Polo-like kinase 4 (PLK4) inhibitors, pharmaceutical compositions, and methods for preparing and using the same - Patents.com

Abstract

Disclosed are compounds of formula (I) and pharma- ceutically acceptable salts, characterized by either an N-(1H-pyrazol-3-yl)pyridin-2-amine or an N-(1H-pyrazol-3-yl)pyrimidin-4-amine core structure. These compounds can be used in the treatment of diseases such as cancer or diseases associated with TRIM37. The compounds disclosed herein can be inhibitors of polo-like kinase 4 (PLK4). Also disclosed are pharmaceutical compositions containing the compounds or pharma- ceutically acceptable salts thereof, methods of preparation and use thereof. JPEG2025506772000186.jpg52170

Description

[Technical field]

[0001] The present invention relates to compounds and pharmaceutical compositions, their preparation and their use in the treatment of diseases or conditions, such as cancer, particularly diseases or conditions sensitive to the inhibition of Polo-like kinase 4. [Background technology]

[0002] Protein kinases are a large group of intracellular and transmembrane signaling proteins in eukaryotic cells. These enzymes are responsible for transferring the terminal (gamma) phosphate from ATP to specific amino acid residues in target proteins. Phosphorylation of specific amino acid residues in target proteins can regulate their activity, resulting in profound changes in cell signaling and metabolism. Protein kinases can be found in structures such as cell membranes, cytosol, organelles, and centrioles, and are responsible for mediating multiple cellular functions, including metabolism, cell proliferation, differentiation, cell signaling, regulation of immune responses, and cell death. Thus, inhibitors of selected kinases or kinase families are expected to be useful in the treatment of cancer and other diseases or conditions.

[0003] Centrioles template the assembly of microtubules and recruit pericentriolar material to form centrosomes. Centriole duplication is tightly controlled, and normal mitotic cells have exactly two centrosomes. Supernumerary centrosomes are common in cancer and have been hypothesized to contribute to tumorigenesis. Polo-like kinase 4 (PLK4) is a key factor in centriole biogenesis. Depletion or inhibition of its kinase activity prevents centriole formation, whereas overexpression leads to the formation of multiple centrioles. Cells can survive by utilizing pericentriolar material for microtubule assembly, even in the absence of centrioles. Importantly, reduction of both centrioles and pericentriolar material significantly impairs cell viability. Thus, tumor cells with low levels of pericentriolar material are sensitive to inhibition of PLK4 activity. Certain genetic factors, such as overexpression of TRIM37, have been previously identified to suppress levels of pericentriolar material and sensitize tumor cells to PLK4 inhibition. Therefore, PLK4 inhibitors are expected to have anti-cancer properties in general, and especially in the specific case of TRIM37 amplification or similar cellular milieu that leads to impaired pericentrosomal function. Summary of the Invention

[0004] In one aspect, the present invention provides a compound of formula (I):

[0005] [ka]

[0006] or a pharma- ceutically acceptable salt thereof, During the ceremony, n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; L is an optionally substituted C 2~9 Heterocyclyl, optionally substituted C 2~9 Heteroaryl, optionally substituted C 6~10 Aryl, or optionally substituted C 3~8cycloalkyl, where L further comprises n occurrences of R 3 Optionally replaced by; R 1a is hydrogen, halogen, or optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Alkoxy, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 cycloalkyl, or nitrile; R 1b is hydrogen; or R 1a and R 1b together with the atom to which they are attached, are a 3- to 5-membered cycloalkyl, cycloalkylene, cycloalkyline, heterocycloalkyl, aryl, or heteroaryl; A is O or S, and R 2A and R 2B are both absent; or A is N and R 2A is absent and R 2B is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 6~10 Aryl C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, optionally substituted C 1~9 Heteroaryl C 1~6 Alkyl or optionally substituted C 1~6 alkylsulfonyl or R 2B and L, together with the atoms to which they are attached, may be optionally substituted C 2~9 Heterocyclyl or optionally substituted C 2~9 forms a heteroaryl; or A is C and R 2Aand R 2B each independently represents hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 6~10 Aryl C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, optionally substituted C 1~9 Heteroaryl C 1~6 Alkyl, or optionally substituted C 1~6 is alkylsulfonyl; Each R 3 are independently selected from halogen, cyano, and optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 6~10 Aryl C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, optionally substituted C 1~9 Heteroaryl C 1~6 Alkyl, -S(O) m R 3A , -N(R 3B )2, or -OR 3B and; R 3A is an arbitrarily substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, -OR 3B , or -N(R 3B )2; Each R 3B are independently hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 6~10 Aryl C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, optionally substituted C 1~9 Heteroaryl C 1~6 Alkyl or optionally substituted C 1~6 alkylsulfonyl; or two R 3B The groups are optionally substituted C 2~9 Forming a heterocyclyl; X is N and R 4 is absent; or X is C and R 4 is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl or optionally substituted C 1~9 is heteroaryl; R 5 is an arbitrarily substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, -CONH2, or -ZR 5A and; Z is an optionally substituted amino, an optionally substituted C 2~9 Heterocyclylene, optionally substituted C 2~9 Heteroarylene, optionally substituted C 6~10 Arylene, or optionally substituted C 3~8 is cycloalkylene; R 5A is hydrogen, halogen, cyano, or an optionally substituted C 1~6 Alkylsulfonyl, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl or optionally substituted C 1~9 is heteroaryl; R 6 is hydrogen, halogen, cyano, or an optionally substituted C 1~6 Alkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, or -OR 6A and R 6A is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6Alkynyl, or optionally substituted C 3~8 It is cycloalkyl.

[0007] In some embodiments, the compound is a compound of formula (II):

[0008] [ka]

[0009] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III):

[0010] [ka]

[0011] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (II-A):

[0012] [ka]

[0013] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III-A):

[0014] [ka]

[0015] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (II-B):

[0016] [ka]

[0017] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III-B):

[0018] [ka]

[0019] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 2A and R 2B In some embodiments, one of R 2A and R 2B One of them is an arbitrarily substituted C 1~6 In some embodiments, R 2A and R 2B One of them is an arbitrarily substituted C 1~6 It is heteroalkyl.

[0020] In some embodiments, R 2B teeth,

[0021] [ka]

[0022] It is. In some embodiments, the compound is a compound of formula (II-C):

[0023] [ka]

[0024] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (III-C):

[0025] [ka]

[0026] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (II-D):

[0027] [ka]

[0028] It is. In some embodiments, the compound is a compound of formula (III-D):

[0029] [ka]

[0030] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 1a and R 1b are independently optionally substituted C 1~6 Alkyl, halo, optionally substituted C 1~6 Alkoxy, optionally substituted alkynyl, or optionally substituted C 3~6 In some embodiments, R 1a and R 1b is independently -CH, -Cl, -OMe, -CHOMe, -CN, -CFH, -CF, -CHF, cyclopropyl, or cyclobutyl. 1a and R 1b together with the atom to which they are attached, is cycloalkyl, cycloalkylene, cycloalkyline, aryl, heterocyclyl, or heteroaryl. In some embodiments, R 1a and R 1b along with the atoms to which they are attached,

[0031] [ka]

[0032] It is. In some embodiments, L is optionally substituted C 6~10 In some embodiments, optionally substituted C 6~10 Aryl is optionally substituted phenyl.

[0033] In some embodiments, L is optionally substituted C 2~9 In some embodiments, L is an optionally substituted C5 heteroaryl. In more particular embodiments, the optionally substituted C5 heteroaryl contains one N. In some embodiments, -L-(R 3 ) n teeth,

[0034] [ka]

[0035] It is. In some embodiments, at least one R 3 is halogen. In some embodiments, at least one R 3 is F. In some embodiments, at least one R 3 is Cl. In some embodiments, at least one R 3 is Br. In some embodiments, at least one R 3 is -S(O) m R 3A In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R 3A is an arbitrarily substituted C 1~6 In some embodiments, R 3A is -CH3. In some embodiments, R 3A is an arbitrarily substituted C 3~8 In some embodiments, R 3Ais optionally substituted cyclopropyl. In some embodiments, at least one R 3 is an arbitrarily substituted C 2~9 In some embodiments, at least one R 3 is -N(R 3B In some embodiments, at least one R 3 -OR 3B It is.

[0036] In some embodiments, -L-(R 3 ) n teeth,

[0037] [ka]

[0038] [ka]

[0039] It is. In some embodiments, -L-(R 3 ) n teeth,

[0040] [ka]

[0041] It is. In some embodiments, -L-(R 3 ) n teeth,

[0042] [ka]

[0043] It is. In some embodiments, -L-(R 3 ) n teeth,

[0044] [ka]

[0045] It is. In some embodiments, -L-(R 3 ) n teeth,

[0046] [ka]

[0047] It is. In some embodiments, -L-(R 3 ) n teeth,

[0048] [ka]

[0049] It is. In some embodiments, -L-(R 3 ) n teeth,

[0050] [ka]

[0051] It is. In some embodiments, R 4 is halogen. In some embodiments, R 4 is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is cyano. In some embodiments, R 4 is an optionally substituted amino. In some embodiments, R 4 is -NH2 or -N(CH3)2. In some embodiments, R 4 is hydrogen. In some embodiments, R 4is -CH3.

[0052] In some embodiments, R 5 is an arbitrarily substituted C 1~9 In some embodiments, R 5 is an optionally substituted C3-C4 heteroaryl or an optionally substituted C4 heterocycle.

[0053] In some embodiments, the optionally substituted C3-C4 heteroaryl or optionally substituted C4 heterocycle contains 1 to 2 N atoms. 5 teeth,

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] It is. In some embodiments, R 5 teeth,

[0059] [ka]

[0060] It is. In some embodiments, the optionally substituted C heteroaryl contains one N atom and one S atom or one O atom.5 teeth,

[0061] [ka]

[0062] It is. In some embodiments, R 5 -ZR 5A In some embodiments, Z is an optionally substituted amino and R 5A teeth,

[0063] [ka]

[0064] In some embodiments, Z is optionally substituted C 2~9 It is a heteroarylene. In some embodiments, R 5 is an arbitrarily substituted C 2~9 In some embodiments, R 5 teeth,

[0065] [ka]

[0066] [ka]

[0067] It is. In some embodiments, R 5 teeth,

[0068] [ka]

[0069] It is. In some embodiments, R 5A teeth,

[0070] [ka]

[0071] It is. In some embodiments, R 5 teeth,

[0072] [ka]

[0073] It is. In some embodiments, R 6 is an arbitrarily substituted C 1~6 In some embodiments, R 6 teeth,

[0074] [ka]

[0075] It is. In some embodiments, R 6 -OR 6A In some embodiments, R 6A is -CH3. In some embodiments, R 6 is an arbitrarily substituted C 3~8 In some embodiments, R 6 is an optionally substituted cyclopropyl. In some embodiments, R 6 teeth,

[0076] [ka]

[0077] It is. In some embodiments, the compound is a compound of formula (IV):

[0078] [ka]

[0079] It is. In some embodiments, the compound is a compound of formula (V):

[0080] [ka]

[0081] It is. In some embodiments, the compound is selected from the group consisting of compounds 1-365, including pharma- ceutically acceptable salts thereof.

[0082] In another aspect, the present invention provides a pharmaceutical composition as described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, hi some embodiments, the composition is isotopically enriched with deuterium.

[0083] In yet another aspect, the present invention relates to a method for inhibiting PLK4 expression in a cell, comprising contacting the cell with any compound described herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the cell overexpresses TRIM37. In some embodiments, the cell is in a subject.

[0084] In yet another aspect, the present invention provides a method of treating a subject in need thereof, comprising administering to the subject a compound as described herein, or a pharma- ceutically acceptable salt thereof.In some embodiments, the subject suffers from a disease or condition with a symptom of cellular hyperproliferation and is in need of treatment therefor.In some embodiments, the disease is cancer.In some embodiments, the cancer is a cancer that overexpresses TRIM37.

[0085] In yet another aspect, the invention provides a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of any compound described herein comprising a pharma- ceutically acceptable excipient, wherein the cancer has previously been identified as a TRIM37-overexpressing cancer.

[0086] In some embodiments, the cancer that overexpresses TRIM37 is uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, or endometrial cancer. In yet another aspect, the present invention provides a method of inducing cell death in a cancer cell that overexpresses TRIM37, the method comprising contacting the cell with an effective amount of a PLK4 inhibitor. In some embodiments, the PLK4 inhibitor is a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0087] In some embodiments, the cell is in a subject. Abbreviation Abbreviations and terms commonly used in the fields of organic chemistry, medicinal chemistry, pharmacology, and medicine and familiar to practitioners in these fields are used herein. Representative abbreviations and definitions are provided below.

[0088] Ac is acetyl [CH3C(O)-]; ACN is acetonitrile; Ac2O is acetic anhydride; AcOH is acetic acid; APC is an antigen-presenting cell; Ar is aryl; aq. is an aqueous solution; 9-BBN is 9-borabicyclo[3.3.1]nonane; BINAP is (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl); Bn is benzyl; Boc is tertbutyloxycarbonyl; n-BuLi is n-butyl lithium; Br2 is bromine; CDI is carbonyldiimidazole; cmpd is a compound; Conc. is concentrated; DCM is dichloromethane; DIAD is diisopropylazodicarboxylate; DIBAL is diisobutylaluminum hydride; DIPEA is diisopropylethylamine; DMA is dimethylacetamide; DMAP is 4-dimethylaminopyridine; DME is dimethoxyethane; DMF is N,N'-dimethylformamide; DMSO is dimethyl sulfoxide; dppf is 1,1'-bis(diphenylphosphino)ferrocene; dtbpf is 1,1'-bis(di-tert-butylphosphino)ferrocene; EDAC (or EDC) is 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide HCl; ESI, electrospray ionization mass spectrometry; Et2O is diethyl ether; Et3N is triethylamine; Et is ethyl; EtOAc is ethyl acetate; EtOH is ethanol; (+ESI) is electron spray ionization in positive mode; 3-F-Ph is 3-fluorophenyl; h is the time; hrs is hours (plural); HATU is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCl is hydrochloric acid; Het is heteroaryl; Hex is hexane; HOBt is 1-hydroxybenzotriazole; HPLC is high performance liquid chromatography; IPA or iPrOH is isopropanol; IPAc is isopropyl acetate; I2 is iodine; LCMS is HPLC with mass spectrometric detection; LiHMDS is lithium bis(trimethylsilyl)amide; LG is a leaving group; M is the molar concentration; mCPBA is metachloroperbenzoic acid; mmol is millimole; Me is methyl; MeI is iodomethane; MeCN is acetonitrile; MeMgBr is methylmagnesium bromide; MeMgCl is methylmagnesium chloride; MeOH is methanol; min is minutes; MOM is methoxymethyl; Ms is methanesulfonyl; MS is mass spectrometry; MTBE is methyl tert-butyl ether; MW is microwave; N is normal; NaBH(OAc)3 is sodium triacetoxyborohydride; NaH is sodium hydride; NaHMDS is sodium bis(trimethylsilyl)amide; NaOAc is sodium acetate; NaOtBu is sodium tert-butoxide; NBS is N-bromosuccinimide; NCS is N-chlorosuccinimide; NIS is N-iodosuccinimide; NMO is N-methylmorpholine N-oxide; NMP is N-methylpyrrolidinone; NMR is nuclear magnetic resonance spectroscopy; PdCl2(dppf) is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PdCl2(dppf).CH2Cl2 is the complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium; PdCl2(PPh3)2 is dichlorobis-(triphenylphosphene)palladium; Pd-PEPPSI™ SIPr is (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride; PE is petroleum ether; PG represents a protecting group; Ph is phenyl; PhMe is toluene; PIV-Cl is pivaloyl chloride, trimethylacetyl chloride; PPh3 is triphenylphosphine; PMB is para-methoxybenzyl; Reagent alcohol is a mixture of 90% ethanol, 5% isopropanol, and 5% methanol; rt or RT is room temperature; RBF is a round bottom flask; Ruphos is 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; RuPhos Pd G1 is chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II); sat. is saturated; SEM is [2-(trimethylsilyl)ethoxy]methyl; SFC is supercritical fluid chromatography; S N Ar is an aromatic nucleophilic substitution reaction; TBAB is tetrabutylammonium bromide; TBAF is tetrabutylammonium fluoride; TBS is tert-butyldimethylsilyl; tBu is tert-butyl; Tf is trifluoromethanesulfonyl; TFA is trifluoroacetic acid; THF is tetrahydrofuran; THP is tetrahydropyran; TLC is thin layer chromatography; TMAD is tetramethylazodicarboxamide; TMS is trimethylsilyl; TPAP is tetrapropylammonium perruthenate; Ts is p-toluenesulfonyl; UPLC is ultra-performance liquid chromatography; UPLC-MS is UPLC with mass spectrometric detection; Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhosPdG2 is chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); XPhosPdG3 is (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0089] definition The term "abnormal" as used herein refers to something different from normal. When used to describe activity, abnormal refers to an activity that is greater than or less than the average of normal control or normal non-disease control samples. Abnormal activity can refer to an amount of activity that results in disease, where returning the abnormal activity to normal or non-disease-related amounts (e.g., by administering a compound or using a method described herein) results in the alleviation of disease or one or more disease symptoms.

[0090] The term "acyl," as used herein, refers to the group -C(=O)-R, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl. Acyl may be optionally substituted as described herein for each respective R group.

[0091] The term "adenocarcinoma," as used herein, refers to a malignant tumor arising from glandular cells present in organs within an organism. Non-limiting examples of adenocarcinomas include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colorectal cancer.

[0092] The term "alkanoyl" as used herein represents a hydrogen or alkyl group attached to the parent molecular group through a carbonyl group, such as formyl (i.e., a carboxaldehyde group), acetyl, propionyl, butyryl, and iso-butyryl. Unsubstituted alkanoyl groups contain 1 to 7 carbons. Alkanoyl groups may be unsubstituted or substituted as described herein for alkyl groups (e.g., optionally substituted C1-7 alkanoyl). The suffix "-oyl" may be added to other groups defined herein, such as aryl, cycloalkyl, and heterocyclyl, to form "aryloyl," "cycloalkanoyl," and "(heterocyclyl)oyl." These groups represent a carbonyl group substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of "aryloyl", "cycloalkanoyl", and "(heterocyclyl)oyl" may be optionally substituted as defined for "aryl", "cycloalkyl", or "heterocyclyl", respectively.

[0093] The term "alkenyl" as used herein refers to an acyclic monovalent straight or branched chain hydrocarbon group containing one, two, or three carbon-carbon double bonds. Non-limiting examples of alkenyl groups include ethenyl, prop-1-enyl, prop-2-enyl, 1-methylethenyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop-1-enyl, 2-methylprop-1-enyl, and 1-methylprop-2-enyl. Alkenyl groups may be optionally substituted as defined herein for alkyl.

[0094] The term "alkenylene" as used herein refers to a divalent alkenyl group. Optionally substituted alkenylene is optionally substituted alkenylene as described herein for alkenyl.

[0095] The term "alkoxy" as used herein refers to a chemical substituent of formula -OR, where R is C, unless otherwise specified. 1~6 It is an alkyl group. In some embodiments, the alkyl group can be further substituted as defined herein. The term "alkoxy" may be combined with other terms defined herein, such as aryl, cycloalkyl, or heterocyclyl, to define "arylalkoxy", "cycloalkylalkoxy", and "(heterocyclyl)alkoxy" groups. These groups represent alkoxy substituted with aryl, cycloalkyl, or heterocyclyl, respectively. Each of "arylalkoxy", "cycloalkylalkoxy", and "(heterocyclyl)alkoxy" may be optionally substituted as defined herein for the individual moieties.

[0096] The term "alkoxyalkyl" as used herein refers to a chemical substituent of formula -LOR, where L is C 1~6 alkylene and R is C 1~6 Optionally substituted alkoxyalkyl is optionally substituted alkoxyalkyl as described herein for alkyl.

[0097] The term "alkyl" as used herein refers to an acyclic straight or branched chain saturated hydrocarbon group, which, if unsubstituted, has from 1 to 12 carbons, unless otherwise specified. In certain preferred embodiments, unsubstituted alkyls have from 1 to 6 carbons. Alkyl groups include, for example, methyl; ethyl, n- and iso-propyl; n-, sec-, iso-, and tert-butyl; neopentyl, and the like, and may be optionally substituted, if valence allows, with one, two, three, or, in the case of alkyl groups of two or more carbons, four or more substituents independently selected from the group consisting of: amino; alkoxy; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; alkylsulfonyl; alkylsulfinyl; alkylsulfenyl; =O; =S; -C(O)R or -SOR, where R is amino; and =NR', where R' is alkyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or, if valence allows, substituted with an unsubstituted substituent(s) as defined herein for each respective group.

[0098] The term "alkylene" as used herein refers to a divalent alkyl group. An optionally substituted alkylene is an alkylene optionally substituted as described herein for alkyl.

[0099] The term “alkylamino” as used herein refers to a group of the formula —N(R N1 )2 or -NHR N1 where R N1 is alkyl as defined herein. The alkyl portion of the alkylamino can be optionally substituted as defined for alkyl. Each of the optional substituents of a substituted alkylamino can itself be unsubstituted or, where valency allows, substituted with an unsubstituted substituent(s) as defined herein for each respective group.

[0100] The term "alkylsulfenyl" as used herein represents a group of formula -S-(alkyl). Alkylsulfenyl may be optionally substituted as defined for alkyl.

[0101] The term "alkylsulfinyl" as used herein represents a group of the formula -S(O)-(alkyl), which may be optionally substituted as defined for alkyl.

[0102] The term "alkylsulfonyl" as used herein represents a group of formula -S(O)-(alkyl), which may be optionally substituted as defined for alkyl.

[0103] The term "alkynyl," as used herein, represents a monovalent straight or branched chain hydrocarbon group of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, e.g., ethynyl, 1-propynyl, etc. Alkynyl groups can be unsubstituted or substituted as defined for alkyl (e.g., optionally substituted alkynyl).

[0104] The term "alkynylene" as used herein refers to a divalent alkynyl group. Optionally substituted alkynylene is optionally substituted alkynylene as described herein for alkynyl.

[0105] The term “amino” as used herein refers to —N(R N1 )2, where if amino is unsubstituted, then both R N1 is H; or if amino is substituted, each R N1 are independently H, -OH, -NO2, -N(R N2 )2, -SO2OR N2 , -SO2R N2 , -SOR N2 , -C(O)OR N2, an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, cycloalkyl, cycloalkenyl, heteroalkyl, or heterocyclyl, provided that at least one R N1 is not H and each R N2 is independently H, alkyl, or aryl. Each of the substituents may itself be unsubstituted or substituted with the unsubstituted substituent(s) defined herein for each respective group. In some embodiments, amino is unsubstituted amino (i.e., -NH2) or substituted amino (e.g., -NHR N1 ) in which R N1 are independently -OH, SO2OR N2 , -SO2R N2 , -SOR N2 , -COOR N2 , optionally substituted alkyl, or optionally substituted aryl, and each R N2 can be an optionally substituted alkyl or an optionally substituted aryl. In some embodiments, the substituted amino can be an alkylamino, where the alkyl group is optionally substituted as described herein for alkyl. In some embodiments, the amino group is -NHR N1 where R N1 is optionally substituted alkyl.

[0106] The term "aryl" as used herein refers to a monocyclic, bicyclic, or polycyclic carbocyclic ring system having one or two aromatic rings. An aryl group may contain from 6 to 10 carbon atoms. All atoms in an unsubstituted carbocyclic aryl group are carbon atoms. Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, and the like. An aryl group may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silyl; -(CH2) n -C(O)OR A -C(O)R; and -SO2R, where R is amino or alkyl, and R A is H or alkyl, and n is 0 or 1. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) as defined herein for each respective group.

[0107] The term "arylalkyl," as used herein, refers to an alkyl group substituted with an aryl group. The aryl and alkyl portions may be optionally substituted as described herein for the individual groups.

[0108] The term "arylene" as used herein refers to a divalent aryl group. An optionally substituted arylene is an arylene optionally substituted as described herein for aryl.

[0109] The term "aryloxy" as used herein represents a chemical substituent of formula -OR, where R is an aryl group, unless otherwise specified. In an optionally substituted aryloxy, the aryl group is optionally substituted as described herein for aryl.

[0110] The term "azido" as used herein refers to a -N3 group. As used herein, the term "cancer" refers to all types of cancer, neoplasms or malignant tumors found in mammals (e.g., humans).

[0111] The term "carbocyclic" as used herein refers to an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure in which the ring is formed by carbon atoms, which may be aromatic or non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl, and certain aryl groups.

[0112] The term "carbonyl" as used herein represents a group of formula -C(O)-. The term "carcinoma", as used herein, refers to a malignant new growth made up of epithelial cells tending to invade surrounding tissues and give rise to metastases.

[0113] The term "cyano," as used herein, represents a group of the formula --CN. The term "cycloalkenyl," as used herein, unless otherwise specified, refers to a non-aromatic carbocyclic group having at least one double bond and from 3 to 10 carbons in the ring (e.g., C 3~10Cycloalkenyl). Non-limiting examples of cycloalkenyl include cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, norbornen-1-yl, norbornen-2-yl, norbornen-5-yl, and norbornen-7-yl. Cycloalkenyl groups can be unsubstituted or substituted as defined for cycloalkyl (e.g., optionally substituted cycloalkenyl).

[0114] The term "cycloalkenylalkyl," as used herein, refers to an alkyl group substituted with a cycloalkenyl group, each as defined herein. The cycloalkenyl and alkyl portions may be optionally substituted as individual groups, as defined herein.

[0115] The term "cycloalkenylene" as used herein refers to a divalent cycloalkenyl group. Optionally substituted cycloalkenylene is cycloalkenylene optionally substituted as described herein for cycloalkyl.

[0116] The term "cycloalkoxy" as used herein refers to a chemical substituent of formula -OR, where R is a cycloalkyl group, unless otherwise specified. In some embodiments, the cycloalkyl group can be further substituted as defined herein.

[0117] The term "cycloalkyl," as used herein, unless otherwise specified, refers to a cyclic alkyl group having from 3 to 10 carbons (e.g., C 3~C10Cycloalkyl). Cycloalkyl groups may be monocyclic or bicyclic. Bicyclic cycloalkyl groups may be of the bicyclo[pq0]alkyl type, where each of p and q is independently 1, 2, 3, 4, 5, 6, or 7, with the proviso that the sum of p and q is 2, 3, 4, 5, 6, 7, or 8. Alternatively, bicyclic cycloalkyl groups may include bridged cycloalkyl structures, such as bicyclo[pqr]alkyl, where r is 1, 2, or 3, and each of p and q is independently 1, 2, 3, 4, 5, or 6, with the proviso that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. A cycloalkyl group may be a spirocyclic group, e.g., spiro[pq]alkyl, where each of p and q is independently 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 4, 5, 6, 7, 8, or 9. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[2.2.1.]heptyl, 2-bicyclo[2.2.1.]heptyl, 5-bicyclo[2.2.1.]heptyl, 7-bicyclo[2.2.1.]heptyl, and decalinyl. Cycloalkyl groups can be unsubstituted or substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; =O; =S; -SOR (where R is an optionally substituted amino); =NR' (where R' is H, alkyl, aryl, or heterocyclyl); and -CON(R A )2(wherein, R A are independently H or alkyl, or both R Aare bonded together with the atom to which they are attached to form a heterocyclyl. Each of the substituents can itself be unsubstituted or substituted with unsubstituted substituent(s) as defined herein for each respective group.

[0118] The term "cycloalkylalkyl," as used herein, refers to an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl moieties may be optionally substituted as the individual groups described herein.

[0119] The term "cycloalkylene" as used herein refers to a divalent cycloalkyl group. Optionally substituted cycloalkylene is cycloalkylene optionally substituted as described herein for cycloalkyl.

[0120] The term "cycloalkynyl," as used herein, unless otherwise specified, refers to a monovalent carbocyclic group having one or two carbon-carbon triple bonds and having 8 to 12 carbons. Cycloalkynyls may contain one transannular bond or bridge. Non-limiting examples of cycloalkynyls include cyclooctynyl, cyclononynyl, cyclodecynyl, and cyclodecadiynyl. Cycloalkynyl groups may be unsubstituted or substituted as defined for cycloalkyl (e.g., optionally substituted cycloalkynyl).

[0121] "Disease" or "condition" refers to a state of life or health of a patient or subject that can be treated with the compounds or methods provided herein. The term "halo," as used herein, refers to a halogen selected from bromine, chlorine, iodine, and fluorine.

[0122] The term "heteroalkyl", as used herein, refers to an alkyl, alkenyl, or alkynyl group interrupted once by one or two heteroatoms; twice, each time independently, by one or two heteroatoms; three times, each time independently, by one or two heteroatoms; or four times, each time independently, by one or two heteroatoms. Each heteroatom is independently O, N, or S. In some embodiments, the heteroatom is O or N. No heteroalkyl group contains two consecutive oxygen or sulfur atoms. Heteroalkyl groups may be unsubstituted or substituted (e.g., optionally substituted heteroalkyl). When a heteroalkyl is substituted and a substituent is attached to a heteroatom, the substituent is selected according to the nature and valence of the heteroatom. Thus, substituents attached to a heteroatom may be, if valence allows, =O, -N(R N2 )2, -SO2OR N3 , -SO2R N2 , -SOR N3 , -COOR N3 , an N-protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, or cyano, N2 is independently H, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl, and each R N3 is independently alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl or heterocyclyl. Each of these substituents may itself be unsubstituted or substituted with the unsubstituted substituent(s) defined herein for each respective group. When a heteroalkyl is substituted and a substituent is bonded to a carbon, the substituent is selected from those described for alkyl, with the exception that the substituent of the carbon atom bonded to the heteroatom is not Cl, Br, or I. It is understood that the carbon atom is found at the terminal end of the heteroalkyl group.

[0123] The term "heteroarylalkyl," as used herein, refers to an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl portions may be optionally substituted as the individual groups described herein.

[0124] The term "heteroarylene" as used herein refers to a divalent heteroaryl. Optionally substituted heteroarylene is optionally substituted as described herein for heteroaryl.

[0125] The term "heteroaryloxy" as used herein refers to the structure -OR, where R is a heteroaryl. Heteroaryloxy can be optionally substituted as defined for heterocyclyl.

[0126] The term "heterocyclyl," as used herein, unless otherwise specified, refers to a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused, bridged, and / or spiro 3-, 4-, 5-, 6-, 7-, or 8-membered rings and containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a "heterocyclyl," unless otherwise specified, is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridged 5-, 6-, 7-, or 8-membered rings and containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. A heterocyclyl may be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclyls have zero or one double bond, non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds, and non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and / or zero or one carbon-carbon triple bond. Heterocyclyl groups contain from 1 to 16 carbon atoms unless otherwise specified. Certain heterocyclyl groups may contain up to 9 carbon atoms. Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, etc. When a heterocyclic ring system has at least one aromatic resonance structure or at least one aromatic tautomer, such structure is an aromatic heterocyclyl (i.e., heteroaryl).Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl (e.g., 1,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, etc. The term "heterocyclyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbon and / or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as quiniclidine, tropane, or diazabicyclo[2.2.2]octane. The term "heterocyclyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocycles are fused to one, two, or three carbon rings, such as an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocycle. Examples of fused heterocyclyls include 1,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene. Heterocyclyl groups may be unsubstituted or substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silyl; cyano; -C(O)R or -SOR, where R is amino or alkyl; =O; =S; =NR', where R' is H, alkyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with the unsubstituted substituent(s) defined herein for each respective group.

[0127] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocyclyl group, each as defined herein. The heterocyclyl and alkyl portions may be optionally substituted as the individual groups described herein.

[0128] The term "heterocyclylene" as used herein refers to a divalent heterocyclyl. Optionally substituted heterocyclylene is optionally substituted as described herein for heterocyclyl.

[0129] The term "(heterocyclyl)oxy" as used herein represents a chemical substituent of formula -OR, where, unless otherwise specified, R is a heterocyclyl group. (Heterocyclyl)oxy can be optionally substituted in the manner described for heterocyclyl.

[0130] The terms "hydroxyl" and "hydroxy" are used interchangeably herein to refer to an --OH group. The term "isotopically enriched" as used herein refers to a pharmacoactive agent in which the isotopic content of one isotope at a given position in the molecule is at least 100 times greater than the natural abundance of this isotope.For example, a composition isotopically enriched with deuterium comprises an active agent that comprises at least one hydrogen atom position with an abundance of deuterium that is at least 100 times greater than the natural abundance of deuterium.Preferably, the isotopic enrichment of deuterium is at least 1000 times greater than the natural abundance of deuterium.More preferably, the isotopic enrichment of deuterium is at least 4000 times greater (e.g., at least 4750 times greater, e.g., up to 5000 times greater) than the natural abundance of deuterium.

[0131] The term "leukemia," as used herein, broadly refers to progressive malignant diseases of the blood-forming organs and is generally characterized by distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the acute or chronic duration and character of the disease, (2) the type of cells involved: bone marrow (myeloid), lymphoid (lymphatic), or monocytic; and (3) increased or non-increased numbers of abnormal cells in the blood leukemia or absence of leukemia (subleukemia).

[0132] The term "lymphoma," as used herein, refers to a cancer arising from cells of immune origin. The term "melanoma", as used herein, is taken to mean a tumor arising from the melanocytic system of the skin and other organs.

[0133] The term "nitro" as used herein refers to a --NO.sub.2 group. The term "oxo," as used herein, represents a divalent oxygen atom (eg, the structure of oxo may be depicted as ═O).

[0134] The term "Ph," as used herein, refers to phenyl. The term "pharmaceutical composition" as used herein refers to a composition containing a compound described herein that is formulated with a pharma- ceutically acceptable excipient and can be manufactured or sold by approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a mammalian disease.The pharmaceutical composition can be formulated, for example, for oral administration in unit dosage form (e.g., tablet, capsule, caplet, gelcap, or syrup), for topical administration (e.g., as a cream, gel, lotion, or ointment), for intravenous administration (e.g., as a sterile solution that does not contain particulate embolic material and in a solvent system suitable for intravenous use), or in any other formulation described herein.

[0135] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" is used interchangeably herein and refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving an active compound) and having the properties of being non-toxic and non-inflammatory in patients. Excipients may include, for example, anti-adhesive agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (coloring agents), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0136] The term "pharmaceutically acceptable salts" as used herein refers to salts that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic responses, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or can be prepared separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Acid salts include, for example, acid salts, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate.Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium cations, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0137] The term "PLK4," as used herein, refers to polo-like kinase 4, also known as serine / threonine-protein kinase PLK4 (gene name PLK4).

[0138] The term "PLK4 inhibitor," as used herein, refers to an inhibitor of PLK4 that, upon contact with the enzyme PLK4, whether in vitro, in cell culture, or in an animal, reduces the measured PLK4 IC 50 is 10 μM or less (e.g., 5 μM or less, or 1 μM or less). For certain PLK4 inhibitors, the PLK4 IC 50 may be 100 nM or less (e.g., 10 nM or less, or 3 nM or less), and may be as low as 100 pM or 10 pM. 50 is 1 nM to 1 μM (e.g., 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM). Even more preferably, the PLK4 IC 50 is less than 20 nm (for example, 1 nM to 20 nM).

[0139] The terms "premalignant" or "precancerous" as used herein refer to a condition that is not malignant but has the potential to become malignant. The term "protecting group" as used herein refers to a group intended to protect a hydroxy, amino, or carbonyl from participating in one or more undesired reactions during chemical synthesis. The term "O-protecting group" as used herein refers to a group intended to protect a hydroxy, or carbonyl group from participating in one or more undesired reactions during chemical synthesis. The term "N-protecting group" as used herein refers to a group intended to protect a nitrogen-containing (e.g., amino, amide, heterocyclic NH, or hydrazine) group from participating in one or more undesired reactions during chemical synthesis. Commonly used O- and N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Exemplary O- and N-protecting groups include alkanoyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, triisopropylsilyloxymethyl, 4,4′-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylpehenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl.

[0140] Exemplary O-protecting groups for protecting carbonyl-containing groups include, but are not limited to, acetals, acylals, 1,3-dithianes, 1,3-dioxanes, 1,3-dioxolanes, and 1,3-dithiolanes.

[0141] Other O-protecting groups include substituted alkyl, aryl, and arylalkyl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2-trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., Examples include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, and diphenylmethylsilyl; carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl, and nitrobenzyl).

[0142] Other N-protecting groups include chiral auxiliaries such as protected or unprotected D,L or D,L-amino acids such as alanine, leucine, phenylalanine, etc.; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, etc.; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α -dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydroxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; arylalkyl groups, such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, benzyloxymethyl, and the like; silylalkyl acetal groups, such as [2-(trimethylsilyl)ethoxy]methyl, and silyl groups, such as trimethylsilyl, and the like. Useful N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, dimethoxybenzyl, [2-(trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0143] The term "tautomer" refers to structural isomers that are readily interconverted, often by rearrangement of a proton. Tautomers are different chemical species that are distinguishable by different spectroscopic characteristics, but generally cannot be individually isolated. Non-limiting examples of tautomers include ketone-enol, enamine-imine, amide-imidic acid, nitroso-oxime, ketene-ynol, and amino acid-ammonium carboxylate.

[0144] The term "sarcoma" generally refers to a tumor made up of a substance like embryonic connective tissue and generally composed of closely packed cells surrounded by fibrillar or homogenous material. The term "subject" as used herein refers to a human or non-human animal (e.g., a mammal) suffering from or at risk for a disease or condition as determined by a qualified professional (e.g., a physician or advanced nursing practitioner) with or without clinical test(s) known in the art of a sample(s) from the subject. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases with symptoms of cellular hyperproliferation, such as cancer.

[0145] "Treatment" and "treating," as used herein, refer to the medical management of a subject with the intent to ameliorate, alleviate, stabilize, prevent, or cure a disease or condition. This term includes active treatment (treatment aimed at ameliorating the disease or condition); causal treatment (treatment directed at the cause of the associated disease or condition); palliative treatment (treatment designed to reduce the symptoms of the disease or condition); preventive treatment (treatment aimed at minimizing or partially or completely inhibiting the onset of the associated disease or condition), and supportive treatment (treatment employed in addition to another therapy).

[0146] The term "TRIM37" refers to tripartite motif-containing protein 37 and its gene. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0147] Generally, the present invention provides compounds, pharmaceutical compositions containing the compounds, methods for preparing the compounds, and methods of use. The compounds of the present invention may be PLK4 inhibitors. These compounds can be used to inhibit PLK4 in cells, for example, cells of a subject (e.g., cells that overexpress TRIM37 or have altered centrosome or centriole function or number). The subject may require treatment for a disease or condition, for example, a disease or condition with symptoms of cell hyperproliferation, for example, cancer. The PLK4 inhibitory activity of the compounds disclosed herein is useful for treating a subject in need of cancer treatment.

[0148] The Polo-like kinase (PLK) family of serine / threonine kinases, characterized by the presence of a Polo box domain, plays an important role in the regulation of mitosis. Of the five members described to date, PLK1, PLK2, PLK3, PLK4, and PLK5, PLK1 is the most studied member, and several PLK1 inhibitors have been described to date. PLK4 is the structurally most divergent member of the family. Unlike PLK1, PLK2, and PLK3, PLK4 has only one Polo box and an active site that is highly homologous to Aurora kinases. PLK4 has a restricted tissue distribution and is only present in proliferating tissues. PLK4 localizes to the centrosome and is a key regulator of centriole duplication. Deregulation of PLK4 leads to loss of numerical integrity of the centrosome, leading to chromosomal instability. It has been shown that PLK4 is upregulated in breast cancer, especially in the basal-like subtype, and high PLK4 levels are associated with poor patient outcome. Consistent with its essential role in centriole biogenesis, inhibition of PLK4 activity or reduction of PLK4 via genetic means has been shown to result in centriole reduction.

[0149] Inhibitors of PLK4 may be particularly useful in treating tumors harboring TRIM37 amplification using synthetic lethal therapeutic strategies. The TRIM37 locus is found at the border between 17q22 and 17q23, a chromosomal region that is amplified in a number of cancers, most notably in about 50-60% of neuroblastomas and approximately 10% of breast cancers. TRIM37 is a ubiquitin E3 ligase that plays a key role in regulating cellular expression of pericentriolar material. Overexpression of TRIM37 promotes the degradation of pericentriolar material. Good microtubule nucleation is a prerequisite for cell division and survival. Cells can survive without centrosomes but rely on pericentriolar material. In situations where the abundance of pericentriolar material is suppressed, such as through overexpression of TRIM37, cells cannot survive after PLK4 inhibition because they are unable to properly form microtubules.

[0150] The compounds of the present invention include, for example, compounds of formula (I):

[0151] [ka]

[0152] or a pharma- ceutically acceptable salt thereof, During the ceremony, n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; L is an optionally substituted C 2~9 Heterocyclyl, optionally substituted C 2~9 Heteroaryl, optionally substituted C 6~10 Aryl, or optionally substituted C 3~8 cycloalkyl, where L further comprises n occurrences of R 3 Optionally replaced by; R 1 is hydrogen, halogen, or optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6Alkynyl, or optionally substituted C 3~8 is cycloalkyl; A is O or S, and R 2A and R 2B are both absent; or A is N and R 2A is absent and R 2B is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 6~10 Aryl C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, optionally substituted C 1~9 Heteroaryl C 1~6 Alkyl or optionally substituted C 1~6 alkylsulfonyl or R 2B and L, together with the atoms to which they are attached, may be optionally substituted C 2~9 Heterocyclyl or optionally substituted C 2~9 forms a heteroaryl; or A is C and R 2A and R 2B each independently represents hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 6~10 Aryl C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, optionally substituted C 1~9 Heteroaryl C 1~6 Alkyl, or optionally substituted C 1~6 is alkylsulfonyl; Each R 3 are independently selected from halogen, cyano, and optionally substituted C1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 6~10 Aryl C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, optionally substituted C 1~9 Heteroaryl C 1~6 Alkyl, -S(O) m R 3A , -N(R 3B )2, or -OR 3B and; R 3A is an arbitrarily substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, -OR 3B , or -N(R 3B )2; Each R 3B are independently hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 6~10 Aryl C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, optionally substituted C 1~9 Heteroaryl C 1~6Alkyl or optionally substituted C 1~6 alkylsulfonyl; or two R 3B The groups are optionally substituted C 2~9 Forming a heterocyclyl; X is N and R 4 is absent; or X is C and R 4 is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl or optionally substituted C 1~9 is heteroaryl; R 5 is an arbitrarily substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 1~9 Heteroaryl, or -ZR 5A and; Z is an optionally substituted C 2~9 Heterocyclylene, optionally substituted C 2~9 Heteroarylene, optionally substituted C 6~10 Arylene, or optionally substituted C 3~8 is cycloalkylene; R 5Ais hydrogen, halogen, cyano, or an optionally substituted C 1~6 Alkylsulfonyl, optionally substituted C 1~6 Alkyl, optionally substituted C 1~6 Heteroalkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 6~10 Aryl, optionally substituted C 2~9 Heterocyclyl or optionally substituted C 1~9 is heteroaryl; R 6 is hydrogen, halogen, cyano, or an optionally substituted C 1~6 Alkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, or -OR 6A and R 6A is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted C 2~6 Alkenyl, optionally substituted C 2~6 Alkynyl, or optionally substituted C 3~8 It is cycloalkyl.

[0153] The compound of the invention can be, for example, a compound listed in Table 1 below, or a pharma- ceutically acceptable salt thereof.

[0154] [Table 1-1]

[0155] [Table 1-2]

[0156] [Table 1-3]

[0157]

Table 1-4

[0158]

Table 1-5

[0159]

Table 1-6

[0160]

Table 1-7

[0161]

Table 1-8

[0162]

Table 1-9

[0163]

Table 1-10

[0164]

Table 1-11

[0165]

Table 1-12

[0166]

Table 1-13

[0167]

Table 1-14

[0168]

Table 1-15

[0169]

Table 1-16

[0170]

Table 1-17

[0171]

Table 1-18

[0172]

Table 1-19

[0173]

Table 1-20

[0174]

Table 1-21

[0175]

Table 1-22

[0176]

Table 1-23

[0177]

Table 1-24

[0178]

Table 1-25

[0179]

Table 1-26

[0180]

Table 1-27

[0181]

Table 1-28

[0182]

Table 1-29

[0183]

Table 1-30

[0184]

Table 1-31

[0185]

Table 1-32

[0186] The present invention includes the individual diastereomers, enantiomers, epimers, and atropisomers of the compounds disclosed herein (if possible), as well as mixtures of their diastereomers and / or enantiomers, including racemic mixtures. Although the specific stereochemistry disclosed herein is preferred, other stereoisomers, including diastereomers, enantiomers, epimers, atropisomers, and mixtures thereof, may also be utilized in the treatment of PLK4-mediated diseases. Inactive or less active diastereoisomers and enantiomers may be useful, for example, in scientific studies of receptors and mechanisms of activation.

[0187] It is understood that a particular molecule may exist in more than one tautomeric form, and the invention includes all tautomers even though only one tautomer may be shown in the examples. The invention also includes pharma- ceutically acceptable salts of the compounds, as well as pharmaceutical compositions comprising the compounds and a pharma- ceutically acceptable carrier. The compounds are particularly useful, for example, in certain types of cancer and for slowing the progression of cancer after it has developed in a patient.

[0188] The compounds disclosed herein may be used in pharmaceutical compositions that include (a) the compound(s) or a pharma- ceutically acceptable salt thereof, and (b) a pharma- ceutically acceptable carrier. The compounds may be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients. The compounds may also be used in pharmaceutical compositions in which the compounds disclosed herein or a pharma- ceutically acceptable salt thereof is the only active ingredient.

[0189] Optical Isomers - Diastereomers - Geometric Isomers - Tautomers The compounds disclosed herein may, for example, contain one or more asymmetric centers and may occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers and / or enantiomers. The present invention includes all such isomeric forms of the compounds disclosed herein. All possible stereoisomers (e.g., enantiomers and / or diastereomers) as pure or partially purified compounds in mixtures (i.e., all possible combinations of asymmetric centers as pure compounds or in mixtures) are intended to be included within the scope of the present invention.

[0190] Some of the compounds described herein may contain bonds with rotational hindrance, such that two distinct rotomers or atropisomers may be separated and found to have different biological activities, which may be advantageous. All possible atropisomers are intended to be included within the scope of the present invention.

[0191] Some of the compounds described herein may contain olefinic double bonds, and unless otherwise specified, are meant to include both E and Z geometric isomers. Some of the compounds described herein exist in different states of hydrogen bonding, called tautomers. One example is a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed by the present invention.

[0192] Compounds disclosed herein that possess one or more asymmetric centers may be separated into diastereoisomers, enantiomers, and the like by methods well known in the art. Alternatively, enantiomers and other compounds containing chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and / or reagents of known configuration.

[0193] Metabolites-Prodrugs The present invention includes therapeutically active metabolites, where the metabolites themselves are within the scope of the claims. The present invention also includes prodrugs, which are compounds that are converted to the claimed compounds when or after being administered to a patient. In some cases, the chemical structures claimed in this application may themselves be prodrugs.

[0194] Isotopically enriched derivatives The present invention includes molecules that are isotopically enriched at one or more positions within the molecule. Thus, deuterium enriched compounds are within the scope of the claims.

[0195] Methods for Preparing the Compounds of the Invention The compounds of the present invention can be prepared using reactions and techniques known in the art and those described herein. Those skilled in the art will understand that the methods for preparing the compounds of the present invention described herein are not limiting, and that steps within the methods can be interchangeable without affecting the structure of the final product.

[0196] Method A Compounds of type I, where A is O or S, or A-R2B is NH, and X-R4 is N, can be prepared in five steps as described in Scheme A. SnAr reaction under basic conditions between appropriately protected aminopyrazole IV and substituted 4,6-dichloro-2-(methylthio)pyrimidine V produces aminopyrazole pyrimidines of type VI. Oxidation of methylthiol VI, followed by Suzuki or Stille coupling with an appropriate boronic acid (R5-B(OH)2) or stannane (R5-SnBu3), gives advanced intermediate methylsulfone pyrimidine VIII. SnAr-type addition of appropriately substituted aniline ((R3)nL-NH2), phenol ((R3)nL-OH), or thiophenol ((R3)nL-SH), followed by removal of the protecting group PG1, can finally give tetrasubstituted pyrimidines of type I.

[0197] [ka]

[0198] Method B Compounds of type I, where A-R2B is N-R2B and X-R4 is N, can be prepared in seven steps as described in Scheme B. Introduction of a protecting group (e.g., SEM, PMB, etc.) of the aminopyrazole pyrimidine of type VI described in Method A, followed by oxidation of methylthiol, can generate the bis-protected aminopyrazole pyrimidine XI. Suzuki or Stille coupling with an appropriate boronic acid (R5-B(OH)2) or stannane (R5-SnBu3) can provide the advanced intermediate methylsulfone pyrimidine XII. SnAr-type addition of an appropriately substituted aniline ((R3)nL-NH2) to XII, followed by alkylation of the aniline, gives intermediate XIV. Removal of the protecting groups PG1 and PG2 can finally provide the tetrasubstituted pyrimidines of type I illustrated in Scheme B.

[0199] [ka]

[0200] Method C Compounds of type I, where A is O or S, or A-R2B is NR2B, X is C, and R4 is H, can be prepared in six steps as described in Scheme C. Suzuki coupling between the appropriate substituted boronic acid (R5-B(OH)2) and 4-bromo-6-chloro-2-fluoropyridin-3-ol regioselectively affords pyridines of type XV. Conversion of the phenol moiety to the corresponding triflate XVI, followed by a second Suzuki coupling, then affords pyridines of type XVII. SnAr-type addition of amino-pyrazole IV to fluoro-chloropyridine XVII regioselectively affords chloro-pyridine XVIII. A second SnAr-type reaction of appropriately substituted anilines ((R3)nL-NH2), phenols ((R3)nL-OH), or thiophenols ((R3)nL-SH) with chloro-pyridines XVIII, followed by PG1 deprotection, can finally provide tetrasubstituted pyridines of type I as illustrated in Scheme C.

[0201] [ka]

[0202] Method D Compounds of type I, where R6 is OMe, A is O or S, or A-R2B is NR2B, X is C, and R4 is not H, can be prepared in six steps as described in Scheme D. Bromination of commercially available phenols of type XX, followed by methylation of the phenol moiety, can provide intermediate dibromo-chloropyridines of type XXII. Buchwald-Hartwig amination of XXI with amino-pyrazole IV, followed by Suzuki coupling with an appropriate substituted boronic acid (R5-B(OH)2), can provide chloro-pyridines of type XXIV. SnAr-type reaction of appropriately substituted anilines ((R3)nL-NH2), phenols ((R3)nL-OH), or thiophenols ((R3)nL-SH) to chloro-pyridines XXIV, followed by PG1 deprotection, can finally provide tetrasubstituted pyridines of type I as illustrated in Scheme D.

[0203] [ka]

[0204] Method E Compounds of type I, where A is O or S, or A-R2B is NR2B, and X-R4 is N, can be prepared in five steps as depicted in Scheme E, starting with the addition of amino-pyrazole IV to trichloropyrimidine XXVI via a SnAr type reaction, instead of method B described above. Protection of the amino group followed by SnAr type reaction of appropriately substituted aniline ((R3)nL-NHRB), phenol ((R3)nL-OH), or thiophenol ((R3)nL-SH) to dichloro-pyrimidine XXVIII can generate intermediate XXIX. Suzuki coupling with appropriately substituted boronic acid (R5-B(OH)2) can provide tetrasubstituted pyrimidines of type XIV as described above. Subsequent deprotection of PG1 and PG2 can finally provide the desired pyrimidines of type I as illustrated in Scheme E.

[0205] [ka]

[0206] Method F Compounds of type I, where A-R2B is NR2B and X-R4 is N and R5 is linked to the core pyrimidine by a C-N bond, can be prepared in four steps from common intermediate XI, as depicted in Scheme F. First, a SnAr-type reaction of an appropriately substituted aniline ((R3)nL-NH2) with chloro-pyrimidine XI produces pyrimidines of type XXX. Substitution of the resulting aniline then gives XXXI, followed by introduction of R5 via Buchwald-Hartwig amination to produce pyrimidines of type XIV. Subsequent deprotection of PG1 and PG2 can finally give the desired pyrimidines of type I, where R5 is linked to the core pyrimidine by a carbon-nitrogen bond.

[0207] [ka]

[0208] Method G Compounds of type I, where A-R2B is NR2B, X-R4 is N, and R5 is linked to the core pyrimidine by either a CN or CC bond, can be prepared in five steps from the common intermediate X, as depicted in Scheme G, using a similar reaction sequence to Method B, but with an alternative reaction sequence. Buchwald-Hartwig amination, Suzuki or Stille coupling is first performed on the thiomethylpyrimidine XXXII, followed by an oxidation step to XII. The remaining three steps from XII to the final compounds of type I are those described in Method B.

[0209] [ka]

[0210] Method H Compounds of type I, where A-R2B is NR2B, X-R4 is N, and R5 is linked to the core pyrimidine by a C-C bond, can be prepared in two steps from the aforementioned intermediate XXXI as depicted in Scheme G. Introduction of R5 via Suzuki or Stille coupling to the chloro-pyrimidine XXXI produces pyrimidines of type XXXIII. Subsequent deprotection of PG1 and PG2 can finally provide the desired pyrimidines of type I, where R5 is linked to the core pyrimidine by a carbon-carbon bond.

[0211] [ka]

[0212] Method I Compounds of type I, where A-R2B is CR2B, X-R4 is N, and R5 is linked to the core pyrimidine by a CC bond, can be prepared in two steps from intermediate XII described above. SnAr-type addition of arylmethyl acetate or arylacetonitrile to intermediate XII under basic conditions can provide pyrimidines of type XXXIV. Saponification of the ester and deprotection of PG1 and PG2 followed by subsequent decarboxylation can finally provide the desired pyrimidines of type I, where R2B is H,H. Direct deprotection of PG1 and PG2 on intermediates of type XXXIV, where R2B is a nitrile, can finally provide the desired pyrimidines of type I, where R2B is a nitrile and A is carbon.

[0213] [ka]

[0214] Treatment method The compounds of the invention can be used to treat diseases or conditions that depend on the activity of PLK4 (eg, cancers that overexpress TRIM37).

[0215] The disease or condition can have a symptom of cellular hyperproliferation. For example, the disease or condition can be cancer (e.g., a cancer that overexpresses TRIM37). Cancers with a high incidence of TRIM37 overexpression include, for example, uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, and endometrial cancer.

[0216] The compounds of the present invention may be administered by a route selected from the group consisting of oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intrathecal, intraperitoneal, intranasal, inhalation, intratumoral, and topical administration.

[0217] Pharmaceutical Compositions The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for in vivo administration. Pharmaceutical compositions typically include the compounds described herein and pharma- ceutical acceptable excipients. Certain pharmaceutical compositions may include one or more additional pharma- ceutical active agents described herein.

[0218] The compounds described herein can also be used in the form of free base, salts, zwitterions, solvates, or as prodrugs or pharmaceutical compositions thereof. All forms are within the scope of the present invention. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof may be administered to a patient in various forms depending on the route of administration selected, as will be understood by those skilled in the art. The compounds used in the methods described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions are formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0219] For human use, the compounds of the invention can be administered alone or in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Thus, pharmaceutical compositions for use according to the invention can be formulated in a conventional manner using one or more physiologically acceptable carriers that include excipients and adjuvants that facilitate processing of the compounds of the invention into pharma- ceutically usable preparations.

[0220] The present invention also includes pharmaceutical compositions that may contain one or more pharma- ceutically acceptable carriers. In making the pharmaceutical compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within a carrier, such as, for example, a capsule, sachet, paper, or other container form. When the excipient functions as a diluent, it may be a solid, semi-solid, or liquid substance (e.g., standard saline solution) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, powder, troche, sachet, cachet, elixir, suspension, emulsion, solution, syrup, and soft and hard gelatin capsules. As is known in the art, the type of diluent may vary depending on the intended route of administration. The resulting composition may contain additional agents, for example, preservatives.

[0221] Excipients or carriers are selected based on the mode and route of administration. Suitable pharmaceutical carriers and pharmaceutical necessities for use in pharmaceutical preparations are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), a reference text well known in the field, and USP / NF (United States Pharmacopeia and the National Formulary). Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Preparations can additionally include lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl and propylhydroxybenzoates; sweeteners; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

[0222] These pharmaceutical compositions can be manufactured in a conventional manner, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or lyophilizing processes. Methods known in the art for preparing formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York. The appropriate formulation depends on the selected route of administration. The formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulations. When preparing a formulation, the active compound can be milled to provide a suitable particle size before combining with other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling, eg about 40 mesh, to provide a substantially uniform distribution in the formulation.

[0223] Dosage The dosage of the compound used in the methods described herein, or its pharma- ceutically acceptable salt or prodrug, or its pharmaceutical composition, can vary depending on a number of factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of symptoms; the frequency of treatment; and the type of concomitant therapy (if any); and the clearance rate of the compound in the treated animal. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound used in the methods described herein may be initially administered at an appropriate dosage, which may be adjusted according to clinical response, if necessary. In general, the appropriate daily dose of the compound of the present invention is the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose generally depends on the above factors.

[0224] The compounds of the present invention may be administered to the patient in a single dose or in multiple doses. When multiple doses are administered, each dose may be separated from the others by, for example, 1 to 24 hours, 1 to 7 days, 1 to 4 weeks, or 1 to 12 months. The compounds may be administered according to a schedule, or the compounds may be administered without a predetermined schedule. The active compounds may be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day, every 2, 3, 4, 5, or 6 days, 1, 2, 3, 4, 5, 6, or 7 times per week, 1, 2, 3, 4, 5, or 6 times per month, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per year. It is understood that for any particular subject, specific dosage regimens must be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0225] Although the attending physician will ultimately determine the appropriate amount and dosing regimen, an effective amount of a compound of the present invention may be, for example, a total daily dosage of 0.05 mg to 3000 mg of any of the compounds described herein. Alternatively, dosages can be calculated using the patient's body weight. Such dosage ranges may include, for example, 10 to 1000 mg (e.g., 50 to 800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of a compound is administered.

[0226] In the methods of the invention, the period during which multiple doses of the compound of the invention are administered to the patient can vary. For example, in some embodiments, doses of the compound of the invention are administered to the patient over a period of 1-7 days, 1-12 weeks, or 1-3 months. In some embodiments, the compound is administered to the patient over a period of, for example, 4-11 months, or 1-30 years. In some embodiments, the compound is administered to the patient at the onset of symptoms. In any of these embodiments, the amount of compound administered can vary during the period of administration. If the compound is administered daily, administration can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day.

[0227] formulation Compounds identified as capable of treating any of the conditions described herein using any of the methods described herein may be administered to a patient or animal in unit dosage form together with a pharma- ceutically acceptable diluent, carrier, or excipient. Chemicals for use in such treatments may be produced and isolated by any standard technique known to those skilled in the art of medicinal chemistry. Conventional pharmaceutical practice may be utilized to provide appropriate formulations or compositions for administering the identified compounds to a patient suffering from a disease or condition. Administration may begin before the patient exhibits symptoms.

[0228] Exemplary routes of administration of the compounds used in the present invention (e.g., compounds of the present invention) or pharmaceutical compositions thereof include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intrathecal, intraperitoneal, intranasal, inhalation, and topical administration. Compounds are desirably administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein, formulated for the treatment of disorders described herein, are also part of the present invention.

[0229] Formulations for oral administration Pharmaceutical compositions contemplated by the present invention include those formulated for oral administration ("oral dosage forms"). Oral dosage forms can be, for example, in the form of a tablet, capsule, liquid solution or suspension, powder, or liquid or solid crystals that contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oils, or talc). Other pharma- ceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0230] Formulations for oral administration can also be presented as chewable tablets, hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets can be prepared in a conventional manner, for example, using a mixer, fluid bed apparatus, or spray drying apparatus, using the ingredients mentioned above for tablets and capsules.

[0231] Controlled release compositions for oral use can be constructed to release the active drug by controlling the dissolution and / or diffusion of the active drug substance. Any of a number of strategies can be implemented to obtain controlled release and a target plasma concentration versus time profile. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, for example, various types of controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microparticles, nanoparticles, patches, and liposomes. In some embodiments, the composition includes a biodegradable, pH, and / or temperature sensitive polymer coating.

[0232] Dissolution or diffusion controlled release can be achieved by suitable coating of the compound's tablet, capsule, pellet, or granule formulation, or by incorporating the compound into a suitable matrix. Controlled release coatings can include one or more of the above-mentioned coating materials, and / or, for example, shellac, beeswax, glycowax, castor bean wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax, and tearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbons.

[0233] Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils, such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0234] Formulations for parenteral administration The compounds described herein for use in the methods of the present invention can be administered in pharma- ceutically acceptable parenteral (e.g., intravenous or intramuscular) formulations as described herein. Pharmaceutical preparations may also be administered parenterally (intravenously, intramuscularly, subcutaneously, etc.) in dosage forms or formulations containing conventional non-toxic pharma- ceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. For example, to prepare such compositions, the compounds of the present invention may be dissolved or suspended in parenterally acceptable liquid vehicles. Among the acceptable vehicles and solvents, water, water adjusted to a suitable pH by the addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution may be used. The aqueous formulation may also contain one or more preservatives, such as methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), which is incorporated herein by reference.

[0235] Parenteral formulations can be any of five general types of preparations identified by the USP-NF as suitable for parenteral administration. (1) Drug injection: a liquid preparation that is a drug substance (e.g., a compound of the invention) or a solution thereof; (2) Injectable drugs: drug substances (e.g., compounds of the present invention) that are dry solids to be mixed with an appropriate sterile vehicle for parenteral administration as drug injections; (3) Drug Injectable Emulsions: Liquid preparations of a drug substance (e.g., a compound of the invention) dissolved or dispersed in a suitable emulsion medium; (4) Drug Injectable Suspensions: liquid preparations of a drug substance (e.g., a compound of the invention) suspended in an appropriate liquid medium; (5) Drugs for Injectable Suspensions: Drug substances (e.g., compounds of the present invention) that are dry solids to be mixed with an appropriate sterile vehicle for parenteral administration as drug injectable suspensions.

[0236] Formulations for parenteral administration include solutions of the compound prepared in water appropriately mixed with surfactant, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, as well as in oils. These formulations may contain preservatives to prevent the growth of microorganisms under normal storage and use conditions. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0237] Formulations for parenteral administration may contain, for example, excipients, sterile water, or saline, polyalkylene glycols, such as polyethylene glycol, vegetable oils, or hydrogenated naphthalene. Biocompatible and biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compound. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain, for example, lactose, or may be aqueous solutions, such as polyoxyethylene-9-lauryl ether, glycocholic acid, and deoxycholic acid, or may be oily solutions for administration in the form of nasal drops or as gels.

[0238] Parenteral formulations can be formulated for immediate release or sustained / extended release of the compound. Exemplary formulations for parenteral release of the compound include aqueous solutions, powders for solution preparation, co-solvent solutions, oil / water emulsions, suspensions, oil-based solutions, liposomes, microparticles, and polymer gels.

[0239] combination The compounds of the invention may be administered to a subject in combination with one or more of the following additional agents, for example:

[0240] (a) cytotoxic drugs; (b) antimetabolites; (c) alkylating agents; (d) anthracyclines; (e) antibiotics; (f) mitotic inhibitors; (g) hormone therapy agents; (h) signal transduction inhibitors; (i) gene expression modulators; (j) apoptosis inducer; (k) angiogenesis inhibitors; (l) immunotherapeutic agents; (m) DNA damage repair inhibitors; Or a combination of these.

[0241] Cytotoxic drugs include, for example, actinomycin D, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, amphotericin, amsacrine, arsenic trioxide, asparaginase, azacitidine, azathioprine, attenuated bovine tuberculosis vaccine (BCG), bendamustine, bexarotene, bevacizumab, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carfilzomib, carmustine, cetuximab, cisplatin, chlorambucil, cladribine, clofarabine, colchicine, chrysanthe Taspase, cyclophosphamide, cyclosporine, cytarabine, cytochalasin B, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, 1-dehydrotestosterone, denileukin, dexamethasone, dexrazoxane, dihydroxyanthraquinone, disulfiram, docetaxel, doxorubicin, emetine, epirubicin, erlotinib, epigallocatechin gallate, epoetin alfa, estramustine, ethidium bromide, etoposide, everolimus, filgrastim, finasunate, furo Cesuridine, fludarabine, flurouracil (5-FU), fulvestrant, ganciclovir, geldanamycin, gemcitabine, glucocorticoids, gramicidin D, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, irinotecan, interferon, interferon alpha 2a, interferon alpha 2b, ixabepilone, lactate dehydrogenase A (LDH-A), lenalidomide, letrozole, leucovorin, levamisole, lidocaine, lomustine, mechlorethamine, melphalan , 6-mercaptopurine, mesna, methotrexate, methoxsalen, metoprine, metronidazole, mithramycin, mitomycin C, mitoxantrone, nandrolone, nelarabine, nilotinib, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, pemetrexed, pentostatin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, procaine, procarbazine, propranolol, puromycin,The agent may be quinacrine, radicicol, a radioisotope, raltitrexed, rapamycin, rasburicase, salinosporamide A, sargramostim, sunitinib, temozolomide, teniposide, tetracaine, 6-thioguanine, thiotepa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, zoledronate, or a combination thereof.

[0242] The antimetabolite can be, for example, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine, cladribine, pemetrexed, gemcitabine, capecitabine, hydroxyurea, mercaptopurine, fludarabine, pralatrexate, clofarabine, cytarabine, decitabine, floxuridine, nelarabine, trimetrexate, thioguanine, pentostatin, or combinations thereof.

[0243] The alkylating agent can be, for example, mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclotosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamineplatinum(II) (DDP) cisplatin, altretamine, cyclophosphamide, ifosfamide, hexamethylmelamine, altretamine, procarbazine, dacarbazine, temozolomide, streptozocin, carboplatin, cisplatin, oxaliplatin, uramustine, bendamustine, trabectedin, semustine, or combinations thereof.

[0244] The anthracycline can be, for example, daunorubicin, doxorubicin, aclarubicin, aldoxorubicin, amrubicin, annamycin, carubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, or combinations thereof.

[0245] Antibiotics include, for example, dactinomycin, bleomycin, mithramycin, anthramycin (AMC), ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, piperacillin, pivampicillin, pivmecillinam, ticarcillin, aztreonam, imipenem, doripenem, ertapenem, meropenem, cephalosporin, clarithromycin, dirithromycin, roxithromycin, telithromycin, lincomycin, pristinamycin, quinupristin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, tobramycin, streptomycin, sulfamethizole, sulfamethoxazole, sulfisoxazole, demeclomycin, The drug may be cycline, minocycline, oxytetracycline, tetracycline, penicillin, amoxicillin, cephalexin, erythromycin, clarithromycin, azithromycin, ciprofloxacin, levofloxacin, ofloxacin, doxycycline, clindamycin, metronidazole, tigecycline, chloramphenicol, metronidazole, tinidazole, nitrofurantoin, vancomycin, teicoplanin, telavancin, linezolid, cycloserine, rifamycin, polymyxin B, bacitracin, viomycin, capreomycin, quinolones, daunorubicin, doxorubicin, 4'-deoxydoxorubicin, epirubicin, idarubicin, plicamycin, mitomycin C, mitoxantrone, or combinations thereof.

[0246] The mitotic inhibitor can be, for example, vincristine, vinblastine, vinorelbine, docetaxel, estramustine, ixabepilone, paclitaxel, maytansinoids, dolastatins, cryptophycins, or combinations thereof.

[0247] The signal transduction inhibitor can be, for example, imatinib, trastuzumab, erlotinib, sorafenib, sunitinib, temsirolimus, vemurafenib, lapatinib, bortezomib, cetuximab, panitumumab, matuzumab, gefitinib, STI 571, rapamycin, flavopiridol, imatinib mesylate, vatalanib, semaxinib, motesanib, axitinib, afatinib, bosutinib, crizotinib, cabozantinib, dasatinib, entrectinib, pazopanib, lapatinib, vandetanib, or combinations thereof.

[0248] The gene expression modulator can be, for example, siRNA, shRNA, antisense oligonucleotide, HDAC inhibitor, or combinations thereof.The HDAC inhibitor can be, for example, trichostatin A, trapoxin B, valproic acid, vorinostat, belinostat, LAQ824, panobinostat, entinostat, tacedinaline, mocethionestat, gibinostat, resminostat, abexinostat, xinostat, rosilinostat, paractinostat, CHR-3996, butyric acid, phenylbutyric acid, 4SC202, romidepsin, sirtinol, cambinol, EX-527, nicotinamide, or combinations thereof.The antisense oligonucleotide can be, for example, custirsen, apatorsen, AZD9150, trabadersen, EZN-2968, LErafAON-ETU, or combinations thereof. The siRNA can be, for example, ALN-VSP, CALAA-01, Atu-027, SPC2996, or a combination thereof.

[0249] The hormonal therapy agent may be, for example, a luteinizing hormone releasing hormone (LHRH) antagonist. The hormonal therapy agent may be, for example, farmagon, leuprorelin, goserelin, buserelin, flutamide, bicalutamide, ketoconazole, aminoglutethimide, prednisone, hydroxyl-progesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, raloxifene, droloxifene, iodoxyfene, 4-hydroxypropyl benzoate, benzoyl peroxide ... It may be roxitamoxifen, trioxyphene, keoxifene, LY117018, onapristone, toremifine citrate, megestrol acetate, exemestane, fadrozole, vorozole, letrozole, anastrozole, nilutamide, tripterelin, hysterelin, albiraterone, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, tretinoin, fenretinide, troxacitabine, or combinations thereof.

[0250] The apoptosis inducer can be, for example, recombinant human TNF-related apoptosis-inducing ligand (TRAIL), camptothecin, bortezomib, etoposide, tamoxifen, or combinations thereof.

[0251] The angiogenesis inhibitor can be, for example, sorafenib, sunitinib, pazopanib, everolimus, or a combination thereof. The immunotherapeutic agent may be, for example, a monoclonal antibody, a cancer vaccine (e.g., a dendritic cell (DC) vaccine), an oncolytic virus, a cytokine, an adoptive T cell therapy, bovine attenuated tuberculosis vaccine (BCG), GM-CSF, thalidomide, lenalidomide, pomalidomide, imiquimod, or a combination thereof. The monoclonal antibody may be, for example, anti-CTLA4, anti-PD1, anti-PD-L1, anti-LAG3, anti-KIR, or a combination thereof. The monoclonal antibody can be, for example, alemtuzumab, trastuzumab, ibritumomab tiuxetan, brentuximab vedotin, trastuzumab, adotrastuzumab emtansine, blinatumomab, bevacizumab, cetuximab, pertuzumab, panitumumab, ramucirumab, obinutuzumab, ofatumumab, rituximab, pertuzumab, tositumomab, gemtuzumab ozogamicin, tositumomab, or combinations thereof. The cancer vaccine can be, for example, Sipuleucel-T, BioVaxID, NeuVax, DCVax, SuVaxM, CIMAvax®, Provenge®, hsp110 chaperone complex vaccine, CDX-1401, MIS416, CDX-110, GVAX Pancreas, HyperAcute™ Pancreas, GTOP-99 (MyVax®), or Imprime PGG®. The oncolytic virus can be, for example, talimogene laherparepvec. The cytokine can be, for example, IL-2, IFNα, or a combination thereof. The adoptive T cell therapy can be, for example, tisagenlecleucel, axicabtageneciloleucel, or a combination thereof.

[0252] The DNA damage repair inhibitor can be, for example, PARP inhibitor, cell checkpoint kinase inhibitor, or a combination thereof.The PARP inhibitor can be, for example, olaparib, rucaparib, veliparib (ABT-888), niraparib (ZL-2306), iniparib (BSI-201), talazoparib (BMN 673), 2X-121, CEP-9722, KU-0059436 (AZD2281), PF-01367338, or a combination thereof.The cell checkpoint kinase inhibitor can be, for example, MK-1775 or AZD1775, AZD7762, LY2606368, PF-0477736, AZD0156, GDC-0575, ARRY-575, CCT245737, PNT-737, or a combination thereof. EXAMPLES

[0253] The following examples are intended to illustrate the invention. These examples are not intended to limit the invention in any way. Typically, unless otherwise noted in the examples below, reactions were carried out at room temperature (rt or RT) under a nitrogen atmosphere using dry solvents (Sure / Seal™). Reactions were monitored by TLC or by injection of small aliquots on a Waters Acquity-H UPLC® Class system using an Acquity® UPLC HSS C18 2.1×30 mm column eluted with a gradient (1.86 min) of acetonitrile (15% to 98%) in water (both containing 0.1% formic acid). Purification by preparative HPLC was performed on a Teledyne Isco Combi Flash® EZ Prep system using either a Phenomenex Gemini® 5 μm NX-C18 110 Angstrom 150×21.2 mm column at a flow rate of 40 mL / min over 12 min (<100 mg or multiple injections of <100 mg) or a HP C18 RediSep® Rf Gold column (>100 mg) eluted with an appropriate gradient of acetonitrile in water (both containing 0.1% formic acid), unless otherwise stated. The gradient was selected based on the retention time observed by reaction monitoring on a Waters Acquity-H UPLC® Class system (see above). Fractions containing the desired compound were combined and finally lyophilized. Purification by silica gel chromatography was performed on a Teledyne Isco Combi Flash® Rf system using an appropriately sized RediSep® Rf silica gel column. The purity of the final compounds was assessed by injection of small aliquots on a Waters Acquity-H UPLC® Class system using an Acquity® UPLC BEH C18 2.1×50 mm column eluted with a gradient (7 min) of acetonitrile (2% to 98%) in water (both containing 0.1% formic acid).

[0254] Example 1. Preparation of Compounds Intermediates The intermediates illustrated in Table 2 were used to prepare the compounds described herein.

[0255] [Table 2]

[0256] Intermediate 1 / 5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine

[0257] [ka]

[0258] Step 1 / 5-Methyl-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole To 5-methyl-3-nitro-1H-pyrazole (50.0 g, 393 mmol) in toluene (1.0 L) was added TFA (6.0 mL, 78.7 mmol) and 3,4-dihydro-2H-pyran (39.5 mL, 433 mmol) in one portion. The reaction mixture was heated to 90° C. The reaction mixture was cooled to room temperature and then poured into 10% KHCO3 (1.0 L). The phases were separated and the aqueous phase was back-extracted twice with EtOAc (2×200 mL). The combined organic phase was washed with brine (200 mL). Activated charcoal (7.5 g, 15% w) was added and the suspension was stirred for 15 min, then anhydrous Na2SO4 (50 g) was added and the suspension was stirred for 30 min. The resulting suspension was filtered through a Celite® pad and the cake was rinsed twice with EtOAc (2×100 mL). The combined organic phase was concentrated in vacuo to give 5-methyl-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (88.04 g, 89% pure, 95% corrected yield). 1H NMR(400MHz,CDCL3)δppm 1.46-1.72(m,3H),1.79-1.89(m,1H),1.98-2.08(m,1H),2.21(s,3H),2.28-2.45(m, 1H),3.40-3.72(m,3H),3.96-4.08(m,1H),5.03(dd,J=10.3,2.4Hz,1H),5.42(s,1H).

[0259] Process 2 / Intermediate 1 5-Methyl-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (78.7 g, 373 mmol) was suspended in methanol (1.25 L) and the suspension was then charged to a 2 gallon Parr pressure reactor. 10% Palladium on charcoal (wet support) (7.9 g, 10% w) was added and the reactor was then purged 3 times with 30 PSI nitrogen and 3 times with 20 PSI hydrogen. The hydrogen pressure was set to 35 PSI and the reaction was stirred at room temperature for 90 minutes. The reactor and filter were rinsed with methanol (2×500 mL) and the solvent was then concentrated to dryness to give 71.9 g of the crude desired compound as a brown oil. The crude product was preabsorbed onto silica gel (80 g) and then purified by silica gel chromatography eluting with a gradient of MeOH (0 to 4%) in DCM. Pure fractions were pooled and concentrated to dryness to give Intermediate 1 (57.7 g, 97% pure at 215 nm by HPLC, 86% corrected yield) as an amber oil. 1 H NMR(400MHz,CDCl3)δppm 1.46-1.72(m,3H),1.79-1.89(m,1H),1.98-2.08(m,1H),2.21(s,3H),2.28-2.45(m, 1H),3.40-3.72(m,3H),3.96-4.08(m,1H),5.03(dd,J=10.3,2.4Hz,1H),5.42(s,1H).

[0260] Intermediate 2 / N,1-bis(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-amine

[0261] [ka]

[0262] Step 1 / 1-(4-Methoxybenzyl)-5-methyl-3-nitro-1H-pyrazole A mixture of 5-methyl-3-nitro-1H-pyrazole (19.2 g, 151 mmol), 1-(chloromethyl)-4-methoxy-benzene (21.6 mL, 159 mmol), K2CO3 (41.8 g, 302 mmol) in MeCN (200 mL) was heated at 80° C. for 3 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting yellow solid was dissolved in DCM and purified by silica gel chromatography eluting with EtOAc (0 to 40%) in hexanes. Relevant fractions were combined and evaporated to give 1-[(4-methoxyphenyl)methyl]-5-methyl-3-nitro-pyrazole (23.0 g, 62% yield).

[0263] Step 2 / 1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-amine To 1-(4-methoxybenzyl)-5-methyl-3-nitro-1H-pyrazole (21.5 g, 87.1 mmol) in MeOH (550 mL) was added zinc (56.9 g, 871 mmol) and NH4HCO2 (54.9 g, 871 mmol) at 0° C. The reaction mixture was stirred for 30 min, filtered through Celite, and evaporated in vacuo to give 1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-amine (15.57 g, 82% yield), which was used in the next step without further purification.

[0264] Process 3 / Intermediate 2 A mixture of 1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-amine (11.67 g, 53.71 mmol) and 4-methoxybenzaldehyde (6.53 mL, 53.7 mmol) in DCM (200 mL) was stirred at room temperature for 30 min. NaBH(OAc)3 (12.52 g, 59.08 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was evaporated in vacuo and purified by silica gel chromatography eluting with EtOAc. The relevant fractions were combined to give intermediate 2 (12.57 g, 69% yield) as a white solid. UPLC-MS (+ESI) m / z = 338.3 (M+H) + .

[0265] Intermediate 3 / 4,6-Dichloro-5-methoxy-2-(methylthio)pyrimidine

[0266] [ka]

[0267] Intermediate 3 was prepared according to the procedure described in WO2016 / 166604 A1. Intermediate 4 / 4,6-Dichloro-5-cyclopropyl-2-(methylthio)pyrimidine

[0268] [ka]

[0269] Step 1 / 5-Cyclopropyl-2-(methylthio)pyrimidine-4,6(1H,5H)-dione A mixture of 1,3-diethyl 2-cyclopropylpropanedioate (111 g, 80% purity, 435 mmol), thiourea (40.0 g, 526 mmol) in MeOH (420 mL) was stirred for 10 min, then a solution of NaOMe in MeOH (25% w / w, 108 g, 500 mmol) was added. The final mixture was heated at 50° C. for 16 h. The mixture was cooled to room temperature and MeI (74.0 g, 522 mmol) was added. The final mixture was stirred at room temperature for 22 h, then quenched with water (500 mL) and acidified to pH ∼1 by adding concentrated HCl solution (10 mL). The mixture was concentrated under reduced pressure to remove most of the methanol. The suspension was cooled to 20° C. and filtered through a Buchner funnel equipped with a paper filter. The cake was rinsed with water (2×100 mL). The solid was dried under vacuum for 3 h to give 5-cyclopropyl 2-(methylthio)pyrimidine-4,6(1H,5H)-dione (80.0 g, 80% yield, 86% purity w / w by quantitative NMR) as a white powder, which was used in the next step without further purification. UPLC-MS (+ESI) m / z=199.1 (M+H). + Process 2 / Intermediate 4 To 5-cyclopropyl 2-(methylthio)pyrimidine-4,6(1H,5H)-dione (76.5 g, 332 mmol) in MeCN (300 mL) and N,N-dimethylformamide (38 mL) was added POCl3 (60 mL, 644 mmol) diluted with MeCN (100 mL) and slowly added over 35 min. The final mixture was heated at 70 °C for 3 h and then at 20 °C for 16 h. The resulting reaction mixture was cooled in a water bath and then quenched by adding water (750 mL) over 20 min. The resulting solid was filtered through a Buchner funnel equipped with a paper filter and rinsed with water (2 x 200 mL). After removing most of the water by suction, the cake was dried under vacuum at 50 °C for 45 h to give intermediate 4 (77.0 g, 89% yield, 89.0% purity at 215 nm by HPLC) as a yellow solid. UPLC-MS (+ESI) m / z = 235.0 (M+H) + Intermediate 5 / 6-Chloro-5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine

[0270] [ka]

[0271] Step 1 / 6-Chloro-5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine A solution of NaHMDS (159.9 mL, 159.9 mmol) was added over 30 min to a solution of intermediate 1 (9.66 g, 53.3 mmol) in THF (320 mL) at room temperature under a N2 atmosphere. Intermediate 3 (12.00 g, 53.31 mmol) was then added and the reaction mixture was stirred at 80° C. for 3 h, at which point UPLC-MS revealed that the starting material was completely consumed. The mixture was allowed to cool to room temperature and then poured into 500 mL of saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc in Hep (0 to 80%) to give 6-chloro-5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (10.0 g, 51% yield) as a pale yellow solid. UPLC-MS (+ESI) m / z=370.0 (M+H). + 1H NMR(400MHz,DMSO-d6)δppm 1.44-1.56(m,2H),1.58-1.74(m,1H),1.83(dd,J=13.0,2.2Hz,1H),1.98(d,J=13.0Hz,1H),2.21-2.28(m,1H),2.30(s,3H), 2.45(s,3H),3.58-3.68(m,1H),3.74(s,3H),3.90(d,J=11.5Hz,1H),5.32(dd,J=9.8,2.2Hz,1H),6.46(s,1H),9.78(s,1H).

[0272] Process 2 / Intermediate 5 Hydrogen peroxide 35% (w / w) in water (12.0 mL, 124 mmol) was added to a mixture of 6-chloro-5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (6.54 g, 17.7 mmol), tetrabutylammonium hydrogen sulfate (960.0 mg, 2.83 mmol), and sodium tungstate dihydrate (583 mg, 1.77 mmol) in EtOAc (106 mL) and THF (106 mL). The mixture was heated at 50° C. for 2 h. The reaction mixture was then cooled to 0° C., diluted with EtOAc, and washed with 10% NaHSO3 (260 mL). The layers were separated and the aqueous layer was back-extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give crude intermediate 5 (7.10 g, 88% purity at 254 nm by HPLC) as a light orange solid. UPLC-MS (+ESI) m / z = 402.0 (M+H). + 1 H NMR(400MHz,DMSO-d6)δppm 1.45-1.57(m,2H),1.59-1.75(m,1H),1.85(dd,J=13.0,2.4Hz,1H),1.94-2.03(m,1H),2.21-2.30(m,1H),2.32(s,3H),3.31-3.32(m ,3H),3.64(td,J=11.0,3.4Hz,1H),3.87(s,3H),3.90(dd,J=11.2,1.7Hz,1H),5.35(dd,J=10.0,2.4Hz,1H),6.55(s,1H),10.50(s,1 H).

[0273] Intermediate 6 / 6-Chloro-5-methoxy-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine

[0274] [ka]

[0275] 4-Methoxybenzyl chloride (5.18 mL, 35.1 mmol) was added to a mixture of intermediate 5 (7.05 g, 17.6 mmol) and K2CO3 (7.28 g, 52.6 mmol) in MeCN (35 mL) under nitrogen atmosphere. The mixture was stirred at 80 °C for 18 h, then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3x) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with Hep / EtOAc (0 to 100%) to give intermediate 6 (5.90 g, 65%) as a white solid. UPLC-MS (+ESI) m / z = 522.0 (M+H) + 1 H NMR(400MHz,DMSO-d6)δppm 1.46-1.56(m,2H),1.57-1.70(m,1H),1.80(dd,J=13.3,2.8Hz,1H),1.90-2.00(m,1H),2.08-2.21(m,1H),2.28(s,3H),3.28 (s,3H),3.32(s,3H),3.56-3.65(m,1H),3.70(s,3H),3.78-3.87(m,1H),5.03(s,2H),5.38(dd,J=9.0,2.2Hz,1H),6.01(s,1 H),6.83(d,J=8.6Hz,2H),7.31(d,J=8.6Hz,2H).

[0276] Intermediate 7 / 6-Chloro-5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine

[0277] [ka]

[0278] Step 1 / 6-Chloro-5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine To a solution of intermediate 1 (10.9 g, 46.4 mmol) dissolved in THF (270 mL) was added NaHMDS (104 mL, 104 mmol, 1 M in THF) followed by intermediate 4 (8.40 g, 46.4 mmol, corrected purity: 89%). The resulting solution was heated to reflux for 30 min, cooled to room temperature and concentrated to dryness. The residue was dissolved in EtOAc (500 mL) and washed with water (250 mL). The aqueous phase was back-extracted twice with EtOAc (2×100 mL) and then the pooled organic phases were washed successively with water (100 mL), brine (100 mL), dried over Na2SO4 and filtered. At this stage, 1.12 g of crude material from a previous run on intermediate 4 was added to the batch. The combined organic phase was partially evaporated to 80 mL and Hep (190 mL) was added to crystallize the product. The solid was collected by filtration, then the cake was washed with heptane (100 mL). The solid was dried under vacuum at 45-50° C. until a constant weight was observed to give 6-chloro-5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (14.06 g, corrected yield 73%) as an off-white solid. 1H NMR(400MHz,CDCL3)δppm 0.73(d,J=4.2Hz,2H),1.18(dd,J=7.9,1.6Hz,2H),1.42-1.81(m,5H),1.89(br d,J=12.2Hz,1H),2.04-2.18(m,1H),2.36(s,4H),2.55(s,3H),3.57-3.75(m,1H),4.11(br d,J=11.5Hz,1H),5.19(dd,J=10.4,2.3 Hz, 1H), 6.67 (s, 1H), 7.84 (s, 1H).

[0279] Process 2 / Intermediate 7 6-Chloro-5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (450 mg, 1.2 mmol) was dissolved in MeOH (10 mL) and water (5 mL). Oxone (398 mg, 2.4 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was poured into water and then extracted with EtOAc (3×). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=15:1) to give intermediate 7 (165 mg, 34% yield) as a white solid. UPLC-MS (+ESI) m / z=412.0 (M+H) + .

[0280] Intermediate 8 / 6-Chloro-5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine

[0281] [ka]

[0282] Step 1 / 6-Chloro-5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine 6-Chloro-5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidine (see intermediate 7, step 1) (14.0 g, 36.9 mmol) and K2CO3 (10.2 g, 73.7 mmol) were suspended in N,N-dimethylacetamide (140 mL) and then 4-methoxybenzyl chloride (6.93 g, 44.2 mmol) was added in one portion. The suspension was heated at 90° C. for 9 h. The reaction mixture was cooled to room temperature and poured onto a mixture of EtOAc (100 mL) and water (700 mL). The phases were separated and the aqueous phase was back-extracted twice with EtOAc (2×100 mL). The pooled organic phase was washed successively with water (2×100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The crude product was suspended in diisopropyl ether (100 mL) and heated to reflux for 30 min. The resulting slurry was slowly cooled to room temperature and then heptane (150 mL) was added. The solid was collected by filtration and washed with a mixture of 15% diisopropyl ether in heptane (50 mL). The solid was dried under vacuum at 45-50° C. until a constant weight was observed to give 6-chloro-5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (14.72 g, 80% yield) as an off-white solid. 1H NMR(400MHz,CDCl3)δppm 0.34(br d,J=5.4Hz,2H),0.53(td,J=8.4,4.9Hz,1H),0.58-0.68(m,1H),1.02-1.12(m,1H),1.51-1.77(m,5H),1.7 9-1.91(m,1H),2.04-2.17(m,1H),2.24-2.39(m,4H),2.44(s,3H),3.57-3.68(m,1H),3.78(s,3H),4.00(br d,J=11.5Hz,1H),5.05-5.14(m,1H),5.18(dd,J=9.5,2.4Hz,1H),5.21-5.29(m,1H),5.70(s,1H),6.81(d,J=8.8Hz,2H),7.34(d,J=8.6Hz,2H).

[0283] Engineering 2 / Intermediate 8 To a solution of 6-chloro-5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (11.71 g, 23.42 mmol) in EtOAc (210 mL) and THF (210 mL) were added successively tetrabutylammonium hydrogen sulfate (1.27 g, 3.75 mmol), sodium tungstate dihydrate (772 mg, 3.35 mmol), and 35% hydrogen peroxide in water (15.9 g, 164 mmol). The resulting solution was heated at 50 °C for 4.5 h. The resulting reaction mixture was cooled to 5-10 °C and poured onto 10% NaHSO3 (0.8 L). The phases were separated and the aqueous phase was back-extracted twice with ethyl acetate (2×100 mL). The pooled organic phases were washed successively with water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated to near dryness. Heptane (100 mL) was added and concentrated to dryness to give 12.5 g of crude product as a pale yellow solid. The solid was suspended in diisopropyl ether (70 mL) and heated to reflux for 45 min. Heating was stopped and the slurry was stirred at room temperature for 0.5 h. Heptane (70 mL) was added and the solid was then collected by filtration. The cake was washed with heptane (35 mL) and finally dried under vacuum at 45-50° C. to give intermediate 8 (11.85 g, 94% yield) as an off-white solid. 1 H NMR(400MHz,CDCl3)δppm 0.31-0.43(m,2H),0.62(td,J=8.5,4.5Hz,1H),0.65-0.75(m,1H),1.14(tt,J=8.4,5.8Hz,1H),1.53-1.77(m,3H),1.85(br dd,J=13.1,2.6Hz,1H),2.03-2.16(m,1H),2.32(s,4H),3.20(s,3H),3.59-3.69(m,1H),3.77(s,3H),4.02(br d,J=11.2Hz,1H),5.05-5.13(m,1H),5.16-5.27(m,2H),5.79(s,1H),6.81(d,J=8.8Hz,2H),7.39(d,J=8.8Hz,2H).

[0284] Intermediate 9 / 6-Chloro-5-cyclopropyl-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine

[0285] [ka]

[0286] Step 1 / 6-chloro-5-cyclopropyl-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine NaHMDS (1M, 6.41 mL, 6.41 mmol) was added to a solution of intermediate 2 (2.16 g, 6.41 mmol) in THF (10 mL) and stirred at room temperature for 10 min. Intermediate 4 (1.37 g, 5.83 mmol) was then added and the resulting mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc in Hep (70%). The relevant fractions were combined to give 6-chloro-5-cyclopropyl-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (1.47 g, 47% yield). UPLC-MS (+ESI) m / z=536.2 (M+H) + .

[0287] Process 2 / Intermediate 9 To 6-chloro-5-cyclopropyl-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (1.47 g, 2.74 mmol) in DCM (10 mL) at 0° C. was added mCPBA (946 mg, 5.48 mmol). The reaction was allowed to warm to room temperature for 1 h. An additional 950 mg of mCPBA was added to drive the reaction to completion. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc in Hep (70 to 100%). Relevant fractions were combined to give intermediate 9 (1.13 g, 73% yield). UPLC-MS (+ESI) m / z=568.2 (M+H) + .

[0288] Intermediate 10 / 6-Chloro-5-methoxy-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine

[0289] [ka]

[0290] Step 1 / 6-chloro-5-methoxy-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine NaHMDS (9.18 mL, 9.18 mmol, 1 M) was added to a solution of intermediate 2 (3.1 g, 9.19 mmol) in THF (20 mL) and stirred at room temperature for 10 min. The resulting mixture was added dropwise via syringe to intermediate 3 (2.07 g, 9.18 mmol) in THF (20 mL) at room temperature. The reaction mixture was evaporated in vacuo and purified by silica gel chromatography eluting with EtOAc (70%) in hexanes. The relevant fractions were combined to give 6-chloro-5-methoxy-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (1.82 g, 38% yield). UPLC-MS (+ESI) m / z=526.2 (M+H) + .

[0291] Process 2 / Intermediate 10 To 6-chloro-5-methoxy-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (1.82 g, 3.46 mmol) in DCM (10 mL) at 0° C. was added mCPBA (1.19 g, 6.92 mmol). The reaction was allowed to warm to room temperature, stirred for 4 h, and left in the refrigerator overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc in Hex (50-100%). Relevant fractions were combined and concentrated to give intermediate 10 (1.14 g, 59% yield). UPLC-MS (+ESI) m / z=558.2 (M+H) + .

[0292] Intermediate 11 / 2,4,6-trichloro-5-cyclopropylpyrimidine

[0293] [ka]

[0294] Step 1 / 5-Cyclopropylpyrimidine-2,4,6(1H,3H,5H)-trione A solution of diethyl 2-cyclopropylmalonate (15.6 g, 77.9 mmol) and urea (4.68 g, 77.9 mmol) in MeOH (390 mL) was maintained at 23° C. for 20 min. Sodium methoxide (25% in MeOH, 17.8 mL, 77.9 mmol) was then added to the reaction mixture. After the addition was complete, the reaction mixture was heated to reflux for 24 h. The resulting mixture was stirred at room temperature overnight and concentrated to dryness. The reaction mixture was cooled to 0° C. and water (25 mL) was added slowly. The precipitate was collected by filtration and washed with water (4 mL). The white solid was then dried under high vacuum. The filtrate, which still contained the desired product, was concentrated to 5 mL and extracted with Me-THF (3×20 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to dryness, which was combined with the precipitate collected by filtration to give 5-cyclopropylpyrimidine-2,4,6(1H,3H,5H)-trione (7.40 g, 56% yield). UPLC-MS (+ESI): m / z=169.1 [M+H] + .

[0295] Process 2 / Intermediate 11 A mixture of 5-cyclopropylpyrimidine-2,4,6(1H,3H,5H)-trione (7.40 g, 44.0 mmol) and N,N-dimethylaniline (16.9 mL, 132 mmol) in POCl3 (82.0 mL, 880 mmol) was heated to reflux for 3 h and then cooled to room temperature. The reaction mixture was poured slowly onto ice under vigorous stirring in an Erlenmeyer flask. After the addition was complete, the mixture was extracted with DCM (3 x 75 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography eluting with EtOAc (0-10%) in hexanes. The desired fractions were combined and concentrated in vacuo to dryness to give intermediate 11 (6.0 g, 61% yield). UPLC-MS (+ESI): m / z = 223.9 [M+H] + .

[0296] Intermediate 12 / 2,6-dichloro-5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine

[0297] [ka]

[0298] Step 1 / 2,6-Dichloro-5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of intermediate 11 (6.00 g, 26.8 mmol) and intermediate 1 (5.35, 29.5 mmol) in dry THF (67 mL) at −78° C. under an inert atmosphere was added NaHMDS solution (1 M in THF, 26.8 mL, 26.8 mmol). The resulting reaction mixture was stirred at this temperature for 30 min, then poured into water (100 mL) at 0° C. and diluted with DCM (100 mL). The layers were partitioned. Brine was added to the aqueous layer and back-extracted with DCM (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with EtOAc (0 to 30%) in hexanes. The desired fractions were combined and concentrated to dryness in vacuo to give 2,6-dichloro-5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine (4.10 g, 41% yield). UPLC-MS (+ESI): m / z=368.1 [M+H] + .

[0299] Process 2 / Intermediate 12 To a solution of 2,6-dichloro-5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine (1.70 g, 4.62 mmol) in DMA (10 mL) was added K2CO3 (1.91 g, 13.9 mmol). The mixture was purged with nitrogen at room temperature for 5 min. 1-(Chloromethyl)-4-methoxy-benzene (1.45 g, 9.23 mmol, 1.25 mL) was added and the mixture was heated at 85° C. for 18 h. The resulting mixture was filtered and purified by preparative HPLC eluting with a gradient of MeCN (10 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give intermediate 12 (1.69 g, 75% yield). UPLC-MS (+ESI) m / z = 488.1 (M+H) + .

[0300] Intermediate 13 / 6-Chloro-5-cyclopropyl-N-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N-(4-methoxybenzyl)-2-(methylsulfonyl)pyrimidin-4-amine

[0301] [ka]

[0302] Step 1 / 6-chloro-5-cyclopropyl-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine To a solution of intermediate 4 (705 mg, 3.00 mmol) in DMF (5 mL) was added 5-cyclopropyl-1H-pyrazol-3-amine (517 mg, 4.20 mmol) and NaI (630 mg, 4.20 mmol). The mixture was stirred at 60 °C for 72 h. The reaction was quenched by adding water and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified on a silica gel column eluted with EtOAc (50-100%) in heptane. The appropriate fractions were combined and concentrated in vacuo to give 6-chloro-5-cyclopropyl-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (586 mg, 61% yield) as a white solid.

[0303] Step 2 / 6-Chloro-5-cyclopropyl-N-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine A mixture of 6-chloro-5-cyclopropyl-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (530 mg, 1.65 mmol), 4-methylbenzenesulfonic acid hydrate (60.0 mg, 315 μmol), 3,4-dihydro-2H-pyran (600 μL, 6.61 mmol) in EtOAc (12 mL) was refluxed for 18 h. The reaction mixture was diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO3 (2 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography eluting with a gradient of EtOAc (10-70%) in heptane. The appropriate fractions were combined and concentrated to give 6-chloro-5-cyclopropyl-N-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (668 mg, 100% yield) as an off-white solid. UPLC-MS (+ESI): m / z=406.5 [M+H] + .

[0304] Step 3 / 6-Chloro-5-cyclopropyl-N-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N-(4-methoxybenzyl)-2-(methylthio)pyrimidin-4-amine To a solution of 6-chloro-5-cyclopropyl-N-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (685 mg, 1.69 mmol) in DMF (8 mL) was added NaH (60% dispersion) (84.0 mg, 2.19 mmol, 60% purity) at 0° C. The mixture was stirred at 0° C. for 10 min, then (chloromethyl)-4-methoxy-benzene (300 μL, 2.21 mmol) and NEt4I (31 mg, 84 μmol) were added. The final mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc (100 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified on a silica gel column eluted with a gradient of EtOAc (0-60%) in heptane. The appropriate fractions were combined and concentrated to give 6-chloro-5-cyclopropyl-N-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N-(4-methoxybenzyl)-2-(methylthio)pyrimidin-4-amine (650 mg, 73% yield) as a semi-solid. UPLC-MS (+ESI): m / z=526.6 [M+H] + .

[0305] Step 4 / Intermediate 13 6-Chloro-5-cyclopropyl-N-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N-(4-methoxybenzyl)-2-(methylthio)pyrimidin-4-amine (650 mg, 1.24 mmol) was charged into a flask and dissolved in THF (10 mL) and EtOAc (10 mL). Tetrabutylammonium hydrogen sulfate (67.0 mg, 197 μmol), sodium tungstate dihydrate (41.0 mg, 124 μmol) and H2O2 (35% in water, 760 μL, 8.60 mmol) were added successively and the resulting solution was heated at 50 °C for 5 h. The reaction mixture was cooled to 5-10 °C and poured onto 10% aqueous NaHSO3 (10 mL). The organic phase was separated and the aqueous phase was then back-extracted twice with ethyl acetate (20 mL). The pooled organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified on a silica gel column eluted with a gradient of EtOAc (20-80%) in heptane. The appropriate fractions were combined and concentrated in vacuo to give intermediate 13 (432 mg, 63% yield) as a white solid. UPLC-MS (+ESI): m / z=558.6 [M+H] + .

[0306] compound Compound 1 / Method A / N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0307] [ka]

[0308] Step 1 / 5-Methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine To a solution of intermediate 5 (1.00 g, 2.40 mmol) and 1-methylpyrazol-4-ylboronic acid (454 mg, 3.6 mmol) in 1,4-dioxane (30 mL) was added XPhosPdG2 (189 mg, 0.24 mmol), K3PO4 (51 mg, 0.24 mmol), and water (3 mL). The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. The solid was filtered off and the crude supernatant was purified by preparative TLC (ethyl acetate / petroleum ether) to give 5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (562 mg, 51% yield) as a light pink solid. UPLC-MS (+ESI) m / z = 448.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),8.46(s,1H),8.09-8.11(s,1H),6.61(s,1H),5.33-5.36(m,1H),3.82-3.95(m,4H),3.67-3.77(m,3H),3.37-3. 62(m,1H),3.31-3.37(m,3H),2.50-2.51(m,4H),2.20-2.33(m,1H),1.97-2.00(m,1H),1.84-1.87(m,1H),1.74-1.84(m,2H).

[0309] Process 2 / N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine To 4-methylsulfonylaniline (13.2 uL, 112 umol) in DMF (0.5 mL) was added NaH (8.90 mg, 223 umol, 60% purity) and stirred at room temperature for 10 min. To this mixture was added 5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (50 mg, 112 umol) and the resulting mixture was stirred at 80° C. for 1 h and then heated at 120° C. for 15 h to complete the reaction. The crude reaction mixture was diluted with water, followed by EtOAc and saturated aqueous NaHCO3. The organic phase was separated, washed with brine, dried over Na2SO4, filtered and finally evaporated in vacuum to give N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (45 mg, 75% yield) was obtained as a brown solid, which was used directly in the next step without further purification. UPLC-MS (+ESI) m / z=539.2 (M+H). + .

[0310] Step 3 / Compound 1 N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4To -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (46 mg, 82 umol) was added 4M HCl in dioxane (2.0 mL). The reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was concentrated. The residue was dissolved in DMSO and purified by preparative HPLC eluting with a gradient of MeCN (25 to 55%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 1 (6.0 mg, 15% yield) as a white solid. UPLC-MS (+ESI) m / z=473.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,1H),8.37(s,1H),8.08(s,1H),7.85-7.73(m,2H),6.00(s,1H),3.96(s,3H),3.68(s,3H),3.23(s,3H),2.18(s,3H).

[0311] Compound 2 / Method B / N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0312] [ka]

[0313] Step 1 / 5-Methoxy-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine To a solution of 5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (compound 1, see step 1) (5.30 g, 11.8 mmol) in MeCN (20 mL) was added 1-(chloromethyl)-4-methoxy-benzene (2.40 mL, 17.8 mmol,) and K2CO3 (4.91 g, 35.5 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 3 h. The crude reaction mixture was diluted with EtOAc, quenched with saturated aqueous NaHCO3, and then extracted with EtOAc. The organic layer was evaporated in vacuum and the residue was purified by silica gel chromatography eluting with EtOAc (50-100%) in heptane. Evaporation of the relevant fractions gave 5-methoxy-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (6.40 g, 95% yield) as an off-white foam. UPLC-MS (+ESI) m / z=568.3 (M+H). + .

[0314] Process 2 / N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine To a solution of 5-methoxy-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (1.4 g, 2.47 mmol) in DMPU (7 mL) was added 2-fluoro-4-methylsulfonyl-aniline (933 mg, 4.93 mmol) and NaH (197 mg, 4.93 mmol, 60% purity). The reaction mixture was stirred at 120° C. for 15 h. The crude reaction mixture was quenched with water, filtered, and purified by preparative HPLC, both eluting with a gradient of MeCN in water containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the desired product N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (761 mg, 46% yield) was obtained as a yellow solid. UPLC-MS (+ESI) m / z=677.3 (M+H) + .

[0315] Step 3 / Compound 2 N in DMF (1 mL) 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4To a solution of -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (98.0 mg, 145 umol) was added NaH (10.4 mg, 434 umol, 60% dispersion), followed after 10 min by MeI (27 uL, 434 umol) and the reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was quenched with water, filtered and purified by preparative HPLC, eluting with a gradient of MeCN in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give intermediate N. 2 -(2-fluoro-4-(methylsulfonyl-phenyl)-5-methoxy-N 4 -[(4-Methoxyphenyl)methyl]-N 2 -Methyl-6-(1-methylpyrazol-4-yl)-N 4 -(5-Methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrimidine-2,4-diamine was obtained as a brown solid. To this intermediate was added TFA (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. The crude reaction mixture was evaporated, diluted with DMSO, filtered and purified by preparative HPLC eluting with a gradient of MeCN (10 to 50%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 2 (18 mg, 24% yield, 94% purity) as a white solid. UPLC-MS (+ESI) m / z=487.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.88(s,1H),8.84(s,1H),8.27(s,1H),7.97(d,J=0.6Hz,1H),7.89-7.79(m,2H),7.79-7 .73(m,1H),5.65(s,1H),3.92(s,3H),3.62(s,3H),3.49(s,3H),3.31(s,3H),2.04(s,3H).

[0316] Compound 3 / Method B / N 2 -Ethyl N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0317] [ka]

[0318] Process 1 / N 2 -Ethyl N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine N in DMF (0.5 mL) 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 To a solution of -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 2, see step 2) (37 mg, 54.67 umol) was added NaH (3.9 mg, 164 μmol) and after 10 min of stirring, iodoethane (8.8 μL, 109 μmol) was added and the reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was quenched with water, filtered and purified by preparative HPLC, eluting with a gradient of MeCN in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give intermediate N. 2 -Ethyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4-(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine was obtained as a brown solid, which was used immediately in the next step without purification.

[0319] Step 2 / Compound 3 Crude N 2 -Ethyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine was added TFA (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. The crude reaction mixture was evaporated, diluted with DMSO, filtered, and purified by preparative HPLC eluting with a gradient of MeCN (10 to 50%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 3 (7 mg, 26% yield from step 1) as a white solid. UPLC-MS (+ESI) m / z=501.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.86(s,1H),8.84(s,1H),8.26(s,1H),7.95(s,1H),7.86(ddd,J=13.2,8.9,2.1Hz,2H),7.74(t,J=7.8H z,1H),5.54(s,1H),4.02(q,J=7.0Hz,2H),3.93(s,3H),3.61(s,3H),2.02(s,3H),1.19(t,J=7.0Hz,3H).

[0320] Compound 4 / Method B / N2-(2-fluoro-4-(methylsulfonyl)phenyl)-N 2 -(4-fluorobenzyl)-5-methoxy-N 4- (5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0321] [ka]

[0322] Process 1 / N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -(4-fluorobenzyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine N in DMF (0.5 mL) 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 To a solution of -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (compound 2, see step 2) (33.0 mg, 48.7 μmol) was added NaH (5.1 mg, 146 μmol, 60% dispersion) and after 10 min of stirring, 1-(bromomethyl)-4-fluoro-benzene (18 uL, 146 μmol) was added and the reaction mixture was stirred at room temperature for 15 h. The crude reaction mixture was quenched with water, filtered and purified by preparative HPLC, eluting with a gradient of MeCN in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give intermediate N. 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -(4-fluorobenzyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine was obtained as a brown solid, which was used in the next step without further purification.

[0323] Step 2 / Compound 4 Crude N from step 1 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -(4-fluorobenzyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine was added TFA (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. The crude reaction mixture was evaporated, diluted with DMSO, filtered and purified by preparative HPLC eluting with a gradient of MeCN (10 to 50%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the desired product, compound 4 (5.1 mg, 18% yield from step 1) as a white solid. UPLC-MS (+ESI) m / z=581.3 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.86(s,1H),8.84(s,1H),8.24(s,1H),7.91(s,1H),7.86-7.76(m,2H),7.72(t,J=7.7Hz,1H),7.37(dd,J=8.6 ,5.7Hz,2H),7.17-7.06(m,2H),5.49(s,1H),5.27(s,2H),3.91(s,3H),3.62(s,3H),3.28(s,3H),2.00(s,3H).

[0324] Compound 5 / Method A / 5-Methoxy-N-(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(5-(methylsulfonyl)indolin-1-yl)pyrimidin-4-amine

[0325] [ka]

[0326] Step 1 / 5-Methoxy-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(5-(methylsulfonyl)indolin-1-yl)pyrimidin-4-amine To a solution of 5-methoxy-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (compound 2, see step 2) (20.0 mg, 35.2 μmol) in DMPU (0.5 mL) was added NaH (2.8 mg, 71 μmol, 60% purity). The reaction mixture was stirred at 120° C. for 15 h. The crude reaction mixture was quenched with water, filtered, and purified by preparative HPLC, eluting with a gradient of MeCN (40 to 70%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 5-methoxy-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(5-(methylsulfonyl)indolin-1-yl)pyrimidin-4-amine as a yellow solid which was used in the next step without further purification.

[0327] Step 2 / Compound 5 To the crude 5-methoxy-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(5-(methylsulfonyl)indolin-1-yl)pyrimidin-4-amine was added TFA (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. The crude reaction mixture was evaporated, diluted with DMSO, filtered, and purified by preparative HPLC eluting with a gradient of MeCN (10 to 50%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 5 (3.0 mg, 18% yield from step 1) as a white solid. UPLC-MS (+ESI) m / z=481.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 9.10(s,1H),8.55(d,J=8.6Hz,1H),8.38(s,1H),8.09(s,1H),7.73(dd,J=8.6,2.1Hz,1H),7.66(d,J=1.9Hz,1H),6.74 (s,1H),6.37(s,1H),4.30(t,J=8.9Hz,2H),3.96(s,3H),3.68(s,3H),3.22(t,J=8.8Hz,2H),3.13(s,3H),2.27(s,3H).

[0328] Compound 6 / Method B / N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 2 -Methyl-6-(1-methyl-1H-pyrazol-3-yl)-N 4 -(5-Methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

[0329] [ka]

[0330] Step 1 / 5-Methoxy-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine To a solution of intermediate 10 (208 mg, 372 μmol) in dioxane (2 mL) was added tributyl-(1-methylpyrazol-3-yl)stannane (152 mg, 410 μmol) and Pd(PPh3)4 (43 mg, 37 μmol). The reaction mixture was stirred at 100 °C for 5 h. The crude reaction mixture was evaporated, dissolved in 2 mL DMSO, filtered, and purified by preparative HPLC, eluting with a gradient of MeCN (40-70%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and evaporated to give 5-methoxy-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine (106 mg, 47% yield). UPLC-MS (+ESI) m / z = 604.3 (M+H) + .

[0331] Process 2 / N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-N 2 -Methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine To 2-fluoro-4-methylsulfonyl-aniline (37 mg, 193 μmol) in DMPU (1 mL) was added NaH (4.4 mg, 193 μmol, 60% dispersion). The mixture was stirred at room temperature for 10 min. To this mixture was added 5-methoxy-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine (106 mg, 176 umol) and the reaction was heated at 130° C. for 5 h. The mixture was then cooled to room temperature and MeI (56 uL, 897 umol) was added and the mixture was stirred at room temperature overnight. The crude mixture was filtered and purified by preparative HPLC eluting with a gradient of MeCN (40-70%) in water, both containing 0.1% formic acid. Combine the appropriate fractions, evaporate and N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-N 2 -methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (10 mg), and the non-methylated intermediate N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (48 mg). To a solution of the latter in DMF (1.5 mL) was added NaH (3.2 mg, 135 μmol, 60% dispersion) followed by MeI (8.4 μL, 135 μmol). The reaction was then stirred at room temperature for 15 min. The crude was purified by preparative HPLC eluting with a gradient of MeCN (40-70%) in water, both containing 0.1% formic acid. Appropriate fractions were combined, evaporated and N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4-(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-N 2 -methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine was obtained, which was mixed with 10 mg of the previously isolated 4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine.

[0332] Step 3 / Compound 6 Mixed N from the previous process 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-N 2 1H-Methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine was dissolved in TFA (2 mL) and heated at 120° C. overnight. The reaction mixture was evaporated in vacuo, dissolved in DMSO, and purified by preparative HPLC eluting with a gradient of MeCN (20-50%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and evaporated to give compound 6 (1.7 mg, 5.2% yield for steps 2 and 3). UPLC-MS (+ESI) m / z=487.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 7.88-7.77(m,2H),7.74(q,J=2.8Hz,2H),7.71(s,0H),6.72(d,J=2.2Hz,1H), 5.63(s,1H),3.91(s,3H),3.62(s,3H),3.45(s,3H),3.27(s,4H),2.01(s,3H).

[0333] Compound 7 / Method B / N 2 -(4-(cyclopropylsulfonyl)-2-fluorophenyl)-5-methoxy-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0334] [ka]

[0335] Process 1 / N 2 -(4-(cyclopropylsulfonyl)-2-fluorophenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine To 5-methoxy-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (compound 2, see step 1) (87 mg, 153 μmol) in DMPU (1 mL) was added 4-cyclopropylsulfonyl-2-fluoro-aniline (73 mg, 339 μmol). Nitrogen gas was bubbled through for 5 min, then NaH (22 mg, 550 μmol, 60% purity) was added at room temperature. The vial was closed and the mixture was heated at 125° C. for 18 h. The mixture was cooled to room temperature, MeI (100 μL, 1.61 mmol) was added, and the mixture was stirred at room temperature for 1 h. 1 mL of MeOH was added to quench the reaction, and the mixture was filtered through a Celite cartridge. The MeOH was removed under reduced pressure. The crude reaction mixture was filtered and purified by preparative HPLC eluting with a gradient of MeCN (35 to 65%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized, and purified by N 2 -(4-Cyclopropylsulfonyl-2-fluoro-phenyl)-5-methoxy-N 4 -[(4-Methoxyphenyl)methyl]-N 2 -Methyl-6-(1-methylpyrazol-4-yl)-N 4 -(5-Methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrimidine-2,4-diamine (39 mg, 36% yield) was obtained.

[0336] Step 2 / Compound 7 TFA (3.0 mL, 39.2 mmol) was dissolved in N 2 -(4-Cyclopropylsulfonyl-2-fluoro-phenyl)-5-methoxy-N 4 -[(4-Methoxyphenyl)methyl]-N 2 -Methyl-6-(1-methylpyrazol-4-yl)-N 4 -(5-Methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrimidine-2,4-diamine (39 mg, 54.4 umol) was added and the mixture was stirred at 90° C. for 2 h. Volatiles were removed under reduced pressure and the residue was dissolved in DMSO and purified by preparative HPLC eluting with a gradient of MeCN (25 to 55%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 7 (14.6 mg, 19% yield). UPLC-MS (+ESI) m / z=513.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.83(s,1H),8.77(s,1H),8.23(s,1H),7.92(s,1H),7.81-7.62(m,3H),5.61(s,1H),3. 89(s,3H),3.58(s,3H),3.46(s,3H),2.01(s,3H),1.20-1.12(m,2H),1.10-1.00(m,2H).

[0337] Compound 8 / Method B / N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0338] [ka]

[0339] Process 1 / N 2-(2,6-difluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine To a solution of 5-methoxy-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (compound 2, see step 1) (50 mg, 88 μmol) and 2,6-difluoro-4-methylsulfonyl-aniline (110 mg, 529 μmol) in DMPU (0.5 mL) was added NaH (21 mg, 529 μmol, 60% dispersion) at room temperature. The reaction mixture was stirred at 80° C. for 15 h. The reaction was quenched with water (0.2 mL). The resulting reaction mixture was filtered and purified by preparative HPLC, eluting with a gradient of MeCN in water, both containing 0.1% formic acid. The appropriate fractions were combined, evaporated and N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (19 mg, 31% yield, 27 μmol) was obtained as a yellow solid. The latter was dissolved in DMF (0.5 mL) and then NaH (10 mg, 250 μmol, 60% dispersion) was added followed by MeI (16.0 μL, 264 μmol) at room temperature. The reaction was stirred for 30 min and then quenched with 0.2 mL of water. The crude reaction mixture was filtered and purified by preparative HPLC, eluting with a gradient of MeCN in water, both containing 0.1% formic acid. The appropriate fractions were combined, evaporated and N 2-(2,6-difluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (13 mg, 53% yield) was obtained as a yellow solid. UPLC-MS (+ESI) m / z=709.3 (M+H) + .

[0340] Step 2 / Compound 8 N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (11 mg, 15.5 μmol) was added TFA (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. The crude reaction mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC eluting with a gradient of MeCN in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 8 (4.3 mg, 55% yield) as a white solid. UPLC-MS (+ESI) m / z=505.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.89(s,1H),8.92(s,1H),8.28(s,1H),7.98(s,1H),7.85(d,J=6.9Hz,2H),5 .45(s,1H),3.92(s,3H),3.62(s,3H),3.42(s,3H),3.37(s,3H),2.04(s,3H).

[0341] Compound 9 / Method A / 2-(2-fluoro-4-(methylsulfonyl)phenoxy)-5-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0342] [ka]

[0343] Step 1 / 2-(2-fluoro-4-(methylsulfonyl)phenoxy)-5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine To 2-fluoro-4-methylsulfonyl-phenol (102 mg, 536 umol) in MeCN (3 mL) was added NaH (22 mg, 550 μmol, 60% dispersion) and the mixture was stirred at room temperature for 15 minutes. To this mixture was added 5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (compound 1, see step 1) (120 mg, 268 μmol) and the reaction was heated in a microwave at 170° C. for 90 minutes. The reaction mixture was evaporated in vacuum, dissolved in DMSO and purified by preparative HPLC, eluting with a gradient of MeCN in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 2-(2-fluoro-4-(methylsulfonyl)phenoxy)-5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (18.6 mg, 13% yield).

[0344] Step 2 / Compound 9 To 2-(2-fluoro-4-(methylsulfonyl)phenoxy)-5-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (18.6 mg, 33.4 μmol) in dioxane (1 mL) was added HCl in dioxane (0.1 mL, 4N) and the mixture was then heated at 50° C. overnight. The reaction mixture was evaporated in vacuum to give the desired product, compound 9 (13.3 mg, 81% yield). UPLC-MS (+ESI) m / z=474.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 9.80(s,1H),8.29(s,1H),7.99(dd,J=9.7,2.2Hz,1H),7.91(d,J=0.7Hz,1H),7.84(dt,J=8.4,1.4Hz,1H),7 .68(dd,J=8.4,7.6Hz,1H),5.63(d,J=0.8Hz,1H),3.89(s,3H),3.64(s,3H),3.29(s,3H),2.16-1.95(m,3H).

[0345] Compound 10 / Method A / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0346] [ka]

[0347] Step 1 / 5-Cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine To a solution of intermediate 7 (523 mg, 1.27 mmol) in dioxane / water (5 mL, 9 / 1) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (396 mg, 1.90 mmol), K2CO3 (526 mg, 3.81 mmol), Pd(dppf)Cl2 (93 mg, 127 μmol) and the mixture was degassed with nitrogen for 2 min. The reaction mixture was then stirred at 120 °C for 5 h. The crude reaction mixture was diluted with EtOAc, quenched with saturated NaHCO3, and then extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude mixture was purified by silica gel chromatography eluting with a gradient of MeOH (0-10%) in DCM. The appropriate fractions were combined and concentrated to give 5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (388 mg, 67% yield) as a yellow solid. UPLC-MS (+ESI) m / z=458.2 (M+H). + .

[0348] Steps 2, 3 / Compound 10 To a solution of 5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (20.0 mg, 43.7 μmol) and 2-fluoro-4-methylsulfonyl-aniline (16.5 mg, 87.4 μmol) in DMPU (0.5 mL) was added NaH (3.5 mg, 87 μmol, 60% purity). The reaction mixture was stirred at 120° C. for 15 h. The crude reaction mixture was quenched with water, filtered, and purified by preparative HPLC, both eluting with a gradient of MeCN in water containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the intermediate 5-cyclopropyl-N 2 -(2-Fluoro-4-methylsulfonyl-phenyl)-6-(1-methylpyrazol-4-yl)-N4 -(5-Methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrimidine-2,4-diamine was obtained as a yellow solid. To the latter was added HCl (2 mL, 4 M) and MeOH (0.1 mL) in dioxane. The reaction mixture was stirred at room temperature for 5 h. The crude reaction mixture was concentrated, diluted with DMSO, filtered, and purified by preparative HPLC eluting with a gradient of MeCN (15 to 45%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 10 (8.0 mg, 38% yield) as a white solid. UPLC-MS (+ESI) m / z=483.1 (M+H). + . 1 HNMR(400MHz,DMSO-d6)δ 8.90(s,1H),8.33(s,1H),8.06(s,1H),7.86-7.70(m,2H),5.89(s,1H),3.94(s,3H),3.23(s ,3H),2.19(s,3H),1.80(td,J=7.8,3.8Hz,1H),1.18(d,J=6.6Hz,2H),0.23(d,J=5.1Hz,2H).

[0349] Compound 11 / Method B / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0350] [ka]

[0351] Step 1 / 5-Cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine To a solution of intermediate 8 (2.00 g, 3.76 mmol) in dioxane (10 mL) and H2O (3 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (939 mg, 4.51 mmol), Pd(dppf)Cl2 (550 mg, 752 μmol), and Cs2CO3 (3.06 g, 9.40 mmol). The resulting mixture was degassed in vacuum and then filled with nitrogen. The resulting reaction mixture was stirred at 90 °C for 3 h, then cooled to room temperature and diluted with EtOAc. The organic phase was extracted, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by preparative HPLC eluting with a gradient of MeCN (10 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (1.45 g, 51% yield, 77% purity). UPLC-MS (+ESI) m / z=578.2 (M+H). + .

[0352] Step 2 / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine To 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (690 mg, 1.05 mmol) in DMPU (6 mL) was added 2-fluoro-4-methylsulfonyl-aniline (259 mg, 1.37 mmol). Nitrogen was bubbled through the reaction mixture for 5 min, then LiHMDS (1 M in THF, 3.15 mL, 3.15 mmol) was added slowly at room temperature. The vial was closed and the mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature, MeI (327 μL, 5.26 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of 1 mL of MeOH, and the mixture was filtered through a Celite cartridge and evaporated to dryness. The filtrate was purified by preparative HPLC eluting with a gradient of MeCN (10 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 5-cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (358 mg, 49% yield) was obtained. UPLC-MS (+ESI) m / z = 701.4 (M+H) + .

[0353] Step 3 / Compound 11 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4To -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (938 mg, 1.34 mmol) was added TFA (21 mL, 268 mmol) and the reaction mixture was stirred at 120° C. for 6 h. TFA was removed under reduced pressure and the residue was purified by preparative HPLC eluting with a gradient of MeCN (10 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 11 (430 mg, 65% yield). UPLC-MS (+ESI) m / z=497.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 8.21(s,1H),7.92(d,J=0.7Hz,1H),7.85-7.77(m,2H),7.71(dd,J=8.2,7.3Hz,1H),5.58(s,1H),3.87(s ,3H),3.45(s,3H),3.27(s,3H),2.05-1.95(m,3H),1.77-1.65(m,1H),1.16-1.00(m,2H),0.18-0.12(m, 2H).

[0354] Compound 12 / Method B / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-6-(1-methyl-1H-pyrazol-3-yl)-N 4 -(5-Methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

[0355] [ka]

[0356] Step 1 / 5-Cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine To a solution of intermediate 8 (312 mg, 586 μmol) in dioxane (2 mL) was added tributyl-(1-methylpyrazol-3-yl)stannane (239 mg, 645 μmol), Pd(PPh3)4 (68 mg, 59 μmol). The reaction mixture was then stirred at 100 °C overnight. The crude was purified by preparative HPLC eluting with a gradient of MeCN (15-45%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the desired product 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine (142 mg, 42% yield). UPLC-MS (+ESI) m / z = 578.3 (M+H) + .

[0357] Step 2 / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine A mixture of 2-fluoro-4-methylsulfonyl-aniline (70.0 mg, 370 μmol) and NaH (9.0 mg, 391 μmol, 60% dispersion) in DMPU (1.5 mL) was stirred at room temperature for 10 min. 5-Cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine (142 mg, 246 μmol) was added and the reaction mixture was heated at 130° C. overnight. The reaction mixture was cooled to room temperature, quenched with a drop of water, and purified by preparative HPLC, both eluting with a gradient of MeCN in water containing 0.1% formic acid. The appropriate fractions were combined, lyophilized, and 5-cyclopropyl-N 2-(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50 mg, 30% yield).

[0358] Step 3 / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine 5-Cyclopropyl-N in DMF (1.5 mL) 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 To -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50 mg, 73 μmol) was added NaH (9.0 mg, 391 μmol, 60% dispersion) and MeI (40 μL, 643 μmol) and the reaction was stirred at room temperature overnight. The reaction mixture was quenched with water (0.2 mL), filtered, and purified by preparative HPLC eluting with a gradient of MeCN (30-80%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized, and 5-cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (35 mg, 69% yield) was obtained. UPLC-MS (+ESI) m / z = 701.4 (M+H) + .

[0359] Step 4 / Compound 12 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 To -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (35 mg, 50 μmol) was added TFA (3 mL) and the mixture was heated at 90 °C for 2 h. The reaction mixture was concentrated and the residue was dissolved in DMSO and purified by preparative HPLC eluting with a gradient of MeCN (20-70%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the desired product, compound 12 (13 mg, 52% yield). UPLC-MS (+ESI) m / z = 497.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.84(s,1H),8.22(s,1H),7.89-7.77(m,2H),7.77-7.62(m,2H),6.55(d,J=2.2Hz,1H),5.59(s,1H),3. 87(s,3H),3.43(s,3H),2.01(s,3H),1.85-1.58(m,1H),0.95-0.73(m,2H),0.00(dt,J=5.7,3.0Hz,2H).

[0360] Compound 13 / Method B / 5-Cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-6-(1-methyl-1H-pyrazol-3-yl)-N 4-(5-Methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

[0361] [ka]

[0362] Step 1 / 5-Cyclopropyl-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine To a solution of intermediate 9 (1.15 g, 2.02 mol) in dioxane (10 mL) was added tributyl-(1-methylpyrazol-3-yl)stannane (790 mg, 2.13 mmol), Pd(PPh3)4 (240 mg, 208 μmol). The reaction mixture was then stirred at 85° C. overnight. The crude mixture was purified by silica gel column chromatography eluting with EtOAc (70%) in heptane. The appropriate fractions were combined and evaporated to give the desired product 5-cyclopropyl-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine (217 mg, 18% yield). UPLC-MS (+ESI) m / z=614.0 (M+H) + .

[0363] Step 2 / 5-Cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine A mixture of 2,6-difluoro-4-methylsulfonyl-aniline (90 mg, 434 μmol) and NaH (18.0 mg, 470 μmol, 60% dispersion) in DMPU (1 mL) was stirred at room temperature for 10 min. To the resulting mixture was added 5-cyclopropyl-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrimidin-4-amine (217 mg, 353 μmol) and the reaction was heated at 130° C. overnight. The reaction mixture was purified by preparative HPLC eluting with a gradient of MeCN (30-70%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the intermediate 5-cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (65 mg, 25% yield) was obtained. UPLC-MS (+ESI) m / z = 741.3 (M+H) + .

[0364] Step 3 / 5-Cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-N 2 -Methyl-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine 5-Cyclopropyl-N in DMF (1 mL) 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4To 1-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (65 mg, 87 μmol) was added NaH (4.0 mg, 104 μmol, 60% dispersion), MeI (20 μL, 321 μmol). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with water (0.2 ml) and purified by preparative HPLC eluting with a gradient of MeCN (30-70%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized and 5-cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine was obtained, which was used immediately in the next step.

[0365] Step 4 / Compound 13 5-Cyclopropyl-N from step 3 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 To -(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine was added TFA (2 mL) and the mixture was heated at 120 °C for 15 h. The reaction mixture was evaporated, diluted with DMSO and purified by preparative HPLC eluting with a gradient of MeCN (30-70%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the desired product, compound 13 (5 mg, 3% yield). UPLC-MS (+ESI) m / z = 515.2 (M+H). + . 1H NMR(400MHz,DMSO-d6)δ 11.86(s,1H),8.29(d,J=26.1Hz,1H),7.82(d,J=6.8Hz,2H),7.68(s,1H),6.56(s,0.3H),5.33(s,1 H),3.88(s,3H),3.35(s,3H),3.33(s,3H),2.00(s,3H),1.78-1.67(m,1H),0.93-0.83(m,2H),0.04- -0.04(m,2H).

[0366] Compound 14 / Method B / 5-Cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0367] [ka]

[0368] Step 1 / 5-Cyclopropyl-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine To a solution of intermediate 9 (1.60 g, 2.82 mmol) in dioxane (40 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (704 mg, 3.38 mmol), Pd(dppf)Cl2 (206 mg, 282 μmol), Cs2CO3 (1.84 g, 5.63 mmol), and water (10 mL). The reaction mixture was then stirred at 80° C. for 1.5 hours. A second portion of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (250 mg, 1.20 mmol) and Pd(dppf)Cl2 (100 mg, 39 μmol) were added and the reaction mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was extracted with EtOAc and the organic phase was evaporated in vacuo. The crude was purified by silica gel chromatography eluting with EtOAc (100%). The appropriate fractions were combined and evaporated to give 5-cyclopropyl-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (800 mg, 46% yield). UPLC-MS (+ESI) m / z=614.3 (M+H). + .

[0369] Step 2 / 5-Cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine A mixture of 2,6-difluoro-4-methylsulfonyl-aniline (122 mg, 589 μmol) and NaH (24.0 mg, 626 μmol, 60% dispersion) in DMPU (1 mL) was stirred at room temperature for 10 min. To this was added 5-cyclopropyl-N-(4-methoxybenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (300 mg, 489 μmol) and the reaction was heated at 130° C. overnight. The reaction mixture was purified by preparative HPLC eluting with a gradient of MeCN (30-70%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized and 5-cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (29 mg, 8% yield) was obtained. UPLC-MS (+ESI) m / z = 741.3 (M+H) + .

[0370] Step 3, 4 / 5-Cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-N 2 -Methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine 5-Cyclopropyl-N in DMF (1 mL) 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4To -(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (29 mg, 39 μmol) was added NaH (3 mg, 75 μmol, 60% dispersion), MeI (10 μL, 161 μmol) and the reaction was stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC eluting with a gradient of MeCN (30-70%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the intermediate 5-cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(1-(4-Methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-N 2 -methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine was obtained. UPLC-MS(+ESI) m / z = 755.9 (M+H) + To the latter intermediate, TFA (2 mL) was added and the mixture was heated at 120 °C overnight. The reaction mixture was evaporated, diluted with DMSO and purified by preparative HPLC eluting with a gradient of MeCN (20-70%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 14 (1.4 mg, 7% yield for two steps). UPLC-MS (+ESI) m / z = 515.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.83(s,1H),8.26(d,J=16.6Hz,2H),7.98(d,J=25.5Hz,1H),7.82(d,J=6.8Hz,2H),6.58(s,0.2H),5.29(s,1H),3. 87(s,3H),3.37(s,3H),3.33(s,3H),2.03(s,3H),1.72(tt,J=7.9,5.5Hz,1H),1.19-0.86(m,2H),0.34-0.07(m,2H).

[0371] Compound 15 / Method B / 5-Cyclopropyl-N 2-(4-(cyclopropylsulfonyl)-2-fluorophenyl)-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0372] [ka]

[0373] Step 1 / 5-Cyclopropyl-N 2 -(4-(cyclopropylsulfonyl)-2-fluorophenyl)-N 4 -(4-Methoxybenzyl)-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine To a solution of 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (compound 11, see step 1) (50.0 mg, 86.6 μmol) and 4-cyclopropylsulfonyl-2-fluoro-aniline (55.9 mg, 260 μmol) in DMPU (0.5 mL) was added NaH (10.4 mg, 260 μmol, 60% dispersion) at room temperature. The reaction mixture was stirred at 120° C. for 3 h. The crude reaction mixture was quenched with water, diluted with EtOAc, quenched with saturated NaHCO3, and then extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated to give the crude desired product 5-cyclopropyl-N 2 -(4-(chloropropylsulfonyl)-2-fluorophenyl)-N 4 -(4-Methoxybenzyl)-N 4-(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (60 mg) was obtained as a yellow solid, which was used in the next step without purification. UPLC-MS (+ESI) m / z=713.4 (M+H). + .

[0374] Step 2 / 5-Cyclopropyl-N 2 -(4-(cyclopropylsulfonyl)-2-fluorophenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine Crude 5-cyclopropyl-N 2 -(4-(cyclopropylsulfonyl)-2-fluorophenyl)-N 4 -(4-Methoxybenzyl)-N 4 To -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (60 mg) was added NaH (10 mg, 240 μmol) followed by MeI (82 μL, 253 μmol) at room temperature for 1 h. The crude reaction mixture was quenched with water, filtered, and purified by preparative HPLC eluting with a gradient of MeCN in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized, and 5-cyclopropyl-N 2 -(4-(cyclopropylsulfonyl)-2-fluorophenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4-(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (23 mg, 37% yield from step 1) was obtained as a beige solid. UPLC-MS (+ESI) m / z=727.4 (M+H). + .

[0375] Step 3 / Compound 15 5-Cyclopropyl-N 2 -(4-(cyclopropylsulfonyl)-2-fluorophenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 To -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (20.0 mg, 27.5 μmol) was added TFA (0.5 mL). The reaction mixture was stirred at 80° C. for 1 h. The crude reaction mixture was evaporated and the residue was dissolved in DMSO and purified by preparative HPLC eluting with a gradient of MeCN in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the desired product, compound 15 (5.2 mg, 36% yield) as a white solid. UPLC-MS (+ESI) m / z=523.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 11.86(s,1H),8.27(d,J=3.9Hz,1H),8.24(s,1H),7.95(s,1H),7.84-7.77(m,2H),7.74(dd,J=8.7,7.0Hz,1H),5.63(s,1H),3.91(s,3H),3.4 9(s,3H),2.96(td,J=8.0,4.8Hz,1H),2.04(s,3H),1.82-1.70(m,1H),1.19(qd,J=4.9,2.3Hz,2H),1.16-1.03(m,4H),0.20(h,J=4.0Hz,2H).

[0376] Compound 16 / Method A / 5-Cyclopropyl-N 2-(2-fluoro-4-(methylsulfonyl)phenyl)-6-(1-methyl-1H-imidazol-4-yl)-N 4 -(5-Methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

[0377] [ka]

[0378] Step 1 / 5-Cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)6-(1-methyl-1H-imidazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine To a solution of intermediate 7 (200 mg, 486 μmol) in dioxane (2 mL) was added tributyl-(1-methylimidazol-4-yl)stannane (198 mg, 534 μmol) and Pd(PPh3)4 (337 mg, 291 μmol). Nitrogen was bubbled through the reaction mixture, which was then stirred at 100° C. for 18 h. The crude reaction mixture was filtered and purified by preparative HPLC, eluting with a gradient of MeCN (10 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-imidazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (30 mg, 14% yield). UPLC-MS (+ESI) m / z=458.3 (M+H). + .

[0379] Steps 2, 3 / Compound 16 To a solution of 5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-imidazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (24 mg, 53 μmol) and 2-fluoro-4-methylsulfonyl-aniline (12 mg, 63 μmol) in DMPU (0.5 mL) was added NaH (4.2 mg, 115 μmol, 60% dispersion). The reaction mixture was stirred at 120° C. for 15 h. The crude reaction mixture was quenched with water, filtered, and purified by preparative HPLC, both eluting with a gradient of MeCN in water containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the intermediate 5-cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine was obtained as a yellow solid. UPLC-MS (+ESI) m / z=567.3 (M+H) + To the latter was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 15 h. The crude reaction mixture was evaporated, diluted with DMSO, filtered and purified by preparative HPLC eluting with a gradient of MeCN in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give the desired product, compound 16 (1.0 mg, 3.8% yield for steps 2 and 3) as a white solid. UPLC-MS (+ESI) m / z=483.2 (M+H). + .

[0380] Compound 17 / Method B / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-6-(1-methyl-1H-imidazol-4-yl)-N 4 -(5-Methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

[0381] [ka]

[0382] Step 1 / 6-Chloro-5-cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine To a solution of intermediate 11 (390 mg, 798 μmol) in DMPU (3 mL) at room temperature was added 2-fluoro-4-methylsulfonyl-aniline (302 mg, 1.60 mmol) followed by NaH (96 mg, 2.4 mmol, 60% dispersion). The mixture was heated at 120 °C for 4 h. The mixture was cooled to room temperature, MeI (500 μL, 7.99 mmol) was added and the mixture was stirred at room temperature for 1 h. MeOH (1 mL) was added and the mixture was filtered through a Celite cartridge, concentrated and purified by preparative HPLC using a gradient of MeCN (10-100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized and 6-chloro-5-cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (255 mg, 49% yield) was obtained as a 9 / 1 mixture of regioisomers in favor of the title compound. Used directly in the next step. UPLC-MS (+ESI) m / z=655.3 (M). + .

[0383] Steps 2, 3 / Compound 17 To a solution of tributyl-(1-methylimidazol-4-yl)stannane (203 mg, 547 μmol) in dioxane (2 mL), 6-chloro-5-cyclopropyl-N 2-(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (112 mg, 171 μmol) and Pd(PPh3)4 (99 mg, 86 μmol) were added. The mixture was degassed (vacuum, then with nitrogen) and stirred at 130 °C for 4 days. The crude reaction mixture was filtered and the supernatant was purified by preparative HPLC eluting with a gradient of MeCN (10-100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized and 5-cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine (45 mg, 38% yield). To the latter, TFA (1.5 mL) was added and the resulting mixture was stirred at 90 °C for 4 h. The mixture was concentrated and the residue was purified by preparative HPLC eluting with a gradient of MeCN (10-25%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 17 (20 mg, 63% yield). UPLC-MS (+ESI) m / z = 497.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 9.33(s,1H),8.25(s,1H),8.11(s,1H),8.07-7.98(m,1H),7.83(s,1H),7.78(dd,J=8.1,1.9Hz,1H),7.71(dd,J=8.1,1.9Hz,1H),5 .48(s,1H),3.97(ddd,J=19.3,10.2,6.0Hz,3H),3.87(s,3H),3.61(s,3H),3.51(dd,J=9.0,4.1Hz,2H),3.03(s,3H),2.03(s,3H).

[0384] Compound 18 / Method A / 5-cyclopropyl-2-(2-fluoro-4-(methylsulfonyl)phenoxy)-N-(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine

[0385] [ka]

[0386] Step 1 / 5-Cyclopropyl-2-(2-fluoro-4-(methylsulfonyl)phenoxy)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine To 2-fluoro-4-methylsulfonyl-phenol (42 mg, 221 μmol) in MeCN (3 mL) was added NaH (10 mg, 250 μmol, 60% dispersion) and stirred at room temperature for 10 min. To this mixture was added 5-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (compound 10, see step 1) (50 mg, 110 μmol) and the reaction mixture was heated in a microwave at 170° C. for 75 min. The reaction mixture was evaporated in vacuo, dissolved in DMSO, and purified by preparative HPLC, both eluting with MeCN (40-70%) in water containing 0.1% formic acid. The relevant fractions were combined and lyophilized to give 5-cyclopropyl-2-(2-fluoro-4-(methylsulfonyl)phenoxy)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (9.2 mg, 15% yield). UPLC-MS (+ESI) m / z=568.2 (M+H). + .

[0387] Step 2 / Compound 18 To 5-cyclopropyl-2-(2-fluoro-4-(methylsulfonyl)phenoxy)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (9.2 mg, 16 μmol) in dioxane (1 mL), HCl / dioxane (0.1 mL, 4N) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated in vacuum to give compound 18 (5.8 mg, 74% yield). UPLC-MS (+ESI) m / z=484.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 8.84(s,1H),8.27(s,1H),7.98(dd,J=9.7,2.1Hz,1H),7.92(d,J=0.7Hz,1H),7.87-7.81(m,1H),7.66(dd,J=8.4,7.6Hz,1H),3.8 7(s,3H),3.29(s,3H),2.01(d,J=0.7Hz,3H),1.78(ddd,J=13.7,8.1,5.7Hz,1H),1.25-1.08(m,2H),0.19(dt,J=6.0,2.9Hz,2H).

[0388] Compound 19 / Method C / N 6 -(2-Fluoro-4-(methylsulfonyl)phenyl)-3-methoxy-N 6 -Methyl-N 2 -(5-methyl-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine

[0389] [ka]

[0390] Step 1 / 4-Bromo-6-chloro-2-fluoropyridin-3-ol In a round bottom flask, 6-chloro-2-fluoropyridin-3-ol (3.00 g, 20.3 mmol) was dissolved in a mixture of MeCN (50 mL) and water (25 mL). Br2 (1.04 mL, 20.3 mmol) was then added dropwise and the reaction was stirred at room temperature. After 2 h, the crude was evaporated to dryness and directly purified by silica gel chromatography eluting with EtOAc (0 to 30%) in heptane. The appropriate fractions were combined and concentrated to give 4-bromo-6-chloro-2-fluoropyridin-3-ol (5.0 g, 99% yield) as an orange oil. UPLC-MS (+ESI) m / z=228.0 (M+H). + . 1 H NMR(400MHz,CDCl3)δppm 6.42(br s,1H),7.38(s,1H). 19 F NMR (377MHz, CDCl3) δppm -83.73(s, 1F).

[0391] Step 2 / 4-Bromo-6-chloro-2-fluoro-3-methoxypyridine In a round-bottom flask, Cs2CO3 (411 mg, 1.26 mmol) was added to a solution of 4-bromo-6-chloro-2-fluoropyridin-3-ol (500 mg, 2.21 mmol) in DMF (14 mL). Then, MeI (275 μL, 4.42 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with MeTHF and washed with a saturated solution of NaHCO3. The organic layer was extracted with MeTHF (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with EtOAc (0 to 30%) in heptane. The appropriate fractions were combined and concentrated to give 4-bromo-6-chloro-2-fluoro-3-methoxypyridine (500 mg, 95% yield) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δppm 4.00(d,J=2.2Hz,3H),7.42(s,1H). 19 F NMR (377MHz, CDCl3) δppm -77.15(s, 1F).

[0392] Step 3 / 6-Chloro-2-fluoro-3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)pyridine A sealable tube was charged with 4-bromo-6-chloro-2-fluoro-3-methoxypyridine (500 mg, 2.08 mmol) in 1,4-dioxane / water (3 / 1). Then, (1-methyl-1H-pyrazol-4-yl)boronic acid (288 mg, 2.29 mmol) and Cs2CO3 (2.00 g, 6.24 mmol) were added and the mixture was sparged with nitrogen for 10 min. Pd(dppf)Cl2 (170 mg, 0.21 mmol) was added and the suspension was sparged with nitrogen for another 10 min. The reaction mixture was stirred at 90 °C for 18 h. The reaction was filtered through a pad of Celite and washed with EtOAc. The combined supernatants were concentrated in vacuo. The residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 95%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 6-chloro-2-fluoro-3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)pyridine (375 mg, 75% yield) as a yellow solid. UPLC-MS (+ESI) m / z=242.2 (M+H). + . 1 H NMR(400MHz,CDCl3)δppm 3.95(d,J=2.2Hz,3H),4.00(s,3H),7.31(s,1H),7.94(s,1H),7.98(s,1H). 19 F NMR (377MHz, CDCl3) δppm -79.93(s, 1F).

[0393] Step 4 / 6-Chloro-3-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine In a sealable tube, a 1M solution of NaHMDS (6.21 mL, 6.21 mmol) in THF was added to a solution of 6-chloro-2-fluoro-3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)pyridine (422 mg, 2.33 mmol) in THF (39 mL) at room temperature. Intermediate 1 (375 mg, 1.55 mmol) was then added and the reaction was sealed and stirred at 80° C. for 3 h. The reaction was quenched with H2O and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 95%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 6-chloro-3-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (484 mg, 77% yield) as a brown solid. UPLC-MS (+ESI) m / z=403.2 (M+H). + . 1 H NMR(400MHz,CDCl3)δppm 1.55-1.62(m,1H),1.65-1.79(m,2H),1.83-1.93(m,1H),2.05-2.16(m,1H),2.37(s,3H),2.38-2.43(m,1H),3.65(s,3H),3.66-3.72 (m,1H),3.99(s,3H),4.08-4.17(m,1H),5.18(dd,J=10.3,2.2Hz,1H),6.78(s,1H),6.80(s,1H),7.74(s,1H),7.90(d,J=3.9Hz,2H).

[0394] Process 5 / N 6 -(2-Fluoro-4-(methylsulfonyl)phenyl)-3-methoxy-N 6 -Methyl-N 2 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine A flame-dried sealable tube was charged with 6-chloro-3-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (50.0 mg, 0.12 mmol) in toluene (1.20 mL). 2-Fluoro-4-methanesulfonyl-N-methylaniline (37.8 mg, 0.190 mmol), Cs2CO3 (121 mg, 0.370 mmol) and + / -BINAP (31 mg, 0.050 mmol) were added and the mixture was sparged with nitrogen for 10 min. Pd(OAc)2 (5.6 mg, 0.025 mmol) was added and the suspension was sparged with nitrogen for an additional 10 min. The reaction mixture was stirred at 95° C. for 18 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc. The solvent was removed in vacuo and the residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 95%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized and purified with N 6 -(2-Fluoro-4-(methylsulfonyl)phenyl)-3-methoxy-N 6 -Methyl-N 2 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine (35 mg, 50% yield) was obtained as a yellow oil. UPLC-MS (+ESI) m / z=570.2 (M+H) + . 1 H NMR(400MHz,CDCl3)δppm 1.82-1.90(m,2H),2.03-2.13(m,2H),2.22(s,3H),2.33-2.41(m,1H),3.11(s,3H),3.47(s,3H),3.60(s,3H),3.62-3.69(m,1H) ),3.98(s,3H),4.07-4.13(m,1H),5.09-5.15(m,1H),6.05(s,1H),6.17(s,1H),7.52-7.55(m,2H),7.68-7.77(m,2H),7.87(s,2 H).

[0395] Step 6 / Compound 19 A solution of 37% HCl in MeOH (735 μL) was dissolved in N 6 -(2-Fluoro-4-(methylsulfonyl)phenyl)-3-methoxy-N 6 -Methyl-N 2 To a solution of -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine (34.0 mg, 0.060 mmol) was added. The reaction mixture was stirred at 50° C. for 4 h. The reaction was concentrated in vacuo and coevaporated with MeCN (2×). The crude residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 95%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 19 (13 mg, 45% yield) as a white solid. UPLC-MS (+ESI) m / z=486.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δppm 2.00(s,3H),3.30(s,3H),3.41(s,3H),3.56(s,3H),3.91(s,3H),5.55(s,1H),6 .43(s,1H),7.66(t,J=7.9Hz,1H),7.75-7.84(m,2H),8.01(s,1H),8.28(s,1H). 19 F NMR (377MHz, CDCl3) δppm -114.57 (br s, 1F).

[0396] Compound 20 / Method C / 3-Cyclopropyl-N 6 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 6 -Methyl-N 2 -(5-methyl-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine

[0397] [ka]

[0398] Step 1 / 6-chloro-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ol In a Schlenk flask under nitrogen, 4-bromo-6-chloro-2-fluoropyridin-3-ol (compound 19, step 1) (600 mg, 2.60 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (607 mg, 2.90 mmol), tri-tert-butylphosphine (530 μL, 0.50 mmol) and K3PO4 (1.10 g, 5.30 mmol) were dissolved in dioxane (12 mL) and water (6 mL). The solution was sparged with nitrogen for 10 minutes. Pd(dba)3 (243 mg, 0.260 mmol) was then added. The mixture was sparged with nitrogen for an additional 10 minutes and the reaction was sealed and stirred at 90°C. After 3 h, the reaction was cooled to room temperature and filtered through a pad of Celite, washing with EtOAc. The organic layer was concentrated and the crude residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 6-chloro-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ol (166 mg, 28% yield) as a pale yellow solid. UPLC-MS (+ESI) m / z=228.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δppm 3.91(s,3H),7.67(s,1H),8.17(s,1H),8.41(s,1H),10.74(br s,1H). 19 F NMR (377MHz, DMSO-d6) δppm -86.28(s, 1 F).

[0399] Step 2 / 6-chloro-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl trifluoromethanesulfonic acid In a round bottom flask under nitrogen, 6-chloro-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ol (166 mg, 0.72 mmol) was dissolved in dry DCM (5 mL). Pyridine (176 μL, 2.20 mmol) was then added, followed by dropwise addition of TfO (135 μL, 0.80 mmol). The reaction was stirred at room temperature for 2 h, then evaporated to dryness and purified by silica gel chromatography eluting with EtOAc (0 to 80%) in heptane. The appropriate fractions were combined and concentrated in vacuo to give 6-chloro-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl trifluoromethanesulfonic acid (126 mg, 48% yield) as a white solid. UPLC-MS (+ESI) m / z=360.0 (M+H) + . 1 H NMR(400MHz,CDCl3)δppm 4.02(s,3H),7.39(s,1H),7.90(s,1H),7.96(s,1H). 19 F NMR(377MHz, CDCl3)δppm -76.41(q,J=15.9Hz,1F),-72.60(d,J=15.0Hz,3F).

[0400] Step 3 / 6-Chloro-3-cyclopropyl-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)pyridine 6-Chloro-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl trifluoromethanesulfonate (126 mg, 0.35 mmol), cyclopropyl-BF3K (62.2 mg, 0.42 mmol), K2CO3 (145 mg, 1.05 mmol), and Ruphos (32.7 mg, 0.070 mmol) were dissolved in a mixture of toluene (3 mL) and water (1.5 mL) in a Schlenk flask under N2. The reaction mixture was sparged with nitrogen for 10 min, then Pd(OAc)2 (7.9 mg, 0.030 mmol) was added and the reaction was sparged for an additional 10 min. The flask was sealed and heated at 90 °C. After 3 h, the reaction was cooled to room temperature and filtered through a pad of Celite, washing with EtOAc. The supernatant was concentrated and the crude residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 6-chloro-3-cyclopropyl-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)pyridine (34 mg, 39% yield) as an off-white solid. UPLC-MS (+ESI) m / z=252.2 (M+H). + . 1 H NMR(400MHz,CDCl3)δppm 0.60-0.66(m,2H),1.00-1.07(m,2H),1.73-1.81(m,1H),4.01(s,3H),7.21(s,1H),7.76(s,1H),7.84(s,1H). 19 F NMR (377MHz, CDCl3) δppm -66.57(s, 1F).

[0401] Step 4 / 6-Chloro-3-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine 6-Chloro-3-cyclopropyl-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)pyridine (47.5 mg, 0.260 mmol) was dissolved in anhydrous THF (3 mL) in a vial under nitrogen. NaHMDS (700 μL, 0.700 mmol) was then added dropwise and stirred at room temperature for 5 min. Intermediate 1 (44.0 mg, 0.17 mmol) was then added and the reaction mixture was sealed and stirred at 80° C. After 1.5 h the reaction was stopped and evaporated to dryness. The crude residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 6-chloro-3-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (53 mg, 73% yield) as a yellow solid. UPLC-MS (+ESI) m / z=413.2 (M+H). + . 1 H NMR(400MHz,CDCl3)δppm 0.34-0.40(m,2H),1.07-1.13(m,2H),1.64-1.69(m,4H),1.86-1.92(m,1H),2.06-2.13(m,1H),2.37(s,3H),2.39-2.49(m,1H),3. 63-3.71(m,1H),3.99(s,3H),4.10-4.16(m,1H),5.18(dd,J=10.4,2.3Hz,1H),6.72(s,1H),6.78(s,1H),7.62(s,1H),7.73(s,2H).

[0402] Step 5 / 3-Cyclopropyl-N 6 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 6 -Methyl-N 2 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine In a vial, 6-chloro-3-cyclopropyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (53 mg, 0.12 mmol) and 2-fluoro-N-methyl-4-(methylsulfonyl)aniline (39 mg, 0.19 mmol) were dissolved in dry toluene (1.25 mL). Cs2CO3 (126 mg, 0.38 mmol) and + / -BINAP (32 mg, 0.051 mmol) were then added. The solution was sparged with nitrogen for 15 minutes. Pd(OAc)2 (5.8 mg, 0.02 mmol) was added and sparging was continued for 5 minutes. The flask was sealed and heated at 95°C. After 3 h, the reaction mixture was cooled to room temperature and filtered through a pad of Celite, washing with EtOAc. The supernatant was concentrated and the crude residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized and the 3-cyclopropyl-N 6 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 6 -Methyl-N 2 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine (30.0 mg, 40% yield) was obtained as a pale yellow solid. UPLC-MS (+ESI) m / z=580.2 (M+H) + . 1 H NMR (400MHz, CDCl3) δppm 0.29-0.35(m,2H),0.97-1.04(m,2H),1.67-1.73(m,J=9.5Hz,4H),1.84-1.8 8(m,1H),2.05-2.12(m,1H),2.22(s,3H),2.34-2.47(m,1H),3.10(s,3H),3.4 6(s,3H),3.59-3.69(m,1H),3.97(s,3H),4.07-4.13(m,1H),5.12(dd,J=10.5 ,2.2Hz,1H),6.05(s,1H),6.08(s,1H),7.52-7.57(m,2H),7.65-7.73(m,3H).19 F NMR (377MHz, CDCl3) δppm -113.50(s, 1F).

[0403] Step 6 / Compound 20 3-Cyclopropyl-N 6 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 6 -Methyl-N 2 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine (27 mg, 0.04 mmol) was dissolved in a 3M HCl solution in MeOH (776 μL, 2.32 mmol) and stirred at room temperature for 1 h, then warmed to 50° C. for 4 h. The crude mixture was evaporated to dryness and the residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 20 (14.7 mg, 65% yield) as a white solid. UPLC-MS (+ESI) m / z=496.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δppm 0.09-0.15(m,2H),1.03-1.10(m,2H),1.77-1.84(m,1H),2.11-2.15(m,3H),3.32(s,3H),3.43(s,3H) ),3.90(s,3H),5.78(s,1H),6.42(s,1H),7.71-7.77(m,1H),7.84-7.90(m,3H),8.19(s,1H),8.95(br s,1H). 19 F NMR (377MHz, DMSO-d6) δppm -115.14(s, 1F).

[0404] Compound 21 / Method C / 6-((2-fluoro-4-(methylsulfonyl)phenyl)thio)-3-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

[0405] [ka]

[0406] Step 1 / 6-chloro-3-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine A 3M solution of HCl in MeOH (10.7 mL, 42.7 mmol) was added to a mixture of 6-chloro-3-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (compound 19, step 4) (344 mg, 0.85 mmol) in MeOH (8.3 mL, 0.1 M). The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was concentrated under vacuum and coevaporated with MeCN. The residue was purified by reverse preparative HPLC eluting with a gradient of MeCN (5 to 95%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 6-chloro-3-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (228 mg, 84% yield) as a brown solid. UPLC-MS (+ESI) m / z=319.2 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δppm 2.35 (s, 3H), 3.67 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 7.33 (s, 1H), 8.12 (s, 1H), 8.41 (s, 1H), 10.03 (s, 1H).

[0407] Step 2 / Compound 21 In a sealed tube, pivalic acid (160 mg, 1.57 mmol) was added to a solution of 6-chloro-3-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (100 mg, 0.31 mmol) in dioxane (1 mL, 0.3 M). Then, 2-fluoro-4-methanesulfonylbenzene-1-thiol (97.1 mg, 0.47 mmol) was added and the reaction mixture was stirred at 120° C. for 6 h. 2-Fluoro-4-methanesulfonylbenzene-1-thiol (97.1 mg, 0.47 mmol) was added again and the reaction mixture was stirred at 120° C. for another 18 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with MeTHF (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 95%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 21 (17 mg, 11% yield) as a white solid. UPLC-MS (+ESI) m / z=489.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δppm 2.02(s,3H),3.29(br s,3H),3.63(s,3H),3.91(s,3H),5.54(s,1H),7.16(br s,1H),7.77-7.83(m,1H),7.83-7.92(m,2H),8.03(s,1H),8.33(s,2H),11.70-11.85(m,1H). 19 F NMR (377MHz, CDCl3) δppm -104.75 (br s, 1F).

[0408] Compound 22 / Method D / 6-((2-fluoro-4-(methylsulfonyl)phenyl)thio)-3-methoxy-5-methyl-N-(5-methyl-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

[0409] [ka]

[0410] Step 1 / 2,4-Dibromo-6-chloro-5-methylpyridin-3-ol To a solution of 6-chloro-5-methylpyridin-3-ol (4.67 g, 32.5 mmol) in MeCN (103 mL) and water (34 mL) was added dropwise (10 min) at room temperature and under nitrogen atmosphere with bromine (3.74 mL, 72.9 mmol). The reaction mixture was stirred at room temperature for 20 h. 10% aqueous Na2S2O3 was added until the red color disappeared, the volatiles were removed in vacuo and the resulting mixture was extracted with DCM (3x). The combined organic phase was washed with H2O, brine, dried over Na2SO4, filtered and concentrated to give 2,4-dibromo-6-chloro-5-methylpyridin-3-ol (10.39 g, quant., crude) as a light yellow solid. The product was used in the next step without further purification. UPLC-MS (+ESI) m / z=301.8 (M+H) + . 1 H NMR (400MHz, CDCl3) δppm 2.51 (s, 3H), 5.88 (br s, 1H).

[0411] Step 2 / 2,4-Dibromo-6-chloro-3-methoxy-5-methylpyridine To a suspension of 2,4-dibromo-6-chloro-5-methylpyridin-3-ol (11.24 g, 37.30 mmol) and Cs2CO3 (24.3 g, 74.6 mmol) in DMF (233 mL) was added dropwise MeI (4.64 mL, 74.6 mmol) at room temperature and under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 15 h and then water (1000 mL) was poured. The mixture was stirred at room temperature for 5 min and the precipitate was collected by filtration. The cake was washed with water and dried in a Buchner funnel in vacuum for 1 h to give a damp solid. The latter was dissolved in DCM (200 mL). The solution was dried over Na2SO4, filtered and concentrated to give 2,4-dibromo-6-chloro-3-methoxy-5-methylpyridine (9.68 g, crude) as an off-white solid. This product was used in the next step without further purification. UPLC-MS (+ESI) m / z = 315.8 (M+H) + .1 H NMR (400MHz, CDCl3) δppm 2.50 (s, 3H), 3.92 (s, 3H).

[0412] Step 3 / 4-Bromo-6-chloro-3-methoxy-5-methyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-2-amine A solution of intermediate 1 (1.90 g, 10.5 mmol), 2,4-dibromo-6-chloro-3-methoxy-5-methylpyridine (3.00 g, 9.51 mmol), Xanthphos (1.65 g, 2.85 mmol) and K2CO3 (3.94 g, 28.5 mmol) in dioxane (51 mL) was sparged with nitrogen for 10 min, then Pd(OAc)2 (320 mg, 1.43 mmol) was added to the mixture. Sparging was resumed for 5 min, the vial was sealed and stirred at 100 °C for 18 h. The reaction mixture was filtered through Celite, concentrated to dryness and purified by silica gel chromatography eluting with EtOAc (0 to 60%) in heptane. The appropriate fractions were combined and concentrated in vacuo to give 4-bromo-6-chloro-3-methoxy-5-methyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-2-amine (2.31 g, 58% yield) as a yellow solid. UPLC-MS (+ESI) m / z=415 (M+H). + . 1 H NMR(400MHz,CDCl3)δppm 1.63-1.79(m,2H),1.83-1.91(m,1H),2.06-2.13(m,1H),2.31-2.38(m,4H),2.38-2.44(m,4H),3.62(dt,J =11.5,2.2Hz,1H),3.84(s,3H),4.05-4.17(m,1H),5.18(dd,J=10.5,2.4Hz,1H),6.72(s,1H),7.43(s,1H).

[0413] Step 4 / 6-Chloro-3-methoxy-5-methyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine A solution of 4-bromo-6-chloro-3-methoxy-5-methyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-2-amine (2.31 g, 5.56 mmol), 1-methylpyrazol-4-ylboronic acid (735 mg, 5.83 mmol), NaHCO3 (1.87 g, 22.2 mmol) in water (11 mL) and dioxane (32 mL) was sparged with nitrogen for 10 min, then Pd(PPh3)4 (642 mg, 0.56 mmol) was added and sparging resumed for 5 min. The vial was sealed and heated at 100 °C for 18 h. The reaction mixture was filtered through a pad of Celite and concentrated to dryness, and the residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 6-chloro-3-methoxy-5-methyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (584 mg, 25% yield) as a pale yellow solid. UPLC-MS (+ESI) m / z=417.2 (M+H). + . 1 H NMR(400MHz,CDCl3)δppm 1.57-1.60(m,1H),1.62-1.81(m,2H),1.84-1.91(m,1H),2.05-2.13(m,1H),2.24(s,3H),2.33-2.45(m,4H),3.38(s,3H),3 .66(dt,J=11.2,2.0Hz,1H),4.00(s,3H),4.11(dt,J=11.6,1.9Hz,1H),5.17(dd,J=10.3,2.4Hz,1H),6.77(s,1H),7.47(br s,1H),7.56(s,1H),7.63(s,1H).

[0414] Step 5 / Compound 22 A solution of 6-chloro-3-methoxy-5-methyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (220 mg, 0.53 mmol) and 2-fluoro-4-(methylsulfonyl)benzenethiol (163 mg, 0.79 mmol) in iPrOH (1 mL) in a sealable tube was sparged with nitrogen for 5 min. The tube was sealed and the mixture was stirred at 120° C. for 15 h. The mixture was concentrated and the residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 22 (48 mg, 17% yield) as a pale yellow solid. UPLC-MS (+ESI) m / z = 503.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δppm 1.93-2.03(m,3H),2.22(s,3H),3.31(s,3H),3.34(s,3H),3.93(s,3H),5.29(s,1H),7.65(s,1H),7.80-7.92(m,3H),7.98(s,1H),8.34(br s,1H),11.58(br s,1H). 19 F NMR (377MHz, DMSO-d6) δppm -103.61 (br s, 1F).

[0415] Compound 23 / Method D / N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-3-methyl-N 6 -(5-methyl-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine

[0416] [ka]

[0417] Process 1 / N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-3-methyl-N6 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine A solution of 6-chloro-3-methoxy-5-methyl-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (compound 22, see step 3) (100 mg, 0.24 mmol), 2-fluoro-4-(methylsulfonyl)aniline (68 mg, 0.36 mmol), Cs2CO3 (235 mg, 0.72 mmol), + / -BINAP (60 mg, 0.096 mmol) in toluene (2.3 mL) was sparged with nitrogen for 15 min, then Pd(OAc)2 (11 mg, 0.048 mmol) was added and sparging resumed for 5 min. The vial was sealed and heated at 95° C. for 18 h. The reaction mixture was filtered through a pad of Celite, concentrated to dryness, and the residue was purified by preparative HPLC eluting with a gradient of MeCN (5 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized, and purified by N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-3-methyl-N 6 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine (120 mg, 85% yield) was obtained as an orange oil. UPLC-MS (+ESI) m / z=570.2 (M+H) + . 1H NMR(400MHz,CDCl3)δppm 1.59-1.63(m,1H),1.66-1.80(m,2H),1.88-1.96(m,1H),2.07-2.14(m,1H),2.18(s,3H),2.32(s,3H),2.36-2.49 (m,1H),3.06(s,3H),3.39(s,3H),3.64-3.69(m,1H),4.02(s,3H),4.14-4.16(m,1H),5.14-5.23(m,1H),6.46(br s, 1H), 6.57-6.62 (m, 1H), 7.41 (s, 1H), 7.56-7.68 (m, 4H), 8.43 (s, 1H).

[0418] Step 2 / Compound 23 N in MeOH (5.4 mL) 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-3-methyl-N 6 To a solution of -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine (120 mg, 0.18 mmol) was added HCl solution (37% in water, 1.0 mL, 12 mmol) and the reaction mixture was stirred at 50° C. until UPLC-MS analysis was complete (approximately 1.5 h). The reaction was quenched with NaOH (1M), concentrated to dryness, and purified by preparative HPLC eluting with a gradient of MeCN (5 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 23 (34 mg, 98% yield) as a pale yellow solid. UPLC-MS (+ESI) m / z=486.1 (M+H). + . 1 H NMR(400MHz,DMSO)δppm 2.03-2.12(m,J=2.9Hz,6H),3.21(s,3H),3.35(s,3H),3.93(s,3H),5.89(br s,1H),7.40-7.66(m,3H),7.70(d,J=1.0Hz,1H),7.95(s,1H),8.15(br s,1H),11.73(br s,1H). 19F NMR (377MHz, DMSO) δppm -123.22 (br s, 1F).

[0419] Compound 24 / Method D / 3-Fluoro N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 2 -Methyl-N 6 -(5-methyl-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine

[0420] [ka]

[0421] Step 1 / 2,4-Dibromo-6-chloro-5-fluoropyridin-3-ol To a solution of 2-chloro-3-fluoro-5-hydroxypyridine (1.35 g, 9.12 mol) in MeCN (30 mL) and water (10 mL) was added Br2 (1.17 mL, 22.81 mmol) at room temperature. The mixture was then stirred at room temperature overnight. The mixture was quenched with 10% Na2S2O3, extracted with DCM (3x), washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography eluting with EtOAc (0 to 30%) in heptane. The appropriate fractions were combined and concentrated in vacuo to give 2,4-dibromo-6-chloro-5-fluoropyridin-3-ol (2.18, 78%) as a white solid. UPLC-MS (+ESI) m / z=305.8 (M+H). + . 19 F NMR (377MHz, CDCl3) δppm -110.55(s, 1F).

[0422] Step 2 / 2,4-Dibromo-6-chloro-5-fluoro-3-methoxypyridine To a mixture of 2,4-dibromo-6-chloro-5-fluoropyridin-3-ol (2.18 g, 7.14 mmol) and Cs2CO3 (4.65 g, 14.3 mmol) in DMF (45 mL) was added I2 (0.890 mL, 14.3 mmol) at room temperature. The mixture was then stirred at room temperature overnight. Water was added and the precipitate was collected by filtration using a Buchner funnel. The solid was rinsed with water, then with heptane, and dried under vacuum to give 2,4-dibromo-6-chloro-5-fluoro-3-methoxypyridine (2.02 g, 89% yield) as a white solid. UPLC-MS (+ESI) m / z=319.4 (M+H). + . 1 H NMR(400MHz,CDCl3)δppm 3.97(s,3H). 19 F NMR (377MHz, CDCl3) δppm -109.88(s, 1F).

[0423] Step 3 / 4-Bromo-6-chloro-5-fluoro-3-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-2-amine A vial was charged with Intermediate 1 (1.25 g, 6.89 mmol), 2,4-dibromo-6-chloro-5-fluoro-3-methoxypyridine (2.00 g, 6.26 mmol), Xantphos (1.09 g, 1.88 mmol), and K2CO3 (2.60 g, 18.8 mmol) in dioxane (33 mL) and the mixture was sparged with nitrogen for 10 min. Pd(OAc)2 (211 mg, 0.94 mmol) was added and sparging continued for 5 min. The vial was sealed and stirred at 100 °C overnight. The reaction mixture was filtered through Celite, concentrated to dryness, and purified by silica gel chromatography eluting with EtOAc (0-30%) in heptane. The appropriate fractions were combined and concentrated in vacuo to give 4-bromo-6-chloro-5-fluoro-3-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-2-amine (1.19 g, 45% yield) as a pale yellow solid. UPLC-MS (+ESI) m / z=421 (M+H). + .1 H NMR(400MHz,CDCl3)δppm 1.59-1.77(m,3H),1.85-1.92(m,1H),2.06-2.13(m,1H),2.32-2.41(m,4H),3.62-3.70(m,1 H),3.91(s,3H),4.08-4.14(m,1H),5.18(dd,J=10.3,2.4Hz,1H),6.70(s,1H),7.46(s,1H).

[0424] Step 4 / 6-Chloro-5-fluoro-3-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine A vial was charged with 4-bromo-6-chloro-5-fluoro-3-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-2-amine (1.19 g, 2.83 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (374 mg, 2.97 mmol), NaHCO3 (950 mg, 11.3 mmol) in dioxane (18 mL) and water (6 mL). The mixture was sparged with N2 for 10 min. Pd(PPh3)4 (490 mg, 0.42 mmol) was added and sparging was continued for 5 min. The vial was sealed and stirred at 100 °C overnight. The reaction mixture was filtered through Celite, concentrated to dryness, and purified by silica gel chromatography eluting with EtOAc (0-70%) in heptane. The appropriate fractions were combined and concentrated in vacuo to give 6-chloro-5-fluoro-3-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (464 mg, 39% yield) as a pale yellow solid. UPLC-MS (+ESI) m / z=421.2 (M+H). + . 1H NMR(400MHz,CDCl3)δppm 1.69-1.79(m,3H),1.85-1.92(m,1H),2.06-2.13(m,1H),2.34-2.44(m,4H),3.63-3.70(m,4H),4.01(s,3H),4.08- 4.14(m,1H),5.18(dd,J=10.3,2.4Hz,1H),6.74(s,1H),7.51(s,1H),7.98(d,J=2.2Hz,1H),8.10(d,J=1.7Hz,1H). 19 F NMR (377MHz, CDCl3) δppm -133.84(s, 1F).

[0425] Step 5 / 3-Fluoro N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 2 -Methyl-N 6 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine A vial was charged with 6-chloro-5-fluoro-3-methoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (75 mg, 0.18 mmol), 2-fluoro-4-methanesulfonyl-N-methylaniline (54.3 mg, 0.27 mmol), Cs2CO3 (174 mg, 0.53 mmol) and + / -BINAP (44.4 mg, 0.070 mmol) in toluene (1.7 mL). The mixture was sparged with nitrogen for 10 minutes. Pd(OAc) 2 (8.0 mg, 0.040 mmol) was added and sparging continued for 5 min. The vial was sealed and stirred at 100° C. overnight. The reaction mixture was filtered through Celite, concentrated to dryness, and purified by preparative HPLC eluting with a gradient of MeCN (5 to 100%) in water, both containing 0.1% formic acid, and the appropriate fractions were combined and lyophilized prior to purification into 3-fluoro-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N 2-Methyl-N 6 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine (36 mg, 33% yield) was obtained as a pale yellow solid. UPLC-MS (+ESI) m / z = 588.2 (M+H) + . 1 H NMR(400MHz,CDCl3)δppm 1.55-1.60(m,1H),1.64-1.69(m,1H),1.84-1.90(m,2H),2.05-2.12(m,1H),2.25(s,3H),2 .31-2.43(m,1H),3.08(s,3H),3.52(s,3H),3.60-3.69(m,4H),3.98(s,3H),4.07-4.13(m,1 H),5.14(dd,J=10.4,2.3Hz,1H),6.24(s,1H),7.23-7.26(m,1H),7.51(s,1H),7.60(dd,J= 11.1,2.1Hz,1H),7.69(dd,J=8.6,1.5Hz,1H),7.94(d,J=1.7Hz,1H),8.06(d,J=1.5Hz,1H).

[0426] Step 6 / Compound 24 To a solution of 3-fluoro-N2-(2-fluoro-4-(methylsulfonyl)phenyl)-5-methoxy-N2-methyl-N6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2,6-diamine (35.0 mg, 0.060 mmol) in MeOH (600 μL) was added HCl solution (320 μL, 1.28 mmol, 4 M in dioxane). The mixture was then heated at 50 °C for 2 h. The solvent was evaporated and the crude was neutralized with 5 M NaOH to pH 7-8 and then purified by preparative HPLC eluting with MeCN (5-100%) in 10 mM aqueous NH4HCO3 to give compound 24 (12 mg, 39% yield) as an orange solid after lyophilization of the appropriate fractions. UPLC-MS (+ESI) m / z = 504.1 (M+H) + . 1H NMR(400MHz,DMSO-d6)δppm 2.07(br s,3H),3.24(s,3H),3.42(s,3H),3.59(s,3H),3.92(s,3H),5.89(br s,1H),7.46-7.55(m,1H),7.66-7.71(m,1H),7.72-7.77(m,1H),7.93(s,1H),8.12(br s,1H),8.24(s,1H),11.75(s,1H). 19 F NMR (377MHz, DMSO-d6) δppm -141.64(s,0.8F), -140.40(s,0.2F), -118.55(s,1F). Rotamers are 19 It is observed in the F NMR spectrum.

[0427] Compound 25 / Method E / 3-Cyclopropyl-N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 6 -Methyl-4-(1-methyl-1H-imidazol-4-yl)-N 2 -(5-Methyl-1H-pyrazol-3-yl)pyridine-2,6-diamine

[0428] [ka]

[0429] Step 1 / 4-Chloro-3-cyclopropyl-N 6 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 2 -(4-Methoxybenzyl)-N 6 -Methyl-N 2 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridine-2,6-diamine To intermediate 12 (300 mg, 614 umol) in DMPU (3 mL) was added 2,6-difluoro-4-methylsulfonyl-aniline (191 mg, 921 μmol). Nitrogen was bubbled through for 5 min, then NaH (73 mg, 1.84 mmol, 60% purity) was added at room temperature. The vial was sealed and the mixture was heated at 120° C. for 4 h. The mixture was cooled to room temperature, MeI (0.38 mL, 6.1 mmol) was added, and the resulting mixture was stirred at room temperature for 1 h. 1 mL of MeOH was added and the mixture was filtered through a Celite cartridge. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC eluting with a gradient of MeCN (10 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized, and 6-chloro-5-cyclopropyl-N 2 -(2,6-difluoro-4-methylsulfonyl-phenyl)-N 4 -[(4-Methoxyphenyl)methyl]-N 2 -Methyl-N 4 -(5-Methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrimidine-2,4-diamine (210 mg, 51% yield) was obtained as a mixture of regioisomers (9 / 1) in favor of the title compound. UPLC-MS (+ESI) m / z=673.3 (M+H). + .

[0430] Step 2 / 5-Cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine To a solution of tributyl-(1-methylimidazol-4-yl)stannane (176 mg, 475 μmol) in dioxane (1.00 mL) was added 6-chloro-5-cyclopropyl-N 2 -(2,6-difluoro-4-methylsulfonyl-phenyl)-N 4-[(4-Methoxyphenyl)methyl]-N 2 -Methyl-N 4 -(5-Methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrimidine-2,4-diamine (100 mg, 149 μmol) and Pd(PPh3)4 (86 mg, 74 μmol) were added. The mixture was degassed in vacuum, then backfilled with nitrogen, and finally stirred at 130° C. for 48 h. The crude reaction mixture was cooled to room temperature, filtered, and the filtrate was purified by preparative HPLC eluting with a gradient of MeCN (30 to 60%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized, and 5-cyclopropyl-N 2 -(2,6-fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine (26 mg, 24% yield) was obtained. UPLC-MS (+ESI) m / z = 673.3 (M+H) + .

[0431] Step 3 / Compound 25 5-Cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4To -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine (26 mg, 36 μmol) was added trifluoroacetic acid (6 mL) and the resulting mixture was stirred at 90° C. for 4 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC eluting with a gradient of MeCN (10 to 25%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 25 (15 mg, 83% yield) as a white solid. UPLC-MS (+ESI) m / z=515.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.91(s,1H),8.56(s,1H),8.09(s,1H),7.84(d,J=6.8Hz,2H),5.25(s,1H),3.86( s,3H),1.98(s,3H),1.74(td,J=7.9,3.9Hz,1H),1.10(s,2H),0.19(d,J=5.0Hz,2H) Compound 26 / Method B (RP-11710) / 5-Cyclopropyl-N 2 -(2-fluoro-4-((propan-2-yl-1,1,1,3,3,3-d6)sulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0432] [ka]

[0433] Step 1 / 3-Fluoro-N,N-bis(methyl-d3)-4-nitrobenzenesulfonamide To a mixture of dimethyl-d6-amine HCl (53.7 mg, 0.607 mmol) in DCM (3 mL) at 0° C. was added triethylamine (187 μL, 1.34 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min, after which 3-fluoro-4-nitrobenzenesulfonyl chloride (150 mg, 0.607 mmol) was added. The reaction mixture was stirred at 0° C. for an additional 30 min. The volatiles were removed in vacuo to give 143 mg of 3-fluoro-N,N-bis(methyl-d3)-4-nitrobenzenesulfonamide, which was used directly in the next step without further purification. 1 HNMR (DMSO-d6, 400MHz): δ 8.37 (1H, t, J = 7.9Hz), 7.98 (1H, d, J = 10.4Hz), 7.78 (1H, d, J = 8.6Hz).

[0434] Step 2 / 4-Amino-3-fluoro-N,N-bis(methyl-d3)benzenesulfonamide To a solution of 3-fluoro-N,N-bis(methyl-d3)-4-nitrobenzenesulfonamide (143 mg, 0.562 mmol) in EtOH (4 mL) and water (2 mL) was added NH4Cl (301 mg, 5.62 mmol) and zinc (263 mg, 3.94 mmol). The resulting reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was then filtered through Celite. EtOAc and saturated aqueous NaHCO3 were added to the filtrate. The layers were separated and the organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give 130 mg of 4-amino-3-fluoro-N,N-bis(methyl-d3)benzenesulfonamide, which was used directly in the next step without further purification. UPLC-MS (+ESI): m / z = 225.1 [M+H] + .

[0435] Step 3 / 5-Cyclopropyl-N 2 -(2-fluoro-4-((propan-2-yl-1,1,1,3,3,3-d6)sulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine To a solution of 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-amine (compound 11, see step 1) (180 mg, 0.312 mmol), 4-amino-3-fluoro-N,N-bis(methyl-d3)benzenesulfonamide (154 mg, 0.685 mmol) in NMP (1.56 mL) was added NaH (37 mg, 1.6 mmol). The resulting reaction mixture was stirred at 125° C. for 16 h. The conversion was not complete. Additional NaH (37 mg, 1.6 mmol) was added and the reaction mixture was stirred at 125° C. for 16 h. The reaction mixture was cooled to room temperature and MeI (194 μL, 3.12 mmol) was added and stirred at room temperature for 18 h. The conversion was not complete. Additional NaH (37 mg, 1.6 mmol) was added and the reaction mixture was stirred for 5 h. Crushed ice and EtOAc (25 mL) were added. The layers were partitioned and the aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc in hexanes (40-100%). The desired fractions were combined and concentrated to dryness and 5-cyclopropyl-N 2 -(2-fluoro-4-((propan-2-yl-1,1,1,3,3,3-d6)sulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (71 mg, 31% yield) was obtained. UPLC-MS (+ESI): m / z = 736.5 [M+H] + .

[0436] Step 4 / Compound 26 5-Cyclopropyl-N 2 -(2-fluoro-4-((propan-2-yl-1,1,1,3,3,3-d6)sulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (71 mg, 97 μmol) was dissolved in TFA (2.2 mL, 29 mmol). The reaction mixture was heated at 80° C. for 1 h. After the reaction mixture was cooled to room temperature, the volatiles were removed in vacuo. The residue was co-evaporated with NEt3 (3×) and the residue was purified by silica gel chromatography eluting with MeCN (10-100%) in DCM. The desired fractions were combined, concentrated to dryness, and lyophilized by redissolving in MeCN / water to give compound 26 (34 mg, 66% yield) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6):δ 11.85(s;1H);8.22(s;2H);7.91(s;1H);7.72(t;J=7.94Hz;1H);7.63-7.65(m;2H);5.64(s;1H);3.88 (s;3H);3.47(s;3H);2.04(s;3H);1.72-1.75(m;1H);1.12(d;J=7.42Hz;2H);0.18(d;J=5.30Hz;2H). UPLC-MS(+ESI):m / z=532.0[M+H] + .

[0437] Compound 108 / Method B / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 Methyl-N 4 -(5-Methyl-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrimidine-2,4-diamine

[0438] [ka]

[0439] Step 1 / 5-Cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylsulfonyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-4-amine A mixture of intermediate 8 (150 mg, 282 μmol), Cs2CO3 (2M in H2O, 423 μL, 846 μmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (104 mg, 423 μmol), Pd(dppf)Cl2 (26 mg, 31 μmol) in dioxane (1.5 mL) was degassed in a microwave reaction vial (three cycles of vacuum / argon atmosphere). The reaction mixture was then heated at 85 °C for 16 h. After the reaction mixture was cooled to room temperature, EtOAc was added and the mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel flash chromatography eluting with EtOAc in hexanes (0 to 100%). The desired fractions were combined and concentrated to dryness in vacuo to give 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylsulfonyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-4-amine (65 mg, 38% yield). UPLC-MS (+ESI): m / z=615.3 [M+H] + .

[0440] Step 2 / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrimidine-2,4-diamine.

[0441] Sodium hydride (60% in mineral oil, 16.9 mg, 423 μmol) was added to a solution of 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylsulfonyl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-4-amine (65 mg, 106 μmol) and 2-fluoro-4-(methylsulfonyl)aniline (46.3 mg, 233 μmol) in NMP (1 mL). The reaction was purged with nitrogen for 5 minutes and heated at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, iodomethane (65.8 μL, 1.06 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc in hexanes (0 to 100%). The desired fractions were combined and concentrated to dryness to give 5-cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrimidine-2,4-diamine (27 mg, 35% yield). UPLC-MS (+ESI): m / z=738.4 [M+H]+.

[0442] Step 3 / Compound 108 5-Cyclopropyl-N in trifluoroacetic acid (2.0 mL, 26.1 mmol) 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4A solution of -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrimidine-2,4-diamine (27.0 mg, 36.6 μmol) was heated at 80° C. for 1 h. After the reaction mixture was cooled to room temperature, the volatiles were removed in vacuo. The residue was purified by preparative HPLC eluting with MeCN (40 to 60%) in 10 mM aqueous NH4HCO3 (pH 3.8). The desired fractions were combined and lyophilized to give compound 108 (2.4 mg, 12% yield). 1 H-NMR (400MHz, DMSO-d6): δ 9.18 (1H,d,J=7.1Hz), 8.63 (1H,s), 8.47 (1H,s), 8.28-8.42 (1H,m), 7.77-7.87 (3H,m), 7.08-7.17 (1H,m), 5.69 (1H,s), 3.48 (3H,s), 2.05 (3H,s), 1.94 (1H,s), 0.63 (2H,d,J=4.3Hz), -0.05 (2H,d,J=3.9Hz). Four protons were hidden by water peaks. UPLC-MS (+ESI): m / z=534.3 [M+H] + .

[0443] Compound 110 / Method F / 5-Cyclopropyl-6-(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-Methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

[0444] [ka]

[0445] Step 1 / 6-Chloro-5-cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4-(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine Sodium hydride (60% in mineral oil, 376 mg, 9.40 mmol) was added to a solution of intermediate 8 (1.00 g, 1.88 mmol) and 2-fluoro-4-(methylsulfonyl)aniline (449 mg, 2.26 mmol) in NMP (2 mL). The reaction was purged with nitrogen for 5 min and heated at 125° C. for 16 h. After the reaction was cooled to room temperature, MeI (1.23 mL, 19.7 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with water, EtOAc, and brine. The layers were partitioned and the organic layer was washed with brine (3×), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography eluting with MeCN (0 to 100%) in DCM. The desired fractions were combined and concentrated to dryness to afford 6-chloro-5-cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (566 mg, 46% yield) was obtained. UPLC-MS (+ESI): m / z=655.3 [M+H] + .

[0446] Step 2 / 5-Cyclopropyl-6-(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine Xantphos (17.7 mg, 30.5 μmol) was dissolved in toluene (1.5 mL) in 6-chloro-5-cyclopropyl-N2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 To a solution of -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (100 mg, 153 μmol), 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (54.7 mg, 382 μmol), Pd2(dba)3 (14.0 mg, 15.3 μmol) and Cs2CO3 (149 mg, 0.458 mmol) was added. The reaction was purged with nitrogen for 5 minutes and heated at 115° C. for 16 hours. After the reaction mixture was cooled to room temperature, the volatiles were removed in vacuo. The residue was diluted with EtOAc and water. The layers were partitioned and the organic layer was washed with brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography eluting with MeCN in DCM (0 to 100%). The desired fractions were combined, concentrated to dryness and purified as 5-cyclopropyl-6-(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (56.1 mg, 49% yield) was obtained. UPLC-MS (+ESI): m / z = 755.4 [M+H] + .

[0447] Step 3 / Compound 110 5-Cyclopropyl-6-(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-N in TFA (0.5 mL) 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4A solution of -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (56.1 mg, 74.2 μmol) was heated at 80° C. for 1 h. After the reaction mixture was cooled to room temperature, the volatiles were removed and coevaporated with triethylamine (3×1 mL). The residue was purified by silica gel chromatography eluting first with MeCN (0-100%) in DCM followed by 10% MeOH in DCM. The desired fractions were combined and concentrated in vacuo to dryness. The residue was then purified by preparative HPLC eluting with MeCN (35 to 55%) in 10 mM NH4HCO3 (pH=10). The desired fractions were combined and lyophilized to give compound 110 (10 mg, 24% yield). 1 H-NMR(400MHz,DMSO-d6):δ 11.84(1H,s),8.33(1H,s),8.01(1H,s),7.88(1H,s),7.82(2H,t,J=9.8Hz),7.74(1H,t,J=7.7Hz),6.86(1H,s),5.67(1H,s) ,4.35-4.44(2H,m),3.90(2H,s),3.39(3H,s),3.29(3H,s),2.05(3H,s),1.39(1H,s),0.65-0.80(2H,m),0.20-0.35(2H,m). UPLC-MS(+ESI):m / z=551.3[M+H] + .

[0448] Compound 111 / Method G / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 Methyl-N 4 -(5-Methyl-1H-pyrazol-3-yl)-6-(3-(methylsulfonyl)piperidin-1-yl)pyrimidine-2,4-diamine

[0449] [ka]

[0450] Step 1 / 5-Cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(3-(methylsulfonyl)piperidin-1-yl)-2-(methylthio)pyrimidin-4-amine N,N-Diisopropylethylamine (190 μL, 1.09 mmol) was added to a solution of 6-chloro-5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (see intermediate 8, step 1) (260 mg, 520 μmol) and 3-(methylsulfonyl)piperidine (163 uL, 780 μmol) in DMSO (1 mL). The resulting reaction mixture was stirred at 140° C. for 16 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and brine. The layers were partitioned and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography eluting with EtOAc in hexanes (0 to 100%). The desired fractions were combined and concentrated to dryness to give 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(3-(methylsulfonyl)piperidin-1-yl)-2-(methylthio)pyrimidin-4-amine (226 mg, 69% yield). UPLC-MS (+ESI): m / z=627.4 [M+H] + .

[0451] Step 2 / 5-Cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylsulfonyl)-6-(3-(methylsulfonyl)piperidin-1-yl)pyrimidin-4-amine Hydrogen peroxide (258 μL, 2.52 mmol) was added to a mixture of 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(3-(methylsulfonyl)piperidin-1-yl)-2-(methylthio)pyrimidin-4-amine (226 mg, 0.360 mmol), Na2WO4.2H2O (11.9 mg, 36.0 μmol) and NBu4(HSO4) (19.6 mg, 57.6 μmol) in THF (7 mL) and EtOAc (7 mL). The reaction mixture was stirred at 50° C. for 3 h. After cooling to room temperature, the reaction mixture was quenched with 5% NaHSO3. The resulting mixture was diluted with EtOAc and brine. The layers were separated and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to dryness to give crude 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylsulfonyl)-6-(3-(methylsulfonyl)piperidin-1-yl)pyrimidin-4-amine (211 mg), which was used directly in the next step without further purification. UPLC-MS (+ESI): m / z=659.4 [M+H] + .

[0452] Step 3 / 5-Cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(3-(methylsulfonyl)piperidin-1-yl)pyrimidine-2,4-diamine Sodium hydride (60% in mineral oil, 27.9 mg, 0.698 mmol) was added to a solution of 5-cyclopropyl-N-(4-methoxybenzyl)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylsulfonyl)-6-(3-(methylsulfonyl)piperidin-1-yl)pyrimidin-4-amine (100 mg, 0.152 mmol) and 2-fluoro-4-(methylsulfonyl)aniline (34.5 mg, 0.182 mmol) in NMP (760 μL). The reaction mixture was purged with nitrogen for 5 minutes and heated at 125° C. for 16 hours. After the reaction mixture was cooled to room temperature, iodomethane (100 μL, 1.59 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, EtOAc, and brine. The layers were separated and the organic layer was washed with brine (3x), dried over anhydrous MgSO4, filtered and concentrated in vacuo to dryness. The residue was purified by silica gel chromatography eluting with MeCN (0 to 100%) in DCM. The desired fractions were combined and concentrated to dryness to afford 5-cyclopropyl-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(3-(methylsulfonyl)piperidin-1-yl)pyrimidine-2,4-diamine (21 mg) was obtained. UPLC-MS (+ESI): m / z=782.3 [M+H]+.

[0453] Step 4 / Compound 111 5-Cyclopropyl-N in TFA (2.0 mL) 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4A solution of -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(3-(methylsulfonyl)piperidin-1-yl)pyrimidine-2,4-diamine (21 mg, 27 μmol) was heated at 80° C. for 1 h. After the reaction mixture was cooled to room temperature, the volatiles were removed in vacuo. The residue was purified by preparative HPLC eluting with MeCN (35 to 75%) in HO, both containing 0.1% formic acid. The desired fractions were combined and lyophilized to give compound 111 (2.5 mg, 16% yield). 1 H-NMR (400 MHz, DMSO-d6): δ 8.06 (1H, s), 7.80 (2H, t, J = 8.5 Hz), 7.71 (1H, t, J = 7.8 Hz), 5.66 (1H, s), 4.45 (1H, d, J = 12.3 Hz), 4.09 (1H, d, J = 12.9 Hz), 3.41 (3H, s), 3.29 (3H, s), 2.86-2.94 (6H, m), 2.16-2.19 (1H, m), 2.04 (3H, s), 1.78 (1H, d, J = 11.9 Hz), 1.53-1.67 (3H, m), 1.00-1.02 (2H, m), 0.35-0.40 (2H, m). One proton was hidden by a water peak. UPLC-MS(+ESI): m / z=578.3[M+H] + .

[0454] Compound 121 / Method H / 5-Cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-N 2 -Methyl-N 4 -(5-Methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

[0455] [ka]

[0456] Step 1 / 6-Chloro-5-cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4-(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine To a nitrogen purged solution of 2,6-difluoro-4-methylsulfonyl-aniline (2.34 g, 11.3 mmol) and intermediate 8 (5.62 g, 10.3 mmol) in DMPU (48 mL) was added NaHMDS (1 M, 22.5 mL, 22.5 mmol) at room temperature. The reaction was heated at 160° C. for 30 min. The reaction mixture was cooled to room temperature and iodomethane (3.19 mL, 51.2 mmol) was added slowly. The remaining mixture was stirred at room temperature for 30 min. The resulting mixture was poured onto a mixture of water (800 mL) and ethyl acetate (200 mL). The phases were separated and then the aqueous phase was back extracted twice with ethyl acetate (2×200 mL). The pooled organic phase was washed with brine (200 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with EtOAc (5 to 10%) in heptane. Appropriate fractions were pooled and concentrated to dryness. The residue was then purified by reverse-phase flash chromatography (HP C18 RediSep® Rf Gold) eluting with a gradient of CH3CN (0 to 100%) in water, both containing 0.1% formic acid. Appropriate fractions were combined and concentrated under reduced pressure to a volume of approximately 20 mL. Poured into saturated aqueous NaHCO3 and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and then dried on a vacuum pump to give 6-chloro-5-cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (3.50 g, 51% yield) was obtained. 1H NMR(400MHz,DMSO-d6)δ 7.76(d,J=8.0Hz,2H),6.64(s,4H),5.92(s,1H),5.21(d,J=9.4Hz,1H),4.55(s,1H),3. 80(d,J=11.5Hz,1H),3.65(s,3H),3.58-3.44(m,1H),3.27(s,3H),3.26(s,3H),2.18(s ,3H),2.13-1.97(m,1H),1.89(d,J=12.5Hz,1H),1.68(d,J=12.9Hz,1H),1.56(d,J=11. 1Hz,1H),1.44(s,2H),0.94(ddd,J=13.8,8.3,5.5Hz,1H),0.43(p,J=9.2Hz,2H),0.26- -0.01(m,2H).UPLC-MS(+ESI):m / z=673.7[M+H] + .

[0457] Step 2 / 5-Cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine To 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (85.8 mg, 386 μmol) in dioxane (1 mL) and HO (250 μL) was added 6-chloro-5-cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl-N 2 -Methyl-N 4-(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (200 mg, 297 μmol), Cs2CO3 (242 mg, 743 μmol) and PdCl2(dppf) (43.5 mg, 59.4 μmol) were added. The mixture was degassed in vacuum, then filled with N2, sealed and stirred at 120 °C for 1 h. The crude reaction mixture was filtered and the filtrate was purified by preparative HPLC eluting with a gradient of CH3CN (55 to 85%) in water, both containing 0.1% formic acid. The appropriate fractions were combined, lyophilized and 5-cyclopropyl-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (73.0 mg, 34% yield) was obtained. UPLC-MS (+ESI): m / z = 733.0 [M+H] + .

[0458] Step 3 / Compound 121 5-Cyclopropyl-N in DCM (1 mL) 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4To -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (73.0 mg, 99.6 μmol) was added trifluoroacetic acid (115 μL, 1.49 mmol). The resulting mixture was heated at 90° C. for 6 h. The volatiles were removed in vacuo and the residue was coevaporated twice with DCM. The residue was dissolved in DCM, washed with NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase flash chromatography eluting with a gradient of CH3CN (15 to 60%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 121 (16.0 mg, 30% yield). 1 H NMR(400MHz,DMSO-d6)δ 11.83(br s;1H);8.22(br s;1H);8.01(s;1H);7.79(d;J=6.80Hz;2H);5.27(br s;1H);3.75(s;3H);3.33(s;3H);3.30(s;3H);2.00(br s;3H);1.59-1.67(m;1H);0.96(d;J=7.60Hz;2H);0.05(d;J=5.20Hz;2H). UPLC-MS(+ESI):m / z=528.8[M+H] + .

[0459] Compound 125 / Method H / 5-Cyclopropyl-N 2 -(2,5-difluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-6-(1-methyl-1H-imidazol-4-yl)-N 4 -(5-Methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

[0460] [ka]

[0461] Step 1 / 6-Chloro-5-cyclopropyl-N 2 -(2,5-difluoro-4-(methylsulfonyl)phenyl)-N 4-(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine To intermediate 8 (5.00 g, 9.40 mmol) and 2,5-difluoro-4-methylsulfonyl-aniline (2.92 g, 14.1 mmol) in DMPU (60 mL) was added NaHMDS (1 M, 21.1 mL, 21.4 mmol) and the reaction mixture was heated at 110° C. for 10 min. The resulting mixture was cooled to room temperature, then MeI (5.9 mL, 94 mmol) was added over 15 min, and the reaction was stirred at room temperature for 45 min. The reaction mixture was poured onto a mixture of water (400 mL) and ethyl acetate (200 mL). The organic phase was separated, then the aqueous phase was back-extracted twice with EtOAc (2×100 mL). The pooled organic phase was washed with brine (200 mL), then dried over anhydrous MgSO4, filtered through a fritted glass Buchner, and the cake was rinsed with ethyl acetate (100 mL). The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with EtOAc (5-10%) in Hex, followed by a second purification by silica gel chromatography eluting with MeOH (10-20%) in DCM. Appropriate fractions were combined and the residue was further purified by reversed-phase flash chromatography (HP C18 RediSep® Rf Gold) eluting with a gradient of CH3CN (10-100%) in water, both containing 0.1% formic acid. Appropriate fractions were combined and lyophilized to afford 6-chloro-5-cyclopropyl-N 2 -(2,5-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (4.00 g, 63% yield) was obtained. UPLC-MS (+ESI): m / z = 674.2 [M+H] + .

[0462] Step 2 / 5-Cyclopropyl-N 2 -(2,5-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine 6-Chloro-5-cyclopropyl-N in 1,4-dioxane (10 mL) 2 -(2,5-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 Nitrogen was bubbled through a solution of -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (600 mg, 891 μmol), tributyl-(1-methylimidazol-4-yl)stannane (700 mg, 1.89 mmol) for 15 min with sonication. XPhosPdG2 (210 mg, 223 μmol) was then added and nitrogen was bubbled through the resulting suspension for another 10 min under sonication. The final reaction mixture was sealed and stirred at 130° C. for 2 h. The resulting suspension was diluted with 10 mL of EtOAc and 3 mL of 1M KF, filtered through Celite, the organic phase was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of MeOH (1 to 8%) in DCM. The appropriate fractions were combined and concentrated in vacuo to give 5-cyclopropyl-N 2 -(2,5-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine (525 mg, 79% yield).

[0463] Step 3 / Compound 125 5-Cyclopropyl-N 2 -(2,5-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methyl-N 4 -(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine (525 mg, 730 μmol) and L-cysteine ​​(180 mg, 1.49 mmol) were dissolved in DCE (5 mL) to which was added TFA (2.25 mL, 29.21 mmol). The mixture was heated at 80° C. under reflux for 1 h. The volatiles were removed in vacuo, coevaporated twice with CH3CN, dissolved in DCM and neutralized with saturated aqueous NaHCO3. The organic layer was separated and concentrated in vacuo. The residue was dissolved in DMSO and purified by preparative HPLC eluting with a gradient of CHCN (15 to 45%) in water containing 10 mM NHHCO (adjusted to pH 10 with NHOH). The appropriate fractions were combined and lyophilized to give compound 125 (71 mg, 19% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 12.45-11.67(m,1H),8.23(s,1H),7.79(dd,J=10.9,5.9Hz,1H),7.72-7.64(m,2H),7.60(d,J=1.4Hz,1H),5.72(s,1H),3.73(s,3H) ),3.54-3.43(m,3H),3.39(s,3H),2.08(d,J=4.9Hz,3H),1.82(p,J=7.5Hz,1H),0.96(h,J=4.3Hz,2H),0.09(td,J=6.0,4.2Hz,2H). UPLC-MS(+ESI):m / z=515.2[M+H] + .

[0464] Compound 144 / Method I / 2-(5-cyclopropyl-4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-2-(4-methylsulfonyl)phenyl)acetonitrile

[0465] [ka]

[0466] Step 1 / 2-(5-cyclopropyl-4-((4-methoxybenzyl)(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-2-(4-methylsulfonyl)phenyl)acetonitrile A 4 mL vial was charged with 5-cyclopropyl-N-[(4-methoxyphenyl)methyl]-6-(1-methylpyrazol-4-yl)-2-methylsulfonyl-N-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrimidin-4-amine (compound 11, see step 1) (100 mg, 173 μmol), 2-(4-methylsulfonyl)phenyl)acetonitrile (50.0 mg, 256 μmol) and DMPU (500 μL). NaHMDS (1M, 350 μL, 350 μmol) was added and the mixture was stirred at 120° C. for 30 min. The cooled reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of EtOAc (0 to 10%) in heptane followed by a gradient of MeOH (0 to 20%) in DCM. The appropriate fractions were combined and concentrated in vacuo to give 2-(5-cyclopropyl-4-((4-methoxybenzyl)(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-2-(4-methylsulfonyl)phenyl)acetonitrile (28 mg, 23% yield). UPLC-MS (+ESI): m / z=693.0 [M+H] + .

[0467] Step 2 / Compound 144 2-(5-Cyclopropyl-4-((4-methoxybenzyl)(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-2-(4-methylsulfonyl)phenyl)acetonitrile (28.0 mg, 40.4 μmol) was dissolved in DCM (1 mL) and TFA (1 mL). L-Cysteine ​​(10.0 mg, 82.5 μmol) was added and the mixture was stirred at 50° C. for 90 min. The mixture was concentrated, then dissolved in DMSO and neutralized with Et3N. The reaction mixture was filtered and the filtrate was purified by preparative HPLC eluting with a gradient of CH3CN (25 to 55%) in water containing 10 mM NH4HCO3 (adjusted to pH 10 with NH4OH). The appropriate fractions were combined and lyophilized to give compound 144 (6.0 mg, 30% yield). 1 H NMR(DMSO-d6)δ:11.98(s,1H),8.65(s,1H),8.25(s,1H),7.99-7.93(m,3H),7.75(d,J=8.2Hz,2H),6.33(s,1H) ,5.90(s,1H),3.88(s,3H),3.16(s,3H),2.17(s,3H),1.85-1.75(m,1H),1.20-1.11(m,2H),0.23-0.15(m,2H). UPLC-MS(+ESI):m / z=489.3[M+H] + .

[0468] Compound 158 / Method I / 5-cyclopropyl-N-(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(4-(methylsulfonyl)benzyl)pyrimidin-4-amine

[0469] [ka]

[0470] Step 1 / Methyl 2-(5-cyclopropyl-4-((4-methoxybenzyl)(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2yl)-2-(4-(methylsulfonyl)phenyl)acetate A 4 mL vial was charged with 5-cyclopropyl-N-[(4-methoxyphenyl)methyl]-6-(1-methylpyrazol-4-yl)-2-methylsulfonyl-N-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)pyrimidin-4-amine (compound 11, see step 1) (100 mg, 173 μmol), methyl 2-(4-methylsulfonylphenyl)acetate (60.0 mg, 263 μmol) and DMPU (500 μL). NaHMDS (1M, 350 μL, 350 μmol) was added and the mixture was stirred at 90° C. for 90 min. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of EtOAc (30 to 100%) in heptane followed by MeOH (0 to 20%) in DCM to give methyl 2-(5-cyclopropyl-4-((4-methoxybenzyl)(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetate (62.0 mg, 49% yield). UPLC-MS (+ESI): m / z=727.0 [M+H] + .

[0471] Step 2 / Compound 158 Methyl 2-(5-cyclopropyl-4-((4-methoxybenzyl)(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)-2-(4-(methylsulfonyl)phenyl)acetate (62.0 mg, 85.4 μmol) was dissolved in methanol (250 μL) and THF (750 μL) and then treated with LiOH (1M, 250 μL, 250 μmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 250 uL of 10% aqueous HCl and then concentrated in vacuo to dryness. L-cysteine ​​(21.0 mg, 173 μmol) was added to the crude product followed by DCM (1 mL) and TFA (1 mL). The mixture was stirred at reflux at 60° C. overnight. The volatiles were evaporated and the crude residue was redissolved in DMSO and basified with a few drops of Et3N. The reaction mixture was filtered and the filtrate was purified by preparative HPLC eluting with a gradient of CH3CN (25 to 55%) in water containing 10 mM ammonium bicarbonate (adjusted to pH 10 with NH4OH). The appropriate fractions were combined and lyophilized to give compound 158 (8 mg, 20% yield). 1 H NMR(DMSO-d6)δ:11.88(s,1H),8.34(s,1H),8.23(s,1H),7.94(s,1H),7.86-7.80(m,2H),7.62-7.54(m,2H),6.11(s,1H) ),4.09(s,2H),3.87(s,3H),3.13(s,3H),2.12(s,3H),1.78(h,J=6.2,5.4Hz,1H),1.16-1.08(m,2H),0.20-0.13(m,2H). UPLC-MS(+ESI):m / z=464.6[M+H] + .

[0472] Compound 228 / Method H / 5-Cyclopropyl-N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine

[0473] [ka]

[0474] Step 1 / 6-Chloro-5-cyclopropyl-N 4 -(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methylpyrimidine-2,4-diamine To a solution of 2,6-difluoro-4-methylsulfonyl-aniline (100 mg, 483 μmol) in DMPU (1.5 mL) was added NaHMDS (1 M, 900 μL, 900 μmol) at room temperature. Then, intermediate 13 (223 mg, 400 μmol) was added and the resulting reaction mixture was stirred at room temperature for 1 h. CH3I (125 μL, 2.01 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 30 min. The reaction was diluted with EtOAc, washed with water, brine (10 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified on a silica gel column eluted with a gradient of EtOAc (50-100%) in heptane. The appropriate fractions were combined and concentrated, and the residue was further purified by preparative HPLC (Phenomenex Gemini) eluting with a gradient of CH3CN (25 to 100%) in water containing 10 mM ammonium bicarbonate (adjusted to pH 10 with NH4OH). The appropriate fractions were combined and lyophilized to give 6-chloro-5-cyclopropyl-N 4 -(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2-Methylpyrimidine-2,4-diamine (128 mg, 46% yield) was obtained as an off-white solid. UPLC-MS (+ESI): m / z=699.8 [M+H] + .

[0475] Step 2 / 5-Cyclopropyl-N 4 -(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine 6-Chloro-5-cyclopropyl-N in dioxane (2 mL) 4 -(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 To a solution of 1-methylpyrimidine-2,4-diamine (60.0 mg, 85.8 μmol) was added tributyl-(1-methylimidazol-4-yl)stannane (65.0 mg, 175 μmol) and XPhosPdG3 (16.0 mg, 17.0 μmol). The mixture was degassed in vacuum and filled with N2 three times, then the resulting mixture was stirred at 120 °C for 1 h. Additional XPhosPdG3 (16 mg, 16.99 μmol) was added and the mixture was stirred at 120 °C for an additional 1 h. The resulting mixture was cooled to room temperature and concentrated. The residue was purified on a silica gel column eluted with a gradient of EtOAc (60-100%) in hexanes. A second purification was performed on a silica gel column eluted with a gradient of MeOH (0-10%) in DCM. The appropriate fractions were combined, concentrated, and 5-cyclopropyl-N 4 -(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4(methylsulfonyl)phenyl)-N 4-(4-Methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine (31 mg, 49% yield) was obtained as an off-white solid. UPLC-MS (+ESI): m / z=746.0 [M+H] + .

[0476] Step 3 / Compound 228 5-Cyclopropyl-N in DCE (500 μL) 4 -(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 To a solution of -(4-methoxybenzyl)-N-methyl-6-(1-methyl-1H-imidazol-4-yl)pyrimidine-2,4-diamine (31.0 mg, 41.6 μmol) was added TFA (500 μL, 6.49 mmol) and L-cysteine ​​(11.0 mg, 90.8 μmol). The resulting mixture was stirred at 80° C. under N for 4 h. After cooling to room temperature, the volatiles were removed in vacuo and the residue was coevaporated with MeOH, then MeOH and TEA. The residue was purified by reversed-phase flash chromatography (HP C18 RediSep® Rf Gold) eluting with a gradient of CH3CN (25 to 100%) in water containing 10 mM ammonium bicarbonate (adjusted to pH 10 with NH4OH). The appropriate fractions were combined and lyophilized to give compound 228 (18.0 mg, 80% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.82(s,1H),8.17(s,1H),7.81(d,J=6.9Hz,2H),7.60(2s,2H),5.58(bs,1H),3.67(s,3H),3.34(s,3 H),3.30(s,3H),1.76(m,1H),1.66(m,1H),1.04-0.82(m,2H),0.79(m,2H),0.44(m,2H),0.06(m,2H). UPLC-MS(+ESI):m / z=541.3[M+H] + .

[0477] Compound 287 / Method H / 4-(5-cyclopropyl-6-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-((2,6-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)pyrimidin-4-yl)-1-methyl-1H-imidazole-2-carbonitrile

[0478] [ka]

[0479] Step 1 / 6-(2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-imidazol-4-yl)-5-cyclopropyl-N 4 -(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methylpyrimidine-2,4-diamine In a 2-5 mL microwave vial equipped with a stir bar, 4 -(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2-Methylpyrimidine-2,4-diamine (compound 228, see step 1) (170 mg, 243 μmol) was dissolved in 1,4-dioxane (2.5 mL). tert-Butyl-dimethyl-[(1-methyl-4-tributylstannyl-imidazol-2-yl)methoxy]silane (360 mg, 489 μmol) was added to the reaction mixture. The reaction mixture was degassed with a stream of N2 for 10 min and Pd(PPh3)4 (70.2 mg, 60.8 μmol) was added. The mixture was again degassed with a stream of nitrogen for 15 min and finally the vial was sealed and the reaction was heated at 130° C. for 16 h. The resulting mixture was cooled to room temperature, diluted with EtOAc and washed with 1M KF. The organic layer was separated, dried over Na2SO4, filtered through Celite and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of EtOAc (0 to 75%) in heptane. The appropriate fractions were combined, concentrated in vacuo and purified to give 6-(2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-imidazol-4-yl)-5-cyclopropyl-N 4 -(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methylpyrimidine-2,4-diamine (124 mg, 57% yield) was obtained. UPLC-MS (+ESI): m / z = 889.5 [M+H] + .

[0480] Step 2 / (4-(5-cyclopropyl-6-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)(4-methoxybenzyl)amino)-2-((2,6-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)pyrimidin-4-yl)-1-methyl-1H-imidazol-2-yl)methanol 6-(2-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-imidazol-4-yl)-5-cyclopropyl-N4 -(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-N 2 -(2,6-difluoro-4-(methylsulfonyl)phenyl)-N 4 -(4-Methoxybenzyl)-N 2 -Methylpyrimidine-2,4-diamine (123 mg, 138 μmol) was dissolved in THF (1.4 mL) and cooled to 0° C. A solution of TBAF (1 M, 166 μL, 166 μmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was poured into H2O and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and dried on high vacuum for 1 h to give (4-(5-cyclopropyl-6-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)(4-methoxybenzyl)amino)-2-((2,6-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)pyrimidin-4-yl)-1-methyl-1H-imidazol-2-yl)methanol (108 mg), which was used directly in the next step without further purification. UPLC-MS (+ESI): m / z=775.2 [M+H] + .

[0481] Step 3 / 4-(5-cyclopropyl-6-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)(4-methoxybenzyl)amino)-2-((2,6-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)pyrimidin-4-yl)-1-methyl-1H-imidazole-2-carbaldehyde (4-(5-cyclopropyl-6-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)(4-methoxybenzyl)amino)-2-((2,6-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)pyrimidin-4-yl)-1-methyl-1H-imidazol-2-yl)methanol (108 mg, 139 μmol) was dissolved in DCM (1.5 mL) and cooled to 0° C. Dess-Martin periodinane (70.9 mg, 167 μmol) was added and the resulting mixture was stirred for 1 h. To drive the reaction to completion, additional Dess-Martin periodinane (29.6 mg, 69.7 μmol) was added and the final mixture was stirred for an additional 1 h. The reaction mixture was quenched by the addition of iPrOH (250 μL) and stirred for 5 min. Aqueous Na2S2O3 (10 mL) was added to the reaction mixture, which was then extracted with CH2Cl2 (3x). The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and dried under high vacuum to give 4-(5-cyclopropyl-6-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)(4-methoxybenzyl)amino)-2-((2,6-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)pyrimidin-4-yl)-1-methyl-1H-imidazole-2-carbaldehyde (107 mg), which was used in the next step without further purification. UPLC-MS (+ESI): m / z=773.2 [M+H] + .

[0482] Step 4 / 4-(5-cyclopropyl-6-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)(4-methoxybenzyl)amino)-2-((2,6-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)pyrimidin-4-yl)-1-methyl-1H-imidazole-2-carbonitrile 4-(5-Cyclopropyl-6-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)(4-methoxybenzyl)amino)-2-((2,6-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)pyrimidin-4-yl)-1-methyl-1H-imidazole-2-carbaldehyde (107 mg, 139 μmol) was dissolved in MeOH (1 mL). HONH2·HCl (20 mg, 288 μmol) and NaOAc (25.0 mg, 305 μmol) were added in one portion. The final mixture was stirred vigorously for 1 h. The resulting mixture was concentrated under reduced pressure. The crude was dissolved in DCM (1.45 mL) and pyridine (55.8 μL, 692.23 μmol) was added followed by (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (78.06 μL, 554 μmol). The reaction mixture was stirred at room temperature for 16 h. Additional pyridine (22.3 μL, 277 μmol) was added and the reaction mixture was heated at 35° C. for 2 h, but the reaction did not proceed further. The volatiles were evaporated under reduced pressure and the crude residue was dissolved in DMSO and purified by reverse phase flash chromatography (HP C18 RediSep® Rf Gold) eluting with a gradient of CH3CN (0 to 100%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give 4-(5-cyclopropyl-6-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)(4-methoxybenzyl)amino)-2-((2,6-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)pyrimidin-4-yl)-1-methyl-1H-imidazole-2-carbonitrile (45.0 mg, 42% yield). UPLC-MS (+ESI): m / z=770.4 [M+H] + .

[0483] Step 5 / Compound 287 4-(5-Cyclopropyl-6-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)(4-methoxybenzyl)amino)-2-((2,6-difluoro-4-(methylsulfonyl)phenyl)(methyl)amino)pyrimidin-4-yl)-1-methyl-1H-imidazole-2-carbonitrile (45.0 mg, 58.5 μmol) was dissolved in 1,2-dichloroethane (1.5 mL). L-Cysteine ​​(21.3 mg, 175 μmol) was added followed by TFA (313 μL, 4.09 mmol). The reaction mixture was stirred at 80° C. for 6 h. Volatiles were evaporated to dryness. The reaction mixture was neutralized with saturated aqueous NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini) eluting with a gradient of CH3CN (10 to 55%) in water, both containing 0.1% formic acid. The appropriate fractions were combined and lyophilized to give compound 287 (24 mg, 73% yield). 1 H NMR(400MHz,DMSO)δ 11.85(s,1H),8.34(s,1H),8.02(s,1H),7.82(d,J=6.9Hz,2H),5.40(s,1H),3.87(s,3H),3.35(s,3H),3.31(s,3H),1 .85-1.72(m,1H),1.66(s,1H),1.02-0.86(m,2H),0.87-0.65(m,2H),0.61-0.28(m,2H),0.02(dd,J=6.0,4.2Hz,2H). 19 F NMR(376MHz,DMSO)δ -113.26.2F. UPLC-MS(+ESI):m / z=566.2[M+H] + .

[0484] Compound 344 / Method G / 5-Cyclopropoxy-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine

[0485] [ka]

[0486] Step 1 / Diethyl 2-cyclopropoxymalonate Rhodium(II) acetate dimer (563 mg, 1.27 mmol) was added followed by cyclopropanol (8.41 mL, 129 mmol) to a solution of diethyl 2-diazomalonate (4.74 g, 25.5 mmol) in DCM (100 mL). The reaction mixture was stirred at 50° C. for 24 h. The volatiles were concentrated and the crude material was purified by silica gel chromatography eluting with EtOAc (0 to 50%) in hexanes. The desired fractions were combined and concentrated in vacuo to dryness to give diethyl 2-cyclopropoxymalonate (3.37 g, 61% yield) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ 4.56(s;1H);4.21-4.31(m;4H);3.55-3.60(m;1H);1.27-1.31(m;6H);0.74-0.75(m;2H);0.49-0.54(m;2H). UPLC-MS(+ESI):m / z=217.1[M+H] + .

[0487] Step 2 / 5-Cyclopropoxy-2-(methylthio)pyrimidine-4,6(1H,5H)-dione Sodium methoxide (25% w / w in MeOH, 3.56 mL, 15.6 mmol) was added to a solution of thiourea (1.19 g, 15.6 mmol) and diethyl 2-cyclopropoxymalonate (3.37 g, 15.6 mmol) in MeOH (62 mL). The reaction mixture was stirred under reflux for 1 h. The reaction mixture was cooled to room temperature and MeI (1.46 mL, 23.4 mmol) was added dropwise. After stirring at room temperature for 5 h, the reaction mixture was quenched with water (minimum amount) and the solvent was removed under reduced pressure to give 3.34 g of crude 5-cyclopropoxy-2-(methylthio)pyrimidine-4,6(1H,5H)-dione (yellow foamy solid), which was used directly in the next step without further purification. 1 H-NMR (400MHz, DMSO-d6): δ 3.96-3.99 (m; 1H); 2.35 (s; 3H); 0.62-0.67 (m; 2H); 0.27-0.32 (m; 2H). UPLC-MS(+ESI):m / z=215.1[M+H] + .

[0488] Step 3 / 4,6-Dichloro-5-cyclopropoxy-2-(methylthio)pyrimidine A suspension of 5-cyclopropoxy-2-(methylthio)pyrimidine-4,6(1H,5H)-dione (3.30 g, 15.4 mmol) in POCl3 (29.0 mL, 308 mmol) was stirred at 80 °C for 3 h. After the reaction mixture was cooled to room temperature, the volatiles were removed under reduced pressure and the residue was dissolved in DCM. This mixture was slowly added to ice water with stirring (an exotherm was observed). The mixture was extracted with DCM (3 x 75 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude material was purified by silica gel chromatography eluting with EtOAc (0 to 40%) in hexanes. The desired fractions were combined and concentrated in vacuo to dryness. The purified residue was redissolved in DCM and washed with 20% aqueous Na2S2O3 (20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 4,6-dichloro-5-cyclopropoxy-2-(methylthio)pyrimidine (1.40 g) as a yellow / brown oil. UPLC-MS (+ESI): m / z=251.0 [M+H]+.

[0489] Step 4 / 6-Chloro-5-cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine To a solution of 4,6-dichloro-5-cyclopropoxy-2-(methylthio)pyrimidine (1.15 g, 4.58 mmol) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (913 mg, 5.04 mmol) was added dropwise at room temperature NaHMDS (1 M in THF, 5.50 mL, 5.50 mmol). The resulting mixture was stirred at 50° C. for 2 h. At this point, additional NaHMDS (1 M in THF, 3.66 mL, 3.66 mmol) was added and the reaction was stirred at 50° C. for an additional 1 h. Saturated aqueous NH4Cl (10 mL) was added and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with EtOAc in hexanes (0 to 100%). The desired fractions were combined and concentrated in vacuo to give 6-chloro-5-cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (1.00 g, 55% yield) as a white solid. 1 H-NMR(400MHz, CDCl3):δ 7.58(s;1H);6.66(s;1H);5.17(dd;J=10.36;2.36Hz;1H);4.15-4.20(m;1H);4.07-4.13(m;1H);3.62-3.68(m;1H);2. 55(s;3H);2.34(s;3H);2.04-2.12(m;1H);1.82-1.90(m;1H);1.63-1.78(m;2H);0.90-0.98(m;2H);0.62-0.68(m;2H). UPLC-MS(+ESI):m / z=396.2[M+H] + .

[0490] Step 5 / 6-Chloro-5-cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine To a mixture of sodium hydride (60% in mineral oil, 40.0 mg, 1.00 mmol) in THF (1 mL) was added a solution of 6-chloro-5-cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)pyrimidin-4-amine (170 mg, 429 μmol) in THF (2 mL) dropwise at room temperature, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (200 μL, 1.13 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction was quenched with H2O (1 mL) and diluted with EtOAc (3 mL). The layers were separated and the aqueous layer was back-extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with EtOAc in hexanes (0 to 40%). The desired fractions were combined and concentrated to dryness to give 6-chloro-5-cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine (180 mg, 80% yield) as a viscous oil. UPLC-MS (+ESI): m / z=548.2 [M+Na] + .

[0491] Step 6 / 5-Cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine A mixture of 6-chloro-5-cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(methylthio)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine (175 mg, 333 μmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (50.3 mg, 399 μmol), NaHCO3 (55.9 mg, 665 μmol), and Pd(PPh3)4 (28.8 mg, 24.9 μmol) in a solvent mixture of DME (1.4 mL) and HO (200 μL) in a vial was first degassed and heated at 85° C. for 18 h. After cooling to room temperature, the reaction was diluted with a 1:1 mixture of brine and water (2 mL) and the aqueous mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in hexanes (0 to 80%). The desired fractions were combined and concentrated to dryness to give 5-cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine (100 mg, 53% yield) as a yellow oil. UPLC-MS (+ESI): m / z=572.3 [M+H] + .

[0492] Step 7 / 5-Cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine To a mixture of 5-cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine (100 mg, 175 μmol), NEt4(HSO4) (9.50 mg, 28.0 μmol), and Na2WO4.2H2O (5.77 mg, 17.5 μmol) in EtOAc (1.5 mL) and THF (1.5 mL) was added H2O2 (179 μL, 1.75 mmol) at room temperature. The reaction mixture was heated at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was quenched with 5% NaHSO3 (2 mL). The layers were partitioned and the aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with water (5 mL), brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give 105 mg of 5-cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine (foamy solid), which was used in the step without further purification. UPLC-MS (+ESI): m / z = 604.3 [M+H] + .

[0493] Step 8 / 5-Cyclopropoxy-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-N 4 -((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4-diamine To a solution of 5-cyclopropoxy-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrimidin-4-amine (105 mg, 174 μmol) and 2-fluoro-4-(methylsulfonyl)aniline (34.6 mg, 174 μmol) in dry NMP (900 μL) was added LiHMDS (1M in THF, 522 μL, 522 μmol) under inert atmosphere and the resulting mixture was stirred at 80° C. for 3 h. The reaction was then cooled to room temperature and MeI (54 μL, 869 μmol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NH4Cl (0.5 mL) and the aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with water (5 mL), brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude material was purified by silica gel chromatography eluting with EtOAc in hexanes (0 to 100%). The desired fractions were combined and concentrated to dryness to afford 5-cyclopropoxy-N 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-N 4 -(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-N 4 -((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4-diamine (60.0 mg, 48% yield) was obtained as a yellow oil. UPLC-MS (+ESI): m / z=727.4 [M+H] + .

[0494] Step 9 / Compound 344 5-Cyclopropoxy-N in TFA (400 μL) and DCM (400 μL) 2 -(2-Fluoro-4-(methylsulfonyl)phenyl)-N 2 -Methyl-N 4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-N 4 A solution of -((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4-diamine (60.0 mg, 82.5 μmol) was stirred at room temperature for 1 h. Upon completion, MeCN (1 mL) was added to the reaction mixture and the volatiles were removed under reduced pressure. The crude residue was purified by preparative HPLC eluting with MeCN (30 to 100%) in HO, both containing 0.1% FA. The desired fractions were combined and lyophilized to give compound 344 (15 mg, 36% yield) as a white solid. 1 H-NMR(400MHz, CDCl3):δ 8.15(s;1H);8.03(s;1H);7.76-7.82(m;2H);7.64(t;J=7.70Hz;1H);7.56(s;1H);5.80(s;1H);3.98(s ;3H);3.75-3.78(m;1H);3.59(s;3H);3.18(s;3H);2.19(s;3H);0.87-0.92(s;2H);0.53-0.60(m;2H). UPLC-MS(+ESI):m / z=513.3[M+H] + .

[0495] Binding assays To determine the affinity of the compounds described herein in the PLK4 NanoBRET target binding assay, HEK293T cells (ATCC product no. CRL-3216) are first transfected with PLK4 NanoLuc fusion vector DNA and transfection carrier DNA using Fugene HD Transfection reagent in Opti-MEM No Phenol Red buffer. After overnight incubation in a 37°C / 5% CO2 incubator, the transfected HEK293T cells are trypsinized, counted, and resuspended in Opti-MEM No Phenol Red buffer at a concentration of 200000 cells / mL. Next, 85uL of cells (17000 cells / well) are plated in a white 96-well plate, to which 5uL of 20x K-5 tracer solution diluted in tracer dilution buffer is added. Finally, 10uL of 10x compound is added to the plate, which is then incubated for 2 hours in a 37°C / 5% CO2 incubator. After incubation, 50 uL of a 3x solution of the substrate / inhibitor mix is ​​added to the cells. The plate is then transferred to an Envision plate reader where the acceptor emission (610 nm) and donor emission (450 nm) are measured.

[0496] Compound IC 50 is determined as follows: 1. Calculate the ratio of acceptor emission (610 nm) / donor emission (450 nm). 2. This ratio is then multiplied by 1000 to obtain mBRET units (multiplying by 1000 is simply an optional step to facilitate interpretation of the data and has no effect on the data set itself).

[0497] 3. The mBRET units are then used in Scigilian Analyze software (https: / / analyze.scigilian.io) to determine IC50 values ​​using a 4-parameter fit analysis.

[0498] Exemplary compounds prepared and their activities are shown in Table 3 below. Compounds were prepared according to methods A, B, C, D, E, F, G described above using intermediates and commercially available reagents described herein, or readily prepared from commercially available reagents as documented by literature precedent. m / z (M+H) + The column indicates the positive ion masses observed by UPLC-MS(+ESI).

[0499] [Table 3-1]

[0500] [Table 3-2]

[0501] [Table 3-3]

[0502] [Table 3-4]

[0503] [Table 3-5]

[0504] [Table 3-6]

[0505] [Table 3-7]

[0506] [Table 3-8]

[0507] [Table 3-9]

[0508] [Table 3-10]

[0509] [Table 3-11]

[0510] [Table 3-12]

[0511] [Table 3-13]

[0512] [Table 3-14]

[0513] [Table 3-15]

[0514] [Table 3-16]

[0515] Other embodiments Various modifications and variations of the described invention will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the present invention.

[0516] Other embodiments are found in the claims.

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, n is 0, 1, 2, 3, or 4; m is 0, 1, or 2; L is an optionally substituted C ２～９ Heterocyclyl, optionally substituted C ２～９ Heteroaryl, optionally substituted C ６～１０ aryl, or optionally substituted C ３～８ cycloalkyl, where L is further selected from n occurrences of R ３ optionally replaced by; R １ａ is hydrogen, halogen, optionally substituted C １～６ Alkyl, optionally substituted C １～６ Alkoxy, optionally substituted C １～６ Heteroalkyl, optionally substituted C ２～６ Alkenyl, optionally substituted C ２～６ Alkynyl, optionally substituted C ３～８ cycloalkyl, or nitrile; R １ｂ is hydrogen; or R １ａ and R １ｂ together with the atom to which they are attached, is a 3- to 5-membered cycloalkyl, cycloalkylene, cycloalkyline, heterocycloalkyl, aryl, or heteroaryl; A is O or S, and R ２Ａ and R ２Ｂ or A is N and R ２Ａ is absent and R ２Ｂ is hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ６～１０ Aryl C １～６ Alkyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted C ６～１０ aryl, optionally substituted C ２～９ Heterocyclyl, optionally substituted C １～９ Heteroaryl, optionally substituted C １～９ Heteroaryl C １～６ Alkyl or optionally substituted C １～６ alkylsulfonyl, or R ２Ｂ and L, together with the atoms to which they are attached, may form an optionally substituted C ２～９ Heterocyclyl or optionally substituted C ２～９ forming a heteroaryl; or A is C and R ２Ａ and R ２Ｂ each independently represents hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ６～１０ Aryl C １～６ Alkyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted C ６～１０ aryl, optionally substituted C ２～９ Heterocyclyl, optionally substituted C １～９ Heteroaryl, optionally substituted C １～９ Heteroaryl C １～６ alkyl, or optionally substituted C １～６ alkylsulfonyl; Each R ３ are independently selected from halogen, cyano, optionally substituted C １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ２～６ Alkenyl, optionally substituted C ２～６ Alkynyl, optionally substituted C ６～１０ Aryl C １～６ Alkyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted C ３～８ Cycloalkenyl, optionally substituted C ６～１０ aryl, optionally substituted C ２～９ Heterocyclyl, optionally substituted C １～９ Heteroaryl, optionally substituted C １～９ Heteroaryl C １～６ Alkyl, —S(O) ｍ R ３Ａ , -N(R ３Ｂ ) ２ , or -OR ３Ｂ and R ３Ａ is an optionally substituted C １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ２～６ Alkenyl, optionally substituted C ２～６ Alkynyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted C ６～１０ aryl, optionally substituted C ２～９ Heterocyclyl, optionally substituted C １～９ Heteroaryl, —OR ３Ｂ , or -N(R ３Ｂ ) ２ and Each R ３Ｂ are independently hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C ６～１０ Aryl C １～６ Alkyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted C ６～１０ aryl, optionally substituted C ２～９ Heterocyclyl, optionally substituted C １～９ Heteroaryl, optionally substituted C １～９ Heteroaryl C １～６ Alkyl or optionally substituted C １～６ alkylsulfonyl; or two R ３Ｂ The groups are optionally substituted C ２～９ forming a heterocyclyl; X is N and R ４ is absent; or X is C and R ４ is hydrogen, halogen, cyano, optionally substituted amino, optionally substituted acyl, optionally substituted C １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ２～６ Alkenyl, optionally substituted C ２～６ Alkynyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted C ３～８ Cycloalkenyl, optionally substituted C ６～１０ aryl, optionally substituted C ２～９ heterocyclyl or optionally substituted C １～９ is heteroaryl; R ５ is an optionally substituted C １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ２～６ Alkenyl, optionally substituted C ２～６ Alkynyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted C ３～８ Cycloalkenyl, optionally substituted C ６～１０ aryl, optionally substituted C ２～９ Heterocyclyl, optionally substituted C １～９ Heteroaryl, —CONH ２ , or -Z-R ５Ａ and Z is optionally substituted amino, optionally substituted C ２～９ Heterocyclylene, optionally substituted C ２～９ Heteroarylene, optionally substituted C ６～１０ arylene, or optionally substituted C ３～８ is cycloalkylene; R ５Ａ is hydrogen, halogen, cyano, optionally substituted C １～６ Alkylsulfonyl, optionally substituted C １～６ Alkyl, optionally substituted C １～６ Heteroalkyl, optionally substituted C ２～６ Alkenyl, optionally substituted C ２～６ Alkynyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted C ３～８ Cycloalkenyl, optionally substituted C ６～１０ aryl, optionally substituted C ２～９ heterocyclyl, or optionally substituted C １～９ is heteroaryl; R ６ is hydrogen, halogen, cyano, optionally substituted C １～６ Alkyl, optionally substituted C ２～６ Alkenyl, optionally substituted C ２～６ Alkynyl, optionally substituted C ３～８ cycloalkyl, or —OR ６Ａ and R ６Ａ is hydrogen, optionally substituted C １～６ Alkyl, optionally substituted C ２～６ Alkenyl, optionally substituted C ２～６ Alkynyl, or optionally substituted C ３～８ The compound, or a pharmaceutically acceptable salt thereof, is cycloalkyl.

2. R ２Ｂ teeth, 【Chemistry 2】 2. The compound of claim 1, wherein:

3. R １ａ and R １ｂ are independently —CH ３ , -Cl, -OMe, -CH ２ OMe, -CN, -CF ２ H, -CF ３ , -CHF ２ , cyclopropyl, or cyclobutyl, or R 1a and R 1b together with the atoms to which they are attached are 【Transformation 3】 2. The compound of claim 1, wherein:

4. L is an optionally substituted C ６～１０ aryl or optionally substituted C 2-9 heteroaryl, wherein said optionally substituted C 6-10 aryl is optionally substituted phenyl or optionally substituted C 5 heteroaryl, or a pharmaceutically acceptable salt thereof.

5. -L-(R ３ ) ｎ teeth, 【Chemistry 4】 5. The compound of claim 4, wherein:

6. At least one R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is a halogen.

7. At least one R ３ is -S(O) ｍ R ３Ａ and m is 1 or 2, or a pharmaceutically acceptable salt thereof.

8. R ３Ａ is -CH ３ 8. The compound of claim 7, wherein:

9. At least one R ３ is an optionally substituted C ２～９ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is heteroaryl, -N(R 3B ) 2 , or -OR 3B.

10. -L-(R ３ ) ｎ teeth, 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 2. The compound of claim 1, wherein:

11. R ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is H, F, Cl, --CH.sub.3, cyano, --NH.sub.2, or --N(CH.sub.3).sub.

2.

12. R ５ teeth, 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 【Chemistry 6-4】 【Transformation 6-5】 【Transformation 6-6】 2. The compound of claim 1, wherein:

13. R ５ is -Z-R ５Ａ and Z is an optionally substituted amino acid, and R 5A is 【Transformation 7】 2. The compound of claim 1, wherein:

14. R ６ teeth, 【Transformation 8】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is optionally substituted cyclopropyl, or -OR 6A, where R 6A is -CH 3 .

15. R ６ teeth, 【Chemistry 9】 2. The compound of claim 1, wherein:

16. The compound is a compound of formula (V): 【Chemistry 10】 2. The compound of claim 1, wherein: 【Request Item 17】 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 【Chemistry 11-5】 【Chemistry 11-6】 【Chemistry 11-7】 【Chemistry 11-8】 【Chemistry 11-9】 【Chemistry 11-10】 【Chemistry 11-11】 [Chemistry 11-12] [Chemistry 11-13] [Chemistry 11-14] 【Chemistry 11-15】 【Chemistry 11-16】 [Chemistry 11-17] [Chemistry 11-18] [Chemistry 11-19] [Chemistry 11-20] 【Chemistry 11-21】 [Chemistry 11-22] [Chemistry 11-23] [Chemistry 11-24] [Chemistry 11-25] [Chemistry 11-26] [Chemistry 11-27] [Chemistry 11-28] [Chemistry 11-29] 【Chemistry 11-30】 【Chemistry 11-31】 【Chemistry 11-32】 【Chemistry 11-33】 [Chemistry 11-34] 【Chemistry 11-35】 [Chemistry 11-36] 【Chemistry 11-37】 [Chemistry 11-38] [Chemistry 11-39] 【Chemistry 11-40】 【Chemistry 11-41】 and pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. 19. The pharmaceutical composition of claim 18 for use in treating a cancer that is a TRIM37 overexpressing or TRIM37 amplified cancer.

20. 20. The pharmaceutical composition of claim 19, wherein the cancer is uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, or endometrial cancer.

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