Pyrimidine derivatives as kinase inhibitors

COMPOUNDS AND COMPOSITIONS USED AS KINASE PROTEIN INHIBITORS

Cross-references to related requests

The present application claims the benefit of the United States Provisional Applications (5) serial number 61/075 583, filed June 25, 2008, and serial number 611155,434, filed February 25, 2009, each of which are incorporated herein by reference in its entirety.

Technical Field The present invention relates to protein kinase inhibitors, and more particularly, to novel pyrimidine derivatives and pharmaceutical compositions thereof, and their use as pharmaceuticals.

Technical background

Insulin-like growth factor (IGF-1) signaling is particularly implicated in cancer, with the IGF-1 receptor (IGF-1R) being predominant. IGR-1 R is important for tumor transformation and survival of malignant cells, but is only partially involved in the growth of normal cells, targeting IGF-1R has been suggested to be a promising option of cancer therapy. (Larsson et al., Br. J. Cancer 92: 2097-2101 '(2005)).

Anaplastic lymphoma kinase (ALK), belonging to the insulin receptor tyrosine kinase superfamily, has been implicated in the oncogenesis of hematopoietic and non-hematopoietic tumors. The aberrant expression of

م

ΜΑ 32497Β1

Cemplet ALK receptor proteins have been reported in neuroblastomas and glioblastomas, and ALK fusion proteins have been involved in anaplastic large cell lymphoma. The study of ALK fusion proteins has also raised the need for new therapeutic treatments for patients with ALK positive malignancies. (Pulford et al., Cell. Mol. Life Sci. 61: 2939-2953 (2004)).

Due to the roles of IGF-1R and ؛'ALK associated with emerging diseases, there is a continuing need for compounds which may be useful in treating and preventing disease, sensitive to inhibition of IGF-1 R and of the ALK.

Description of the invention

The present invention relates to novel pyrimidine derivatives and pharmaceutical compositions thereof, and their use as pharmaceuticals.

In one aspect, the present invention provides a compound of Formula (1):

<img file="MA32497B1_D0001.tif" />

or a physiologically acceptable salt thereof;

wherein ring E may optionally contain a double bond:

one of z١ Z² and Z³ is NR٩ NR) o or S (O) i-2, and the others are CR2:

R 1 is halogen or optionally halogenated C1-6 alkyl:

R² is a monocyclic pyridin-2-onyl, azepan-2-onyl or heteroaryl of 5-6 atoms having 1-3 heteroatoms selected from N, 0 and s: each of which is optionally substituted with R⁹, where R⁹ is C1-6alkyl, C1-6 haloalkyl or C3-7 cycloalkyl:

R³ and R4 are each H:

ΜΑ 32497Β1

R٥ is halogen, hydroxyl, C1-6alkyl, C1-6alkoxy, halogen-substituted C1-6alkyl, halogen-substituted C1-6alkoxy, cyano or C (0) Oo.iR٥;

R⁶ is H; C 1-6 alkyl, C alkenyl₂٠6 or C2.6 alkynyl, each of which may be optionally substituted by halogen and / or hydroxyl groups: 5 (CR₂) p-OR7, - (CR₂) CHCH (OH) C٠F₂m where t is 1-3. (CR₂) P-CN; (CR₂) p

NR (R7) ٠ (CR₂) p C (O) OR7) (CR₂) pNR (CR₂) pOR7, (CR₂) pNR-lC (O) R8, C (O) (CR₂) qOR٥, -C (O) O- (CR₂) p NRR7٠ -c (o) - (CR₂) p-OR7, LY, LC (O) R7, -LC (O) -NRR7, -LC (O) -NR- (CR₂) p-NRR7.-1C (O) NR (CR₂) pOR7, -LC (O) (CR₂) q-NR-C (O) -R8, -LC (O) NR (CR₂) pSR7, -LC (O) NR (CR₂) pS (O) i-₂R8, -LS (O)₂R٥, 10 LS (0)₂- (CR₂) q-NRR7, -LS (0)₂NR (CR₂) pNR (R7) or LS (O)₂NR (CR₂) pOR7:

according to another solution, R⁶ is a radical selected from formula (a), (b), (c) or (d):

<img file="MA32497B1_D0002.tif" />

<img file="MA32497B1_D0003.tif" />

(d)

R٦٥ is O, S, NR٠ where r17 is H, C1-6 alkyl, SOR or CO₂R^8a ;

Rll, R₂, Ri3, R14, Ri5 and R¹⁶ are independently selected from H: C 1-6 alkoxy: C 1-6 alkyl, C alkenyl₂-6 or C-alkynyl₂.6, each optionally being substituted with a halogen, amino or hydroxyl group; or R^٦1 and R1٩ r¹² and RI 5, R ^ ٥ and R٩8. r13 and r14, or r13 and R٩ as well as the atoms to which they are attached, can form a saturated, unsaturated, or partially unsaturated ring of

1 3-atom containing 1 to 3 heteroatoms selected from N, o and s, and optionally substituted with an oxo and 1 to 3 R groups⁵ :

l is (CR₂) i-4 or a link:

Y is a C3-7 carbocyclic, Ceo aryl or heteroaryl ring of 5-10 atoms or a heterocyclic ring of 4-10 atoms, each optionally substituted with 1-3 R٥ groups:

MY

32497Β1

R⁷, r8 and R٥ are independently C1-6 alkyl, C2-6 alkenyl or C2-61 alkynyl each of which may be optionally substituted with halogen, amino, hydroxyl or cyano; (CR2) gY or C1-6 alkoxy: or R⁷ is H:

each R is independently H or C1-6 alkyl;

R and R⁷, as well as N in each NRR⁷ can form a 5-6 atom ring containing 1-3 heteroatoms selected from N, o and s, and optionally substituted with an oxo and 1-3 R groups⁵ ;

m is 2-4:

n is 1-3;

P is 1-4; and q is 0-4.

In one embodiment, the present invention provides a compound of Formula (2):

<img file="MA32497B1_D0004.tif" />

in which one of R^Her, R^Sb and R^5٠ is H and the others are independently halogen, C1-6alkyl, C1-6alkoxy, C1-6alkyl substituted with halogen, cyano or C (0) 0o. R in which R⁸ is C1-6alkyl: and R١ r², R³, r4٠ e, Z ', Z² and Z³ are as defined in Formula (1).

In some examples, Z³ in Formula (2) above is NR⁶ or N (R⁸) O; and

Ζ^Ί and Z² are CH. In other examples, R⁶ is H, C1-6alkyl optionally substituted with halogen and / or hydroxyl groups; - (CR2) POR⁷, - (CR2) p-CH (OH) C ؛ F2t + i, where t is 1-3, LY,

VIA 32497Β1 (CR2) p-CN: (CR2) p-NR (R7), - (CR2) pC (O) OR7, C (O) (CR2) ٩OR٥٠ -C (0) 0- (CR2) p

NRR

-LC (0) R7, -LC (O) -NRR7, -L — C (O) -NR- (CR2) p-NRR7, -L — C (0) - (CR2) ٩-NR-C (0 ) 5 -LS (0) 2R٥, -LS (O) 2- (CR2) q-NRR7, or one of the radicals of formula (a), (b), (c) or (d):

Ria r14 (b)

R٦٥is O, S, MRI ?, where Rest H, C1-6alkyl, SO2ROU CO₂R٥^at : R٥^atis C1-6 alkyl: and r7, r⁸, R1٥, R11 r12 r13 r14 r15 r16 r. L, Y, p and q are as defined in

Formula 1).

In Formula (1) and (2) above, r2 can be pyrazolyl, isoxazolyl, pyridin-2-onyl or azepan-2-onyl. cliacun being optionally substituted by C 1-6 alkyl. C1-6 haloalkyl or C3-7 cycloalkyl.

In another aspect, the present invention provides a compound of Formula (3):

r (3)

OR a tautomer of it:

ΜΑ 32497Β1 where R is H: and R⁵⁹ and R are independently halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 halogen-substituted, cyano or C (0) Oo٠R wherein R8 is C1-6 alkyl:

z٦ and Z2 are CH² :

Z³ is IR or N (R®) o:

R⁶ is H, C1-6 alkyl optionally substituted by halogen and / or hydroxyl groups: - (CR2) P-OR7, - (CR₂) p-CH (OH) CtF2t٠i, where t is 1-3, (CR2) p-CN: (CR2) pNR (R7),

- (CR2) pC (O) OR7, C (O) (CR2) qOR٥, -C (O) O- (CR2) p NRR7, LY, -lC (0) R7, -LC (O) 10 NRR7, - LC (O) -NR- (CR2) pNRR7, -lC (O) - (CR2) ٩-NR-C (O) -R8, -LS (O) 2R٥,

-l_-S (O) 2- (CR2) qNRR7, or one of the radicals of formula (a), (b), (c) or (d):

جي ٠ ٠

(d) ٥ ٥ (٠) (¢ ٥ (ه)

R1٥ is O, S, NR7 where R١7 is H, C1-6 alkyl, SO2R8⁹ or CO2R8⁹ ; R٥^atis C1-6alkyl; and

Ri, R٥٠ R4, R7, r8, Rio, Rii, Riz, R٩ R. r15٠ r16٠ r. ٠ ا γ٠ ρ٠ g and E are as defined in Formula (1).

In the Fomnula (3) above, R⁵⁹ may be halogen and Rest C-alkyl. In some examples, rG is C1-6 alkyl or a radical of formula (a) or (c); and Resto.

In Formulas (1), (2) and (3) above. Ri can be a halogen. In specific examples. Ri is a chloro. In other examples, R³ and r4 are H.

In another aspect, the present invention provides a compound of Formula (4):

ΜΑ 32497Β1 (4)

جد ٠

R ، &lt;Λ مي or a physiologically acceptable salt thereof:

wherein X is a monocyclic heterocycle of 5 to 6 atoms containing from 1 to 3 heteroatom (s) selected from N, 0 and s, and optionally substituted on a carbon substitutable with oxo and any nitrogen substitutable with R®:

Ri is halogen;

R³ and r4 are each H:

R® is halogen, hydroxyl, C1-6alkyl, C1-6alkoxy, halogen-substituted C1-6alkyl, halogen-substituted C1-6alkoxy, cyano or C (0) 0o-R;

R® is H: C1-6 alkyl, C2-6 alkenyl or 2.6 ء alkynyl&gt; each of which may be optionally substituted with halogen and / or hydroxyl groups; (CR2) p-OR7٠ - (CR2) p-CH-CH (OH) C٠F2fi where t is 1-3, (CR2) P-CN: (CR2) P NR (r7) ٠ - (CR2) pC (O ) OR7, (CR2) pNR (CR2) pOR7, (CR2) pNR-tC (O) R٥,

C (O) (CR2) qOR®, -C (O) O- (CR2) p-NRR7, -C (O) _ (CR2) pOR7.1-Υ,

-LC (O) R7, -LC (O) -NRR7, -lC (0) -NR- (CR2) pNRR7, -LC (0) NR (CR2) pOR7٠ -lc (o) (CR2) ٩-NR- C (O) -R®٠ -LC (O) NR (CR2) pSR7. -LC (O) NR (CR2) pS (O) i.2R8, LS (O) 2R8, -LS (O) 2- (CR2) q-NRR7٠ -LS (O) 2NR (CR2) pNR (R7) or LS (O) 2NR (CR2) pOR7:

according to another solution, r8 is a radical selected from the formula (a), (b), (c) or (d):

٠ جت؟ 1 ؛

(d) ٥٠ (٠) (b) ٠ ده)

Rio is O, S, nR7, where r17 is H, C1-6alkyl, S٠2R8a or CO₂R^8a ;

//

32497Β1

Ru, R, Ri3, Ri4. Ris and R٦٠s٥nt independently selected from H: C1-6 alkoxy: C6 alkyl C2-6 alkenyl or C alkynyl₂-6&gt; each of which may be optionally substituted with a halogen, amino or hydroxyl group; or R11 and r12, r12 and Rⁱ⁵, Ris and Ri⁶, r13 and R٦4٠ or R١³ and r15, along with the atoms to which they are attached, may form a saturated, unsaturated, or partially unsaturated ring of 3 to 7 atoms containing 1 to 3 heteroatoms selected from N, o and s, and optionally substituted with an oxo and 1 to 3 groups R⁵ :

L is (CR₂) i-4 or a bond;

Y is a C3-7 carbocycle, C 1-10 aryl or heteroaryl of 5-10 atoms or a heterocycle of 4-10 atoms, each optionally substituted with 1-3 groups

R⁵;

R⁷, R٥ and R٥a are independently C 1-6 alkyl, C 1-6 alkenyl₂.6 or C-alkynyl₂.6 each of which may be optionally substituted with halogen, amino, hydroxyl or cyano; (CR₂) gY or C1-6 alkoxy: or R⁷ is H;

each R is independently H or C1-6alkyl:

R and R⁷, as well as N in each NRR⁷ can form a 5-6 atom ring containing 1-3 heteroatoms selected from N, o and s, and optionally substituted with an oxo and 1-3 R groups⁵ ;

mest 2-4:

n is 1-3:

p is 1-4; and q is 0-4.

In the foregoing Formula (4), X may be morpholinyl, piperazinyl, piperazin2-0nyl, oxazolidin-2-onyl or piperidin-2-onyl, each being substituted on any nitrogen which can be substituted by C1-6 alkyl: or X is a tetrahydro-2H-pyran-2-onyl; and R¹ is a chloro.

ΜΑ 32497Β1

In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formulas (1), (2), (3) and (4), and a physiologically acceptable excipient.

In another aspect, the invention provides methods for inhibiting IGFI R in a cell, comprising contacting the cell with an effective amount of the compound of Formulas (1), (2), (3) and ( 4) or a pharmaceutical composition thereof.

[001 The present also provides methods for treating, ameliorating or preventing a condition responsive to inhibition of IGF-1R or anaplastic lymphoma kinase (AlK) in a mammal suffering from said condition, comprising administration to said mammal in a therapeutically effective amount of a compound of Formulas (1), (2), (3) and (4) or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent. According to another solution, the present invention provides for the use of a compound of Formulas (1), (2), (3) and (4), and optionally in combination with a second therapeutic agent. in the manufacture of a medicament for treating a condition mediated by IGF-IR or ALK. The compounds of the invention can be administered, for example, to a mammal suffering from an autoimmune, posttransplantation, infectious disease or a proliferative cell disorder. In particular examples, the compounds of the invention can be used alone or in combination with a chemotherapeutic agent to treat a proliferative disorder of cells, including, but not limited to, multiple myeloma, neuroblastoma, synovial, sarcoma. Ewing, hepatocellular carcinoma, synovial or solid tumor, selected from osteosarcoma, melanoma, and breast, kidney, prostate, colorectal, thyroid, ovarian, panceatic, pulmonary, uterine or gastrointestinal.

Definitions "Alkyl" refers to a moiety and as a structural element other groups, for example, halogen-substituted alkyl and alkoxy, can be straight chain or branched. An optionally substituted alkyl, alkenyl, or alkynyl, as used herein may be optionally halogen (eg, CF3), or may have one or more carbon atoms substituted or replaced by one.

WA 32497Β1 heteroatom, such as an NR, o or s (eg, -OCHCHO-, alkylthiols, thioalkoxy, alkylamines, etc.).

"Aryl" actually refers to a fused monocyclic or bicyclic aromatic ring containing carbon atoms. The term arylene denotes a divalent radical derived from an aryl group. For example, an aryl group can be a phenyl. indenyl, indanyl, naphthyl. or 1,2,3,4-tetrahydronaphthalenyl, which may be optionally substituted in the ortho, meta or para position.

The term "heteroaryl," as used herein, is defined as for aryl above, where one or more of the ring members are heteroatoms. For example, a heteroaryl substituent used in the compounds of the invention may be a monocyclic or bicyclic heteroaryl of 5-10 atoms containing 1-4 heteroatoms selected from N, o, and s. Examples of he roaryls include, but are not limited to, pyridyl, pyrazinyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl. benzothiopyranyl. benzofisdioxole. imidazolyl, benzoimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyrazolyl, thienyl, pyrrolyl, isoquinolinyl, purinyl, tliiazolyl, tetrazinyl, benzothiazolyl. benzoxadiazolyl, etc.

A "carbocyclic ring" for the purposes of the present refers to a saturated or partially unsaturated, fused bicyclic or bridged polycyclic ring containing carbon atoms, which may be optionally substituted, for example, by = 0's. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.

A "heterocyclic ring" for the purposes of the present is as defined for a carbocyclic ring above, wherein one or more carbon atoms of the ring is a heteroatom. For example, a heterocycle used in the compounds of the invention may be a 4-7 atom heterocycle containing 1-3 heteroatoms selected from N, 0 and s or a combination thereof, such as -S (0) or -S (O) 2-. Examples of erocyclics include, but are not limited to, azetidinyl, morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, 1,4-dioxa-8-aza-spiro [4] dec-8 -yl, 1,2,3,4-tetrahydroquinolinyl, etc.

ΜΑ 32497Β1

Heterocycles as used herein can include bicyclic amines and diamines.

For the purposes herein, an H atom in all substituent groups (eg, CH) includes all suitable isotopic variants, eg H, ²H and ³H.

the term "drug combination", as used herein, refers to a product obtained from the mixture or combination of the active ingredients, and includes both fixed and unfixed combinations of the latter. The term "fixed combination" means that the active substances, for example a compound of Formula (1) and a co-agent, are both administered to a patient simultaneously as a single unit or pharmaceutical presentation. . The term "non-fixed combination" means that the active ingredients, for example, a compound of Formula (1) and a co-agent, are both administered to a patient as separate entities, simultaneously, concomitantly or sequentially, without specific limits regarding the intervals between doses, such administration ensuring therapeutically effective levels of the active ingredients in the body of the patient. This latter consideration also applies to multiple therapy, eg administration of one or more active substances.

Mammal actually referred to any animal classed as such, including man, domestic and female animals, and ZOO, sport, OR pets, such as dogs, cats, cattle, horses, sheep, pigs, goats , rabbits, etc. In particular examples, the mammal is man.

The term "administration" of the object compound means the provision of a compound of the invention and a drug precursor thereof to a subject in need of treatment. Administration in combination with one OR more other therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order, and by any route of administration.

An effective amount of a compound is an amount sufficient to achieve a specific purpose. An effective amount can be determined empirically and routinely, in relation to the specific objective.

VIA 32497Β1 the term therapeutically effective amount refers to an amount of a compound (eg, IGF-1R) effective to treat a disorder mediated by IGF-1R in a subject or mammal. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells, reduce the size of tumors, inhibit (slow down to a certain degree and preferably stop) the infiltration of cancer cells into peripheral organs, inhibit (slow down to some degree and preferably stop) tumor metastasis; to inhibit tumor growth to some degree, and / or to relieve to some degree one or more of the symptoms associated with cancer. See definition of treatment herein. Since the drug can inhibit the growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic.

The term cancer refers to the physiological state of mammals which is generally characterized by unregulated cell growth / proliferation. Examples of cancer include, but are not limited to: carcinoma, lymphoma, blastoma and leukemia. More specific examples of cancer include, but are not limited to: chronic lymphocytic leukemia (CLL), lung, including, non-small cell lung cancer (NSCLC), breast, ovaries, cervix 1 'uterus. endometrium, prostate, colon, bowel carcinoid, bladder, gastric, pancreatic, hepatic (hepatocellular), hepatoblastoma, esopliageal, pulmonary adenocarcinoma, mesothelioma, synovial sarcoma, osteosarcoma, epidermoid carcinoma of the head and elbow , juvenile nasopharyngeal angiofibromas, liposarcoma, thyroid, melanoma, basal cell carcinoma (CBC), medulloblastoma and desmoid.

Treat, cure or relief refers to both therapeutic treatment and propliylactic or preventive measures, in which the object is to prevent or slow down (alleviate) the disease or disorder. people in need of treatment include those who already have the disorder, those who may have it, and those in whom prevention of the disorder should be done (prophylaxis). When the IGF-1R mediated disorder is cancer, a subject or mammal is successfully treated or has reduced tumor mass if, after receiving a therapeutic amount of 1GF-1R antagonist according to

VIA

32497Β1 the methods of the present invention, the patient shows an observable and / or measurable reduction in one or more of the following: reduction in the number of cancer cells or absence thereof; reduction in tumor size: inhibition (slowing down to a certain degree and preferably stopping) the infiltration of cancer cells into peripheral organs, including the spread of cancer to soft tissues or bones: inhibition (( slowing to a certain degree and preferably arresting tumor metastasis; inhibition, to some degree, of tumor growth: and / or relief to some degree of one or more symptom (s) associated) with the specific cancer, reduced morbidity and mortality, and improvement quality of life. Since the 1GF-1R antagonist can inhibit the growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. The patient may also feel the reduction of these signs or symptoms.

Carriers as used herein, include pharmaceutically acceptable carriers, excipients or stabilizers non-toxic to the cell or mammal exposed at the dosages and concentrations employed. The physiologically carrier is often a buffer solution at aqueous pH. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids: antioxidants including ascorbic acid: low molecular weight polypeptide (less than about 10 residues): proteins, such as serum albumin , gelatin, or immunoglobulins: hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine or lysine: monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins: chelating agents such as EDTA: sugar alcohols, such as mannitol or sorbitol: opposite salifiable ions such as sodium; and / or nonionic surfactants such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.

A chemotherapeutic agent is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include agents such as thiotepa and cyclosphospliamide CYTOXAN®: alkylsulfonates such as

MY

32497Β1 busulfan, improsulfan, and piposulfan: aziridines such as benzodopa, carboquone, meturedopa, and uedopa; ethylenimines and methylamelamines comprising altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolmelamine: acetogenines (in particular bullatacin and bullatacinone): delta-9-tetrahydrocannabinol (dronOL®); beta-lapachone: lapacliol: colcilicins: betulinic acid: camptothecin (including the synthetic analogue topotecan (HYCAMTIN®), CPT11 (irinotecan, CAMPTOSAR®), acetylcamptothecine, scopoletin, and 9aminocamptothecine): bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelsin and bizelesin): podophyllotoxin; podophyllinic acid; teniposide: cryptophycins (in particular cryptophycin 1 and cryptophycin 8): dolastatin: duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1): eleutherobin: pancratistatin: sarcodictyin: spongistatin: nitrogen mustards, such as as chlorambucil, chlornaphazine, chlophosphamide. estramustine, ifosfamide, mechloethamine, mechloethamine oxide hydrochloride, melphalan, novembichine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitroso-urees, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (eg, calicheamicin, especially calicheamicin gamma II and calicheamicin omega II (see, eg, Agnew, Chem Intl. Ed. Eng., 33: 183-186 (1994)); dynemicin, including dynemicin A: esperamicin; as well as the chromophore neocarzinostatin and related antibiotic chromophores enediyne chromoproteins), aclacinomysins, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, 6X-detunia-0-0-0 n0rleucine, doxorubicin ADRIAMYCIN® (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, such as mitomycin c, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimexor, zubicin, zubicin, zubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterine, methotrexate, pteropterine, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine,

MA 32497131 thiamiprine, thioguanine: pyrimidine analogues such as ancitabine, azacytidine, eazauridin, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol. mepitiostane, testolactone: anti-adrenal agents such as aminoglutethimide, mitotane, trilostane: folic acid renewal agents such as frolinic acid: aceglatone; aldophosphamide-glycoside: aminolevulinic acid: eniluracil; amsacrine: bestrabucile; bisantene; edatraxate; defofamine: demecolcine: diaziquone; elfornithin; Elliptinium acetate: an epothilone: ​​etoglucide; gallium nitrate:! 'hydroxyuree: lentinan; lonidamine: maytansinoids such as maytansine and ansamitocins; mitoguazone: mitoxantrone; mopidamol; nitracin; pentostatin; phênamet; pirarubicin; losoxantrone; 2ethylhydrazide; procarbazine; the PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.): razoxane: rhizoxin: sizofuran: spirogermanium; tenuazonic acid: triaziquone: 2,2 ', 2٠ trichlorotriethylamine: trichothecenes (in particular Τ-2 toxin, verracurin A, roridin A and anguidin); urethane: vindesine (EtDISINE®, FILDESIN®): dacarbazine; mannomustine: mitobronitol; mitolactol; pipobroman: gacytosine; arabinoside (Ara-C): thiotepa: taxoids, p. eg, TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ). ABRAXANE ™ Cremophor-free, nanoparticulate formulation of paclitaxel, made from albumin (American Pharmaceutical Partners, Schaumberg, III.), And doxetaxel TAXOTERE® (Rhone-Poulenc Rorer, Antony, France): chlorambucil; gemcitabine (GEMZAR®); 6-thioguanine: mercaptopurine; methotrexate: platinum analogs such as cisplatin and carboplatin; Vinblastine (VELBAN®); platinum: etoposide (VP-16); ifosfamide: mitoxantrone; vincristine (ONCOVIN®); oxaliplatin; leucovovine; vinorelbine (NAVELBINE®); novantrone: edatrexate; daunomycin:! Aminopterin: ibandronate; the RFS 2000 topoisomerase inhibitor: difluoromethylonithine (DMFO); retinoids such as etinoic acid: capecitabine (XEIODA®): pharmaceutically acceptable salts, acids, or derivatives of any of the aforementioned compounds, such as CHOP, short for a combined therapy of cyclophosphamide, doxorubicine, vincristine , and prednisolone, and FOLFOX,

كر

MA 32497131 Abbreviation of a treatment regimen with oxaliplatin (ElOXATIN) in combination with 5-FU and leucovovine.

In addition, a chemotherapeutic agent may include anti-hormonal agents whose action regulates, reduces, blocks or inhibits the effects of hormones that cause cancer growth, and which often take the form of treatment. systemic or whole body. It could be the hormones themselves. Examples include antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen NOLVADEX®), raloxifene EVISTA®, droloxifene, 410 hydroxytamoxifene, trioxifene, keoxifene, LYL17018, onapristone, and toremifene FARESTON®; anti-progesterones: negative regulators of estrogen receptors (ERDs); agents responsible for ovarian suppression or arrest of ovarian function, for example, luteinostimulin releasing hormone (LHRH) agonists such as LUPRON® and leuprolide acetate ELIGARD®, goserelin acetate, acetate buserelin and triterelin: other anti-androgens such as flutamide, nilutamide and bicalutamide: and aromatase inhibitors which inhibit the aromatase enzyme regulating estrogen production in the adrenal glands, such as, for example, 4 (5) -imidazoles, aminoglutethimide, megestrol acetate MEGASE®, exemestane AROIMASIN ®, formestane, fadrozole, vorozole RIVISOR®, leprozole FEMARA®, and anastrozole ARIIMIDEX®. This definition of chemotherapeutic agents further includes bisphosphonates such as clodronate (eg, BONEFOS® or OSTAC®), etidronate DIDROCAl®, ΝΕ-58095, zoledronic acid / zoledronate ZOMETA®, alendronate FOSAIMAX®, pamidronate

AREDIAO, SKELID® tiludronate, or ACTONEL® risedronate; as well as troxacitabine (cytosine nucleoside analogue 1,3-diOX0lane): antisense oligonucleotides, in particular those which inhibit the expression of genes in signaling pathways involved in aberrant cell proliferation, such as, for example, PKC- alpha, Raf, Η-Ras, and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® and gene therapy, for example, ALIOVECTIN®, IEUVECTIN®, and VAXID®; LURTO7ECAN® topoisomerase I inhibitor; ABARELIX® rmRH: lapatinibe ditosylate (small molecule inhibitor of the double tyrosine kinase ErbB-2 and EGFR, also

ΜΑ 32497Β1 known under the name GW572O16): and pharmaceutically acceptable salts, acids or derivatives of any of the above compounds.

Embodiments of the invention

The invention provides novel pyrimidine derivatives and their pharmaceutical compositions, and methods of using them.

In one aspect, the present invention provides a compound of Formula (1):

<img file="MA32497B1_D0005.tif" />

or a physiologically acceptable salt thereof:

wherein ring E may optionally contain a double bond:

one of z١ Z² and Z³ is NR٩ N (R⁶)⁺-O٠ or s (o) i.2 and the others are CR2; R is halogen or C1-6 alkyl optionally halogen:

R² is a pyridin-2-onyl, azepan-2-onyl or monocyclic heteroaryl of 5-6 atoms having 1-3 heteroatoms selected from N, o and s: each of which is optionally substituted by R⁹, where R⁹ is C1-6 alkyl, haloalkyl

C1-6 or C3-7 cycloalkyl;

R³ and R4 are each H:

r5 is halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, halogen-substituted C1-6 alkyl, halogen-substituted C1-6 alkoxy, cyano or C (0) 0o-R;

R⁶ is H: C1-6alkyl, C2-6alkenyl or C2-6alkynyl, each of which may be optionally substituted with halogen and / or hydroxyl groups: (CR2) p-OR7. - (CR2) p-CH-CH (OH) CrF2fi where t is 1-3, (CRz) p-CN; (CRz) p NR), - (CR2) pC (O) OR7. (CR2) pNR (CR2) pOR7, (CR2) pNR-LC (O) R³,

C (O) (CR2) ٩OR8, -C (O) O- (CR2) p-NRR7, -c (o) _ (CR2) pOR7, LY,

I 32497Β1

-l - C (O) R⁷, -LC (0) -NRR7, -LC (O) -NR- (CR2) pNRR7٠-LC (O) NR (CR2) pOR٢, -tc (o) (CR2) ٩-NR-C (O) -R٥ , -LC (O) NR (CR2) pSR⁷, -LC (O) NR (CR2) pS (O) i.2R٥٠ LS (O) 2R8٠ -LS (O) 2- (CR2) q-NRR۶٠ -LS (O) 2NR (CR2) pNR (R⁷) or LS (O) 2NR (CR2) pOR⁷;

according to another solution) R⁶ is a radical selected from formula (a), (b), 5 (c) or (d):

<img file="MA32497B1_D0006.tif" />

<img file="MA32497B1_D0007.tif" />

-جي

R 0 is O, S, NR٦ where r17 is H٠ C alkyl₁-6, SO₂R^8a or CÜ2R٥^at ;

Rii. r12 r¹³, r14 Ri® and R³® are independently selected from H: C1-6 alkoxy: C1-6 alkyl, C2.6 alkenyl or ا6-2ء alkynyl each of which may be optionally substituted with a halogen, amino or hydroxyl group; or R11 and r12, R¹² and R¹®, Ri® and Ri®, R¹³ and r14, or R^٦3 and Ri®, as well as the atoms to which they are attached, may form a saturated, unsaturated, or partially unsaturated ring of 3 to 7 atoms containing 1 to 3 heteroatoms selected from N. O and s, and optionally substituted with an oxo and 1 with 3 R® groups:

L is (CR2) 14 or a bond:

Y is a C3-7 carbocycle, C &amp; 10 aryl or heteroaryl of 5-10 atoms or a heterocycle of 4-10 atoms, each optionally substituted with 1-3 groups

R®;

R⁷, R٥ and r8٥ are independently C1-6 alkyl, C2.6 alkenyl or C2-6 alkynyl, each of which may be optionally substituted with halogen, amino, hydroxyl or cyano: (CR2) gY or C1 alkoxy. 6: or R⁷ is H: each R is independently H or C1-6 alkyl;

R and R⁷, as well as N in each NRR⁷ can form a 5-6 atom ring containing 1-3 heteroatoms selected from N, O and s, and optionally substituted with an oxo and 1 -3 R® groups:

را

ΜΑ 32497Β1 mest 2-4:

n is 1-3;

p is 1-4; and q is 0-4.

In one embodiment, the present invention provides a compound of Formula (2):

<img file="MA32497B1_D0008.tif" />

<img file="MA32497B1_D0009.tif" />

wherein one of R, R and R is H and the others are independently halogen, C1-6alkyl, C1-6alkoxy, halogen-substituted C1-6alkyl, cyano or C (0) Oo-R , wherein R٥is C1-6alkyl: and

Ri, R2, r³, r4, e, Z), Z² and Z³ are as defined in Formula (1).

In another aspect, the present invention provides a compound of Formula (3):

NOT

R³

N γ ٢ R r4 r

OR a tautomer of it:

in which R⁵٥ is H; and R^Her and R^sc are independently halogen, C1-6alkyl, C1-6alkoxy, halogen-substituted C1-6alkyl, cyano or C (0) Oo.iR٥, wherein R³ is C1-6 alkyl:

zi and Z² are CH²;

MY

32497Β1

Z³ is NR® or N (R®) 0;

R® is H, C1-6 alkyl optionally substituted with halogen and / or hydroxyl groups; - (CR2) P OR ?, - (CR2) P CH (OH) CtF2t +, where t is 1-3) (CR2) P-CN: (CR2) p-NR (R?) ٠ - (CR2) pC (O) OR? ٠ C (O) (CR2) ٩OR8, -C (O) O- (CR2) p-NRR ?, LY, -L5 C (O) R? ٠ -lC (O) -NRR? ٠ C (O) -NR- (CR2) P-NRR ?. -LC (O) - (CR2) ٩-NR-C (O) -R8, -LS (O) 2R8,

-lS (O) 2- (CR2) q-NRR? ٠ or a radical of formula (a), (b), (c) or (d):

<img file="MA32497B1_D0010.tif" />

<img file="MA32497B1_D0011.tif" />

&lt;Μ

<img file="MA32497B1_D0012.tif" />

<img file="MA32497B1_D0013.tif" />

ج ٠ ل

R is O, S, NR¹⁷ in which Ri? is H, C1-6alkyl SO2R83 or ORSa: R٥a 10 is C1-6alkyl: and

Ri, R³, R⁴, R ?, R٥, Ri٥, R11, r12٠ r13, r14٠ R٦ r16٠ r. l٠ y, p, q and e are as defined in Formula (1).

In another aspect, the present invention provides a compound of Formula (4):

X

R³ R 4) طر ١)

OR a physiologically acceptable salt thereof;

wherein X is a monocyclic h erocycle of 5 to 6 atoms containing from 1 to 3 he ro atom (s) selected from N, o and s, and optionally substituted on a carbon which can be substituted with oxo and any nitrogen which can be substituted with R®:

Ri is halogen:

R³ and R⁴ are each H:

ΜΑ 32497Β1

R⁵ is halogen, hydroxyl, C1-6alkyl, C1-6alkoxy, halogen-substituted C1-6 alkyl, Chalogene-substituted alkoxy, cyano or C (O) O٥-iR٥;

R⁶ is H: C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, each of which may be optionally substituted with halogen and / or hydroxyl groups: 5 (CR2) p-OR7, - (CR2 ) p-CH (OH) C ، F2fi٠ where t is 1-3, (CR2) P-CN: (CR2) P

NR (R7), ٠ (CR2) pC (O) OR7, (CR2) pNR (CR2) pOR7, (CR2) pNR-LC (O) R8, C (0) (CR2) OR8, -C (O) O - (CR2) p-NRR7, -C (O) - (CR2) p-OR7, LY,

-LC (O) R7, -1-C (O) -NRR7, -LC (O) -NR- (CR2) p-NRR7, -1-C (O) NR (CR2) pOR7, -Lc (o) - (cr2) ٩-nr-c (o) -r٥, -LC (O) NR (CR2) pSR7, -LC (O) NR (CR2) pS (O) i-2R٥,

-LS (O) 2R8, -LS (O) 2- (CR2) q-NRR7, -LS (O) 2NR (CR2) pNR (R7) or

-lS (O) 2NR (CR2) pOR7:

according to another solution, R⁶ is a radical selected from formula (a), (b), (c) or (d):

هب ه '1 ؛

(٠) (b) ٠ (ع) (d)

R is O, S, NR, where Rest H, C1-6 alkyl, SO2R^8a0 or C٠2R ^:

R11, R12, R13 R¹٥, Ri⁵ and Ri^eare independently selected from H; C1-6 alkoxy; C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl each of which may be optionally substituted with a halogen, amino or hydroxyl group: or R ”and r12, R12 and R٦ r15 and Ri⁶, R¹³ and R٦ or r13 and R1⁵, as well as the atoms to which they are attached, can form a saturated, unsaturated, or partially unsaturated ring of 1 to 3 he roatoms selected from N, o and s, and optionally substituted with an oxo and 1 to 3 groups R³ ;

L is (CR2) t-4 or a bond;

ΜΑ 32497Β1

Y is a C3.7 carbocycle, C aryl_6٠1O or heteroaryl of 5-10 atoms or a heterocycle of 4-10 atoms, each optionally substituted with 1-3 groups

R٥;

R⁷, R⁸ and R٥3 are independently C1-6alkyl, C2.6alkenyl or 5 ا6-2ء alkynyl each optionally being substituted by halogen, amino, hydroxyl or cyano: (CR2 Y or C1-6 alkoxy; or R⁷ is H:

each R is independently H or C1-6 alkyl:

R and R⁷, as well as N in each NRR⁷ can form a 5-6 atom ring containing 1-3 heteroatoms selected from N, 0 and s, and optionally substituted with an oxo and 1-3 R groups⁸ :

m is 2-4;

n is 1-3;

pest 1-4: and q is 0-4.

In another aspect, the present invention provides compounds of Formula (5):

<img file="MA32497B1_D0014.tif" />

or physiologically acceptable salts thereof:

where X is a 4-7 atom heterocycle containing NR⁸, ٠ ، علمخ Q ٥٧ s, and optionally substituted by 1-3 groups R⁸ :

wherein R is halogen, C1-6alkyl or halogenated C1-6alkyl substitutes:

/

MY

32497Β1

R² is a 5-7 atom heterocycle or an optionally substituted 5-6 atom heteroaryl, each having 1-3 heteroatoms selected from N, 0 and s and optionally substituted with 1-3 R groups⁹ :

R³ and r4 are independently H, C (O) R٥, C 1-6 alkyl or halogen-substituted C1-6 alkyl:

R³ and R⁹ are independently C1-6 alkyl, C2-6 alkenyl or C26 alkynyl, each of which may be optionally substituted with a halogen, amino or hydroxyl group; or R³ and R⁹ are independently C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy. halogen, nitro, cyano, CR (OR7) r7, OR7, O (CR2) p-OR7, NR (R7),

CR (R7) NRR7. (CR2) i-eNR (CR2) pOR7٠ (CR2) i.6NR (CR2) ٩C (O) R³, -C (O) - (CR2) q-NRC (O) -R٥, (CRz) qY, C (0) Oo.iR7, C (O) NR (R7), C (O) CRR7-NR (R7 ),

C (O) NR (CR2) pNR (R7), C (O) NR (CR2) pOR7٠ C (O) NR (CR2) pSR7, C (O) NR (CR2) pS (O) i. 2R8, S (0) o.2R8, S (O) 2NRR7, S (O) 2NR (CR2) pNR (R7), or S (O) 2NR (CR2) p٠R7;

r8 is H: C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, each of which may be optionally substituted with halogen, amino, hydroxyl or alkoxy; - (CR2) P-CN:

C (O) H, CR (OR7) r7) (CR2) p OR7, (CRz) p-NR (R7), CR (R7) NRR7, -LY, -lc (0) 0o.i (CR2) q- R٥, - (CR2) pC (0) Oo.i-R7, -ic (o) -nrr7. -lc (o) Oo-i-cr (r7) -nrr7٠ -lc (o) NR- (CR2) p nrr7. -LC (O) NR (CR2) pOR7, -LC (O) - (CR2) q-NR-C (O) -R8, -LC (O) NR (CR2) pSR7, -LC (٠) NR (CR2 ) pS (O) i-2R8, -LS (٠) 2R8, (CR2) pNR (CR2) pOR7, (CR2) pNR-tC (O) R٥, -LS (O) 2NRR7, -LS (O) 2NR ( CR2) pNR (R7) or LS (O) 2NR (CR2) pOR7 according to another solution, R⁶ is a radical selected from formula (a), (b), (c) or (d):

<img file="MA32497B1_D0015.tif" />

<img file="MA32497B1_D0016.tif" />

<img file="MA32497B1_D0017.tif" />

X

<img file="MA32497B1_D0018.tif" />

(d) in which R r12 r1٩ r14 r and R¹⁶ are independently selected from H or C1-6 alkyl, C1-6 alkoxy; C2.6 alkenyl or C2-6 alkynyl. each of which may be optionally substituted with a halogen, amino or hydroxyl group; or r ”

VIA 32497Β1 and R, R '؛ and R١٥, R¹⁵ and R١٠, R¹³ and R '³, or R '³ and R '؛, together with the atoms of carbon and / or nitrogen to which they are attached, can form a saturated, unsaturated, or partially unsaturated ring of 3 to 3 atoms optionally containing up to 3 atoms or groups selected from c (o), N, o and So-2:

R isOouSOsR

L is (CR2) i-4 or a bond:

Y is a C3.7 carbocycle, C6.10 aryl or heteroaryl of 5-10 atoms or a heterocycle of 4-10 atoms, each optionally substituted with 1-3 groups R⁵;

r7 and R٥ are independently C1-6 alkyl, C2-6 alkenyl or C2 alkynyl. 6, each of which may be optionally substituted with halogen, amino, hydroxyl or cyano: (CR2Y or C1-6 alkoxy: or R? Is H:

each R is H or C1-6alkyl:

m is 2-4:

n is 1-3;

p is 1-4; and q is 0-4.

In Formula (5) above, examples of groups R² 5-7 atom heteroaryl or 5-6 heteroaryl ring include, but are not limited to, the following: pyrazolyl, pyrrolyl, thiophenyl, pyrimidinyl, isoxazolyl, pyridyl, azepan-2-onyl, 2H-thipyran, 3Η- thipyran, 4H-thipyran, tetrahydrothiopyran, 2H-pyran, 4H-pyran, tetrahydropyran, 1,2dithieridine, tetrahydropyran, 1,2dithiéridine, 2-dithiane, 1,3-dithiine, 1, 3-dithiane, 1,4dithüne, 1,4-dithiane, 1,2-dioxin, 1,2-dioxane, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,225 oxathiine, 1,2-0xathiane, 4H-1,3٠oxathiine, 1,3-oxathiane, 1,4-oxathüne, 1,4oxathiane, 2H-1,2 -thiazine, tetrahydro-1,2-thiazine٠ 2Η-1, 3-thiaz ؛ ne٠ 4Η-1, 3-thiazine, 5,6-dihydro-4H-thiazine. 4Η-1, 4-thiazine, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, 4Η-1, 2-0xazine, 6H-1,2-oxazine, 2H-1,3-oxazine, 4H- 1,3-oxazine, 4Η-1, 4-0xazine,

ΜΑ 32497Β1 morpholine, trioxane, 4Η-1, 2,3-trithine, 1,2,3-trithiane, 1,3,5-trithiane, hexahydro1,3, 5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,2dioxole, 1,2-diOXOlane, 1,3-dioxole, 1,3-diOXOlane. 3H-1,2-dithiole, 1,2-dithiOlane, 1.35 dithiole. 1,3-Dithi0lane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, thiazoline, thiozolidine, 3H-1,2-oxathiole, 1.2-0xathi0lane, 5H-1,2-oxathiole, 1,3-oxathiol, 1,3oxathiolane, 1, 2,3-trithiole, 1,2,3-trithiolane, 1,2,4-trithiolane, 1,2,3-trioxole, 1,2,3trioxolane. 1,2,4-triOXOlane, 1,2, 3-triazoline and 1,2, 3-triazolidine.

In each of the above formulas, any asymmetric carbon atom can be present in the (R) -, (S) - or (R, s) configuration. The compounds can thus be present in the form of mixtures of isomers or in the form of pure isomers, for example in the form of enantiomers or of diastereoisomers. The invention further encompasses possible tautomers of compounds thereof.

All formulas presented herein are also intended to represent unlabeled and isotopically labeled forms of the compounds. The structures of isotopically labeled compounds are described by the formulas presented in this document, except that one or more atoms is / are replaced by an atom having an atomic mass or a selected mass number). Examples of isotopes which can be incorporated into compounds of the invention include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ²H, ٥H, ”c, 1٥C, c. N, ٦٥F 31p. 32p. 35٠ ا 25 ا (اح 36 (ج respectively.

The invention includes various isotopically labeled compounds, as defined herein, for example, those having radioactive isotopes, such as ٥H, c, and c. These isotopically labeled compounds are used in metabolic studies (with, for example,¹⁴C), reaction kinetics (with, for example ²H or ³H), detection or imaging techniques, such as positron emission tomography (PET) or gammatomography (GT) including tests for the distribution of drugs or tissue substrates, or in the radioactive treatment of patients. In other examples, a 1٥F or compound mark can be used for PET or GT studies. Isotopic variations of compounds have the potential to alter the metabolic fate of a compound and / or / 7

VIA

32497Β1 create small changes in physical properties, such as hydrophobicity, and the like.

Isotopic variations also have the potential to improve efficacy and safety, improve bioavailability and half-life, modify protein binding, modify biodistribution, increase the proportion of active metabolites and / or decrease the formation of reactive metabolites or toxic. The isotopically branded compounds of the present invention and the drug precursors thereof can generally be prepared by performing the procedures outlined in the Schemes or Examples and preparations described below, substituting an isotopically branded reagent, available, for a nonisotopically labeled reagent.

In each of the above formulas, each optionally substituted moiety may be substituted with C 1-6 alkyl, C 1-6 alkenyl₂-6 or an alkynyl in 0₃ه, each of which may optionally be halogen or optionally having a carbon atom which may be replaced or substituted by N, s, O, or a combination thereof (eg, hydroxyl-C1-C8alkyl&gt; C1-C6-alkoxy . C1-Cg alkyl): halogen, amino, amidino, C1-6 alkoxy: hydroxyl, methylenedioxy, carboxy: C 8 alkylcarbonyl, C-8 alkoxycarbonyl, carbamoyl, C 1-8 alkylcarbamoyl sulfamoyl, cyano, oxo, nitro, or an optionally substituted carbocyclic ring) a heterocyclic ring or an aryl or heteroaryl as previously described.

Pharmacology and utility

The compounds of the invention and the pharmaceutically acceptable salts thereof exhibit evaluable pharmacological properties when tested in vitro in cell-free kinase assays and in cellular assays, and are therefore used as pharmaceuticals.

In one aspect, the compounds of the invention can inhibit insulin-like growth factor receptor 1 (IGF-1R), and can be used in the treatment of diseases mediated by IGF-1R. Examples of diseases mediated by IGF-1R include, but are not limited to, proliferative diseases, such as tumors, eg, kidney tumors, prostate cancer, colorectal cancer, thyroid cancer. , ovarian cancer, cancer of the

ΜΑ 32497Β1 pancreas, brain tumors, uterine cancer, gastrointestinal tumors, as well as osteosarcomas and melanomas, the efficacy of the compounds of the invention as inhibitors of the tyrosine kinase activity of IGF-1R can be demonstrated using the EllSA cell capture assay. This analysis makes it possible to determine the activity of the compounds of the invention as a function of the autophosphorylation induced by IGF-1 R.

(In another aspect, the compounds of the invention may inhibit the tyrosine kinase activity of the anaplastic lymphoma kinase (ALK) and the NPMALK fusion protein. This protein tyrosine kinase results from the fusion of the nucleophosmin genes. (NPM) and ΙΆΙΚ, making the activity of this protein independent of that of the ALK ligand. NPM-ALK plays a key role in signal transmission in several hematopoietic cells and other human cells, leading to hematologic and neoplastic diseases, for example, in anaplastic large cell lymphoma (ALCl) and non-Hodgkin lymphomas (NHL) , and more especially, in ΑΙΚ + NHL or ALKomes, inflammatory myofibroblastic tumors (IMT) and neuroblastomas. (Duyster et coli. 2001 Oncogene 20, 56235637). In addition to NPM-ALK, other gene fusions have been identified in human hematologic and neoplastic diseases: for example, ΤΡΜ3-ΑΙΚ (fusion of non-muscular tropomyosin with ALK).

Inhibition of ALK tyrosine kinase activity can be demonstrated using known methods, for example, using the recombinant ALK kinase domain by analogy with the analysis of VEGF-R kinase activity described. in j. Wood and coli. Cancer Res. 60, 2178-2189 (2000). In general, in vitro enzyme assays using GSF-ALK protein tyrosine kinase are performed in 96-well plates as a filter binding assay in 20 mM Tris HCl, pH = 7.5, 3 mM MgC, 10 mM MnC, 1 mM DTT, 0.1 pCi / assay (= 30 μΙ) [γ-3٥Ρ] -ΑΤΡ, 2 μΜ ATP, 3 pg / mL poly (Glu, ٢yr 4: 1) Poly-ΕΥ (Sigma Ρ-0275 ), 1 ٠/٠ DMSO, 25 ng ALK enzyme. The samples are incubated for 10 min at room temperature. The reactions are stopped by adding 50 μΙ of 125 mM EDTA, and the reaction mixture is transferred to a MAIP Multiscreen plate (Millipore, Bedford, MA, USA), previously moistened with methanol, and rehydrated for 5 min with HO. After washing (0.5 ٠/٠ Η3ΡΟ4), the plates are counted in a scintillator at

MY

32497Β1 liquid. IC50 values ​​are calculated by linear regression analysis of percent inhibition.

The compounds of the invention can potentially inhibit the growth of murine BaF3 cells overexpressing ΝΡΜ-ALK in humans (DSMZ Deutsche

Sammlung von Mikroorganismen und Zelikulturen GmbH, Germany). The expression of ΝΡΜ-ALK can be obtained by transfection of the BaF3 cell line with a pCIneo ™ expression vector (Promega Corp., Madison Wl, USA) encoding ΝΡΜ-ALK and the subsequent selection of cells resistant to G418 . Untransfected BaF3 cells depend on IL-3 for cell survival. On the other hand, the BaF3 cells expressing ΝΡΜ-ALK (designated BaF3-NPM-ALK below) can proliferate in the absence of IL-3, since they receive a proliferative signal by the ΝΟΜ-ΑΙΚ kinase. Putative ΝΡΜ-ALK kinase inhibitors therefore suppress the growth signal which may result in antiproliferative activity. The antiproliferative activity of putative NPM15 ALK kinase inhibitors, however, can be compensated by the addition of IL-3, which provides growth signals through a mechanism independent of ΝΡΜ-ALK. An analogous cellular system using the FL٢3 kinase has also been described (see, E. Weisberg et al. Cancer Cell: 1, 433-443 (2002)).

The balancing activity of the compounds of the invention can be determined as follows:

Typically, BaF3-NPM-ALK cells (15,000 / well microtiter plates) are transferred to 96 well microtiter plates. The test compounds dissolved in dimethylsulfoxide (DMSO) are added in a series of concentrations (dilution series) so that the final concentration of DMSO does not exceed 1% (v / v). After the addition, the plates are incubated for two days during which the control cultures without test compound are able to undergo two cycles of cell division. The growth of BaF3-NPMALK cells is measured by YOPRO ™ staining [T Idziorek et coli. j. Immunol. Methods: 185: 249-258 (1995)]: 25 µl of lysis buffer comprising 20 mM sodium citrate, pH 4.0, 26.8 mM sodium chloride, 0.4% à40 and 20 mM d 'EDTA.

are added to each well.

WA 32497Β1

Cell lysis is carried out in 60 min at room temperature, and the total amount of YOPROTh bound to the DNA is determined by the 96-well Cytofluor II 96 reader (PerSeptive Biosystems) with the following parameters:

Excitation: 485/20 nm and emission: 530/25 nm. The compounds of the invention may also be useful in the treatment and / or prevention of acute or chronic inflammatory diseases, autoimmune disorders or diseases, eg. e.g. rheumatoid arthritis, artlirosis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes (type I and II) and associated disorders, respiratory diseases, such as asthma or inflammatory liver disease, inflammatory glomerular involvement, skin manifestations of immunologically mediated disorders or diseases, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact eczema, irritant contact dermatitis and other eczematous dermatitis, seborrheic dermatitis), inflammatory eye diseases, eg. eg, syndrome

Sjoegren, keratoconjunctivitis or uveitis, abdominal inflammatory disease, Crohn's disease or ulcerative colitis.

From the above, the present invention provides:

(1) a compound of the invention used as a pharmaceutical;

(2) a compound of the invention uses an IGF-1R inhibitor, for example, in all of the particular pathologies mentioned above;

(3) a pharmaceutical composition, eg. eg, used in all the pathologies mentioned above, comprising a compound of the invention as active principle, as well as one or more diluents or pharmaceutically acceptable carriers:

(4) a method for the treatment of any particular pathology mentioned above in a subject in need thereof, comprising administering an effective amount of a compound of the invention or of a pharmaceutical composition comprising it;

(5) The use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition.

ΜΑ 32497Β1 pathological in which (which) activation of IGF-1R plays a role or is involved:

(6) the method as defined previously under (4), comprising the COadministration, p. eg, simultaneously or sequentially, a therapeutically effective amount of a compound of the invention and one or more other medicinal substances, which are useful in all of the particular pathologies mentioned above:

(7) a combination comprising a therapeutically effective amount of a compound of the invention and one or more other medicinal substances, which are useful in all of the particular pathologies mentioned above:

(8) use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease responsive to inhibition of anaplastic lymphoma kinase;

(9)! The use according to (8), wherein the disease to be treated is selected from anaplastic large cell lymplioma, non-Hodgkin lymphomas, inflammatory myofibroblastic tumors (IMT), neuroblastomas and neoplastic diseases;

(10) the use according to (8) or (9), wherein the compound is any of the examples OR a pharmaceutically acceptable salt thereof;

(11) a method for the treatment of a disease responsive to inhibition of anaplastic lymphoma kinase, in particular, a disease selected from anaplastic large cell lymphoma, non-Hodgkin lymphoma, inflammatory myofibroblastic tumors (IIMT) , neuroblastomas and neoplastic diseases, comprising the administration of an effective amount of a compound of the invention or of a pharmaceutically acceptable salt thereof.

Pharmaceutical administration and compositions

In general, the compounds of the invention will be administered in therapeutically effective amounts according to any of the usual and acceptable modes known in the art, either alone or in combination with one or more.

ΜΑ 32497Β1 several therapeutic agents. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the activity of the compound used, and other factors known to those skilled in the art. For example, for the treatment of neoplastic diseases and disorders of the immune system, the regained dosage will also vary depending on the mode of administration, the particular condition to be treated and the effect desired.

In general, satisfactory results are obtained systemically with a daily dosage of about 0.01 to about 100 mg / kg by body weight or, in particular, from about 0.03 to 2.5 mg / kg by body weight. A recommended daily dosage in large mammals, e.g. humans, is in the range of about 0.5 mg to about 2000 mg or more particularly, about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times a day, or in a depot form. The single-dose pharmaceutical forms suitable for oral administration comprise approximately 1 to 50 mg of active principle.

the compounds of the invention can be administered in the form of pharmaceutical compositions by any conventional route, in particular, enterally, for example, orally, for example, in the form of tablets or capsules, or parenterally, for example, in the form of injectable solutions or suspensions, topically, for example, in the form of lotions, gels, ointments or creams, or by the nasal route or alternatively in the form of suppositories.

Pharmaceutical compositions comprising a compound of the present invention in free form or in the form of a pharmaceutically acceptable salt, in association with at least one pharmaceutically acceptable carrier or diluent, can be manufactured in a conventional manner by methods of mixing, granulation, coating, dissolution or lyophilization. For example, the pharmaceutical compositions comprising a compound of the invention in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit presentations for

Oral administration contain, for example, from about 0) 1 mg to about 500 mg of active ingredient.

In one embodiment, the pharmaceutical compositions are solutions of the active ingredient, including, suspensions or dispersions, such as isotonic aqueous solutions. In the case of lyophilized compositions comprising the active principle alone or with a support, such as mannitol, dispersions or suspensions can be prepared before use. The pharmaceutical compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solubilization promoters, salts intended to regulate the osmotic pressure and / or buffers. Suitable preservatives include, but are not limited to, antioxidants, such as ascorbic acid or microbicides, such as sorbic or benzoic acid. The solutions or suspensions may further include viscosity increasing agents, including, but not limited to sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrroiidone, gelatins or solubilizers, e.g. eg, fween 80 (polyoxyethylene-20-sorbitan mono-oleate).

Suspensions in oil may include, as a component of the oil, vegetable, synthetic or semi-synthetic oils customary for injection.

Examples include fatty acid esters containing, as an acid component, a long chain fatty acid having 8 to 22 carbon atoms, or in some embodiments, 12 to 22 carbon atoms. Suitable fatty acid esters include, but are not limited to lauric, tridecylic, myristic, pentadecylic, palmitic, margaric, stearic, arachidic, behenic, or corresponding unsaturated acids, for example, oleic, elaidic, erucic acid. , brassidic and linoleic, and optionally may contain antioxidants, for example, vitamin E, 3-caotene or 3,5-di-tert-butylhydroxytoluene. The alcohol component of these fatty acid esters can have six carbon atoms and be monovalent or polyvalent, for example, mono-, di- or trivalent alcohol. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or isomers thereof; glycol and glycerol.

ر

ΜΑ 32497Β1

Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate. isopropyl palmitate, LABRAFIL® IM 2375. (polyoxyethylene glycerol), LABRAFIL® M 1944 CS (unsaturated polyglycolated glycerides prepared by alcoholysis of apricot kernel oil and comprising glycerides and polyethylene glycol ester), LABRASOl (saturated polyglycolated glycerides prepared by alcoholysis of TCM and comprising glycerides and a polyethylene glycol ester: all available from GaKefosse, France), and / or IMIGLYOL® 812 (long chain C to C 12 saturated fatty acid triglyceride from Hills AG, Germany), and vegetable oils, such as cottonseed oil, cottonseed oil, fine, olive, castor, sesame, soy or peanut.

Pharmaceutical compositions intended for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, and, optionally, by granulating a resulting mixture and treating it or the granules with the inclusion! additional excipients, to form tablets or cores.

Suitable carriers include, but are not limited to, fillers, such as sugars, for example, lactose, saccliarose, mannitol or sorbitol, cellulose preparations, and / or calcium phosphates, for example, tricalcium phosphate or calcium hydrogenphosphate, as well as binders, such as starches, for example, corn, wheat, rice or potato, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, and / or, optionally, disintegrators, such as the aforementioned starches, carboxymethyl, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow conditioners and lubricants, for example, silicic acid, talc, stearic acid OR salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol or derivatives thereof. this.

The cores may have suitable enterosoluble coatings, optionally using, inter alia, concentrated sugar solutions which may include gum arabic) talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings

MA 32497131 enterosoluble, solutions of suitable cellulose preparations, such as acetylcellulose or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to the tablets or tablet coatings, for example, for the purposes of identifying or characterizing the different doses of active principle.

Pharmaceutical compositions for oral administration may also include hard capsules comprising gelatin or soft capsules comprising gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules can contain the active principle in the form of granules, for example, in admixture with fillers, such as corn starch, binders, and / or slip agents, such as talc or magnesium stearate, and stabilizers, optional. In soft capsules, the active principle can be dissolved or suspended in suitable liquid excipients, such as fatty acids, paraffin oil or liquid polyethylene glycols or esters of fatty acids of ethylene or propylene glycol, to which stabilizers and detergents, for example, of the polyoxyethylene-sorbitan fatty acid ester type, can also be added.

Pharmaceutical compositions suitable for rectal administration are, for example, suppositories comprising a combination of the active ingredient and a suppository base. Suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

Pharmaceutical compositions suitable for parenteral administration may comprise aqueous solutions of an active ingredient in water soluble form, for example, of a water soluble salt or aqueous suspensions for injection containing substances. , increasing the viscosity, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and, optionally, stabilizers. The active principle, optionally with excipients, can also be in the form of a lyophilisate and can be prepared in a solution before parenteral administration by the addition of suitable solvents. Solutions such as those used, for example, for parenteral administration can also be employed as an infusion solution. The manufacture of injectables is usually carried out under sterile conditions.

22497ΒΛ as for filling, for example, ampoules or vials or even sealing containers.

the compounds of the invention can be administered as the sole active principle or with other drugs useful against neoplastic diseases or for immunomodulating regimens. For example, the compounds of the invention can be used according to the invention in combination with pharmaceutical compositions effective in various diseases described above, p. e.g., with the compounds cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, cisplatin, carboplatin, vincristine, Vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan, doxorubicin, gefitinib, or also with asatinibamycinospins, or eucamycins: or eecamycins or their immunosuppressive analogues, eg. eg, cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids, eg. e.g., prednisone, cyclophosphamide, azathiopene, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil, Sdeoxyspergualine, immunosuppressive monoclonal antibodies, e.g. eg, anti-leukocyte receptor monoclonal antibodies, eg. e.g., MHC, CD2, CD3, CD4, CD7, CD25, CD28, I CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, lFA-1, YLA-4 or their ligands, or other immunomodulatory compounds, eg. eg, CTlA41g.

the invention also provides a pharmaceutical combination, for example a kit, comprising a) the first agent which is a compound of the invention as described herein, in free form or in the form of a pharmaceutically acceptable salt, and b) at least one co-agent. The kit may include instructions for its administration.

Methods of preparing the compounds of the invention

General procedures for the preparation of the compounds of the invention are described in the Examples, below. In the reactions described, reactive functional groups, for example, hydroxy, amino, imino, thio or carboxy groups, when these are desired in the final product, can be protected in order to avoid their unwanted participation in the reactions. Conventional protecting groups can be used according to standard practice (see, for example, Tw Greene and /

32497Β1

PGM Wuts in Protective Groups in Organic Chemistry, John Wiley and Sons, 1991).

The compounds of the invention, including their salts, can also be obtained in the form of hydrates or their crystals, can include, for example, the solvent which was used for crystallization (present as solvates). The salts can usually be converted to compounds in free form, e.g. eg, by treating them with suitable basic agents, for example, with alkali metal carbonates, alkali metal hydrogenocarbonates or alkali metal hydroxides, such as potassium carbonate or potassium hydroxide. A compound of the invention in its sc (base addition) form can be converted to the corresponding free acid by treating it with a suitable acid (eg hydrochloric acid, etc.). In view of the close relationship between new compounds in free form and those in the form of their salts, including which salts may be used as intermediates, for example, in the purification or identification of the first mentioned, any reference to the compounds free should also be understood as referenced to the corresponding salts, as appropriate.

The salts of the compounds of the invention with a salt-forming group can be prepared in a manner known per se. Acid addition salts of compounds of Formula (1), (2), (3) and (4). can therefore be obtained by treatment with an acid or with a suitable anion exchange reagent. Pharmaceutically acceptable salts of the compounds of the invention can be formed, for example, as acid addition salts, with organic or inorganic acids, from compounds of Formula (1), (2), (3) and (4), with a basic nitrogen atom.

Suitable inorganic acids include, but are not limited to, halogen acids, such as hydrochloric, sulfuric or phosphoric acid. Suitable organic acids include, but are not limited to, carboxylic, phosphoric, sulfonic or sulfamic acids, for example, acetic, propionic, octanoic, decanoic, dodecanoic, glycolic, lactic, fumaric, succinic, adipic, pimelic, suberic acids, azelaic, malic, tartaric, citric, amino acids, such as glutamic or aspartic acid, maleic, hydroxymaleic, methylmaleic, cyclohexanecarboxylic, adamantanecarboxylic, benzoic, salicylic, 4-aminosalicylic, phthalic.

MA 32497131 phenylacetic, mandelic, cinnamic, methane- or ethanesulfonic, 2hydroxyethanesulfonic, étliane-1,2-disulfonlque, benzenesulfonique, 2naphthalenesulfonique, IS-naphthalene-disulfonic, 2-, 3- or 4methylbenzenesulfonic, methylsulfuric5, ethylbenzenesulfonic, methylsulfuric5 cyclohexylsulfamlque, Ν-methyl-, Ν-ethyl- or N-propyl-sulfonic or other organic protonic acids, such as ascorbic acid. For isolation or purification it is also possible to use pharmaceutically unacceptable salts, for example, picrates or perchlorates. Only pharmaceutically acceptable salts or free compounds are used for therapeutic purposes (where appropriate, in the form of pharmaceutical preparations).

Compounds of the invention in unoxidized form can be prepared from N-oxides of compounds of the invention by treating them with a reducing agent (eg, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, borohydride. sodium, phosphorus trichloride or tribromide, or the like) in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, or the like) at a temperature of 0 to 80 ٠c.

The precursor drug derivatives of the compounds of the invention can be prepared according to methods known to those skilled in the art (for example, for further details, see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry

Letters, Vol. 4, p. 1985). For example, suitable drug precursors can be prepared by reacting a non-derivative compound of the invention with a suitable carbamylating agent (eg, I٠1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be prepared according to methods known to those skilled in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in Tw Greene, "Protecting Groups in Organic Synthesis", 3^th edition, dohn Wiley &amp; Sons, Inc. 1999.

The compounds of the invention can also be prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of.

32497Β1 diastereomeric compounds, by separating the diastereoisomers and recovering the optically pure enantiomers. The resolution of enantiomers can be achieved by using covalent diastereomeric drifts of the compounds of the invention, or by using dissociable complexes (eg, crystalline diastereomeric salts). Diastereoisomers exhibit distinct physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) and can be easily separated by taking advantage of these dissimilarities. Diastereoisomers can be separated by fractional crystallization, chromatography or, by separation / solution techniques based on differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any convenient means which does not result in racemization. A more detailed description of techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques André Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions '', John Wiley &amp; Sons, Inc. (1981 ).

In summary, the compounds of the invention can be obtained by a process described in the examples: and (a) the optional conversion of a compound of the invention into a pharmaceutically acceptable salt:

(b) the optional conversion of a salt form of a compound of the invention into a non-salt form:

(c) optional conversion of an unoxidized form of a compound of the invention to a pharmaceutically acceptable N-oxide:

(d) optional conversion of an N-oxide form of a compound of the invention to its unoxidized form:

(e) optional resolution of an individual isomer of a compound of the invention from a mixture of isomers:

(f) optional conversion of a non-derivatized compound of the invention to a pharmaceutically acceptable drug precursor derivative: and

ΜΑ 32497Β1 (h) optional conversion of a precursor drug derivative of a compound of the invention to its non-deratted form.

When their production is not specifically described, the starting materials are known or can be prepared analogously to methods known in the art or described in the examples below. Those skilled in the art will recognize that the above transformations are only representative of the methods of preparing the compounds of the present invention, and that other well known methods may also be used. The present invention is illustrated in more detail, but not limited to, by the following examples which describe the preparation of compounds of the invention.

Intermediate 1

2.5-dichloro-N- (5-meth٧l-1H-pvrazol-3-٧l١p٧rimidin-4-amine

A mixture of 5-methyl-1 H-pyrazol-3-amine (3.90 g, 30.9 mmol), 2,4,515 trictiloropyrimidine (5.67 g, 30.9 mmol, 1 equiv.) And NO (3 , 60 g, 34.0 mmol, 1.1 equiv.) In EtOH (100 mL) was heated at 40 ٠c for 24 h. The solvent was removed in vacuo. The resulting residue was partitioned between EtOAc (350 mL)) and water (100 mL). The EtOAc layer was washed with water (3 times), saturated aqueous NaCl solution, (1 times) and dried over N2SO4. The resulting EtOAc solution was concentrated in vacuo, to provide the product 2,5-dichloro-N- (5-methyl1H-pyrazol-3-yl) pyrimidin-4-amine; SEMS m / z 244.0 (M + H٢).

Intermediate 2

2-chl٠ro-N- (5-meth٧l-1-H-p٧razol-3-yl) -5- (trifluorometh٧l) p٧rimidin-4-amine

HN N Cl

ν, Α 32497Β1

A mixture of 2,4-dichl0r0-5- (trifluor0methyl) pyrimidine (1.06 g, 4.86 mmol), 5methyl-1 H-pyrazol-3-amine (472.2 mg, 4.86 mmol) and carbonate of sodium (2.06g, 19.4mmol) in 100ml EtOH was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude solid was partitioned between EtOAc and water. The combined organic extracts were dried (NSO, *), concentrated in vacuo, and purified on silica gel chromatography (EtOAc / hexanes: 1/1) to give 2-chloro-N- (5-methyl-1H-pyrazol -3-yl) -5 (trifluoromethyl) pyrimidin-4amine; ESMS m / z 278.0 (M f H *).

Intermediate 3

2-chloro-5-methyl-N- (5-methyl-1 H-pvrazol-3-vl) pvrimidin-4-amine

<img file="MA32497B1_D0019.tif" />

A mixture of 5-methyl-1 H-pyrazo! -3-amine (3.00 g, 30.9 mmol), 2,4,5trichloropyrimidine (5.03 g, 30.9 mmol, 1 equiv.) And NO (3.60 g, 34.0 mmol, 1.1 equiv.) In EtOH (100 mL) was heated at 40 ٠c for 24 h. The solvent was removed in vacuo, the resulting residue was partitioned between EtOAc (350 mL) and water (100 mL). The EtOAc layer was washed with water (3 times), saturated aqueous NaCl solution, (1 times), dried over ΝδO 4, and concentrated in vacuo. The resulting crude product was sonicated in Et2O (200 mL) and the resulting precipitate collected by filtration. This powder was further washed with Ι'ΕΪ2O, to provide the product 2-chloro-5-methyl-N- (5-methyl-1 H-pyrazol-3-yl) pyrimidin-4-amine; SEMS mlz 224.1 (M + H⁺).

Intermediate 4

N- (2.5-dichloropyrimidin-4-vl) -5-methvlisoxazol-3-amine

<img file="MA32497B1_D0020.tif" />

/

MA 32497131 the mixture of 5-methylis0xaz0l-3-amine (98 mg, 1.0 mmol), 2,4,5trichloropyrimidine (344 pL, 3.0 mmol), and sodium carbonate (106 mg, 1.0 mmol) in 3 ml of EtOH, was heated at 6O٠C overnight, the reaction mixture was concentrated, then partitioned between EtOAc and brine, the collected organic extracts were dried (Νδθ4), concentrated in vacuo, and purified by chromatography on silica gel (IMeOH / DCM: 1/9) to give Ν- (2.5dichloropyrimidin-4-yl) -5-methylisoxazol-3-amine; SEMS m / z 245.0 (M + H).

Intermediate 5

2,5-dichl0r0-N- (5-c٧cl0pr0pvl-1H-pvraz0l-3-yl) pvrimidin-4-amine

NOT

HN

A mixture of 5-cycl0pr0pyl-1H-pyraz0l-3-amine (246 mg, 2.00 mmol), 2,4,5trichloropyrimidine (367 mg, 2.00 mmol, 1 equiv.) And NO (233 mg, 2, 20 mmol, 1.1 equiv.) In EtOH (10 ml) was heated at 40 ٥c for 16 h. the crude reaction mixture was diluted with EtOAc then washed with: water (3 times) and saturated aqueous NaCl solution (1 time), the resulting EtOAc layer was dried over N2SO4, then concentrated in vacuo , to provide 2,5-dichloro-N- (5-cyclopropyl-1 Hpyrazol-3-yl) pyrimidin-4-amine: SEMS m / z 270.0 (MFH).

Intermediate 6

3- (2, 5-dichloropvrimidin-4-vlamino١azepan-2-one

A mixture of (ia-amino-e-caprolactam (256 mg, 2.0 mmol), 2,4,5trichloropyrmidine (366 mg, 2.0 mmol, 1 equiv.) And NaHO (168 mg, 2 mmol, 1 equiv. .), in a mixture of MeOH (12 ml) and o (6 ml), was stirred at temperature

ΜΑ 32497Β1 ambient for 15 h. The resulting precipitate was collected by vacuum filtration and washed with small amounts of MeOH and water, to provide the product 3- (2,5dichloropyrimidin-4-ylamino) azepan-2-one: SEMS m / z 275, 0 (M + H).

Intermediate 7

3- (2.5-dichl0r0Dvrimidin-4-vlamin0١Pvridin-2 (1H١-0ne

علملميم

A mixture of 3-aminopyridin-2 (1 H) -one (99 mg, 0.90 mmol), 2,4,5 trichloropyrimidine (165 mg, 0.90 mmol, 1 equiv.) And NaHO (76 mg, 0, 90 mmol, 1 equiv.), In a mixture of MeOH (6 mL) and HO (3 mL), was stirred at room temperature for 24 h. The resulting precipitate was collected by vacuum filtration and washed with small amounts of MeOH and water, to provide the product 3- (2,5dichloropyrimidin-4-ylamino) pyridin-2 (1H) -one: SEMS m / z 257.0 (M + H٠).

Intermediate 8

2,5-Dichloro-N- (5-methvl-l- (tetrahvdro-2ll-pvran-2-v1) -1H-Dvrazol-3-vl) pyrimidin-415 amine

<img file="MA32497B1_D0021.tif" />

Has a mixture of 2,5-dicl٦loro-bl- (5-metli١ / l-1H-pyrazol-3-yl) pyrimidin-4amine (2.44 g, 10 mmol) and 4-toluenesulfonic acid monohydrate (1, 9g, 10mmol) in THE (200ml), was added DHP (4.25g, 50mmol). After stirring overnight, the reaction cleared up. After concentration, the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of NO. The organic layer was then washed with brine, dried over sodium sulfate and concentrated in vacuo to give 2,5-dichloro-N- (5-methyl-1- (tetrahydro-2Hpyran-2-yl) -1 H-pyrazol-3-yl) pyrimidin-4-amine in the form of a light yellow solid,

Used in subsequent reactions without further purification; SEMS m / z

WA 32497Β1

244 (Μ-ΤΗΡ + Η +); TLC Rf = 0.6 (Silica; ethyl acetate / hexanes 1: 1; starting material Rf = 0.2).

Intermediate 9

2,5-dichl0r0-N- (5- (triflu0r0methvl-1H-pvraz0l-3-vl) pyrimidin-4-amine

٠٠ ، Step 1: 5- (Trifluorometh٧l) -1 H-pyrazol-3-amine

A mixture of (E) -4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (5.00 g, 27 mmol) and hydrazine (1.05 g) in of anhydrous EtOH (20 mL) was stirred at 80 ° C in a sealed flask overnight. The reaction was quenched by adding water (50mt), and extracted with EtOAc (100ml, then 2x50ml). The EtOAc layers were combined then washed with water (25 mL), brine (25 mL), dried over N2SO4 and evaporated to give a slightly brown oily residue. The crude product was purified by chromatography on silica gel (gradient of EtOAc in hexanes: 30-100٠ / ٠) to give 5- (trifluoromethyl) 1H-pyraz0l-3-amine as a cassis white solid: SEMS m / z 152.0 (Μ + Η).

Step 2: 2.5-Dichl0r0-N- (5- (triflu0r0méthvl-1H-pyraz0l-3-vl١pvrimidin-4-amine

A mixture of 5- (triflu0r0methyl) -1H-pyraz0l-3-amine (500 mg, 3.3 mmol), 2,4,5trichloropyrimidine (607 mg, 3.3 mmol) and sodium carbonate (525 mg, 5 mmol ) in dry EtOH (10 mL), was stirred at rt. After one day, a CLSM showed that the reaction was not over. Additional 2,4,5-trichloropyrimidine (0.15 mL) and sodium carbonate (525 mg) were added and the reaction continued for another two days. The solvent was evaporated and the residue extracted with DCM (3x20 mL). The combined DCM layers were washed in brine (10 mL), dried over NSO ؛ and evaporated. The crude product was purified by chromatography on silica gel (gradient of EtOAc in hexanes: O-5O٠ / o) to give 2,5-did٦loro-hJ- (5-trifluoromethyl) -1H-pyrazol-3- yl) pyrimidin-4-amine in the form of a light brown yellow solid: SEMS m / z 297.9 (M + H٠).

VIA 32497Β1

Intermediate 10

2.5-dichloro-N- (5-ethvl-1H-Dvrazol-3-vl) pyrimidin-4-amine

<img file="MA32497B1_D0022.tif" />

A mixture of 5-ethyl-1 H-pyrazol-3-amine (1.00 g, 6.77 mmol), 2.4.5 5 trichloropyrimidine (1.24 g, 6.77 mmol) and NO (1, 79 g, 16.9 mmol) in isopropanol (15 mL) was stirred in a sealed vial at rt for two days. Water (10 mL) was added. The solid was collected by filtration, washed with water (10 mL) and dried to give 2,5-dichloro-N- (5-ethyl-1H-pyrazol-3-yl) pyrimidin4-amine as of light yellow solid: SEMS m / z 258.0 (Μ + Η).

Intermediate 11

1-chl0r0-5-methvl-4-nitr0-2- (triflu0r0meth٧l) benzene

To a solution of 2-chl0r0-4-methyl-1- (trifluoromethyl) benzene (6.65 g, 34.1 mmol) in conc. Sulfuric acid. (25 mL) at 0 c, potassium nitrate (3.46 g, 34.1 mmol) in sulfuric acid (15 mL) was added. After stirring at o٥c for 1.5 hours, the reaction mixture was poured into 500 mL of ice water. The precipitate was collected by filtration and washed with copious amounts of water, to give 1-chl0r0-5-fluoro0-4-nitro-2- (trifluoromethyl) benzene as an orange solid: 1 H NMR (400 MHz, chloroform-d) δ 8.356 (s, 1Η), 7.543 (s, 1Η), 2.660 (s.

3Η).

Intermediate 12

2-Brom0-4-methvl-5-nitr0benz0nitrile

MA 32497131

Br

OzN

After the same procedure as that described in Intermediate 11, starting with 2-bromo-4-methylbenzonitrile, 2-bromo-4-methyl-5nitrobenzonitrile was obtained as a yellow solid: NMR. ¹H (400 MHz, chloroform-d) δ

8) 290 (s, 1Η), 7.742 (s, 1Η), 2.683 (s, 3Η).

Intermediate 13

5-amin0-2-br0m0-4-meth٧lbenz0nitrile

ر

To a solution of 2-Bromo-4-methyl-5-nitr0benzonitrile (500mg, 2.07mmol) in ethanol (20ml) was added tin chloride (785mg, 4.14mmol). the mixture was heated under reflux for 5 h. After cooling to room temperature) was added triethylamine (1.01 g, 10 mmol). The mixture was concentrated and purified by chromatography on silica gel (gradient of ethyl acetate in hexanes: 3050%) to give 5-amin0-2-br0m0-4-methylbenzonitrile as a beige solid; SEMS m / z 211 (MH).

Intermediate 14

Methvl 2-br0m0-4-methvl-5-nitr0benz0ate ^ OOMe

غ

After the same procedure as that described in Intermediate 11, starting with methyl 2-brom0-4-methylbenz0ate, the title compound was obtained as a white solid: H NMR (400 MHz, chloroform-d) δ 8.505 (s, 1Η), 7.711 (s,

1Η), 3.967 (s, 3Η), 2.640 (s, 3Η).

ΜΑ 32497Β1

Intermediaries

Methyl 5-amin0-2-br0m0-4-methvlbenz0ate

<img file="MA32497B1_D0023.tif" />

After the same procedure as that described in Intermediate 13, the referenced compound 5 was obtained as a beige solid; SEMS m / z 244 (M + H).

Intermediate 1 fi

4-Bromo-5-methox٧-2-methvlaniline

Step 1: N- (5-methoxv-2-methylphén٧l١acétamide

To a solution of triethylamine (2.9 g, 14.4 mmol) and 5-methoxy-2-methylaniline (1.0 g, 7.2 mmol) in DCM (30 mL) at 0 ٥c, was added dropwise acetyl chloride (0.57 g, 7.2 mmol) dropwise. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride, and the corresponding product extracted with DCM.

The organic layer was dried over Νδθ4 and concentrated to give N (5-methoxy-2-methylphenyl) acetamide in the form of needle-shaped crystals. The crude product was taken up in the next step without further purification.

Step 2: N- (4-bromo-5-methoxv-2-methvlphénvl١acetamide To a solution of N- (5-methoxy-2-methylphenyl) acetamide in acetic acid (40 mL), Br ( 3 g, 19 mmol). The mixture was mouthful and stirred at 50 ٠c for 5 h. The reaction was cooled to room temperature, then neutralized by adding an aqueous solution of sodium sulphite, and the corresponding product extracted with ethyl acetate (3 X 50 mL). The combined organic layer was dried over Na2S٠4 and concentrated to give N- (4٠bromo-5MA

32497Β1 methoxy-2-methylphenyl) acetamide crude as a brown oil, taken to the next step without further purification.

Step 3: 4-bromo-5-methox٧-2-methvlaniline

N- (4-Bromo-5-methoxy-2-methylphenyl) acetamide was dissolved in methanol (15ml) and concentrated HCl (30ml). The mixture was refluxed at 95 c overnight. After cooling to room temperature, the mixture was poured into ice-water, and made basic to pH = 12 with a conc aqueous solution. of NaOH. the mixture was then extracted with ethyl acetate (3 X 50 mL). The combined organic layer was dried over Na₂S٠4 and 10 concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate in hexanes: 15%) to give 4-bromo-5-methoxy-2methylaniline in the form of a beige solid: NMR¹H MR (400 mHz, CDCI3) 7.20 (s, 1Η), 6.37 (s, 1Η), 4.6 (br, 211), 3.82 (s, 3Η), 2.12 (s, 3Η).

Intermediate 17

2-Fluoro-5-methvl-4- (4,4,5,5-tetrameth٧l-1,3,2-dioxaborolan-2-yl) aniline

<img file="MA32497B1_D0024.tif" />

A mixture of 4-bromo-2-fluoro-5-meth١ / laniline (2.0 g, 9.8 mmol), bis (pinacolatodiboron (2.74 g, 10.8 mmol), tricyclohexylphosphine (274.8 mg, 0.98 mmol), Pd₂(dba) 3 (448.9 mg, 0.49 mmol), and potassium acetate (1.92 g,

19.6 mmol) in 60 mt of 1,4-dioxane was degassed and purged with nitrogen. The reaction mixture was heated to 8O٠C overnight, then cooled to room temperature. The mixture was partitioned between EtOAc and water, and the collected organic extracts dried (Na₂SO4), concentrated in vacuo, and purified by chromatography on silica gel (EtOAc / Hexanes: 20/80) to give 225 fluoro-5-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) aniline, SEMS m / z 252.2 (M + H.

ΜΑ 32497Β1

Intermediate 18

2-lsopropox٧-5-meth٧l-4- (1-meth٧l-piperidin-4-٧l) -phen٧lamine

<img file="MA32497B1_D0025.tif" />

Step 1: 1-Br٠mp-5-fluprp-2-methvl-4-nitr٠benzene

To a solution of 2-br٠m٠-4-flu٠r٠-l-meth١ (lbenzene (5 g, 26.4 mmel) dissolved in concentrated sulfuric acid (20 ml) was added potassium nitrate (2.67 g ,

26.4 mmol) in sulfuric acid (5 ml) at o٠c for 1 h. After stirring at o٠c for 1 h, the reaction mixture was diluted in water, then extracted into ethyl acetate (3 X 40 ml). The combined organic folds were successively washed in saturated sodium bicarbonate solution and in brine, then dried over NSO ،. The crude product obtained after concentration was purified by chromatography on a silica gel column with a mixture of hexane / EtOAc solvents (95/5) to give 1-br0m0-5-flu0r0-2-methyl-4-nitr0benzene in the form of solid orange. NMR^٦H (400 MHz, chloroform-d) δ 7.93 (d, 1Η, 7.6 = ل

Hz), 7.50 (d, 1Η, 10 = ر Hz), 2.43 (s, 3Η).

Step 2: 1-Br0m0-5-isQpr0P0xv-2-methvl-4-nitr0benzene

Has a selutien of 1-br٥mo-5flu٠ro-2-methyl-4-nitr٠benzene (Step 1, 1.5 g,

6.4 mmpl) in 2-pr٠pan٠l (30 mL), added cesium carbonate (5.3 g, 16 mmol). The reaction mixture is heated to 5O٠C overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and the residue purified by column chromatography on silica gel with 5% ethyl acetate in hexane to give 1-bromo-5isopropoxy-2-methyl-4-nitrobenzene as 'a yellow solid.

Step 3: 4- (5-lsopropoxv-2-methvl-4-nitrophénvl ovridine

Has a mixture of 1-br0m0-5-is0pr0p0xy-2-methyl-4-nitr0benzene (Step 2, 1 g, 3.65 mmol), pyridine-4-boronic acid (490 mg, 4 mmol), 2dicyclohexylphosphino -2'.6'-dimethoxybiphenyl (300 mg, 0.73 mmol) and potassium phosphate (I, 55g, 7.3 mmol) in a mixture of dioxane solvents

ΜΑ 32497Β1 (15ml) and water (7.5ml), tris (dibenzylidene-acetone) dipalladium (0) (334 mg, 0.36 mmol) were added. This mixture was poured into a sealed tube and purged with nitrogen for 3 minutes, then heated to 12O٥C for 5 hours. It was then cooled to room temperature, filtered, before concentrating the filtrate. After concentration, the crude product was purified by column chromatography on silica gel (60% ethyl acetate in hexane) to give 4- (5-isopropoxy-2-methyl-4nitrophenyl) pyridine under yellow solid form: SM-ES m / z 273.2 (M + H).

Step 4: 4- (5-lsopropoxv-2-methvl-4-nitro-phenvl) -1-methvl-pyridinium lodide

4- (5-isopropoxy-2-methy! -4-nitro-phenyl) -pyridine was dissolved (Step 3,

217 mg, 0.797 mmol) in anhydrous THF (9 mL). Iodomethane (0.10 mL, 1.61 mmol, 2 equiv.) Was added, then the reaction mixture was stirred at 40٠C in a sealed tube for 2 days. The volatile compounds were removed in vacuo to give 4- (5-isopropoxy٠-2-metl٦yl-4-nitro-phenyl) -1-methyl-pyridinium iodide as a brown solid: SM-ES m / z 287.1 (Μ + -).

Steps 5 and 6: 2-lsopropoxv-5-methvl-4- (1-methvl-piperidin-4-vl١-phenvlamine

4- (5-Isopropoxy-2-methyl-4-nitro-phenyl) -1-methylpyridinium iodide (Step 4, 0.697 mmol) was dissolved in CHOH (20 mL) and then cooled. to where. When the addition was complete, the cooling bath was removed and the reaction mixture stirred at room temperature for 1 h. the reaction was then quenched by slow addition of 1N aqueous HCl (14 mL). The CHOH was partially removed in vacuo. The resulting residue was partitioned between EtOAc and 1N aqueous NaOH. 50٠/٠ aqueous NaOH was again added until an aqueous layer of pH&gt; 12 was obtained. The EtOAc layer was washed twice with 1N aqueous NaOH, then the organic layer dried over sodium sulfate, filtered and concentrated in vacuo.

After concentration, the crude product (175 mg) was dissolved in ethanol (10 mL). TFA (0.15 mL, 3 equiv.) And PO (53mg. 30٠ / ο wt / wt) were added, then the reaction mixture was hydrogenated at a pressure of 3.5 bar in a Parr stirrer for 14 h. The reaction mixture was then filtered, and the filtrate concentrated in vacuo. The resulting residue was partitioned between EtOAc and 1N aqueous NaOH. 50% aqueous NaOH was again added until an aqueous layer of pH&gt; 12 was obtained. The EtOAc layer was washed twice with 1N aqueous NaOH, then the organic layer dried over sodium sulfate, filtered and concentrated in vacuo to /

VIA 32497Β1 give 2-isopropoxy-5-methyl-4- (1-mett٦yl-piperidin-4-yl) -pl٦enylamine, which was used in subsequent steps without further purification: SM-ES m / z

263.2 (M + H).

Intermediate 19

Tert-butyl 4- (4-Amino-5-fluoro-2-methvlphénvl) piperidine-1-carboxvlate

Step 1: 4-triflu0r0methanesulf0nvl0xv-3.6-dihvdr0-2Hpyridine-1-carboxylic acid tert-butyl ester

A solution of N-tert-butoxycarbonyl-4-piperidone (10.17 g, 0.05 mol) in THF (100 mL) was added dropwise to a cooled (-78٥c) vigorously stirred solution of IDA (40 mL of a 1.5Μ solution in cyclohexane, 0.06 mol) in THF (100 mL), under N The reaction mixture was left at 78٠c for 30 min before adding a solution of phenyl trifluorosulfonimide (19 , 85 g, 0.055 mol) in THF (50 mL). The reaction mixture was then warmed to room temperature and stirred for 3 h. The reaction was neutralized to o٠c with 100 ml of saturated aqueous NHC solution and filtered through Celite. The filtrate was added to 100 ml of EtOAc, and the layers separated. The organic layer was washed in water, dried over MgS٠4 and concentrated. The crude product was purified by column chromatography on silica gel (eluent: 0-30% EtOAc in hexane, checked by TLC with 2% KMn٠4 in EtOH) to give the tert-ester. 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridin-1carboxylic acid butyl acid as a yellow oil.

Step 2: tert-butyl 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-vl) -5,6-dihvdropyridine-1 (2H) carboxylate

A solution of tert-butyl 4- (trifluoromethylsulfonyloxy) -5,6-dihydropyridine-1 (2H) -carboxylate (16.0 g, 48.2 mmol) in DMSO (200 mL) was treated with bis ( pinacolato) diboron (12.6 g, 49.6 mmol), potassium acetate (14.65 g.

ΜΑ 32497Β1

149 mmol) and Pd (dppf) C (790 mg, 0.96 mmol). The solution was purged with N (g) for 5 minutes, then sealed and heated at 80 ° C for 15 h. the reaction mixture was cooled to room temperature and poured into ice water. The mixture was then extracted with ethyl acetate (3 X 100 mL). The combined organic phase was washed in brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (15% ethyl acetate in hexane) to give 4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl) -5,6-dil٦ydropyridin-1 (2H) -carboxylate of tert-butyl in the form of a white solid.

Steps 3 and 4: tertbutyl 4- (4-Amin0-5-flu0r0-2-methvlphénvl) piperidine-1-carb0x٧late

Has a mixture of 5'-chloro-N.2'-dimethyl-4'-nitrob ؛ phenyl-4-carboxamide (204 mg, 1 mmel), 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -5,6-dihydropyridine1 (2H) -carb٠xylate of tert-butyl (370 mg, 1.2 mmel) and spdium carbpnate (742 mg, 7 mmel) in a mixture of DMFHO (12/3 mL), added tetrakis (triphenylphosphine) palladium (0) (58 mg, 5٠ / ο mmol). The reaction tube was sealed, the mixture purged with N for 3 min, then heated to 9O٠C under N₂overnight. The reaction mixture was cooled to room temperature, and poured into a saturated aqueous solution of ammonia chloride. The crude mixture was then extracted into ethyl acetate (3 X 15 mL). The organic extracts were combined, washed in brine and concentrated. The crude product was purified by chromatography on silica gel column (20٠/ d'ethyl acetate in hexane) to give 4- (4-amino-5-fluoro-2-methylphenyl) -5, Tert-butyl 6-dihydropyridine-1 (2H) carboxylate as a yellow oil. The resulting oil was dissolved in methanol (20 mL). Pd / C (10٥/٠) was then added to the solution. The reaction mixture was degassed, purged several times with H then stirred under H (1 atm) overnight. The mixture was filtered and concentrated to give tert-butyl 4- (4 amino-5-fluoro-2-methylphenyl) piperidine-1-carboxylate as a white solid. SM-ES n / z 207 (M-Boc + H٠).

Intermediate 20 2,5-Dimeth٧l-4- (piperidine-2-vl) aniline

A mixture of 1-bromo-2,5-dimethyl-4-nitrobenzene (185 mg, 1 mmol) and 2 (tributylstannyl) pyridine (202 mg, 1.1 mmol) in DMF (4 mL), we have add some

ΜΑ 32497Β1 tetrakis (triphenylphosphine) palladium (0) (58 mg, 5% mmol). The reaction tube was sealed, the mixture purged with N for 3 min, then heated to 12O٠C under N overnight. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of ammonia chloride. The crude mixture was then extracted into ethyl acetate (3 X 15 mL). The organic extracts were combined, washed in brine and concentrated. The crude product was purified by column chromatography on silica gel (60% ethyl acetate in hexane) to give 2- (2,5-dimethyl-4-nitrophenyl) pyridine as a solid. White. The solid obtained was dissolved in a mixture of acetic acid / TFA (15ml_ / 200pL). PO (10% w / w) was then added to the solution. The reaction mixture was degassed, purged several times with H, then stirred under 1 atmosphere of H overnight. The mixture was filtered and concentrated to give 2,5-dimethyl-4- (piperidin-2-yl) aniline as a yellow oil. SM-ES m / z 205 (M + H٠).

Intermediate 21

3- (4-Amino-2,5-diméthvlphénvl) azetidine-1-carboxvlatedetert-butvle

<img file="MA32497B1_D0026.tif" />

Eje342,5-Dimethyl-4-nitrophenyl) azetidine-1-carboxvlate detert-butvle

Prepared from tert-butyl 3-iodoazetidine-1-carboxylate and 1-bromo-2,520 dimethyl-4-nitrobenzene using the general protocol as described in Billotte,

S. Synfeff 1998, 379.

Step 2: tert-butyl 3- (4-Amin0-2,5-dimethylphenyl) azetidine-1-carbOxvlate

Tert-butyl 3- (2,5-dimethyl-4-nitr0phenyl) azetidine-1-carboxylate was reduced to tert-butyl 3- (4-amino-2,5-dimethylphenyl) azetidine-1-carboxylate by hydrogenation in the presence of Raney nickel at room temperature using MeOH as solvent.

/

VIA 32497Β1

Intermediate 22

5-Ethvl-2-methyl-4- (piperidin-4-vl) aniline

<img file="MA32497B1_D0027.tif" />

Step 1: 4- (4-Amino-5-méthvl-2-vinvlphénvl١-5.6-dihvdropyridine-1 (2H) -carboxvlate detert-butvle

Has a mixture of 4-br٥m٥-5-chl٥r٠-2-methylaniline (500 mg, 2,27mmol), of 4 (4,4,5,5-tetramethyl-1,3,2-di٥xab٠r٥lan-2-yl) - 5,6-dihydr٥pyridine-1 (2H) ٠ tert-butylcarb dexylate (840 mg, 3.73 mmpl) and sodium carbonate (2.52 g, 15.9 mmol) in a mixture of DMFHO (20/5 mL ), tetrakis (triphenylphosphine) palladium (0) (131 mg, 5 mol%) was added. The reaction tube was sealed, the mixture purged with N for 3 min, then heated to 100 ° C under N overnight. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of ammonia chloride. The crude mixture was then extracted into ethyl acetate (3 X 15 mL). The organic extracts were combined, washed in brine and concentrated. The crude product was purified by column chromatography on silica gel (80٠ / ο ethyl acetate in hexane) to give 4- (4-amino-2-chloro-5-methylphenyl) -5, Tert-butyl 6-dihydropyridine-1 (2H) carboxylate as a yellow oil. The product thus obtained (322 mg, 1 mmol) was dissolved in a mixture of dioxane / ΝΜΡ (anhydrous, 4 mL, 3/1). To this solution were added tributyl (vinyl) stannane (380 mg, 1.2 mmol), cesium fluoride (304 mg, 2 mmol) and bis (tri-tert-butyl-phosphine) palladium (51 mg, 10 mol٠ / ٠). This mixture was purged with N for 3 minutes, then heated in a sealed tube at 12O٠C overnight. The mixture was cooled to room temperature and diluted in ethyl acetate. The resulting mixture was successively washed in a saturated aqueous solution of ammonium chloride and brine, then finally dried over sodium sulfate. After concentration, the crude product was purified by column chromatography on silica gel (10٠/٠ of ethyl acetate in hexane) to give 4- (4-amino-5-methyl-2-vinylphenyl) -5,6-dihydropyridineΜΑ 32497Β1

Tert-butyl 1 (2H) -carboxylate in pale yellow oil form: SM-ES m / z 215.2 (M -Boc + H).

Step 2: 5-Ethyl-2-methvl-4- (piperidin-4-vl) aniline

The product obtained in the previous step was dissolved in methanol (20 mL). To this solution was added concentrated aqueous HCl (200 µL) and platinum oxide (23 mg, 0.1 mmol). The reaction mixture was degassed, purged several times with H and vigorously stirred 1 atmosphere of H for 3 h. The mixture was filtered and concentrated to give 5-ethyl-2-methyl-4- (piperidin-4-yl) aniline as a yellow oil. SM-ES m / z 219.2 (M + H *).

LO lnLermiddle23

2.5-Dimethyl-4- (piperidin-3- aniline

HgN

<img file="MA32497B1_D0028.tif" />

Step 1: 2.5-Dimethvl-4- (pyridin-3- aniline

A suspension of 4-br٠m٥-2,5-dimethylaniline (4.00 g, 20 mmel), pyridin-315 ylbprcnic acid (2.70 g, 11 mmol), Pd₂(dba) 3 (0.55 g, 0.6 mmol), 2dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (0.98 g, 1.2 mmol) and Na₂CC&gt; 3 (10.6 g, 100 mmol) in n-BuOH (50 mL) was degassed with a stream of argon gas for 15 min. The reaction vial was sealed and placed in a preheated oil bath (115٠C). After stirring overnight, the reaction mixture was cooled and filtered. The filter cake was washed in DCM, and the filtrate concentrated in vacuo. The resulting residue was dissolved in EtOAc (150 mL). EtOAC was washed successively in water (20 mL), brine (20 mL), dried over Na₂S٠4 and removed by evaporation. The crude product was purified by chromatography on silica gel (gradient of 0-50% EtOAc in hexane) to give 2,5-dimethyl-425 (pyridin-3-yl) aniiine as a solid. yellow; SM-ES m / z 199.1 (Μ + Η).

Step 2: 2,5-Dimethvl-4- (piperidin-3-vl aniline

ΜΑ 32497Β1

2,5-Dimethyl-4- (pyridin-3-yl) aniline (403 mg, 2.03 mmol) was dissolved in

MeOH (5 mL) and concentrated aqueous HCl (1 mL), then PO (40 mg) was added.

The flask was purged with Η2 and the reaction mixture stirred vigorously at room temperature under H (1 atm). Two days later, LC-MS showed the reaction to be complete. The catalyst was removed by filtration and the remaining solution concentrated in vacuo to give 2,5-dimethyl-4- (piperidin-3-yl) aniline as a white solid, which can subsequently act as a reagent without purification. additional: SM-ES m / z 205.2 (M + H٠).

Intermediate 24

L-ftert-butoxvcarbonvKmethvDaminocvclopropanecarboxvliaue acid

<img file="MA32497B1_D0029.tif" />

To a solution of 1- (tert-butoxycarbonylamino) cyclopropanecarboxylic acid (201 mg, 1.0 mmol) in DMF (2 mL) was added NaH (120 mg, 3.0 mmol) at o٠c. the resulting mixture was then stirred at oc for 10 min, followed by addition of Mel (568 mg, 4.0 mmol). The mixture was warmed to room temperature and stirred for 2 hours. Saturated aqueous NH4Cl solution (20 mL) was added to the mixture, and the resulting solution extracted into EtOAc (3 x 10 mL). The combined organic layers were concentrated, and the residue dissolved in MeOH (3ml) with NaOH (3Ν, 1ml). This mixture was stirred at 8O٠C for 1 h, and cooled to room temperature. The clear solution was purified directly by preparative HPLC to give 1- (tertbutoxycarbonyl (methyl) amino cyclopropane arboxylic acid. MS-ES m / z 238.2 (M + Na).

Intermediate 25 (R) -2-bromopropanamide

بر o

ΜΑ 32497Β1

Step 1: (R) -2-bromopropanoyl chloride

Under nitrogenous atmosphere, was successively added to the solution of (R) -2bromopropanoic acid (5.0 g, 32.68 mmol) in 100 mL of DCM, thionyl chloride (7.1 mL, 98.04 mmol) and 1 mL of DMF at o٠c. The reaction mixture was stirred at room temperature overnight, and concentrated in vacuo. The resulting crude product was used as is in the next reaction without further purification.

Step 2: (R) -2-bromopropanamide

(R) -2-Bromopropanoyl chloride was added slowly to a 37٠/٠ aqueous solution of ammonia hydrochloride cooled to 0c. After allowing the reaction mixture to warm to room temperature, it was stirred for 2 h.

The product was extracted into EtOAc, and the collected organic extracts dried over N2SO4 and then concentrated in vacuo to give (R) -2bromopropanamide.

Intermediate 26 (R) -2-br0m0-N-methy | pr0Panamide

١ بر

(R) -2-Bromopropanoyl chloride was slowly added to an aqueous solution of methylamine cooled to o٥c. After allowing the reaction mixture to warm to room temperature, it was stirred for 2 h. The product was extracted into EtOAc, and the collected organic extracts dried over NSO4 then concentrated in vacuo to give (R) -2-br0m0-N-methylpr0panamide.

Intermediate 27

1- (tert-butoxvcarbonvKéthvl) amino) cvclopropanecarboxylic acid ة ٦ Step ٦. · ٩- (Tert-butoxvca٢bonvKéthv١١amino١cvciopropanecarboxvlate ethyl

ΜΑ 32497Β1

Under a nitrogen atmosphere, to the solution of 1- (tertbutoxycarbonylamino) cyclopropanecarboxylic acid (201.2 mg, 1.0 mmol) in 4 mL of DMF, was added to the solution of NaH (120.0 mg, 3.0 mmol) at where. After stirring for 30 min, iodoethane (0.4 mL, 5.0 mmol) was added to the reaction mixture. The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (N2SO4) and then concentrated in vacuo to yield crude ethyl 1- (tert-butoxycarbonyl (ethyl) amino) cyclopropanecarboxylate, which served as a reagent in the next step without further purification.

Step 2:! - (tert-butoxvcarbonvKéthvDamino) cyclopropanecarboxylic acid

The crude product obtained in Step 1 was dissolved in a mixture of EtOH (4.0 mL) and water (1.0 mL), then LiOH (82.0 mg, 2.0 mmol) a been added to the reaction. The reaction mixture was heated to 12O٠C in a microwave reactor for

10 min. It was then concentrated in vacuo, before partitioning the crude product between EtOAc and water. The aqueous layer was neutralized with 4Ν aqueous HCl solution to pH 4, then extracted with EtOAc. The combined organic extracts were dried over Νδθ4 and then concentrated in vacuo to give 1- (tert-butoxycarbonylethyljaminojcyclopropanecarboxylic acid.

Intermediate 28

Lert-butoxvcarbonvKethvDaminocvclobutanecarboxvliaue acid

<img file="MA32497B1_D0030.tif" />

Step 1:! - (Tert-butoxvcarbonvKéthvDaminojcvclobutanecarboxylate ethyl

Under nitrogenous atmosphere, to the solution of 1- (tert-butoxycarbonylamino) cyclobutanecarboxylic acid (430.0 mg, 2.0 mmol) in 4 mL of

DMF, NaH (240.0 mg, 6.0 mmol) at o٠c. After stirring for 30 min, iodoethane (0.8 mL, 10.0 mmol) was added to the reaction mixture. The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and water. The

ΜΑ 32497Β1 combined organic extracts were dried over NSO4 and then concentrated in vacuo to give ethyl 1- (tert-butoxycarbonyl (ethyl) amino) cyclobutanecarboxylate.

Step 2: l-rtert-butoxvcarbonvKéthvDaminolcvclobutanecarboxvliaue Acid The crude product obtained in Step 1 was dissolved in EtOH (4.0 mL) and water (1.0 mL). LiOH (164.0 mg, 4.0 mmol) was then added to the reaction. The reaction mixture was heated at 12O٠C in a microwave reactor for 10 min. It was then concentrated in vacuo, before partitioning the crude product between EtOAc and water. The aqueous layer was neutralized with 4Ν aqueous HCl solution to pH 4, then extracted with EtOAc. The combined organic extracts were dried over Na₂SO4 then concentrated in vacuo to give 1- (tert-butoxycarbonyl (ethyl) amino) cyclobutanecarboxylic acid.

Intermediate 29

1- (tert-butoxvcarbonvl (methvl) amino) cvclobutanecarboxvliaue acid

<img file="MA32497B1_D0031.tif" />

Step 1: 1 - (methyl lert-butoxvcarbonvl ethvDaminocvclobUanecarboxvlate

Under nitrogenous atmosphere, to the solution of 1- (tertbutoxycarbonylaminocyclobutanecarboxylic acid (430.0 mg, 2.0 mmol) in 4 mL of DMF, was added NaH (240.0 mg, 6.0 mmol) at o٠c. After stirring for 30 min iodomethane (0.62 mL, 10.0 mmol) was added to the reaction mixture. The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was stirred. partitioned between! 'EtOAc and water. The combined organic extracts were dried over Na₂SO4 then concentrated in vacuo to give methyl 1- (tert-butoxycarbonyl (ethyl) amino) cyclobutanecarboxylate.

Step 2: 1- (tert-butoxvcarbonvl (méthvl١amino) cyclobutanecarboxvlique acid

The crude product obtained in Step 1 was dissolved in MeOH (4.0 mL) and water (1.0 mL). LiOH (164.0 mg, 4.0 mmol) was then added to the reaction. The reaction mixture was heated at 12O٠C in a microwave reactor for 10 min. It was then concentrated in vacuo, before partitioning the crude product between ν, Α 32497Β1! 'EtOAc and water. The aqueous layer was neutralized with 4Ν aqueous HCl solution to pH 4, then extracted with EtOAc.

The combined organic extracts were dried over NSO4 and then concentrated in vacuo to give 1- (tert-butoxycarbonyl (methyl) amino) cyclobutanecarboxylic acid.

Intermediate 30 2-bromobutanamide βγ / ν ^

Under a nitrogen atmosphere, was successively added to a solution of bromobutanoic acid 210 (2.0 g, 12.0 mmol) in DCM (50 ml) at o٠c, thionyl chloride (2.6 ml, 35.9 mmol) and 0.5 mL of DMF. The reaction mixture was allowed to warm to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo and cooled to o٠c. Then ml of 37% aqueous ammonia hydroxide solution was slowly added. After allowing the mixture to warm to room temperature, it was stirred for 2 h before extracting with EtOAc. The combined organic extracts were dried over

Νδθ4 and concentrated in vacuo to give 2-bromobutanamide.

Intermediate 31 2-bromo-N-methvlbutanamide b١١h

حم 20

Under a nitrogen atmosphere, to a solution of 2bromobutanoic acid (2.0 g, 12.0 mmol) in DCM (50 ml) at o٠c, thionyl chloride (2.6 ml, 35 , 9 mmol) and 0.5 mL of DMF. The reaction mixture was allowed to warm to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo and cooled to o٠c. Then slowly added 30 mL of aqueous methylamine solution 40 à / ο. After leaving the mixture

VIA 32497-1 warm to room temperature, stirred for 2 h before extracting with EtOAc. The combined organic extracts were dried over NSO * and concentrated in vacuo to give 2-bromo-N-methylbutanamide.

Intermediate 32

2-bromo-N-ethvlbutanamide

مإدإ ٢١ ج

Under a nitrogen atmosphere, was successively added to a solution of 2bromobutanoic acid (2.0 g, 12.0 mmol) in DCM (50 ml) at o٠c, thionyl chloride (2.6 mL, 35 , 9 mmol) and 0.5 mL of DMF. The reaction mixture was allowed to warm to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo and cooled to o٠c. 30 mL of 40% aqueous ethylamine solution was then added slowly. After allowing the mixture to warm to room temperature, it was stirred for 2 h before extracting with EtOAc. The combined organic extracts were dried over N2SO4 and concentrated in vacuo to give 2-bromo-N-ethylbutanamide.

Intermediate 33

1- (Meth٧lsulfonvl) azetidin-3-0ne

<img file="MA32497B1_D0032.tif" />

To a mixture of 3-azetidinone hydrochloride (471 mg, 3.28 mmol) and K2CO3 (1.50 g, 11 mmol) in a mixture of CHCIHO (515 mL) was added methanesulfonic anhydride ( I, 14g, 6.57 mmol) all at once at o٠c. After stirring for 2 h, the reaction mixture was diluted with saturated aqueous NaHCO3 solution (5 mL) and extracted into DCM (3x25 mL). The combined DCM layers were washed in brine (5 mL), dried over N2SO4 and removed by evaporation to give 1- (methylsulfonyl) azetidin-3-0ne as a

ΜΑ 32497Β1 broken white solid, which served as a reagent without further purification; NMR¹H (400 MHz, CDC) δ 4.82 (s, 4Η), 3.05 (s, 3Η).

Example 1

5-Chloro-N2- (2-fluoro-5-méthvl-4- (1-méthvlDiDéridin-4-vl١Dhénvl) -N4- (5-méthvl-1H5 pvrazol 3 vl١pyrimidine-2.4-diamine (1)

<img file="MA32497B1_D0033.tif" />

Step 1: A mixture of 2,5-dichloro-N- (5-methyl٠1H-pyrazol-3-yl) pyrimidin-4-amine (Intermediate 1, 132 mg, 0.54 mmol) and 4- (4-amino Tert-butyl -5-fluoro-2methylphenyl) piperidine-1-carboxylate (Intermediate 19, 166 mg,

0.54 mmol) in 2-propanol (15 mL) was treated with concentrated aguous HCl (14 drops). The reaction mixture was poured into a sealed tube and heated in a microwave reactor at 13O٠C for 60 min. It was then concentrated to give 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl1H-pyrazol-3-yl) pyrimidin -2,4-diamine as a yellow solid. A portion of the crude product was purified by preparative PI-HPLC to give 5-chloro-N2- (2fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1H -pyrazol-3-yl) pyrimidin-2,4diamine in the form of a white solid: SM-ES m / z 416.1 (M + H⁺). The remaining crude product was used directly for the next reaction without further purification.

Step 2: To a solution of the crude product obtained in the previous step in THF (5 ml) and methanol (5 ml), formaldehyde (100 μL, 1.3 mmol) and 10 drops of methanol were successively added. AcOH. The reaction mixture was stirred at room temperature for 1 h, then sodium cyanoborohydride (175 mg, 2.78 mmol) was added all at once, and the reaction was stirred for an additional 30 minutes. The reaction was then neutralized with saturated aqueous NHCl and concentrated in vacuo to give an oily residue. The residue was purified by preparative PI-HPLC to give 5-chloro-N2- (2-fluoro-5-methyl-4 (1-methylpiperidin-4-yl) pl٦enyl) -N4- (5-methyl-1H -pyrazol-3-yl) pyrimidin-2,4-diamine in the form of a white solid. H NMR (400 MHz, DMSO-de) δ 10.33 (br, 1Η), 9.90 (br.

VIA 32497Β1

1Η), 9.60 (br, 1Η), 8.22 (s, 1Η), 7.56 (d, 1Η), 7.00 (d, 1Η), 6.20 (s, 1Η), 3, 53-3.50 (m, 2Η), 3.16-3.10 (m, 2Η), 2.97-2.92 (m, 1H), 2.81 (d, 3Η), 2.26 ( s, 3Η), 2.16 (s, 3Η), 1.94-1.91 (m, 2Η), 1.83-1.73 (m, 2Η); SM-ES m / z 430.1 (M + H).

Example 2

5-chloro-N2-f2-fluoro-5-methvl-4- (piDeridin-4-vl) phenvl) -N4- (5-methvl-1H-pvrazol-3vl) pyrimidine-2.4-diamine (2)

<img file="MA32497B1_D0034.tif" />

A mixture of 2,5-dichl٠ro-N- (5-methyl-1H-pyraz٠l-3-yl) pyrimidin-4-amine (Intermediate 1, 132 mg, 0.54 mmel) and 4- (4-amino- Tert-Butyl 5-fluoro-210 methylphenyl) piperidine-1-carboxylate (Intermediate 19, 166 mg,

0.54 mmol) in 2-propanol (15 ml) was treated with concentrated aqueous HCl (14 drops).

The reaction mixture was poured into a sealed tube and heated in a microwave reactor at 13O٠C for 60 min. He was then focused on giving

5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1H-pyrazol-3yl) pyrimldine-2,4-diamine as yellow solid.

A portion of the crude product was purified by preparatory CIHP-ΡΙ to give

5-Chloro-N2- (2-Fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1H-pyrazol-3yl) pyrimidin-2,4-diamine as white solid: SM-ES m / z 416.1 (M + H٠).

Examples 3 and 4 (S) -3- (5-chloro-2- (2-fluoro-5-méth٧l-4- (1-méth٧lpipéridin-4-٧l١phén٧lamino) pvrimidin4-ylamin0) azepan-2-0ne (10)

<img file="MA32497B1_D0035.tif" />

WA 32497Β1 (R) -3- (5-chloro-2- (2-fluoro-5-methvl-4- (1-methvlpiperidin-4-vl) phenvlamino) pvriridin4-vlamin0) azepan-2-0ne (11)

<img file="MA32497B1_D0036.tif" />

(±) -3- (5-chloro-2 (2-flu٥ro5-methyl-4- (1-methylpiperidin-45 yl) phenylamino) pyrimidin-4-ylamino) azepan-2-pne was synthesized by same procedures as those described in Example 1 taking as reagents Intermediate 6 and Intermediate 19. The chiral separation of the racemic mixture was carried out by HPLC in normal phase using a ChiralPaK AD column and with the following solvent system: hexane (80%) and iPrOH (20٠ / ο) with 0.1 ٠/٠ diethylamine. The two purified enantiomers were collected separately: (S) -3- (5-chloro-2- (2-fluoro5-methyl-4- (1-methylpiperidin-4-yl) phenylamin0) pyrimidin-4-ylamin0) azepan- 2-0neet (R) -3- (5-chl٠ro-2- (2-flu٠ro-5-methyl-4- (1-methylpiperidin-4-yl) phenylamino) pyrimidin4-y! Amino) azepan-2-one; the two peaks: SM-ES m / z 461.2 (M + H⁺). The first elution peak (RT = 7.26 min) and the last elution peak (RT 10.17 min) were arbitrarily associated with the (S) and (R) enantiomers, respectively.

Example 5

5-Chloro-N2- (4- (1 - ((3.5-dimethvlisoxazol-4-vl) méthvl) piperidin-4-vl) -2-fluoro-5méthvlphénvl) -N4- (5-methvl-1 H-pyrazol- 3-vl) pvrimidine-2.4-diamine f 19)

<img file="MA32497B1_D0037.tif" />

Has a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine (0.12 mmol) and triethylamine (83 pL, 0.6 mmol) in DMF (1.5 mL), 4- (chloromethyl) -3,5dimethylisoxazole (35 mg, 0.24 mmol) was added ). The mixture is stirred for 3 hours at room temperature. The residue was filtered, and the filtrate purified by preparative PI-HPLC to give 5-chloro-N2- (4- (1 - ((3,5-dimethylisoxazol-4ΜΑ 32497Β1 yl) methyl) piperidin-4-yl ) -2-fluoro-5-methylphenyl) -N4- (5-methyl-1H-pyrazol-3yl) pyrimidin-2,4-diamine as a white solid. H NMR (400 MHz, MeOD-d4) 8.12 (s, 1Η), 7.75 (d, 1Η), 7.03 (s, 1Η), 6.27 (s, 1Η), 4.25 ( s, 2Η), 3.69-3.67 (m, 2Η). 3.27-3.20 (m, 3Η), 2.54 (s, 3Η), 2.37 (s, 3Η), 2.34 (s, 3Η), 2.30 (s, 31-1) , 2.10-1.95 (m, 4Η): SM-ES m / z 525.1 (M + Η +).

Example 6

2- (4- (4- (5-Chloro-4- (5-meth٧l-1H-p٧razol-3-٧lamino) p٧rimidin-2-٧lamino) -5-fluoro-2méthvlphénvl) piperidin-1-vl١ethanol (22١

<img file="MA32497B1_D0038.tif" />

5-Chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4٠ (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4- was dissolved diamine (0.12 mmol) in anhydrous DMF (1 ml). Then TEA (50 µL, 0.36 mmol. 3 equiv.) Was added, followed by 2-bromoethanol (0.018 mL, 0.24 mmol, 2 equiv.) Dissolved in anhydrous DMF (0.7 mL). The reaction tube was sealed and heated in a microwave reactor at 100٥C for 20 min. After cooling to room temperature, the reaction mixture was concentrated and the crude product purified by preparatory ΟΙΗΡ-ΡΙ to give 2- (4- (4- (5-chIoro-4- (5-methyl-1 H-pyrazol- 3-ylamino) pyrimidin-2-ylamino) 5-fluoro-2-methylphenyl) piperidin-1-yl) ethanol in the form of a white solid: SM-ES m / z 460.2 (Μ + Η +).

Example 7

5-Chloro-N2- (2-fluoro-5-methvl-4- (1- (3,3,3-trifluoropropvl) piperidin-4-vl) phenvl) -N4 (5-methyl-1H-pvraz0l-3- vl) pyrimidine-2.4-diamine (24١

<img file="MA32497B1_D0039.tif" />

VIA 32497Β1

The mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl1H-pyrazol-3-yl) pyrimidin-2,4-diamine (0.12 mmol), 3-bromo-1,1.1trifluoropropane (85.0 pL, 0.60 mmol) and triethylamine (102.0 pL, 0.6 mmol) in 2 mL of DMF was stirred for a night. The reaction mixture was purified by

Preparatory HPLC to give 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (3,3,3triflu0r0pr0pyl) piperidin-4-yl) phenyl) -N4- (5-methyl -1H-pyraz0l-3-yl) pyrimidin-2,4diamine. SM-ES m / z 512.2 (M + H *).

Example 8

3- (4- (4- (5-Chloro-4- (5-meth٧l-1H-pvrazol-3-٧lamino) p٧rimidin-2-٧lamino) -5-fluoro-210 methylphenvl) piperidin-1-vl) -1.1 .1 -triflu0r0Pr0Pan-2-0l (301

<img file="MA32497B1_D0040.tif" />

The mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl1H-pyrazol-3-yl) pyrimidin-2,4-diamine (0.12 mmol) and 2- (trifluoromethyl) oxirane (67.8 mg, 0.60 mmol) in 2 ml of DMF was stirred overnight. The reaction mixture was purified by preparative HPLC-ΡΙ to give 3- (4- (4- (5-chloro4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2-ylam ؛ no) - 5-fluoro-2methylphenyl) piperidin-1-yl) -1,1, 1-trifluoropropan-2-ol. SM-ES m / z 528.2 (M t H *).

Example 9

2- (4- (4- (5-Chloro-4- (5-meth٧l-1H-p٧razol-3-vlamino) pvrimidin-2-vlamino) -5-fluoro-2méhlphénvDpiperidin-l-viaetamide / 39)

<img file="MA32497B1_D0041.tif" />

Has a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine (0.12 mmol) and triethylamine (50 µL, 0.36 mmol) in DMF (1.5mL), 2-br0m0-acetamide (33 mg, 0.24 mmol) was added. The mixture is stirred for 2 hours at

ΜΑ 32497Β1 room temperature, the reaction mixture was filtered, and the filtrate purified by preparatory ΡΙ HPLC to give 2- (4- (4- (5-chloro-4- (5-methyl! -1H-pyrazol- 3ylamino) pyrimidin-2-ylamino) -5-fluoro-2-methylphenyl) piperidin-1-yl) acetamide as a white solid: NMR ¹H (400 MHz, Me0D-d4) δ 8.11 (s, 1Η), 7.76 (d 1Η),

7.09 (d, 1Η), 6.27 (s, 1Η), 4.0 (s, 2Η), 3.75-3.73 (m, 2Η), 3.22-3) 13 (m, 3Η), 2.34 (s,

3Η), 2.30 (s, 3Η), 2.04 -2.00 (m, 4Η): SM-ES m / z 473.2 (M + H).

Example 10

5-Chloro-N2- (2-fluoro-5-méth٧l-4- (1- (2- (méth٧lsulfon٧néth٧l) pipéridin-4-vl) phen٧nN4- (5-methyl-1 H-p٧razol-3-٧l١p٧rimidine-2, 4-diamine (55)

<img file="MA32497B1_D0042.tif" />

z \ / S02Me

Has a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine (0.12 mmol) and triethylamine (83 µl, 0.6 mmol) in DMF (1.5 mL), methylvinyl sulfone (38 mg, 0.36 mmol) was added. The mixture was stirred at room temperature for

1 the hour. The reaction mixture was filtered, and the filtrate purified by preparative PI-HPLC to give 5-chlora-N2- (2-fluoro-5-methyl-4- (1- (2 (methylsulfonyl) ethyl) piperidin- 4-yl) phenyl) -N4- (5-methyl-1H-pyrazol-3-yl) pyrimidin2.4-diamine as a white solid. SM-ES m / z 522.1 (M + Η +).

Example 11

5-Chloro-N2- (2-fluoro-5-méth٧l-4- (1- (méth٧lsulfon٧l١pipéridin-4-٧l١phén٧l١-N4- (5methyl-1 H-p٧raz٠l-3-٧l) p٧rimidine-2.4-diamine (621 &lt;

Has a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2.4-diamine ( 0.12 mmpl) and triethylamine (50 μΐ, 0.36 mmol) in DMF (1.5 mL), methanesulfonyl chloride (18 μΐ, 0.24 mmol) was added. The mixture is stirred for

ΜΑ 32,497Β1 hours at room temperature. The reaction mixture was filtered, and the filtrate purified by preparative HPLC-ΡΙ to give 5-chloro-N2- (2-fluoro-5-methyl-4 (1- (methylsulfonyl) piperidin-4-yl) phenyl ) -N4- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2,4diamine as a white solid: MS-ES m / z 494.2 (M + H *).

Example 12

4- (4- (5-Chloro-4- (5-methvl-1H-pvrazol-3-ylamino) p٧rimidin-2-٧l-amino) -5-fluoro-2methylphenylloioeridine-1-carboxylate from ethyl (66)

<img file="MA32497B1_D0043.tif" />

هل / \

Has a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (510 methyl-1H-pyrazol-3-yl) pyrimidin-2,4 -diamine (0.12 mmol) and triethylamine (50 µL, 0.36 mmol) in DMF (1.5 mL), ethyl cliloroformate (26 mg, 0.24 mmol) was added. The mixture is stirred for 2 hours at room temperature. The reaction mixture was filtered, and the filtrate purified by preparative HPLC-ΡΙ to give 4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-315 ylamino) pyrimidin-2-ylamino) Ethyl -5-fluoro-2-methylphenyl) piperidine-1-carboxylate in the form of a white solid:

NMR ¹H (400 MHz, Me0D-d4) δ 8.13 (s, 1Η), 7.54 (d, 1Η), 7.10 (d, 1Η), 6.28 (s, 1Η), 4.30- 4.26 (m, 2Η), 4.14 (q, 2Η), 2.99-2.96 (m, 3Η), 2.33 (s, 3Η), 2.29 (s, 3Η), 1 , 81.77 (m, 211), 1,641.55 (m, 2Η), 1.28 (t, 3Η): SM-ES m / z 488.2 (M + Η +).

Example 13

4- (4- (5-Chloro-4- (5-meth٧l-1H-pvrazol-3-٧lamino) p٧rimidin-2-٧lamino) -5-fluoro-2methylphenyD-NN-dimethvIpiperidine-1-carboxamide (69)

<img file="MA32497B1_D0044.tif" />

ΜΑ 32497Β1

Has a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine (0.12 mmol) and triethylamine (83 µL, 0.6 mmol) in DMF (1.5 mL), dimethylcarbamic chloride (39 mg, 0.36 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate purified by preparative PI-HPLC to give 4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamino) - 5-Flu0r0-2-methylphenyl) -N, N-dimethylpiperidine-1carboxamide as a white solid.

SM-ES m / z 487.2 (M + Η +).

Example 14

1- (4- (4- (5-Chloro-4- (5-méhl-1H-p٧razel-3-vlamino١pvrimidin-2-vlamino١-5-fluoro-2méth٧lphénvl١piperidin-1-vl١-2- (diméthvlamin0١éthan0ne (73١

<img file="MA32497B1_D0045.tif" />

Has a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (515 methyl-1H-pyrazol-3-yl) pyrimidin-2,4 -diamine (0.12 mmol) and triethylamine (50 pL, 0.36 mmol) in DMF (1.5 ml), 2 (dimethylamino) acetyl chloride (38 mg, 0.24 mmol) was added . The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate purified by preparative PI-HPLC to give 1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-320 ylamino) pyrimidin-2) -ylamino) -5-fluoro-2-methylphenyl) piperidin-1-yl) -2 (dimethylamino) ethanone in white solid form: NMR 400) برا MHz, MeOD-d δ 8.08 (s, IH), 7 , 71 (d, 1H), 7.03 (d, 1H), 6.26 (s, 1H), 4.71-4.67 (m, 2Η), 3.81-3.77 (m, 2Η ), 3.14-3.12 (ni, 2Η), 2.98 (s, 3Η), 2.96 (s, 3Η), 2.90-2.83 (m, 11-1), 2, 34 (s,

3Η), 2.28 (s, 3Η), 1.87 (d, 2Η), 1.76-1.55 (m, 2Η); SM-ES m / z 501.2 (M + H *).

Examples

1- (4- (4- (5-Chloro-4- (5-methyl-1-H-p٧razo: 3-vlamino): imidin-2-vla: ino) -5-fluoro-2-;

ΜΑ 32497Β1

<img file="MA32497B1_D0046.tif" />

To the solution of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3yl) pyrimidin-2,4-diamine ( 100.0 mg, 0.24 mmol) in 4 mL of DCM, 2-chloroace Ichloride (23.0 μΙ_, 0.29 mmol), and triethylamine (67.0 pL, 0.46 mmol). The reaction mixture was stirred at room temperature for 1 h, then washed in brine. The organic extract was dried over N2SO4, then concentrated in vacuo to give a crude product. The crude product was mixed with 1-methylpiperazine (116.0 mg, 1.16 mmol) in 3 mL of DMF, and the reaction mixture stirred overnight at room temperature.

The reaction mixture was purified by preparative ΡΙ-HPLC to give 1 (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2-ylamino) - 5-Fluoro-2methylpheny) piperidin-iy) -2- (4-methylpiperazin-1-yl) ethane. SM-ES m / z 556.3 (Μ + Η).

Example 16

Azetidin-3-yl (4- (4- (5-chloro-4- (5-meth٧l-1H-p٧razol-3-vlamino) Dvrimidin-2-vlamino١5fluoro-2-méthvlphén vl) piperidin-1-vl١methanone (131١

<img file="MA32497B1_D0047.tif" />

Has a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazoi-3-yi) pyrimidin-2,4- diamine (0.12 mmol), di20 isopropylethylamine (50 pt, 0.36 mmol) and HATU (55 mg, 0.14 mmol) in DMF (1.5 ml), acid 1 was added - (tert-butoxycarbonyl) azetidine-3-carboxylic acid (29 mg, 0.14 mmol). After stirring at room temperature for 4 hours, the mixture was diluted in methanol (1 mL) and concentrated aqueous HCl (1 mL). The mixture was stirred at 5O٠C for 30 min. The resulting mixture was then filtered and purified by preparatory ΡΙ HPLC to give azet! Din-3-yl (4- (4- (5-chloro70

ΜΑ 32497131

4- (5-methyl-1 H-pyrazol-3-ylamino) pyrimidin-2-ylamino) -5-fluoro-2methylphenyl) piperidin-1-yl) methane in the form of a white solid. NMR^٦H (400 MHz, MeODd) δ 8.08 (s, IH), 7.68 (d, 2Η), 7.04 (d, 2Η), 6.26 (s, IH), 4.74-4, 68 (m, 2Η), 4.39-4.35 (m, 1H), 4.29-4.24 (m, 2Η), 4.11 -4.07 (m, 1H), 3.74- 3.71 (m, 1H),

3.25 -3.24 (m, 1H), 3.07-3.04 (m, 1H), 2.87-2.80 (m, 1H), 2.33 (s, 3Η), 2.28 ( s, 3Η),

1.87-1.84 (m, 211), 1.66-1.56 (m, 2Η); SM-ES m / z 499.2 (M + H *).

Example 17

5-Chloro-N2- (2-fluoro-5-meth٧l-4- (1- (tetrahvdro-1,1-dioxydo-3-thienvl) piperidin-4yl) phenyl) -N4- (5-methyl-1 H- p٧raz0l-3-yl) p٧rimidin-2,4-diamine (145)

<img file="MA32497B1_D0048.tif" />

Has 5-Chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1 Hpyrazol-3-yl) pyrimidin-2,4-diamine (30 mg, 0.072 mml) in EtOH (0.5 ml), thiophene-2,3-dihydro-1,1-dioxide (17 mg, 0.144 mmol) was added. The reaction mixture was then heated at 13O٠C for 2 h. After cooling to room temperature, the mixture was concentrated and purified by preparative PI-HPLC to give 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (tetrahydro-1,1dioxydo-3 -thienyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2,4diamine. SM-ES m / z 534.2 (M + H).

Example 18

5-Chloro-N2- (2,5-dimeth٧l-4- (1- (tetrahvdro-1,1-dioxydo-2H-thiop٧ran-4-yl) piperidin-4yl) gjeyî) N (5-j-néhl-1 H-p٧razpl-3-yl) pyrimidin-2.4-diamine (1461 /

ΜΑ 32497Β1

<img file="MA32497B1_D0049.tif" />

Step 1: To a solution of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4 -diamine (30 mg, 0.073 mmol) in acetonitrile (1 mL), CS2CO3 (47 mg, 0.15 mmol) and iodotetrahydroH-thiopyran (48 mg, 0.22 mmol) were added. This reaction mixture was stirred at 8O٠C for 16 h. After cooling to room temperature, the mixture was treated with saturated aqueous NHC solution (3ml) and extracted into EtOAc (3x3ml). The organic layers were combined and concentrated. The residue was purified by chromatography on a silica gel column (gradient 0-8٠ / ο de

MeOH / CHC with ΝΗ3) to give 5-chloro-N2- (2,5-dimethyl-4- (1 (tetrahydro-2H-thiopyran-4-yl) piperidin-4-yl) phenyl) -N4- ( 5-methyl-1H-pyrazol-3y!) Pyrimidin-2,4 diamine as a white solid. SM-ES m / z 512.2 (M + H).

Step 2: With 5-chloro-N2- (2,5-dimethyl-4- (1- (tetrahydro-2H-thiopyran-4-yl) piperidin4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine (18 mg,

0.035 mmol) in CH2Cl2 (1 mL), m-CPBA (16 mg, 0.71 mmol) was added at o٠c. The mixture was warmed to room temperature and stirred for 30 min: then a saturated aqueous solution of NaHO (3ml) was added, and the crude product was extracted with CCI (3٠x3٠mL). The combined organic layers were concentrated and purified by preparatory thin layer chromatography (silica gel, 12% MeOH / CHC with ΝΗ3) to give 5-chloro-N2- (2,5-dimethyl4- (1- (tetrahydro -1,1-dioxydo-2H-thiopyran-4-yl)) piperidin-4-yl) phenyl) -N4- (5-methyl1H-pyrazol-3-yl) pyrimidin-2,4-diamine. SM-ES m / z 544.2 (M + H⁺).

ΜΑ 32497Β1

Examples

5-Chloro-N2- (2-fluoro-5-méthvl-4- (1- (1.1-diox٧do-3-thietanvl) pioeridin-4-vl) phen٧l) N4- (5-méthvl-1H-pvrazol-3- vl) p٧rimidine-2.4-diamine (148)

A 5-Chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1Hpyrazol-3-yl) pyrimidin-2,4-diamine ( 30 mg, 0.072 mmol) in MeOH (1 ml), 3-bromothietane 1,1-dioxide (15 mg, 0.079 mmol) was added followed by TEA (15 mg). The reaction mixture was stirred at room temperature for 5 h and concentrated. The resulting residue was purified by preparative PI-HPLC to give 5-chloroN2- (2-fluoro-5-methyl-4- (1- (1,1-dioxydo-3-thietanyl) piperidin-4-yl) phenyl ) N4- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine. H NMR (400 MHz, DMSO-de + 1 drop of ΙΟ) δ 8.02 (s, 1Η), 7.37 (s, 1Η), 7.02 (s, 1Η), 6.23 (s, 1Η ), 4,284,22 (m, 2Η), 4,12-4,07 (m, 2Η), 3,22-3,18 (m, 1Η), 2.95-2.92 (m, 2Η), 2.68-2.62 (m, 1Η), 2.22 (s, 3Η), 2.13 (s, 3Η), 2.07-2.01 (m, 2Η), 1.71-1.55 ( m, 4Η). SM-ES m / z 520.2 (M

Example 20

5-Chloro-N2- (4- (1- (5-ethvlp٧rimidin-2-٧l١pipéridin-4-٧l) 2-fluoro-5-méth٧lphén٧l) -N4 (5-meiyl-1H-0٧razol-3-٧l) p٧rimidine- 2.4-diamine (149١

<img file="MA32497B1_D0050.tif" />

I

VIA 32497Β1

Has a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyraz0l-3-yl) pyrimidin-2,4- dîamine (0.10 mmol) and triethylamine (83 μΙ_, 0.6 mmol) in DMF (1.5 mL), 2-chloro-5-et! ٦y١pyrimidine (27 mg, 0.20 mmol) was added ). The reaction mixture was heated in the microwave at 12O٠C for 10 min. The mixture was filtered and purified by preparatory ΡΙ HPLC to give 5-chloro-N2- (4- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) -2-fluoro-5methyliphenyl) -N4- (5-methyl-1H-pyrazol-3-yl) pyr ؛ midin-2,4-diamine as a white solid. SM-ES m / z 522.2 (M + Η +).

Example 2110 4- (4- (5-Chloro-4- (5-methvl-1H-pvrazol-3-vlamino١Dvrimidin-2-vlamino) -2,5diméth٧lphénvl) piperidin-2-one (151)

٠١١

<img file="MA32497B1_D0051.tif" />

Step 1: In a 5 mL microwave reaction tube, was added 2- (2,5dimethyl-4-nitrophenyl) -4,4.5.5-tetramethyl-1,3,2-dioxaborolane (143 mg ,

0.516 mmol, prepared from 1-bromo-2,5-dimethyl-4-nitrobenzene following a standard protocol), 1- (4-methoxybenzyl) -5,6-dihydropyridin-2 (1H) -one ( 56 mg, 0.26 mmol, prepared following a procedure similar to that described by Lerchner, etc. in Chem. Eur. J. 2006, 12, 8208), chloro (1,5-cyclooctadiene) rhodium (I) dimer (13 mg, 0.26 mmol), KOH (0.13 ml of IN aqueous solution) and dioxane (1.2 ml). The tube was degassed, filled with N and sealed. The reaction tube was then heated at 100٠C in a microwave reactor for 10 min, then, after opening, its contents were treated with a saturated aqueous solution of NCI (3 mL) eL extracted in EtOAc (3x4 mL ). The organic layers were combined and concentrated. The residue was then purified by flash chromatography (silica gel, EtOAc / hexane gradient at 0-70٠ / ٠) to give 4- (2,5-dimethyl-4nitr0phenyl) -1- (4-meth0xybenzyl) piperidin -2-0ne. SM-ES m / z 369.2 (M + H.

ΜΑ 32497Β1

Step 2: A solution of 4- (2,5-dimethyl-4-nitrophenyl) -1- (4methoxybenzyl) piperidin-2-one (63 mg, 0.17 mmol) in MeOH (10 mL), we have added 10% w / w Pd / C (6 mg), then the mixture was degassed and stirred under H at room temperature for 14 hr. After removing the catalyst by filtration, the filtrate was concentrated to give 4- (4-amino-2١5-dimethylphenyl) -1- (4methoxybenzyl) piperidin-2-one as a pale yellowish oil. MS-ES m / z 339.2 (M + H).

Step 3: Has a mixture of 4- (4-amino-2,5-dimethylphenyl) -1- (4methoxybenzyl) piperidin-2-one (23 mg, 0.094 mmol) and 2,5-dichloro-N- (5 -methyl10 1H-pyrazol-3-yl) pyrimidin-4-amine (29 mg, 0.086 mmol) in iPrOH (1 mL), HCl (60 µl, 4Ν in dioxane) was added. The vessel containing the reaction mixture was then sealed and heated at 13O٠C for 4 h. After cooling to room temperature, the mixture was treated with saturated aqueous NaHO solution (3 mL) and extracted into EtOAc (3x4 mL). The organic layers were combined and concentrated. The residue was then purified by flash chromatography (silica gel, MeOH / CHC gradient at 0-10٠ / ٥) to give 4- (4- (5-chloro-4- (5-methyl-1H-pyrazol -3-ylamino) pyrimidin-2-ylamino) _ 2,5-dimethylphenyl) -1- (4-methoxybenzyl) piperidin-2-one. SM-ES m / z 546.2 (M + H).

Step 4: A salt of 4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin20 2-ylamino) -2.5-dimethylphenyl) -1- (4-methoxybenzyl) piperidin -2-one (45mg) in ٢FA (0.5 mL) was heated at 100٠C for 24 h. After cooling to room temperature, the mixture was concentrated and purified by preparative PI-HPLC to give 4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamino) pyrimidin-2-ylamino) ) -2,5-dimethylphenyl) piperidin-2-one. SM-ES m / z 426.2 (M + H).

Example 22

ChooN2- (2-fluoro-4- (4-methvlpiperazin-1-vl١-5- (trifluoromethvl١phénvl١-N4- / 5methyl-1H-pvrazol-3-yl) pvrimidin-2,4-diamine (157)

ΜΑ 32497Β1

<img file="MA32497B1_D0052.tif" />

<img file="MA32497B1_D0053.tif" />

Step 1: To a microwave reaction tube was added 4-bromo-2-fluoro-5- (trifluoromethyl) aniline (256 mg, 1.0 mmol), 1methylpiperazine (300 mg, 3 mmol) ld (dba) 3 (91.5 mg, 0.1 mmol,), di-tert5 butyl (2'.4 ', 6-triis0pr0pylbiphenyl-2-yl) ph0sphine (60 mg, 0.2 mmol), NaOtBu (144 mg, 1.5 mmol) and THF (3 mL). After degassing the reaction tube and filling it with N, it was heated to 12O٠C in a microwave reactor for 40 min. The mixture was then poured into saturated aqueous NHC solution (10 mL) and extracted into EtOAc (3 X 10 mL). The organic layers were combined and concentrated. The residue was purified by flash chromatography (silica gel, gradient of MeOH / CHCls to 0-10٠ / ٠) to give 2-fluoro-4- (4methylpiperazin-1-yl) -5- (trifluoromethyl) aniline under form of white solid. SM-ES m / z 278.1 (Μ + Η).

Step 2: Has a mixture of 2-fluoro-4- (4-methylpiperazin-ly!) - 515 (trifluoromethyl) aniline (37 mg, 0.133 mmol) and 2,5-dichloro-N- (5-methyl-1 Hpyrazol-3-yl) pyrimidin-4-amine (36 mg, 0.147 mmol) in iPrOH (1 mL), HCl (100 μΐ, 4Ν in dioxane) was added. The vessel containing the reaction mixture was then sealed and heated at 13O٠C for 4 h. After cooling to room temperature, the mixture was treated with a saturated aqueous solution of

NaHCO3 (5 mL) and extracted into EtOAc (3x4 mL). The organic layers were then combined and concentrated. The residue was purified by preparatory thin layer chromatography (silica gel, gradient of MeOH / CHC at 8٠ / ο) to

VIA 32497131 give 5-chloro-N2- (2-fluoro-4- (4-methylpiperazin-1-yl) -5 (trifluoromethyl) phenyl) -N4- (5-methyl-1 H-pyrazol-3-yl ) pyrimidine-2,4-diamine: SMES m / z 485.2 (MH).

Example 23 (S) -2- (4- (4- (5-methvl-1H-t٧razol-3-vlamino) Drimidin-2-vlamino) -5-fluoro-2mhvlphénvl) piperidin-1 -vloropanamide (163)

<img file="MA32497B1_D0054.tif" />

A mixture of 5-Chloro-N2- (2-Fluorine-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine (50.0 mg, 0.12 mmel), (R) -210 bromopropanamide (90.6 mg, 0.60 mmel) and triethylamine (102.0 pL, 0.60 mmol) in 2 mt of DMF a was heated to 15O٥C in a microwave reactor for 30 min. The reaction mixture was directly purified by preparative ΡΙ-HPLC to give (S) -2- (4- (4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2-ylamino) -5fluoro -2-methylphenyl) piperidin-1-yl) propanamide: SM-ES m / z 487.2 (M + H).

Example 24 (S) -2- (4- (4- (5-chloro-4- (5-methyl-1H-pvrazol-3-vlamino) p٧rimidin-2-vlamino) -5-fluoro2-methvlphenyl) piperidin-1 -vl) -N-meth٧lpropanamide (164١

<img file="MA32497B1_D0055.tif" />

A mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (520 methyl-1 H-pyrazol-3-yl) pyrimidin-2,4 -diamine (50.0 mg, 0.12 mmol), (R) -2methylpropanamide (100.0 mg, 0.60 mmol) and triethylamine (102.0 pL, 0.60 mmol) in 2 ml of DMF was heated to 15O٥C in a microwave reactor for min. The reaction mixture was directly purified by preparatory ΡΙ HPLC

ΜΑ 32497Β1 to give (S) -2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2ylamino) -5-fluoro-2-methylphenyl) piperidin-1-yl) -N-methylpropanamide: SM-ES m / z 501.2 (M + H).

Example 25 (S) -2-4- (4- (5-chloro-4- (5-meth٧l-1H-pvrazol-3-vlamino) p٧rimidin-2-ylamino) -2.5dimethylphénvDpiperidin-1-vDpropanamided)

<img file="MA32497B1_D0056.tif" />

A mixture of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1Hpyrazol-3-yl) pyrimidin-2,4-diamine (50 , 0 mg, 0.12 mmol), (R) -210 bromopropanamide (90.6 mg, 0.60 mmol) and triethylamine (102.0 µl, 0.60 mmol) in 2 mL of DMF was heated at 15O٠C in a microwave reactor for 30 min. The reaction mixture was directly purified by preparative PI-HPLC to give (S) -2- (4- (4- (5-chloro-1H-pyrazol-3-ylamino) pyrimidin-2-ylamino) -2, 5dimethylphenyl) piperidin-1-yl) propanamide: SM-ES m / z 483.2 (M + H٠).

Example 26 (4- (4- (5-chloro-4- (5-methvl-1H-pyrazol-3-vlamino١pvrimidin-2-vlamino١-5-fluoro-2méhlphén٧l) piperidin-1-٧l) (1- (éhlamine١cvcleprop٧l١methanone / 169١

<img file="MA32497B1_D0057.tif" />

A mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (520 metl٦yl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine (67.3 mg, 0.17 mmol), 1- (tertbutoxycarbonyl (ethyl) aminocyclopropanecarboxylic acid (38.0 mg, 0.17 mmol),

HATU (63.0 mg, 0.17 mmol) and diisopropylethylamine (57 µL. 0.34 mmol) in 1 ml of DMF was stirred at room temperature overnight. The mixture of

ΜΑ 32497Β1 reaction was partitioned between EtOAc and water, and the combined organic extracts dried over NSO4 then concentrated in vacuo. The resulting crude mixture was dissolved in 5 mL of DCM and 4 mL of TFA, then stirred for 2 h and concentrated in vacuo. The crude product was purified by ΡΙ HPLC to give (4- (4- (55 chl0r0-4- (5-methyl-1H-pyraz0l-3-ylamin0) pyrimidin-2-ylamin0) -5-flu0ro- 2methylphenyl) piperidin-1-yl) (1- (ethylamino) cyclopropyl) methanone: MS-ES m / z 527.2 (M + H *).

Example 27

1- (4- (4- (5-Chloro-4- (5-methvl-1H-pvrazol-3-ylamino) pyrimidin-2-ylamino) -2,510 dimethvlphénvl) piperidin-1-٧l) -2- (ethvlamino) -2-meth٧lpropan-1-one (175١

<img file="MA32497B1_D0058.tif" />

Has a solution of 2-amino-1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2.5-dimethylphenyl) piperidin-1-yl ) -2-methylpr0pan-1one (6mg, 0.012mmol) in acetone (0.5ml), K2CO3 (11mg,

0.079 mmol). The mixture was stirred at room temperature for 10 min, then Etl (6 mg, 0.038 mmol) was added thereto. The resulting mixture was then stirred at room temperature for 14 h before being treated with saturated aqueous NH4Cl solution (1 mL) and extracted into EtOAc (3x2 mL). The organic layers were combined and concentrated, and the residue purified by preparatory thin layer chromatography (silica gel, 8٠/٠ MeOH / DCM / NH3) then subjected to further purification by preparatory ΡΙ HPLC to give 1 - (4- (4- (5cl٦loro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2-ylamino) -2,5dimethylphenyl) piperidin-1-yl) -2- (ethylamin0) -2 -methylpr0pan-1-0ne; SM-ES m / z 525.3 (Μ + H).

Example 28 (4- (4- (5-Chloro-4- (5-méthvl-1H-pvrazol-3-vlamino١Dvrimîdin-2-vlamino١-5-fluoro-2methylphenvl) piperidin-1-vl) (1- (ethvlamin0١cvcl0butvlneméthan0 176١

ΜΑ 32497Β1

<img file="MA32497B1_D0059.tif" />

A mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine (50.0 mg, 0.12 mmol), 1- (tertbutoxycarbonylethyl) aminocyclopropanecarboxylic acid (29.2 mg, 0.12 mmol),

HATU (45.8 mg, 0.12 mmol) and diisopropylethylamine (20 µl, 0.12 mmol) in 1 mL of DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried over Νδθ4 and concentrated in vacuo. The resulting crude mixture was dissolved in 5 ml of DCM and 4 ml of TFA, then stirred for 2 h and concentrated in vacuo. The crude product was purified by ΡΙ HPLC to give (4- (4- (5chl0r0-4- (5-methyl-1H-pyraz0l-3-ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2methylphenyl ) piperidin-1-yl) (1- (ethylamino) cyclobutyl) methanone: SM-ES m / z 541.3 (M + H⁺).

Example 29 (4- (4- (5-Chloro-4 (5-methyl-1 H-pyraz0l-3-ylamin0) pvrimidin-2-vlamin0) -5-flu0r0-2méthvlphénvl) piperidin-1-vl) (1- (methvlamin0) cvcl0butyl) methane (177)

<img file="MA32497B1_D0060.tif" />

A mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine (50.0 mg, 0.12 mmol), 1- (tert-butoxycarbonyl (methyl) aminocyclobutanecarboxylic acid (27.5 mg, 0.12 mmol), HATU (45.8 mg, 0.12 mmol) and of diisopropylethylamine (20 µL, 0.12 mmol) in 1 mL of DMF was stirred at room temperature overnight The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried over Νδθ4 and concentrated in vacuo. The resulting crude mixture was

ΜΑ 32497Β1 dissolved in 5 mL of DCM and 4 mL of TFA, then stirred for 2 h and concentrate in vacuo. The crude product was purified by ΡΙ HPLC to give (4- (4- (5chloro-4- (5-metl٦yl-1H-pyrazol-3-ylamino) pyrimidin-2-ylamino) -5-fluoro-2methylphenyl ) piperidin-1-yl) (1- (methylamino) cyclobutyl) methanone; SM-ES m / z

527.2 (M + H).

Example 30 (S١-3-14- (2.5-dimethvl-4- (5-méthvl-4- (5-méthvl-1H-pvrazol-3-vlamino) pyrimidin-2vlamino) phen٧l) piperidin-1-vl-1, 1,1-trifluoropropan-2-ol (179)

<img file="MA32497B1_D0061.tif" />

To a solution of N2- (2.5-dimethyl-4- (piperidin-4-yl) phenyl) -5métl٦yl-hl4- (5-métl٦yl-1H-p١rrazol-3-yl) pyrimidin-2,4-diamine ( 36.0 mg, 0.084 mmol) in DMF (0.5 ml), TEA (23.4 pL, 0.168 mmol) and (S) -2 (trifluoromethyl) oxirane (72.8 pL, 0 , 84 mmol). The reaction mixture was stirred at room temperature overnight, and purified by preparative CIHP-ΡΙ to give (S) -3- (4- (2,5-dimethyl-4- (5-methyl-4- (5-methyl-1H-pyrazol-3ylamino) pyrimidin-2-ylamino) phenyl) piperidin-1-yl) -1,1, l-trifluoropropan-2-ol: SM-ES m / z 504.3 (M + H٠).

Example 31

2- (2- (4- (5-Chloro-4- (5-meth٧l-1H-p٧razol-3-vlamino) pyrimidin-2-٧lamino) -2,5-

<img file="MA32497B1_D0062.tif" />

Has a mixture of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-2-yl) phenyl) -N4- (5-methyl1H-pyrazol-3-yl) pyrimidin-2,4-diamine ( 0.12 mmol) and triethylamine (83 pt, 0.6 mmol) in DMF (1.5 mL), 2-bromoace mide (35 mg.

ΜΑ 32497Β1

0.24 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was then filtered, then the filtrate purified by PI-HPLC to give 2- (2- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2) -ylamino) -2,5dimethylphenyl) piperidin-1-yl) ac amide in the form of a white solid; NMR^٦H (400

MHz, MeOD-d ") 8.09 (s, 1Η), 7.65 (d, 1Η), 7.43 (s, 1Η), 6.41 (s, 1Η), 4.79-4.74 (m, 2Η), 3.83-3.48 (m, 2Η), 2.71 (s, 3Η), 2.42 (s, 3Η), 2.34 (s, 6Η), 2.15- 1.84 (m, 7Η):

MS-ES m / z 469.2 (M + H).

Examples 32 and 33 (SI 5-Chloro-N2- (2.5-dimethvl-4- (1-méthvlpiperidin-2-vl) phenvl) -N4- (5-méthvl-1Hp٧razpl-3-vl) pvrimidine-2.4-diamine ( 183) (R) 5-Chloro-N2- (2.5-dimeth٧l-4- (1-methylpiperidin-2-٧l) phen٧l) -N4- (5-meth٧l-1Hp٧razp | -3-٧l) pyrimidine-2.4-diamine ( 184١

Step 1: To a mixture of 1-br٥mo-2,5-dimethyl-4-nitr٥benzene (185 mg, 1 mmel) and 2- (tributylstannyl) pyridine (202 mg, 1.1 mmol) in DMF (4 mL) ), tetrakis (triphenylphosphine) palladium (0) (58 mg, 0.05 mmol) was added. I_e reaction tube was sealed, the mixture purged with N for 3 min, then heated to 12O٠C under N overnight. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of ammonia chloride. The crude mixture was then extracted into ethyl acetate (3 X 15mL). The organic extracts were combined, washed in brine and concentrated. The crude product was purified by column chromatography on silica gel (60٠/٠ ethyl acetate in hexane) to give 2- (2,5-dimethyl-4-nitrophenyl) pyridine as a solid. White. The solid obtained was dissolved in a mixture of acetic acid / TFA (15mL7200 µl). PO (10% w / w) was then added to the

ΜΑ 32497Β1 solution. The reaction mixture was degassed, purged several times with H then vigorously stirred under 1 atmosphere of H overnight. The mixture was filtered, and the filtrate concentrated to give 2,5-dimethyl-4- (piperidin-2-yl) aniline as a yellow oil; SM-ES m / z 205 (M + H⁺).

Step 2: A mixture of 2,5-dichloro-N- (5-methyl-1 H-pyrazol-3-yl) pyrimidin-4-amine (120 mg, 0.49 mmol) and 2.5-dimethyl-4- (piperidin-2-yl) aniline (100 mg, 0.49 mmol) in 2-propanol (10 ml) was treated with concentrated aqueous HCl (7 drops). The vessel containing the reaction mixture was poured into a sealed tube and heated in a microwave reactor at 13O٠C for 45 min. It was then concentrated to give 5-chloro-N2- (2,5-dimethyl-4- (piperidin-2-yl) phenyl) -N4- (5-methyl1H-pyrazol-3-yl) pyrimidin-2 , 4-diamine: SM-ES m / z 412.1 (M + H). The crude product was used directly in the next reaction without further purification.

Step 3: To a solution of the crude product obtained in the previous step in THF (1 mL) and methanol (1 ml), formaldehyde (100 μl,

1.3 mmol) and 5 drops of AcOH. The reaction mixture was stirred at room temperature for 1 h, then sodium cyanoborohydride (160 mg, 2.45 mmol) was added all at once, and the reaction was stirred for an additional 30 minutes. The reaction was then neutralized with saturated aqueous NHC and concentrated in vacuo to give an oily residue. The residue was purified by PI-HPLC to give (±) -5-chloro-N2- (2,5-dimethyl-4- (1methylpiperidin-2-yl) phenyl) -N4- (5-methyl-1H -py٢azol-3-yl) pyrimidin-2,4-diam ؛ ne as a white solid; SM-ES m / z 426.2 (M + H *).

Step 4: The chiral separation of the racemic mixture was carried out by HPLC in normal phase using a ChiralPaK AD column and with the following solvent system: hexane (95٠ / ο), EtOH (2.5%), MeOH (2.5٠ / ο). The two purified enantiomers were collected separately: (R) -5-chloro-N2- (2,5-dimethyl-4- (1-methylpiperidin-2yl) phenyl) -N4- (5-methyl-1 H-pyrazol- 3-yl) pyrimidin-2,4-diamine and (S) -5-chloro-N2 (2,5-dimethyl-4- (1-methylpiperidin-2-yl) phenyl) -N4- (5-methyl-1H -pyrazol-3yl) pyrimidin-2,4-diamine; the two peaks: SM-ES m / z 426.2 (M + H). The first elution peak was arbitrarily associated with the (R) enantiomer.

WA 32497131

Example 34

5-Chloro-N2- (2,5-dimeth٧l-4- (1- (3-m٠rpholinopropylsulfonyl) piperidin-4-٧l) phenvl) N4- (5-methvl-1 H-pyrazol-3-vl١Pvrimidine-2,4 -diamine (194١

<img file="MA32497B1_D0063.tif" />

Step 1: To a mixture of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-2-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4 -diamine (78 mg, 0.19 mmol) and TEA (0.52 mL, 3.78 mmol) in DCM (10 mL), 3chloropropane-1-sulfonyl chloride (63 mg, 0, 36 mmol, in 1 mL of DCM). After stirring for one hour, EtOAc (100 mL) was added. The mixture was successively washed with water (10 mL) and brine (10 mL), dried over N2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc 0-100٠ / ο in hexane) to give 5-chloro-N2- (4- (1- (3cl٦loropropylsulfonyl) piperidin-4- yl) -2,5-dimethylplienyl) -1١l4- (5-methyl-1H-pyraz ^ ol-3yl) pyrimidin-2,4-diamine as an off-white solid; SM-ES m / z 552.2 (Μ + Η).

Step 2: The product obtained in Step 1 was stirred in pure morpholine (0.5 mL) at 100٠C in a sealed flask for one hour. The reaction mixture was purified by PI-HPLC to give 5-chloro-N2- (2.5-dimethyl-4- (1- (3morpholinopropylsulfonyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H -pyrazol-320 yl) pyrimidin-2,4-diamine in the form of white powder: SM-ES m / z 603.2 (Μ + Η).

Example 35

1 - ((4- (4- (5-Chloro-4- (5-méthvl-1 H-pvraz0l-3-ylamin0١pvrimidin-2-vlamin0١-2,5diméthvlphénvl) piperidin-1-vl) methvl) cyclopropanecarbonitrile (198)

<img file="MA32497B1_D0064.tif" />

/

ΜΑ 32497Β1

Has a solution of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl1H-pyrazol-3-yl) pyrimidin-2,4-diamine ( 30 mg, 0.078 mmol) in acetonitrile (1.0 mL) was added (1-cyanocyclopropyl) methyl 4-methylbenzenesulfonate (16 mg, 0.10 mmol, prepared according to the procedure described in the patent.

WO2005063247), then DIEA (30 mg, 0.23 mmol) and K1 (catalytic amount).

The reaction mixture was heated at 7O٠C for 14 hours, then allowed to cool to room temperature. The reaction mixture was directly purified by preparative PI-HPLC to give 1 - ((4- (4- (5-chloro-4- (5-methyl-1H-pyrazol3-ylamin0) pyrimidin-2-ylamin0) - 2,5-dimethylphenyl) -piperidin-110 yl) methyl) cyclopropanecarbonitrile: SM-ES m / z 491.2 (M + H *).

Example 36

2- (4- (4- (5-Chloro-4- (5-methvl-1H-Pvrazol-3-vlamino) ovrimidin-2-vlamino) -5-fluoro-2méthvlphenvl) piperidin-1-٧l) acetonitrile (199 )

<img file="MA32497B1_D0065.tif" />

Has a solution of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine (20 mg, 0.048 mmol) in acetonitrile (0.5 mL), CS2CO3 (31 mg, 0.096 mmol) and chloroacetonitrile (7 mg, 0.096 mmol) were added. The resulting mixture was stirred at room temperature for 14 h before being treated with saturated aqueous NCI solution (1 mL) and extracted into EtOAc (3 X 2 mL). The organic layers were combined, concentrated, and the residue purified by preparative PI-HPLC to give 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamino) pyrimidin-2) -ylamino) -5-fluoro-2-methylphenyl) piperidin-1-yl) acetonitrile; SMES m / z 455.2 (M + H *).

Example e37

3- (4- (4- (5-Chloro-4- (5-methyl-1H-p٧razol-3-٧lamino) p٧rimidin-2-٧lamino) -5-fluoro-2méthvlphenvl) pioeridin-1-vl١DroDanenitrile / 2001

VIA 32497Β1

<img file="MA32497B1_D0066.tif" />

صم

Has a solution of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine (20 mg٠ 0.048 mmol) in MeOH (0.5 mL), acrylonitrile (5 mg, 0.096 mmol) was added. The resulting mixture was stirred at room temperature for 14 h, then purified by preparative ΡΙ HPLC to give 3- (4- (4- (5-chloro-4- (5-methyl-H-pyrazol-3-ylamino ) pyrimidin-2ylamino) -5-fluoro-2-methylphenyl) piperidin-1-yl) propanenitrile; SM-ES m / z 469.2 (M

Examples 38 and 39 (R) -2- (3- (4- (5-chloro-4- (5-methvl-1H-pvrazol-3-vlamino) pvrimidin-2-ylamino) -2,5dimethphénvDpiperidinl-yll-N -methvlacetamide 12071 (S) -2- (3- (4- (5-chloro-4- (5-méthvl-1H-Pvrazol-3-vlamino١pvrimidin-2-vlamino 1-2.5diméthvlphénvl) piperidin-1-vl١-N -methvlacetamide (2081

A solution of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-3-yl) phenyl) -N4- (5-methyl-1Hpyrazol-3-yl) pyrimidin-2,4-diamine (700 mg, 1.70 mmol), 2-bromo-N-methylacetamide (258 mg, 1.70 mmol) and TEA (1.2 mL, 8.5 mmol) in DMF (4 mL) was stirred at room temperature for 30 min. The chiral separation of

ΜΑ 32497Β1 racemic mixing was performed by chiral HPLC (ChiralCel 0D-H, Ηβχ: ΕΟΗ: ΜβΟΗ / 80: 10: 10, elution time 15 min, 1 ml / min). The two purified enantiomers were collected separately (in solid form): (R) -2- (3- (4 (5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2-ylamino) ) -2.55 dimethylphenyl) piperidin-1-yl) -N-methylacetamide and (S) -2- (3- (4- (5-chloro-4- (5methyl-1H-pyrazol-3-ylamino) pyrimidin- 2-ylamino) -2,5-dimethylphenyl) piperidin-1-yl) N-methylacetamide; the two peaks: SM-ES m / z 483.2 (Μ + Η). The first elution peak (elution time: 5.63 min, versus elution time = 7.62 min) was arbitrarily associated with the (R) enantiomer.

Example 40

5-Chloro-N2- (2-fluoro-5-méthvl-4- (1-etrah٧dro-2H-Dvran-4-٧l١pipéridin-4-vl) Dhén٧l) N4- (5-méthvl-1 H-p٧razol-3- ٧l) p٧rimidine-2,4-diamine (209)

Has a suspension of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (515 methyl-1H-pyrazol-3-yl) pyrimidin-2,4 -diamine (2.50 g, 6.0 mmol) in a solvent mixture composed of MeOH (42 mL) and DCM (10 mL), dihydro2H-pyran-4 (3H) -one (3, 33 mL, 36.0 mmol) and TEA (8.36 mL, 60.0 mmol). The reaction mixture was heated at 6O٠C for 1 h, then NaCNBH (1.66 g,

26.4 mmol) was added. The mixture was heated at 6O٠C for an additional 2 hrs, cooled to room temperature, diluted in DCM (60 mL), poured into a silica gel column (12.5 g), and purified by gel column chromatography. silica (gradient from DCM with 1 ٠/٠ NH to 10% MeOH in DCM with 1٠ / o NH) to give 5-chloro-N2- (2-fluoro-5-methyl-4- ( 1 (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H-pyrazol-325 yl) pyrimidin-2,4-diamine as a white solid: H NMR (DMS0-d6, 400 MHz) S 12.08 (br, 1Η), 9.58 (br, 1Η), 8.65 (d,, 1 = 28.4 Hz, 1Η), 8.02 ( s, 1Η), 7.36 (d, ل =

8.4 Hz, 1Η), 7.03 (d, 12.4 = ل Hz, 1Η), 6.08 (br, 1Η), 3.89 (dd, 3.6, 10.8 = ل Hz, 2Η) ,

ΜΑ 32497Β1

3.28 (t, 10.4 = ل Hz, 2Η), 2.99 (d, j = 10.8 Hz, 2Η), 2.64-2.43 (m, 2Η), 2.24-2 , 15 (m, 8Η), 1.71-1.40 (m, 8Η); SM-ES m / z 500.2 (M + H *).

Example 41

5-Chloro-N2- (4- (1-cvclopropvlpipéridin-4-vl) -2-fluoro-5-méth٧lphén٧l) -N4- (5-méth٧l5 1 H-pyrazol-3-vl١p٧rimidine-2.4-diamine (210)

<img file="MA32497B1_D0067.tif" />

Has a solution of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine (30 mg, 0.072 mmol) in MeOH (0.7 mL), AcOH (35 mg, 0.58 mmol), (110 ethoxycyclopropoxyjtrimethylsilane (37 mg, 0.216 mmol) and a small amount were added 4Α molecular sieves The mixture was stirred at room temperature for 1 h, then Na (CN) BH3 (14 mg, 0.216 mmol) was added. The reaction mixture was then heated at 6O٠C for 14 hours, then allowed to cool to room temperature. Saturated aqueous NHC solution (2 mL) was added to the mixture, and the resulting mixture extracted into EtOAc (3x3 mL). The combined organic layers were concentrated and purified by preparative HPLC-ΡΙ to give 5-chloro-N2- (4- (1-cyclopropylpiperidin-4-yl) -2-fluoro-5métl٦ylp, enyl) -N4- (5 -methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine: H NMR (400 MHz, MeOD-d4) s 7.97 (s, 1Η), 7.84 (d, 1Η), 7, 50 (s, 1Η), 6.93 (d, 1Η), 6.29 (s, 1Η),

5.33 (s, 1Η), 2.80 (m, 1Η), 2.58 (s, 2Η), 2.28 (s, 3Η), 2.24 (s, 3Η), 1.96 (m , 1Η), 1.80I, 85 (m, 2Η), 1.65-1.75 (m, 2Η), 0.2-0.7 (m, 6Η): SM-ES m / z 456.2 (M + H).

Example 42

N2- (4- (1- (3- (azetidin-1-vlsulfonvl١Dropvl١DiDéridin-4-vl١-2.5-riiméth hn! ١-R-fhrnNLSjhyHpya3yl) p٧rimidine-2,4-diamine (214)

ΜΑ 32497Β1

<img file="MA32497B1_D0068.tif" />

Step 1: To a solution of azetidine (12 mg, 0.21 mmol) and TEA (0.1 mL, 0.71 mmol) in DCM (5 ml), was slowly added a solution of chloride of 3 -chloropropane-1-sulfonyl (34 mg, 0.19 mmol) in DCM (1 mL). After stirring at room temperature overnight, the solvent was removed in vacuo. The crude 1- (3-chloropropylsulfonyl) azetidine thus obtained was dissolved in NMP (1.9 mL, 0.1 mmol / mL) and used in the next step without further purification: SM-ES m / z 198.0 (Μ + Η).

Step 2: A mixture of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-4-yl) phenyl) -N4- (510 methyl-1H-pyraz0l-3-yl) pyrimidin-2,4 -diamine (42 mg, 0.1 mmol), 1- (3chloropropylsulfonylazetidine (Step 1, 0.1 mmol), TEA (70 µl) and sodium iodide (150 mg) in NMP (1 mL) was poured into a sealed flask which was heated in a microwave reactor for 30 min at 15O٠C. The reaction mixture was purified by ΡΙ HPLC to give N2- (4- (1- (3- (azetidin-115 ylsulfonyl) propyl) piperidin-4-yl) -2,5-dimethylphenyl) -5- chloro-N4- (5-methyl-1Hpyrazol-3-yl) pyrimidin-2.4-diamine in white powder form: MS-ES m / z 573.3 (MH).

Example 43

1- (4- (4- (5-Chloro-4- (5-methvl-1H-pyrazol-3-vlamino) pvrimidin-2-vlamino١-2.520 dimethylphenyl) piperidin-1-vl) -4-m0rph0lin0butan-1- 0ne (224)

<img file="MA32497B1_D0069.tif" />

Step 1: To a solution of HAM (95 mg, 0.255 mmol) and 4-chlorobutanoTque acid (36 mg, 0.25 mmol) in DMF (1 mL) was added DIEA (0.1 mL) . After stirring at room temperature for 3 min, 5-chloro-N2- (2,5ΜΑ 32497Β1 dimethyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1H-pyrazol-) was added. 3-yl) pyrimidin-2,4diamine (100 mg, 0.24 mmol) in DMF (2 ml). The reaction mixture was stirred at room temperature for 90 min: CLSM performed at this precise time indicated complete completion of the reaction, as well as obtaining 45 chloro-1- (4- (4- (5 -chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2-ylamino) -2,5dimethylphenyl) piperidin-1-yl) butan-1-one: SM-ES m / z 516.1 (M + H *).

Step 2: Morpholine (0.5ml) was added directly to the crude reaction mixture obtained in Step 1 (1ml). The resulting solution was stirred at 100٠c in a sealed flask for 1.5 hours. The crude product was purified by

HPLC-ΡΙ to give 1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamino) pyrimidin-2-ylamino) -2,5-dimethylphenyl) piperidin-1-yl ) -4-morpholinobutan1-one in white powder form: SM-ES m / z 567.3 (Μ + Η).

Example 44

1- (4- (4- (5-Chloro-4- (5-methvl-1H-p٧razol-3-vlamino١pvrimidin-2-ylamino) -2,515 dimethylphen٧l) piperidin-1-vl) -3-m0rph0lin0Dr0Pan-1-Qne (225)

هجممؤ

Step 1: A solution of HATU (108 mg, 0.28 mmol), 3-chloropropanoic acid (30 mg, 0.28 mmol) and DIEA (0.1 mL) in DMF (1 mL) was stirred at room temperature. 3 min later, this solution was transferred to a vial filled with a solution of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H -pyrazol-3-yl) pyrimidin-2,4-diamine (111 mg, 0.27 mmol) in DMF (10 mL). The resulting mixture was stirred overnight at room temperature. The reaction was quenched by adding water (20 mL) and extracted into EtOAc (3x30 mL). The combined EtOAc layers were washed in brine (10 mL), dried over NSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (MeOH at 0-10٠ / ٠ in a DCM gradient with N at 1٥ / ο) to give 1- (4- (4- (5-chloro- 4- (5methyl-1

ΜΑ 32497Β1

H-pyrazol-3-ylamino) pyrimidin-2-ylamino) -2,5-dimethylphenyl) piperidin-1yl) prop-2-en1-one as a light brown oil: ESMS m / z 466.1 (Μ + Η).

Step 2: A splution of 1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5-dimethylphenyl) pipeidin-1-yl ) pr0p-2-en-1-0ne (41 mg, 0.88 mmol) and morpholine (0.1 ml) in DMF (1 ml) was stirred at room temperature overnight. The crude product was purified by PI-HPLC to give 1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2ylamin0) -2,5- dimethylphenyl) piperidin-1-yl) -3-m0rph0iin0pr0pan-1-0ne as a white powder; SM-ES m / z 553.2 (M + H).

Example 45 (S) -4- (4- (5-chloro-4- (5-méthvl-1H-p٧razol-3-٧lamino) pyrimidin-2-ylamino) -2.5diméthvlphénvloxazelidin-2-one (230)

<img file="MA32497B1_D0070.tif" />

Step 1: To a microwave reaction tube was added a mixture of 115 brom0-2,5-dimethyl-4-nitr0benzene (1.15 g, 5.0 mmol), dibutyl vinylboronate (1.16 g, 6.3 mmol), Pd (PPh3) 4 (289 mg, 0.25 mmol), CsF (2.28 g, 15 mmol) and a solvent mixture (1 ٠2-dimethoxyethane / MeOH = 2: 1 , 15 ml). The tube was degassed, filled with N₂ and seals. The reaction tube was then heated at 13O٠C in a microwave reactor for 15 min, then, after opening, the mixture was poured into a saturated aqueous solution of HCl (30 mL) and extracted into EtOAc (3 X 50 mL). The combined organic layers were washed in brine and dried (MgS٥4). After removing the dehydrating agent by filtration, the filtrate was concentrated and purified by flash chromatography (silica gel, gradient of EtOAc 0-30٠ / ٠ in hexane) to give 1,4-dimethyl-2 -nitrous-5-vinylbenzene in the form of needle-shaped crystals; SM-ES m / z 178.1 (M + H).

Step 2: 1,4-dimethyl-2-nitro-5-vinylbenzene was reacted by means of the asymmetric synthesis method described by N. Barta et al. (Org. Lett. 2000, 2,

ΜΑ 32497Β1

2821), before subjecting it to preparatory ΡΙ HPLC purification to give (S) -4- (2,5-dimethyl-4-nitrophenyl) oxazolidin-2-one; SM-ES m / z 237.1 (Μ + Η *).

Step 3: To a solution of (S) -4- (2,5-dimethyl-4-nitrophenyl) oxazolidin-2-one (55 mg, 0.23 mmol) in MeOH (5 mL) was added Pd / C (5 mg, 10% w / w).

The mixture was degassed and stirred at room temperature under 1 atmosphere of H for 14 h. The Pd / C was removed by filtration through Celite. The filtrate was concentrated to give (S) -4- (4-amino-2.5-dimethylphenyl) -oxazolidin-2-one which was used in the next step without further purification: SM-ES m / z 207 , 1 (M + Η *).

Step 4: In a reaction tube, added (S) -4- (4-amino-2.5dimethylphenyl) oxazolidin-2-one (48 mg, 0.23 mmol), 2,5-dichloro -N- (5-methyl1H-pyrazol-3-yl) pyrimidin-4-amine (77 mg, 0.32 mmol), iPrOH (2 mL) and HCl (0.13 mL, 0.52 mmol , 4Ν in dioxane). The tube was then sealed and heated to

13O٠C for 6 h. After cooling to room temperature, the mixture was concentrated and purified by HPLC-ΡΙ to give (S) -4- (4- (5-chloro-4- (5-methyl1H-pyrazol-3-ylamino) pyrimidin- 2-ylamino) -2,5-dimethylphenyl) oxazolidin-2-one; MS-ES m / z 414.1 (MH).

Example 46

5-Chloro-N2- (4- (1-eth٧lpipéridin-4-٧l) -2-fluoro-5-méth٧lphénvl) -N4- (5-methvl-1Hovrazol-3-vl) pvrimidine-2.4-diamine (2321

<img file="MA32497B1_D0071.tif" />

A mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine (400 mg, 0.96 mmol), iodoethane (92.5 pL, 1.2 mmol) and triethylamine (201.5 pL, 1.4 mmol) in 4 mL of DMF was heated at 6O٠C for 2 h. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried over NSO- * and

ΜΑ 32497Β1 vacuum concentrates. The crude product was purified by column chromatography on silica gel (MeOH / DCIM: 1/9) to give 5-chloro-N2- (4- (1ethylpiperidin-4-yl) -2-fluoro-5- methylphenyl) -N4- (5-methyl-1H-pyrazol-3-yl) pyrimidin2,4-diamine: NMR¹H (DMSO-de) δ 8.01 (s, 1Η), 7.35 (m, 1Η), 7.02 (d, 1Η), 6.22 (H), 2.97 (d, 2Η), 2.62 (m, 1Η), 2.34 (q, 2Η), 2.21 (s, 3Η), 2.13 (s, 3Η), 1.98 (t,

2Η), 1.64 (m, 4Η), 1.01 (t, 3Η): SM-ES m / z 444.2 (M + H).

Example 47

5-Chloro-N2- (4- (1 - ((2,2-difluorocvclopropvl) methyl) piperidin-4-yl) -2-fluoro-5méthvlphenyl) -N4- (5-methvl-1H-pvrazol-3-vl ) pvn'midine-2٩4-diamine (235)

<img file="MA32497B1_D0072.tif" />

A mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine (40 mg, 0.096 mmpl), 2 (bromomethyl) -1,1-difluorocyclopropane (32.8 mg, 0.19 mmol) and triethylamine (20.2 pL, 0.14 mmol) in 1 mL of DMF a was heated to 15O٠C in a microwave reactor for 30 min. The crude product was purified by preparative PI-HPLC to give 5-chloro-N2- (4- (1 - ((2,2-difluorocyclopropyl) methyl) piperidin-4-yl) -2fluoro-5-methylphenyl) -N4- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine: MS-ES m / z 506.2 (MH).

Example 48

3 (4 ^ (Co ^ Shyi-H-pyrazol-3-ylamino) pvrimidin-2-vlamino١-2.5dimethylphenvDpiperidin-1-vhpropanamide (236١

<img file="MA32497B1_D0073.tif" />

ΜΑ 32497Β1

A solution of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1Hpyrazol-3-yl) pyrimidin-2,4-diamine (41 mg, 0.1 mmol), acrylamide (24 mg, 0.33 mmol) and DIEA (87 pL. 0.5 mmol) in NMP (1 ml) was stirred at 8O٠C for 10 h. A CLSM performed at this precise time indicated that the reaction was not complete; therefore a further addition of acrylamide (2x36 mg) was made, then the reaction was allowed to continue until a new CLSM indicated its complete completion. The crude product was purified by ΡΙ-HPLC to give

3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2-ylamino) -2,5dimethylphenyl) piperidin-1-yl) propanamide in powder form white: SM-ES m / z 483.2 (Μ + 1).

Example 49

4- (4- (4- (5-Chloro-4- (5-methvl-1H-pyrazol-3-ylamino) pvrimidin-2-ylamino) -5-fluoro-2méthvlphenvl) piperidin-1-yl) -1- m0rph0lin0butan-1-0ne (246)

A mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5met! I١ / 1-1H-pyraz٠l-3-yl) pyrimidin-2 , 4-diamine (41 mg, 0.1 mmol), 4-chloro-1morpholinobutan-1-one (29 mg, 0.15 mmol) and DIEA (0.1 ml, 0.58 mmol) in NMP (1 ml) was stirred at 8O٠C. 10 hours later, 4chloro-1-morpholinobutan-1-one (51 mg) was added again, and the reaction was allowed to continue overnight. The crude product was purified by ΡΙ HPLC to give 4- (4- (4 (5-chloro-4- (5-methyl-1H-pyrazol-3-ylamino) pyrimidin-2-ylamino) -5-fluoro -2methylphenyl) piperidin-1-yl) -1-morpholinobutan-1-one as a white powder; SM-ES m / z 571.3 (MH⁺).

Example 50

N2- (4- (1 - ((2,2-difluorocvclopropvl) methvl) piperidin-4-vl) -2-fluoro-5-methylphenyl) -N4 (5-methvl-1H-pvraz0l-3-vl) -5 - (trifluoromethyl) pyrimidine-2.4-diamine (251)

VIA

32497Β1

<img file="MA32497B1_D0074.tif" />

A mixture of N2- (2-Fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1Hpyrazol-3-yl) -5- (trifluoromethyl) pyrimidin-2,4 -diamine (100 mg, 0.22 mmol), 2 (bromomethyl) -ll-difluorocyclopropane (76.4 mg, 0.45 mmol) and triethylamine (60.6 µl, 0.42 mmol) in 1 ml of DMF was heated at 6O٠C in a microwave reactor for 2 h. The crude product was purified by PI-HPLC to give N2- (4- (1 - ((2,2-difluorocyclopropyl) methyl) piperidin-4-yl) -2-fluoro-5-methylphenyl) -N4 ( 5-met! ٦yl-1lt-pyrazol-3-yl) -5- (trifluo-romet, iyl) pyrimidin-2,4-diamine; SM-ES m / z 540.2 (MH).

Example 51

N2- (2.5-dimeth٧l-4- (piperidin-4-vl) phenvl) -N4- (5-meth٧l-1H-pvrazol-3-٧l١-5 (trifluoromethvl) pyrimidine-2,4-diamine (257)

<img file="MA32497B1_D0075.tif" />

A mixture of 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidin-415 amine (513.0 mg, 0.9 mmol), tert-butyl-4 - (4-amino-2,5-dimethylphenyl) piperidine-1-carboxylate (282.7 mg, 0.9 mmol), and concentrated aqueous HCl (10 drops) in i-PrOH (12 mL) was heated to 15O٠C in a microwave reactor for 30 min. The crude product was purified by PI-HPLC to give N2- (2,5-dimethyl4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1H-pyrazol-3-yl) -5 - (trifluoromethyl) pyrimidine20 2,4-diamine; SM-ES m / z 446.2 (M + H).

Example 52

ΜΑ 32497Β1

5-Chloro-N2- (2-fluoro-4- (1 - ((3-isopropvl-1,2,4-oxadiazol-5-vl) methvl) piperidin-4-vl١-5méthvlphénvl) -N4- (5- methvl-1H-pyrazol-3-٧l) p٧rimidine-2,4-diamine ، 259)

A mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (55 methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine (42 mg, 0.1 mmol) and 5 (ch! 0romethyl) -3-is0pr0pyl-1,2,4-0xadiazole (17 mg, 0.10 mmol) and DIEA (86 pL, 0.5 mmol ) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was diluted in EtOAc (50 mL) and washed in water (2x5 mL). The EtOAc coating was dried over NSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (gradient of EtOAc at 5O-100٥ / o in hexane) to give 5-chloro-N2- (2-fluoro-4- (1- ((3-isopropyl1,2,4-oxadiazol-5-yl) methyl) piperidin-4-yl) -5-methylphenyl) -N4- (5-methyl-1H-pyrazol3-y!) Pyrimidin-2,4- diamine in the form of a white solid; SM-ES m / z 540.2 (MH).

Example 53 (4- (4- (5-Chloro-4- (5-methyl-1H-pvrazol-3-vlamino) pvrimidin-2-vlamino) -5-fluoro-2méthvlphénvl) piperidin-1-vl) (3- is0pr0pyl-1,2,4-0xadiaz0l-5-vl) methane (265)

Step 1: A solution of isobutyronitrile (4.49 mL, 50 mmol) and hydroxylamine (12.3 mL, 200 mmol) in anhydrous ethanol (20 mL) was stirred at 6O٠C for two days. The solvent was removed by evaporation. The residue was evaporated simultaneously in several steps with toluene to give (E) -Nhydroxyisobutyrimidamide as a pale yellow liquid: H NMR (400 MHz, CDCls) δ 7.50 (br s, 1Η), 4.52 (br s, 2Η), 2.43 (septet, Jz 6.8 Hz, 1Η), 1.15 (d, 6.8 = ر

Hz, 6Η).

/7

ΜΑ 32497Β1

Step 2: A solution of (E) -N-hydroxyisobutyrimidamide (0.51 g, 5 mmol) and trichloroacetic anhydride (2.31 g, 7.5 mmol) in toluene (20 mL) was stirred at 8O٥C . 4 h later the reaction mixture was diluted in EtOAc (50 mL), washed in saturated aqueous NaHO solution (2x10 mL), dried over Na2S٠4 and evaporated to give 3-is0pr0pyl-5- (trichl0r0methyl) -1 ٠2,4-oxadiazole as a clear liquid which was used without further purification; NMR^٦H (400 MHz, CDC) δ 3.16 (septet, j = 7.2 Hz, 1H), 1.39 (d, j = 6.8 Hz, 6Η).

Step 3: A mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4 (5-methyl-1H-pyraz0l-3-yl) pyrimidin-2 , 4-diamine (42 mg, 0.1 mmol), 3-isopropyl10 5- (trichloromethyl) -1,2.4-oxadiazole (46 mg, 0.2 mmol) and DIEA (40 µl, 0.23 mmol) in MeOH (1 mL) was stirred at 7O٠C overnight. The crude reaction mixture was purified by PI-HPLC to give (4- (4- (5-chloro-4 (5-methyl-1H-pyrazol-3-١'lamino) pyrimidin-2- ylamino) -5-fluoro-2methylphenyl) piperidin-1-yl) (3-is0pr0pyl-1 ١2,4-oxadiazo! -5-yl) methanone as a white solid; H NMR (400 MHz, CDC) δ 9.67 (br s, 2Η), 8.50 (s, IH), 8.07 (s, IH), 7.57 (d, 8.4 = ر Hz, 1H), 7.05 (d, / = 12.4Hz, 1H), 6.16 (s, 1H), 5.53 (s, 1H), 3.98 (d, 13.2 = ل Hz, 1H), 3.34 (dt, j = 2.0, 2.8Hz, 1H), 3.15 (m, 1H), 2) 82 (m, 2Η), 2.62 (t, 4.8 = ل Hz, 2Η), 2.34 (s, 3Η), 2.25 9s, 3Η), 1.90 (m, 2Η), 1.76 (2H); SM-ES m / z 554.2 (Μ + Η).

Example 54

5-Chloro-N2- (4- (1- (2- (3-isopropvl-1,2,4-oxadiazol-5-yl) ethvl١piperidin-4-yl) -2,5diméthvlphénvl) -N4- (5-methvl -1H-p٧razol-3-vl) pvrimidine-2,4-diamine (269)

٠

Step 1: A mixture of (E) -N-hydroxyisobutyrimidamide (510 mg, 5 mmol), 3-chloropropanoic acid (542 mg, 5 mmol) and dicyclohexylcarbodiimide (1.24 g, mmol) in anhydrous dioxane (20 mL) was stirred at o٠c for 1 h, then at room temperature for an additional 1 h. The reaction mixture was then heated at 80 ° C. for 18 h, then filtered. The filtrate was then evaporated. The residue

The resulting ΜΑ 32497Β1 was purified by column chromatography on silica gel (gradient of EtOAc at 0-100٠ / ٠ in hexane) to give 5- (2-chloroethyl) -3-isopropyl-1,2,4oxadiazole; H NMR (400 MHz, CDCIa) δ 3.85 (t, 7.2 = ل Hz, 2Η), 3.27 (t, j = 7.2 Hz, 2Η), 3.03 (septet, 7.2 = لHz, 1H), 1.13 (d, j = 7.2Hz, 6Η); ESMS m / z 175.1 (Μ + Η).

نقجحئ A mixture of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine ( 14 mg, 0.033 mmol), 5- (2chl0r0ethyl) -3-ÎS0pr0pyl-1,2,4-0xadiazole (9 mg, 0.053 mmol) and DIEA (29 pL, 0.17 mmol) in NMP (1 mL ) was stirred at 5O٥C for 3 days, the crude reaction mixture was purified by PI-HPLC to give 5-chloro-N2- (410 (1- (2- (3-isopropyl-1,2,4-oxadiazol-5-yl) ethyl) piperidin-4-yl) -2,5-dimethylphenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine as a white solid; SM-ES m / z 550.3 (MH).

Example 55

5-Chloro-N2- (2-fluoro-5-méth٧l-4- (1- (6-méth٧lp٧ridazin-3-٧l١pipéridin-4-٧1 ١phén٧l١15 N4- (5-methyl-1 H-pyrazol-3-٧l) p٧rimidine -2.4-diamin (277)

<img file="MA32497B1_D0076.tif" />

A suspension of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine (20 mg, 0.05 mmol), 3-chloro-6methylpyridazine (13 mg, 0.1 mmol) and CS2CO3 (33 mg, 0.1 mmol) in dioxane (1 ml) was stirred at 15O٥C in a sealed bottle. 15 hours later, 3-chloro-6-methylpyridazine (26 mg) and CS2CO3 (66 mg) were added. the reaction was continued for 3 h. The crude reaction mixture was purified by PI-HPLC to give 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (6-methylpyridazin-3yl) piperidin-4 -yl) phenyl) -N4- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine in the form of a white solid: MS-ES m / z 508.2 (M + H *).

Examples 56 and 57

VIA 32497Β1

5-Chloro-N2- (2-fluoro-5-méthvl-4 - ((trans) -2-méthvlpiperidin-4-vl) phenvl) -N4- (5méthvl-1H-pyrazol-3-vl) Dvrimidine-2.4- diamine (279)

<img file="MA32497B1_D0077.tif" />

5-Chloro-N2- (2-fluoro-5-méthvl-4 - ((cis) -2-méthvlpipérdin-4-vl) phenvl) -N4 (5-methvl1 H-Dvrazol-3-vl) Dvrimidine-2.4- diamine (280)

Step 1: A solution of tert-butyl-2-methyl-4-oxopiperidine-1-carboxylate (1 g, 4.69 mmel) in THF (20 ml) was poured drop by drop into a cooled solution (-78٠c ) and vigorously stirred with LDA (3.75 mt of a 1.5Μ solution in cyclohexane. 5.63 mmol) in THF (20 mL), under an N atmosphere The reaction mixture was stirred at -78٠c for 30 min , then a solution of phenyl trifluorosulfonimide (1.84 g, 5.16 mmol) in THF (20 ml) was added thereto. After this addition, the reaction mixture was warmed to room temperature and stirred for 3 h. The reaction was then cooled to o٠c and neutralized with

100 mL of saturated aqueous HCl solution, then filter through Celite. The filtrate was added to 100 mL of EtOAc, and the layers separated. The organic layer was washed in water, dried over MgSg4 and concentrated. The crude product was purified by chromatography on a silica gel column (gradient of EtOAc at 0-30٠ / ο in hexane, then checked by TLC with 2% of KMn٠4 in EtOH) to give

2-methyl-4- (trifluoromethylsulfonyloxy) -5.6-dihydropyridine-1 (2H) -carboxylatedetertbutyl as a yellow solid.

2nd step :

Has a mixture of 2-fluoro-5-methyl-4- (4,4,5,5-tetramethyl-1,3.2-dioxaborolan-2yl) aniline (587 mg, 2.33 mmol), 2-methyl-4 - (trifluoromethylsulfonyloxy) -5.625 tert-butyl dihydropyridine-1H-carboxylate (968 mg, 2.80 mmol) and

ور

ΜΑ 32497Β1 sodium carbonate (1.73 g, 16.35 mmol) in a mixture of DMFHO (20/5 ml), tetrakis (triphenylphosphine) palladium (0) (135 mg, 5% mmol) was added. The reaction tube was sealed, and the mixture purged with N for 3 min then heated to

1OO٠C under N for 8 h. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of ammonia chloride. The crude mixture was then extracted into ethyl acetate (3 X 15 ml). The organic extracts were combined, washed in brine and concentrated. The crude product was purified by column chromatography on silica gel (50٠ / ο ethyl acetate in hexane) to give 4- (4-amino-5-fluoro-2-methylphenyl) -6-. 5,610-methyl-1-dihydropyridine (2H) -carboxylate tert-butyl as a yellow oil. The resulting oil was dissolved in methanol (20 mL). Pd / C (10٠ / ο) was then added to the solution. The reaction mixture was degassed, purged several times with H and vigorously stirred under 1 atmosphere of H overnight. The mixture was filtered and the filtrate concentrated to give 4- (4-amino-5-fluoro-2-methylphenyl) -215 methylpiperidine-1-carboxylate as a white solid. SM-ES m / z 267 (ΙΜ-56 + H).

Step 3: A mixture of 2,5-dichloro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine (346 mg, 1.42 mmol) and 4- (4-amino- Tert-Butyl 5-fluoro-2-methylphenyl) -2-methylpiperidine-1carboxylate (352 mg, 1.09 mmol) in 2-propanol (10 mL) was treated with concentrated aqueous HCl (12Ν, 0.43 mL). The mixture was sealed and heated in a microwave reactor at 13O٥C for 45 min. The mixture was then concentrated.

The residue was purified by preparative HPLC-ΡΙ to give 5-chloro-N2- (2fluoro-5-methyl-4- (2-methylpiperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-325 yl) pyrimidin-2,4-diamine as a white solid.

SM-ES m / z 430.1 (MH).

Step 4: 5-Chloro-N2- (2-fluoro-5-methyl-4- (2-methylpiperidin-4yl) phenyl) -N4- (5-methyl-1H-pyrazol-3-yl) was dissolved pyrimidine-2,4-diamine (20 mg, 0.046 mmol) in a solvent mixture of DCM and methanol (0.5 mL, 10/1 v / v + 0.175 NH).

The mixture was subjected to preparatory TLC in order to separate the cis and trans stereoisomers (eluent: 6% MeOH in DCM with 0.1Ν NH) from 5-chloro-N2- (2-fluoro-5-methyl- 4- (2-Methylpiperidin-4-yl) phenyl) -N4- (5-methyl-1Hpyrazol-3-yl) pyrimidin-2,4-diamine as white solids. Isomers

ΜΑ 32497Β1

100 trans and cis corresponded respectively to the upper and lower band of the

Preparatory TLC: SM-ES m / z 430.1 (M + H⁺); cis stereoisomer ٦H NMR (400

MHz, Me0D-d4): δ 8.03 (s, 1Η), 7.84 (d, 1Η), 7.02 (d, 1Η), 6.24 (d, 1Η), 3.90-3.85 ( m, 1Η), 2.32 (s, 3Η), 2.27 (s, 3Η), 2.03-1.84 (m, 2Η), 1.65-1.54 (m, 1Η), 1 , 55 (d.

311), 1.38-1.19 (m, 4H).

Example 58

3- (4- (4- (5-Chloro-4- (5-méthvl-1H-p٧razol-3-vlamino) pvrimidin-2-ylamino) -5-fluoro-2méthvlphénvl) piperidin-1-yl) cyclopent-2 -en-one (282)

A mixture of 5-ch! Oro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4 -diamine (43 mg, 0.1 mmol), cyclopentane1,3-dione (89 mg, 9.1 mmol), sodium cyanoborohydride (19 mg, 0.3 mmol) and DIEA (0.2 ml, 11 mmol) in MeOH (1 ml) was stirred in a sealed flask at 6O٠C. 2 ½ hours later, sodium cyanoborohydride (19 mg, 0.3 mmol) was added, followed by stirring of the mixture at 60٥0 overnight. The mixture was purified by ΡΙ HPLC to give 3- (4- (4- (5-chloro-4- (5methyl-1H-pyraz0l-3-ylamin0) pyrimidin-2-ylamin0) -5-flu0r0- 2-methylphenyl) pÎperidin1-yl) cyclopent-2-en-one as a white solid: H NMR (400 MHz, DMSO-de) δ 9.97 (br s, 1Η), 9.83 (br s, 1H ), 8.90 (s, 1Η), 8.32 (d, J = 6.8Hz, 1Η), 7.88 (d, J = 12.8

Hz, 1Η), 6.97 (s, 1Η), 6.04 (s, 1Η), 5.30 (br s, 1Η), 4.71 (d, 12.0 = ل Hz, 2Η), 4 , 04 (t,

12.4 = ل Hz, 2Η), 3.84 (in, 1Η), 3.53 (m, 2Η), 3.13 (in, 2Η), 3.08 (s, 31-1), 2, 96 (s, 3Η), 2.59-2.40 (m, 4Η): SM-ES m / z 496.2 (Μ + Η).

Example 59

4- (4- (5-Chl٠re-4- (5-méthvl-1H-pvrazel-3-vlamine١Pvrimidin-2-vlamino١-5-fltiero-2methylphénvD-iethv lpiperidine-loxvde / 289)

101

MA 32497131

<img file="MA32497B1_D0078.tif" />

Has a solution of 5-chloro-N2- (4- (1-ethylpiperidin-4-yl) -2-fluoro-5-methylphenyl) -N4 (5-methyl-1H-pyrazol-3-yl) pyrimidin-2, 4-diamine (22.2 mg, 0.05 mmol) in DCM (10 ml) and MeOH (1 ml), MCPBA (11) 2 mg, 0.07 mmol) was added. The reaction mixture was stirred overnight at room temperature, the reaction mixture was partitioned between DCM and saturated aqueous NO solution, and the combined organic extracts dried over Na2SO4 then concentrated in vacuo. The crude product was purified by ΡΙ HPLC to give 4- (4- (5-chloro-4- (5-methyl-1 H-pyraz0l-3-ylamin0) pyrimidin-2-ylamin0) -510 flu0r0-2 -methylphenyl) ٠1-ethylpiperidine-1-0xyde; NMR^٦H (Me0D-d4) δ 7.91 (s, 1H), 7.69 (d, 1Η), 7.00 (d, 1Η), 6.15 (s, 1Η), 3.28 (m, 4Η), 2.91 (rn, 1Η), 2.32 (in, 2Η), 2.20 (s, 3Η), 2.16 (s, 3Η), 1.83 (s, 2Η), 1, 64 (cl, 2Η), 1.31 (t, 3Η); SM-ES m / z 460.2 (M +

H ♦)

Example 60

5-Chloro-N2- (2-fluoro-5-méthvl-4- (1- (pvrimidin-5-vlméthvl١piPéridin-4-vl١phénvl) -N4 (5-méthvl-1H-pvraz0l-3-yl) pyrimidine-2, 4-diamine (314)

Has a solution of 5-Chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine (45 mg, 0.1 mmol) and pyrimidin-520 carbaldehyde (32 mg, 0.3 mmol) in DCM (1.5 mL), NaBH (0Ac) 3 (64 mg, 0, 3 mmol), then ΙΆοΟΗ (12 pl). After stirring at room temperature in a sealed vial for 16 h, the reaction was quenched with EtOAc (50 mL). The reaction mixture was successively washed in water (10 mL) and brine (5 mL), dried over Na2S٠4 and concentrated in vacuo, the resulting residue was

ΜΑ 32497Β1

102 purified by column chromatography on silica gel (gradient of MeOH 0-10O / ٠ in EtOAc with 1% NH in additive MeOH) to give 5-chloro-N2 (2-fluoro-5 -methyl-4- (1- (pyrimidin-5-ylmethyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1Hpyrazol-3-yl) pyrimidin-2.4-diamine as white solid: H NMR (400 MHz,

CDO) δ 9.09 (s, 1Η), 8.81 (s, 2Η), 8.00 (s, 1Η), 7.73 (d, J = 8.4Hz, 1Η), 6.99 ( d, ل = 13.2 Hz, 1Η), 6.23 (br s, 1Η), 3.65 (s, 2Η), 3.03 (m, 2Η), 2.76 (m, 1Η), 2 , 27 (s, 3Η), 2.25 (s, 3Η), 2.25 (m, 2Η), 1.80-1.68 (m, 4Η); SM-ES m / z 508.2 (Μ + Η).

The following compounds of Table 1 are obtained by repeating the procedures described in the previous examples and using the appropriate reagents.

ΜΑ 32497Β1

103

Table 1

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 1</td><td>هبجها 5-chloro-N2- (2-fluoro-5-methyl-4- (1- methylpiperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>١H NMR (400 MHz, DMSO- de) 5 10.33 (br, 1Η), 9.90 (br, 1Η), 9.60 (br, 1Η), 8.22 (s, 1Η), 7.56 (d, 1Η), 7, 00 (d, 1Η), 6.20 (s, 1Η), 3.53-3.50 (m, 2Η), 3.16-3.10 (m, 2Η), 2.97-2.92 ( m, 1Η), 2.81 (d, 3Η), 2.26 (s, 3Η), 2.16 (s, 3Η), 1.94-1.91 (m, 2Η), 1.83-1.73 (m, 2Η); SM-ES m / z 430.1 (M + H).</td><td> 0,011</td>

<td> 2</td><td></td><td>SM-ES m / z 416.1 (M + H٠).</td><td> 0,050</td>

<td></td><td>ركد ٠</td><td></td><td></td>

<td></td><td>5-chlor٠-N2- (2-fluoro-5-methyl-4- (piperidin-4- yl) phenyl) -N4- (5-methyl-1H-pyrazol-3-yl) py٢imidin- 2,4-diamine</td><td></td><td></td>

<td> 3</td><td></td><td>SM-ES m / z 470.2 (M + H).</td><td> 0,104</td>

<td></td><td>امد</td><td></td><td></td>

<td></td><td>5-Chloro-N2- (2-isopropoxy٠5-methyl-4 (methylpiperidin-4-yl) phenyl) -N4- (5-methyl-1 Hpyraz٠l-3-yl) py٢imidin-2,4-diamine</td><td></td><td></td>

<td> 4</td><td>ΗΝ٠٠ „٦ بيعي : ^ كآب '١</td><td>SM-ES m / z 450.2 (M + H).</td><td> 0,150</td>

<td></td><td>N2- (2-flu٥ro-5-methyl-4- (piperidin-4-yl) phenyl) - N4- (5-methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) pyrimidine-2,4-diamine</td><td></td><td></td>

<td> 5</td><td></td><td>SM-ES m / z 450.3 (MH).</td><td> 0,805</td>

<td></td><td> &lt;&lt;</td><td></td><td></td>

<td></td><td>N2- (2-isopropoxy-5-methyl-4- (1-methylpiperidin-4yl) phenyl) -5-methyl-N4- (5-methyl-1H-pyraz٥l-3٧l١r ، ٧nmirlin٠.9 zl-Hiamino</td><td></td><td></td>

WA 32497Β1

104

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>1GF-1R Ba / F3 IC50 (uM)</td>

<td> 6</td><td>٠١٢ 5-chloro-N2- (2,5-dimethyl-4- (1-methylpiperidiM- yl) phenyl) -N4- (5-methyl-1H-py٢azo! -3- yJ) pyrimidin-2,4-diamine</td><td>ESMS m / z462.2 (M + H ').</td><td> 0,015</td>

<td> 7</td><td>٠٩٢&gt; 5-chlora-N2- (5-chloro-2-methyl-4- (1- methy) piperidin-4-yl) phenyl) -N4- (5-methyl- 1Hpyraz٥l-3-yl) pyrimidin-2,4-di'amine</td><td>SM-ES m / z 446.1 (M + H).</td><td> 0,015</td>

<td> 8</td><td>رسليلا 5-chloro-N2- (4-fluoro-2-methyl-5- (piperidin-4- yl) phenyl) -N4- (5-methyl-1H-py٢azol-3- yl) pyrimidin2,4-diamine</td><td>SM-ES m / z 461.2 (M + (T).</td><td> 1,93</td>

<td> 9</td><td>٠٢ 3- (5-chloro-2- (2-flu٥ro-5-methyl-4- (1- methylpiperidin-4-yl) phenylamino) pyrimidirt-4- ylamin٠) azepan-2-0ne</td><td>SM-ES m / z 461.2 (M + H).</td><td> 0,087</td>

VIA 32497Β1

105

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 10</td><td>مزا (S) -3- (5-chlo٢o-2- (2-fluoro-5-methyl4- {1- methylpiperidin-4-yl) phenylamino) pyrimidin-4- ylamîn٠) azépan-2-٠ne</td><td>SM-ES m / z 461.2 (M + h ').</td><td> 0,869</td>

<td> 11</td><td>دب,% ٦ (R) -3- (5-chloro-2- (2-fluoro-5-methyl-4- (1- methylpiperidir4yl) phenylamino) pyrimidin-4- ylamÎn٠) azépan-2-on ©</td><td>MS-ES m / z 461.2 (MH).</td><td> 0,065</td>

<td> 12</td><td>دممعؤ 5-chloro-N2- (4- (1-isopropylpiperidin-4٠yl) -2_&gt;5- dimethylphenyl) -N4- (5-methyl-1H-pyrazo! -3- yl) pyrimidin-2,4-diamine '</td><td>SM-ES m / z 454.2 (M + H).</td><td> 0,010</td>

<td> 13</td><td>4 ٦CI حبدومح 5-chloro-N2- (4-fluoro-5- (1-isopropylpiperidin-4-yl) ٠ 2-methylphenyl) -N4- (5-methyl-1H-pyrazol-3- yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 458.2 (M + H٠).</td><td></td>

ν, Α 32497Β1

106

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 14</td><td>مبؤئج 5-chloro-N2- (2,5-dimethyl-4- (piperidin-2-y ؛) phenyl) N4S m ethyl-1 H-pyrazol-3-yl) py٢imidin-2,4diamine</td><td>SM-ES m / z412.2 (M + H ').</td><td> 0,016</td>

<td> 15</td><td>زكعج 5-chloro-N2 (2,5-dimethyl-4- (piperidin-3-yl) phenyl) - N4- (5-methyl-1H-pyrazol-3-yl) py٢imidin-2,4- diamine</td><td>SM-ES m / z 412.2 (M + H).</td><td> 0,050</td>

<td> 16</td><td>'Cl— حكنظ — و ح 5-chloro-N2- (2,5-dimethyl-4- (1-methylpiperidin-2- yl) pheny)) - N4- (5-methyl-1H-pyrazol-3- yl) pyrimidine-2,4٠diamine</td><td>MS-ES m / z 462.2 (M + H).</td><td> 0,019</td>

<td> 17</td><td>حجم ٠ 5-chl٥ro-N4- (5-cyclopropyl-1H-pyrazol-3-yl) -N2- (2- fluor٥-5-methyl-4- (piperid! n-4-yl) phenyl) pyrimidine- 2,4-diamine</td><td>SM-ES m / z 442.2 (M + H٠).</td><td> 0,160</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 18</td><td>ا ٠ حم ... . . 5-chloro-N4- (5-cyclopropyl-1H-pyrazo3 - ؛ - yl) -N2- (2,5-dimethyl-4- (piperidin-4-yl) phenyl) pyrimidin- 2,4-diamine</td><td>SM-ES m / z438.2 (M + H٠).</td><td> 0,095</td>

<td> 19</td><td>5-chlo٢o-N2- (4- (1 - ((3,5-dimethylisoxazol-4- yl) methyl) piperidin4-yl) -2-fluo٢o-5-methylphenyl) - N4- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine</td><td>H NMR (400 MHz, MeOD-d3.12 (s. 1Η), 7.75 (d, 1Η), 7.03 (s, 1Η), 6.27 (s, 1Η), 4.25 (s, 2Η), 3.69-3.67 (m, 2Η), 3.27-3.20 (m, 3Η), 2.54 (s, 3Η), 2.37 (s, 3Η), 2.34 (s, 3Η), 2.30 (s, 3Η), 2.10-1.95 (m, 4Η); SMES m / z 525.1 (M + Η +).</td><td> 0,056</td>

<td> 20</td><td>يرملمرهت 5-chloro-N2- (4- (1 - ((3,5-dI-methylisoxazol-4- yl) methyl) piperidin-4-yl) -2,5-dimethylphenyl) -N4- (5- methyl1-1H-pyrazo3-yl) pyrimidin-2,4-diamine</td><td>ESMS m / z 521.2 (MH).</td><td> 0,011</td>

<td> 21</td><td>ج 5-chloro-N2- (2,5-dimethyl-4- (1- (pyridazin-4- ylmethyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) py٢imidin-2.4-diamine</td><td>SM-ES m / z 504.2 (M + H).</td><td> 0,002</td>

آكر

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 22</td><td>٠Γ 2- (4- (4- (5-chlo٢o-4- (5-methyl-1 H-py٢azol-3ylamin٠) py٢imidin-2-ylamino) -5-flu٠٢٠-2methylphenyl) piperidin-t-yl) ethanol</td><td>SM-ES m / z460.2 (M + H٠).</td><td> 0,059</td>

<td> 23</td><td>هم ٠ 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) ethanol</td><td>SM-ES m / z 456.21 (M + H).</td><td> 0,006</td>

<td> 24</td><td>د 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (3,3,3- t٢ifluoroprOpyl) p ؛ peridin-4-yl) phenyf) -N4- (5-methyl- 1H-pyrazol-3-yt) pyrimidin-2,4-diamine</td><td>SM-ES m / z 512.2 (M + H٠).</td><td> 0,085</td>

<td> 25</td><td>٩ لمد 5-chloro-N2- (2,5-dimethyl-4- (1- (3,3,3- trifluorop٢opyl) piperid ؛ n-4-yl) phenyl) -N4- (5-methyl- 1H-p٣azol-3-yl) pyrimidin &amp; 2,4-diamine</td><td>SM-ES m / z 508.2 (M + H٠).</td><td> 0,031</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R IC50 (uM)</td>

<td> 26</td><td>ج 5-chloro-N2- (2-fluaro-5-methyl-4- (1- (2,2,2- trifluoroethyt) pipér ؛ din-4-yl) phenyl) -N4- (5-methyt- 1H-p٣azol-3-yl) pyimidin ^ 2,4-diamine</td><td>SM-ES m / z 498.2 (M + H.</td><td> 0,142</td>

<td> 27</td><td>5-chlo٢oN2- (5-chlo٢o-2-methyl-4- (1- (3,3,3trifluoropropyl) pipé٢idin-4-yl) phenyl) -N4- (5-methyl1H-py٢aol-3-y٠) pyrimidin-2 , 4- ^ iamine</td><td>SM-ES m / z 528.2 (Μ + H).</td><td> 0,044</td>

<td> 28</td><td>٦٠٢ 5-chloro-N2- (4-fluoro-2-methyl-5- (1- (3,3,3- triflu٥ropr٥pyl) piperidin-4-yl) phenyl) -N4- (5-methyl٠ 1H-pyrazo٠-3-y!) Pyrimidine-2,4-diamine</td><td>SM-ES rn / z512.2 (M t Η +).</td><td> 5,46</td>

<td> 29</td><td>مرغ 3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylpheny) pipé٢idin-1-yl) -1,1, Itrifluoropropan2- 01</td><td>MS-ES m / z 524.2 (M + H).</td><td> 0,023</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 30</td><td>'بمغ% 3- (4- (4- (5-chlo٢o4- (5-methyl-1 H-py٢azol-3ylamin0) pyrimidin-2-ylamin0) -5-fluoro-2methylphenyl) pÎperidin-1-yl) -1,1,1 -triflu0r0propan- ا 2.0</td><td>SM-ES m / z 528.2 (M + H٠).</td><td> 0,071</td>

<td> 31</td><td>ع: ٠ متلايص ودبر MN \ F ٠ ^ 3- (4- (5- (5-chlo٢o-4- (5-méthyt-1H-pyrazol-3ylamino) p٣imidin-2٠Mamino) -2-flu٥ro-4٠ methylphenyl) piperidin-1-yl) -1.1,1-t٢iflu0r0pr0pan2 -0,</td><td>SM-ES m / z 528.2 (M + H٠).</td><td> 6,47</td>

<td> 32</td><td>2- (4- (4- (5-chloro-4- (5-cyclop٢opyt-1H-pyrazol-3y! Am ؛ no) p١nmidin-2-ylamino) -5-fluoro-2methylpheny ؛) piperidin-1-yl) -N-methylacetamide</td><td>SM-ES m / z 513.2 (M + H).</td><td> 0,042</td>

<td> 33</td><td>نم ٩ 2- (4- (4- (5-chloro-4- (5-cyclopropyl-1 H-pyrazo (-3ylamÎno) p ^ imidin-2-ylamino) -2,5dimethylphenyl) piperidin-1yl) -N-methylacetamide</td><td>SM-ES m / z 509.2 (M + H⁺).</td><td> 0,006</td>

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<td> 34</td><td>٠٠١٠٧٠٦ 2- (4- (4- (5-chlora-4- (5-cyclop٢opyl-1H-pyrazol-3ylamin٥) pyrimidin-2-y (amÎno) ٠5-fluoro-2٠ methyl phenyl) piperidin-1-yl) acetamide</td><td>SM-ES m / z 499.2 (Μ + H ').</td><td> 0,049</td>

<td> 35</td><td>٠٦١ 2- (4- (4- (5-chlo٢o-4- (5-cyclop٢opyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) acetamide</td><td>MS-ES m / z 495.2 (MH).</td><td> 0,011</td>

<td> 36</td><td>ت ٦١ 2- (4- (4- (5-chloro-4- (5-methyl-1 H-pyraz٠l-3ylam ؛ n٠) py٢lmidin-2-ylamino) -5-fluoro-2 (trifluoromethyl) phenyl) piperidin-l- yl) acetamide</td><td>SM-ES m / z 527.2 (M + H).</td><td> 0,019</td>

<td> 37</td><td>مسة 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) py٢imidin-2-ylamin٥) -2.5- dimethylphenyl) piperidin-1-yl) acetamide</td><td>MS-ES m / z 469.2 (M + H).</td><td> 0,013</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 38</td><td>V 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -2.5- dimethylphenyl) piperidin-1-yl) -N-methylacetamide</td><td>SM-ES m / z 483.2 (M + H٠).</td><td> 0,010</td>

<td> 39</td><td>٠f 2- (4- (4Schlora-4- (5-methyl-1 H-pyraz٥l-3ylamin0) pyrimidin-2-y٠amin0) -5-flu0ro-2methylphenyl) piperidin-1-yl) acetamide</td><td>H NMR (400 MHz, MeOD-dS8٠11 (s, 1H), 7.76 (dIH), 7.09 (d, 1H), 6.27 (s, 1H), 4.0 (s, 2Η), 3 , 75-3.73 (m, 2Η), 3,223,13 (m, 3Η), 2.34 (s, 3Η), 2.30 (s, 3Η), 2,042.00 (m, 4Η): SM- ES m / z 473.2 (MH).</td><td> 0,019</td>

<td> 40</td><td>2- (4- (4- (5-chloro-4- (5-methyl-1 H-py٢azol-3ylamino) pyrim ؛ din-2٠y) amino) -2,5dimethylphenyi) piperidin-1-y,) acetamide</td><td>SM-ES m / z 469.2 (M + H٠).</td><td></td>

<td> 41</td><td>'اي ؛ 2- (3- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) acetamide</td><td>MS-ES m / z 469.2 (M + H).</td><td> 0,026</td>

//

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 1C5O (uM)</td>

<td> 42</td><td>٠Γ 2- (4- (4- (5-chloro-4- (5-methyf-1 H-pyrazol-3lam. Ylamino) pyrimidin-2-ylamino) -5-fluoro-2methylphenyl) piperidin-1-yl) -N -methylacetamide</td><td>MS-ES m / z 487.2 (MH).</td><td> 0,019</td>

<td> 43</td><td>٠r 2- (4- (4- (5-chlo٢o-4- (5-mhyl-1 H-pyrazo ، -3ylamino) py ؛ ٢midin-2-ylamino) -2,5dimethylphenyl) piperidin-1-yl) -N- methylacetamide</td><td>MS-ES m / z 483.2 (M + H).</td><td></td>

<td> 44</td><td>كلبو ملم ٦٩٦٠١ 2- (3- (4- (5-cT, lo٢o-4- (5-methyl-1H-pyrazol-3- ylamino) pyrimidin-2-y (amin٥) -2.5- dimethylphenyl) piperidin-1-yl) -N-methylacetamide</td><td>SM-ES m / z 483.2 (M + H٠).</td><td> 0,015</td>

<td> 45</td><td>iff 2- (4- (2-chloro4- (5-chlor٠-4- (5-methyl٠1H-pyrazol- 3-ylamin0) pyrimidin-2-ylamin0) -5- methylphenyl) piperidin-1-yl) -N-methylacetamide</td><td>SM-ES m / z 503.2 (Μ + H).</td><td> 0,018</td>

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<td> 46</td><td>مبرجي 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -2-meth0xy-5- methylphenyl) piperidin-1-yl) -N-methylacetamide</td><td>SM-ES m / z 499.2 (M + H ').</td><td> 0,013</td>

<td> 47</td><td>H ، N٣ ٩٠ ج 2- (4- (4- (5-chloro-4- (5-methyl-1 H٠pyrazol-3٠ ylamino) pyrimÎd ؛ n-2-ylamino) -5-methyl-2 (trifluoromethyl) phenyl) piperidin-1-yl ) acetamide</td><td>SM-ES m / z 523.2 (Μ + H *).</td><td> 0,022</td>

<td> 48</td><td>جة ٠ ذلمم NH F 2- (4- (5- (5-chloro-4- (5-methyl-1H-pyrazol-3j4amin٠) pyrimidin-2-Mamino) -2-fluo٢o-4methyl phenyl) piperidin-1-yl) p٢opanamide</td><td>SM-ES m / z 487.2 (M +٠ H٠).</td><td> 3,68</td>

<td> 49</td><td>) ٦ ^ x V 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2methylphenyl) piperidin-1-yl) p٢opanamide</td><td>SM-ES m / z 487.2 (Μ + H).</td><td> 0,015</td>

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<td> 50</td><td>٧ 2- (4- (4- (5-choro-4- (5-methyl-1H-pyrazol-3- ylamino) p۴im, idin-2-ylamino) -5-flu٠ro٠2- .. methylphenyOpiperidin-1-ylJ-N-methylpropanamide</td><td>SM-ES m / z 510.2 (M + H ').</td><td> 0,022</td>

<td> 51</td><td>تجا 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamino) py٢imidin-2-ylamîno) -2,5diméthyfphenyllpiperidin-1-yllpropanamide</td><td>MS-ES m / z 483.2 (M + H).</td><td> 0,009</td>

<td> 52</td><td>تجاد 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) pyrim ؛ d ؛ n-2-ylamino) -2٠5-. d ؛ methy) phenyl) piperidin-1-yl) -N٠ methylpropanamide</td><td>. (؛ SM-ES m / z 497.2 (M + H</td><td> 0,006</td>

<td> 53</td><td>جزتج 2- (4- (5-fluoro-2-methyl-4- (4- (5-methyl-1H-pyrazol- 3-ylamin0) -5- (triflu0r0methyl) pyrimidin-2- ylamino) phenyl) piperidin-1-yl) propanamide</td><td>SM-ES m / z 521.2 (M + H ').</td><td> 0,078</td>

رك

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<td> 54</td><td>مده H ٦ د سؤ 2- (4- (4- (5-Chloro-4- (5-methyl-1 H-pyraz٠l-3ylamino) pyrimidin-2-ylamino) -5-fluoro-2methylphenyl) piperidin-1-yl) propanoic acid</td><td>MS-ES m / z 488.2 (MH).</td><td> 1,53</td>

<td> 55</td><td>٠f 5-chloro-N2- (2-fluoro-5-methyl٠4- {1- (2- (methylsulfonyi) ethyl) piperidin-4-yl) pher, yl) -N4- (5- methyl-1H-pyrazo1-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 522.2 (M + H).</td><td> 0,024</td>

<td> 56</td><td>. . . ملآ ٥٩٦ ميدبير I ؤد -2) -1) -4-5-chloro-N2- (2,5-dimethyl -5) -methylsulfonyl) ethyl) piperidin٠4-yl) phenyl) -N4) methyl-1 H-pyrazoi-3-yl) pyrimidine -2,4-diamine</td><td>SM-ES rn / z518.2 (M + H).</td><td> 0,006</td>

<td> 57</td><td>5-chloro-N2- (4- (1- (2- (ethylsulfonyl) ethyl) piperidin- 4-yl) -2-fluoro-5-methylphenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 536.2 (M + H٠).</td><td> 0,021</td>

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<td> 58</td><td>أم 2- (4- (4- (5-chloro-4- (5-methyl-1H-py٢azol-3- ylamin٥) pyrimidin-2-ylam ؛ n٥) -5-fluoro-2- methylphenyl) piperidin-1-yl) -N, N- dimethytethanesulfonamide</td><td>SM-ES m / z 551.2 (M + H٠).</td><td> 0,036</td>

<td> 59</td><td>^ΗΛ (\ ميبي ٩ ٠ 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin٥) pyrimidin-2-y [amino) -5-fluor٥-2- methylphenyl) piperidin-1-yl) ethanesulfonamide</td><td>SM-ES m / z 523.2 (M + H).</td><td> 0,038</td>

<td> 60</td><td>٦٩ Ν2- &lt;4- (1 - {2- (azetidin-1 -ylsulfonylteth ^ ipiperidirMyl) -5-chloro-2-methylphenyl) -5-chloro-N4- (5methyl-1H-py٢azol-3-y) pyrimidin-2 , 4-diamir, e</td><td>SM-ES m / z 579.2 (M + H.</td><td> 0,011</td>

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<td> 61</td><td>أني N2- (4- (1- (2- (azetidin-1-ylsulfonyl) ethyl) piperidin-4- y) -2-fluo٢o-5-methylphenyl) -5-chloro-N4- (5-methyl- 1H-pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 563.2 (M + H).</td><td> 0,056</td>

<td> 62</td><td>أ 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (methylsulfonyl) pipé٢idin-4-yl) phenyl) -N4- (5- methyt-1H-pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 494.2 (M +٠ H).</td><td> 0,005</td>

<td> 63</td><td>ه 5-chlo٢o-N2- (2,5-dimethyl-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) -N4- (5- methyl-1H-pyrazo ، -3-yl) pyrimidin2,4-diamine</td><td>SM-ES m / z 490.2 (M + H٠).</td><td> 0,002</td>

<td> 64</td><td>/ ٠١ 5-chlo٢o-N2- (4- (1- (cyclop٢opylsulfonyl) piperidin-4- yl) -2-fluoro-5-methylphenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 520.2 (M + H).</td><td> 0,059</td>

را

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 65</td><td>١ مص 5-Chloro-N2- (2-Fluoro-5-methyl-4- (1- (pyridin-3ylsulfonyl) piperidin-4-yl) phenyi) -N4- (5-methyl-1 Hpyrazot-3-yl) pyrimidin- 2,4-diamine</td><td>SM-ES m / z 557.2 (M + H ').</td><td> 0,076</td>

<td> 66</td><td> مم ٠ Ethyl 4- (4- (5-choro-4- (5-methyl-1H-pyrazol-3ylam ؛ no) pyrimidin-2-ylamin٥) -5-fluor٥-2methylphenyl) piperidine-1-carboxylate</td><td>H NMR (400 MHz, MeOD-d, *) δ 8.13 (s, 1H), 7.54 (d, 1H), 7.10 (d, 1H), 6.28 (s, 1H), 4.304.26 (m, 2Η), 4.14 (٩, 2Η), 2.99-2.96 (m, 3Η), 2.33 (s, 3Η), 2.29 (s, 3Η), 1.8-1.77 (m, 2Η), 1.64- 1.55 (m, 2Η), 1.28 (1, 3Η); SM-ES m / z 488.2 (Μ + Η +).</td><td> 0,064</td>

<td> 67</td><td>ممي ٠ Ethyl 4- (2-chloro٠4- (5-chloro4٠ (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-y (amin0) -5methylphenyl) piperidine-1-carboxylate</td><td>SM-ES m / z 504.2 (Μ + H).</td><td> 0,182</td>

<td> 68</td><td>'٠٢ Isopropyl 4- (4- (5-chlor٥-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamino) -5-flu0r0-2methylphenyl) piperidine-1-carboxyl</td><td>SM-ES m / z 502.2 (M + H٠).</td><td> 0,080</td>

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<td> 69</td><td>'منمحجي 4- (4- (5-chloro-4- (5-١iieth ^ Î-1H-pyrazol-3- ylamino) p۴imid ؛ n-2, -Mamino) -5-fluoro-2- methylphenyN.N-dimethylpiperIdine-1- carboxamide.</td><td>MS-ES m / z 487.2 (M + H).</td><td> 0,011</td>

<td> 70</td><td>'مم ٠ 4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) pyrÎmidin-2-ylamino) ٠2٠5-dimethylphenyl) - N, N-dimethylpiperidine-1-carboxamide</td><td>SM-ES m / z 483.2 (M + H ⁺ ).</td><td> 0,006</td>

<td> 71</td><td>، (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) pyrimidin-2-ylamino) -2, S-dimethylphenyl) - N-ethylpiperidine-1-carboxamide</td><td>MS-ES m / z 483.2 (M + H).</td><td> 0,002</td>

<td> 72</td><td>'٠٥ 4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylam ؛ no) py٢imidin-2-ylamino) -2,5- dimethylphenyl) pipé٢idine-1-carboxamide</td><td>MS-ES m / z 455.2 (MH).</td><td> 0,006</td>

//

ΜΑ 32497Β1

121

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 73</td><td>٠٢ 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazo! -3ylamin0) pyrimidin-2-ylamin0) -5-flu0٢0-2methylphenyl) piperidin-1 -yl) -2-</td><td>NMR ^٦H (400 MHz, MeOD-٥4) δ 8.08 (s, 1Η) ٠ 7.71 (d, 1Η), 7.03 (d, 1Η), 6.26 (s, 1Η), 4.714.67 ( m, 2Η), 3.81-3.77 (m, 2Η), 3.14-3.12 (m, 2Η), 2.98 (s, 3Η), 2.96 (s, 3Η), 2 , 90-2.83 (m, 1Η), 2.34 (s, 3Η), 2.28 (s, 3Η), 1.87 (d, 2Η), 1.76-1.55 (m, 2H ); MS-ES m / z 501.2 (MH).</td><td> 0,019</td>

<td> 74</td><td>(dimethylamino) ethanone ^ 1 د 1- (4- (2-chloro-4- (5-chloro-4- (5-methyl-1 H-pyrazol3-y! Amino) pyrimidin-2-ylamîno) -5methyfphenyl) piperidîn-1-yl) -2 (dimethylamino) ethanone</td><td>SM-ES m / z 517.2 (M + H).</td><td> 0,007</td>

<td> 75</td><td>'٠٢ 1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin٥) pyrim ؛ din-2-ylamino) -2.5 * dimethylphenyl) pipérÎdÎn-1-yf) -2- (dimethylamino) ethanone</td><td>SM-ES m / z497.2 (M + H٠).</td><td> 0,011</td>

<td> 76</td><td>'٩٩٢ 1- (4- (4- (5-chIoro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2-meth0xy-5methylphenyl) piperidin-1-yl) -2 (dimethylamino) ethanone</td><td>MS-ES rn / z513.2 (MH).</td><td> 0,009</td>

VIA 32497Β1

122

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 ICO (uM)</td>

<td> 77</td><td>'٩٢٠٠٢ 1- (4- (2,5-dichloro-4- (5-chloro-4- (5-methyl-1 Hpyrazol-3-١4amino) pyrimîdin-2ylamin0) phenyl) piperidin-1-yl) -2 (dimethylamino) ethanone</td><td>MS-ES m / z 537.1 (MH).</td><td> 0,007</td>

<td> 78</td><td>٠٢ 1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) pyrimÎdin-2-y, am ؛ no) -5-fluoro-2- methytphenyl) pipefidin-1-yl) ٠3- (dimethylamino) propan-1-οηβ</td><td>SM-ES m / z 515.2 (M -ا H).</td><td> 0,138</td>

<td> 79</td><td>'٠٢ 2-amino-1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol- 3-ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2- methylphenyl) piperidin-1-yl) ethanone</td><td>MS-ES m / z 437.2 (M + H).</td><td> 0,075</td>

را

ΜΑ 32497Β1

123

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 80</td><td>نم ٠٩ 1- (4- (4- (5-chlo٢o-4- (5-rnethyl-1 H-pyrazo! -3ylamino) pyrimidin-2-ylamino) -5-fluoro-2méthyfpheny ؛) piperidin-1-yl) -2 (methylamino) ethanone</td><td>SM-ES m / z 487.2 (M + H٠).</td><td> 0,103</td>

<td> 81</td><td>معنأنج 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-py٢azol-3ylamin0) pyrimidin-2-y1amin0) -5-flu0r0-2methylphenyl) piperidin-1-yl) -2 (diethylamino ) ethanone</td><td>SM-ES m / z 529.3 (Ml H).</td><td> 0,030</td>

<td> 82</td><td>دي ؛ ' 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3_ ylamin0) pyrimidin-2-ylamin0) -5-flU0ro-2methylphenyl) piperidin-1-yl) -2 ( methylamino) ethanone</td><td>SM-ES m / z 487.2 (M + H).</td><td></td>

WA 32497Β1

124

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 83</td><td>إجمهجئ 1 - (2- (4- (5-chloro-4- (5-methyl-1 H-pyrazo! -3yla (uino) p٣imidin-2٠ylamino) ٠2,5dÎmethylphenyl) piperidin-1-yl) -2 (dimethylaminolethanone</td><td>SM-ES m / z 497.2 (M + H.</td><td> 0,013</td>

<td> 84</td><td>٦ م 1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) pyrimÎd ؛ n-2-ylamÎno) -5-fluoro-2- meth ^ phenyl٠) piperidin-1-yt) -2- (diethylaniino) ethanorte</td><td>SM-ES m / z 529.3 (M + H⁺).</td><td></td>

<td> 85</td><td>V 1 - (4- (4- (5-ho٢o4- (5-methyl-1 H-py٢azol-3yam ؛ no) pyrimidin-2-ylam ؛ no) -5-fluo٢o-2methylphenyl) piperidin-1ÿI) -2- ( methylamin0) propan-1-οηβ</td><td>SM-ES m / z 501.2 (M + H٠).</td><td> 0,042</td>

VIA 32497Β1

125

STRUCTURE

NMR or SM-ES

IGF-1R Ba / F3 IC50 (uM)

<img file="MA32497B1_D0079.tif" />

MS-ES m / z 487.2 (M + H).

0,141

2-amino-1- (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol3-y, amino) pyrimidin-2-ylamino) -5٠fluoro-2٠ mhytphenyl) piperidin-1 -yl ) propan-1 -one

<img file="MA32497B1_D0080.tif" />

- (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3٠ ylamino) pyrimidin-2-ylamino) -5-fluoro-2methylphenyl) piperidin-1-yi) -2-methyl -2 (methylamino) propan-1-one

<img file="MA32497B1_D0081.tif" />

SM-ES m / z 531.2 (M + H).

0,007

- (4- (2-chloro-4- (5-chloro-4- (5-methyl-1 H-py٢azol3-ylamino) py٢imidin-2-ylam ؛ no) -5methylphenyl) piperidin-1-yl) -2- 2-methyl (methylamino) propan-1-one

ΜΑ 32497Β1

126

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 89</td><td>¥ 2-Amino-1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol3-ylamin0) pyrimidin-2-ylamina) -2,5dimethylphenyl) piperidin-1-yl) -2- methyl propan-lone</td><td>MS-ES m / z 497.2 (MH).</td><td> 0,023</td>

<td> 90</td><td>٧ (4- (4- (5-chloro-4- (5-methyl-1 Hpyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) (1 (methylamino) cyclopropyl) methanone</td><td>SM-ES m / z 509.2 (M + H٠).</td><td> 0,005</td>

<td> 91</td><td>جس مآ نأر (l-aminocyclobutyl) (4- (4- (5-chloro-4- (5-methyl-1Hpy٢azol-3-ylamino) py٢imidin-2-ylamino) -2,5dimethylphenyl) pipé٢idin-1-yl) methanone</td><td>SM-ES m / z 509.2 (M + H).</td><td> 0,052</td>

ΜΑ 32497Β1

127

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 92</td><td>٧ (4- (4- (5-chloro-4- (5-methyl-1H-py٢azol-3ylamino) p٣imidin-2-Mamino) -2٠5dimethylphenyl) pipedin-1- yl) (1 (dimethylamlno) cyclobutyl) methanone</td><td>SM-ES m / z 537.2 (M + H⁺).</td><td> 0,015</td>

<td> 93</td><td>عق (1-aminocyclopropyl) (4- (4- (5-chlo٢o-4- (5-methyl- 1H-pyraz0l-3-ylamin0) pyrimidifi-2-ylamin0) -5- fluoro-2-methylphenyl) piperidin-1-yl) methanone</td><td>SM-ES m / z 499.2 (M + H *).</td><td> 0,033</td>

<td> 94</td><td>لمنمة (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3١ ^ lamino) pyrimidin-2-ylamino) -5-fluo٢٥-2methylphenyl) piperidin-1 -yl) (I (dimethylamino) cyclopropyl) methanone</td><td>SM-ES m / z 527.2 (M + H٠).</td><td> 0,013</td>

ΜΑ 32497Β1

128

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 95</td><td>جل مه Xf 1- (4- (2-chlo٢o4- (5-chlo٢o-4- (5-methyl - 1H-pyrazol- 3-ylamino) pyrimidin-2-ylamino) -5- methylphenyt) piperidin-1-yl) -2-mofpholinoethanone</td><td>SM-ES m / z 559.2 (Μ + H).</td><td> 0,006</td>

<td> 96</td><td>جس مآ ر 2- (azetidin-1-yl) - 'l- (4- (2-chloro-4- (5-chloro-4- (5٠ methyl-1H-pyrazol٠3-ylamino) pyrimidin-2-ylamino) - 5-methyphenyl) piperidin-1-y) ethane</td><td>SM-ES m / z 529.2 (M + H).</td><td> 0,024</td>

<td> 97</td><td>جف زخة ”تج مآ ٥٢ 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3_ ylamin0) pyrimidin-2-ylamin0) -5-flu00-2methylphenyl) piperidin-1-yl) -2- morpholinoethanone</td><td>SM-ES m / z 543.2 (M + H).</td><td> 0,020</td>

i

ΜΑ 32497Β1

129

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td></td><td></td><td>SM-ES rn / z513.2 (M + H).</td><td> 0,064</td>

<td> 98</td><td>ا آ ةى مآ د 2- (azetidin-1-yl) -1- (4- (4- (5-chloro-4- (5-methyl-1H- pyrazol-3-ylamino) pyrimidin-2-ylam! n٥) -5-flu٥٢o-2- methy) pheny ،) pipérÎd ؛ n-1-y) ethanone</td><td></td><td></td>

<td></td><td></td><td>SM-ES m / z 527.2 (M + H).</td><td> 0,038</td>

<td> 99</td><td>ا ٢٢ مل ​​٢ لك ٨ م ج ٦ دق</td><td></td><td></td>

<td></td><td>1- (4- (4- (5-chloro-4- (5-methyt-1H-pyrazol-3ylamino) pyrimidîn-2-yamin٠) -5-flu٠ro-2methylphenyl) piperidin-1 -yl) -2- (pyrrolidin -1 ylethanone</td><td></td><td></td>

<td></td><td></td><td>SM-ES m / z 523.2 (M + H٠).</td><td> 0,025</td>

<td> 100</td><td>حرلابمدكم ر ٦ “ثم ٠ ٢ ره</td><td></td><td></td>

<td></td><td>1- (4- (4- (5-Chloro-4- (5-methyl-1H-pyrazol-3ylamin٥) pyrim ؛ din-2-ylamin٥) -5-fluoro-2methylphenyl) piperidin-1 -yl) -2- (1 H-pyrrolyl) ethanone</td><td></td><td></td>

ΜΑ 32497Β1

130

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 101</td><td>مآ لاق 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3٠ ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) -2- (piperidin -1yQethanone</td><td>SM-ES m / z 537.3 (Μ + H).</td><td> 0,007</td>

<td> 102</td><td>ع جخ ١ ذ ٢ أمركج ج ٦ ده 1 - (4- (4- (5-chloro-4- (5-methyl-1 Η-py azol-3ylamin0) pyrimidin-2-ylamin0} -2,5dimethylphenyl) piperidin-1-yl) -٠2morpholinoethanone</td><td>MS-ES m / z 539.3 (M + H).</td><td> 0,009</td>

<td> 103</td><td>ع 1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) -2- (2,6dimethylpiperidin -l-ylethanone</td><td>MS-ES m / z 565.3 (MH).</td><td> 0,009</td>

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131

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 104</td><td>عم ١٨ ح مه بآ بغ 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazo! -3ylamin0) pyrimidin-2-ylamin0) -2,5dimhylphenyl) piperidin-1-yl) -2- (2 , 2,6,6tetramethylpiperidin-1-yl) ethanone</td><td>MS-ES m / z 539.3 (M + H).</td><td> 0,018</td>

<td> 105</td><td>تمرؤ 1 - (4- (4- (5-Chlora-4- (5-methyl-1 H-pyrazo! -3ylamino) pyrîmidîn-2-ylamino) -5-fluo٢o-2methyl phenyl) piperidin-1٠yl) -2- ( 4-nr٦ethylpiperazin1-yl) ethane</td><td>SM-ES m / z 556.3 (Μ + H).</td><td> 0,051</td>

<td> 106</td><td>سجاً 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-py٢azol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) pipé٢idin-1-yl) -2-meth0xyéthan0ne</td><td>SM-ES m / z 484.2 (M + H).</td><td> 0,002</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 107</td><td>٦ منح ٠١ N- (2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamino) pyrimîdin-2-١4amino) -5-fluoro-2methyl phenyl) piperidin-1-yl) - 2oxoethyl) acetamide</td><td>SM-ES m / z 515.2 (M + H).</td><td> 0,057</td>

<td> 108</td><td>'ممنحراً 4- (4- (5-chloro-4- (5-methyl-1 H-pyrazo! -3ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2methylphenyl) piperidine-1-carboxylate (dimethylamino) ethyl</td><td>SM-ES m / z 531.2 (Μ + H).</td><td> 0,053</td>

<td> 109</td><td> مجعجبمي 4- (4- (5-chloro-4- (5-methy (-1 H-py٢azol-3ylamino) pyrimidin-2-ylamino) -5-fluoro-2methylphenyl) -Ν- (2- (dimethylamino) ethyl) piperidine-1-carboxamide</td><td>SM-ES m / z 530.2 (M + - H٠).</td><td> 0,060</td>

<td> 110</td><td>س ٠ 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-py٢azol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) ethanone</td><td>SM-ES m / z 454.2 (M + H).</td><td> 0,013</td>

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133

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 111</td><td>ه مد ٠ ل (4- (4- (5-chloro-4- (5-mehyl-1H-pyrazol-3ylamÎno) pyrimÎdin-2-ylam ؛ no) -5٠fluoro-2methylphenyl) piperidin-1 yl) (morpholino) methanone</td><td>. (؛ SM-ES m / z 529.2 (M -t- H</td><td> 0,008</td>

<td> 112</td><td>ع مم ٠ (4- (4- (5-chloro-4- (5-methyl-1 H-py٢azol-3ylamino) pyrimidin-2-ylamino) -5-fluoro-2methy (phenyl) pipé٢idin-1-yl) (4-methylpiperazin -1yfimethanone</td><td>SM-ES m / z 542.2 (Μ + H٠).</td><td> 0,021</td>

<td> 113</td><td>ى مدحني 1 - (4- (4- (5-chloro4- (5-methy) -1 H-pyrazol-3٠ ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidine-1-carbonyl) imidazolidin2-one</td><td>SM-ES m / z 569.2 (M ٠ H٠).</td><td> 0,013</td>

<td> 114</td><td>٢ م ٠ (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5dÎmethylphenyl) piperidin-1-yl) -2-meth0xyethane</td><td>SM-ES m / z 569.2 (M + H٠).</td><td> 0,048</td>

ΜΑ 32497Β1

134

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R IC50 (uM)</td>

<td> 115</td><td>علممدميه (4- (4- (5-chlo٢o-4- (5methyl-1 H-py٢azol-3ylamin0) pyrimidîn-2-ylamin0) -5-flu0ro-2methylphenyl) piperidin-1-yl) (piperidin ~ 4yl) mhanone</td><td>SM-ES m / z 527.2 (M +٠ H *).</td><td> 1,57</td>

<td> 116</td><td>لآمنحججي (S) - (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) p٣imidin-2٠١4amino) -5-fluoro-2- methylphenyl) piperidin-1-yl) (pyrrolidin-2- yl) mè ، han٥ne</td><td>MS-ES rn / z513.2 (MH).</td><td> 0,137</td>

<td> 117</td><td>'٩٩٢ (4- (4- (5-chloro-4- (5٠methyl-1H-py٢azol-3- ylamino) pyrim ؛ din-2-ylam ؛ no) -5-fluo٢o-2- methylphenyl) pipé٢idin-1-yl) (1-methylazetidin-3- yl) methanone</td><td>SM-ES m / z 513.3 (M + H *).</td><td> 0,099</td>

ΜΑ 32497Β1

135

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 118</td><td>٠٢ . (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- y, amino) py٢imidin-2-y! amino) -5-fluoro-2- methylphenyl) piperid ؛ n-1-yl) (1-methylpÎper! din-4- yl) methanone</td><td>SM-ES m / z 541.2 (MH).</td><td> 0,081</td>

<td> 119</td><td>لمجتأ 3- (4- (4- (5-ch! O٢o-4- (5-methyl-1 H-py٢azol-3ylamin0) pyrimidin-2-ylamin0) -5-flu0ro-2methylphenyl) piperidin-1-carbonyl) (1métfiylphenyl -4-yl) methanone</td><td>MS-ES rn / z513.3 (MH).</td><td> 2,99</td>

<td> 120</td><td>'٠٠٢٠ 4- (4- (4- (5-Chloro-4- (5-methyl-1 H-pyrazo! -3Mamino) pyrimidin-2-Mamino) -2,5-2dimethylphenyl) piperidin-1yl) (1-methylazetidin- 3y ؛) methane</td><td>SM-ES m / z 509.2 (M + H).</td><td> 0,025</td>

<td> 121</td><td>٠٢ (S) - (4- (4- (5-Chloro-4- (5-methyl-1H-pyrazol-3ylamino) pyrimidin-2-ylamino) -2,5-2dimethylphenyl) piperidin-1 -yl) (1 - mé1hy! pyrro! ؛ din-3yl) methanone</td><td>SM-ES m / z 523.2 (M + H٠).</td><td> 0,017</td>

ا

ΜΑ 32497Β1

136

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>1GF-1R Ba / F3 IC50 (uM)</td>

<td> 112</td><td>٠٢ (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazo! -3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) (1-methylpiperidin-4yl) methanone</td><td>SM-ES m / z 537.2 (M + H).</td><td></td>

<td> 123</td><td>امتجنم. 4- (4- (5-chlo٢o-4- (5-methyl-1H-pyrazol-3ylamino) py٢imidir&gt; -2-ylamino) -2,5dimethylphenyl) piperidin-1-yl) ((2R, 4R) -4- hydroxy1-methylpyrrolidin-2-yl) methanone</td><td>SM-ES m / z 539.3 (M + H٠).</td><td> 0,048</td>

<td> 124</td><td>حق (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2methylphenyl) piperidin-1-yl) (1H-pyrrol-2yl) methanone</td><td>SM-ES m / z 509.2 (M + H).</td><td> 0,145</td>

ΜΑ 32497Β1

137

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 125</td><td>و ٦ ذ نح مآ ¾. (S) - (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) pyrirdin-2-ylamino) -5-fluoro-2- mhy) pheny!) piperidin-1-yl) (1-! s0pr0pylpiperidin-2- yljmethanone</td><td>SM-ES m / z 569٠3 (M + H).</td><td> 0,012</td>

<td> 126</td><td>لرح ١ نحه ٦ هخد (S) - (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2- methylphenyl) piperidin-1-y) (4-isopropytmorpholin- 3-y!) Methanone</td><td>SM-ES m / z 571.3 (M + H٠).</td><td> 0,029</td>

<td> 127</td><td>ز (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin٠2-ylamin0) -5-flU0r0-2- mehphenyl) pipér ؛ din-1-yl) (2,4-dimethyloxazol-5- yl) methanone</td><td>SM-ES m / z 539.2 (M + H *).</td><td> 0,027</td>

ΜΑ 32497Β1

138

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>1GF-1R Ba / F3 IC50 (uM)</td>

<td> 128</td><td>, هتجبر (4- (4- (5-Chloro-4- (5-methyl! -1 H-pyrazo! -3ylamino) primidÎn-2-١ ^ lamino) -5-fluoro-2methylphenyl) piperidin-1-yl) (( 2S) -4-hydroxy-1methylpyrrolidin-2-yl) methanone</td><td>SM-ES m / z 543.2 (Μ + H).</td><td> 0,175</td>

<td> 129</td><td>٩٠ (4- (4- (5-chloro-4 (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-y! Amin0) -5-flu0٢0-2methylphenyl) piperidin-1٠yl) (1,3,5-trimethyl -1H٠ pyrazûl-4-yl) methanone</td><td>SM-ES m / z 552.2 (M + H.</td><td> 0,025</td>

<td> 130</td><td>زبددغلاهم (4- (4- (5-chloro-4٠ (5-methyl-1 H-pyrazo! -3ylamin0) pyrimidin-2-ylamin0) -5-flu0ro-2methyl) phenyl) piperidin-1-yl) (1-methyl -5 (trifluor0methyl) -1H-pyraz0l-4-yl) methane</td><td>MS-ES m / z 592.2 (MH).</td><td> 0,061</td>

ر /

ΜΑ 32497Β1

139

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 131</td><td>Ί٢٠ azetidin-3-yl (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol- 3-y (amino) pyrimidin-2-ytamino) -5-fluo! O-2- me ^ h ^ phenyl) piperidin-1-yl) nieth۶one</td><td>NMR Ή (400 MHz, MeOD-d4) §8.08 (s, 1Η), 7.68 (d. 2Η), 7.04 (d, 2Η), 6.26 (s, 1Η), 4.74- 4.68 (m, 2Η), 4.39-4.35 (m, 1Η), 4.29-4.24 (m, 2Η), 4.11-4.07 (m, 1Η), 3.74- 3.71 (m, 1Η), 3,253.24 (m, 1Η), 3.07-3.04 (m, 1Η), 2.87-2.80 (m, 1Η), 2.33 (s, 3Η), 2.28 (s, 3Η), 1.87-1.84 (m, 2Η), 1.66-1.56 (m, 2Η); SMES m / z 499.2 (MH).</td><td> 0,059</td>

<td> 132</td><td>? ١ (S) -azetidin-2-yl (4- (4- (5-chloro-4- (5-methyl-1H- pyraz0l-3-yfamin0) pyrimidin-2-ylamin0) -5-flu0r0-2- methylphenyl) piperidin-1-yl) methaoe</td><td>MS-ES m / z 499.2 (MH).</td><td> 0,161</td>

<td> 133</td><td>٦ ل (R) - (4- (4- (5-chloro-4- (5-methyl-1H-py٢azol-3- ylamino) pyrimidîn-2-y! amino) -2.5- dimethylphenyt) piperidin-1-y) (1methylpyrrolidin-2- yl) methanone</td><td>MS-ES m / z 523.3 (MH).</td><td> 0,013</td>

كر

ΜΑ 32497Β1

140

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 134</td><td>م مظ عتذ (R) - (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) pyrimidiri-2-ylamino) -5-fluoro-2- methylphenyl) piperidin-1-yl) -methylpyrrolidin-2- yl) methanone</td><td>SM-ES m / z 527.2 (M + H).</td><td> 0,021</td>

<td> 135</td><td>"٥٩ (R) - (4- (4- (5-chloro-4- (5-methy1- ؛ H-pazol-3ylamino) pyrimidin-2-ylamino) -5fluoro-2methylphenyl) piperidin-1-yl) (1opisopropylpyrrolidin2-yl ) methane</td><td>SM-ES m / z 555.3 (M + H).</td><td> 0,048</td>

<td> 136</td><td>و ٦ ثمه خ V (4- (4- (5-chloro4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -5-flu0ro-2methylphenyl) piperidin-1-yl) (4-methyl0xaz0l-5yl) methanone</td><td>SM-ES m / z 525٠2 (M +٠ H٠).</td><td> 0,035</td>

//

ΜΑ 32497Β1

141

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 1C5O (uM)</td>

<td> 137</td><td>٦٩ ٢ آمبفص (4- (4- (5٠chloro-4- (5-methyl-1 H-pyrazol-3٠ ylamino) pyrimidirt-2-ylamino) -5-fluoro-2meth ^ pheny ؛) pipérîdin-1-y) (3.5-dimethylisoxazol4ÿ !) methanone</td><td>SM-ES m / z 539٠2 (M + H٠).</td><td> 0,018</td>

<td> 138</td><td>جح ١ ٢ اً٢هب 0 (S) - (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -5-fluar0-2- methMphenyl) pIperidin-1-yl) (2-methylpyrrolidin-2- yl) methanone</td><td>SM-ES m / z 527.2 (M + H٠).</td><td> 0,091</td>

<td> 139</td><td>١ تمأ (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2- methylphenyl) piperidin-1-yl) ((2S, 3R) -3-hydroxy-1- methylpyrrolidin-2-yl) methanone</td><td>SM-ES m / z 543.2 (M + H٠).</td><td> 0,175</td>

ΜΑ 32497Β1

142

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 140</td><td>جس ا ٦ ح ٥٢٥٢٢ ة (4- (4- (5-chlo٢o-4- (5-methyl-1H-pyrazol-3ylamino) pyrimidin-2-ylamino) -5-fluoro-2methylpheny!) PiperidÎn-1-y!) (1H-tetrazol- 1yfimethanone</td><td>SM-ES m / z 512.2 (M + H٠).</td><td> 0,139</td>

<td> 141</td><td>ؤتمص (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazo! -3ylamin0) pyrindin-2-ylaminG) -5-flu0r0-2methylphenyl) piperidin-1-yl) (2-methyl- 5 (trifluoromethyl) oxazol-4-y1) methanone</td><td>SM-ES m / z 593.2 (M + H).</td><td> 0,069</td>

<td> 142</td><td>ة ل ل د Ν١1 د Η 6- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamÎn0) -5-flu00-2methylphenyl) piperidine-1-carbonyl) piperidin-2-one</td><td>SM-ES m / z 541.2 (M + H٠).</td><td> 0,282</td>

ν, Α 32497Β1

143

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 143</td><td>جأؤ OvnCtV ا ٢ ق ή ٩ مئ Η (S) - (4- (4- (5-chlo٢o-4- (5-methyi-1H-py٢azol-3- ylamin٠) pyrimidin-2-ylamin٥) -5٠flu٥r٥-2- methylphenyl) piperidin-1-yl) (morpholin-3- yl) methanone</td><td>SM-ES m / z 529.2 (M + H⁺).</td><td> 0,071</td>

<td> 144</td><td>٠ جآ ٢ ن 5-chlo٢o-N2- (2-methyl-5-chlora-4- (1- (tetrahydro- 1,1-dioxydo-3-thienyl) piperidin-4-yl) phenyl) -N (5- methy) -1H-pyraz٥l-3-yl) pydmidii٦e-2,4-diamine</td><td>SM-ES m / z 550.1 (M + H).</td><td> 0,007</td>

<td> 145</td><td>أضئ 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (tetrahydro- 1,1-dioxydo-3-thienyl) pipé٢idin-4-yl) phenyl) -N (5- metli ^ -1H-p۴az٥l-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 534.2 (M + H *).</td><td> 0,018</td>

<img file="MA32497B1_D0082.tif" />

WA 32497Β1

144

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 146</td><td>ف غ 5-Chloro-N2- (2,5-dimethyl4- (1- (tetrahydro-1,1dioxydo-2H-thiopyran4ÿl)) pÎpé٢idin-4ÿl) phenyl) N4- (5-methyl-1 H-pyraz0l-3-yl) pyrimidine-2,4diamine</td><td>SM-ES m / z 544.2 (M + H٠).</td><td> 0,258</td>

<td> 147</td><td>ي 5-chloro-N2- (2-ctiloro-5-methyl-4- (1- (1,1-dioxydo- 3-thietanyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 536.1 (M + H *).</td><td> 0,016</td>

<td> 148</td><td>، ٠ 5-chloro-N2- (2-fluoro-5-metTiyl-4- (1- (1,1-dioxydo-3- thietanyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-dia٠٩</td><td>SM-ES m / z 520.2 (M + H٠). ١H NMR (400 MHz, DMS0-d6 + 1 drop of D2O) δ 8.02 (s, 1Η), 7.37 (s, 1Η). 7.02 (s, 1Η), 6.23 (s, 1Η), 4.28-4.22 (m, 2Η), 4.124.07 (m, 2Η), 3.22- 3.18 (m, 1H), 2.952.92 (m, 2Η), 2.68-2.62 (m, 1Η), 2.22 (s, 31-1), 2.13 (s, 3Η), 2.07-2 , 01 (m, 2Η), 1.71-1.55 (m, 4Η).</td><td> 0,018</td>

<td> 149</td><td>5-Chloro-N2- (4- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) -2-fluoro-5-methylphenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 522.2 (M + H٠).</td><td> 0,955</td>

٦/

VIA 32497Β1

145

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 150</td><td>مد ٠ 5-chloro-N2- (2-fluoo-5-methyl-4 (1,2,3,6- tetrahyd٢opyridin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazot * 3-yl) pyrimidin-2٠4-diamine</td><td>SM-ES m / z 414.1 (MH).</td><td> 0,025</td>

<td> 151</td><td>/ ٠ 4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin٥) pyrimidir١-2-ylamino) -2,5dimethylphenyl) piperidirt-2-one</td><td>SM-ES m / z 426.2 (M + H٠).</td><td> 0,009</td>

<td> 152</td><td>عوق ، 4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) tetrahydro-2H-pyrart-2-one</td><td>SM-ES m / z 427.2 (M + H).</td><td> 0,155</td>

<td> 153</td><td>٠ 5-chloro-N2- (2-fluoro-4-mo٢pholino-5- (trifluo٢omethyl) phenyl) -N4- (5-methyl-1 H-pyraz٠l-3yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 472.1 (M + H⁺).</td><td> 0,091</td>

را

ΜΑ 32497Β1

146

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 154</td><td>'ملحج 5-chloro-N2- [4- (1,1-dioxo-tetrahydra-1٨٥-thiophen- 3-yl) -2,5-dimethyl-phenyl] ٠N4- (5-methyl1- ؛ H- pyrazol-3-yl) -py٢imidîne-2,4-diamine</td><td>SM-ES m / z 447.1 (M + H).</td><td> 0,012</td>

<td> 155</td><td>y 1 - (4- (5-chloro4- (5-methyl-1 H-pyrazol-3_ ylamin0) pyrimidin-2-ylamin0) -2,5dimethylpheny) piperazin-2-one</td><td>SM-ES m / z427.2 (M + H٠).</td><td> 1,65</td>

<td> 156</td><td>٠١ 5-Chloro-N4- (5-methyl-1H-pyrazol-3-yl) -N2- (2- methyl4- (4-methylpiperazin-1-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2,4diamine</td><td>SM-ES m / z 481.2 (M + H).</td><td> 0,040</td>

<td> 157</td><td>أحلا: مدي 5-Chloro-N2- (2-fluoro-4- (4-methylpipé٢azin-1-yl) -5- (t ؛ ٢fluoromethyl) phenyl) -N4- (5-methyl-1H-pyrazol-3- yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 485.2 (M + H).</td><td> 0,075</td>

ΜΑ 32497Β1

147

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 158</td><td>٠-٠ 3- (5-chlo٢o-2- (2,5-dimethyl-4- (piperidÎn4- yl) phenylamino) pyrimidin-4-ylamino) pyridin-2 (1H) ٠one</td><td>MS-ES m / z 425.2 (MH).</td><td> 0,062</td>

<td> 159</td><td>V 5-ch ؛ oro-N2- (2-fluoro-5-methyl-4- (1- methytpiperidir, -4-y () phenyl) -N4- (5-methylisoxazol- 3-yl) pyrimidin-2,4-d ؛ amine</td><td>SM-ES m / z 431.1 (M + H٠).</td><td> 0,073</td>

<td> 160</td><td>أديا 3- (5-chloro-2- (2,5-dimethyl-4- (piperidin-4- yl) phenylamino) pyrimidin-4-ylamino) pyridin٠2 (tH) - One ؛</td><td>SM-ES m / z425.2 (M + H٠).</td><td></td>

<td> 161</td><td>, أهيه 5-chlo٢o-N2- (2-isop٢opoxy-5-methyl-4- (1- methylpiperidin-4-yl) phenyl) -N4- (1H-py٢azol-3- yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 456.2 (M + H٠).</td><td> 0,332</td>

ΜΑ 32497Β1

148

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 162</td><td>جس دك دء ٢ هب ١ 4- (4- (5-chloro-4- (5-methyl-1 H-pyraz٥l-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethyl phenyl) piperidine-1-ethyl carboxylate</td><td>SM-ES m / z 438.9 (M + H).</td><td> 0,013</td>

<td> 163</td><td>تم ٦ (S) -2- (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3٠ ylamino) pyfimidin-2-ylamino) -5-fluo٢o-2methylphenyl) piperidin-1-yl ) propanamide</td><td>MS-ES m / z 487.2 (MH).</td><td> 0,056</td>

<td> 164</td><td>ثمة (S) -2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2- methylphenyl) piperidin-1-yl) -N-methylp٢opanamide</td><td>SM-ES m / z 501.2 (M + Η +); H NMR (MeOD-d4) δ 8.25 (s, 1Η), 7.56 (m, 1Η), 7.20 (d, 1Η), 6.46 (s, 1Η), 3.97 (m, 1Η), 3.79 (m, 1Η), 3.62 (m, 1Η). 3.25 (m, 3Η), 2.84 (s, 3Η), 2.40 (d, 6Η), 2.08 (m, 4Η), 1.62 (m, 3Η).</td><td> 0,033</td>

ΜΑ 32497Β1

149

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 165</td><td>ادو (R) -2- (4- (4- (5-chloro-4- (5-mettiyl-1H-pyrazol-3ylamino) pyrimidin-2-ylamino) -5-fluoro-2methylphenyl) piperidin-1-yl) propanamide</td><td>MS-ES m / z 487.2 (M + H٠); NMR ٦H (MeOD-di) δ 8.22 (s, 1Η), 7.61 (t, 1Η), 7.18 (d, 1Η), 6.40 (s, 1Η), 3.79 (m, 1Η), 3.65 (m, 1Η), 3.54 (m, 1Η), 3.22 (m, 3Η), 2.39 (d, 6Η), 2.08 (m, 4Η), 1.66 (d, 3Η).</td><td> 0,038</td>

<td> 166</td><td>/ ةلآ (S) -2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol٠3- ylamino) p٣imldin-2٠Mamino) -2.5- dimethylphenyl) piperidin-1-yl) p٢opanamide</td><td>MS-ES m / z 483.2 (MH).</td><td> 0,007</td>

<td> 167</td><td>(R) -2- (4- (4- (5-chloro4- (5-methyl-1H-py٢azol-3- ylamin0) pyrimidin-2-ylamin0) -2.5- dimethylphenyl) piperidin-1-yl) propanamide</td><td>MS-ES m / z 483.2 (M + H).</td><td> 0,006</td>

ν, Α 32497Β1

150

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 168</td><td>سؤ (S) -2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) p٣imidÎn-2-ylamino) -2.5- dimethylphenyl) piperidÎn-1-yl) -N- methylpropanamide</td><td>MS-ES m / z 497.2 (M + H).</td><td> 0,01</td>

<td> 169</td><td>٦ ثم ٠ (4- (4- (5-chloro-4- (5٠methyl-1 H-pyraz٥l-3ylamÎno) pyrimidin-2-y٠amÎno) -5-fluoro-2methyl phenyl) piperidin-1 yl) (1 (hylamino) cyclop٢opyl) methanone</td><td>MS-ES m / z 527.2 (M + H); RMN برا (MeOD-di) 8 8.24 (s, 1Η), 7.49 (d, 1Η), 7.23 (d, 1Η), 6.47 (s, 1Η), 4.52 (d, 2Η), 3.26 ( q, 2Η), 3.18 (m, 3Η), 2.40 (s, 6H). 1.91 (d, 2H), I, 71 (m, 2Η), 1.49 (m, 3Η), 1.39 (t, 3Η).</td><td> 0,004</td>

<td> 170</td><td>٠۴٦ (4- (4- (5-chlo٢o-4- (5-methyl-1H-pyrazol-3ylamino) py٢imidin-2-y! Amino) -2,5dimethylphenyl) piperidin-1-yl) (1 (ethylamino) cyclopropyl) methanone</td><td>SM-ES m / z 527.2 (M + H ').</td><td> 0,003</td>

ΜΑ 32497Β1

151

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> ١٦٩</td><td>١ هم ٠ طحلم ، 5-chlo٢o-N2- (2-fluoro-5-methyl-4- (piperidin-4- yl) phenyl) -N4- (5٠ (trffluoromethyl) -1H-pyrazol٠3- yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 470.1 (M + H).</td><td> 0,067</td>

<td> 172</td><td>م ١ 2- (4- (4- (5-chloroA- (5- (trifluoromethyl) -1H-py٢azol- 3-yfamin0) pyrimidin-2-ylamin0) -5-flu0ro-2- methylphenylJpiperidin-1-ylN-methylacetamide</td><td>SM-ES m / z 541.2 (MH).</td><td> 0,069</td>

<td> 173</td><td>، سمكيهب · 2- (4- (4- (5-chloroA- (5- (trifluoromethyl) -1H-pyrazol- 3-ylamin0) pyrimidin-2-ylamin0) -5-flu0ro-2- methylphenyl) piperidin-1-yl) acetamide</td><td>SM-ES m / z 527.2 (M + H).</td><td> 0,049</td>

ΜΑ 32497Β1

152

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td></td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 174</td><td>٧ 5-chloro-N2- (2,5-dimethyl-4- (1- (tetrahydro-2H- thiopyran-4-yl) piperidin-4-yl) phenyl) -N4- (5-methyl- 1H-pyrazol-3-yl) pyrimicline-2,4-diamine</td><td>SM-ES rn / z512.2 (M +</td><td>H).</td><td> 0,008</td>

<td> 175</td><td>ا ٠ جهض „لآ 1- (4- (4- (5-chloro-4- (5-methyl-1H-py٢azol-3ylamin0) pyrimidin-2-ylamin0) -2,5dime ، hylphenyl) piperidin-1-yl) -2- (ettiylamino ) -2methylpopan-1-one</td><td>SM-ES m / z 525.3 (M +٠</td><td>H).</td><td> 0,005</td>

<td> 176</td><td>اثمد (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -5-fluor0-2methylphenyl) piperidin-1-yl) (1 (ethylamino) cyclobutyl) methanone</td><td>SM-ES m / z 541.3 (Μ +</td><td>H٠).</td><td> 0,084</td>

WA 32497Β1

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> ٩٦٦</td><td>Æ باً (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamino) pyrimidin-2-ylamino) -5-fluo٢o-2methyl phenyl) piperidin-1-yl) (1 (methylamino) cyclobutyl ) methanone</td><td>SM-ES m / z 527.2 (M + H).</td><td> 0,08</td>

<td> 178</td><td>بر ٢ ركعخي N2- (2,5-dimethyl-4- (pipé٢idin-4-yl) phenyl) -5- methyl-N4- {5-methyl-1H-pyrazo ، -3-yl) pyrimidin &amp; 2٠4-diamine</td><td>SM-ES m / z 392.2 (M + H).</td><td> 3,229</td>

<td> 179</td><td>سلأ (S) -3- (4- (2.5-dimethyl-4- (5-methyl-4- (5-methyl-1H- pyrazol-3-ylamino) pyrimidin-2- ylamino) phenyl) piperidin-1-yl) - 1,1,1-trifluoropropan-2-ol</td><td>SM-ES m / z 504.3 (Μ + H).</td><td> 0,12</td>

ΜΑ 32497Β1

154

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 180</td><td>: 1- (3- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -2.5- dimethy (phenyl) piperidin-1-yl) -2٠ (dimethylamino) hanone</td><td>MS-ES m / z 497.2 (M + H).</td><td> 0,025</td>

<td> 181</td><td>١٢٠ HN ۶ ع — اي Ν ^ ١ ~ ١ 2- (2- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamino) py٢imidin-2-ylamino) -2,5٠ dimethylphenyl) piperidin-1-yl) acetamide</td><td>MS-ES m / z 469.2 (M + H).</td><td> 0,024</td>

<td> 182</td><td>2- (2- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) -N-methylacetamide</td><td>SM-ES m / z483.2 (M + H٠).</td><td> 0,019</td>

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155

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 183</td><td>سج (S) -5-chloro-N2- (2,5-dimethyl-4- (1-methylpiperidin2-yl) phenyl) -N4- (5-methyl-1 H-pyrazol-3_ y ،) pyrimidine-2٠4-diamine</td><td>SM-ES m / z 426٠2 (M + H).</td><td></td>

<td> 184</td><td>هأدلا (R) -5-chloro-N2- (2,5-dimethyl-4- (1-methylpipé٢idin2-yl) phenyl) -N4- (5-methyl-1 H-pyrazol-3٠ yl) pyrimidin-2,4- diamine</td><td>SM-ES m / z 426.2 (M + H).</td><td></td>

<td> 185</td><td>٧ 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -2.5- dimethylphenyl) piperidin-1-yl) butanamide</td><td>MS-ES m / z 497.2 (M + H).</td><td> 0,009</td>

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156

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 186</td><td>لأض 1- (4- (4- (5-chloro-4- (5-cyclopropyl-1 H-py٢azol-3ylamino) p۴imi (iin-2-ylamino) -2,5dimethyl pheny ؛) piperidin-1-yl) -2 (dimethylamino) ethanone</td><td>SM-ES m / z 523.3 (M + H *) -</td><td> 0,012</td>

<td> 187</td><td>٠ لمتض (l-aminocyclopropyl) (3- (4- (5-chloro-4- (5-methy ؛ 1H-pyrazol-3-ylam (no) pyrimidin-2-ylamino) -2,5dimethyl phenyl) piperidin-1-yl ) methanone</td><td>MS-ES m / z 495.2 (MH).</td><td> 0,095</td>

<td> 188</td><td>١٠ (1-aminocyclopropyl) (4- (4- (5-chloro-4- (5- cyclopropyl-1H-pyrazol-3-ylamino) pyrimidin-2- ylamino) -2,5-dimethylphenyl) pIperidin-1- yl) methanone</td><td>SM-ES m / z 521.2 (M + H٠).</td><td> 0,019</td>

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157

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 189</td><td>V 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidirt-2-ylamin0) -2,5dimethylphenyl) pipé٢idin-1-yl) -N-methylbutanamide</td><td>SM-ES m / z 511.3 (M + H.</td><td> 0.007</td>

<td> 190</td><td>جس ΗΝ١٨ نجد مآ ب 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- y! amino) pyfimidin-2-y! amino) -2,5- dimethylphenyl) piperidin-1-yl) -N-ethylbutanamide</td><td>SM-ES m / z 525.3 (Μ + H ').</td><td> 0,007</td>

<td> 191</td><td>ع عج 5-chloro-N2- (4- (1 - ((3.5-dimethylisoxazol-4- yl) methyl) piperidin-2-yl) -2,5-dimethylphenyl) N4- (5- methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 521.2 (M ٠ H).</td><td> 0,113</td>

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158

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 192</td><td>م ٧ (4- (4- (5-chloro-4- (5-methylf-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -5-flu0٢a-2- methytphenyl) piperidin-1-yl) (1- hydroxycyclop٢opy)) methanone</td><td>SM-ES m / z 500.2 (M + H٠).</td><td> 0,021</td>

<td> 193</td><td>٠٠٠ a— هحسجع (2- (4- (5-ch ؛ oro-4- (5-methyl-1 H-pyrazo (-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) (1hydroxycyclopropyl) methanone</td><td>SM-ES m / z 496.2 (M + H).</td><td> 0,076</td>

<td> 194</td><td>5-Chlora-N2- (2,5-dimethyl-4- (1- (3morpholinopropylsulfonyl) piperidin-4-yl) phenyl) -N4 (5-methyl-1H-pyraz0l-3-yl) pyrimidin-2,4- diamine</td><td>SM-ES m / z 603.3 (M + H٠).</td><td> 0,013</td>

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159

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 195</td><td>ا N2- (4- (1- (3- (azetidin-1-yl) propylsulfonyl) pipé٢idin- 4-yl) -2,5-dimethylphenyl) -5-chloro-N4- (5-methyl- 1H-pyraz0l-3٠yl) pyrimidin-2,4-dîamine</td><td>SM-ES m / z 573.3 (Μ + H).</td><td> 0,027</td>

<td> 196</td><td>م ο =؟ = ο ج جك ١ بآ ٦٦ اهم (3R, 4R) -1- (3- (4- (4- (5-chloro-4- (5-methyl-1H- pyraz0l-3ÿlamin0) pyrimidin-2-ylamin0) -2.5- dimethylphenyl) piperidin-1- ylsulfonyl) propyl) pyiTolidin-3,4-diol</td><td>SM-ES m / z 619.3 (M + H).</td><td> 0,37</td>

<td> 197</td><td>جمتلى..ي (2S) -3- (2- (4- (5-chloro4- (5-methyl-1H-pyrazol-3ylamino) pyrimidin-2-y! AmÎno) -2,5dimethylphenyl) piperidin-1-yl) -1, 1,1trifluoropropan-2-ol</td><td>SM-ES m / z 524.2 (M + H *).</td><td> 0,021</td>

ΜΑ 32497Β1

160

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 198</td><td>/ ٠ مةت 1 - ((4- (4- (5-chloro-4- (5-methyl'1 H-pyrazo! -3ylamino) py٢imidin-2-yam! No) -2,5dimethylphenyl) piperidin-1yQméthyQcyclopropanecarbonitrile</td><td>SM-ES m / z 491.2 (M + H).</td><td> 0,022</td>

<td> 199</td><td>مبؤل 2- (4- (4- (5-chlo٢o-4- (5-methyl-1 H-py٢azol-3ylamino) pyrimidin-2-ylamino) -5-fIuora-2methyl phenyl) piperidin-1-yl) acetonitrile</td><td>SM-ES m / z455.2 (M + H٠).</td><td> 0,077</td>

<td> 200</td><td>رتمج 3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2methylphenyl) piperidin-1-yl) propanenitri1e</td><td>MS-ES m / z 469.2 (M + H).</td><td> 0,036</td>

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161

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 201</td><td>غمم دج (2S) -3- (3- (4- (5-chloro-4- (5-methyl-1 H-pyrazo! -3ylamÎno) p۴imidin-2-ylamino ^ 2,5dimethylphenyl) piperidin-1-yl) -1 , 1,1trifluoropropan-2-ol</td><td>SM-ES m / z 524.2 (M + H *).</td><td> 0,046</td>

<td> 202</td><td>٠٢ 2- (4- (2,5-dimethyl-4- (4- (S-methyt-1H-pyrazol-3ylamino) -5- (trifluoromethyl) pyrimidin-2ylamino) phenyl) piperidin-1-yl) acetamide</td><td>MS-ES m / z 503.2 (M + H٠); H NMR (MeOD-di) δ 8.23 ​​(s, 1Η), 7.26 (s, 1Η), 7.20 (s, 1Η), 6.20 (s, 1Η), 4.00 (s, 2Η), 3.7S (d, 2Η), 3, SS (m, 2Η), 3.14 (m, 1Η), 2.36 (s, 3Η), 2.26 (s, 3Η), 2.24 (s, 3Η), 2.08 (m, 4H).</td><td> 0.02</td>

<td> 203</td><td>2- (4- (2,5-dimethyl-4- (4- (5-methyl-1H-pyrazol-3- ylamino) -5- (trifluoromethyl) pyrimidin-2- ylamino) phenyl) piperidin-1-yl) -N-methylacetamide</td><td>SM-ES rn / z517.3 (M + H٠).</td><td> 0,015</td>

<td> 204</td><td>احيلا ايب ٦ آ 2- (4- (4- (5-chloro-4- (5-cyclopropyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1 -yl) ethanol</td><td>MS-ES m / z 482.2 (M + H).</td><td> 0,016</td>

ΜΑ 32497Β1

162

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 205</td><td>يده 5-chloo-N4- (5-cyclopropyl-1 H-pyrazol-3-yl) -N2- (4 (1 -ethylpiperidin-4-yl) -2.5dimethylphenyl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 466.2 (Μ + H).</td><td> 0,019</td>

<td> 206</td><td>٧ 4- {4- (5-chloro-4- (5-methyl-1 H-pyraz٥l-3ylamin0) pyrimidin-2-ylamifi0) -5-flu0r0-2methyl phenyl) pipé٢idine-1-ca٢baldehyde</td><td>SM-ES m / z 444.2 (M + H.</td><td> 0,03</td>

<td> 207</td><td>٠٠١ يما (R) -2- (3- (4- (5-chloro-4- (5-methyl-1H-py٢azol-3ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) piperidin-1-yl) -N- methylacetamide</td><td>MS-ES m / z 483.2 (M + H).</td><td> 0,026</td>

<td> 208</td><td>١ تئتلأميلا دلا (S) -2- (3- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -2.5- dimethylphenyl) piperidin-1-yl) -N-methylacemide</td><td>SM-ES m / z 4832 ا (M + H⁺).</td><td> 0,01</td>

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163

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 209</td><td>هسؤ 5-chloro-N2- (2-fluoro-5-methy1) -4 - ؛-( tetrahydro-2H- pyran-4-yl) piperidin-4-yt) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 500.2 (M + H٠); H NMR (DMSO-de, 400 MHz) δ 12.08 (br, 1Η), 9.58 (br, 1Η), 8.65 (d, 28.4 = ر Hz, 1Η), 8.02 (s , 1Η), 7.36 (d, 8.4 = ر Hz, 1Η), 7.03 (d, 12.4 = لى Hz, 1Η), 6.08 (br, 1Η), 3.89 (dd , 3.6, 10.8 = لى Hz, 2Η), 3.28 (1, 10.4 = لى Hz, 2Η), 2.99 (d, 10.8 = ر Hz, 2Η). 2.64-2.43 (m, 2Η), 2.24-2.15 (m, 8Η), 1.71-1.40 (m, 8Η).</td><td> 0,027</td>

<td> 210</td><td>W</td><td>SM-ES m / z 456.2 (M + H٠).</td><td> 0,032</td>

<td></td><td></td><td></td><td></td>

<td></td><td>5-Chloro-N2- (4- (1-Cyclopropylpiperidin-4-yl) -2fluoro-5-methylphenyl) -N4- (5-methyl-1 H-pyrazo ، -3yl) pyrimidin-2٠4-diamine</td><td></td><td></td>

<td></td><td>\ كدكل ه</td><td>SM-ES m / z 440.2 (M + H).</td><td> 0,009</td>

<td> 211</td><td></td><td></td><td></td>

<td></td><td>5-chlo٢o-N2- (4- (1-ethylpiperidin-4-yl) -2.5- dimethylphenyl) -N4- (5-methyl-1H-pyrazol-3- yl) pyrimidin-2,4-diamine</td><td></td><td></td>

ر

ΜΑ 32497Β1

164

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 212</td><td>ئ 5-Chloro-N2- (4- (1- (2-methoxyethyl) piperidin-4-yl) - 2,5-Dimethylphenyl) -N4- (5-methyl-1H-pyrazol-3- yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 470.2 (M + H).</td><td> 0,013</td>

<td> 213</td><td>V fS) -3-f4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2-meth0xy-5mhylpérypiperidin-l -yl) -1,1, 1 -trifluorop٢opan2-01</td><td>SM-ES m / z 540.2 (Μ + H).</td><td> 0,012</td>

<td> 214</td><td>٢NH غ HN ^ CI لإم N2- (4- (1- (3- (azetidin-1-ylsulfonyl) propyl) piperidin- 4-yl) -2.5-dimethylphenyl) -5-chloro-N4- (5-methyl- 1H-pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 573.2 (M + H٠).</td><td> 0,04</td>

ر /

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165

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 215</td><td>أء ٠^محآ ٢ 5-Chloro-N2- (2٠5-dimethyl-4- (piperidin-4-yl) phenyl) Ν4- (5- (trifluoromethyl) -1 H-pyrazol-3-yl) pyrimidin2,4-diamine</td><td>SM-ES m / z 466.2 (M + - H٠).</td><td> 0,047</td>

<td> 216</td><td>٠١ 5-Chloro-N2- (2-fluoro-4- (1-methyfpiperidin-4-yl) -5 (trifluoromethyl) phenyl) -N4- (5-methyl-1 H-pyrazo! -3yl) pyrimidin-2,4 -dlamine</td><td>SM-ES m / z 484.2 (M + H ').</td><td> 0,047</td>

<td> 217</td><td>ا ٠ 2- (4- (4- (5-chloro-4- (5- (trifluoromethyt) -1H-pyrazol- 3ÿlamino) pyrimidin-2-ylamino) ٠2.5- dimethylphenyl) piperidin-1-yl) acetamide . . . .</td><td>SM-ES m / z 523.2 (M + H).</td><td> 0,034</td>

<td> 218</td><td>٠١ 5٠chloro-N4- (5-methyl-1H.pyrazol-3-yl) -N2- (2- methyl-4- (1-methylpiperidin-4-yl) -5- (trifluoromethyl) phenyl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 480.2 (M + H).</td><td> 0,026</td>

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166

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 219</td><td>¾0 ^ 5-chloro-N2- (5-methoxy-2-methyl-4- (1- methylpipé٢idin4-yl) phenyl) -N4- (5-methyl-1H- pyrazo! -3-yl) pyrimidin (3-2,4-diamine٠</td><td>SM-ES m / z 442.2 (M + H *).</td><td> 0,009</td>

<td> 220</td><td>2- (4- (4- {5-chloro-4- (5- (trifluoromethyl) -1H-pyrazol- 3-yamino) pyrimidin-2-ylamino) -2.5- dimethylphenyl) piperidin-1-yl) -N-methylacetamide</td><td>MS-ES m / z 537.2 (M + H).</td><td> 0,037</td>

<td> 221</td><td>٠٦ N2- (4- (1-ethylpipé٢idin-4-yl) -2,5-dimethylphenyl) N4- (5-methyl-1 H-pyrazol-3-yl) -5 (t٢ifluoromethyl) pyrimidin-2,4-diamine</td><td>SM-ES m / z474.3 (M ۶ H٠).</td><td> 0,034</td>

VIA 32497Β1

157

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 222</td><td>'٠ 2- (4- (2.5-dimethyl-4- (4- (5-methyl-1H-pyrazol-3ylamino) -5- (trifluoromethyl) pyrimidin-2ylamino) phenyl) piperidin-1-yl) ethanol</td><td>SM-ES m / z 490.2 (M + H *).</td><td> 0,038</td>

<td> 223</td><td>٦٦١٨ نج و ب 1- (4- (4- (5-chloro-4- (5- (trifluo٢omethyt) -1 H-pyrazol- 3-ylamino) p٣imidin-2-ylamino) -2.5- dimethyphenyl) p ؛ per ؛ din-1-yl) -2- (dinehylamino) ethanone</td><td>SM-ES m / z 551.2 (M + H).</td><td> 0,036</td>

<td> 224</td><td>H٩ a. م م ٠ بر 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3٠ ylamin0) pyrimidin-2-ylamin0) -2,5dimethylphenyl) pipé٢idin-1-yl) -4-morpholinobutan1- one</td><td>MS-ES m / z 567.3 (MH).</td><td> 0,02</td>

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168

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 225</td><td>مأيم 1 - (4٠ (4- (5-chloro-4- (5-methyl-1 H-pyrazo! -3ylamino) pyrimidin-2-ylannino) -2,5dimethylphenyl) piperidin-1 -yt۶ 3-morpholinopropan-l-one</td><td>SM-ES m / z 553.3 (M + H).</td><td> 0,017</td>

<td> 226</td><td>1 - (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazo! -3ylamin0) pyrimidin-2-ylamin0) -2,5dÎmethylphenyl) piperidin-1-yl) -3- (pyrr0lidin -1yl) propan-1-0ne</td><td>SM-ES m / z 537.3 (M + - H *).</td><td> 0,061</td>

<td> 227</td><td>W 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3٠ yamino) py٢imidin-2-ylam ؛ no) -2,5dimethylphenyl) piperidin-1-yl) -4- (pyrolîdin-1yl) butan-1-0ne</td><td>SM-ES m / z 551.3 (M + H *). -—</td><td> 0,123</td>

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169

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 228</td><td>٠٠٨٥ (R) -3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -2-meth0xy-5- methylphenyl) piperidin-1-yl) -1,1,1-trIfluo٢opropan- ؛ 0-2</td><td>SM-ES m / z 540.2 (MH).</td><td> 0,023</td>

<td> 229</td><td>"مل (2R) -3- (2- (4- (5-chloro-4- (5-methyl-1 H-pyrazo٠-3ylamino) pyrimîdin-2-y) amino) -2,5dimethylphenyl) piperidin-1-yl) ٠1,1٠1-trif1u0r0pr0pan-</td><td>MS-ES m / z 524.2 (M + H).</td><td> 0,211</td>

<td> 230</td><td>2-ol م 7 حل (S) -4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamino) pyr ؛ mîdin٠2-ylamino) -2,5diméthyi phenyl) oxazolidin-2-οηβ</td><td>SM-ES m / z 414.1 (M + H).</td><td> 0,04</td>

<td> 231</td><td>دنملاهر ١ Ç-NH (R) -4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -2.5- dimethylphenyl) 0xaz0üdin-2-0ne</td><td>SM-ES m / z 414.1 (M + H⁺).</td><td> 0,05</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 1C5O (uM)</td>

<td> 232</td><td>ج 5-chlo٢o-N2- (4- (1-ethylpipé٢idirt-4-yl) -2-fluoro-5- methylphenyl) -N4- (5-methyl-1H-pyrazol-3- yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 444٠2 (M + H٠); H NMR (DMSO-ds) δ 8.01 (s, 1Η), 7.35 (m, 1Η), 7.02 (d, 1Η), 6.22 (s, 1H), 2.97 (d, 2Η), 2.62 (m, 1Η), 2.34 (q, 2Η), 2.21 (s, 3Η), 2.13 (s, 3Η), 1.98 (t, 2Η), 1, 64 (m, 4Η), 1.01 (t, 3H).</td><td> 0,020</td>

<td> 233</td><td>rO HN ا 5-chlo٢o-N2- (2,5-dimethyl-4- (1 - (3- (pyrrolidin-1 yl) pr0pylsulfonyl) piperidin-4-yt) phenyl) N4- (5methyl-1H-pyrazol-3-yl) pyrimidine-2,4-diamine</td><td>SM-ES m / z 587.3 (Ml H *).</td><td> 0,054</td>

<td> 234</td><td>(R) -1- (3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -2.5- dimethylphenyl) piperidin-1- ylsulfonyl) propyl) pyolidin-3-ol</td><td>SM-ES m / z 603.3 (Μ + H).</td><td> 0,073</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 235</td><td>^٠١Γ٠ 5-0 ^ 00- ^ 2 .- (4-0 - ((2., 2- difluorocyclopropyl) methyl) piperidin-4-yl) -2-fluoro- 5-methylphenyl) -N4- (5-methyl-1H-pyrazol-3- yt) pyrimidin-2,4-diamine</td><td>SM-ES m / z 506.2 (M + H).</td><td> 0,063</td>

<td> 236</td><td>٠ نمل ١ ئاحج 3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamino) py٢Îmidin-2-ylamino) -2.5- dimethylphenyl) piperidin-1-yl) propanamide</td><td>SM-ES m / z 483.2 (M + H٠).</td><td> 0,059</td>

<td> 237</td><td>ملعجد N2- (4- (azetidin-3-yl) -2,5-dimethytphenyt) -5-chloroN4- (5-methyl-1 H-pyrazol-3-yl) pyrimidin-2٠4٠ diamine</td><td>SM-ES m / z 384.2 (M + H٠).</td><td> 0,41</td>

<td> 238</td><td>٣٩ 3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -2.5- dimethylphenyl) piperidin-1-yl) -1- (pyrrolidin-1- yl) propan-1-0ne</td><td>SM-ES m / z 537.3 (M + H *).</td><td> 0,039</td>

تجر

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 239</td><td>V 1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol٠3- ylam ؛ no) pyrimidin-2-y! amino) -2٠5- dimethyl, phenyl) piperidin-1-yl) -3- (dimethylamino) propan-1-one ... .</td><td>SM-ES m / z 511.3 (M + H).</td><td> 0,073</td>

<td> 240</td><td>جبهغأ 5-Chloro-N2- (4- (1-ethylpiperidir, -4-yl) -2-fluoro-5- (t٢ifluoromethyl) phenyl) ٠N4- (5-methyl-1H-pyrazol-3- yl) pyrimidin-2,4-diamine</td><td>MS-ES m / z 498.2 (M + H).</td><td> 0,102</td>

<td> 241</td><td>١٩٠ 5-Chloro-N2- (4- (1-ethylpiperidin-4-yl) -2-methyl-5 (trifluoromethyl) phenyl) -N4- (5-methyl-1 H-py٢azol-3yl) pyrimidin-2,4- diamine</td><td>SM-ES m / z 494.2 (Μ + H).</td><td> 0,068</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (UM)</td>

<td> 242</td><td>٠ ô مآ 3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2٠ methylphenyl) piperidin-1٠yl) -1- (pyrr0lidin-1- yl) propan-1-0ne</td><td>SM-ES m / z 541.3 (Μ + H).</td><td> 0,06</td>

<td> 243</td><td>ياً دئجيني N2- (4- (1- (3- (azetidin-1-ylsulfonyl) propyl) piperidin- 4-yl) -2-fluo٢o-5-methylphenyl) -5-chloro-N4- (5- methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 577.2 (M + H٠).</td><td> 0,076</td>

<td> 244</td><td>غلأآل٠.ء 0 5-chlo٢o-N2- (2-fluoro-5-methyl-4- (1- (3- (pyrrolidin-1- ylsulfonyl) p٢opyl) piperidin-4-yl) pheny!) - N4- (5- methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 591.2 (M - + H٠).</td><td> 0,084</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 245</td><td>٥Η HN Cl خبص 0١٩ 5-chlo٢o-N2- (2-fluoro-5-methy! -4- (1- (3 (morpholinosulfonyl) propyl) piperidin-4-yl) phenyl) N4- (5-methyl-1H-pyrazol-3ÿl) pyrimidine -2.4diamine</td><td>SM-ES m / z 607.2 (M + H⁺).</td><td> 0,077</td>

<td> 246</td><td>ؤصص 4- (4- (4- (5-chloro4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -5-flu0ro-2- methylphenyl) piperidin-1-yl) -1-m0rph0lin0butan-1- one</td><td>SM-ES m / z 571.3 (M + H *).</td><td> 0,058</td>

<td> 247</td><td>٣٠٠٦١ 3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2- methylphenyl) piperidin-1-yl) -N- cyclopropylpropanamide</td><td>SM-ES m / z 527.2 (M + H⁺).</td><td> 0,062</td>

<img file="MA32497B1_D0083.tif" />

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 248</td><td>هميدج 3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamino) pyrimidin-2-ylamino) -5-fluoro-2methylphenyl) pipé٢idin-1-y) pjopanamide</td><td>SM-ES m / z 487.3 (M + H *).</td><td> 0,14</td>

<td> 249</td><td>ملآل 5-chloro-N2- (4- (1 - ((2.2- diflu0r0cyclopr0pyl) methyl) piperidÎn-4-yl) -2.5- dimethylphenyl) -N4- (5-methyt-1H-pyrazol-3- yl) pyrimidin-2٠4-diamine</td><td>SM-ES m / z 502.2 (M + H ').</td><td> 0,032</td>

<td> 250</td><td>V 5-Chloro-N2- (4- (1-Cyclopropylpiperidin-4-yl) -2.5- dimethylphenyl) -N4- (5-methyl-1H-pyrazol-3- yl) pyrimidin-2٠4-diamine</td><td>MS-ES m / z 452.2 (MH).</td><td> 0,025</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 251</td><td>مج ١ ل N2٠ (4٠ (1٠ ((2.2-difluorocyclopropyl) methyl) piperidin- 4-yl) -2-fluoro-5-methylphenyl) -N4- (5-methyl-1 Hpyrazol-3-yl) -5- (trifluoromethyl) p ^ imid ؛ ne-2,4diamine</td><td>SM-ES m / z 540.2 (M + H).</td><td> 0,052</td>

<td> 252</td><td>V 5-chloro-N2- (2,5-dimethyl-4- (1- (tetrahydro-2H- pyran-4-yl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3ÿl) pyrimidin-2٠4-diamine</td><td>SM-ES m / z 496.3 (M + H).</td><td> 0,014</td>

<td> 253</td><td>H &lt;١0c ٠٠ لآ 5-chloro-N2٠ (2-fluoro-4- (pÎpêridin-4-yl) -5- (trifluoromethyl) p (ienyl) -N4- (5-methyl, -1H-pyrazol-3- yl) pyrimidin-2,4-diamine ٨</td><td>SM-ES m / z 470.1 (M + H).</td><td> 0,075</td>

<td> 254</td><td>HN٩ 5-Chloro-N4- (5-methyl-1H-pyrazol-3-yl) -N2- (2- methyl-4- (piperidin-4-yl) -5- (trifluoromethyl) phenyl) pyrimIDine-2,4-diamine</td><td>SM-ES m / z 466.2 (M + H٠).</td><td> 0,07</td>

ا

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 255</td><td>١٠ 5-chlora-N4- (5-cyc! Opropyl-1 H-pyrazol-3-yl) ٠N2- (4 (1-c١œlopropylpiperidin-4-yl) -2-fluoro-5méthy! Pheny) pyrimidine-2,4- dîamîne</td><td>SM-ES m / z 482.2 (M + H).</td><td> 0,228</td>

<td> 256</td><td>ركعحة 5-Chloro-N2- (2,5-dimethyl-4- (piperidin-4-yl) phenyl) - N4- (5-methyl-1H * pyrazol-3-yl) pyrimidin-2,4- diamine</td><td>SM-ES m / z412.2 (M + H٠).</td><td> 0,044</td>

<td> 257</td><td>٩ فعي ٢ N2- (2,5-dimethyl-4- (pipè٢idin4-yl) phenyl) -N4- (5methyl-1 H-pyrazol-3-yl) -5 (trifluoromethyl) pyrimidin-2,4-diamine ٨</td><td>SM-ES m / z 446.2 (M + H٠).</td><td> 0,064</td>

<td> 258</td><td>٠ 5-Chloro-N4- (5-Cyclopropyl-1H-pyrazol-3-yl) -N2- (4- (1-cyclopropylpiperid! N-4-yl) -2.5- dimethylphenyl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 487.2 (M + H٠).</td><td> 0,026</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 259</td><td>5-chloro-N2٠ (2-fluoro-4- (1 ٠ ((3-isopropyl-1,2٠4oxadiazol-5-yl) methyl) piperidin-4-yl) -5methylpheny ؛) - N4- (5-methyl-1 H-pyrazol-3٠ yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 540.2 (M + H٠).</td><td> 0,064</td>

<td> 260</td><td>٦r 5-Chloro-N2- (4- (1 - ((3-isopropyl'l. 2,4-oxadiazol-5yl) methyl) piperidin-4-yl) -2,5-dimethylphenyl) -N4- (5methyl-1H -pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 536.3 (M + H).</td><td> 0,018</td>

<td> 261</td><td>١٢ 2- (4- (4- (5-chloro4- (5-methyl-1H-pyrazol-3- y! amino) pyrimidin-2-y ؛ amino) -2-ethyl-5- methylphenyl) piperidin-1-yl) acetamide</td><td>SM-ES m / z 483.2 (M + H٠).</td><td> 0,027</td>

<td> 262</td><td>V 2- (4- (4- (5-chlo٢o4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -2-meth0xy-5methylphenyl) piperidin-1-yl) acetamide</td><td>SM-ES m / z 485.2 (Μ + H).</td><td> 0,019</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 263</td><td>٦٦Η لس ١ مد سم 2- (4- (4- (5-ch ؛ oro-4- (5-ethyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2methyl phenyl) piperidin-1-yl) acetamide</td><td>SM-ES m / z 487.2 (M + H *) -</td><td> 0,033</td>

<td> 264</td><td>-, 'ر, عن ٢ كبمكم 0 ح ١ أ ٠ 5-chtoro-N2- [4- [1- (1,1-dioxo-1٨®-thietan-3-yl) - piperidin-4-yl] -2-fluoro-5-methylpheny)) - N4- (5- ethyl-1H-pyraz0l-3-yl) -pyrimidin-2,4-diamine .</td><td>SM-ES m / z 534.2 (M + H٠).</td><td> 0,021</td>

<td> 265</td><td>مخبة (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2methylphenyl) piperidin-1 -yl) (3-isopropyl-1, 2,4oxadiazol-5-yl) methanone</td><td>SM-ES m / z 554.2 (M + H) H NMR (400 MHz, CDIg) δ 9.67 (br s, 2Η), NNH 8.50 (s, 1Η), 8.07 (s, 1Η ), 7.57 (d, 8.4 = ر Hz, 1Η), 7.05 (d, 12.4 = ر Hz, Hl), 6.16 (s, 1Η), 5.53 (s, 1Η ), 3.98 (d, ر = 13.2 Hz, 1Η), 3.34 (dt, ر = 2.0, 2.8 Hz, 1Η), 3.15 (m, 1Η), 2.82 (m, 2Η), 2.62 (t, 4.8 = ل Hz, 2Η), 2.34 (s, 3Η), 2.25 9s, 3Η), 1.90 (m, 2Η), 1, 76 (2Η).</td><td> 0,091</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 266</td><td>٠٩ بة ٦ N2- (4- (1 - ((5-tert-butyl-'l, 2,4-oxadiazol-3- yl) methyl) piperidin-4-yl) -2,5-dimethylphenyl) -5- chloro-N4- (5-methyt-'IH-py٢azol-3-yl) py٢imidin- 2,4-diamine</td><td>SM-ES m / z 550.3 (Μ + H).</td><td> 0.025</td>

<td> 267</td><td>١ مبة ٦ Ν2- (4- (1 - ((5-tert-butyl-1.2.4-oxadiazol-3yl) methyl) piperidîn-4-yl) -2-fluoro-5-methylphenyl) 5-chloro-N4- (5- methyl-1 H-pyrazol-3-yl) pyrimidin2,4-diamine</td><td>SM-ES m / z 554.3 (M + H٠).</td><td> 0,077</td>

<td> 268</td><td>V 5-Chloro-N4- (5-ethyl-1H-pyrazol-3-yl) -N2- (4- (1- ethylpiperidin-4-yl) -2-fluoro-5- methytphenyl) pyrimidine-2,4-diamine</td><td>SM-ES m / z 458.2 (Μ + H).</td><td> 0,022</td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 269</td><td>٠ جذ ٢ آ 0 م ١ مإم 5-chloro-N2- (4- (1- (2- (3-isopropyl-1,2,4-oxadiazol- 5-yl) ethyl) piperidin-4-yl) -2,5-dinnethylphenyl) -N4- (5- methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 550.3 (M + H).</td><td> 0,039</td>

<td> 270</td><td>(4- (4- (5-chloro-4- (5-methyl-1 H-pyraz٥l * 3ylamino) pyrim! D! N٠2-ylamino) -2٠5dimethylphenyl) piperidin-1-yl) (3-isopopyl-1,2 , 4oxadiazol-5-yl) methanone</td><td>SM-ES m / z 550.2 (M + H *).</td><td> 0,018</td>

<td> 271</td><td>ج 5-chloro-N4- (5-ethyl-1H-pyrazol-3-yl) -N2- (2-fluo٢o- 5-methyl-4- (1-methylpiperidin-4- yl) p (iény!) pyrimidin-2,4-diamine</td><td>SM-ES m / z 444.2 (Μ + H ').</td><td> 0,013</td>

//

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 272</td><td>/ ١ 5-chloro-N2- (4- (1-cyclobutylpipeiidin-4-yl) -2-fluoro- 5-methylphenyl) -N4- (5-methyl-1H-pyrazol-3- yl) pyrimidin-2,4-diamlne</td><td>SM-ES m / z 470.2 (M + H).</td><td> 0,050</td>

<td> 273</td><td>٦ رم 5-ch ؛ oro-N2- (2-fluoro-5-methyl-4- (2methyl piperidin-4-yl) phenyl) -N4٠ (5-methyl-1 Hpyrazol-3-yl) pyrlmldine-2,4-diamine</td><td>SM-ES m / z 430.2 (MH).</td><td> 0,018</td>

<td> 274</td><td>2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3ylamin0) pyrimidin-2-ylamin0) -5-flu0ro-2methylphenyl) -2-methylpiperidin-1-yl) acetamide</td><td>MS-ES m / z 487.2 (M + H).</td><td> 0,006</td>

<img file="MA32497B1_D0084.tif" />

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 275</td><td>مح عج 5-chloro-N2- (4- (1,2-dimethylpiperidin-4-yl) -2-fluoro- 5-methylphenyl) -N4- (5-methyl-1H-pyrazol-3- y () pyrimidin-2,4-diamine</td><td>SM-ES m / z 444.2 (M + H⁺).</td><td> 0,009</td>

<td> 276</td><td>كلآ N2- (4٠ (1,4'-bipipé٢idin-4-yl) -2-fluoro-5methylphenyl) -5-chloro-N4- (5-methyl-1 H-pyraz٥l-3yl) pyrimidin-2,4-dlamine</td><td>SM-ES m / z 499.2 (Μ + H).</td><td> 0,437</td>

<td> 277</td><td>تجه 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (6- methylpyridazin-3-yl) piperidin4-yl) phenyl) N4- (5- methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 508.2 (M + H).</td><td> 0,097</td>

دد

VIA

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 278</td><td>٩ ١ 5-chloro-N2- (2-fiuoro-5-methyl-4- (1'- (methylsulfonyl) -1,4'-bipiperidin-4-yl) phenyl) -N4- (5methyl-1 H-pyrazol-3-yl) pyrimidin-2,4-dîamine</td><td>SM-ES m / z 577٠2 (M + H).</td><td> 0,009</td>

<td> 279</td><td>5-chloro-N2- (2-fluoro-5-methyl-4 - ((trans) -2- methylpiperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 430.2 (M + H).</td><td> 0,064</td>

<td> 280</td><td>طاًه ٠ 5-chloro-N2- (2-fluoro-5-methyl-4 - ((cis) -2- methylpiperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 430.2 (M + H٠).</td><td> 0,163</td>

ا

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 281</td><td>م ٦</td><td>SM-ES m / z 507.2 (M + H٠).</td><td> 0,087</td>

<td></td><td>5-Chloro-N2- (2-Fluoro-5-methyl-4- (1- (pyridin-2ylmethyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1 Hpyrazo! -3-yl) pyrimidin -2.4-diamin</td><td></td><td></td>

<td> 282</td><td>٧ 3- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazo3- ؛ ylamino) pyrimidin-2-ylamino) -5-fluoro-2methylphenyl) piperidin-1-yl) cycl0pent-2- en0ne</td><td>MS-ES m / z 496.2 (M + H٠); H NMR (400 MHz, DMSO-de) δ 9.97 (br s, 1Η), 9.83 (hr s, 1Η), 8.90 (s, 1Η), 8.32 (d, 6.8 = ر Hz, 1Η), 7.88 (d, 12.8 = ل Hz, 1Η), 6.97 (s, 1Η), 6.04 (s, 1Η), 5.30 (br s, 1Η), 4.71 (d, 12.0 = ل Hz, 2Η), 4.04 (t, 12.4 = ل Hz, 2Η), 3.84 (m, 1Η), 3.53 (m, 2Η), 3.13 (m, 2Η), 3.08 (s, 3Η), 2.96 (s, 3Η), 2.59-2.40 (m, 4Η).</td><td> 0,048</td>

<td></td><td></td><td>SM-ES m / z 556.3 (M + H).</td><td> 0,016</td>

<td> 283</td><td>٩٠ متن Ν2- (4- (1 - (1,4-dioxaspiro [4,5] decan-8-yl) piperidin-4yl) -2-fluoro-5-methylphenyl) -5-chloro-N4- (5-methyl1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td></td><td></td>

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<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 284</td><td>٩٢٦ 5-chloro-N2- (4- (1 - ((3-ethyl-1,2,4-oxadiazol-5- yl) methyl) piperidin-4-yl) -2-fluo٢o-5-methylphenyl) - N4 (5-methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine</td><td>MS-ES m / z 526.2 (MtH).</td><td> 0,033</td>

<td> 285</td><td>٩ ه ٦ 5-Chloro-N2- (2-fluoro-4- (1 - ((5٠isopropyl-1,2.4oxadiazol-3-yl) methyl) pipé٢idin-4-yl) -5methylphenyl) -N4- (5-methyl-1H- pyrazol-3y,) pyrimidine-2٠4diamine ١ A</td><td>SM-ES m / z 540.2 (M + H٠).</td><td> 0,068</td>

<td> 286</td><td>٠ ج 5- (5-chloro4- (5-methyl-1H-pyrazol-3- ylamino) pyrimîdin-2-ylamino) -4-methyl-2 - ('l- methytpiperidin-4-yl) benzoçitri1e</td><td>SM-ES m / z 437.2 (Μ + H).</td><td> 0,037</td>

<td> 287</td><td>; ٢ ممعذج Methyl 5- (5-chloro-4- (5-methyl-1 H-py٢azol-3ylamino) pyrimidin-2-ylamino) -4-methyl-2- (1methylpiperidin-4-yl) benzoate</td><td>SM-ES m / z 470.2 (M + H *).</td><td> 0,027</td>

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187

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 288</td><td>٠ ، Γ 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (pyridin-4- ylmethyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 507.2 (M -t- H *).</td><td> 0,093</td>

<td> 289</td><td>V 4- (4- (5-chloro-4- (5-methyl-1 H-pyraz0l-3ylamin0) pyrimidin-2-ylamin0) -5-flu0io-2methylphenyl) -l-ethylpiperidine-1-oxide</td><td>SM-ES m / z 460.2 (M + Η +); H NMR (MeOD-d *) δ 7.91 (s, 1Η), 7.69 (d, 1Η), 7.00 (d, 1Η), 6.1S (s, 1Η). 3.28 (m, 4Η), 2.91 (m, 1Η), 2.32 (m, 2Η), 2.20 (s, 3Η), 2.16 (s, 3Η), 1.83 (s , 2Η), 1.64 (d, 2Η), 1.31 (t, 3Η).</td><td> 0,37</td>

<td> 290</td><td>لأض ع ١ ذ جندم 4- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2- methylphenyl) piperidin-1-yl) cyclohexanone</td><td>SM-ES rn / z512.2 (MH).</td><td> 0,023</td>

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188

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 291</td><td>١ ص 3- (4- (4- (5-chloro4- (5-methyl-1H-pyrazol-3ylamino) pyrimidin-2-yamino) -5-fluoro-2methytphenyl) piperidin-1-yl) pyrrolidine-1carboxylate tert-butyl</td><td>SM-ES m / z 585.3 (M + H⁺).</td><td> 0,067</td>

<td> 292</td><td>جأمإبيفى 5-chlo٢o-N2- (2-fluoro-5-methyl-4- (1 - ((5-methyl1,2,4-oxadiazol-3-yl) methyl) piperidin-4-yl) phenyl) N4- (5 -methyl-1 H-pyrazo! -3-yl) pyrimidin-2,4diamine</td><td>SM-ES m / z 512.2 (M + H).</td><td> 0,023</td>

<td> 293</td><td>5-chloro-N2- (2-fluoro-5-methyl-4- (1 - ((3-methyl- 1,2,4-oxadiazol-5-yl) methyl) pipé٢idin-4-yl) phenyl) - N4- (5-methyl-1H-pyrazol-3-yl) pyrimidin-2,4- diamine</td><td>SM-ES rn / z512.2 (M + H٠).</td><td> 0,026</td>

189

2&gt; 24٩7Β٩

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 294</td><td>مح كل عج 4 (4- (5-chloro-4 (5-methyl-1 H-pyrazol-3_ ylamin0) pyrimidin-2-ylamina) -5-flu0r0-2methylphenyl) -1- (tetrahydro-2H-py٢an-4yl) pÎperidin- 1-0xyde</td><td>SM-ES rn / z516.2 (M + H٠).</td><td> 0,064</td>

<td> 295</td><td>ي 5-chloro-N2- [4- [1- (1,1-dioxo-1٨®-thietan-3-yl) -1- oxid (3-piperidin ^ -M] -2-fluoro-5-methylphenylJ-fJ4- (5-ethyl-1H-pyrazol٠3٠yl) -pyrimidine٠2&gt; 4-dîamine</td><td>SM-ES m / z 536.2 (M + H٠),</td><td> 0,039</td>

<td> 296</td><td>V N2- (4- (1- (azetidin-3-yl) piperidin-4-yl) -2-fluoro-5- methylphenyl) -5-chloro-N4- (5-methyl-1H-pyrazol-3- yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 471.2 (M + H).</td><td> 0,101</td>

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190

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 297</td><td>اتيؤ- 5-chloro-N2٠ (2-fluoro-5-methyl-4- (1- (pyridin-3- ylmethyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 507.2 (M + H).</td><td> 0,079</td>

<td> 298</td><td>عم ج ٦ ذ به ٠. 4- (4- (4- (5-chloro4- (5-methyl-1 H-py٢azol-3ylamin0) pyrimidin-2-ylamin0) -5-flu0r0-2methylphenyl) piperidin-1-yl) cyclohexanol</td><td>SM-ES m / z 514.2 (M + H).</td><td> 0,026</td>

<td> 299</td><td>V 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (pyr٢olidin-3- yl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H-pyrazol- 3-yl) py٢imidin-2,4-diamine</td><td>SM-ES m / z 485.2 (M + H).</td><td> 0,101</td>

را

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191

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td></td><td> ٩</td><td>SM-ES m / z 549.2 (M + H).</td><td> 0,032</td>

<td> 300</td><td> ٦</td><td></td><td></td>

<td></td><td>5-Chloro-N2- (2-Fluoro-5-methyl-4- (1- (1- (methylsulfonyl) azetiin-3-yl) piperidin-4-yl) phenyl) - N4- (5-methyt-1H-pyazol-3-yl) pyrimidin-2,4- diamine</td><td></td><td></td>

<td></td><td></td><td>MS-ES m / z 563.2 (MH).</td><td> 0,038</td>

<td> 301</td><td> /</td><td></td><td></td>

<td></td><td>٥٢o 5-Chloro-N2- (2-fluoro-5-methyl-4- (1- (1 (methylsulfonyl) pyrrolidin-3-yl) piperidin-4yl) phenyl) -N4- (5-methyl-1 H٠py٢azo (-3٠ yl) pyrimidin-2,4-diamine</td><td></td><td></td>

<td> 302</td><td>املآ</td><td>SM-ES m / z 508.2 (M + H).</td><td> 0,006</td>

<td></td><td>5-chloro-N2- (2,5-dimethyl-4- (1 - ((3-methyl-1,2,4- oxadiazol-5-yl) methyl) piperidin-4-yl) phenyl) -N4- (5- methyl-1H-pyrazol-3-yl) pyrimidin-2,4-diamine</td><td></td><td></td>

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192

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 303</td><td>م ٩ 5-chloro-N2- (4- (1 - ((3-ethyl-1_&gt;2,4-oxadiazol٠5- yl) methyl) piperidin-4-yl) -2,5-dimethylphenyt) -N4- (5- methyl-1H-pyrazo3 - ؛ - yl) pyrimidin-2,4-dianiine</td><td>SM-ES m / z 522.2 (M + H).</td><td> 0,006</td>

<td> 304</td><td>r 5-Chloro-N2- (2,5-dimethyl-4- (1 - ((5-methyl-1,2,4oxadiazol-3-yl) methyl) piperidin-4-yl) phenyl) -N4- (5methyl- 1H-pyrazol3yl) py٢imidine-2,4diamine</td><td>SM-ES m / z 508.2 (M + H).</td><td> 0,005</td>

<td> 305</td><td>5-Chloro-N2- (4- (1 - ((5-isop٢opyl-1,2,4-oxadiazol-3yl) methyl) pipé٢idin-4-yl) ٠2,5-dimethylphenyl) -N4- (5methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 536.3 (M + H٠).</td><td> 0,025</td>

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193

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 306</td><td>/ ١٦٠٢ ' 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (oxetan-3- yl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H-pyrazol- 3-yl) pyrimidin-2,4-d ؛ amine</td><td>SM-ES m / z472.2 (M + H٠).</td><td> 0,015</td>

<td> 307</td><td>V 5-Chloro-N2- (2,5-dimethyt-4- (1- (py٢idin-2ylmethyl) piperidin-4-yl) phenyQ-N4- (5-methyl-1 Hpyrazol-3-yt) pyrimidin-2,4diamine</td><td>SM-ES m / z 503.2 (M + H).</td><td> 0,007</td>

<td> 308</td><td>١٢٢٠٦٠ 5-chloro-N2- (2,5-dimethyl-4- (1- (pyridin-3- ylmethyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 503.2 (Μ -1- H *).</td><td> 0,006</td>

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194

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 309</td><td>٠١f ؛ 5-chloro-N2- (2,5-dimethyt-4- (1- (pyridin-4- ylmethyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 503.2 (M + H٦</td><td> 0,008</td>

<td> 310</td><td>Ία ، T rans-4- (4- (4- (5-chloro-4- (5-methyl-1 H-pyraz٥l-3ylamin0) pyrimidin-2-ylamino) -5-flu0r0-2methylphenyl) piperidin-1-y٠) cyclohexanol</td><td>SM-ES rn / z514.2 (M + H).</td><td> 0,027</td>

<td> 311</td><td>٠ مهس Cis-4- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3- ylamin0) pyr ، midin-2-ylamin0) ٠5-flu0ro2- methylphenyl) pipé٢idin-1-yl) cyclohexanol</td><td>SM-ES m / z 514.2 (M + H).</td><td> 0,021</td>

<td> 312</td><td>٨ (R) -5-chloro-N2- (2-fluoro-5-methyl-4- (1- (1 (methylsulfonyl) pyrrolidin-3-yl) piperidin-4yl) phenyl) -N4- (5-methyl-1H -pyrazol-3yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 563.2 (M + H٠).</td><td> 0,025</td>

ν, Α 32497Β1

195

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 IC50 (uM)</td>

<td> 313</td><td>جه ص (S) -5-chloro-N2- (2-fluoro-5-metl١yl-4- (1- (1- (methylsulfonyl) pyrrolidin-3-yl) piperidin-4- yl) phenyl) -N4- (5-methyl-1H-pyrazol-3- yl) pyrimidine-2,4-d amine</td><td>SM-ES m / z 563.2 (M + H٠).</td><td> 0,030</td>

<td> 314</td><td>م ا 5-chlo٢o-N2- (2-fluoro-5-methyl4- (1- (pyrimidin-5ylmethyl) piperidin-4-yl) phenyl) N4- (5-methyl-1 Hpyrazol-3-yl) pyrimidin-2,4 -diamine</td><td>MS-ES m / z 508.2 (M + H '); NMR ¹H (400 MHz, CDaOD) δ 9.09 (s, IH), 8.81 (s, 2Η), 8.00 (5, IH), 7.73 (d, 8.4 = ل Hz, IH) , 6.99 (d, 13.2 = ر Hz, 1H), 6.23 (br s, IH), 3.65 (s, 2Η), 3.03 (m, 2Η), 2.76 (m , 1H), 2.27 (s, 3Η), 2.25 (s, 3Η), 2.25 (m, 2Η), 1.80-1.68 (m, 4Η).</td><td> 0,037</td>

<td> 315</td><td>5-chloro-N2- (2-fluoro-5-methyl-4- (1- (pyrazin-2- ylmethyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H- py٢azol-3-yl) pyrimîdîne-2,4-diamine</td><td>SM-ES m / z 508.2 (M + H).</td><td> 0,036</td>

سر

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196

<td></td><td>STRUCTURE</td><td>NMR or SM-ES</td><td>IGF-1R Ba / F3 1C5O (uM)</td>

<td> 316</td><td>5-chloro-N2- (2-fluoro-5-methyl-4- (1- (pyridazin4 ylmethyl) piperidin٠4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 508.2 (M + H ').</td><td> 0,027</td>

<td> 317</td><td>5-chloro-N2- (2,5-dimethyl-4- (1- (pyrimidÎn-5- ytmethyl) piperidin-4-yl) phenyt) -N4- (5-methyl-1H- pyrazol-3-yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 504.2 (M + H).</td><td> 0,004</td>

<td> 318</td><td>مأب 5-chloro-N2- (2,5-dimethyl-4- (1- (pyrazin-2- ylmethyl) piperidin-4-yl) phenyl) -N4- (5-methyl-1H- pyrazol-3٠yl) pyrimidin-2,4-diamine</td><td>SM-ES m / z 504.2 (M + H).</td><td> 0,010</td>

ا

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197

Testing

The Co of a drug is calculated by plotting a dose-response curve from which the effect of the antagonist at varying concentrations on the activity of the inverse agonist is evaluated. To determine the IC50 values ​​of a given antagonist, the concentration required to inhibit half of the maximum biological response of the agonist is calculated. IC50 values ​​are obtained from a set of dose-response data (eg. e.g., drug concentrations denoted xi, x2, .... xn, and growth inhibition represented by yl, y2, ..., yn, respectively, with y values ​​ranging from 0 to 1). These values ​​can be calculated using a computerized system by applying the formula:

y = Dq (AD) / (1 + 1Ο (* Ι٠9 (Ι٠5٥) Β) where A denotes the growth inhibition ratio between the minimum drug concentration and the control: B the slope of the sigmoidal curve I: and D the growth inhibition ratio between the maximum drug concentration and the control.

The value of the IC50 is such that the concentration of the test compound inducing the inhibition of growth is less than half that obtained with the control in the absence of the inhibitor. The compounds of the invention existing in free form or in the form of a pharmaceutically acceptable salt can exhibit important pharmacological properties, for example those indicated in the in vitro tests described in the present application. In general, the values ​​of the IC50 of the compounds of the invention are between 1 nM and 10 μΜ. In some examples, the IC50 values ​​of the compounds of the invention are between 0.01 μΜ and 5 pM. In other examples, the IC50 values ​​of the compounds of the invention are between 0.01 pM and 1 pM, or more particularly between 1 nM and 1 pM. In still other examples, the IC50 values ​​of the compounds of the invention are less than 1 nM or greater than 10 pM. The percent inhibition of the compounds of the invention may exceed 5O٠ / o, or, in other embodiments, may exceed 70٠/٠ against IGF-1R aiOpM.

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198

Range of Ba / F3 cell lines and reagents

Ba / F3 is a murine IL-3 dependent pro-Β lymphoma cell line. The parental Ba / F3 cells are used to generate a range of sublines whose proliferation and survival are made independent of IL-3 by stable transduction with individual tyrosine kinases activated by fusion with the amino-terminal part of TEL. (amino acids 1-375) or BCR. To generate Ba / F3 cell lines transformed with 1-7yrOSin Kinase (TK) fusions, the parental Ba / F3 cells are infected with retrovirus harboring each TEL fusion kinase and subjected to puromycin selection and suppression. IL-3 to obtain transformed Ba / F3 cells independent thereof.

Each transformed Ba / F3 cell is cultured in RPMI1640 medium (Gibco Cat # 11875093, Carlsbad. CA) supplemented with 10% FBS (Hyclone Cat # SV3OO14.O3. Logan, UT), 4.5 g / l glucose (Sigma # G54OO. St. Louis, MO), 1.5 g / l sodium bicarbonate (Biowhittaker # 17-613Ε, Walkersville. MD) and Pen / Strep (Gibco # 10378-016, Carlsbad, CA ). The cells are divided twice a week.

Ba / F3 Cell Viability Inhibition Assay

The dose of test compounds against various Ba / F3 lines transformed with 1TK is determined as follows. Exponentially growing BaF3 ITK cells are diluted in fresh medium at a rate of 75,000 cells / mL and seeded in 384-well plates (3,750 cells / well) at 50 μΙ / well using a reagent dispenser. pFill (Biok, Winooski, VT, USA). Double plates are provided for each cell line. Test compounds and control compounds are successively diluted in DMSO and placed in a 384-well polypropylene plate. 50 µl was transferred to the assay plates using transfer needles, then the plates were incubated at 37٠c (5% O) for 48 hours. Then 25μΙ of Britelite (Perkin Elmer) is added, and the luminescence is quantified with a GT Analyst (Molecular Devices). Specific analytical adjustment software is used to correct cell viability (expressed as a percentage) for the logarithm of the concentration of the inhibitor. We deduce by interpolation the value of the IC50, COrreSDOndant at the nnnnantratinn do pnmr١ft٠٥ nipapppim -AJ ..: - د- rnη / IΜΑ 32497Β1

199 cell viability of a DMSO control. The parental Ba / F3 cells which are preserved and cultured in the presence of III-3 (final concentration: 1 ng / ml) are diluted in a fresh medium containing ΙΊΙ-3 (final concentration: 1 ng / ml) to obtain a maximum concentration of 75,000 cells / ml using the same procedure as previously described.

Enzymatic HTRF assay

IGF-1R and INSR (insulin receptor) are purchased from Upstate. The following reagents are prepared in-house: 10 X Buffer Kinase (KB) (200 mM Tris (pH 7.0), 100 mM MgC, 30 mM MnClz, 50 nM NaV٠4), 10 mM ATP, 100 mg / ml BSA, EDTA 0.5 M, KF 4 M. A PerkinElmer Proxip) ate-384 was used in the test.

All HTRF reagents including the substrate (Biotin-poly-GF (61GT0BLB), Mab ΡΤ66-Κ, (61T66KLB), Streptavidin-XL® '(611SAXLB)) were purchased from CIS-US, Inc.

The substrate / ΑΤΡ mixture is prepared by adding ΙΆΤΡ (final concentration: 3 μΜ) and biotinyl poly-GT (final concentration: IOng / μΙ) in 1 X KB, and distributed in the Proxip! Ate-384 at the rate of 5 μΙ / well using pFill (Bio-TEK). The compounds, successively diluted in DMSO, are transferred to a plate with a 50 µl needle head. With pFill (Bio-ΤΕΚ), 5 μΙ of the enzymatic mixture prepared (enzyme [at the final concentration of 5 ng / μΙ] mixed with ABS and DTT in 1 X KB) is added to trigger the kinase reaction. The test plates are incubated at room temperature for 2 hours. The detection mixture is prepared by adding Mab ΡΤ66-Κ and Streptavidin-XL® 'in 0.5 X KB solution containing KF (final concentration: 125 mM), EDTA (final concentration: 50 mM) and ABS (final concentration: 100 µg / ml). At the end of the reaction, 10 µl of detection mixture is added and incubated for 30 minutes at room temperature before starting the measurements. The HTRF signal is detected using a GF (Molecular Devices) Analyst.

Cancer cell proliferation inhibition assay

To luciferize the cancer cell line, this cell line is

ΜΑ 32497Β1

200 transduced by an ampholytic etrovirus simultaneously carrying the luciferase gene and the puromycin resistant gene, the expression of which is derived from the LTR. The etroviral vector pMSCV-Puro-Luc is transfected into the Phoenix cell line using the Fugenee (Roche) following the manufacturer's instructions. Two days after transfection, the supernatant containing the virus is harvested and filtered through a 0.2 µm filter. The harvested virus is immediately used or stored at -8O٠C. To achieve infection, the cultured cancer cells are harvested and seeded (5 × 10 ج cells / well in 1 ml medium) on a 6-well culture plate. For each well, 3 ml of viral supernatant is added to 400 µl of SBF, 40 µl of 1 M HEPES (pH 8.0) and 4 µl polybene (10 µg / ml, Specialty medium). The plate is centrifuged for 90 minutes at 2500 rpm and transferred to an incubator overnight to effect infection. The next day, the infected cell line is transferred to a ٢-75 flask containing fresh medium and incubated for one day. Two days after infection, puromycin at the final concentration of 1 µg / ml is added to begin selection. Within one or two weeks, the puromycin resistant cell line is created after at least two successive fractionations, and stored to constitute a lucifee stock.

Each cell line is harvested during exponential pliasis by trypsinization and diluted in a suitable medium at an appropriate density before being inoculated. The cells are distributed with pFill (BioTK) in the white-coated plates with a transparent bottom (Greiner - special GNF) at a rate of 50 μl / well. They are then placed in an incubator (37٠c. 5% O) overnight. The compounds are transferred with a Pintool 50 µl / well via Platemate (Matrix), then the test plates returned to the incubator for 3 days. On the third day following the transfer of the compounds, BRITELITE® (Perkin El mer, diluted according to the manufacturer's recommendations) is added to the test plates, before the values ​​indicated by the GT Analyst (Molecular Devices) or the Envision system (Perkin Elmer). The raw data is produced by the RLU.

Tumor activity of exemplary compounds

Fresh 4 X 10® SK-N-MC human neuroblastoma cells were placed in the HR.؟.؟ Pt mplannppp ة from matrinpl to ٩Ω% nnt pfp iniprtppc

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201 subcutaneously (0.05 ml / mouse) to nude female mice (HsdNpa: athymic / nu) aged 10-12 weeks. Treatments were started when the tumor reached an average volume of 150-200 mm3. Body weight and tumor volume were recorded three times per week. The tumor volume was measured with a caliper to be calibrated and calculated by applying the formula: length X diameter 2 X 71/6. In addition to the fractional changes in tumor volume that occurred during treatment, the antitumor activity was expressed as% T7C (mean change in tumor volume in treated animals / mean tumor volume in control animals) x 100. The efficacy of the control compounds was evaluated by performing an oral dosage on the 1st day following the cell injection, after having carried out a random distribution of the mice intended to guarantee a similar average tumor volume in each group. The dosage was continued for 7 days, respecting a suitable schedule and taking into account the health of the animals. All test compounds were formulated in NMP / PEG300 (10:90) and administered daily by gavage. The vehicle consisted of NMP / PEG300 (10:90). The volume administered has always been equal to 5 ml / kg. The activity of the exemplary compounds of the invention on tumor growth is shown in Tables 2 to 4.

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Table 2

Tumor response

<td>Treatment</td><td>٦IC (%)</td><td>Reg. (%)</td><td>Δ Tumor volume (mean mm٥ ± SEM)</td><td>Coefficient of variation tumor growth</td>

<td>NMP / PEG300 (10/90) 5 ml / kg po q8 / 16h</td><td> 100</td><td> 0</td><td> 334 ±59</td><td> 3,1 ±0,3</td>

<td>Test compound 1 20 mg / kg, q8 / 16h, po</td><td> 53</td><td></td><td> 231±145</td><td> 2,1 ±0,4</td>

<td>Test compound 1 40 mg / kg, ٩8 / 16h. po</td><td> 35</td><td></td><td> 107 ±48*</td><td> 1,7 ±0,2*</td>

<td colspan="5">Table 3</td>

<td colspan="5">Tumor response</td>

<td></td><td rowspan="2">٢ / C (٠/٠)</td><td rowspan="2">Reg. (%)</td><td>Δ Volume</td><td>Coefficient of variation</td>

<td>Treatment</td><td>tumor (mm ^ mean ± SEM)</td><td>tumor growth</td>

<td>NMP / PEG300 (10190)</td><td rowspan="2"> 100</td><td rowspan="2"> 0</td><td rowspan="2"> 334 ±59</td><td rowspan="2"> 3,1 ±0,3</td>

<td>5 ml / kg po q8 / 16h</td>

<td>Test compound 2 12.5 mg / kg, q8 / 16h, po</td><td> 69</td><td></td><td> 232±103</td><td> 2,5 ±0,4</td>

<td>Test compound 2 25 mg / kg, q8 / 16h, po</td><td> 22</td><td></td><td> 42 ±10*</td><td> 1,5 ±0,2*</td>

Table 4

<td colspan="5">Tumor response</td>

<td>Treatment</td><td>T / C (%)</td><td>Reg. (%)</td><td>Δ Tumor volume (mean mm٥ ± SEM)</td><td>Coefficient of variation of tumor growth</td>

<td>NMP / PEG300 (10/90) 5 ml / kg po q8 / 16h</td><td> 100</td><td> 0</td><td> 334 ±59</td><td> 3,1 ±0,3</td>

<td>Test compound 3 12.5 mg / kg, q8 / 16h, po</td><td> 58</td><td></td><td> 220±67</td><td> 2,2 ±0,3</td>

<td>Test compound 3 25 mg / kg, q8 / 16h, po</td><td> 26</td><td></td><td> 102 ±40*</td><td> 1,6 ±0,3*</td>

* p &lt;0.05 compared to control vehicles - ANOVA by row and Dunnett test.

It is understood that the examples and embodiments described in this document are given exclusively for the purposes of illustration and that consequently, the modifications or variations whatever they may be.

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203 suggested to those skilled in the art are included within the spirit and scope of the present application and within the scope of the appended claims. All publications, patents and patent applications cited in this document are incorporated herein by reference for all purposes.