21-2.20 (m, 5H), 1.77 (b, 3H); LCMS: purity; 99%; MS (m / z); 526 (M + H)⁺;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (cyclopropyl) metylo2,5-diazabicyclo [2.2.1] heptane-2-yl) phenyl) pyrimidine-2-amine, compound No. 37, ¹H

NMR (300 MHz, d6-DMSO): δ 9.18 (b, 1H), 8.89 (b, 1H), 8.35-8.22 (m, 2H), 7.467.42 (d, J = 12.1 Hz, 2H), 7.21-7.19 (m, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 3.88 (b, 1H), 3.68 (b, 4H), 3.57 (b, 4H), 3.15 (s, 2H), 2.87 (d, J = 8.8 Hz, 1

-173H), 2.69 (d, J = 9.3 Hz, 1H), 2.48 (b, 1H), 2.34 (d, J = 5.7 Hz, 2H), 2.18 (s, 3H), 1.71 (d, J = 6.3 Hz, 2H), 0.78 (b, 1H), 0.40 (t, J = 7.7 Hz, 2H), 0.06 (b, 2H); LCMS: purity;

98%; MS (m / z); 498 (M + H)⁺;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5- (aminosulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 38, ¹H NMR (300 MHz, d6-DMSO): δ 11.50 (d, J = 7.7 Hz, 1H), 9.47 (b, 1H), 8.73 (d, J = 6.33 Hz, 1 H), 8.46 (t, J = 13.2 Hz, 1H), 8.02 (d, J = 7.1 Hz, 1H), 7.53-7.33 (m, 4H), 6.94 (b, 3H), 4.23 (d, J = 7.7 Hz, 2H), 3.37 (m, 4H), 1.92-1.85 (m, 2H), 1.47-1.38 (m, 8H); LCMS; cleanliness; 100%; MS (m / z); 537 (M + H)⁺;

4- (3-fluoro-2- (morpholin-4-yl) pyridin-4-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidine-2-amine, compound 39, ¹H NMR (DMSO-d6): δ 9.68 (s, 1H), 8.55 (dd, 1H, J = 1.4 and 4.9 Hz), 8.15 (d, 1H, J = 4.9 Hz),

7.62 (d, 1H, J = 15.4 Hz), 7.31-7.28 (m, 2H), 7.15-7.14 (m, 1H), 6.67 (t, 1H, J = 9.1 Hz), 4.15 (s, 1H), 3.73 -3.71 (m, 4H), 3.39-3.37 (m, 5H), 3.15 (apparent d, 1H, J = 6.1 Hz), 2.70 (d, 1H, J = 9.0 Hz), 2.57 (d, 1H, J = 9.0 Hz), 2.22 (s, 3H), 1.79 (d, 1H, J = 9.0 Hz), 1.68 (d, 1H, J = 9.0 Hz); LCMS: purity: 99%; MS (m / e): 480 (MH⁺);

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 40, ¹H NMR (CD3OD, 300 MHz): δ 9.02 (s, 2H), 8.26 (d, 1H), 7.45 (d, 2H), 7.08 (d, 1H), 6.63 (d, 2H), 4.31 (s , 1H), 3.89 (m, 4 H), 3.75 (m, 4 H), 3.45 (m, 2 H), 2.81 (m, 2 H), 2.65 (m, 2 H), 2.39 (m, 2 H), 2.37 (s , 3H), 1.98 (m, 2H); LCMS (m / z): 445.54 (MH⁺);

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 41, ¹1 H NMR (CD 3 OD, 300 MHz): δ 9.02 (s, 2 H), 8.54 (s, 1H), 8.29 (d, 1H), 7.38 (m, 1H), 7.08 (d, 1H), 6.87 (d, 1H), 4.00 (s, 1H), 3.89 (m, 4H), 3.75 (m, 4H), 3.56 (m, 1H), 3.42 (m, 1H), 3.25 (m, 1H), 3.04 (m , 1H), 2.86 (m, 1H), 2.65 (m, 1H), 2.49 (s, 3H), 2.29 (m, 3H), 1.96 (m, 2H); LCMS (m / z): 459.57 (MH⁺);

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl ) phenyl) pyrimidine-2-amine, compound 42, ¹H NMR (CD3OD, 300 MHz): δ 9.02 (s, 2H), 8.32 (m, 1H), 7.96 (m, 1H), 7.38 (m, 1H), 7.12 (m, 1H), 6.80 (m, 1H), 4.58 (s, 1H), 4.07 (m, 1H), 3.85 (m, 2H), 3.81 (m, 1H), 3.76 (m, 2H), 3.36 (m, 1) H), 3.34 (s, 3 H), 3.00 (m, 1H), 2.86 (m, 1H), 2.66 (m, 1H), 2.29 (m, 2H), 2.20 (m, 2H), 2.01 ( m, 1H), 1.89 (m, 1H); LCMS (m / z): 446.39 (MH⁺);

4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 43, ¹1 H NMR (CD 3 OD, 300 MHz): δ 9.03 (s, 2 H), 8.53 (s, 1H), 8.33 (d, 1H), 7.57 (m, 1H), 7.23 (d,

1 H), 7.13 (d, 1H), 6.74 (m, 1 H), 4.46 (s, 1H), 3.90 (m, 4 H), 3.76 (m, 4 H), 3.66 (m, 1).

H), 3.40 (m, 1H), 3.36 (m, 1H), 3.14 (m, 1H), 2.96 (m, 1H), 2.57 (m, 1H), 2.52 (s,

3H), 2.04 (m, 2H); LCMS (m / z): 463 (MH⁺);

-1744- (2 - ((cyclopropyl) carbonylamino) -pyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine, compound 44, ¹1 H NMR (CD 3 OD, 300 MHz): δ 9.17 (s, 2 H), 8.36 (s, 1H), 7.41 (d, 1H), 7.18 (m,

1H), 7.08 (d, 1H), 6.80 (d, 1H), 4.30 (s, 1H), 4.16 (m, 1H), 4.05 (m, 1H), 3.78 (m, 1H). , 3.58 (m, 1H), 3.32 (m, 1H), 2.89 (s, 3H), 2.47 (m, 1H), 2.65 (m, 1H), 2.26 (m, 3H), 2.21 (m , 1H), 1.13 (m, 2H), 0.92 (m, 2H); LCMS (m / z): 457 (MH⁺);

4- (4- (4,5-dihydro-thiazol-2-ylcarbamoyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound 45,

LCMS (m / z): 500 (MH⁺);

4- (4- (1,1-dimethylethyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound 46, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.34 (m, 2 H), 8.04 (m, 2 H), 7.56 (m, 1 H), 7.53 (m, 2 H), 7.20 (m, 1 H), 6.97 (m , 1H), 4.25 (d, 2H), 3.80 (m, 1H), 3.5 (m, 2H), 2.97 (m, 3H), 2.30 (m, 6H), 1.36 (m, 9H); LCMS (m / z): 428 (MH⁺);

4- (4- (morpholin-4-yl) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine. TFA salt, compound 47, ¹H NMR (DMSO-d6): δ 9.54-9.42 (2H, m), 8.39 (1H, d, J = 5.5 Hz), 8.04 (2H, d, J = 8.8 Hz), 7.80 (1H, dd, J = 16.4, 2.3 Hz), 7.41 (1H, dd, J = 8.7, 2.1 Hz), 7.27 (1H, d, J = 5.2 Hz), 7.05 (2H, d, J = 9.1 Hz), 6.84 ( 1 H, t, J = 9.6 Hz), 4.48 (1H, s), 4.27 (1H, s), 3.79-3.67 (6H, m), 3.34 (1H, d, J = 10.7 Hz), 3.26 (4H, astr. T, J = 4.7 Hz), 3.09 (1H, d, J = 11.6 Hz), 2.87 (2H, d, J = 5.0 Hz), 2.82 (1H, d, J = 5.0 Hz) 2.35 (1H, d, J = 11.0 Hz), 2.11 (1H, d, J = 11.0 Hz); MS: 461 (M + H)⁺;

4- (4 - ((methyl) aminocarbonylmethyl) -phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine. TFA salt, compound No. 48, ¹1 H, d, J = 6.1 Hz), 8.15 (2H, d, J = 8.5 Hz), 7.46 (3H, d, J = 8.5 Hz), 7.42 (2H, d, J = 6.1 Hz), 7.02 (1H, d, J = 8.3 Hz), 4.32 (2H, br s), 3.98 (1H, d, J = 11.3 Hz), 3.60 (2H, s), 3.52 (2H); , d, J = 9.4 Hz), 3.18 (1H, d, J = 11.6 Hz), 3.00 (3H, s), 2.75 (3H, s), 2.40-2.28 (5H, m); MS: 443 (M + H) -TFA⁺;

4- (4 - ((cyclopropyl) aminocarbonyl-methyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 49, ¹H NMR (CD3OD): δ 8.31 (1H, d, J = 6.1 Hz), 8.15 (2H, d, J = 8.5 Hz), 7.47-7.43 (5H, m), 7.03 (1H, d, J = 8.3 Hz), 4.33 (2H, d, J = 7.2 Hz), 3.99 (1H, d, J = 11.0 Hz), 3.60-3.47 (4H, m), 3.18 (1H, d, J = 11.8 Hz), 3.00 (3H, s), 2.71-2.66 (1H, m), 2.40-2.28 (5H, m), 0.77-0.71 (2H, m), 0.53-0.48 (2H, m); MS: 469 (M + H)⁺;

4- (6- (methylaminocarbonyl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 50, ¹1 H NMR (CD 3 OD): δ 9.31-9.3 (1H, m), 8.60 (1H, dd, J = 8.3, 2.2 Hz), 8.51-8.44 (2H, m), 8.16 (1H, d, J = 8.3 Hz), 7.54 (1H, dd, J = 8.7, 2.6 Hz), 7.49 (1H, d, J = 2.2 Hz), 7.33 (1H, d, J = 5.0 Hz), 6.96 (1H, d, J = 8.5 Hz), 4.26 (2H, d, J = 11.6 Hz), 3.77 (1H, d, J = 11.3 Hz), 3.54 (1H, d, J = 11.3 Hz), 3.45 (1H); , dd, J = 11.4, 2.6 Hz), 3.26 (1H, dd, J =

-17511.3, 2.2 Hz), 3.00 (3H, s), 2.97 (3H, s), 2.32 (3H, s), 2.30 (2H, d, J = 2.8 Hz); MS: 430 (M + H)⁺;

4- (7-oxo-5,6,7,8-tetahydro-1,8-naphthyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine. TFA salt, compound No. 51x, ¹H NMR (DMSO-d6): δ 10.75 (1H, s), 9.44 (1H, s), 8.90 (1H, d, J = 1.9 Hz), 8.46 (1H, d, J = 5.2 Hz) 8.29 (1H, s), 7.59-7.51 (2H, m), 7.34 (1H, d, J = 5.2 Hz), 6.93 (1H, d, J = 8.8 Hz), 4.28-4.22 (2H, m), 3.43-3.38 (2H, m), 3.06-2.87 (7H, m), 2.61-2.53 (4H, m), 2.34-2.08 (3H, m), MS: 442 (M + H) -TFA⁺;

4- (5 - ((morpholin-4-yl) carbonyl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine. TFA salt, compound 52,¹H NMR (CD3OD): δ9.36 (1H, d, J = 2.2 Hz), 8.74 (1H, d, J = 1.9 Hz), 8.59 (1H, dd, J = 2.2, 1.9 Hz), 8.49 ( 1 H, d, J = 5.2 Hz), 8.47 (1H, s), 7.53-7.50 (2H, m), 7.37 (1H, d, J = 5.2 Hz), 6.97 (1H, d, J = 9.4 Hz), 4.27 (2H, d, J = 11.0 Hz), 3.80-3.66 (8H, m), 3.54 (2H, d, J = 11.6 Hz), 3.47 (2H, dd, J = 11.6, 2.5 Hz) 2.97 (3H, s), 2.33 (3H, s), 2.30 (2H, br s); MS: 486 (M + H)⁺;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-cyano-4 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 53, ¹H NMR (DMSO-d6): δ 11.50 (1H, s), 9.69 (1H, s), 8.73 (1H, s), 8.52 (1H, d, J = 5.2 Hz), 8.13 (1H , d, J = 1.9 Hz), 8.03 (1H, s), 7.78 (1H, d, J = 9.4 Hz), 7.43 (1H, d, J = 5.0 Hz), 7.01 (1H, d, J = 9.1 Hz), 4.71 (1H, s), 4.36 (1H, s), 3.98 (1H, d, J = 9.1 Hz), 3.72 (2H, d, J = 10.7 Hz), 3.12 (1H, d, J = 10.7 Hz), 2.86 (2H, d, J = 4.4 Hz), 2.80 (1H, brs), 2.41 (1H, d, J = 11.8 Hz), 2.18 (1H, d, J = 10.7 Hz), 1.47 (6H, s); MS: 483 (M + H)⁺;

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine, compound No. 59, ICMS: purity: 99%; MS (m / e): 476 (MH⁺);

4- (5-Methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 60, ICMS: purity: 99%; MS (m / e): 472 (MH⁺);

5- methyl-4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 67, ICMS: purity: 99%; MS (m / e): 472 (MH⁺);

5-methyl-4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 68, ICMS: purity: 99%; MS (m / e): 476 (MH⁺);

4- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine, compound 69, ICMS: purity: 99%; MS (m / e): 487 (MH⁺);

-1764- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 70,

LCMS: purity: 99%; MS (m / e): 505 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound 71, ¹H NMR (DMSO-d6): δ 9.81 (s, 1H), 9.23 (s, 1H), 8.95 (m, 1)

H), 8.52 (s, 1H), 7.88 (m, 3H), 7.24 (d, 1H, J = 3.6 Hz), 4.29 (s, 1H), 3.82 (s, 2H), 3.69 (s, 2H), 3.20 (m, 2H), 2.98 (s, 4H), 2.77 (s, 2H), 2.70 (s, 2H), 1.95 (s, 6H); LCMS: purity: 99%; MS (m / e): 476 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 72, ¹H NMR (DMSO-d6): δ 9.29 (s, 1H), 8.92 (d, 1H, J = 2.4 Hz), 8.37 (d, 1H, J = 5.4 Hz), 8.25 (m, 1H) , 7.54 (m, 2H), 7.24 (d, 1H, J = 5.4 Hz), 6.95 (d, 1H, J = 9.3 Hz), 6.85 (d, 1 HJ = 9.3 Hz), 4.07 (s, 1 H), 3.69 (m, 4 H), 3.58 (m, 4 H), 3.32 (m, 4 H), 2.65 (s, 3 H), 2.19 (s, 3 H), 1.95 (m, 2 H); LCMS: purity: 99%; MS (m / e): 458 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4 - (( 1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound 73, LCMS: purity: 99%; MS (m / e): 476 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 74, LCMS: purity: 99%; MS (m / e): 462 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl ) phenyl) pyrimidine-2-amine, compound No. 75, ¹H NMR (DMSO-d6): δ 8.92 (d, 1H, J = 2.1 Hz), 8.38 (d, 1H, J = 5.1 Hz), 8.25 (m, 1H), 7.56 (m, 3H), 7.25 (d, 1H, J = 4.8 Hz), 6.95 (d, 1H, J = 9.3 Hz), 3.68 (m, 4H), 3.58 (m, 4H), 3.31 (m, 8H), 2.91 (s , 2H), 2.31 (s, 3H), 0.87 (s, 6H); LCMS: purity: 99%; MS (m / e): 514 (MH⁺);

4- (6- (dimethylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine, compound 76, LCMS: purity: 99%; MS (m / e): 472 (MH⁺);

4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine, compound No. 77, LCMS: purity: 99%; MS (m / e): 526 (MH⁺);

4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound 78, LCMS: purity: 99%; MS (m / e): 470 (MH⁺);

4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 79, LCMS: purity: 99%; MS (m / e): 474 (MH⁺);

-1774- (6- (benzylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 80, LCMS:

purity: 99%; MS (m / e): 478 (MH⁺);

4- (6- (benzylamino) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 81, LCMS: purity: 99%; MS (m / e): 482 (MH⁺);

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonane -3-yl) phenyl) pyrimidine-2-amine, compound No. 82, LCMS:

purity: 99%; MS (m / e): 532 (MH⁺);

4- (6- (dimethylamino) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine, compound No. 83, LCMS:

purity: 99%; MS (m / e): 476 (MH⁺);

4- (4- (dimethylamino) phenyl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidin-2-amine , compound No. 84, LCMS:

purity: 99%; MS (m / e): 475 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl ) phenyl) pyrimidine-2-amine, compound No. 85, LCMS:

purity: 99%; MS (m / e): 518 (MH⁺);

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2 , 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound

86, LCMS: purity: 99%; MS (m / e): 430 (MH⁺);

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2 , 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 87, LCMS: purity: 99%; MS (m / e): 434 (MH⁺);

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1,5,7-trimetylo3,7 -diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine-2-amine, compound No. 88,

LCMS: purity: 99%; MS (m / e): 486 (MH⁺);

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (1,5,7-trimetylo3,7 -diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine-2-amine, compound No. 89,

LCMS: purity: 99%; MS (m / e): 490 (MH⁺);

4- (6- (benzyl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine, compound No. 90, LCMS:

purity: 99%; MS (m / e): 534 (MH⁺);

4- (6- (benzyl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine, compound No. 91, LCMS:

purity: 99%; MS (m / e): 538 (MH⁺);

-1784- (2- (propyl) aminopyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 92, LCMS:

purity: 99%; MS (m / e): 431 (MH⁺);

4- (2- (propyl) aminopyrimidin-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 93, LCMS: purity: 99%; MS (m / e): 435 (MH⁺);

4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-tifluoromethyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 94, LCMS: purity: 99%; MS (m / e): 524 (MH⁺);

4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 95, LCMS: purity: 99%; MS (m / e): 451 (MH⁺);

4- (6- (dimethylamino) pyridin-3-yl) -N- (3-tifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 96, LCMS: purity: 99%; MS (m / e): 470 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-tifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 97, LCMS: purity: 99%; MS (m / e): 512 (MH⁺);

4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-trifluoromethyl-4 - ((1S, 4S) 5-methyl- 2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine, compound No. 98, LCMS: purity: 99%; MS (m / e): 484 (MH⁺);

4- (6 - ((2- (cyclopropylsulfonyl) aminoethyl) -amino) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 99, LCMS: purity: 99%; MS (m / e): 535 (MH⁺);

4- (6 - ((2- (cyclopropylsulfonyl) aminoethyl) -amino) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-oxa-2-azabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 100, LCMS: purity: 99%; MS (m / e): 522 (MH⁺);

4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 101, LCMS: purity: 99%; MS (m / e): 455 (MH⁺);

4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-tifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 102, LCMS: purity: 99%; MS (m / e): 505 (MH⁺);

4- (imidazo [1,2-a] pyridin-6-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- ylo) phenyl) pyrimidine-2-amine, compound No. 103, ¹H NMR (CD3OD, 300 ΜΙ Iz): δ 9.29 (s, 1H), 8.42 (m, 1H), 8.06 (m, 1H), 7.96 (s, 1H), 7.64 (m, 2H), 7.55 (m, 1H), 7.49 (m, 1H), 7.27 (m, 1H), 6.99 (m, 1H), 4.29 (m, 2H), 3.79 (m, 1H), 3.52 (m) , 3H), 2.99 (s, 3H), 2.32 (m, 5H); MS (ES) 412.0 (M + H);

-1794- (4- (5- (4-dimethylaminophenyl) oxazol-2-yl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 104, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.32 (m, 1 H), 8.22 (m, 2 H), 8.06 (m, 2 H), 7.61 (m, 2 H), 7.43 (m, 4 H), 6.98 (m, 3H), 4.31 (m, 2H), 3.98 (m, 1H), 3.52 (m, 2H), 3.17 (m, 1H), 3.05 (m, 9H), 2.33 (m, 5H); MS (ES) 558.1 (M + H);

4- (6-methoxy-1H-indol-2-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 105, ¹H NMR (CD3OD, 300 MHz): δ 7.98 (m, 1H), 7.51 (m, 1H), 7.44 (s, 1H), 7.37 (m, 1H), 7.28 (m, 2H), 7.03 (m, 1H), 6.93 (m, 1H), 6.76 (m, 1H), 4.34 (m, 2H), 3.98 (m, 1H), 3.85 (s, 3H), 3.54 (m, 3H); ), 2.99 (s, 3H), 2.32 (m, 5H); MS (ES) 441.1 (M + H);

4- (1- (3-chlorophenyl) -1H-pyrazol-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine, compound No. 106, ¹H NMR (CD3OD, 300 MHz): δ9.10 (m, 1H), 8.35 (m, 1H), 8.20 (m, 1H), 7.92 (m, 1H), 7.79 (m, 1H), 7.50 (m, 1H), 7.40 (m, 3H), 7.27 (m, 1H), 7.03 (m, 1H), 4.34 (m, 2H), 3.98 (m, 1H), 3.54 (m, 2H), 3.18 (m, 1H), 2.99 (s, 3H), 2.32 (m, 5H); MS (ES) 472.0 (M + H);

4- (1-methylbenzimidazol-6-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine, compound No. 107, ¹H NMR (CD3OD, 300 MHz): δ 9.41 (s, 1H), 8.73 (s, 1H), 8.47 (m, 2H), 7.96 (m, 1H), 7.53 (m, 3H), 7.02 ( m, 1H), 4.31 (m, 2H), 4.21 (s, 3H), 3.97 (m, 1H), 3.51 (m, 2H), 3.19 (m, 1H), 2.99 (s, 3H), 2.34 (m, 5H); MS (ES) 426.1 (M + H); 4- (5

-cyano-1H-indol-2-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine, compound 108, ¹H NMR (CD3OD, 300 MHz): δ 8.17 (m, 1H), 8.01 (m, 1H), 7.56 (m, 1H), 7.39 (m, 5H), 7.01 (m, 1H), 4.32 ( m, 2H), 3.97 (m, 1H), 3.53 (m, 2H), 3.16 (m, 1H), 2.99 (s, 3H), 2.31 (m, 5H); MS (ES) 436.1 (M + H);

4- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine, compound No. 109, ¹H NMR (CD3OD, 300 MHz): δ 8.75 (s, 1H), 8.26 (m, 2H), 7.79 (m, 2H), 7.46 (m, 2H), 7.23 (m,

2H), 7.00 (m, 1H), 6.93 (m, 1H), 4.22 (m, 2H), 3.73 (m, 1H), 3.53 (m, 1H), 3.33 (m, 1H), 3.22 (m, 1H), 2.94 (s, 3H), 2.28 (m, 5H); MS (ES) 456.0 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (7-aza-bicyclo [2.2.1] heptan-7-yl) phenyl) pyrimidine-2-amine, compound No. 110, ¹H NMR (CD3OD, 300 MHz): δ 8.87 (m, 1H), 8.58 (m, 1H), 8.50 (m, 1H), 7.81 (m, 2H), 7.60 (m, 1H), 7.36 (m, 2 H), 4.80 (m, 2 H), 3.85 (m, 4 H), 3.76 (m, 4 H), 2.57 (s, 3 H), 2.22 (m, 4 H), 1.98 (m, 4 H); MS (ES) 443.1 (M + H);

4- (6-Cyano-pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine, compound No. 111, ¹1 H NMR (CD 3 OD, 300 MHz): δ 9.48 (m, 1H), 8.64 (m, 2H), 8.05 (m, 1H), 7.90 (m, 2H), 7.64 (m, 1H), 7.46 ( m, 1H), 4.31 (m, 2H), 3.97 (m, 1H), 3.50 (m, 2H), 3.18 (m, 1H), 2.99 (s, 3H), 2.30 (m, 5H); MS (ES) 398.1 (M + H);

-1804- (6-cyanopyridin-3-yl) -N- (3-methyl-4- (7-aza-bicyclo [2.2.1] heptan-7-yl) phenyl) pyrimidine-2-amine, compound No. 112, ¹1 H NMR (CD 3 OD, 300 MHz): δ 9.47 (m, 1 H), 8.66 (m, 2 H), 8.03 (m, 1 H), 7.87 (m, 2 H), 7.60 (m, 1 H), 7.51 ( m, 1H), 4.81 (m, 2H), 2.57 (s, 3H), 2.22 (m, 4H), 1.98 (m, 4H); MS (ES) 383.0 (M + H); 4- (2-oksoindolin-5-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine, compound No. 113,¹1 H NMR (CD 3 OD, 300 MHz): δ 8.25 (m, 3 H), 7.41 (m, 3 H), 7.02 (m, 2 H), 4.32 (m, 2 H), 3.98 (m, 1 H), 3.54 (m, 2H), 3.18 (m, 1H), 2.99 (m, 5H), 2.33 (m, 5H); MS (ES) 427.0 (M + H);

4- (5-cyano-pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine, compound No. 114, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.82 (m, 2 H), 7.42 (m, 4 H), 6.97 (m, 2 H), 4.30 (m, 2 H), 3.97 (m, 1 H), 3.49 (m, 2H), 3.17 (m, 1H), 2.98 (s, 3H), 2.30 (m, 5H); MS (ES) 398.1 (M + H);

4- (6- (1H-tetrazol-5-yl) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine, compound No. 115, ¹H NMR (CD3OD, 300 MHz): δ9.49 (m, 1H), 8.72 (m, 1H), 8.51 (m, 1H), 8.36 (m, 1H), 7.53 (m, 2H), 7.40 (m, 1H), 6.98 (m, 1H), 4.29 (m, 2H), 3.96 (m, 1H), 3.49 (m, 2H), 3.16 (m, 1H), 2.65 (s, 3H); ), 2.32 (m, 5H); MS (ES) 441.1 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-Acetyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 116, ¹H NMR (CD3OD, 300 MHz): δ 8.79 (m, 1H), 8.39 (m, 1H), 8.31 (m, 1H), 7.86 (m, 1H), 7.59 (m, 1H), 7.29 (m, 1H), 7.12 (m, 1H), 6.87 (m, 1H), 4.04 (m, 2H), 3.80 (m, 4H), 3.58 (m, 8H), 2.07 (m, 5H); ); MS (ES) 497.1 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 117, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.83 (m, 1H), 8.41 (m, 1H), 8.32 (m, 1H), 7.88 (m, 1H), 7.60 (m, 1H), 7.34 ( m, 1 H), 7.17 (m, 1 H), 6.93 (m, 1 H), 4.55 (m, 2 H), 4.04 (m, 3 H), 3.82 (m, 5 H), 3.73 (m, 4 H), 2.96 (s , 3H), 2.01 (m, 2H); MS (ES) 533.1 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 118, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.83 (m, 1H), 8.49 (m, 1H), 8.39 (m, 1H), 8.00 (m, 1H), 7.74 (m, 1H), 7.33 ( m, 1 H), 7.22 (m, 1 H), 6.98 (m, 1H), 4.83 (m, 1H), 4.41 (m, 1H), 4.05 (m, 3H), 3.85 (m, 4H), 3.74 (mp); m, 4H), 3.65 (m, 1H), 3.00 (s, 3H), 2.39 (m, 2H); MS (ES) 469.1 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-cyclopentyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 119, ¹ H

NMR (CD3OD, 300 MHz): δ 8.83 (m, 1H), 8.49 (m, 1H), 8.40 (m, 1H), 8.01 (m, 1

H), 7.75 (m, 1H), 7.34 (m, 1H), 7.23 (m, 1H), 6.99 (m, 1H), 4.57 (m, 1H), 4.08 (m,

H), 3.81 (m, 11H), 3.46 (m, 1H), 2.33 (m, 2H), 1.76 (m, 8H); MS (ES) 523.1 (M + H);

-1814- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2- amine, compound No. 120, ¹H NMR (CD3OD, 300 ΜΙΙ /): δ 8.93 (m, 1H), 8.40 (m, 1H), 8.29 (m, 1H), 7.74 (m, 1H), 7.52 (m, 2H), 7.29 (m, 1 H), 7.19 (m, 1H), 7.05 (m, 1 H), 3.97 (m, 1 H), 3.82 (m, 4 H), 3.69 (m, 9 H), 3.37 (m, 1H), 3.14 (m, 2H), 2.37 (s, 3H), 2.16 (m, 2H); MS (ES) 458.1 (M + H);

4- (2-Oxoindolin-5-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidine-2-amine, Compound No. 121, ¹H NMR (CD3OD, 300 ΜΙΙ /): δ 8.20 (m, 3H), 7.44 (m, 3H), 7.12 (m, 2H), 3.95 (m, 1H), 3.60 (m, 5H), 3.36 (m, 1H), 3.10 (m, 4H), 2.37 (s, 3H), 2.16 (m, 2H); MS (ES) 427.0 (M + H);

(1-methylbenzimidazol-6-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidine-2-amine, compound No. 122, ¹1 H NMR (CD 3 OD, 300 Μ): δ 8.40 (m, 2 H), 8.24 (m, 1 H), 8.14 (m, 1H), 7.76 (m, 1H), 7.67 (m, 1H), 7.60 (m, 1H), 7.39 (m, 1H), 7.14 (m, 1H), 3.99 (s, 3H), 3.94 (m, 1H), 3.60 (m, 5H), 3.36 (m, 1H), 3.14 (m, 2H), 2.38 (s, 3H), 2.16 (m, 2H); MS (ES) 426.1 (M + H);

4- (imidazo [1,2-a] pyridin-6-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine, compound 123, ¹1 H NMR (CD 3 OD, 300 Μ): δ 9.30 (m, 1H), 8.45 (m, 1H), 8.39 (m, 1H), 8.07 (m, 1H), 7.96 (m, 1H) 7.60 (m, 3H), 7.30 (m, 1 H), 7.15 (m, 1H), 3.95 (m, 1 H), 3.60 (m, 5H), 3.36 (m, 1H), 3.14 (m, 2H), 2.37 (s, 3H), 2.16 (m, 2H); MS (ES) 412.1 (M + H);

4- (2H-benzo [b] [1,4] oxazin-3 (4H) -one-6-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2 5-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 124, ¹H NMR (CD3OD, 300 ΜΙ Iz): δ 8.36 (m, 1H), 7.75 (m, 3H), 7.33-6.77 (m, 4H), 4.63 (s, 2H), 4.59 (s, 1H), 4.31 (s, 1 H), 3.92 (m, 2 H), 3.41 (m, 1H), 3.15 (m, 1H), 2.97 (s, 3H), 2.33 (m, 2H); MS (ES) 447.09 (M + H);

4- (2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, Compound No. 125, ¹1 H NMR (CD 3 OD, 300 MHz) 8.80 (m, 1 H), 8.39 (m, 1 H), 8.01 (m, 2 H), 7.55 (m, 2 H), 7.26 (m, 1 H), 6.98 (m, 1 H) ), 4.63 (s, 1H), 4.31 (s, 1H), 4.25 (s, 1H), 3.50 (m, 4H), 3.28 (m, 2H), 2.99 (s, 3H), 2.32 (m , 5H), 1.54 (m, 6H); MS (ES) 486.21 (M + H);

4- (2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 126, ¹1 H NMR (CD 3 OD, 300 μl): δ 8.75 (m, 1H), 8.39 (m, 2 H), 7.96 (m, 1H), 7.65 (m, 1H), 7.25 (m, 2H), 6.79 ( m, 1H), 4.57 (s, 1H), 4.29 (s, 1H), 3.84 (m, 2H), 3.48 (m, 5H), 3.30 (m, 6H), 2.94 (m, 3H), 2.30 (m, 2H); MS (ES) 490.19 (M + H);

4- (5- (3-methyl-piperidin-1-yl) pyrazin-2-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidine-2-amine, compound No. 127, ¹H NMR (CD3OD, 300 ΜΙ): δ 9.00 (m, 1H), 8.31 (m, 2H), 7.57 (m, 2H), 7.31 (m, 1H), 6.85 (m, 1H), 4.64 ( s, 1H), 4.45 (m, 2H), 4.33 (s, 1H), 4.29 (s, 1H), 3.96 (m, 2H), 3.45 (m,

-1821H), 3.19 (m, 1H), 3.07 (m, 1H), 2.98 (s, 3H), 2.74 (m, 2H), 2.35 (m, 2H), 1.19-1.26 (m, 4H), 1.00 ( d, J = 5.4 Hz, 3H); MS (ES) 475.48 (M + H);

4- (4- (t-butylcarbonylamino) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine, compound No. 128, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.42 (m, 2 H), 8.10 (m, 2 H), 7.75 (m, 3 H), 7.25 (m, 2 H), 4.57 (s, 1 H), 4.26 (s, 1H), 3.81 (m, 2H), 3.46 (m, 2H), 2.93 (s, 3H), 2.29 (m, 2H), 1.34 (s, 9H); MS (ES) 475.12 (M + H);

4- (4- (t-butylcarbonylamino) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine, compound 129, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.34 (m, 2 H), 8.10 (m, 2 H), 7.72 (m, 2 H), 7.51 (m, 2 H), 7.22 (m, 1 H), 6.95 (m, 1H), 4.29 (s, 1H), 4.22 (s, 1H), 3.76 (m, 2H), 3.47 (m, 2H), 2.97 (m, 3H), 2.31 (m, 5H), 1.32 ( s, 9H); MS (ES) 471.15 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 130, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.68 (m, 1 H), 8.48 (m, 1 H), 8.39 (m, 1 H), 7.49 (m, 2 H), 7.27 (m, 1 H), 6.96 (m , 1H), 4.23 (m, 2H), 3.72 (m, 1H), 3.50 (m, 2H), 3.26 (m, 1H), 2.95 (s, 3H), 2.66 (m, 1H), 2.32 (s, 3H), 2.30 (m, 2H), 1.54 (s, 6H); MS (ES) 472.22 (M + H);

4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 132, ¹1 H NMR (CD 3 OD, 300 MHz): δ 9.02 (m, 1 H), 8.42 (m, 2 H), 8.21 (m, 2 H), 7.52 (m, 2 H), 7.23 (m, 1 H), 6.97 (m , 1H), 4.29 (s, 1H), 4.30 (s, 1H), 4.24 (s, 1H), 3.77 (m, 1H), 3.52 (m, 2H), 2.97 (s, 3H). , 2.31 (m, 5H), 2.21 (s, 3H); MS (ES) 430.07 (M + H);

4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- ylo) phenyl) pyrimidine-2-amine, compound No. 133, ¹H NMR (CD3OD, 300 MHz): δ 8.50-8.15 (m, 6H), 8.00 (m, 1H), 7.73 (m, 1H), 7.39 (m, 4H), 6.83 (m, 1H), 4.61 (s, 1H), 4.32 (s, 1H), 3.92 (m, 3H), 3.44 (m, 1H), 3.18 (m, 1H), 2.97 (s, 3H), 2.37 (m, 2H); MS (ES) 496.05 (M + H);

4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2- ylo) phenyl) pyrimidine-2-amine, compound No. 134, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.45-7.96 (m, 8 H), 7.50 (m, 4 H), 6.99 (m, 1 H), 4.61 (s, 1 H),

4.30 (m, 2H), 3.98 (m, 1H), 3.50 (m, 2H), 3.15 (m, 1H), 2.99 (s, 3H), 2.33 (m, 5H); MS (ES) 492.08 (M + H);

4- (4- (methylsulfonylamino) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine, compound No. 135, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.36 (m, 1 H), 8.13 (m, 2 H), 7.65 (m, 2 H), 7.32 (m, 3 H), 6.83 (m, 1 H), 4.62 (s , 1H), 4.32 (s, 1H), 3.92 (m, 2H), 3.39 (m, 1H), 3.20 (m, 1H), 3.05 (s, 3H), 2.97 (s, 3H), 2.34 (m, 2H); MS (ES) 469.03 (M + H);

-1834- (4- (methylsulfonylamino) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine, compound No. 136, ¹H NMR (CD3OD, 300 MHz): δ 8.21 (m, 3H), 7.39 (m, 5H), 7.01 (m, 1H), 4.34 (m, 2H), 3.99 (m, 1H), 3.77 (m). , 1H), 3.53 (m, 2H), 3.20 (m, 1H), 3.07 (s, 3H), 2.99 (s, 3H), 2.66 (m,

H), 2.33 (m, 5H); MS (ES) 465.05 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 137, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.67 (m, 1 H), 8.48 (m, 1 H), 8.39 (m, 2 H), 7.98 (m, 1 H), 7.54 (m, 2 H), 7.20 (m, 1H), 6.69 (m, 2H), 4.63 (s, 1H), 4.33 (s, 1H), 3.72 (m, 2H), 3.37 (m, 1H), 3.24 (m, 1H), 2.93 (s, 3 H), 2.34 (s, 2 H), 1.54 (s, 6H); MS (ES) 458.21 (M + H);

4- (4- (3-cyklopropyloureido) phenyl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine , compound 139, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.28 (m, 1H), 8.18 (m, 1H), 8.03 (m, 2H), 7.55 (m, 3H), 7.13 (m, 2H), 6.69 (m , 2H), 4.64 (s, 1H), 4.35 (s, 1H), 3.77 (m, 2H), 3.36 (m, 2H), 2.95 (s, 3H), 2.61 (m, 1H), 2.35 (m, 3H), 0.76 (m, 1H), 0.53 (m, 3H); MS (ES) 456.52 (M + H);

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 141, ¹H

NMR (CD3OD, 300 MHz): δ9.10 (m, 1H), 8.51 (m, 2H), 8.39 (m, 1H), 7.49 (m, 2H),

7.31 (m, 1H), 6.99 (m, 1H), 4.28 (m, 4H), 3.97 (m, 6H), 3.48 (m, 4 H), 3.34 (m, 1H),

3.21 (m, 1H), 2.99 (s, 3H), 2.32 (m, 6H); MS (ES) 515.72 (M + H);

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine, compound 142, ¹H NMR (CD3OD, 300 MHz): δ9.10 (m, 1H), 8.51 (m, 1H), 8.36 (m, 2H), 7.52 (m, 2H), 7.32 (m, 1H), 6.73 ( m, 1H), 4.66 (s, 1H), 4.36 (s, 1H), 4.26 (s, 1H), 4.12-3.78 (m, 6H), 3.46 (m, 4H), 3.21 (m, 2H), 2.97 (s, 3H), 2.33 (m, 3H); MS (ES) 501.06 (M + H);

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 143, ¹H

NMR (CD3OD, 300 MHz): δ 9.05 (m, 1H), 8.51 (m, 1H), 8.24 (m, 2H), 7.66 (m, 1H),

7.29 (m, 2 H), 6.80 (m, 1H), 4.66 (s, 1H), 4.59 (m, 1H), 4.31 (s, 1H), 3.80 (m, 6H), 3.50 (m, 1H), 3.26 (m, 2H), 2.96 (s, 3H), 2.64 (m, 4H), 2.32 (m, 3H); MS (ES) 519.06 (M + H);

4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine, compound No. 147, ¹H NMR (CD3OD, 300 MHz): δ 9.03 (m, 1H), 8.42 (m, 2H), 8.22 (m, 2H), 7.41 (m, 1H), 7.20 (m, 1H), 6.88 ( m, 1H), 4.58 (s, 1H), 4.17 (s, 1H), 4.05 (m, 1H), 3.82 (m, 1H), 3.23 (m, 2H), 2.28 (m, 3H); ), 2.21 (s, 3H), 2.03 (m, 1H), 1.91 (m, 1H); MS (ES) 416.97 (M + H);

4- (6-aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine, compound No. 148, ¹H NMR

-184 (CDsOD, 300 ΜΙ Iz): δ 8.65 (m, 1H), 8.38 (m, 2H), 8.06 (m, 1H), 7.40 (m, 2H), 7.14 (m, 1H), 6.89 ( m, 1H), 4.65 (s, 1H), 4.23 (s, 1H), 4.19 (m, 1H), 3.70-3.36 (m, 3H), 2.65 (s, 3H), 2.44 (m, 2H), 2.37 (s, 3H), 2.14-1.89 (m, 2H), 1.14 (m, 2H); MS (ES) 430.02 (M + H);

4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 149, ¹1 H NMR (CD 3 OD, 300 ΜΙ Iz): δ 9.03 (m, 1H), 8.39 (m, 2H), 8.22 (m, 2H), 7.42 (m, 2H), 7.21 (m, 1H), 6.91 ( m, 1H), 4.65 (s, 1H), 4.25 (s, 1H), 3.68-3.32 (m, 5H), 2.66-2.32 (m, 2H), 2.29 (s, 3H), 2.21 (s , 3H), 2.08-1.82 (m, 2H), 1.14 (m, 2H); MS (ES) 472.06 (M + H);

4- (6-aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine, compound No. 150, ¹H NMR (CD3OD, 300 ΜΙ Iz): δ 8.68 (m, 1H), 8.28 (m, 2H), 8.09 (m, 1H), 7.41 (m, 2H), 7.09 (m, 1H), 6.75 (m, 1H), 4.65 (s, 1H), 4.20 (m, 1H), 4.19 (m, 1H), 3.71-3.39 (m, 3H), 2.66-2.39 (m, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 2.13-1.88 (m, 2H), 1.14 (m, 2H); MS (ES) 451.99 (M + H);

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 151, ¹1 H NMR (CD 3 OD, 300 ΜΙ Iz): δ 8.96 (m, 1H), 8.43 (m, 1H), 8.30 (m, 1H), 7.54 (m, 2H), 7.23 (m, 1H), 7.15 (m, 1H), 6.97 (m, 1H), 4.30 (s, 1H), 4.25 (s, 1H), 3.80-3.37 (m, 3H), 3.23 (m, 2H), 2.98 (s, 3H), 2.66 (m, 2H), 2.32 (br s, 6H); MS (ES) 466.03 (M + H);

4- (6- (2- (dimethylamino) acetamido) -pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidine-2-amine, compound No. 152, ¹1 H NMR (CD 3 OD, 300 ΜΙ Iz): δ 8.52 (m, 1H), 8.31 (m, 1H), 8.20 (m, 1H), 7.52 (m, 2H),

7.21 (m, 2H), 6.96 (m, 1H), 4.31 (s, 1H), 4.24 (s, 1H), 3.91-3.48 (m, 5H), 2.99 (s, 3H), 2.83 (s , 3H), 2.65 (s, 3H), 2.32 (m, 6H); MS (ES) 473.04 (M + H);

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 153, ¹H NMR (CD3OD, 300 ΜΙ Iz): δ 8.94 (m, 1H), 8.39 (m, 3H), 7.62 (m, 1H), 7.22 (m, 3H), 6.78 (m, 1H), 4.56 (s, 1H), 4.29 (s, 1H), 3.79-3.43 (m, 5H), 2.93 (m, 2H), 2.66 (m, 1H), 2.30 (m, 3H); MS (ES) 469.99 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine , compound 155, ¹H NMR (CD3OD, 300 ΜΙΙ /): δ 8.90 (m, 1H), 8.49 (m, 1H), 8.25 (m, 2H), 7.59 (m, 2H), 7.13 (m, 1H), 6.94 (m, 1H), 6.87 (m, 1H), 3.93 (m, 2H), 3.78 (m, 4H), 3.61 (m, 6H), 3.13 (m, 2H), 2.81 (s, 3H), 2.19 (m, 4H); MS (ES) 458.03 (M + H);

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine-2-amine, compound No. 156 . ¹H NMR (CD3OD, 300 ΜΙ Iz): δ 8.90 (m, 1H), 8.36 (m, 3H), 7.75 (m, 1H), 7.56 (m, 2H), 7.13

-185 (m, 2 H), 6.91 (m, 2 H), 3.97 (m, 2 H), 3.72 (m, 2 H), 3.19 (m, 2 H), 2.83 (s, 3 H), 2.25 (m,

5H); MS (ES) 466.03 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (8-methyl-3 , 8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine-2-amine, compound No. 157, ¹H NMR (CD3OD, 300 MHz): δ 8.67 (m, 1H), 8.38 (m, 1H), 7.99 (m, 1H), 7.59 (m, 2H), 7.21 (m, 1H), 6.95 (m, 2 H), 3.97 (m, 2 H), 3.68 (m, 2 H), 3.17 (m, 3 H), 2.85 (s, 3 H), 2.65 (m, 1 H), 2.22 (m, 4 H), 1.55 (s, 6H); MS (ES) 472.09 (M + H);

4- (6-aminopyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine-2-amine, compound No. 158, ¹H NMR (CD3OD, 300 MHz): δ 8.87 (m, 1H), 8.28 (m, 2H), 8.15 (m, 1H), 7.58 (m, 2H), 7.09 (m, 1H), 6.93 ( m, 2H), 6.65 (m, 1H), 4.03 (m, 2H), 3.68 (m, 2H), 3.25 (m, 3H), 2.89 (s, 3H), 2.64 (m, 1H), 2.23 (m, 4H); MS (ES) 388.04 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.2] nonane-4-yl) phenyl) pyrimidin-2-amine , compound 159, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.27 (m, 3 H), 7.51 (m, 2 H), 7.15 (m, 2 H), 6.86 (m, 1 H), 3.80 (m, 4 H), 3.60 (m, 7H), 3.46 (m, 4H), 3.30 (m, 2H), 2.41 (m, 2H), 2.35 (s, 3H), 2.07 (m, 2H); MS (ES) 472.12 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1 , 4-diazabicyclo [3.2.2] nonan-4-yl) phenyl) pyrimidine-2-amine, compound No. 160, ¹H NMR (CD3OD, 300 MHz): δ 8.64 (m, 1H), 8.47 (m, 1H), 8.38 (m, 1H), 7.95 (m, 1H), 7.51 (m, 2H), 7.14 ( m, 2H), 3.51-3.43 (m, 9H), 2.40 (m, 2H), 2.34 (s, 3H), 2.34 (m, 2H), 1.54 (s, 6H); MS (ES) 486.11 (M + H);

4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.2] nonan-4-yl) phenyl) pyrimidine-2-amine, compound 161, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.47-8.22 (m, 4 H), 8.10 (m, 3 H), 7.84 (m, 1 H), 7.60 (m, 2 H),

7.35-7.15 (m, 3H), 3.61-3.48 (m, 9H), 2.44 (m, 2H), 2.37 (s, 3H), 2.12 (m, 2H); MS (ES) 506.06 (M + H);

4- (4- (acetamido) phenyl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine-2-amine, compound No. 162, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.34 (m, 1 H), 8.10 (m, 2 H), 7.66 (m, 4 H), 7.19 (m, 1 H), 6.95 (m, 2 H), 3.99 (m, 2 H). ), 3.68 (m, 2 H), 3.13 (m, 2 H), 2.86 (s, 3 H), 2.23 (m, 4 H), 2.16 (s, 3H); MS (ES) 429.32 (M + H);

4- (2- (diethylamino) thiazol-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 163, ¹H NMR (CD3OD, 300 MHz): δ 8.37 (m, 1H), 7.53 (m, 1H), 7.46 (m, 2H), 7.29 (m, 1H), 6.95 (m, 1H), 4.31 (s, 1H), 4.23 (s, 1H), 3.56 (m, 6H), 2.99 (s, 3H), 2.31 (br s, 5H), 1.27 (m, 8H); MS (ES) 450.30 (M + H);

4- (2- (diethylamino) thiazol-4-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 164, ¹H NMR (CD3OD, 300 MHz): δ 8.47 (m, 1H), 8.38 (m, 1H), 7.70 (m, 1H), 7.45 (m, 1H), 7.29

-186 (m, 2 H), 6.77 (m, 1H), 4.54 (s, 1H), 4.23 (s, 1H), 3.60 (m, 5H), 3.03 (m, 1H), 2.91 (s , 3H), 2.29 (m, 2H), 1.27 (m, 8H); MS (ES) 454.00 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (8) -methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine-2-amine, compound No. 165, ¹H NMR (CD3OD, 300 MHz): δ 8.70 (m, 1H), 8.42 (m, 1H), 8.01 (m, 1H), 7.56 (m, 2H), 7.27 (m, 3H), 4.01 ( brs, 2H), 3.25-3.10 (m, 3H), 2.89 (s, 3H), 2.41 (s, 3H), 2.31 (m, 5H), 1.55 (s, 6H); MS (ES) 486.08 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine -2-amine, compound No. 166, ¹H NMR (CD3OD, 300 MHz): δ 8.88 (m, 1H), 8.42 (m, 1H), 8.31 (m, 1H), 7.48 (m, 2H), 7.35 (m, 1H), 7.21 (m, 2H), 4.03 (br s, 2H), 3.85-3.74 (m, 7H), 3.34 (m, 1H), 3.12 (m, 2H), 2.89 (s, 3H), 2.67 (s, 3H). 2.40 (m, 6H); MS (ES) 472.13 (M + H);

4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine , compound 167, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.39 (m, 1 H), 8.15 (m, 2 H), 7.56 (m, 2 H), 7.34 (m, 2 H), 7.26 (m, 2 H), 7.16 (m, 2H), 4.01 (br s, 2H), 3.44-3.10 (m, 3H), 3.24 (m, 1H), 3.05 (s, 3H), 2.89 (s, 3H), 2.28 (m, 6H); MS (ES) 479.08 (M + H);

4- (4- (tert-butylcarbonylamino) phenyl) -N- (3-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine-2-amine, compound No. 168, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.33 (m, 1H), 8.15 (m, 2 H), 7.78 (m, 2 H), 7.54 (m, 2 H), 7.41 (m, 1H), 7.20 (m, 1) H), 4.02 (br s, 2H), 3.30-3.08 (m, 3H), 3.08 (s, 3H), 2.66 (s, 3H), 2.40 (m, 5H), 1.32 (s, 9H); MS (ES) 485.62 (M + H);

4- (1H-pyrrol-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine, compound No. 169, ¹H NMR (CD3OD, 300 MHz): δ 8.27 (m, 1H), 8.17 (m, 1H), 7.51 (m, 3H), 6.94 (m, 2H), 4.30 (s, 1H), 4.22 ( s, 1H), 3.76 (m, 1H), 3.46 (m, 2H), 3.29 (s, 3H), 2.97 (s, 3H), 2.31 (m, 4H); MS (ES) 361.07 (M + H);

4- (1H-pyrrol-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine, compound 170, e¹H NMR (CD3OD, 300 MHz): δ 8.10 (m, 1H), 7.52 (m, 3H), 6.93 (m, 2H), 6.80 (m, 1H), 6.70 (m, 2H), 4.63 (s , 1H), 4.35 (s, 1H), 3.75 (m, 2H), 3.34 (m, 2H), 2.95 (s, 3H), 2.34 (m, 2H); MS (ES) 347.04 (M + H);

4- (1H-pyrrol-3-yl) -N- (3-trifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine, compound No. 171, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.41 (m, 2 H), 8.23 ​​(m, 1H), 7.82 (m, 1H), 7.55 (s, 1H), 7.38 (m,

1 H), 6.99 (m, 1H), 6.81 (m, 1H), 6.73 (m, 1H), 4.33 (s, 1H), 4.03 (s, 1H), 3.70 (m, 3H), 3.24 (m, 2H), 2.97 (s, 3H), 2.34 (m, 2H); MS (ES) 415.04 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-trifluoromethyl-4 - (( 1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 172, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.69 (m, 1 H), 8.48 (m, 2 H),

8.31 (m, 1H), 8.03 (m, 1H), 7.86 (m, 1H), 7.33 (m, 2H), 4.33 (s, 1H), 4.08 (s, 1H),

-1873.65-3.55 (m, 3H), 3.22 (m, 1H), 2.97 (s, 3H), 2.34 (m, 2H), 1.55 (s, 6H); MS (ES)

526.11 (M + H);

4- (6-ethoxypyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine, compound No. 173, ¹H NMR (DMSO-d6): δ 9.30 (s, 1H), 8.92 (s, 1H), 8.42 (d, 1H, J = 4.3Hz), 8.37 (dd, 1H, J =

2.3 and 8.8 Hz), 7.47 (d, 1H, J = 8.8 Hz), 7.42 (s, 1H), 7.28 (d, 1H, J = 4.9 Hz), 6.93 (d, 1H, J = 8.5 Hz), 6.74 (d, 1H, J = 8.5 Hz), 4.36 (qt, 2H, J = 7.0 Hz), 3.88 (s, 1H), 3.17 (apparent qt, 2H, J = 9.1 Hz), 2.73 ( d, 1H, J = 9.0 Hz), 2.66 (d, 1H, J = 9.0 Hz), 2.25 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J = 9.0 Hz) , 1.68 (d, 1H, J = 9.0 Hz), 1.32 (t, 3H, J = 7.0 Hz); LCMS: purity: 99%; MS (m / e): 417 (MH⁺);

4- (6-ethoxypyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine, compound No. 174, LCMS: purity: 99%; MS (m / e): 421 (MH⁺);

4- (2- (dimethylamino) thiazol-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 175, ¹H NMR (DMSO-d6): δ 9.24 (s, 1H), 8.43 (d, 1H, J = 4.9 Hz), 7.53 (d, 1H, J = 16.7 Hz), 7.51 (m, 1H), 7.44 (s, 1H), 7.19 (d, 1H, J = 4.9 Hz), 6.76 (d, 1H, J = 8.5 Hz), 3.90 (s, 1H), 3.42 (s, 1H), 3.19 (apparent qt, 2H, J = 9.1 Hz), 3.08 (s, 6H), 2.78 (s, 2H), 2.34 (s, 3H), 2.18 (s, 3H), 1.83 (d, 1H, J = 9.0 Hz), 1.73 (d, 1H, J = 9.0 Hz); LCMS: purity: 99%; MS (m / e): 422 (MH⁺);

4- (2- (dimethylamino) thiazol-4-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 176, ¹H NMR (DMSO-d6): δ 9.43 (s, 1H), 8.45 (d, 1H, J = 4.9 Hz), 7.53 (d, 1H, J = 16.7 Hz), 7.51 (m, 1H), 7.38 (d, 1H, J = 7.3 Hz), 7.21 (d, 1H, J = 4.9 Hz), 6.68 (t, 1H, J = 9.1 Hz), 4.14 (s, 1H), 3.39 (d , 1H, J = 9.3 Hz), 3.16 (d, 1H, J = 9.3 Hz), 3.08 (s, 6H), 2.72 (d, 1H, J = 9.0 Hz), 2.59 (d, 1H, J = 9.0 Hz), 2.23 (s, 3H), 1.79 (d, 1H, J = 9.0 Hz), 1.69 (d, 1H, J = 9.0 Hz); LCMS: purity: 99%; MS (m / e): 426 (MH⁺);

4- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 178, ¹H NMR (DMSO-d6): δ 9.27 (s, 1H), 8.98 (s, 1H), 8.43 (d, 1H, J = 4.9Hz), 8.40 (s, 1H), 7.49 (d, 1H, J = 8.8 Hz), 7.42 (s, 1H), 7.36 (d, 1H, J = 4.9 Hz), 6.75 (d, 1H, J = 8.8 Hz),

3.88 (s, 1H), 3.69-3.67 (m, 8H), 3.17 (apparent qt, 2H, J = 9.1 Hz), 2.73 (d, 1H, J = 9.1 Hz), 2.66 (d, 1H, J = 9.1 Hz), 2.25 (s, 3H), 2.19 (s, 3H), 1.76 (d, 1H, J = 8.8 Hz), 1.69 (d, 1H, J = 8.8 Hz); LCMS: purity: 90%; MS (m / e): 459 (MH⁺);

4- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 179, ¹H NMR (DMSO-d6): δ 9.48 (s, 1H), 8.98 (s, 1H), 8.47 (d, 1H, J = 4.9Hz), 8.42 (s, 1H), 7.64 (d, 1) H, J = 16.7 Hz), 7.40-7.34 (m, 2H), 6.71 (d, 1H, J = 9.1 Hz), 4.16 (s, 1H), 3.693.68 (m, 8H), 3.39 (d, 1H, J = 9.6 Hz), 3.17 (d, 1H, J = 9.6 Hz), 2.72 (d, 1H, J = 9.1

-188 Hz), 2.59 (d, 1H, J = 9.1 Hz), 2.22 (s, 3H), 1.79 (d, 1H, J = 8.8 Hz), 1.69 (d, 1H, J =

8.8 Hz); LCMS: purity: 99%; MS (m / e): 463 (MH⁺);

4- (4- (1-ethoxyethyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine, compound No. 181, LCMS: purity: 99%; MS (m / e): 444 (MH⁺);

4- (4- (1-ethoxyethyl) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine, compound No. 182, LCMS: purity: 99%; MS (m / e): 447 (MH⁺);

4- (6- (dimethylamino) pyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine, compound 183, ¹H NMR (DMSO-d6): δ 9.09 (s, 1H), 8.87 (s, 1H), 8.29 (d, 1H, J = 4.9Hz), 8.19 (d, 1H, J =

8.8 Hz), 7.53 (d, 2H, J = 8.5 Hz), 7.14 (d, 1H, J = 5.3 Hz), 6.73 (d, 1H, J = 9.1 Hz),

6.53 (d, 2H, J = 8.5 Hz), 4.21 (s, 1H), 3.35 (s, 1H), 3.26 (s, 1H), 3.09-3.04 (m, 7H),

2.73 (d, 1H, J = 9.6 Hz), 2.21 (s, 3H), 1.82 (d, 1H, J = 8.8 Hz), 1.73 (d, 1H, J = 8.8 Hz); LCMS: purity: 99%; MS (m / e): 402 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 184, ¹H NMR (DMSO-d6): δ 9.13 (s, 1H), 8.90 (d, 1H, J = 2.0Hz), 8.33 (d, 1H, J = 4.7Hz), 8.24 (dd, 1H, J = 2.0 and 8.8 Hz), 7.52 (d, 2H, J = 8.8 Hz), 7.18 (d, 1H, J = 4.7 Hz), 6.94 (d, 1H, J = 8.8 Hz), 6.53 (d, 2H, J = 8.8 Hz), 4.20 (s, 1H), 3.69-3.67 (m, 4H), 3.56 (br s, 4H), 3.35 (s, 1H), 3.27 (s, 1H), 3.09 (d, 1H, J = 8.8 Hz), 2.73 (d, 1H, J = 8.8 Hz),

2.21 (s, 3H), 1.82 (d, 1H, J = 8.8 Hz), 1.73 (d, 1H, J = 8.8 Hz); LCMS: purity: 99%; MS (m / e): 444 (MH⁺);

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4 - ((1S, 4S) -5-methyl-2 , 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound

185, ¹H NMR (DMSO-d6): δ 9.08 (s, 1H), 8.49 (d, 1H, J = 1.8Hz), 8.28 (d, 1H, J =

4.9 Hz), 7.58 (d, 1H, J = 1.8 Hz), 7.49 (d, 2H, J = 8.8 Hz), 7.14 (d, 1H, J = 4.9 Hz),

6.53 (d, 2H, J = 8.8 Hz), 4.21 (s, 3H), 3.51-3.50 (m, 2H), 3.35 (s, 1H), 3.26 (s, 1H),

3.10 (s, 3H), 3.06 (d, 1H, J = 8.8 Hz), 2.73 (d, 1H, J = 8.8 Hz), 2.21 (s, 3H), 1.82 (d, 1H, J = 9.1 Hz), 1.72 (d, 1H, J = 9.1 Hz; LCMS: purity: 99%; MS (m / e): 430 (MH);⁺);

4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidine-2-amine, compound No. 186, LCMS: purity: 99%; MS (m / e): 474 (MH⁺);

4- (6- (cis-2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound no

187 ¹H NMR (DMSO-d6): δ 9.20 (s, 1H), 8.89 (d, 1H, J = 2.3Hz), 8.34 (d, 1H, J =

5.3 Hz), 8.24 (dd, 1H, J = 2.3 and 9.1 Hz), 7.48 (d, 1H, J = 9.1 Hz), 7.44 (s, 1H), 7.21 (d, 1H, J = 5.3 Hz), 6.97 (d, 1H, J = 9.1 Hz), 6.74 (d, 1H, J = 9.1 Hz), 4.30-4.26 (m, 2H), 3.88 (s, 1H), 3.61-3.56 (m , 2H), 3.21-3.13 (m, 2H), 2.73 (apparent qt, 2H, J = 9.1

-189 Hz), 2.27 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J = 9.0 Hz), 1.68 (d, 1H, J = 9.0 Hz), 1.15 (d, 6H, J = 6.2 Hz); LCMS: purity: 99%; MS (m / e): 486 (MH⁺);

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound 188, ¹H NMR (DMSO-d6): δ 9.14 (s, 1H), 8.78 (s, 1H), 8.30 (d, 1H, J = 5.3Hz), 8.06 (d, 1H, J = 8.8Hz), 7.49 (d, 1H, J = 8.5 Hz), 7.43 (s, 1H), 7.13-7.12 (m, 2H), 6.75 (d, 1H, J = 8.8 Hz), 6.54 (d, 1H, J); = 8.8 Hz), 3.89 (s, 1H), 3.28-3.14 (m, 5H), 2.76-2.79 (m, 2H), 2.29 (s, 3H), 2.18 (s, 3H), 1.79 (d, 1H); , J = 9.1 Hz), 1.69 (d, 1H, J = 9.1 Hz), 1.60-1.48 (m, 2H), 0.90 (t, 3H, J = 7.3 Hz); LCMS: purity: 99%; MS (m / e): 430 (MH⁺);

4- (6- (2- (dimethylamino) methylmorpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 189, ¹H NMR (DMSO-d6): δ 9.20 (s, 1H), 8.90 (s, 1H), 8.35 (d, 1H, J = 4.9Hz), 8.25 (apparent d, 1H, J = 8.8Hz ), 7.48 (d, 1H, J = 8.5 Hz), 7.43 (s, 1H), 7.21 (d, 1H, J = 4.9 Hz), 6.94 (d, 1H, J = 8.5Hz), 6.74 (d, 1H, J = 8.8 Hz), 4.34 (d, 1H, J = 12.4 Hz), 4.14 (d, 1H, J = 12.4 Hz), 3.94-2.88 (m, 2H), 3.57-3.49 ( m, 2H), 3.21-3.10 (m, 3H), 2.96-2.92 (m, 1H), 2.74-2.58 (m, 3H), 2.41-2.30 (m, 2H), 2.30 (s, 3H), 2.18 (overlapping s, 9H), 1.77 (d, 1H, J = 9.1 Hz), 1.68 (d, 1H, J = 9.1 Hz); LCMS: purity: 99%; MS (m / e): 515 (MH⁺);

4- (6- (piperidin-1-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 190, ¹H NMR (DMSO-d6): δ9.17 (s, 1H), 8.86 (s, 1H), 8.33 (d, 1H, J = 5.3 Hz), 8.20-8.17 (d, 1H, J = 9.1 Hz ), 7.49 (d, 1H, J = 8.8 Hz), 7.43 (s, 1H), 7.17 (d, 1H, J = 5.3 H), 6.91 (d, 1H, J = 8.8 Hz), 6.73 (d, 1H, J = 8.8 Hz), 3.87 (s, 1H), 3.62 (br s, 4H), 3.29 (s, 1H), 3.213.12 (m, 2H), 2.72 (d, 1) H, J = 9.1 Hz), 2.66 (d, 1H, J = 9.1 Hz), 2.26 (s, 3H), 2.18 (s, 3H), 1.77-1.52 (m, 8H); LCMS: purity: 99%; MS (m / e): 456 (MH⁺);

4- (6- (3- (aminocarbonyl) piperidin-1-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 191, LCMS: purity: 99%; MS (m / e): 499 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 192, ¹H NMR (DMSO-d6): δ 9.48 (s, 1H), 8.92 (s, 1H), 8.35 (s, 1H), 8.29 (d, 1H, J = 8.8 Hz), 7.47 (apparent s) , 2H), 7.28 (s, 1H), 7.01 (d, 1H, J = 9.1 Hz), 6.91 (d, 1H, J = 8.8 Hz), 4.35 (s, 1H), 4.18 (s, 1H), 3.68 (br s, 4H), 3.60 (br s, 4H), 3.40-3.37 (m, 4H), 2.96 (s, 3H),

2.21 (s, 3H), 1.90-1.85 (m, 2H); LCMS: purity: 99%; MS (m / e): 522 (MH⁺);

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S) - 5-methylsulfonyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 193, ¹H NMR (DMSO-d6): δ9.37 (s, 1H), 8.51 (s, 1H), 8.32 (d, 1H, J = 4.3Hz), 7.64 (s, 1H), 7.48 (s, 2H), 7.23 (d, 1H, J = 4.3 Hz), 6.89 (d, 1H, J =

8.8 Hz), 4.34 (s, 1H), 4.23-4.17 (m, 3H), 3.53 (s, 2H), 3.42-3.23 (m, 4H), 3.12 (s, 3H),

-1902.95 (s, 3H), 2.21 (s, 3H), 1.91 (d, 1H, J = 9.1 Hz), 1.82 (d, 1H, J = 9.1 Hz); LCMS:

purity: 99%; MS (m / e): 508 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl ) phenyl) pyrimidine-2-amine, compound No. 194, ¹H NMR (DMSO-d6): δ 9.24 (s, 1H), 8.91 (s, 1H), 8.36 (d, 1H, J = 5.3Hz), 8.25 (d, 1H, J = 9.1Hz) , 7.52-7.47 (m, 2H), 7.22 (d, 1H, J = 5.2 Hz), 6.95 (d, 1H, J = 9.1 Hz), 6.80 (d, 1H, J = 8.5 Hz), 4.50 (s, 1H), 4.12 (s, 1H), 3.89 (d, 1H, J = 7.3Hz), 3.69-3.67 (br m, 5H), 3.57 (br m, 5H), 3.04 (d, 1H, J = 9.6Hz), 2.18 (s, 3H), 1.87 (d, 1H, J = 8.5Hz), 1.75 (d, 1H, J = 8.5Hz); LCMS: purity: 99%; MS (m / e): 445 (MH⁺);

4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S) - 5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 195, ¹H NMR (DMSO-d6): δ 9.23 (s, 1H), 8.51 (d, 1H, J = 1.8Hz), 8.32 (d, 1H, J = 5.3Hz), 7.62 (d, 1H, J); = 1.8 Hz), 7.47 (s, 2H), 7.19 (d, 1H, J = 5.3 Hz), 6.81 (d, 1H, J = 9.1 Hz), 4.51 (s, 1H), 4.24-4.21 ( m, 2H), 4.14 (s, 1H), 3.89 (d, 1H, J = 7.3Hz), 3.70 (d, 1H, J = 7.3Hz), 3.53-3.50 (m, 2H), 3.33 ( d, 1H, J = 9.1 Hz), 3.11 (s, 3H), 3.06 (d, 1H, J = 8.2 Hz), 2.18 (s, 3H), 1.87 (d, 1H, J = 9.1 Hz) 1.76 (d, 1H, J = 9.1 Hz); LCMS: purity: 99%; MS (m / e): 431 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 196, ¹H NMR (DMSO-d6): δ 9.24 (s, 1H), 8.92 (d, 1H, J = 2.0 Hz), 8.36 (d, 1H, J = 5.3 Hz), 8.25 (dd, 1H, J = 2.3 and 9.1 Hz), 7.52-7.47 (m, 2H), 7.22 (d, 1H, J = 5.3 Hz), 6.95 (d, 1H, J =

8.8 Hz), 6.81 (apparent t, 1H, J = 8.8 Hz), 4.68 (s, 0.5 H), 4.55 (s, 0.5 Hz), 4.17 (s, 0.5 H), 4.11 (s, 0.5 Hz), 3.69-3.59 (m, 4H), 3.56-3.55 (m, 4H), 3.51-3.43 (m, 3H), 3.37-3.30 (m, 1H), 3.13-3.03 (m, 1H), 2.36-2.25 (m, 1H), 2.18 (s, 3H), 2.13-2.10 (m, 1H), 1.961.73 (m, 2H), 0.97 (t, 3H, J = 7.6 Hz); LCMS: purity: 99%; MS (m / e): 500 (MH⁺);

4- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5etylokarbonylo-2,5-diazabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 197, LCMS: purity: 99%; MS (m / e): 543 (MH⁺);

4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidine-2-amine, compound No. 198, ¹H NMR (DMSO-d6) δ 9.11 (s, 1H), 8.79 (d, 1H, J = 2.0Hz), 8.30 (d, 1H, J =

5.3 Hz), 8.06 (dd, 1H, J = 2.3 and 9.1 Hz), 7.48-7.45 (m, 2H), 7.13-7.09 (m, 2H), 6.75 (d, 1H, J = 8.8 Hz), 6.54 (d, 1H, J = 8.8 Hz), 3.88 (s, 1H), 3.30 (m, 3H), 3.22-3.14 (m, 2H), 2.75-2.66 (m, 2H), 2.27-2.24 ( m, 5H), 2.18 (s, 3H), 2.12 (s, 6H), 1.79-1.62 (m, 4H); LCMS: purity: 99%; MS (m / e): 473 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-amidino-2,5- diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 199, ¹H NMR (DMSO-d6): δ9.32 (s, 1H), 8.92 (s, 1H), 8.37 (d, 1H, J = 5.3Hz), 8.25 (d, 1H, J =

9.1 Hz), 7.55 (d, 1H, J = 9.1 Hz), 7.51 (s, 1H), 7.31 (s, 2H), 7.24 (d, 1H, J = 5.3 Hz),

7.17 (br s, 1H), 6.96 (d, 1H, J = 8.8 Hz), 6.83 (d, 1H, J = 8.8 Hz), 4.70 (s, 1H), 4.28

-191 (s, 1H), 3.69-3.68 (br m, 4H), 3.57-3.56 (br m, 4H), 3.51-3.40 (m, 3H), 3.17 (d, 1H, J = 9.3 Hz) 2.20 (s, 3H), 2.06-1.93 (m, 2H); LCMS: purity: 92%; MS (m / e): 486 (MH⁺-TFA);

4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 200, ¹H NMR (DMSO-d6): δ9.17 (s, 1H), 8.80 (d, 1H, J = 2.3Hz), 8.31 (d, 1H, J = 5.3Hz), 8.07 (dd, 1H, J = 2.3 and 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.46 (d, 1H, J = 2.0 Hz), 7.14-7.09 (m, 2H), 6.80 (d, 1H, J = 8.8 Hz), 6.54 (d, 1H, J = 8.8 Hz), 4.50 (s, 1H), 4.11 (s, 1H),

3.89 (d, 1H, J = 7.3Hz), 3.70 (d, 1H, J = 7.3Hz), 3.41-3.29 (m, 7H), 3.04 (d, 1H, J =

9.3 Hz), 2.17 (s, 3H), 1.86 (d, 1H, J = 7.3 Hz), 1.78-1.73 (m, 3H), 1.09 (t, 3H, J = 7.3 Hz); LCMS: purity: 99%; MS (m / e): 461 (MH⁺);

4- (6-cis-2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptane-2-yl) phenyl) pyrimidine-2-amine, compound No. 201, LCMS: purity: 99%; MS (m / e): 473 (MH⁺);

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine, compound No. 202, ¹H NMR (DMSO-d6): δ 9.20 (s, 1H), 8.76 (s, 1H), 8.32 (d, 1H, J = 4.7 Hz), 8.11 (d, 1H, J = 8.8

Hz), 7.51-7.49 (m, 1H), 7.45 (s, 1H), 7.32 (m, 1H), 7.15 (s, 1H), 6.80 (d, 1H, J = 8.8Hz), 6.60 (d, 1H, J = 8.8 Hz), 4.50 (s, 1H), 4.12 (s, 1H), 3.89 (d, 1H, J = 7.3Hz), 3.70 (d, 1H, J = 7.3 Hz), 3.32-3.24 (m, 3H), 3.04 (d, 1H, J = 8.8 Hz), 2.17 (s, 3H), 1.86 (d, 1H, J = 7.3 Hz), 1.76 (d, 1 H, J = 8.8 Hz), 1.55-1.49 (m, 2H), 0.91 (t, 3H, J = 7.3 Hz); LCMS: purity: 99%; MS (m / e): 417 (MH⁺);

4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oksa2-azabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound 203, ¹H NMR (DMSO-d6): δ9.17 (s, 1H), 8.80 (s, 1H), 8.31 (d, 1H, J = 5.3Hz), 8.07 (dd, 1H, J = 2.3 and 9.1 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.46 (s, 1H), 7.14-7.13 (m, 2H), 6.80 (d, 1H, J = 8.5 Hz), 6.53 (d, 1H); , J = 8.8 Hz), 4.50 (s, 1H), 4.12 (s, 1H), 3.89 (d, 1H, J =

7.3 Hz), 3.70 (d, 1H, J = 7.3 Hz), 3.30-3.26 (m, 4H), 3.03 (d, 1H, J = 8.8 Hz), 2.27 (t, 2H, J = 7.0 Hz) , 2.17 (s, 3H), 2.11 (s, 6H), 1.87 (d, 1H, J = 7.3Hz), 1.76 (d, 1H, J = 8.5Hz), 1.65 (q, 2H, J = 7.0 Hz); LCMS: purity: 99%; MS (m / e): 460 (MH⁺);

4- (6- (1,4-oxazepan-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptane -2-yl) phenyl) pyrimidine-2-amine, compound No. 204, ¹H NMR (DMSO-d6): δ 9.20 (s, 1H), 8.87 (d, 1H, J = 2.0Hz), 8.33 (d, 1H, J = 5.3Hz), 8.21 (d, 1H, J = 2.0 and 8.8 Hz), 7.53 (apparent d, 1H, J = 8.8 Hz), 7.45 (d, 1H, J = 2.0 Hz), 7.19 (d, 1H, J = 5.3 Hz), 6.82 ( d, 1H, J = 8.8 Hz), 6.80 (d, 1H, J = 8.8 Hz), 4.50 (s, 1H),

4.12 (s, 1H), 3.90-3.65 (m, 7H), 3.59 (t, 2H, J = 5.8 Hz), 3.05-2.97 (m, 2H), 2.18 (s, 3H), 1.87-1.73 (m , 2H), 1.14 (t, 2H, J = 7.3 Hz); LCMS: purity: 99%; MS (m / e): 459 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-isobutyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 205, ¹H NMR

-192 (DMSO-d6): δ 9.19 (s, 1H), 8.91 (s, 1H), 8.35 (d, 1H, J = 5.3Hz), 8.25 (dd, 1H, J =

2.3 and 8.8 Hz), 7.47-7.44 (apparent m, 2H), 7.20 (d, 1H, J = 5.3 Hz), 6.95 (d, 1H, J = 8.8 Hz), 6.72 (d, 1H, J = 8.8 Hz), 3.89 (s, 1H), 3.70-3.68 (m, 4H), 3.59 - 3.57 (m, 4H), 3.36 (s, 1H), 3.21-3.14 (m, 2H), 2.80 ( d, 1H, J = 9.1 Hz), 2.66 (d, 1H, J = 8.5 Hz), 2.31-2.22 (m, 2H), 2.18 (s, 3H), 1.70 (d, 1H, J = 8.5 Hz); ), 1.66 (d, 1H, J = 9.1 Hz), 1.56-1.52 (m, 1H), 0.83 (d, 6H, J = 6.4Hz), LCMS: purity: 99%; MS (m / e): 500 (MH⁺);

4- (6- (1,4-oxazepan-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 206, ¹H NMR (DMSO-d6): δ9.16 (s, 1H), 8.87 (d, 1H, J = 2.0Hz), 8.33 (d, 1H, J = 5.3Hz), 8.22 (dd, 1H, J = 2.3 and 9.1 Hz), 7.50 (d, 1H, J = 8.8 Hz), 7.42 (d, 1H, J = 2.3 Hz), 7.18 (d, 1H, J = 5.3 Hz), 6.82 (d , 1H, J = 8.8 Hz), 6.74 (d, 1H, J = 8.8 Hz), 3.87 (s, 1H), 3.82 -3.71 (m, 6H), 3.61-3.57 (m, 2H), 3.21- 3.12 (m, 2H), 2.73 (d, 1H, J = 9.1 Hz), 2.66 (d, 1H, J = 9.1 Hz), 2.62 (s, 3H), 2.18 (s, 3H), 1.91-1.83 ( m, 2H), 1.76 (d, 1H, J = 9.1 Hz), 1.68 (d, 1H, J = 9.1 Hz); LCMS: purity: 99%; MS (m / e): 472 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1 , 5.7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine-2-amine, compound No. 207, ¹H NMR (DMSO-d6): δ11.51 (s, 1H), 9.57 (s, 1H), 8.75 (d, 1H, J = 2.0Hz), 8.50 (d, 1H, J = 5.3Hz) , 8.04 (d, 1H, J = 2.0 Hz), 7.66 (d, 1H, J = 2.0 Hz), 7.59 (dd, 1H, J = 2.0 and 8.8 Hz), 7.41 (d, 1H, J = 5.3 Hz), 7.11 (d, 1H, J = 8.8 Hz),

3.53 (d, 2H, J = 10.8 Hz), 3.03 (d, 2H, J = 10.8 Hz), 2.94-2.85 (apparent t, 2H, J = 9.9 Hz), 2.75 (s, 3H), 2.67 (d, 2H, J = 10.8 Hz), 2.31 (s, 3H), 1.54-1.46 (m, 2H), 1.45 (s, 6H), 0.92 (s, 6H); LCMS: purity: 99%; MS (m / e): 528 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (1 , 5.7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine-2-amine, compound No. 208, ¹H NMR (DMSO-d6): δ 11.53 (s, 1H), 9.79 (s, 1H), 8.75 (d, 1H, J = 2.0Hz), 8.53 (d, 1H, J = 5.3Hz) , 8.04 (d, 1H, J = 1.7 Hz), 7.85 (dd, 1 H, J =

2.3 and 17.0 Hz), 7.46-7.41 (m, 2H), 7.09 (t, 1H, J = 9.1 Hz), 3.44 (d, 2H, J = 11.4 Hz), 3.15 (d, 2H, J = 10.8 Hz). ), 2.94-2.87 (t, 2H, J = 9.9 Hz), 2.75 (s, 3H), 2.67 (d, 2H, J =

10.8 Hz), 1.54-1.39 (m, 2H), 1.46 (s, 6H), 0.92 (s, 6H); LCMS: purity: 99%; MS (m / e): 532 (MH⁺);

4- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 209, ¹H NMR (DMSO-d6): δ 11.53 (s, 1H), 9.16 (s, 1H), 8.55 (d, 1H, J = 2.0Hz), 8.31 (d, 1H, J = 5.3Hz) 7.62 (s, 1H), 7.47-7.42 (m, 2H), 7.18 (d, 1H, J = 5.3Hz), 6.73 (d, 1H, J = 8.5Hz), 4.29 (s, 2H) , 3.81 (s, 1H), 3.21-3.14 (m, 3H), 2.72 (d, 1H, J = 9.1 Hz), 2.66 (d, 1H, J = 9.1 Hz), 2.26 (s, 3H), 2.19 (s, 3H), 1.76 (d, 1H, J = 9.1 Hz), 1.68 (d, 1H, J = 9.1 Hz); LCMS: purity: 99%; MS (m / e): 444 (MH⁺);

4- (3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) 5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 210,

-193¹H NMR (DMSO-d6): δ 11.53 (s, 1H), 9.35 (s, 1H), 8.70 (d, 1H, J = 1.8Hz), 8.45 (d, 1H, J = 5.3Hz) 7.99 (d, 1H, J = 1.8 Hz), 7.49 (s, 1H), 7.45 (d, 1H, J = 8.8 Hz), 7.33 (d, 1H, J = 5.3 Hz), 6.80 ( d, 1H, J = 8.8 Hz), 4.72 (s, 2H), 4.50 (s, 1H), 4.13 (s, 1H),

3.89 (d, 1H, J = 7.3Hz), 3.71 (d, 1H, J = 7.3Hz), 3.04 (d, 1H, J = 9.3Hz), 2.18 (s, 3H), 1.86 (d, 1H, J = 9.3 Hz), 1.75 (d, 1H, J = 9.3 Hz), LCMS: purity: 99%; MS (m / e): 431 (MH⁺);

4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl ) pyrimidine-2-amine, compound No. 211, ¹H NMR (DMSO-d6): δ 9.19 (s, 1H), 8.79 (s, 1H), 8.32 (d, 1H, J = 4.9 Hz), 8.08 (d, 1H, J = 2.6 and 9.1 Hz) 7.52 (d, 1H, J = 9.1 Hz), 7.48 (s, 1H), 7.16-7.11 (m, 2H), 6.86 (d, 1H, J =

8.8 Hz), 6.54 (d, 1H, J = 8.8 Hz), 3.44-3.32 (m, 6H), 3.15-3.13 (m, 2H), 2.85 (d, 2H, J = 9.6 Hz), 2.71 (d , 2H, J = 9.6 Hz), 2.30 (s, 3H), 2.13-2.11 (m, 1H), 2.08 (s, 3H), 1.801.73 (m, 5H), 1.10 (t, 3H, J = 7.3 Hz), 0.82 (s, 6H); LCMS: purity: 99%; MS (m / e): 530 (MH⁺);

4- (6 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7trimetylo-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine-2-amine, compound No. 212, LCMS: purity: 99%; MS (m / e): 542 (MH⁺);

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine -2-amine, compound No. 213, ¹H NMR (DMSO-d6): δ 9.18 (s, 1H), 8.78 (s, 1H), 8.32 (d, 1H, J = 5.3Hz), 8.07 (dd, 1H, J = 2.6 and 9.1 Hz), 7.54 (d, 1H, J = 8.2 Hz), 7.48 (s, 1H), 7.16-7.11 (m, 2H), 6.86 (d, 1H, J = 8.2Hz), 6.54 (d, 1H, J = 9.1 Hz), 3.26-3.24 (m, 2H), 2.85 (d, 2H, J = 10.2 Hz), 2.70 (d, 2H, J = 12.5 Hz), 2.30 (s, 3H), 2.08 (s, 3H), 1.76 (d, 2H, J = 9.6 Hz), 1.54 (q, 2H, J = 7.3 Hz), 1.19-1.03 (m, 2H), 0.09 (t, 3H, J = 7.3 Hz) 0.82 (s, 6H); LCMS: purity: 99%; MS (m / e): 486 (MH⁺);

4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N- (3-methyl-4- (1,5,7-trimetylo3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl ) pyrimidine-2-amine, compound No. 214, ¹H NMR (DMSO-d6): δ 9.18 (s, 1H), 8.78 (d, 1H, J = 2.3Hz), 8.32 (d, 1H, J = 5.3Hz), 8.07 (dd, 1H, J = 2.3 and 8.8 Hz), 7.52 (d, 1H, J = 8.5 Hz), 7.49 (d, 1H, J = 2.3 Hz), 7.157.09 (m, 2H), 6.85 (d, 1H); J = 8.5 Hz), 6.54 (d, 1H, J = 8.8 Hz), 2.86 (d, 2H, J = 10.8 Hz), 2.71 (d, 2H, J = 10.8 Hz), 2.30 (s, 3H), 2.25-2.23 (m, 3H), 2.11 (s, 6H), 2.08 (s, 3H), 1.78 (d, 2H, J = 9.5 Hz), 1.68 (q, 2H, J = 7.3 Hz), 1.19 (d , 1H, J = 12.0 Hz), 1.07 (d, 1H, J = 12.0 Hz), 0.82 (s, 6H); LCMS: purity: 99%; MS (m / e): 529 (MH⁺);

4- (6 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4- ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 215, ¹H NMR (DMSO-d6): δ9.16 (s, 1H), 8.87 (d, 1H, J = 2.3 Hz), 8.33 (d,

H, J = 5.3 Hz), 8.21 (dd, 1H, J = 2.0 and 8.8 Hz), 7.49 (d, 1H, J = 9.1 Hz), 7.43 (d, 1H,

J = 5.3 Hz), 7.18 (d, 1H, J = 5.3 Hz), 7.74 (d, 1H, J = 8.8 Hz), 6.64 (d, 1H, J = 8.8

Hz), 4.95 (s, 1H), 4.67 (s, 1H), 3.88 (s, 1H), 3.79 (d, 1H, J = 6.7Hz), 3.65 (d, 1H, J = 7.6 Hz), 3.50 (d, 1H, J = 10.3 Hz), 3.21-3.12 (m, 2H), 2.73 (d, 1H, J = 9.4 Hz), 2.67

-194 (d, 1H, J = 9.4 Hz), 2.27 (s, 3H), 2.19 (s, 3H), 1.93 (d, 1H, J = 9.4 Hz), 1.87 (d, 1H, J = 9.4 Hz), 1.77 (d, 1H, J = 9.1 Hz), 1.68 (d, 1H, J = 9.1 Hz); LCMS: purity: 99%; MS (m / e): 470 (MH⁺);

4- (6 - ((1S, 4S) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -N- (3-methyl-4- ((1S, 4S ) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 216, ¹H NMR (DMSO-d6): δ 9.19 (s, 1H), 8.86 (s, 1H), 8.33 (d, 1H, J = 5.3Hz),

8.21 (dd, 1H, J = 2.0 and 8.8 Hz), 7.52 (d, 1H, J = 8.5 Hz), 7.45 (s, 1H), 7.18 (d, 1H, J = 5.3 Hz), 6.81 (d, 1H, J = 8.5 Hz), 6.62 (d, 1H, J = 8.8 Hz), 4.95 (s, 1H), 4.68 (s, 1H), 4.50 (s, 1H), 4.12 (s , 1H), 3.89 (d, 1H, J = 7.3Hz), 3.79 (d, 1H, J = 7.3Hz), 3.70 (d, 1H, J = 7.0Hz), 3.49 (d, 1H, J = 9.9 Hz), 3.2 (d, 1H, J = 9.9 Hz), 3.04 (d, 1H, J = 9.6 Hz), 2.18 (s, 3H), 1.94-1.85 (m, 3H), 1.75 ( d, 1H, J = 9.1 Hz); LCMS: purity: 99%; MS (m / e): 457 (MH⁺);

4- (6- (3-methylbutyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidine-2-amine, compound No. 217, ¹H NMR (DMSO-d6): δ 9.12 (s, 1H), 8.79 (d, 1H, J = 2.3Hz), 8.29 (d, 1H, J = 4.7Hz), 8.06 (dd, 1H, J = 2.3 and 8.8 Hz), 7.47 (d, 1H, J = 8.8 Hz), 7.43 (d, 1H, J = 2.3 Hz), 7.12 (d, 1H, J = 4.7 Hz), 7.06 (t , 1H, J = 5.3 Hz), 6.74 (d, 1H, J = 8.8 Hz), 6.53 (d, 1H, J =

8.8 Hz), 3.87 (s, 1H), 3.21-3.12 (m, 2H), 2.72 (d, 1H, J = 9.3 Hz), 2.66 (d, 1H, J = 9.3 Hz), 2.26 (s , 3H), 2.18 (s, 3H), 1.73 (d, 1H, J = 8.5 Hz), 1.69-1.63 (m, 2H), 1.46-1.39 (apparent qt, 2H, J = 7.3 Hz), 0.89 ( d, 6H, J = 6.7 Hz); LCMS: Purity: 99%; MS (m / e): 458 (MH⁺);

4- (6- (3,3-dimethylbutyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 218, ¹H NMR (DMSO-d6): δ9.12 (s, 1H), 8.79 (d, 1H, J = 2.3Hz), 8.30 (d, 1H, J = 5.3Hz), 8.06 (dd, 1H, J = 2.3 and 8.8 Hz), 7.48 (d, 1H, J = 8.5 Hz), 7.43 (d, 1H, J = 2.3 Hz), 7.13 (d, 1H, J = 5.3 Hz), 7.01 (t , 1H, J = 5.3 Hz), 6.74 (d, 1H, J = 8.5 Hz), 6.51 (d, 1H, J = 9.1 Hz), 3.88 (s, 1H), 3.16-3.12 (m, 2H); ), 2.73 (d, 1H, J = 9.3 Hz), 2.68 (d, 1H, J = 9.3 Hz), 2.27 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J) = 9.3 Hz), 1.68 (d, 1H, J = 9.3 Hz), 1.491.43 (m, 2H), 0.92 (s, 9H); LCMS: Purity: 99%; MS (m / e): 472 (MH⁺);

4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine, compound No. 219, ¹H NMR (DMSO-d6): δ9.16 (s, 1H), 8.86 (d, 1H, J = 2.3Hz), 8.32 (d, 1H, J =

5.3 Hz), 8.20 (dd, 1H, J = 2.3 and 9.1 Hz), 7.49 (d, 1H, J = 8.5 Hz), 7.43 (d, 1H, J = 2.3 Hz), 7.18 (d, 1 H, J = 5.3 Hz), 6.77 (d, 1H, J = 9.1 Hz), 6.74 (d, 1H, J = 8.5Hz), 3.88 (s, 1H), 3.75 (t, 2H, J = 5.8 Hz), 3.51 (t, 2H, J = 5.3 Hz), 3.23 (apparent s, 3H), 3.183.12 (m, 2H), 3.08 (s, 3H), 2.73 (d, 1H, J = 9.1 Hz). ), 2.66 (d, 1H, J = 9.1 Hz), 2.26 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J = 9.4 Hz), 1.68 (d, 1H, J = 9.3 Hz). LCMS: Purity: 99%; MS (m / e): 460 (MH⁺);

4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2- ylo) phenyl) pyrimidine-2-amine, compound No. 220, ¹H NMR

-195 (DMSO-d6): δ 9.19 (s, 1H), 8.87 (d, 1H, J = 2.3Hz), 8.33 (d, 1H, J = 5.3Hz), 8.20 (dd, 1H, J = 2.3 and 9.1 Hz), 7.53 (d, 1H, J = 9.1 Hz), 7.45 (d, 1H, J = 2.3 Hz), 6.81 (d, 1H, J = 9.1 Hz), 6.75 (d, 1H, J = 9.1 Hz), 4.50 (s, 1H), 4.12 (s, 1H), 3.89 (d, 1H, J =

7.3 Hz), 3.78-3.69 (m, 3H), 3.51 (t, 3H, J = 5.3 Hz), 3.23 (s, 3H), 3.08 (s, 3H), 3.03 (d, 1H, J = 9.6 Hz). ), 2.18 (s, 3H), 1.87 (d, 1H, J = 9.1 Hz), 1.75 (d, 1H, J = 9.1 Hz); LCMS: Purity: 99%; MS (m / e): 447 (MH⁺);

4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimetylo3,7-diazabicyclo [3.3.1] nonane-3- ylo) phenyl) pyrimidine-2-amine, compound No. 221, ¹H NMR (DMSO-d6): δ 9.23 (s, 1H), 8.87 (d, 1H, J = 2.3Hz), 8.34 (d, 1H, J = 5.3Hz), 8.20 (dd, 1H, J = 2.3 and 9.1 Hz), 7.55 (d, 1H, J = 8.5 Hz), 7.48 (d, 1H, J = 2.3 Hz), 7.20 (d, 1H, J = 5.3 Hz), 6.86 (d , 1H, J = 8.8 Hz), 6.76 (d, 1H, J = 9.1 Hz), 3.76 (t, 2H, J =

5.3 Hz), 3.51 (t, 2H, J = 5.3 Hz), 3.23 (s, 3H), 3.08 (s, 3H), 2.85 (d, 2H, J = 10.8 Hz), 2.70 (d, 2H, J = 10.8 Hz), 2.31 (s, 3H), 2.07 (s, 3H), 1.76 (d, 2H, J = 11.4 Hz), 1.191.02 (m, 2H), 0.82 (s, 6H); LCMS: Purity: 99%; MS (m / e): 516 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4R) -2-aza [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine, compound No. 222, ¹H NMR (DMSO-d6): δ9.17 (s, 1H), 8.91 (d, 1H, J = 2.3Hz), 8.34 (d, 1H, J = 5.3Hz), 8.25 (d, 1H, J = 2.3 and 8.8 Hz), 7.45 (d, 1H, J = 8.5 Hz), 7.41 (d, 1H, J = 2.0 Hz), 7.20 (d, 1H, J = 5.3 Hz), 6.95 (d , 1H, J = 8.8 Hz), 6.73 (d, 1H, J = 8.8 Hz), 3.81 (s, 1H), 3.69-3.67 (m, 4H), 3.57-3.55 (m, 4H), 2.75 (d, 1H, J = 8.5 Hz), 2.18 (s, 3H), 1.81-1.56 (m, 4H), 1.38-1.29 (m, 2H); LCMS: Purity: 99%; MS (m / e): 443 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4R) -2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 223, LCMS: Purity: 99%; MS (m / e): 457 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (2 -methylsulfonyl-2-azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidine-2-amine and 4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-] b] [1,4] oxazin-7-yl) -N (3-methyl-4- (2-methylsulfonyl-2-aza-bicyclo [2.2. 1] heptan-6-yl) -phenyl) pyrimidine-2-amine (68:31 ), compound No. 224, Mixture: LCMS: Purity: 99% (68:31); MS (m / e): 521 (MH⁺); 4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (2 -metylosulfonylo-2-azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidin-2-amine¹H NMR (DMSO-d6): δ 11.50 (s, 1H), 9.52 (s, 1H),

8.75 (d, 1H, J = 2.3 Hz), 8.49 (d, 1H, J = 5.3 Hz), 8.04 (d, 1H, J = 2.3 Hz), 7.62 (s, 1 H), 7.55 (dd , 1H, J = 2.3 and 8.5 Hz), 7.39 (d, 1H, J = 5.3 Hz), 7.13 (d, 1H, J = 8.5 Hz), 4.10 (s, 1H), 3.26-3.25 (m, 1 H), 3.12-3.05 (m, 2H), 2.91 (s, 3H), 2.62 (s, 1H), 2.27 (s, 3H), 2.20-2.17 (m, 1H), 1.70-1.60 (m, 3H); ), 1.45 (s, 6H); LCMS: Purity: 95%; MS (m / e): 535 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (2-methylsulfonyl-2azabicyklo [2.2.1] heptan-5-yl) phenyl) pyrimidine-2 -amin and 4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (2-methylsulfonyl-2-aza-bicyclo [2.2.1] heptane-6-196-yl) phenyl) pyrimidine-2-amine (85:15), compound No. 225, Mixture: LCMS:

Purity: 97% (85:15); MS (m / e): 521 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (2-2metylosulfonylo -azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidine-2-amine, compound No. 226, ¹H NMR (DMSO-d6): δ11.51 (s, 1H), 9.61 (s, 1H), 8.74 (d, 1H, J = 1.8 Hz), 8.50 (d, 1H, J = 4.3 Hz), 8.03 ( s, 1H), 7.70-7.69 (d, 2H, J = 8.8 Hz), 7.40 (d, 1H, J = 4.3 Hz), 7.20 (d, 1H, J = 8.5 Hz), 4.10 (s, 1H), 3.26-3.23 (m, 1H), 3.09-2.99 (m, 2H), 2.90 (s, 3H), 2.58 (s, 1H), 2.20-2.13 (m, 1H), 1.79- 1.53 (m, 3H), 1.45 (s, 6H); LCMS: Purity: 96%; MS (m / e): 521 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (2-methylsulfonyl-2azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidine-2-amine, compound No. 227, ¹H NMR (DMSO-d6): δ 9.62 (s, 1H), 8.90 (s, 1H), 8.43 (d, 1H, J = 5.5Hz), 8.32 (apparent d, 2H, J = 9.1Hz) , 7.72-7.69 (m, 2H), 7.33 (d, 1H, J = 5.5 Hz), 7.20 (d, 1H, J = 8.8 Hz), 7.04 (d, 1H, J = 9.1 Hz), 4.11 (s, 1H), 3.71-3.69 (m, 4H), 3.62-3.60 (m, 4H), 3.25-3.22 (m, 1H), 3.10-2.99 (m, 2H), 2.90 (s, 3H) , 2.59 (s, 1H), 2.20-2.13 (m, 1H), 1.78-1.54 (m, 3H); LCMS: Purity: 96%; MS (m / e): 507 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (2-2metylosulfonylo -azabicyclo [2.2.1] heptan-6-yl) phenyl) pyrimidine-2-amine, compound No. 228, ¹H NMR (DMSO-d6): δ11.51 (s, 1H), 9.64 (s, 1H), 8.74 (d, 1H, J = 1.8 Hz), 8.50 (d, 1H, J = 5.3 Hz), 8.03 ( d, 1H, J = 1.8 Hz), 7.72 (d, 2H, J = 8.8 Hz), 7.41 (d, 1H, J = 5.3 Hz), 7.17 (d, 2H, J = 8.8 Hz), 4.01 (s , 1H), 3.22-3.17 (m, 2H), 2.98-2.95 (d, 1H, J = 8.2 Hz), 2.91 (s, 3H), 2.67 (s, 1H), 1.92-1.86 (m, 2H); ), 1.60-1.50 (m, 2H), 1.45 (s, 6H); LCMS: Purity: 97%; MS (m / e): 521 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (2-methylsulfonyl-2azabicyclo [2.2.1] heptan-6-yl) phenyl) pyrimidine-2-amine, compound No. 229, ¹H NMR (DMSO-d6): δ9.59 (s, 1H), 8.92 (s, 1H), 8.42 (d, 1H, J = 5.0 Hz), 8.31 (d, 1H, J = 9.1 Hz) 7.73 (d, 2H, J = 8.5 Hz), 7.32 (d, 1H, J = 5.0 Hz), 7.16 (d, 2H, J = 8.5 Hz), 7.02 (d, 1H, J = 9.1 Hz) , 4.01 (s, 1H), 3.70-3.68 (m, 4H), 3.61-3.59 (m, 4H), 3.23-3.16 (m, 2H), 2.98-2.95 (d, 1H, J = 8.2 Hz) 2.91 (s, 3H), 2.67 (s, 1H), 1.92-1.89 (m, 2H), 1.60-1.47 (m, 2H); LCMS: Purity: 87%; MS (m / e): 507 (MH⁺);

4- (6- (tiamorfolin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 230, ¹H NMR (DMSO-d6): δ 9.19 (s, 1H), 8.88 (s, 1H), 8.34 (d, 1H, J = 5.3 Hz), 8.22 (d, 1H, J = 8.8 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.44 (s, 1H), 7.20 (d, 1H, J = 5.3 Hz), 6.96 (d, 1H, J = 9.1 Hz), 6.74 (d, 1H); , J = 9.1 Hz), 3.99 (s, 4H), 3.88 (s, 1H), 3.19 (d, 1H, J = 9.1 Hz), 3.15 (d, 1H, J = 9.1 Hz), 2.73 (d, 1H); , J = 9.1 Hz), 2.67 (d, 1H, J = 9.1 Hz), 2.61 (s, 4H), 2.26 (s, 3H), 2.18 (s, 3H), 1.77 (d, 1H, J = 9.1 Hz), 1.68 (d, 1H, J = 9.1 Hz); LCMS: Purity: 99%; MS (m / e): 474 (MH⁺);

-1974- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine in the form of hemisuccinate salt, compound No. 231;

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) phenyl) pyrimidine-2-amine, compound No. 232, ¹H NMR (DMSO-d6, 300 MHz): δ 9.27 (s, 1H), 8.72 (m, 2H), 8.50 (s, 1H), 8.43 (d, 1H, J = 5.4Hz), 8.09 (d, 1H, J = 8.7 Hz), 7.92 (m, 2H), 7.75 (dd, 2H, J = 1.5 &amp; 4.3 Hz), 7.51 (m, 2H), 7.35 (d, 1H, J = 5.4 Hz), 6.92 (d, 1H, J = 3.3 Hz), 6.76 (d, 1H, J = 8.4 Hz), 3.90 (s, 1H), 3.19 (m, 3H), 2.72 (q, 2H, J = 8.4 Hz), 2.28 (s, 3H), 2.22 (s, 3H), 1.79 (d, 1H, J = 9.3 Hz), 1.70 (d, 1H, J = 8.7 Hz); LCMS (m / z): 488 (MH⁺);

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) phenyl) pyrimidine-2-amine, compound No. 233, ¹H NMR ((DMSO-d6, 300 MHz): δ 9.48 (s, 1H), 8.71 (d, 1H, J = 5.1Hz), 8.49 (s, 1H), 8.46 (d, 1H, J = 5.4 Hz), 8.25 (s, 1H), 8.09 (d, 1H, J = 8.7 Hz), 7.92 (m, 2H), 7.74 (m, 2H), 7.39 (d, 2H, J = 4.8 Hz); ), 6.92 (d, 1H, J = 3.3 Hz), 6.71 (t, 1H, J = 9.9 Hz), 4.19 (s, 1H),

3.22 (m, 3H), 2.72 (q, 2H, J = 8.4 Hz), 2.29 (s, 3H), 1.84 (d, 1H, J = 9.6 Hz), 1.74 (d, 1H, J = 9.3 Hz) ; LCMS (m / z): 492 (MH⁺);

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) phenyl) pyrimidine-2-amine, compound No. 234, ¹H NMR ((DMSO-d6, 300 MHz): δ 9.28 (s, 1H), 8.72 (d, 2H, J = 6.0 Hz), 8.50 (s, 1H), 8.42 (d, 1H, J = 5.4 Hz), 8.09 (d, 1H, J = 9.0 Hz), 7.92 (m, 2H), 7.75 (d, 2H, J = 6.0 Hz), 7.50 (m, 2H), 7.35 (d, 1H, J = 5.4 Hz), 6.92 (d, 1H, J = 3.6 Hz), 6.76 (d, 1H, J = 8.7 Hz), 3.93 (s, 1H), 3.49 (s, 1H), 3.19 ( s, 3H), 2.80 (m, 2H), 2.22 (s, 3H), 1.74 (m, 3H), 0.98 (t, 3H, J = 7.2 Hz); LCMS (m / z): 502 (MH);⁺);

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-isobutyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) phenyl) pyrimidine-2-amine, compound No. 235, ¹H NMR ((DMSO-d6, 300 MHz): δ 9.27 (s, 1H), 8.72 (m, 2H), 8.50 (s, 1H), 8.42 (d, 1H, J =

5.4 Hz), 8.09 (d, 1H, J = 8.7 Hz), 7.92 (m, 2H), 7.75 (dd, 2H, J = 1.5 &amp; 4.3 Hz), 7.51 (m, 2H), 7.35 (d, 1). H, J = 5.4 Hz), 6.92 (d, 1H, J = 3.6 Hz), 6.74 (d, 1H, J = 8.7 Hz), 3.91 (s, 1H), 3.39 (m, 1H), 3.20 (s, 2H), 2.81 (s, 1H)), 2.69 (s, 1H), 2.25 (s, 2H), 2.20 (s, 3H), 1.73 (m, 2H), 1.56 (s, 1) H), 0.85 (d, 6H, J = 6.3 Hz); LCMS (m / z): 530 (MH⁺);

4- (7-oxo-5,6,7,8-tetahydro-1,8-naphthyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) 2,5--5metylosulfonylo diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 237, ¹H NMR (DMSO-d6): δ 10.75 (1H, s), 9.38 (1H, s), 8.89 (1H, d, J =

8.5 Hz), 8.45 (1H, d, J = 5.2 Hz), 8.34-8.32 (m, 1H), 7.56 (1H, s), 7.48 (1H, d, J =

8.5 Hz), 7.32 (1H, d, J = 5.2 Hz), 6.89 (1H, d, J = 8.8 Hz), 4.35 (1H, s), 4.17 (1H, s), 3.07-2.97 (7H); , m), 2.58-2.57 (4H, m), 2.23 (3H, s), 1.88 (2H, dd, J = 25.2, 9.2 Hz); MS: 506 (M + H);

4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 238, ¹H NMR

-198 (DMSO-d6): δ 9.23 (s, 1H), 8.77 (s, 1H), 8.33 (d, 1H, J = 5.3Hz), 8.11 (d, 1H, J = 9.1Hz), 7.53 (d, 1H, J = 8.5 Hz), 7.48 (s, 1H), 7.31 (br s, 1H), 7.16 (d, 1H, J = 5.3 Hz), 6.88 (d, 1H, J = 8.5 Hz); ), 6.60 (d, 1H, J = 9.1 Hz), 4.33 (s, 1H), 4.14 (s, 1H), 3.413.22 (m, 6H), 2.95 (s, 3H), 2.19 (s , 3H), 1.90 (d, 1H, J = 9.1 Hz), 1.88 (d, 1H, J = 9.1 HZ), 1.55 (m, 2H), 0.90 (t, 3H, J = 7.4 Hz); LCMS: Purity: 99%; MS (m / e): 494 (MH⁺);

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 239, ¹H NMR (CD3OD, 300 MHz): δ 8.33 (m, 2H), 8.12 (s, 1H), 7.91 (m, 1H), 7.56 (m, 3H), 7.08 (m, 2H), 6.69 (m, 1 H), 4.62 (s, 1H), 4.33 (s, 1H), 3.81 (m, 1H), 3.70 (m, 3H), 2.93 (s, 3H), 2.34 (m, 2H), 2.31 ( m, 2H); MS (ES) 445.03 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 240, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.35 (m, 1 H), 7.75 (m, 2 H), 7.52 (m, 2 H), 7.20 (m, 1 H), 6.96 (m, 2 H), 4.25 (m, 2H), 3.95 (m, 1H), 3.48 (m, 2H), 3.16 (m, 1H), 2.97 (s, 3H), 2.32 (m, 5H), 1.50 (s, 6H); MS (ES) 471.06 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S ) -5-methylsulfonyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 241, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.31 (m, 1H), 7.71 (m, 2 H), 7.46 (m, 2 H), 7.10 (m, 2 H), 6.95 (m, 2 H), 4.44 (s, 1) H), 4.19 (s, 1H), 3.63-3.37 (m, 4H), 2.94 (s, 3H), 2.31 (s, 3H), 2.03 (m, 2H), 1.51 (s, 6H); MS (ES) 535.12 (M + H);

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 242, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.38 (m, 1 H), 8.04 (m, 2 H), 7.52 (m, 2 H), 7.20 (m, 2 H), 7.25 (m, 1 H), 7.10 (m, 1H), 6.96 (m, 1H), 4.30 (s, 1H), 4.24 (s, 1H), 3.79 (m, 1H), 3.48 (m, 2H), 3.24 (m, 1H), 2.97 (s , 3H), 2.88 (m, 2H), 2.33 (m, 9H); MS (ES) 455.14 (M + H);

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5metylosulfonylo-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 243, ¹H NMR (CD3OD, 300 MHz): δ 8.23 ​​(m, 1H), 8.16 (m, 2H), 7.52 (m, 3H), 7.15 (m, 2H), 4.50 (s, 1H), 4.42 (s, 1H), 3.65 (m, 4H), 2.97 (s, 3H), 2.88 (m, 2H), 2.36-2.11 (m, 9H); MS (ES) 519.13 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((6R, 9S ) -6,9-methano-octahydro-1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidine-2-amine, compound No. 244, ¹H NMR (CD3OD, 300 MHz): δ 8.42 (s, 1H), 8.36 (m, 1H),

7.76 (m, 2 H), 7.55 (m, 2 H), 7.21-7.10 (m, 2 H), 6.97 (m, 1 H), 3.95 (m, 2 H), 3.70-3.48 (m, 3 H), 2.58 (m, 1H), 2.41 (m, 1H), 1.34 (s, 3H), 1.97-1.66 (m, 6H), 1.51 (s, 6H); MS (ES) 511.13 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((6R, 9S) -6,9-metanooktahydro1H-pyrido [1,2-a] pyrazin -2-yl) phenyl) pyrimidine-2-amine, compound No. 245, ¹H NMR

-199 (CD 3 OD, 300 MHz): δ 8.90 (m, 1H), 8.40 (s, 1H), 8.32-8.21 (m, 2H), 7.49 (m, 2H),

7.13 (m, 2H), 6.87 (m, 1H), 4.01-3.91 (m, 2H), 3.81-3.48 (m, 11 H), 3.13 (m, 2H), 2.56 (m, 1H), 2.39 (m, 1H), 2.39 (m, 1H), 2.33 (s, 3H), 1.91-1.66 (m, 6H), 1.51 (s, 6H);

MS (ES) 498.13 (M + H);

4- (6- (dimethylamino) pyridin-3-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl ) pyrimidine-2-amine, compound 54, LCMS: purity: 99%; MS (m / e): 403 (MH⁺);

4- (6- (methylcarbonylamino) pyridin-3-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl ) pyrimidine-2-amine, compound No. 55, LCMS: purity: 99%; MS (m / e): 417 (MH⁺);

4- (4- (dimethylamino) phenyl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2 -amine, compound 56, ¹H NMR (DMSO-d6): δ 9.15 (s, 1H), 8.44 (s, 1H), 8.28 (d, 1H, J = 6Hz), 7.91 (m, 3H), 7.15 (d, 1H); , J = 5.6 Hz), 6.78 (d, 2H, J = 10 Hz), 6.57 (d, 1H, J = 11.5 Hz), 4.65 (s, 1H), 3.51 (m, 2H), 2.98 (s , 6H), 2.69 (m, 2H), 2.57 (s, 3H), 2.08 (m, 1H), 1.93 (m, 1 Hz); LCMS: purity: 99%; MS (m / e): 402 (MH⁺);

4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) pyridin-3-yl) pyrimidine-2-amine, compound No. 57, ¹H NMR (DMSO-d6): δ 9.21 (s, 1H), 8.88 (s, 1H), 8.41 (s, 1H), 8.34 (d, 1H, J = 6Hz), 8.20 (m, 1 H), 7.83 (m, 1H), 7.22 (d, 1H, J = 5.1 Hz), 6.95 (d, 1H, J = 9.3 Hz), 6.53 (d, 1H, J = 9.3 Hz), 4.60 (s, 1 H), 3.59 (m, 12 H), 2.92 (m, 1H), 2.44 (s, 3H), 2.01 (m, 4H), 1.79 (m, 1H); LCMS: purity: 99%; MS (m / e): 486 (MH⁺);

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) pyridin-3-yl) pyrimidin-2-amine, compound No. 58, LCMS: purity: 99%; MS (m / e): 459 (MH⁺);

4- (6- (dimethylamino) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridine -3-yl) pyrimidine-2-amine, compound No. 61, LCMS: purity: 99%; MS (m / e): 417 (MH⁺);

4- (4- (dimethylamino) phenyl) -N- (5-methyl-6 - ((1S, 4S) - (5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3- ylo) pyrimidine-2-amine, compound No. 62, LCMS: purity: 99%; MS (m / e): 416 (MH⁺);

4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2-yl) pyridin-3-yl) pyrimidine-2-amine, compound No. 63, LCMS: purity: 99%; MS (m / e): 500 (MH⁺);

4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) pyridin-3-yl) pyrimidin-2-amine, compound No. 64, LCMS: purity: 99%; MS (m / e): 473 (MH⁺);

-2004- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (5-methyl-6 ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine, compound No. 65, LCMS: purity: 99%; MS (m / e): 445 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) pyridin-3-yl) pyrimidine-2-amine, compound No. 66, LCMS: purity: 99%; MS (m / e): 459 (MH⁺);

4- (4- (t-butylcarbonylamino) phenyl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3 -yl) pyrimidine-2-amine, compound No. 131, ¹1 H NMR (CD 3 OD, 300 Μ): δ 9.26 (m, 1H), 8.64 (m, 1H), 8.41 (m, 1H), 8.11 (m, 2H), 7.90 (m, 1H), 7.74 (m, 2H), 7.37 (m, 1H), 4.29 (s, 1H), 4.40 (m, 2H), 3.99 (m, 2H), 3.36 (m, 1H), 3.24 (m, 1 H), 3.01 (s, 3H), 2.40 (m, 5H), 1.33 (s, 9H); MS (ES) 472.12 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (5-methyl-6 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine, compound No. 138, ¹1 H NMR (CD 3 OD, 300 ΜΙΙ / L: δ 8.69 (m, 1H), 8.56 (m, 1H), 8.45 (m, 1H), 8.00 (m, 2H), 7.90 (m, 1H), 7.31 (m, 1H), 4.78 (m, 1H), 4.38 (s, 1H), (m, 1H), 4.08 (m, 1H), 3.96 (m, 1H), 3.63 (m, 1H), 3.23 (m, 1H), 3.00 (s, 3H), 2.38 (m, 5H), 1.54 (s, 6H), MS (ES) 473.10 (M + H);

4- (4- (3-cyklopropyloureido) phenyl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3 -yl) pyrimidine-2-amine, compound No. 140, ¹1 H NMR (CD 3 OD, 300 ΜΙ Iz): δ 8.46 (m, 1H), 8.33 (m, 1H), 8.15 (m, 1H), 8.03 (m, 2H), 7.85 (m, 1H), 7.53 (m, 2H), 7.20 (m, 1H), 4.65 (s, 1H), 4.31 (s, 1H), 3.92 (m, 2H), 3.58 (m, 1H), 2.96 (s, 3H), 2.61 (m, 1H), 2.30 (m, 5H), 0.76 (m, 2H), 0.53 (m, 3H); MS (ES) 471.57 (M + H);

4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2. 1] heptan-2-yl) pyridin-3-yl) pyrimidin-2-amine, compound No. 144, ¹H NMR (CD3OD, 300 MHz): δ9.10 (m, 1H), 8.53 (m, 3H), 8.25 (m, 1H), 7.87 (m, 1H), 7.33 (m, 1H), 4.23 (m, 4 H), 3.98 (m, 4 H), 3.46 (m, 4 H), 3.34 (m, 1H), 3.23 (m, 1H), 2.99 (s, 3H), 2.35 (m, 6H); MS (ES) 516.07 (M + H);

4- (6-aminopyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3- ylo) pyrimidine-2-amine, compound No. 145, ¹H NMR (CD3OD, 300 ΜΙ Iz): δ 8.70 (m, 1H), 8.39 (m, 1H), 8.33 (m, 1H), 8.20 (m, 3H), 7.84 (m, 1H), 7.14 (m, 1H), 6.66 (m, 1H), 4.64 (s, 1H), 4.30 (s, 1H), 3.99 (m, 1H), 3.86 (m, 1H), 3.58 ( m, 1H), 2.96 (s, 3H), 2.65 (m, 1H), 2.30 (m, 5H); MS (ES) 389.01 (M + H);

4- (6- (acetamido) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridine -3-yl) pyrimidine-2-amine, compound No. 146, ¹H NMR (CD3OD, 300 ΜΙ Iz): δ 9.02 (m, 1H), 8.44 (m, 2H), 8.23 ​​(m, 2H), 7.83 (m, 1H), 7.25 (m, 1H), 4.65 (s, 1H), 4.30 (s, 1H), 4.00 (m, 1H), 3.85 (m, 1H), 3.59 (m, 2H), 2.96 (s, 3H), 2.65 (m, 1 H), 2.30 (s, 3H), 2.21 (m, 2H); MS (ES) 431.05 (M + H);

-2014- (6- (methylsulfonylamino) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine, compound No. 154, ¹H NMR (CD3OD, 300 MHz): δ 8.96 (m, 1H), 8.41 (m, 2H), 8.20 (m, 2H), 7.83 (m, 1H), 7.20 (m, 2H), 4.65 (s , 1H), 4.30 (s, 1H), 4.02-3.57 (m, 3H), 2.97 (s, 3H), 2.30 (m, 6H); MS (ES) 467.02 (M + H);

4- (2- (dimethylamino) thiazol-4-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl ) pyrimidine-2-amine, compound No. 177, ¹H NMR (DMSO-d6): δ 9.20 (s, 1H), 8.41 (d, 1H, J = 4.7Hz), 8.33 (s, 1H), 7.86 (d, 1H, J = 8.5Hz) 7.47 (s, 1H), 7.18 (d, 1H, J = 4.7 Hz), 6.47 (d, 1H, J = 9.1 Hz), 4.48 (s, 1H), 3.40-3.37 (m, 2H) , 3.23 (d, 1H, J = 9.7 Hz), 3.07 (s, 6H), 2.77 (d, 1H, J = 9.1 Hz), 2.42 (d, 1H, J = 9.7 Hz), 2.24 (s , 3H), 1.83 (d, 1H, J = 9.1 Hz), 1.70 (d, 1H, J = 9.1 Hz); LCMS: purity: 99%; MS (m / e): 409 (MH⁺);

4- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridine -3-yl) pyrimidine-2-amine, compound No. 180, ¹H NMR (DMSO-d6): δ 9.25 (s, 1H), 8.94 (s, 1H), 8.42-8.36 (m, 3H), 7.83 (dd, 1H, J = 2.0 and 9.1 Hz), 7.35 (d, 1H, J = 4.9 Hz), 6.51 (d, 1H, J = 9.1 Hz), 4.50 (s, 1H), 3.693.67 (m, 8H), 3.41-3.38 (m, 2H) , 3.23 (d, 1H, J = 9.4 Hz), 2.77 (d, 1H, J = 9.4 Hz), 2.43 (d, 1H, J = 9.4 Hz), 2.23 (s, 3H), 1.83 (d , 1H, J = 9.7 Hz), 1.71 (d, 1H, J = 9.7 Hz); LCMS: purity: 90%; MS (m / e): 446 (MH⁺);

4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) pyridin-3-yl) pyrimidine-2-amine, compound No. 236, ¹H NMR ((DMSO-d6, 300 MHz): δ 9.33 (s, 1 H), 8.72 (d, 2H, J = 6.3 Hz), 8.50 (s, 1H), 8.48 (s, 1H), 8.43 (d, 1H, J = 5.1 Hz), 8.32 (s, 1H), 8.07 (d, 1H, J = 9.0 Hz), 7.92 (m, 2H), 7.79 (s, 1H), 7.75 ( d, 2H, J = 6.3 Hz), 7.38 (d, 1H, J = 5.4 Hz), 6.91 (d, 1H, J =

3.6 Hz), 4.36 (s, 1H), 3.38 (m, 2H), 2.79 (m, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.77 (d, 1H, J = 8.7). Hz), 1.64 (d, 1H, J = 9.0 Hz); LCMS (m / z): 489 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 246, ¹H NMR (DMSO-d6, 300 MHz): δ 11.48 (b, 1H), 9.44 (d, J = 4.96 Hz, 1H), 8.73 (b, 1H), 8.46 (d, J = 4.95 Hz, 1H), 8.02 (b, 1H), 7.57 (tr, J = 19.53Hz, 2H), 7.37 (d, J = 4.40Hz, 1H), 6.94 (m, 1H), 2.25-2.08 (m , 8H), 1.47 (s, 6H), 1.36-1.23 (m, 9H); LCMS: purity; 95%; [M + H]⁺ = 500;

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 247, ¹H NMR (DMSO-d6, 300 MHz): δ

11.48 (b, 1H), 9.44 (d, J = 4.96 Hz, 1H), 8.73 (b, 1H), 8.46 (d, J = 4.95 Hz, 1H), 8.02 (b, 1H), 7.57 (tr, J = 19.53 Hz, 2H), 7.37 (d, J = 4.40 Hz 1H), 6.94 (m, 1H), 2.5 (b,

8H), 2.21 (b, 3H), 1.86 (b, 1H), 1.47 (s, 6H), 0.91-0.87 (b, 4H); LCMS: purity;

100% [M + H] ⁺= 498;

-2024- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-chloro-4- ( (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 248, ¹H NMR (CD3OD, 300MHz): δ 8.68 (s, 1H), 8.42 (m, 1H), 8.31 (s, 1H), 7.98 (m, 2H), 7.53 (m, 1H), 7.27 ( m, 1H), 7.08 (m, 1H), 4.40 (m, 2H), 3.81 (m, 2H), 3.61 (m, 1H), 2.97 (s, 3H), 2.66 (m, 4H), 2.29 (m, 2 H), 1.55 (s, 6H); LCMS (m / z): 492.09 (MH⁺);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-chloro-4 - (( 1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 249, LCMS (m / z): 556.00 (ELSD);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-cyclopentyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 250, ¹H NMR (CD3OD, 300 MHz): δ 8.44 (m, 2H), 8.09 (m, 1H), 8.00 (m, 1H), 7.77 (m, 1H), 7.27 (m, 1H), 6.95 (m, 1H), 4.78 (m, 1H), 4.50 (m, 1H), 4.05 (m, 1H), 3.71 (m, 3H), 3.51 (m, 1H), 2.31 (s, 3H), 2.27 (m, 4H), 1.74 (m, 4H), 1.54 (s, 6H) ppm; MS (ES) 526.2 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - (( 1S, 4S) -5-acetyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 251, ¹1 H NMR (CD 3 OD, 300 Μ): δ 8.67 (m, 1 H), 8.42 (m, 1 H), 8.00 (m, 2 H), 7.71 (m, 1 H), 7.24 (m, 1 H), 6.88 ( m, 1H), 3.63 (m, 3H), 3.38 (m, 3H), 2.15 (s, 3H), 2.01 (m, 2H), 1.54 (s, 6H) ppm; MS (ES) 500.2 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1 , 4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidine-2-amine, compound No. 252, ¹1 H NMR (CD 3 OD, 300 μl): δ 8.71 (m, 1H), 8.41 (m, 1H), 7.59 (m, 2H), 7.25 (m, 2H), 7.12 (m, 1H), 3.91 (m, 1H), 3.57 (m, 5H), 3.27 (m, 2H), 3.07 (m, 1H), 2.36 (s, 3H), 2.13 (m, 2H), 1.54 (s, 6H) ppm ; MS (ES) 472.1 (M + H);

4- (5- (1-methylethoxy) karbonylopropylo-6-amino-pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane-2-yl) phenyl) pyrimidine-2-amine, compound No. 253, ¹1 H NMR (DMSO-6,600): δ9.16 (s, 1H), 8.62 (b, 1H), 8.30 (d, J = 5.23Hz, 1H), 7.94 (b, 1H), 7.53 (b, 1H), 7.43 (d, J = 8.53Hz, 1H), 7.16 (d, J = 5.22Hz, 1H), 6.78 (d, J = 8.52Hz, 1H), 6.37 (b , 2H), 4.88-4.84 (m, 1H), 2.82 (b, 1H), 2.49-2.48 (m, 5H), 2.39-2.30 (m, 3H), 2.20 (s, 3H), 1.85-1.76 (m, 5H), 1.16 (d, J = 6.5 Hz, 9H); LCMS: purity; 96.5%; [M + H]⁺ = 516;

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) phenyl) pyrimidin-2-amine; compound 254,¹1 H NMR (DMSO-d6, 300 Iz): δ 9.18 (s, 1H), 8.90 (b, 1H), 8.35 (d, J = 5.22 Hz, 1H), 8.26 (d, J = 9.08 Hz, 1H), 7.48 (b, 2H), 7.21 (d, J = 5.23Hz, 1H), 6.96 (d, J = 9.36Hz, 1H),

6.76 (d, J = 8.80 Hz, 1H), 3.93 (b, 1H), 3.70 (d, J = 4.4Hz, 4H), 3.59 (d, J = 4.67Hz, 4H) 2.87 (b, 2H) 2.49 (b, 3H), 2.20 (s, 3H), 1.95 (b, 1H), 1.74 (d, J = 4.68 Hz, 2H), 0.37 (d, J = 23.39 Hz, 4H); LCMS: purity; 97%; [M + H]⁺ = 484;

-2034- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine, compound No. 255, ¹H NMR (CD3OD, 300MHz): δ 8.94 (s, 1H), 8.34 (m, 1H), 8.32 (s, 1H), 8.22 (m, 1H), 7.82 (m, 1H), 7.53 (M, 1H), 7.19 (m, 1H), 7.08 (m, 1H), 6.82 (m, 1H), 4.36 (m, 2H), 3.79 (m, 6H), 3.61 (m, 6H); ), 2.97 (s, 3H), 2.29 (m, 2H); LCMS (m / z): 478.05 (MH⁺);

4- (2- (trifluoromethyl) pyridin-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidine-2-amine, compound No. 256, LCMS (m / z): 441.05 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptane -2-yl) phenyl) pyrimidine-2-amine, compound No. 257, LCMS (m / z): 541.00 (ELSD);

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptane-2-yl) phenyl) pyrimidine-2-amine, compound No. 258, LCMS (m / z): 557.02 (MH⁺);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5-Acetyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 259, LCMS (m / z): 506.01 (MH⁺);

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5-Acetyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 260, LCMS (m / z): 521.08 (MH⁺);

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 261, ¹H NMR (CD3OD, 300 MHz): δ 8.89 (m, 1H), 8.36 (m, 2H), 7.55 (m, 1H), 7.45 (m, 1H), 7.18 (m, 1H), 6.99 (m , 1H), 6.88 (m, 1H), 5.28 (m, 1H), 4.25 (m, 2H), 3.94 (m, 2H), 3.76 (m, 1H), 3.55 (m, 5H), 2.97 (s , 3H), 2.30 (s, 3H), 2.06 (m, 3H), 1.76 (m, 3H) ppm; MS (ES) 473.2 (M + H);

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5cyklopentylo-2,5-diazabicyclo [2.2.1] heptan-2 -yl) phenyl) pyrimidine-2-amine, compound No. 262, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.88 (m, 1H), 8.42 (m, 1H), 8.34 (m, 1H), 8.05 (m, 1H), 7.79 (m, 1H), 7.23 (m, 1H), 6.94 (m, 1H), 6.86 (m, 1H), 5.29 (m, 1H), 4.00 (m, 4H), 3.62 (m, 7H), 2.32 (m, 7H), 1.75 (m, 10H) ppm; MS (ES) 527.2 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5- (1-methylethyl) -2,5 di azabicyclo [2.2. 1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 263,¹H NMR (DMSO-d6, 300 MHz): δ 9.18 (s, 1H), 8.90 (b, 1H), 8.35 (d, J = 5.22Hz, 1H), 8.26 (d, J = 9.08Hz, 1H), 7.48 (b, 2H), 7.21 (d, J = 5.23 Hz, 1H), 6.96 (d, J = 9.36 Hz, 1H), 6.76 (d, J = 8.80 Hz, 1H), 3.93 (b, 1H), 3.70 (d, J = 4.4 Hz, 4H), 3.59 (d, J = 4.67 Hz, 4H), 3.23-2.96 (m, 3 H), 2.49 (b, 3 H), 2.20 ( s, 3H), 1.72 (b, 2H), 0.97 (d, J = 4.13 Hz, 6H); LCMS: purity; 99.7%; [M + H]⁺ = 486;

-2044- (6 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4- ((1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 264, ¹H NMR (DMSO-d6): δ 9.30 (s, 1H), 8.84 (s, 1H), 8.35 (d, 1H, J = 5.0 Hz), 8.25 (d, 1H, J = 7.3 Hz) 7.53 (d, 1H, J = 8.8 Hz), 7.47 (s, 1H), 7.22 (d, 1H, J = 5.0 Hz), 6.88 (d, 1H, J = 8.5 Hz), 6.72 ( d, 1H, J = 7.3Hz), 4.98 (s, 1H), 4.69 (s, 1H), 4.33 (s, 1H), 4.15 (s, 1H), 3.79 (d, 1H, J = 6.7 Hz), 3.66 (d, 1H, J = 6.7Hz), 3.53-3.39 (m, 6H), 2.95 (s, 3H), 2.20 (s, 3H), 1.95-1.80 (m, 4H). LCMS: Purity: 99%; MS (m / e): 534 (MH &lt;+&gt;);

4- (6 - ((1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4- ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 265, ¹H NMR (DMSO-d6): δ 9.27 (s, 1H), 8.87 (d, 1H, J = 2.3Hz), 8.33 (d, 1H, J = 5.3Hz), 8.21 (dd, 1H, J = 2.0 and 8.8 Hz), 7.56 (d, 1H, 9.1 Hz), 7.48 (d, 1H, J = 5.3 Hz), 7.20 (d, 1H, J = 5.3 Hz), 6.86 (d, 1 H, J = 8.8 Hz), 6.64 (d, 1H, J = 8.8 Hz), 4.96 (s, 1H), 4.68 (s, 1H), 3.79 (d, 1H, J = 6.7 Hz), 3.65 (d, 1H, J = 7.6 Hz), 3.5 (d, 1H, J = 10.2 Hz), 3.16 (m, 2H), 2.75 (d, 1H, J = 9.3Hz), 2.67 (d, 1 H, J = 9.3 Hz), 2.29 (s, 3H), 2.20 (s, 3H), 1.90 (m, 4H); LCMS: purity: 99%; MS (m / e): 470 (MH⁺);

4- (6 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (5-methyl-6 ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine, compound No. 266, ¹H NMR (DMSO-d6): δ 9.22 (s, 1H), 8.85 (s, 1H), 8.34-8.33 (m, 2H), 8.18 (d, 1H, J = 6.7 Hz), 7.70 (s, 1 H) ), 7.20 (d, 1H, J = 5.3 Hz), 6.65 (d, 1H, J = 8.8 Hz), 4.96 (s, 1H), 4.67 (s, 1H), 4.34 (s, 1H); ), 3.78 (d, 1H, J = 7.0 Hz), 3.64 (d, 1H, J = 7.0 Hz), 3.49 (d, 1H, J = 9.5 Hz), 3.42-3.36 (m, 4H), 2.74 (s, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.92 (d, 1H, J = 9.1 Hz), 1.85 (d, 1H, J = 9.1 Hz), 1.74 (d , 1H, J = 9.1 Hz), 1.62 (d, 1H, J = 9.1 Hz). LCMS: Purity: 99%; MS (m / e): 471 (MH &lt;+&gt;);

4- (6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 267, ¹H NMR (DMSO-d6, 300 MHz): δ 9.24 (b, 1H), 8.47 (d, J = 5.50 Hz, 1H), 8.20 (b, 1H), 7.88 (d, J = 7.1 6Hz, 1H), 7.55 (d, J = 5.50 Hz, 1H), 7.38 (b, 1H), 7.24-7.17 (m, 2H), 6.74 (d, J = 8.52 Hz, 1H), 3.91 (b, 1H), 3.20 (b, 4H), 3.05 (b, 3H), 8.30 (m, 3H), 2.32 (s, 3H), 2.18 (s, 3H), 1.81-1.71 (m, 5H); LCMS: purity; 98.1% [M + H]⁺ = 466;

4- (6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 268, ¹H NMR (DMSO-d6, 300 MHz): δ 9.24 (b, 1H), 8.47 (d, J = 5.50 Hz, 1H), 8.20 (b, 1H), 7.88 (d, J = 7.16 Hz, 1H), 7.55 (d, J = 5.50 Hz, 1H), 7.38 (b, 1H), 7.29-7.17 (m, 2H), 6.86 (b, 1H), 4.34 (b, 1H), 4.17 (b, 2H), 3.37 -3.25 (m, 5H), 3.04 (b, 1H), 2.96 (s, 3H), 2.67 (b, 2H), 2.20 (b, 3H), 1.89-1.81 (m, 5H); LCMS: purity; 98.7%; [M + H]⁺ = 530;

4- (4- (trifluoromethyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine, compound 269, LCMS (m / z): 440.09 (MH⁺);

-2054- (7,8,9,9a-tetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepin-10 (11H) -one-3-yl) N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 270, ¹1 H NMR (CD 3 OD, 300 MHz): δ 9.28 (m, 1 H), 8.63 (m, 1 H), 8.43 (m, 1 H), 7.42 (m, 3 H), 7.01 (m, 1 H), 4.78 (m, 2 H). ), 4.55 (m, 1H), 4.41 (m, 2H), 4.30 (s, 1H), 3.99 (m, 3H), 3.50-3.36 (m, 3H), 3.16 (m, 1H), 2.99 ( s, 3 H), 2.82 (m, 1H), 2.32 (m, 5H), 2.10 (m, 3H); MS (ES) 497.10 (M + H);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-cyano-4 ((1 S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 271, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.39 (m, 2 H), 8.16 (m, 1 H), 7.72 (m, 3 H), 7.20 (m, 1 H), 6.94 (m, 2 H), 4.76 (s, 1H), 4.32 (s, 1H), 4.04 (m, 1H), 3.69 (m, 2H), 3.31 (m, 2H), 2.93 (s, 3H), 2.35 (m, 2H), 1.51 ( s, 6H); MS (ES) 482.08 (M + H);

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-cyano-4 - ((1S, 4S) -5-methyl-2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 272, ¹H NMR (CD3OD, 300 MHz): δ 8.41 (m, 3H), 8.08 (s, 1H), 7.99 (m, 1H), 7.66 (m, 1H), 7.28 (m, 1H), 7.11 (m, 1H), 6.93 (m, 1H), 4.77 (s, 1H), 4.34 (s, 1H), 4.07 (m, 1H), 3.69 (m, 2H), 3.35 (m, 2H), 2.95 (s, 3H), 2.89 (m, 2H), 2.32 (m, 6H); MS (ES) 466.08 (M + H);

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-cyano-4 - ((1S, 4S) -5-methyl-2 , 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 273, ¹H NMR (CD3OD, 300 MHz): δ 8.39 (m, 2H), 8.12 (s, 1H), 7.93 (m, 1H), 7.71 (m, 1H), 7.23 (m, 1H), 7.05 (m , 1H), 6.92 (m, 1H), 4.77 (s, 1H), 4.30 (s, 1H), 4.07 (m, 1H), 3.69 (m, 2H), 3.48 (s, 2H) 3.30 (m, 3H), 2.93 (s, 3H), 2.33 (m, 2H); MS (ES) 470.06 (M + H);

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2 , 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine, compound No. 274, ¹H NMR (CD3OD, 300 MHz): δ 8.36 (m, 2H), 8.17 (s, 1H), 7.91 (m, 1H), 7.48 (m, 2H), 7.19 (m, 1H), 7.04 (m , 1 H), 6.96 (m, 1 H), 4.29 (s, 1H), 4.24 (s, 1H), 3.81 (m, 1H), 3.52 (m, 4H), 2.97 (s, 3H), 2.33 (s , 3H), 2.31 (s, 2H); MS (ES) 459.07 (M + H);

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine compound 275, ¹H NMR (CD3OD, 300 MHz): δ 8.92 (m, 1H), 8.38 (m, 2H), 7.62 (m, 1H), 7.53 (m, 1H), 7.21 (m, 1H), 7.11 (m, 1H), 6.88 (m, 1H), 5.30 (m, 1H), 3.95 (m, 4H), 3.58 (m, 8H), 3.11 (m, 1H), 2.35 (s, 3H); ), 2.12 (m, 4H), 1.78 (m, 3H) ppm; MS (ES) 473.2 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((R) -1,4diazabicyklo [3.2.1] octan-4-yl) phenyl) pyrimidine -2-amine, compound 276, ¹H NMR (CD3OD, 300 MHz): δ 8.92 (m, 1H), 8.32 (m, 1H), 8.24 (m, 1H), 7.59 (m, 1H), 7.55 (m, 1H), 7.13 (m, 2H), 6.86 (m, 1H), 3.92 (m, 1H), 3.79 (m, 4H), 3.61 (m, 9H), 3.31 (m, 1H), 3.10 (m, 2H). ), 2.35 (s, 3H), 2.13 (m, 2H) ppm; MS (ES) 458.1 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((S) -1,4-diazabicyclo [3.2.1] oktan4-yl) phenyl) pyrimidine -2-amine, compound 277, ¹H NMR (CD3OD, 300 MHz): δ

-2068.92 (m, 1H), 8.31 (m, 1H), 8.25 (m, 1H), 7.58 (m, 2H), 7.14 (m, 2H), 6.88 (m, 1H),

3.93 (m, 1H), 3.77 (m, 4H), 3.59 (m, 9H), 3.32 (m, 1H), 3.11 (m, 2H), 2.36 (s, 3H),

2.14 (m, 2H) ppm; MS (ES) 458.1 (M + H);

4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-methyl-4 - ((6R, 9S) -6,9metanooktahydro- 1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidine-2-amine, compound No. 278, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.37 (m, 2 H), 8.05 (m, 2 H), 7.58 (m, 1 H), 7.25 (m, 1 H), 7.10 (m, 2 H), 4.01 (m, 3 H) ), 3.55 (m, 5H), 3.14 (m, 2H), 2.88 (m, 2H), 2.57 (m, 1H), 2.34 (m, 7H), 1.80 (m, 6H); MS (ES) 495.14 (M + H);

4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-methyl-4 - ((6R, 9S) -6,9metanooktahydro -1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidine-2-amine, compound No. 279, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.34 (m, 1H), 8.21 (s, 1H), 7.98 (m, 1H), 7.53 (m, 2H), 7.32 (m, 1H), 7.08 (m , 2H), 4.03 (s, 1H), 3.96 (m, 2H), 3.63 (m, 5H), 3.12 (m, 3H), 2.59 (s, 2H), 2.37 (s, 3H), 1.92-1.63 (m, 6H); MS (ES) 499.04 (M + H);

4- (6 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4 (1,4- diazabicyclo [3.2.2] nonan-4-yl) phenyl) pyrimidine-2-amine, compound No. 280, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.88 (m, 1 H), 8.32 (m, 3 H), 7.52 (m, 2 H), 7.22 (m, 2 H), 6.63 (m, 1 H), 4.74 (s , 1H), 3.92-3.81 (m, 2H), 3.58 (m, 4H), 3.43 (m, 4H), 2.65 (m, 2H), 2.43 (m, 2H), 2.36 (s, 3H), 2.13 -2.03 (m, 4H); MS (ES) 484.16 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4- (3,9-diazabicyclo [3.3.2] decan-10on-3-yl) phenyl) pyrimidine -2-amine, compound 281, ¹1 H NMR (CD 3 OD, 300 MHz): δ 8.88 (s, 1H), 8.37 (d, 1H), 8.25 (m, 1H), 8.17 (d, 1H), 7.82 (m, 1H), 7.24 (m, 2H) , 6.87 (d, 1H), 3.80 (m, 4 H), 3.62 (m, 4 H), 3.41 (m, 2 H), 3.14 (m, 2 H), 2.85 (m, 1H), 2.25 (m, 4 H); ), 2.01 (m, 2H), 1.55 (m, 1H); LCMS (m / z): 510.00 (ELSD);

4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-cyano-4- (3 , 9-diazabicyclo [3.3.2] decan-10-on-3-yl) phenyl) pyrimidine-2-amine, compound No. 282, ¹H NMR (DMSO, 300MHz): δ11.5 (s, 1H), 9.87 (s, 1H), 8.73 (s, 1H), 8.54 (d, 1H), 8.24 (s, 1H), 8.03 ( d, 1H), 7.84 (m, 2H), 7.46 (d, 1H), 7.31 (d, 1H), 3.41 (m, 1H), 3.11 (m, 1H), 3.02 (m, 2H), 2.68 (m , 1 H), 2.11 (m, 4 H), 1.83 (m, 1H), 1.46 (s, 6H); LCMS (m / z): 525.01 (MH⁺);

4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (3- (dimethylamino) -8- azabicyclo [3.2.1] octan-8-yl) phenyl) pyrimidine -2-amine, compound 283, ¹H NMR (CD3OD, 300 MHz): δ 8.90 (m, 1H), 8.36 (m, 2H), 7.46 (m, 2H), 7.17 (m, 1H), 6.86 (m, 2H), 5.28 (m , 1H), 3.94 (m, 4H), 3.60 (m, 3H), 2.86 (s, 6H), 2.37 (s, 3H), 2.02 (m, 9H), 1.79 (m, 3H) ppm; MS (ES) 515.2 (M + H);

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (3- (morpholin-4-yl) -8-azabicyclo [3.2.1] octan-8-yl ) phenyl) pyrimidine-2-amine, compound No. 284, ¹H NMR (CD3OD, 300 MHz): δ 8.92 (m, 1H), 8.26 (m, 2H), 7.46 (m, 2H), 7.12 (m, 1H), 6.87 (m, 2H), 3.82 (m 11 H), 3.55 (m, 6 H), 2.37 (s, 3 H), 2.06 (m, 8 H), 1.78 (m, 2 H) ppm;

MS (ES) 542.3 (M + H);

-2074- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (3- (morpholin-4-yl) -8-azabicyclo [3.2.1] octan-8- ylo) phenyl) pyrimidine-2-amine, compound No. 285, ¹H NMR (CD3OD, 300 Μ!): Δ 8.93 (m, 1H), 8.25 (m, 2H), 7.47 (m, 2H), 7.13 (m, 1H), 6.88 (m, 2H), 5.28 ( m, 1H), 3.84 (m, 11H), 3.54 (m, 6H), 2.37 (s, 3H), 2.08 (m, 8H), 1.79 (m, 2H) ppm; MS (ES) 557.3 (M + H); and

4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (3- (dimethylamino) -8- azabicyclo [3.2.1] octan-8-yl) phenyl) pyrimidine -2-amine, compound 286, ¹1 H NMR (CD 3 OD, 300 Μ): δ 8.89 (m, 1H), 8.27 (m, 1H), 8.21 (m, 1H), 7.45 (m, 2H), 7.08 (m, 1H), 6.84 (m, 2 H), 3.87 (m, 2 H), 3.77 (m, 2 H), 3.54 (m, 3 H), 2.84 (s, 6 H), 2.37 (s, 3 H), 2.02 (m, 9 H), 1.77 (m, 3H) ppm; MS (ES) 500.3 (M + H).

TESTING OF COMPOUNDS OF THE INVENTION [0351] Exemplary compounds of the invention were tested in the following bioassays for their ability to inhibit JAK activity.

BIOLOGICAL EXAMPLE 1

Test for the B Cell Line of Ramos of Stimulated IL-4 [0352] Interleukin-4 (IL-4) stimulated cytokine B cells activate the JAK / Stat pathway by phosphorylating the kinases of the JAK family, JAK-1 and JAK-3, which in turn phosphorylate and activate Stat-6 transcription factor. One of the up-regulated genes using activated Stat6 is the low affinity IgE receptor, CD23. To study the effect of inhibitors on JAK family kinases, human Ramos B cells are stimulated by human IL-4.

[0353] The Ramos B cell line was obtained from ATCC (Catalog No. ATCC CRL-1596). Cells were grown in RPMI 1640 (Cellgro, MediaTech, Inc., Herndon, VA, Cat. No. 10-040CM) with 10% fetal bovine serum (FBS), heat-inactivated (JRH Biosciences, Inc, Lenexa, Kansas, Cat. No. 12106 -500M) according to the ATCC propagation protocol. The cells were maintained at a density of 3.5 x 10⁵. On the day before the experiment, Ramos B cells were diluted to 3.5 x 10⁵ cells / mL to ensure that they were in the logarithmic growth phase.

[0354] Cells were centrifuged and resuspended in RPMI with 5% serum. 5 x 10⁴ cells were used per point in a 96-well tissue culture plate. The cells were pre-incubated with compound or control with DMSO (Sigma-Aldrich, St. Louis, MO, Cat. No. D2650) for 1 hour at 37 ° C incubator.

[0355] The cells were then stimulated with IL-4 (Peprotech Inc., Rocky Hill, NJ, Cat. No. 200-04) for a final concentration of 50 units / mL for 20-24 hours. The cells were then centrifuged and stained with anti-CD23-PE (BD Pharmingen, San Diego, CA, Cat. No. 555711) and analyzed by FACS (Fluoroescence Activated Cell Sorting). Detection was performed using a BD LSR I System Flow Cytometer, purchased from Becton Dickinson Biosciences of San Jose, California.

BIOLOGICAL EXAMPLE 2

Assay for Proliferation of Primary Human T-Cells Stimulated IL-2 [0356] Primary human T-cells derived from peripheral blood and pre-activated by stimulation of the T-cell receptor and CD28, are proliferated in vitro in response to the Interleukin-2 (IL-2) cytokine. This proliferative response is dependent on the activation of JAK-1 and JAK-3 tyrosine kinases, which phosphorylate and activate the Stat-5 transcription factor.

[0357] Human primary T cells were prepared as follows. Whole blood was obtained from a healthy volunteer, mixed 1: 1 with PBS, applied to Ficoll Hypaque (Amersham Pharmacia Biotech, Piscataway, NJ, Catalog No. 17-1440-03) at a 2: 1 ratio of blood / PBS: ficoll and centrifuged for 30 minutes. min at 4 ° C at 1750 rpm. Serum lymphocytes: Ficoll was recovered and washed twice with 5 volumes of PBS. Cells were resuspended in media in Yssel (Gemini Bio-products, Woodland, CA, Catalog No. 400103) containing 40 U / mL of recombinant IL2 (R and D Systems, Minneapolis, MN, Catalog No. 202-IL (20 μg)) and seeded in flask pre-coated with 1 μg / mL anti-CD3 (BD ​​Pharmingen, San Diego, CA, Catalog No. 555336) and 5 μg / mL anti-CD28 (Immunotech, Beckman Coulter of Brea California, Catalog No. IM1376). Primary T cells were stimulated for 3-4 days,

[0358] Primary T cells were washed twice with PBS to remove IL-2 and resuspended in Yssel medium at 2 x 10⁶ cells / mL. A cell suspension, 50 μL, containing 80 U / mL IL-2 was added to each well of a flat bottom 96-well black plate. For unstimulated controls, IL-2 was omitted from the last column on the plate. The compounds were serially diluted in dimethyl sulfoxide (DMSO, 99.7% purity, tested in cell culture, Sigma-Aldrich, St. Louis, MO, Catalog No. D2650) from 5 mM in 3-fold dilutions and then diluted 1: 250 in Yssel's medium. The compound was added, 50 μL per well, (prepared in duplicate, two rows for the dilution factor) and the cells were allowed to proliferate for 72 hours at 37 ° C.

[0359] Proliferation was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega), which determines the number of viable cells in the culture, based on the quantification of ATP present, as an indicator of metabolically active cells. The substrate was thawed and allowed to reach ambient temperature. After mixing the Cell Titer-Glo reagent and diluent together, 100 μL was added to each well. The plates were mixed on an orbital shaker for two minutes to induce lysis and incubated at ambient temperature for a further ten minutes to reach equilibrium. Detection was carried out using a Wallac Victor2 1420 counter multilabel counter purchased from Perkin Elmer, Shelton, CT.

BIOLOGICAL EXAMPLE 3

Stat5 assay using Primary Human T Cells or CTLL-2 Murine Leukemia Cells from IL-2 Stimulated T Cells [0360] Stimulation of pre-activated primary human T cells or mouse CTLL-2 cells with Interleukin-2 (IL-2) gives signal tyrosine kinases JAK-1 and JAK-3 to

To phosphorylate their immediate downstream target, Stat5 transcription factor. The effects can be quantified using FACS.

[0361] Pre-activated human primary T cells are prepared as described in Biological Example 2. CTLL-2 cells are grown in RPMI containing 10% FBS and 10% T-STIM with Con A (Becton Dickinson).

[0362] CTLL-2 cells or human primary T cells that were washed twice with PBS to remove IL-2 residues were resuspended in RPMI medium with 10% FBS at 2 x 10⁶ cells / mL of 40 μL T cells and 50 μL 2X test compound are added to each well of a 96-well round bottom plate and mixed. After 1 hour of incubation with the test compound at 37 ° C, the cells are stimulated by adding 10 μL per well 10x IL-2 (400 U / mL) so that the final concentration is 40 U / mL. The cells are then incubated at 37 ° C for 15 min. Stimulation is stopped and the cells are fixed by the addition of 100 μL per well of 3.2% para-formaldehyde and incubated for 10 min at ambient temperature. After washing, the cells are permeabilized by adding 150 μL per well of ice cold methanol and incubating at 4 ° C for 30 min. Pelleted cells are washed once with 150 μL per well of FACS buffer (PBS + 2% FCS) and stained with 50 μL per anti-phospho-Stat5 AlexaFluor488 1: 100 well in FACS buffer. After overnight incubation at ambient temperature,

BIOLOGICAL EXAMPLE 4

Stat5 Test of Unstimulated SET2 Cells of Human Erythroleukemia and Mouse Pre-B Ba / F3 Cells with the Expression of Human JAK2 V617F Kinase [0363] Both SET2 human erythroleukemic cells and murine pre-B Ba / F3 cells express constitutively active form of JAK2 containing the V617F mutation in the pseudokinase domain enzyme, leading to constitutive phosphorylation of Stat5 transcription factor in the absence of stimulation.

[0364] 40 μL of appropriate cell suspension and 50 μL of 2X test compound are mixed together in each well of a 96-well round bottom plate and incubated for 1 hour at 37 ° C. The reaction is stopped by adding 100 μL per well of 3.2% para-formaldehyde for 10 min, followed by a permeabilization step of 150 mL of ice cold methanol at 4 ° C for 30 min. After washing, the cells are stained with 50 μL per anti-phospho-Stat5 AlexaFluor488 1: 100 in FACS buffer. After overnight incubation at ambient temperature, the samples are analyzed by FACS.

BIOLOGICAL EXAMPLE 5

A549 Epithelial Lineage Stimulated IFNγ [0365] A549 lung epithelial cells up-regulate surface expression of ICAM-1 (CD54) in response to a variety of different stimuli. Therefore, using expression

ICAM-1, as read, the effects of compounds on different signaling pathways can be assessed in the same cell type. IFNγ regulates upward ICAM-1 by activating the JAK / Stat pathway.

In this example, up-regulation of ICAM-1 by IFNγ was assessed.

[0366] The A549 epithelial lung carcinoma cell line was from the American Type Culture Collection. The routine culture was with F12K media (Mediatech Inc., Lenexa, KS, Cat. No. 10-025-CV) with 10% fetal bovine serum, 100 IU penicillin and 100 ng / mL streptomycin (complete F12k medium). The cells were incubated in a humidified 5% CO2 atmosphere at 37 ° C. Before use in the assay, A549 cells were washed with PBS and trypsinized (Mediatech Inc., Cat. No. 25-052-Cl) to raise cells. The trypsinized cell suspension was neutralized with complete F12k media and centrifuged to pelletize the cells. The cell plates were resuspended in complete F12k media at a concentration of 2.0x10⁵/ ML. Cells were plated at 20,000 per well, 100 μL total volume, in a flat bottom tissue culture plate, and allowed to adhere overnight.

[0367] On the other day, A549 cells were pre-incubated with the test compound or DMSO (control) (Sigma-Aldrich, St. Louis, MO, Catalog No. D2650) for 1 hour. The cells were then stimulated with IFNγ (75 ng / mL) (Peprotech Inc., Rocky Hill, NJ, Cat. No. 300-02) and allowed to incubate for 24 hours. The final dose range of the test compound was 30 μΜ to 14 nM in 200 μL F12K media containing 5% FBS, 0.3% DMSO.

[0368] On the third day, the cell medium was removed and the cells were washed with 200 PL of PBS (phosphate buffered saline). Each well was trypsinized to dissociate the cells and then neutralized by the addition of 200 μL of complete F12k medium. Cells were pelleted and stained with APC-conjugated mouse anti-human ICAM-1 antibody (CD54) (BD Pharmingen, San Diego, CA, Catalog No. 559771) for 20 minutes at 4 ° C. The cells were washed with ice-cold FACS buffer (PBS + 2% FBS) and the surface expression of ICAM-1 was analyzed by flow cytometry. Detection was performed using a BD LSR I cytometer System Flow Cytometer, purchased from BD Biosciences of San Jose, California. Events were gated for real time scattering and the geometric mean was calculated (Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, NJ).

BIOLOGICAL EXAMPLE 6

FACS ICAM1 IFNγ U937 Test [0369] The U937 human monocyte cell line regulates upward surface expression of ICAM-1 (CD54) in response to a variety of different stimuli. Accordingly, by using ICAM-1 expression as a reading, one can evaluate the effects of compounds on different signaling pathways in the same cell type. IFNγ regulates upward ICAM-1 by activating the JAK / Stat pathway. In this example, the up-regulation of ICAM-1 by IFNγ was evaluated.

[0370] The U937 human monocyte cell line was obtained from the ATCC of Rockville

Maryland, catalog number CRL-1593.2, and grown in medium RPM1-1640 containing

10% (v / v) FCS. U937 cells were grown in 10% RPMI. The cells were then plated at a concentration of 100,000 cells per 160 μL in 96 well flat bottom plates. Test compounds

These were diluted as follows: 10 mM of test compound was diluted 1: 5 in DMSO (3 μL of 10 mM test compound in 12 μL DMSO), followed by serial dilutions of 1: 3 test compound in DMSO (6 μL test compound serially diluted in 12 μL DMSO to obtain 3-fold dilutions). Then 4 μL of the test compound was transferred to 76 μL of 10% RPMI to give a 10X solution (100 μΜ of the test compound, 5% DMSO). For control wells, 4 μL DMSO was diluted in 76 μL 10% ΚΡΜΙ.

The test was performed in duplicate with 8 points (8 3-fold dilutions from 10 μΐ.) And with 4 wells only DMSO (control wells) under stimulated conditions and 4 wells DMSO only under unstimulated conditions.

[0372] The dilute compound plate was mixed with 2X using a multimeter (Beckman Coulter of Brea, Calif.) And then 20Pl of diluted compounds were transferred to a 96 well plate containing 160 μΐ cells, which were then mixed two more times at low speeds. Cells and compounds were then incubated for 30 minutes at 37 ° C with 5% CO 2.

[0373] The 10X stimulation mix was made by preparing 100 ng / mL of human IFNγ solution in 10% RPMI. Cells and compound were then stimulated with 20 μΐ. IFN? stimulation mix to give a final concentration of 10 ng / mL IFN ?, 10 μΜ of the test compound, and 0.5% DMSO. Cells were maintained under conditions suitable for stimulation for 18-24 hours at 37 ° C with 5% CO 2.

[0374] Cells were transferred to a 96-well round-bottom plate for staining and then kept on ice for the duration of the staining procedure. The cells were centrifuged at 1000 rpm for 5 minutes at 4 ° C, after which the supernatant was removed. After removal of the supernatant, 1 μΐ of APC conjugated mouse anti-human ICAM-1 antibody was added per 100 μΐ of FACS buffer. The cells were then incubated on ice in the dark for 30 minutes. After incubation, 150 μΐ of FACS buffer was added and the cells were centrifuged at 1000 rpm for 5 minutes at 4 ° C, after which the supernatant was removed. After removing the supernatant, 200 μΐ of FACS buffer was added and the cells resuspended. After suspension, the cells were centrifuged at 1000 rpm for 5 min at 4 ° C. The supernatant was then removed before resuspending the cells in 150 μΐ of FACS buffer.

[0375] Detection was performed using a BD LSR I System Flow Cytometer purchased from BD Biosciences of San Jose, California. Viable cells were gated for real time scattering and the ICAM-APC geometric mean was calculated (BectonDickinson CellQuest software version 3.3, Franklin Lakes, NJ). Both% of live cells and ICAM-1 expression were analyzed. Tests for test compounds were carried out in parallel with the control compound of known activity. The EC50 for the control compound is usually 40-100 nM.

BIOLOGICAL EXAMPLE 7

Kinase Test Using Fluorescence Polarization

-212 [0376] This assay can be used to determine the potency of a compound of the invention against certain JAK kinases and the selectivity of a compound of the invention in inhibiting certain JAK kinase activities in vitro.

Reagents and buffers [0377]

Tyrosine Kinase Kit Green (Invitrogen, Cat. No. P2837)

Acetylated Bovine Gamma Globulina (BGG) (Invitrogen, Cat. No. P2255)

Active JAK1 (Carna Biosciences)

Active JAK2 (Carna Biosciences)

Active JAK3 (Carna Biosciences)

TK2 peptide (Biotin-EGPWLEEEEEAYGWMDF-CONH2) (SynPep Custom Synthesis)

Methods [0378] Test compounds were serially diluted in DMSO starting from 500x the desired final concentration, then diluted to 1% DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.1 mg / mL acetylated BGG). The test compound in 1% DMSO (0.2% final DMSO) was mixed with ATP and substrate in kinase buffer at ambient temperature.

[0379] Kinase reactions were performed in a final volume of 20 μL containing the peptide substrate and ATP and initiated by adding kinase in the kinase buffer. The reactions were allowed to proceed at ambient temperature. The final concentrations of substrate, ATP and enzyme and reaction times in various kinase assays are listed in Table 1.

TABLE 1: FINAL CONCENTRATION OF SUBSTRATE, ATP, ENZYMIUM AND REACTION TIME

<td>Enzyme</td><td>The amount of Enzyme per Reaction</td><td>substratum</td><td>Concentration substrate</td><td>Concentration ATP</td><td>Time test</td>

<td>JAK1</td><td>20 ng</td><td>TK2</td><td>10 μΜ</td><td>5 μΜ</td><td>20 min</td>

<td>JAK2</td><td>0.3 ng</td><td>TK2</td><td>10 μΜ</td><td>5 μΜ</td><td>20 min</td>

<td>JAK3</td><td>2 ng</td><td>TK2</td><td>10 μΜ</td><td>5 μΜ</td><td>20 min</td>

[0380] Reactions were stopped by the addition of 20 μL stopper PTK containing EDTA / anti-phosphotyrosine antibody (1X final) / phosphopeptide fluorescent label (0.5X final) diluted in the Thinning Buffer FP according to the manufacturer's instructions (Invitrogen). The plates were incubated for 30 minutes in the dark at ambient temperature and then read on a Polarion plate reader for fluorescence polarization (Tecan).

[0381] The data was converted to the present amount of phosphopeptide using a calibration curve generated by competition with the phosphopeptide competitor provided in the Tyrosine Kinase Assay Kit, Green (Invitrogen). To determine the IC 50, the compounds were tested at eleven concentrations in duplicate and the curve fit was performed by non-linear regression analysis using Matlab version 6.5 (MathWorks, Inc., Natick, MA, USA).

BIOLOGICAL EXAMPLE 8

Proliferation test

Reagents and Buffers [0382]

Dimethylsulfoxide (DMSO) (Sigma-Aldrich, Cat. No. D2650) (Control)

Iscove's DMEM, ATCC Catalog No. 30-2005

M HEPES, Cellgro Catalog number 25-060-Cl (100 mL)

100 mM Sodium Pyruvate, Cellgro Cat. No. 25-000-Cl (100 mL)

Penicillin / Streptomycin, 10,000 U / mL each, Cellgro Catalog No. 30-002-Cl (100 mL)

RPMI 1640 (Cellgro, Cat. No. 10-040-CM)

Fetal Bovine Serum (JRH, Cat. No. 12106-500M)

Horse Serum, Derived from the donor, Hyclone Catalog No. SH30074.02 (100 mL) μΜ hydrocortisone solution, Sigma Catalog No. H6909-10ml (10 mL)

Growth conditions [0383] Ba / F3 V617F cells are maintained and seeded in RPMI with 10% FBS. The seeding density of these cells is 1 X 10⁵ cells / mL.

[0384] UKE-1 is maintained and sowed in Iscove's DMEM containing 10% FBS, 10% horse serum, 1% penicillin / streptomycin and 1 μM hydrocortisone. The seeding density of these cells is 0.4 X 10⁶ cells / mL.

[0385] SET2 cells are maintained and seeded in RPMI with 20% FBS. The seeding density of these cells is 2 X 10⁵ cells / mL.

[0386] CTLL-2 cells are maintained and seeded in RPMI containing 10% FBS and 10% TSTIM with Con A (Becton Dickinson). The seeding density of these cells is 0.4 X 10⁵cells / mL

Methods [0387] Cells were resuspended in the appropriate medium at the required cell density (see above). 100 μl of the cell suspension was added to each well bottom-bottom well

-214 white 96-well plate. The compound was serially diluted in DMSO from 5 mM in 3-fold dilutions, and then diluted 1: 250 in RPMI 1640 medium containing 5% FBS and pen / strept. 100 μΕ of the resulting 2X solution of the compound was added per well in duplicate and the cells were allowed to proliferate for 72 hours at 37 ° C.

[0388] Proliferation was measured using Cell Titer-Glo. The substrate was thawed and allowed to reach ambient temperature. After removing the top 100 μΕ of medium from each well, 100 μΕ of the previously mixed Cell Titer-Glo reagent was added to each well. The plates were mixed on an orbital shaker for three minutes to induce lysis and incubated at ambient temperature for an additional five minutes to allow for equilibration of the signal. Luminescence was read on the Wallac Plate Reader.

[0389] The results of the ability of compounds of the invention to inhibit JAK2 activity, in a test in the above assay using Ba / F3 V617F cells, are shown in Tables 2-3 below, wherein the activity level (i.e., IC50) for each compound is given in Tables 2 -3. The compound numbers given in Tables 2-3 refer to the compounds disclosed herein as produced by the methods disclosed herein:

Compounds 128, 129, 162, 168 of Table 2 and compound 131 of Table 3 are reference examples

-215-

<img file="PL2265607T3_D0046.tif" />

TABLE 2 Activity

IC50:

A = &lt;1 μΜ B = 1 to 10 μΜ

C =&gt; 10 to 20 μΜ

D =&gt; 20 μΜ

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>1</td><td>4- (6- (N, N-dimethylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ΓΥ^H3° 'n^ANDn- AND ch₃</td><td></td><td>AND</td>

<td>2</td><td>4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-methyl-N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2ylo) phenyl) pyrimidin-2-amine</td><td>1</td><td>1</td><td>H</td><td>CH3</td><td>CH3</td><td>ff^H3C'n^ANDn- AND ch₃</td><td>&lt;&gt; N '^CH3</td><td>AND</td>

<td>3</td><td>4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-trifluoromethyl-N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1] heptane -2ylo) phenyl) pyrimidin-2-amine</td><td>1</td><td>1</td><td>H</td><td>CH3</td><td>CF3</td><td>ΓΥ^H3° 'n^ANDn- AND ch₃</td><td>^ N '^CH=</td><td>B</td>

-216-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>1C50</td>

<td>4</td><td>4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-fluoro-N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2ylo) phenyl) pyrimidin-2-amine</td><td>1</td><td>1</td><td>H</td><td>CH3</td><td>-F</td><td>1 ch₃</td><td></td><td>AND</td>

<td>5</td><td>4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-fluoro-N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2ylo) phenyl) pyrimidin-2-amine</td><td>1</td><td>1</td><td>H</td><td>-F</td><td>-F</td><td>and Y^h=^c'nV AND ch₃</td><td></td><td>B</td>

<td>6</td><td>4- (6- (N, N-dimethylamino) pyridin-3-yl) -5-methyl-N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2ylo) phenyl) pyrimidin-2-amine</td><td>1</td><td>1</td><td>H</td><td>-F</td><td>CH3</td><td>1 ch₃</td><td></td><td>AND</td>

<td>7</td><td>4- (6- (N, N-dimethylamino) pyridin-3-yl) -N- (3 fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>ίΎ^η° = 'ν^Λν⁴AND ch₃</td><td>&lt;X^CH3</td><td>AND</td>

<td>8</td><td>4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5metylo -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>From*^t'N^ANDN^&lt;J1 ch₃</td><td>&lt;X^CH3</td><td>AND</td>

-217-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>9</td><td>4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4 - ((1S, 4S) -5metylo -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>r ° rf 1 ch₃</td><td>&lt;? N '^CH3</td><td>AND</td>

<td>10</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ABOUT</td><td>&lt;X^CH3</td><td>AND</td>

<td>11</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>'' j '' N ' oU</td><td>&lt;On '^ch=</td><td>AND</td>

<td>12</td><td>4- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) N- (3-methyl-4- (4-methylpiperazin- 1-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>Jżf &lt;In h₃C</td><td>^ N '^ch' \ABOUT</td><td>B</td>

<td>13</td><td>4- (6 - ((1S, 4S) -5- (4-fluorophenyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) N- (3-methyl-4- ( 4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ΧΤ h₃C</td><td>rr^cH'= \ABOUT</td><td>AND</td>

-218-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>14</td><td>4- (4- (N, N-dimethylamino) phenyl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>/ Ύ^h'^c-_n%AND AND ch₃</td><td>&lt;? N '^CHi\ _^ν^ Χ</td><td>AND</td>

<td>15</td><td>4- (4- (N, N-dimethylamino) phenyl) -N- (3-fluoro-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>χΎ^H'!^C'_N%AND 1 ch₃</td><td>&lt;? N '^CHi</td><td>B</td>

<td>16</td><td>4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>xy^Η3θγΝ ^&gt; 0</td><td>fCN-^CH =</td><td>AND</td>

<td>19</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- ((1 S , 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>H₃C r, " -i xy H</td><td>&lt;? N '^CH3</td><td>AND</td>

<td>20</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C _ns* 1Y5 H</td><td></td><td>AND</td>

-219-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>21</td><td>4- (1H-indol-6-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2- amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>^H 5 What</td><td>| &lt;N '^CH3</td><td>AND</td>

<td>22</td><td>4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan2 yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>«s H ^N</td><td>&lt; 'N'^ch'^:</td><td>AND</td>

<td>23</td><td>4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-fluoro-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan2 yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>OT H ^N</td><td>&lt;1n '^CH3OY</td><td>AND</td>

<td>24</td><td>4- (6- (dimethylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ly AND ch₃</td><td>FÖJ ^ CHG</td><td>AND</td>

<td>25</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>-SR 'Ά' · / AND</td><td>X^Nin&gt;</td><td>AND</td>

<td>26</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1 N, 45) -5 - ((ethylamino) carbonyl) -2,5</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-220-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>ABOUT "</td><td>0 X</td><td></td>

<td>27</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4S) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C ns TM H</td><td>M?</td><td>AND</td>

<td>28</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4S) -5- (ethylcarbonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C _n " TM H</td><td>0</td><td>AND</td>

<td>29</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C _ns"ΤΠ H</td><td>O. q and &lt;? n "ch₃</td><td>AND</td>

<td>thirty</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C _n " "MYTH H</td><td>FON ^ CHG</td><td>AND</td>

-221-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>31</td><td>4- (3'-oxo-3 ', 4'-dihydrospiro [cyclobutane-1,2'pirydo [3,2-b] [1,4] oxazine] -7'-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H</td><td></td><td>AND</td>

<td>32</td><td>4- (3'-oxo-3 ', 4'-dihydrospiro [cyclobutane-1,2'pirydo [3,2-b] [1,4] oxazine] -7'-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>OAA / H</td><td>FON ^ CHG</td><td>AND</td>

<td>33</td><td>4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4 ((1 S, 4S) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>OT ί! ^N</td><td>6?</td><td>AND</td>

<td>34</td><td>4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4- ((1S, 4S) -5- (2,2,2-trifluoroethyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ccf ii ^N</td><td>^ ^ Cn of₃</td><td>AND</td>

<td>35</td><td>4- (1H-pyrrolo [2,3-b] pyridin-5-yl) -N- (3-methyl-4- ((1S, 4S) -5- (cyclopropyl) methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>CQ^VH ^N</td><td></td><td>AND</td>

<td>36</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((15 ', 45) -5- (2,2,2-trifluoroethyl) -2,5</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>B</td>

-222-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>..ΓΑ ABOUT "</td><td>FON ^ CF₃</td><td></td>

<td>37</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (cyclopropyl) methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ABOUT "</td><td></td><td>AND</td>

<td>38</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4S) -5- (aminosulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C _ns* 1Y5 H</td><td>NH₂</td><td>AND</td>

<td>39</td><td>4- (3-fluoro-2- (morpholin-4-yl) pyridin-4-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>F</td><td>&lt;X^CH3</td><td>B</td>

<td>40</td><td>4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>/ χΛ J ΐ NN</td><td>&lt;&gt; N '^CH3</td><td>B</td>

-223-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>41</td><td>4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>n ^ aA ann</td><td>"AND</td><td>AND</td>

<td>42</td><td>4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl ) pirymidyno2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>on AJ ANN AT</td><td></td><td>B</td>

<td>43</td><td>4- (2- (morpholin-4-yl) pyrimidin-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>N-A ΑνΆ at</td><td>&lt;.N '^ch" '</td><td>AND</td>

<td>44</td><td>4- (2 - ((cyclopropyl) carbonylamino) -pyrimidin-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) -phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>0 n ^ A · ot⁷</td><td>He'^ch' xⁿAND</td><td>AND</td>

<td>45</td><td>4- (4- (4,5-dihydro-thiazol-2-ylcarbamoyl) phenyl) N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>O ^ yo '</td><td>&lt;? N '^CH3</td><td>B</td>

-224-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>46</td><td>4- (4- (1,1-dimethylethyl) phenyl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>..cjA^h=^cAh₃</td><td>&lt;ςχ^0Η3</td><td>AND</td>

<td>47</td><td>4- (4- (morpholin-4-yl) phenyl) -N- (3-fluoro-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine. TFA salt</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>.θ '¹' &lt;u</td><td>&lt;? N '^CH?\ _^NAND</td><td>B</td>

<td>48</td><td>4- (4 - ((methyl) aminocarbonylmethyl) -phenyl) -N (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine. TFA salt</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ΗΑ, ΧΧί H</td><td>^ N '^ch' "</td><td>B</td>

<td>49</td><td>4- (4 - ((cyclopropyl) aminocarbonylmethyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H</td><td>phone'^CH3</td><td>B</td>

<td>50</td><td>4- (6- (methylaminocarbonyl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>0</td><td>&lt;? N '^CHi</td><td>AND</td>

-225-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>51</td><td>4- (7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [ 2.2.1] heptane-2-yl) phenyl) pyrimidine-2-amine. TFA salt</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>pff CT H</td><td>ΙΟΝ- ' "' s ^ O¹</td><td>AND</td>

<td>52</td><td>4- (5 - ((morpholin-4-yl) carbonyl) pyridin-3-yl) N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidine-2-amine. Sodium bis TFA</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>0 «ον</td><td>&lt;X^CH3</td><td>AND</td>

<td>53</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-cyano-4 ((1 S , 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CN</td><td>-</td><td>c / W H</td><td>&lt;? N '^CH?</td><td>AND</td>

<td>59</td><td>4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>^Η3 ° γ ^ γΥ at</td><td>&lt;X^CH3</td><td>AND</td>

<td>60</td><td>4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>^Η3 ° γ ^ γΥ Γ'Ν'Μ xj °</td><td>f £ X^CH3yK /¹</td><td>AND</td>

<td>67</td><td>5-methyl-4- (6- (morpholin-4-yl) pyridin-3-yl) -N- / 3-methyl-4 - ((15 ', 45) -5-methyl-2,5-</td><td>1</td><td>1</td><td>H</td><td>CH3</td><td>CH3</td><td></td><td></td><td>AND</td>

-226-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>^ 'N''N⁵&lt;U</td><td>&lt;X^CH3JEM</td><td></td>

<td>68</td><td>5-methyl-4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>1</td><td>1</td><td>H</td><td>-F</td><td>CH3</td><td>JCT oO "</td><td>&lt;&gt; N '^CH3</td><td>AND</td>

<td>69</td><td>4- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>H</td><td>&lt;? N '^CH3\.^NP</td><td>B</td>

<td>70</td><td>4- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>? p Pf A^N^ 'PP H</td><td>ABOUT^CH3</td><td>AND</td>

<td>71</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 R , 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C r, " -p Ό (Λν'κ H</td><td>&lt;Vn '^CH3</td><td>AND</td>

<td>72</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1 R, 4 R) - 5-methyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-227-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>.- 'N''N⁵</td><td>ΜΓ</td><td></td>

<td>73</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- ((1 R , 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>F</td><td>-</td><td>H₃C _n " TM H</td><td>ΜΓ</td><td>AND</td>

<td>74</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4 - ((1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>F</td><td>-</td><td>&lt;u</td><td></td><td>AND</td>

<td>75</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan3-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>THEM</td><td>Λτ</td><td>AND</td>

<td>76</td><td>4- (6- (dimethylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan3-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ff^HbC'N^ANDN, N AND ch₃</td><td>Λγ</td><td>AND</td>

<td>77</td><td>4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-228-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>α, -σ H</td><td>Υγ ™³\ NxYcH₃</td><td></td>

<td>78</td><td>4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>and, yy H</td><td>&lt;x^CH3</td><td>AND</td>

<td>79</td><td>4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>ο, -σ H</td><td>&lt;N '^CH3</td><td>AND</td>

<td>80</td><td>4- (6- (benzyl) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>IT</td><td>&lt;? N '^CH3</td><td>AND</td>

<td>81</td><td>4- (6- (benzyl) pyridin-3-yl) -N- (3-fluoro-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td></td><td>&lt;? N^CH3From</td><td>AND</td>

<td>82</td><td>4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td></td><td></td><td>AND</td>

-229-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>&lt;U</td><td>Α'ν '⁰"³</td><td></td>

<td>83</td><td>4- (6- (dimethylamino) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan3-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>^Η3° 'ν^Λν ^ AND ch₃</td><td>with"'</td><td>AND</td>

<td>84</td><td>4- (4- (dimethylamino) phenyl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>.μ 1 ch₃</td><td>ar</td><td>AND</td>

<td>85</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan3-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>IT at</td><td>CH ar</td><td>AND</td>

<td>86</td><td>4- (3,4-dihydro-2H-pyrido [3,2-jld] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl) 2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>CTF H</td><td>&lt;X^CH3</td><td>AND</td>

<td>87</td><td>4- (3,4-dihydro-2H-pyrido [3,2-jld] [1,4] oxazin-7-yl) -A- (3-fluoro-4 - ((15 ', 45) -5-methyl -2,5</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td></td><td></td><td>AND</td>

-230-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>(ΎΤ 'ν^Λ,? H</td><td></td><td></td>

<td>88</td><td>4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>fty H</td><td>7 ' "· \^NXXh₃</td><td>AND</td>

<td>89</td><td>4- (3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>^kNV H</td><td></td><td>B</td>

<td>90</td><td>4- (6- (benzyl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidine 2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>(Fy QT " ⁿ"</td><td>7'n '^CH3\^N\ / ^ ~ CH₃</td><td>AND</td>

<td>91</td><td>4- (6- (benzyl) pyridin-3-yl) -N- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidine 2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>0Γ a ^N"</td><td>[J &lt;% '^CH3</td><td>AND</td>

<td>92</td><td>4- (2- (propyl) aminopyrimidin-5-yl) -N- (3-methyl-4 - ((15 ', 45) -5-methyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-231-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>H</td><td>^ N '^ch' χΎ¹</td><td></td>

<td>93</td><td>4- (2- (propyl) aminopyrimidin-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>Naa^h3C ^ x \_nA&gt;_n&gt; H</td><td>^ n^XH3χΆ¹</td><td>AND</td>

<td>94</td><td>4- (6- (cyclohexylamino) pyridin-3-yl) -N- (3-trifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CF3</td><td>-</td><td>Q "A H</td><td>^ N '^ch' χΎ¹</td><td>AND</td>

<td>95</td><td>4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>V, l J N</td><td>cn '^CH3X^NY</td><td>AND</td>

<td>96</td><td>4- (6- (dimethylamino) pyridin-3-yl) -N- (3-trifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CF3</td><td>-</td><td>"C W π ^ 'ιΑιΓ 1 ch₃</td><td>&lt;? N '^CH3χΆ¹</td><td>AND</td>

<td>97</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-trifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CF3</td><td>-</td><td></td><td>&lt;X^CH3χΆ¹</td><td>AND</td>

-232-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>yy from</td><td></td><td></td>

<td>98</td><td>4- (3,4-dihydro-2H-pyrido [3,2-c] [1,4] oxazin-7-yl) -N- (3-trifluoromethyl-4 - ((1S, 4S) -5-methyl2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CF3</td><td>-</td><td>H</td><td>^ N '^ch= From</td><td>AND</td>

<td>99</td><td>4- (6 - ((2- (cyclopropylsulfonyl) aminoethyl) -amino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>Λ H jfY oo ^H</td><td>kebab "</td><td>B</td>

<td>100</td><td>4- (6 - ((2- (cyclopropylsulfonyl) aminoethyl) -amino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5oksa-2-azabicyclo [2.2.1] heptane -2ylo) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>Λ Η PY Λ M ^N"</td><td></td><td>AND</td>

<td>101</td><td>4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>^{H: C} in</td><td>&lt;X^CH3From</td><td>AND</td>

<td>102</td><td>4- (5- (methyl) sulfonylopirydyn-3-yl) -N- (3-trifluoromethyl-4 - ((1S, 4S) -5-methyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>CF3</td><td>-</td><td></td><td>From</td><td>AND</td>

-233-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>V,^HSC YOU</td><td></td><td></td>

<td>103</td><td>4- (imidazo [1,2-a] pyridin-6-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>-and-</td><td>&lt;. 'N'^ch=</td><td>AND</td>

<td>104</td><td>4- (4- (5- (4-dimethylaminophenyl) oxazol-2-yl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>_(VABOUT^vHGC; N ch₃</td><td>&lt;? N '^CH3</td><td>B</td>

<td>105</td><td>4- (6-methoxy-1H-indol-2-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>h₃c XjQ ^ ·^AT H</td><td>&lt;&gt; N '^CH3</td><td>AND</td>

<td>106</td><td>4- (1- (3-chlorophenyl) -1H-pyrazol-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>"Ό</td><td>^? N^ch=</td><td>B</td>

-234-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>107</td><td>4- (1-methylbenzimidazol-6-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>^h3c V0 '</td><td>2QN '^CH3</td><td>AND</td>

<td>108</td><td>4- (5-cyano-1H-indol-2-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>"Ό0 + H</td><td>&lt;7n '^{CH ^}</td><td>AND</td>

<td>109</td><td>4- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>, τ0 F</td><td>&lt;X^CH3χΌ '¹</td><td>AND</td>

<td>110</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (7-azabicyclo [2.2.1] heptan-7-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>at</td><td></td><td>B</td>

<td>111</td><td>4- (6-Cyano-pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>jlY In NCF ^</td><td>&lt;X^CH=</td><td>B</td>

-235-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>112</td><td>4- (6-Cyano-pyridin-3-yl) -N- (3-methyl-4- (7azabicyklo [2.2.1] heptan-7-yl) phenyl) pirymidyno2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ry Nc "l \ T</td><td>X</td><td>B</td>

<td>113</td><td>4- (2-oksoindolin-5-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>° ro^vH</td><td>&lt;? N '^CH35JO¹</td><td>AND</td>

<td>114</td><td>4- (5-cyanopyridin-3-yl) -N- (3-methyl-4 ((1S, 4S) 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-one amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td>&lt;X^CH3Χ¹^¹</td><td>B</td>

<td>115</td><td>4- (6- (1H-tetrazol-5-yl) pyridin-3-yl) -N- (3-methyl-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>Η And Ι \ Κ Λ Z / 7r N V!</td><td>&lt;? N '^CH3χ'Κ /¹</td><td>C</td>

<td>116</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-Acetyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CN</td><td>-</td><td>AND -'νΧ ABOUT</td><td>0 ^ N ^ ch₃</td><td>AND</td>

<td>117</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S ', 4S) -5-methylsulfonyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>CN</td><td>-</td><td></td><td></td><td>AND</td>

-236-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>-SR^ζ'·. ·' · Ι.^;AND</td><td>%&gt; ° Αχ oh₃</td><td></td>

<td>118</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CN</td><td>-</td><td>AND at</td><td>s</td><td>AND</td>

<td>119</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyano-4 - ((1S, 4S) -5-cyclopentyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CN</td><td>-</td><td>AND AT</td><td>AND</td><td>AND</td>

<td>120</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND -'Ν'Ν * AND</td><td>about. \^N\AND</td><td>AND</td>

<td>121</td><td>4- (2-oksoindolin-5-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND' H</td><td>about - \^NAND</td><td>AND</td>

-237-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>122</td><td>(1-methylbenzimidazol-6-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>_H3C in</td><td>P " in</td><td>AND</td>

<td>123</td><td>4- (imidazo [1,2-a] pyridin-6-yl) -N- (3-methyl-4 (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>cf \ = J</td><td>P \^N\ __ /</td><td>AND</td>

<td>124</td><td>4- (2H-benzo [o] [1,4] oxazin-3 (4H) -one-6-yl) -N^L(3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>H ΧΌ '</td><td>&lt;Yn '^CH3ρθ</td><td>AND</td>

<td>125</td><td>4- (2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ( (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C r \ " IN 1 ch₃</td><td>f £ X^CH3after¹</td><td>AND</td>

<td>126</td><td>4- (2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-fluoro-4 ( (1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>H₃C n «, "ΪΠ 1 ch₃</td><td>&lt;X^CH3</td><td>AND</td>

<td>127</td><td>4- (5- (3-methylpiperidin-1-yl) pyrazin-2-yl) -N (3-fluoro-4 - ((15 ', 47) -5-methyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td></td><td></td><td>B</td>

-238-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>-N. V^H3Cqa ^</td><td>ABOUT'^CH3ΥΡ</td><td></td>

<td>128</td><td>4- (4- (t-butylcarbonylamino) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>^ΗΡη₃^H</td><td>&lt;? N '^CH3</td><td>AND</td>

<td>129</td><td>4- (4- (t-butylcarbonylamino) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>^ΗΡη₃^H</td><td>&lt;? N '^CH3\ _ⁿP</td><td>AND</td>

<td>130</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C _n " IN H</td><td>^ N '^CH3</td><td>AND</td>

<td>132</td><td>4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃ZnAP³ H</td><td>ABOUT'^CH3</td><td>AND</td>

<td>133</td><td>4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-fluoro-4 - ((1P, 4P) -5-methyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td></td><td></td><td>B</td>

-239-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>Η PO 0</td><td>&lt;? N '^CH3From</td><td></td>

<td>134</td><td>4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>hr 0</td><td>^ n^CH3From</td><td>AND</td>

<td>135</td><td>4- (4- (methylsulfonylamino) phenyl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>f? PY^μΆ&gt; Ρ 0 H</td><td>&lt;? N '^CH3From</td><td>AND</td>

<td>136</td><td>4- (4- (methylsulfonylamino) phenyl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>9 PY^H3C- ,? '_NAM 0 H</td><td>&lt;.N '^ch'· From</td><td>AND</td>

<td>137</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>H₃C ~ " -x Ό Cry ^ hr H</td><td>&lt;? N '^CH3From</td><td>AND</td>

<td>139</td><td>4- (4- (3-cyclopropylureido) phenyl) -N- (4 ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td></td><td></td><td>AND</td>

-240-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Gajo * Η H</td><td>A n-^CH3</td><td></td>

<td>141</td><td>4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>O ^ A 0 H</td><td>A n '^CH3</td><td>AND</td>

<td>142</td><td>4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>O ^^ A 0 N '^X% V O ^ and_naJ H</td><td>ΑΧ ™³ί / Ο¹</td><td>B</td>

<td>143</td><td>4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>O ^^ A 0 N '^X% V O ^ and_naJ H</td><td>OA "</td><td>B</td>

<td>147</td><td>4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>he'^x^ AV '³ H</td><td>,AND</td><td>AND</td>

<td>148</td><td>4- (6-aminopyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ν "ΑΥ H₂N, N</td><td>0</td><td>AND</td>

-241-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>149</td><td>4- (6- (acetamido) pyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>0 nA^WITH_H3aA³ H</td><td>0</td><td>AND</td>

<td>150</td><td>4- (6-aminopyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>νΆ h₂AND</td><td>O. q Αν '"ch₃</td><td>AND</td>

<td>151</td><td>4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>o nAV ^H3C-i_NAN 0 H</td><td>&lt;X^CH3χΆ¹</td><td>B</td>

<td>152</td><td>4- (6- (2- (dimethylamino) acetamido) -pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ch₃ about³ H</td><td>&lt;? N '^CH3xO</td><td>AND</td>

<td>153</td><td>4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>she^zh3^c1_nAND 0 H</td><td>&lt;&gt; '^CH3X^NIN</td><td>B</td>

<td>155</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td></td><td></td><td>AND</td>

-242-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>AND oZ</td><td>ι / Ά^Η3AND</td><td></td>

<td>156</td><td>4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>0 Ν ^ ν^h3^cAND_nAJJ 0 H</td><td>- / 'Ν'θΠ'¹</td><td>B</td>

<td>157</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (8-metylo3,8 diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>H₃C ~ " -i xr cAhAhT H</td><td>y / "^³, vA</td><td>AND</td>

<td>158</td><td>4- (6-aminopyridin-3-yl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>H_2Nr</td><td>y / ^ N '⁰"³AND</td><td>AND</td>

<td>159</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.2] nonane-4-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND^withvv AT</td><td>p, - \^Nv ^</td><td>AND</td>

<td>160</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4-</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-243-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>(1,4-diazabicyclo [3.2.2] nonane-4-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>H₃C _n " "Mime H</td><td></td><td></td>

<td>161</td><td>4- (4 - ((pyridin-2-yl) aminocarbonyl) phenyl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.2] nonane-4-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>⁰</td><td>\^Nx-&gt;</td><td>AND</td>

<td>162</td><td>4- (4- (acetamido) phenyl) -N- (4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>h₃AJO^v³ H</td><td>\ Ά</td><td>AND</td>

<td>163</td><td>4- (2- (diethylamino) thiazol-4-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C ν-φ^νΆ h₃c - m ĄJ</td><td>&lt;? N '^CH3χ^ΝΜ ^</td><td>AND</td>

<td>164</td><td>4- (2- (diethylamino) thiazol-4-yl) -N- (3-fluoro-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>h₃C NM / A h₃c ^ A_sJ</td><td>&lt;Tn '^{CH :!}X^NM ^</td><td>AND</td>

<td>165</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (8- methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>^HsC _n " "TM H</td><td>γ / 'ν' ™³\ Ά</td><td>AND</td>

-244-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>166</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>iP ABOUT "</td><td>ΟΡι '™³\ N7</td><td>AND</td>

<td>167</td><td>4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (3-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>0 0 Η</td><td>^³h-^CH:</td><td>AND</td>

<td>168</td><td>4- (4- (t-butylcarbonylamino) phenyl) -N- (3-methyl-4- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>• ρΧ^HSC ch₃^h</td><td>PN^CH!</td><td>AND</td>

<td>169</td><td>4- (1H-pyrrol-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2- amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>HLC ^</td><td>&lt;X^CH3after¹</td><td>B</td>

<td>170</td><td>4- (1H-pyrrol-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>hnCH</td><td>&lt;? N '^CH3P &amp; lt;</td><td>B</td>

<td>171</td><td>4- (1H-pyrrol-3-yl) -N- (3-trifluoromethyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CF3</td><td>-</td><td>hnCX</td><td></td><td>AND</td>

-245-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ABOUT'^CH3yp</td><td></td>

<td>172</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-trifluoromethyl-4 - ((1S, 4S) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CF3</td><td>-</td><td>H₃C ns CAN ^ k H</td><td>p "</td><td>AND</td>

<td>173</td><td>4- (6-ethoxypyridin-3-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C 0 N</td><td>&lt;&gt; N '^CH3For example,</td><td>AND</td>

<td>174</td><td>4- (6-ethoxypyridin-3-yl) -N- (3-fluoro-4 - ((1S, 4S) 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>^ jQ^vH₃C 0 N</td><td>&lt;? N '^CH3For example,</td><td>B</td>

<td>175</td><td>4- (2- (dimethylamino) thiazol-4-yl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C _M .^J χ l \ k V For example, h₃c</td><td>&lt;? N '^CH3</td><td>B</td>

<td>176</td><td>4- (2- (dimethylamino) thiazol-4-yl) -N- (3-fluoro-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>^H3C'/ NpV H₃C '^NP /</td><td>&lt;X^CH3</td><td>B</td>

-246-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>178</td><td>4- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ly about^rAND</td><td>&lt;X^CH3X^NY</td><td>B</td>

<td>179</td><td>4- (5- (morpholin-4-yl) pyrazin-2-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>ly '' '' / 'Ί Y</td><td>&lt;X^CH3χΥ</td><td>B</td>

<td>181</td><td>4- (4- (1-ethoxyethyl) phenyl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>and Y ch₃</td><td>&lt;X^CH3χΥ</td><td>B</td>

<td>182</td><td>4- (4- (1-ethoxyethyl) phenyl) -N- (3-fluoro-4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine 2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>and Y ch₃</td><td>&lt;X^CH3χΥ</td><td>B</td>

<td>183</td><td>4- (6- (dimethylamino) pyridin-3-yl) -N- (4- ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2- amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>and Y^H'IN AND ch₃</td><td>fQ_N'^CH3χΥ</td><td>AND</td>

-247-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>184</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4 ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>yy o </td><td>SQN '^CH3From</td><td>AND</td>

<td>185</td><td>4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4 - ((1S, 4S) -5-metylo2,5 diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>° C xy 1 ch₃</td><td>SQN '^CH3From</td><td>AND</td>

<td>186</td><td>4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H</td><td>&lt;y^CH3From</td><td>AND</td>

<td>187</td><td>4- (6- (cis-2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>rf H₃Cx JJ³ TNN V ch₃</td><td>&lt;YN '^CH3From</td><td>AND</td>

<td>188</td><td>4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ΓΤ H</td><td>&lt;x^CH3From</td><td>AND</td>

-248-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>189</td><td>4- (6- (2- (dimethylamino) methylmorpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>oO ^NV^CH3 1 ch₃</td><td>&lt;X^CH3</td><td>AND</td>

<td>190</td><td>4- (6- (piperidin-1-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td>&lt;X^CH3</td><td>AND</td>

<td>191</td><td>4- (6- (3- (aminocarbonyl) piperidin-1-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>jQ^vpname h₂n ^ o</td><td>2QN '^CH3</td><td>B</td>

<td>192</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ϊΑ &lt;U</td><td>V fOlSl 'OH₃</td><td>AND</td>

<td>193</td><td>4- (4-methyl-3,4-dihydro-2H-pyrido [3,2]] [1,4] oxazin-7-yl) - # - (3-methyl-4 - ((15,45) -5 -</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-249-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>methylsulfonyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>XY ° C '' Ν'Ά 1 ch₃</td><td>V &lt;? N '"CH₃</td><td></td>

<td>194</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND oZ</td><td>AND</td><td>AND</td>

<td>195</td><td>4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5oksa -2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>Tf ° C 1 ch₃</td><td>AND</td><td>AND</td>

<td>196</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethylcarbonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND ABOUT "</td><td>0</td><td>AND</td>

<td>197</td><td>4- (6- (2- (morpholin-4-yl) ethyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-etylokarbonylo2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>P iV H</td><td>0</td><td>B</td>

<td>198</td><td>4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N^r- (3-methyl-4 - ((15 ', 45) -5-methyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>B</td>

-250-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>NNN ch₃^h</td><td>&lt;X^CH3after¹</td><td></td>

<td>199</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-amidino-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine. TFA salt</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>^ 'N''N⁵&lt;U</td><td>NH and &lt;O'N⁴^ NH₂PO TFA</td><td>B</td>

<td>200</td><td>4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) pirymidyno2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>cT ^ CHO AJ H</td><td>X</td><td>AND</td>

<td>201</td><td>4- (6-cis-2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan 2-yl) phenyl) pirymidyno2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>V ch₃</td><td></td><td>AND</td>

<td>202</td><td>4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>iT Η</td><td></td><td>AND</td>

<td>203</td><td>4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N^r- (3-methyl-4 - ((15 ', 45) -5-oxa-2-</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-251-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>azabicyclo [2.2.1] heptan-2-yl) phenyl) pirymidyno2-amine</td><td></td><td></td><td></td><td></td><td></td><td>JFV ch₃^h</td><td></td><td></td>

<td>204</td><td>4- (6- (1,4-oxazepan-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2 -yl) phenyl) amine pirymidyno2</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>V</td><td></td><td>AND</td>

<td>205</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-isobutyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>xT about</td><td>^ Ny^CH3 CH₃</td><td>AND</td>

<td>206</td><td>4- (6- (1,4-oxazepan-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane -2ylo) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ABOUT</td><td>&lt;? N '^CH3</td><td>AND</td>

<td>207</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 (1 5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C ~ " -i xy H</td><td>_and&gt; En '^CH3</td><td>AND</td>

<td>208</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-o] [1,4] oxazin-7-yl) -N^r- (3-fluoro-4-</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td></td><td></td><td>B</td>

-252-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>(1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonane-3-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>H₃C _ns* 1Y5 H</td><td>af^H' \^Nx&gt; &lt;CH₃</td><td></td>

<td>209</td><td>4- (3-oxo-3,4-dihydro-2H-pyrido [3,2b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ΛΥ H</td><td>AND"'</td><td>AND</td>

<td>210</td><td>4- (3-oxo-3,4-dihydro-2H-pyrido [3,2b] [1,4] oxazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -oxa) -2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>and XY ° (τΆΐί H</td><td>AND</td><td>AND</td>

<td>211</td><td>4- (6- (3-ethoxypropyl) aminopyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>cAYh₃ ΑγΥ H</td><td>Λ^{ν 3}\^N\ A ~ CH₃</td><td>AND</td>

<td>212</td><td>4- (6 - ((2S, 6R) -2,6-dimethyl-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (1,5,7trimetylo-3,7-diazabicyclo [3.3 .1] nonane-3-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AA Y ch₃</td><td>AND'"' ^^Nx&gt; &lt;CH₃</td><td>AND</td>

-253-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>213</td><td>4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan3-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>rf H3C ^_nAND_{n &lt;}J H</td><td>ar \^Nx&gt; &lt;CH₃</td><td>AND</td>

<td>214</td><td>4- (6- (3-dimethylamino) propyloaminopirydyn-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ch₃^h</td><td>CH AND ³\^N\ A ~ CH₃</td><td>B</td>

<td>215</td><td>4- (6 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND © "</td><td>AND'"·</td><td>AND</td>

<td>216</td><td>4- (6 - ((1S, 4S) -5-oxa-2-azabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5oksa-2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND © "</td><td>AND</td><td>AND</td>

<td>217</td><td>4- (6- (3-methylbutyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine -2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>aa / T H₃CNN^about H</td><td></td><td>AND</td>

-254-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>218</td><td>4- (6- (3,3-dimethylbutyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>^h3Y³ xt³ H</td><td>SQN '^CH3From</td><td>AND</td>

<td>219</td><td>4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>fT ch₃</td><td>· ρ ' "·</td><td>AND</td>

<td>220</td><td>4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-oxa-2azabicyklo [2.2.1] heptan-2-yl) phenyl) -amine pirymidyno2</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>o ^ n^Yh₃c '"^ nn ch₃</td><td>x0</td><td>AND</td>

<td>221</td><td>4- (6- (2-methoxyethyl) (methyl) aminopyridin-3-yl) -N- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3.1] nonan-3-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ΓΎ ch₃</td><td>\ⁿ\ Z ^ CH₃</td><td>AND</td>

<td>222</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4R) -2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>and Y P; N hT from</td><td>&gt; V</td><td>AND</td>

-255-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>223</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4R) -2-azabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>h₃c ~ " (Λν'κ H</td><td>X</td><td>AND</td>

<td>224</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- (2- methylsulfonyl-2-azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidine-2-amine and 4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2b] [1, 4] oxazin-7-yl) -N- (3-methyl-4- (2-methylsulfonyl-2-aza-bicyclo [2.2.1] heptan-6-yl) phenyl) pyrimidin-2-amine (68:31)</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C n " "Oiy H</td><td>vZ7^NT^CH3and AND,," cr "ch₃</td><td>AND</td>

<td>225</td><td>4- (6- (Morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (2-methylsulfonyl-2-aza-bicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidine-2-amine and 4- (6-morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (2-methylsulfonyl-2-aza-bicyclo [2.2.1] heptan-6-yl) phenyl) pyrimidine-2-amine (85:15)</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>X ABOUT "</td><td>y ^ pN-S-CH₃and Oh, o '"CHj</td><td>B</td>

<td>226</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (2-</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td></td><td>λ ° A \&gt; ns-ch₃about</td><td>B</td>

-256-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>methylsulfonyl-2-azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>H₃C _ns*! D H</td><td></td><td></td>

<td>227</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (2metylosulfonylo-2-azabicyclo [2.2.1] heptan-5-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>ABOUT "</td><td>λ ° A \&gt; ns-ch₃0</td><td>AND</td>

<td>228</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (4- (2metylosulfonylo-2-aza- [2.2.1] heptan-6-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>H₃C _n " IN H</td><td>χΥη o = s- ° \ ch₃</td><td>AND</td>

<td>229</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (4- (2metylosulfonylo-2-azabicyclo [2.2.1] heptan-6-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>xA AT</td><td>χΥη o = s- ° \ ch₃</td><td>B</td>

<td>230</td><td>4- (6- (tiamorfolin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((15,45) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>la about</td><td>&lt;X^CH3</td><td>AND</td>

-257-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>231</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>IT ° P</td><td>&lt;1n '^CH3</td><td>AND</td>

<td>232</td><td>4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ca d&gt; l \ r</td><td>&lt;&gt; N '^CH3</td><td>AND</td>

<td>233</td><td>4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-fluoro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>-F</td><td>-</td><td>ca about</td><td>&lt;X^CH3</td><td>AND</td>

<td>234</td><td>4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4 - ((1S, 4S) -5-ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ca about N- ^</td><td>^ N ^ CHG</td><td>AND</td>

<td>235</td><td>4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N- (3-methyl-4 - ((1S ', 4S) -5-isobutyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-258-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>What* 0 No.</td><td>AP CH₃</td><td></td>

<td>237</td><td>4- (7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-metylosulfonylo2,5-diazabicyclo [ 2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>Ltd. * H</td><td>θ ^ ο fOhl "CH₃</td><td>AND</td>

<td>238</td><td>4- (6- (propylamino) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>ΓΤ H</td><td>O. q &lt;? N '"CH₃</td><td>AND</td>

<td>239</td><td>4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>"AND "aJ</td><td>&lt;X^CH3</td><td>AND</td>

<td>240</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((1S, 4S) - 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C ~ "^H'XO H</td><td>&lt;? N '^CH3X^NP</td><td>AND</td>

<td>241</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [o] [1,4] oxazin-7-yl) -A- (3-methyl-4-</td><td>0</td><td>1</td><td>H</td><td>-CHs</td><td>-</td><td></td><td></td><td>AND</td>

-259-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>((15 ', 45) -5-methylsulfonyl-2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>H₃C _n " TM ' H</td><td>%&gt; Of &lt;On "ch₃</td><td></td>

<td>242</td><td>4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2 , 5diazabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>WHAT' 0 H</td><td>&lt;X^CH3</td><td>AND</td>

<td>243</td><td>4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-metylosulfonylo2,5- diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>WHAT' 0 H</td><td>&lt;? N^WITH OH₃</td><td>AND</td>

<td>244</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2Hbenzo [b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((6R, 9S) - 6,9-metanooktahydro-1H-pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C _n " XXX H</td><td></td><td>AND</td>

<td>245</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((6R, 9S) -6,9-metanooktahydro-1H-pyrido [1,2-a] pyrazin-2 yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AT</td><td>,?</td><td>AND</td>

<td>246</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4- ((15 ', 45) -5- (1-methylethyl) -2,5</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-260-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>H₃C ~ " -i xt H</td><td>ch₃</td><td></td>

<td>247</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C _n " IN H</td><td></td><td>AND</td>

<td>248</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-chloro-4 ((1 S , 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>Cl</td><td>-</td><td>h₃c ~ " -i xt Cr lAli H</td><td>^ N '^ch'</td><td>AND</td>

<td>249</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-chloro-4 ((1 S , 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>Cl</td><td>-</td><td>H₃C ns cAiAit H</td><td>PZ / ° &lt;3! ' "·</td><td>AND</td>

<td>250</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4S) -5-cyclopentyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C ns * fto cAiAit H</td><td></td><td>AND</td>

-261-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>251</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 ((1 S , 4S) -5-acetyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C _ns* 1Y5 H</td><td>0 &lt;Yn ^ ch₃</td><td>AND</td>

<td>252</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (3-methyl-4 (1 4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H₃C ~ "^hscand iy H</td><td>AND -IN</td><td>AND</td>

<td>253</td><td>4- (5- (1-methylethoxy) karbonylopropylo-6aminopirydyn-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine;</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>^Η3θγ ° γ ^ χ γ-% ΛΤ^CH'° A</td><td>AND"'</td><td>AND</td>

<td>254</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>χΥ at</td><td>γΥ</td><td>AND</td>

<td>255</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>Cl</td><td>-</td><td>XY at</td><td>&lt;X^CH3χΥ¹</td><td>AND</td>

<td>256</td><td>4- (2- (trifluoromethyl) pyridin-4-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>-CHs</td><td>-</td><td></td><td></td><td>AND</td>

-262-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>PY cf₃</td><td>^&gt; N '^CH3From</td><td></td>

<td>257</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl ) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>Cl</td><td>-</td><td>yy .9 "</td><td>CL .o &lt;On^zxch₃</td><td>AND</td>

<td>258</td><td>4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptane 2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>Cl</td><td>-</td><td>op</td><td>zz ° x-5 "</td><td>B</td>

<td>259</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5-Acetyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>Cl</td><td>-</td><td>yy .9 "</td><td>0</td><td>AND</td>

<td>260</td><td>4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-chloro-4 - ((1S, 4S) -5-Acetyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>Cl</td><td>-</td><td>opy</td><td>0 &lt;Yn ^ CH₃</td><td>B</td>

<td>261</td><td>4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4 - ((1P, 45) -5-methyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-263-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>OAA</td><td></td><td></td>

<td>262</td><td>4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4 - ((15,45) -5-cyclopentyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>UG</td><td></td><td>AND</td>

<td>263</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-chloro-4 - ((15.45) -5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] heptane -2ylo) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>&lt;U</td><td>ch₃&lt;IAH₃\.^N-&gt;</td><td>AND</td>

<td>264</td><td>4- (6 - ((15,45) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4 - ((15.45) -5 (methylsulfonyl) -2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND* And "</td><td>0. .O^xch₃</td><td>AND</td>

<td>265</td><td>4- (6 - ((1R, 4R) -2-oxa-5-aza-bicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4 - ((15.45) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND* "A"</td><td>&lt;X^CH3</td><td>AND</td>

<td>267</td><td>4- (6,7,8,9-tetrahydro-5H-pyrido [2,3-o] indol-3-yl) -N^r- (3-methyl-4 - ((15,45) -5-methyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>B</td>

-264-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>Opa</td><td>&lt;? N '^CHs</td><td></td>

<td>268</td><td>4- (6,7,8,9-tetrahydro-5H-pyrido [2,3-b] indol-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5- (methylsulfonyl) 2 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td>O.o. för ^xch₃</td><td>B</td>

<td>269</td><td>4- (4- (trifluoromethyl) phenyl) -N- (3-methyl-4 ((1 S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2- amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>"AND</td><td>&lt;? N '^CH3</td><td>AND</td>

<td>270</td><td>4- (7,8,9,9a-tetrahydro-5H-pyrido [2,3-e] pyrrolo [1,2-a] [1,4] diazepin-10 (11H) -one-3-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>IN 0 H</td><td>^ N '^ch' pts¹</td><td>AND</td>

<td>271</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -N- (3-cyano-4- ((1S, 4S) - 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CN</td><td>-</td><td>H₃C _n s "THIS H</td><td>p ^ T¹</td><td>AND</td>

<td>272</td><td>4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin7-yl) -N^r- (3-cyano-4 - ((15 ', 47) -5-methyl-2,5-</td><td>0</td><td>1</td><td>H</td><td>CN</td><td>-</td><td></td><td></td><td>AND</td>

-265-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>diazabicyclo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>DA 0 H</td><td>&lt;? N '^ch' χ'Ρ</td><td></td>

<td>273</td><td>4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-cyano-4 - ((1S, 4S) -5-methyl-2 , 5diazabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CN</td><td>-</td><td>"AND</td><td>&lt;? N '^ch'</td><td>AND</td>

<td>274</td><td>4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-methyl-4 - ((1S, 4S) -5-methyl-2 , 5diazabicyklo [2.2.1] heptan-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>"AND μ</td><td>&lt;? N '^CH?χΡ</td><td>AND</td>

<td>275</td><td>4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>UD *</td><td>D -IN</td><td>AND</td>

<td>276</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((R) -1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>_r.D *</td><td>ABOUT-</td><td>AND</td>

<td>277</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4 - ((S) -1,4-diazabicyclo [3.2.1] octan-4-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td></td><td></td><td>AND</td>

-266-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>AND -'''AND-·.³AND</td><td>AND</td><td></td>

<td>278</td><td>4- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin7-yl) -N- (3-methyl-4 - ((6R, 9S) -6,9metanooktahydro-1H- pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>QA 0 H</td><td>0</td><td>AND</td>

<td>279</td><td>4- (3-oxo-3,4-dihydro-2H-benzo [b] [1,4] thiazin-7-yl) -N- (3-methyl-4 - ((6R, 9S) 1 H--6,9metanooktahydro pyrido [1,2-a] pyrazin-2-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND AA ο-A¹</td><td>0</td><td>AND</td>

<td>280</td><td>4- (6 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (3-methyl-4- (1,4-diazabicyclo [3.2 .2] nonane-4-yl) phenyl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>AND AND"</td><td>in</td><td>AND</td>

<td>281</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-cyjano4- (3,9-diazabicyclo [3.3.2] decan-10-one-3-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CN</td><td>-</td><td>_rAND'^!</td><td>.0</td><td>-</td>

<td>282</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H pyrido [3,2-f] [1,4] oxazin-7-yl) -A- (3-cyano-4-</td><td>0</td><td>1</td><td>H</td><td>CN</td><td>-</td><td></td><td></td><td>-</td>

-267-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td>(3,9-diazabicyclo [3.3.2] decan-10-one-3-yl) phenyl) pyrimidin-2-amine</td><td></td><td></td><td></td><td></td><td></td><td>H₃C _ns* 1Y5 H</td><td>.0 Ά "</td><td></td>

<td>283</td><td>4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (3- (dimethylamino) -8- azabicyclo [3.2.1] octan-8-yl) phenyl) pirymidyno2- amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>αχ</td><td>CFH₃XP^B'</td><td>AND</td>

<td>284</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (3- (morpholin-4-yl) -8-azabicyclo [3.2.1] octan-8-yl) phenyl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>about</td><td>x °</td><td>AND</td>

<td>285</td><td>4- (6- (tetrahydropyran-4-yloxy) pyridin-3-yl) -N- (3-methyl-4- (3- (morpholin-4-yl) -8-azabicyclo [3.2.1] octan-8-yl) phenyl) -amine pirymidyno2</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>αχ</td><td>,and'·'</td><td>AND</td>

<td>286</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (3-methyl-4- (3- (dimethylamino) -8-azabicyclo [3.2.1] octan-8-yl) phenyl) pyrimidine-2 -amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>&lt;U</td><td>CFH₃</td><td>AND</td>

-268-

<td colspan="10">TABLE 3</td>

<td colspan="10">IC50 activity: A = &lt;1 μΜ (^R^ (r²v _s B = 1 to 10 μΜ fp 1 y jj (I-2) C =&gt; 10 to 20 μΜ D =&gt; 20 μΜ</td>

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>54</td><td>4- (6- (dimethylamino) pyridin-3-yl) -N- (6 - ((1S, 4S) -5-metylo2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl ) pirymidyno2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>JFY H₃(k X &lt;0³ NN 1 ch₃</td><td>&lt;N '^CH3</td><td>B</td>

<td>55</td><td>4- (6- (methylcarbonylamino) pyridin-3-yl) -N- (4 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine -2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>And JJ h₃cnn³ H</td><td>&lt;N '^CH3</td><td>B</td>

<td>56</td><td>4- (4- (dimethylamino) phenyl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>1 ch₃</td><td>&lt;&gt; N^ch' "</td><td>B</td>

<td>57</td><td>4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) pyridin-3-yl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td></td><td>^? N '^CH3</td><td>B</td>

-269-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Xn n HsC ^ nA 0</td><td></td><td></td>

<td>58</td><td>4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (6 - ((15,45) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) pyridin-3-yl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>^Η3 °% γ Α ' &lt;V</td><td>an '^CH3χΜ</td><td>B</td>

<td>61</td><td>4- (6- (dimethylamino) pyridin-3-yl) -N- (5-methyl-6 - ((15,45) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridine -3ylo) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>JFY^h'^c'n^ANDAND AND CHG</td><td>A A "'</td><td>AND</td>

<td>62</td><td>4- (4- (dimethylamino) phenyl) -N- (5-methyl-6 - ((15,45) - (5-metylo2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3- yl) pirymidyno2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>pr^v^H3% AX 1 CHG</td><td>&lt;X^CH3\ 'V</td><td>B</td>

<td>63</td><td>4- (6- (4-acetyl-piperazin-1-yl) pyridin-3-yl) -N- (5-methyl-6 ((15,45) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>XT H₃C nJ 0</td><td>an '^CH3</td><td>B</td>

-270-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>64</td><td>4- (5-methyl-6- (morpholin-4-yl) pyridin-3-yl) -N- (5-methyl-6 ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>&lt;V</td><td>P&gt; N '^CH' From</td><td>AND</td>

<td>65</td><td>4- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) N- (5-methyl-6 - ((1S, 4S) - 5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>° C xy NN 1 ch₃</td><td>P&gt; n '^CH3From</td><td>AND</td>

<td>66</td><td>4- (6- (morpholin-4-yl) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2 yl) pyridin-3-yl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>^ yy ABOUT "</td><td>&lt;N '^CH3From</td><td>B</td>

<td>131</td><td>4- (4- (t-butylcarbonylamino) phenyl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>^H3_tionAND_nXX^HSC ch₃^h</td><td>&lt;X^CH3From</td><td>AND</td>

<td>138</td><td>4- (2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -N- (5-methyl-6 - (( 1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>h₃c π "^ηΎΎΥ H</td><td>&lt;N '^CH3From</td><td>AND</td>

-271-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>140</td><td>4- (4- (3-cyklopropyloureido) phenyl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl ) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>Η H</td><td>&lt;&gt; N '^CH3</td><td>B</td>

<td>144</td><td>4- (6- (2- (morpholin-4-yl) acetamido) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>H</td><td>&lt;? N '^CH3</td><td>B</td>

<td>145</td><td>4- (6-aminopyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3- yl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>eg "</td><td>&lt;X^CH3</td><td>AND</td>

<td>146</td><td>4- (6- (acetamido) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridine -3ylo) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>0 h₃AP³ H</td><td>&lt;X^CH3</td><td>B</td>

<td>154</td><td>4- (6- (methylsulfonylamino) pyridin-3-yl) -N- (5-methyl-6 ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>0^H3^CP_NA&gt; 0 H</td><td>&lt;Ν ' "³</td><td>D</td>

<td>177</td><td>4- (2- (dimethylamino) thiazol-4-yl) -A- (6 - ((1α, 45) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3 yl) pyrimidin-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>^HP ISL _Ve.g. yp h₃Æ</td><td>&lt;N '^CH3</td><td>D</td>

-272-

<td>No. Winner.</td><td>The name of the Union</td><td>n</td><td>m</td><td>R¹</td><td>R²</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>IC50</td>

<td>180</td><td>4- (5- (morpholin-4-yl) pyrazin-2-yl) -N^r- (6 - ((15,45) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine</td><td>0</td><td>0</td><td>H</td><td>-</td><td>-</td><td>° P</td><td>&lt;? N '^CH3χΟ¹</td><td>B</td>

<td>236</td><td>4- (1- (pyridin-4-yl) -1H-indol-5-yl) -N^r- (5-methyl-6 - ((15 ', 45) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidin-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>What* 0</td><td>&lt;Tn '^CH3x^NP</td><td>AND</td>

<td>266</td><td>4- (6 - ((15 ', 45) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-3-yl) -N- (5-methyl-6 - ((1S, 4S ) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) pyrimidine-2-amine</td><td>0</td><td>1</td><td>H</td><td>CH3</td><td>-</td><td>O * O ^N</td><td>&lt;Tn '^CH3χΆ</td><td>AND</td>

Dorota Rzążewska Patent attorney

-273-