MX2010014568A - Pyrimidine derivatives as kinase inhibitors. - Google Patents

Abstract

The invention" provides novel pyrimidine derivatives of formula (I) and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of insulin- like growth factor (IGF-IR) or analplastic lymphoma kinase (ALK).

Description

DERIVATIVES OF PYRIMIDINE AS KINASE INHIBITORS Cross Reference to Related Requests This application claims the benefit of the Provisional Patent Application of the United States of America with Serial Number 61 / 075,583, filed on June 25, 2008, which is hereby incorporated by reference in its entirety.

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

Background Technique Insulin-like growth factor (IGF-1) signaling is highly implicated in cancer, with the IGF-1 receptor (IGF-1R) 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 towards IGF-1R 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 The family of insulin receptors of receptor tyrosine kinases has been implicated in oncogenesis in hematopoietic and non-hematopoietic 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 malignancies positive for ALK. (Pulford et al., Cell, Mol.Life Sci.61: 2939-2953 (2004)).

Due to the disease-related functions that are arising 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-1 R and ALK.

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

In one aspect, the invention provides a compound of the formula (1): or a physiologically acceptable salt thereof; where W is or W; W is pyridyl, isoquinolinyl, quinolinyl, naphthalenyl, cinolin-5-yl or [3- (alkyl of 1 to 6 carbon atoms) - (2,3,4,5-tetrahydro-1 H -benzo- [d] - azepin-7-yl], each of which is optionally substituted with 1 to 3 R9, and the pyridyl, isoquinolinyl, quinolinyl and naphthalenyl are each substituted on a carbon atom of the ring with X is -C (R) = N-0-R7, C (0) NRR7, C (0) NR- (CR2) n-NRR7, - (CR2) P NRR, wherein two R groups, together with N in NRR, they form a ring of 5 to 6 members containing from 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with 1 to 3 R9, or a carbocycle of 5 to 7 carbon atoms optionally substituted with oxo, = N-OH or R9; or X is quinolinyl, (1,2,3,4-tetrahydro-isoquinolin-6-yl) or a 5- to 6-membered heteroaryl having from 1 to 3 heteroatoms selected from N, O, and S, each of which is optionally substituted with 1 to 3 R9; R1 is halogen, alkyl of 1 to 6 carbon atoms, or an alkyl of 1 to 6 carbon atoms substituted by halogen; R2 is a 5-6 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms carbon, or cycloalkyl of 3 to 7 carbon atoms; each R3 is H; R4 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) O0-iR8; R6 is H, alkyl of 1 to 6 carbon atoms, carbon 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, F2t + 1 wherein t is from 1 to 3, (CR2) P-CN; (CR2) P-NR (R7), - (CR2) P-C (0) OR7, (CR2) pNR (CR2) pOR7, (CR2) pNR-L-C (0) R8, C (0) - (CR2) qOR8, -C (0) 0- (CR2) p-NRR7, -C (0) - (CR2) p-OR7, L-Y, -L-C (0) R7, -L-C (0) -NRR7, -L-C (0) -NR- (CR2) p-NRR7, -L-C (O) NR (CR2) pOR7, -L-C (0) - (CR2) q-NR-C (0) -R8, -L-C (0) NR (CR2) pSR7, -L-C (0) NR (CR2) pS (0) 1.2R8, -L-S (0) 2R8, -L-S (0) 2- (CR2) q-NRR7, -L-S (0) 2NR (CR2) PNR (R7) or -L-S (0) 2NR (CR2) POR7; in an alternative manner, R6 is a radical selected from formula (a), (b), (c) or (d): R10 is O, S, NR17 wherein R17 is H, alkyl of 1 to 6 carbon atoms, SOzR8a or C02R8a; 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 alkinyl of 2 to 6 carbon atoms, each of which may be optionally substituted with halogen, amino, or hydroxyl groups; or R11 and R2, 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 saturated, unsaturated, or partially unsaturated ring of 3 to 7 members containing from 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and from 1 to 3 R9 groups; L is (CR2) 1.4 or a link; Y is a carbocyclic ring of 3 to 7 carbon atoms, aryl of 6 to 10 carbon atoms, or a heteroaryl of 5 to 10 members, or a heterocyclic ring of 4 to 10 members, each of which is optionally substituted with 1 to 3 groups R9; R7, R8 and R8a 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, NRR7a, hydroxyl or cyano; (CR2) qY or alkoxy of 1 to 6 carbon atoms; or R7 is H; R9 is R4, C (0) NRR7 or NRR7; R and R7a are independently H or alkyl of 1 to 6 carbon atoms; R and R7, together with N in each NRR7, and R and R7a, together with N in NRR7a, can form a 5 to 6 member ring containing from 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and from 1 to 3 R4 groups; m is from 2 to 4; n and p are independently from 1 to 4; Y q is from 0 to 4.

In formula (1) above, R 2 can be pyrazolyl, or isoxazolyl, each of which is substituted by alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms.

In one embodiment, the invention provides a compound of the formula (2): where W is W; W is pyridyl optionally substituted with alkyl of 1 to 6 carbon atoms, isoquinolinyl, quinolinyl, naphthalenyl, cinolin-5-yl optionally substituted by alkyl of 1 to 6 carbon atoms, or [3- (alkyl of 1 to 6 carbon atoms) carbon) - (2,3,4,5-tetrahydro-1 H -benzo- [d] -azepin-7-yl]; and the pyridyl, isoquinolinyl, quinolinyl and naphthalenyl are each substituted on a carbon atom of the ring with R6 is 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 by halogen, amino, hydroxyl or alkoxy; - (CR2) p-CH (OH) CtF2t + 1 where t is 1, -L-C (0) -NRR7 or -L-S (0) 2R8; L is (CR2) 1.4; R and R7 are independently H or alkyl of 1 to 6 carbon atoms; R8 is alkyl of 1 to 6 carbon atoms; Y R and R3 are as defined in formula (1).

In another embodiment, the invention provides a compound of the formula (3): wherein Z is NH or O; R 4 is halogen, or alkyl of 1 to 6 carbon atoms; O JR6 R5 is H or ¿; R6 is H; Y R1 and R3 are as defined in formula (1).

In yet another embodiment, the invention provides a compound of the formula (4): wherein one of R, R and R 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, or alkoxy of 1 to 6 atoms carbon substituted by halogen; Y X is as defined in formula (1).

In the above formula (4), X can be -C (R) = N-0-R7, C (0) NRR7, C (0) NR- (CR2) n-NRR7 or - (CR2) PNRR, where two R groups, together with N in NRR, form morpholinyl; R7 is H or alkyl of 1 to 6 carbon atoms optionally substituted with hydroxyl or NRR7a; each R is H or alkyl of 1 to 6 carbon atoms; R and R7, together with N in each NRR7, and R and R7a, together with N in NRR7a, can form a 5- to 6-membered ring containing from 1 to 2 heteroatoms selected from N, O, and S; ynyp are independently from 1 to 4. Alternatively, X can be quinolinyl, (1, 2,3,4-tetrahydro-isoquinolin-6-yl), or a 5- to 6-membered heteroaryl selected from pyrazolyl, pyridyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl or thiazolyl, each of which is optionally substituted with alkyl of 1 to 6 carbon atoms, hydroxyl, or C (0) NRR7; R7 is H or alkyl of 1 to 6 carbon atoms; and R is H or alkyl of 1 to 6 carbon atoms.

In another embodiment, the invention provides a compound of the formula (5): wherein one of R4a, R4b and R4c 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, or C 1 -C 6 alkoxy substituted by halogen; ring E is a carbocycle of 6 carbon atoms optionally substituted with oxo, = N-OH or R9; R9 is hydroxyl or NRR7; R is H or alkyl of 1 to 6 carbon atoms; R7 is alkyl of 1 to 6 carbon atoms, or (CR2) qY, and Y is cycloalkyl of 3 carbon atoms; alternatively, R and R7, together with N in NRR7, form morpholinyl, piperidinyl, piperazinyl, (C 1 -C 6 alkyl) -piperazinyl, or pyrrolidinyl, each of which is optionally substituted with hydroxyl; Y R1 and R3 are as defined in formula (1).

In the above formulas (4) and (5), R b can be H. In other examples, R 4a and R 40 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, or alkoxy of 1 to 6 carbon atoms substituted by halogen.

In the formulas (1) to (5) above, R1 is chloro or an alkyl of 1 to 6 carbon atoms substituted by halogen. In other examples, R3 is H.

In another aspect, the present invention provides pharmaceutical compositions comprising a compound having the formula (1), (2), (3), (4) or (5), and a physiologically acceptable excipient.

In yet another aspect, the invention provides methods for inhibiting IGF-1R in a cell, which comprises contacting the cell with an effective amount of a compound having the formula (1), (2), (3), ( 4) or (5), or a pharmaceutical composition thereof.

The invention also provides methods of treating, alleviating, 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), (4) or (5), or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent. In an alternative manner, the present invention provides the use of a compound having the formula (1), (2), (3), (4) or (5), and optionally in combination with a second therapeutic agent, in the manufacture of a medicament 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 disorder proliferative cell 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's sarcoma, or a solid tumor selected from 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 alkyl and alkoxy substituted by halogen, and may be straight or branched chain. An optionally substituted alkyl, alkenyl or alkynyl, as used herein, may be optionally halogenated (e.g., CF3), or 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, indanyl, 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 members of the Ring is a heteroatom. For example, a heteroaryl substituent for use in the compounds of the invention may be a 5- or 10-membered monocyclic or bicyclic heteroaryl containing from 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, benzo-furanyl, benzo-pyranyl, benzo-thiopyranyl, benzo- [1, 3] -dioxol, imidazolyl, benzoimidazolyl, 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 monocyclic, fused bicyclic, or bridged, saturated, or partially unsaturated polycyclic ring containing carbon atoms, which may be optionally substituted, for example, with = 0. Examples of 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 is 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 from 1 to 3 heteroatoms selected from N, O, and S, or a combination thereof, such as -S (O) or -S (0) 2-. The Examples of heterocyclic rings include, but are not limited to, azetidinyl, morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, 1,4-dioxa-8-aza-spiro- [4.5] -dec-8. -yl, 1, 2,3,4-tetrahydro-quinolinyl, etc. Heterocyclic rings, as used herein, may encompass bicyclic amines and bicyclic diamines.

As used herein, an H atom in any substituent groups (e.g., CH2), encompasses all suitable isotopic variations, e.g., 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 the 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 in a simultaneous manner 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, wherein 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 the 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 (e.g., an IGF-1 R antagonist) effective to "treat" 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 the size of the tumor; inhibit (that is, slow down to some degree and preferably stop) the infiltration of cancer cells into peripheral organs; inhibit (ie, slow down to some degree and preferably stop) tumor metastasis; inhibit, to some degree, tumor growth; and / or alleviating to some degree one or more of the symptoms associated with cancer. See the definition here 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. More 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, bladder, gastric, pancreatic, hepatic (hepatocellular) carcinoid, hepatoblastoma, esophageal, pulmonary adenocarcinoma, mesothelioma, synovial sarcoma, osteosarcoma, squamous cell carcinoma of the head and neck, juvenile nasopharyngeal angiofibromas, liposarcoma, thyroid, melanoma, carcinoma of basal cells (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 in need of treatment include those who already have the disorder, as well as those who are susceptible to the disorder, or those in whom the disorder must be prevented (prophylaxis). When the IGF-1R mediated disorder is cancer, a subject or mammal is "successfully" treated or shows a reduced tumor burden if, after receiving a therapeutic amount of an IGF-1R antagonist according to the methods of the present invention. 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 (ie, slowing down to some degree and preferably stopping) of the infiltration of cancer cells into peripheral organs, including the spread of cancer into soft tissue and bone; inhibition (ie, slowing down to some degree and preferably stopping) of the tumor metastasis; inhibition, to some degree, of tumor growth; and / or relief to some degree, from one or more of the symptoms associated with the specific cancer; reduced pathology and mortality, and improvement in quality of life. To the extent that the IGF-1R antagonist can prevent growth and / or kill 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 the pharmaceutically acceptable carriers, excipients, or stabilizers that are not toxic to the cell or mammal being exposed to them at the dosages and concentrations employed. Frequently, the physiologically acceptable vehicle 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 (less than about 10 residues); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic 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 counterions, such as sodium; and / or nonionic surfactants, such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.

A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of the chemotherapeutic agents include alkylating agents, such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonates, such as busulfan, improsulphan and piposulfane; aziridines, such as benzodopa, carbocuone, meturedopa, and uredopa; ethylene imines and methyl melamines, including altretamine, triethylene-melamine, triethylene- phosphoramide, triethylene-thiophosphoramide and trimethylol-melamine; acetogenins (especially bulatacin and bulatacinone); delta-9-tetrahydro-canabinol (dronabinol, MARINOL®); beta-lapacona; lapacol; Colchicines; betulinic acid; a camptothecin (including the synthetic topotecan analog (HYCAMTIN®), CPT-11 (irinotecane, CAMPTOSAR®), acetyl-camptothecin, scopolectin, and 9-amino-camptothecin); Bryostatin; Callistatin; CC-1065 (including its synthetic analogs of adozelesin, carzelesin and bizelesin); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (in particular cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189 and CB1-T 1); eleutherobin; pancratistatin; a sarcodictine; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterin, prednimustine, trofosfamide, uracil mustard; nitroso-ureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enodiin antibiotics (eg, calicheamicin, especially gammall calicheamicin and omegall calicheamicin (see, for example, Agnew, Chem Intl. Ed. Engl., 33: 183-186 (1994)), dinemicin, including dynemycin A, a esperamycin, as well as the chromatofocus neocarzinostatin and chromoprotein-related chromodrug antibiotic chromodrugs), aclacinomycins, actinomycin, autramycin, azaserin, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorrubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® doxorubicin (including morpholino-doxorubicin, cyano-morpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxidoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins, such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, chelamicin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites, such as methotrexate and 5-fluoro-uracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercapto-purine, tiamiprin, thioguanine; pyrimidine analogues, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxy-uridine, doxifluridine, enocythabin, floxuridine; androgens, such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; anti-adrenal, such as amino-glutethimide, mitotane, trilostane; folic acid filler, such as frolinic acid; aceglatone; aldophosphamide glycoside; amino-levulinic acid; enyl-uracil; amsacrine; bestrabuchil; bisantrene; edetrexate; defofamin; demecolcine; diazicuone; elomomycin; eliptinium acetate; an epothilone; etoglucide; gallium nitrate; hydroxy urea; lentinan; lonidainin; maytansinoids, such as maytansin and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; fenamet; pirarubicin; losoxantrone; 2-ethyl hydrazide; procarbazine; 2! PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triazicuone; 2,2 ', 2"-trichloro-triethyl-amine, trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine), urethane, vindesine (ELDISINE®, FILDESIN®), dacarbazine, manomustine, mitobronitol; mitolactol, pipobroman, gacitosin, arabinoside ("Ara-C"), thiotepa, taxoids, for example, TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANEMR without Cremophor, formulation of paclitaxel in nanoparticles designed with albumin ( American Pharmaceutical Partners, Schaumberg, III), and docetaxel TAXOTERE® (Rhóne-Poulenc Rorer, Antony, France), chlorambucil, gemcitabine (GEMZAR®), 6-thioguanine, 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 treatment regimen with oxaliplatin (ELOXATINMR) combined with 5- FU and leucovorin.

Additionally, a "chemotherapeutic agent" can include anti-ormonal agents that act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer, and which are often in the form of a systemic or of the whole body. They can be the hormones themselves. Examples include anti-estrogens and selective modulators of estrogen receptors (SERMs), including, for example, tamoxifen (including tamoxifen NOLVADEX®), EVISTA® raloxifene, droloxifene, 4-hydroxy-tamoxifen, trioxifene, cheoxifen, LY117018, onapristone , and FARESTON® toremifene; anti-progesterone; sub-regulators of estrogen receptors (ERDs); agents that function 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) -midazoles, amino-glutethimide, megestrol acetate MEGASE®, AROMASIN® exemestane, formestane, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® anastrozole. In addition, this definition of chemotherapeutic agents includes bisphosphonates, such as clodronate (eg, 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 nucleoside analog of 1,3-dioxolane cytosine); anti-sense oligonucleotides, in particular those that inhibit the expression of genes in the signaling pathways involved in aberrant cell proliferation, such as, for example, PKC-alpha, Raf, H-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 inhibitor LURTOTECAN®; ABARELIX® rmRH; lapatinib ditosylate (a small molecule inhibitor of double tyrosine kinase ErbB-2 and EGFR 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): or a physiologically acceptable salt thereof; W is pyridyl, isoquinolinyl, quinolinyl, naphthalenyl, cinolin-5-yl or [3- (alkyl of 1 to 6 carbon atoms) - (2,3,4,5-tetrahydro-1 H- benzo- [d] - azepin-7-yl], each of which is optionally substituted with 1 to 3 R9, and the pyridyl, isoquinolinyl, quinolinyl and naphthalenyl are each substituted on a carbon atom of the ring with X is -C (R) = N-0-R7, C (0) NRR7, C (0) NR- (CR2) n-NRR7, - (CR2) P NRR, wherein two R groups, together with N in NRR, they form a ring of 5 to 6 members containing from 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with 1 to 3 R9, or a carbocycle of 5 to 7 carbon atoms optionally substituted with oxo, = N-OH or R9; or X is quinolinyl, (1,2,3,4-tetrahydro-isoquinolin-6-yl), or a 5- to 6-membered heteroaryl having from 1 to 3 heteroatoms selected from N, O, and S, each one of which is optionally substituted with 1 to 3 R9; R1 is halogen, alkyl of 1 to 6 carbon atoms, or an alkyl of 1 to 6 carbon atoms substituted by halogen; R2 is a 5-6 membered heteroaryl having from 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; each R3 is H; R4 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) O0-iR8; R6 is 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 from 1 to 3, (CR2) P-CN; (CR2) P-NR (R7), - (CR2) p-C (0) OR7, (CR2) pNR (CR2) pOR7, (CR2) pNR-L-C (0) R8, C (0) - (CR2) pOR8, -C (0) 0- (CR2) p-N RR7, -C (0) - (CR2) p-OR7, L-Y, -L-C (0) R7, -L-C (0) -NRR7, -L-C (0) -NR- (CR2) p-NRR7, -L-C (O) NR (CR2) pOR7, -L-C (0) - (CR2) q-NR-C (0) -R8, -L-C (0) NR (CR2) pSR7, -L-C (0) NR (CR2) pS (0) 1.2R8, -L-S (0) 2R8, -L-S (0) 2- (CR2) p-NRR7, -L-S (0) 2NR (CR2) pNR (R7) or -L-S (0) 2NR (CR2) pOR7; in an alternative manner, R6 is a radical selected from formula (a), (b), (c) or (d): R10 is O, S, NR17 wherein R17 is H, alkyl of 1 to 6 carbon atoms, S02R8a or C02R8a; R11, R12, R13, R14, R5 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 alkinyl 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 to which they are attached, can form a saturated, unsaturated, or partially unsaturated ring of 3 to 7 members containing from 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and from 1 to 3 R9 groups; L is (CR2) i.4 or a link; Y is a carbocyclic ring of 3 to 7 carbon atoms, aryl of 6 to 10 carbon atoms, or a heteroaryl of 5 to 10 members, or a heterocyclic ring of 4 to 10 members, each of which is optionally substituted with 1 to 3 groups R9; R7, R8 and R8a 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, NRR7a, hydroxyl or cyano; (CR2) qY or alkoxy of 1 to 6 carbon atoms; or R7 is H; R9 is R \ C (0) NRR7 or NRR7; R and R7a are independently H or alkyl of 1 to 6 carbon atoms; R and R7, together with N in each NRR7, and R and R7a, together with N in NRR7a, can form a 5 to 6 member ring containing from 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and from 1 to 3 R4 groups; m is from 2 to 4; n and p are independently from 1 to 4; Y q is from 0 to 4.

In one embodiment, the invention provides a compound of the formula (2): where W is W; W is pyridyl optionally substituted with alkyl of 1 to 6 carbon atoms, isoquinolinyl, quinolinyl, naphthalenyl, cinolin-5-yl optionally substituted with alkyl of 1 to 6 carbon atoms, or [3- (alkyl of 1 to 6 carbon atoms) - (2,3,4,5-tetrahydro-1 H -benzo- [d] -azepin-7-yl]; and pyridyl, soquinolinyl , quinolinyl and naphthalenyl are each substituted on a carbon atom of the ring with ; R6 is 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 by halogen, amino, hydroxyl or alkoxy; - (CR2) p-CH (OH) C, F2t + i where t is 1, -L-C (0) -NRR7 or -L-S (0) 2R8; R and R7 are independently H or alkyl of 1 to 6 carbon atoms; R is alkyl of 1 to 6 carbon atoms; Y R1 and R3 are as defined in formula (1).

In another embodiment, the invention provides a compound of the formula (3): (3) wherein Z is NH or O; R 4 is halogen, or alkyl of 1 to 6 carbon atoms; R6 is H; Y R1 and R3 are as defined in formula (1).

In yet another embodiment, the invention provides a compound of the formula (4): wherein one of R, R and R 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, or C 1 -C 6 alkoxy substituted by halogen; Y X is as defined in formula (1).

In another embodiment, the invention provides a compound of the formula (5): (5) wherein one of R, R and R 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, or C 1 -C 6 alkoxy substituted by halogen; ring E is a carbocycle of 6 carbon atoms optionally substituted with oxo, = N-OH or R9; R9 is hydroxyl or NRR7; R is H or alkyl of 1 to 6 carbon atoms; R7 is alkyl of 1 to 6 carbon atoms, or (CR2) qY, and Y is cycloalkyl of 3 carbon atoms; alternatively, R and R7, together with N in NRR7, form morpholinyl, piperidinyl, piperazinyl, (C 1 -C 6 alkyl) -piperazinyl, or pyrrolidinyl, each of which is optionally substituted with hydroxyl; Y R1 and R3 are as defined in formula (1).

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 the pure enantiomers or diastereomers. The invention also covers the possible tautomers of the compounds of the invention.

Any formula given here also purports to represent unmarked forms as well as forms isotopically labeled compounds. The isotopically labeled compounds have the structures illustrated by the formulas given herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number selected. Examples of the isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 11C, 3C, 14C, 15N, 18F 31P , 32P, 35S, 36CI, 125L respectively.

The invention includes different isotopically labeled compounds as defined herein, for example, those in which radioactive isotopes, such as 3 H, 3 C, and 14 C are present. These isotopically labeled compounds are useful in metabolic studies (with, for example, 14C), reaction kinetic 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 tests of drug or substrate distribution in the tissue, or in the radioactive treatment of patients. In other examples, an 18F or labeled compound can be used 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 the efficacy and safety, to improve bid availability and half-life, to alter protein binding, to change biodistribution, to increase the proportion of active metabolites, and / or to decrease the formation of reactive or toxic metabolites. The isotopically-labeled compounds of this invention and the prodrugs 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 utilizing an isotopically-labeled reagent readily available to replace a non-isotopically labeled reagent.

In each of the above formulas, each optionally substituted moiety 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 optionally being 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 1 to 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, methylenedioxyl, carboxyl; alkyl of 1 to 8 carbon atoms-carbonyl, alkoxy of 1 to 8 carbon atoms-carbonyl, carbamoyl, alkyl of 1 to 8 carbon atoms-carbamoyl, sulfamoyl, cyano, oxo, nitro, or a carbocyclic ring, heterocyclic ring , aryl, or heteroaryl optionally substituted, 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 cell-free kinase assays and in cell assays, and, therefore, are useful as pharmaceuticals.

In one aspect, the compounds of the invention can inhibit the insulin-like growth factor I receptor (IGF-1R), and may be useful in the treatment of diseases mediated by IGF-1R. Examples of diseases mediated by IGF-1R include, but are not limited to, proliferative diseases, such as tumors, eg, breast, renal, prostate, colo-rectal, thyroid, ovarian, pancreatic, 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-1R can be demonstrated using a cell capture ELISA. In this assay, the activity of the compounds of the invention against the 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 the anaplastic lymphoma kinase (ALK), and the NPM-ALK fusion protein. This protein tyrosine kinase results from a genetic fusion of nucleophosmin (NP) and ALK, which causes protein kinase activity tyrosine of the ALK ligand is independent. NPM-ALK has a key role in the transmission of signals in a number of hematopoietic cells and other human cells that lead to hematological and neoplastic diseases, for example in anaplastic macrocellular lymphoma (ALCL), and in non-Hodgkin's lymphomas (NHL) ), specifically in ALK + NHL or Alcomas, in inflammatory myofibroblastic tumors (IMT), and in neuroblastomas. (Duyster et al., 2001 Oncogene 20, 5623-5637). In addition to NPM-ALK, other genetic fusions have been identified in human hematological and neoplastic diseases; for example, TPM3-ALK (a non-muscular tropomyosin fusion with ALK).

Inhibition of ALK tyrosine kinase activity can be demonstrated using known methods, for example using the recombinant kinase domain of ALK in analogy to the VEGF-R kinase assay described in J. Wood et al., Cancer Res. , 2178-2189 (2000). In general, enzymatic assays are carried out in vitro using tyrosine protein kinase GST-ALK, in 96-well plates, as a filter-binding assay in 20 mM Tris HCl, pH = 7.5, MgCI23 mM, 10 mM MnCl2, 1 mM DTT, 0.1 pCi / assay (= 30 microliters) [? -33?] - ???, ATP 2 μ ?, 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 an AIP Multiscreen plate (Millipore, Bedford, MA, USA), previously moistened with methanol, and rehydrated for 5 minutes with H20. Following washing (0.5% H3P04), the plates are counted in a liquid scintillation counter. The IC50 values are calculated by linear regression analysis of the inhibition percentage.

The compounds of the invention can potently inhibit the growth of murine BaF3 cells that overexpress human NP-ALK (DSMZ Deutsche Sammiung von ikroorganismen und Zelikulturen GmbH, Germany). Expression of NPM-ALK can be achieved by transfection of the BaF3 cell line with a pClneo R expression vector (Promega Corp., Madison Wl, USA) coding for NPM-ALK, and the subsequent selection of the resistant cells. G418 The non-transfected BaF3 cells depend on IL-3 for cell survival. In contrast, BaF3 cells expressing NPM-ALK (referred to as BaF3-NPM-ALK hereinafter) can proliferate in the absence of IL-3, because they obtain the proliferative signal through the NPM-ALK kinase. Accordingly, the putative inhibitors of the NPM-ALK kinase eliminate the growth signal, and may result in anti-proliferative activity. The anti-proliferative activity of the putative inhibitors of the NPM-ALK kinase, however, can be overcome by the addition of IL-3, which provides growth signals through a independent mechanism of NPM-ALK. An analogous cell system using the 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-NPM-ALK cells (15,000 / well microtitre plate) are transferred to 96-well microtiter plates. The 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 the control cultures without test compound are capable of undergoing two cycles of cell division. The growth of BaF3-NPM-ALK cells is measured by YOPROMR staining [T Idziorek et al., J. Immunol. Methods; 185: 249-258 (1995)]: To each well is added 25 microliters of lysis buffer comprising 20 mM sodium citrate, pH 4.0, 26.8 mM sodium chloride, 0.4 percent NP40, and 20 mM EDTA to each well. The cell lysis is completed within 60 minutes at room temperature, and the total amount of YOPROMR bound to the DNA is determined, by means of a measurement that uses the 96 well reader Cytofluor II (PerSeptive Biosystems) with the following positions: Excitation (nanometer) 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 the disorders associated therewith, respiratory diseases, such as asthma or inflammatory lesion of the liver, inflammatory glomerular lesion, cutaneous manifestations of immunologically mediated disorders or diseases, inflammatory and hyperproliferative diseases of the skin (such as psoriasis, atopic dermatitis, dermatitis allergic by contact, irritant contact dermatitis and other eczematous dermatitis, seborrheic dermatitis), inflammatory diseases of the eyes, 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 inhibitor of IGF-1R, 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 set forth hereinbefore, which comprises a compound of the invention as an active ingredient, together with one or more diluents or pharmaceutically acceptable vehicles; (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, wherein IGF-1R activation has a role or is involved; (6) the method as defined above under (4), which comprises the 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 drugs, 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, with 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 the kinase of anaplastic lymphoma; (9) use according to (8), wherein the disease to be treated is selected from anaplastic macrocellular lymphoma, non-Hodgkin's lymphomas, inflammatory myofibroblastic tumors, neuroblastomas, and neoplastic diseases; (10) use according to (8) or (9), wherein the compound is of the formula (1), (2), (3), (4), or (5), or of 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's 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 modes 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 the field. For example, for treatment of neoplastic diseases and disorders of the immune system, the required dosage 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 satisfactory results are obtained systemically at daily dosages from about 0.01 to about 100 milligrams / kilogram of body weight, or in particular, from about 0.03 to 2.5 milligrams / kilogram of body weight. A reported daily dosage in the higher 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. Suitable unit dosage forms for oral administration comprise from 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 Composition of the present invention in free form or in pharmaceutically acceptable salt form, in association with at least one pharmaceutically acceptable carrier or diluent, can be manufactured in a conventional manner by the mixing, granulating, coating, dissolving, or lyophilizing processes. 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, The unit dosage forms for oral administration they 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 carrier such as mannitol, dispersions or suspensions may be formed before use. The pharmaceutical compositions can be sterilized and / or can contain adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts for regulating the 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 carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinyl pyrrolidone, gelatins, or solubilizers, for example, Tween 80 (mono polyoxyethylene sorbitan oleate (20)).

Suspensions in oil may comprise, as the oil component, 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 from 8 to 22 carbon atoms, or in some embodiments, from 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, erucic acid, brasidic acid, and linoleic acid, and, if desired, may contain antioxidants, for example vitamin E, -carotene, or 3,5-diterbutyl-hydroxy-toluene. The alcohol component of these fatty acid esters can have six carbon atoms, and can 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, (polyoxyethylene glycerol), LABRAFIL® M 1944 CS (polyglycolized unsaturated glycerides prepared by alcoholysis of apricot seed oil and comprising glycerides and polyethylene glycol ester), LABRASOLMR (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 (triglyceride of saturated fatty acids of a chain length of 8 to 12 carbon atoms, from Hüls AG, Germany), and vegetable oils, such as cottonseed oil, 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 the inclusion of 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 starch, wheat, rice, or potato, methyl-cellulose, hydroxy-propyl-methyl-cellulose, sodium carboxy-methyl-cellulose, and / or polyvinyl-pyrrolidone, and / or, if desired, disintegrants, such as starches above, carboxymethyl starch, crosslinked polyvinyl 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 coatings, optionally enteric, through the use of, inter alia, concentrated sugar solutions, which may comprise gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or sodium dioxide. titanium, or coating solutions in solvents or mixtures of suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetyl-cellulose phthalate or hydroxy-propyl-methyl-cellulose phthalate . Dyes or pigments may be added to tablets or tablet coatings, for example, for identification purposes, or to indicate different doses of the active ingredient. s 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. Capsules duras can contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and / or skimmers, 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 or propylene glycol, which are also they can add 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 suspensions 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, may also be in the form of a lyophilizate, and may be made in a solution prior to parenteral administration. by adding suitable solvents. The solutions, such as 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 filling, for example, in ampoules or flasks, and the sealing of the containers.

The compounds of the invention can be administered as the sole 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, gemcitabine, cisplatin, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan, doxorubicin, gefitinib, or imatinib; or also with cyclosporins, rapamycins, ascomycins or their immunosuppressant analogs, 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-espergualine, mono-clonal immuno-suppressor antibodies, for example, monoclonal antibodies to leukocyte receptors, eg, MHC, CD2, CD3, CD4, CD7, CD25, CD28, I CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-, VLA-4 or its ligands, or other immunomodulatory 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 pharmaceutically acceptable salt form , and b) at least one co-agent. The kit may comprise instructions for its administration.

Processes for the Elaboration of Compounds of the Invention The General Procedures for the preparation of the compounds of the invention are described in the Examples that follow later. In the reactions described, the reactive functional groups, for example the hydroxyl, amino, methyl, thio, or carboxyl groups, where these are desired in the final product, can be protected to avoid their unwanted participation in the reactions. Conventional protecting groups can be used according to standard practice (see, for example, T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry," John Wiley and Sons, 1991).

The compounds of the invention, including their salts, may 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 the 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 base addition salt form can be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.). In view of the close relationship between 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 novel compounds, any reference to free compounds hereinafter and hereinafter, 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), (2A), (2B), (3A), and (3B), therefore, can be obtained by treatment with an acid or a reagent of adequate anion exchange The pharmaceutically acceptable salts of the compounds of the invention can be formed, by. example, as the acid addition salts, with organic or inorganic acids, from the compounds of the formula (1), (2A), (2B), (3A), and (3B) with a basic nitrogen atom .

Suitable inorganic acids include, but are not limited to a, 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, suberic acid, azelaic acid, melic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantane-carboxylic acid, benzoic acid, salicylic acid, 4-amino-salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methano- or ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, acid ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalene sulphonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3-, or 4-methylbenzenesulfonic acid, ac Methyl-sulfuric acid, ethyl-sulfuric acid, dodecyl-sulfuric acid, N-cyclohexyl-sulfamic acid, N-methyl-, N-ethyl-, or N-propyl-sulfamic acid, or other organic protonic acids, such as acid ascorbic For the purpose 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 are used (where applicable, in the form of pharmaceutical preparations).

The compounds of the invention in a non-oxidized form, are they 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, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or similar) in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, or the like) from 0 ° C to 80 ° C.

The pro-drug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (eg, for further details, see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters. , Volume 4, page 1985). For example, appropriate pro-drugs can be prepared by the reaction of a non-derivative compound of the invention with a suitable carbamylating agent (eg, 1,1-acyloxy-alkyl-carbano-chloridate, para-nitro-phenyl carbonate). , or similar).

The protected derivatives of the compounds of the invention can be made by means known to 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 T. W. Greene, "Protecting Groups in Organic Chemistry," 3rd Edition, John Wiley and Sons, Inc., 1999.

The compounds of the invention can be prepared as their individual stereoisomers by reaction of a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric 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 (e.g., 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, along with the resolving 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; Y (a) optionally converting a compound of the invention to a pharmaceutically acceptable salt; (b) optionally converting a salt form of a compound of the invention to a non-salt form; (c) optionally converting a non-oxidized form of a compound of the invention to a pharmaceutically acceptable N-oxide; (d) optionally converting an N-oxide form of a 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 non-derivative compound of the invention to a pharmaceutically acceptable prodrug derivative; Y (g) optionally converting a pro-drug derivative of a compound of the invention to its non-derivatized form.

As far as the 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 similarly employed. The present invention is further exemplified, but not limited, by the following Examples that illustrate the preparation of the compounds of the invention.

Intermediary 1 2,5-dichloro-N- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-4-amine A mixture of 5-methyl-1 H-pyrazol-3-amine (3.00 grams, 30.9 millimoles), 2,4,5-trichloro-pyrimidine (5.67 grams, 30.9 millimoles, 1 equivalent), and Na2C03 (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 Na2SO4. The resulting EtOAc solution was concentrated in vacuo to give the product of 2,5-dichloro-N- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-4-amine; ESMS m / z 244.0 (M + H +).

Intermediary 2 2-Chloro-N- (5-methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) -pyrimidin-4-amine A mixture of 2,4-dichloro-5- (trifluoromethyl) -pyrimidine (1.06 grams, 4.86 millimoles), 5-methyl-1 H-pyrazol-3-amine (472.2 milligrams, 4.86 millimoles), and sodium carbonate (2.06 grams, 19.4 millimoles) in 100 milliliters of EtOH, was stirred at temperature atmosphere during the night. The reaction mixture was concentrated in vacuo. The crude solid was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO), concentrated in vacuo, and purified by chromatography on silica (EtOAc / hexanes: 1/1), to provide 2-chloro-N- (5-methyl-1 H-pyrazole -3-yl) -5- (trifluoromethyl) -pyridin-4-amine; ESMS m / z 278.0 (M + H +).

Intermediary 3 2,5-dimethyl-4- (3-methyl-isoxazol-5-yl) -anilin Step 1: 1 - (2,5-dimethyl-4-nitro-phenyl) -ethanone To a mixture of 1-bromo-2,5-dimethyl-4-nitro-benzene (1 gram, 4.34 millimoles), and tributyl- (1-ethoxy-vinyl) -steno (1.88 grams, 5.2 millimoles) in N, N dimethyl-formamide (20 milliliters), tetrakis- (triphenyl-phosphine) -palladium (0) (250 milligrams, 5 percent millimolar) was added. The reaction tube was sealed, the mixture was purged with N2 for 3 minutes, and then it was heated at 90 ° C under N2 overnight. The reaction was cooled to room temperature, and poured into aqueous HCl (1N, 100 milliliters). The mixture was stirred for 1 hour, and then extracted with ethyl acetate (100 milliliters, 3 times). The organic extracts were combined, washed with brine, and concentrated. The crude product was purified by chromatography on silica gel (20% ethyl acetate in hexanes), provide 1 - (2,5-dimethyl-4-nitro-phenyl) -ethanone as a yellow solid.

Step 2: 1 - (2,5-dimethyl-4-nitro-phenyl) -3- (dimethylamino) -but-2-en-1 -one A mixture of 1 - (2,5-dimethyl-4-nitro-phenyl) -ethanone (step 1, 300 milligrams, 1.55 millimoles), and 1, 1-dimethoxy-N, N-dimethyl-ethanamine (1 milliliter) was heated in a microwave reactor at 130 ° C for 10 minutes. The crude product was purified by chromatography on silica gel (60% ethyl acetate in hexanes), to give 1 - (2,5-dimethyl-4-nitro-phenyl) -3- (dimethylamino) - but-2-en-1 -one as a yellow solid.

Steps 3 and 4: 2,5-dimethyl-4- (3-methyl-isoxazol-5-yl) -aniline A mixture of - (2,5-dimethyl-4-nitro-phenyl) -3- (dimethylamino) -but-2-en-1 -one (step 2, 100 milligrams, 0.38 millimole) and mono-hydrochloride hydroxylamine (132 milligrams, 1.9 mmol) in ethanol (3 milliliters), was heated in a microwave reactor at 100 ° C for 15 minutes. The 5- (2,5-dimethyl-4-nitro-phenyl) -3-methyl-isoxazole obtained was dissolved in methanol (10 milliliters). To this 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 give 2,5-dimethyl-4- (3-methyl-isoxazol-5-yl) -aniline. ESMS m / z 203 (M + H +).

Intermediary 4 2,5-dimethyl-4- (oxazol-5-yl) -aniline Step 1: To a mixture of 2,5-dimethyl-4-nitro-benzaldehyde (75 milligrams, 0.42 millimoles), and toluene-sulfonyl-methyl isocyanide (TOSMIC) (98 milligrams, 0.5 millimoles) in methanol (2 milliliters), sodium methoxide was added (68 milligrams, 1.26 millimoles). The mixture was sealed and heated at 90 ° C for 15 hours. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated. The 5- (2,5-dimethyl-4-nitro-phenyl) -oxazole obtained was used in the next step without purification.

Step 2: The 5- (2,5-dimethyl-4-nitro-phenyl) -oxazole obtained in the last step was dissolved in methanol (10 milliliters). To the solution was added Pd / C (at 10 percent). The reaction mixture was degassed and purged with H2 several times, and then stirred under 1 atmosphere of hydrogen gas overnight. The mixture was filtered and concentrated to give 2,5-dimethyl-4- (oxazol-5-yl) -aniline as a white solid. ESMS m / z 189 (M + H +).

Intermediary 5 2,5-dimethyl-4- (3-methyl-1 H-pyrazole-5-iD-aniltna) A mixture of 1 - (2,5-dimethyl-4-nitro-phenol) -3- (di-methyl-1-amino) -but-2-en-1 -one (100 milligrams, 0.38 millimole ), and hydrazine (60 microliters, 1.9 mmol) in ethanol (3 milliliters), was heated in a microwave reactor at 100 ° C for 15 minutes. The obtained 5- (2,5-dimethyl-4-nitro-phenyl) -3-methyl-pyrazole was dissolved in methanol (10 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 1 atmosphere of hydrogen gas overnight. The mixture was filtered and concentrated to give 2,5-dimethyl-4- (3-methyl-1H-pyrazol-5-yl) -aniline. ESMS m / z 202 (M + H +).

Intermediary 6 2,5-dimethyl-4- (2-methyl-thiazol-4-yl) -aniline Step 1: To a mixture of 1 - (2,5-dimethyl-4-nitro-phenyl) -ethanone (300 milligrams, 1.55 millimoles) in HBr (48 percent) (5 milliliters) / methanol (2.4 milliliters), He added bromine (250 milligrams, 1.55 millimoles). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with water, and extracted with ethyl acetate (20 milliliters, 2 times). The organic layer was washed with brine and concentrated. The residue was purified by silica gel column chromatography (10 percent ethyl acetate in hexanes), to give 2-bromo-1- (2,5-dimethyl-4-nitro-phenyl) - Ethanone as a white solid.

Step 2: A mixture of 2-bromo-1 - (2,5-dimethyl-4-nitro-phenyl) -ethanone (70 milligrams, 0.26 mmol), and ethan-thioamide (30 milligrams, 0.4 mmol) in ethanol (2 milliliters), was heated in a microwave reactor at 150 ° C for 20 minutes. The 4- (2,5-dimethyl-4-nitro-phenyl) -2-methyl-thiazole obtained was dissolved in methanol (10 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 1 atmosphere of hydrogen gas overnight. The mixture was filtered and concentrated to give 2,5-dimethyl-4- (2-methyl-thiazol-4-yl) -aniline. ESMS m / z 219 (M + H +).

Intermediary 7 2, 5-dimethyl-4- (1-met-1-1 H-imidazol-2-yl) -aniline To a solution of 2- (2,5-dimethyl-4-nitro-phenyl) -1 H-imidazole (50 milligrams, 0.23 mmol) in N, N-dimethylformamide (2 milliliters), NaH (11 mL) was added. milligrams, 0.46 millimoles) at 0 ° C. After stirring for 15 minutes, iodo-methane (65 milligrams, 046 millimoles) was added dropwise. The mixture was stirred at 0 ° C for 1 hour, and quenched by the addition of a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (15 milliliters, 3 times). The organic layer was washed with brine and dried over sodium sulfate. After concentration, the residue was dissolved in methanol (10 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 1 atmosphere of hydrogen gas overnight. The mixture was filtered and concentrated to give 2,5-dimethyl-4- (1-methyl-1 H-imidazol-2-yl) -annine. ESMS m / z 202 (M + H +).

Intermediary 8 2,5-dimethyl-4- (pyridin-3-yl) -aniline A suspension of 4-bromo-2,5-dimethyl-aniline (4.00 grams, 20 millimoles), pyridin-3-yl-boronic acid (2.70 grams, 11 millimoles), Pd2 (dba) 3 (0.55 grams, 0.6 millimoles) , 2-dicyclohexyl-phosphino-2 ', 6'-dimethoxy-biphenyl (0.98 grams, 1.2 mmol), and Na 2 CO 3 (10.6 grams, 100 mmol) in n-BuOH (50 milliliters), was degassed by a gas stream of Argon 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 Na 2 SO 4 and It vanished. The crude product was purified by chromatography on silica (gradient of 0 to 50 percent EtOAc in hexanes), to give 2,5-dimethyl-4- (pyridin-3-yl) -aniline as a yellow solid; ESMS m / z 199.1 (M + H +).

Intermediary 9 8- (2,5-dimethyl-4-n-phenyl) -1,4-dioxaespiro- [4.5l-dec-7-ene] A mixture of 4,4,4,4-tetramethyl-2- (1, 4-dioxaespiro- [4,5] -dec-7-en-8-yl) -1, 3,2-dioxaborlane (200 milligrams, 0.86 millimoles), 1-bromo-2,5-dimethyl-4-nitro-benzene (228 milligrams, 0.86 millimoles), tetrakis- (triphenyl-phosphine) -palladium (0) (98 milligrams, 0.09 millimoles), and cesium fluoride (392 milligrams, 2.58 millimoles) in a mixture of 1,2-dimethoxy-ethane (2 milliliters) and methanol (1 milliliter), was degassed for 5 minutes, and then heated at 130 ° C in a microwave reactor for 15 minutes. minutes The reaction was concentrated in vacuo, and purified by chromatography on silica (EtOAC / hexanes: 3/7), to give 8- (2,5-dimethyl-4-nitro-phenyl) -1,4-dioxaespiro- [ 4.5] -dec-7-ene; ESMS m / z 290.2 (M + H +).

Intermediary 10 2,5-dimethyl-4- (1,4-dioxaespiro-r4.5l-decan-8-i0-aniline A mixture of 8- (2,5-di-methyl-4-nitro-phenol) -1,4-dioxaespiro- [4,5] -decano (130.2 milligrams, 0.45 mmol), and Pd-C at 10 percent (13.0 milligrams) in methanol (20 milliliters), was degassed and then reacted under 1 atmosphere of H2. After completion of the reaction, Pd-C was removed by filtration, and the filtrate was concentrated in vacuo to give 2,5-dimethyl-4- (1,4-dioxaespiro- [4.5] -decan-8-yl). )-aniline; ESMS m / z 262.2 (M + H +).

Intermediary 11 2-fluoro-5-methyl-4- (1,4-dioxaespiro- [4.51-dec-7-en-8-yl) -aniline A mixture of 4,4,4,4-tetramethyl-2- (1,4-dioxaespiro- [4.5] -dec-7-en-8-yl) -1,2,2-dioxaborlane (532.0 milligrams, 2.0 millimoles ), 4-bromo-2-fluoro-5-methyl-aniline (406.0 milligrams, 2.0 millimoles), tetrakis- (triphenyl-phosphine) -palladium (0) (231.1 milligrams, 0.2 milli- moles), cesium fluoride (912.0 milligrams, 6.0 mmol), 1,2-dimethoxy-ethane (4 milliliters), and methanol (2 milliliters), degassed for 5 minutes, and then heated to 130 ° C in a reactor microwave for 15 minutes. The reaction was concentrated in vacuo, and purified by chromatography on silica (EtOAC / Hexanes: 3/7), to give 2-fluoro-5-methyl-4- (1,4-dioxaespiro- [4.5] -decide). 7-en-8-yl) -aniline; ESMS m / z 264.1 (M + H +).

Intermediary 12 2-fluoro-5-dimethyl-4- (1,4-dioxaespiro-r4.51-decan-8-yl) -aniline A mixture of 2-fluoro-5-methyl-4- (1,4-dioxaespiro- [4.5] -dec-7-en-8-yl) -aniline (130 milligrams, 0.50 mmol), and Pd-C at 10 percent (13.0 milligrams) in methanol (20 milliliters) was degassed, and then reacted under 1 atmosphere of H2. After completion of the reaction, Pd-C was removed by filtration, and the filtrate was concentrated in vacuo to give 2-fluoro-5-dimethyl-4- (1,4-dioxaespiro- [4.5] -decan-8). -yl) -aniline; ESMS m / z 266.2 (M + H +).

Intermediary 13 4- (5-Fluoro-2-methyl-4- (4- (5-methyl-1 H -pyrazol-3-yl-amino) -5- (trifluoromethyl) -pyrimidin-2-yl-amino) - phenyl) -cyclohexanone A mixture of 2-fluoro-5-methyl-4- (1,4-d-oxaspiro- [4.5] -decan-8-yl) -anMna (318.6 milligrams, 1.2 mmol), 2-chloro-N - (5-methyl-1 H -pyrazol-3-yl) -5- (trifluoromethyl) -pyrimidin-4-amine (333.0 milligrams, 1.2 mmol), and HCl (4 N in water, 0.3 milliliters, 1.2 mmol ) in 1- PrOH (4.0 milliliters), was heated at 125 ° C in an oil bath overnight. The reaction mixture was concentrated in vacuo. The resulting crude mixture was dissolved in tetrahydrofuran (4 milliliters), methanol (2 milliliters), and HCl (4N in water, 0.3 milliliters, 1.2 mmol), and stirred at room temperature for an additional 2 hours. The reaction mixture was concentrated in vacuo, and purified by chromatography on silica (gradient from 0 to 100 percent EtOAc in hexanes), to provide 4- (5-fluoro-2-methyl-4- (4- ( 5-methyl-1 H -pyrazol-3-ylamino) -5- (trifluoromethyl) -pyrimidin-2-yl-amino) -phenyl) -cyclohexanone; ESMS m / z 463.2 (M + H +).

Intermediary 14 N- (2,5-dichloro-pyrimidin-4-yl) -5-methyl-isoxazole-3-amine The mixture of 5-methyl-5-oxazol-3-amino (98 milligrams, 1.0 mmol), 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 (Na 2 SO 4), concentrated in vacuo, and purified by chromatography on silica gel (MeOH / DCM: 1/9), to give the N- (2,5-dichloro-pyrimidin-4-). il) -5-methyl-isoxazol-3-amine; ESMS m / z 245.0 (M + H +).

Intermediary 15 2,5-dichloro-N- (5-cyclopropyl-1 H -pyrazol-3-iQ-pyrimidin-4-amine 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 Na2C03 (233 milligrams, 2.20 millimoles, 1.1 equivalents) in EtOH (10 milliliters), 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 Na 2 SO 4, and then concentrated in vacuo to afford 2,5-dichloro-N- (5-cyclopropyl-1 H -pyrazol-3-yl) -pyridimid-4-. amine; ESMS m / z 270. 0 (M +? -G).

Intermediary 16 4- (6-amino-5-fluoro-1-oxo-iso-indolin-2-yl) -piperidin-1-tert-butylcarbonylate Step 1: 4- (2-chloro-4-fluoro-5-nitro-benzamido) -piperidin-1-tert-butylcarboxylate Under N2, to the solution of 2-chloro-4-fluoro-5-nitro-benzoic acid (1.0 grams, 4.56 millimoles) in 40 milliliters of dichloromethane at 0 ° C, thionyl chloride (1.0 milliliters, 13.68 millimoles), and 0.1 milliliters of dimethyl formamide in sequence. The reaction mixture was gradually warmed to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo to provide 2-chloro-4-fluoro-5-nitro-benzoyl chloride. The crude product was dissolved in 40 milliliters of DCM, and 1-boc-4-amino-piperidine (910 milligrams, 4.56 millimoles), and triethylamine (1.29 milliliters, 9.12 millimoles) were added to the solution in sequence. After stirring at room temperature for 1 hour, the reaction mixture was washed with 20 milliliters of water. He organic extract was dried (Na2SO4), followed by concentration in vacuo, to give 4- (2-chloro-4-fluoro-5-nitro-benzamido) -piperidin-1-tertbutylcarboxylate; ESMS m / z 402.1 (M + H +).

Step 2: 4- (4-Fluoro-5-nitro-2-vinyl-benzamido) -piperidin-1-tert-butylcarboxylate.

Under nitrogen, the mixture of 4- (2-chloro-4-fluoro-5-nitro-benzamido) -piperidin-1-tert-butylcarboxylate (step 1, 1.52 grams, 3.88 mmol), dibutyl ester of vinyl boronic acid (0.86 milliliters, 3.88 millimoles), dichloro-bis- (triphenyl-phosphine) -palladium (II) (136 milli-grams, 0.2 millimoles), and sodium carbonate (2.9 grams, 27.2 millimoles) in tetrahydrofuran (40 milliliters) and water (10 milliliters), was heated at 90 ° C overnight. The reaction mixture was cooled to room temperature, partitioned between EtOAc and brine. The organic extracts were dried (Na2SO4), concentrated, and purified by chromatography on silica gel (EtOAc / Hexanes: 1/4), to provide 4- (4-fluoro-5-nitro-2-vinyl-benzamido). ) -piperidin-1-tert-butyl carboxylate; ESMS m / z 394.2 (M + H +).

Step 3: 4- (5-Fluoro-6-nitro-1-oxo-iso-indolin-2-yl) -piperidine-1-carboxylate terbutyl The 4- (4-fluoro-5-nitro-2-vinyl-benzamido) -piperidine-1-carboxylic acid terbutyl ester (step 2, 1.1 grams, 2.77 mmol) in 50 milliliters of dichloromethane was cooled to -78 ° C. . Ozone was passed through the solution until the starting material was consumed, and then nitrogen was passed through the solution for 5 minutes. The reaction mixture was heated to room temperature. Resin was added The reaction mixture was dissolved in 10 ml of phosphorus (2.77 grams) in 10 milliliters of dichloromethane, and stirred for another 1.5 hours. The resin was filtered, and the solution was concentrated in vacuo. The resulting crude product was dissolved in dichloromethane (15 milliliters), and to this solution were added trifluoroacetic acid (15 milliliters), and triethylsilane (1.0 milliliters, 5.9 millimoles), in sequence. The reaction was stirred at room temperature for 2 hours. After concentration, the crude product of the reaction was poured into 10 milliliters of water, neutralized to a pH of 8 with saturated aqueous NaHCO 3, followed by the addition of (Boc) 20 (603 milligrams, 2.77 millimoles) in 10 milliliters. of dichloromethane. The reaction was stirred at room temperature for 1.5 hours, and then extracted with dichloromethane. The organic extracts were dried (Na 2 SO 4), concentrated in vacuo, and purified by chromatography on silica gel (EtOAc / Hexanes: 1/4), to give 4- (5-fluoro-6-nitro-1 -oxo -iso-indolin-2-yl) -piperidin-1-tert-butylcarboxylate; ESMS m / z 380.2 (M + H +).

Step 4: 4- (6-amino-5-fluoro-1-oxo-iso-indolin-2-yl) -piperidin-1-tert-butylcarboxylate The mixture of 4- (5-fluoro-6-nitro-1-oxo-iso-indolin-2-yl) -piperidin-1-tert-butylcarboxylate (step 3, 240 milligrams, 0.72 mmol), Pd (10 percent) in weight on activated carbon, 24 milligrams), and methanol (20 milliliters) was evacuated to remove the air, and then the reaction was stirred under a hydrogen balloon until the starting material was consumed. The Pd / C was filtered, and the solution was concentrated in vacuo, to give 4- (6-amino-5-fluoro-1-oxo- Sod-indolyl-2-yl) -p -perdin-1-tert-butylcarboxylate; ESMS m / z 350.2 (M + H +).

Intermediary 17 4- (4-amino-naphthalen-1-yl) -piperidin-1-tert-butylcarboxylate Boc Step 1: 4- (4-amino-naphthalen-1 -yl) -5,6-dihydro-pyridin-1 (2H) -tertbutylcarboxylate A mixture of 4-bromo-naphthalene-1-amines (1.0 grams, 4.5 thousand i moles), 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) - 5,6-dihydro-pyridine-1 (2H) -butylcarboxylate (1.7 grams, 5.4 millimoles), Pd (PPh3) 4 (26.01 milligrams, 0.02 millimoles), and Na2C03 (3.34 grams, 31.5 millimoles) in 10 milliliters of dimethylformamide and 5 milliliters of water was degassed and purged with nitrogen. The reaction was heated at 100 ° C for 5 hours, and cooled to room temperature. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na 2 SO 4), concentrated in vacuo, and purified by silica gel chromatography (MeOH / DCM: 5/95), to give 4- (4-amino-naphthalen-1-yl) -5,6-dihydro-pyridin-1 (2 H) -tertbutylcarboxylate.

Step 2: 4- (4-amino-naphthalen-1-y-piperidin-1-tertbutylcarboxylate) To a solution of 4- (4-amino-naphthalen-1 -yl) -5,6-dihydro-pyridin-1 (2H) -butylcarboxylate in 50 milliliters of methanol, 10 percent Pd-C was added. in weight (100 milligrams). The reaction was degassed to remove air, and stirred under 1 atmosphere of H2 until the starting material was consumed. The Pd-C was removed by filtration, and the resulting solution was concentrated in vacuo, to give 4- (4-amino-naphthalen-1-yl) -piper-dine-1-tert-butylcarboxylate.

Intermediary 18 3-ethyl-2,3,4,5-tetrahydro-1 H-benzo-rdl-azepin-7-amine 3-Ethyl-2,3,4,5-tetrahydro-1 H-benzo- [d] -azepin-7-amine was synthesized by the method described in the literature reference: Pecherer, B. et al., J Heterocyclic Chem 1971, 8 (5), 779-783, in conjunction with the conventional synthetic methodology.

Example 1 -2- Hydroxy-ethyl-oxime of 1- (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -pyrimidin-2-yl-amino) -2, 5-dimethyl-phenyl) -ethanone (28) Step 1: To a solution of N2- (4-bromo-2,5-dimethyl-phenol) -5-chloro-N4- (5-methyl-1H-pyrazol-3-yl) -pyrimidine-2,4 -diamine (280 milligrams, 0. 69 millimoles) in tetrahydrofuran (3 milliliters), p-TSA (119 milligrams, 0.69 millimoles), and 3,4-dihydro-2H-pyran (348 milligrams, 2.86 millimoles) were added. The mixture was stirred at room temperature for 14 hours, and then poured into a saturated aqueous solution of NaHCO 3 (10 milliliters). The resulting mixture was extracted with EtOAc (10 milliliters, 3 times), and the combined organic layers were concentrated. The resulting residue was purified by flash column chromatography (silica gel, gradient of 0 to 50 percent EtOAc in hexanes), to give the N2- (4-bromo-2,5-dimethyl-phenyl) -5 -chloro-N 4 - (5-methyl-1 - (tetra idro-2 H -pyran-2-yl) -1 H -pyrazol-3-yl) -pyrimidine-2,4-diamine as a white solid; ESMS m / z 491.1 (M + H +).

Step 2: A mixture of N2- (4-bromo-2,5-dimethyl-phenyl) -5-chloro-N4- (5-methyl-1 - (tetrahydro-2H-pyran-2-yl) -1 H -pyrazol-3-yl) -pyrimidine-2,4-diamine (166 milligrams, 0.34 millimoles), tributyl- (1-ethoxy-vinyl) -stannate (146 milligrams, 0.41 millimoles), and Pd (PPh3) 4 (39 milligrams, 0.034 millimoles) in toluene (2 milliliters), degassed and heated to 100 ° C under N2 for 14 hours. After cooling to room temperature, the mixture was concentrated. The resulting residue was redissolved in acetonitrile (2 milliliters), and treated with 1 N HCl (2 milliliters) for 14 hours. After extraction with EtOAc (15 milliliters, 3 times), the combined organic layers were treated with saturated aqueous KF (10 milliliters). The resulting organic layer was collected and treated with brine, and dried over MgSO4. After removing the drying agent by filtration, the filtrate was concentrated and purified by flash column chromatography (silica gel, gradient from 0 to 100 percent EtOAc in hexanes), to give 1- (4- (5-chloro-4- (5- methyl-1 - / - pyrazol-3-ylamino) -pyrimidin-2-ylamino) -2,5-dimethyl-phenyl) -ethanone as a white solid; ESMS m / z 371.1 (M + H +).

Step 3: To a solution of 1 - (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl-amino) -2,5- dimethyl-phenyl) -ethanone (60 milligrams, 0.16 millimoles) in methanol (1 milliliter), AcOH (15 milligrams, 0.25 millimoles) was added, followed by the addition of 2- (amino-oxy) -ethanol (20 milligrams, 0.26 millimoles). The mixture was heated at 60 ° C for 14 hours, and cooled to room temperature. The mixture was then purified directly by RP-HPLC preparation, to give the α-2-hydroxyethyl oxime of 1- (4- (5-chloro-4- (5-methyl-1 H-pyrazole-3- il-amino) -pyrimidin-2-ylamino) -2,5-dimethyl-phenyl) -ethanone; ESMS m / z 430.2 (M + H +).

Example 2 4- (5-chloro-4- (5-methyl-1 Hp -razol-3-yl-amino) -pyrimidin-2-yl-amino) -N- (2- (dimethylamino) -eti -2,5-dimethyl-benzamide (31) To a solution of 4- (5-chloro-4- (5-methyl-1 - (tetrahydro-2H-pyran-2-yl) -1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl -amino) -2,5-dimethyl- benzoic acid (35.0 milligrams, 0.077 millimoles) in NN-dimethylformamide (0.5 milliliters), were added HATU (29.1 milligrams, 0.077 millimoles), DIEA (26.7 microliters, 0.153 millimoles), and N'.N1- dimethyl-ethan- 1,2-diamine (25.2 microliters, 0.230 mmol). The reaction mixture was stirred at room temperature overnight. Then an aqueous solution of 1N HCl (0.5 milliliters) was added, and the reaction mixture was heated at 100 ° C for 1.5 hours to remove the protective group of tetrahydro-2H-pyran-2-yl. The mixture was purified by RP-HPLC preparation to give 4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl-amino) -N- (2- (dimethylamino) -ethyl) -2,5-dimethyl-benzamide; ESMS m / z 443.2 (M + H +).

Example 3 4- (4- (5-Chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl-amino) -2,5-dimethyl-phenyl) -cyclohexyl oxime anona (33) To a solution of 4- (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -pyrimidin-2-yl-amino) -2,5-dimethyl- phenyl) -cyclohexanone (15 milligrams, 0.033 millimoles) in methanol (0.5 milliliters), NaOAc (6 milligrams, 0.073 millimoles), and NH2OH-HCI (5 milligrams, 0.073 millimoles) were added. The resulting mixture was stirred at 70 ° C for 2 hours. hours, and then cooled to room temperature. The mixture was purified directly by RP-HPLC preparation to give the oxime of 4- (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-a m ino) -pyr m id? -2-yl-am i no) -2,5-di methyl-phen i I) -exanone cyclone; ESMS m / z 440.2 (M + H +).

Examples 4 and 5 5-Chloro-N2- (2,5-dimethyl-4- (4-frans-morpholino-cyclohexyl) -phenyl) -N - (5-methyl-1 H -pyrazol-3-yl) -pyrimidine-2,4 -diamine (37) 5-chloro-N 2 - (2,5-dimethyl-4- (4-cis-morpholino-cyclohexyl) -phenin-N 4 - (5-methyl-1-pyrazol-3-yl) -pyrimidine-2,4-diamine ( 38) Step 1: A mixture of 1-bromo-2,5-dimethyl-4-nitro-benzene (100 milligrams, 0.43 mmol), 4,4,5,5-tetramethyl-2- (1,4-dioxaespiro- [4.5 ] -dec-7-en-8-il) -1, 3,2-dioxaborlane (112 milligrams, 0.43 milli-moles), Pd (PPh3) 4 (49 milligrams, 0.043 millimoles), and CsF (196 milligrams, 1.29 millimoles) in a mixture of dimethyl-ethylene glycol and water (2: 1, 1.5 milliliters), degassed and heated under N2 at 130 ° C. in a microwave reactor for 15 minutes. After cooling to room temperature, the reaction mixture was treated with a saturated aqueous solution of NH 4 Cl (5 milliliters), and extracted with EtOAc (4 milliliters, 3 times). The combined organic layers were concentrated and purified by flash column chromatography (silica gel, gradient from 0 percent to 30 percent EtOAc in hexanes), to provide 8- (2,5-dimethyl-4-). nitro-phenyl) -1,4-dioxaespiro- [4.5] -dec-7-ene as a white solid; ESMS m / z 290.1 (M + H +).

Step 2: A mixture of 8- (2,5-dimethyl-4-nitro-phenyl) -1,4-dioxaespiro- [4.5] -dec-7-ene (105 milligrams, 0.36 mmol), and Pd / C ( 10 milligrams) in EtOH, degassed and stirred under 1 atmosphere of H2 at room temperature for 14 hours. The Pd / C was removed by filtration, and the filtrate was concentrated to give 2,5-dimethyl-4- (1,4-dioxaespiro- [4.5] -decan-8-yl) -aniline, which was used in the next step without further purification; ESMS m / z 262.2 (M + H +).

Step 3: A mixture of 2,5-dimethyl-4- (1,4-dioxaespiro- [4,5] -decan-8-yl) -aniline (86 milligrams, 0.33 mmol), and 2, 5-dichloro- N- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-4-amine (104 milligrams, 0.43 mmol) in 'PrOH (3 milliliters), was treated with HCl (82 microliters, 4N in dioxane, 0.33. millimoles), and heated to 125 ° C in a sealed tube for 14 hours. After cooling to room temperature, the mixture was concentrated and treated with acetone (2 milliliters) and HCI (330 microliters, 4N in dioxane) at room temperature for 5 hours. Mix then treated with a saturated aqueous solution of NaHCO3 (10 milliliters), and extracted with EtOAc (10 milliliters, 3 times). The organic layers were combined, concentrated, and purified by flash column chromatography (silica gel, gradient from 0 percent to 100 percent EtOAc in hexanes), to give the 4- (4- (5- Chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -pyrimidin-2-yl-amino) -2,5-dimethyl-phenyl) -cyclohexanone as a white solid; ESMS m / z 425.2 (M + H +).

Step 4: To a solution of 4- (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl-amino) -2,5- dimethyl-phenyl) -cyclohexanone (30 milligrams, 0.071 millimoles) in 1,2-dichloro-ethane (1 milliliter), morpholine (9 milligrams, 0.11 mmol) was added, followed by AcOH (6.5 milligrams, 0.11 millimoles), and 4Á molecular sieves. The mixture was stirred at room temperature for 1 hour before the addition of sodium triacetoxy borohydride (22.5 milligrams, 0.11 millimole). The mixture was stirred at room temperature for 14 hours, at which point, morpholine (5 milligrams, 0.058 millimoles), and additional sodium triacetoxy borohydride (10 milligrams, 0.047 millimoles) were added, and stirred at room temperature for 5 hours. additional The reaction mixture was then treated with a saturated aqueous solution of NH CI (3 milliliters), and extracted with EtOAc (4 milliliters, 3 times). The combined organic layers were concentrated and purified by thin layer chromatography on silica preparation (7 percent MeOH / CH2Cl2 with 0.2 percent NH3), to give 5-chloro-N2- (2,5-dimethyl- 4- (4-cis-morpholino-cyclo-exyl) -phenyl) -N- (5-methyl-1 / -pi-razol -3-i I) -pyrimidin-2,4-diamine as the less polar isomer; 1 H NMR (400 MHz, DMSO-d 6) d 12.01 (br, 1H), 8.49 (br, 2H), 7.98 (s, 1H), 7.10 (s, 1H), 7.00 (s, 1H), 6.13 (br, 1H), 3.64 (m, 4H), 2.75 (m, 1H), 2.41 (m, 4H), 2.24 (s, 3H), 2.00-2.20 (m, 9H), 1.70-1.85 (m, 2H), 1.35 -1.55 (m, 4H); ESMS m / z 496.3 (M + H +), and 5-chloro-N 2 - (2,5-dimethyl-4- (4-rrans-morpholino-cyclohexyl) -phenyl) -N - (5-methyl-1 H- pyrazol-3-yl) -pyrimidin-2,4-diamine as the most polar isomer; 1 H NMR (400 MHz, DMSO-d 6) d 12.01 (br, 1H), 8.47 (br, 2H), 7.98 (s, 1H), 7.14 (s, 1H), 7.02 (s, 1H), 6.13 (br, 1H), 3.57 (br, 4H), 2.60 (m, 1H), 2.50 (br, 4H), 2.32 (m, 1H), 2.22 (s, 3H), 2.13 (s, 3H), 2.10 (s, 3H) ), 1.93 (b, 2H), 1.79 (b, 2H), 1.30-1.55 (m, 4H); ESMS m / z 496.3 (M + H +).

Example 6 5-chloro - / \ / 2- (2,5-dimethyl-4- (morpholino-methyl) -phenyl) -A / 4- (5-methyl-1 H-pyrazol-3-yl) -pyrimidin-2, 4-d-amines (39) Step 1: A mixture of 2,5-dichloro- / V- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-4-amine (732 milligrams, 3 mmol), 4-bromo-2,5 dimethyl-aniline (554 milligrams, 2 mmol), and concentrated aqueous HCl (1.5 milliliters) in / so-propanol (15 milliliters) was heated in a microwave reactor for 40 minutes at 130 ° C. The LCMS showed that the reaction was not complete, and additional 2,5-dichloro- / V- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-4-amine (732 milligrams, 3 milli- moles) to the reaction. The reaction was heated again in a microwave reactor for an additional 60 minutes at 130 ° C. The crude reaction mixture was then diluted with EtOAc (100 milliliters), washed sequentially with saturated aqueous NaHCO3 (20 milliliters, 2 times), and brine (10 milliliters), dried over Na2CO3 and concentrated in vacuo. The crude product was purified by chromatography on silica (gradient from 0 to 10 percent methanol in EtOAc with 1 percent NH3 additive), to give the α2- (4-bromo-2,5-dimethyl-phenyl) ) -5-chloro- / V4- (5-methyl-1 H -pyrazol-3-yl) -pyrimidine-2,4-diamine as a grayish solid; ESMS m / z 407.2 (M + H +).

Step 2: A mixture of the / V2- (4-bromo-2,5-dimethyl-phenyl) -5-chloro- / V4- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-2, 4-diamine (41 milligrams, 0.1 millimoles), 1-potassium trifluoroborate / methyl-morpholine (43 milligrams, 0.2 millimoles), Pd (OAc) 2 (3 milligrams, 0.013 millimoles), Xantphos (12 milligrams, 0.025 millimoles), and Cs2C03 (98 milligrams, 0.3 mmol) in tetrahydrofuran (1 milliliter) / H20 (0.1 milliliters), was degassed by a stream of argon gas. The flask was sealed and heated in a microwave reactor for 30 minutes at 160 ° C. Potassium trifluoroborate / methylmorpholine (69 milligrams), Xantphos (18 milligrams), and Cs2C03 (98 milligrams) were added. The reaction was heated again in the microwave reactor for an additional 30 minutes at 160 ° C. The crude product was purified by RP-HPLC to give 5-chloro-N2- (2,5-dimethyl-4- (morpholino-methyl) -phenyl) -N4- (5-methyl-1 H-pyrazole-3- il) -pyrimidine-2,4-diamine as a white powder; ESMS m / z 428.2 (M + H +).

Example 7 4- (2,5-Dimethyl-4- (4- (5-methyl-1 H -pyrazol-3-yl-arrtino) -5- (trifluoromethyl) -pyrimidin-2-yl-amino) -phenyl) -cyclohexanone (40) A mixture of 2,5-dimethyl-4- (1,4-dioxaespiro- [4,5] -decan-8-yl) -aniline (111.3 milligrams, 0.43 mmol), 2-chloro-N- (5-methyl-1) H-pyrazol-3-yl) -5- (trifluoromethyl) -pyrimidin-4-amine (119.6 milligrams, 0.43 mmol), HCl (4 N in water, 0.11 milliliters, 0.43 mmol) in -PrOH (4.0 milliliters) ), was heated to 125 ° C in an oil bath overnight. The reaction mixture was concentrated in vacuo. The crude product was dissolved in tetrahydrofuran (2 milliliters), methanol (1 milliliter), and HCl (4N in water, 0.11 milliliters, 0.43 mmol), and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, followed by purification by chromatography on silica (gradient from 0 to 100 percent EtOAc in hexanes), to give 4- (2,5-dimethyl-4- (4- (5- methyl-1 H -pyrazol-3-ylamino) -5- (trifluoromethyl) -pyrimidin-2-yl-amino) -phenyl) - | cyclohexanone; ESMS m / z 459.2 (M + H +).

Example '8 frans-4- (2,5-dimethyl-4- (4- (5-methyl-1 H -pyrazol-3-yl-amino) -5- (trifluoro- methyl) -pyrimidin-2-yl-amino) -phenyl) -cyclohexanol (41) To a solution of 4- (2,5-dimethyl-4- (4- (5-methyl-1 H -pyrazol-3-yl-amino) -5- (trifluoro-methyl) ) -pyrimidin-2-α-amino) -phenyl) -cyclohexanone (100 milligrams, 0.22 mmol) in methanol (15 milliliters), was added NaBH 4 (33.2 milligrams, 0.87 millimoles). The reaction was stirred for 30 minutes, concentrated, and purified by chromatography on silica (MeOH / DC: 8:92), to give trans-4- (2,5-dimethyl-4- (4- (5- methyl-1 H-pyrazol-3-yl-amino) -5- (trifluoromethyl) -pyrimidin-2-yl-amino) -phenyl) -cyclohexanol; Rf: 0.35 (silica; methanol / dichloromethane, 8:92); ESMS m / z 461.2 (M +? -G).

Example 9 c / s-4- (2,5-dimethyl-4- (4- (5-methyl-1 H -pyrazol-3-yl-amino) -5- (trifluoromethyl) -pyrimidin-2-yl-amino ) -phenyl) -cyclohexanol (42) To a solution of 4- (2,5-dimethyl-4- (4- (5-methyl-1 H -pyrazol-3-yl-) -5- (trifluoromethyl) -pyrimidin-2-yl-amino ) -phenyl) -cicloh exanone (100 milligrams, 0.22 millimoles) in methanol (15 milliliters), NaBH4 (33.2 milligrams, 0.87 millimoles) was added. The reaction was stirred for 30 minutes, concentrated, and purified by chromatography on silica (MeOH / DCM: 8:92), to give c / 's-4- (2,5-dimethyl-1 H-pyrazole). 3-yl-amino) -5- (trifluoromethyl) -pyrimidin-2-yl-amino) -phenyl) -cyclohexanol; R: 0.45 (silica; methanol / dichloromethane, 8:92); ESMS m / z 461.2 (M + H +).

Example 10 N2- (2-fluoro-5-methyl-4- (c / s-4- (piperidin-1-yl) -cyclohexyl) -phenyl) -N 4 - (5-methyl-1 H -pyrazol-3-yl) -5- (trifluoro-methyl) -pyrimidine-2,4-d-amine (62) A mixture of 4- (5-fluoro-2-methyl-4- (4- (5-methyl-1 H -pyrazol-3-yl-amino) -5- (trifluoromethyl) -pyrimidin-2-yl amino) -phenyl) -cyclohexanone (30 milligrams, 0.065 millimoles), piperidine (30 microliters, 0.174 millimoles), and acetic acid (75 microliters, 0.13 millimoles), was stirred at room temperature for 1 hour. Sodium triacetoxy borohydride (27.4 milligrams, 0.13 millimole) was added to the reaction, and the reaction mixture was stirred overnight. The mixture was concentrated and purified by chromatography on silica (MeOH / DCM, 8:92), to provide N2- (2-fluoro-5-methyl-4- (c / 's-4-). (piperidin-1-yl) -cyclohexyl) -phenyl) -N 4 - (5-methyl-1 H -pyrazol-3-yl) -5- (trifluoromethyl) -pyrimidin-2,4-diamine; Rf: 0.41 (Silica; methanol / dichloromethane, 8:92); ESMS m / z 532.3 (M + H +).

Example 11 N2- (2-Fluoro-5-methyl-4- (trans -4- (iperidin-1-yl) -cyclohexyl) -phenyl) -N4- (5-methyl-1 H -pyrazol-3-yl) -5 - (trifluoromethyl) -pyrimidine-2,4-diamine (63) A mixture of 4- (5-fluoro-2-methyl-4- (4- (5-methyl-1 Hp -razol-3-yl-amino) -5- (trifluoromethyl) -pyrimidin-2- il-amino) -phenyl) -cyclohexanone (30 milligrams, 0.065 millimoles), piperidine (30 microliters, 0.174 millimoles), and acetic acid (75 microliters, 0.13 millimoles), was stirred at room temperature for 1 hour. Sodium triacetoxy borohydride (27.4 milligrams, 0.13 millimole) was added to the reaction, and the reaction mixture was stirred overnight. The mixture was concentrated and purified by chromatography on silica (MeOH / DCM, 8:92), to give N2- (2-fluoro-5-methyl-4- (trans-4- (piperidin-1-yl) - cyclohexyl) -phenyl) -N 4 - (5-methyl-1 H -pyrazol-3-yl) -5- (trifluoromethyl) -pyrimidine-2,4-diamine; Rf: 0.32 (Silica; methanol / dichloromethane: 8:92); ESMS m / z 532.3 (M + H +).

Example 12 N2- (2,5-Dimethyl-4- (cs-4-morpholino-cyclohexyl) -phenyl) -N4- (5-methyl-1H-pyrazol-3-yl) -5- (trifluoromethyl) -pyrimidine -2,4-diamine (66) A mixture of 4- (2,5-dimethyl-4- (4- (5-methyl-1 H -pyrazol-3-yl-amlno) -5- (trifluoro-methyl) -pyrimidin-2-yl) amino) -phenyl) -cyclohexanone (40 milligrams, 0.087 mmol), morpholine (15 microliters, 0.174 mmol), and acetic acid (75 microliters, 0.13 mmol), was stirred at room temperature for 1 hour. Sodium cyanoborohydride (8.2 milligrams, 0.13 millimole) was added to the reaction, and the reaction mixture was stirred overnight. The mixture was concentrated and purified by chromatography on silica (eOH / DCM, 8:92), to give N2- (2,5-dimethyl-4- (c / s-4-morpholino-cyclohexyl) -phenyl) - N 4 - (5-methyl-1 H -pyrazol-3-yl) -5- (trifluoromethyl) -pyrimidine-2,4-diamine; R, 0.50 (silica; methanol / dichloromethane, 8:92); ESMS m / z 530.3 (M + H +).

Example 13 N2- (2,5-dimethyl-4- (trans-4-morpholino-cyclohexyl) -phenyl) - N - (5-methyl-1H-pyrazol-3-yl) -5- (trifluoro-methyl) -pyrimidine-2,4-diamine (67) A mixture of 4- (2,5-dimethyl-4- (4- (5-methyl-1H-pyrazol-3-yl-amino) -5- (tr-fluoro-methyl) -p Rimidin-2-M-amino) -phenol) -cyclohexanone (40 milligrams, 0.087 millimoles), morpholine (15 microliters, 0.174 millimoles), and acetic acid (75 microliters, 0.13 millimoles), was stirred at room temperature for 1 hour. Sodium cyanoborohydride (8.2 milligrams, 0.13 millimole) was added to the reaction, and the reaction mixture was stirred overnight. The mixture was concentrated and purified by chromatography on silica (eOH / DCM, 8:92), to give the N2- (2,5-dimethyl-4- (trans-4-morpholino-cyclohexyl) -phenyl) -N4- (5-methyl-1 H -pyrazol-3-yl) -5- (trifluoromethyl) -pyrimidine-2,4-diamine; R, 0.38 (Silica; methanol / dichloromethane, 8:92); ESMS m / z 530.3 (M + H +).

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

Table 1 I V Example 14 6- (5-Chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl-amino) -5-fluoro-2- (piperidin-4-yl) -iso -indolin-1-one (79) To the solution of 4- (6-amino-5-fluoro-1-oxo-iso-indolin-2-yl) p-per-din-1-tertbutylcarboxylate (Intermediate 20, 18 milligrams 0. 05 mmol), and 2,5-dichloro-4- (5-methyl-1 Hp -razol-3-yl) -pyrimidine (12 milligrams, 0.05 mmol) in 1 milliliter of i-PrOH, was added 5 g. drops of concentrated aqueous HCI. The reaction mixture was heated at 150 ° C in a microwave reactor for 20 minutes, followed by concentration and purification with RP-HPLC preparation, to provide 6- (5-chloro-4- (5-methyl-1 H -pyrazol-3-ylamino) -pyrimidin-2-yl-amino) -5-fluoro-2- (piperidin-4-yl) -iso-indolin-1-one; ESMS m / z 457.2 (M + H +).

Example 15 6- (5-chloro-4- (5-metM-isoxazol-3-ylamino) -pyrimidin-2-yl-amino) -5-fluoro-2- (piperidin-4-ih-iso-indolin-1) -one (80) To the solution of 4- (6-amino-5-fluoro-1-oxo-iso-indolin-2-yl) -piperidin-1-tert-butylcarboxylate (35 milligrams, 0.1 mmol), and 5-chloro-4- (5-methyl-isoxazol-3-yl) -pyrimidin-2-amine (25 milligrams, 0.1 mmol) in 1 milliliter of i-PrOH, was added 5 drops of concentrated aqueous HCl. The reaction mixture was heated to 50 ° C in a microwave reactor for 20 minutes, followed by concentration and purification with RP-HPLC preparation, to provide 6- (5-chloro-4- (5-methyl-isoxazole). 3-yl-amino) -pyrimidin-2-yl-amino) -5-fluoro-2- (piperidin-4-yl) -iso-indol-1-one; ESMS m / z 458. 1 (M + H +).

Example 16 2- (4- (6- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrirnidin-2-ylamino) -4-methyl-pyridin-3-yl ) -piperidin-1-yl) -acetamide (84) Step 1: To a mixture of 5-bromo-4-methy1-pyridin-2-amine (200 milligrams, 1.07 mmol), 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -5,6-dihydro-pyridin-1 (2H) -tertbutylcarboxylate (370 milligrams , 1.2 mmol), and sodium carbonate (400 milligrams, 1.28 mmol) in N, N-dimethyl-formamide / H20 (8/2 milliliters), tetrakis (triphenyl-phosphine) -palladium (0) (62) was added. milligrams, 5 percent millimolar). 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 column chromatography (80 percent ethyl acetate in hexanes), to give 4- (6-amino-4-methyl-pyridin-3-yl) -5, 6-Dihydro-pyridin-1 (2H) -butylcarboxylate as a yellow oil. The obtained oil was dissolved in methanol (20 milliliters). To the solution was added Pd / C (at 10 percent weight / weight). The reaction mixture was degassed and purged with H2 several times, and then stirred under 1 atmosphere of H2 overnight. The mixture was filtered and concentrated to provide 4- (6-amino-4-methyl-pyridin-3-yl) -piperidin-1-tert-butylcarboxylate as a yellow solid; ESMS m / z 236 (M -56 + H +).

Step 2: To a mixture of 2,5-dichloro-N- (5-methyl-1 - (tetrahydro-2 H -pyran-2-yl) -1 H -pyrazol-3-yl) -pyrimidin-4 -amine (150 milligrams, 0.45 millimoles), 4- (6-amino-4-methyl-pyridin-3-yl) -piperidin-1-tert-butylcarboxylate (120 milligrams, 0.41 millimoles), Xantphos (24 milligrams, 0.04 millimoles) ), and cesium carbonate (270 milligrams, 0.82 millimoles) in tetrahydrofuran (4 milliliters), palladium acetate (5 milligrams, 0.02 millimoles) was added. The mixture was purged with nitrogen and the tube was sealed. The mixture was heated in an oil bath at 100 ° C for 5 hours. The mixture was filtered and concentrated. The residue was purified by chromatography on silica (70 percent ethyl acetate in hexanes), to give 4- (6- (5-chloro-4- (5-methyl-1 - (tetrahydro-2H-pyran-2) -yl) -1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl-amino) -4-methyl-pyridin-3-yl) -piperidin-1-tert-butylcarboxylate as a yellow solid; ESMS m / z 583 (M + H +).

Step 3: To a solution of 4- (6- (5-chloro-4- (5-methyl-1 - (tetrahydro-2H-pyran-2-yl) -1 H -pyrazol-3-yl-amino) - pyrimidin-2-yl-amino) -4-methyl-pyridin-3-yl) -piperidin-1-terbutylcarboxylate in dichloromethane (1 * milliliter), trifluoroacetic acid (1 milliliter) was added. Mix it was stirred for 1 hour, and concentrated, to provide 5-chloro-N 4 - (5-methyl-1 H -pyrazol-3-yl) -N 2 - (4-methyl-5- (piperidin-4-yl) -pyridin-2-yl) -pyrimidine-2,4-diamine as a chestnut oil. The product was used directly for the following reactions without further purification. Step 4: To a mixture of 5-chloro-N 4 - (5-methyl-1 H -pyrazol-3-yl) -N 2 - (4-methyl-5- (piperidin-4-yl) -pyridin-2- il) -pyrimidine-2,4-diamine (50 milligrams, 0.12 millimoles) and triethylamine (50 microliters, 0.36 millimoles) in, N-dimethylformamide (1.5 milliliters), 2-bromoacetamide (25 milligrams, 0.18 millimoles). The mixture was stirred at room temperature for 2 hours. The reaction was filtered, and the filtrate was purified by RP-HPLC, to give 2- (4- (6- (5-chloro-4- (5-methyl-1H-pyrazol-3-yl-amino) -pyrimidin -2-yl-amino) -4-methyl-pyridin-3-yl) -piperidin-1-yl) -acetamide as a white solid; 1 H NMR (400 MHz, MeOD-d 4) d 8.30 (s, 1 H), 8.21 (s, 1 H), 7.28 (s, 1 H), 6.19 (s, 1 H), 4.0 (s, 2 H), 3.80-3.73 ( m, 2H), 3.33-3.21 (m, 3H), 2.61 (s, 3H), 2.37 (s, 3H), 2.37-2.32 (m, 2H), 2.20 -2.16 (m, 2'H); ESMS m / z 456.2 (M + H +).

Example 17 5-chloro-N 4 - (5-methyl-1 Hp -razol-3-yl) -N 2 - (4- (piperidin-4-yl) -naphthalen-1-yl-pyrimidine-2,4-diamine (85 ) A mixture of the 2,5-dichloro-N- (5-methyl-1 - (tetrahydro-2H-pyran-2-yl) -1 H -pyrazol-3-yl) -pyrimidin-4-amine (202.7 milligrams, 0.62 milli-moles), 4- (4-amino-naphthalen-1-yl) -piperidin-1-terbutyl-carboxylate (202.0 milligrams, 0.62 millimoles), Xantophos (35.9 milligrams, 0.062 millimoles), palladium (II) acetate (7.0 milligrams, 0.031 millimoles), and cesium carbonate (40.3 milligrams, 0.12 millimoles) in 5.0 milliliters of tetrahydrofuran, was heated at 150 ° C in a microwave reactor for 25 minutes. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was dissolved in 5 milliliters of dichloromethane and 4 milliliters of trifluoroacetic acid. This reaction mixture was stirred at room temperature for 2 hours, followed by concentration in vacuo. The crude product was purified by RP-HPLC, to give 5-chloro-N- (5-methyl-1 H -pyrazol-3-yl) -N2- (4- (piperidin-4-yl) -naphthalen-1 -yl) -pyrimidine-2,4-diamine; ESMS m / z 434.2 (M + H +) Example 18 2- (4- (4- (5-chloro-4- (5-methyl-1H-pyrazol-3-yl-amino) -pyrimidin-2-ylamino) -naphthalen-1-yl) -piperidin-1 -yl) -acetamide (86) A mixture of 5-chloro-N 4 - (5-methyl-1 H -pyrazol-3-yl) -N 2 - (4- (piperidin-4-yl) -naphthalen-1-yl) -pyrimidine-2,4-diamine (30.8 milligrams, 0.07 mmol), 2-bromoacetamide (19.6 milligrams, 0.14 milli-moles), and triethylamine ( 30.0 microliters, 0.21 mmol) in 2 milliliters of dimethylformamide was heated at 130 ° C in a microwave reactor for 20 minutes. The crude product was purified by RP-HPLC, to give 2- (4- (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl) -amino) -naphthalen-1-yl) -piperidin-1-yl) -acetamide; ESMS m / z 491.2 (M + H +).

Example 19 3- (4- (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-ylamino) -naphthalen-1-yl) -piperidine- 1-yl) -1,1,1-trifluoro-propan-2-ol (88) A mixture of 5-chloro-N4- (5-methyl-1 H -pyrazol-3-yl) -N2- (4- (piperidin-4-yl) -naphthalen-1-yl) -pyrimidin-2,4 Diamine (30.8 milligrams, 0.07 millimoles), and 2- (trifluoromethyl) -oxirane (39.2 milligrams, 0.35 millimoles) in 1 milliliter of dimethyl formamide, was stirred at room temperature overnight. The crude mixture was purified by RP-HPLC, to give 3- (4- (4- (5-chloro-4- (5-methyl-1 H -pyrazol-3-yl-amino) -pyrimidin-2-yl. -amino) -naphthalen-1-yl) -piperidin-1-yl) -1,1,1-trifluoro-propan-2-ol; ESMS m / z 546.2 (M + H +).

The following compounds of Table 2 are obtained by repeating the buildings described in the previous Examples, and using appropriate starting materials.

Table 2 essays The IC50 of a drug can be determined by constructing a dose response curve, and by examining the effect of different Antagonist concentrations on the reversal of agonist activity. The IC 50 values for a given antagonist can be calculated by determining the concentration necessary to inhibit half of the maximum biological response of the agonist. To calculate the IC50 values, a series of dose response data is generated (e.g., drug concentrations x1, x2 xn, and growth inhibitions y1, y2, and n, where the values of y are in the range of 0 to 1). The IC50 values can be determined by a computer-aided system, using the formula: y = D + ((A-D) / (1 + 10 (X IO9 (IC50) B) wherein A is the ratio of growth inhibition between the lowest concentration of drug and the control; B is the inclination of the sigmoidal curve; and D is the ratio of growth inhibition between the highest concentration of drug and the control.

The IC so value is given as the concentration of the test compound which 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 pharmaceutically acceptable salt form can exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application. In general, the compounds of the invention have IC50 values from 1nM to 10μ ?. In some examples, the compounds of the invention have IC 50 values from 0.01 μ? up to 5 μ ?. In other examples, the compounds of the invention have IC 50 values from 0.01 μ? up to 1 μ, or more in particular from 1 nM to 1 μ ?. In still other examples, the compounds of the invention have IC50 values of less than 1 nM or more than 10 μ ?. The compounds of the invention may exhibit a percent inhibition greater than 50 percent, or in other embodiments, they may exhibit a percentage inhibition of greater than about 70 percent, against 10 μF IGF-1R.

Cell line panel Ba / F3 and reagents Ba / F3 is a pro-B lymphoma cell line dependent on murine IL-3. Progenitor Ba / F3 cells are used to generate a panel of sub-lines whose proliferation and survival becomes independent of IL-3 through 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 tyrosine Tel-kinase (TK) fusions, the Ba / F3 progenitor cells are infected with the retrovirus harboring each TEL fusion kinase, and are subjected to selection with puromycin and removal of IL-3, to obtain transformed Ba / F3 cells, independent of IL-3.

Each of the transformed Ba / F3 cells is grown in RPMI-1640 medium (Gibco Cat # 11875093, Carlsbad, CA) supplemented with 10 percent fetal bovine serum (Hyclone Cat # SV30014.03, Logan, UT), 4.5 grams / liter of glucose (Sigma # G5400, St. Louis, MO), 1.5 grams / liter of sodium bicarbonate (Biowhittaker # 17-613E, Walkersville, MD), and penicillin / streptavidin (Pen / Strep) (Gibco # 10378-016, Carlsbad, CA) . The cells are divided 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. BaF3 Tel-TK cells that grow exponentially are diluted in fresh medium to 75,000 cells / milliliter, and seeded in 384-well plates (3.750 cells / well) at 50 microliters / well, using a pFill liquid dispenser (BioTek, Winooski, VT, USA). Duplicate plates are run for each cell line. The test and control compounds are serially diluted with dimethyl sulfoxide, and fixed 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 5% CO 2) 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 concentration of the inhibitor. The IC5o is interpolated as the concentration of the compound necessary to reduce cell viability to 50 percent of a dimethyl sulfoxide control. The Ba / F3 progenitor cells that are maintained and Cultures 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 Test IGF-1R and INSR (insulin receptor) are purchased in Upstate. The following reagents are prepared internally; kinase regulator 10 x (KB) (200 mM Tris (pH of 7.0), 100 mM MgCl 2, 30 mM MnCl 2, 50 nM NaV04), 10 mM ATP, 100 milligrams / milliliter of bovine serum albumin, 0.5 · EDTA, KF 4 M. A Proxiplate-384 from Perkin-Elmer is used for the establishment of the assay. All HTRF reagents, including the substrate (Biotin-poly-GT (61GT0BLB), Mab PT66-K, (61T66KLB), Streptavidin-XLent (611SAXLB)) are purchased from CIS-US, Inc.

The substrate / ATP mixture is prepared by the addition of ATP (final concentration of 3 μ?), And biotinylated poly-GT (final concentration of 10 nanograms / microliter) in 1x KB, and dosed in Proxiplate-384 at 5 microliters / well, using μ? R i 11 (Bio-TEK). Compounds diluted in series (in dimethyl sulfoxide) are transferred to the plate using a 50 nanoliter peak head. Add 5 microliters of the prepared enzyme mixture (enzyme (final concentration of 5 nanograms / microliter), mixed with bovine serum albumin and DTT in KB 1x), to start the kinase reaction, using Fill (Bio-TEK). The assay plate is incubated at room temperature for 2 hours. The Detection mixture is prepared by adding both the Mab PT66-K and Streptavidin-XLent in a 0.5x KB solution containing KF (final concentration of 125 mM), EDTA (final concentration of 50 mM), and serum albumin bovine (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. Briefly stated, 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 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 1 M HEPES (pH of 8.0), and 4 microliters of Polybrene (10 micrograms / milliliter, Specialty Media). The plate is centrifuged for 90 minutes at 2,500 revolutions per minute to Centrifugal infection, and transferred to an incubator for infection overnight. The next day, the infected cell line is transferred to a T-75 flask which contains the fresh medium, and incubated for a day. Two days after infection, puromycin is added at a final concentration of 1 microgram / milliliter, to initiate the selection. Within 1 to 2 weeks, the puromycin resistant cell line is established after at least two subsequent divisions, and is retained as the luciferized supply.

Each cell line is harvested while growing in the log phase by trypsinization, and diluted in the respective medium to the appropriate density before application to the plate. The cells are dosed using pFill (BioTeK) at 50 microlitres / well, on transparent bottom plates and white walls (Greiner - custom made for GNF). The cells are then placed in the incubator at 37 ° C, supplying C02 at 5 percent overnight. The compounds are transferred using 50 nanoliters / well Pintool technology by means of 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 read in the Analyst GT (Molecular Devices) or Envision (Perkin Elmer). The raw data is generated in RLU.

* * * * * It is understood that the Examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes will be suggested in light thereof, to those skilled in the art, and should be included within the spirit and scope of the invention. this application and within the scope of the appended claims. All publications, patents, and patent applications cited herein, are hereby incorporated by reference for all purposes.

Claims (20)

1. A compound of the formula (1): or a physiologically acceptable salt thereof; where W is or W; W is pyridyl, isoquinolinyl, quinolinyl, naphthalenyl, cinolin-5-yl or [3- (alkyl of 1 to 6 carbon atoms) - (2, 3,4,5-tetrahydro-1 H -benzo- [d] - azepine-7-yl], each of which is optionally substituted with 1 to 3 R 9, and the pyridyl, isoquinolinyl, quinolinyl and naphthalenyl are each substituted on an atom carbon ring with X is -C (R) = N-0-R7, C (0) NRR7, C (0) NR- (CR2) n-NRR7, - (CR2) PNRR, wherein two R groups, together with N in NRR , they form a ring of 5 to 6 members that contains de. 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with 1 to 3 R9, or a carbocycle of 5 to 7 carbon atoms optionally substituted with oxo, = N-OH or R; or X is quinolinyl, (1,2,3,4-tetrahydro-isoquinolin-6-yl), or a 5- to 6-membered heteroaryl having from 1 to 3 heteroatoms selected from N, O, and S, each one of which is optionally substituted with 1 to 3 R9; R1 is halogen, alkyl of 1 to 6 carbon atoms, or an alkyl of 1 to 6 carbon atoms substituted by halogen; R2 is a 5-6 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms carbon, or cycloalkyl of 3 to 7 carbon atoms; each R3 is H; R4 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) O0-iR8; O JR6 R5 is H or c; R6 is 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) CtF2, + 1 where t is from 1 to 3, (CR2) P-CN; (CR2) P-NR (R7), - (CR2) p-C (0) OR7, (CR2) pNR (CR2) pOR7, (CR2) pNR-L-C (0) R8, C (0) - (CR2) qOR8, -C (0) 0- (CR2) p-NRR7, -C (0) - (CR2) p-OR7, L-Y, -L-C (0) R7, -L-C (0) -NRR7, -L-C (0) -NR- (CR2) p-NRR7, -L-C (0) NR (CR2) pOR7, -L-C (0) - (CR2) q-NR-C (0) -R8, -L-C (0) NR (CR2) DSR7, -L-C (0) NR (CR2) pS (0) 1.2R8, -L-S (0) 2R8, -L-S (0) 2- (CR2) q-NRR7, -L-S (0) 2NR (CR2) p NR (R7) or -L-S (0) 2NR (CR2) pOR7; in an alternative manner, R6 is a radical selected from formula (a), (b), (c) or (d): R10 is O, S, N R17 wherein R17 is H, alkyl of 1 to 6 carbon atoms, S02R8a or C02R8a; R 1, R 12, R 13, R 14, R 15 and R 16 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 alkinyl 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, R5 and R16, R13 and R14, or R13 and R5, together with the atoms to which they are attached, can form a satured ring, unsaturated, or partially Saturated from 3 to 7 members containing from 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and from 1 to 3 R9 groups;; L is (CR2) 1.4 or a link; Y is a carbocyclic ring of 3 to 7 carbon atoms, aryl of 6 to 10 carbon atoms, or a heteroaryl of 5 to 10 members, or a heterocyclic ring of 4 to 10 members, each of which is optionally substituted with 1 to 3 groups R9; R7, R8 and R8a 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, NRR7a, hydroxyl or cyano; (CR2) qY or alkoxy of 1 to 6 carbon atoms; or R7 is H; R9 is R4, C (0) NRR7 or NRR7; R and R7a are independently H or alkyl of 1 to 6 carbon atoms; R and R7, together with N in each NRR7, and R and R7a, together with N in NRR7a, can form a 5 to 6 member ring containing from 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with oxo and from 1 to 3 R4 groups; m is from 2 to 4; n and p are independently from 1 to 4; Y q is from 0 to 4.

2. The compound of claim 1, wherein R2 is pyrazolyl, or isoxazolyl, each of which is substituted with alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms.

3. The compound of claim 1, wherein said compound is of the formula (2): where W is W; W is pyridyl optionally substituted with alkyl of 1 to 6 carbon atoms, isoquinolinyl, quinolinyl, naphthalenyl, cinolin-5-yl optionally substituted with alkyl of 1 to 6 carbon atoms, or [3- (alkyl of 1 to 6 carbon atoms) - (2,3,4, 5-tetrahydro-1 H-benzo- [d] -azepin-7-yl], and the pyridyl, isoquinolinyl, quinolinyl and naphthalenyl are each substituted on a carbon atom of the ring with R6 is 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 by halogen, amino, hydroxyl or alkoxy; - (CR2) p-'CH (OH) C | F2i + i where t is 1, -L-C (0) -NRR7 or -L-S (0) 2R8; L is (CRZ), 4; R and R7 are independently H or alkyl of 1 to 6 carbon atoms; R8 is alkyl of 1 to 6 carbon atoms; Y R1 and R3 are as defined in claim 1.

'4. The compound of claim 1, wherein said compound is of the formula (3): wherein Z is NH or O; R 4 is halogen, or alkyl of 1 to 6 carbon atoms; R6 is H; Y R1 and R3 are as defined in claim 1.

5. The compound of claim 1, wherein the said compound is of the formula (4): wherein one of R, R and R 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, or C 1 -C 6 alkoxy substituted by halogen; Y X is as defined in claim 1.

6. The compound of claim 5, wherein X is -C (R) = N-0-R7, C (0) NRR7, C (0) NR- (CR2) n-NRR7 or - (CR2) PNRR, wherein two R groups, together with N in NRR, form morpholinyl; R7 is H or alkyl of 1 to 6 carbon atoms optionally substituted with hydroxyl or NRR7a; each R is H or alkyl of 1 to 6 carbon atoms; R and R7, together with N in each NRR7, and R and R7a, together with N in NRR7a, can form a 5- to 6-membered ring containing from 1 to 2 heteroatoms selected from N, O, and S; Y n and p are as defined in claim 1.

7. The compound of claim 6, wherein X is quinolinyl, (1, 2,3,4-tetrahydro-isoquinolin-6-yl), or a 5- to 6-membered heteroaryl selected from pyrazolyl, pyridyl, thiophenyl, furanyl , imidazolyl, isoxazolyl, oxazolyl or thiazolyl, each of which is optionally substituted with alkyl of 1 to 6 carbon atoms, hydroxyl, or C (0) NRR7; R7 is H or alkyl of 1 to 6 carbon atoms; and R is H or alkyl of 1 to 6 carbon atoms.

8. The compound of claim 1, wherein the compound mentioned is of the formula (5): wherein one of R, R ° and R c 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 , or alkoxy of 1 to 6 carbon atoms substituted by halogen; ring E is a carbocycle of 6 carbon atoms optionally substituted with oxo, = N-OH or R9; R9 is hydroxyl or NRR7; R is H or alkyl of 1 to 6 carbon atoms; R7 is alkyl of 1 to 6 carbon atoms, or (CR2) qY and Y is cycloalkyl of 3 carbon atoms; alternatively, R and R7, together with N in NRR7, form morpholinyl, piperidinyl, piperazinyl, (C 1 -C 6 alkyl) -piperazinyl, or pyrrolidinyl, each of which is optionally substituted with hydroxyl; Y R1 and R3 are as defined in claim 1.

9. The compound of any of claims 5 to 8, wherein R 4 is H.

10. The compound of any of claims 5 to 8, wherein R 4a and R 4c 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, or alkoxy of 1 to 6 carbon atoms substituted by halogen

11. The compound of any of claims 1 to 10, wherein R1 is chloro or an alkyl of 1 to 6 carbon atoms substituted by halogen.

12. The compound of any of claims 1 to 10, wherein each R3 is H.

13. The compound of claim 1, wherein said station is selected from the group consisting of (4-morpholino-cyclohexyl) -phenyl) -N 4 -methyl 1-1, 2,3,4-tetrahydro- (5-methyl-1 H -pyrazol-3-yl) -pyrimidin-β-quinolin-6- il) -phenyl) -N 4 - (5- 2,4-diamine methyl-1 H -pyrazol-3-yl) -pyrimidine-2,4-diamine Cis-5-chloro-N 2 - (2,5-dimethyl-4- (4-morpholino-cyclohexyl) -phenyl) -N 4 - (5-methyl-1 H -pyrazol-3-yl) -pyrimidin- 2,4 -diamine

14. A pharmaceutical composition, which comprises a therapeutically effective amount of a compound of any of claims 1 to 13, and a physiologically acceptable carrier.

15. A method for inhibiting IGF-1R in a cell, which comprises contacting the cell with an effective amount of a compound of any of claims 1 to 13, or with a pharmaceutical composition thereof.

16. A method for the treatment of a condition mediated by IGF-1R in a mammal suffering from it, which comprises administering to the mammal an amount therapeutically effective of a compound of any of claims 1 to 13, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent; wherein this condition is an autoimmune disease, a disease by transplantation, an infectious disease, or a cell proliferative disorder.

17. The method of claim 16, wherein this condition is a cell proliferative disorder.

18. The method of claim 17, wherein said cell proliferative disorder is multiple myeloma, neuroblastoma, synovial, hepatocellular, Ewing's sarcoma, or a solid tumor selected from an osteosarcoma, melanoma, and breast, renal, or prostate tumor , colo-rectal, thyroid, ovarian, pancreatic, lung, uterine, or a gastrointestinal tumor.

19. The method of claim 16, wherein the second therapeutic agent is a chemotherapeutic agent.

20. The use of a compound of any of claims 1 to 13, or of a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a condition mediated by IGF-1R or by anaplastic lymphoma kinase, and optionally in combination with a second therapeutic agent, wherein this condition is an autoimmune disease, a disease by transplantation, an infectious disease, or a cell proliferative disorder.