Untitled record

Descriptive memory

Technical Field

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

Background Technique

Insulin-like growth factor (IGF-1) signaling is highly implicated in cancer, with the IGF-1 receptor (IGF-1 R) as the predominant factor. IGR-1R is important for tumor transformation and survival of malignant cells, but is only partially involved in the growth of normal cells. It has been suggested that the direction to IGF1R is a promising option for cancer therapy. (Larsson et al., Br. J. Cancer 92: 2097-2101 (2005)).

Anaplastic lymphoma kinase (ALK), a member of the super family of insulin receptors of receptor tyrosine kinases, has been implicated in oncogenesis in hematopoietic and nonhematopoietic tumors. Aberrant expression of full-length ALK receptor proteins has been reported in neuroblastomas and glioblastomas; and ALK fusion proteins have been presented in anaplastic macrocellular lymphoma. The study of ALK fusion proteins has also presented the possibility of new therapeutic treatments for patients with ALK positive malignancies. (Pulford et al., Cell. Mol. Life Sci. 61: 2939-2953 (2004)).

Due to the disease-related roles that are emerging from IGF-1R and ALK, there is a continuing need for compounds that may be useful for the treatment and prevention of a disease that responds to the inhibition of IGF-1R and ALK.

Description of the Invention

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

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

<img file="CU23952B1_D0001.tif" />

or a physiologically acceptable salt thereof;

wherein ring E may optionally contain a double bond;

one of Z¹, Z² and Z³ it's NR⁶, N (R⁶)⁺-O 'or S (O)_V2 and the others are

CR₂;

R¹ it is halogen or an alkyl of 1 to 6 optionally halogenated carbon atoms;

R² it is pyridin-2-onyl, azepan-2-onyl or a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, O and S; each of which is optionally substituted with R^s where R⁹ it is alkyl of 1 to 6 carbon atoms, halo-alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms;

R³ and R⁴ they are each H;

R⁵ it is halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkoxy of 1 to 6 carbon atoms substituted by halogen, cyano or C (O) OR₀-to go⁸;

R⁶ it's H; alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen and / or hydroxyl groups; - (CR2) P-OR⁷, - (CR2)_p-CH (OH) C_tF_{2t +}i where t is 1 to 3, (CR₂)_P-CN; (CR₂)_P-NR (R⁷), - (CR₂)_P-C (O) OR⁷, (CR₂)_PNR (CR₂)_POR⁷, (CR2) pNR-LC (O) R⁸, C (O) - (CR2)_thatOR⁸, -C (O) O (CR2) p-NRR⁷, -C (O) - (CR2)_p-OR⁷, LY, -LC (O) R⁷, -LC (O) -NRR⁷, -lC (O) -NR- (CR2) p-NRR⁷, -LC (O) NR (CR2)_pOR⁷, -LC (O) - (CR2) q-NRC (O) -R⁸, -LC (O) NR (CR2)_PMR⁷, -LC / OjNRÍCRJpSÍOb ^ R⁸, -LS (O) 2R⁸, -LS (O) 2- (CR₂)_that-NRR⁷, -LS (O)₂NR (CR₂)_PNR (R⁷) or -L4

SW)₂NR (CR₂)_POR⁷;

in an alternative way, R⁶ it is a radical selected from the formula (a), (b), (c) or (d):

<img file="CU23952B1_D0002.tif" />

<img file="CU23952B1_D0003.tif" />

_R11 _R12 r15 / AR¹³ R¹⁴oo (d)

R¹⁰ is O, S, NR¹⁷ where R¹⁷ is H, alkyl of 1 to 6 carbon atoms, SO2R^8a or CO2R^8a;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently selected from H; alkoxy of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, amino, or hydroxyl groups; or R¹¹ and R¹², R¹² and R¹⁵, R¹⁵ and R¹⁶, R¹³ and R¹⁴, or R¹³ and R¹⁵, together with the atoms with which they are attached, can form a 3 to 7-membered, saturated, unsaturated, or partially unsaturated ring containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and 1 to 3 R groups⁵;

L is (CR₂) i-4 or a link;

Y is a carbocyclic ring of 3 to 7 carbon atoms, aryl of 10 carbon atoms, or a 5-10 membered heteroaryl or 4 to 10 membered heterocyclic ring, each of which is optionally substituted with 1 to 3 R groups⁵;

R⁷, R⁸ and R^Sa they are independently alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, amino, hydroxyl or cyano; (CR₂)_thatY or alkoxy of 1 to 6 carbon atoms; or R⁷ it's H;

each R is independently H or alkyl of 1 to 6 carbon atoms;

R and R⁷ along with N in each NRR⁷ they can form a 5 to 6 member ring containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and 1 to 3 R groups⁵;

m is from 2 to 4;

n is 1 to 3; p is 1 to 4; and q is from 0 to 4.

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

<img file="CU23952B1_D0004.tif" />

where one of R^5th, R^5b and R^5c is H, and the others are independently halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, cyano or C (O) O₀-to go⁸ where R⁸ it is alkyl of 1 to 6 carbon atoms; and

R¹, R², R³, R⁴, E, Ζ¹, Z² and Z³ they are as defined in formula (1).

In some examples, Z³ in formula (2) above is NR⁶ or N (R^S)⁺-OR'; and Z¹ and Z² They are CH2. In other examples, R⁶ is H, alkyl of 1 to 6 carbon atoms optionally substituted with halogen and / or hydroxyl groups; - (CR2)_P-OR⁷, - (CR2) p-CH (OH) C, F2t + 1 where t is 1 to 3, LY, (CR2) P-CN; (CR2) P-NR (R⁷), - (CR2)_P-C (O) OR⁷, C (O) - (CR2) qOR⁸, -C (O) O- (CR2)_p-NRR⁷, -LC (O) R⁷, -LC (O) -NRR⁷, -LC (O) -NR- (CR2) p-NRR⁷, -LC (O) - (CR2)_that-NR-C (O) -R⁸, -LS (O) 2R⁸, -LS (O) 2- (CR₂)_that-NRR⁷, or a radical selected from the formula (a), (b), (c) or (d):

<img file="CU23952B1_D0005.tif" />

1-2 oW (a)

<img file="CU23952B1_D0006.tif" />

1-2

R¹³ R¹⁴(b)

<img file="CU23952B1_D0007.tif" />

R¹⁰ is O, S, NR¹⁷ where R¹⁷ is H, alkyl of 1 to 6 carbon atoms, SO2R^8a or CO2R^8a;

R^8a it is alkyl of 1 to 6 carbon atoms; and

<img file="CU23952B1_D0008.tif" />

They are defined in formula (1).

In formulas (1) and (2) above, R² it can be pyrazolyl, isoxazolyl, pi ri d ¡η-2-οη i I oo azepan-2-one, each of which is substituted with alkyl of 1 to 6 carbon atoms, halo-alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms.

In another embodiment, the invention provides a compound of the formula (3):

<img file="CU23952B1_D0009.tif" />

or a tautomer thereof;

where R^5b it's H; and R^5th and R^5c they are independently halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, cyano or C (O) O₀.to go⁸ where R⁸ it is alkyl of 1 to 6 carbon atoms;

Z¹ and Z² they are CH²;

Z³ it's NR⁶ or N (R⁶) ⁺ -OR;

R⁶ is H, alkyl of 1 to 6 carbon atoms optionally substituted with halogen and / or hydroxyl groups;

- (CR₂)_p-OR⁷, - (CR2) p-CH (OH) CtF2t + 1 where t is 1 to 3, (CR2) P-CN; (CR2) p-NR (R⁷), - (CR2)_p-C (O) OR⁷, C (O) - (CR₂)_thatOR⁸,

-C (O) O- (CR₂)_P-NRR⁷, LY, -LC (O) R⁷, -LC (O) -NRR⁷, -LC (O) -NR (CR2) p-NRR⁷, -L — C (O) - (CR2)_that-NR-C (O) -R⁸, -LS (O) 2R⁸, -LS (O) 2 (CR₂)_that-NRR⁷, or a radical selected from the formula (a), (b), (c) or (d):

<img file="CU23952B1_D0010.tif" />

R¹¹ R¹² R¹⁵ W i-2 _r^-^Re &gt; f °² fl R¹³ R¹⁴ ' ^Λ

O (b) (c) / 4 oo

R¹,¹_r12 R15

<img file="CU23952B1_D0011.tif" />

NR

0-1

R¹³ R¹⁴ (d)

R¹⁰ is O, S, NR¹⁷ where R¹⁷ is H, alkyl of 1 to 6 carbon atoms, SO2R^8a or CO2R^8a;

R^8a it is alkyl of 1 to 6 carbon atoms; and

R¹, R³, R⁴, R⁷, R®, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R, L, Y, p, q and E are as defined in formula (1).

In the formula (3) above, R^5th can be halogen and R^5c it is alkyl of 1 to 6 carbon atoms. In some examples, R⁶ is alkyl of 1 to 6 carbon atoms, or a radical of the formula (a) or

<td>(c); and R¹⁰</td><td>that</td><td></td><td></td><td></td>

<td>In</td><td>the</td><td>formulas (1),</td><td>(2), and (3) above</td><td>, R¹ can be</td>

<td>halogen</td><td>In</td><td>the examples</td><td>individuals, R¹ is</td><td>chlorine. In others</td>

<td>examples,</td><td>R³ and</td><td>R⁴ they are H.</td><td></td><td></td>

<td>In</td><td>other</td><td>appearance, the</td><td>present invention</td><td>provide a</td>

compound of the formula (4):

<img file="CU23952B1_D0012.tif" />

or a physiologically acceptable salt thereof;

wherein X is a 5- to 6-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted on an oxo-replaceable ring carbon atom and on any nitrogen atom of the ring replaceable by R⁶;

R¹ it is halogen;

R³ and R⁴ they are each H;

R⁵ it is halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkoxy of 1 to 6 carbon atoms substituted by halogen, cyano or C (O) OR₀-to go⁸;

R⁶ it's H; alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen and / or hydroxyl groups; - (CR₂)_P-OR⁷, - (CR2) p-CH (OH) CtF2t + 1 where t is 1 to 3, (CR2) P-CN; (CR2) P-NR (R⁷), - (CR2)_P-C (O) OR⁷, (CR₂)_PNR (CR₂)_POR⁷, - (CR2) PNR-LC (O) R⁸, C (O) - (CR2)_thatOR⁸, -C (O) O (CR2) p-NRR⁷, -C (O) - (CR2)_p-OR⁷, LY, -LC (O) R⁷, -LC (O) -NRR⁷, -LC (O) -NR- (CR2) p-NRR⁷, -LC (O) NR (CR2)_POR⁷, -LC (O) - (CR2) qN RC (O) -R⁸, -LC (O) NR (CR2)_PMR⁷, -LC (O) NR (CR2) pS (O) 1.2R⁸, -LS (O) 2R⁸, -LS (O) 2- (CR2) q-NRR⁷, -LS (O) 2N R (CR₂)_pNR (R⁷) or -LS (O)₂NR (CR₂)_POR⁷;

in an alternative way, R⁶ it is a radical selected from the formula (a), (b), (c) or (d):

<img file="CU23952B1_D0013.tif" />

R¹³ R¹⁴(b)

<img file="CU23952B1_D0014.tif" />

r!¹ r¹² R¹⁵

<img file="CU23952B1_D0015.tif" />

1-2

OR

R¹⁰ is O, S, NR¹⁷ where R¹⁷ is H, alkyl of 1 to 6 carbon atoms, SO₂R^8a or CO₂R^8a;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently selected from H; alkoxy of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, aml, or hydroxyl groups; or R¹¹ and R¹², R¹² and R¹⁵, R¹⁵ and R¹⁶, R¹³ and R¹⁴, or R¹³ and R¹⁵, together with the atoms with which they are attached, can form a 3- to 7-membered, saturated, unsaturated, or partially unsaturated ring containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and 1 to 3 R groups⁵;

L is (CR₂) '- 4 or a link;

Y is a carbocyclic ring of 3 to 7 carbon atoms, aryl of 10 carbon atoms, or a 5-10 membered heteroaryl or 4 to 10 membered heterocyclic ring, each of which is optionally substituted with 1 to 3 R groups⁵;

R⁷, R⁸ and R^8a they are independently alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, amino, hydroxyl or cyano; (CR₂)_thatY or alkoxy of 1 to 6 carbon atoms; or R⁷ it's H;

each R is independently H or alkyl of 1 to 6 carbon atoms;

R and R⁷ along with N in each NRR⁷ they can form a 5 to 6 member ring containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and 1 to 3 R groups⁵;

m is from 2 to 4;

n is 1 to 3;

p is 1 to 4; and q is from 0 to 4.

In the formula (4) above, X may be morpholinyl, piperazinyl, piperazin-2-onyl, oxazolidin-2-onyl or piperidin-2-onyl, each of which is substituted on any nitrogen atom of the alkyl substitutable ring from 1 to 6 carbon atoms; or X is tetrahydro2H-pyran-2-onyl; and R¹ It is chlorine.

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

In yet another aspect, the invention provides methods for inhibiting IGF-1R in a cell, which comprise contacting the cell with an effective amount of a compound having the formula (1), (2), (3), and (4) or a pharmaceutical composition thereof.

The invention also provides methods for treating, ameliorating, or preventing a condition that responds to the inhibition of

IGF-1R or anaplastic lymphoma kinase (ALK) in a mammal suffering from this condition, which comprises administering to the mammal a therapeutically effective amount of a compound having the formula (1), (2), (3), and (4), or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent. Alternatively, the present invention provides the use of a compound having the formula (1), (2), (3), and (4), and optionally in combination with a second therapeutic agent, in the manufacture of a medication for the treatment of a condition mediated by IGF-1R or ALK. The compounds of the invention can be administered, for example, to a mammal suffering from an autoimmune disease, a transplant disease, an infectious disease, or a cell proliferative disorder. In particular examples, the compounds of the invention can be used alone or in combination with a chemotherapeutic agent to treat a cell proliferative disorder, including, but not limited to, multiple myeloma, neuroblastoma, synovial, hepatocellular, Ewing sarcoma, or a solid tumor selected from an osteosarcoma, melanoma, and breast, renal, prostate, colo-rectal, thyroid, ovarian, pancreatic, lung, uterine, or gastrointestinal tumor.

Definitions "Alkyl" refers to a fraction, and as a structural element of other groups, for example halogen substituted alkyl and alkoxy, and may be straight or branched chain. An optionally substituted alkyl, alkenyl or alkynyl, as used herein, may be optionally halogenated (eg, CF₃), or it may have one or more carbon atoms substituted or replaced with a heteroatom, such as NR, O or S (for example, -OCH₂CH₂O-, thioalkyls, thioalkoxy, alkyl amines, etc.).

"Aryl refers to a fused monocyclic or bicyclic aromatic ring containing carbon atoms. "Arylene" means a divalent radical derived from an aryl group. For example, an aryl group may be phenyl, indenyl, n-nyl, naphthyl, or 1,2,3,4-tetrahydro-naphthalenyl, which may be optionally substituted in the ortho, meta, or para position.

"Heteroaryl, as used herein, is as defined for aryl above, wherein one or more of the ring members is a heteroatom. For example, a heteroaryl substituent for use in the compounds of the invention may be a 5 to 10 membered monocyclic or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S. Examples of heteroaryls include, but are not limited to, pyridyl, pyrazinyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzo-plranyl, benzo-tlopiranyl, benzo- [1,3] -doxoxol, imidazolyl, benzo -imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyrazolyl, thienyl, pyrrolyl, isoquinolinyl, purinyl, thiazolyl, tetrazinyl, benzo-thiazolyl, oxadiazolyl, benzoxadiazolyl, etc.

A carbocyclic ring, as used herein, refers to a fused, saturated or partially unsaturated monocyclic, bicyclic, or polycyclic ring containing carbon atoms, which may be optionally substituted, for example, with = O. Examples of the carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.

A heterocyclic ring, as used herein, is as defined for a carbocyclic ring above, wherein one or more ring carbon atoms are a heteroatom. For example, a heterocyclic ring for use in the compounds of the invention may be a 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S, or a combination thereof, such as -S (O) or -S (O)₂-. Examples of the heterocyclic rings include, but are not limited to, azetidinyl, morpholino, pyrrolidinyl, pi rrol id ini l-2-one, piperazinyl, piperidinyl, piperidinilone, 1,4-dioxa-8-aza-spiro- [4.5 ] -dec-8-ilo,

1,2,3,4-tetrahydroquinolinyl, etc. Heterocyclic rings, as used herein, may encompass bicyclic amines and bicyclic diamines.

As used herein, an atom of H in any substituent groups (eg, CH₂), covers all appropriate isotopic variations, for example, H, ²H and ³H.

The term "pharmaceutical combination, as used herein, refers to a product obtained from the mixture or combination of the active ingredients, and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example, a compound of the formula (1), and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, for example, a compound of the formula (1), and a co-agent, are both administered to a patient as separate entities, either concurrently, concurrently, or in sequence, without specific time limits, where this administration provides therapeutically effective levels of the active ingredients in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

"Mammal" refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats , rabbits, etc. In particular examples, the mammal is a human being.

The term "administration" or "administering to the subject the compound" means providing a compound of the invention and pro-drugs thereof to a subject in need of treatment. Administration "in combination with" one or more additional therapeutic agents includes simultaneous (concurrent) administration, and consecutive administration, in any order, and by any route of administration.

An "effective amount" of a compound is an amount sufficient to carry out a specifically mentioned purpose. An "effective amount" can be determined empirically and in a routine manner, in relation to the aforementioned purpose.

The term "therapeutically effective amount" refers to an amount of a compound (for example, an IGF1R antagonist) effective for "treating a disorder mediated by IGF-1R in a subject or in a mammal. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce tumor size; inhibit (that is, slow down to some degree and preferably stop) the infiltration of cancer cells into peripheral organs; inhibit (that is, slow down to some degree and preferably stop) tumor metastasis; inhibit, to some degree, tumor growth; and / or relieve to some degree one or more of the symptoms associated with cancer. See the definition herein of "trying." To the extent that the drug can prevent growth and / or annihilate existing cancer cells, it can be cytostatic and / or cytotoxic.

The term "cancer" refers to the physiological condition in mammals that is typically characterized by unregulated cell growth / proliferation. Examples of cancer include, but are not limited to: carcinoma, lymphoma, blastoma, and leukemia. The most particular examples of cancers include, but are not limited to: chronic lymphocytic leukemia (CLL), lung cancer, including non-microcellular lung cancer (NSCLC), breast, ovarian, cervical, endometrial, prostate, colo-rectal, intestinal carcinoid, bladder, gastric, pancreatic, hepatic (hepatocellular ), hepatoblastoma, esophageal, pulmonary adenocarcinoma, mesothelioma, synovial sarcoma, osteosarcoma, squamous cell carcinoma of the head and neck, juvenile nasopharyngeal angiofibromas, liposarcoma, thyroid, melanoma, basal cell carcinoma (BCC), medulloblastoma, and desmoid.

"Treating or treatment or relief" refers to both therapeutic and prophylactic treatment, or preventive measures, where the object is to prevent or slow down (decrease) the disease or pathological condition or directed disorder. Those who need treatment include those who already have the disorder, as well as those susceptible to having the disorder, or those in whom the disorder should be prevented (prophylaxis). When the IGF-1R mediated disorder is cancer, a subject or mammal is successfully treated or shows a reduced tumor load if, after receiving a therapeutic amount of an IGF-1R antagonist according to the methods of the present invention, the patient shows an observable and / or measurable reduction in, or an absence of, one or more of the following: reduction in the number of cancer cells or absence of cancer cells; reduction in tumor size; inhibition (that is, slowing down to some degree and preferably stopping) the infiltration of cancer cells into the peripheral organs, including the spread of cancer into soft tissue and bone; inhibition (that is, slowing down to some degree and preferably stopping) of tumor metastasis; inhibition, to some extent, of tumor growth; and / or relief to some degree, of one or more of the symptoms associated with the specific cancer; reduced pathology and mortality, and improvement in the quality of life. To the extent that the IGF-1 R antagonist can prevent the growth and / or annihilate existing cancer cells, it can be cytostatic and / or cytotoxic. The reduction of these signs or symptoms can also be felt by the patient.

“Vehicles, as used herein, include pharmaceutically acceptable carriers, excipients, or stabilizers that are not toxic to the cell or mammal that is being exposed to them in the dosages and concentrations employed. Frequently, the physiologically acceptable carrier is an aqueous pH regulating solution. Examples of physiologically acceptable carriers include regulators, such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight polypeptide (of less than about 10 residues); proteins, such as serum albumin, gelatin, or immunoglobulins; h id rof ί I ios polymers, such as polyvinyl pyrrolidone; 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; salt-forming counter-ions, such as sodium; and / or non-ionic 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 alkylating agents, such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonates, such as busulfan, mprosulfan and piposulfan; aziridines, such as benzodopa, carbocuone, meturedopa, and uredopa; ethyleneimines and methyl-melamines, including altretamine, triethylene melamine, triethylene phosphoramide, triethylene tlofosforamlda and trimethylol-melamma; acetogenins (especially bulatacin and bulatacinone); delta-9 tetrahydro-canabinol (dronabinol, MARINOL®); beta-lapacona; lapacol; colquiclnas; betulinic acid; a camptothecin (including synthetic topotecan analogue (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetll-camptothecin, scopolectin, and 9-amino-camptothecin); biostatin; calistatin; CC-1065 (including its synthetic analogs of adozelesin, carzelesin and bizelesin); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (in particular crlptoficlna 1 and cryptoflcina 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictiin; spongistatin; nitrogen mustards, such as chlorambucll, chlornafazine, colophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, novembiquina, phenesterine, prednimustine, trophophamide, uracil mustard; nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enodiine antibiotics (for example, caliqueamycin, especially gammall caliqueamycin and omegall caliqueamycin (see, for example, Agnew, Chem Intl. Ed. Engl., 33: 183-186 (1994)); dynemycin, including dynemycin A; a speramycin; as well as the neocarzinostatin chromophore and the related chromoprotein enodiine antibiotic chromophores), clarichomycins, actinomycin, autramycin, azaserine, bleomycins, cactinomícina, carabicina, caminomycin, carzinophilin, cromomycins, dactinomycin, daunorubic-6-dia-thuborzoic-6 Lnorleucine, ADRIAMYCIN® doxorubicin (including morpholinodoxorubicin, cyano-morpholino-doxorubicin, 2-pyrrolinodoxorubicin and deoxyoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins, such as mitomycin C, mycophenolic acid, nogalamicin, olivomycins, peplomycin, potfiromycin, puromycin, chelamicin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercapto-purine, thiamiprin, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6azauridine, carmofur, cytarabine, dideoxy uridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals, such as amino-glutethimide, mitotane, trilostane; folic acid filler, such as frolinic acid; aceglatone; aldophosphamide glycoside; amino-levulinic acid; eniluracil; amsacrine; bestrabucilo; bisantrene; edatraxate; defofamine; demecolcina; diazicuone; elfomitin; elliptinium acetate; an epothilone; ethoglucida; gallium nitrate; hydroxy urea; lentinano; lonidainin; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerin; pentostatin; fenamet; pyrarubicin; losoxantrone; 2-ethyl hydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oregon); razoxane: rhizoxin; slzofuran; spirogermanium; tenuazonic acid; triazicuone; 2,2 ', 2-trichloro-triethyl-amine; trichothecenes (especially T-2 toxin, verracurin A, roridine A, and anguidine); urethane; vindesine (ELDISINE®, FILDESIN®); dacarbazine;

manomustine; mitobronitol; mitolactol; pipobroman; gacitosina; arabinoside ("Ara-C"); thiotepa; taxoids, for example, TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE^mr without Cremophor, paclitaxel formulation in nanoparticles designed with albumin (American Pharmaceutical Partners, Schaumberg, III), and docetaxel TAXOTERE® (Rhóne-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine (GEMZAR®); 6thioguanine; mercapto purine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine (VELBAN®); platinum;

etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (ONCOVIN®); oxaliplatin; leucovorin; vinorelbine (NAVELBINE®); novantrone; edatrexate; daunomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoro-methyl-ornithine (DMFO); retinoids, such as retinoic acid; Capecitabine (XELODA®); pharmaceutically acceptable salts, acids or derivatives of any of the foregoing; as well as combinations of two or more of the above, such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for the oxaliplatin treatment regimen (ELOXATIN^MR) combined with 5-FU and leucovorin.

Additionally, a "chemotherapeutic agent" may include anti-hormonal agents that act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer, and that are often in the form of a systemic treatment or of the whole body. They can be the hormones themselves. Examples include anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen NOLVADEX®), EVISTA® raloxifene, droloxifene, 4-hydroxy-tamoxifen, trioxyphene, queoxifen, LY117018, onapristone , and toremifene FARESTON®; antiprogesterones; estrogen receptor sub-regulators (ERDs); agents that work to suppress or deactivate the ovaries, for example, leutinizing hormone releasing hormone agonists, such as LUPRON® and ELIGARD®, leuprolide acetate, goserelin acetate, buserelin acetate, and tripterelin; other anti-androgens, such as flutamide, nilutamide and bicalutamide; and aromatase inhibitors that inhibit the aromatase enzyme, which regulates the production of estrogen in the adrenal glands, such as, for example, 4 (5) -imidazoles, amino-glutethimide, megestrol acetate MEGASE®, AROMASIN® exemestane, formestane , fadrozol, RIVISOR® vorozol, FEMARA® letrozole, and ARIMIDEX® anastrozole. In addition, this definition of chemotherapeutic agents includes bisphosphonates, such as clodronate (for example, BONEFOS® or OSTAC®), DIDROCAL® etidronate, NE-58095, ZOMETA® zoledronic acid / / zoledronate, FOSAMAX® alendronate, AREDIA® pamidronate, SKELID® tiludronate, or ACTONEL® risedronate; as well as troxacitabine (a 1,3-dioxolane cytosine nucleoside analog); anti-sense oligonucleotides, particularly those that inhibit gene expression 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 the THERATOPE® vaccine, and gene therapy vaccines, for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase I LURTOTECAN® inhibitor; ABARELIX® rmRH; Lapatinib ditosylate (a small molecule inhibitor of ErbB-2 and EGFR double tyrosine kinase also known as GW572016); and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.

Modes for carrying out the invention

The invention provides novel pyrimidine derivatives and pharmaceutical compositions thereof, and methods for using these compounds.

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

<img file="CU23952B1_D0016.tif" />

or a physiologically acceptable salt thereof;

wherein ring E may optionally contain a double bond;

one of Ζ¹, Z² and Z³ it's NR⁶, N (R⁶)⁺-O 'or 8 (0) 4.2 and the others are

CR₂;

R¹ it is halogen or an alkyl of 1 to 6 optionally halogenated carbon atoms;

R² is pi r id i η-2-οη i I o, azepan-2-onyl or a 5 to 6 membered monocyclic heteroaryl having 1 to 3 heteroatoms selected from N, O and S; each of which is optionally substituted with R⁹ where R⁹ it is alkyl of 1 to 6 carbon atoms, halo-alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms;

R³ and R⁴ they are each H;

R⁵ it is halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkoxy of 1 to 6 carbon atoms substituted by halogen, cyano or C (O) OR₀-to go⁸;

R⁶ it's H; alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen and / or hydroxyl groups; - (CR₂)_P-OR⁷, - (CR2) p-CH (OH) CtF2t + i where t is 1 to 3, (CR2) P-CN; (CR2) P-NR (R⁷), - (CR2)_P-C (O) OR⁷, (CR₂)_PNR (CR₂)_POR⁷, (CR2) PNR-LC (O) R⁸, C (O) - (CR2)_thatOR⁸, -C (O) O (CR2) P-NRR⁷, -C (O) - (CR2)_p-OR⁷, LY, -LC (O) R⁷, -LC (O) -NRR⁷, -LC (O) -NR- (CR2) p-NRR⁷, -LC (O) NR (CR2)_pOR⁷, -LC (O) - (CR2) qN RC (O) -R⁸, -LC (O) NR (CR2)_PMR⁷, -LC (O) NR (CR2) PS (O) 1.2R⁸, -LS (O) 2R⁸, -LS (O) 2- (CR2) q-NRR⁷, -LS (O) 2NR (CR₂)_PNR (R⁷) or -L15 S (O)₂NR (CR₂)_POR⁷;

in an alternative way, R⁶ it is a radical selected from the formula (a), (b), (c) or (d):

<img file="CU23952B1_D0017.tif" />

<img file="CU23952B1_D0018.tif" />

<img file="CU23952B1_D0019.tif" />

<img file="CU23952B1_D0020.tif" />

R¹⁰ is O, S, NR¹⁷ where R¹⁷ is H, 1 carbon alkyl, SO2R^8a or CO2R^8a;

at 6 atoms

R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R^1S are independently selected from H; alkoxy of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, amino, or hydroxyl groups; or R¹¹ and R¹², R¹² and R¹⁵, R¹⁵ and R¹⁶, R¹³ and R¹⁴, or R¹³ and R¹⁵, together with the atoms with which they are attached, can form a 3 to 7-membered ring, saturated, saturated, or partially unsaturated, containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and 1 to 3 R groups⁵;

L is (CR₂)_V4 or a link;

Y is a carbocyclic ring of 3 to 7 carbon atoms, aryl of 10 carbon atoms, or a 5-10 membered heteroaryl or 4 to 10 membered heterocyclic ring, each of which is operationally substituted with 1 to 3 R groups⁵;

R⁷, R⁸ and R^8a they are independently alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, amino, hydroxyl or cyano; (CR₂)_thatY or alkoxy of 1 to 6 carbon atoms; or R⁷ it's H;

each R is independently H or alkyl of 1 to 6 carbon atoms;

R and R⁷ along with N in each NRR⁷ they can form a 5 to 6 member ring containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and 1 to 3 R groups⁵;

m is from 2 to 4;

n is 1 to 3;

p is 1 to 4; and q is from 0 to 4.

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

<img file="CU23952B1_D0021.tif" />

where one of R^5th, R^5b and R^5c is H, and the others are independently halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, cyano or C (O) O₀-to go⁸ where R⁸ it is alkyl of 1 to 6 carbon atoms; and

R¹, R², R³, R⁴, E, Z¹, Z² and Z³ they are as defined in formula (1).

In another embodiment, the invention provides a compound of the formula (3):

<img file="CU23952B1_D0022.tif" />

or a tautomer thereof;

where R^5b it's H; and R^5th and R^5c they are independently halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, cyano or C (O) O₀-to go⁸ where R⁸ it is alkyl of 1 to 6 carbon atoms;

Z¹ and Z² they are CH²;

Z³ it's NR⁶ or N (R^and)⁺-OR';

R⁶ is H, alkyl of 1 to 6 carbon atoms optionally substituted with halogen and / or hydroxyl groups; - (CR2) P-OR⁷, - (CR2)_PCH (OH) C_tF_{2t +}i where t is 1 to 3, (CR₂)_P-CN; (CR₂)_P-NR (R⁷), - (CR₂)_p-C (O) OR⁷, C (O) - (CR2) qOR⁸, -C (O) O- (CR2)_P-NRR⁷, LY, -LC (O) R⁷, -LC (O) -NRR⁷, -LC (O) -NR- (CR₂)_P-NRR⁷, -LC (O) - (CR₂)_thatNR-C (O) -R⁸, -LS (O) 2R⁸, -LS (O) 2- (CR₂)_that-NRR⁷, or a radical selected from the formula (a ), (b), (c) or (d):

<img file="CU23952B1_D0023.tif" />

<img file="CU23952B1_D0024.tif" />

<img file="CU23952B1_D0025.tif" />

<img file="CU23952B1_D0026.tif" />

R¹⁰ is O, S, NR¹⁷ where R¹⁷ is H, alkyl of 1 to 6 carbon atoms, SO2R^8a or CO2R^8a;

R^8a it is alkyl of 1 to 6 carbon atoms; and

R¹, R³, R⁴, R⁷, R⁸, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R, L, Y, p, q and E are as defined in formula (1).

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

<img file="CU23952B1_D0027.tif" />

or a physiologically acceptable salt thereof;

wherein X is a 5- to 6-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted on an oxo-replaceable ring carbon atom and on any nitrogen atom of the ring replaceable by R^s;

R¹ it is halogen;

R³ and R⁴ they are each H;

R⁵ it is halogen, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted by halogen, alkoxy of 1 to 6 carbon atoms substituted by halogen, cyano or C (O) OR₀-to go⁸;

R⁶ it's H; alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen and / or hydroxyl groups; - (CR2) P-OR⁷, - (CR2) p-CH (OH) C_tF_{2t +}i where t is 1 to 3, (CR₂)_P-CN; (CR₂)_P-NR (R⁷), - (CR₂)_P-C (O) OR⁷, (CR₂)_PNR (CR₂)_POR⁷, (CR2) pNR-LC (O) R⁸, C (O) - (CR2)_thatOR⁸, -C (O) O (CR2) p-NRR⁷, -C (O) - (CR2) p-OR⁷, LY, -LC (O) R⁷, -LC (O) -NRR⁷, -lC (O) -NR- (CR2) p-NRR⁷, -LC (O) NR (CR2)_pOR⁷, -LC (O) - (CR2) q-NRC (O) -R⁸, -LC (O) NR (CR2)_pMR⁷, -LC (O) NR (CR₂)_pSW)₁.₂R⁸, -l30

SW)₂R⁸, -LS (O) 2- (CR2) p-NRR⁷, -LS (O) 2NR (CR₂)_pNR (R⁷) or -LS (O)₂NR (CR₂)_pOR⁷;

in an alternative way, R^s it is a radical selected from the formula (a), (b), (c) or (d):

<img file="CU23952B1_D0028.tif" />

<img file="CU23952B1_D0029.tif" />

<img file="CU23952B1_D0030.tif" />

R¹⁰ is O, S, NR¹⁷ where R¹⁷ is H, alkyl of 1 to 6 carbon atoms, SO2R^8a or CO2R^8a;

R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently selected from H; alkoxy of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, amino, or hydroxyl groups; or R¹¹ and R¹², R¹² and R¹⁵, R¹⁵ and R¹⁶, R¹³ and R¹⁴, or R¹³ and R¹⁵, together with the atoms with which they are attached, can form a 3 to 7-membered ring, saturated, saturated, or partially unsaturated, containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and 1 to 3 R groups⁵;

L is (CR₂)₁.₄ or a link;

Y is a carbocyclic ring of 3 to 7 carbon atoms, aryl of 10 carbon atoms, or a 5-10 membered heteroaryl or 4 to 10 membered heterocyclic ring, each of which is optionally substituted with 1 to 3 R groups⁵;

R⁷, R⁸ and R^8a they are independently alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, amino, hydroxyl or cyano; (CR₂)_thatY or alkoxy of 1 to 6 carbon atoms; or R⁷ it's H;

each R is independently H or alkyl of 1 to 6 carbon atoms;

R and R⁷ along with N in each NRR⁷ they can form a 5 to 6 member ring containing 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and 1 to 3 R groups⁵;

m is from 2 to 4;

n is 1 to 3;

p is 1 to 4; and q is from 0 to 4.

In yet another aspect, the invention provides the compounds of the formula (5):

<img file="CU23952B1_D0031.tif" />

or the physiologically acceptable salts thereof; where X is a 4- to 7-membered heterocyclic ring that

O 'contains NR⁶, ^—N⁺R⁶, O or S, and optionally substituted with 1 to 3 R groups⁵;

where R¹ it is halogen, alkyl of 1 to 6 carbon atoms, or an alkyl of 1 to 6 carbon atoms substituted by halogen;

R² it is an optionally substituted 5 to 6 membered heteroaryl or a 5 to 7 membered heterocyclic ring, each having 1 to 3 heteroatoms selected from N, O and S and optionally substituted with 1 to 3 R groups⁹;

R³ and R⁴ are independently H, C (O) R⁸, alkyl of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms substituted by halogen;

R⁵ and R⁹ they are independently alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, aml, or hydroxyl groups; or R⁵ and R⁹ are independently alkoxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms substituted by halogen, halogen, nitro, cyano, CR (OR⁷) R⁷, OR⁷, OR (CR2) P-OR⁷, NR (R⁷), CR (R⁷) NRR⁷, (CR2)₁.₆NR (CR₂)_pOR⁷, (CR₂)₁.₆NR (CR₂)_thatC (O) R⁸, -C (O) - (CR2) q-NR-C (O) -R⁸, (CR2)_thatY, C (O) O₀-to go⁷, C (O) NR (R⁷), C (O) CRR⁷-NR (R⁷), C (O) NR (CR2) pNR (R⁷), C (O) NR (CR2)_pOR⁷, C (O) NR (CR2) pSR⁷, C (O) NR (CR2) pS (O)_V2R⁸, S (O) 0.2R⁸, S (O) 2NRR⁷, S (O) 2NR (CR2) PNR (R⁷), or S (O) 2NR (CR₂)_pOR⁷;

R⁶ it's H; alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, 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, (CR2)_p-NR (R⁷), CR (R⁷) NRR⁷, -LY, -LCfOjOo-HCR ^ -R⁸, - (CR ^ p-CfOjOo -.- R⁷, -LC (O) -NRR⁷, -LC (O) O0. 1-CR (R⁷) -NRR⁷, -LC (O) -NR- (CR2)_p-NRR⁷, -LC (O) NR (CR2) by⁷, -LC (O) - (CR2)_that-N RC (O) -R⁸, -LC (O) NR (CR2) pSR⁷, -LC (O) NR (CR2)_pS (OR₂R⁸, -LS (O) 2R⁸, (CR2)_pNR (CR₂)_pOR⁷, (CR2) pNR-LC (O) R⁸, -lS (O) 2NRR⁷, -LS (O) 2NR (CR2) pNR (R⁷) or -LS (O) 2NR (CR₂)_pOR⁷;

in an alternative way, R⁶ it is a radical selected from the formula (a), (b), (c) or (d):

<img file="CU23952B1_D0032.tif" />

<img file="CU23952B1_D0033.tif" />

<img file="CU23952B1_D0034.tif" />

<img file="CU23952B1_D0035.tif" />

where R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently selected from H or alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which it may be optionally substituted with halogen, amino, or hydroxyl groups; or R¹¹ and R¹², R¹² and R¹⁵, R¹⁵ and R¹⁶, R¹³ and R¹⁴, or R¹³ and R¹⁵ together with the carbon and / or nitrogen atoms with which they are attached, they can form a 3 to 7-membered, saturated, saturated, or partially saturated ring that optionally contains up to 3 atoms or groups selected from C (O ), N,

O and S (O)₀-₂;

R¹⁷ is O or SO₂R⁸;

L is (CR₂) i-4 or a link;

Y is a carbocyclic ring of 3 to 7 carbon atoms, aryl of 10 carbon atoms, or a 5-10 membered heteroaryl or 4 to 10 membered heterocyclic ring, each of which is optionally substituted with 1 to 3 R groups⁵;

R⁷ and R⁸ they are independently alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, amino, hydroxyl or cyano; (CR₂)_thatY or alkoxy of 1 to 6 carbon atoms; or R⁷ it's H;

each R is H or alkyl of 1 to 6 carbon atoms;

m is from 2 to 4;

n is 1 to 3; p is 1 to 4; and q is from 0 to 4.

In the formula (5) above, in the examples of 5-membered heteroaryl or of a 5- to 7-membered heterocyclic ring, the R groups² they include, but are not limited to, pyrazolyl, pyrrolyl, thiophenyl, pyrimidinyl, isoxazolyl, pyridyl, azepan-2-onyl, 2H-thiopyran, 3H-thiopyran, 4H-thiopyran, tetrahydro-thiopyran, 2H-pyran, 4H-pyrano, tetrahydro- pyran, piperidine, 1,2-dithiine, 1,2-dithian, 1,3-dithiine, 1,3-dithian, 1,4-dithiine, 1,4-dithian, 1,2-dioxin, 1,2-dioxane, 1,3-dioxin,

1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,2-oxatiine, 1,2oxyatian, 4H-1,3-oxatiine, 1,3-oxathian, 1,4-oxatiine, 1,4-oxatiano, 2H-1,2-thiazine, tetrahydro-1,2-thiazine, 2H-1,3-thiazine, 4H-1,3-thiazine,

5, 6-dihydro-4 Ht azi na, 4H-1, 4-thiazine, tetrahydro-1, 4-thiazine, 2H1.2-oxazine, 4H-1,2-oxazine, 6H-1,2-oxazine , 2H-1,3-oxazine, 4H1.3-oxazine, 4H-1, 4-oxazine, morpholine, trioxane, 4H-1,2,3-tritiine,

1.2.3- tritiano, 1,3,5-tritiano, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,2-dioxol, 1, 2-dioxolane, 1,3-dioxol, 1,3-dioxolane, 3H-1,2-dithiol, 1,2-dithiolane, 1,3-dithiol, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, thiazoline, thiozolidine, 3H-1,2-oxatiol, 1,2-oxathiolane, 5H-1,2-oxatiol, 1,3-oxatiol, 1,3-oxathiolane, 1,2,3-triti or I,

1.2.3- trithiol a no, 1,2,4-trithiolane, 1,2,3-trioxol, 1,2,3-trioxolane, 1,2,

4-trioxolane, 1,2,3-triazoline, and 1,2,3-triazolidine.

In each of the above formulas, any asymmetric carbon atoms may be present in the configuration (R), (S), or (R, S). The compounds, therefore, may be present as mixtures of isomers or as pure isomers, for example, as pure enantiomers or diastereomers. The invention further encompasses the possible tautomers of the compounds of the invention.

Any formula given herein is also intended to represent unlabelled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures illustrated by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of the isotopes that can be incorporated into the compounds of the invention include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ²H ³H ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁸CI, ¹²⁵l respectively.

The invention includes different isotopically labeled compounds as defined herein, for example, those where radioactive isotopes are present, such as ³H ¹³C, and ¹⁴C. These isotopically labeled compounds are useful in metabolic studies (with, for example, ¹⁴C), reaction kinetics studies (with, for example ²H or ³H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate distribution assays in the tissue, or in the radioactive treatment of patients. In other examples, a^1SF or labeled compound for PET or SPECT studies. Isotopic variations of the compounds have the potential to change the metabolic fate of a compound and / or to create small changes in physical properties, such as hydrophobicity, and the like. Isotopic variations also have the potential to improve efficacy and safety, to improve the availability and half-life, to alter the protein bond, to change biodistribution, to increase the proportion of active metabolites, and / or to decrease the formation of reactive or toxic metabolites.

optionally substituted, as described above.

Pharmacology and Utility

The compounds of the invention and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when

The isotopically labeled compounds of this invention and the pro-drugs thereof can be prepared in general terms by carrying out the procedures disclosed in the schemes or in the Examples and preparations described below, by the use of an isotopically labeled reagent readily available to replace a non-isotopically labeled reagent.

In each of the above formulas, each optionally substituted fraction may be substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 3 to 6 carbon atoms, each of which may be optionally halogenated, or may optionally have a carbon atom that can be replaced or substituted with N, S, O, or a combination thereof (eg, hydroxy-alkyl of 8 carbon atoms, alkoxy of 1 to 8 carbon atoms alkyl of 1 to 8 carbon atoms); halogen, amino, amidino, alkoxy of 1 to 6 carbon atoms; hydroxyl, methylenedioxy, carboxyl; alkyl of 1 to 8 carbon-carbonyl atoms, alkoxy of 1 to 8 carbon-carbonyl atoms, carbamoyl, alkyl of 1 to 8 carbon-carbamoyl atoms, sulfamoyl, cyano, oxo, nitro, or a carbocyclic ring, heterocyclic ring , optionally substituted aryl, or heteroaryl, as described above.

Pharmacology and Utility

The compounds of the invention and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when tested in vitro in cellless kinase assays and in cellular assays, and are therefore useful as pharmaceuticals.

In one aspect, the compounds of the invention may inhibit the insulin-like growth factor receptor (IGF-1R), and may be useful in the treatment of diseases mediated by IGF-1R. Examples of diseases mediated by IGF-1 R include, but are not limited to, proliferative diseases, such as tumors, for example of breast, renal, prostate, rectal colo10, thyroid, ovarian, pancreas, neuronal , of lung, uterine, and 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-1 R can be demonstrated using a cell capture ELISA. In this assay, the activity of the compounds of the invention against self-phosphorylation induced by (IGF-1) of IGF-1R is determined.

In another aspect, the compounds of the invention can inhibit the tyrosine kinase activity of anaplastic lymphoma kinase (ALK), and the NPM-ALK fusion protein. This protein tyrosine kinase results from a genetic fusion of nucleophosmin (NPM) and ALK, which makes ALK ligand protein tyrosine kinase activity independent. NPM-ALK has a key role in the transmission of signals in a number of hematopolytic cells and other human cells that lead to hematological and neoplastic diseases, for example in anaplastic macrocellular lymphoma (ALCL), and in non-Hodgkin lymphomas (NHL ), specifically in ALK + NHL or Alkomas, in inflammatory myofibroblastic tumors (IMT), and in neuroblastomas. (Duyster et al., 2001 Oncogene 20, 56235637). In addition to NPM-ALK, other genetic fusions have been identified in human hematological and neoplastic diseases; for example, TPM3-ALK (a 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 in analogy to the VEGF-R kinase assay described in J. Wood et al. Cancer Res. 60 , 2178-2189 (2000). In general, in vitro enzymatic assays are carried out using GST-ALK protein tyrosine kinase, in 96-well plates, as a 20 mM Tris HCI filter binding assay, pH-7.5, MgCI₂ 3 mM, MnCI₂ 10 mM, 1 mM DTT,

0.1 pCi / assay (= 30 microliters) [and-³³P] -ATP, 2 μΜ ATP, 3 micrograms / milliliter of poly- (Glu, Tyr 4: 1) Poly-EY (Sigma P-0275), 1 percent dimethyl sulfoxide, and 25 nanograms of ALK enzyme. The assays are incubated for 10 minutes at room temperature. The reactions are terminated by the addition of 50 microliters of 125 mM EDTA, and the reaction mixture is transferred to a MAIP Multiscreen plate (Millipore, Bedford, MA, USA), previously moistened with methane, and rehydrated for 5 minutes with H₂O. Immediately after washing (H₃PO₄ at 0.5 percent), the plates are counted in a liquid waistband counter. IC values₅₀ they are calculated by linear regression analysis of the percentage of inhibition.

The compounds of the invention can potently inhibit the growth of murine BaF3 cells that overexpress human NPM-ALK (DSMZ Deutsche Sammiung von Mikroorganismen und Zelikulturen GmbH, Germany). NPM-ALK expression can be achieved by transfecting the BaF3 cell line with a pClneo expression vector.^MR (Promega Corp., Madison WI, USA) coding for NPM-ALK, and subsequent selection of G418 resistant cells. Untransfected BaF3 cells depend on IL-3 for cell survival. In contrast, BaF3 cells expressing NPM-ALK (referred to as BaF3NPM-ALK hereinafter) may proliferate in the absence of IL-3, because they obtain the proliferative signal through the NPM-ALK kinase. Accordingly, the supposed NPM-ALK kinase inhibitors eliminate the growth signal, and can result in an anti-proliferative activity. The anti-proliferative activity of the supposed NPM-ALK kinase inhibitors, however, can be overcome by the addition of IL3, which provides growth signals through an independent mechanism of NPM-ALK. An analogous cellular system using FLT3 kinase has also been described (see, E Weisberg et al., Cancer Cell; 1, 433-443 (2002)).

The inhibitory activity of the compounds of the invention can be determined as follows. In general, BaF3-NPMALK cells (15,000 / microtiter plate well) are transferred to 96-well microtiter plates. Test compounds dissolved in dimethyl sulfoxide (DMSO) are added in a series of concentrations (dilution series), such that the final concentration of dimethyl sulfoxide is not greater than 1 percent (volume / volume). After the addition, the plates are incubated for two days, during which time, control cultures without test compound are capable of undergoing two cycles of cell division. BaF3-NPM-ALK cell growth is measured by YOPRO staining.^mr [T Idziorek et al., J. Immunol. Methods; 185: 249-258 (1995)]: 25 microliters of lysis regulator comprising 20 mM sodium citrate, pH 4.0, 26.8 mM sodium chloride, 0.4 percent NP40, and 20 mM EDTA are added to each well to each well. Cell lysis is completed within 60 minutes at room temperature, and the total amount of YOPRO is determined^mr linked to DNA, using a measurement that uses the Cytofluor II (PerSeptive Biosystems) 96-well reader with the following positions: Excitation (nanometers) 485/20 and Emission (nanometers) 530/25.

The compounds of the invention may also be useful in the treatment and / or prevention of acute or chronic inflammatory diseases or disorders, or autoimmune diseases, for example, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes (types I and II) and disorders associated with it, respiratory diseases, such as asthma or inflammatory liver injury, glomerular inflammatory lesion, skin manifestations of immunologically mediated disorders or diseases, inflammatory and hyper-proliferative diseases of the skin (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and other eczematous dermatitis, seborrheic dermatitis), inflammatory eye diseases , for example, Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease, or ulcerative colitis.

In accordance with the foregoing, the present invention provides:

(1) a compound of the invention for use as a pharmaceutical product;

(2) a compound of the invention for use as an IGF-1R inhibitor, for example for use in any of the particular indications set forth hereinbefore, (3) a pharmaceutical composition, for example, for use in any of the indications stipulated hereinbefore, which comprises a compound of the invention as an active ingredient, together with one or more pharmaceutically acceptable diluents or carriers;

(4) a method for the treatment of any particular indication stipulated hereinbefore, in a subject in need thereof, which comprises administering an effective amount of a compound of the invention or 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, where the activation of IGF-1R has a role or is involved;

(6) the method as defined above under (4), which comprises co-administration, for example, in a concomitant or sequential manner, of a therapeutically effective amount of a compound of the Invention, and one or more substances of additional drug, this additional drug substance being useful in any of the particular Indications stipulated hereinbefore;

(7) a combination comprising a therapeutically effective amount of a compound of the invention, and one or more additional drug substances, this additional drug substance being useful in any of the particular indications set forth hereinbefore;

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

(9) the use according to (8), wherein the disease to be treated is selected from anaplastic macrocellular lymphoma, non-Hodgkin lymphomas, inflammatory myofibroblastic tumors, 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 that responds to the inhibition of anaplastic lymphoma kinase, especially a disease selected from anaplastic macrocellular lymphoma, non-Hodgkin lymphomas, inflammatory myofibroblastic tumors, neuroblastomas, and neoplastic diseases, which it comprises administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. Administration and Pharmaceutical Compositions

In general, the compounds of the invention will be administered in therapeutically effective amounts by any of the usual and acceptable ways known in the art, either individually or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors known to those of ordinary experience in this field. For example, for the treatment of neoplastic diseases and immune system disorders, the dosage required will also vary depending on the mode of administration, the particular condition to be treated, and the desired effect.

In general, it is indicated that systemic satisfactory results are obtained in daily dosages of about 0.01 to about 100 milligrams / kilogram of body weight, or in particular, of about 0.03 to 2.5 milligrams / kilogram of body weight. A daily dosage indicated in the upper mammal, for example, in humans, may be in the range of about 0.5 milligrams to about 2,000 milligrams, or more particularly, from about 0.5 milligrams to about 100 milligrams, conveniently administered, for example, in divided doses up to four times a day or in a delayed form. Unit dosage forms suitable for oral administration comprise about 1 to 50 milligrams of active ingredient.

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

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 mixing, granulating, coating processes. , dissolution, or lyophilization. For example, 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 dosage forms for oral administration contain, for example, from about 0.1 milligrams to about 500 milligrams of active substance.

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 ingredient alone or together with a vehicle such as mannitol, dispersions or suspensions may be formed before use. The pharmaceutical compositions may be sterilized and / or may contain adjuvants, such as preservatives, stabilizers, humectants or emulsifiers, solution promoters, salts for regulating osmotic pressure and / or pH regulators. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid. The solutions or suspensions may comprise viscosity increasing agents, including, but not limited to, sodium carboxy methyl cellulose, carboxy methyl cellulose, dextran, polyvinyl pyrrolidone, gelatins, or solubilizers, for example, Tween 80 (mono - polyoxyethylene sorbitan oleate (20).

The oil suspensions may comprise, as the oil component, the vegetable, synthetic, or semi-synthetic oils customary for injection purposes. Examples include esters of liquid fatty acids containing, as the acid component, a long chain fatty acid having 8 to 22 carbon atoms, or in some embodiments, 12 to 22 carbon atoms. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecyl acid, myristic acid, pentadecyl acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or the corresponding unsaturated acids, for example oleic acid, elaidic acid, euchrocic acid, brazilic acid, and linoleic acid, and, if desired, may contain antioxidants, for example vitamin E, 3-carotene, or 3,5-diterbutyl-dhrox-toluene. The alcohol component of these fatty acid esters may have six carbon atoms, and may be monovalent or polyvalent, for example a mono-, di-, or tri-valent alcohol. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol, or isomers thereof; glycol and glycerol.

Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL® M 2375, (po I ¡ox ¡et ¡I e ng I ¡ce ro I), LABRAFIL ® M 1944 CS (unsaturated polyglycolized glycerides prepared by alcoholization of apricot kernel oil and comprising glycerides and polyethylene glycol ester), LABRASOL^MR(saturated polyglycolized glycerides prepared by the alcoholysis of TCM, and comprising glycerides and polyethylene glycol ester; all available in Gatefossé, France), and / or MIGLYOL® 812 (saturated fatty acid triglyceride with a chain length of 8 to 12 carbon atoms, from Huís AG, Germany), and vegetable oils, such as seed oil from cotton, almond oil, olive oil, castor oil, sesame oil, soybean oil, or peanut oil.

Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, and if desired, a resulting mixture is granulated, and the mixture or granules are processed by including additional excipients, to form tablets or tablet cores.

Suitable carriers include, but are not limited to, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations, and / or calcium phosphates, for example calcium triphosphate or calcium acid phosphate, and also binders, such as starches, for example corn, wheat, rice, or potato starch, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxy methyl cellulose, and / or polyvinyl pyrrolidone, and / or, if desired, disintegrants, such as the aforementioned starches, carboxy methyl starch, crosslinked polyvinyl49 pyrrolidone, 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.

The tablet cores may be provided with suitable, optionally enteric, coatings, through the use of, among other things, concentrated sugar solutions, which may comprise gum arabic, talcum powder, polyvinyl or lpyro I idon a, polyethylene glycol and / or titanium dioxide, or coating solutions in solvents or mixtures of suitable organic solvents, or, for the preparation of enteric coatings, suitable cellulose preparation solutions, such as acetyl cellulose phthalate or hldroxy-propyl methyl cellulose phthalate. Dyes or pigments can be added to tablets or tablet coatings, for example, for identification purposes, or to indicate different doses of the active ingredient.

Pharmaceutical compositions for oral administration may also include hard capsules, which comprise gelatin, or soft sealed capsules, which comprise gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as cornstarch, binders, and / or skids, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient can be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil, or liquid polyethylene glycols, or esters of fatty acids of ethylene ethylene ro I and ng I icol, at which can also be added stabilizers and detergents, for example, of the polyoxyethylene sorbitan fatty acid ester type.

Pharmaceutical compositions suitable for rectal administration are, for example, suppositories, which comprise a combination of the active ingredient and a suppository base. Suitable 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 a water-soluble form, for example of a water-soluble salt, or aqueous suspension for injection containing viscosity-increasing substances, for example carboxy-methyl. sodium cellulose, sorbitol and / or dextran, and, if desired, stabilizers. The active ingredient, optionally together with excipients, can also be in the form of a lyophilisate, and can be made in a solution before parenteral administration by the addition of suitable solvents. Solutions, such as they are used, for example, for parenteral administration, can also be used as infusion solutions. The manufacture of injectable preparations is usually carried out under sterile conditions, as well as the filling, for example, in ampoules or bottles, and the sealing of the containers.

The compounds of the invention can be administered as the only active ingredient, or together with other drugs useful against neoplastic diseases or useful in immunomodulatory regimens. For example, the compounds of the invention can be used according to the invention in combination with pharmaceutical compositions effective in different diseases as described above, for example, with cyclophosphamide, 5-fluoro-uracil, fludarabine, gemcltabine, cisplatin, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan, doxorubicin, gefitinib, or imatinib; or also with cyclosporins, rapamycins, ascomycins or their immunosuppressive analogues, for example, cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids, for example, prednisone, cyclophosphamide, azathioprene, methotrexate, gold salts, sulfasalazine, anti -malaria, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate-mofetil, 15-deoxy-spergualin, immuno-suppressor monoclonal antibodies, for example, monoclonal antibodies to leukocyte receptors, for example, MHC, CD2, CD3, CD4, CD7, CD25, CD28, I CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA- 4 or its ligands, or other immuno-modulatory compounds, for example, CTLA41g.

The invention also provides pharmaceutical combinations, for example, a kit, which comprises: a) a first agent, which is a compound of the invention as disclosed 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 administration.

Processes for the Preparation of the Compounds of the Invention

The General Procedures for the preparation of the compounds of the invention are described in the Examples below. In the reactions described, the reactive functional groups, for example the hydroxyl, amino, amino, uncle, or carboxyl groups, where these are desired in the final product, can be protected to avoid their desired participation in the reactions. Conventional protecting groups can be used in accordance with standard practice (see, for example, TW Greene and PGM Wuts in "Protective Groups in Organic Chemlstry", 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 may include, for example, the solvent used for crystallization (present as solvates). The salts can usually be converted to the compounds in free form, for example, by treatment with suitable basic agents, for example with alkali metal carbonates, alkali metal acid carbonates, or alkali metal hydroxides, such as potassium carbonate or sodium hydroxide A compound of the invention in a form of base addition salt can be converted to the corresponding free acid by treatment with a suitable acid (for example, hydrochloric acid, etc.). In view of the close relationship between the novel compounds in free form and those in the form of their salts, including salts that can be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds Previously herein and subsequently herein, it should be understood to also refer 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. The acid addition salts of the compounds of the formula (1), (2), (3), and (4), therefore, can be obtained by treatment with an acid or with an appropriate 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 the compounds of the 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 acid, sulfuric acid, or phosphoric acid. Suitable organic acids include, but are not limited to, carboxylic, phosphoric, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid , adipic acid, pimelic acid, subic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxy-maleic acid, methylmaleic acid, cyclohexane carboxylic acid, adamantan carboxylic acid, benzoic acid, salicylic acid, 4-amino-salicylic acid, italic acid, fenll-acetic acid, mandelic acid, cinnamic acid, methane or ethanesulfonic acid, 2 -hydroxy-ethan-sulfonic acid, ethan1,2-disulfonic acid, benzene-sulfonic acid, 2-naphthalene-sulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3-, or 4-methyl-benzenesulfonic acid, methyl acid -sulfuric, ethyl-sulfuric acid, dodecyl sulfuric acid, N-cyclohexyl sulfamic acid, N-methyl1-, N-ethyl-, or Npropyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.

For the purposes of isolation or purification, it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds (where applicable, in the form of pharmaceutical preparations) are used.

The compounds of the invention in a non-oxidized form can be prepared from N-oxides of the compounds of the invention by treatment with a reducing agent (for example, sulfur, sulfur dioxide, triphenyl phosphine, borohydride). lithium, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (for example, acetonitrile, ethanol, aqueous dioxane, or the like) from 0 ° C to 80 ° C.

Pro-drug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (for example, for more details, see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters , Volume 4, page 1985). For example, the appropriate pro-drugs can be prepared by reacting a compound not derived from the invention with a suitable carbamilating agent (for example, 1,1-acyloxyalkyl-carbaryl chloridate, para-nitro-phenyl carbonate, or Similar).

Protected derivatives of the compounds of the invention can be made by known means by those of ordinary experience in this field. 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 Chemistry”, 3^to Edition, John Wiley and Sons, Inc., 1999.

The compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolution agent to form a pair of diastereomeric compounds, the diastereomers are separated, and the optically pure enantiomers are recovered. The resolution of the enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, or by the use of dissociable complexes (for example, crystalline diastereomeric salts). The diastereomers have different physical properties (for example, melting points, boiling points, solubilities, reactivity, etc.), and can be easily separated by taking advantage of these differences. The diastereomers can be separated by fractional crystallization, chromatography, or by separation / resolution techniques, based on differences in solubility. The optically pure enantiomer is then recovered, together with the resolution agent, by any practical means that does not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of the compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981.

In summary, the compounds of the invention can be made by a process as described in the Examples; and (a) optionally converting a compound of the invention into a pharmaceutically acceptable salt;

<td>(b)</td><td>optionally</td><td>convert</td><td>a form of salt</td><td>from</td><td>a</td>

<td>compound</td><td>of the invention</td><td>up to one</td><td>non salt form;</td><td></td><td></td>

<td>(c)</td><td>optionally</td><td>convert</td><td>an oxidized form</td><td>from</td><td>a</td>

<td>compound</td><td colspan="2">of the invention until</td><td colspan="3">a pharmaceutically N-oxide</td>

<td>acceptable;</td><td></td><td></td><td></td><td></td><td></td>

<td>(d)</td><td>optionally</td><td>convert</td><td>a form of N-oxide</td><td>from</td><td>a</td>

compound of the invention to its non-oxidized form;

(e) optionally resolving an individual isomer of a compound of the invention from a mixture of Isomers;

(f) optionally converting a compound not derived from the invention to a pharmaceutically acceptable pro-drug derivative; and (g) optionally converting a pro-drug derivative of a compound of the invention to its non-derivative form.

As far as production of the starting materials is not particularly described, the compounds are known or can be prepared in a manner analogous to methods known in the art, or as disclosed in the Examples hereinafter. One skilled in the art will appreciate that the above transformations are only representative of the methods for the preparation of the compounds of the present invention, and that other well known methods can be used slmilarly. The present invention is further exemplified, but not limited, by the following Examples illustrating the preparation of the compounds of the invention.

Intermediate it 1

2,5-dichloro-N- (5-met¡l-1 Hp¡razol-3-¡) -p¡r¡m¡din-4-am¡na

<img file="CU23952B1_D0036.tif" />

H

A mixture of 5-methyl-1 H-pyrazol-3-amine (3.00 grams, 30.9 mmol), 2,4,5-trichloro-pyrimidine (5.67 grams, 30.9 mmol, 1 equivalent), and Na₂CO₃ (3.60 grams, 34.0 millimoles, 1.1 equivalents) in EtOH (100 milliliters) was heated at 40 ° C for 24 hours. The solvent was removed in vacuo. The resulting residue was partitioned between EtOAc (350 milliliters), and water (100 milliliters). The EtOAc layer was washed with water (3 times), saturated aqueous NaCl (1 time), and dried over Na₂SW₄. The resulting EtOAc solution was concentrated in vacuo to give the product of 2,5-dichloro-N- (5methyl-1 H -pyrazol-3-yl) -pyrimidin-4-amine; ESMS m / z 244.0 (M + H⁺ ).

Intermediary 2

2-Chloro-N- (5-methyl-1 H-pyrazol-3-yl) -5- (trifl uoro-methyl) -p¡ rimid i η-4-ami na 'Cl

A mixture of 2,4-dichloro-5- (trifluoro-methyl) -pyrimidine (1.06 grams, 4.86 millimoles), 5-methyl-1 H-pyrazol-3-amine (472.2 milligrams, 4.86 millimoles), and carbonate of sodium (2.06 grams, 19.4 millimoles) in 100 milliliters of EtOH, 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 (Na₂SW₄), were concentrated in vacuo, and purified by silica chromatography (EtOAc / hexanes: 1/1), to provide 2-chloro-N- (5-methyl-1 H-pyrazol-3l) -5- (trfluoro-methyl) -p¡r¡m¡d¡n-4-am¡na; ESMS m / z 278.0 (M + H⁺).

Intermediary 3

2-Chloro-5-methyl-N- (5-methyl-1 H-pyrazol-3-yl) -p¡midin-4-amine

<img file="CU23952B1_D0037.tif" />

A mixture of 5-methyl-1 Hprazol-3-amine (3.00 grams, 30.9 mmol), 2,4-dichloro-5-methyl-pyrimidine (5.03 grams, 30.9 mmol, 1 equivalent), and Na₂CO₃ (3.60 grams, 34.0 millimoles, 1.1 equivalents) in EtOH (100 milliliters) was heated at 40 ° C for hours. The solvent was removed in vacuo. The resulting residue was partitioned between EtOAc (350 milliliters), and water (100 milliliters). The EtOAc layer was washed with water (3 times), saturated aqueous NaCl (1 time), dried over Na₂SW₄, and concentrated in vacuo. The resulting crude product was sonlized in Et₂O (200 milliliters), and the resulting precipitate was collected by filtration. This powder was washed further with Et₂Or, providing the product of 2-chloro-5methyl-N- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-4-amine; ESMS m / z 224.1 (M + H⁺).

Intermediary 4

N- (2,5-dichloro-pyrim¡d¡n-4-l) -5-methyl-isoxazol-3-amine

<img file="CU23952B1_D0038.tif" />

The mixture of 5-methyl-isoxazol-3-amine (98 milligrams, 1.0 millimoles), 2,4,5-trichloro-pyrimidine (344 microliters, 3.0 millimoles), and sodium carbonate (106 milligrams, 1.0 millimoles) in 3 milliliters of

EtOH was heated at 60 ° C overnight. The reaction mixture was concentrated and then partitioned between EtOAc and brine. The collected organic extracts were dried (Na₂SW₄), were concentrated in vacuo, and purified by silica gel chromatography (MeOH / DCM: 1/9), to provide the N- (2,5-dichloropyrimimin-4-yl) -5-methyl -isoxazol-3-amine; ESMS m / z 245.0 (M + H⁺).

Intermediary 5

2,5-dichloro-N- (5-cyclopropyl-1H-pyrazol-3-yl) -pyrimidin-4-amine

<img file="CU23952B1_D0039.tif" />

ci

A mixture of 5-cyclopropyl-1 H-pyrazol-3-amine (246 milligrams, 2.00 millimoles), 2,4,5-trichloro-pyrimidine (367 milligrams, 2.00 millimoles, 1 equivalent), and Na₂CO₃ (233 milligrams, 2.20 millimoles, 1.1 equivalents) in EtOH (10 milliliters) was heated at 40 ° C for 16 hours. The crude reaction mixture was diluted with EtOAc, and washed sequentially with: water (3 times), and saturated aqueous NaCl (1 time). The resulting EtOAc layer was dried over Na₂SW₄ and then concentrated in vacuo, providing 2,5-dichloro-N- (5-cyclopropyl-1 H -pyrazol-3-yl) -pyrimidin-4-amine; ESMS m / z 270.0 (M + H⁺ ).

Intermediary 6

3- (2,5-dichloro-pyrim¡d¡n-4-¡-l-am¡no) -azepan-2-one

HN

A mixture of (±) -a-amino-e-caprolactam (256 milligrams, 2.0 millimoles), 2,4,5-trichloro-pyrimidine (366 milligrams, 2.0 millimoles, 1 equivalent), and NaHCO₃ (168 milligrams, 2 millimoles, 1 equivalent) in a mixture of methanol (12 milliliters), and H₂O (6 milliliters) was stirred at room temperature for 15 hours. The resulting precipitate was collected by vacuum filtration, and washed with small amounts of methanol and water, yielding the product of 3- (2,5-dichloro-p¡r¡m¡d¡n-4-il-am¡ no) -azepan-2-one; ESMS m / z 275.0 (M + H⁺ ).

Intermediary 7

3- (2,5-dichloro-p¡r¡m¡din-4-il-am¡no) -pyridin-2 (1 H) -one

<img file="CU23952B1_D0040.tif" />

A mixture of 3-amine-pyridine-2 (1 H) -one (99 milligrams, 0.90 mmol), 2,4,5-trichloro-pyrimidine (165 milligrams, 0.90 millimoles, 1 equivalent), and NaHCO₃ (76 milligrams, 0.90 millimoles, 1 equivalent) in a mixture of methanol (6 milliliters), and H₂O (3 milliliters) was stirred at room temperature for 24 hours. The resulting precipitate was collected by vacuum filtration, and washed with small amounts of methanol and water, yielding the product of 3- (2,5-dichloro-pyrmidmidin-4-l-amine) - pridin-2 (1 H) -one; ESMS m / z 257.0 (M + H⁺ ).

Intermediary 8

2,5-di chloro-N- (5-met¡ 1-1 - (tetrahydro-2H-p¡ran-2-yl) -1 H-pyrazol-3-yl) 25 pyrimidin-4-amine

ΤΗΡ

<img file="CU23952B1_D0041.tif" />

Ν Ν CI Η

To a mixture of 2,5-d ¡cl or ro-Ν- (5-meti I-1 H-pyrazol-3-yl) pimidin-4-amine (2.44 grams, 10 millimoles), and monohydrate of 4-toluene sulfonic acid (1.9 grams, 10 millimoles) in tetrahydrofuran (200 milliliters), DHP (4.25 grams, 50 millimoles) was added. After stirring overnight, the reaction became transparent. After concentration, the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of Na₂CO₃. The organic layer was then washed with brine, dried over sodium sulfate, and concentrated in vacuo, to provide 2,5-dichloro-N- (5-methyl-1 - (tetrahydro-2H-piraη-2-iI ) -1 H-pi razol-3-yl) pyrimidin-4-amine as a light yellow solid, which was used in the following reactions without further purification; ESMS m / z 244 (MTHP + H⁺); TLC Rf = 0.6 (Silica; 1: 1 ethyl acetate / hexanes; starting material Rf = 0.2).

Intermediary 9

2,5-dichloro- / V- (5- (trifluoro-methyl) -1 Hp¡razol-3-yl) -p¡r¡m¡d¡n-4-am¡na

H

Step 1: 5- (trifluoro-methyl) -1 H-pyrazol-3-amine

A mixture of (£) -4-amino-4-ethox¡-1,1,1-trifluoro-but-3-in-2one (5.00 grams, 27 mmol), and hydrazine (1.05 grams) in anhydrous EtOH (20 milliliters) was stirred at 80 ° C in a sealed bottle overnight. The reaction was quenched with water (50 milliliters), and extracted with EtOAc (100 milliliters, and then 50 milliliters, 2 times). The EtOAc layers were combined and washed in sequence with water (25 milliliters), brine (25 milliliters), dried over Na₂SW₄ and evaporated, to give a light brown oily residue. The crude product was purified by silica chromatography (30 to 100 percent gradient of EtOAc in hexanes), to give 5- (trifluoromethyl) -1 / 7-pyrazol-3-amine as a grayish solid; ESMS m / z 152.0 (M + H⁺).

Step 2: 2,5-dichloro - / \ / - (5- (trfluoro-methyl) -1 / - / - pyrazol-3-¡) -pyrimidin4-amine

A mixture of 5- (trifl uoro-meti i) -1 H-pyrazol-3-amine (500 milligrams, 3.3 millimoles), 2,4,5-trichloro-pyrimidine (607 milligrams, 3.3 millimoles), and sodium carbonate (525 milligrams, 5 millimoles) in

Anhydrous EtOH (10 milliliters) was stirred at room temperature. After one day, the LCMS showed that the reaction was not complete. Additional 2,4,5-trichloro-pyrimidine (0.15 milliliters), and additional sodium carbonate (525 milligrams) were added, and the reaction was continued for two more days. The solvent was evaporated, and the residue was extracted with dichloromethane (20 milliliters, 3 times). The combined dichloromethane layers were washed with brine (10 milliliters), dried over Na₂SW₄ and evaporated. The crude product was purified by silica chromatography (gradient from 0 to 50 percent EtOAc in hexanes), to give 2,5-dichloro- / V- (5- (trifluoro25 methyl) -1 H-pyrazole-3- il) -pyrimin-4-amine as a light tan solid; ESMS m / z 297.9 (M + H⁺).

Intermediary 1 0

2,5-dichloro- / V- (5-et¡l-1/7-p¡razol-3-¡l) -p¡r¡m¡d¡n-4-amine

Cl

Ν N Cl H

A mixture of 5-ethyl-1 Wp.razole-3-amine (1.00 grams, 6.77 mmol), 2,4,5-trichloro-pyrimidine (1.24 grams, 6.77 mmol), and Na₂CO₃ (1.79 grams, 16.9 millimoles) in isopropanol (15 milliliters) was stirred in a sealed bottle at room temperature for two days. Water (10 milliliters) was added. The solid was collected by filtration, washed with water (10 milliliters), and dried to give the 2,5-chloro-N- (5-ethyl-1 Hp.razole-3-l) -p¡r¡ midin-4-amine as a light yellow solid; ESMS m / z 258.0 (M + H⁺).

Inter mediate it 11

- chloro-5-methyl-4-nitro-2- (trifluoro-methyl) -benzene

CF,

OR₂N

<img file="CU23952B1_D0042.tif" />

Cl

To a solution of 2-chloro-4-methyl-1- (trifluoro-methyl) -benzene (6.65 grams, 34.1 mmol) in concentrated sulfuric acid (25 milliliters) at 0 ° C, potassium nitrate (3.46 grams) was added , 34.1 millimoles) in sulfuric acid (15 milliliters). After stirring at 0 ° C for 1.5 hours, the reaction mixture was poured into 500 milliliters of ice water. The precipitate was collected by filtration and washed with copious amounts of water, providing 1-chloro-565 fluoro-4-nucleus 2- (trifluoro-methyl) -benzene as an orange solid; ¹H NMR (400 MHz, chloroform-d) δ 8.356 (s, 1H), 7.543 (s, 1H), 2.660 (s, 3H).

Intermediary 12

2-Bromo-4-methyl-5-nitro-benzo nitrile

CN

<img file="CU23952B1_D0043.tif" />

Following the same procedure as described for Intermediary 11, starting with 2-bromo-4-methyl-benzonitrile, 2-bromo-4-methyl-5-nitro-benzontrile was obtained as a yellow solid; ¹H NMR (400 MHz, chloroform-d) δ 8,290 (s, 1 H), 7,742 (s, 1 H), 2,683 (s, 3 H).

Intermediary 13

5-am i no-2-bromo-4-methyl-benzon itrile

CN

<img file="CU23952B1_D0044.tif" />

h₂n

To a solution of 2-bromo-4-methyl-5-nitro-benzontrile (500 20 milligrams, 2.07 millimoles) in ethanol (20 milliliters), tin chloride (785 milligrams, 4.14 millimoles) was added. The mixture was refluxed for 5 hours. After cooling to room temperature, triethyl amine (1.01 grams, 10 mmol) was added. The mixture was concentrated and purified by silica chromatography (30 to 50 percent gradient of ethyl acetate in hexanes), to provide 5-amino-2-bromo-4-methyl-benzonitrile as a beige solid; ESMS m / z 211 (M + H⁺ ).

Intermediary 14

Methyl 2-bromo-4-methyl-5-nitro-benzoate

<img file="CU23952B1_D0045.tif" />

Following the same procedure as described for Intermediary 11, starting with methyl 2-bromo-4-methyl-benzoate, the title compound was obtained as a white solid; ¹H NMR (400 MHz, chloroform-d) δ 8.505 (s, 1H), 7.711 (s, 1H), 3.967 (s, 3H), 2.640 (s, 3H).

Intermediary 15

Methyl 5-amino-2-bromo-4-methyl-benzoate h₂n

<img file="CU23952B1_D0046.tif" />

Following the same procedure as described for Intermediary 13, the title compound was obtained as a beige solid; ESMS m / z 244 (M + H⁺).

Intermediary 16

4-bromo-5-methox¡-2-met¡ I-aniline

<img file="CU23952B1_D0047.tif" />

Step 1: N- (5-methoxy-2-methyl-phenol) -acetamide

To a solution of triethyl-amine (2.9 grams, 14.4 millimoles), and 5-methoxy-2-methyl-aniline (1.0 grams, 7.2 millimoles) in dichloromethane (30 milliliters) at 0 ° C, was added drip chloride acetyl (0.57 grams, 7.2 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with a saturated aqueous solution of ammonium chloride, and extracted with dichloromethane. The organic layer was dried over Na₂SW₄ and concentrated, to give the N- (5-methoxy-2-methyl-phenol) -acetamide as needle-shaped crystals. The crude product was used in the next step without further purification.

Step 2: N- (4-bromo-5-methoxy-2-methyl-phenyl) -acetamide

To a solution of N- (5-methoxy-2-methyl-phenyl) -acetamide in acetic acid (40 milliliters), Br was added₂ (3 grams, 19 millimoles) slowly. The mixture was capped and stirred at 50 ° C for 5 hours. The reaction was cooled to room temperature, then quenched with an aqueous solution of sodium sulphite, and extracted with ethyl acetate (50 milliliters, 3 times). The combined organic layer was dried over Na₂SW₄ and concentrated, to give the crude N- (4-bromo-5-methoxy-2-methyl-phenyl) -acetamide as a brown oil, which was used in the next step without further purification.

Step 3: 4-bromo-5-methoxy-2-methyl-aniline

The N- (4-bromo-5-methoxy-2-methyl-phenyl) -acetamide was dissolved in methanol (15 milliliters), and concentrated HCI (30 milliliters). The mixture was refluxed at 95 ° C overnight. After cooling to room temperature, the mixture was poured into ice water, and basified to pH = 12 with a concentrated aqueous solution of NaOH. The mixture was then extracted with ethyl acetate (50 milliliters, 3 times). The combined organic layer was dried over

Na₂SW₄ and concentrated. The crude product was purified by chromatography on silica (15 percent ethyl acetate in hexanes), to give 4-bromo-5-methoxy-2-methyl-aniline as a beige solid;¹H NMR (400 mHz, CDCI₃) 7.20 (s, 1H), 6.37 (s, 1H), 4.6 (br, 2H), 3.82 (s, 3H), 2.12 (s, 3H).

Intermediary 17

2-fluoro-5-meti 1-4- (4,4,5,5-tetramethyl-1,3,2-dioxa bo rol a n-2-I) -an¡l¡na

<img file="CU23952B1_D0048.tif" />

A mixture of 4-bromo-2-fluoro-5-methyl-aniline (2.0 grams, 9.8 millimoles), bis- (pinacolato) -d¡boro (2.74 grams, 10.8 millimoles), tricyclohexyl phosphine (274.8 milligrams, 0.98 millimoles ), Pd₂(dba)₃(448.9 milligrams, 0.49 millimoles), and potassium acetate (1.92 grams, 19.6 millimoles) in 60 milliliters of 1,4-dioxane was degassed and purged with nitrogen. The reaction mixture was heated at 80 ° C overnight, and then cooled to room temperature. The mixture was partitioned between EtOAc and water, and the collected organic extracts were dried (Na₂SW₄), were concentrated in vacuo, and purified by silica chromatography (EtOAc / Hexanes: 20/80), to provide 2-fluoro-5-methyl-4- (4,4,5,569 tetrametI-1 , 3,2-dioxaboroIan-2-I) -analyne; ESMS m / z 252.2 (M + H⁺).

Intermediary 1 8

2-i sopro poxi-5-m eti 1-4- (1-methyl-piperidin-4-¡) -phenyl-amine

<img file="CU23952B1_D0049.tif" />

Step 1: 1-bromo-5-fluoro-2-methyl-4-n -trobenzene

To a solution of 2-bromo-4-fluoro-1-methyl-benzene (5 grams, 26.4 millimoles) dissolved in concentrated sulfuric acid (20 milliliters), potassium nitrate (2.67 grams, 26.4 millimoles) in sulfuric acid was added (5 milliliters) at 0 ° C. After stirring at 0 ° C for 1 hour, the reaction was diluted with water, extracted with ethyl acetate (40 milliliters, 3 times). The combined organic phases were washed with a saturated solution of sodium bicarbonate and brine in sequence, and then dried over Na₂SW₄. The crude product obtained after concentration was purified by silica gel column chromatography with mixed solvent of hexanes / EtOAc (95/5), to provide 1-bromine-5-fluoro-2-methyl4-nitro-benzene as An orange solid.¹H NMR (400 MHz, chloroform-d) δ 7.93 (d, 1H, J = 7.6 Hz), 7.5 0 (d, 1H, J = 10 Hz), 2.43 (s, 3H).

Step 2: 1-Bromo-5-Sopropoxy-2-Methyl-4-N -trobenzene

To a solution of 1-bromo-5-fluoro-2-methyl-4-nitro-benzene (step 1, 1.5 grams, 6.4 millimoles) in 2-propanol (30 milliliters), cesium carbonate (5.3 grams, 16 millimoles). The mixture was heated at 50 ° C overnight. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and the residue was purified by silica gel column chromatography with 5 percent ethyl acetate in hexanes, to provide 1-bromo-5-sopropoxy-2-methyl-4-n Trobenzene as a yellow solid.

Step 3: 4- (5-Sopropoxy-2-methyl-4-n -tro-phenol) -pyridine

To a mixture of 1-bromo-5-sopropox¡-2-meti-4-n -trobenzene (step 2, 1 gram, 3.65 mmol), pyrldln-4-boronic acid (490 milligrams, 4 millimoles ), 2-dicyclohexyl-phosphine-2 ', 6'-dimethox-b -phenyl (300 milligrams, 0.73 mmol), and potassium phosphate (1.55 grams, 7.3 millimoles) in a mixed solvent of dioxane (15 milliliters), and water (7.5 milliliters), was added tr-s- (d¡benc¡l¡den-acetone) -d¡palad¡o (0) (334 milligrams, 0.36 millimoles). This mixture was sealed and purged with nitrogen for 3 minutes, and then heated at 120 ° C for 5 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. After concentration, the crude product was purified by flash column chromatography on silica gel (60 percent ethyl acetate in hexanes), to provide 4- (5-isopropoxy-2-methyl-4nitro-feη I) -pyridine a as a yellow solid: ESMS m / z 273.2 (M + H⁺ ).

Step 4: 4- (5-Isopropoxy-2-methyl-4-n-phenyl) -1-methylpyridinium iodide

4- (5-Sopropoxy-2-methyl-4-n¡tro-fen¡l) -p¡r¡d¡na (step 3, 217 milligrams, 0.797 millimoles) was dissolved in anhydrous tetrahydrofuran (9 milliliters) . Iodine-methane (0.10 milliliters, 1.61 millimoles, 2 equivalents) was added, and the reaction was stirred at 40 ° C in a sealed tube for 2 days. The volatiles were removed in vacuo, generating the iodide of 4- (5-sopropox¡-2-methyl-4-n -tro-phenol) -1-methyl-pyridinium as a brown solid: ESMS m / z 287.1 (M +).

Steps 5 and 6: _2-isopropoxy-5-methyl-4- (1-methyl-piperidin-4-yl) -phenylamine

The 4- (5-isopropoxy-2-methyl-4-nitro-phenyl) -1-methylpyridinium iodide (step 4, 0.697 mmol) was dissolved in CH₃OH (20 milliliters), and cooled to 0 ° C. NaBH was slowly added₄ (264 milligrams, 6.97 millimoles, 10 equivalents). After this addition was completed, the cooling bath was removed, and the reaction was stirred at room temperature for 1 hour. The reaction was quenched by the slow addition of 1N aqueous HCI (14 milliliters). The CH₃OH was partially removed in vacuo. The resulting residue was partitioned between EtOAc and 1N aqueous NaOH. An additional 50 percent aqueous NaOH was added until the aqueous layer had a pH&gt; 12. The EtOAc layer was washed with 1 N aqueous NaOH (2 times), the organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. After concentration, the crude product (175 milligrams) was dissolved in acetic acid (10 milliliters). Trifluoroacetic acid (0.15 milliliters, 3 equivalents), and PtO were added₂ (53 milligrams, 30 percent by weight / weight), and the reaction was placed under H gas₂ at 50 psi (3.5 kg / cm²) on a Parr shaker for 14 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was divided by

EtOAc and 1N aqueous NaOH. Additional 50 percent aqueous NaOH was added until the aqueous layer had a pH&gt; 12. The layer of

EtOAc was washed with aqueous 1 N NaOH (2 times), the organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo, to give 2-sopropox-5-methyl-4- (1-metllperperd-4-yl) -phenlamine, which was used in the following steps without further purification: ESMS m / z 263.2 (Μ + H +).

Intermediary 19

4- (4-am-5-fluoro-2-methyl-phenol) -pperidium n-1-carboxylic acid ter

<img file="CU23952B1_D0050.tif" />

Pasol: 4-Trifluoro-methanesulfon¡lox¡-3,620 dihydro-2H-pyridi n-1-carboxylic acid terbutyl ester

A solution of A / -butoxy-carbonyl-4-piperidone (10.17 grams, 0.05 moles) in tetrahydrofuran (100 milliliters), was added dropwise to a cooled (-78 ° C) and vigorously stirred solution of LDA (40 milliliters of a 1.5M solution in cyclohexanes, 0.06 moles) in tetrahydrofuran (100 milliliters), under N₂. The reaction mixture was left at -78 ° C for 30 minutes before adding a solution of phenyl-trifluoro-sulfonimide (19.85 grams, 0.055 moles) in tetrahydrofuran (50 milliliters). Then the reaction mixture was heated to room temperature, and stirred for 3 hours. The reaction was quenched at 0 ° C with 100 milliliters of NH₄Saturated aqueous CI, and filtered through Celite. The filtrate was added to 100 milliliters of EtOAc, and the layers were separated. The organic layer was washed with H₂Or, dried over MgSO₄ and concentrated. The crude product was purified by silica gel chromatography (0 to 30 percent EtOAc in hexanes as eluent, and verified by TLC stained with KMnO₄ 2 percent in EtOH), to provide the 4-trifluoro-methane-suifonyloxy3,6-dih id ro-2H-pi r? di n-1-carboxylic acid terbutyl ester. Step 2: 4- (4,4,5,5-tetramet¡ 1-1,3,2-dioxaborolan-2-yl) -5,6-dihydropyridin-1 (2H) -butyl carboxylate

A solution of 4- (trifluoro-methyl-sulfonyloxy) -5,6-dihydropyridin-1 (2H) -butylcarboxylate (16.0 grams, 48.2 mmol) in dimethyl sulfoxide (200 milliliters) was treated with bis- (pinacholate) diboro (12.6 grams, 49.6 millimoles), potassium acetate (14.65 grams, 149 millimoles), and Pd (dppf) CI₂ (790 milligrams, 0.96 millimoles). The solution was purged with N₂ (g) for 5 minutes, and then sealed and heated at 80 ° C for 15 hours. The reaction was cooled to room temperature, and poured into ice water. The mixture was extracted with ethyl acetate (100 milliliters, 3 times). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (15 percent ethyl acetate in hexanes), to provide 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-1) -5,6-d ihydro-pyrid and n-1 (2H) -butyl carboxylate as a white solid.

Steps 3 and 4: _4- (4-amine-5-fluoro-2-methyl-phenol) -pperidin-1 terbutyl carboxylate

To a mixture of 5'-chloro-N, 2'-dimethyl-4'-nitrobiphenyl-4-carboxamide (204 milligrams, 1 millimol), 4- (4,4,5,5-tetramethyl-1,3,2d oxa boron la n-2-yl) -5,6-d ihydro-pyrid in-1 (2H) -butyl carboxylate (370 milligrams, 1.2 millimoles), and sodium carbonate (742 milligrams, 7 millimoles) in N, Nd¡met¡l-formam¡da / H₂Or (12/3 milliliters), tetrakis- (trifenii-phosphine) -palladium (0) (58 milligrams, 5 millimolar percent) was added. The reaction tube was sealed, the mixture was purged with N₂ for 3 minutes, and then heated at 90 ° C under N₂ overnight. The reaction was cooled to room temperature, and poured into a saturated aqueous solution of ammonium chloride. The crude reaction mixture was extracted with ethyl acetate (15 milliliters, 3 times). The organic extracts were combined, washed with brine, and concentrated. The crude product was purified by silica gel chromatography (20 percent ethyl acetate in hexanes), to provide 4- (4-amino-5-fiuoro2-methyl-phenyl) -5,6-dihydro-pyrid¡ n-1 (2H) -butyl carboxylate as a yellow oil. The oil obtained was dissolved in methanol (20 milliliters). To the solution was added Pd / C (at 10 percent). The reaction mixture was degassed and purged with H₂ several times, and stirred under H₂ (1 atmosphere) overnight. The mixture was filtered and concentrated, to provide terbutyl 4- (4-amino-5-fluoro-2-methyl-phenyl) piperidin-1-earboxylate as a white solid. ESMS m / z 207 (M -Boc + H⁺).

Intermediary 20

2,5-d¡met¡l-4- (piper¡d¡n-2-il) -aniline

<img file="CU23952B1_D0051.tif" />

To a mixture of 1-bromo-2,5-dimethyl-4-nitro-benzene (185 milligrams, 1 millimol), and 2- (tributyl-stanyl) -pyridine (202 milligrams, 1.1 millimoles) in Ν, N-dimethyl -formamide (4 milliliters), tetrakis- (triphenyl phosphine) -palladium (0) (58 milligrams, 5 millimolar percent) was added. The reaction tube was sealed, the mixture was purged with N₂for 3 minutes, and then heated at 120 ° C under N₂ overnight. The reaction was cooled to room temperature, and poured into a saturated aqueous solution of ammonium chloride. The crude reaction mixture was extracted with ethyl acetate (15 milliliters, 3 times). The organic extracts were combined, washed with brine, and concentrated. The crude product was purified by silica gel column chromatography (60 percent ethyl acetate in hexanes), to provide 2- (2,5-dim et i I-4-n it ro-f eni I) Pyridine as a white solid. The solid obtained was dissolved in acetic acid / trifluoroacetic acid (15 ml / 200 microliters). PtO was added to this solution.₂ (at 10 percent by weight / weight). The reaction mixture was degassed and purged with H₂ several times, and stirred under 1 atmosphere of hydrogen gas overnight. The mixture was filtered and concentrated to provide 2,5-dimethyl-4 (pi pe rid i n-2-i I) -ani I ina as a yellow oil. ESMS m / z 205 (M + H⁺ ).

Intermediary 21

3- (4-am ino-2,5-d imethyl-feniPazetid and n-1-terbutyl carboxylate

<img file="CU23952B1_D0052.tif" />

Neither

Boc

Step 1: 3- (2,5-dimethyl-4-nitro-phenyl) azetine-1-carboxylate terbutyl

It was prepared from 3-iodo-azetidin-1-carboxylate of terbutyl and 1-bromo-2,5-dimethyl-4-nitrobenzene, following the general protocol as described in Billotte, S. Synlett 1998, 379.

Step 2: 3- (4-amino-2.5-d¡met¡l-phenyl) azetidin-1-terbutyl carboxylate

Terbutyl 3- (2,5-dimethyl-4-nitro-phenyl) -azetidine-1-carboxylate was reduced to 3- (4-amino-2,5-dimethyl-phenyl) -azetidin-1- terbutyl carboxylate by conventional hydrogenation with Nickel

Raney at room temperature using methanol as the solvent.

Intermediary 22

5-ethyl-2-methyl-4- (piperidin-4-¡l) -aniline

<img file="CU23952B1_D0053.tif" />

Step 1: 4- (4-am-5-methyl-2-vinyl-phenyl) -5,6-dihydro-pridrid-1 (2H) terbutyl carboxylate

To a mixture of 4-bromo-5-chloro-2-methyl-aniline (500 milligrams, 2.27 millimoles), 4- (4,4,5,5-tetra meti 1-1,3,2-di oxa boron lan-2-¡1) -5,6-dihydro-pyridin-1 (2H) -butyl carboxylate (840 milligrams, 3.73 millimoles), and sodium carbonate (2.52 grams, 15.9 millimoles) in N, Nd¡met¡l -formam¡da / H₂0 (20/5 milliliters), tetrakis (triphenyl-phosphine) -paladine (0) (131 milligrams, 5 mole percent) was added. The reaction tube was sealed, the mixture was purged with N₂ for 3 minutes, and then heated at 100 ° C under N₂ overnight. The reaction was cooled to room temperature, and poured into a saturated aqueous solution of ammonium chloride. The crude reaction mixture was extracted with ethyl acetate (15 milliliters, 3 times). The organic extracts were combined, washed with brine, and concentrated. The crude product was purified by silica gel chromatography (80 percent ethyl acetate in hexanes), to provide 4- (4-amino-2-chloro-5-methyl-phenol) -5, 6d I hid ro-p ir id in -1 (2H) -butyl carboxylate as a yellow solid. This product obtained (322 milligrams, 1 millimol) was dissolved in dioxane / NMP (anhydrous, 4 milliliters, 3/1). To this solution was added tributyl- (v¡n¡l) -tantane (380 milligrams, 1.2 millimoles), cesium fluoride (304 milligrams, 2 millimoles), and bis- (tri-terbutyl-phosphine) -palladium (51 milligrams, 10 mole percent). This mixture was purged with N₂ for 3 minutes, and then heated in a sealed tube at 120 ° C overnight. The mixture was cooled to room temperature, and diluted with ethyl acetate. The resulting mixture was washed in sequence with saturated aqueous ammonium chloride and brine, and finally dried over sodium sulfate. After concentration, the crude product was purified by silica gel chromatography (10 percent ethyl acetate in hexanes), to provide 4- (4-amino-5-methyl-2-vinyl) phenyl) -5,6-dihydro-pyridin1 (2H) -butyl carboxylate as a light yellow oil; ESMS m / z 215.2 (M -Boc + H⁺ ).

Step 2: 5-ethyl-2-methyl-4- (piperidin-4-yl) -aniline

The product obtained from the previous step was dissolved in methanol (20 milliliters). To this solution was added concentrated aqueous HCI (200 microliters), and platinum oxide (23 milligrams, 0.1 millimoles). The reaction mixture was degassed and purged with H₂ several times and stirred vigorously under 1 atmosphere of H₂during 3 hours. The mixture was filtered and concentrated to give 5-et-I-2-methyl-4- (pi pe ri di n-4-i I) -ani I ina as a yellow solid. ESMS m / z 219.2 (M + H⁺ ).

Intermediary 23

2,5-dimethyl-4- (piperidin-3-¡) -anil¡na

<img file="CU23952B1_D0054.tif" />

Step 1: 2,5-dim eti I-4- (pi rid i η-3-i I) -an i I i na

A suspension of 4-bromo-2,5-dimethyl-anllna (4.00 grams, 20 millimoles), pyridin-3-yl-boronic acid (2.70 grams, 11 millimoles), Pd₂(dba)₃ (0.55 grams, 0.6 mmol), 2-dicyclohexyl-phosphine-2 ', 6-dimethoxy-biphenyl (0.98 grams, 1.2 millimoles), and Na₂CO₃ (10.6 grams, 100 millimoles) in n-BuOH (50 milliliters), was degassed by a stream of argon gas for 15 minutes. The reaction flask was sealed and placed in a previously heated oil bath (115 ° C). After stirring overnight, the reaction was cooled, and filtered. The filter cake was washed with dichloromethane, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in EtOAc (150 milliliters). The EtOAC was washed in sequence with water (20 milliliters), brine (20 milliliters), dried over Na₂SW₄ and evaporated. The crude product was purified by silica gel chromatography (gradient from 0 to 50 percent EtOAc in hexanes), to give 2,5-dm and i-4- (pd di n-3 -i I) -an ¡ina as a yellow solid; ESMS m / z 199.1 (M + H⁺).

Step 2: 2,5-dimetl-4- (pperid-3-yl) -an¡l¡na

The 2,5-d ¡met¡ I-4- (p¡ r¡ d¡ η-3-¡l) -an i I na (403 milligrams, 2.03 millimoles) was dissolved in methanol (5 milliliters), and Concentrated aqueous HCI (1 milliliter), followed by the addition of PtO₂ (40 milligrams). The flask was purged with H₂ and the reaction was vigorously stirred at room temperature under H₂ (1 atmosphere). After two days, the LCMS showed the termination of the reaction. The catalyst was removed by filtration and the remaining solution was concentrated in vacuo to give 2,5-dimethyl-4- (pi pe rid i-3-i-I) -ani Ii na as a white solid, which can be used in the following reactions without further purification; ESMS m / z 205.2 (M + H⁺).

Broker 24

1- (Terbutox¡-carbonyl- (methyl) -amino) -cyclopropan-carboxylic acid

OH

<img file="CU23952B1_D0055.tif" />

Boc

To a solution of 1- (terbutoxycarbonyl-amino) cyclopropan-carboxylic acid (201 milligrams, 1.0 millimoles) in Ν, imedimethyl-formamide (2 milliliters), NaH (120 milligrams, 3.0 millimoles) was added at 0 ° C . The resulting mixture was stirred at 0 ° C for 10 minutes, before the addition of Mel (568 milligrams, 4.0 millimoles). The mixture was then heated to room temperature, and stirred for 2 hours. To the mixture was added a saturated aqueous NH solution₄CI (20 milliliters), and the solution was extracted with EtOAc (10 milliliters, 3 times). The combined organic layers were concentrated, and the residue was dissolved in methanol (3 milliliters) with NaOH (3 N, 1 milliliter). This mixture was stirred at 80 ° C for 1 hour, and cooled to room temperature. The clear solution was purified directly on HPLC in the reverse phase of preparation, to provide 1- (terbutoxycarbonyl- (methyl) -amino) cyclopropancarboxylic acid. ESMS m / z 238.2 (M + Na⁺ ).

Intermediary 25 (R) -2-b romo-pro pan amida

Br

<img file="CU23952B1_D0056.tif" />

OR

Step 1: (R) -2-Bromo-propanoyl chloride

Under nitrogen, to the solution of (R) -2-bromo-propanoic acid (5.0 grams, 32.68 mmol) in 100 milliliters of dichloromethane, thionyl chloride (7.1 milliliters, 98.04 millimoles), and 1 milliliter of dimethyl formamide in sequence at 0 ° C. The reaction was stirred at room temperature overnight, and concentrated in vacuo. The resulting crude product was used directly in the next step without further purification.

Step 2: (R) -2-Bromo-propanamide

The (R) -2-bromo-propanoyl chloride was added slowly to a solution of 37 percent ammonium hydroxide in water, cooled to 0 ° C. The reaction was allowed to warm to room temperature, and stirred for 2 hours. The product was extracted with EtOAc, and the collected organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to provide (R) -2-bromopropanamide.

Intermediary 26 (R) -2-b rom o- / V-meti lp Ropana mida

Br

<img file="CU23952B1_D0057.tif" />

The (F?) - 2-bromo-propanoyl chloride was added slowly to a solution of methyl amine / water cooled to 0 ° C. The reaction was allowed to warm to room temperature, and stirred for 2 hours. The product was extracted with EtOAc, and the collected organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to provide (R) -2-bromo- / V-methyl propanamide.

Intermediary 27

Acid 1 - (terbutoxycarbonyl- (ethyl) -amino) -cyclopropan-carboxylic acid

HO

Step 1: 1 - (te rb u toxi-ca rbon i l- (eti l) -am i no) -ci cio propan-carboxy ethyl can

Under nitrogen, to the solution of 1- (terbutoxycarbonylamino) -cyclopropan-carboxylic acid (201.2 milligrams, 1.0 millimoles) in 4 milliliters of dimethyl formamide, NaH (120.0 milligrams, 3.0 millimoles) was added at 0 ° C. After 30 minutes of stirring, iodine-ethane (0.4 milliliters, 5.0 millimoles) was added to the reaction. The reaction was gradually heated to room temperature, and stirred overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to provide the

- (terbutoxy-ca rbo n ¡l- (et¡l) -am¡no) -ciopropan-ethyl ethyl carboxylate, which was used in the next step without further purification. Step 2: 1- (terbutoxycarbonyl- (etl) -amino) -cyclopropancarboxylic acid

The crude product from step 1 was dissolved in a mixture of EtOH (4.0 milliliters) and water (1.0 milliliters). To the reaction was added LIOH (82.0 milligrams, 2.0 millimoles). The reaction was heated at 120 ° C in a microwave reactor for 10 minutes. The reaction was concentrated in vacuo, and the crude product was partitioned between

EtOAc and water. The water layer was neutralized with 4N aqueous HCI at a pH of 4, and then extracted with EtOAc. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to provide 1- (terbutoxycarbonyl- (ethyl) -amino) c-clop n-carboxylic acid.

Broker 28

Acid 1 - (terbutox ¡-carbonyl- (ethyl) -am¡no) -cyclobutan-carb oxy Ileo

<img file="CU23952B1_D0058.tif" />

Step 1: 1- (terbutox¡-carbon¡l- (et¡l) -am¡no) -c¡clobutan-carboxylate

Under nitrogen, to the solution of 1- (terbutoxycarbonylamine) -cyclobutane-carboxylic acid (430.0 milligrams, 2.0 millimoles) in 4 milliliters of dimethylformamide, NaH (240.0 milligrams,

6.0 millimoles) at 0 ° C. After stirring for 30 minutes, iodine-ethane (0.8 milliliters, 10.0 millimoles) was added to the reaction. The reaction was gradually heated to room temperature, and stirred overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to provide crude ethyl 1- (terbutoxycarbonyl (ethyl) -amino) -cyclobutan-carboxylate.

Step 2: 1- (Terbutoxycarbonyl- (ethyl) -amino) -cyclobutanecarboxylic acid

The crude product from step 1 was dissolved in EtOH (4.0 milliliters), and water (1.0 milliliters). LiOH (164.0 milligrams, 4.0 millimoles) was added to the reaction. The reaction was heated at 120 ° C in a microwave reactor for 10 minutes. The reaction was concentrated in vacuo, and the crude product was partitioned between EtOAc and water. The water layer was neutralized with 4N aqueous HCI at a pH of 4, and then extracted with EtOAc. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to provide 1 - (terbutoxycarbonyl- (ethyl) -amino) -cyclobutan-carboxylic acid.

Broker 29

1 - (Terbutoxycarbonyl- (methyl) -amino) -cyclobutan-carboxylic acid

<img file="CU23952B1_D0059.tif" />

Step 1: M1 - (terbutoxycarbonyl- (ethyl) -amino) -cyclobutane-ethyl carboxylate

Under nitrogen, to the solution of 1- (terbutoxycarbonyl85 ammonium) -cyclobutane-carboxylic acid (430.0 milligrams, 2.0 millimoles) in 4 milliliters of dimethyl formamide, NaH (240.0 milligrams, 6.0 millimoles) at 0 ° C. After stirring for 30 minutes, iodine-methane (0.62 milliliters, 10.0 millimoles) was added to the reaction. The reaction was gradually heated to room temperature, and stirred overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to give the crude ethyl ethyl M1- (terbutoxycarbonyl (ethyl) -amino) -cyclobutanecarboxylate.

Step 2: 1- (Terbutoxycarbonyl- (methyl) -amino) -cyclobutanecarboxylic acid

The crude product from step 1 was dissolved in methanol (4.0 milliliters), and water (1.0 milliliters). LiOH (164.0 milligrams, 4.0 millimoles) was added to the reaction. The reaction was heated to

120 ° C in a microwave reactor for 10 minutes. The reaction was concentrated in vacuo, and the crude product was partitioned between EtOAc and water. The water layer was neutralized with 4N aqueous HCI at a pH of 4, and then extracted with EtOAc. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to provide 1- (terbutoxycarbonyl- (methyl) -amino) -cyclobutanecarboxylic acid.

Intermediary 30

2-Bromo-Butanamide

Br

NH25

Under nitrogen, to a solution of 2-bromo-butanoic acid (2.0 grams, 12.0 millimoles) in dichloromethane (50 milliliters) at 0 ° C, thionyl chloride (2.6 milliliters, 35.9 millimoles) was added in sequence, and 0.5 milliliters of Ν, Ν-dimethylformamide. The reaction was allowed to warm to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo, and then cooled to 0 ° C. Thirty (30) milliliters of 37 percent aqueous ammonium hydroxide was slowly added. The reaction was allowed to warm to room temperature, and stirred for 2 hours, followed by extraction with EtOAc. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to provide the

2-bromo-butanam¡da.

Intermediary 31

2-bromo- / V-met¡l-butanam¡da

<img file="CU23952B1_D0060.tif" />

NH

Under nitrogen, to a solution of 2-bromo-butanoic acid (2.0 grams, 12.0 millimoles) in dichloromethane (50 milliliters) at 0 ° C, were added in sequence, thionyl chloride (2.6 milliliters, 35.9 millimoles), and 0.5 milliliters of Ν, Ν-dimethyl formamide. The reaction was allowed to warm to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo, and then cooled to 0 ° C. Thirty (30) milliliters of a 40 percent methyl amine / water solution was added slowly. The reaction was allowed to warm to room temperature, and stirred for 2 hours, followed by extraction with EtOAc. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to provide the

2-bromo- / V-met¡ l-bu tana measure.

Broker 32

2-Bromo- / V-ethyl-butanamide

Br ·

Under nitrogen, to a solution of 2-bromo-butanoic acid (2.0 grams, 12.0 millimoles) in dichloromethane (50 milliliters) at 0 ° C, thionyl chloride (2.6 milliliters, 35.9 millimoles) was added in sequence, and 0.5 milliliters of N, N-dimethylformamide. The reaction was allowed to warm to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo, and then cooled to 0 ° C. Thirty (30) milliliters of a 40 percent ethyl-amine / water solution was added slowly. The reaction was allowed to warm to room temperature, and stirred for 2 hours, followed by extraction with EtOAc. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo, to provide the

2-Bromo- / V-ethyl-butanamide.

Intermediary 33

- (met¡l-sulfon¡l) -azet¡d¡n-3-one

<img file="CU23952B1_D0061.tif" />

To a mixture of 3-azetidinone hydrochloride (471 milligrams, 3.28 millimoles), and K₂CO₃ (1.50 grams, 11 millimoles) in CHCI₃/ H₂Or (5/5 milliliters), methanesulfonic anhydride (1.14 grams, 6.57 millimoles) was added in a portion at 0 ° C. After stirring for 2 hours, the reaction was diluted with NaHCO₃ saturated aqueous (5 milliliters), and extracted with dichloromethane (25 milliliters, 3 times). The combined dichloromethane layers were washed with brine (5 milliliters), dried over Na₂SW₄ and evaporated, to provide 1- (methyl-sulfonyl) -azetidin-3-one as a grayish solid, which was used without further purification; ¹H NMR (400 MHz, CDCI₃) δ 4.82 (s, 4H), 3.05 (s, 3H).

Example 1

5-Chloro-N2- (2-fluoro-5-methyl-4- (1-methyl-piperidn-4-l) -fen¡l) -N4- (5methyl-1 H-pyrazole-3-yl ) -pyrimid n-2,4-dinamine (1)

<img file="CU23952B1_D0062.tif" />

Step 1: A mixture of 2,5-dichloro-N- (5-methyl-1 H-pyrazol-3-yl) pyrimidin-4-amine (Intermediary 1, 132 milligrams, 0.54 millimoles), and 4- (4 -amino-5-fluoro-2-methyl-phenyl) -piperidine-1-terbutyl carboxylate (Intermediary 19, 166 milligrams, 0.54 mmol) in 2-propanol (15 milliliters) was treated with concentrated aqueous HCI (14 drops ). The mixture was sealed and heated in a microwave reactor at 130 ° C for 60 minutes. The mixture was concentrated to provide 5-chloro-N225 (2-f luoro-5-met¡ 1-4- (pperperd-4-yl) -phenyl) -N4- (5 -met¡ 1-1 H-pyrazol-3-i I) pyrmidium-2,4-diamine as a yellow solid. A portion of the crude product was purified by reverse phase HPLC of preparation, to provide 5-chloro-N2- (2-fluoro-5-methyl-4 (pi perid in-4-yl) -phenyl) -N4- ( 5-meti 1-1 H-pi razo l-3-yl) -pyrimid and n-2,4-diamine as a white solid; ESMS m / z 416.1 (M + H⁺). The rest of the crude product was used directly for the next step without further purification.

Step 2: To a solution of the crude product from the previous step in tetrahydrofuran (5 milliliters), and methanol (5 milliliters), formaldehyde (100 microliters, 1.3 millimoles), and 10 drops of AcOH were added in sequence. The reaction mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (175 milligrams, 2.78 mmol) was added in one portion, and the reaction was stirred for an additional 30 minutes. The reaction was quenched with NH₄Saturated aqueous CI and concentrated in vacuo to give an oily residue. The residue was purified by reverse phase HPLC of preparation, to provide 5-chloroN2- (2-fluoro-5-methy 1-4- (1-methyl-piperine-4-yl) -phenyl) -N4- (5-methyl-1 Hpyrazol-3-yl) -pyrimidin-2,4-diamine as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 10.33 (br, 1H), 9.90 (br, 1H0, 9.60 (br, 1H), 8.22 (s, 1H), 7.56 (d, 1H), 7.00 (d, 1H ), 6.20 (s, 1H), 3.53-3.50 (m, 2H), 3.16-3.10 (m, 2H), 2.97-2.92 (m, 1H), 2.81 (d, 3H), 2.26 (s, 3H), 2.16 (s, 3H), 1.94-1.91 (m, 2H), 1.83-1.73 (m, 2H); ESMS m / z 430.1 (M + H ⁺ ).

Example 2

5-Chloro-N2- (2-fluoro-5-methyl-4- (piper¡d¡n-4-¡l) -fen¡l) -N4- (5-methyl-1 Hp¡razol-3-¡ l) -p¡r¡m¡d¡n-2,4-d¡amina (2)

<img file="CU23952B1_D0063.tif" />

A mixture of 2,5-dichloro-N- (5-methyl-1 H-pi razo I-3-i I) -pi ri m id i n4-amine (Intermediary 1, 132 milligrams, 0.54 millimoles), and 4 - (4-amino-5-fluoro-2-methyl-phenyl) -p¡per¡d¡n-1-terbutyl carboxylate (Intermediary 19, 166 milligrams, 0.54 millimoles) in 2-propanol (15 milliliters) was treated with HCI aqueous concentrated (14 drops). The mixture was sealed and heated in a microwave reactor at 130 ° C for 60 minutes. The mixture was concentrated to provide 5-chloro-N2 (2-fluoro-5-methyl-4- (piperidin-4-yl) -phenyl) -N4- (5-methyl-1 H-pyrazol-3-yl) pyrimidin-2,4-diamine as a yellow solid. A portion of the crude product was purified by reverse phase HPLC of preparation, to provide 5-chloro-N2- (2-fluoro-5-methyl-4 (pi pe rid i n-4-i I) -fe ni I ) -N4- (5-m eti I-1 H-pyrazol-3-yl) -pyrimin-2,4-diamine as a white solid; ESMS m / z 416.1 (M + H⁺).

Examples 3 and 4 (S) -3- (5-chloro-2- (2-fluoro-5-methyl-4- (1-methyl-piperidin-4-yl) -phenylamino) pyrimidin-4- L-amino) -azepan-2-one (10)

<img file="CU23952B1_D0064.tif" />

(/?) - 3- (5-Chloro-2- (2-fluoro-5-met¡ 1-4- (1 -meti l-piperidin-4-yl) -phenyllamino) pyrimidin-4-yl- amino) -azepan-2-one (11)

<img file="CU23952B1_D0065.tif" />

La (±) -3- (5-Chloro-2- (2-fluoro-5-methyl-4- (1-methyl-piperidin-4-¡) phenyl-amine) -primimin- 4-yl-amne) -azepan-2-one was synthesized by the same series of procedures as described in Example 1, using Intermediary 6 and Intermediary 19. Chiral separation of the racemic mixture was conducted by normal phase HPLC using a ChiralPaK AD column using the following solvent system: hexanes (80 percent), and PrOH (20 percent) modified with 0.1 percent diethyl amine . The two peaks of the purified enantiomers were collected separately: (S) -3 (5-Chloro-2- (2-fluoro-5-methyl-4- (1-methyl-piperidin-4-yl) -phenyl -amino) pyrimidin-4-yl-amino) -azepan-2-one and (R) -3- (5-chloro-2- (2-fluoro-5m eti 1-4- (1-methyl-piperid i n -4-yl) -feni l-am ino) -pi rimid i η-4-i l-am i no) 25 azepan-2-one; Both peaks: ESMS m / z 461.2 (M + H⁺). The earliest elution peak (Rt = 7.26 minutes.), And the latest elution peak (Rt = 10.17 minutes.) Were arbitrarily assigned as the enantiomers (S) and (R), respectively.

Example 5

5-cl or ro-N 2- (4- (1 - ((3,5-d¡methyl-¡soxazol-4-yl) -methyl) -piper¡d¡n-4-¡l) -2fluoro- 5-met¡l-fen il) -N4- (5-met¡ 1-1 H-pi razo l-3-i I) -p¡ rim ¡di n-2,4-dia mine £ 191

<img file="CU23952B1_D0066.tif" />

To a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (pperidin-4-yl) phenyl) -N4- (5-methyl-1 H-pi razol-3- il) -pyrimid ID n-2,4-diamine (0.12 mmol) and triethyl amine (83 microliters, 0.6 millimoles) in Ν, Ν-dimethylformamide (1.5 milliliters), 4- (chloro-methyl) was added - 3,5-dimethylisoxazole (35 milligrams, 0.24 millimoles). The mixture was stirred at room temperature for 3 hours. The reaction was filtered, and the filtrate was purified by reverse phase HPLC of preparation to provide 5-chloro-N2- (4- (1 - ((3,5-dimethyl-isoxazol-4-l) methyl ) -piperid¡n-4-¡l) -2-fluoro-5-methyl-phenyl) -N4- (5-methyl-1 H-pyrazol-3-yl) -p¡rim¡din-2,4-diam¡ Na as a white solid. ¹H NMR (400 MHz, MeOD-d4) 8.12 (s, 1H), 7.75 (d, 1H), 7.03 (s, 1H), 6.27 (s, 1H), 4.25 (s, 2H), 3.69-3.67 (m , 2H), 3.27-3.20 (m, 3H), 2.54 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 2.10-1.95 (m, 4H); ESMS m / z 525.1 (M + H +).

Example 6

2- (4- (4- (5-Chloro-4- (5-Methyl-1 Hp¡razol-3-L-Amne) -p¡r¡mid¡n-2-Lamino) -5-fluoro-2-methyl-phenol -piper-1-U-ethanol (22)

<img file="CU23952B1_D0067.tif" />

N

H

Ν NH

F

5-Chloro-N2- (2-fluoro-5-met¡l-4- (p¡per¡d¡n-4-¡l) -fen¡l) -N4- (5met¡l-1 H- Plrazol-3-¡) -p¡rim¡d¡n-2,4-d¡am¡na (0.12 mmol) was dissolved in anhydrous Ν, Ν-dimethyl-formamide (1 milliliter). Triethyl-amine (50 microliters, 0.36 millimoles, 3 equivalents) was added, followed by 2-bromo-ethanol (0.018 milliliters, 0.24 millimoles, 2 equivalents) dissolved in Ν, Ν-dimethyl-formamide anhydrous (0.7 milliliters). The reaction vessel was sealed and heated in a microwave reactor at 100 ° C for 20 minutes. After cooling to room temperature, the reaction was concentrated and the crude product was purified using reverse phase HPLC of preparation to give 2- (4- (4- (5-clo ro-4- (5-methyl) 1 H-pi razol-3-il-am¡no) -p¡ rim idin-2-¡Ιθ mino) -5-f I uo ro-2-m eti If eni I) -pi pe r ¡d ¡n -1 - i I) -eta η ol as a white solid: ESMS m / z 460.2 (Μ + H +).

Example 7

5-chloro-N²- (2-fluoro-5-meti 1-4- (1 - (3,3,3-trfluoro-propyl) -pperidin-4-yl) phenol) -N⁴- (5-methyl-1 Hp¡razol-3-¡) -pirlm¡d¡n-2,4-d¡am¡na (24)

<img file="CU23952B1_D0068.tif" />

The mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperine-4-hel) phenolic) -N4- (5-methyl-1 H -pyrazol-3-¡) -p¡r¡m¡din-2,4-d¡am¡na (0.12 millimoles), 3-bromo-1,1,1-trifluoro-propane (85.0 microliters, 0.60 millimoles ), and trieti l-ami na (102.0 microliters, 0.60 mmol) in 2 milliliters of dimethyl formamide was stirred overnight. The reaction mixture was purified by reverse phase HPLC of preparation to provide 5-chloro-N2- (2-fluoro-5-methyl-4- (1 (3,3,3-trifluoro-propyl) -piperidin-4 -yl) -phenyl) -N4- (5-methyl-1 H -pyrazol-3i) -p¡ ri m id i n-2,4-d ¡mi mi a. ESMS m / z 512.2 (M + H⁺).

Example 8

3- (4- (4- (5-Chloro-4- (5-methyl-1 H-pyrazol-3-yl-amino) -pyrimin-2-ylamino) -5-fluoro-2-methyl -phenyl) -piperidin-1-yl) -1,1, 1 - trifluoro-propan-2ol (30)

<img file="CU23952B1_D0069.tif" />

The mixture of 5-clo ro-N2- (2-fl uoro-5-methyl-4- (pipe rid i n-4-Ijfen il) -N4- (5-meti 1-1 H-pi razol-3 -il) -pyrm id in-2,4-d amine (50.0 milligrams, 0.12 millimoles), and 2- (trifluoro-methyl) -oxyran (67.8 milligrams, 0.60 millimoles) in 2 milliliters of dimethyl formamide is He stirred overnight. The reaction mixture was purified by reverse phase HPLC of preparation to provide 3- (4- (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2 -yl-amine) -5-fluoro2-methyl-phenyl) -piperidin-1 -iI) -1,1,1 -triflu oro-pro pan-2-ol. ESMS m / z

528.2 (M + H⁺).

Example 9

2- (4- (4- (5-clo ro-4- (5-met i 1-1 Hp¡razol-3-il-am¡no) -pir¡m¡d¡n-2-ilam¡ no ) -5-fluoro-2-met¡ l-fen¡l) -p¡per¡d¡ n-1 - II) -acetamide (39)

To a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (pperidin-4-yl) phenolic) -N4- (5-methyl-1 H-pyrazole- 3-yl) -pyrimidin-2,4-diamine (0.12 millimoles), and trletll-amine (50 microliters, 0.36 millimoles) in N, Nd¡met¡lformamlda (1.5 milliliters), 2-bromo-acetamlda was added ( 33 milligrams, 0.24 millimoles). The mixture was stirred at room temperature for 2 hours. The reaction was filtered, and the filtrate was purified by reverse phase HPLC of preparation to give the 2 (4- (4- (5-chloro-4- (5-methyl-1 H-pi razol-3-1-) am¡ no) -p¡r¡m ¡di n-2-¡-am-no) 5-fluoro-2-met¡l-fen¡l) -p¡per¡d¡n-1-ll) -acetam¡da as a white solid: ¹H NMR (400 MHz, MeOD-d₄) δ 8.11 (s, 1H), 7.76 (d 1H), 7.09 (d, 1H), 6.27 (s, 1H), 4.0 (s, 2H), 3.75-3.73 (m, 2H), 3.22-3.13 (m , 3H), 2.34 (s, 3H), 2.30 (s, 3H), 2.04 -2.00 (m, 4H); ESMS m / z 473.2 (M + H⁺ ).

Example 10

5-c parrot-N2- (2-fluoro-5-met ¡1-4- (1 - (2- (methyl-sulfon¡l) -et¡l) -p¡per¡d¡n-4il ') -phenyl ') - N4- (5-methyl-1 H -pyrazol-3-yl) -pyrmidine-2,4-diamine (55)

<img file="CU23952B1_D0070.tif" />

To a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1 Hp¡razol-3-yl) -p¡ r¡m¡d¡n-2,4-d¡am¡na (0.12 millimoles), and triethyl amine (83 microliters, 0.6 millimoles) in Ν, Νdimethylformamide (1.5 milliliters), methyl vinyl was added -sulfone (38 milligrams, 0.36 millimoles). The mixture was stirred at room temperature for 1 hour. The reaction was filtered, and the filtrate was purified by reverse phase HPLC of preparation, to provide 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (2- (methyl-sulfonyl)) - ethyl) -piperidin-4l) -phenyl) -N4- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-2,4-day as a white solid. ESMS m / z 522.1 (Μ + H +).

Example 11

5-Chloro-N2- (2-fluoro-5-methyl-4- (1 - (methyl-sulfonyl) -piperidin-4-yl) -phenyl) N4- (5-methyl-1 H-pyrazole-3 -il) -p¡r¡m¡din-2,4-d¡amina (621

<img file="CU23952B1_D0071.tif" />

SW₂Me

To a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) 97 phenyl) -N4- (5-methyl-1 Hp¡razol-3-yl) -pi rimine di n-2,4-di amine (0.12 mmol), and triethyl amine (50 microliters, 0.36 mmol) in Ν, Ν-dimethylformamide (1.5 milliliters), methanesulfonyl chloride (18 microliters) was added. 0.24 millimoles). The mixture was stirred at room temperature for 2 hours. The reaction was filtered, and the filtrate was purified by reverse phase HPLC to give 5clo ro-N2- (2-fluoro-5-methyl-4- (1 - (methylsulfonyl) -pi perid in-4-yl) -phenyl) N4- (5-methyl-1 H-pyrazol-3-yl) -p¡r¡m¡din-2,4-diamine as a white solid: ESMS m / z 494.2 (M + H ⁺ ).

Example 12

4- (4- (5-Chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl-amino) -5fluoro-2-methyl-phenyl) -piperidine -1-ethyl carboxylate (66)

<img file="CU23952B1_D0072.tif" />

<img file="CU23952B1_D0073.tif" />

To a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidine-4-yl) phenyl) -N4- (5-methyl-1 H -pyrazol-3-yl) - pyrimide-2,4-day (0.12 mmol), and triethyl amine (50 microliters, 0.36 mmol) in Ν, Ν-dimethylformamide (1.5 milliliters), ethyl chloro-format was added (26 milligrams, 0.24 millimoles). The mixture was stirred at room temperature for 2 hours. The reaction was filtered, and the filtrate was purified by reverse phase HPLC of preparation, to give the

4- (4- (5-Chloro-4- (5-methyl-1 H -pyrazol-3-ll-amine) -pyrimidin-2-yl-amino) -5fluoro-2-methyl- phenyl) -piperidin-1-ethyl carboxylate as a white solid: ¹H NMR (400 MHz, MeOD-d₄) δ 8.13 (s, 1H), 7.54 (d, 1H), 7.10 (d, 1H), 6.28 (s, 1H), 4.30-4.26 (m, 2H), 4.14 (q, 2H), 2.99-2.96 ( m, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.8-1.77 (m, 2H), 1.64-1.55 (m, 2H), 1.28 (t, 3H); ESMS m / z 488.2 (M + H⁺).

Example 13

4- (4- (5-Chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl-amine) -5fl uoro-2-methyl-phenyl ) -N, N-di meti l-pic perid in-1 -carboxamide (69)

<img file="CU23952B1_D0074.tif" />

To a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperine-4-yl) phenyl) -N4- (5-methyl-1 H-pyrazol-3-yl ) -pyrimidin-2,4-diamine (0.12 mil, 15 moles), and triethyl amine (83 microliters, 0.6 millimoles) in Ν, Ν-dimethylformamide (1.5 milliliters), dimethylcarbamic chloride (39 milligrams, 0.36 millimoles). The mixture was stirred at room temperature for 1 hour. The reaction was filtered, and the filtrate was purified by reverse phase HPLC of preparation, to provide the

4- (4- (5-Chloro-4- (5-methyl-1 H -pyrazol-3-yl-amine) -pyrimin-2-yl-amino) -5fluoro-2-methyl-phenyl) -N, N-dimethyl-piperidin-1-carboxamide as a white solid. ESMS m / z 487.2 (Μ + H +).

Example 14

- (4- (4- (5-Chloro-4- (5-methyl-1 H-pyrazol-3-yl-amino) -pyrimidin-2-yl25 ammonium) -5-fluoro-2-methyl -fen ¡l) -p¡per¡d¡ n-1 - ¡l) -2- (dimethyl-amino) -ethanone £ Ζ31

<img file="CU23952B1_D0075.tif" />

<img file="CU23952B1_D0076.tif" />

To a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperine-4-yl) phenolic) -N4- (5-methyl-1H-p¡ razol-3-¡) -p¡r¡m¡d¡n-2,4-diamna (0.12 millimoles), and triethyl amine (50 microliters, 0.36 millimoles) in Ν, Ν-dimethylformamide (1.5 milliliters ), 2- (dimethyl-amino) acetyl chloride (38 milligrams, 0.24 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was filtered, and the filtrate was purified by reverse phase HPLC of preparation, to give 1- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3-yl-amino) ) pyrmidine-2-yl-amino) -5-fIuoro-2-methyl-phenyl) -piperidin-1 -ii) -2- (dimethylamino) -ethanone as a white solid: ¹H NMR (400 MHz, MeOD-d₄) δ 8.08 (s, 1H), 7.71 (d, 1H), 7.03 (d, 1H), 6.26 (s, 1H), 4.71-4.67 (m, 2H), 3.81-3.77 (m, 2H), 3.14- 3.12 (m, 2H), 2.98 (s, 3H), 2.96 (s, 3H), 2.90-2.83 (m, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 1.87 (d, 2H) , 1.76-1.55 (m, 2H); ESMS m / z 501.2 (M + H⁺).

Example 15

- (4- (4- (5-Chloro-4- (5-methyl-1 Hp¡razol-3-yl-amino) -pimidin-2-ylamino) -5-fluoro-2-methyl-phenyl) -piperidin-1 -il) -2- (4-meti l-pipe razi n-1 -il) ethanone (105)

100

<img file="CU23952B1_D0077.tif" />

To the solution of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidine-4-yl) phenyl) -N4- (5-methyl-1 H-pyrazole-3- il) -p¡rim idi n-2,4-d amine (100.0 milligrams, 0.24 millimoles) in 4 milliliters of dichloromethane were added 2-chloro-acetyl chloride (23.0 microliters, 0.29 millimoles), and triethyl -amine (67.0 microliters, 0.48 millimoles), in sequence. The reaction was stirred at room temperature for 1 hour, and then washed with brine. The organic extract was dried over Na₂SW₄, followed by vacuum concentration, to provide a crude product. The crude product was mixed with 1-methylpiperazine (116.0 milligrams, 1.16 millimoles) in 3 milliliters of dimethyl formamide, and the reaction was stirred overnight at room temperature. The reaction mixture was purified by preparation HPLC, to provide 1- (4- (4- (5-chloro-4- (5methyl-1 H-pi razo l-3-yl-amino) -pyrim id in-2-i l-am ¡no) -5-f luo ro-2-methylfen¡l) -piperid¡n-1 -¡l) -2- (4-methyl-piperazin-1 - il) -ethanone . ESMS m / z 556.3 (M + H⁺ ).

Example 16

Azetid ¡n-3-¡- (4- (4- (5-chloro-4- (5-met¡ 1-1 Hp¡razol-3-l-am¡no) -p¡rimíd¡n2- ¡L-am¡no) -5-fluoro-2-met¡l-fen¡D-plperídln-1 - ¡l) -methanone (131)

101

<img file="CU23952B1_D0078.tif" />

To a mixture of 5-chloro-N2- (2-fluoro-5-meti-4- (p¡perld¡n-4-ll) fenll) -N4- (5-metll-1 Hp¡razol-3 -il) -p¡mid¡n-2,4-d¡amlna (0.12 mmol), di-isopropyl-ethyl-amine (50 microliters, 0.36 mmol), and

HATU (55 milligrams, 0.14 millimoles) in Ν, Ν-dimethyl-formamide (1.5 milliliters), 1- (terbutoxyl-carbon) -azetidine-3-carboxylic acid (29 milligrams, 0.14 millimoles) was added. After stirring at room temperature for 4 hours, the mixture was diluted with methanol (1 milliliter), and concentrated aqueous HCI (1 milliliter). The mixture was stirred at 50 ° C for 30 minutes. The mixture was filtered and purified by reverse phase HPLC preparation, to give the azetin-3-1- (4- (4- (5-chloro-4- (5-methyl-1H-p Razol-3-l-am¡no) -p¡r¡mldin2-l-am not) -5-fluoro-2-met¡ l-fen¡l) -piperid¡ n-1 - il) -meta nona as a white solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.08 (s, 1H), 7.68 (d,

2H), 7.04 (d, 2H), 6.26 (s, 1H), 4.74-4.68 (m, 2H), 4.39-4.35 (m, 1 H),

4.29-4.24 (m, 2H), 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, 3H), 2.28 (s, 3H), 1.87-1.84 (m, 2H), 1.66-1.56 (m, 2H); ESMS m / z 499.2 (M + H⁺ ).

Example 1 7

5-chloro-N²- (2-Fluoro-5-methyl-4- (1 - (tetrahydro-1,1-dioxide-3-thienyl) 102 p? Perddn-4-l) -phenyl) -N⁴- (5-met¡ 1-1 / 7-p¡razol-3-¡) -p¡ rim ¡di n-2,4-d ¡amina

<img file="CU23952B1_D0079.tif" />

To 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) -phenyl) -N4- (5m eti I-1 Hp and I-3-i I) -pi ri m id i n-2,4-di am i na (30 milligrams, 0.072 millimoles) in EtOH (0.5 milliliters), thiophene-2,3-dihydro1,1-dioxide (17 milligrams, 0.144 millimoles) was added. The resulting mixture was then heated at 130 ° C for 2 hours. After cooling to room temperature, the mixture was concentrated and purified by reverse phase HPLC of preparation, to provide 5-cl or ro-N2- (2-fluoro-5-met i 1-4- (1 - ( tetra hyd ro-1,1-dioxide-3-thienyl) pi pe ri di n-4-i I) -fe ni I) - N4- (5-met i I-1 H-pi razo I-3-il ) -pi rim id i n-2,4-d iam i na. ESMS m / z 534.2 (M + H⁺ ).

Example 18

5-cl or ro-N²- (2,5-di meti 1-4- (1 - (tetrahydro-1,1-dioxide-2H-thiopiran-4-yl)) piperidin-4-yl) -phenyl) -N⁴- (5-methyl-1 H-pyrazol-3-yl) -pyrmidine-2,4-diamine (146)

103

<img file="CU23952B1_D0080.tif" />

Step 1: At a solution of 5-chloro-N2- (2,5-dimethyl-4- (piperidn-4yl) -phenyl) -N4- (5-methyl-1 H-pyrazole-3- L) -p¡r¡m¡d¡n-2,4-d¡am¡na (30 milligrams, .073 millimoles) in acetonitrile (1 milliliter), Cs were added₂CO₃ (47 milligrams, 0.15 millimoles), and 4-iodo-tetrahydro-2Hthiopyran (48 milligrams, 0.22 millimoles). This mixture was then stirred at 80 ° C for 16 hours. After cooling to room temperature, the mixture was treated with a saturated aqueous solution of

NH₄CI (3 milliliters), and extracted with EtOAc (3 milliliters, 3 times). The organic layers were combined and concentrated. The residue was purified by silica gel chromatography (Gradient of approximately 0 to 8 percent MeOH / CH₂CI₂ with NH₃), to provide 5-chloro-N2- (2,5-d-methyl-4- (1- (tetrahydro-2Ht iopi ra n-4-i I) -p iper id i n-4-i I) -fe or I) -N4- (5-met ¡I -1 H -pyrazol-3-yl) pyrimidin-2,4-diamine as a white solid. ESMS m / z 512.2 (M + H⁺)·

Step 2:

To 5-chloro-N2- (2,5-dimethyl-4- (1 - (tetrahydro-2H-t¡op¡ran-4104 il) -piper¡d¡n-4-¡) -phenyl) - N4- (5-methyl-1 H-pyrazol-3-l) -pyrmidium-2,4-diamine (18 milligrams, .035 millimoles) in CH₂CI₂ (1 milliliter), m-CPBA (16 milligrams, .0.71 millimoles) was added at 0 ° C. The mixture was then heated to room temperature, and stirred for

30 minutes; then a saturated aqueous solution of

NaHCO₃ (3 milliliters) and the crude product was extracted with CH₂CI₂ (3 milliliters, 3 times). The combined organic layers were concentrated and purified by preparation thin layer chromatography (silica gel, 12 percent MeOH / CH₂CI₂ with NH₃), to provide 5-chloro-N2- (2,5-dimethyl-4- (1- (tetrahydro-1,1 d ¡ox ¡d o-2 H-ti op I ra n-4-11)) -p ¡pe rid¡ n-4-¡I) -fe ni I) -N4- (5-meti I-1 Hp i razo I3-il) -pirimid¡n-2,4-diamine. ESMS m / z 544.2 (M + H⁺ ).

Example 19

5-chloro-N²- (2-Fluoro-5-met¡ 1-4- (1 - (1,1-dioxido-3-tethane) -p¡perid¡n-415 il) -phenyl) -N⁴- (5-methyl-1 H-pyrazol-3-yl) -pyrimidin-2,4-damine (148)

<img file="CU23952B1_D0081.tif" />

To 5-chloro-N2- (2-fluoro-5-methyl-4- (plperidin-4-yl) -phenyl) -N4- (525 methyl-1 H -pyrazol-3-yl) -pyrimidin- 2,4-diamine (30 milligrams, 0.072

105 millimoles) in methanol (1 milliliter), 1,1-3-bromo-tiethane dioxide (15 milligrams, 0.079 millimoles) was added, followed by triethylamine (15 milligrams). The resulting mixture was stirred at room temperature for 5 hours, and then concentrated. The resulting residue was purified by reverse phase HPLC of preparation, to provide 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (1,1-dioxide-3tietanyl) -p¡ perdin-4-yl) -phenyl) -N4- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-2,4-diamine.¹H NMR (400 MHz, DMSO-d6 + 1 drop of D₂O) δ 8.02 (s, 1H), 7.37 (s, 1H), 7.02 (s, 1H), 6.23 (s, 1H), 4.28-4.22 (m, 2H), 4.1210 4.07 (m, 2H), 3.22- 3.18 (m, 1H), 2.95-2.92 (m, 2H), 2.68-2.62 (m,

1H), 2.22 (s, 3H), 2.13 (s, 3H), 2.07-2.01 (m, 2H), 1.71-1.55 (m, 4H). ESMS m / z 520.2 (M + H⁺ ).

Example 20

5-chloro-N 2- (4- (1 - (5-et¡lp¡r¡m¡din-2-¡l) -p¡per¡d¡n-4-il) -2-fluoro-5 -methyl15 phenyl) -N4- (5-methyl-1 Hp¡ razol-3-l) -p¡r¡m id¡ n-2,4-d amine (149)

<img file="CU23952B1_D0082.tif" />

To a mixture of 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin- 2,4-diamine (0.10 mmol), and triethyl amine (83 microliters, 0.6 millimoles) in Ν, Ν-dimethylformamide (1.5 milliliters), 2-chloro-5-ethyl-pyrimidine (27 milligrams, 0.20 millimoles) was added ). The mixture was heated in a microwave reactor at 120 ° C for 10 minutes. The reaction was filtered, and the

106 The filtrate was purified by reverse phase HPLC preparation, to provide the 5-c! gold-N2- (4- (1- (5-et¡-pi-rm, di-2-i)) pe rid i n4-¡l) -2-fluoro-5-methyl-feml) -N4- (5-methyl-1 H-pyrazol-3-yl) -pyrimidin-2,4-diamine as a white solid . ESMS m / z 522.2 (Μ + H +).

Example 21

4- (4- (5-Chloro-4- (5-met¡l-7H-p¡razol-3-l-am¡no) -p¡r¡m¡d¡n-2-¡l- amino) 2,5-d-methyl-phenol) -pperidin-2-one (151)

<img file="CU23952B1_D0083.tif" />

Step 1: 2- (2,5-di methyl-4-η itro-fen i 1) -4,4,5,5-tetrameti 1-1,3 were added to a 5-milliliter microwave reaction tube, 2-dioxaborolane (143 milligrams, 0.516 mmol, was prepared from 1-bromine-2,5-dimethyl-4-nitrobenzene by conventional protocol), 1- (4-methoxy-benzyl) -5.6- dihydro-pridin-2 (1 H) -one (56 milligrams, 0.26 millimoles, was prepared following a procedure similar to that reported by Lerchner et al., in Chem. Eur. J. 2006, 12, 8208), chloro- (1,5-cyclo-octadiene) -rodium (I) dimer (13 milligrams, .026 millimoles), KOH (0.13 milliliters, 1N aqueous solution), and dioxane (1.2 milliliters) . The tube was degassed, filled with N₂ and it was sealed. The reaction tube was then heated at 100 ° C in a microwave reactor for 10 minutes. After it opened

107 the reaction tube, the mixture was treated with a saturated aqueous NH solution₄CI (3 milliliters), and extracted with EtOAc (4 milliliters, 3 times). The organic layers were combined and concentrated. The residue was purified by flash column chromatography (silica gel, gradient from 0 percent to about 70 percent EtOAc / hexane), to provide 4- (2,5-dimethyl-4-mtro-phenyl) ) -1 - (4-methoxy-benzyl) piperine-2-one. ESMS m / z 369.2 (M + H⁺ ).

Step 2: At 4- (2,5-dimethyl-4-nitro-phenyl) -1- (4-methoxy-benzyl) 10 piperidin-2-one (63 milligrams, 0.17 mmol) in methanol (10 milliliters), 10 percent by weight / weight of Pd / C (6 milligrams) was added, the mixture was degassed and stirred under H₂ at room temperature for 14 hours. After the catalyst was removed by filtration, the filtrate was concentrated to provide 4- (4-amino-2,5-dimethyl-phenyl) -1- (4-methoxy-benzyl) piperidin-2-one as a pale yellowish oil. ESMS m / z 339.2 (M + H⁺ ).

Step 3: To a mixture of 4- (4-amino-2,5-dimethyl-phenol) -1 - (4-methoxy-benzyl) -piperidin-2-one (23 milligrams, 0.094 millimoles), and

2,5-dichloro-N- (5-methyl-1 Hp¡razol-3-¡) -p¡r¡m¡d¡n-4-am¡na (29 milligrams, 0.086 millimoles) in ¡ PrOH (1 milliliter), HCI (60 microliters, 4N in dioxane) was added. The reaction vessel was then sealed and heated at 130 ° C for 4 hours. After cooling to room temperature, the mixture was treated with a saturated aqueous NaHCO solution.₃ (3 milliliters), and extracted with EtOAc (4

108 milliliters, 3 times). The organic layers were combined and concentrated. The residue was purified by flash column chromatography (silica gel, gradient from 0 to about 10 percent MeOH / CH₂CI₂), to provide 4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3-yl-amino) pyrimidin-2-yl-amino) -2,5-dimethyl-phenyl) -1 - (4-methox i-be nci I) -pipe rid i n-2ona. ESMS m / z 546.2 (M + H⁺ ).

Step 4: A solution of 4- (4- (5-Chloro-4- (5-methyl-1H-pyrazol-3-lamino) -pyrimin-2-¡-l-amine) -2.5 -d-methyl-phenyl) -1 - (4-methoxy-benzyl) 10 piperidin-2-one (45 milligrams) in trifluoroacetic acid (0.5 milliliters) was heated at 100 ° C for 24 hours. After cooling to room temperature, the mixture was concentrated and purified by reverse phase HPLC of preparation, to provide the

4- (4- (5-Chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -p¡r¡m¡d¡n-2-l-amine) 15 2 , 5-dimethyl-phenyl) -peridin-2-one. ESMS m / z 426.2 (M + H⁺ ).

Example 22

5- c I gold-N²- (2-fluoro-4- (4-methyl-pipe razi n-1 -il) -5- (trifl uoro-methyl) -fen i I) N⁴- (5-meti 1-1 / 7-pyrazol-3-yl) -p¡ rim id i n-2,4-d amine (157)

<img file="CU23952B1_D0084.tif" />

Step 1:

To a microwave reaction tube was added 4109 bromo-2-fluoro-5- (trfluoro-methyl) -an¡l¡na (256 milligrams, 1.0 millimoles), 1-methyl-piperazine (300 milligrams, 3 millimoles), Pd₂(dba)₃(91.5 milligrams, 0.1 millimoles), diterbutyl- (2 ', 4', 6'-tr¡-¡sopropilb¡phenyl-2-yl) -phosphine (60 milligrams, 0.2 millimoles), NaOtBu (144 milligrams, 1.5 millimoles) , and tetrahydrofuran (3 milliliters). After the reaction tube was degassed and filled with N₂, the tube was heated at 120 ° C in a microwave reactor for 40 minutes.

The mixture was then poured into a saturated aqueous solution of

NH₄CI (10 milliliters), and extracted with EtOAc (10 milliliters, 3 times).

The organic layers were combined and concentrated. The residue was purified by column chromatography by flash evaporation (silica gel, MeOH / CH gradient₂CI₂, from 0 to about 10 percent), to provide 2-fluoro-4 (4-m et i I - piperazin -1 - i I) -5- (trifluo ro-m eti I) -aniiine as a solid White. ESMS m / z 278.1 (M + H⁺ ).

Step 2: To a mixture of 2-fluoro-4- (4-methyl-p¡perazin-1-yl) -5 (trifluoro-methyl) -aniline (37 milligrams, 0.133 millimoles), and 2,5-dichloro-N - (5-methyl-1 H-pyrazol-3-yl) -pyrimidin-4-amine (36 milligrams, 0.147 millimoles) in PrOH (1 milliliter), HCI (100 microliters, 4N in dioxane) was added. The reaction vessel was then sealed and heated at 130 ° C for 4 hours. After cooling to room temperature, the mixture was treated with a saturated aqueous NaHCO solution.₃ (5 milliliters), and extracted with EtOAc (5 milliliters, 3 times). The organic layers were combined and concentrated. The residue was purified by layer chromatography.

110 thin preparation (silica gel, 8 percent MeOH / CH₂CI₂), to provide 5-chloro-N2- (2-fluoro-4- (4-methyl-p¡perazin-1-yl) -5 (trifluoro-methyl) -phenyl) -N4- (5-met L-1 Hp¡razol-3-¡) -p¡rimidin-2,4diamine. ESMS m / z 485.2 (M + H⁺).

Example 23 (S) -2- (4- (4- (5-methyl-1H-pyrazol-3-yl-amine) -pyrimin-2-l-amine) - 5fluoro-2-methyl-phenyl) -peridin-1-ll) -propanamide (163)

<img file="CU23952B1_D0085.tif" />

A mixture of 5-chloro-N²- (2-fluoro-5-met¡l-4- (plper¡d¡n-4-ll) phenyl) -N⁴- (5-metll-1 H-ρ I razo l-3-il) -p¡ rim ¡di n-2,4-di amine (50.0 milligrams, 0.12 millimoles), (/?) - 2-bromo-propanamide (90.6 milligrams,

0.60 millimoles), and triethyl amine (102.0 microliters, 0.60 millimoles) in milliliters of dimethyl formamide, was heated at 150 ° C in a microwave reactor for 30 minutes. The reaction mixture was purified directly by reverse phase HPLC of preparation, to give the (S) -2- (4- (4- (5-methyl-1 Hp¡ razo l-3-l-am¡ no)) -pyri mid-n-220-yl-amino) -5-fluoro-2-methyl-phenyl) -piperin-1-yl) -propanamide; ESMS m / z 487.2 (M + H⁺ ).

Example 24 (S) -2- (4- (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-ylamine) -5-fluoro -2-met¡l-fen¡l) -p¡perid¡n-1-¡l) -N-met¡l-propanam¡da (164) lll

<img file="CU23952B1_D0086.tif" />

A mixture of 5-chloro-N²- (2-Fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N⁴- (5-met¡l-1 H-pyrazol-3-yl) -p¡mid¡n-2,4-d¡am¡na (50.0 milligrams, 0.12 mmol), (R) -2-bromine - / V-methyl propanamide (100.0 milligrams, 0.60 millimoles), and triethyl amine (102.0 microliters, 0.60 millimoles) in 2 milliliters of dimethyl formamide, was heated at 150 ° C in a microwave reactor for 30 minutes. The reaction mixture was purified directly by reverse phase HPLC of preparation, to provide the (S) -2- (4- (4- (5-chloro-4- (5-methyl-1 Hpirazol-3-yl -am ino) -pi rim idi n-2-i l-am ¡no) -5-fluoro-2-meti l-fen i I) piperidin-1-¡) -N-methyl-propanam¡da; ESMS m / z 501.2 (M + H⁺).

Example 25 (S) -2- (4- (4- (5-chloro-4- (5-met¡ 1-1 H-pyrazol-3-l-amine) -p¡rim¡d¡n -2-lamino) -2,5-d¡met¡l-fen¡l) -p¡per¡d¡n-1 - P-propanamide (166)

<img file="CU23952B1_D0087.tif" />

A mixture of 5-chloro-N²- (2,5-dimethyl-4- (p¡per¡d¡n-4-¡l) fen¡l) -N⁴- (5-met¡l-1 Hp¡razol-3-¡) -p¡r¡m¡d¡n-2,4-d¡amine (50.0 milligrams, 0.12 millimoles), (R) -2- Bromo-propanamide (90.6 milligrams, 0.60 mmol), and triethyl amine (102.0 microliters, 0.60 millimoles) in

112 milliliters of dimethyl formamide, heated at 150 ° C in a microwave reactor for 30 minutes. The reaction mixture was purified directly by reverse phase HPLC of preparation, to provide the (S) -2- (4- (4- (5-clo ro-1 Hp¡razol-3-¡-am-no)) -p¡rlm ¡di n5 2-¡-amino) -2,5-dimethyl-phenyl) -piperidin-1-yl) -propanamide; ESMS m / z 483.2 (M + H⁺ ).

Example 26 (4- (4- (5-Chloro-4- (5-met¡l-1 Hp¡razol-3-¡-l-am¡no) -p¡r¡m¡d¡n-2-¡ l-amino) 5-fl uoro-2-met¡ l-fen il) -piperidi n-1-¡1) - (1 - (eti l-am ino) -cyclopropyl) 10 methanone (169)

<img file="CU23952B1_D0088.tif" />

A mixture of 5-chloro-N²- (2-fluoro-5-methyl-4- (piper¡din-4-¡l) fenll) -N⁴- (5-met¡l-1 Hp¡razol-3-¡) -p¡r¡m¡d¡n-2,4-dlam¡na (67.3 milligrams, 0.17 mmol), acid 1- (terbutoxy) carbonyl- (ethyl) -amino) cyclopropan-carboxylic acid (38.0 milligrams, 0.17 millimoles), HATU (63.0 milligrams, 0.17 millimoles), and di-isopropyl-ethyl-amine (57 microliters, 0.34 millimoles) in 1 milliliter of dimethyl formamide stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water, the combined organic extracts dried (Na₂SW₄), and then concentrated in vacuo. The resulting crude mixture was dissolved in 5 milliliters of

113 dichloromethane and 4 milliliters of trifluoroacetic acid, and then stirred for 2 hours, followed by concentration in vacuo. The crude product was purified by reverse phase HPLC, to provide the (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3-yl-amino)) 5 pyrimidin- 2-yl-amino) -5-fluoro-2-methyl-phenyl) -piperidin-1-i 1) - (1 - (eti I amino) -cyclopropyl) -methanone; ESMS m / z 527.2 (M + H⁺)·

Example 27

- (4- (4- (5-Chloro-4- (5-met¡l-1/7-p¡razol-3-il-am¡no) -pir¡m¡d¡n-2-term ) -2,5-dimethyl-phenyl) -piperidine-1-l) -2- (ethyl-amino) -2-methyl-propan-

<img file="CU23952B1_D0089.tif" />

To a solution of 2-amino-1- (4- (4- (5-chloro-4- (5-methyl-1 / - / pyrazol-3-yl-amine) -pyrim¡d¡ n-2-yl-amino) -2,5-dimethyl-phenyl) -pperidin-1l) -2-methyl-propan-1-one (6 milligrams, 0.012 mmol) in acetone ( 0.5 milliliters), K was added₂CO₃ (11 milligrams, 0.079 millimoles).

The mixture was stirred at room temperature for 10 minutes, before the addition of Eti (6 milligrams, 0.038 mmol). The resulting mixture was then stirred at room temperature for 14 hours before being treated with NH₄Saturated aqueous CI (1 milliliter), and extracted with EtOAc (2 milliliters, 3 times). The organic layers are

114 combined, concentrated, and the residue was purified by thin layer chromatography (silica gel, 8 percent MeOH / DCM / ΝH₃), followed by further purification by reverse phase HPLC of preparation, to provide 1 - (4- (4- (5-chloro-4- (5-methyl-1 / - / - pi I-3) -i la mi no) -pi ri m id i n-2-i imamino) -2,5-dimethyl-phenyl) -piperidin-1-yl) -2- (ethyl-amino) -2-methyl-propan1- ona; ESMS m / z 525.3 (M + H⁺).

Example 28 (4- (4- (5-chloro-4- (5-methyl-1 Hp¡razol-3-¡-amino) -primidin-2-l-amine) 5-fluoro- 2-metyl-phen) -pperidin-1-l) - (1- (et-l-amine) -c¡clobutyl) methanone (1 76)

A mixture of 5-chloro-N²- (2-fluoro-5-methyl-4- (piperidin-4-yl) phenol) -N⁴- (5-methyl-1H-p¡razol-3-¡) -p¡r¡midin-2,4-diamna (50.0 milligrams, 0.12 mmol), 1- (terbutoxycarbonyl- (ethyl) acid -amino) cyclobutan-carboxylic acid (29.2 milligrams, 0.12 millimoles), HATU (45.8 milligrams, 0.12 millimoles), and di-lsopropyl-ethyl-amine (20 microliters, 0.12 millimoles) in 1 milliliter of dimethyl formamide was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo. Raw mix

115 The resulting was dissolved in 5 milliliters of dichloromethane and 4 milliliters of trifluoroacetic acid, and then stirred for 2 hours, followed by concentration in vacuo. The crude product was purified by reverse phase HPLC, to provide the (4- (4- (5-chloro-4- (5-methyl5 1 H-pi razol-3-yl-amino) -pyrimidin-2-yl- amino) -5-fluo ro-2-met ¡l-fe nil) piperidin-1-yl) - (1 - (ethyl-amino) -cyclobutyl) -methanone; ESMS m / z 541.3 (M + H⁺ ).

Example 29 (4- (4- (5-cl or ro-4- (5-met¡ 1-1 H-pyrazol-3-¡-l-amn)) -p¡r¡m¡d¡n-2 -yl-amino) 10 5-fl uoro-2-m eti l-fe n ¡I) -p ¡perid¡n-1 - yl) - (1 - (methyl-amino) -cyclobutyl) methanone (1 77)

<img file="CU23952B1_D0090.tif" />

A mixture of 5-chloro-N²- (2-Fluoro-5-methyl-4- (piper¡d¡n-4-¡) phenyl) -N⁴- (5-Methyl-1 Hp¡razole-3-yl) -pyrin mid ¡n-2,4-damine (50.0 milligrams, 0.12 mmol), 1- (terbutoxycarbonyl- (methyl) acid -amino) 20 cyclobutane-carboxylic acid (27.5 0.12 mmol), HATU (45.8 milligrams, 0.12 mmol), and di-isopropyl-ethyl-amine (20 microliters, 0.12 mmol) in 1 milliliter of dimethyl formamide, stirred at room temperature overnight. The reaction mixture was divided between

EtOAc and water. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo. The resulting raw mixture is

116 dissolved in 5 milliliters of dichloromethane and 4 milliliters of trifluoroacetic acid, and stirred for 2 hours, followed by concentration in vacuo. The crude product was purified by reverse phase HPLC, to provide the (4- (4- (5-chloro-4- (5-methyl-1 H5 pyrazol-3-yl-amine) -pyrimin) -2-yl-amine) -5-fluoro-2-methyl-phenyl) piperidin-1-yl) - (1 - (methyl-amino) -cyclobutyl) -methanone; ESMS m / z 527.2 (M + H⁺ ).

Example 30 (S) -3- (4- (2,5-dimethyl-4- (5-methyl-4- (5-methyl-1 H-pi razo l-3-i l-am ino)) pir¡m¡d¡n-2-¡l-am¡no) -fen¡l) -piper¡din-1 -il) -1,1,1 -trifluoro-propan-2-ol (179)

<img file="CU23952B1_D0091.tif" />

To a solution of N hydrochloride²- (2,5-dimethyl-4- (piperidin-4yl) -phenyl) -5-methyl-N⁴- (5-methyl-1 H-pyrazol-3-yl) -pyrimidin-2,4-diamine (36.0 milligrams, 0.084 millimoles) in N, N-dimethylformamide (0.5 milliliters), triethyl amine (23.4 microliters, 0.168 millimoles), and (S) -2- (trifluoro-methyl) -oxane (72.8 microliters, 0.84 mmol). The reaction mixture was stirred at room temperature overnight, and purified by reverse phase HPLC of preparation, to provide the (S) -3- (4- (2,5- dimethyl-4- (5-methyl-) 425 (5-methyl-1 H-pyrazol-3-¡-l-am¡no) -p¡rimidin-2-¡l-am¡no) -fen¡l) -p¡per¡d¡n-1 117 il) -1,1,1-trfluoro-propan-2-ol; ESMS m / z 504.3 (M + H⁺).

Example 31

2- (2- (4- (5-Chloro-4- (5-methyl-1 H-pyrazol-3-yl-amine) -p¡r¡m¡d¡n-2-ilam no) -2,5-di metí l-fen¡l) -p¡per¡d¡ n-1 -II) -acetam da (181)

<img file="CU23952B1_D0092.tif" />

To a mixture of 5-chloro-N2- (2,5-dimethyl-4- (piperidin-2-yl) -phenyl) N4- (5-metll-1 Hp, I-3-11) -pi rim id i n-2,4-d¡am I na (0.12 mmol), and triethyl amine (83 microliters, 0.6 millimoles) in Ν, Ν-dimethylformamide (1.5 milliliters), 2-bromo-acetamide was added ( 35 milligrams, 0.24 millimoles). The mixture was stirred at room temperature for 3 hours. The reaction was filtered, and the filtrate was purified by reverse phase HPLC, to provide 2- (2- (4- (5-chloro-4- (5-methyl-1 Hp, I-3-I) am ino) -pyrmidin-2-l-am i no) -2,5-d ¡meti l-fen i I) -pi pe rid i n-1 ¡l) -acetamlda as a white solid; ¹H NMR (400 MHz, MeOD-d4) 8.09 (s, 1H), 7.65 (d, 1H), 7.43 (s, 1H), 6.41 (s, 1H), 4.79-4.74 (m, 2H), 3.83-3.48 (m, 2H), 2.71 (s, 3H), 2.42 (s, 3H), 2.34 (s, 6H), 2,151.84 (m, 7H); ESMS m / z 469.2 (M + H⁺).

Examples 32 and 33 (S) 5-Chloro-N2- (2,5-dmethyl-4- (1-methyl-piperidin-2-yl) -phenyl) -N4- (5-methyl1 Hp ¡razo l- 3-yl) -pyrimid and n-2,4-d amine (183)

118

<img file="CU23952B1_D0093.tif" />

methyl-1 H-pyrazol-3-l) -pyrmm-din-2,4-damine (184)

<img file="CU23952B1_D0094.tif" />

Step 1: To a mixture of 1-bromo-2,5-d-methyl-4-n -trobenzene (185 milligrams, 1 millimol), and 2- (tributyl-staniI) -pyridine (202 milligrams, 1.1 millimoles ) in Ν, Ν-dimethyl-formamide (4 milliliters), tetrakis- (triphenyl-phosphine) -palladium (0) (58 milligrams, 0.05 millimoles) was added. The reaction tube was sealed, the mixture was purged with N₂ for 3 minutes, and then heated at 120 ° C under N₂ overnight. The reaction was cooled to room temperature, and poured into a saturated aqueous solution of ammonium chloride. The crude reaction mixture was extracted with ethyl acetate (15 milliliters, 3 times). The organic extracts were combined, washed with brine, and concentrated. The crude product was purified by silica gel chromatography (60 percent ethyl acetate in hexanes), to provide 2- (2,5-dimethyl-4-nitro-phenyl) -pyridine as a white solid. The solid obtained was dissolved in acetic acid / trifluoroacetic acid (15 ml / 200 microliters). PtO was added to this solution.₂ (at 10 percent by weight / weight). The

119 reaction mixture was degassed and purged with H₂ several times and then stirred vigorously under 1 atmosphere of H₂ overnight. The mixture was filtered, and the filtrate was concentrated, to provide 2,5-dim et i-4- (piperidi n-2-i I) -ani I ina as a yellow oil; ESMS 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 milligrams, 0.49 millimoles), and 2.5 -dimethyl-4 (piperidin-2-l) -aniline (100 milligrams, 0.49 millimoles) in 2-propanol (10 milliliters) was treated with concentrated aqueous HCI (7 drops). The mixture was sealed and heated in a microwave reactor at 130 ° C for 45 minutes. The mixture was concentrated, to provide 5-chloro-N2- (2,5-dimethyl-4- (piperidin-2-yl) -phenyl) -N4- (5-methyl-1 H -pyrazol-3 I) -pyrimid ID n-2,4-diamine; ESMS m / z 412.1 (M + H⁺). The crude product was used directly for the next step without further purification.

Step 3: To a solution of the crude product from the previous step in tetrahydrofuran (1 milliliter) and methanol (1 milliliter), formaldehyde (100 microliters, 1.3 millimoles) and 5 drops of AcOH were added in a formaldehyde sequence. The reaction mixture was stirred at room temperature for 1 hour, and then sodium cyano-borohydride (160 milligrams, 2.45 mmol) was added in one portion, and the reaction was stirred for an additional 30 minutes. The reaction was quenched with NH₄Saturated aqueous CI and concentrated in vacuo to give an oily residue. The residue was purified by reverse phase HPLC, to provide the (±) -5-chloro-N2- (2,5-dimethyl-4- (1-methyl-piperidin-2-yl) 25 fe ni I) - N4- (5-m eti l-1 H-pyrazol-3-yl) -p¡r¡m¡d¡n-2,4-diamine as a

120 white solid; ESMS m / z 426.2 (M + H⁺ ).

Step 4: The chiral separation of the racemic mixture was conducted by normal phase HPLC using a ChiralPaK column

AD-H using the following solvent system: hexanes (95 percent), EtOH (2.5 percent), methanol (2.5 percent). The two peaks of the purified enantiomers were collected separately: (R) -5-cl gold-N2- (2,5-d imeti 1-4- (1-meti lp ¡perid ¡n-2-il) -fen L) -N4- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-2,4-damine and (S) -5-chloro-N2- (2,5d i met i 1- 4- (1-methyl-piperidin-2-yl) -phenyl) -N4- (5-methyl-1 H-pyrazol-3-yl) 10 pyramidin-2,4-diamine; Both peaks: ESMS m / z 426.2 (M + H⁺ ). The earliest elution peak was arbitrarily assigned as the enantiomer (R).

Example 34

5-chloro- / V²-(2₁5-d imeti l-4- (1 - (3-morpholinopropyl-sulfonyl) -piperidine-4-l) 15 phenyl) - / V⁴- (5-methyl-1/7-p¡razol-3-yl) -pyrmidine-2,4-diamine (1 94)

<img file="CU23952B1_D0095.tif" />

Step 1: To a 5-chlorine solution - / \ /²- (2,5-dimethyl-4- (piperidin4-iI) -feniI) - / V⁴- (5-Methyl-1 Rp¡razol-3-yl) -pyrimidin-2,4-d¡amine (78 milligrams, 0.19 millimoles), and triethyl amine (0.52 milliliters, 3.78 millimoles) in dichloromethane (10 milliliters), chloride was added

3-chloropropan-1-sulfonyl (63 milligrams, 0.36 millimoles, in 1 milliliter of dichloromethane). After stirring at temperature

121 ambient for one hour, EtOAc (100 milliliters) was added. The mixture was washed sequentially with water (10 milliliters), brine (10 milliliters), dried over Na₂SW₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography (gradient from 0 to 100 percent EtOAc in hexanes), to give 5-chloroN 2- (4- (1 - (3-c parrot prop! L or Ifon i I) -pi pe rid ¡n-4-¡l) -2,5-di metí l-fen i I) -N4 (5-met¡l-1 Hp¡razol-3-¡l) -p¡rim Dln-2,4-damine as a grayish solid; ESMS m / z 552.2 (M + H⁺ ).

Step 2: The product from step 1 was stirred in pure morpholine (0.5 milliliters) at 100 ° C in a sealed bottle for one hour. The reaction was purified by reverse phase HPLC, to give 5-chloro-N2- (2,5-dimethyl-4- (1 - (3-morpholnopropyl-sulfonyl) -pyperine-4 -yl) phenyl) -N4- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-2,4-damine as a white powder; ESMS m / z 603.2 (M + H⁺).

Example 35

1 - ((4- (4- (5-clo ro-4- (5-methyl-1 H-pyrazol-3-yl-amino) -p¡r¡m¡din-2-ylamine) -2 , 5-d¡met¡l-fen¡l) -p¡per¡d¡n-1 - ¡l) -methyl) -c¡clopropan-carbo nitrile

<img file="CU23952B1_D0096.tif" />

To a solution of 5-chloro-N²- (2,5-dimethyl-4- (piperid¡n-4-¡) 25 fen I l) -N⁴- (5-met¡ 1-1 H-pyrazole-3-yl) -plr¡m¡d¡n-2,4-d¡am¡na (30 milli122 grams, 0.078 millimoles) in acetonitrile (1.0 milliliters), it was added

4-Methyl-benzene-sulfonate (1-cyano-cyclopropyl) -methyl (16 milligrams, 0.10 millimoles, was prepared according to the procedure described in International Publication Number W02005063247), followed by DIEA (30 milligrams , 0.23 millimoles), and KI (catalytic amount). The resulting mixture was heated at 70 ° C for 14 hours, and then cooled to room temperature. The resulting mixture was directly purified by reverse phase HPLC of preparation, to provide 1 - ((4- (4- (5-chloro-4- (5-methyl-1-Hpyrazol-3-yl-amino)) -pyrimidin-2 -yl-amino) -2,5-dimethyl-phenyl) -piperidin-1-yl) -methyl) -cyclopropan-carbonitrile; ESMS m / z 491.2 (M + H⁺ ).

Example 36

2- (4- (4- (5-Chloro-4- (5-methyl-1 Hp¡razol-3-l-amino) -pyrimidin-2-lamino) -5-fluoro-2-methyl -fen¡l) -piperidin-1 -yl) -acetonitr¡lo (199)

HN

To a solution of 5-chloro-N²- (2-Fluoro-5-methyl-4- (piperidin-4-yl) phenyl) -N⁴- (5-methyl-1/7-pyrazol-3-yl) -pyrimidin-2,4-diamine (20 milligrams, 0.048 millimoles) in acetonitrile (0.5 milliliters), Cs were added₂CO₃ (31 milligrams, 0.096 millimoles), and chloroacetonitrile (7 milligrams, 0.096 millimoles). The resulting mixture was stirred at room temperature for 14 hours before being treated with

123

NH₄Saturated aqueous CI (1 milliliter), and extracted with EtOAc (2 milliliters, 3 times). The organic layers were combined, concentrated, and the residue was purified by reverse phase HPLC to provide 2- (4- (4- (5-chloro-4- (5-methyl-1 / - / pyrazole) -3-ii-amino) -pyrammid-2-yl-amine) -5-fluoro-2-methyl-phenyl) piperidin-1-yl) -a keto or tri lo; ESMS m / z 455.2 (M + H⁺).

Example 37

3- (4- (4- (5-Chloro-4- (5-methyl-1/7-p¡razol-3-l-amino) -plr¡m¡d¡n-2-ylam) no) -5-fluoro-2-m eti l-feni l) -piper¡d¡ n-1 -il) -propane-n-trilo (200)

To a solution of 5-chloro-N²- (2-fluoro-5-methyl-4- (piperidin-4¡l) -fen il) -N⁴- (5-methyl-1 / - / - pyrazol-3-1) -pyrmidium-2,4-dinamine (20 milligrams, 0.048 mmol) in methanol (0.5 milliliters), acrylonitrile was added (5 milligrams, 0.096 millimoles). The resulting mixture was stirred at room temperature for 14 hours, and then directly purified by HPLC in reverse phase of preparation, to provide 3- (4- (4- (5-chloro-4- (5-metll-1H-) pyrazol-3-ylamino) -pyrimin-2-yl-amino) -5-fluoro-2-methyl-phenyl) -piperin-1-yl) propane-nitrile; ESMS m / z 469.2 (M + H⁺ ).

Examples 38 and 39 (R) -2- (3- (4- (5-chloro-4- (5-met! 1-1 H-pyrazol-3-yl-amine) -pyrimin- 2-il124 am¡no) -2,5-d¡methyl-fen¡l) -p¡per¡d¡n-1 - ¡l) -N-met¡l-acetam¡da (207)

ΙΟ (S) -2- (3- (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-lamino) - 2,5-di meti l-fen il) -piperidi n-1 - l) -N-methyl-acetamide (208)

A solution of 5-chloro-A /²- (2,5-dimethyl-4- (pperidin-3-yl) -phenyl) / V⁴- (5-met! 1-1 H-pi razol-3-il) -pyrim id i n-2,4-d amine (700 milligrams,

1.70 millimoles), 2-bromo- / V-methyl-acetamide (258 milligrams, 1.70 millimoles), and triethyl amine (1.2 milliliters, 8.5 millimoles) in Ν, Ν dimethyl formamide (4 milliliters) was stirred at room temperature for 30 minutes The reaction was purified by reverse phase HPLC, to give the product as a racemate; ESMS m / z 483.2 (M + 1). The chiral separation of the racemic mixture was conducted with chiral HPLC (ChiralCel OD-H, Hex: EtOH: MeOH / 80: 10: 10, run time of 15 minutes, 1 milliliter / minute). The two peaks of the purified enantiomers were collected separately, both as white solids: (R) -2- (3- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3-ylamino)) -pyrimin-2-yl-amine) -2,5-d-methyl-phenyl) -p¡per¡d¡n-1-yl) -N-methalacetamide and (S) -2- (3- (4- (5-Chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) pyrimidin-2-l-amino) -2,5-dimethyl-phenol ) -pperidin-1 -i I) -N-meti Ι125 acetamide; Both peaks: ESMS m / z 483.2 (M + H⁺ ). The earliest elution peak (rt = 5.63 minutes, against rt = 7.62 minutes.) Was arbitrarily assigned as the enantiomer (R).

Example 40

5-chloro-N²- (2-Fluoro-5-methyl-4- (1 - (tetra hydro-2H-pyre n-4-l) -piper¡ di n-4¡I) -fen¡I) -N⁴- (5-metiI-1 Hp¡razol-3-¡) -p¡r¡m¡d¡n-2,4-d¡amina (209)

<img file="CU23952B1_D0097.tif" />

To a 5-chloro-N suspension²- (2-fluoro-5-met¡l-4- (piper¡din-4¡l) -fenll) -N⁴- (5-met¡l-1 Hp¡razol-3-¡) -p¡r¡mld¡n-2,4-d¡am¡na (2.50 grams, 6.0 millimoles) in a mixed solvent of methanol ( 42 milliliters), and dichloromethane (10 milliliters), dihydro-2Hplran-4 (3H) -one (3.33 milliliters, 36.0 millimoles), and triethyl amine (8.36 milliliters, 60.0 millimoles) were added. The reaction mixture was heated at 60 ° C for 1 hour before adding NaCNBH₃ (1.66 grams, 26.4 millimoles). The mixture was heated at 60 ° C for another 2 hours, cooled to room temperature, diluted with dichloromethane (60 milliliters), loaded dry on silica gel (12.5 grams), and purified by gel chromatography. silica (gradient of dichloromethane with 1 percent NH₃ up to 10 percent methanol in dichloromethane with 1 percent NH₃), to provide 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (tetrahydro-2H-pyran126

4-¡I) -pi pe ri di η-4-i I) -fe ni I) - N 4- (5-m eti I-1 H-pyrazol-3-yl) -pyrimidine-2,4-diamine as a white solid; ¹H NMR (DMSO-d₆, 400 ΜΗζ) δ 12.08 (br, 1H), 9.58 (br, 1H), 8.65 (d, J = 28.4 Hz, 1H), 8.02 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H) , 7.03 (d, J = 12.4 Hz, 1H), 6.08 (br, 1H), 3.89 (dd, J = 10.8, 3.6 Hz, 2H), 3.28 (t, J = 10.4 Hz, 2H), 2.99 (d, J = 10.8 Hz, 2H), 2.64-2.43 (m, 2H), 2.24-2.15 (m, 8H), 1.71-1.40 (m, 8H); ESMS m / z 500.2 (M + H⁺ ).

Example 41

5-chloro-N²- (4- (1-Cyclopropyl-piperidn-4-yl) -2-fluoro-5-methyl-phenyl) -N⁴(5-methyl-1/7-pyrazol-3-yl) -p¡rimid¡n-2,4-d¡am¡na (210)

<img file="CU23952B1_D0098.tif" />

To a solution of 5-chloro-N²- (2-Fluoro-5-methyl-4- (p¡per¡din-4il) -phenyl) -N⁴- (5-methyl-1/7-pyrazol-3-yl) -pyrimidin-2,4-diamine (30 milligrams, 0.072 millimoles) in methanol (0.7 milliliters), AcOH (35 milligrams, 0.58 millimoles) was added, (1-ethoxy-cyclopropoxy) -trimethylsilane (37 milligrams, 0.216 mmol), and a small amount of 4 Angstroms molecular sieves. The mixture was stirred at room temperature for 1 hour before the addition of Na (CN) BH₃ (14 milligrams, 0.216 millimoles). The resulting mixture was then stirred at 60 ° C for 14 hours, and cooled to room temperature. NH added₄Saturated aqueous CI (2 milliliters), and the

127 mixture was extracted with EtOAc (3 milliliters, 3 times). The combined organic layers were concentrated and purified by reverse phase HPLC of preparation, to provide 5-chloroN²- (4- (1-Cyclopropyl-piperidin-4-yl) -2-fluoro-5-methyl-phenyl) -N⁴- (5-methyl1 / 7-pyrazol-3-yl) -pyrimin-2,4-damine; ¹H NMR (400 MHz, MeOD-d4) δ 7.97 (s, 1H), 7.84 (d, 1H), 7.50 (s, 1H), 6.93 (d, 1H), 6.29 (s, 1H), 5.33 (s, 1H), 2.80 (m, 1H), 2.58 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.96 (m, 1H), 1.80-1.85 (m, 2H), 1.65-1.75 (m, 2H), 0.2-0.7 (m, 6H); ESMS m / z 456.2 (M + H⁺).

Example 42

N²- (4- (1 - (3- (azetidin-1 - i l-su Ifon il) -propyl) -piperid i n-4-yl) -2,5-di methylphenyl) -5-chloro - / \ /⁴- (5-met¡ 1-1 H-pi razol-3-il) -p¡ rim id in-2,4-d ¡amina (214)

<img file="CU23952B1_D0099.tif" />

Step 1: To a solution of azetidine (12 milligrams, 0.21 millimoles), and triethyl amine (0.1 milliliters, 0.71 millimoles) in dichloromethane (5 milliliters), a solution of 3-chloropropan-1-sulfonyl chloride was slowly added (34 milligrams, 0.19 millimoles) in dichloromethane (1 milliliter). After stirring at room temperature overnight, the solvent was removed in vacuo. The resulting 1- (3-chloropropyl sulfonyl) -azetidine crude product was dissolved in NMP (1.9 milliliters, 0.1 mmol / ml), and was used in the next step without further purification; ESMS m / z 198.0 (M + H⁺).

128

Step 2: A mixture of 5-Chloro-A /²- (2,5-d¡met¡l-4- (p¡per¡din-4-¡l) faith η 11) -Λ /⁴- (5-m et ¡I-1 Hp¡razol-3-¡l) -p¡rim¡d¡n-2,4-d¡am¡na (42 milligrams, 0.1 millimoles), 1- (3- chloroprop¡l-sulfon¡l) -azet¡d¡na (step 1,

0.1 millimoles), triethyl amine (70 microliters), and sodium iodide (150 5 milligrams) in NMP (1 milliliter), was placed in a sealed vial, which was heated in a microwave reactor for 30 minutes at

150 ° C The reaction was purified by reverse phase HPLC, to give the N2- (4- (1 - (3- (azetidin-1-l-sulfonyl) -propll) -p¡per¡d¡n-4-yl) -2,5dlmetyl-phenyl) -5-chloro-N4- (5-methyl-1 H -pyrazol-3-yl) -plimidine-2,410 diamine as a white powder; ESMS m / z 573.3 (M + H⁺ ).

Example 43

1- (4- (4- (5-Chloro-4- (5-met¡l-1/7-p¡razol-3-¡-l-amino) -p¡r¡m¡d¡n-2- ¡Lam¡no) -2,5-d ¡methyl-fen ¡l) -p¡per¡d¡n-1-¡) -4-morpholinobutan-1-one (224)

<img file="CU23952B1_D0100.tif" />

Step 1: To a solution of HATU (95 milligrams, 0.255 millimoles), and 4-chloro-butanoic acid (36 milligrams, 0.25 millimoles) in Ν, Ν-dimethyl-formamide (1 milliliter), DIEA (0.1 milliliters) was added ). After stirring at room temperature for 3 minutes, 5-cl or ro-N was added²- (2,5-dimeti I-4- (pi pe ridi n-4-i I) -fe ni I) -N^TO25 (5-methyl-1/7-p¡razol-3-¡l) -pir¡m¡d¡n-2,4-diamna (100 milligrams, 0.24

129 millimoles) in Ν, Ν-dimethylformamide (2 milliliters). The reaction was stirred at room temperature for 90 minutes, at which point the LCMS indicated that the reaction was complete, and that 4-chloro-1 - (4- (4- (5-chloro-4- (5 -methyl-1 H-pyrazol-3-ll-amino) 5-pyrm-d-n-2-yl-amne) -2,5-dimethyl-phenol-pper d¡n-1-¡l) -butan-1-one; ESMS m / z 516.1 (M + H⁺).

Step 2: Morpholine (0.5 milliliters) was added directly to the crude reaction mixture from step 1 (1 milliliter). The resulting solution was stirred at 100 ° C in a sealed bottle for 1.5 hours.

The crude product was purified by reverse phase HPLC, to give the 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3-11-amine) -pyrim¡ d¡n-2-lamino) -2,5-d¡methyl-fen¡l) -p¡per¡din-1-¡) -4-morpholnobutan-1 -one as a white powder; ESMS m / z 567.3 (M + H⁺ ).

Example 44

1 - (4- (4- (5-cl gold-4- (5-methyl-1/7-p¡razol-3-¡-l-amino) -pyrmm-d-n-2-ylam) no) -2,5-di metyl-phenyl) -peridin-1-yl) -3-morphol-propan-1-one (225)

<img file="CU23952B1_D0101.tif" />

Step 1:

A solution of HATU (108 milligrams, 0.28 millimoles), 3-chloro-propanoic acid (30 milligrams, 0.28 millimoles), and DIEA

130 (0.1 milliliters) in Ν, Ν-dimethylformamide (1 milliliter) was stirred at room temperature. After 3 minutes, this solution was transferred to a 5-chlorine solution - / \ /²- (2,5-d ¡methyl-4- (piperid¡n-4-il) fen i I) - / V⁴- (5-m eti I-1 H-pyrazol-3-yl) -pyrimidin n-2,4-d-amine (111 milligrams, 0.27 mmol) in Ν, Ν-dimethylformamide (10 milliliters). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (20 milliliters), and extracted with EtOAc (30 milliliters, 3 times). The combined EtOAc layers were washed with brine (10 milliliters), dried over Na₂SW₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography (gradient from 0 to 10 percent methanol in dichloromethane with NH additive₃ 1 percent), to give the 1 - (4- (4- (5-chloro-4- (5-methyl-1/7-pyrazol-3-yl-amino) -pyrmidium-2 -¡Lam i no) -2,5-dimethyl-fen i I) -pi perid i n-1-yl) -prop-2-e n-1 -one as a light brown oil; ESMS m / z 466.1 (M + H⁺).

Step 2: A solution of 1 - (4- (4- (5-chloro-4- (5-methyl-1/7-pyrazol-3-amino) -pyrimidin-2-yl-amino) - 2,5-d¡met¡l-fen¡l) -piper¡din-1 - il) -prop-2en-1-one (41 milligrams, 0.88 millimoles), and morpholine (0.1 milliliters) in Ν, Ν- dimethyl formamide (1 milliliter) was stirred at room temperature overnight. The crude product was purified by reverse phase HPLC, to give the 1- (4- (4- (5-chloro-4- (5-methyl-1Hp¡ razo I-3-i l-am i no) -pi rim idi n-2-yl-amino) -2,5-d ¡mei l-fen il) -piperid¡ n-1 yl) -3-morpholino-propan-1-one as a white powder; ESMS m / z 553.2 (M + H⁺).

131

Example 45 (S) -4- (4- (5-chloro-4- (5-methyl-1/7-p¡razol-3-¡-m-amno) -p¡rim¡d¡n-2 -¡Lam ¡no) -2,5-d ¡meti l-fen il) -oxazol ¡di n-2-one (230)

<img file="CU23952B1_D0102.tif" />

Step 1: A microwave reaction vessel was added

Ίq a mixture of 1-bromo-2,5-dimethyl-4-nitro-benzene (1.15 grams, 5.0 millimoles), dibutyl vinyl boronate (1.16 grams, 6.3 millimoles), Pd (PPh₃)₄ (289 milligrams, 0.25 millimoles), CsF (2.28 grams, 15 millimoles), and a mixed solvent (1,2-dimethoxy-ethane / MeOH = 2: 1, 15 milliliters). The mixture was degassed and sealed with N₂. The reaction vessel was then heated at 130 ° C in a microwave reactor for 15 minutes. After opening the reaction vessel, the mixture was poured into a saturated aqueous NH solution.₄CI (30 milliliters), and extracted with EtOAc (50 milliliters, 3 times). The combined organic layers were washed with brine, and dried (MgSO₄). After removing the drying agent by filtration, the filtrate was concentrated and purified by flash column chromatography (silica gel, gradient from 0 to 30 percent EtOAc in hexanes), to provide 1,4-dimethyl. -2-nitro-5-vinyl benzene as needle-shaped crystals; ESMS m / z 178.1 (M + H⁺ ).

132

Step 2: The 1,4-dimethyl-2-nitro-5-vinylbenzene was reacted by means of the asymmetric synthetic method reported by N. Barta et al. (Org. Lett. 2000, 2, 2821 ), followed by purification with reverse phase HPLC of preparation, to provide the (S) 5 4- (2,5-dimethyl-4-n-phenyl) -oxazol-dn-2-one; ESMS m / z 237.1 (M + H⁺ ).

Step 3: To a solution of (S) -4- (2,5-dimethyl-4-n -tro-phenol) oxazolidin-2-one (55 milligrams, 0.23 millimoles) in methanol (5 milliliters), Pd / C (5 milligrams, 10 percent by weight / weight) was added. The mixture was degassed and stirred at room temperature under 1 atmosphere of H₂ for 14 hours The Pd / C was removed by filtration through Celite. The filtrate was concentrated to provide (S) -4- (4-amino-2,5-dimethyl-phenyl) oxazolidin-2-one, which was used in the next step without further purification; ESMS m / z 207.1 (M + H⁺).

Step 4: To a reaction tube were added (S) -4- (4-amino2.5-dimethyl-phenol) -oxazolidin-2-one (48 milligrams, 0.23 millimoles),

2.5- d icio ro-N- (5-methyl-1/7-pi razol-3-il) -pi rim id i n-4-a mi na (77 milligrams, 0.32 millimoles), 'PrOH (2 milliliters) , and HCI (0.13 milliliters,

0.52 millimoles, 4N in dioxane). The tube was then sealed and heated at 130 ° C for 6 hours. After cooling to room temperature, the mixture was concentrated and purified by reverse phase HPLC of preparation, to provide the (S) -4- (4 (5-chloro-4- (5-methyl-1/7 -pyrazol-3-yl-amine) -pyrm-din-2-l-amine) -2,525 methyl-phenyl) -oxazolidin-2-one; ESMS m / z 414.1 (M + H⁺).

133

Example 46

5-chloro-N²- (4- (1 -et¡l-piper¡d¡n-4-¡l) -2-fluoro-5-met¡l-fen¡l) -N⁴- (5-met¡l1 Hp¡razol-3-¡) -p¡r¡m¡din-2,4-diamna (232)

<img file="CU23952B1_D0103.tif" />

A mixture of 5-chloro-N²- (2-fluoro-5-methyl-4- (piperidin-4-yl) 10 phenol) -N⁴- (5-metll-1 Hp¡razol-3-ll) -p¡rlm¡d¡n-2,4-d¡am¡na (400 milligrams, 0.96 millimoles), iodine-ethane (92.5 microliters, 1.2 millimoles ), and triethyl amine (201.5 microliters, 1.4 millimoles) in 4 milliliters of dimethyl formamide was heated at 60 ° C for 2 hours. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na₂SW₄), and concentrated in vacuo. The crude product was purified by silica gel chromatography (MeOH / DCM: 1/9), to provide 5-chloro-N²- (4- (1-ethylpiperidin-4-¡) -2-fluoro-5-methyl-phenol) -N⁴- (5-Methyl-1 H-pyrazol-3-1) pyrimidin-2,4-diamine; ¹H NMR (DMSO-ó_s) δ 8.01 (s, 1H), 7.35 (m,

1H), 7.02 (d, 1H), 6.22 (s, 1H), 2.97 (d, 2H), 2.62 (m, 1H), 2.34 (q,

2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.98 (t, 2H), 1.64 (m, 4H), 1.01 (t, 3H); ESMS m / z 444.2 (M + H⁺)·

Example 47

5-chloro-N²- (4- (1 - ((2,2-difluorocyclopropyl) -methyl) -p¡perid¡n-4-¡) -225 fluoro-5-methyl-phenol) -N⁴- (5-met¡l-1 Hp¡razol-3-¡) -p¡r¡m¡din-2,4-d¡am¡na

134 .(235).

<img file="CU23952B1_D0104.tif" />

A mixture of 5-chloro-N²- (2-fluoro-5-methyl-4- (p¡per¡d¡n-4-¡l) phenyl) -N⁴- (5-methyl-1 Hp and I-3-yl) -plr¡ mid ¡n-2,4-d amine (40 milligrams, 0.096 mmol), 2- (bromo-methyl) -1, 1-Difluoro-clclopropane (32.8 milligrams, 0.19 mmol), and triethyl amine (20.2 microliters, 0.14 mmol) in 1 milliliter of dimethyl formamide, was heated at 150 ° C in a microwave reactor for 30 minutes. The crude product was purified by reverse phase HPLC, to provide 5-chloro-N²- (4- (1 - ((2,2-dif luoroci cio pro pil) -m ethyl) -p¡ pe ridi n-4-il) -2fluoro-5-m eti l-feni l) -N⁴- (5-meti 1-1 Hp¡razol-3-yl) -pyrim id i n-2,4-d amine; ESMS m / z 506.2 (M + H⁺ ).

Example 48

3- (4- (4- (5-Chloro-4- (5-metii-1/7-pyrazol-3-yl-amino) -pyrimidin-2-ylamino) -2,5-di meti l-feni l) -piperid¡ n-1 -il) -propanam da (236)

<img file="CU23952B1_D0105.tif" />

A solution of 5-chloro-A /²- (2,5-dimethyl-4- (piperidin-4-yl) -fen¡I) 135 / V⁴- (5-methyl - // 7-pyrazol-3-yl) -pyrimidin-2,4-diamine (41 milligrams, 0.1 millimoles), acrylamide (24 milligrams, 0.33 millimoles), and DIEA (87 microliters, 0.5 millimoles) in NMP (1 milliliter) was stirred at 80 ° C for 10 hours. The LCMS at this point showed that the reaction was not complete, so that additional acrylamide (36 milligrams, 2 times) was added, and the reaction was continued until the LCMS showed that the reaction was complete. The crude product was purified by reverse phase HPLC, to give 3- (4- (4- (5-chloro4- (5-meth and 1-1 H-pyrazol-3-yl-amine) -pyr) midin-2-¡-amino) -2,5-dimethlfe or I) -pi pe r id in -1 -il) -propanamide as a white powder; ESMS m / z 483.2 (M + 1).

Example 49

4- (4- (4- (5-Chloro-4- (5-methyl-1 / - / - pyrazol-3-yl-amino) -p¡rim¡d¡n-2-ilam no) -5 -fluoro-2-m eti l-feni l) -piperid i n-1 - il) -1 -m orfoli no bufa n-1 -ona (246)

<img file="CU23952B1_D0106.tif" />

A mixture of 5-chloro-A /²- (2-Fluoro-5-methyl-4- (piperidin-4-yl) phenyl) - / V⁴- (5-methyl-1 Hp i razo J-3-il) -pyri midin-2,4-diam ina (41 milligrams, 0.1 millimoles), 4-chloro-1 -morpholino-butan-1 -one (29 milligrams , 0.15 millimoles), and DIEA (0.1 milliliters, 0.58 millimoles) in NMP (1 milliliter) was stirred at 80 ° C. After 10 hours, 4136 additional chloro-1-morpholnobutan-1 -one (51 milligrams) was added, and the reaction was continued overnight. The crude product was purified by reverse phase HPLC, to give 4- (4- (4- (5-chloro-4- (5-methyl-1 Hp¡razol-3-l-am-ino)) -p¡ rim ¡di n-2-¡-l-am¡no) -5-fluoro-2-met¡l-fen! I) 5 piperidin-1 -il) -1 -morpholinobutan-1 -one as a white powder; ESMS m / z 571.3.3 (M + H⁺).

Example 50

N²- (4- (1 - ((2,2-dfluoroocclopropll) -methyl) -p¡perid¡n-4-yl) -2-fluoro-5methyl-phenyl) -N⁴- (5-met¡l-1 H-pi razol-3-¡) -5- (tr¡f luoro-methyl) -piri mid ¡n-

<img file="CU23952B1_D0107.tif" />

A mixture of the N2- (2-fluoro-5-methyl-4- (pperperin-4-yl) -phenyl) N4- (5-methyl-1 Hp¡razol-3-yl ) -5- (trifluoro-methyl) -p¡r¡m¡din-2,4-d amine (100 milligrams, 0.22 millimoles), 2- (bromo-methyl) -1,1-difluorocyclopropane (76.4 milligrams, 0.45 millimoles), and triethyl amine (60.6 microliters, 0.42 millimoles) in 1 milliliter of dimethyl formamide, was heated at 60 ° C in a microwave reactor for 2 hours. The crude product was purified by reverse phase HPLC, to provide the N²- (4- (1 - ((2,2-d¡fluoro-cycloprop¡l) -methyl) -p¡perid¡n-4¡l) -2-fluoro-5-m eti l-fen il) - N⁴- (5-methyl-1 Hp¡razol-3-yl) -5- (trifluoro25 methyl) -p¡r¡mld¡n-2,4-d¡am¡na; ESMS m / 2 540.2 (M + H⁺).

137

Example 51

N²'(2,5-d ¡meti 1-4- (piperid¡ n-4-il) -phenyl) -N⁴- (5-m eti 1-1 H-pyrazole-3-yl) -5 (trifl uoro-meti l) -p¡ rim ¡di n-2,4-d amine (257)

<img file="CU23952B1_D0108.tif" />

A mixture of 2-chloro-N- (5-methyl-1 H -pyrazol-3-yl) -5- (trifluoromethyl) -pyrimin-4-amine (513.0 milligrams, 0.9 millimoles), 4- (4-amino-2,5-dimetl-fen¡l) -p¡per¡d¡n-1-terbutyl carboxylate (282.7 milligrams, 0.9 millimoles), and concentrated aqueous HCI (10 drops) in / -PrOH ( 12 milliliters) was heated at 150 ° C in a microwave reactor for 30 minutes. The crude product was purified by reverse phase HPLC, to provide the N²'(2,5-dim et i l-4- (pi pe r id i n-4-I) phenyl) -N⁴- (5-met¡l-1 Η - pi razol-3-¡l) -5- (t rif luoro-meti l) -pi rimid ¡n-2,4diamine; ESMS m / z 446.2 (M + H⁺).

Example 52

5-chloro-A /²- (2-Fluoro-4- (1 - ((3-¡soprop¡l-1,2,4-oxadiazol-5-yl) -methyl) p¡perid¡ n-4-¡I) -5-meti l-fen il) - / V⁴- (5-meti 1-1 / - / - pirazol-3-¡) -p¡r¡m¡d¡n-2,4diamine (259)

<img file="CU23952B1_D0109.tif" />

F

138

A mixture of 5-chloro-A /²- (2-fluoro-5-met¡l-4- (p¡per¡d¡n-4-il) fen i I) - / V⁴- (5-meti-1 Hp¡razol-3-yl) -pyrimidi n-2,4-damine (42 milligrams, 0.1 mmol), 5- (chloro-methyl) -3-isopropyl- 1,2,4-oxadiazole (17 milligrams, 0.10 millimoles), and DIEA (86 microliters, 0.5 millimoles) in

N, N-dimethylformamide (1 milliliter) was stirred at room temperature overnight. The reaction was diluted with EtOAc (50 milliliters), and washed with water (5 milliliters, 2 times). The EtOAc layer was dried over Na₂SW₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography (gradient of 50 to 100 percent EtOAc in hexanes), to give 5-chloro-N2- (2-fluoro-4- (1 ((3-isopropyl-1 , 2,4-oxadiazol-5-yl) -methyl) -piperidin-4-1) -5-methyl-phenyl) N4- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin- 2,4-diamine as a white solid; ESMS m / z 540.2 (M + H⁺).

Example 53 (4- (4- (5-chloro-4- (5-methyl-1/7-pyrol-3-l-amine) -pyramid-2 L-amine) 5-fluoro-2-methyl-fen¡l) -p¡per¡din-1-yl) - (3-isopropyl-1,2,4-oxadiazol-5-yl) methanone ( 265)

<img file="CU23952B1_D0110.tif" />

Step 1: A solution of isobutyronitrile (4.49 milliliters, 50 millimoles) and hydroxylamine (12.3 milliliters, 200 millimoles) in anhydrous ethanol (20 milliliters) was stirred at 60 ° C for two days. Solvent

139 It vanished. The residue was repeatedly co-evaporated with toluene, to give the (E) - / V'-hydroxy-isobutimamdamda as a light yellow liquid;¹H NMR (400 MHz, CDCI₃) δ 7.50 (br s, 1H), 4.52 (br s, 2H), 2.43 (septet, J = 6.8 Hz, 1H), 1.15 (d, J = 6.8 Hz, 6H).

Step 2: A solution of (E) - / V'-h¡drox¡-isobutir¡midamide (0.51 grams, 5 millimoles), and trichloro-acetic anhydride (2.31 grams, 7.5 millimoles) in toluene (20 milliliters) is stirred at 80 ° C. After 4 hours, the reaction was diluted with EtOAc (50 milliliters), washed with NaHCO₃ saturated aqueous (10 milliliters, 2 times), dried over Na₂SW₄ and evaporated, to give 3-sopropyl-5- (trichloro-methyl) -1,2,4oxadiazole as a clear liquid, which was used without further purification; ¹H NMR (400 MHz, CDCI₃) δ 3.16 (septet, J = 7.2 Hz, 1H), 1.39 (d, J = 6.8 Hz, 6H).

Step 3: A mixture of 5-chloro- / V²- (2-fluoro-5-methyl-4- (p¡peridin4-¡I) -fen¡I) -Λ /⁴- (5-methy-1 H-pyrazol-3-¡) -p¡r¡m¡d¡n-2,4-diamna (42 milligrams, 0.1 millimoles), 3-isopropyl-5- (trichloro -methyl) -1,2,4-oxadiazole (46 milligrams, 0.2 millimoles), and DIEA (40 microliters, 0.23 millimoles) in methanol (1 milliliter) was stirred at 70 ° C overnight. The crude reaction mixture was purified by reverse phase HPLC, to give the (4- (4- (5-chloro-4- (5-methyl-1 H-plrazol-3-11-amino) pimim) id ¡n-2-il-amlno) -5-fluoro-2-met¡ l-fen il) -pi perid ¡n-1 -il) - (3-soprop¡l1,2,4-oxad¡azoi -5-¡) -methanone as a white solid; ¹H NMR (400 MHz, CDCIa) δ 9.67 (br s, 2H), 8.50 (s, 1H), 8.07 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 12.4 Hz, 1H), 6.16 (s, 1H), 5.53 (s, 1H), 3.98 (d, J = 13.2 Hz, 1H), 3.34 (dt, J = 2.0, 2.8 Hz, 1H), 3.15 (m, 1H ),

140

2.82 (m, 2H), 2.62 (t, J = 4.8 Hz, 2H), 2.34 (s, 3H), 2.25 9s, 3H), 1.90 (m, 2H), 1.76 (2 H); ESMS m / z 554.2 (M + H⁺ ).

Example 54

5-chloro - / \ /? - (4- (1 - (2- (3-sopropyl-1,2,4-oxadiazol-5-yl) -ethyl) -piperidin-4l) -2,5-dimethyl -fen¡l) -A /₄- (5-methyl-1 Hp¡ razol-3-l) -p¡ rim ¡di n-2,4-d ¡amina (269)

<img file="CU23952B1_D0111.tif" />

Step 1: A mixture of (E) - / V'-hydroxy-sobutyrimidamide (510 milligrams, 5 millimoles), 3-chloro-propanoic acid (542 milligrams, 5 millimoles), and dicyclohexyl-carbodi-imide (1.24 grams , 6 millimoles) in anhydrous dioxane (20 milliliters), stirred at 0 ° C for 1 hour, and then at room temperature for an additional 1 hour. The reaction was then heated at 80 ° C for an additional 18 hours. The reaction was filtered, and the filtrate was evaporated. The resulting residue was purified by silica gel chromatography (gradient from 0 to 100 percent EtOAc in hexanes), to give 5- (2-chloro-ethyl) -3isopropyl-1,2,4-oxadiazole; ¹H NMR (400 MHz, CDCI₃) δ 3.85 (t, J = 7.2 Hz, 2H), 3.27 (t, J = 7.2 Hz, 2H), 3.03 (septet, J = 7.2 Hz, 1H), 1.13 (d, J = 7.2 Hz, 6H); ESMS m / z 175.1 (M + H⁺ ).

Step 2: A mixture of 5-chloro- / V₂- (2,5-d¡met¡l-4- (piper¡din-4-¡l) faith ni I) - / V₄- (5-m et i I -1 / - / - pyrazol-3-¡l) -pyrimidin-2,4-d-amine (14 milli141 grams, 0.033 mmol), 5- (2-chloro-ethyl) - 3-Isopropyl-1,2,4-oxadiazole (9 milligrams, 0.053 millimoles), and DIEA (29 microliters, 0.17 millimoles) in NMP (1 milliliter), was stirred at 50 ° C for 3 days. The crude reaction mixture was purified by reverse phase HPLC, to give 5-chloro-N2- (4- (1- (2- (3-isopropyl-1,2,4-oxadiazol-5-yl) -ethyl) ) piperidin-4-¡l) -2,5-d ¡meí l-phenyl) -N4- (5-met¡ 1-1 H-pyrazole-3-¡) -pyrmidium2,4-diamine as a white solid; ESMS m / z 550.3 (M + H⁺).

Example 55

5-Chloro - / \ /? - (2-fluoro-5-methyl-4- (1- (6-methyl-pyridazin-3-yl) -piperidin-4-l) 10 phenyl) - / \ / 4- (5-met¡l-1 Hp¡razol-3-¡) -p¡r¡ mid ¡n-2,4-di amine (277)

<img file="CU23952B1_D0112.tif" />

A 5-chlorine suspension - / \ /²- (2-fluoro-5-met¡l-4- (p¡per¡d¡n4-i i) -fe ni I) - / V⁴- (5-m eti I -1 H-pyrazol-3-yl) -p¡r¡m¡d¡n-2,4-d¡amina (20 milligrams, 0.05 mmol), 3-chloro-6-methyl -piridazine (13 milligrams, 0.1 millimoles), and Cs₂CO₃ (33 milligrams, 0.1 millimoles) in dioxane (1 milliliter), stirred at 150 ° C in a sealed bottle. After 15 hours, 3-chloro-6-methyl-pyrdazine (26 milligrams), and Cs were added₂CO₃ (66 milligrams) additional. The reaction was continued for an additional 3 hours. The crude reaction mixture was purified by reverse phase HPLC, to give 5-chloro-N2- (2-fluoro-525 methyl-4- (1 - (6-methyl-pl ridazin-3-yl) -pi perid ¡n-4-yl) -fen¡l) -N4- (5-met-1-1 H142 prazol-3-yl) -pyrmidine-2,4-diamine as a white solid; ESMS m / z 508.2 (M + H⁺ ).

Examples 56 and 57

5-Chloro-N2- (2-fluoro-5-methyl-4 - ((frans) -2-methyl-piperine-4-yl) -phenyl) 5 N 4- (5-m eti 1-1 H-pi razol-3-il) -piri mid i n-2,4-d amine (279)

<img file="CU23952B1_D0113.tif" />

5-Chloro-N2- (2-fluoro-5-methyl-4 - ((c / s) -2-methyl-p¡peridin-4-¡l) -phenyl) -N410 (5-meti 1-1 Hp Razol-3-yl) -pyrimidin-2,4-diamna (280)

<img file="CU23952B1_D0114.tif" />

Step 1: A solution of 2-methyl-4-oxo-piperidine-1-carboxylate of terbutyl (1 gram, 4.69 mmol) in tetrahydrofuran (20 milliliters), was added dropwise to a cooled solution (-78 ° C) and vigorously stirred LDA (3.75 milliliters of a 1.5M solution in chlorchloxanes, 5.63 mmol) in tetrahydrofuran (20 milliliters), under

N₂. The reaction mixture was stirred at -78 ° C for 30 minutes before adding a solution of phenyl-trifluoro-sulfonimide (1.84 grams, 5.16 mmol) in tetrahydrofuran (20 milliliters). Following this addition, the reaction mixture was heated to room temperature, and stirred for 3 hours. The reaction was cooled to 0 ° C, and quenched with

100 milliliters of NH₄Saturated aqueous CI, followed by filtration at

143 through Celite. The filtrate was added to 100 milliliters of EtOAc and the layers were separated. The organic layer was washed with water, dried over MgSO₄ and concentrated. The crude product was purified by silica gel chromatography (gradient from 0 to 30 percent of

EtOAc in hexanes, and was verified by TLC stained with KMnO₄ 2 percent in EtOH), to provide 2-metll-4- (trifluoro-metols or I fo or I oxy) - 5,6-dihydro-pyridin -1 (2H) -butyl carboxylate As a yellow solid.

Step 2: To a mixture of 2-fluoro-5-methyl-4- (4,4,5,5-tetramethyl10,3,2-dloxaborolan-2-yl) -aniline (587 milligrams , 2.33 millimoles), 2-methyl-4- (trifluoro-methyl¡l-su Ifonloxy) -5,6-d ¡hid ro-p¡r¡d¡ n-1 (2H) terbutyl carboxylate (968 milligrams, 2.80 millimoles), and sodium carbonate (1.73 grams, 16.35 millimoles) in Ν, dime-dimethylformamide / H₂Or (20/5 milliliters), tetrakis- (triphenyl-phosphine) 15 palladium (O) (135 milligrams, 5 percent millimoles) was added. The reaction tube was sealed, the mixture was purged with N₂ for 3 minutes, and then heated at 100 ° C under N₂ for 8 hours The reaction was cooled to room temperature, and poured into a saturated aqueous solution of ammonium chloride. The crude reaction mixture was extracted with ethyl acetate (15 milliliters, 3 times). The organic extracts were combined, washed with brine, and concentrated. The crude product was purified by silica gel chromatography (50 percent ethyl acetate in hexanes), to provide 4- (4-amino-5-fluoro-2-methyl-phenyl) -6-methyl. 1-5,6-dihydro25 pyridin-1 (2H) -carboxylate of terbutyl as a yellow oil.

144

The oil obtained was dissolved in methanol (20 milliliters). To the solution was added Pd / C (at 10 percent). The reaction mixture was degassed and purged with H₂ several times, and stirred vigorously under 1 atmosphere of H₂ overnight. The mixture was filtered, and the filtrate was concentrated, to provide terbutyl 4- (4-amino-5-fluoro-2-methyl-phenyl) -2-methyl-piperidine-1-carboxylate as a white solid. ESMS m / z 267 (M -56+ H⁺ ).

Step 3: A mixture of 2,5-dichloro - / \ / - (5-methyl-1 H-pyrazol-3-yl) pyrimidin-4-amine (346 milligrams, 1.42 millimoles), and 4- ( 4-amino-5fIuoro-2-methyl-phenyl) -2-methyl-piperidin-1-carboxylate of terbutyl (352 milligrams, 1.09 millimoles) in 2-propanol (10 milliliters) was treated with concentrated HCI (12N, 0.43 milliliters) . The mixture was sealed and heated in a microwave reactor at 130 ° C for 45 minutes. The mixture was concentrated. The residue was purified by reverse phase HPLC, to provide 5-chloro-N2- (2-fluoro-5-methyl-4- (2-methyl), i r r id i n-4-i) -fen i I) - N4- (5-m et i I-1 H-pyrazol-3-yl) -pyrmidium-2,4-damine as a white solid. ESMS m / z 430.1 (M + H⁺).

Step 4: The 5-chloro-N2- (2-fluoro-5-methyl-4- (2-methyl-piperidn-4-yl) phenyl) -N4- (5-methyl-1 H-pi razo l -3-i I) - pi rim id i n-2,4-d-amine (20 milligrams, 0.046 mmol) was dissolved in a mixture of dichloromethane and methanol solvents (0.5 milliliters, 10/1 by volume / volume + NH₃ 0.175N). The mixture was applied to preparation thin layer chromatography in order to separate the c / s and trans stereoisomers (eluent: 6 percent methanol in dichloromethane with NH₃0.1N) of 5-Chloro-N2- (2-fluoro-5-methyl-4- (2-methyl) -perld-4-l) 145 phenyl) -N4- (5-methyl -1 H-pyrazol-3-yl) -pyrimidin-2,4-diamine as white solids. The trans isomer was the upper band of the thin layer chromatography of preparation, and the cis isomer was the lower band of the thin layer chromatography of preparation; ESMS m / z 430.1 (M + H⁺); cis stereoisomer:¹H NMR (400 MHz, MeODd4): δ 8.03 (s, 1H), 7.84 (d, 1H), 7.02 (d, 1H), 6.24 (d, 1H), 3.90-3.85 (m, 1H), 2.32 (s , 3H), 2.27 (s, 3H), 2.03-1.84 (m, 2H), 1.65-1.54 (m, 1H), 1.55 (d, 3H), 1.38-1.19 (m, 4H).

Example 58

3- (4- (4- (5-Chloro-4- (5-methyl-1/7-pyrazol-3-yl-amine) -pyrimin-2-ylamino) -5- fluoro-2-methyl-phenol) -piperidin-1-yl) -cyclopent-2-en-one (282)

<img file="CU23952B1_D0115.tif" />

A mixture of 5-chlorine - / \ /²- (2-Fluoro-5-methyl-4- (piperidin-4-yl) phenyl) - / \ /⁴- (5-Methyl-1 H-pyrazol-3-L) -pyrimidin-2,4-d amine (43 milligrams, 0.1 millimoles), cyclopentane-1,3-dione (89 milligrams, 9.1 millimoles) , sodium cyano-borohydride (19 milligrams, 0.3 millimoles), and DIEA (0.2 milliliters, 11 millimoles) in methanol (1 milliliter) was stirred in a sealed bottle at 60 ° C. After 2.5 hours, additional sodium clano-borohydride (19 milligrams, 0.3 millimoles) was added, and the reaction was continued stirring at 60 ° C overnight. The mixture was purified by reverse phase HPLC, to

146 give the 3- (4- (4- (5-chloro-4- (5-met1-1 H-pyrazol-3-yl-amine) -p¡r¡m¡d¡n-2- M m no) -5-f luoro-2-me ti l-fenll) -p¡ perid ¡n-1 -il) -cyclopent-2-in-one as a grayish solid; ¹H NMR (400 MHz, DMSO-d_and) δ 9.97 (br s, 1H), 9.83 (br s, 1H), 8.90 (s, 1H), 8.32 (d, J = 6.8 Hz, 1H), 7.88 (d, J =

12.8 Hz, 1H), 6.97 (s, 1H), 6.04 (s, 1H), 5.30 (br s, 1H), 4.71 (d, J =

12.0 Hz, 2H), 4.04 (t, J = 12.4 Hz, 2H), 3.84 (m, 1H), 3.53 (m, 2H), 3.13 (m, 2H), 3.08 (s, 3H), 2.96 (s, 3H), 2.59-2.40 (m, 4H); ESMS m / z 496.2 (M + H⁺).

Example 59

1 - 4- (4- (5-Chloro-4- (5-methyl-1 Hp¡razol-3-yl-amine) -p¡r¡m¡d¡n-2il-amine) oxide -5-fluoro-2-methyl-phenyl) -1 -ethyl-piperidine (289)

<img file="CU23952B1_D0116.tif" />

To a solution of 5-clo ro-N ²- (4- (1 -eti l-piperid ¡n-4-¡l) -2fluoro-5-met¡l-phenyl) -N⁴- (5-methyl-1 Hp¡razol-3-yl) -pyrmidium-2,4-diamine (22.2 milligrams, 0.05 millimoles) in dichloromethane (10 milliliters), and methanol (1 milliliter), MCPBA was added (11.2 milligrams, 0.07 millimoles). The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and NaHCO.₃ saturated aqueous, the combined organic extracts dried (Na₂SW₄), and concentrated in vacuo. The raw product is

147 purified by reverse phase HPLC, to provide the 1-oxide of 4- (4- (5-chloro-4- (5-methyl-1 H-pyrazol-3-i-ami no) -pi rim idi η- 2-llamino) -5-fluoro-2-methyl-phenyl) -1-ethyl-piperidine; ¹H NMR (MeOD-d₄) 07.91 (s, 1H), 7.69 (d, 1H), 7.00 (d, 1H), 6.15 (s, 1H), 3.28 (m, 4H),

2.91 (m, 1H), 2.32 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 1.83 (s, 2H),

1.64 (d, 2H), 1.31 (t, 3H) .; ESMS m / z 460.2 (M + H⁺ ).

Example 60

5-chloro-A /²- (2-fluoro-5-methyl-4- (1 - (pyrimidin-5-yl-methyl) -pperidin-4-yl) phenyl) - / \ /⁴- (5-m ethyl-1 / - / - pyrazol-3-yl) -pi rim idi n-2,4-d amine (314)

<img file="CU23952B1_D0117.tif" />

To a solution of 5-chloro- / V²- (2-fluoro-5-meti-4- (piperidin-415 i I) -fe ni I) - Λ /⁴- (5-met i I -1 H-pi razo i-3-i I) -pi ri m id i n-2,4-diamine (45 milligrams, 0.1 millimoles), and pyrimidin-5-carbaldehyde (32 milligrams , 0.3 millimoles) in dichloromethane (1.5 milliliters), NaBH (OAc) was added₃ (64 milligrams, 0.3 millimoles), followed by the addition of AcOH (12 microliters). After stirring at room temperature in a sealed bottle for 16 hours, the reaction was quenched with EtOAc (50 milliliters). The reaction mixture was washed sequentially with water (10 milliliters), brine (5 milliliters), dried over Na₂SW₄ and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0 to 10 percent methanol in an EtOAc gradient with an NH additive₃ at 1 percent in

148 methanol), to give 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (p¡r¡m¡d¡n-5-ilmetil) -piperid¡n-4- L) -fen¡l) -N4- (5-methyl-1 H-pyrazol-S-yl-pirlmidln ^^ dlamine as a grayish solid; ¹H NMR (400 MHz, CD₃OD) δ 9.09 (s, 1H), 8.81 (s, 2H), 8.00 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 13.2 Hz, 1H), 6.23 ( br s, 1H), 3.65 (s, 2H), 3.03 (m, 2H), 2.76 (m, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.25 (m, 2H), 1.80- 1.68 (m, 4H); ESMS m / z 508.2 (M + H⁺ ).

The following compounds in Table 1 are obtained by repeating the procedures described in the previous Examples, and using the appropriate starting materials.

Table 1

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC_K(p.m)</td>

<td></td><td></td><td>¹H NMR (400</td><td></td>

<td></td><td></td><td>MHz, DMSO-d6)</td><td></td>

<td></td><td>ι X</td><td></td><td></td>

<td></td><td>hn - n^ck^_n Χ '~ γΧΧ</td><td>δ 10.33 (br,</td><td></td>

<td></td><td></td><td>1H), 9.90 (br,</td><td></td>

<td></td><td>H ^H F</td><td>1 H0, 9.60 (br,</td><td></td>

<td>X</td><td>5-chloro-N2- (2-fluoro-5-met¡ 1-4- (1 -</td><td>1H), 8.22 (s,</td><td> 0.011</td>

<td></td><td>methyl-p¡per¡din-4-¡l) -fen¡l) -N4- (5-</td><td>1H), 7.56 (d,</td><td></td>

<td></td><td>met 1-1 Hp¡ razo l-3-¡l) -pirim ¡din-</td><td>1 H), 7.00 (d,</td><td></td>

<td></td><td>2,4-diamlna</td><td>1H), 6.20 (s,</td><td></td>

<td></td><td></td><td>1H), 3.53-3.50</td><td></td>

149

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3</td>

<td></td><td></td><td>(m, 2H), 3.16- 3.10 (m, 2H), 2.97-2.92 2.81 (d, 3H), 2.26 (s, 3H), 2.16 (s, 3H), 1.94-1.91 (m, 2H), 1.83- 1.73 (m, 2H); ESMS m / z 430.1 (M + H ⁺ ).</td><td></td>

<td>X</td><td>ι X ΗΝ-Νθ'γ ^ Ν ν Ν ^ γ Η ^Η F 5-chloro-N2- (2-fluoro-5-methyl-4- (ρ i pe r id i n-4-i 1) -fe ni 1) - N 4- (5-m eti 1 - 1 H-pyrazol-3-¡l) -pyrimidin-2,4- diamine</td><td>ESMS m / z 416.1 (M + H ⁺ ).</td><td> 0.050</td>

150

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθκι (pM)</td>

<td>X</td><td>I HN-n^CI^ Y ^ N \ n^/&lt;:t H H ' Ύ 5-cl gold-N2- (2-isop ropoxy-5-methyl - 4- (1 -met ¡lp¡pe ridi η-4-i I) -fe ni l) -N4- (5-methyl-1 H-pyrazol-3-yl) -p¡ rim id i n- 2,4-diamine</td><td>ESMS m / z 470.2 (M + H⁺).</td><td> 0.104</td>

<td></td><td>HN '^ b^h.ⁿ~ NN ^ N^hf + f F N2- (2-fluoro-5-methyl-4- (piperidine) 4-¡) -phenyl) -N4- (5-methyl-1 H-pyrazole- 3-yl) -5- (trifluoro-methyl) -pyrimidin- 2,4-diamine</td><td>ESMS m / z 450.2 (M + H⁺).</td><td> 0.150</td>

<td>X</td><td>IP 'Ή- ν Ή N Η Η I Ύ</td><td>ESMS m / z 450.3 (M + H⁺).</td><td> 0.805</td>

151

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ΙθεοίρΜ)</td>

<td></td><td>N 2- (2-sopro pox¡-5-meti 1-4- (1 - met¡l-piper¡d¡n-4-¡l) -phenyl) -5-methyl- N4- (5-methyl-1 H-pyrazol-3-i I) - p¡ r¡ m id¡ n-2,4-d¡amina</td><td></td><td></td>

<td>X</td><td>ι P \ N Η Η | 5. Chloro-N 2- (2,5-d got 1-4- (1-methyl- p¡peridi n-4-¡I) -feni I) -N4- (5-m eti I- 1 H-pyrazol-3-yl) -pyrimidin-2,4- diamine</td><td>ESMS m / z 426.2 (M + H ⁺ ).</td><td> 0.015</td>

<td>X</td><td>Cl d '' ' hn-n^ci&gt; ^ n Pf Η Η I 5-Chloro-N2- (5-Chloro-2-Methyl-4- (1- methyl-piperld¡n-4-¡l) -phenyl) -N4- (5- methyl-1H-p¡razol-3-il) -p¡mid¡n- 2,4-diamine</td><td>ESMS m / z 446.1 (M + H⁺).</td><td> 0.015</td>

<td></td><td></td><td>ESMS m / z 461.2 (M + H⁺).</td><td> 1.93</td>

152

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoípM)</td>

<td rowspan="2">X</td><td>Η Η __γγ ^Ν γ^Ν γ ^ΝΗΝΝ / Χν / Ν X. Jk, ΜΝ (γ \ / / _F5-chloro-N2- (4-fluoro-2-methyl-5- (piperidin-4-yl) -phenyl) -N4- (5-methyl- 1 Hp¡razol-3-¡) -p¡r¡m¡d¡n-2,4- diamine</td><td></td><td></td>

<td>I 0 ^{H H} F 3- (5-Chloro-2- (2-fluoro-5-methyl-4- (1 - m eti Ip i pe rid ¡n-4-¡I) -fe ni Ia mino) - pyrimidin-4-¡-l-amino) -azepan-2-one</td><td>ESMS m / z 461.2 (M + H⁺).</td><td> 0.087</td>

<td></td><td>° h?^H i YY Ά λλ&gt; 1 AJ Ν NY (S) -3- (5-chloro-2- (2-fluoro-5-methyl- 4- (1-methyl-piperidin-4-yl) -phenyl- amino) -pyrimidin-4-yl-amino) -</td><td>ESMS m / z 461.2 (M + H⁺).</td><td> 0.869</td>

153

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC ^ pM)</td>

<td></td><td>azepan-2-one</td><td></td><td></td>

<td></td><td>^hnQ _r. or Η Γ 117 To rW^H F (R) -3- (5-chloro-2- (2-fluoro-5-methyl- 4- (1 -meti lp ¡pe rid ¡n-4-¡1) -fe ni 1- amino) -pyrimidin-4-ii-amino) - azepan-2-one</td><td>ESMS m / z 461.2 (M + H⁺).</td><td> 0.065</td>

<td></td><td>HnXI 1 N NH 4 ^ Ν ' TO Η I 5-chloro-N2- (4- (1-isopropyl- piperid¡n-4-il) -2,5-d¡met¡l-phenyl) - N4- (5-methyl-1H-pyrazol-3-yl) - pyrimidin-2,4-diamine</td><td>ESMS m / z 454.2 (M + H⁺).</td><td> 0.010</td>

154

<td></td><td>STRUCTURE</td><td>NMR or</td><td>ESMS</td><td>IGF-1R Ba / F3 ICgo (pM)</td>

<td></td><td>N ~ HN— (^z 7 — Cl V _y /ⁿ'^nh / ^N /-\ /- ^HNF</td><td>ESMS</td><td>m / z</td><td></td>

<td></td><td>5-chloro-N2- (4-fluoro-5- (1-</td><td>458.2 (M</td><td>+ H ⁺ ).</td><td></td>

<td></td><td>Sopropil-pipe rid ¡n-4-il) -2-methyl-</td><td></td><td></td><td></td>

<td></td><td>phenyl) -N4- (5-methyl-1 H-plrazol-3-yl) -</td><td></td><td></td><td></td>

<td></td><td>pir¡m¡d¡n-2,4-d¡am¡na</td><td></td><td></td><td></td>

<td></td><td>\ and — NH^hn'nv = n / \ Cl — 4 NH ^X—N</td><td>ESMS</td><td>m / z</td><td></td>

<td></td><td>5-chloro-N2- (2,5-d¡met¡l-4-</td><td>412.2 (M</td><td>+ H +).</td><td> 0.016</td>

<td></td><td>(piperid i n-2-i I) -fe ni l) -N4- (5-m ethyl-</td><td></td><td></td><td></td>

<td></td><td>1 Hp i razo I-3-i I) -piri mid ¡n-2,4-</td><td></td><td></td><td></td>

<td></td><td>diamlna</td><td></td><td></td><td></td>

<td></td><td>NH</td><td></td><td></td><td></td>

<td></td><td>AND#^HN'N \ = N / A Cl 4 /) - NH</td><td colspan="2">ESMS m / z 412.2 (M + H ⁺ ).</td><td> 0.050</td>

<td></td><td>5-chloro-N2- (2,5-dimethyl-4-</td><td></td><td></td><td></td>

<td></td><td>(piperid¡n-3-il) -fen¡l) -N4- (5-methyl-</td><td></td><td></td><td></td>

155

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθίο (μΜ)</td>

<td></td><td>1 H-pyrazol-3-¡) -p¡rimid¡n-2,4- diamine</td><td></td><td></td>

<td></td><td>—N}^hnn \ = n / = / Cl - /) - NH —N 5-clo ro-N2- (2,5-d I got 1-4- (1 -mei I- plperid¡n-2-¡) -phenyl) -N4- (5-methyl- 1 H-pyrazol-3-yl) -p¡rim¡d¡n-2,4- diamine</td><td>ESMS m / z 426.2 (M + H⁺).</td><td> 0.019</td>

<td></td><td>Η Η V HN 'N \ / NH 5-chloro-N4- (5-cyclopropyl-1 H- pyrazol-3-yl) -N2- (2-fluoro-5-methyl- 4- (pipe ridi n-4-11) -fe ni I) -p I rl mid ¡n- 2,4-diamine</td><td>ESMS m / z 442.2 (M + H⁺).</td><td> 0.160</td>

156

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ICsoftjM)</td>

<td></td><td>Η Η 1 ^ γ ^ γ Ν γΝ γΝ γ ^</td><td></td><td></td>

<td></td><td></td><td>ESMS m / z</td><td></td>

<td></td><td>\ / ΝΗ</td><td>438.2 (M + H⁺).</td><td> 0.095</td>

<td></td><td>5-chloro-N4- (5-cyclopropyl-1H-</td><td></td><td></td>

<td></td><td>prazol-3-yl) -N2- (2,5-d-methyl-4-</td><td></td><td></td>

<td></td><td>(pperid¡n-4-¡l) -phenyl) -pyrmidine-2,4-</td><td></td><td></td>

<td></td><td>diamine</td><td></td><td></td>

<td></td><td></td><td>¹H NMR (400</td><td></td>

<td></td><td></td><td>MHz, MeOD-d4)</td><td></td>

<td></td><td>i '^N</td><td>8.12 (s, 1H),</td><td></td>

<td></td><td>ΗΝ-Νθ'Ύ ^ -Ν / ⁰</td><td>7.75 (d, 1 H),</td><td></td>

<td></td><td>H ^H F</td><td>7.03 (s, 1H),</td><td></td>

<td></td><td>5-chloro-N2- (4- (1 - ((3,5-di methyl-</td><td>6.27 (s, 1 H),</td><td> 0.056</td>

<td></td><td>isoxazol-4-yl) -methyl) -piperidin-4-yl) -</td><td>4.25 (s, 2H),</td><td></td>

<td></td><td>2-fluoro-5-met ¡l-phenyl) -N4- (5-methyl-</td><td>3.69-3.67 (m,</td><td></td>

<td></td><td>1 H-pyrazol-3-yl) -pyrimidin-2,4-</td><td>2H), 3.27-3.20</td><td></td>

<td></td><td>diamine</td><td>(m, 3H), 2.54 (s,</td><td></td>

<td></td><td></td><td>3H), 2.37 (s,</td><td></td>

<td></td><td></td><td>3H), 2.34 (s,</td><td></td>

157

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθ50 (pM)</td>

<td></td><td></td><td>3H), 2.30 (s,</td><td></td>

<td></td><td></td><td>3H), 2.10-1.95</td><td></td>

<td></td><td></td><td>(m, 4H); ESMS</td><td></td>

<td></td><td></td><td>m / z 525.1 (M +</td><td></td>

<td></td><td></td><td>H +).</td><td></td>

<td></td><td> ¥ / ^HN'P / Ν NH ip ' ^N VO^C'Y ^ N PV ^</td><td></td><td></td>

<td></td><td>XX-Xp</td><td>ESMS m / z</td><td></td>

<td></td><td>Η I</td><td>521.2 (M + H⁺).</td><td> 0.011</td>

<td></td><td>5-Chloro-N 2- (4- (1 - ((3,5-di methyl-</td><td></td><td></td>

<td></td><td>Soxazol-4-¡l) -met¡l) -p¡per¡din-4-il) -</td><td></td><td></td>

<td></td><td>2,5-dimethyl-phenyl) -N4- (5-methyl-1H-</td><td></td><td></td>

<td></td><td>pyrazol-3-yl) -pyrimidin-2,4-diamine</td><td></td><td></td>

<td></td><td>hn ^ ~ X Ν NH ι Ρ N Xp | j</td><td></td><td></td>

<td></td><td>^{C |}\ A APP V</td><td></td><td></td>

<td></td><td>vaV</td><td>ESMS m / z</td><td></td>

<td></td><td>Η I</td><td></td><td> 0.002</td>

<td></td><td>5-cl gold-N 2- (2,5-di meti 1-4- (1 -</td><td>504.2 (M + H ⁺ )</td><td></td>

<td></td><td>(pyridazin-4-¡-mel) -piper¡din-4-</td><td></td><td></td>

<td></td><td>il) -phenyl) -N4- (5-methyl-1 H-pyrazol-3-</td><td></td><td></td>

158

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICjofpM)</td>

<td></td><td>L) -pir¡m¡d¡n-2,4-d ¡amina</td><td></td><td></td>

<td></td><td>i X ' H Nn ^ClH ^H F 2- (4- (4- (5-Chloro-4- (5-methyl-1 H-) pyrazol-3-l-amino) -p¡r¡m¡d¡n-2-il- amino) -5-fluoro-2-methyl-phenol) - piperidin-1-yl) -ethanol</td><td>ESMS m / z 460.2 (Μ + H +).</td><td> 0.059</td>

<td>X</td><td>JpN ^ °^Hhn -N ^Cl γ ^ Ν ^ 'n \ Ν ^ γ Η H | 2- (4- (4- (5-Chloro-4- (5-methyl-1 H-) pyrazol-3-l-amino) -pyrimidin-2-yl- am¡no) -2,5-d ¡methyl-fen ¡l) -p¡per¡d¡n- 1-yl) -ethanol</td><td>ESMS m / z 456.21 (M + H⁺)·</td><td> 0.006</td>

159

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθ5θ (ρΜ)</td>

<td></td><td>i HN -ν ^CI And ^_N PP ^ H ^H F 5-chloro-N²- (2-fluoro-5-m eti 1-4- (1 - (3,3,3-trifluoro-propyl) -piperidin-4- iI) -fen¡I) - N⁴- (5-meti-1 H-pyrazole-3- i I) -pi ri m ¡di n-2,4-diam ina</td><td>ESMS m / z 512.2 (M + H ⁺ ).</td><td> 0.085</td>

<td></td><td>pY^Nil ΠΤ Τ '⁰Y — NJ Η_Νγνf Ny H 5-Chloro-N2- (2,5-dimethyl-4- (1 - (3,3,3-trifluoro-propyl) -piperidine-4- i I) -fe ni I) -N4- (5-met¡ I-1 H-pyrazole-3- il) -pyrmidine-2,4-diamine</td><td>ESMS m / z 508.2 (M + H ⁺ ).</td><td> 0.031</td>

<td></td><td>^hnP. Cl. ^_: llj F ^Fhe ^N l ΊΓ ί A. XJ Ν Ν γ^H F 5-Chloro-N 2- (2-fluoro-5-m eti 1-4- (1 -</td><td>ESMS m / z 498.2 (M + H ⁺ ).</td><td> 0.142</td>

160

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICgo (pM)</td>

<td></td><td>(2,2,2-trifluoro-ethyl) -piperidine-4-yl) -</td><td></td><td></td>

<td></td><td>phenyl) -N4- (5-methyl-1 H-pyrazol-3-yl) -</td><td></td><td></td>

<td></td><td>pimirin-2,4-day</td><td></td><td></td>

<td></td><td>^hTO_n„ „ _Γνα;^cA γί ^</td><td></td><td></td>

<td></td><td>Η I</td><td>ESMS m / z</td><td></td>

<td></td><td>5-cl gold-N2- (5-chloro-2-m eti 1-4- (1 -</td><td>528.2 (M + H⁺).</td><td> 0.044</td>

<td></td><td>(3,3,3-trifluoro-propyl) -p¡per¡d¡n-4-</td><td></td><td></td>

<td></td><td>il) -phenyl) -N4- (5-methyl-1 H-pyrazol-3-</td><td></td><td></td>

<td></td><td>il) -pyrimidin-2,4-diamine</td><td></td><td></td>

<td></td><td>η h HN'N_{c |}/ Vn AA_F</td><td>ESMS m / z</td><td></td>

<td></td><td>5-chloro-N2- (4-fluoro-2-met i 1-5- (1 -</td><td>512.2 (M + H⁺).</td><td> 5.46</td>

<td></td><td>(3,3,3-trifluoro-propyl) -piperidine-4-</td><td></td><td></td>

<td></td><td>il) -phenyl) -N4- (5-methyl-1 H-pyrazol-3-</td><td></td><td></td>

<td></td><td>il) -pirim¡d¡n-2,4-d¡am¡na</td><td></td><td></td>

161

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC50 (pM)</td>

<td></td><td>Η Xn _Fx-Λλ χ- XJ NH I [ ^N | F^{c |}for_n LÁOH OH γ H 1</td><td>ESMS m / z</td><td></td>

<td></td><td></td><td>524.2 (M + H⁺).</td><td> 0.023</td>

<td></td><td>3- (4- (4- (5-chloro-4- (5-methyl-1 H-</td><td></td><td></td>

<td></td><td>pyrazol-3-yl-amino) -pyriminctin-2-yl-</td><td></td><td></td>

<td></td><td>am i no) -2,5-d ¡meí l-fen il) -piperidin-</td><td></td><td></td>

<td></td><td>1 -i I) -1,1,1 -trifluoro-propan-2-ol</td><td></td><td></td>

<td></td><td>s HN, JV^FΝ NH i A'p_Fci ^ A_n ^ xx-x ^oh^H F</td><td>ESMS m / z</td><td></td>

<td></td><td>3- (4- (4- (5-chloro-4- (5-methyl-1 H-</td><td>528.2 (M + H⁺).</td><td> 0.071</td>

<td></td><td>pyrazol-3-i-l-no) pyrimidin-2-yl-</td><td></td><td></td>

<td></td><td>am i no) -5-fluoro-2-met¡ l-feni I) -</td><td></td><td></td>

<td></td><td>piperidin-1-yl) -1,1,1-tri fluoro-</td><td></td><td></td>

<td></td><td>propan-2-ol</td><td></td><td></td>

162

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICgo (pM)</td>

<td></td><td>η η n ^^F, ρ-γ ^Ν γΝ γ Ν ΟΗ</td><td></td><td></td>

<td></td><td>hn-Nci-L · AA_F</td><td>ESMS m / z</td><td></td>

<td></td><td>3- (4- (5- (5-chloro-4- (5-methyl-1 Η-</td><td>528.2 (Μ + H +).</td><td> 6.47</td>

<td></td><td>pyrazole- 3-¡-l-am¡no) -p¡r¡midín-2-if-</td><td></td><td></td>

<td></td><td>amlno) -2-fluoro-4-methyl-phenol) -</td><td></td><td></td>

<td></td><td>pi perid ¡n-1 - il) -1,1,1 -trifluoro-</td><td></td><td></td>

<td></td><td>propan-2-ol</td><td></td><td></td>

<td></td><td rowspan="2">HN, 3. _ ¡¡ Ν NH AN CI ^ X. J'xA-J or A | N p || Ν ^ Ν ^ γ ^^H F</td><td>ESMS m / z</td><td></td>

<td></td><td>513.2 (M + H⁺).</td><td> 0.042</td>

<td></td><td>2- (4- (4- (5-chloro-4- (5-clclopropyl-</td><td></td><td></td>

<td></td><td>1 H-pyrazol-3-¡-amino) -p¡r¡mid¡n-2-</td><td></td><td></td>

<td></td><td>L-am ino) -5-fluoro-2-met¡ l-fen i I) -</td><td></td><td></td>

<td></td><td>pipe rid ¡n-1 - ll) -N-met¡l-acetamide</td><td></td><td></td>

163

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθ5θ (ρΜ)</td>

<td></td><td>HN, 3 _Λ b Ν NH i GN 'IJ' ' and «AU ° ¡L a áJ Ν Ν And</td><td>ESMS m / z</td><td></td>

<td></td><td>Η I</td><td>509.2 (M + H ⁺ ).</td><td> 0.006</td>

<td></td><td>2- (4- (4- (5-chloro-4- (5-cyc opro pil-</td><td></td><td></td>

<td></td><td>1 Hp¡razol-3-yl-amino) -pyrim¡d¡n-2-</td><td></td><td></td>

<td></td><td>i l-am i no) -2,5-dimethyl-phenyl) -</td><td></td><td></td>

<td></td><td>piperidin-1 -i I) -N-methyl-aceta mid a</td><td></td><td></td>

<td></td><td>Η Η ΐ^N ' _tTO^N TO^N</td><td></td><td></td>

<td></td><td>hn-n_ciXn or¹-Λη,</td><td>ESMS m / z</td><td></td>

<td></td><td>2- (4- (4- (5-chloro-4- (5-cyclopropyl-</td><td>499.2 (M + H ⁺ ).</td><td> 0.049</td>

<td></td><td>1 H-pyrazol-3-yl-amino) -pyrimidin-2-</td><td></td><td></td>

<td></td><td>il-amino) -5-fluoro-2-methyl-phenyl) -</td><td></td><td></td>

<td></td><td>piperidin-1-yl) -acetamide</td><td></td><td></td>

<td></td><td>Η H</td><td>ESMS m / z</td><td></td>

<td></td><td>hn-ñ_C| A, n yy- ^ ₀</td><td>495.2 (M + H ⁺ ).</td><td> 0.011</td>

<td></td><td>2- (4- (4- (5-chloro-4- (5-cyclopropyl-</td><td></td><td></td>

164

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICgo (pM)</td>

<td></td><td>1 H-pirazoi-3-yl-amino) -p¡r¡midin-2- My no) -2,5-di metí l-fen i I) - pperidin-1 - il) -acetam¡da</td><td></td><td></td>

<td></td><td>h₂n ^ 0 TO N ^ -^Cl N-NH F and HH 2- (4- (4- (5-Chloro-4- (5-methyl-1 H-) p¡razol-3-il-am¡no) -pyrimidin-2-¡- amino) -5-fluoro-2- (trifluoro-methyl) - faith ni I) -piperidin-1 - il) -acetam¡da</td><td>ESMS m / z 527.2 (M + H⁺).</td><td> 0.019</td>

<td></td><td>ϊΡ 'nh i A fA²⁰H 2- (4- (4- (5-Chloro-4- (5-methyl-1 H-) pyrazol-3-yl-amine) -p¡midin-2-yl- amino) -2,5-d¡metí l-fen¡l) -p¡peridin- 1-yl) -acetamide</td><td>ESMS m / z 469.2 (M + H⁺).</td><td> 0.013</td>

165

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (μΜ)</td>

<td></td><td>^hvF, ρ, οΑ^Cl fi rr ^ ⁰</td><td></td><td></td>

<td></td><td>Η I</td><td>ESMS m / z</td><td></td>

<td></td><td>2- (4- (4- (5-Chloro-4- (5-methyl-1 H-)</td><td>483.2 (M + H⁺).</td><td> 0.010</td>

<td></td><td>pyrazol-3-l-am¡no) -p¡r¡m¡din-2-¡l-</td><td></td><td></td>

<td></td><td>am¡no) -2,5-dimethyl-phenyl) -p¡per¡d¡n-</td><td></td><td></td>

<td></td><td>1-¡) -N-met! La ceta mida</td><td></td><td></td>

<td></td><td></td><td>¹H NMR (400</td><td></td>

<td></td><td></td><td>MHz, MeOD-d₄)</td><td></td>

<td></td><td></td><td>δ 8.11 (s, 1H),</td><td></td>

<td></td><td rowspan="2">I pN-V^H2hn-n^ciF ^ n ° H ^H F</td><td>7.76 (d 1H), 7.09 (d, 1H),</td><td></td>

<td></td><td>6.27 (s, 1 H), 4.0</td><td></td>

<td></td><td>2- (4- (4- (5-Chloro-4- (5-methyl-1 H-)</td><td>(s, 2H), 3.75-</td><td> 0.019</td>

<td></td><td>pyrazol-3-l-amine) -pyrimidin-2-l-</td><td>3.73 (m, 2H),</td><td></td>

<td></td><td>amine) -5-fluoro-2-methyl-phenyl) -</td><td>3.22-3.13 (m,</td><td></td>

<td></td><td>piperidin-1-yl) -acetic acid</td><td>3H), 2.34 (s,</td><td></td>

<td></td><td></td><td>3H), 2.30 (s,</td><td></td>

<td></td><td></td><td>3H), 2.04 -2.00</td><td></td>

<td></td><td></td><td>(m, 4H); ESMS</td><td></td>

166

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθω (pM)</td>

<td></td><td></td><td>m / z 473.2 (M + H ⁺ ).</td><td></td>

<td></td><td>^HNb- ^z\/^nhtwo Ν NH ι [ ^N Π ° Xn Y Η I 2- (4- (4- (5-Chloro-4- (5-Methyl-1 H- pyrazol-3-l-amine) -pyrimidin-2-yl- am¡no) -2,5-d¡meti l-fen¡l) -piper¡din- 1 -ll) -acetamide</td><td>ESMS m / z 469.2 (M + H⁺).</td><td></td>

<td></td><td>^h\ X Ν NH i &lt;η 0^αγ_Ν ΛΛ-Π'Αη, Η I 2- (3- (4- (5-chloro-4- (5-methyl-1H-) pyrazol-3-yl-amino) -pyrimidin-2-yl- amlno) -2,5-dimethyl-fe nil) -piperidin- 1 -il) -acetam¡da</td><td>ESMS m / z 469.2 (M + H⁺).</td><td> 0.026</td>

167

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ICso (| jM)</td>

<td></td><td>1 PA^K.í- _H Aj '' ^ °</td><td></td><td></td>

<td></td><td>ν AN '^ T H ^H F</td><td>ESMS m / z</td><td></td>

<td>X</td><td>2- (4- (4- (5-Chloro-4- (5-Methyl-1 H-</td><td>487.2 (M + H⁺).</td><td> 0.019</td>

<td></td><td>p¡razol-3-¡l-am¡no) -p¡r¡m¡d¡n-2-¡l-</td><td></td><td></td>

<td></td><td>am¡no) -5-fluoro-2-met¡ l-fen¡ I) -</td><td></td><td></td>

<td></td><td>p Iperld ¡n-1 - ll) -N-methyl-aceta measure</td><td></td><td></td>

<td></td><td>I ζχ, ΝΗ I ij^N π ΗΝ-Ν^εΐΎ ^ Ν A \ A \ A 0</td><td></td><td></td>

<td></td><td>'^ NA N' ^ T Η H |</td><td>ESMS m / z</td><td></td>

<td>X</td><td>2- (4- (4- (5-Chloro-4- (5-Methyl-1 H-</td><td>483.2 (M + H⁺).</td><td></td>

<td></td><td>pyrazol-3-¡-amino) -p¡r¡mid¡n-2-¡-</td><td></td><td></td>

<td></td><td>amino) -2,5-d¡met¡l-fen¡l) -piper¡din-</td><td></td><td></td>

<td></td><td>1 - ll) -N-methyl-acetam¡da</td><td></td><td></td>

168

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθδο (μΜ)</td>

<td></td><td>w N &lt;,&gt; ci γ Ar^NHNyN</td><td></td><td></td>

<td></td><td>HN ... / γ .., / Il TH</td><td>ESMS m / z</td><td></td>

<td></td><td>\ A or</td><td>483.2 (M + H ⁺ ).</td><td> 0.015</td>

<td></td><td>2- (3- (4- (5-chloro-4- (5-methyl-1 H-</td><td></td><td></td>

<td></td><td>pyrazol-3-l-am¡no) -p¡r¡m¡d¡n-2-¡l-</td><td></td><td></td>

<td></td><td>am¡no) -2,5-dimeti l-fen I) -pipe ridin-</td><td></td><td></td>

<td></td><td>1 - ll) -N-me you l-aceta measure</td><td></td><td></td>

<td></td><td>ci A ^ 'n' ^ A 'ⁿ'^xhn-n^c'V^{? x}n aSt ^ °</td><td></td><td></td>

<td></td><td>\ AA χΑ Λ AxA</td><td></td><td></td>

<td></td><td>Ν Ν Ν, Η H |</td><td>ESMS m / z</td><td></td>

<td>X</td><td>2- (4- (2-chloro-4- (5-chloro-4- (5-methyl)</td><td>503.2 (M + H ⁺ ).</td><td> 0.018</td>

<td></td><td>1 Hp¡razol-3-¡-l-am¡no) -p¡r¡m¡dln-2-</td><td></td><td></td>

<td></td><td>L-am¡no) -5-met¡ l-fen¡l) -p¡per¡d¡ n-1 -</td><td></td><td></td>

<td></td><td>il) -N-met¡l-acetam¡da</td><td></td><td></td>

169

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (pM)</td>

<td></td><td>I OMe N '^Xand'^NHΗΝ-_Ν^ΟιγΥ-_Ν PPP 0</td><td></td><td></td>

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

<td></td><td>Ν Ν Ν γ Η H |</td><td>ESMS m / z</td><td></td>

<td>X</td><td>2- (4- (4- (5-Chloro-4- (5-Methyl-1 H-</td><td>499.2 (M + H⁺).</td><td> 0.013</td>

<td></td><td>pyrazol-3-l-am¡no) -p¡rimíd¡n-2-¡l-</td><td></td><td></td>

<td></td><td>amino) -2-methoxy-5-met¡l-fen¡ I) -</td><td></td><td></td>

<td></td><td>piperidin-1 -i I) -N-meti l-aceta m da</td><td></td><td></td>

<td></td><td>h₂n. ^ o</td><td></td><td></td>

<td></td><td>L neither</td><td></td><td></td>

<td></td><td>Ργγ pf^clP p ^ '' ¥ '_N and F \ Η H</td><td>ESMS m / z</td><td></td>

<td></td><td>2- (4- (4- (5-Chloro-4- (5-methyl-1 H-)</td><td>523.2 (M + H⁺).</td><td> 0.022</td>

<td></td><td>pyrazol-3-yl-amino) -p¡r¡m¡din-2-¡-</td><td></td><td></td>

<td></td><td>amino) -5-me ti I-2- (tr and fluoro-methyl) -</td><td></td><td></td>

<td></td><td>fen i I) -pi perid ¡n-1 - il) -acetam ida</td><td></td><td></td>

170

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθδο (μΜ)</td>

<td></td><td>^νΆ HN— / / —Cl \ //^N'nh / ^N /-\ /- ^HNnh₂ F</td><td>ESMS m / z</td><td></td>

<td></td><td>2- (4- (5- (5-chloro-4- (5-methyl-1 H-)</td><td>487.2 (M + H⁺).</td><td> 3.68</td>

<td></td><td>p¡razol-3-yl-amino) -pyrm-din-2-¡-</td><td></td><td></td>

<td></td><td>am¡no) -2-fluoro-4-met¡ l-fen¡ I) -</td><td></td><td></td>

<td></td><td>piperidin-1- il) -propanam¡da</td><td></td><td></td>

<td></td><td>V Η₂Ν_γ0^ην\ Λ X Ν NH / N</td><td></td><td></td>

<td></td><td>CK X. X-X'-X YN f l</td><td></td><td></td>

<td></td><td>4 X AP Ν Ν γ^H F</td><td>ESMS m / z</td><td></td>

<td></td><td>2- (4- (4- (5-Chloro-4- (5-Methyl-1 H-</td><td>487.2 (M + H⁺).</td><td> 0.015</td>

<td></td><td>p razo l-3-l-am¡no) -p¡ rim ¡din-2-il-</td><td></td><td></td>

<td></td><td>amno) -5-fluoro-2-metl-fen-il) -</td><td></td><td></td>

<td></td><td>piperidin-1- il) -propanam¡da</td><td></td><td></td>

171

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoftiM)</td>

<td></td><td>Á, ±^ci-TO nX ^ζγ ^h ; 2- (4- (4- (5-Chloro-4- (5-methyl-1 H-) pyr azol-3-yl-amino) -pyrimidin-2-yl- am i no) -5-fluoro-2-meti l-fen¡ I) - pi pe rid i n-1 - I) -N-I got I- propanamide</td><td>ESMS m / z 501.2 (Μ + H +).</td><td> 0.022</td>

<td></td><td>Vh_?N ^ O^h\ A a Ν NH i &lt;N 'n ^ V η I 2- (4- (4- (5-Chloro-4- (5-methyl-1 H-) pyrazol-3-yl-amino) -pyrmm-d-n-2-l- am¡no) -2,5-d ¡methyl-fen ¡l) -piperid i n- 1 -il) -propanamide</td><td>ESMS m / z 483.2 (M + H⁺).</td><td> 0.009</td>

172

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICg) (pM)</td>

<td></td><td>V hAo HN, JI NNH if ^ 'N' ° 'Ά λΧ ¢. to xj Ν Ν And Η I 2- (4- (4- (5-chloro-4- (5-met i 1-1 H- p¡ razol-3-i l-am ¡no) -pi rimid in-2-il- am i no) -2,5-d ¡meti l-fen iI) -piperid i n- 1-yl) -N-methyl-propanamide</td><td>ESMS m / z 497.2 (M + H⁺).</td><td> 0.006</td>

<td></td><td>V and v X HN — I^F TO ⁿ^nh\ N / H₂N N = (/ = \ / - \ pO hn — and /) - (n- ( F 2- (4- (5-fluoro-2-methyl-4- (4- (5- methyl-1 H-pyrazol-3-yl-amino) -5- (trifl uoro-meti I) -pi r im idi η-2-il- amino) -phenyl) -piperidin-1-yl) - propanamide</td><td>ESMS m / z 521.2 (M + H⁺).</td><td> 0.078</td>

172

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ICgo (| jM)</td>

<td></td><td>X HN ^ O hn, i N 'NH i AA'^ci&gt; A λλ ^ KA Ν Ν γ H 2- (4- (4- (5-Chloro-4- (5-Methyl-1 H- pyrazol-3-l-am¡no) -pyrim¡d¡n-2-¡l- amino) -2,5-d¡methyl-fen¡l) -p¡per¡d¡n- 1-¡) -N-met¡l-propanam¡da</td><td>ESMS m / z 497.2 (M + H⁺).</td><td> 0.006</td>

<td></td><td>V / V^F Go n-nh \ N / Η, Ν^{N =}K í = \ / - \ A ° HN — nA F 2- (4- (5-fluoro-2-met¡l-4- (4- (5- methyl-1H-pyrazol-3-l-amine) -5- (trifl uoro-meti I) -pi rim ¡di n-2-I - amino) -phenyl) -pperidin-1-yl) - propanamide</td><td>ESMS m / z 521.2 (M + H⁺).</td><td> 0.078</td>

174

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICAMP)</td>

<td></td><td> \ &lt;.0 ^N_\ xA T ^ NH KA nA n '^nhhn ~ A z ~ c \ N- ^ 5-clo ro-N2- (2,5-di meti 1-4- (1 - (2- (methyl-sulfon¡l) -et¡l) -p¡per¡din-4-¡l) - phenyl) -N4- (5-methyl-1 H-pyrazol-3-yl) - pyrimidin-2,4-diamine</td><td>ESMS m / z 518.2 (M + H ⁺ ).</td><td> 0.006</td>

<td></td><td>HN ^ A ° g ^ Ν NH i An '' A¡ n κ ii n ^ n / ^^H F 5-Chloro-N2- (4- (1- (2- (ethyl-sulfonyl)) - ethyl) -pi perid in-4-yl) -2-fluoro-5- methyl-phenyl) -N4- (5-methyl-1 H-pyrazole- 3-i I) -p ¡rim id i n-2,4-di ami na</td><td>ESMS m / z 536.2 (M + H⁺).</td><td> 0.021</td>

175

STRUCTURE

NMR or ESMS

IGF-1R

Ba / F3

IC_ffl(p.m)

<img file="CU23952B1_D0118.tif" />

2- (4- (4- (5-Chloro-4- (5-methyl-1 Hp¡razol-3-¡-m-am)) -p¡rim¡d¡n-2-lamino) -5 -fluoro-2-methyl-phenyl) piperidin-1-yl) -N, N-dimethyl-ethanesulfonamide

ESMS m / z

551.2 (M + H⁺).

0.036 &lt;F^SC_

<img file="CU23952B1_D0119.tif" />

ESMS m / z

523.2 (Μ + K

0.038 amino) -5-fluoro-2-methyl-phenyl) pipertdin-1-yl) -ethan-su Ifon amide

2- (4- (4- (5-Chloro-4- (5-methyl-1 Hpyrazol-3-yl-amino) -pyrimidin-2-yl

176

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ICgo (pM)</td>

<td></td><td>/ ^ N ciY Ύνη / HN'V_ XX Λ ^^ΝΗ OR Cl 2— \^X \ &lt;0 °^SM Ϊ3 N2- (4- (1 - (2- (azetidin-1 -1 ls or Ifon 11) - ethyl) -piper¡din-4-¡l) -5-chloro-2-methyl- phenol) -5-chloro-N4- (5-methyl-1 H- p ¡razo Ι-3-Μ) -plrimid ¡n-2,4-d ¡amina</td><td>ESMS m / z 579.2 (M + H ⁺ ).</td><td> 0.011</td>

<td></td><td>Cl — CY NH F ηνΛ / ^N XX yU&gt; -^NH OR N^X \ &lt;0 ° 'b N2- (4- (1- (2- (azet¡din-1-ll-sulfonyl)) - et¡l) -p¡per¡d¡n-4-il) -2-fluoro-5- metl l-fen¡l) -5-chloro-N4- (5-met¡l- 1 Hp¡razol-3-¡l) -pir¡m¡d¡n-2,4- dlamlna</td><td>ESMS m / z 563.2 (M + H⁺).</td><td> 0.056</td>

177

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ^ (μΜ)</td>

<td></td><td>ΗΝ-Νθ'γ ^ Ν A &lt;P '^ A \ Ν V H ^H F 5-Chloro-N2- (2-fluoro-5-methyl-4- (1- (met¡l-sulfon¡l) -p¡per¡d¡n-4-¡l) - phenyl) -N4- (5-methyl-1 H-pyrazol-3-yl) - pyrimidin-2,4-diamine</td><td>ESMS m / z 494.2 (M + H⁺).</td><td> 0.005</td>

<td>X</td><td>, SO_?Me II ^N^ 'AN PV Η Η I 5-Chloro-N2- (2,5-di meti 1-4- (1 - (methyl- sulfonyl) -piperidin-4-yl) -phenyl) -N4- (5-methyl-1 H-pi razol-3-il) -pyrim idin- 2,4-diamine</td><td>ESMS m / z 490.2 (M + H⁺).</td><td> 0.002</td>

178

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoípM)</td>

<td></td><td>&lt;Λ 7 HNAx Ί yy _Νγ n '^nhF HN - (\ / YCI N— 5-Chloro-N2- (4- (1- (cyclopropyl- sulfon¡l) -piper¡d¡n-4-¡l) -2-fluoro-5- methyl-phenyl) -N4- (5-methyl-1H-pyrazole- 3-yl) -pyrimidin-2,4-diamine</td><td>ESMS m / z 520.2 (M + H ⁺ ).</td><td> 0.059</td>

<td></td><td>IH Λί^ΝΤ^Ν7ι Nz / x Γ i τ i ^Cl° V^NA hn ^_n&gt;/ 'VAT NH (J ⁰ H N ' 5-chloro-N2- (2-fluoro-5-methyl-4- (1- (p¡r¡d¡n-3-¡l-sulfon¡l) -p¡per¡d¡n-4- L) -fen¡l) -N4- (5-methyl-1 H-pyrazole-3- il) -pyrimidin-2,4-damine</td><td>ESMS m / z 557.2 (M + H⁺).</td><td> 0.076</td>

179

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθδο (ρΜ)</td>

<td></td><td>0 j &lt;NO __ ^^Ν'Ν^εΐχγ ^ Ν P [^ N '^ T H ^H F 4- (4- (5-Chloro-4- (5-Methyl-1 H- pirazol-3-il-am¡no) -p¡r¡m¡d¡n-2-ü- amine) -5-fluoro-2-methyl-phenyl) - ethyl piperidin-1-carboxylate</td><td>¹H NMR (400 MHz, MeOD-d₄) δ 8.13 (s, 1H), 7.54 (d, 1 H), 7.10 (d, 1H), 6.28 (s, 1 H), 4.30-4.26 (m, 2H), 4.14 (q, 2H), 2.99-2.96 (m, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.8-1.77 (m, 2H), 1.64- 1.55 (m, 2H), 1.28 (t, 3H); ESMS m / z 488.2 (M + H⁺).</td><td> 0.064</td>

<td>X</td><td>0 X- A -X ΗΝ-Νθ'Ύ ^ Ν A'n \ n) / Η H |</td><td>ESMS m / z 504.2 (M + H⁺).</td><td> 0.182</td>

180

STRUCTURE

NMR or ESMS

IGF-1R

Ba / F3

ICsoípM)

4- (2-Chloro-4- (5-Chloro-4- (5-met1l1 Hp¡razol-3-¡-l-am¡no) -pir¡m¡d¡n-2i l-am ino) -5-meti l-fen i I) -pi pe rid in-1ethyl carboxylate

<img file="CU23952B1_D0120.tif" />

4- (4- (5-Chloro-4- (5-methyl-1 Hp¡razol-3-l-amine) -p¡r¡m¡d¡n-2-amino) -5- Isopropyl Fluoro-2-Methyl-Phenyl) Piperidine-1-Carboxylate

ESMS m / z

502.2 (M + H⁺).

0.080

<img file="CU23952B1_D0121.tif" />

0.011

4- (4- (5-Chloro-4- (5-Methyl-1 Hpyrazol-3-l-amino) -p¡rldin-2-lalamine) -5-Fluoro-2- metl-phenol) -N, NESMS m / z

487.2 (Μ + H +).

181

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 Ιθ5ο (ρΜ)</td>

<td></td><td>di meti lp ¡pe rid i n-1 -carboxamide</td><td></td><td></td>

<td>X</td><td>0 / x A / i Ann jnAAa ^^ 'NAN' A ^ Η Η I 4- (4- (5-Chloro-4- (5-methyl-1 H- pyrazol-3-yl-amino) -pyrmidium-2-l- amino) -2,5-dimethyl-phenyl) -N, N- d ¡meti lp i pe rid i n-1 -carboxamide</td><td>ESMS m / z 483.2 (M + H ⁺ ).</td><td> 0.006</td>

<td>X</td><td>0 TO i Ann Ck / X YEAR ^Hhn-n An^VAA Ν ^ γ Η H | 4- (4- (5-Chloro-4- (5-methyl-1 H- pyrazol-3-yl-amino) -pyrimidin-2-l- am i no) -2,5-d ¡meti l-fen il) -N-ethyl- pipe rid i n-1 -carboxamide</td><td>ESMS m / z 483.2 (M + H⁺).</td><td> 0.002</td>

<td>X</td><td>0 TO- // | AN NH₂JJⁿ'n^CIxAn ^ AA n^zTO Η H |</td><td>ESMS m / z 455.2 (M + H⁺).</td><td> 0.006</td>

182

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (μΜ)</td>

<td></td><td>4- (4- (5-Chloro-4- (5-Methyl-1 H-</td><td></td><td></td>

<td></td><td>pyrazol-3-yl-amine) -pyrimidin-2-yl-</td><td></td><td></td>

<td></td><td>am¡no) -2,5-d ¡meti l-fen ¡l) -p¡per¡d¡n-</td><td></td><td></td>

<td></td><td>1-carboxamide</td><td></td><td></td>

<td></td><td></td><td>¹H NMR (400</td><td></td>

<td></td><td></td><td>MHz, MeOD-d₄)</td><td></td>

<td></td><td>⁰ I I \ ^Nhn-n^c'A ^ n H ^H F</td><td>δ 8.08 (s, 1 H), 7.71 (d, 1 H), 7.03 (d, 1H), 6.26 (s, 1 H), 4.71-4.67 (m, 2H), 3.81-3.77</td><td></td>

<td>X</td><td>1 - (4- (4- (5-chloro-4- (5-methyl-1 H-</td><td>(m, 2H), 3.14-</td><td> 0.019</td>

<td></td><td>pyrazol-3-yl-amino) -pyrimin-2-yl-</td><td>3.12 (m, 2H),</td><td></td>

<td></td><td>amino) -5-f luoro-2-methyl-phenyl) -</td><td>2.98 (s, 3H),</td><td></td>

<td></td><td>pipe rid i n-1 -ll) -2- (d¡ metí l-am ¡no) -</td><td>2.96 (s, 3H),</td><td></td>

<td></td><td>ethanone</td><td>2.90-2.83 (m,</td><td></td>

<td></td><td></td><td>1H), 2.34 (s,</td><td></td>

<td></td><td></td><td>3H), 2.28 (s,</td><td></td>

<td></td><td></td><td>3H), 1.87 (d,</td><td></td>

<td></td><td></td><td>2H), 1.76-1.55</td><td></td>

183

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ^ (μΜ)</td>

<td></td><td></td><td>(m, 2H); ESMS m / z 501.2 (M + H⁺).</td><td></td>

<td>X</td><td>0 ι 'X / N. ,, Cl &lt;Ν '-' HN-_N^ClyYj XmtXJ '^ n ^xn Ν '^χΛϊγ Η Η | 1 - (4- (2-chloro-4- (5-chloro-4- (5-methyl) 1 Hp¡razol-3-¡-l-am¡no) -p¡r¡m¡d¡n-2- L-am¡no) -5-met¡l-fen¡l) -p¡perid¡n-1- L) -2- (d¡met¡l-am¡no) -ethanone</td><td>ESMS m / z 517.2 (M + H⁺).</td><td> 0.007</td>

<td>X</td><td>or IX ^ N ,. I | ^Nhn-n °^KXn ^ 'n A Ν' ^ γ Η H | 1 - (4- (4- (5-chloro-4- (5-methyl-1 H- p¡razol-3-¡l-am¡no) -p¡r¡m¡d¡n-2-¡l- am¡no) -2,5-d ¡meti l-fen il) -p¡per¡d¡n- 1-yl) -2- (dimethyl-amine) -ethanone</td><td>ESMS m / z 497.2 (M + H ⁺ ).</td><td> 0.011</td>

184

<td></td><td>STRUCTURE</td><td>NMR or</td><td>ESMS</td><td>IGF-1R Ba / F3 ^ (μΜ)</td>

<td></td><td>or I OMe &lt;Ν '</td><td></td><td></td><td></td>

<td></td><td>HN-_n^ciXX ^_n X || A ^ P '_N ^ A Η H |</td><td>ESMS</td><td>m / z</td><td></td>

<td>X</td><td>1 - (4- (4- (5-chloro-4- (5-methyl-1 H-)</td><td>513.2 (M</td><td>+ H⁺).</td><td> 0.009</td>

<td></td><td>p¡razol-3-il-am¡no) -p¡r¡m¡d¡n-2-ll-</td><td></td><td></td><td></td>

<td></td><td>am¡no) -2-methox¡-5-met¡l-fen¡l) -</td><td></td><td></td><td></td>

<td></td><td>piperid¡n-1-¡l) -2- (d¡met¡l-amino) -</td><td></td><td></td><td></td>

<td></td><td>ethanone</td><td></td><td></td><td></td>

<td></td><td rowspan="2">oi X ^ A / Y Cl &lt;N \ hn-n^ciX ^ n ApA \ Ay ¿H ¿,</td><td></td><td></td><td></td>

<td></td><td>ESMS</td><td>m / z</td><td></td>

<td>X</td><td>1 - (4- (2,5-dichloro-4- (5-chloro-4- (5-</td><td>537.1 (M</td><td>+ H⁺).</td><td> 0.007</td>

<td></td><td>methyl-1 Hp¡ra zol-3-l-am¡no) -</td><td></td><td></td><td></td>

<td></td><td>p¡r¡mld¡n-2-ll-am¡no) -fen¡l) -</td><td></td><td></td><td></td>

<td></td><td>pl perid ¡n-1 -ll) -2- (d¡metí l-am ¡no) -</td><td></td><td></td><td></td>

<td></td><td>ethanone</td><td></td><td></td><td></td>

185

<td></td><td>STRUCTURE</td><td colspan="2">NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθεο (pM)</td>

<td></td><td>0 ι Ρ Ν N</td><td></td><td></td><td></td>

<td></td><td>hn - _N^C'and-_N PPP</td><td></td><td></td><td></td>

<td></td><td>N ^XN í-j γ Η H ¿</td><td></td><td></td><td></td>

<td></td><td></td><td>ESMS</td><td>m / z</td><td></td>

<td>X</td><td>1- (4- (4- (5-Chloro-4- (5-methyl-1 H-)</td><td>515.2 (M</td><td>+ H⁺).</td><td> 0.138</td>

<td></td><td>pyrazol-3-yl-amino) -pyrmidine-2-l-</td><td></td><td></td><td></td>

<td></td><td>a mino) -5-fl uoro-2-met¡ l-fen¡ I) -</td><td></td><td></td><td></td>

<td></td><td>piperidin-1-yl) -3- (di meti l-am i no) -</td><td></td><td></td><td></td>

<td></td><td>propan-1 -one</td><td></td><td></td><td></td>

<td></td><td>0 .A, nh₂I (N</td><td></td><td></td><td></td>

<td></td><td>hn-_n^ckAnd ^_n ΛΑ</td><td></td><td></td><td></td>

<td></td><td>\ fl / H ^H F</td><td>ESMS</td><td>m / z</td><td></td>

<td>X</td><td>2-amino-1 - (4- (4- (5-cl gold-4- (5-</td><td>473.2 (M</td><td>+ H⁺).</td><td> 0.075</td>

<td></td><td>methyl-1 H-pyrazol-3-yl-amino) -</td><td></td><td></td><td></td>

<td></td><td>pyrimid¡n-2-l-am¡no) -5-fluoro-2-</td><td></td><td></td><td></td>

<td></td><td>methyl-phenyl) -piper¡d¡n-1 -yl) -ethanone</td><td></td><td></td><td></td>

186

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICkjÜJM)</td>

<td></td><td>F _r F ^ Yn-V^H 1 1 - (4- (4- (5-chloro-4- (5-methyl-1 H- pyrazol-3-yl-amino) -pyrimidin-2-¡- amno) -5-fluoro-2-methyl-phenol) - pe rid i n-1 - il) -2- (met¡l-am¡no) - ethanone</td><td>ESMS m / z 487.2 (M + H⁺).</td><td> 0.103</td>

<td></td><td>ΐ H ΓΎ ^NT^N4 ΓΤΤ T ^ClO ^ NP ¹ HN 1 P^NHTO 1- (4- (4- (5-Chloro-4- (5-methyl-1H-) pirazol-3-il-am¡no) -pir¡m¡d¡n-2-¡l- am ino) -5-fluoro-2-met¡ l-fen¡ I) - p¡per¡d¡n-1 - il) -2- (d¡etil-am¡no) - ethanone</td><td>ESMS m / z 529.3 (M + H⁺).</td><td> 0.030</td>

187

STRUCTURE

<img file="CU23952B1_D0122.tif" />

H

TO

Ό

- (4- (4- (5-Chloro-4- (5-methyl-1 Hpirazol-3-l-amine) -pyrimin-2 -lamine) -5- fluoro-2-methyl-phenyl) pperine-1-yl) -2- (methyl-amino) ethanone

<img file="CU23952B1_D0123.tif" />

1- (2- (4- (5-Chloro-4- (5-methyl-1 HRMN or ESMS

ESMS m / z

487.2 (M + H⁺).

ESMS m / z

497.2 (M + H⁺).

IGF-1R

Ba / F3 ιθ5ο (μΜ)

0.013 p¡razol-3-¡l-am¡no) -p¡r¡m¡d¡n-2-¡lam i no) -2,5-d ¡meti l-fen i 1) -p¡ perid ¡N1 -¡I) -2- (d ¡metí l-am ¡no) -ethanone

188

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICmftjM)</td>

<td></td><td>ϊ Η (Τ^ΝΤ^ΝΊ ΓΤΤ Τ ⁰¹Τ Α^ΝΗ1 - (4- (4- (5-chloro-4- (5-met¡l-1 Η- pyrazol-3-l-am¡no) -p¡r¡m¡din-2-il- amino) -5-fluoro-2-meti l-feni I) - p¡peridi η-1 -il) -2- (diethyl-am ino) - ethanone</td><td>ESMS m / z 529.3 (M + H ⁺ ).</td><td></td>

<td></td><td>-τ Λ^ciaAn aax L. χ XX Ν NY^H F 1 - (4- (4 - (5-cl or ro-4- (5-me ti I -1 H- p¡razol-3-il-am¡no) -plr¡m¡d¡n-2-¡l- am¡no) -5-flu oro-2-met¡ l-fen¡ I) - piperid¡n-1-il) -2- (met¡l-am¡no) - propan-1 -one</td><td>ESMS m / z 501.2 (M + H ⁺ ).</td><td> 0.042</td>

189

<td></td><td colspan="3">STRUCTURE</td><td colspan="2">NMR or ESMS</td><td>IGF-1R Ba / F3 ICgo (pM)</td>

<td></td><td>^hnAND</td><td colspan="2">H₂N ^ y</td><td></td><td></td><td></td>

<td></td><td></td><td>NH go N</td><td> 0</td><td></td><td></td><td></td>

<td></td><td>Cl \ /</td><td>A App</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>ρ Ap</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ν NY H ¹</td><td></td><td colspan="2">ESMS m / z</td><td></td>

<td></td><td></td><td>F</td><td></td><td rowspan="2">487.2 (M</td><td rowspan="2">+ H⁺).</td><td rowspan="2"> 0.141</td>

<td></td><td>2-aminc</td><td colspan="2">&gt; -1- (4- (4- (5-chloro-4- (5-</td>

<td></td><td colspan="3">meti-1 H-pyrazol-3-yl-amino) -</td><td></td><td></td><td></td>

<td></td><td>pyrimidin</td><td colspan="2">-2-¡-l-am¡no) -5-f luoro-2-</td><td></td><td></td><td></td>

<td></td><td colspan="3">m eti l-feni I) -pi pe ri di n-1 -il) -propan-</td><td></td><td></td><td></td>

<td></td><td></td><td>1 -one</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> \</td><td></td><td></td><td></td><td></td>

<td></td><td>V</td><td>HN -</td><td></td><td></td><td></td><td></td>

<td></td><td>HN J rP</td><td>NH ι PP</td><td>^xor</td><td></td><td></td><td></td>

<td></td><td>ΟΙ_{Χ /}</td><td>To AyP</td><td></td><td></td><td></td><td></td>

<td></td><td>IL</td><td>ρ AJ</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Ν NY H ¹</td><td></td><td colspan="2">ESMS m / z</td><td></td>

<td></td><td></td><td>^Π F</td><td></td><td rowspan="2">515.2 (M</td><td rowspan="2">+ H⁺).</td><td rowspan="2"> 0.017</td>

<td></td><td colspan="2">1 - (4- (4- (5-chloro-4- (5-methyl-</td><td>1 HOUR-</td>

<td></td><td>pyrazole-3</td><td>-¡L-am¡no) -p¡rimidin</td><td>-2-il-</td><td></td><td></td><td></td>

<td></td><td colspan="3">amino) -5-fluoro-2-methyl-phenol) -</td><td></td><td></td><td></td>

<td></td><td colspan="3">piperidin-1-yl) -2-methyl-2- (methyl-</td><td></td><td></td><td></td>

<td></td><td colspan="2">amino) -propan-1-one</td><td></td><td></td><td></td><td></td>

190

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (pM)</td>

<td></td><td>To HN^ΗΝ\ Λ γ. TO yW Η I 1 - (4- (2-chloro-4- (5-chloro-4- (5-methyl) 1 Hp¡razol-3-¡-l-am¡no) -pirimld¡n-2- L-am¡no) -5-met¡l-fen¡l) -p¡per¡d¡n-1 - L) -2-methyl-2- (methyl-amino) -propan- 1 -one</td><td>ESMS m / z 531.2 (M + H⁺).</td><td> 0.007</td>

<td></td><td>λ = η nh₂^hn\ AA n nh i Year^ciyA AA-A to x. AA Ν Ν And Η | 2-am¡no-1 - (4- (4- (5-chloro-4- (5- met¡l-1 Hp¡razol-3-l-am¡no) - p¡r¡m¡d¡n-2-¡-amino) -2,5-d¡met¡l- phenyl) -plperidn-1 -yl) -2-methyl propan-1 -one</td><td>ESMS m / z 497.2 (M + H⁺).</td><td> 0.023</td>

191

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICgo (pM)</td>

<td></td><td>Yx^cYn xx ^ Ay-Y Η 1 (4- (4- (5-Chlorine ~ 4- (5-Methyl-1 H- pyrazol-3-¡-amino) -p¡r¡midin-2-¡- amino) -2,5-d¡met¡l-fen¡l) -p¡per¡d¡n- 1-¡) - (1- (methyl-amino) -cyclopropyl) - methanone</td><td>ESMS m / z 509.2 (M + H ⁺ ).</td><td> 0.005</td>

<td></td><td>IH γ ¥^ντΧ i II i ^Cl¹ HN..N, T NH h₂n Y²(1 -am¡no-c¡clobut¡l) - (4- (4- (5-chloro- 4- (5-Methyl-1 H-pyrazol-3-yl-amino) - pir¡mid in-2-¡-l-am¡no) -2,5-d¡methylphenyl) -p ¡perid¡ n-1 - il) -methanone</td><td>ESMS m / z 509.2 (M + H⁺).</td><td> 0.052</td>

192

STRUCTURE

NMR or ESMS

IGF-1R

Ba / F3

ICsoIMM)

<img file="CU23952B1_D0124.tif" />

(4- (4- (5-chloro-4- (5-met¡ 1-1 HESMS m / z 537.3 (M + H⁺).

0.015 pyrazol-3-yl-amino) -pyrim¡d-n-2-ylamino) -2,5-dimethyl-phenyl) -p¡perid¡n1-1) - (1 - (d! -am ino) -cyclobutyl) methanone

<img file="CU23952B1_D0125.tif" />

<img file="CU23952B1_D0126.tif" />

H (1-a mi non-ciclop ropi 1) - (4- (4- (5ESMS m / z

499.2 (M + H⁺).

0.033 chloro-4- (5-methyl-1 H -pyrazol-3-ylfluoro-2-methyl-phenyl) -piperidin-1-yl) methanone amino) -pyrimidin-2-yl-amino) -5193

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ΙΟ_κ(μΜ)</td>

<td></td><td>Η N'N 0 \ , p «AA CI \ ^ A_N^H F (4- (4- (5-cl gold-4- (5-meti 1-1 H- p¡razol-3-¡l-am¡no) -p¡r¡m¡d¡n-2-¡l- amno) -5-fluoro-2-methyl-phenol) - piperidin-1-yl) - (1- (dimethyl-amine) - c¡cloprop¡l) -methanone</td><td>ESMS m / z 527.2 (M + H⁺).</td><td> 0.013</td>

<td></td><td>IH rY^NAND^NTl r ^ TT τ ^ClO ^ N ^ J Cl HN ^ N , ..... / v 1 - (4- (2-Chloro-4- (5-Chloro-4- (5-methyl-) 1 Hp¡razol-3-yl-amino) -p¡r¡m¡d¡n-2- L-am¡no) -5-met¡l-fen¡l) -p¡per¡d¡n-1- 11) -2-m orfol ¡no-eta nona</td><td>ESMS m / z 559.2 (M + H⁺).</td><td> 0.006</td>

194

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsofpM)</td>

<td></td><td>1 Η ργτ τ¹- Cl ΗΝ. J \ J J ρ^ΝΗο \ 2- (azetidin-1 - i 1) -1 - (4- (2-chloro-4- (5- chloro-4- (5-methyl-1 Hp¡razol-3-yl- amino) -p¡rim¡din-2-¡-amino) -5- meti l-fen¡l) -p¡per¡d¡ n-1-il) -ethanone</td><td>ESMS m / z 529.2 (M + H ⁺ ).</td><td> 0.024</td>

<td></td><td>i H Pppp PTI t ^ClO ^ NJ ¹ hn ^ n F o..A 1 - (4- (4- (5-chloro-4- (5-methyl-1 H- p¡ razol-3-il-am¡no) -p¡ rim ¡din-2-¡l - amino) -5-fluoro-2-methyl-phenyl) - piperidin-1 - l) -2-morpholino-ethanone</td><td>ESMS m / z 543.2 (M + H ⁺ ).</td><td> 0.020</td>

195

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ΙθεοίμΜ)</td>

<td></td><td>ί Η ΡγΝγΝ | | | I^Cl¹ HNWX JW *^Hor \ 2- (azetidin-1-yl) -1- (4- (4- (5-chloro-4- (5-me ti 1-1 H-pyrazol-3-yl-amino) - pimidin-2-yl-amino) -5-fluoro-2- methyl-phenyl) -piperidin-1 - yl) -ethanone</td><td>ESMS m / z 513.2 (M + H⁺).</td><td> 0.064</td>

<td></td><td>ϊ H Λ^νυ^ν1 γΎΥ ^νΡ '¹ HN ^ N J γ OR 1 - (4- (4- (5-chloro-4- (5-methyl-1 hl- pyrazole -3-i l-am ino) -pi rim id i n-2-il- ami no) -5-fl or gold-2-meti l-fen! I) - pi pe rid i n-1 - i 1) -2- (pyrrole id i n-1 -il) - ethanone</td><td>ESMS m / z 527.2 (M + H⁺).</td><td> 0.038</td>

196

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ιθ »(μΜ)</td>

<td></td><td>ϊ Η γυ^ντΊ Γγγ ^ΝΛ AA-Α a ν J Α /^ΝΗΟ 1 - (4- (4- (5-chloro-4- (5-met¡l-1 Η- pyrazol-S-yl-aminoj-pyrimidin ^ -yl- amno) -5-fluoro-2-methyl-phenol) - pi pe rid i n-1-i 1) -2- (1 H-pyrrole-1 -i I) - ethanone</td><td>ESMS m / z 523.2 (M + H⁺).</td><td> 0.025</td>

<td></td><td>ArAA Ay ⁿTO^ciTOⁿto ^hn\TO ...... JC, 0 1 - (4- (4- (5-chloro-4- (5-methyl-1 H- pyrazol-3-l-am¡no) -pyrididin-2-l- am¡no) -2,5-dimethyl-phenyl) -p¡per¡d¡n- 1 - il) -2- (p¡perid¡n-1 -ll) -ethanone</td><td>ESMS m / z 537.3 (M + H⁺).</td><td> 0.007</td>

197

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICg) (pM)</td>

<td></td><td>1 Η χΥγ-ΝγΝ ΓΥΤ ^Ντ ^Cl° &lt;ν^ΝΑ ην ν AND θΑ 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-) pyrazol-3-l-amino) -pyrimidin-2-yl- am¡no) -2,5-d ¡meí l-phenyl) -p¡per¡d¡n- 1 -il) -2-morpholno-ethanone</td><td>ESMS m / z 539.3 (M + H⁺).</td><td> 0.009</td>

<td></td><td>IH ίΓΎ ^ΝΥ^ΝΊι ΓΥΥ Y^CiΥγΑ 'HN N FOR 1- (4- (4- (5-Chloro-4- (5-methyl-1 H-) p¡razol-3-¡-a-amino) -p¡r¡m¡d¡n-2-¡l- amno) -2,5-d-methyl-phenyl) -piper¡d¡n- 1 - il) -2- (2,6-d¡methyl-p¡perid¡n-1 - il) - ethanone</td><td>ESMS m / z 565.3 (M + H⁺).</td><td> 0.009</td>

198

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC® (pM)</td>

<td></td><td>1 Η ΧγΝγΝχ ΓΤΤ Τ ^Cl^ο-γ.γΡ ην_ν Υ X</td><td>ESMS m / z</td><td></td>

<td></td><td>\ 1 - (4- (4- (5-chloro-4- (5-got 1-1 Η-</td><td>593.3 (M + H ⁺ ).</td><td> 0.018</td>

<td></td><td>ρ ¡razol-3-i l-am ¡no) -pirimid in-2-i I-</td><td></td><td></td>

<td></td><td>amino) -2,5-dimethyl-phenyl) -piperidin-</td><td></td><td></td>

<td></td><td>1 - i 1) -2- (2,2,6,6-tetramethyl-</td><td></td><td></td>

<td></td><td>pipe rid i n-1 - il) -ethanone</td><td></td><td></td>

<td></td><td>0 Y ^ Y</td><td></td><td></td>

<td></td><td>hn-Y'Y ^ n AP Yn'YY H ^H F</td><td></td><td></td>

<td></td><td>1 - (4- (4- (5-chloro-4- (5-methyl-1 H-) pyrazol-3-yl-amino) -pyrimidin-2-¡-</td><td>ESMS m / z 556.3 (M + H⁺).</td><td> 0.051</td>

<td></td><td>amino) -5-fluoro-2-methyl-phenyl) -</td><td></td><td></td>

<td></td><td>piperidin-1 - ii) -2- (4-methyl-piperazin-</td><td></td><td></td>

<td></td><td>1 -il) -ethanone</td><td></td><td></td>

199

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (pM)</td>

<td></td><td>0 / κ Α / f eleven ^N</td><td></td><td></td>

<td></td><td>jnF'Fv ÍAI ^ FF ν γ _nFkf Η Η I</td><td>ESMS m / z</td><td></td>

<td>X</td><td>1 - (4- (4- (5-chloro-4- (5-methyl-1 H-</td><td>484.2 (M + H⁺).</td><td> 0.002</td>

<td></td><td>p¡razol-3-¡l-am¡no) -pirim¡d¡n-2-¡l-</td><td></td><td></td>

<td></td><td>amino) -2,5-dimethyl-phenyl) -piperidin-</td><td></td><td></td>

<td></td><td>1 - il) -2-methox¡-ethanone</td><td></td><td></td>

<td></td><td>hn ~ n^c'y ^ n ⁰F nA Η Η 1</td><td>ESMS m / z</td><td></td>

<td>X</td><td>N- (2- (4- (4- (5-chloro-4- (5-m eti 1-1 H-</td><td>515.2 (M + H⁺).</td><td> 0.057</td>

<td></td><td>pyrazol-3-yl-amino) -pyrimidin-2-yl-</td><td></td><td></td>

<td></td><td>aim¡no) -5-fluoro-2-methyl-phenyl) -</td><td></td><td></td>

<td></td><td>piperidin-1-yl) -2-oxoethyl) -acetam ida</td><td></td><td></td>

<td>X</td><td>⁰ I | &lt;N 0 ^ ' ΗΜ-γΎ ^ AAA ^ A f nA ^ Η Η I 2- (d¡met¡l-am¡no) -4- (4- (5-chloro-4-</td><td>ESMS m / z 531.2 (M + H⁺).</td><td> 0.053</td>

<td></td><td>(5-me ti 1-1 H-pyrazol-3-yl-amino) -</td><td></td><td></td>

<td></td><td>pyrimidin-2-yl-amino) -5-fluoro-2-</td><td></td><td></td>

200

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC® (μΜ)</td>

<td></td><td>methyl-phenyl) -piper¡d¡n-1-carboxylate of ethyl</td><td></td><td></td>

<td>X</td><td>To A._Cl 1 Aj ΗΝ-_Ν^ΜγΥ '^' N 'n' n '' 'Y Η ^H p 4- (4- (5-Chloro-4- (5-methyl-1H- pyrazol-3-yl-amino) -pyrim¡d¡n-2-il- amino) -5-fluoro-2-methyl-phenyl) -N- (2- (dimethyl-amino) -ethyl) -piperidin- 1-carboxamide</td><td>ESMS m / z 530.2 (M + H⁺).</td><td> 0.060</td>

<td>X</td><td>0 , TO HN-Yp'N Η H | 1 - (4- (4- (5-chloro-4- (5-methyl-1 H-) pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -2,5-dimethyl-phenyl) -piperidin- 1 -il) -ethanone</td><td>ESMS m / z 454.2 (M + H⁺).</td><td> 0.013</td>

201

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 Ιθκ (ρΜ)</td>

<td></td><td rowspan="2">0 FOR ι ι τ yi ΗΝ-Υ'γ ^ Ν X ° H ^H F</td><td></td><td></td>

<td></td><td>ESMS m / z</td><td></td>

<td>X</td><td>(4- (4- (5-Chloro-4- (5-Methyl-1 H-</td><td>529.2 (M + H⁺).</td><td> 0.008</td>

<td></td><td>p¡razol-3-il-am¡no) -pyrimid¡n-2-il-</td><td></td><td></td>

<td></td><td>am¡no) -5-fluoro-2-met¡ l-fen¡ I) -</td><td></td><td></td>

<td></td><td>plperldln-1- ¡l) - (morpho linen) -</td><td></td><td></td>

<td></td><td>methanone</td><td></td><td></td>

<td></td><td>0 IIIO^VΝ ^ΑΑγ H ^H F</td><td>ESMS m / z</td><td></td>

<td>X</td><td>(4- (4- (5-chloro-4- (5-metll-1 H-</td><td>542.2 (M + H ⁺ ).</td><td> 0.021</td>

<td></td><td>p¡razol-3-il-am¡no) -p¡r¡m¡d¡n-2-¡l-</td><td></td><td></td>

<td></td><td>amino) -5-fluoro-2-methyl-phenyl) -</td><td></td><td></td>

<td></td><td>p¡perld¡n-1-il) - (4-met¡lp¡perazin-1 -</td><td></td><td></td>

<td></td><td>L) -metanone</td><td></td><td></td>

202

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (μΜ)</td>

<td>X</td><td>oo | f NH N NH η i x7 x \ A b— / J¡^N'L p N NAU f Η Η I 1 - (4- (4- (5-chloro-4- (5-methyl-1 H- p¡razol-3-¡-a-amino) -p¡r¡m¡d¡n-2-¡l- am¡no) -2,5-d ¡meti l-fen¡l) -p¡ perid ¡n- 1 -carbo n il) -imidazole idin-2-one</td><td>ESMS m / z 524.2 (M + H⁺).</td><td> 0.013</td>

<td>X</td><td> 0 ⁴ALREADY _NAND ⁰Η Η I _ν(4- (4- (5-chloro-4- (5-methyl-1 Η- p¡razol-3-il-am¡no) -pyrimidin-2-¡- am¡ η o) -2,5-d ¡m eti l-fe n ¡I) -piperid i n- 1 - ll) -2-methox¡-ethanone</td><td>ESMS m / z 569.2 (M + H⁺).</td><td> 0.048</td>

<td>X</td><td>0 ι hⁿ'n^ciYn AfY ^{/ NH χγ}Ύ A n^/;TO H ^H F (4- (4- (5-Chloro-4- (5-Methyl-1 H- p¡razol-3-il-am¡no) -pirim¡din-2-il- amno) -5-fluoro-2-methyl-phenol) -</td><td>ESMS m / z 527.2 (M + H⁺).</td><td> 1.57</td>

203

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC® (pM)</td>

<td></td><td>piperidin-1 - i I) - (piperidi n-4-iI) -</td><td></td><td></td>

<td></td><td>methanone</td><td></td><td></td>

<td></td><td rowspan="2">pp&gt; ΗΝ--_Ν°^μγ · '_Ν APA to / Υι νΆχ H ^H p</td><td></td><td></td>

<td></td><td>ESMS m / z</td><td></td>

<td>X</td><td>(S) - (4- (4- (5-chloro-4- (5-methyl-1 H-)</td><td>513.2 (M + H⁺).</td><td> 0.137</td>

<td></td><td>pyrazol-3-yl-amino) -p¡rim¡din-2-il-</td><td></td><td></td>

<td></td><td>amino) -5-fluoro-2-methyl-phenyl) -</td><td></td><td></td>

<td></td><td>piperidin-1 -il) - (pyrrole di η-2-il) -</td><td></td><td></td>

<td></td><td>methanone</td><td></td><td></td>

<td></td><td> 0 , _rAND_rPI _Λ 1 1 j XN. HN'N^CIX'N —Y '1 L 1 Y and i'n n Η Η 1.</td><td>ESMS m / z</td><td></td>

<td>X</td><td>(4- (4- (5-Chloro-4- (5-metii-1 H-</td><td>513.2 (M + H⁺).</td><td> 0.099</td>

<td></td><td>pyrazol-3-yl-amino) -pyrimidin-2-yl-</td><td></td><td></td>

<td></td><td>amino) -5-fluoro-2-methyl-phenyl) -</td><td></td><td></td>

<td></td><td>piperidin-1-yl) - (1-methylazetid i n-3-</td><td></td><td></td>

<td></td><td>il) -methanone</td><td></td><td></td>

204

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (pM)</td>

<td>X</td><td>0 ι Γ ™ 'n^CIAA ^X^^N' A N '^ y H ^H F (4- (4- (5-Chloro-4- (5-Methyl-1 H- pirazol-3-il-am¡no) -p¡r¡m¡d¡n-2-¡l- amino) -5-fluoro-2-methyl-phenyl) - pi pe rid i n-1 -il) - (1-methyl-piperidin-4- il) -methanone</td><td>ESMS m / z 541.2 (M + H⁺).</td><td> 0.081</td>

<td>X</td><td>⁰ n Go to π 1 1 J V-NH Η Ν ~ N ^C N To ya^JH ^H F 3- (4- (4- (5-Chloro-4- (5-methyl-1 H-) pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -5-fluoro-2-methyl-phenyl) - piperidin-1 -carbon il) -azet idi n-2- ona</td><td>ESMS m / z 513.2 (M + H⁺).</td><td> 2.99</td>

<td>X</td><td>¡¡ Ck Á Á JA hn ~ n yA \ ANA ^ Η H |</td><td>ESMS m / z 509.2 (M + H⁺).</td><td> 0.025</td>

205

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ICsoípM)</td>

<td></td><td>(4- (4- (5-Chloro-4- (5-methyl-1 H- pyrazol-3-yl-amino) -pyrimidin-2-yl- am i no) -2,5-d ¡meti l-fen ¡l) -p¡per¡d¡n- 1 -i 1) - (1 -meti lazetidin-3-il) - methanone</td><td></td><td></td>

<td>X</td><td>ui 1 P^N To&gt; H nn ^Cl YN AP ^ PF N'P ^ Η H | (S) - (4- (4- (5-chloro-4- (5-methyl-1H-) pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -2_]5-dimethyl-phenyl) -piperidin- 1-i 1) - (1 -meti lp i rro lid in-2-il) - methanone</td><td>ESMS m / z 523.2 (M + H⁺).</td><td> 0.01 7</td>

<td>X</td><td>irp jp'P AA ^ af^2;AF nP Η H | (4- (4- (5-Chloro-4- (5-methyl-1 H- pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -2,5-dimethyl-phenyl) -piperidin- 1-yl) - (1-methyl-piperidin-4-yl) -</td><td>ESMS m / z 537.2 (M + H⁺).</td><td></td>

206

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICgo (pM)</td>

<td></td><td>methanone</td><td></td><td></td>

<td></td><td>IH ίίΊ ^ΝΤΧ / nXA I heard^Cl\&gt; v^NAnd 'hn ^ n, fl T NH HO OX</td><td>ESMS m / z</td><td></td>

<td></td><td>(4- (4- (5-Chloro-4- (5-methyl-1 H-</td><td>539.3 (M + H⁺).</td><td> 0.048</td>

<td></td><td>pyrazol-3-l-am¡no) -p¡rim¡d¡n-2-il-</td><td></td><td></td>

<td></td><td>am¡ no) -2,5-d¡ meti l-fe n ¡l) -pi perid ¡n-</td><td></td><td></td>

<td></td><td>1 - ll) - ((2R, 4R) -4-h¡drox¡-1 -methyl-</td><td></td><td></td>

<td></td><td>pl rrol ¡d I n-2-il) -meta nona</td><td></td><td></td>

<td></td><td>ΐ H 0yⁿtO i ι li ^Cl</td><td></td><td></td>

<td></td><td>YY-X HN „, n T Tx</td><td></td><td></td>

<td></td><td>γ</td><td>ESMS m / z</td><td></td>

<td></td><td>(4- (4- (5-Chloro-4- (5-methyl-1H-)</td><td>509.2 (M + H⁺).</td><td> 0.145</td>

<td></td><td>p¡razol-3-ll-am¡no) -p¡r¡m¡d¡n-2-il-</td><td></td><td></td>

<td></td><td>amino) -5-fluoro-2-methyl-phenol) -</td><td></td><td></td>

<td></td><td>pipe rid i n-1 - il) - (1 H-pyrrole-2-il) -</td><td></td><td></td>

<td></td><td>methanone</td><td></td><td></td>

207

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoÜjM)</td>

<td></td><td>ί Η ίγτ^Ν1 &lt;γγ ^Νγ \ ι Λ Λ, 'ΙΟ' (S) - (4- (4- (5-chloro-4- (5-methyl-1H-) pyrazol-3-yl-amino) -pyrimidin-2-ll- amino) -5-fluoro-2-methyl-phenyl) - ρ ¡perid in-1 -0) - (1 -isopropyl- piperid¡n-2-¡l) -methanone</td><td>ESMS m / z 569.3 (M + H ⁺ ).</td><td> 0.012</td>

<td></td><td>ΐ H Λύυ Πτ τ ^Cl, Ο · ν ·^ΝΆ ' AND Here (S) - (4- (4- (5-chloro-4- (5-metii-1 H- p ¡razol-3-¡l-am i no) -p ¡rim ¡di η-2-il- amino) -5-fluoro-2-methyl-phenyl) - piperidin-1-yl) - (4-isopropyl- morpholin-3-yl) -methanone</td><td>ESMS m / z 571.3 (M + H⁺).</td><td> 0.029</td>

208

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ΙΟ „(μΜ)</td>

<td></td><td>^ηΆ chap Ao ΝγΝ^ΗΝΑχ 0 (4- (4- (5-chloro-4- (5-met¡ 1-1 H- pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -5-fluoro-2-methyl-phenyl) - pi pe rid i n-1 - il) - (2,4-dimethyl-oxazol- 5-il) -methanone</td><td>ESMS m / z 539.2 (M + H⁺).</td><td> 0.027</td>

<td></td><td> 1 ^H_rv I heard ^N TO^ClΟΥ HO OR γ (4- (4- (5-Chloro-4- (5-methyl-1 H- pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -5-fluoro-2-metii-phenyl) - piperidin-1-yl) - ((2S) -4-hydroxy-1 - methyl-pyrrolidin-2-yl) -methanone</td><td>ESMS m / z 543.2 (M + H⁺).</td><td> 0.175</td>

209

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoípM)</td>

<td></td><td> \ ⁰Αρ l_zⁿ \ p-PA and yp γn^xn 'n' ''²η h (4- (4- (5-Chloro-4- (5-Methyl-1 H- pyrazol-3-yl-amino) -pyrimidin-2-l- amino) -5-fluoro-2-methyl-phenyl) - p¡per¡d¡n-1 - ¡1) - (1,3,5-trimet¡ 1-1 ΙΊ- pi razo l-4-¡l) -meta non a</td><td>ESMS m / z 552.2 (M + H⁺).</td><td> 0.025</td>

<td></td><td>ΫΥ, aA ίa^ci to γΡ f ρ Η H (4- (4- (5-Chloro-4- (5-methyl-1 H- pyrazol-3-yl-amino) -pyrmidium-2-yl- amino) -5-fluoro-2-methyl-phenyl) - piperidin-1-yl) - (1-methyl-5- (trifl uoro- meti l) -1 H-pyrazol-4-yl) -methanone</td><td>ESMS m / z 592.2 (M + H⁺).</td><td> 0.061</td>

210

<td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICgo (pM)</td>

<td> 0</td><td>¹H NMR (400 MHz, MeOD-d₄) δ 8.08 (s, 1 H), 7.68 (d, 2H), 7.04 (d, 2H), 6.26 (s, 1 H), 4.74-4.68 (m,</td><td></td>

<td>1 Ρ / Ανη</td><td>2H), 4.39-4.35</td><td></td>

<td>ΗΝ-_Ν^0Κγ-_Ν</td><td></td><td></td>

<td></td><td>(m, 1H), 4.29-</td><td></td>

<td>Ν νΧ '</td><td></td><td></td>

<td>Η Η ρ</td><td>4.24 (m, 2H),</td><td></td>

<td>azet¡d¡n-3-¡- (4- (4- (5-chloro-4- (5-</td><td>4.11 -4.07 (m,</td><td> 1.25</td>

<td>methyl-1 H-pyrazol-3-yl-amino) -</td><td>1 H), 3.74-3.71</td><td></td>

<td>p¡r¡mid¡n-2-¡l-am¡no) -5-fluoro-2-</td><td>(m, 1 H), 3.25 -</td><td></td>

<td>meti l-fen i I) -pi perid I n-1 -il) -</td><td>3.24 (m, 1 H),</td><td></td>

<td>methanone</td><td>3.07-3.04 (m,</td><td></td>

<td></td><td>1H), 2.87-2.80 (m, 1H), 2.33 (s, 3H), 2.28 (s, 3H), 1.87-1.84 (m, 2H), 1.66- 1.56 (m, 2H);</td><td></td>

211

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC $ o (pM)</td>

<td></td><td></td><td>ESMS m / z 499.2 (M + H⁺).</td><td></td>

<td></td><td>k A » HN, J _ J. n nh i Year^{C |}\ X AyX-X || No. Yk nnA^H F (S) -azetidin-2-yl- (4- (4- (5-chloro-4- (5-Methyl-1 H-pyrazol-3-yl-amino) - pyrimidin-2-yl-amino) -5-fluoro-2- meti I-fe n ¡I) -p ¡perid i n-1 -il) - methanone</td><td>ESMS m / z 499.2 (Μ + H +).</td><td> 0.161</td>

<td></td><td>IH xtⁿyO XfT T^CI °^^NX ^ΗΝ^&gt; Ν And V (R) - (4- (4- (5-clo ro-4- (5-meti 1-1 H- pyrazol-3-yl-amino) -pyrmidium-2-yl- amino) -2,5-dimethyl-phenyl) -piperidine- 1 - i 1) - (1-methyl-pyrrolidin-2-yl) -</td><td>ESMS m / z 523.3 (M + H⁺).</td><td> 0.013</td>

212

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ic »(μΜ)</td>

<td></td><td>methanone</td><td></td><td></td>

<td></td><td>ΐ H ΥγΝγΜ Γγτ τ ^ciAND^N, Ν (R) - (4- (4- (5-chloro-4- (5-methyl-1H-) pyrazol-3-l-amino) -pyrimidin-2-yl- amino) -5-fluoro-2-methyl-phenyl) - piperid i n-1 - ¡1) - (1 -meti l-pi rrol ¡di n-2- L) -metanone</td><td>ESMS m / z 527.2 (M + H ⁺ ).</td><td> 0.021</td>

<td></td><td> 1 ^Hv YJ A1_CI/Ν,.π r Y τ i ^c^hYn_H(R) - (4- (4- (5-cl gold-4- (5-met¡ 1-1 H- pyrazol-3-yl-amino) -p¡r¡m¡d¡n-2-il- amino) -5-fluoro-2-methyl-phenyl) - p ¡perid ¡n-1 - ¡I) - (1 -isopro p ¡I- pyrrolidin-2-yl) -methanone</td><td>ESMS m / z 555.3 (M + H⁺).</td><td> 0.048</td>

213

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ic® (μΜ)</td>

<td></td><td>ΐ Η Αγ^ΝγΝχ γγΑΡ Ν γΑ₀₁θκγΡ HN. JN FF Α (4- (4- (5-chloro-4- (5-met¡l-1 Η- pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -5-fluoro-2-methyl-phenyl) - ρ i pe rid i n-1 -il) - (4-methyl-oxazol-5-¡l) - methanone</td><td>ESMS m / z 525.2 (M + H⁺).</td><td> 0.035</td>

<td></td><td>ΐ H Λ^ΝγΝι rrY Y^ci0-V '^NP hn ^ n XF NO (4- (4- (5-Chloro-4- (5-methyl-1 H- pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -5-fluoro-2-methyl-phenyl) - pi pe rid in-1 -il) - (3,5-dimethyl- isoxazol-4-yl) -methanone</td><td>ESMS m / z 539.2 (M + H⁺).</td><td> 0.018</td>

214

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoftiM)</td>

<td></td><td>ί Η Oh ^ χχ.χΑΑ νΑ i AI γ ο ΟχΝ, Ο ¹ ΗΝ_ν, Α \ Α HN Α \ (S) - (4- (4- (5-chloro-4- (5-methyl-1H-) pyrazol-3-yl-amino) -pyrimidin-2-¡- am i no) -5-fluoro-2-meti l-feni I) - p¡perid i n-1 -il) - (2-methyl-pi rrolid in-2- il) -methanone</td><td>ESMS m / z 527.2 (M + H⁺).</td><td> 0.091</td>

<td></td><td> 1 ^HΑγΝ ^ Ν ix \ AA nAP Λ^η Ol T ^ClΟτ^Ν^ ^ΗΝγΑ oh ° a (4- (4- (5-Chloro-4- (5-methyl-1H-) pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -5-fluoro-2-methyl-phenyl) - pe r i n-1 - il) - ((2S, 3R) -3-hydroxy- 1 -metí lp i rrol id ¡n-2-ü) -methanone</td><td>ESMS m / z 543.2 (M + H⁺).</td><td> 0.175</td>

215

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>1GF-1R Ba / F3 ICgoftiM)</td>

<td></td><td>ΐ Η ΑγΝχ ΓΎτ Τ ^α^HNW μ'Ά ^Ν^Ν^Ν / Η Ν-Ν (4- (4- (5-chloro-4- (5-met¡l-1 Η- pyrazol-3-l-amino) -pyrimidin-2-yl- am¡no) -5-flu oro-2-meti l-fen ¡I) - pi pe rid i n-1 - i I) - (1 H-tetrazol-1-yl) - methanone</td><td>ESMS m / z 512.2 (M + H⁺).</td><td> 0.139</td>

<td></td><td>ί H Oh ^Nand^Nand ΓΥτ τ ^Cl, 0 NX HN ^^^F δχ ^H(4- (4- (5-Chloro-4- (5-methyl-1 H- pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -5-fluoro-2-methyl-phenyl) - piperidin-1-yl) - (2-methyl-5- (trifluoro- m eti l) -oxazol-4-yl) -m ethane na</td><td>ESMS m / z 593.2 (M + H⁺).</td><td> 0.069</td>

216

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ic® (μΜ)</td>

<td></td><td>ΐ Η ΓϊΆΥ f '^ Pf ^Νγ ^xci ° γ^ΝΡ ^ηνΆ- ΗνΑ ^Ν~^Ν'η Q PA 6- (4- (4- (5-chloro-4- (5-met¡l-1 Η- pyrazol-3-yl-amino) -p¡rimidin-2-¡- am ino) -5-flu or ro-2-meti l-fen ¡I) - piperidin-1 -carbon il) -pi perid i n-2- ona</td><td>ESMS m / z 541.2 (M + H⁺).</td><td> 0.282</td>

<td></td><td>ΐ H Λνχ Ατ ⁿto^ciθγΜ ' ^HNvy_ hnA A Po ^H(S) - (4- (4- (5-chloro-4- (5-methyl-1 hl- pyrazol-3-i l-am i no) -pi rim id i n-2-il- ami no) -5-fluoro-2-methyl-phenyl) - pi pe rid i n-1 -il) - (morfolin-3-il) - methanone</td><td>ESMS m / z 529.2 (M + H⁺).</td><td> 0.071</td>

217

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICg, (pM)</td>

<td></td><td>1 HOUR íaAyA YA A \ γ i τ Y ^ClCL Cl HN N_xcAJ T&gt; 5-chloro-N²- (2-met¡l-5-chloro-4- (1 - (tetrahydro-1,1-doxox-3-tenyl) - p¡ pe rid l n-4-¡l) -fe n ¡I) -N⁴- (5-met¡ I- 1 B-pyrazol-3-¡) -p¡rim¡d¡n-2,4- diamlna</td><td>ESMS m / z 550.1 (M + H⁺).</td><td> 0.007</td>

<td></td><td>AyX n ^ x i and ^ClΟχ / ν^ΝΆ HN N_v_ORAJ 5-chloro-N²- (2-fluoro-5-m eti 1-4- (1 - (tetrahydro-1,1-dioxido-3-thienyl) - piper¡dln-4-¡l) -fenll) -N⁴- (5-met¡l- 1 Hp¡ razol-3-¡l) -p¡r¡m¡din-2,4- dlamlna</td><td>ESMS m / z 534.2 (M + H⁺).</td><td> 0.018</td>

218

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoOjM)</td>

<td></td><td>ΗΝ-Υγν 'N- / V ° Μ Μ V / V- / 0 &lt;7 Ν ^χC! ΗΝ-γ ^ 5-cl or ro-N2- (2,5-di meti 1-4- (1 - (tetrahydro-1,1-dioxide-2H- tiopi ra n-4-i I)) - pi pe ridi n-4-i I) -fe ni I) - N4- (5-methyl-1H-pyrazol-3-yl) - p¡r¡m¡d¡n-2,4-d amine</td><td>ESMS m / z 544.2 (M + H⁺).</td><td> 0.258</td>

<td></td><td>^H% X x^s° Ά AY ΑυΎ Η I 5-chloro-N2- (2-chloro-5-m eti 1-4- (1 - (1,1-Dioxide-3-Tietanyl) -piperidin-4- il) -phenyl) -N4- (5-methyl-1 H-pyrazol-3- il) -pyrimidin-2,4-diamine</td><td>ESMS m / z 536.1 (M + H⁺).</td><td> 0.016</td>

219

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Κ&gt; 5θ (μΜ)</td>

<td></td><td>F, hn YX nA M Y-⁷ or N ⁷And &lt;Ynh Cl HN —Y 7 5-chloro-N2- (2-fluoro-5-met¡ 1-4- (1 - (1,1-Dioxide-3-Tietanyl) -piperidin-4- il) -phenyl) -N4- (5-metll-1 H-pyrazole-3- i I) -p¡ rim idi n-2,4-d ¡amina</td><td>ESMS m / z 520.2 (M + H⁺). ¹H NMR (400 MHz, DMSO-d₆+ 1 drop D₂O) δ 8.02 (s, 1H), 7.37 (s, 1 H), 7.02 (s, 1H), 6.23 (s, 1H), 4.28-4.22 (m, 2H), 4.12-4.07 (m, 2H), 3.22- 3.18 (m, 1 H), 2.95-2.92 (m, 2H), 2.68-2.62 (m, 1H), 2.22 (s, 3H), 2.13 (s, 3H), 2.07-2.01 (m, 2H), 1.71- 1.55 (m, 4H).</td><td> 0.018</td>

220

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ιθδοίμΜ)</td>

<td></td><td>, AT 1 1 j ^N</td><td></td><td></td>

<td></td><td>hn-_n^c'and ^_n Tie</td><td></td><td></td>

<td></td><td>TF ν γ Ν ^ γ Η Η</td><td></td><td></td>

<td></td><td></td><td>ESMS m / z</td><td> 0.955</td>

<td></td><td>5-Chloro-N 2- (4- (1 - (5-ethyl-pyrimidin-</td><td>522.2 (Μ + H +).</td><td></td>

<td></td><td>2-¡) -piperid¡n-4-¡) -2-fluoro-5-</td><td></td><td></td>

<td></td><td>meti l-fen ¡l) -N4- (5-met¡ 1-1 H-pi razol-</td><td></td><td></td>

<td></td><td>3-i I) -pyri mid ¡n-2,4-di amine</td><td></td><td></td>

<td></td><td rowspan="2">i P^NHην-Τ'ύΤι H ^H F</td><td></td><td></td>

<td></td><td>ESMS m / z</td><td></td>

<td>X</td><td>5-chloro-N2- (2-fluoro-5-methyl-4-</td><td>414.1 (M + H⁺).</td><td> 0.025</td>

<td></td><td>(1,2,3,6-tet rah id ro-p i rid i n-4-i I) -</td><td></td><td></td>

<td></td><td>fenll) -N4- (5-methyl-1 H-pyrazol-3-yl) -</td><td></td><td></td>

<td></td><td>pimirin-2,4-diamna</td><td></td><td></td>

<td></td><td> 0</td><td></td><td></td>

<td></td><td>to go ^NH</td><td>ESMS m / z</td><td></td>

<td>X</td><td>ΗΝ-Ν^αγΥ | Η Η I</td><td>426.2 (M + H⁺).</td><td> 0.009</td>

<td></td><td>4- (4- (5-Chloro-4- (5-Methyl-1 H-</td><td></td><td></td>

221

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoftjM)</td>

<td></td><td>pyrazol-3-yl-amino) -pyrmm-d-n-2-l- amno) -2,5-d-methyl-fen¡l) -piper¡d¡n- 2-one</td><td></td><td></td>

<td></td><td>\ X^orA ρ ci— &lt;O ~ NH ^X4- (4- (5-Chloro-4- (5-Methyl-1 H- p¡razol-3-¡l-am¡no) -p¡r¡mid¡n-2-¡l- amino) -2,5-dimethyl-phenyl) - tetrahydro-2H-pyran-2-one</td><td>ESMS m / z 427.2 (M + H⁺).</td><td> 0.155</td>

<td></td><td>OR O / N χ - ^ / CI ml, x ^ XY Ν γ N^nh_XY '' _N 0 F and HH 5-chloro-N2- (2-fluoro-4-morpholino- 5- (t rif I uoro-methyl) -phenyl) -N4- (5- methyl-1 Hp¡razol-3-il) -pyrimid¡n- 2,4-diamine</td><td>ESMS m / z 472.1 (Μ + H +).</td><td> 0.091</td>

222

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (mM)</td>

<td></td><td>&lt;χ ° Cl — A // - NH ^xN 9 5-chloro- / V - [4- (1,1-dioxo- tetrah¡dro-1] ®-t¡ofen-3-¡) -2,5- d ¡methyl-fe n¡l] -A / ^ - (5-met¡ 1-1 H- pyrazol-3-¡) -p¡r¡m¡d¡n-2,4-d¡amina</td><td>ESMS m / z 447.1 (M + H⁺).</td><td> 0.012</td>

<td></td><td>^ NH And and J CH \ /&gt; - NH ^X1 - (4- (5-c! Gold-4- (5-methyl-1 H- pyrazol-3-¡-amino) -p¡r¡midln-2-il- am i no) -2,5-dimethyl-phenyl) - piperazin-2-one</td><td>ESMS m / z 427.2 (M + H⁺).</td><td> 1.65</td>

<td></td><td>Η H ^F\,F γγ^ΝγΥ^Νγγ hn'N_{c |}/ Vn 5-chloro-N4- (5-methyl-1 Hp and razol-3-</td><td>ESMS m / z 481.2 (M + H ⁺ )</td><td> 0.040</td>

223

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICgjÜJM)</td>

<td></td><td>il) -N2- (2-methyl-4- (4-methyl) piperazin-1-yl) -5- (trfluoro-methyl) - phenyl) -pyrimidin-2,4-diamine</td><td></td><td></td>

<td></td><td>^Clrx HN N NH Fr^Fή ΖΧχ H ^F3^C ! 0 ¡¡ 5-chloro-N2- (2-fluoro-4- (4-methyl) p¡perazin-1-yl) -5- (trfluoro-methyl) - phenyl) -N4- (5-methyl-1H-pyrazol-3-l) - pi rim idi n-2,4-di amina</td><td>ESMS m / z 485.2 (M + H⁺).</td><td> 0.075</td>

<td></td><td>Av rrr ° Ά ^HNf HnV^H3- (5-Chloro-2- (2,5-dimethyl-4- (piperidn-4-yl) -phenyl-amine) - pimidin-4-yl-amino) -pridin-2 (1 H) -</td><td>ESMS m / z 425.2 (M + H ⁺ ).</td><td> 0.062</td>

224

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (pM)</td>

<td></td><td>ona</td><td></td><td></td>

<td></td><td>/ N NH i AN CI \ AA \ A \ A TOⁿ χ χ nny^H F 5-Chloro-N2- (2-fluoro-5-methyl-4- (1- methyl-piperidin-4-yl) -phenyl) -N4- (5- m eti l-¡soxazol-3-¡I) -p ¡rim id in-2,4- diamine</td><td>ESMS m / z 431.2 (M + H⁺).</td><td> 0.073</td>

<td></td><td>Q LJ LJ I^ηΛΎϊ^νΛ and oh TO/^NH3- (5-Chloro-2- (2,5-dimethyl-4- (piperidin-4-¡l) -phenyl-amino) - pyrimid¡n-4-yl-amino) -p¡r¡din-2 (1 H) - ona</td><td>ESMS m / z 425.2 (M + H⁺).</td><td></td>

<td></td><td>H hA^N and ^N and ^N and% hn'N _Cl .Jy-N k, Ay ·,</td><td>ESMS m / z 456.2 (M + H⁺).</td><td> 0.332</td>

225

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ICsoftiM)</td>

<td></td><td>5-chloro-N2- (2-isopropoxy-5-methyl- 4- (1 -met¡lp¡per¡d¡n-4-¡l) -phenyl) -N4- (1 Hp¡razol-3-¡l) -pirim¡din-2,4- diamine</td><td></td><td></td>

<td></td><td>H γ / ΥγΑ II Ί H |ⁿA ^ c,^ΗΝχ%_Η4- (4- (5-Chloro-4- (5-Methyl-1 H- pyrazol-3-yl-amino) -p¡rimidin-2-¡- am i no) -2,5-dimethyl-fen i I) - p ¡perid ¡n- 1-ethyl carboxylate</td><td>ESMS m / z 438.9 (M + H⁺).</td><td> 0.013</td>

<td></td><td>AND ^H2^NAnd^HN' TO ):^cAnd ΛΥ L γ χ, ..- ν ν γ^H F (S) -2- (4- (4- (5-chloro-4- (5-methyl-1H-) pyrazol-3-yl-amino) -p¡rim¡d¡n-2-il- amlno) -5-fluoro-2-methyl-phenyl) - pi pe rid i n-1 -II) -propa na mida</td><td>ESMS m / z 487.2 (M + H⁺)</td><td> 0.056</td>

226

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθ5θ (μΜ)</td>

<td></td><td></td><td>ESMS m / z</td><td></td>

<td></td><td></td><td>501.2 (M + H⁺)¡</td><td></td>

<td></td><td></td><td>¹H NMR (MeOD-</td><td></td>

<td></td><td>\ I \ HN ^ O HN P). Ν NH i A Ν^CIAnd ^^Nn ^ np</td><td>d₄) δ 8.25 (s, 1H), 7.56 (m, 1H), 7.20 (d, 1H), 6.46 (s,</td><td></td>

<td></td><td>^H F</td><td>1H), 3.97 (m,</td><td> 0.033</td>

<td></td><td>(S) -2- (4- (4- (5-chloro-4- (5-methyl-1 H-)</td><td>1H), 3.79 (m,</td><td></td>

<td></td><td>pyrazol-3-l-amino) -pyrimidin-2-yl-</td><td>1H), 3.62 (m,</td><td></td>

<td></td><td>amino) -5-fluoro-2-methyl-phenyl) -</td><td>1H), 3.25 (m,</td><td></td>

<td></td><td>piperidin-1-yl) -N-methyl-</td><td>3H), 2.84 (s,</td><td></td>

<td></td><td>propanamide</td><td>3H), 2.40 (d,</td><td></td>

<td></td><td></td><td>6H), 2.08 (m,</td><td></td>

<td></td><td></td><td>4H), 1.62 (m,</td><td></td>

<td></td><td></td><td>3H).</td><td></td>

<td></td><td>V Η₂ΝγΟ HN 'A f ν^Λνη i ALREADY | ¡N [II^H F</td><td>ESMS m / z 487.2 (M + H⁺); ¹H NMR (MeOD- d₄) δ 8.22 (s, 1H), 7.61 (t,</td><td> 0.038</td>

227

STRUCTURE (R) -2- (4- (4- (5-Chloro-4- (5-Methyl-1 Hpyrazol-3-L-Amne)) -prim¡d¡n-2- Lamino) -5-fluoro-2-methyl-phenyl) pi perid n-1 -yl) -propanam¡da

<img file="CU23952B1_D0127.tif" />

.0 'v (S) -2- (4- (4- (5-chloro-4- (5-methyl-1 Ham¡no) -2,5-dimethyl-phenyl) -p¡per¡din1 -il ) -propanamide

NMR or ESMS

<td>1H), 7</td><td> .18</td><td>(d,</td>

<td>1H), 6</td><td> .40</td><td>(s,</td>

<td>1H), 3.</td><td> 79</td><td>(m,</td>

<td>1H), 3.</td><td> 65</td><td>(m,</td>

<td>1H), 3.</td><td> 54</td><td>(m,</td>

<td>1H), 3.</td><td> 22</td><td>(m,</td>

<td>3H), 2</td><td> .39</td><td>(d,</td>

<td>6H), 2.</td><td> 08</td><td>(m,</td>

<td>4H), 1</td><td> .66</td><td>(d,</td>

3H)

ESMS m / z

483.2 (M + H⁺)

IGF-1R

Ba / F3

ICsoípM)

0.007 pyrazol-3-yl-amino) -p¡rim¡din-2-¡l25

228

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (pM)</td>

<td></td><td>TO ^Η2ΝγΟ^h\ AA^clpA yAJ l Λ XJ Ν NY Η I (R) -2- (4- (4- (5-Chloro-4- (5-Methyl-1H-) pyrazol-3-yl-amine) -pyrmidium-2-yl- amino) -2,5-dimeti l-feni I) - pi perid i n- 1 -il) -propanamide</td><td>ESMS m / z 483.2 (M + H⁺)</td><td> 0.006</td>

<td></td><td>A hAo^HNx Α / X): ΝΝΗ i [N ci x A AAA and NM | nAO η I (S) -2- (4- (4- (5-chloro-4- (5-methyl-1 H-) pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -2,5-d-methyl-fen¡l) -piper¡din- 1 - il) -N-met¡ lp clothes namida</td><td>ESMS m / z 497.2 (M + H⁺)</td><td> 0.01</td>

229

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθ »(μΜ)</td>

<td></td><td>Ϊ Η ΑΥγΑ Υττ ^ΝΪ ^ClθγΧΑ ¹ ΗΝ ν, Λ Q (4- (4- (5-chloro-4- (5-met¡l-1 Η- pyrazol-3-¡-l-am¡no) -pir¡m¡d¡n-2-il- amino) -5-fluoro-2-methyl-phenol) - pi perid i n-1 - il) - (1 - (eti l-am ¡no) - c¡cloprop¡l) -methanone</td><td>ESMS m / z 527.2 (M + H⁺); ¹H NMR (MeOD- d₄) δ 8.24 (s, 1H), 7.49 (d, 1 H), 7.23 (d, 1H), 6.47 (s, 1H), 4.52 (d, 2H), 3.26 (q, 2H), 3.18 (m, 3H), 2.40 (s, 6H), 1.91 (d, 2 H), 1.71 (m, 2H), 1.49 (m, 3H), 1.39 (t, 3H).</td><td> 0.004</td>

<td></td><td>I Η Αγ^Νγ^Νχ AyV A , ~ YQ (4- (4- (5-Chloro-4- (5-Methyl-1 H-</td><td>ESMS m / z 523.3 (M + H⁺)</td><td> 0.003</td>

230

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoftjM)</td>

<td></td><td>p¡razol-3-¡-l-amino) -pyrimidin-2-¡- am no) -2,5-di meti l-fen il) -pi perid ¡n- 1 - i 1) - (1 - (ethyl-amino) -cyclopropyl) - methanone</td><td></td><td></td>

<td></td><td>f Η Η T fX-fv^N To γ^N Af F ΗΝ^ν0 | Α_Χ/ Ν P / NH 5-chloro-N2- (2-fluoro-5-methyl-4- (piperidin-4-yl) -phenyl) -N4- (5- (trifluo ro-meti l) -1 H-pyrazol-3-yl) - pyrimid¡n-2,4-dinamine</td><td>ESMS m / z 470.1 (M + H ⁺ )</td><td> 0.067</td>

<td></td><td>AND Vf^FHN, To you N NH i fNy^CIV Xji ° N N'HT^H í 2- (4- (4- (5-cl gold-4- (5- (trifl uoro- methyl) -1 H-pyrazol-3-yl-amino) - pyrimid¡n-2-l-am¡no) -5-fluoro-2- m eti I-fe ni I) -pi per id i n-1 -il) -N-methyl-</td><td>ESMS m / z 541.2 (M + H ⁺ )</td><td> 0.069</td>

231

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (μΜ)</td>

<td></td><td>acetamide</td><td></td><td></td>

<td></td><td>c Η HV fy ΧΎ ^N Ά And ^N Me F Η »'· .-'.»,¹, '0 2- (4- (4- (5-chloro-4- (5- (trif luoro- methyl) -1 Hp¡razol-3-yl-amino) - p¡r¡m¡din-2-l-am¡no) -5-fluoro-2- meti l-fen¡l) -piperid¡ n-1 -il) - acetamide</td><td>ESMS m / z 527.2 (M + H⁺)</td><td> 0.049</td>

<td></td><td>PA^cixP_N AP OH Η I 5-chloro-N2- (2,5-dimethyl-4- (1- (tetrah¡dro-2H-tiop¡ran-4-¡l) - pperidin-4-¡) -phenyl) -N4- (5-methyl) 1H-p¡razol-3-il) -pyrimin-2,4- diamine</td><td>ESMS m / z 512.2 (M + H ⁺ )</td><td> 0.008</td>

232

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ΙθωψΜ)</td>

<td></td><td>I Η Λζ ^Nalready Ν · Χ \ ι III ^Clοαα ^{1 ΗΝ}ΆΥ 1 Τ ΝΗ ΝΗ Α ? 1- (4- (4- (5-chloro-4- (5-methyl-1 Η- pyrazol-3-yl-amino) -pyrimidin-2-yl- am¡no) -2,5-dimethyl-phenyl) -p¡per¡d¡n- 1-¡) -2- (ethyl-amine) -2-methyl-propan- 1 -one</td><td>ESMS m / z 525.3 (M + H⁺)</td><td> 0.005</td>

<td></td><td> 1 ^Hí j 1 1 Γττ τ ^ClOy-nx ¹ HN Ν ' 1 T nh hn and · (4- (4- (5-Chloro-4- (5-methyl-1 H- p¡razol-3-¡l-am¡no) -pir¡mid¡n-2-¡l- amino) -5-fluoro-2-methyl-phenyl) - pi peri di n-1 -¡ 1) - (1 - (eti l-am i no) - cyclobutyl) -methanone</td><td>ESMS m / z 541.3 (M + H⁺)</td><td> 0.084</td>

233

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (pM)</td>

<td></td><td>i H ίίΊ ^NT^N^ ^N J ^ CI Ογχ-Ν-Υ ¹ HN N_xT NH HN (4- (4- (5-Chloro-4- (5-Methyl-1 H- pyrazol-3-yl-amino) -p¡r¡m¡din-2-il- amno) -5-fluoro-2-methyl-phenol) - pi pe rid in-1 -i 1) - (1 - (me l-am i no) - cyclobutyl) -methanone</td><td>ESMS m / z 527.2 (M + H⁺)</td><td> 0.08</td>

<td></td><td>&lt;~ NH hn ^ Y^N'^H TO#^HN'N YN —4 Y^NH^V N N2- (2,5-di meti I-4- (pipe ridin -4-il) - phenyl) -5-methyl-N4- (5-methyl-1 H- pyrazol-3-yl) -pyrimidin-2,4-damine</td><td>ESMS m / z 392.2 (M + H⁺)</td><td> 3.229</td>

234

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 iCsoípM)</td>

<td></td><td>HnYX zz zZ ^FAND^FN NH i X AA ^0Hn ^ Aj AY Η I (S) -3- (4- (2,5-dimethyl-4- (5-methyl-4- (5-methyl-1 H-pyrazol-3-yl-amino) - pimimin-2-yl-amine) -phenyl) - pi pe rid i n-1 -¡I) -1,1,1 -trifluoro- propan-2-ol</td><td>ESMS m / z 504.3 (M + H⁺)</td><td> 0.12</td>

<td></td><td>AND ο, γ AND^NHΝγΝ HNz / Yz / -N_x1- (3- (4- (5-Chloro-4- (5-methyl-1H-) pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -2,5-dimethyl-phenyl) -piperidin- 1-yl) -2- (dimethyl-amino) -ethanone</td><td>ESMS m / z 497.2 (M + H ⁺ )</td><td> 0.025</td>

235

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsofpM)</td>

<td></td><td>\ Αν nh₂Ύ = \ / Y M. ci FX^nh—N</td><td>ESMS m / z 469.2 (M + H⁺)</td><td> 0.024</td>

<td></td><td>2- (2- (4- (5-Chloro-4- (5-methyl-1 H-)</td><td></td><td></td>

<td></td><td>pi razol-3-i I-am ino) -pi ri m id i n-2-i I-</td><td></td><td></td>

<td></td><td>amino) -2,5-dimethyl-phenyl) -piperidin-</td><td></td><td></td>

<td></td><td>1-yl) -acetamide</td><td></td><td></td>

<td></td><td>πνΧ c,^N0 TO^nh^NAND^N or^HN\ / W Λ / Τ Ί I ^ΝAAJ^Η</td><td>ESMS m / z 483.2 (Μ + H *)</td><td> 0.019</td>

<td></td><td>2- (2- (4- (5-chloro-4- (5-methyl-1 Η-</td><td></td><td></td>

<td></td><td>pyrazol-3-yl-amino) -pyrimidin-2-yl-</td><td></td><td></td>

<td></td><td>amino) -2,5-dimethyl-phenyl) -piperidine-</td><td></td><td></td>

<td></td><td>1 - il) -N-methyl-acetamide</td><td></td><td></td>

236

STRUCTURE

NMR or ESMS

IGF-1R

Ba / F3

IC_M(p.m)

<img file="CU23952B1_D0128.tif" />

ESMS m / z

426.2 (M + H⁺) (S) -5-clo ro-N2- (2,5-dimethyl-4- (1meti¡-p¡per¡din-2-¡) -phenyl) -N4- (5m et ί I -1 H -pyrazol-3-yl) -pyrimidin2,4-diamine

<img file="CU23952B1_D0129.tif" />

426.2 (M + H (R) -5-Chloro-N2- (2,5-dimethyl-4- (1-methyl-pperidin-2-yl) -phenyl) -N4- (5met¡l-1 H-pi razo l-3-il) -p¡r¡ mid ¡n2,4-diamine

<img file="CU23952B1_D0130.tif" />

ESMS m / z

497.2 (M + H⁺)

0.009

2- (4- (4- (5-chloro-4- (5-methyl-1 H237

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 IC® (μΜ)</td>

<td></td><td>p¡razol-3-¡-a-amino) -p¡r¡midin-2-¡- am i no) -2,5-d ¡meti l-fen ¡l) -p¡per¡d¡n- 1 -l) -butanam¡da</td><td></td><td></td>

<td></td><td>IH Ρ^ΝγΛ IIII ^Clhn ^ n . JX /^NHΝ Λ 1 - (4- (4- (5-cl or ro-4- (5-c¡ clop ropi I- 1 H-pyrazol-3-yl-amino) -p¡r¡midin-2- L-amine) -2,5-dimethyl-phenol) - piperidin-1 -il) -2- (dimethyl-amine) - ethanone</td><td>ESMS m / z 523.3 (M + H ⁺ )</td><td> 0.012</td>

<td></td><td>P_NH Π^CpS Í T ^{X / N}'A1H₂F X .. X or Ν NY Η I (1 -ami non-cyclopropi 1) - (3- (4- (5- chloro-4- (5-methyl-1 H-pyrazol-3-yl- amino) -pyrm-d-n-2-l-am) -2.5-</td><td>ESMS m / z 495.2 (M + H ⁺ )</td><td> 0.095</td>

238

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoftjM)</td>

<td></td><td>d ¡meti l-fen ¡l) -p¡per¡d¡ n-1 - il) - methanone</td><td></td><td></td>

<td></td><td>TO , ΡΡγΑ nA 'n-nh | Η H (1-amino-cyclopropyl) - (4- (4- (5- Chloro-4- (5-Cycle Opropi 1-1 H-Pirazol-3- il-amino) -pyrimin-2-l-amino) -2,5- di meti l-fen il) -pi perid i n-1 - il) - methanone</td><td>ESMS m / z 521.2 (M + H⁺)</td><td> 0.019</td>

<td></td><td>And Ϋ ” Ν NH ι Ρ Ν&gt;^αγΧ AA L v AJ Ν NY Η I 2- (4- (4- (5-Chloro-4- (5-methyl-1 H-) pyrazol-3-yl-amino) -pyrimidin-2-yl- amino) -2,5-dimethyl-phenyl) -piperine- 1-¡) -N-methyl-butanam¡da</td><td>ESMS m / z 511.3 (M + H⁺)</td><td> 0.007</td>

239

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθ »(pM)</td>

<td></td><td>I Η Λ-χγ ΧΥτ τ ^Cl/ \ jX ^HN\ Yt X and^H0 NH \ 2- (4- (4- (5-Chloro-4- (5-Methyl-1 H- pyrazol-3-yl-amine) -pyrimin-2-yl amine) -2,5-dimethyl-phenyl) -piperidin- 1 -yl) -N-ethyl-butanamide</td><td>ESMS m / z 525.3 (M + H⁺)</td><td> 0.007</td>

<td></td><td>γ ZOXnh ¿0 'f^N^HN'N \ = n / - \' ci-A / Anh ^x^ -N 5-chloro-N2- (4- (1 - ((3,5-dimethyl- isoxazol-4-¡l) -methyl) -p¡perid¡n-2-¡l) - 2,5-dimethyl-phenyl) -N4- (5-methyl-1 H- pyrazol-3-yl) -pyrim¡d¡n-2,4-diamna</td><td>ESMS m / z 521.2 (M + H⁺)</td><td> 0.113</td>

240

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (pM)</td>

<td></td><td>A- oh^HN\ A y- λ Ν NH ι ON 0 Cl \ AA ·. AA X ^N I) Xf AAf^H F (4- (4- (5-Chloro-4- (5-Methyl-1 H- pyrazol-3-¡-amino) -pyrimid¡n-2-¡- amino) -5-fluoro-2-methyl-phenyl) - p¡peridin-1-¡l) - (1-h¡drox¡- c¡cloprop¡l) -methanone</td><td>ESMS m / z 500.2 (M + H ⁺ )</td><td> 0.021</td>

<td></td><td>Yv Xp HN Ρ ^N\^H X fí ^{0 0H}^hn'n Y = n χχ Clp ZpNH ^X^ —N (2- (4- (5-Coro-4- (5-Methyl-1 H- p ¡razol-3-¡l-am ino) -plr¡ mid ¡n-2-il- am¡no) -2,5-d ¡methyl-fen¡l) -p¡ perid¡ n- 1 -i 1) - (1 - h id roxi-ci clop rop i I) - methanone</td><td>ESMS m / z 496.2 (M + H ⁺ )</td><td> 0.076</td>

241

STRUCTURE

<img file="CU23952B1_D0131.tif" />

5-Chloro-N2- (2,5-dimethyl-4- (1- (3morpholinopropyl-sulfonyl) -piperin-4-yl) -phenyl) -N4- (5-methyl-1 H- pyrazol3-i I) -pi rim id i n-2,4-d amine

<img file="CU23952B1_D0132.tif" />

NMR or ESMS

ESMS m / z

603.3 (M + H ⁺ )

ESMS m / z 573.2 (M + H ⁺ )

IGF-1R

Ba / F3

ICajftjM)

0.013

0.027

N2- (4- (1- (3- (azetidin-1-yl) -propylsulfonyl) -piperidin-4-yl) -2,5-dimethylphenyl) -5-chloro-N4- (5-methyl-1 Hpi razo l-3-yl) -pyrimid and n-2,4-d amine

242

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 Ιθδο (ρΜ)</td>

<td></td><td>z^0Ho = s = o I AND^N-1 H HNyNy / Nyy ^^NA%, N-_Nh (3R, 4R) -1- (3- (4- (4- (5-chloro-4- (5- methyl-1H-pyrazol-3-yl-amino) - pyrimidin-2-yl-amino) -2,5-dimethyl- phenyl) -piperidin-1-yl-sulfonyl) - prop¡l) -p¡rrol¡d¡n-3,4-diol</td><td>ESMS m / z 619.3 (M + H ⁺ )</td><td> 0.37</td>

<td></td><td>Ν^-λ \ HN— (^Z / ^Clno H "ly AA^F \ / (2S) -3- (2- (4- (5-chloro-4- (5-methyl) 1 H-pyrazol-3-yl-amino) -pyrimidin-2- i l-am i no) -2,5-dimethyl-phenyl) -</td><td>ESMS m / z 524.2 (M + H⁺)</td><td> 0.21</td>

243

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsqOjM)</td>

<td></td><td>piper¡din-1-il) -1,1, 1-trifl uoro- propan-2-ol</td><td></td><td></td>

<td></td><td>TO HN, Λ λ Ν NH ι AA A^ciand ^ⁿ fW / η I 1 - ((4- (4- (5-chloro-4- (5-methyl-1 H-) p ¡razol-3-¡l-am¡ no) -plr¡ mid I n-2-i I - amino) -2,5-d-methyl-phenyl) -p¡perid¡n- 1 -il) -met¡l) -c¡clopropan- carbonitrile</td><td>ESMS m / z 491.2 (M + H ⁺ )</td><td> 0.022</td>

<td></td><td>TO HN, J Ν NH i Y'N'Y ^ A] Ν AA^H Do you 2- (4- (4- (5-Chloro-4- (5-Methyl-1 H- p¡ razol-3-i l-am¡ no) -plr¡ mid¡ η-2-il- amino) -5-fluoro-2-methyl-phenyl) - pi perid i n-1 -yl) -acetonicl</td><td>ESMS m / z 455.2 (M + H⁺)</td><td> 0.077</td>

244

<td></td><td colspan="2">STRUCTURE</td><td>NMR or E</td><td>ESMS</td><td>IGF-1 R Ba / F3 ΙθδοίρΜ)</td>

<td></td><td>^hiand x.</td><td>T^N</td><td></td><td></td><td></td>

<td></td><td>N nh i Τ '</td><td></td><td></td><td></td><td></td>

<td></td><td>αΤ T.TT H ^N he V ^</td><td></td><td></td><td></td><td></td>

<td></td><td>'n N ^ T^H ¿</td><td></td><td>ESMS</td><td>m / z</td><td> 0.036</td>

<td></td><td>F</td><td></td><td>469.2 (M</td><td>+ H ⁺ )</td><td></td>

<td></td><td>3- (4- (4- (5-chloro-4- (5-methyl-</td><td>1 HOUR-</td><td></td><td></td><td></td>

<td></td><td colspan="2">p¡razol-3-¡l-am¡no) -p¡r¡m¡d¡n-2-¡l-</td><td></td><td></td><td></td>

<td></td><td colspan="2">amno) -5-fluoro-2-methyl-phenol) -</td><td></td><td></td><td></td>

<td></td><td colspan="2">piperidin-1 -¡I) -p clothes no-n i tri lo</td><td></td><td></td><td></td>

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

<td></td><td>Ν NH i TF—</td><td>-F</td><td></td><td></td><td></td>

<td></td><td>^clp_N ΛτΑ</td><td>Th</td><td></td><td></td><td></td>

<td></td><td>FT \ AP</td><td></td><td></td><td></td><td></td>

<td></td><td rowspan="2">Ν Ν γ H</td><td></td><td colspan="2">ESMS m / z</td><td></td>

<td></td><td></td><td></td><td></td><td> 0.046</td>

<td></td><td colspan="2">(2S) -3- (3- (4- (5-chloro-4- (5-methyl)</td><td>524.2 (M</td><td>+ H⁺)</td><td></td>

<td></td><td colspan="2">1 H-plrazol-3-¡-l-amino) -p¡r¡m¡d¡n-2-</td><td></td><td></td><td></td>

<td></td><td colspan="2">¡Mi mi no) -2,5-d ¡meti l-fen ¡I) -</td><td></td><td></td><td></td>

<td></td><td colspan="2">piperidin-1 -11) -1,1,1 -trif luoro-</td><td></td><td></td><td></td>

<td></td><td>propan-2-ol</td><td></td><td></td><td></td><td></td>

245

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ΙθδοφΜ)</td>

<td></td><td></td><td>ESMS m / z</td><td></td>

<td></td><td></td><td>503.2 (M + H ⁺ );</td><td></td>

<td></td><td></td><td>^ηΗ NMR (MeOD-</td><td></td>

<td></td><td></td><td>d₄) δ 8.23 ​​(s,</td><td></td>

<td></td><td>and</td><td>1 H), 7.26 (s,</td><td></td>

<td></td><td>TO '^NH - \ / NH₂F HN N i Y Ν γ ²</td><td>1H), 7.20 (s,</td><td></td>

<td></td><td>For</td><td>1H), 6.20 (s,</td><td></td>

<td></td><td>NN ^ A Η I</td><td>1H), 4.00 (s,</td><td> 0.02</td>

<td></td><td>2- (4- (2,5-dimethyl-4- (4- (5-methyl-1 H-</td><td>2H), 3.75 (d,</td><td></td>

<td></td><td>pyrazol-3-yl-amine) -5- (trif luoro-</td><td>2H), 3.55 (m,</td><td></td>

<td></td><td>met¡l) -p¡r¡m¡d¡n-2-¡l-am¡no) -fen¡l) -</td><td>2H), 3.14 (m,</td><td></td>

<td></td><td>piperidin-1- il) -a keta measure</td><td>1H), 2.36 (s,</td><td></td>

<td></td><td></td><td>3H), 2.26 (s,</td><td></td>

<td></td><td></td><td>3H), 2.24 (s,</td><td></td>

<td></td><td></td><td>3H), 2.08 (m,</td><td></td>

<td></td><td></td><td>4H).</td><td></td>

<td></td><td>_F γηνΑ, fA</td><td>ESMS m / z</td><td> 0.015</td>

<td></td><td>At j ° N nAY</td><td>517.3 (M + H⁺)</td><td></td>

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

<td></td><td>Η I</td><td></td><td></td>

<td></td><td>2- (4- (2,5-d-methyl-4- (4- (5-metü-1H-</td><td></td><td></td>

246

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoftjM)</td>

<td></td><td>p¡ razol-3-l-am¡no) -5- (tr ifl uoro- meti l) -pi rim ¡di n-2-l-am¡ no) -feri¡l) - piperidin-1-yl) -N-methyl-acetam ida</td><td></td><td></td>

<td></td><td>Η H XX'P '^N Ά γ ^N γΡ ÍHN 'Ν _{C |} / AN YEAR 2- (4- (4- (5-cl or ro-4- (5-cycle propi I- 1H-pyrazol-3-yl-amine) -p¡r¡m¡d¡n-2- il-am ino) -2,5-dimethyl-phenyl) - piperidin-1 -il) -eta η or I</td><td>ESMS m / z 482.2 (M + H ⁺ )</td><td> 0.016</td>

<td></td><td>/ ~ N \ Anh and^HN'NVW ci y // nh 5-Chloro-N4- (5-cyclopropyl-1 H- pyrazol-3-yl) -N2- (4- (1-ethyl- p¡perid i n-4-il) -2,5-di meti l-feni I) - pyrimidin-2,4-day</td><td>ESMS m / z 466.2 (M + H ⁺ )</td><td> 0.019</td>

247

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso &amp; jM)</td>

<td></td><td>k^hnTO" , _rz_Hci \ X / XXX ll ^N \\ X^H F 4- (4- (5-Chloro-4- (5-methyl-1 H- p¡razol-3-¡l-am¡no) -p¡r¡mid¡n-2-¡l- amino) -5-fluoro-2-methyl-phenol) - piperid i n-1 -carbaldehyde</td><td>ESMS m / z 444.2 (M + H⁺)</td><td> 0.03</td>

<td></td><td>ην-^νπΧ /^ν XX /) \ ^or AK nh^HN\ AND TO (R) -2- (3- (4- (5-Chloro-4- (5-Methyl-1 H- ρίΓ3ζοΙ-3-ϊΙ-3Πΐϊηο) -ρίΓίΓηίόίη-2-ϊΙ- amino) -2,5-dimethyl-fenl) -piperine-n 1 - il) -N-methyl-acetamide</td><td>ESMS m / z 483.2 (M + H ⁺ )</td><td> 0.026</td>

<td></td><td>Χτ'Χϊ'ϊΎ / λ ΗΝ-Νρ, / Α / Ν) \^Ul To κ NH^HNx 0 (S) -2- (3- (4- (5-Chloro-4- (5-Methyl-1H-)</td><td>ESMS m / z 483.2 (M + H ⁺ )</td><td> 0.01</td>

248

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ICso (pM)</td>

<td></td><td>p¡razol-3-¡l-am¡no) -pir¡m¡d¡n-2-¡l- amino) -2,5-dimethyl-phenyl) -peridin- 1 -i I) -N-meti l-aceta measure</td><td></td><td></td>

<td></td><td>P π Ν NH, 1 | ^N fl^H Do you 5-chloro-N2- (2-fluoro-5-methyl-4- (1 - (tetra hld ro-2H-pira η-4-il) - piperidin-4-yl) -phenyl) -N4- (5-methyl) 1 H-pyrazol-3-yl) -pi rim idi n-2,4- diamine</td><td>ESMS m / z 500.2 (M + H⁺); ¹H NMR (DMSO- c / s, 400 MHz) 5 12.08 (br, 1H), 9.58 (br, 1H), 8.65 (d, J = 28.4 Hz, 1H), 8.02 (s, 1 H), 7.36 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 12.4 Hz, 1H), 6.08 (br, 1H), 3.89 (dd, J = 10.8, 3.6 Hz, 2H), 3.28 (t, J = 10.4 Hz, 2H), 2.99 (d, J =</td><td> 0.027</td>

249

<td></td><td colspan="2">STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC® (pM)</td>

<td></td><td></td><td></td><td>10.8 Hz, 2H),</td><td></td>

<td></td><td></td><td></td><td>2.64-2.43 (m,</td><td></td>

<td></td><td></td><td></td><td>2H), 2.24-2.15</td><td></td>

<td></td><td></td><td></td><td>(m, 8H), 1.71-</td><td></td>

<td></td><td></td><td></td><td>1.40 (m, 8H)</td><td></td>

<td></td><td>X HN_X „</td><td>FOR</td><td></td><td></td>

<td></td><td>N</td><td>NH and YN</td><td></td><td></td>

<td></td><td>Ck</td><td>Pn PpA</td><td></td><td></td>

<td></td><td></td><td>k TO AP</td><td>ESMS m / z</td><td></td>

<td></td><td></td><td>ν ν γ H '</td><td></td><td> 0.032</td>

<td></td><td></td><td>F</td><td>456.2 (M + H ⁺ )</td><td></td>

<td></td><td colspan="2">5-cl gold-N 2- (4- (1-c¡cloprop i I-</td><td></td><td></td>

<td></td><td colspan="2">pi perid ¡n-4-yl) -2-fluoro-5-methyl-</td><td></td><td></td>

<td></td><td colspan="2">phenyl) -N4- (5-methyl-1 H-pi razol-3-i I) -</td><td></td><td></td>

<td></td><td colspan="2">pyrimidin-2,4-d amine</td><td></td><td></td>

<td></td><td colspan="2"></td><td></td><td></td>

<td></td><td>N</td><td>NH | N</td><td></td><td></td>

<td></td><td></td><td></td><td>ESMS m / z</td><td></td>

<td></td><td>Cl</td><td>xPⁿ PP ^</td><td></td><td> 0.009</td>

<td></td><td></td><td>THE PP Μ Μ And</td><td>440.2 (M + H⁺)</td><td></td>

<td></td><td></td><td>Η I</td><td></td><td></td>

<td></td><td>5-chlorine</td><td>-N2- (4- (1 -eti l-pipe rid i n-4-</td><td></td><td></td>

<td></td><td>L) -2.5-</td><td>di methyl-phenyl) -N4- (5-methyl-</td><td></td><td></td>

250

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθ5θ (ρΜ)</td>

<td></td><td>1H-pyrazol-3-yl) -pyrimidin-2,4- diamine</td><td></td><td></td>

<td></td><td>Ά ν '' -'- Ζ'θζ^ciXn ΛΧΑ L to AA ν nr Η I 5-chloro-N2- (4- (1 - (2-methoxy-ethyl) - piperine-4-yl) -2,5-dimethyl-fe ni I) - N4- (5-methyl-1H-pyrazol-3-yl) - pyrimin-2,4-diamna</td><td>ESMS m / z 470.2 (M + H ⁺ )</td><td> 0.013</td>

<td></td><td>^hnA χζ Xv^{c |}yU_N yAJ oh xX AAy Η I (S) -3- (4- (4- (5-chloro-4- (5-methyl-1 H-) pyrazol-3-yl-amino) -pyrmm-din-2-l- amino) -2-methoxy-5-methyl-phenyl) - pi pe rid i n-1 -il) -1,1,1 -trifluoro- propan-2-ol</td><td>ESMS m / z 540.2 (M + H ⁺ )</td><td> 0.012</td>

251

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICgo (pM)</td>

<td></td><td>Ah γΝ HN Cl_x AND YAyA % AND TO</td><td>ESMS m / z 573.2 (M + H⁺)</td><td> 0.04</td>

<td></td><td>N 2- (4- (1 - (3- (azet¡d¡ n-1 - ¡l-su Ifoni I) -</td><td></td><td></td>

<td></td><td>p rop ¡I) -p ¡perid¡ n-4-¡l) -2,5-d ¡methyl-</td><td></td><td></td>

<td></td><td>phenyl) -5-chloro-N4- (5-methyl-1 H-</td><td></td><td></td>

<td></td><td>p¡razol-3-il) -pyrimid¡n-2,4-diamna</td><td></td><td></td>

<td></td><td>F Η η I f YY ⁿ γ^Ν γ ^nxAND F HN^NC | -A-^N</td><td></td><td></td>

<td></td><td>Anh 5-chloro-N2- (2,5-dimethyl-4-</td><td>ESMS m / z 466.2 (M + H⁺)</td><td> 0.047</td>

<td></td><td>(piperidin-4-yl) -fenif) -N4- (5-</td><td></td><td></td>

<td></td><td>(trifl u oro-meti l) -1 Hp i razol-3-i I) -</td><td></td><td></td>

<td></td><td>pir¡m¡d¡n-2,4-diam¡na</td><td></td><td></td>

252

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ic »(μΜ)</td>

<td></td><td>Η H ^F\ .F / NOW γΝγγΡ &lt;_:HN _{C |}/ _F γ Αν_χ5-chloro-N2- (2-fluoro-4- (1-methyl) p¡perid¡ n-4-il) -5- (trífluoro-met¡l) - fen i I) -N4- (5-met il-1 H-pyrazole -3-i I) - pyrimidin-2,4-diamine</td><td>ESMS m / z 484.2 (M + H ⁺ )</td><td> 0.047</td>

<td></td><td>c Η H f 4fy^N Α and^N Ύί F hn-n_{c |}Jy / N PA ₀nh₂2- (4- (4- (5-chloro-4- (5- (tr¡f luoro- meti l) -1 H-pyrazol-3-yl-amino) - p¡ rim ¡di n-2-l-am¡ no) -2,5-d¡ meditate! l) -p¡ pe rid¡ n-1 -il) -acetam da</td><td>ESMS m / z 523.2 (M + H ⁺ )</td><td> 0.034</td>

<td></td><td>Η H ^F\/F —AA '^N tⁿ and ^N χΑγ^{: hn}'ⁿciP ^ⁿ ΡΡγι 5-cl gold-N4- (5-met¡ 1-1 H-pyrazole-3- il) -N2- (2-m eti 1-4- (1 -meti lp i pe ridin-</td><td>ESMS m / z 480.2 (M + H ⁺ )</td><td> 0.026</td>

253

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC »(μΜ)</td>

<td></td><td>4-¡) -5- (trifluoro-methyl) -phenyl) - p¡ rim id ¡n-2,4-d ¡amina</td><td></td><td></td>

<td></td><td>^h\ X / N NH &lt;N^ειγ ^_Ν yJJ Η I 5-chloro-N2- (5-methoxy-2-methyl-4- (1- methyl-piperidin-4-yl) -phenyl) -N4- (5- methyl-1 H-pyrazol-3-yl) -pyrimidin- 2,4-diamine</td><td>ESMS m / z 442.2 (M + H⁺)</td><td> 0.009</td>

<td></td><td>V^Fand_ HN 'and ¡i NNH ia^ciTOⁿ Xi ° Η I 2- (4- (4- (5-clo ro-4- (5- (tr¡ fluo ro- methyl) -1 H-pyrazol-3-yl-amino) - pyrim¡d¡n-2-il-am¡no) -2,5-dimethyl- faith ni I) -pi pe ri di n-1 -yl) -N-methylacetamide</td><td>ESMS m / z 537.2 (M + H⁺)</td><td> 0.037</td>

254

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoftjM)</td>

<td></td><td>X ^^NH XX F HN Ν, Y Ν '^NGOES Η I N 2- (4- (1 -eti l-pipe rid i n-4-i 1) -2,5- dimeti l-feni l) -N4- (5-meti 1-1 H- p razo I-3-il) -5- (trifl uoro-meti I) - piri mid i n-2,4-di ami na</td><td>ESMS m / z 474.3 (M + H⁺)</td><td> 0.034</td>

<td></td><td>X /^H / χ ^ χ / ΟΗ F HN Ν, YN AA Ν NY Η I 2- (4- (2,5-dimethyl-4- (4- (5-methyl-1 H- pi razo I-3-i l-am i no) -5- (trif luoro- meti l) -pyrimidin-2-¡-amino) -fen¡l) - piperidin-1 -il) -eta η or I</td><td>ESMS m / z 490.2 (M + H⁺)</td><td> 0.038</td>

255

STRUCTURE

NMR or ESMS

IGF-1R

Ba / F3

ICsoípM)

<img file="CU23952B1_D0133.tif" />

<img file="CU23952B1_D0134.tif" />

0.036

- (4- (4- (5-cl gold-4- (5- (trfluorom et i)) -1 H -pyrazol-3-ll-amino) pyrimidin-2-l-amino) - 2,5-d¡met¡lfenil) -p¡perid¡n-1 -¡l) -2- (d¡metüam¡no) -ethanone

ESMS m / z 551.2 (M + H⁺)

<img file="CU23952B1_D0135.tif" />

ESMS m / z

567.3 (M + H⁺)

0.02 am¡no) -2,5-dimethyl-fen¡l) -pi perid i n1 - il) -4-morpholinobutan-1 -one

- (4- (4- (5-Chloro-4- (5-methyl-1 Hpyrazol-3-yl-amine) -pyrimidin-2-l

256

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC »(pM)</td>

<td></td><td>^hX α^ΝΧ Λ^νηΝγΝ HN, // / ΥΥρ, γ-ο Υ / Νγ · /, / Ν, Υ 0 1 - (4- (4- (5-chloro-4- (5-methyl-1 Η- p¡razol-3-¡l-am¡no) -p¡rim¡d¡n-2-¡l- amino) -2,5-dimethyl-phenyl) -piperine- 1 - I) -3-mo rfo I ¡η ο-ρ clothes η-1 -ona</td><td>ESMS m / z 553.3 (M + H⁺)</td><td> 0.017</td>

<td></td><td>HN- / N,_;./ ci γ TO^nhΝγΝ 0 1- (4- (4- (5-Chloro-4- (5-Methyl-1 H- pyrazol-3-l-amine) -p¡r¡midin-2-il- am ¡no) -2,5-d ¡meti l-fen i I) - pi perid ¡n- 1 - ll) -3- (p¡rrol ¡din-1 -il) -pro pan-canvas</td><td>ESMS m / z 537.3 (M + H⁺)</td><td> 0.061</td>

257

STRUCTURE

<img file="CU23952B1_D0136.tif" />

- (4- (4- (5-Chloro-4- (5-Methyl-1 Hprazol-3-yl-amino) -pyramidin-2-lamino) -2,5-d¡met L-phenyl) -p¡per¡d¡n1 - il) -4- (p¡rrol¡d¡n-1 -il) -butan-1-one

<img file="CU23952B1_D0137.tif" />

(R) -3- (4- (4- (5-chloro-4- (5-methyl-1HRMN or ESMS)

ESMS m / z

551.3 (M + H⁺)

ESMS m / z

540.2 (M + H⁺)

IGF-1R Ba / F3 ICso (μΜ)

0.123

0.023 p¡razol-3-¡-l-am¡no) -pir¡m¡din-2-¡lam¡no) -2-metox¡-5-met¡l-phenyl) piper¡din-1 -il) -1,1,1 -trifluoropropan-2-ol

258

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (μΜ)</td>

<td></td><td>\ HNpAxCI AN = &lt;N-_nhHQ \ and HN — 4 I AA F 4 / (2 R) -3- (2- (4- (5-cl or ro-4- (5-m eti I- 1 H-pyrazol-3-yl-amino) -pyrimidin-2- L-amino) -2,5-d-methyl-phenyl) - piperidin-1-yl) -1,1,1 -trif luo ro- propan-2-ol</td><td>ESMS m / z 524.2 (M + H ⁺ )</td><td> 0.211</td>

<td></td><td>&lt;° r ° AH ™ ~ NK_N W Cl — 4 X NH ^x^ N (S) -4- (4- (5-chloro-4- (5-methyl-1 H- pyrazol-3-¡-amino) -p¡r¡m¡din-2-¡l- am¡no) -2,5-d ¡metí l-fen¡ I) - oxazolldin-2-one</td><td>ESMS m / z 414.1 (M + H ⁺ )</td><td> 0.04</td>

259

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC® (μΜ)</td>

<td></td><td>&lt;γ \. · NH ι Ονη do i HN- / l_n w Cl — γ A NH ^X(R) -4- (4- (5-chloro-4- (5-m eti 1-1 H- pirazol-3-il-am¡no) -p¡r¡m¡d¡n-2-¡l- amino) -2,5-di meti l-feni I) - oxazolidin-2-one</td><td>ESMS m / z 414.1 (M + H ⁺ )</td><td> 0.05</td>

<td></td><td>πΡχ χχ Ν NH ι &lt;N -^ckA ΛΛ&gt; l A ÁJ Ν NY^H5-Chloro-N 2- (4- (1-ethyl-piperidin-4- il) -2-fluoro-5-methyl-phenyl) -N4- (5- methyl-1 H-pyrazol-3-yl) -p¡midin- 2,4-diamine</td><td>ESMS m / z 444.2 (M + H⁺); ¹H NMR (DMSO- de) δ 8.01 (s, 1H), 7.35 (m, 1H), 7.02 (d, 1H), 6.22 (s, 1 H), 2.97 (d, 2H), 2.62 (m, 1H), 2.34 (q, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.98 (t,</td><td> 0.020</td>

260

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoftJVI)</td>

<td></td><td></td><td>2H), 1.64 (m, 4H), 1.01 (t, 3H).</td><td></td>

<td></td><td>/ —Ν Ί and ° HN A NH α N H 5-Chloro-N2- (2,5-dimethyl-4- (1- (3- (pyrrolidin-1-yl) -prop¡l-sulfon¡l) - p¡per¡d¡n-4-¡l) -fen¡l) -N4- (5-met¡l- 1 H-pyrazol-3-yl) -pi rim id i n-2,4- diamine</td><td>ESMS m / z 587.3 (M + H ⁺ )</td><td> 0.054</td>

<td></td><td>hnY HO^CW^H J^{n =}&lt;Ax hn — vy— ( (R) -1- (3- (4- (4- (5-chloro-4- (5-methyl-)</td><td>ESMS m / z 603.3 (M + H ⁺ )</td><td> 0.073</td>

261

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ICsoOjM)</td>

<td></td><td>1 Hp¡razol-3-¡-l-am¡no) -p¡r¡m¡d¡n-2- ¡L-am ¡no) -2,5-dimethyl-fen¡ I) - piperine-1-yl-sulfonyl) -propyl) - pi rro I ¡d¡ η-3-ol</td><td></td><td></td>

<td></td><td>N NH i &lt;N yy h ^N fl AT ^FFΝ Ά 'γ^H F 5-chloro-N2- (4- (1 - ((2,2-difluoro- cio propyl) -methyl) -pipe rid ¡n-4-I) -2- fluoro-5-met¡l-fen¡l) -N4- (5-methyl- 1 H-pyrazole-3-¡) -p¡rim¡d¡n-2,4- diamine</td><td>ESMS m / z 506.2 (M + H⁺)</td><td> 0.063</td>

<td></td><td>^H% Y γ- N NH and AN NH₂AYY L and Υγ Ν NY Η I 3- (4- (4- (5-chloro-4- (5-methyl-1 H- pyrazol-3-yl-amino) -p¡r¡m¡d¡n-2-¡l- amno) -2,5-dimethyl-phenyl) -pperidin-</td><td>ESMS m / z 483.2 (M + H⁺)</td><td> 0.059</td>

262

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso &amp; jM)</td>

<td></td><td>1 -il) -propanamide</td><td></td><td></td>

<td></td><td>yH^HNN and yy^Cl \\ /TO^NH^ N N 2- (4- (azet ¡di n-3-¡l) -2,5-d ¡methyl- phenyl) -5-chloro-N4- (5-methyl-1 H- pyrazol-3-yl) -pyrim¡d¡n-2,4-diamna</td><td>ESMS m / z 384.2 (M + H⁺)</td><td> 0.41</td>

<td></td><td>IH ΑγΝχ Ay J n Ak Ifl 1 Cl^HN\ ^ N_S1 NH 0 \ 3- (4- (4- (5-Chloro-4- (5-Methyl-1 H- pyrazol-3-yl-amino) -p¡r¡m¡din-2-¡- am i no) -2,5-d ¡meti l-fen il) -piperidin- 1 -yl) -1 - (pyrrolidin-1 - yl) -propan-1 - ona</td><td>ESMS m / z 537.3 (M + H⁺)</td><td> 0.039</td>

263

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (pM)</td>

<td></td><td>Yy Ν N NH i YN 0 ClA AAJ X ^N \\\ '' n '^' n '^ y Η I 1 - (4- (4- (5-chloro-4- (5-methyl-1 H- pyrazol-3-¡-amino) -p¡r¡mid¡n-2-¡- am i no) -2,5-di metí l-fen¡l) -piperid¡ n- 1 -il) -3- (d ¡metí l-am ino) -propa n-1 - ona</td><td>ESMS m / z 511.3 (M + H⁺)</td><td> 0.073</td>

<td></td><td>TO nA^ci n-nh AA Y n '^ F and HH 5-Chloro-N2- (4- (1-ethyl-p¡per¡d¡n-4- L) -2-fluoro-5- (trifluoro-met¡l) - phenol) -N4- (5-methyl-1 H-pyrazol-3-yl) - pyrimidin-2,4-diamine</td><td>ESMS m / z 498.2 (M + H⁺)</td><td> 0.102</td>

264

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ICjd (mM)</td>

<td></td><td>Τ</td><td></td><td></td>

<td></td><td>Ργγ νΑΥΤνη</td><td></td><td></td>

<td></td><td>F and Η Η</td><td>ESMS m / z</td><td> 0.068</td>

<td></td><td>5-Chloro-N 2- (4- (1-ethyl-piperid i n-4-</td><td>494.2 (M + H ⁺ )</td><td></td>

<td></td><td>il) -2-methyl-5- (trifluoro-methyl) -phenyl) -</td><td></td><td></td>

<td></td><td>N4- (5-methyl-1 H-plrazol-3-ll) -</td><td></td><td></td>

<td></td><td>pyrimine-2,4-diamine</td><td></td><td></td>

<td></td><td>ΐ H APA / AA nTx ||| I Cl</td><td></td><td></td>

<td></td><td>¹ HN_N ' i Ρ^ΝΗO \</td><td>ESMS m / z</td><td> 0.06</td>

<td></td><td>3- (4- (4- (5-cl gold-4- (5-m eti 1-1 H-</td><td>541.3 (M + H ⁺ )</td><td></td>

<td></td><td>p¡razol-3-il-amino) -p¡rim¡din-2-il-</td><td></td><td></td>

<td></td><td>am¡no) -5-fluoro-2-meti l-fen il) -</td><td></td><td></td>

<td></td><td>piperidin-1 -11) -1 - (pyrrolidin-1 - il) -</td><td></td><td></td>

<td></td><td>propan-1 -one</td><td></td><td></td>

265

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoftjM)</td>

<td></td><td>Anh γ-Ν^HX cf ° N2- (4- (1 - (3- (azetidin-1-yl-sulfonyl)) - p ro pi I) -pi peridin-4-il) -2-fl uoro-5- methyl-phenyl) -5-chloro-N4- (5-methyl- 1 H-pyrazol-3-i I) -pi rim id i n-2,4- diamine</td><td>ESMS m / z 577.2 (M + H ⁺ )</td><td> 0.076</td>

<td></td><td>ϊ H CrVi / —Í N _x TO. Ap Fji Ni ^ClHN N, or T nh c 5-c parrot-N2- (2-fluoro-5-met i 1-4- (1 - (3- (pirro lid ¡n-1 -il-sulfon¡l) -propil) - piperine-4-yl) -phenyl) -N4- (5-methyl- 1 H-pyrazol-3-yl) -pyrimin-2,4- diamine</td><td>ESMS m / z 591.2 (M + H⁺)</td><td> 0.084</td>

266

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsofpM)</td>

<td></td><td>Anh / = N HN Cl \ TO F OR or-¹5-Chloro-N2- (2-fluoro-5-methyl-4- (1- (3- (morpholino-sulfonyl) -propyl) - Perid in-4-yl) -phenyl) -N4- (5-methyl) 1 H-pyrazol-3-yl) -pyrimidin-2,4- diamine</td><td>ESMS m / z 607.2 (M + H ⁺ )</td><td> 0.077</td>

<td></td><td>ί H Aryi⁰ IT ^N t^cioO to 4- (4- (4- (5-Chloro-4- (5-methyl-1 H-) pyrazol-3-¡-amino) -pyrimidin-2-¡- amino) -5-fluoro-2-methyl-phenyl) - piperidin-1-il) -1-morpholinobutan-1- ona</td><td>ESMS m / z 571.3 (M + H ⁺ )</td><td> 0.058</td>

267

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICaftjM)</td>

<td></td><td>ΐ Η Αγ^Νγ^Νχ rpr τ ^ClI Τ ΝΗ γ^ΝΗ 0 3- (4- (4- (5-chloro-4- (5-methyl-1 Η- pyrazol-3-yl-amino) -p¡mid¡n-2-yl- amino) -5-fluoro-2-methyl-phenyl) - piperidin-1-yl) -N-cyclopropyl- propanamide</td><td>ESMS m / z 527.2 (M + H ⁺ )</td><td> 0.062</td>

<td></td><td>X^ηνΑ „, υ„ -Λη₂^C'TO ^ n ^ n γ⁷^H í 3- (4- (4- (5-chloro-4- (5-methyl-1 H- p¡razol-3-¡-l-am¡no) -pyrimidin-2-¡- amino) -5-fluoro-2-methyl-phenol) - pi per id ¡n-1 - il) -propa namida</td><td>ESMS m / z 487.2 (M + H ⁺ )</td><td> 0.14</td>

268

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1 R Ba / F3 ICso (pM)</td>

<td></td><td>^h\ X Ν NH ι XN&gt; —7 cAy AAxJ A h 7 íi Γ ^FFand A AA Ν Ν And Η I 5-chloro-N2- (4- (1 - ((2,2-dfluoro- c¡cfoprop¡l) -metH) -p¡per¡d¡n-4-¡l) - 2,5-dimethyl-phenol) -N4- (5-methyl-1 H- p¡razol-3-¡l) -pir¡m¡din-2,4-d¡amina</td><td>ESMS m / z 502.2 (M + H ⁺ )</td><td> 0.032</td>

<td></td><td>^hnA χ- χ Ν NH ι XN^Clyk already Η I 5-Chloro-N2- (4- (1-Cyclopropyl- pperid¡n-4-¡l) -2,5-dimethyl-phenyl) - N4- (5-meti-1 H-pyrazol-3-ϋ) - p¡rim¡d¡n-2,4-d¡amina</td><td>ESMS m / z 452.2 (M + H⁺)</td><td> 0.025</td>

269

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθδο (μΜ)</td>

<td></td><td>TO L, NH F HN An, AnA — 7 NI Ϊ ^FFF X. XX ν ν γ^H F N2- (4- (1 - ((2,2-difluoro- cycloprop¡l) -met¡I) -piperid i n-4-¡I) -2- fluoro-5-methyl-phenol) -N4- (5-methyl- 1 H-pyrazol-3-yl) -5- (trifluoro-methyl) - pyrimidin-2,4-diamine</td><td>ESMS m / z 540.2 (M + H⁺)</td><td> 0.052</td>

<td></td><td>P χ Ν 'ΝΗ XN' '- ^^cip_N A / P \ x AXA ν ν γ H 5-Chloro-N2- (2,5-d¡met¡l-4- (1- (tetrahydro-2H-p¡ran-4-¡l) - p¡ pe rid¡ η-4-il) -phenyl) -N4- (5-met¡ I- 1 H-pyrazol-3-i I) -pi rim ¡di n-2,4- diamine</td><td>ESMS m / z 496.3 (M + H ⁺ )</td><td> 0.014</td>

270

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICsoftjM)</td>

<td></td><td>HN A fP^CI And p AP Ν N⁷'''⁷F and HH 5-chloro-N2- (2-fluoro-4- (piperidin- 4-yl) -5- (trfluoro-methyl) -phenyl) -N4- (5-meti 1-1 H-pi razol-3-il) -p¡ rim idi n- 2,4-diamine</td><td>ESMS m / z 470.1 (M + H ⁺ )</td><td> 0.075</td>

<td></td><td>HN A ; AY pJVp F and HH 5-cl gold-N4- (5-met i 1-1 H-pi razol-3- il) -N2- (2-methyl-4- (piper¡din-4-il) -5- (trifluoro-methyl) -phenyl) -pyrmidium- 2,4-diamine</td><td>ESMS m / z 466.2 (M + H ⁺ )</td><td> 0.07</td>

<td></td><td>P i AA¹ to&gt; to ρ Η H 5-Chloro-N4- (5-cyclopropyl-1 H- pi razol-3-yl) -N 2- (4- (1-prop propipi cycle i-n-4-yl) -2-fluoro-5-methyl-</td><td>ESMS m / z 482.2 (M + H ⁺ )</td><td> 0.228</td>

271

<td></td><td colspan="2">STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 Ιθ® (pM)</td>

<td></td><td colspan="2">fen¡l) -pir¡mid¡n-2,4-d¡am¡na</td><td></td><td></td>

<td></td><td></td><td>/ - NH</td><td></td><td></td>

<td></td><td>^hn'NAⁿ TO ci— / Anh n</td><td></td><td rowspan="2">ESMS m / z 412.2 (M + H⁺)</td><td> 0.044</td>

<td></td><td colspan="2">5-cl gold-N 2- (2,5-d ¡meti 1-4-</td><td></td>

<td></td><td colspan="2">(piperidin-4-¡l) -fen¡l) -N4- (5-met¡l-</td><td></td><td></td>

<td></td><td colspan="2">1H-pyrazol-3-yl) -pyrmidine-2,4-</td><td></td><td></td>

<td></td><td>diamine</td><td></td><td></td><td></td>

<td></td><td>HN ^ A</td><td></td><td></td><td></td>

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

<td></td><td colspan="2">_NH</td><td></td><td></td>

<td></td><td colspan="2">^h,ⁿNo</td><td></td><td></td>

<td></td><td>Vk kk</td><td>to</td><td>ESMS m / z</td><td></td>

<td></td><td>N H</td><td></td><td></td><td> 0.064</td>

<td></td><td>F-</td><td>-F</td><td rowspan="2">446.2 (M + H ⁺ )</td><td></td>

<td></td><td colspan="2">F</td><td></td>

<td></td><td colspan="2">N2- (2,5-dimethyl-4- (pipe ri din-4-i I) -</td><td></td><td></td>

<td></td><td colspan="2">phenyl) -N4- (5-methyl-1 H-pi razol-3-i I) -</td><td></td><td></td>

<td></td><td colspan="2">5- (trfluoro-methyl) -pyrimidin-2,4-</td><td></td><td></td>

<td></td><td>dlamine</td><td></td><td></td><td></td>

272

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICgoftjM)</td>

<td></td><td>AND Ν η i ΧΑΥ A^CI τΆ I Η H 5-cl gold-N4- (5-c¡clop rop 1-1 H- p¡razol-3-ll) -N2- (4- (1 -cyclop rop ¡I- p ¡perid¡ n-4-il) -2,5-d ¡met i l-fe ni I) - pimirin-2,4-damine</td><td>ESMS m / z 478.2 (M + H⁺)</td><td> 0.026</td>

<td></td><td>to^hnA „, ργ /^cl'zY and^h ΐ 5-chloro-N2- (2-fluoro-4- (1 - ((3- isopropyl-1,2,4-oxadolzol-5-yl) - methyl) -p¡ perid ¡n-4-il) -5-met¡l-phenyl) - N4- (5-met¡l-1 H-pi razol-3-i I) - pyrimidin-2,4-diamine</td><td>ESMS m / z 540.2 (M + H⁺)</td><td> 0.064</td>

<td></td><td>^HNb- -χ / N / Ν NH ι Κ Ν γ \ ( An AfY ​​° Χ GOES/ H</td><td>ESMS m / z 536.3 (M + H ⁺ )</td><td> 0.018</td>

273

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICjo (pM)</td>

<td></td><td>5-chloro-N2- (4- (1 - ((3-isopropyl- 1,2,4-oxadiazol-5-yl) -methyl) - p¡per¡d¡n-4-yl) -2,5-dimethyl-phenyl) - N4- (5-met¡l-1 Hp¡ razol-3-¡I) - p¡r¡m¡din-2,4-d¡am¡na</td><td></td><td></td>

<td></td><td>And Z Ν NH &lt;Ν γ^ciXn yyA ⁰N ^ nAX Η I 2- (4- (4- (5-chloro-4- (5-methyl-1H-) p¡razol-3-¡l-am¡no) -p¡r¡m¡d¡n-2-il- amino) -2-ethyl-5-met¡ l-fen¡ I) - pi pe rid ¡n-1 -il) -acetam¡da</td><td>ESMS m / z 483.2 (M + H ⁺ )</td><td> 0.027</td>

<td></td><td>Y- Y^NHtwo Ν NH Y Ν γ ^¿Χν yJJ o HI 2- (4- (4- (5-chloro-4- (5-m eti 1-1 H- pyrazol-3-yl-amino) -pyrimidin-2-yl- am i no) -2-methoxy-5-meti l-phenyl) -</td><td>ESMS m / z 485.2 (M + H ⁺ )</td><td> 0.019</td>

274

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 IC® (μΜ)</td>

<td></td><td>piperidin-1-yl) -acetic acid</td><td></td><td></td>

<td></td><td>PP, and_Nand f^NH2^ciPn APP ⁰L to PA Ν Ν T^H F 2- (4- (4- (5-chloro-4- (5-ethyl-1 H-) pyrazol-3-yl-amine) -pyrimidin-2-yl- amino) -5-fluoro-2-methyl-phenyl) - piperidin-1-¡) -acetam¡da</td><td>ESMS m / z 487.2 (M + H ⁺ )</td><td> 0.033</td>

<td></td><td>IH rf^NT^N'il / \ AP NxA iii Y ^Cl° AA^NH° A 5-c parrot-N2- {4- [1 - (1,1-dioxo-1 Λ6- tietan-3-¡) -p¡per¡din-4-¡l] -2-fluoro- 5-m eti l-fe ni I} -N4- (5-et¡ I-1 H- pyrazol-3-¡l) -p¡r¡m¡din-2,4-diam¡na</td><td>ESMS m / z 534.2 (M + H ⁺ )</td><td> 0.021</td>

275

<td></td><td>STRUCTURE</td><td>NMR or ESMS</td><td>IGF-1R Ba / F3 ICso (pM)</td>

<td></td><td></td><td>ESMS m / z</td><td></td>

<td></td><td></td><td>554.2 (M + H⁺);</td><td></td>

<td></td><td></td><td>¹H NMR (400</td><td></td>

<td></td><td></td><td>MHz, CDCI₃) δ</td><td></td>

<td></td><td>z</td><td>9.67 (br s, 2H),</td><td></td>

<td></td><td>hnY c, V TO^NHN &lt;._ZN</td><td>8.50 (s, 1 H), 8.07 (s, 1H), 7.57 (d, J = 8.4</td><td></td>

<td></td><td>^HNYV and</td><td>Hz, 1 H), 7.05</td><td></td>

<td></td><td>N'Y</td><td>(d, J = 12.4 Hz,</td><td></td>

<td></td><td>Ci_rv</td><td>1H), 6.16 (s,</td><td> 0.091</td>

<td></td><td> 0</td><td>1H), 5.53 (s,</td><td></td>

<td></td><td>(4- (4- (5-Chloro-4- (5-Methyl-1 H-</td><td>1H), 3.98 (d, J =</td><td></td>

<td></td><td>pirazol-3-il-am¡no) -p¡r¡m¡d¡n-2-¡l-</td><td>13.2 Hz, 1H),</td><td></td>

<td></td><td>amino) -5-fluoro-2-methyl-phenol) -</td><td>3.34 (dt, J =</td><td></td>

<td></td><td>pperidin-1-yl) - (3-isopropyl-1,2,4-</td><td>2.0, 2.8 Hz,</td><td></td>

<td></td><td>oxad¡azol-5-¡l) -methanone</td><td>1H), 3.15 (m,</td><td></td>

<td></td><td></td><td>1H), 2.82 (m,</td><td></td>

<td></td><td></td><td>2H), 2.62 (t, J =</td><td></td>

<td></td><td></td><td>4.8 Hz, 2H),</td><td></td>

<td></td><td></td><td>2.34 (s, 3H),</td><td></td>

276

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICgp (pM)</td>

<td></td><td></td><td>2.25 9s, 3H), 1.90 (m, 2H), 1.76 (2 H)</td><td></td>

<td></td><td>A HN, λ Ni NH ι X Ν^ci&gt;A Λ/x ^NX Ay-V V Η I N2-(4-(1 -((5-terbutil-1,2,4- oxadiazol-3-¡l)-met¡l)-p¡per¡d¡n-4- I I)-2,5-d i m et i I-f e n ¡ I)-5-c I o ro-N 4-(5- meti 1-1 H-p¡ razo l-3-¡l)-p¡r¡ midin- 2,4-diamina</td><td>ESMS m/z 550.3 (M + H ⁺ )</td><td> 0.025</td>

<td></td><td>A HN, J _ _Λn^nh i ΑνΆ^Ν'ο ci/X AÁA ny Váya V ν ν γ ^x^H F N2-(4-(1 -((5-terbut¡l-1,2,4- oxad ¡azo I-3-¡ l)-m etil )-p¡ pe ridi n-4- ¡ l)-2-fluoro-5-met¡ l-fen ¡l)-5-cloro- N4-(5-met¡l-1 H - p ¡ razo I - 3-¡ I) -</td><td>ESMS m/z 554.3 (M + H ⁺ )</td><td> 0.077</td>

277

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICsoftjM)</td>

<td></td><td>p¡r¡m¡din-2,4-d¡amina</td><td></td><td></td>

<td></td><td>Ν NH I N^^cY AY ν ν γ^H F 5-cl oro-N4-(5-et¡ 1-1 H-pi razol-3-il)- N2-(4-(1-etil-p¡per¡d¡n-4-il)-2- fluoro-5-metil-fen¡l)-p¡r¡mid¡n-2,4- diamina</td><td>ESMS m/z 458.2 (M + H ⁺ )</td><td> 0.022</td>

<td></td><td>I H nVC \ I i I ^Cl,Ο^χ,./ΝΡ ' HN N, Ν // T NH A 4 5-cloro-N 2-(4-( 1 -(2-(3-¡sop ropi I- 1,2,4-oxadiazol-5-il)-etil)- piperidin-4-il)-2,5-dimetil-fenil)- N4-(5-met i 1-1 H-pirazol-3-il)- p¡ rimidin-2,4-diamina</td><td>ESMS m/z 550.3 (M + H⁺)</td><td> 0.039</td>

278

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1 R Ba/F3 ICg)(pM)</td>

<td></td><td>hnP nA ci γ Ar ΙΜγΝ χ p AVy o (4-(4-(5-cloro-4-(5-met¡l-1 H- p¡razol-3-¡l-am¡no)-pirim¡d¡n-2-¡l- amino)-2,5-d¡met¡l-fenil)-piperidin- 1 - il)-(3-isopropil-1,2,4-oxadiazol- 5-¡l)-metanona</td><td>ESMS m/z 550.2 (M + H ⁺ )</td><td> 0.018</td>

<td></td><td>wxX Ν NH i y'N^clFpx |A^X/Jl a IF Ν N Y^H F 5-cloro-N4-(5-et¡l-1H-p¡razol-3-¡l)- N2-(2-fluoro-5-met¡l-4-(1 -metilpiperid ¡n-4-¡l)-fenil )-p¡ rim id ¡n-2,4- diamina</td><td>ESMS m/z 444.2 (M + H ⁺ )</td><td> 0.013</td>

279

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1 R Ba/F3 ICso (pM)</td>

<td></td><td>^h\X Y Ν NH ι X N A y l a yy ν ν γ^H F 5-cloro-N2-(4-(1-c¡clobut¡l- piper¡din-4-¡l)-2-fluoro-5-met¡l- fen¡l)-N4-(5-met¡l-1 H-p¡razol-3-¡l)- p¡rim¡d¡n-2,4-d¡am¡na</td><td>ESMS m/z 470.2 (M + H⁺)</td><td> 0.050</td>

<td></td><td>yNH yynh A HN'f, &lt;l_n y Cl—δ /)—NH F 5-cloro-N2-(2-fluoro-5-met¡l-4-(2- metil-piper¡d¡n-4-¡l)-fen¡l)-N4-(5- m eti 1-1 H-p¡razol-3-il)-p¡r¡m¡din- 2,4-diamina</td><td>ESMS m/z 430.2 (M + H⁺)</td><td> 0.018</td>

280

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICsoftjM)</td>

<td></td><td>vf NH i Y NAf^NH2^clyP_N 0 Ν N Y^H F</td><td>ESMS m/z 487.2 (M + H⁺)</td><td> 0.006</td>

<td></td><td>2-(4-(4-(5-cloro-4-(5-meti 1-1 H-</td><td></td><td></td>

<td></td><td>pirazol-3-il-amino)-pirimidin-2-il-</td><td></td><td></td>

<td></td><td>amino)-5-fluoro-2-meti l-feni l)-2-</td><td></td><td></td>

<td colspan="2">me ti l-pi pe rid i n-1 -il)-acetamida</td><td></td><td></td>

<td></td><td>/ /— N</td><td></td><td></td>

<td></td><td>^axnh XX Hp v pp Cl—d ))—NH F ^-N</td><td>ESMS m/z 444.2 (M + H⁺)</td><td> 0.009</td>

<td></td><td>5-cloro-N2-(4-(1,2-d i m eti I-</td><td></td><td></td>

<td></td><td>piperid i n-4-il)-2-fluoro-5-metil-</td><td></td><td></td>

<td></td><td>fenil)-N4-(5-met¡l-1H-pirazol-3-il)-</td><td></td><td></td>

<td></td><td>pirim¡din-2,4-diamina</td><td></td><td></td>

281

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICso(pM)</td>

<td></td><td>Yi V^NHHN, Λ 1 j N NH i A n^cY Y\YV A| ^N í|^H F N 2-(4-(1,4'-bipiperidin-4-il)-2- fluoro-5-metil-fenil)-5-cloro-N4-(5- metil-1 H-p¡ razol-3-i l)-p¡ rim idi n- 2,4-diamina</td><td>ESMS m/z 499.2 (M + H⁺)</td><td> 0.437</td>

<td></td><td>H ,N_X x A¹ AA \ N NH n=n /—\ Αγ An F 5-cloro-N2-(2-fluoro-5-metil-4-(1 - (6-met ¡ l-pi r¡ dazi n-3-i I )-piperid i n-4- ¡l)-fenil)-N4-(5-metil-1 H-pirazol-3- ¡l)-pirimidin-2,4-diamina</td><td>ESMS m/z 508.2 (M + H ⁺ )</td><td> 0.097</td>

282

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICsoftjM)</td>

<td></td><td>γ—Ν Cl—Ύ A^{NH F}ηνΛ /⁼ⁿ P L Onh c X X- N O, a° 0 \ 5-cloro-N2-(2-fluoro-5-met¡l-4-(1'- (metí l-su Ifon ¡l)-1,4'-biplper¡d¡n-4- il)-fenil)-N4-(5-met¡l-1 H-p¡razol-3- ¡l)-p¡r¡m¡din-2,4-d¡am¡na</td><td>ESMS m/z 577.2 (M + H⁺)</td><td> 0.009</td>

<td></td><td>Η H^N γ^Ν χγ ^N χγΥ/^hnⁿci^/A^{n nh}Η Χ---γ 5-cloro-N2-(2-fluoro-5-met¡l-4- ((trans)-2-met¡l-plper¡din-4-il)- fen¡l)-N4-(5-met¡l-1H-p¡razol-3-il)- p¡r¡m¡d¡n-2,4-diamina</td><td>ESMS m/z 430.2 (M + H⁺)</td><td> 0.064</td>

<td></td><td>Η H y/Vz^Ny^Ny/ HN^Nc|Py-N ρΡχΡχΑ^^NH</td><td>ESMS m/z 430.2 (M + H⁺)</td><td> 0.163</td>

283

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 IC50 (μΜ)</td>

<td></td><td>5-cloro-N2~(2-fluoro-5-met¡l-4-</td><td></td><td></td>

<td></td><td>((c¡s)-2-m eti l-p ¡ perid in-4-¡l)-fen¡l)-</td><td></td><td></td>

<td></td><td>N4-(5-met¡l-1 H-pi razoI-3-¡I)-</td><td></td><td></td>

<td></td><td>pir¡mid¡n-2,4-d¡amina</td><td></td><td></td>

<td></td><td>^HN^X Y- Y/\</td><td></td><td></td>

<td></td><td>N 'NH i</td><td></td><td></td>

<td></td><td>^c,/A_n ΥΛΥ A</td><td></td><td></td>

<td></td><td>Νγ H '</td><td>ESMS m/z</td><td> 0.087</td>

<td></td><td>F</td><td>507.2 (M + H ⁺ )</td><td></td>

<td></td><td>5-cl oro-N2-(2-fluoro-5-metí 1-4-(1 -</td><td></td><td></td>

<td></td><td>(p ¡ridi n-2-i l-meti l)-p¡ perid ¡ n-4-¡ I)-</td><td></td><td></td>

<td></td><td>fenll)-N4-(5-met¡l-1 H-pi razol-3-i I)-</td><td></td><td></td>

<td></td><td>pirim¡d¡n-2,4-d ¡amina</td><td></td><td></td>

<td></td><td> \ /</td><td>ESMS m/z</td><td></td>

<td></td><td>^HNOb . jo</td><td>496.2 (M + H⁺);</td><td></td>

<td></td><td>N 'NH i kX CI\Á XXyV ll ν k γ ·^</td><td>¹H RMN (400</td><td></td>

<td></td><td rowspan="2">'fi hi γ^H ¿</td><td>MHz, DMSO-d₆)</td><td> 0.048</td>

<td></td><td>δ 9.97 (br s,</td><td></td>

<td></td><td>3-(4-(4-(5-cloro-4-(5-met¡l-1 H-</td><td>1 H), 9.83 (br s,</td><td></td>

<td></td><td>p¡razol-3-¡l-am¡no)-pir¡m¡din-2-¡l-</td><td>1H), 8.90 (s,</td><td></td>

<td></td><td>am¡no)-5-fluoro-2-met¡ l-fen ¡I)-</td><td>1H), 8.32 (d, J =</td><td></td>

284

<img file="CU23952B1_D0138.tif" />

285

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICso(pM)</td>

<td></td><td>decan-8-il)-p¡peridin-4-il)-2-fluoro- 5-met¡ l-fen ¡ l)-5-cloro-N4-( 5-met ¡I- 1 H-pirazol-3-¡l)-p¡rimid¡n-2,4- diamina</td><td></td><td></td>

<td></td><td>X HN_X J _ .. nXh i y nA\_^CI^A_N °'^n/N nA^H ΐ 5-cloro-N2-(4-(1-((3-etil-1,2,4- oxad¡azol-5-¡l)-met¡l)-piper¡d¡n-4- ¡l)-2-fluoro-5-met¡ l-fen il)-N4-(5- met¡l-1 H-p¡ razol-3-¡l)-p¡ rim ¡di n- 2,4-diamina</td><td>ESMS m/z 526.2 (M + H⁺)</td><td> 0.033</td>

<td></td><td>ΗΙψ 3 zz zz M N NH i YnA^N'_o^cA yyY γ ν ν γ^H F 5-cloro-N2-(2-fluoro-4-(1 -((5- isopropil-1,2,4-oxadiazol-3-il)- m eti I)-p i pe rid i η-4-i I)-5-metí l-fe n i I)-</td><td>ESMS m/z 540.2 (M + H ⁺ )</td><td> 0.068</td>

286

ESTRUCTURA

RMN o ESMS

IGF-1R

Ba/F3

ICso(pM)

N4-(5-metil-1 H-pirazol-3-il)p¡ rim ¡di n-2,4-d ¡amina

<img file="CU23952B1_D0139.tif" />

5-(5-cloro-4-(5-metil-1 H-pirazol-3¡l-amino)-p¡rimidin-2-il-amino)-4ESMS m/z

437.2 (M + l-f

0.037 meti 1-2-(1 -me ti I-piperidin-4-i I)benzonitrilo

<img file="CU23952B1_D0140.tif" />

ESMS m/z

470.2 (M + H

0.027 m eti 1-2-(1 - met i l-p i per id i n-4-i I )benzoato de metilo il-amino)-pirimidin-2-il-amino)-4287

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ΙθβοφΜ)</td>

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

<td></td><td>n 'nh i p fil</td><td></td><td></td>

<td></td><td>^cixA ApY Y</td><td></td><td></td>

<td></td><td></td><td>ESMS m/z</td><td></td>

<td></td><td>N N Y H '</td><td></td><td> 0.093</td>

<td></td><td>F</td><td>507.2 (M + H⁺)</td><td></td>

<td></td><td>5-cloro-N 2-(2-fluoro-5-metí 1-4-(1 -</td><td></td><td></td>

<td></td><td>(pi rid i n-4-¡ l-meti l)-piperidin-4-¡l)-</td><td></td><td></td>

<td></td><td>fen¡l)-N4-(5-met¡l-1 H-pirazol-3-il)-</td><td></td><td></td>

<td></td><td>p¡rimid¡n-2,4-d¡amina</td><td></td><td></td>

<td></td><td></td><td>ESMS m/z</td><td></td>

<td></td><td></td><td>460.2 (M + H⁺);</td><td></td>

<td></td><td>Ai</td><td>¹H RMN (MeOD-</td><td></td>

<td></td><td>hn_x A 7</td><td></td><td></td>

<td></td><td>Ν NH I γΆ⁺-ο-</td><td>d₄) δ 7.91 (s,</td><td></td>

<td></td><td>^cipN ΑγΧ</td><td>1 H), 7.69 (d,</td><td></td>

<td></td><td>Ν N Y^H F</td><td>1H), 7.00 (d,</td><td> 0.37</td>

<td></td><td>1-óxido de 4-(4-(5-cloro-4-(5-</td><td>1H), 6.15 (s,</td><td></td>

<td></td><td>metii-1 H-pirazol-3-il-amino)-</td><td>1H), 3.28 (m,</td><td></td>

<td></td><td>p¡r¡mid¡n-2-¡l-am¡no)-5-fluoro-2-</td><td>4H), 2.91 (m,</td><td></td>

<td></td><td>metí l-fen ¡l)-1 -eti I-pipe rid i na</td><td>1H), 2.32 (m,</td><td></td>

<td></td><td></td><td>2H), 2.20 (s,</td><td></td>

<td></td><td></td><td>3H), 2.16 (s,</td><td></td>

288

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICsoftjM)</td>

<td></td><td></td><td>3H), 1.83 (s, 2H), 1.64 (d, 2H), 1.31 (t, 3H).</td><td></td>

<td></td><td>i ^HÁfY /xA·? N&lt;Y\ ι T T i ^Cl/x./nP ¹ hn n, „J3 4-(4-(4-(5-cloro-4-(5-met¡l-1 H- p¡razol-3-il-amino)-p¡r¡mid¡n-2-il- amino)-5-fluoro-2-metil-fenil)- p i pe rid i n-1 -il)-ciclohexanona</td><td>ESMS m/z 512.2 (M + H ⁺ )</td><td> 0.023</td>

<td></td><td>i H /XA./ na, ί I I γ ci o /V/N,/ ' HNz^N I Λ~Ν I T NH Y ^J f 3-(4-(4-(5-cloro-4-(5-metil-1 H- pirazol-3-il-amino)-pirimidin-2-il- a mi no)-5-fluoro-2-met¡ l-fen ¡I)- piperidín-1-il)-pirrolidin-1-</td><td>ESMS m/z 585.3 (M + H⁺)</td><td> 0.067</td>

289

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1 R Ba/F3 ICg)(pM)</td>

<td></td><td>earboxilato de terbutilo</td><td></td><td></td>

<td></td><td>s HN' J nnh i Α^ν/^ά₀γγ y Άν Ay^H F 5-cloro-N2-(2-fluoro-5-metil-4-(1 - ((5-meti 1-1,2,4-oxadiazol-3-il)- metil)-piperid¡n-4-¡l)-fen¡l)-N4-(5- metil-1 H-pirazol-3-il)-pirimidin- 2,4-diamina</td><td>ESMS m/z 512.2 (M + H ⁺ )</td><td> 0.023</td>

<td></td><td>Α , ρ-γΛ ^caA_n^o'^n/l a yy ν ν γ^H F 5-cloro-N2-(2-fluoro-5-metil-4-(1 - ((3-metil-1,2,4-oxadiazol-5-il)- m eti I)-pi pe ri d i n-4-¡ I )-fen i I)-N4-(5- metil-1 H-pirazol-3-il)-pirimidin- 2,4-diamina</td><td>ESMS m/z 512.2 (M + H ⁺ )</td><td> 0.026</td>

290

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1 R Ba/F3 ιθδοίμΜ)</td>

<td></td><td>Ό Y^X 0 r-N⁺\y^^hn'n l=n V\ ci—y /A^{nh f}N 1-óxido de 4-(4-(5-cloro-4-(5- m eti 1-1 H-p¡razol-3-¡l-amino)- p¡r¡m¡din-2-¡l-amino)-5-fluoro-2- meti l-fen i l)-1 -(tetra hid ro-2H-p¡ran- 4-¡ I)-p i pe rid i na</td><td>ESMS m/z 516.2 (M + H⁺)</td><td> 0.064</td>

<td></td><td>Y \ Ynh y /&gt; hn ν y_nCl· A /)—NH F ^N 5-cl oro-N2-{4-[1-(1,1 -d¡oxo-1 Λ6- tietan-3-il)-1 -óxido-piperidin-4-il]- 2-fluoro-5-met ¡l-fe ni l}-N4-(5-etil- 1 H-pirazol-3-il)-pir¡midin-2,4- diamina</td><td>ESMS m/z 536.2 (M + H ⁺ )</td><td> 0.039</td>

291

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICso(pM)</td>

<td></td><td>^HNX // Y^NHΝ NH i k N ci\A XX\V k ^N X^H F N 2-(4-(1 -(azetidin-3-il)-piperidin- 4-il)-2-fluoro-5-met¡l-fen¡l)-5-cloro- N 4-(5-m eti 1-1 H-p¡ razol-3-¡Ο- ρ ¡rim id ¡n-2,4-d ¡amina</td><td>ESMS m/z 471.2 (M + H⁺)</td><td> 0.101</td>

<td></td><td>A HN, J N'nh i k^ Vi ν fX^A/ X ' A X XX Ν Ν T^H F 5-cl oro-N2-(2-fluoro-5-meti 1-4-(1 - (piridi n-3-i l-metil )-p i per id i η-4-il)- fen¡l)-N4-(5-metil-1 H-pirazol-3-il)- pirimidin-2,4-d ¡amina</td><td>ESMS m/z 507.2 (M + H ⁺ )</td><td> 0.079</td>

292

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>-! IGF-1 R Ba/F3 ICsoftjM)</td>

<td></td><td>ϊ ^HPi ζχΑζ nA ι ι ι ι ^Clζν^ΝΧ ^ΗΝΥ&lt; HoT Ff 4-(4-(4-(5-cloro-4-( 5-metil -1 H- p¡razol-3-¡l-amino)-pir¡mid¡n-2-il- am¡no)-5-fluoro-2-metil-fenil)- piperidin-1-il)-ciclohexanol</td><td>ESMS m/z 514.2 (M + H⁺)</td><td> 0.026</td>

<td></td><td>HN' 3 f NH ν^Λνη i p^/x/^CI'^XJ^'N 'N Yp^H F 5-cloro-N2-(2-fluoro-5-metil-4-(1- (pirrolidin-3-¡l)-piperid¡n-4-il)- fen¡l)-N4-(5-metll-1 H-plrazol-3-il)- pirim ¡di n-2,4-d ¡amina</td><td>ESMS m/z 485.2 (M + H ⁺ )</td><td> 0.101</td>

293

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 IC» (pM)</td>

<td></td><td>λ—ν ci—X A^nh / hnA P PC ij—NH \ / X-N A οΛ 5-cl oro-N2-(2-fluoro-5-met¡ 1-4-(1 - (1 -(metil-sulfonil)-azetidin-3-il)- p¡ perid ¡ η-4-U )-fen ¡ l)-N4-(5-met¡ I- 1 H-p¡razol-3-¡l)-pirimid¡n-2,4- diamina</td><td>ESMS m/z 549.2 (M + H ⁺ )</td><td> 0.032</td>

<td></td><td>. H^c\ HN—/Y v _/yN n-J _z^NH/A O N 5-cloro-N2-(2-fluoro-5-metll-4-(1- (1 -(metí l-su Ifon i l)-p¡ rro lid i n-3-i i)-</td><td>ESMS m/z 563.2 (M + H⁺)</td><td> 0.038</td>

294

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICso (pM)</td>

<td></td><td>piperidin-4-il)-fenil)-N4-(5-metil- 1 H-p¡ razol-3-¡l)-p¡ rim ¡di n-2,4- diamina</td><td></td><td></td>

<td></td><td>X nAh i γ^-^C'xAn AA^ °~^NL x AY Ν N r Η I 5-cloro-N2-(2,5-d i metil-4-( 1-((3- m eti 1-1,2,4-oxadiazol-5-il)-metil)- p¡ perid i η-4-i I )-fen i I)- N4-(5-met¡ I- 1 H-pirazol-3-il)-pirimid¡n-2,4- diamina</td><td>ESMS m/z 508.2 (M + H⁺)</td><td> 0.006</td>

<td></td><td>HN, 3 ZZ ZZ M N NH i Y N XA__^CYn ΧγΉΗ °'N XAX Η I 5-cloro-N2-(4-(1-((3-etil-1,2,4- oxadiazol-5-il)-metil)-piperidin-4- il)-2,5-dimetil-fenil)-N4-(5-metil- 1 H-pirazol-3-il)-pirimidin-2,4- d i a m i n a</td><td>ESMS m/z 522.2 (M + H ⁺ )</td><td> 0.006</td>

295

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICsoftjM)</td>

<td></td><td>Ρ HN, Λ _ n^nh i A ^Ν Υ^Νο^ciP_N AJP P VA H | 5-cl o ro-N2-(2,5-d ¡meti 1-4-(1 -((5- metil-1,2,4-oxadiazol-3-il)-metil)- piperidin-4-il)-fenil)-N4-(5-metil- 1 Η - p ¡ razo I-3-i I )-p i rim id i n-2,4- diamina</td><td>ESMS m/z 508.2 (M + H⁺)</td><td> 0.005</td>

<td></td><td>P HN, A N^NH i A^Cl yⁿ γα ν yVy / Η I 5-clo ro-N 2-(4-(1 -((5-isopropí I- 1,2,4-oxadiazol-3-¡l)-metil)- piperidin-4-il)-2,5-dimet ¡l-fe nil)- N4-(5-metil-1 H-pirazol-3-il)- p¡ rimid i n-2,4-d ¡amina</td><td>ESMS m/z 536.3 (M + H ⁺ )</td><td> 0.025</td>

296

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1 R Ba/F3 ic® (μΜ)</td>

<td></td><td>X v. y° Ν NH i k N ckÁ AXJ ¡¡ ν k^H5-cloro-N2-(2-fluoro-5-met¡ 1-4-(1 - (oxetan-3-i l)-p¡ perid i n-4-il)-fen i ΟΝ 4-( 5-m eti 1-1 H-pi razo l-3-i 0- ρ ¡rim id ¡n-2,4-d ¡amina</td><td>ESMS m/z 472.2 (M + H⁺)</td><td> 0.015</td>

<td></td><td>^HVAh | Yn-Y¡] cia_n ajy y Η I 5-clo ro-N 2-(2,5-d i meti 1-4-(1 - (p¡ridin-2-il-metiI)-piperidin-4-il)- fenil)-N4-(5-metil-1 H-pirazol-3-il)- pirimidin-2,4-d ¡amina</td><td>ESMS m/z 503.2 (M + H ⁺ )</td><td> 0.007</td>

297

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1 R Ba/F3 ic» (pivi)</td>

<td></td><td>^HAnh , ΥΎ) “A JyY V Any Η | 5-cl oro-N2-( 2,5-d ¡metí 1-4-(1 - (p¡ rid ¡η-3-i l-metil )-p¡per¡d¡n-4-¡ rifen i l)-N4-(5-met¡l-1 H-pi razo l-3-il)- p¡r¡m¡din-2,4-d¡am¡na</td><td>ESMS m/z 503.2 (M + H⁺)</td><td> 0.006</td>

<td></td><td>^HNAnh | Ay ^εΆ Y^NΗ I 5-cloro-N2-(2,5-dimetil-4-(1- (p¡r¡d¡n-4-¡l-met¡l)-piper¡d¡n-4-¡l)- fe nil)-N4-(5-met¡ 1-1 H-pi razol-3-il)- pi rim ¡di n-2,4-d ¡amina</td><td>ESMS m/z 503.2 (M + H⁺)</td><td> 0.008</td>

<td></td><td>-γτΎΥϊΎ H ^x-- T rans-4-(4-(4-(5-cloro-4-(5-metil-</td><td>ESMS m/z 514.2 (M + H⁺)</td><td> 0.027</td>

298

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICsoÜJM)</td>

<td></td><td>1 H-pirazol-3-il-am¡no)-pirimid¡n-2- ¡ l-am ino)-5-fluoro-2-meti l-fen ¡I)- p ¡pe rid i n-1 - il)-c¡clohexanol</td><td></td><td></td>

<td></td><td>Η H^Np 7 OH H Cis-4-(4-(4-(5-cloro-4-(5-metil-1 H- p ¡razo I-3-i l-am ¡no)-piri mid ¡n-2-¡I- amino)-5-fluoro-2-metil-fen¡l)- p¡ pe rid ¡n-1 - il)-c¡clohexanol</td><td>ESMS m/z 514.2 (M + H ⁺ )</td><td> 0.021</td>

<td></td><td>F rprVL Υ-Ύ Ηϊ&gt; X (R)-5-cloro-N2-(2-fluoro-5-metil-4- (1 - (1 - (metil-sulfonil)-p¡rrol¡d¡n-3- ¡l)-piperidin-4-¡l)-fen¡l)-N4-(5- metil-1 H-pi razol-3-¡l)-p¡r¡ mid ¡n- 2,4-diamina</td><td>ESMS m/z 563.2 (Μ + H + )</td><td> 0.025</td>

299

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICsoÜJM)</td>

<td></td><td>F 2 H Γ V^NYY M vk-X/ YY Yojx ' ^CY Ao</td><td></td><td></td>

<td></td><td>(S)-5-cloro-N2-(2-fluoro-5-metil-4- (1 -(1 -(metí l-su Ifon i l)-pirrolidin-3-</td><td>ESMS m/z 563.2 (M + H ⁺ )</td><td> 0.030</td>

<td></td><td>il)-piperidin-4-il)-fenil)-N4-(5-</td><td></td><td></td>

<td></td><td>met ¡1-1 H-pi razol-3-i l)-pirim¡din-</td><td></td><td></td>

<td></td><td>2,4-diamína</td><td></td><td></td>

<td></td><td></td><td>ESMS m/z</td><td></td>

<td></td><td></td><td>508.2 (M + H⁺);</td><td></td>

<td></td><td>A</td><td>¹H RMN (400</td><td></td>

<td></td><td>HN, A n nh i ArAV'N ciYk AY U / Al Ν Ζ n Ν ή'Υ^H F</td><td>MHz, CD₃OD) δ 9.09 (s, 1H), 8.81 (s, 2H),</td><td> 0.037</td>

<td></td><td>5-cloro-N2-(2-fluoro-5-met¡ 1-4-(1 -</td><td>8.00 (s, 1H),</td><td></td>

<td></td><td>(pirim¡din-5-il-metil)-p¡peridin-4-</td><td>7.73 (d, J = 8.4</td><td></td>

<td></td><td>¡l)-fen¡l)-N4-(5-metil-1H-pirazol-3-</td><td>Hz, 1H), 6.99</td><td></td>

<td></td><td>¡l)-pirimid¡n-2,4-diam¡na</td><td>(d, J = 13.2 Hz,</td><td></td>

<td></td><td></td><td>1 H), 6.23 (br s,</td><td></td>

<td></td><td></td><td>1H), 3.65 (s,</td><td></td>

300

ESTRUCTURA

RMN o ESMS

IGF-1R

Ba/F3

ICsoftjM)

<img file="CU23952B1_D0141.tif" />

5-cl oro-N2-(2-fluoro-5-met¡ 1-4-(1 (pirazin-2-il-metil)-p¡ perid ¡n-4 -iljfen ¡l)-N4-(5-met¡ 1-1 H-pirazol-3-il)p i r im id i n-2,4-d ¡amina

<img file="CU23952B1_D0142.tif" />

<td>2H),</td><td> 3.03</td><td>(m,</td>

<td>2H),</td><td> 2.76</td><td>(m,</td>

<td>1H),</td><td> 2.27</td><td>(s,</td>

<td>3H),</td><td> 2.25</td><td>(s,</td>

<td>3H),</td><td> 2.25</td><td>(m,</td>

<td>2H),</td><td> 1.80-</td><td> 1.68</td>

(m, 4H)

ESMS m/z

508.2 (M + H ⁺ )

ESMS m/z

508.2 (M + H⁺)

0.036

0.027

5-clo ro-N 2-(2-fluoro-5-met¡ 1-4-(1301

<td></td><td>ESTRUCTURA</td><td>RMN o ESMS</td><td>IGF-1R Ba/F3 ICsoftjM)</td>

<td></td><td>(piridazin-4-il-metil)-piperidin-4- ¡l)-fenil)-N4-(5-metil-1 H-pirazol-3- il)-pirimidin-2,4-diamina</td><td></td><td></td>

<td></td><td>ΗΝ^Ργ /χ /x. xx Ν NH ι { ' ν Α’'' N^aX AAJ x n^;n^;7 Η I 5-cloro-N2-(2,5-dimetil-4-(1- (pirimidin-5-il-met¡l)-piperidin-4- il)-fenil)-N4-(5-metil-1 H-pirazol-3- il)-pirim¡din-2,4-d¡am¡na</td><td>ESMS m/z 504.2 (M + H⁺)</td><td> 0.004</td>

<td></td><td>HN, J „ Ν NH i ( N A N i I l II^clpXj ΑγΑ ⁿA Η I 5-cloro-N2-(2,5-d¡met¡l-4-(1- (p¡ razi n-2-¡l-m etil )-p ¡perid ¡n-4-¡I)- fenil)-N4-(5-metil-1 H-pi razol-3-iI)- pi rim idi n-2,4-d ¡amina</td><td>ESMS m/z 504.2 (M + H⁺)</td><td> 0.010</td>

302

essays

IC₅₀ of a drug can be determined by constructing a dose response raven, and examining the effect of different concentrations of the antagonist on the reversal of agonist activity. IC values ​​can be calculated₅₀ for a given antagonist by determining the concentration necessary to inhibit half of the maximum biological response of the agonist. To calculate IC values₅₀, a series of dose response data is generated (for example, drug concentrations x1, x2, ..., xn, and growth inhibitions y1, y2, ..., yn, where the values ​​of y are in the range of 0 to 1). IC values₅₀ They can be determined by a computer-aided system, using the formula:

y = D + ((AD) / (1 + 10^{&lt;x, og (ICSO) B}) where A is the proportion of growth inhibition between concentrations lower ation of drug and control; B is the inclination of the sigmoidal curve; and D is the proportion of growth inhibition between the highest drug concentration and the control.

IC value₅₀ it is given as the concentration of the test compound that results in a growth inhibition that is 50 percent lower than that obtained using the control without inhibitor. The compounds of the invention in free form or in the form of a pharmaceutically acceptable salt can exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application. In general, the

303 compounds of the invention have IC values₅₀ from 1nM to 10μΜ. In some examples, the compounds of the invention have IC values₅₀ from 0.01 μΜ to 5 μΜ. In other examples, the compounds of the invention have IC values.₅₀ from 0.01 μΜ to 1 μΜ, or more in particular from 1 nM to 1 μΜ. In still other examples, the compounds of the invention have IC values₅₀ less than 1 nM or more than 10 μΜ. The compounds of the invention may exhibit a percentage of inhibition greater than 50 percent, or in other embodiments, may exhibit a percentage of inhibition greater than about 70 percent, against IGF-1R at 10 μΜ.

Panel of the Ba / F3 cell line and reagents

Ba / F3 is a pro-B lymphoma cell line dependent on murine IL3. Progenitor Ba / F3 cells are used to generate a panel of sub-lines whose proliferation and survival becomes independent of IL-3 by stable transduction with individual tyrosine kinases activated by fusion with the amino-terminal portion of TEL (amino acids 1-375) or BCR. In order to generate the Ba / F3 cell lines transformed by the Tyrosine Tel-Kinase (TK) fusions, the progenitor Ba / F3 cells are infected with a retr ovirus that hosts each TEL fusion kinase, and undergo puromycin selection and IL-3 removal, to obtain transformed Ba / F3 cells, IL-3 independent.

Each of the transformed Ba / F3 cells is cultured in RPMI-1640 medium (Gibco Cat # 11875093, Carlsbad, CA) supplemented with 10 percent fetal bovine serum (Hyclone Cat

304 # SV30014.03, Logan, UT), 4.5 grams / liter of glucose (Sigma # G5400, St. Louis, MO), 1.5 grams / liter of baking soda (Biowhittaker # 17-613E, Walkersville, MD), and penicillin / streptavidin (Pen / Strep) (Gibco # 10378-016, Carlsbad, CA). The cells divide twice a week.

Ba / F3 cell viability inhibition assay

The potency of the test compounds against different Ba / F3 lines transformed by Tel-TK is determined as follows. Exponentially growing BaF3 Tel-TK cells are diluted in the fresh medium to 75,000 cells / milliliter, and seeded n in 384 well plates (3,750 cells / well) at 50 microliters / well, using a pFill liquid dispenser (BloTek, Wlnooski, VT, USA). Duplicate plates are executed for each cell line. The test and control compounds are diluted to be with dimethyl sulfoxide, and arranged in a 384 well polypropylene plate. 50 nanoliters of the compound are transferred to the test plates using a peak transfer device, and the plates are incubated at 37 ° C (with CO₂ 5 percent) for 48 hours. 25 microliters of Britelite (Perkin Elmer) are added, and the luminescence is quantified using the Analyst GT (Molecular Devices). The custom curve adjustment software is used to produce a logistic adjustment of the percentage of cell viability as a function of the logarithm of the inhibitor concentration. IC₅₀ interpolated as the concentration of the compound necessary to reduce cell viability until 50 percent of a sulfoxide control

305 tell me Progenitor Ba / F3 cells that are maintained and cultured in the presence of IL-3 (1 nanogram / milliliter at the end) are diluted in the fresh medium containing IL-3 (1 nanogram / milliliter at the end) up to 75,000 cells / milliliter following the same procedure as described above.

HTRF Enzyme Assay

IGF-1R and INSR (insulin receptor) are purchased from Upstate. The following reagents are prepared internally; 10 χ kinase regulator (KB) (200 mM Tris (7.0 pH), MgCI₂ 100 mM, MnCI₂ 30 mM, NaVO₄ 50 nM), 10 mM ATP, 100 milligrams / milliliter of bovine serum albumin, 0.5 M EDTA, 4M KF. A Perkin-Elmer Proxiplate-384 is used to establish the assay. All HTRF reagents, including the substrate (Biotin-poly-GT (61GT0BLB), Mab PT66-K, (61T66KLB), Streptavidin-XL^ent (611SAXLB)) is acquired at CIS-US, Inc.

The substrate / ATP mixture is prepared by adding ATP (final concentration of 3 μΜ), and biotinylated poly-GT (final concentration of 10 nanograms / microliter) in KB 1x, and dosed in Proxiplate-384 at 5 microliters / well, using μFi11 (Bio-TEK). The serially diluted compounds (in dimethyl sulfoxide) are transferred to the plate using a 50 nanoliter peak head. 5 microliters of the prepared enzyme mixture (enzyme (final concentration of 5 nanograms / microliter), mixed with bovine serum albumin and DTT in 1x KB) are added, to start the kinase reaction, using pFill (Bio-TEK). Plate

306 Assay is incubated at room temperature for 2 hours. The detection mixture is prepared by adding both Mab PT66-K and Streptavidin-XL^ent in a solution of KB 0.5x containing KF (final concentration of 125 mM), EDTA (final concentration of 5 0 mM), and bovine serum albumin (final concentration of 100 micrograms / milliliter). At the end of the reaction, 10 microliters of detection mixture is added, and incubated for 30 minutes at room temperature before measurement. The HTRF signal is detected using the Analyst-GT (Molecular Devices).

Cancer cell proliferation inhibition assay

To luciferize the cancer cell line, each cell line is transduced by ampholytic retroviruses carrying both the luciferase gene and the puromycin resistant gene whose expression is driven by LTR. Put briefly, the retroviral vector pMSCV-Puro-Luc is transfected into the Phoenix cell line using Fugene6 (Roche) according to the manufacturer's instructions. Two days after transfection, the supernatant containing the virus is harvested, and filtered with a 0.2 micron filter. The harvested virus is used immediately or stored at -80 ° C.

For infection, cultured cancer cells are harvested and applied (5x10⁵ cells / well in 1 milliliter of the medium) to a 6-well tissue culture plate. For each well, 3 milliliters of virus supernatant is added, along with 400 microliters of fetal bovine serum, 40 microliters of 1M HEPES (pH 8.0), and 4 microliters of Polibrene (10 micrograms / milliliter, Specialty Media). The plate is

307 centrifuge for 90 minutes at 2,500 revolutions per minute for centrifugal infection, and transfer to an incubator for infection overnight. The next day, the infected cell line is transferred to a T-75 flask containing the fresh medium, and incubated for a day. Two days after infection, puromlcin is added in a final concentration of 1 microgram / milliliter, to start the selection. Within 1 to two weeks, the puromycin-resistant cell line is established after at least two days. subsequent visions, and is preserved as the luclferlzado supply.

Each cell line is harvested while growing in the log phase by trlpsinlzaclón, and diluted in the respective medium to the appropriate density before application to the plate. The cells are dosed using pFill (BioTeK) at 50 microliters / well, on transparent bottom plates and white walls (Grelner - tailored for GNF). The cells are then placed in the incubator at 37 ° C, supplying CO₂ at 5 percent overnight. The compounds are transferred using 50 nanolltros / well of Plntool technology through Platemate (Matrix). Then the test plates are placed back in the incubator for 3 days. On the third day following the transfer of the compounds, BRITELITE® (Perkin Elmer, diluted according to the manufacturer's suggestion) is added to the test plates, and they are read in the Analyst GT (Molecular Devices) or Envision (Perkin Elmer) Raw data is generated in RLU.

308

Tumor Activity of the Example Compounds

3 to 4 x 10® SK-N-MC human neuroblastoma cells were resuspended in HBSS, and mixed in 50 percent Matrigel, where mice (HsdNpa were injected subcutaneously (0.05 milliliters / mouse)) Atimics / nu) hairless females 10 to 12 weeks old. The treatments were started when the average tumor volumes were approximately 150 to 200 cubic millimeters. Body weights and tumor volumes were recorded three times per week. Tumor volumes were measured with calipers, and were determined according to the formula: length x diameter² x tt / 6. In addition to presenting fractional changes in tumor volumes during treatment courses, anti-tumor activity was expressed as T / C% (average change in tumor volume of treated animals / average change in tumor volume of control animals) χ 100. The efficacy of the test compounds was determined by initiating an oral dosage on day 19 after the injection of the cells followed by random selection of the mice, such that each group has a similar average tumor size. Dosing was continued with an appropriate schedule for 7 days, based on the general health condition of the animals. All test compounds were formulated in NMP / PEG300 (10:90), and applied daily by oral intubation. The vehicle consisted of NMP / PEG300 (10:90). All application volumes were 5 milliliters /

309 kilogram. The activity of the example compounds of the tumor growth invention is shown in Tables 2 to

Table 2

<td></td><td colspan="4">Tumor Response</td>

<td>Treatment</td><td>T / C (%)</td><td>Regr. (%)</td><td>Δ Volume of the tumor (mm³average ± SEM)</td><td>Veces de cambio promedio en crecimiento tumoral</td>

<td>NMP/PEG300 (10/90) 5 mL/kg po q8/1 6h</td><td> 100</td><td> 0</td><td> 334 ± 59</td><td> 3.1 ± 0.3</td>

<td>Compuesto de Prueba 1 20 mg/kg, q8/16h, Po</td><td> 53</td><td> -</td><td> 231 ± 145</td><td> 2.1 ± 0.4</td>

<td>Compuesto de Prueba 1 40 mg/kg, q8/16h, P°</td><td> 35</td><td> -</td><td> 107 ± 48*</td><td> 1.7 ± 0.2*</td>

310

Tabla 3

Respuesta del Tumor

T ratamiento

NMP/PEG300 (10/90) 5 mL/kg po q8/1 6h

Compuesto de

Prueba 2

12.5 mg/kg, q8/16h,

PO

Compuesto de

Prueba 2 mg/kg, q8/1 6 h,

P°

T/C (%)

100

Regr.

(%)

Δ Volumen del tumor (mm³ promedio ± SEM)

334 ± 59

232 ± 103

Veces de cam bio promedio en crecimiento tumoral

3.1 ± 0.3

2.5 ± 0.4 ± 10*

1.5 ± 0.2*

310

Tabla 3

<td></td><td colspan="4">Respuesta del Tumor</td>

<td>T ratamiento</td><td>T/C (%)</td><td>Regr. (%)</td><td>Δ Volumen del tumor (mm³promedio ± SEM)</td><td>Veces de cambio promedio en crecimiento tumora l</td>

<td>NMP / PEG300 (10/90) 5 mL / kg po q8 / 1 6h</td><td> 100</td><td> 0</td><td> 334 ± 59</td><td> 3.1 ± 0.3</td>

<td>Compound Test 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>Compound Test 2 25 mg / kg, q8 / 1 6h, PO</td><td> 22</td><td> -</td><td> 42 ± 1 0*</td><td> 1.5 ± 0.2*</td>

312