Heteroaromatic hydrocarbons, pharmaceutical compositions containing heteroaromatic hydrocarbons, and methods of use thereof

Abstract

Compounds and pharmaceutically acceptable salts thereof are disclosed that are useful in the treatment of a subject in need thereof. The compounds disclosed herein can be inhibitors of tyrosine and threonine specific cdc2 inhibitory kinase (Myt1). Also disclosed are pharmaceutical compositions containing the compounds, or pharmaceutically acceptable salts thereof, as well as methods of their preparation and use.

Description

Technical Field

[0001] This invention relates to compounds and pharmaceutical compositions, their preparation, and their use in treating diseases or conditions such as cancer, and particularly those that depend on the activity of membrane-associated tyrosine and threonine-specific cdc2 inhibitory kinase (Myt1) (e.g., cancers with CCNE1 amplification / overexpression or FBXW7 mutations). Background Art

[0002] DNA is constantly subjected to both endogenous (e.g., stalled replication forks, reactive oxygen species) and exogenous (UV, ionizing radiation, chemical substances) damage that can lead to DNA harm. Therefore, cells have developed complex mechanisms to counteract these harmful events, which would otherwise compromise genome integrity and lead to genomically unstable diseases such as cancer. These mechanisms are collectively known as the DNA Damage Response (DDR). A component of the entire DDR is the activation of various checkpoint pathways that regulate specific DNA repair mechanisms at different stages of the cell cycle, including the G1, S, G2, and mitotic checkpoints. Due to p53 mutations, most cancer cells have lost their G1 checkpoints and therefore rely on the G2 checkpoint for necessary DNA damage correction before entering mitosis and dividing into two daughter cells.

[0003] New anti-cancer treatments are needed, such as those that utilize small molecules, especially therapies that allow for targeted cancer treatment. Summary of the Invention

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

[0005]

[0006] Or its pharmaceutically acceptable salt.

[0007] in

[0008] R 1 yes:

[0009]

[0010] n is 0, 1, or 2;

[0011] R 2 and R 3 Each is independently hydrogen, halogen, or optionally substituted C. 3-4 cycloalkyl or optionally substituted C 1-6 alkyl;

[0012] Each R 4 It is a halogen on its own;

[0013] R 5 It is hydrogen, halogen, hydroxyl, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 alkoxy, or -N(R) 5A )2;

[0014] Each R 5A Independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C3-8 cycloalkyl;

[0015] R 6 It is -C(O)NH(R) 6A -SO2R 6B , or -C(O)R 6C ;

[0016] R 6A It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, or optionally substituted C 1-9 Mixed aromatics;

[0017] R 6B It is an optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, or -NH(R) 6A );

[0018] R 6C It is an optional substituted C1-6 alkyl group;

[0019] A 1 and A 2 Each is either N or C independently;

[0020] R 7 It is a non-existent, hydrogen, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, or -OR 10 ;R 8 It is hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-8 alkynyl group, optionally substituted C3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Mixed aromatics, -OR 10 、-N(R 11 )2, or -LR 8A ; or R 7 and R 8 The atoms they are attached to combine to form optionally substituted C atoms. 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, or optionally substituted C 2-12 heteroaryl; and R 9 It is a non-existent, hydrogen, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or -OR 10 ;

[0021] or

[0022] R 8 It is hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-8 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Mixed aromatics, -OR 10 、-N(R 11 )2, or -LR 8A ; and R 9 It is a non-existent, hydrogen, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C6-10 aryl, optionally substituted C 1-9 heteroaryl, or -OR 10 ; or R 8 and R 9 The atoms they are attached to combine to form optionally substituted C atoms. 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, or optionally substituted C 1-12 heteroaryl; and R 7 It is a non-existent, hydrogen, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or -OR 10 ;

[0023] L is an optional substitution of C 2-9 Heterocyclic groups, optionally substituted C 2-9 Heteroaryl, optionally substituted C 6-10 Aromatic, or optionally substituted C 3-8 Cycloalkylene;

[0024] R 8A It is hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Mixed aromatics, -OR 10 or -N(R) 11 )2.

[0025] R 10 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9Heterocyclic groups, optionally substituted C 6-10 aryl or optionally substituted C 1-9 Mixed aromatics;

[0026] Each R 11 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted acyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, or optionally substituted C 1-9 heteroaryl, or -SO2R 11A , or two R 11 The groups combine to form optionally substituted C2-9 heterocyclic groups; and

[0027] Each R 11A Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, or optionally substituted C 1-9 Mixed aromatic compounds.

[0028] In some implementation schemes, R 5 It is N(R 5A 2. In some implementations, each R 5A They're all hydrogen.

[0029] In some implementation schemes, R 1 yes

[0030]

[0031] In some embodiments, the compound has formula (II-A):

[0032]

[0033] In some embodiments, the compound has the formula (II-Ai):

[0034]

[0035] In some implementation schemes, R 1 yes In some embodiments, the compound has the formula (II-B):

[0036]

[0037] In some embodiments, the compound has the formula (II-Bi):

[0038]

[0039] In some implementation schemes, A 1 It is C. In some implementations, A 2 It is C. In some implementations, A 2 It is N. In some implementations, A 1 It's N.

[0040] In some implementation schemes, R 7 In some embodiments, R 7 and R 8 The atoms they are attached to combine to form optionally substituted C atoms. 2-12 Mixed aromatic compounds.

[0041] In some implementation schemes, R 8 It's hydrogen.

[0042] In some embodiments, the compound has the formula (II-Ba):

[0043]

[0044] In some embodiments, the compound has the formula (II-Bb):

[0045]

[0046] In some embodiments, the compound has the formula (II-Bc):

[0047]

[0048] In some embodiments, the compound has the formula (II-Bd):

[0049]

[0050] In some embodiments, the compound has the formula (II-Aa):

[0051]

[0052] In some embodiments, the compound has the formula (II-Ab):

[0053]

[0054] In some embodiments, the compound has the formula (II-Ac):

[0055]

[0056] In some embodiments, the compound has the formula (II-Ad):

[0057]

[0058] In some embodiments, the compound has the formula (II-C):

[0059]

[0060] In some embodiments, the compound has the formula (II-D):

[0061]

[0062] In some embodiments, the compound has the formula (II-E):

[0063]

[0064] In some embodiments, the compound has the formula (II-F):

[0065]

[0066] In some implementation schemes, R 6 It is -C(O)NH(R) 6A In some implementations, each R 6A Both are H.

[0067] In some implementation schemes, R 2 is H. In some embodiments, R 3 is H. In some embodiments, R 2 and R 3 One is H and the other is an optional substituted C. 1-6 Alkyl group. In some embodiments, R 2 and R 3 One of them is H and the other is -CH3. In some implementations, R 2 and R 3 Each is an optional replacement of C 1-6 Alkyl group. In some embodiments, R 2 and R 3 Each is -CH3. In some implementations, R 2In some embodiments, R 2 Is Cl. In some embodiments, R 2 is F. In some embodiments, R 3 In some embodiments, R 3 Is Cl. In some embodiments, R 3 It is F.

[0068] In some implementations, n is 0. In some implementations, n is 1.

[0069] In some implementation schemes, R 4 In some embodiments, R 4 It is F.

[0070] In some implementation schemes, R 1 yes:

[0071]

[0072] In some implementation schemes, R 8 C is an optional substitute 6-10 Aryl. In some implementations, R 8 It is an optionally substituted phenyl group. In some embodiments, R 8 C is an optional substitute 1-9 heteroaryl. In some implementations, R 8 Yes -LR 8A .

[0073] In some embodiments, L is an optionally substituted pyrimidinyl group. In some embodiments, L is an optionally substituted pyridinyl group. In some embodiments, L is an optionally substituted indazole group. In some embodiments, L is an optionally substituted pyrazolyl group. In some embodiments, L is an optionally substituted imidazolyl group. In some embodiments, L is an optionally substituted thiazolyl group. In some embodiments, L is an optionally substituted pyridazinyl group. In some embodiments, L is an optionally substituted indoleyl group. In some embodiments, L is an optionally substituted furanyl group.

[0074] In some implementation schemes, R 8 It is an optionally substituted bicyclic heteroaryl group.

[0075] In some embodiments, -LR 8A yes:

[0076]

[0077] Among them A 3 and A 4 Each can be either N or CH independently.

[0078] In some implementation schemes, A 3 It is N. In some implementations, A 4 It is N. In some implementations, A 3 It is CH. In some implementations, A 4 It is CH.

[0079] In some implementation schemes, R 8A Yes - OR 10 In some implementations, R 10 C is an optional substitute 1-6 Alkyl group. In some embodiments, R 10 is -CH3. In some embodiments, R 10 C is an optional substitute 2-9 Heterocyclic group. In some implementations, R 10 C is an optional substitute 6-10 Aryl.

[0080] In some implementation schemes, R 8A Yes-N(R 11 )2. In some implementations, an R 11 It is H. In some implementations, an R 11 C is an optional substitute 1-6 Alkyl group. In some embodiments, each R 11 Both are H. In some implementations, both R... 11 The groups combine to form optional substituted C2-9 heterocyclic groups.

[0081] In some embodiments, -LR 8A yes:

[0082]

[0083] Each R 14 It is independently a cyano, halogen, or optionally substituted C group. 1-6 Alkyl group, -S(O)2R 14A Or optional replacement of C 1-8 Heteroalkyl;

[0084] R 14A C is an optional substitute 1-6 alkyl;

[0085] A 5 It is N or CH; and

[0086] p can be 0, 1, 2, 3, or 4.

[0087] In some embodiments, -LR 8A yes

[0088]

[0089] Where R 11 It is an acyl group that is optionally substituted.

[0090] In some embodiments, -LR 8A yes:

[0091]

[0092] Where R 15 、R 16 、R 17 、R 18 and R 19 Each can be independently a cyano group, hydrogen, halogen, -CH3, -CF3, or -OCH3.

[0093] In some embodiments, -LR 8A yes

[0094]

[0095] In some embodiments, -LR 8A yes

[0096]

[0097] Where R 11 C is an optional substitute 1-9 Heteroaryl. In some embodiments, the optionally substituted C 1-9 A heteroaryl group is a 6-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, the 6-membered heteroaryl ring contains a total of 2 nitrogen atoms.

[0098] In some embodiments, -LR 8A yes

[0099]

[0100] Where R 11 yes:

[0101] Each R 11B C is halogen or optionally substituted independently. 1-6 Alkyl; and

[0102] q can be 0, 1, 2 or 3.

[0103] In some implementations, q is 0. In other implementations, q is 2.

[0104] In some embodiments, -LR 8A yes

[0105]

[0106] Where R 11 C is an optional substitute 6-10 Aryl. In some embodiments, the optionally substituted C 6-10 The aryl group is an optional substituted phenyl group.

[0107] In some embodiments, -LR 8A yes

[0108]

[0109] Where R 11 C is an optional substitute 2-9 Heterocyclic group.

[0110] In some embodiments, -LR 8A yes

[0111]

[0112] Where R 11 Yes-S(O)2R 11A .

[0113] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2.

[0114] In some implementations, each R 14 It is halogen independently. In some implementations, each R... 14 All are F.

[0115] In some implementation schemes, A 5 It is CH. In some implementations, A 5 It's N.

[0116] In some embodiments, -LR 8A yes:

[0117]

[0118] In some implementation schemes, R 8 C is an optional substitute 3-8 Cycloalkyl.

[0119] In some embodiments, the compound is selected from the group consisting of compounds 1 to 977 and their pharmaceutically acceptable salts.

[0120] In another aspect, the present invention provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the composition is enriched with the isotope deuterium.

[0121] In another aspect, the present invention provides a method for inhibiting Myt1 in cells expressing Myt1, the method comprising contacting the cells with the compounds disclosed herein.

[0122] In some implementations, the cells overexpress CCNE1. In some implementations, the cells are in the body of a subject.

[0123] In another aspect, the present invention provides a method for treating a subject in need, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0124] In some embodiments, the subject suffers from a disease or condition characterized by excessive cell proliferation and requires treatment for said disease or condition. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is cancer that overexpresses CCNE1.

[0125] In another aspect, the present invention provides a method for treating cancer in a subject, the method comprising administering a therapeutically effective amount of a Myt1 inhibitor to the subject in need, wherein the cancer has been previously identified as cancer overexpressing CCNE1.

[0126] In another aspect, the present invention provides a method for treating cancer in a subject, the method comprising administering a therapeutically effective amount of a Myt1 inhibitor to the subject in need, wherein the cancer is a cancer that overexpresses CCNE1.

[0127] In another aspect, the present invention provides a method for inducing cell death in cancer cells overexpressing CCNE1, the method comprising contacting the cells with an effective amount of a Myt1 inhibitor.

[0128] In some embodiments, the cells are in the body of a subject. In some embodiments, the Myt1 inhibitor is a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer overexpressing CCNE1 is uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, or endometrial cancer.

[0129] In another aspect, the present invention provides a method for treating cancer in a subject, the method comprising administering a therapeutically effective amount of a Myt1 inhibitor to the subject in need, wherein the cancer has been previously identified as cancer with an inactivating mutation in the FBXW7 gene.

[0130] In another aspect, the present invention provides a method for treating cancer in a subject, the method comprising administering a therapeutically effective amount of a Myt1 inhibitor to the subject in need, wherein the cancer has an inactivating mutation in the FBXW7 gene.

[0131] In another aspect, the present invention provides a method for inducing cell death in FBXW7-mutant cancer cells, the method comprising contacting the cells with an effective amount of Myt1 inhibitor.

[0132] In some embodiments, the cells are in the body of a subject. In some embodiments, the cancer is uterine cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer. In some embodiments, the Myt1 inhibitor is a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0133] abbreviation

[0134] This article uses abbreviations and terms commonly used in the fields of organic chemistry, medicinal chemistry, pharmacology, and medicine, and which are familiar to practitioners in these fields. Representative abbreviations and definitions are provided below:

[0135] Ac is an acetyl group [CH3C(O)-];

[0136] ACN stands for acetonitrile;

[0137] Ac2O is acetic anhydride;

[0138] AcOH is acetic acid;

[0139] APCs are antigen-presenting cells;

[0140] Ar is an aryl group;

[0141] aq. means water;

[0142] 9-BBN is 9-boronbicyclo[3.3.1]nonane;

[0143] BINAP is (2,2'-bis(diphenylphosphine)-1,1'-binaphthyl);

[0144] Bn is benzyl;

[0145] Boc is tert-butyloxycarbonyl;

[0146] n-BuLi is n-butyllithium;

[0147] CDI is carbonyl diimidazole;

[0148] cmpd is a compound;

[0149] conc. means concentrated;

[0150] DCM stands for dichloromethane;

[0151] DIAD stands for diisopropyl azodicarbonate.

[0152] DIBAL is diisobutylaluminum hydride;

[0153] DIPEA is diisopropylethylamine;

[0154] DMA is dimethylacetamide;

[0155] DMAP is 4-dimethylaminopyridine;

[0156] DME stands for dimethoxyethane;

[0157] DMF is N,N-dimethylformamide;

[0158] DMSO is dimethyl sulfoxide;

[0159] dppf is 1,1'-bis(diphenylphosphine)ferrocene;

[0160] dtbpf is 1,1'-bis(di-tert-butylphosphine)ferrocene;

[0161] EDAC (or EDC) is 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide HCl;

[0162] ESI stands for electrospray ionization mass spectrometry.

[0163] Et2O is diethyl ether;

[0164] Et3N is triethylamine;

[0165] Et is an ethyl group;

[0166] EtOAc is ethyl acetate;

[0167] EtOH is ethanol;

[0168] 3-F-Ph is 3-fluorophenyl.

[0169] h represents hours;

[0170] HATU is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

[0171] HCl is hydrochloric acid;

[0172] Het is a heteroaryl group;

[0173] Hex is hexane;

[0174] HOBt is 1-hydroxybenzotriazole;

[0175] HPLC is High Performance Liquid Chromatography;

[0176] IPA stands for isopropanol;

[0177] IPAc is isopropyl acetate;

[0178] LCMS is an HPLC system with mass spectrometry detection.

[0179] LiHMDS is bis(trimethylsilyl)aminolithium;

[0180] LG is a leaving group;

[0181] M is the mole;

[0182] mCPBA is m-chloroperbenzoic acid;

[0183] mmol is millimole;

[0184] Me is a methyl group;

[0185] MeCN stands for acetonitrile;

[0186] MeMgBr is methyl magnesium bromide;

[0187] MeMgCl is methyl magnesium chloride;

[0188] MeOH is methanol;

[0189] min means minutes;

[0190] MOM stands for methoxymethyl;

[0191] Ms is methanesulfonyl group;

[0192] MS stands for mass spectrometry.

[0193] MTBE is methyl tert-butyl ether;

[0194] MW stands for microwave.

[0195] N is normal;

[0196] NaHMDS is sodium bis(trimethylsilyl)amino.

[0197] NaOAc is sodium acetate;

[0198] NaOtBu is sodium tert-butoxide;

[0199] NBS is N-bromosuccinimide;

[0200] NCS is N-chlorosuccinimide;

[0201] NIS is N-iodosuccinimide;

[0202] NMO is N-methylmorpholine N-oxide;

[0203] NMP is N-methylpyrrolidone;

[0204] NMR stands for Nuclear Magnetic Resonance Spectroscopy.

[0205] PdCl2(dppf) is [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II);

[0206] PdCl2(dppf).CH2Cl2 is [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II), which is complexed with dichloromethane;

[0207] Pd2(dba)3 is tris(dibenzylacetone)dipalladium;

[0208] PdCl2(PPh3)2 is bis(triphenylphosphine)dichloropalladium;

[0209] Pd-PEPPSI TM -SIPr is (1,3-bis(2,6-diisopropylphenyl)imidazolyl)(3-chloropyridinyl)dichloropalladium(II);

[0210] PG represents the protective group;

[0211] Ph stands for phenyl;

[0212] PhMe is toluene;

[0213] PIV-Cl is neopentanoyl chloride and trimethylacetyl chloride;

[0214] PPh3 is triphenylphosphine;

[0215] PMB is a methoxybenzyl group;

[0216] The reagent alcohol is a mixture of 90% ethanol, 5% isopropanol and 5% methanol;

[0217] rt or RT is room temperature;

[0218] RBF is a round-bottom flask;

[0219] RuPhos Pd G1 is chloro-(2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II);

[0220] sat. means saturated;

[0221] SEM is [2-(trimethylsilyl)ethoxy]methyl;

[0222] SFC stands for supercritical fluid chromatography.

[0223] S N Ar is a nucleophilic aromatic substitution;

[0224] TBAB is tetrabutylammonium bromide;

[0225] TBAF is tetrabutylammonium fluoride;

[0226] TBS is tert-butyldimethylsilyl;

[0227] tBu is tert-butyl;

[0228] Tf is trifluoromethanesulfonyl;

[0229] TFA stands for trifluoroacetic acid;

[0230] THF stands for tetrahydrofuran;

[0231] THP stands for tetrahydropyran;

[0232] TLC is thin-layer chromatography;

[0233] TMAD stands for tetramethylazodicarbonamide;

[0234] TMS stands for trimethylsilyl;

[0235] TPAP stands for tetrapropylammonium perruthenate.

[0236] Ts is p-toluenesulfonyl group;

[0237] UPLC is ultra-high performance liquid chromatography;

[0238] Xantphos is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthanium.

[0239] definition

[0240] As used herein, the term “abnormal” means different from normal. When used to describe activity, abnormal refers to an activity that is greater than or less than the average value of a normal control or a normal non-pathological control sample. Abnormal activity may refer to an amount of activity that causes disease, wherein returning abnormal activity to a normal or non-disease-related amount (e.g., by administering a compound or using methods as described herein) results in a reduction of disease or one or more disease symptoms.

[0241] As used herein, the term "acyl" signifies a group -C(=O)-R, where R is an alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, or heterocyclic group. The acyl group may be optionally substituted, as described herein with respect to each corresponding R group.

[0242] As used herein, the term "adenocarcinoma" refers to a malignant tumor caused by glandular cells arranged along organs within an organism. Non-limiting examples of adenocarcinoma include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colorectal cancer.

[0243] As used herein, the term "alkanoyl" refers to a hydrogen or alkyl group attached to a parent molecule group via a carbonyl group, and is exemplified by a formyl group (i.e., a carboxylaldehyde group), an acetyl group, a propionyl group, a butyryl group, and an isobutyryl group. An unsubstituted alkanoyl group contains 1 to 7 carbons. As described herein with respect to alkyl groups, an alkanoyl group can be unsubstituted or substituted (e.g., optionally substituted C1-7 alkanoyl groups). The terminating "-oyl" can be added to another group defined herein, such as an aryl, cycloalkyl, and heterocyclic group, to define "aromatic acyl," "cycloalkanoyl," and "(heterocyclic)acyl." These groups represent carbonyl groups substituted with aryl, cycloalkyl, or heterocyclic groups, respectively. Each of "aromatic acyl," "cycloalkanoyl," and "(heterocyclic)acyl" can be optionally substituted, as defined herein with respect to "aryl," "cycloalkyl," or "heterocyclic."

[0244] As used herein, the term "alkenyl" refers to a non-cyclic monovalent straight-chain or branched hydrocarbon group containing one, two, or three carbon-carbon double bonds. Non-limiting examples of alkenyl groups include vinyl, propenyl, propenyl, 1-methylvinyl, butenyl, butenyl, butenyl, 3-methylpropenyl, 1-methylpropenyl, 2-methylpropenyl, and 1-methylpropenyl. Alkenyl groups may be optionally substituted as defined herein with respect to alkyl groups.

[0245] As used herein, the term "alkenyl" refers to a divalent alkenyl group. Optionally substituted alkenyl groups are those that have been optionally substituted as described herein with respect to alkenyl groups.

[0246] Unless otherwise specified, as used herein, the term "alkoxy" is expressed as a -OR chemical substituent, where R is C 1-6 Alkyl group. In some embodiments, the alkyl group may be further substituted as defined herein. The term “alkoxy” may be combined with other terms defined herein (e.g., aryl, cycloalkyl, or heterocyclic) to define “arylalkoxy,” “cycloalkylalkoxy,” and “(heterocyclic)alkoxy” groups. These groups respectively represent alkoxy groups substituted with aryl, cycloalkyl, or heterocyclic groups. Each of “arylalkoxy,” “cycloalkylalkoxy,” and “(heterocyclic)alkoxy” may be optionally substituted, as defined herein with respect to each individual part.

[0247] As used herein, the term "alkoxyalkyl" represents a -LOR chemical substituent, where L is C. 1-6 Alkylene, and R is C 1-6Alkyl. Optionally substituted alkoxyalkyl is an alkoxyalkyl that has been optionally substituted as described herein with respect to alkyl.

[0248] Unless otherwise specified, as used herein, the term "alkyl" refers to a non-cyclic straight-chain or branched saturated hydrocarbon group having 1 to 12 carbons when unsubstituted. In some preferred embodiments, the unsubstituted alkyl group has 1 to 6 carbons. Alkyl groups are exemplified by methyl; ethyl; n-propyl and isopropyl; n-butyl, sec-butyl, isobutyl and tert-butyl; neopentyl, etc., and may optionally (where the valence permits) be substituted by one, two, three, or, in the case of an alkyl group having two or more carbons, by four or more substituents independently selected from the group consisting of: amino; alkoxy; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; haloyl; heterocyclic; (heterocyclic)oxy; heteroaryl; hydroxyl; nitro; thiol; silyl; cyano; alkylsulfonyl; alkylsulfinyl; alkylsulfoxide; =O; =S; -C(O)R or -SO2R (where R is amino); and =NR' (where R' is H, alkyl, aryl or heterocyclic). Each of the substituents may be unsubstituted itself or (where the valence permits) substituted by an unsubstituted substituent as defined herein for each respective group.

[0249] As used herein, the term "alkylene" refers to a divalent alkyl group. Optionally substituted alkylene groups are alkylene groups that have been optionally substituted as described herein with respect to alkyl groups.

[0250] As used herein, the term "alkylamino" refers to an amino group having the formula -N(R N1 )2 or -NHR N1 The group, wherein R N1 It is an alkyl group, as defined herein. As defined with respect to alkyl, the alkyl moiety of an alkylamino group may be optionally substituted. Each optional substituent on a substituted alkylamino group may be unsubstituted itself or (where the valence allows) substituted with an unsubstituted substituent as defined herein with respect to each corresponding group.

[0251] As used herein, the term "alkylsulfonyl" denotes a group of the formula -S-(alkyl). As defined with respect to alkyl, the alkylsulfonyl group may be optionally substituted.

[0252] As used herein, the term "alkylsulfinyl" denotes a group of the formula -S(O)-(alkyl). As defined with respect to alkyl, the alkylsulfinyl group may be optionally substituted.

[0253] As used herein, the term "alkylsulfonyl" denotes a group of the formula -S(O)2-(alkyl). As defined with respect to alkyl, the alkylsulfonyl group may be optionally substituted.

[0254] As used herein, the term "alkynyl" means a monovalent straight-chain or branched hydrocarbon group containing two to six carbon atoms and having at least one carbon-carbon triple bond, and is exemplified by ethynyl, 1-propynyl, etc. As defined with respect to alkyl, alkynyl can be unsubstituted or substituted (e.g., optionally substituted alkynyl).

[0255] As used herein, the term "ethynyl" refers to a divalent ethynyl group. Optionally substituted ethynyl groups are ethynyl groups that have been optionally substituted as described herein with respect to ethynyl groups.

[0256] As used herein, the term "amino" signifies -N(R) N1 )2, where if the amino group is unsubstituted, then the two R groups are... N1 All are H; or, if the amino group is substituted, each R N1 Independently, it is H, -OH, -NO2, -N(R) N2 )2、-SO2OR N2 、-SO2R N2 -SOR N2 、-C(O)OR N2 The protected group is N, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, cycloalkyl, cycloalkenyl, heteroalkyl, or heterocyclic, provided that at least one R is present. N1 Not H, and each of the R's N2 Independently, it is H, alkyl, or aryl. Each of the substituents may be unsubstituted or substituted by an unsubstituted substituent as defined herein for each respective group. In some embodiments, the amino group is an unsubstituted amino group (i.e., -NH2) or a substituted amino group (e.g., -NHR). N1 ), where R N1 Independently -OH, SO2OR N2 、-SO2R N2 -SOR N2 -COOR N2 Optionally substituted alkyl or optionally substituted aryl, and each R N2 It can be an optionally substituted alkyl or optionally substituted aryl group. In some embodiments, the substituted amino group can be an alkylamino group, wherein the alkyl group is optionally substituted as described herein with respect to alkyl. In some embodiments, the amino group is -NHR. N1 , where R N1 It is an alkyl group that is optionally substituted.

[0257] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic carbocyclic system having one or two aromatic rings. An aryl group may contain 6 to 10 carbon atoms. All atoms within 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, indenyl, indenyl, etc. An aryl group 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; alkylsulfonyl; alkylsulfonyl; amino; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halogen; heteroalkyl; heterocyclic; (heterocyclic)oxy; hydroxyl; nitro; thiol; silyl; -(CH2) n -C(O)OR A -C(O)R; and -SO2R, where R is an amino or alkyl group, R A It is H or alkyl, and n is 0 or 1. Each of the substituents may be unsubstituted or substituted by an unsubstituted substituent as defined herein for each respective group.

[0258] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. The aryl and alkyl moiety may be optionally substituted as separate groups as described herein.

[0259] As used herein, the term "arylene" refers to a divalent aryl group. Optionally substituted arylene groups are arylene groups that have been optionally substituted as described herein with respect to aryl groups.

[0260] Unless otherwise specified, as used herein, the term "aryloxy group" is expressed as -OR chemical substituent, where R is an aryl group. In optionally substituted aryloxy groups, the aryl group is optionally substituted, as described herein with respect to the aryl group.

[0261] As used herein, the term "azido" refers to the -N3 group.

[0262] As used in this article, the term “cancer” refers to all types of cancer, growths, or malignant tumors found in mammals (e.g., humans).

[0263] As used herein, the term "carbocyclic" refers to an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure in which the ring, whether aromatic or non-aromatic, is formed from carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloynyl, and certain aryl groups.

[0264] As used herein, the term "carbonyl" refers to a -C(O)- group.

[0265] As used in this article, the term “cancer” refers to a malignant new growth consisting of epithelial cells that tend to infiltrate surrounding tissues and metastasize.

[0266] As used herein, the term "cyano" refers to the -CN group.

[0267] As used interchangeably in this document, "CCNE1" and "cyclin E1" refer to G1 / S-specific cyclin E1 (gene name: CCNE1). Cells overexpressing CCNE1 exhibit higher CCNE1 activity than cells that normally express CCNE1. For example, CCNE1-overexpressing cells are those exhibiting at least three copies compared to diploid normal cells with two copies. Therefore, cells exhibiting more than three copies of CCNE1 are CCNE1-overexpressing cells. CCNE1 overexpression can be measured by identifying the expression levels of gene products in cells (e.g., CCNE1 mRNA transcript count or CCNE1 protein level).

[0268] Unless otherwise specified, as used herein, the term "cycloalkenyl" refers to a non-aromatic carbocyclic group having at least one intracyclic double bond and three to ten carbons (e.g., C10, C20, C30, C40, C50, C60, C7 ...60, C60, C60, C60, 3-10 (Cycloalkenyl). Non-limiting examples of cycloalkenyl include cyclopropenyl-1-enyl, cyclopropenyl-2-enyl, cyclobutenyl-1-enyl, cyclobutenyl-1-enyl, cyclobutenyl-2-enyl, cyclopentenyl-1-enyl, cyclopentenyl-2-enyl, cyclopentenyl-3-enyl, norbornenyl-1-enyl, norbornenyl-2-enyl, norbornenyl-5-enyl, and norbornenyl-7-enyl. As described with respect to cycloalkyl, the cycloalkenyl may be unsubstituted or substituted (e.g., optionally substituted cycloalkenyl).

[0269] As used herein, the term "cycloalkenylalkyl" refers to an alkyl group substituted with a cycloalkenyl group, each as defined herein. The cycloalkenyl and alkyl moieties may be substituted as separate groups as defined herein.

[0270] As used herein, the term "cycloene imide" refers to a divalent cycloene group. Optionally substituted cycloene imide groups are those that have been optionally substituted as described herein with respect to cycloalkyl groups.

[0271] Unless otherwise specified, as used herein, the term "cycloalkoxy" is expressed as -OR chemical substituent, where R is a cycloalkyl group. In some embodiments, the cycloalkyl group may be further substituted as defined herein.

[0272] Unless otherwise specified, as used herein, the term "cycloalkyl" refers to a cycloalkyl group having three to ten carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 3-C10Cycloalkyl groups. Cycloalkyl groups can be monocyclic or bicyclic. Bicyclic cycloalkyl groups can be of the bicyclic [pq0]alkyl type, wherein each of p and q is independently 1, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 2, 3, 4, 5, 6, 7, or 8. Alternatively, bicyclic cycloalkyl groups can include bridged cycloalkyl structures, such as bicyclic [pqr]alkyl groups, wherein r is 1, 2, or 3, and each of p and q is independently 1, 2, 3, 4, 5, or 6, provided that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. Cycloalkyl groups can be spirocyclic, such as spiro[pq]alkyl groups, wherein 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 groups 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 decahydronaphthyl. Cycloalkyl groups may be unsubstituted or substituted by one, two, three, four, or five independently selected substituents from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfonyl; alkylsulfonyl; amino; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; haloyl; heteroalkyl; heterocyclic; (heterocyclic)oxy; heteroaryl; hydroxyl; nitro; thiol; silyl; cyano; =O; =S; -SO2R (where R is an optionally substituted amino); =NR' (where R' is H, alkyl, aryl, or heterocyclic); and -CON(R A )2 (where each R A It is independently H or alkyl, or two Rs A Together with the atoms to which they are attached, they combine to form a heterocyclic group. Each of the substituents may be unsubstituted or substituted by an unsubstituted substituent as defined herein for each corresponding group.

[0273] As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl moiety may be optionally substituted as separate groups as described herein.

[0274] As used herein, the term "cycloalkylene" refers to a divalent cycloalkyl group. Optionally substituted cycloalkylene groups are cyclic alkylene groups that have been optionally substituted as described herein with respect to cycloalkyl groups.

[0275] Unless otherwise specified, as used herein, the term "cycloynyl" refers to a monovalent carbon cyclic group having one or two carbon-carbon triple bonds and having eight to twelve carbons. A cycloynyl group may contain a transcyclic bond or bridge. Non-limiting examples of cycloynyl groups include cyclooctyynyl, cyclononyynyl, cyclodecynyl, and cyclodecadiynyl. As defined with respect to cycloalkyl groups, a cycloynyl group may be unsubstituted or substituted (e.g., optionally substituted cycloynyl groups).

[0276] "Disease" or "symptom" refers to the state or health condition of a patient or subject who can be treated with the compounds or methods provided herein.

[0277] As used herein, the term “FBXW7” refers to a protein 7 gene, transcript, or protein containing an F-box / WD repeat sequence. A gene with a mutation in FBXW7 (also described herein as an FBXW7 gene with an inactivating mutation) is a gene that cannot produce functional FBXW7 protein in cells or produces a reduced amount of FBXW7 protein.

[0278] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, and fluorine.

[0279] As used herein, the term "heteroalkyl" refers to an alkyl, alkenyl, or ynyl group that is interrupted once by one or two heteroatoms; interrupted twice independently by one or two heteroatoms each time; interrupted three times independently by one or two heteroatoms each time; or interrupted four times independently by one or two heteroatoms each time. Each heteroatom is independently O, N, or S. In some embodiments, the heteroatom is O or N. None of the heteroalkyl groups contain two consecutive oxygen or fluorine atoms. The heteroalkyl group can be unsubstituted or substituted (e.g., optionally substituted heteroalkyl groups). When a heteroalkyl group is substituted and a substituent is bonded to a heteroatom, the substituent is selected based on the nature and valence of the heteroatom. Therefore, the substituents bonded to the heteroatom (where the valence allows) are selected from the group consisting of: =O, -N(R N2 )2、-SO2OR N3 、-SO2R N2 -SOR N3 -COOR N3 ,N protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclic or cyano, wherein each R N2 Independently, it is H, alkyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, or heterocyclic, and each R N3Independently, these are alkyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, or heterocyclic groups. Each of these substituents may be unsubstituted itself or substituted by an unsubstituted substituent as defined herein for each respective group. When a heteroalkyl group is substituted and the substituent is bonded to a carbon atom, the substituent is selected from those substituents described for the alkyl group, provided that the substituent bonded to the carbon atom of the heteroatom is not Cl, Br, or I. It should be understood that the carbon atom is found at the end of the heteroalkyl group.

[0280] As used herein, the term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl moieties may be optionally substituted as separate groups as described herein.

[0281] As used herein, the term "hybrid aryl" refers to a divalent heteroaryl. Optionally substituted heteroaryl is a heteroaryl that has been optionally substituted as described herein with respect to heteroaryl.

[0282] As used herein, the term "heteroaryloxy group" refers to the structure -OR, where R is a heteroaryl group. As defined for heterocyclic groups, the heteroaryloxy group may be optionally substituted.

[0283] As used herein, the term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic, or tetracyclic system having fused, bridged, and / or spirocyclic 3-, 4-, 5-, 6-, 7-, or 8-membered rings, which, unless otherwise specified, contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a "heterocyclic group" is a monocyclic, bicyclic, tricyclic, or tetracyclic system having fused or bridged 5-, 6-, 7-, or 8-membered rings, which, unless otherwise specified, contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclic groups can be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclic groups have zero or one double bond, non-aromatic 6- and 7-membered heterocyclic groups have zero to two double bonds, and non-aromatic 8-membered heterocyclic groups have zero to two double bonds and / or zero or one carbon-carbon triple bond. Unless otherwise specified, heterocyclic groups contain 1 to 16 carbon atoms. Some heterocyclic groups can contain up to nine carbon atoms. Non-aromatic heterocyclic groups include pyrrolinyl, pyrrolylalkyl, pyrazolinyl, pyrazolylalkyl, imidazolinyl, imidazolinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, thiomorpholinyl, thiazolinyl, isothiazolyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, dihydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyranyl, dihydropyranyl, dithiazolinyl, etc. If a heterocyclic system has at least one aromatic resonance structure or at least one aromatic tautomer, then this structure is an aromatic heterocyclic group (i.e., a heteroaryl). Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophene, benzooxazolyl, furanyl, imidazolyl, indolyl, isoinzolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purine, pyrrole, pyridinyl, pyrazinyl, pyrimidinyl, quinazolinyl, quinolinyl, thiadiazolyl (e.g., 1,3,4-thiadiazolyl), thiazolyl, thiophene, triazolyl, tetrazolyl, etc. The term "heterocyclic group" also refers to heterocyclic compounds having a bridged polycyclic structure in which one or more carbon atoms and / or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as quinuclidine, tropane, or diazabicyclo[2.2.2]octane. The term "heterocyclic group" includes bicyclic, tricyclic, and tetracyclic groups, wherein any of the aforementioned heterocycles is fused to one, two, or three carbon rings, such as aromatic rings, cyclohexane rings, cyclohexene rings, cyclopentane rings, cyclopentene rings, or other monocyclic heterocycles. Examples of fused heterocyclic groups include 1,2,3,5,8,8a-hexahydroindoleazine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene.Heterocyclic groups can be unsubstituted or substituted by one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfonyl; alkylsulfonyl; amino; aryl; aryloxy; azide; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; haloyl; heteroalkyl; heterocyclic; (heterocyclic)oxy; hydroxyl; nitro; thiol; silyl; cyano; -C(O)R or -SO2R (where R is amino or alkyl); =O; =S; =NR' (where R' is H, alkyl, aryl, or heterocyclic). Each of the substituents can be unsubstituted itself or substituted by an unsubstituted substituent as defined herein for each corresponding group.

[0284] As used herein, the term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, each as defined herein. The heterocyclic and alkyl moieties may be optionally substituted as separate groups as described herein.

[0285] As used herein, the term "subheterocyclic group" refers to a divalent heterocyclic group. Optionally substituted subheterocyclic groups are optionally substituted subheterocyclic groups as described herein with respect to heterocyclic groups.

[0286] Unless otherwise specified, as used herein, the term "(heterocyclic)oxy group" is expressed as -OR chemical substituent, where R is a heterocyclic group. The (heterocyclic)oxy group may optionally be substituted in the manner described for the heterocyclic group.

[0287] As used interchangeably in this document, the term "hydroxyl (hydroxyl and hydroxy)" refers to the -OH group.

[0288] As used herein, the term "isotopically enriched" refers to a pharmaceutically active agent in which the isotopic abundance of an isotope at a predetermined position within the molecule is at least 100 times greater than the natural abundance of that isotope. For example, a composition enriched with deuterium contains an active agent in which the abundance of deuterium at at least one hydrogen atom position is at least 100 times greater than the natural abundance of deuterium. Preferably, the deuterium enrichment is at least 1000 times greater than the natural abundance of deuterium. More preferably, the deuterium enrichment is at least 4000 times greater than the natural abundance of deuterium (e.g., at least 4750 times greater, e.g., up to 5000 times greater).

[0289] As used herein, the term “leukemia” broadly refers to a progressive malignant disease of the hematopoietic organs and is typically characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is usually classified clinically based on (1) the duration and characteristics of the disease—acute or chronic; (2) the cell type involved; bone marrow (myelopathic), lymphoid (lymphoid), or monocytic; and (3) an increase or non-increase in the number of abnormal cells in the blood—leukemic or non-leukemic (subleukemic).

[0290] As used in this article, the term "lymphoma" refers to cancer caused by immune-originating cells.

[0291] As used in this article, the term "melanoma" refers to a tumor caused by the melanocyte system of the skin and other organs.

[0292] As used in this article, the term "Myt1" refers to membrane-associated tyrosine and threonine-specific cdc2 inhibitory kinase (Myt1) (gene name PKMYT1).

[0293] As used herein, the term "Myt1 inhibitor" refers to the reduction of Myt1 activity upon contact with the enzyme Myt1, whether in vitro, in cell culture, or in vivo, to achieve a measured Myt1 IC50. 50 It is a compound with a concentration of 10 μM or less (e.g., 5 μM or less, or 1 μM or less). For some Myt1 inhibitors, the Myt1 IC50 value is... 50 It can be 100 nm or smaller (e.g., 10 nm or smaller or 3 nm or smaller) and can be as low as 100 pM or 10 pM. Preferably, Myt1 IC 50 It 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, Myt1 IC 50 Less than 20 nm (e.g., 1 nM to 20 nM).

[0294] As used in this article, the term "nitro" refers to the -NO2 group.

[0295] As used herein, the term "oxo" refers to a divalent oxygen atom (e.g., an oxo structure can be represented as =O).

[0296] As used in this article, the term "Ph" refers to phenyl.

[0297] As used herein, the term "pharmaceutical composition" means a composition containing the compounds described herein formulated together with pharmaceutically acceptable excipients and manufactured or marketed with the approval of a government regulatory agency as part of a treatment regimen for treating a disease in mammals. Pharmaceutical compositions may be formulated, for example, for oral administration in unit dosage forms (e.g., tablets, capsules, lozenges, gelcapsules, or syrups); for topical administration (e.g., as creams, gels, lotions, or ointments); for intravenous administration (e.g., as a sterile solution in a particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation form described herein.

[0298] As used interchangeably herein, the terms "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable carrier" refer to any component other than the compounds described herein that has non-toxic and non-inflammatory properties in a patient (e.g., a medium capable of suspending or dissolving an active compound). Excipients may include, for example: anti-adhesives, antioxidants, adhesives, coatings, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, flow enhancers (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or bound water. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dialkali), calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium carboxyacetic acid starch, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0299] As used herein, the term "pharmaceutically acceptable salt" means that salt is suitable for use in contact with tissues in humans and animals without excessive toxicity, irritation, anaphylactic reactions, etc., and in proportion to a reasonable benefit / risk ratio, within the bounds of reasonable medical judgment. 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, (edited by P.H. Stahl and C. G. Germuth), Wiley-VCH, 2008. The salts may be prepared in situ during the final isolation and purification of the compounds described herein, or individually by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, gluconate, glyceryl phosphate, hemisulfate, heptaate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0300] As used in this article, the term "precancerous lesion" or "precancerous" refers to a non-malignant condition that has the potential to become malignant.

[0301] As used herein, the term "protecting group" refers to a group intended to protect a hydroxyl, amino, or carbonyl group during chemical synthesis from participating in one or more undesirable reactions. As used herein, the term "O-protecting group" refers to a group intended to protect a hydroxyl or carbonyl group during chemical synthesis from participating in one or more undesirable reactions. As used herein, the term "N-protecting group" refers to a group intended to protect a nitrogen-containing (e.g., amino, amide, heterocyclic NH, or hydrazine) group during chemical synthesis from participating in one or more undesirable reactions. Commonly used O-protecting 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-protecting groups and N-protecting groups include alkyl, aromatic, or carbamoyl groups, such as formyl, acetyl, propionyl, neopentyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, tert-butyldimethylsilyl, triisopropylsilyloxymethyl, 4,4'-dimethoxytriphenylmethyl, isobutyryl, phenoxyacetyl, 4-isopropylphenoxyacetyl, dimethylformamidinyl, and 4-nitrobenzoyl.

[0302] Exemplary O-protecting groups for protecting carbonyl groups include, but are not limited to: acetal, acylal, 1,3-dithiane, 1,3-dioxane, 1,3-dioxotropane, and 1,3-dithiatropane.

[0303] Other O-protecting groups include, but are not limited to: substituted alkyl, aryl, and arylalkyl ethers (e.g., triphenylmethyl ether; methylthiomethyl ether; methoxymethyl ether; benzyloxymethyl ether; silaneoxymethyl ether; 2,2,2-trichloroethoxymethyl ether; tetrahydropyranyl ether; tetrahydrofuranyl ether; ethoxyethyl ether; 1-[2-(trimethylsilyl)ethoxy]ethyl ether; 2-trimethylsilylethyl ether; tert-butyl ether; p-chlorophenyl ether, p-methoxyphenyl ether, p-nitrophenyl ether, benzyl ether, p-methoxybenzyl ether, and nitrobenzyl ether); silyl ethers (e.g., trimethylsilyl ether; triethylsilyl ether; triisopropylsilyl ether; dimethylisopropylsilyl ether; tert-butyldimethylsilyl ether; tert-butyldiphenylsilyl ether; tribenzylsilyl ether; triphenylsilyl ether and diphenylmethylsilyl ether); carbonates (e.g., methyl esters, methoxymethyl esters, 9-fluorenylmethyl esters; ethyl esters; 2,2,2-trichloroethyl esters; 2-(trimethylsilyl)ethyl esters; vinyl esters, allyl esters, nitrobenzene esters, benzyl esters; methoxybenzyl esters; 3,4-dimethoxybenzyl esters; and nitrobenzyl esters).

[0304] Other N-protecting groups include, but are not limited to, chiral auxiliaries, such as protected or unprotected D, L, or D,L-amino acids, such as alanine, leucine, phenylalanine, etc.; sulfonyl groups, such as benzylsulfonyl, p-toluenesulfonyl, etc.; and groups that form carbamates, 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-biphenyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, and benzyloxycarbonyl (benzhydryloxy) Carbonyl groups, such as tert-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentoxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, etc.; arylalkyl groups, such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, benzyloxymethyl, etc.; silylalkyl acetal groups, such as [2-(trimethylsilyl)ethoxy]methyl; and silyl groups, such as trimethylsilyl, etc. Available N-protecting groups are formyl, acetyl, benzoyl, neopentyl, tert-butylacetyl, alanyl, benzyl, dimethoxybenzyl, [2-(trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), tert-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0305] The term "tautomer" refers to structural isomers that are readily interchangeable through proton migration. Tautomers are different chemical species that can be identified by different spectral characteristics, but are usually not separable individually. Non-limiting examples of tautomers include keto-enols, enamine-imines, amide-imines, nitroso-oximes, enone-alkynols, and amino acid-ammonium formates.

[0306] The term "sarcoma" generally refers to a tumor composed of a substance similar to embryonic connective tissue and typically consists of tightly packed cells embedded in fibrous or isomorphic material.

[0307] As used herein, the term "subject" means a human or non-human animal (e.g., a mammal) that is determined by a qualified professional (e.g., a physician or nursing practitioner) to have or be at risk of having a disease or condition, with or without laboratory testing known in the art on samples from the subject. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases in which the symptom is excessive cell proliferation, such as cancer.

[0308] As used herein, “treatment” refers to the medical management of a subject aimed at improving, ameliorhyming, stabilizing, preventing, or curing a disease or symptom. This term includes active treatment (treatment involving the improvement of a disease or symptom); etiological treatment (treatment involving the cause of a related disease or symptom); palliative treatment (treatment designed to relieve symptoms of a disease or symptom); preventive treatment (treatment involving minimizing or partially or completely suppressing the development of a related disease or symptom); and supportive treatment (treatment used to complement another therapy). Attached Figure Description

[0309] Figure 1A The bar chart shows CCNE1 amplification / overexpression in tumors sequenced by TCGA PanCancer Atlas.

[0310] Figure 1B This is a scatter plot showing CCNE1 gene expression data from the TCGA PanCancer Atlas.

[0311] Figure 2A The bar chart shows FBXW7 mutations in tumors sequenced by TCGA PanCancer Atlas.

[0312] Figure 2B This is a lollipop plot showing the frequency of FBXW7 mutations in the gene. The plot highlights three common arginine hotspot mutations (R465, R479, and R505) within the third and fourth WD40 repeat sequences, which disrupt the recognition of cyclin E1 substrates and are classified as harmful.

[0313] Figure 3A The bar chart shows the proliferation assay results of RPE1-hTERT Cas9TP53- / - and CCNE1 overexpression clones treated with different doses of compound A.

[0314] Figure 3BThis is a series of images illustrating the results of a colony-forming survival assay using RPE1-hTERT Cas9TP53- / - and CCNE1-overexpressing clones transduced with PKMYT1 sgRNA. Infected cells were seeded at low density to measure their ability to form colonies of >50 cells. After 10 days of growth, the colonies were stained, imaged, and quantified. The results were normalized to the survival rates of RPE1-hTERT Cas9TP53- / - parental clones and CCNE1-overexpressing clones transduced with non-targeted LacZ control sgRNA.

[0315] Figure 3C The graph is a line graph showing the proliferation assay results of RPE1-hTERT Cas9TP54- / - and CCNE1 overexpression clones treated with different doses of compound A.

[0316] Figure 4A This is a bar chart showing the effects of using FT282-hTERT TP53 transduced with PKMYT1 sgRNA. R175H Results of colony formation survival assays for CCNE1-overexpressing cells. Infected cells were seeded at low density to measure their ability to form colonies of >50 cells. After 10 days of growth, the colonies were stained, imaged, and quantified. Results were normalized to FT282-hTERT TP53 transduced with AAVS1 control sgRNA. R175H Survival rate of CCNE1-overexpressing cells.

[0317] Figure 4B It is a series of images that show Figure 4A The stained colonies described in the text.

[0318] Figure 4C This is a line graph showing FT282-hTERT TP53 treated with different doses of compound A. R175H Proliferation assay results of CCNE1 overexpression clones.

[0319] Figure 5A , Figure 5B and Figure 5CResults of a colony-forming survival assay for stable RPE1-hTERT Cas9 TP53- / - parental and CCNE1-overexpressing clones expressing wild-type or catalytic death FLAG-labeled PKMYT1 sgRNA resistance ORFs are presented. These stable cell lines were transduced with LacZ-untargeted sgRNA or PKMYT1 sgRNA #4 and seeded at low density to measure their ability to form colonies of >50 cells. After 10 days of growth, the colonies were stained, imaged, and quantified. Results were normalized to the survival rate of RPE1-hTERT Cas9 TP53- / - CCNE1-overexpressing clones transduced with untargeted LacZ control sgRNA and... Figure 5C The results are represented as a bar chart. In this study, clone 2 and clone 21 showed similar performance.

[0320] Figure 6 The graph shows the proliferation assay results of a group of CCNE1 wild-type and CCNE1-amplified / overexpressing cancer cell lines treated with different doses of compound B. The IC50 values ​​for each cell line are plotted. 50 The values ​​showed that, compared with the CCNE1 WT cell line, the CCNE1 overexpressing cell line exhibited enhanced sensitivity to Myt1 inhibitors.

[0321] Figure 7 The graph shows the proliferation assay results of a group of FBXW7 wild-type and FBXW7 mutant cancer cell lines treated with different doses of compound C. IC50 values ​​for each cell line are plotted, and it is shown that the FBXW7 mutant cell lines exhibit enhanced sensitivity to Myt1 inhibitors compared to the FBXW7 WT cell line. Detailed Implementation

[0322] Generally, this invention provides compounds, pharmaceutical compositions containing the same, methods for preparing the compounds, and methods of using them. The compounds of this invention can be Myt1 inhibitors. These compounds can be used to inhibit Myt1 in cells (e.g., cells of a subject (e.g., cells overexpressing CCNE1 or having an inactivating mutation in the FBXW7 gene)). The subject may need treatment for a disease or condition, such as a disease or condition with symptoms of excessive cell proliferation, such as cancer. The Myt1 inhibitory activity of the compounds disclosed herein can be used to treat subjects who require cancer treatment.

[0323] Myt1 is a cell cycle-regulated kinase primarily located in the endoplasmic reticulum and Golgi complex. It is part of the Wee kinase family, which includes Wee1 and Wee1b. It participates in the negative regulation of the CDK1-cyclin B complex, which promotes cell progression from G2 phase to the mitotic phase (M phase) of the cell cycle. During DNA damage, Myt1, along with Wee1 (which mediates only Tyr15 phosphorylation), drives phosphorylation on both Tyr15 and Thr14 of CDK1, thereby maintaining the kinase complex in an inactive state in G2 as part of the G2 checkpoint response and preventing entry into mitosis until the damage is repaired. Furthermore, it has been proposed that Myt1 interact directly with the CDK1 complex in the cytoplasm and prevent their nuclear translocation, thereby inhibiting cell cycle progression.

[0324] Myt1 is considered a potentially important cancer target because it is essential in many cancer cells. Overexpression of Myt1 has been observed in various cancers, including hepatocellular carcinoma and clear cell renal cell carcinoma. Downregulation of Myt1 plays a minor role in undisturbed cells but a more prominent role in cells exposed to DNA damage. Furthermore, in addition to defective G1 checkpoint regulation, cells exhibiting high levels of replication stress may be particularly sensitive to loss of Myt1 function, as these cells are prone to premature mitosis, genomic material damage, and ultimately, mitotic failure.

[0325] Inhibitors of Myt1 are regulators of the G2-M transition and may be particularly useful in treating tumors with CCNE1 amplification or FBXW7 loss-of-function mutations using synthetic lethal therapy strategies.

[0326] Cyclin E1 (encoded by the CCNE1 gene) is involved in the cell cycle transition from G1 to S phase. In late G1 phase, it complexes with cyclin-dependent kinase 2 (CDK2) to promote E2F transcription factor activation and entry into S phase. Cyclin E1 levels are tightly regulated during the normal cell cycle, accumulating during the G1 / S transition and being completely degraded at the end of S phase. Cycle-dependent proteasome degradation of cyclin E1 is facilitated by SCF. FBW7 The ubiquitin ligase complex mediates the transition to S phase. Once activated in late G1, the cyclin E1 / CDK2 complex promotes the transition to S phase via phosphorylation and inactivation of RB1 and subsequent release of E2F transcription factors. S phase is promoted by E2F-mediated transcription of multiple genes involved in DNA replication, including the pre-replication complex subunits ORC1, CDC6, CDT1, and MCM helicase factors.

[0327] CCNE1 is frequently amplified and / or overexpressed in human cancers (Figure 1). CCNE1 amplification has been reported in several cancer types, including endometrial cancer, ovarian cancer, breast cancer, and gastric cancer, with frequencies ranging from 5% to 40%. Importantly, numerous studies have confirmed that cyclin E1 is a driver of tumorigenesis in these indications, and CCNE1 amplification has been observed in more aggressive subtypes, including uterine carcinosarcoma (UCS; approximately 40%), uterine serous carcinoma (USC; approximately 25%), high-grade serous ovarian cancer (HGSOC; approximately 25%), and triple-negative breast cancer (TNBC; approximately 8%). Patients with evidence of cyclin E1 overexpression in tumor biopsies, as shown by immunohistochemical and / or genomic copy number analysis, have lower overall survival compared to patients with normal cyclin E1 levels. HGSOC patients with cyclin E1 overexpression have lower response rates to cisplatin (the current standard of care).

[0328] SCF FBW7 The proteolysis of cyclin E1-deficient cell cycle regulation by the ubiquitin ligase complex is another mechanism of CCNE1 overexpression observed in tumors. The F-box protein gene FBXW7 is frequently mutated in several cancer types, including endometrial, colorectal, and gastric cancer, with frequencies ranging from 5% to 35% (Figure 2). Similar to CCNE1, FBXW7-driven mutations are observed in more aggressive endometrial cancer subtypes, including UCS (approximately 35%) and USC (approximately 25%). FBXW7 exhibits a diverse loss-of-function mutation spectrum in cancer, including truncation mutations throughout the gene and missense mutations within cyclin E1 that recognize the WD40 repeat sequence. FBW7 functions as a homodimer within the SCF complex, and many of the noxious missense mutations within the WD40 repeat sequence are mostly heterozygous and dominant-negative. Notably, several recurring hotspot missense mutations were found in the WD40 repeat sequence, including R465, R479, and R505—all of which disrupt cyclin E1 binding and ubiquitination.

[0329] Overexpression of cyclin E1 and / or loss of FBXW7 function are thought to drive tumorigenesis by inducing genomic instability, such as increased origin activation, defective nucleotide libraries, transcriptional-replication conflicts, and / or fork instability. Cyclin E1 overexpression has been shown to induce replication stress, characterized by slowed or arrested replication forks and loss of heterozygosity at vulnerable sites. The primary mechanism by which cyclin E1 overexpression induces replication stress is increased origin activation in early S phase, followed by depletion of replication factors, including nucleotide libraries. The overall reduction in replication proteins and nucleotides slows fork progression and leads to arrest and subsequent collapse or reversal.

[0330] The compounds of the present invention may be, for example, compounds of formula (I):

[0331]

[0332] Or its pharmaceutically acceptable salt.

[0333] in

[0334] R 1 yes:

[0335]

[0336] n is 0, 1, or 2;

[0337] R 2 and R 3 Each is independently hydrogen, halogen, or optionally substituted C. 3-4 cycloalkyl or optionally substituted C 1-6 alkyl;

[0338] Each R 4 It is a halogen on its own;

[0339] R 5 It is hydrogen, halogen, hydroxyl, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 alkoxy, or -N(R) 5A )2;

[0340] Each R 5A Independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C3-8 cycloalkyl;

[0341] R 6 It is -C(O)NH(R) 6A -SO2R 6B , or -C(O)R 6C ;

[0342] R 6A It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, or optionally substituted C 1-9 Mixed aromatics;

[0343] R 6B It is an optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, or -NH(R) 6A );

[0344] R 6C It is an optional substituted C1-6 alkyl group;

[0345] A 1 and A 2 Each is either N or C independently;

[0346] R 7 It is a non-existent, hydrogen, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, or -OR 10 ;R 8 It is hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-8 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Mixed aromatics, -OR 10 、-N(R 11 )2, or -LR 8A ; or R 7 and R 8 The atoms they are attached to combine to form optionally substituted C atoms. 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, or optionally substituted C 2-12 heteroaryl; and R 9 It is a non-existent, hydrogen, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or -OR 10 ;

[0347] or

[0348] R 8 It is hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-8 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Mixed aromatics, -OR 10 、-N(R 11 )2, or -LR 8A ; and R 9 It is a non-existent, hydrogen, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, or -OR 10 ; or R 8 and R 9 The atoms they are attached to combine to form optionally substituted C atoms. 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, or optionally substituted C 1-12 heteroaryl; and R 7 It is a non-existent, hydrogen, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl or -OR 10 ;

[0349] L is an optional substitution of C 2-9 Heterocyclic groups, optionally substituted C 2-9 Heteroaryl, optionally substituted C 6-10 Aromatic, or optionally substituted C 3-8 Cycloalkylene;

[0350] R 8A It is hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, optionally substituted C 1-9 Mixed aromatics, -OR 10 or -N(R) 11 )2.

[0351] R 10 It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl or optionally substituted C 1-9 Mixed aromatics;

[0352] Each R 11 Independently hydrogen, halogen, or optionally substituted C 1-6 Alkyl, optionally substituted acyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, or optionally substituted C 1-9 heteroaryl, -SO2R 11A , or two R 11 The groups combine to form optionally substituted C2-9 heterocyclic groups; and

[0353] Each R 11A Independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 3-8Cycloalkenyl, optionally substituted C 2-9 Heterocyclic groups, optionally substituted C 6-10 aryl, or optionally substituted C 1-9 Mixed aromatic compounds.

[0354] The compounds of the present invention may be, for example, the compounds listed in Table 1 below or their pharmaceutically acceptable salts.

[0355] Table 1

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430] This invention includes (where possible) individual diastereomers, enantiomers, epiomers, and transisomers of the compounds disclosed herein, as well as mixtures of their diastereomers and / or enantiomers, including racemic mixtures. While the specific stereochemistry disclosed herein is preferred, other stereoisomers, including diastereomers, enantiomers, epiomers, transisomers, and mixtures thereof, may also be used to treat Myt1-mediated diseases. Inactive or less active diastereomers and enantiomers may be used, for example, in scientific research related to receptors and activation mechanisms.

[0431] It should be understood that some molecules can exist in multiple tautomer forms. Although only one tautomer may be indicated in the examples, the present invention includes all tautomers.

[0432] The present invention also includes pharmaceutically acceptable salts of the compounds and pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers. The compounds are particularly useful for, for example, certain types of cancer and for slowing the progression of cancer when it develops in a patient.

[0433] The compounds disclosed herein can be used in pharmaceutical compositions comprising (a) one or more compounds or pharmaceutically acceptable salts thereof and (b) a pharmaceutically acceptable carrier. The compounds can be used in pharmaceutical compositions comprising one or more other active pharmaceutical ingredients. The compounds can also be used in pharmaceutical compositions in which the compounds disclosed herein or pharmaceutically acceptable salts thereof are the sole active ingredient.

[0434] Optical isomers - diastereomers - geometric isomers - tautomers

[0435] The compounds disclosed herein may contain, for example, one or more stereoisomeric source centers and may exist as racemates, racemic mixtures, single enantiomers, single diastereomers, and mixtures of diastereomers and / or enantiomers. This invention includes all such isomeric forms of the compounds disclosed herein. It is intended that all possible stereoisomers (e.g., enantiomers and / or diastereomers) of the compounds, whether in mixture form or as pure or partially purified compounds, be included within the scope of this invention (i.e., all possible combinations of stereoisomeric source centers, either as pure compounds or in mixture form).

[0436] Some of the compounds described herein may contain rotationally hindered bonds, allowing two separate rotational isomers or trans-isomers to be isolated and found to have potentially advantageous different biological activities. It is intended that all possible trans-isomers be included within the scope of this invention.

[0437] Some of the compounds described herein may contain olefinic double bonds, and unless otherwise specified, both E and Z geometric isomers are intended to be included.

[0438] Some of the compounds described herein can exist at different hydrogen attachment sites, referred to as tautomers. Examples include ketones and their enol forms, referred to as keto-enol tautomers. Individual tautomers and mixtures thereof are covered by this invention.

[0439] The compounds disclosed herein that have one or more asymmetric centers can be isolated into diastereomers, enantiomers, etc., by methods well known in the art.

[0440] Alternatively, enantiomers and other compounds with chiral centers can be synthesized by stereotactic synthesis using optically pure starting materials and / or reagents with known configurations.

[0441] Metabolites – Prodrugs

[0442] This invention includes therapeutically active metabolites, wherein the metabolites themselves fall within the scope of the claims. This invention also includes prodrugs, which are compounds converted into the claimed compound when or after being administered to a patient. In some cases, the claimed chemical structure of this application may itself be a prodrug.

[0443] Isotope-enriched derivatives

[0444] This invention includes molecules enriched with isotopes at one or more sites within the molecule. Therefore, compounds enriched with deuterium fall within the scope of the claims.

[0445] Method for preparing the compounds of the present invention

[0446] The compounds of the present invention can be prepared using reactions and techniques known in the art, as well as those described herein. Those skilled in the art will understand that the methods for preparing the compounds of the present invention described herein are non-limiting, and that the steps within the methods can be interchanged without affecting the structure of the final product.

[0447] Method A

[0448] The compounds of the present invention can be prepared as shown in Scheme A and described herein. Known 8-bromoquinoline-7-amine can be converted to 7-aminoquinoline-8-carboxynitrile in the presence of copper cyanide, which can then be converted to intermediate A by bromination with NBS. Intermediate A can be arylated via a metal-mediated step, followed by nitrile hydrolysis to provide the compounds of the present invention. Depending on the nature of the Ar group, a protecting group may be required prior to the cross-coupling step. In the case where the Ar group is protected, a deprotection step may be required before nitrile hydrolysis using an acid, base, and / or fluoride to obtain the compounds of the present invention.

[0449] Plan A

[0450]

[0451] Method B

[0452] The compounds of the present invention can be prepared as shown in Scheme B and described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidin-4-carboxylate and (5-(methoxymethoxy)-2-methylphenyl)boronic acid can be cross-coupled using a metal-mediated step to provide intermediate B, which can be converted to intermediate C via a two-step sequence of hydrolysis and amide formation or via a one-step transamidation with ammonia. Intermediate C can be arylated using a metal-mediated cross-coupling step, and subsequently deprotected under acidic conditions to obtain the compounds of the present invention.

[0453] Option B

[0454]

[0455] Method C

[0456] The compounds of the present invention can be prepared as shown in Scheme C and described herein. Commercially available 3-amino-6-chloropyridinecarboxylic acid can be esterified by treatment with a base (such as potassium carbonate and ethyl iodide) to provide ethyl 3-amino-6-chloropyridinecarboxylic acid, which can be brominated with NBS to provide intermediate D. This intermediate can be converted to intermediate E via a two-step sequence comprising a metal-mediated arylation followed by a transamidation reaction using ammonia. Intermediate E can be arylated using a second metal-mediated cross-coupling step, and subsequent deprotection with boron tribromide yields the compounds of the present invention. Depending on the nature of the aryl group cross-coupled with intermediate E, a mixture of trans-isomers can be obtained. In such cases, it may be necessary to isolate the trans-isomers of interest to obtain the compounds of the present invention.

[0457] Plan C

[0458]

[0459] Method D

[0460] The compounds of the present invention can be prepared as shown in Scheme D and described herein. Intermediate E can be arylated using a metal-mediated cross-coupling step, followed by oxidation of the furan ring to give intermediate F. This intermediate can be deprotected with boron tribromide and converted to an amide using an aromatic amine and amide bond-forming agent to provide the compounds of the present invention.

[0461] Plan D

[0462]

[0463] Method E

[0464] The compounds of the present invention can be prepared as shown in Scheme E and described herein. Intermediate D can be arylated using a metal-mediated cross-coupling step with substituents indazole-4-boronic acid. The resulting ester can be converted to a primary amide by treatment with ammonia, and then arylated using metal-mediated coupling to obtain the compounds of the present invention. Depending on the nature of the substituents on the indazole group, a mixture of trans-isomers can be obtained. In such cases, it may be necessary to isolate the trans-isomers of interest to obtain the compounds of the present invention.

[0465] Option E

[0466]

[0467] Method F

[0468] The compounds of the present invention can be prepared as shown in Scheme F and described herein. Commercially available kynurenyl quinoline ester can be esterified in acidic methanol solution, followed by chlorination with NCS to methyl 3-chlorokynurenyl quinoline ester. This ester can be converted to trifluoromethanesulfonate, which can then be cross-coupled with boric acid via a metal-mediated step, followed by transamidation to provide the compounds of the present invention. In the case of a protecting Ar group, a deprotection step may be required to obtain the compounds of the present invention.

[0469] Option F

[0470]

[0471] Method G

[0472] The compounds of the present invention can be prepared as shown in Scheme G and described herein. Compound 74 can be reduced under Pd-catalyzed conditions to provide the compounds of the present invention.

[0473] Option G

[0474]

[0475] Method H

[0476] The compounds of the present invention can be prepared as shown in Scheme H and described herein. Commercially available methyl 2,5,6-trichloropyrimidine-4-carboxylate can be arylated with a substituent indazole-4-boronic acid using a metal-mediated cross-coupling step. A second arylation can then be performed using a metal-mediated cross-coupling step, in which the ester may undergo hydrolysis. An amide is then formed with ammonia or its synthetic equivalent to provide the compounds of the present invention.

[0477] Option H

[0478]

[0479] Method I

[0480] The compounds of the present invention can be prepared as shown in Scheme I and described herein. Commercially available methyl 2,6-dichloropyrimidin-4-carboxylate can be arylated with a substituent indazole-4-boronic acid using a metal-mediated cross-coupling step. A second arylation can then be performed using a metal-mediated cross-coupling step, in which the ester may undergo hydrolysis. An amide is then formed with ammonia or its synthetic equivalent to provide the compounds of the present invention.

[0481] Option I

[0482]

[0483] Method J

[0484] The compounds of the present invention can be prepared as shown in Scheme J and described herein. Commercially available 5-amino-2-chloroisonicotinic acid can be esterified by treatment with a base (such as potassium carbonate and ethyl iodide) to provide ethyl 5-amino-2-chloroisonicotinic acid, which can be brominated with NBS to provide intermediate G. This intermediate can be converted to intermediate H via a two-step sequence comprising a metal-mediated coupling followed by a transamidation reaction using ammonia. Intermediate H can be arylated using a metal-mediated cross-coupling step and subsequently deprotected with boron tribromide to obtain the compounds of the present invention.

[0485] Scheme J

[0486]

[0487] Method K

[0488] The compounds of the present invention can be prepared as shown in Scheme K and described herein. Known 2-amino-5-bromo-3-iodobenzamide can be arylated using a metal-mediated cross-coupling step, followed by boration using a second metal-mediated cross-coupling to provide intermediate I. This intermediate can be arylated using a metal-mediated cross-coupling step, followed by deprotection with zinc bromide and 1-propanethiol to give the compounds of the present invention, thereby obtaining a mixture of trans-isomers. In such cases, it may be necessary to isolate the trans-isomers of interest to obtain the compounds of the present invention.

[0489] Option K

[0490]

[0491] Method L

[0492] The compounds of the present invention can be prepared as shown in Scheme L and described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidin-4-carboxylate can be arylated using a metal-mediated cross-coupling step with a substituent indazole-4-boronic acid. The ester is hydrolyzed with aqueous NaOH, and then an amide is formed using NH4Cl, HATU, and DIPEA to provide a primary amide, which can then be further arylated using a metal-mediated cross-coupling step to provide the compounds of the present invention. In the case of a protecting aryl group, a deprotection step using an acid, base, and / or fluoride may be necessary to obtain the compounds of the present invention. In the case of a racemic additive on the aryl group, a chiral separation step via SFC may be necessary to obtain the compounds of the present invention.

[0493] Option L

[0494]

[0495] Method M

[0496] The compounds of the present invention can be prepared as shown in Scheme M and described herein. Commercially available ethyl 5-amino-2-chloropyrimidin-4-carboxylate can be arylated with phenylboronic acid using a metal-mediated cross-coupling step, followed by bromination with NBS to provide intermediate L. This intermediate is then arylated with an N-THP-protected indazole-4-boronic acid pinacol ester with substituents, followed by amino-mediated transamidation and acidic deprotection of the indazole, to provide the compounds of the present invention.

[0497] Option M

[0498]

[0499] Method N

[0500] The compounds of the present invention can be prepared as shown in Scheme N and described herein. Intermediate G can be arylated using a metal-mediated cross-coupling step with a substituent indazole-4-boronic acid. The resulting ester can be converted to a primary amide after treatment with ammonia, and then arylated using a second metal-mediated cross-coupling to obtain the compounds of the present invention.

[0501] Option N

[0502]

[0503] Method O

[0504] The compounds of the present invention can be prepared as shown in Scheme O and described herein. Known 2-amino-5-bromo-3-iodobenzamide can be arylated with (5-methyl-1H-indazol-4-yl)boronic acid using a metal-mediated cross-coupling step, followed by a second metal-mediated cross-coupling to provide the compounds of the present invention, thereby yielding a mixture of transisomers. In such cases, it may be necessary to isolate the transisomers of interest to obtain the compounds of the present invention.

[0505] Option O

[0506]

[0507] Method P

[0508] The compounds of the present invention can be prepared as shown in scheme P and described herein. Intermediate K can be arylated with 2-(methylthio)-4-(tributyltinyl)pyrimidine using a metal-mediated cross-coupling step. The resulting methyl sulfide can be oxidized to methyl sulfone using an oxidizing agent (such as Oxone) to provide intermediate N. This intermediate can undergo an SNAr reaction with various alcohols, possibly containing other protected moieties, to give the compounds of the present invention after deprotection, thereby yielding a mixture of trans-isomers. In such cases, it may be necessary to isolate the trans-isomers of interest to obtain the compounds of the present invention.

[0509] Plan P

[0510]

[0511] Method Q

[0512] The compounds of the present invention can be prepared as shown in Scheme Q and described herein. Intermediate N can undergo an SNAr reaction with various amines to give the compounds of the present invention, thereby obtaining a mixture of trans-isomers. In such cases, it may be necessary to isolate the trans-isomer of interest to obtain the compounds of the present invention.

[0513] Solution Q

[0514]

[0515] Method R

[0516] The compounds of the present invention can be prepared as shown in Scheme R and described herein. Intermediate K can be arylated with 2-fluoro-6-(tributyltinalkyl)pyridine using a metal-mediated cross-coupling step to provide intermediate O. This intermediate can undergo an SNAr reaction with various alcohols to give the compounds of the present invention, thereby obtaining a mixture of trans-isomers. In such cases, it may be necessary to isolate the trans-isomers of interest to obtain the compounds of the present invention.

[0517] Solution R

[0518]

[0519] Method S

[0520] The compounds of the present invention can be prepared as shown in Scheme S and described herein. Intermediate K can be arylated using a metal-mediated cross-coupling step with tributyl(aryl)tinane, in which the n-butylated product can be separated into byproducts to obtain the compounds of the present invention.

[0521] Option S

[0522]

[0523] Method T

[0524] The compounds of the present invention can be prepared as shown in Scheme T and described herein. Substituted 4-bromo- or 4-chloro-1-(THP)-1H-indazoles can be borated using a metal-mediated cross-coupling step to provide pinacol (THP)-1H-indazole-4-yl)boronic esters. These boronic esters can undergo a metal-mediated cross-coupling step with intermediate P to provide a THP-protected ester, which can be transamidized with ammonia and deprotected under acidic conditions to give the compounds of the present invention, thereby obtaining a mixture of trans-isomers. In such cases, it may be necessary to isolate the trans-isomers of interest to obtain the compounds of the present invention.

[0525] Solution T

[0526]

[0527] Method U

[0528] The compounds of the present invention can be prepared as shown in Scheme U and described herein. Commercially available 3-amino-5-methylpyridine carboxylate salts can be converted to a primary amide using HATU and an ammonia substitute. This primary amide can then be brominated to provide 3-amino-4,6-dibromo-5-methylpyridine carboxamide. This compound can be diarylated using a metal-mediated cross-coupling step with 2-(tributyltinyl)pyridine and pinacol (1H-indazol-4-yl)boronic acid ester to obtain the compounds of the present invention.

[0529] Solution U

[0530]

[0531] Method V

[0532] The compounds of the present invention can be prepared as shown in Scheme V and described herein. Intermediate O can undergo an SNAr reaction with various amines to give the compounds of the present invention, thereby obtaining a mixture of trans-isomers. In such cases, it may be necessary to isolate the trans-isomer of interest to obtain the compounds of the present invention.

[0533] Plan V

[0534]

[0535] Method W

[0536] The compounds of the present invention can be prepared as shown in Scheme W and described herein. Intermediate J can be arylated using a metal-mediated cross-coupling step with (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid. Deprotection under acidic conditions, followed by an SNAr reaction with a substituted 2-halopyrimidine, provides the compounds of the present invention.

[0537] Solution W

[0538]

[0539] Method X

[0540] The compounds of the present invention can be prepared as shown in Scheme X and described herein. Intermediate K can be protected with di-tert-butyl dicarbonate and then amination with aniline using a metal-mediated cross-coupling step to provide the compounds of the present invention, thereby obtaining a mixture of trans-isomers. In such cases, it may be necessary to isolate the trans-isomers of interest to obtain the compounds of the present invention.

[0541] Option X

[0542]

[0543] Method Y

[0544] Intermediates used to prepare the compounds of the present invention may be prepared as shown in Scheme Y and as described herein. Commercially available substituted 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline may be acylated with acyl chlorides or by using carboxylic acids and amide forming agents (such as HATU) to obtain pinacol boronic acid esters, which may be used in conjunction with the methods described herein to provide the compounds of the present invention.

[0545] Option Y

[0546]

[0547] Method Z

[0548] Intermediates used to prepare the compounds of the present invention can be prepared as shown in Scheme Z and as described herein. Commercially available substituted 2-bromoanilines can be alkylated using alkyl halides or halide-like compounds. These alkylated anilines can then be borated using a metal-mediated cross-coupling step to obtain pinacol borate esters, which can be used in conjunction with the methods described herein to provide the compounds of the present invention.

[0549] Option Z

[0550]

[0551] Method AA

[0552] Intermediates used to prepare the compounds of the present invention can be prepared as shown in Scheme AA and as described herein. Commercially available substituted 2-bromoanilines can be alkylated using an aldehyde or ketone in a reductive amination reaction. These alkylated anilines can then be borated using a metal-mediated cross-coupling step to obtain pinacol borate esters, which can be used in conjunction with the methods described herein to provide the compounds of the present invention.

[0553] Plan AA

[0554]

[0555] Method AB

[0556] The compounds of the present invention can be prepared as shown in Scheme AB and described herein. A commercially available 5-bromo-6-fluoroindoline-2,3-dione can be arylated with (2-hydroxyphenyl)boronic acid using a metal-mediated cross-coupling step, followed by cyclization with a base such as potassium tert-butoxide to provide 1H-benzofurano[3,2-f]indoline-2,3-dione. This compound can then be hydrolyzed and oxidized in a one-pot process with NaOH and H₂O₂, subsequently converted to a primary amide using standard amide coupling agents such as HATU and ammonium chloride. This formamide can then be brominated with a brominating agent such as NBS, followed by arylation with (5-methyl-1H-indazole-4-yl)boronic acid using a metal-mediated cross-coupling step to provide the compounds of the present invention.

[0557] Plan A and B

[0558]

[0559] Method AC

[0560] The compounds of the present invention can be prepared as shown in scheme AC and described herein. Intermediate J can be arylated with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline, which can be substituted using a metal-mediated cross-coupling step, followed by sulfonation with sulfonyl chloride to provide the compounds of the present invention.

[0561] Solution AC

[0562]

[0563] Method AD

[0564] The compounds of the present invention can be prepared as shown in Scheme AD and described herein. 5-amino-2-chloro-6-(1H-indazol-4-yl)pyrimidin-4-carboxamides with substituents on the indazole moiety can be arylated using a metal-mediated cross-coupling step with boronized or tin-alkylated substituted anilines, followed by N-arylation under acidic SNAr conditions to provide the compounds of the present invention.

[0565] Plan AD

[0566]

[0567] Method AE

[0568] Intermediates used to prepare the compounds of the present invention may be prepared as shown in Scheme AE and as described herein. Commercially available substituted 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline may be acylated with an acyl chloride or by using a carboxylic acid and an amide forming agent (such as HATU) to obtain an amide, which may then be reduced with a reducing agent (such as borane) to provide pinacol borate ester, which is used in conjunction with the methods described herein to provide the compounds of the present invention.

[0569] Solution AE

[0570]

[0571] Method AF

[0572] The compounds of the present invention can be prepared as shown in scheme AF and described herein. Intermediate J can be arylated with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline, which can be substituted using a metal-mediated cross-coupling step, followed by acylation with an acyl chloride or carboxylic acid and an amide forming agent (such as HATU) to provide the compounds of the present invention.

[0573] Scheme AF

[0574]

[0575] Method AG

[0576] The compounds of the present invention can be prepared as shown in Scheme AG and described herein. Commercially available 6-amino-3-bromo-2-fluorobenzonitrile can be protected with 2,5-hexanedione under acidic conditions, followed by cross-coupling with intermediate V in a metal-mediated step to provide protected 7-aminobenzofurano[3,2-b]pyridin-6-carboxynitrile. This intermediate can be hydrolyzed to an amide under basic conditions, deprotected with hydroxylamine, brominated with a brominating agent (such as NBS), and subsequently arylated with (5-methyl-1H-indazol-4-yl)boronic acid using a metal-mediated cross-coupling step to provide the compounds of the present invention.

[0577] Solution AG

[0578]

[0579] Method AH

[0580] Intermediates used to prepare the compounds of the present invention can be prepared as shown in Scheme AH and as described herein. Commercially available substituted 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline can be reductively amination with a ketone or aldehyde using a reducing agent (such as sodium cyanoborohydride) to obtain pinacol boronic acid esters, which can be used in conjunction with the methods described herein to provide the compounds of the present invention.

[0581] Solution AH

[0582]

[0583] Method AI

[0584] The compounds of the present invention can be prepared as shown in Scheme AI and described herein. Commercially available methyl 2,6-dichloropyrimidin-4-carboxylate can be arylated using a metal-mediated cross-coupling step with N-THP-protected pinacol indazole-4-boronate containing a substituent. A second metal-mediated cross-coupling step can be used to attach a 3-(2-amino-pyridyl) group, which may also contain a substituent. A primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0585] AI Solution

[0586]

[0587] Method AJ

[0588] The compounds of the present invention can be prepared as shown in scheme AJ and described herein. Commercially available ethyl 2,6-dichloro-5-fluoropyrimidin-4-carboxylate can be arylated using a metal-mediated cross-coupling step with N-THP-protected pinacol indazole-4-boronate with substituents. A second metal-mediated cross-coupling step can be used to attach a 3-(2-amino-pyridyl) group, which may also have substituents. A primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0589] Solution AJ

[0590]

[0591] Method AK

[0592] The compounds of the present invention can be prepared as shown in scheme AK and described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidin-4-carboxylate can be arylated using a metal-mediated cross-coupling step with N-THP-protected pinacol indazole-4-boronate with substituents. A second metal-mediated cross-coupling step can be used to attach a 3-(2-amino-pyridyl) group, which may also have substituents. A primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0593] Solution AK

[0594]

[0595] Method AL

[0596] The compounds of the present invention can be prepared as shown in scheme AL and described herein. Intermediate J can be arylated using a suitable boric acid or ester or a suitable tributyltinane via a metal-mediated cross-coupling step to attach a 3-(2-fluoropyridinyl) group, which may also contain substituents. These 2-fluoropyridines can then be placed together with a primary amine under SNAr reaction conditions to provide the compounds of the present invention.

[0597] Solution AL

[0598]

[0599] Method AM

[0600] Intermediates used to prepare the compounds of the present invention can be prepared as shown in Scheme AM and as described herein. Commercially available substituent-containing 2-bromo-1-iodobenzene can be N-arylated using a commercially available aromatic or heteroaromatic amine via a metal-mediated cross-coupling step. These secondary anilines can then be borated using a metal-mediated cross-coupling step to obtain pinacol borate esters, which can be used in conjunction with the methods described herein to provide the compounds of the present invention.

[0601] Solution AM

[0602]

[0603] Method AN

[0604] The compounds of the present invention can be prepared as shown in Scheme AN ​​and described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidin-4-carboxylate can be arylated using a metal-mediated cross-coupling step with N-THP-protected pinacol indazole-4-boronate containing substituents. A second metal-mediated cross-coupling step can be used to attach a 3-(4-fluoropyridyl) group, which may also contain substituents. These 2-fluoropyridines can then be placed with a primary amine under SNAr reaction conditions, followed by transamidation with ammonia and deprotection under acidic conditions to provide the compounds of the present invention.

[0605] Solution AN

[0606]

[0607] Method AO

[0608] The compounds of the present invention can be prepared as shown in scheme AO and described herein. Intermediate J can be tin-alkylated using a metal-mediated cross-coupling step with bis(tributyltin) to provide intermediate X. A second metal-mediated cross-coupling step can be used to mount an aryl or heteroaryl group with or without substituents to provide the compounds of the present invention.

[0609] Solution AO

[0610]

[0611] Method AP

[0612] The compounds of the present invention can be prepared as shown in scheme AP and described herein. Intermediate J can be first boronized with bis(pinacol)diboron using a metal-mediated cross-coupling step, and then arylated using a second metal-mediated cross-coupling step to install an aryl or heteroaryl group with or without substituents to provide the compounds of the present invention.

[0613] Solution AP

[0614]

[0615] Method AQ

[0616] The compounds of the present invention can be prepared as shown in scheme AQ and described herein. Intermediate Z can be subjected to an SNAr reaction using an alcohol and a base (such as NaH). The resulting intermediate can be hydrolyzed to a primary amide using a Ghaffar-Parkins catalyst to provide the compounds of the present invention, thereby yielding a mixture of trans-isomers. In such cases, it may be necessary to isolate the trans-isomers of interest to obtain the compounds of the present invention.

[0617] Solution AQ

[0618]

[0619] Method AR

[0620] The compounds of the present invention can be prepared as shown in scheme AR and described herein. An amine can be used to perform an SNAr reaction on intermediate Z. The resulting intermediate can be hydrolyzed to a primary amide using a Ghaffar-Parkins catalyst to provide the compounds of the present invention, thereby yielding a mixture of trans-isomers. In such cases, it may be necessary to isolate the trans-isomer of interest to obtain the compounds of the present invention.

[0621] AR Solution

[0622]

[0623] Method AS

[0624] The compounds of the present invention can be prepared as shown in Scheme AS and described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidin-4-carboxylate can be arylated using a metal-mediated cross-coupling step with N-THP-protected pinacol indazole-4-boronate containing a substituent. A second metal-mediated cross-coupling step can be used to attach a 3-(2-amino-phenyl) group, which may also contain a substituent. A primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0625] Solution AS

[0626]

[0627] Method AT

[0628] The compounds of the present invention can be prepared as shown in Scheme AT and described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidin-4-carboxylate can be arylated using a metal-mediated cross-coupling step with N-THP-protected pinacol indazole-4-boronate with substituents. This chloropyrimidinium can be tin-alkylated using a metal-mediated cross-coupling step with bis(tributyltin). A third metal-mediated cross-coupling step can be used for cross-coupling with aryl or heteroaryl groups with substituents. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0629] Solution AT

[0630]

[0631] Method AU

[0632] The compounds of the present invention can be prepared as shown in scheme AU and described herein. A tin-alkylated N-THP-protected 5-amino-6-(1H-indazol-4-yl)pyrimidin-4-carboxamide with a substituent at the indazole moiety can be arylated with 3-bromopyridine using a metal-mediated cross-coupling step to attach a 3-(2-amino-pyridinyl) group, which may also have a substituent. A primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0633] Solution AU

[0634]

[0635] Method AV

[0636] The compounds of the present invention can be prepared as shown in Scheme AV and described herein. Tin-alkylated N-THP-protected 5-amino-6-(1H-indazol-4-yl)pyrimidin-4-carboxamide with a substituent at the indazole moiety can be arylated with 2-bromoaniline using a metal-mediated cross-coupling step to attach a 3-(2-aminophenyl) group, which may also have a substituent. The primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0637] Solution AV

[0638]

[0639] MethodAW

[0640] The compounds of the present invention can be prepared as shown in Scheme AW and described herein. Commercially available substituted 2-halo-3-bromopyridines can be reacted with primary amines in an SNAr reaction. These 2-amino-3-bromopyridines can then be cross-coupled with tin-alkylated N-THP-protected 5-amino-6-(1H-indazol-4-yl)pyrimidine-4-carboxamides with substituents on the indazole moiety using a metal-mediated cross-coupling step. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0641] Solution AW

[0642]

[0643] Method AX

[0644] The compounds of the present invention can be prepared as shown in Scheme AX and described herein. N-alkylated or N-protected 3-amino-4-bromopyrazoles can first react with a ketone under reductive amination conditions, followed by boration with bis(pinacol)diboron using a metal-mediated cross-coupling step to obtain 4-borated pyrazoles. These pyrazoles can undergo a second metal-mediated cross-coupling step with 4-chloropyrimidines (such as intermediate AB), followed by transamidation with ammonia and cleavage of the THP group under acidic conditions to provide the compounds of the present invention.

[0645] Solution AX

[0646]

[0647] Method AY

[0648] The compounds of the present invention can be prepared as shown in scheme AY and described herein. N-alkylated 3-amino-4-bromopyrazoles can be first borated with bis(pinacol)diboron using a metal-mediated cross-coupling step, followed by cross-coupling with a 4-chloropyrimidine (such as intermediate AB) using a second metal-mediated cross-coupling step. These primary 3-aminopyrazoles can then be N-arylated with a heteroaryl halide using a metal-mediated cross-coupling step. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0649] Plan AY

[0650]

[0651] Method AZ

[0652] The compounds of the present invention can be prepared as shown in scheme AZ and described herein. The intermediate BT can be arylated using a metal-mediated cross-coupling step to attach a 3-(2-amino-pyridyl) group, which may also contain substituents. The primary amine can then be N-arylated using a heteroaryl halide via a metal-mediated cross-coupling step. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0653] Solution AZ

[0654]

[0655] Method BA

[0656] The compounds of the present invention can be prepared as shown in Scheme BA and described herein. Ethyl 5-amino-2-chloro-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidin-4-carboxylate with a substituent at the indazole moiety can be arylated using a metal-mediated cross-coupling step. These arylated intermediates can be transamidized with ammonia, followed by cleavage of the THP group under acidic conditions to provide the compounds of the present invention.

[0657] Solution BA

[0658]

[0659] Method BB

[0660] The compounds of the present invention can be prepared as shown in Scheme BB and described herein. Ethyl 5-amino-2-chloro-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidin-4-carboxylate with a substituent at the indazole moiety can be arylated via a one-pot borylation / Suzuki cross-coupling step using a metal-mediated cross-coupling process. The primary amine can then be N-arylated with a heteroaryl halide via a metal-mediated cross-coupling step. Transamidation with ammonia followed by cleavage of the THP group under acidic conditions provides the compounds of the present invention.

[0661] Plan BB

[0662]

[0663] Method BC

[0664] The compounds of the present invention and their synthetic routes have been described in the following example compounds.

[0665] Method BD

[0666] The compounds of the present invention can be prepared as shown in scheme BD and described herein. Intermediate D can be arylated with (3-methoxy-2,6-dimethylphenyl)boronic acid using a metal-mediated cross-coupling step, followed by transamidation with ammonia, and then deprotection with boron tribromide to give intermediate CO. This intermediate can be arylated using a second metal-mediated cross-coupling step to give the compounds of the present invention. Depending on the nature of the aryl group cross-coupled with intermediate CO, a mixture of trans-isomers can be obtained. In such cases, it may be necessary to isolate the trans-isomer of interest to obtain the compounds of the present invention.

[0667] Solution BD

[0668]

[0669] Treatment

[0670] The compounds of the present invention can be used to treat diseases or conditions that depend on Myt1 (gene name PKMYT1) activity (e.g., cancers that overexpress CCNE1 or have inactivating mutations in the FBXW7 gene).

[0671] The disease or symptom may present with symptoms of excessive cell proliferation. For example, the disease or symptom could be cancer (e.g., cancer that overexpresses CCNE1 or has an inactivating mutation in the FBXW7 gene).

[0672] Cancers with a high incidence of CCNE1 overexpression include, for example, uterine cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, and endometrial cancer.

[0673] Cancers lacking FBXW7 include, for example, uterine cancer, colorectal cancer, breast cancer, lung cancer, and esophageal cancer.

[0674] The compounds of the present invention can be administered via routes selected from the group consisting of: oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intravenous, intraspinal, intranasal, intratumoral, intraspinal, intranasal, inhalation, intratumoral, and local administration.

[0675] Pharmaceutical Composition

[0676] The compounds used in the methods described herein are preferably formulated as pharmaceutical compositions for administration to human subjects in a biocompatible form suitable for in vivo administration. Pharmaceutical compositions typically comprise the compounds described herein and pharmaceutically acceptable excipients. Some pharmaceutical compositions may comprise one or more additional pharmaceutically active agents described herein.

[0677] The compounds described herein may also be used in the form of free bases; as salts, zwitterions, solvates; or as prodrugs or pharmaceutical compositions thereof. All forms are within the scope of this invention. As those skilled in the art will understand, the compounds, their salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions may be administered to a patient in various forms, depending on the chosen route of administration. The compounds used in the methods described herein may be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, via patch, pump, or transdermally, and pharmaceutical compositions may be formulated accordingly. Parenterally administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and local administration. Parenterally administration may be performed by continuous infusion over a selected time period.

[0678] For human use, the compounds of the present invention can be administered alone or in combination with a drug carrier chosen with regard to the intended route of administration and standard pharmaceutical practice. Therefore, pharmaceutical compositions according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants, which facilitate the processing of the compounds of the present invention into pharmaceutically acceptable formulations.

[0679] This invention also includes pharmaceutical compositions that may contain one or more pharmaceutically acceptable carriers. In preparing the pharmaceutical compositions of this invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in a carrier, such as a capsule, sachet, paper, or other container. When the excipient acts as a diluent, it can be a solid, semi-solid, or liquid substance (e.g., physiological saline) that serves as a medium, carrier, or mediator of the active ingredient. Therefore, the composition can be in the form of tablets, powders, lozenges, capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending on the intended route of administration. The resulting composition may contain additional agents, such as preservatives.

[0680] Excipients or carriers are selected based on the method and route of administration. Suitable drug carriers and essential pharmaceutical ingredients for pharmaceutical formulations are described in well-known references in the art, such as Remington: The Science and Practice of Pharmacy, 21st edition, Gennaro, ed., Lippincott Williams & Wilkins (2005) and USP / NF (United States Pharmacopeia and National Formulary). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Formulations may additionally include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, edited by Rowe et al., Pharmaceutical Press (2009).

[0681] These pharmaceutical compositions can be manufactured by conventional methods, such as conventional mixing, dissolving, granulation, sugar-coated pelleting, grinding, emulsification, encapsulation, embedding, or lyophilization processes. Methods well-known in the art for preparing formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Gennaro, ed., Lippincott Williams & Wilkins (2005) and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J.C. Boylan, eds., 1988–1999, Marcel Dekker, New York. The appropriate formulation depends on the chosen route of administration. Formulations and preparations of such compositions are well-known to those skilled in the art of pharmaceutical formulation. In preparing formulations, the active compound may be ground to provide an appropriate particle size before being combined with other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size may be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0682] dose

[0683] The dosage of the compound used in the methods described herein, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, may vary depending on a number of factors, such as the pharmacodynamic properties of the compound; the route of administration; the recipient's age, health status, and weight; the nature and severity of symptoms; the frequency of treatment and the type of concurrent treatment (if any); and the clearance rate of the compound in the treated animal. Those skilled in the art can determine an appropriate dosage based on the above factors. The compound used in the methods described herein may initially be administered at a suitable dosage, which may be adjusted as needed based on clinical response. Generally, the appropriate daily dose of the compound of the present invention will be the amount of the minimum dose at which the compound effectively produces a therapeutic effect. This effective dose will generally depend on the factors described above.

[0684] The compounds of this invention can be administered to a patient in a single dose or in multiple doses. When multiple doses are administered, the doses can be spaced out, for example, every 1-24 hours, 1-7 days, 1-4 weeks, or 1-12 months. The compounds can be administered according to a schedule or without a predetermined schedule. For example, the active compound can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times daily; every 2 days, every 3 days, every 4 days, every 5 days, or every 6 days; every 1, 2, 3, 4, 5, 6, or 7 times weekly; every 1, 2, 3, 4, 5, or 6 times monthly; or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times annually. It should be understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0685] Although the attending physician will ultimately determine the appropriate dosage and dosing regimen, the effective amount of the compounds of the present invention can be, for example, the total daily dose of any of the compounds described herein, ranging from 0.05 mg to 3000 mg. Alternatively, the dosage can be calculated using the patient's weight. Such dosage ranges can include, for example, between 10 and 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 the compound is administered.

[0686] In the method of the present invention, the time periods for administering multiple doses of the compound of the present invention to a patient can vary. For example, in some embodiments, the dose of the compound of the present invention is administered to the patient over a time period of 1-7 days; 1-12 weeks; or 1-3 months. In some embodiments, the compound is administered to the patient over a time 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 time period of administration. When the compound is administered daily, administration can occur, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day.

[0687] preparation

[0688] Compounds identified as capable of treating any of the conditions described herein using any of the methods described herein may be administered to patients or animals in unit dosage forms together with pharmaceutically acceptable diluents, carriers, or excipients. Chemical compounds used for such therapies may be produced and isolated using any standard techniques known to those skilled in the art of medicinal chemistry. Suitable formulations or compositions may be provided using routine pharmaceutical practices to administer the identified compounds to patients suffering from the disease or condition. Administration may be initiated before the patient experiences symptoms.

[0689] Exemplary routes of administration for the compounds used in this invention (e.g., the compounds of this invention) or pharmaceutical compositions thereof include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intravenous, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. The compounds are ideally administered with a pharmaceutically acceptable carrier. Formulations of pharmaceutical preparations of the compounds described herein for the treatment of the conditions described herein are also part of this invention.

[0690] Formulations for oral administration

[0691] The pharmaceutical compositions contemplated by this invention include those formulated for oral administration (“oral dosage forms”). Oral dosage forms may be, for example, tablets, capsules, liquid solutions or suspensions, powders, or liquid or solid crystals, containing an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient. These excipients can be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch (including potato starch), calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives (including microcrystalline cellulose), starch (including potato starch), croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginate, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-sticking agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0692] Formulations intended for oral administration may also be presented as chewable tablets, hard gelatin capsules (where 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 (where the active ingredient is mixed with an aqueous or oil medium (e.g., peanut oil, liquid paraffin, or olive oil)). Powders, granules, and pills may be prepared using the ingredients mentioned above under tablets and capsules, in a conventional manner using, for example, mixers, fluidized bed apparatus, or spray drying equipment.

[0693] Controlled-release compositions for oral administration can be constructed to release the active drug substance by controlling the dissolution and / or diffusion of the active pharmaceutical ingredient. Any of several strategies can be employed to obtain controlled release and target plasma concentration versus time profiles. In one example, controlled release is achieved by appropriately selecting various formulation parameters and components, 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, microspheres, nanoparticles, patches, and liposomes. In some embodiments, the composition comprises a biodegradable, pH- and / or temperature-sensitive polymer coating.

[0694] Controlled release through dissolution or diffusion can be achieved by appropriately coating a compound into tablet, capsule, pill, or granule formulation or by incorporating the compound into a suitable matrix. Controlled-release coatings may contain coating substances mentioned above and / or one or more of the following: shellac, beeswax, sugar wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3-butanediol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled-release matrix formulations, matrix materials may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbomer 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene and / or halogenated fluorocarbons.

[0695] The compounds and compositions of the present invention may be incorporated herein in liquid form for oral administration, including aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical carriers.

[0696] Preparations for parenteral administration

[0697] The compounds described herein for use in the methods of this invention can be administered as pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulations as described herein. Pharmaceutical formulations can also be administered parenterally (intravenously, intramuscularly, subcutaneously, etc.) in dosage forms or formulations containing conventionally non-toxic, pharmaceutically acceptable carriers and adjuvants. Specifically, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. For example, to prepare such compositions, the compounds of this invention can be dissolved or suspended in parenteral-acceptable liquid media. Acceptable media and solvents that may be used are water, water adjusted to a suitable pH by adding appropriate amounts of hydrochloric acid, sodium hydroxide, or suitable buffers, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. Aqueous formulations may also contain one or more preservatives, such as methylparaben, ethylparaben, or n-propylparaben. Further information on parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), which is incorporated herein by reference.

[0698] Parenteral preparations may be any of the five general types of preparations identified by USP-NF as suitable for parenteral administration:

[0699] (1) Drug injection: a liquid preparation of an active pharmaceutical ingredient (e.g., the compound of the present invention) or a solution thereof;

[0700] (2) Injectable drug: Active pharmaceutical ingredient (e.g., the compound of the present invention) in dry solid form, which will be combined with a suitable sterile medium for parenteral administration in the form of a drug injection solution;

[0701] (3) Drug injection emulsion: a liquid preparation of an active pharmaceutical ingredient (e.g., the compound of the present invention) dissolved or dispersed in a suitable emulsion medium;

[0702] (4) Drug injection suspension: a liquid preparation of an active pharmaceutical ingredient (e.g., the compound of the present invention) suspended in a suitable liquid medium; and

[0703] (5) Injection suspension: The active pharmaceutical ingredient (e.g., the compound of the present invention) is in dry solid form and will be combined with a suitable sterile medium for parenteral administration in the form of an injection suspension.

[0704] Formulations intended for parenteral administration include solutions of compounds prepared in water with a surfactant (e.g., hydroxypropyl cellulose). Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, mixtures thereof (with or without alcohol), and in oils. Under normal storage and use conditions, these preparations may contain preservatives to prevent microbial growth. Routine procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Gennaro, ed., Lippincott Williams & Wilkins (2005) and The United States Pharmacopeia: The National Formulary (USP 36NF31), published in 2013.

[0705] Formulations for parenteral administration may contain, for example, excipients, sterile water or saline, polyalkylene glycols (e.g., polyethylene glycol), plant-derived oils, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolic acid copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control compound release. Other potentially available parenteral delivery systems for the compound include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients (e.g., lactose), or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or may be oily solutions administered as nasal drops or gels.

[0706] Parenteral formulations can be formulated for rapid release or for sustained / extended release of compounds. Exemplary formulations for parenteral release of compounds include: aqueous solutions, reconstituted powders, cosolvent solutions, oil / water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymer gels.

[0707] combination

[0708] The compounds of the present invention can be administered to a subject in combination with one or more other agents, for example:

[0709] (a) Cytotoxic agents;

[0710] (b) Antimetabolites;

[0711] (c) Alkylating agents;

[0712] (d) Anthracycline drugs;

[0713] (e) Antibiotics;

[0714] (f) Antimitotic agents;

[0715] (g) Hormone therapy;

[0716] (h) Signal transduction inhibitors;

[0717] (i) Gene expression regulators;

[0718] (j) Apoptosis inducers;

[0719] (k) Angiogenesis inhibitors;

[0720] (l) Immunotherapy agents;

[0721] (m) DNA damage repair inhibitors;

[0722] or

[0723] Its combination.

[0724] Cytotoxic agents can include, for example, actinomycin D, alemtuzumab, alitretinoin, allopurinol, altretamine, aifostine, amphotericin C, amsacrine, arsenic trioxide, asparaginase, azacitidine, azathioprine, and Bacille Calmette-Guérin.BCG, bendamustine, bexarotene, bevacuzimab, bleomycin, bortezomib, busulphan, capecitabine, carboplatin, carfilzomib, carmustine, cetuximab, cisplatin, chlorambucil, cladribine, clofarabine, colchicine, crisantaspase, cyclophosphamide, cyclosporine, cytarabine, cytochalasin B B) Dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, 1-dehydrotestosterone, denileukin, dexamethasone, dexrazoxane, dihydroxyanthracin dione, disulfiram, docetaxel, doxorubicin, emetine, epirubicin, erlotinib, epigallocatechin gallate, epietin alfa, estramustine, ethidium bromide bromide, etoposide, everolimus, filgrastim, finasunate, floxuridine, fludarabine, 5-fluorouracil5-FU), fulvestrant, ganciclovir, geldanamycin, gemcitabine, glucocorticoids, gramicidin D, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, irinotecan, interferon, interferon α-2a, interferon α-2b, ixabepilone, lactate dehydrogenase A. A,LDH-A), lenalidomide, letrozole, leucovorin, levamisole, lidocaine, lomustine, mechlorethamine, melphalan, 6-mercaptopurine6-MP), 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 disodium, plicamycin, porfimer sodium, procaine, procarbazine, propranolol, puromycin, quinacrine, radicicol, radioactive isotopes, 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 combinations thereof.

[0725] Antimetabolites can be, for example, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine, cladribine, pemetrexed, gemcitabine, capecitabine, hydroxyurea, mercaptopurine, fludarabine, pralatrexate, clofarabine, cytarabine, decitabine, fluorouridine, nerabine, trimetrexate, thioguanine, pentostatin, or combinations thereof.

[0726] Alkylating agents can be, for example, nitrogen mustard, thiotepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum(II) (DDP), cisplatin, atratamine, cyclophosphamide, ifosfamide, hexamethylmelamine, atratamine, procarbazine, dacarbazine, temozolomide, streptozotocin, carboplatin, cisplatin, oxaliplatin, uromustine, bendamustine, trabectedin, semustine, or combinations thereof.

[0727] Anthracycline drugs can be, for example, daunorubicin, doxorubicin, alaroxorubicin, ammoniarubicin, anasmycin, carbim, epirubicin, idarubicin, mitoxantrone, vararubicin, or combinations thereof.

[0728] Antibiotics can include, for example, bleomycin, photomycin, anthraxycin (AMC), ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, piperacillin, pinipacillin, pimecrolimus, ticarcillin, aztreonam, imipenem, doripenem, ertapenem, meropenem, cephalosporins, clarithromycin, erythromycin, roxithromycin, telithromycin, lincomycin, pristinamycin, quinupristin, amikacin, etc. Gentamicin, Kanamycin, Neomycin, Netilmicin, Paromomycin, Tobramycin, Streptomycin, Sulfamethoxazole, Sulfamethoxazole, Sulfaisoxazole, Demeclocycline, Minocycline, Oxytetracycline, Tetracycline, Penicillin, Amoxicillin, Cephalexin, Erythromycin, Clarithromycin, Azithromycin, Ciprofloxacin, Levofloxacin, Ofloxacin, Doxycycline, Clindamycin, Metronidazole, Tigecycline, Chloramphenicol, Metronidazole, Tinidazole, Nitrofurantoin, Vancomycin, Teicoplanin, Tervacin, Linezolid, Cycloserine, Rifamycins, Polymyxin B) Bacitracin, viomycin, capreomycin, quinolones, daunorubicin, doxorubicin, 4'-deoxydoxorubicin, epirubicin, idarubicin, procainamide, mitomycin-c, mitoxantrone or combinations thereof.

[0729] Antimitotic agents can be, for example, vincristine, vinorelbine, docetaxel, estradiol, ixapril, paclitaxel, maytansinoid, dolastatin, cryptophycin, or combinations thereof.

[0730] Signal transduction inhibitors may be, for example, imatinib, trastuzumab, erlotinib, sorafenib, sunitinib, tesiromoximib, vemurafenib, lapatinib, bortezomib, cetuximab, panitumumab, matezumab, gefitinib, STI 571, rapamycin, flavonoidipiperidol, imatinib mesylate, vatalanib, cermatinib, motracenib, axitinib, afatinib, bosutinib, crizotinib, cabozantinib, dasatinib, entrectinib, pazopanib, lapatinib, vandetanib, or combinations thereof.

[0731] Gene expression regulators can be, for example, siRNA, shRNA, antisense oligonucleotides, HDAC inhibitors, or combinations thereof. HDAC inhibitors can be, for example, trichostatin A, triporaneous B, valproic acid, vorinostat, beristat, LAQ824, pabisostat, entecavir, tasildenafil, mocetionstat, givenolol, resmectin, abexinostat, quisinostat, rocilinostat, practinostat, CHR-3996, butyric acid, phenylbutyric acid, 4SC202, romidesin, sirtinol, cambinol, EX-527, nicotinamide, or combinations thereof. Antisense oligonucleotides may be, for example, custirsen, apatorsen, AZD9150, trabadersen, EZN-2968, LErafAON-ETU, or combinations thereof. siRNAs may be, for example, ALN-VSP, CALAA-01, Atu-027, SPC2996, or combinations thereof.

[0732] Hormone therapy can be, for example, luteinizing hormone-releasing hormone (LHRH) antagonists. Hormone therapy can include, for example, firmagon, leuproline, goserelin, buserelin, flutamide, bicalutamide, ketoconazole, aminoglutethimide, prednisone, hydroxyl-progesterone caproate, medroxy-progesterone acetate, megestrol acetate, diethylstil-bestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoromethorphan, flutamide, raloxifene, droloxifene, iodofen, 4-hydroxytamoxifen, trivoxifen, naoxifene, LY117018, onanasone, toremifene citrate, and megestrol acetate. Acetate), exemestane, faldazole, vorazole, letrozole, anastrozole, nilutel, tripterene, histerelin, abiraterone, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluorometholone, retinoic acid, fenivel-Amin, trisatabine or combinations thereof.

[0733] Apoptosis inducers can be, for example, recombinant human TNF-associated apoptosis-inducing ligand (TRAIL), camptothecin, bortezomib, etoposide, tamoxifen, or combinations thereof.

[0734] Angiogenesis inhibitors may be, for example, sorafenib, sunitinib, pazopanib, everolimus, or combinations thereof.

[0735] Immunotherapy agents can be, for example, monoclonal antibodies, cancer vaccines (e.g., dendritic cell (DC) vaccines), oncolytic viruses, cytokines, adoptive T-cell therapy, BCG, GM-CSF, thalidomide, lenalidomide, pomalidomide, imiquimod, or combinations thereof. Monoclonal antibodies can be, for example, anti-CTLA4, anti-PD1, anti-PD-L1, anti-LAG3, anti-KIR, or combinations thereof. Monoclonal antibodies can be, for example, alemtuzumab, trastuzumab, ibritumomab tiuxetan, brentuximab vedotin, trastuzumab, ado-trastuzumab bemtansine, blinatumomab, bevacizumab, cetuximab, pertuzumab, panitumumab, ramucirumab, obbituzumab, oframumab, rituximab, pertuzumab, tosimomab, gemtuzumab ozogamicin, tosimomab, or combinations thereof. Cancer vaccines can be, for example, Sipuleucel-T, BioVaxID, NeuVax, DCVax, SuVaxM, etc. HSP110 chaperone complex vaccine, CDX-1401, MIS416, CDX-110, GVAX Pancreas, HyperAcute TM Pancreas, GTOP-99 or Imprime Oncolytic viruses can be, for example, talimogene laherparepvec. Cytokines can be, for example, IL-2, IFNα, or combinations thereof. Adoptive T-cell therapy can be, for example, tisagenlecleucel, axicabtagene ciloleucel, or combinations thereof.

[0736] DNA damage repair inhibitors can be, for example, PARP inhibitors, cell checkpoint kinase inhibitors, or combinations thereof. PARP inhibitors can be, for example, olaparib, rucaparib, veliparib (ABT-888), niraparib (ZL-2306), iniparib (BSI-201), tazopanib (BMN 673), 2X-121, CEP-9722, KU-0059436 (AZD2281), PF-01367338, or combinations thereof. Cell checkpoint kinase inhibitors can be, for example, MK-1775 or AZD1775, AZD7762, LY2606368, PF-0477736, AZD0156, GDC-0575, ARRY-575, CCT245737, PNT-737, or combinations thereof.

[0737] Example

[0738] The following examples are intended to illustrate the invention. They are not intended to limit the invention in any way.

[0739] Unless otherwise described in the examples below, the reaction is typically performed using an anhydrous solvent (Sure / Seal). TM The reaction was carried out under a nitrogen atmosphere at room temperature (rt or RT). The reaction was measured by TLC or by Waters Acquity-H The Class system uses a small aliquot of sample injected for monitoring. UPLC HSS C182.1 x 30 mm column, eluted with a gradient of acetonitrile (15% to 98%) in water (both containing 0.1% formic acid) for 1.86 min. Unless otherwise specified, purification was performed by preparative HPLC at Teledyne Isco Combi. The following two methods are used on the EZ Prep system: Phenomenex 5μm NX-C18 150x21.2mm column, flow rate 40mL / min, duration 12min (<100mg or multiple injections <100mg); or HP C18 Rf gold column (>100 mg), eluted with an appropriate gradient of acetonitrile in water (both containing 0.1% formic acid). According to the method described at WatersAcquity-H The retention time selection gradient observed by reaction monitoring on the Class system (see above). Fractions containing the desired compounds were combined and finally lyophilized. Purification by silica gel chromatography was performed at Teledyne Isco Combi. Use an appropriate size on the Rf system The reaction was performed using an Rf silica gel column. The purity of the final compound was determined by Waters Acquity- The Class system uses a small aliquot of sample for evaluation. UPLC BEH C18 2.1x50mm column, eluted with a gradient of acetonitrile (2% to 98%) in water (both containing 0.1% formic acid) for 7 min.

[0740] Example 1. Preparation of the compound

[0741] intermediates

[0742]

[0743] Intermediate A (7-amino-6-bromoquinoline-8-formonitrile)

[0744] Step 1. 8-Bromoquinoline-7-amine (100 mg, 448.3 μmol), copper cyanide (50 mg, 558 μmol), and NMP (2 mL) were charged into a microwave reaction tube. Nitrogen gas was bubbled through the reaction solution for 10 minutes, and the mixture was heated in a microwave reactor at 170 °C for 1.5 h. The reaction mixture was purified by preparative HPLC to provide 7-aminoquinoline-8-carboxynitrile (33 mg, 44% yield). MS: [M+H] + :170.2.

[0745] Step 2. Acetic acid (150 μL) and N-bromosuccinimide (55 mg, 307 μmol) were added to 7-aminoquinoline-8-carboxynitrile (40 mg, 236 μmol) in ACN (3 mL). The mixture was stirred at 90 °C for 17 h. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography, eluting with an EtOAc gradient in 0 to 95% hexane to provide 7-amino-6-bromo-quinoline-8-carboxynitrile (15 mg, 26% yield). MS: [M+H] + :248.0.

[0746]

[0747] Intermediate B (ethyl 5-amino-2-chloro-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-4-carboxylate)

[0748] To a solution of ethyl 5-amino-2,6-dichloro-pyrimidin-4-carboxylate (800 mg, 3.4 mmol) in dioxane (9 mL), [5-(methoxymethoxy)-2-methyl-phenyl]boronic acid (680 mg, 3.5 mmol), Pd(PPh3)4 (200 mg, 173 μmol), and 2 M sodium carbonate aqueous solution (3.2 mL, 6.4 mmol) were added. The mixture was degassed under vacuum, backfilled with N2, and stirred at 100 °C for 5 h. The mixture was diluted with EtOAc (80 mL), washed successively with water and brine, dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by rapid silica gel chromatography, eluting with EtOAc / hexane 0–40% to provide ethyl 5-amino-2-chloro-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidin-4-carboxylate (760 mg, 64% yield). MS: [M+H] + 352.2; 1¹H NMR (400 MHz, chloroform-d) δ 7.31–7.16 (m, 1H), 7.02 m, 1H), 6.92 (m, 1H), 5.71 (s, 2H), 5.11 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 3.41 (s, 3H), 2.09 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).

[0749]

[0750] Intermediate C(5-amino-2-chloro-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-4-carboxamide)

[0751] Step 1. Add 1M sodium hydroxide aqueous solution (3 mL, 3 mmol) to a solution of intermediate B (760 mg, 2.16 mmol) in MeOH (3 mL) and THF (10 mL). Stir the mixture at rt for 2 h. Then acidify it to pH 4 with 1M HCl aqueous solution and extract with EtOAc 3X. Wash the combined organic extracts with brine, dry with sodium sulfate, filter and concentrate to provide 5-amino-2-chloro-6-[5-(methoxymethoxy)-2-methyl-phenyl]pyrimidine-4-carboxylic acid (590 mg, yield 84%). MS: [M+H]+: 320.2.

[0752] Step 2. To a solution of 5-amino-2-chloro-6-[5-(methoxymethoxy)-2-methylphenyl]pyrimidine-4-carboxylic acid (520 mg, 1.61 mmol) in DMF (20 mL), HATU (780 mg, 2.05 mmol), a solution of 0.5 M ammonia in dioxane (10 mL, 5 mmol), and triethylamine (330 μL, 2.37 mmol) were added. The mixture was stirred at 50 °C for 1 h. The mixture was concentrated to a small volume under vacuum, then diluted with water, stirred at rt for 20 min, and filtered. The solid was washed with water and dried under vacuum to obtain 5-amino-2-chloro-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-4-carboxamide (420 mg, 81% yield).

[0753]

[0754] Intermediate D (ethyl 3-amino-4-bromo-6-chloropyridinecarboxylate)

[0755] Step 1. To a solution of 3-amino-6-chloro-pyridine-2-carboxylic acid (60.0 g, 347.7 mmol) in DMF (650 mL), K₂CO₃ (50.6 g, 366.11 mmol), iodoethane (31 mL, 385.60 mmol), and tetrabutylammonium iodide (579 mg, 1.74 mmol) were added. The mixture was stirred overnight at rt, then transferred to a 4 L Erlenmeyer flask and cooled in an ice bath. The mixture was diluted with water (2 L) and stirred for 90 min. The solid was collected by filtration, washed with water, and dried under vacuum to give ethyl 3-amino-6-chloro-pyridine-2-carboxylate (61.5 g, 88% yield). MS: [M+H]+: 201.1.

[0756] Step 2. NBS (15.0 g, 84.3 mmol) was added to a solution of ethyl 3-amino-6-chloro-pyridine-2-carboxylate (13.08 g, 65.2 mmol) in DMF (130 mL). The mixture was stirred overnight at rt. The mixture was cooled in an ice bath and water (260 mL) was added dropwise. The solid was collected by filtration through a Buchner funnel. This solid was suspended in a 20% by weight aqueous solution of Na₂S₂O₃ (60 mL) and a saturated aqueous solution of NaHCO₃ (130 mL), and stirred at rt for about 30 min. The solid was collected by filtration through a Buchner funnel, washed with water, and then dried under vacuum to give ethyl 3-amino-4-bromo-6-chloro-pyridine-2-carboxylate (13.68 g, 75% yield). MS: [M+H] + 278.9. 1 ¹H NMR (400MHz, chloroform-d) δ 7.54 (s, 1H), 6.36 (s, 2H), 4.43 (q, J = 7.1Hz, 2H), 1.41 (t, J = 7.1Hz, 3H).

[0757]

[0758] Intermediate E (3-amino-6-chloro-4-(3-methoxy-2,6-dimethylphenyl)pyridinecarboxamide)

[0759] Step 1. To a solution of intermediate D (6.0 g, 21.5 mmol) in toluene (100 mL), add 2-(3-methoxy-2,6-dimethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (6.00 g, 22.9 mmol), 2M Na₂CO₃ aqueous solution (21 mL, 42 mmol), 1M tri-tert-butylphosphine solution in toluene (4.2 mL, 4.20 mmol), and Pd₂(dba)₃ (1.95 g, 2.13 mmol). Degas the mixture under vacuum, then backfill with N₂, and stir at 90 °C for 2 h. Volatile substances were removed under vacuum, and the residue was purified by rapid silica gel chromatography, eluting with EtOAc / hexane 0–30% to provide ethyl 3-amino-6-chloro-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxylate (4.56 g, 63% yield). MS: [M+H] + :335.2.

[0760] Step 2. In a 150 mL pressure vessel, add ethyl 3-amino-6-chloro-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxylate (1.45 g, 4.32 mmol) and a solution of 7N ammonia in MeOH (50 mL, 350 mmol). Seal the vessel and stir overnight at 70 °C. Cool the mixture to rt and then concentrate to dryness. Purify the residue by rapid silica gel chromatography, eluting with EtOAc / hexane 0-50% to provide 3-amino-6-chloro-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxamide (1.13 g, 86% yield). MS: [M+H] + :306.2.

[0761]

[0762] Intermediate F (5-amino-6-carbamoyl-4-(3-methoxy-2,6-dimethylphenyl)pyridinecarboxylic acid)

[0763] Step 1. In a MW vial, add 3-amino-6-chloro-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxamide (500 mg, 1.64 mmol), 2-furanylboronic acid (300 mg, 2.68 mmol), and Pd(dppf)Cl2·DCM (133 mg, 162.86 μmol). Add DMF (9 mL) and 2M sodium carbonate aqueous solution (2.0 mL, 4.0 mmol), and bubble the solution through N2. Cap the vial and transfer it to a preheated (120 °C) heating block for 1 h. Cool the mixture to rt and pass it through Celite. TMThe mixture was filtered through a tube and washed in fractions with EtOAc (50 mL total) and water (25 mL total), then diluted with saturated NH4Cl (25 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography, eluting with EtOAc / hexane 0-100% to provide 3-amino-6-(2-furanyl)-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxamide (544 mg, 99% yield). MS: [M+H]+: 338.3.

[0764] Step 2. Potassium permanganate (1.34 g, 8.49 mmol) was added in a single addition to a suspension of 3-amino-6-(2-furanyl)-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxamide (575 mg, 1.70 mmol) in t-BuOH (10 mL) and water (2.5 mL). The solution was sonicated and then stirred at rt. After 75 min, the solution was subjected to Celite... TM The mixture was filtered, washed with MeOH, and concentrated. The residue was purified by reversed-phase rapid chromatography (MeCN in water, both containing 0.1% formic acid) to provide 5-amino-6-carbamoyl-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxylic acid (140 mg, 26% yield). MS: [M+H]+: 316.3.

[0765]

[0766] Intermediate G (ethyl 3-amino-2-bromo-6-chloroisonicotinic acid)

[0767] Step 1. To a solution of 5-amino-2-chloro-pyridine-4-carboxylic acid (5 g, 29.0 mmol) in DMF (55 mL), K₂CO₃ (4.40 g, 31.9 mmol) and iodoethane (2.5 mL, 31.1 mmol) were added. The mixture was stirred overnight at rt for 18 h. 0.2 equivalents of K₂CO₃ (0.8 g, 5.8 mmol) and 0.2 equivalents of iodoethane (465 μL, 5.8 mmol) were added, and the mixture was stirred again at rt for 24 h. The mixture was slowly diluted with water (2 volumes) and stirred for 30 min. The solid was collected by filtration through a Buchner funnel, washed with water, and air-dried overnight to produce ethyl 5-amino-2-chloro-pyridine-4-carboxylate (4.4 g, 76% yield). MS: [M+H]+: 201.1.

[0768] Step 2. NBS (4.7 g, 26.4 mmol) was added to a solution of ethyl 5-amino-2-chloro-pyridine-4-carboxylate (4.4 g, 21.9 mmol) in DMF (50 mL). The mixture was stirred at rt for 2 h. Water (twice the volume) was slowly added and the precipitate was recovered by filtration to produce ethyl 3-amino-2-bromo-6-chloroisonicotinic acid (5.1 g, 83% yield). MS: [M+H] + 278.9; 280.9; 282.9.

[0769]

[0770] Intermediate H (3-amino-6-chloro-2-(3-methoxy-2,6-dimethylphenyl)isonicotinamide)

[0771] Step 1. Add 2-(3-methoxy-2,6-dimethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.05 g, 4.01 mmol), Pd2(dba)3 (330 mg, 360.37 μmol), and 2M K3PO4 aqueous solution (3.6 mL, 7.2 mmol) to a solution of intermediate G (1.0 g, 3.58 mmol) in dioxane (20 mL). Degas the mixture under vacuum and then backfill with N2. Add tri-tert-butylphosphine tetrafluoroborate (210 mg, 723.8 μmol) and degas the mixture twice more, then stir at 90 °C for 2 h. Volatile substances were removed under vacuum, and the residue was purified by rapid chromatography, eluting with EtOAc / hexane 0-30% to provide ethyl 3-amino-6-chloro-2-(3-methoxy-2,6-dimethyl-phenyl)pyridine-4-carboxylate (1.05 g, 88% yield). MS: [M+H] + :335.2.

[0772] Step 2. A solution of 7N ammonia in MeOH (10 mL, 70 mmol) was added to ethyl 3-amino-6-chloro-2-(3-methoxy-2,6-dimethyl-phenyl)pyridine-4-carboxylate (500 mg, 1.49 mmol) in a Parr pressure vessel. The vessel was sealed with Teflon and heated to 130 °C for 4 h. After cooling to RT, the solution was concentrated to dryness. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in hexane to provide 3-amino-6-chloro-2-(3-methoxy-2,6-dimethyl-phenyl)pyridine-4-carboxamide (200 mg, 44% yield) and methyl 3-amino-6-chloro-2-(3-methoxy-2,6-dimethyl-phenyl)pyridine-4-carboxylate (175 mg, 37%). MS: [M+H] + :306.2.

[0773]

[0774] Intermediate I (2-amino-3'-(methoxymethoxy)-2',6'-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-[1,1'-biphenyl]-3-carboxamide)

[0775] Step 1. In a pressure vessel, add 2-amino-5-bromo-3-iodobenzamide (0.5 g, 1.47 mmol), dioxane (5 mL), water (1 mL), Na₂CO₃ (0.233 g, 2.19 mmol), and (3-(methoxymethoxy)-2,6-dimethylphenyl)boronic acid (0.436 g, 1.49 mmol). Purge the mixture with N₂ for 10 min, then add Pd(PPh₃)₄ (0.084 g, 0.073 mmol). Seal the vessel and stir the mixture at 80 °C for 5 h. Quench the reaction mixture in water (20 mL) and extract with EtOAc (3 x 10 mL). Dry the combined organic layers with Na₂SO₄, filter, and concentrate. The residue was purified by silica gel chromatography, eluting with EtOAc in 35% hexane to provide 2-amino-5-bromo-3'-(methoxymethoxy)-2',6'-dimethyl-[1,1'-biphenyl]-3-carboxamide (0.107 g, 16%). MS: [M+H] + 379.4

[0776] Step 2. In a pressure vessel, add 2-amino-5-bromo-3'-(methoxymethoxy)-2',6'-dimethyl-[1,1'-biphenyl]-3-carboxamide (0.1 g, 0.264 mmol), dioxane (3 mL), Cs₂CO₃ (0.215 g, 0.659 mmol), and bis(pinacol)diboron (0.133 g, 0.527 mmol). Purge the vessel with N₂ gas for 10 min, then add PdCl₂(dppf) (0.038 g, 0.0527 mmol). Seal the vessel and stir the reaction mixture at 100 °C for 2 h. Quench the reaction mixture with water (10 mL) and extract with EtOAc (3 x 10 mL). Dry the combined organic layers with Na₂SO₄, filter, and concentrate. The residue was purified by silica gel chromatography, eluting with EtOAc in 35% hexane to provide 2-amino-3'-(methoxymethoxy)-2',6'-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-[1,1'-biphenyl]-3-carboxamide (0.08 g, 71%). MS: [M+H] + 427.2.4

[0777]

[0778] Intermediate J (5-amino-2-chloro-6-(5-methyl-1H-indazol-4-yl)pyrimidin-4-carboxamide)

[0779] Step 1. Degas the mixture of ethyl 5-amino-2,6-dichloropyrimidin-4-carboxylate (4.92 g, 20.84 mmol), (5-methyl-1H-indazole-4-yl)boronic acid (3.67 g, 20.84 mmol), and Na₂CO₃ (3.53 g, 33.35 mmol) in dioxane (50 mL) and water (5 mL) by bubbling in N₂. Then add Pd(PPh₃)₄ (1.44 g, 1.25 mmol). Degas the solution again and heat at 80 °C overnight. Cool the reaction mixture to rt, pour into water (100 mL), and extract with EtOAc (2 × 50 mL). Wash the combined organic layers with brine, dry with Na₂SO₄, filter, and concentrate under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in heptane to give ethyl 5-amino-2-chloro-6-(5-methyl-1H-indazol-4-yl)pyrimidine-4-carboxylate (3.86 g, 56% yield). MS: [M+H] + :332.0.

[0780] Step 2. To a suspension of ethyl 5-amino-2-chloro-6-(5-methyl-1H-indazol-4-yl)pyrimidine-4-carboxylic acid (3.86 g, 11.64 mmol) in THF (17 mL) and MeOH (17 mL), 4M sodium hydroxide aqueous solution (28 mL, 112 mmol) was added. After stirring for 70 min, the pH was adjusted to 4–5 with 3N HCl aqueous solution and diluted with water (50 mL). The resulting suspension was stirred at 0 °C for 2 h, and the solid was collected by filtration and washed with water. The solid was air-dried overnight to provide 5-amino-2-chloro-6-(5-methyl-1H-indazol-4-yl)pyrimidine-4-carboxylic acid (2.73 g, 77% yield). MS: [M+H] + :304.0.

[0781] Step 3. In a pressure vessel, charge 5-amino-2-chloro-6-(5-methyl-1H-indazol-4-yl)pyrimidine-4-carboxylic acid (2.62 g, 8.63 mmol), ammonium chloride (2.31 g, 43.10 mmol), and HATU (3.90 g, 10.27 mmol). Add DMF (27 mL), followed by DIPEA (9.2 mL, 52.82 mmol). Seal the vessel and stir at 80 °C for 75 min. While stirring, slowly add water to the cooled reaction mixture. Collect the precipitate by filtration, wash with water, and air-dry overnight to provide 5-amino-2-chloro-6-(5-methyl-1H-indazol-4-yl)pyrimidine-4-carboxamide (2.19 g, 84% yield). MS: [M+H] + :303.0; 1 H NMR (400MHz, DMSO-d6) δ13.16(s,1H),8.23(s,1H),7.89(s,1H),7.69(s,1H),7.60(d,J=8.5Hz,1H),7.35(d,J=8.5Hz,1H),6.50(br s,2H),2.20(s,3H).

[0782]

[0783] Intermediate K (3-amino-6-chloro-4-(5-methyl-1H-indazol-4-yl)pyridinecarboxamide)

[0784] Step 1. To a solution of intermediate G (30.10 g, 107.7 mmol) and (5-methyl-1H-indazole-4-yl)boronic acid (22.66 g, 128.8 mmol) in dioxane (200 mL) and 2M K3PO4 aqueous solution (110 mL, 220 mmol), Pd2(dba)3 (2.50 g, 2.73 mmol) and 1M tri-tert-butylphosphine in toluene (10.7 mL, 10.7 mmol) were added. The mixture was degassed by bubbling N2 and stirred at 90 °C for 4.5 h. The cooled reaction mixture was concentrated. Water (600 mL) was added dropwise. The solid was collected by filtration, washed with water, air-dried, and ground with heptane (250 mL) to provide ethyl 3-amino-6-chloro-4-(5-methyl-1H-indazole-4-yl)pyridine-2-carboxylate (25.63 g, 72% yield). MS:[M+H] + :331.1.

[0785] Step 2. Ethyl 3-amino-6-chloro-4-(5-methyl-1H-indazole-4-yl)pyridine-2-carboxylate (9.24 g, 27.9 mmol) in a solution of 7N ammonia in MeOH (300 mL, 2.1 mol) was heated to 100 °C overnight in a pressure vessel. The mixture was cooled to rt, concentrated to dryness, co-evaporated with DCM / MeOH, then co-evaporated with DCM / heptane, and dried under vacuum to provide 3-amino-6-chloro-4-(5-methyl-1H-indazole-4-yl)pyridine-2-carboxamide (8.35 g, 99% yield). MS: [M+H] + 302.0

[0786]

[0787] Intermediate L (ethyl 5-amino-6-bromo-2-phenylpyrimidine-4-carboxylate)

[0788] Step 1. Ethyl 5-amino-2-chloro-pyrimidin-4-carboxylate (3.97 g, 19.7 mmol), phenylboronic acid (3.59 g, 29.4 mmol), and Pd(dppf)Cl2 (1.43 g, 1.95 mmol) were charged into an RBF. Dioxane (80 mL) and 2 M Na2CO3 aqueous solution (30 mL, 60 mmol) were added, and the mixture was bubbled through with N2. The flask was equipped with a condenser and heated to 100 °C for 2 h. The cooled reaction mixture was diluted with water (150 mL) and extracted with DCM (2 x 50 mL). The combined organic extracts were washed with water and brine (100 mL each), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in heptane to give ethyl 5-amino-2-phenyl-pyrimidin-4-carboxylate (3.99 g, 83% yield). MS: [M+H] + :244.2.

[0789] Step 2. Add NBS (2.21 g, 12.4 mmol) to a solution of ethyl 5-amino-2-phenyl-pyrimidin-4-carboxylate (2.06 g, 8.47 mmol) in DMF (20 mL). Stir the solution at rt for 45 min. Add more NBS (292 mg, 1.64 mmol) and stir the solution at rt for another 90 min. Dilute the reaction mixture with EtOAc (80 mL) and saturated NaHCO3 aqueous solution (80 mL). Extract the aqueous layer with EtOAc (2 x 40 mL) and wash the combined organic layers with 20% (w / w) Na2S2O4 aqueous solution (40 mL) and brine (40 mL), dry over Na2SO4, filter and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of EtOAc (0 to 50%) in heptane to give ethyl 5-amino-6-bromo-2-phenyl-pyrimidin-4-carboxylate (1.07 g, 39% yield). MS:[M+H] + 324.1; 1 ¹H NMR (400MHz, chloroform-d) δ 8.38–8.20 (m, 2H), 7.50–7.35 (m, 3H), 6.22 (br s, 2H), 4.49 (q, J = 7.1Hz, 2H), 1.49 (t, J = 7.1Hz, 3H).

[0790]

[0791] Intermediate M (3-amino-6-chloro-2-(5-methyl-1H-indazol-4-yl)isonicotinamide)

[0792] To a solution of intermediate G (5 g, 17.9 mmol) in dioxane (100 mL), (5-methyl-1H-indazol-4-yl)boronic acid (3.5 g, 19.9 mmol), Pd2(dba)3 (1.65 g, 1.80 mmol), and 2M K3PO4 aqueous solution (18 mL, 36 mmol) were added. The mixture was degassed under vacuum, backfilled with N2, and stirred at 90 °C for 2 h. Volatiles were removed under vacuum, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide ethyl 3-amino-6-chloro-2-(5-methyl-1H-indazol-4-yl)pyridine-4-carboxylate (5.3 g, 90% yield). MS: [M+H] + :302.0.

[0793]

[0794] Intermediate N(3-amino-4-(5-methyl-1H-indazol-4-yl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridinecarboxamide)

[0795] Step 1. In a pressure vessel, intermediate K (0.39 g, 1.29 mmol) and DMF (4 mL) were charged. LiCl (0.5 M in THF) (5.2 mL, 2.38 mmol) was added, followed by 2-(methylthio)-4-(tributyltinyl)pyrimidine (0.644 g, 1.68 mmol). The reaction mixture was purged with N2 gas, and then CuI (0.039 g, 0.192 mmol) and Pd(ddpf)Cl2·DCM (0.105 g, 0.129 mmol) were added. The resulting mixture was stirred at 120 °C for 4 h. The cooled reaction mixture was quenched in water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluted with methanol in 2% dichloromethane to provide 3-amino-4-(5-methyl-1H-indazol-4-yl)-6-(2-(methylthio)pyrimidin-4-yl)pyridinecarboxamide (0.28 g, 55% yield). MS: [M+H] + :392.2.

[0796] Step 2. 3-Amino-4-(5-methyl-1H-indazole-4-yl)-6-(2-(methylthio)pyrimidin-4-yl)pyridinecarboxamide (0.28 g, 0.7161 mmol) and THF (3 mL) were charged into a pressure vessel. This solution was added in portions to a stirring solution of water (1 mL) and Oxone (0.88 g, 2.864 mmol), and the reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with water (30 mL) and then extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The residue was ground with n-pentane to provide 3-amino-4-(5-methyl-1H-indazole-4-yl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridinecarboxamide (0.2 g, 66% yield). MS: [M+H] + :424.5.

[0797]

[0798] Intermediate O (5-amino-6'-fluoro-4-(5-methyl-1H-indazol-4-yl)-[2,2'-bipyridine]-6-carboxamide)

[0799] The suspensions of tributyl-(6-fluoro-2-pyridyl)stanane (3.84 g, 9.94 mmol), 3-amino-6-chloro-4-(5-methyl-1H-indazol-4-yl)pyridine-2-carboxamide (3 g, 9.94 mmol), copper iodide (I) (239 mg, 1.26 mmol), LiCl (870 mg, 20.5 mmol), and Pd(dppf)Cl2·DCM (761 mg, 968.1 μmol) in DMF (30 mL) were degassed, backfilled with N2, and then stirred at 120 °C for 2 h. The crude reaction mixture was filtered, and the filtrate was purified by preparative HPLC using a C18 column, eluting with ACN / water / 0.1% formic acid to provide 3-amino-6-(6-fluoro-2-pyridyl)-4-(5-methyl-1H-indazol-4-yl)pyridine-2-carboxamide (2.12 g, 59% yield). MS: [M+H] + :363.1.

[0800]

[0801] Intermediate P(5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole)

[0802] Step 1. To a suspension of 5-bromo-4-chloro-1H-indazole (2 g, 8.64 mmol) in DCM (49 mL), p-toluenesulfonic acid monohydrate (164 mg, 0.86 mmol) and 3,4-dihydro-2H-pyran (2.4 mL, 26.31 mmol) were added at rt. The mixture was stirred at rt for 4 h. A saturated aqueous solution of NaHCO3 was slowly added. The layers were partitioned and the organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 5-bromo-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.0 g, 73% yield). 1 H-NMR (400MHz, DMSO): δ8.18 (s; 1H); 7.69-7.70 (m; 2H); 5.88 (dd; J=9.44; 2.35Hz; 1H); 3.83-3.86 (m ; 1H); 3.68-3.76 (m; 1H); 2.28-2.37 (m; 1H); 1.94-2.02 (m; 2H); 1.70-1.74 (m; 1H); 1.42-1.60 (m; 2H).

[0803] Step 2. A mixture of 5-bromo-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.7 g, 11.7 mmol) and pinacol vinylborate (3 mL, 17.7 mmol) in dioxane (37 mL) and 2M Na₂CO₃ aqueous solution (8.8 mL, 17.6 mmol) was degassed under a nitrogen atmosphere, followed by the addition of Pd(PPh₃)₄ (677 mg, 0.586 mmol). The mixture was degassed again and heated to 100 °C for 18 h. After cooling to rt, the mixture was diluted with EtOAc and water and passed through Celite. TM Filtration. The layers were partitioned and the organic layer washed with brine, dried over MgSO4, filtered, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 45%) in heptane to provide 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl-1H-indazole (2.5 g, 81%). MS: [M+H] + :263.1.

[0804] Step 3. To a solution of 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl-1H-indazole (2.5 g, 9.5 mmol) in THF (50 mL) and water (12.5 mL), add OsO4 (4% in water, 6 mL, 0.944 mmol) and NaIO4 (10 g, 46.7 mmol). Stir the reaction mixture at rt for 18 h. Add EtOAc (120 mL) and water (120 mL). Distribute the layers and extract the aqueous layer with EtOAc (120 mL). Wash the combined organic layers with brine, dry over MgSO4, filter, and concentrate to dryness. Purify the residue by silica gel chromatography, eluting with a gradient of EtOAc (0 to 45%) in heptane to provide 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxaldehyde as a colorless oil. (1.1g, yield 44%). MS: [M-THP+H] + :181.0.

[0805] Step 4. Under reflux, XtalFluor-E (2.0 g, 8.73 mmol) was added to a solution of 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxaldehyde (1.1 g, 4.16 mmol) in DCM (40 mL), followed by the addition of triethylamine trihydrofluoride (1.4 mL, 8.59 mmol). The reaction mixture was stirred under reflux for 18 h. A saturated aqueous solution of NaHCO3 was added dropwise to adjust the pH to approximately 8. The layers were partitioned and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 40%) in heptane to provide 4-chloro-5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.69 g, 58% yield). MS:[M-THP+H] + :203.0.

[0806] Step 5. To a solution of 4-chloro-5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (250 mg, 0.872 mmol) in dioxane (3 mL), add bis(pinacol)diboron (443 mg, 1.75 mmol), KOAc (260 mg, 2.62 mmol), tricyclohexylphosphine (61 mg, 0.218 mmol), and Pd2(dba)3 (40 mg, 0.044 mmol). Degas the mixture and refill with argon (3 cycles), and heat to 100 °C for 3 h. After cooling to rt, add water (40 mL) and EtOAc (35 mL). Distribute the layers, and extract the aqueous layer with EtOAc (25 mL). Wash the combined organic layers with brine, dry over MgSO4, filter, and concentrate under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 40%) in heptane to provide 5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole. MS: [M+H] + :379.2[M+1]+.

[0807]

[0808] Intermediate Q (ethyl 5-amino-4-bromo-[2,3'-bipyridine]-6-carboxylate)

[0809] Step 1. A mixture of ethyl 3-amino-6-chloropyridinecarboxylate (2.8 g, 14.0 mmol), 3-(tributyltinyl)pyridine (7.7 g, 20.9 mmol), CuI (532 mg, 2.79 mmol), LiCl (1.21 g, 27.9 mmol), and DMF (28 mL) was degassed and backfilled under a nitrogen atmosphere. Pd(dppf)Cl2·DCM (570 mg, 0.698 mmol) was added. The mixture was then degassed and backfilled again under a nitrogen atmosphere. The mixture was heated to 120 °C for 18 h. After cooling to rt, the mixture was diluted with EtOAc and water and passed through Celite. TM Filtration. The layers were partitioned and the aqueous layer was extracted again with EtOAc. The combined layers were washed with brine and dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a MeOH gradient (0 to 6%) in EtOAc to provide ethyl 5-amino-[2,3'-bipyridine]-6-carboxylate (1.38 g, 46% yield). MS: [M+H] + :244.1[M+1]+; 1 ¹H NMR (400MHz, chloroform-d) δ(s; 1H); 8.58 (d; J = 4.70 Hz; 1H); 8.27–8.29 (m; 1H); 7.71 (d; J = 8.67 Hz; 1H); 7.37 (dd; J = 7.97; 4.78 Hz; 1H); 7.16 (d; J = 8.66 Hz; 1H); 5.85 (s; 2H); 4.46 (q; J = 7.13 Hz; 2H); 1.48 (t; J = 7.12 Hz; 3H).

[0810] Step 2. Sulfuric acid (0.32 mL, 6.0 mmol) was added to a suspension of ethyl 5-amino-[2,3'-bipyridine]-6-carboxylate (730 mg, 3.0 mmol) in water (20 mL) at 5 °C. Bromine (0.19 mL, 3.71 mmol) in acetic acid (2 mL, 34.94 mmol) was added dropwise, and the mixture was stirred at rt for 3 h. The reaction mixture was diluted with water (40 mL) and neutralized by adding solid NaHCO3 (exothermic quenching). The mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed sequentially with saturated NaHCO3 aqueous solution, water, and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (30 to 100%) in heptane to provide ethyl 5-amino-4-bromo-[2,3'-bipyridine]-6-carboxylate (0.66 g, 75% yield). MS:[M+H] + :322.0 / 324.0.

[0811]

[0812] Intermediate R(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-N-(2,2,2-trifluoroethyl)aniline)

[0813] Step 1. Add Na₂CO₃ (5.00 g, 47.17 mmol) to a solution of 2-bromoaniline (5.06 g, 29.41 mmol) in Et₂O (30 mL). Cool the mixture to 0 °C and add trifluoroacetic anhydride (5.39 mL, 38.3 mmol) dropwise. Remove the ice bath and stir the reaction mixture at rt for 5.5 h. Pour the reaction mixture into water and extract with EtOAc (3X). Wash the combined organic layers with brine, dry over Na₂SO₄, filter, and concentrate to provide N-(2-bromophenyl)-2,2,2-trifluoroacetamide (7.67 g, 97% yield). MS: [M+H] + 268.2; 1 ¹H NMR (400MHz, chloroform-d) δ 8.45 (br s, 1H), 8.32 (dd, J = 8.2, 1.6Hz, 1H), 7.61 (dd, J = 8.1, 1.4Hz, 1H), 7.40 (ddd, J = 8.1, 7.5, 1.5Hz, 1H), 7.13 (ddd, J = 8.2, 7.5, 1.6Hz, 1H).

[0814] Step 2. Add a 1M borane THF solution (15 mL, 15 mmol) to a solution of N-(2-bromophenyl)-2,2,2-trifluoroacetamide (2.04 g, 7.61 mmol) in THF (5 mL). Stir the mixture under reflux overnight. Add MeOH (5 mL) dropwise to the cooled reaction mixture, and then stir under reflux for 2 h, followed by concentration. Purify the residue by silica gel chromatography, eluting with a gradient of EtOAc (0 to 50%) in heptane to provide 2-bromo-N-(2,2,2-trifluoroethyl)aniline (463 mg, 24% yield). 1 ¹H NMR (400MHz, chloroform-d) δ 7.46 (dd, J = 7.9, 1.5Hz, 1H), 7.21 (ddd, J = 8.6, 7.4, 1.5Hz, 1H), 6.80–6.73 (m, 1H), 6.68 (td, J = 7.6, 1.4Hz, 1H), 4.68 (br s, 1H), 3.83 (qd, J = 8.8, 7.0Hz, 2H).

[0815] Step 3. Add dioxane (8 mL) to a MW vial containing 2-bromo-N-(2,2,2-trifluoroethyl)aniline (463 mg, 1.82 mmol), bis(pinacol)diboron (555 mg, 2.19 mmol), and KOAc (533 mg, 5.43 mmol). Bubble the solution through N2 and add Pd(dppf)Cl2·DCM (157 mg, 192.25 μmol). Bubble the solution through N2 again, cap the vial, and transfer it to a preheated (100 °C) heating block for 1 h. Dilute the cooled reaction mixture with DCM and adsorb it onto silica gel. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in heptane to provide 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-N-(2,2,2-trifluoroethyl)aniline (265 mg, 48% yield). MS: [M+H] + :302.0.

[0816]

[0817] Intermediate S(1-methyl-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)cyclopropane-1-carboxamide)

[0818] 1-Methylcyclopropanecarboxylic acid (5.00 g, 49.94 mmol) was added to a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (10 g, 45.6 mmol), HATU (19.1 g, 50.2 mmol), and DIPEA (16.70 mL, 95.9 mmol) in DMF (100 mL). The reaction mixture was stirred at RT for 18 h. Water (300 mL) was slowly added and the white precipitate was recovered by filtration, washed with water, and dried under an air stream for 5 h to provide 1-methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl]cyclopropanecarboxamide (11.1 g, 81% yield). 1 H NMR (400MHz, chloroform-d) δ9.62(s,1H),8.48(dd,J=8.5,1.0Hz,1H),7.75(dd,J=7.4,1.7Hz,1H),7.41(ddd,J=8.8,7. 3,1.8Hz,1H),7.03(td,J=7.4,1.1Hz,1H),1.72(s,1H),1.36(s,12H),1.30(q,J=3.9Hz,2H),0.68–0.63(m,2H).

[0819]

[0820] Intermediate T(5-amino-2-(2-aminophenyl)-6-(5-methyl-1H-indazol-4-yl)pyrimidin-4-carboxamide)

[0821] To a solution of intermediate J (0.4 g, 1.32 mmol) in dioxane (6 mL), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (320 mg, 1.46 mmol), an aqueous solution of 2MK₂CO₃ (1.9 mL, 3.8 mmol), and Pd(dppf)Cl₂ (80 mg, 109.3 μmol) were added. The mixture was degassed under vacuum, backfilled with N₂, and stirred at 110 °C for 8 h. The mixture was diluted with water and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (50 to 100%) in heptane to provide 5-amino-2-(2-aminophenyl)-6-(5-methyl-1H-indazol-4-yl)pyrimidin-4-carboxamide (330 mg, 69% yield). MS: [M+H] + 360.2.

[0822]

[0823] Intermediate U(N-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline)

[0824] To a MW vial containing bis(pinacol)diboron (336 mg, 1.32 mmol), Pd(dppf)Cl2·DCM (110 mg, 134.7 μmol), and KOAc (356 mg, 3.63 mmol), 2-bromo-N-tert-butylaniline (263 mg, 1.15 mmol) and dioxane (4 mL) were added. The solution was bubbled through with N2, the vial was capped, and the vial was transferred to a preheated (100 °C) heating block overnight. The cooled reaction mixture was diluted with DCM and adsorbed onto silica gel. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in heptane to provide N-tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (135 mg, 43% yield). MS: [M+H] + :276.2.

[0825]

[0826] Intermediate V(2-(tributyltinyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine)

[0827] Step 1. At 0 °C, Et3N (2.8 mL, 20.1 mmol) was added to a solution of 2-bromopyridin-3-ol (2.5 g, 14.4 mmol) in DMF (13 mL), followed by 2-(trimethylsilyl)ethoxymethyl chloride (2.7 mL, 15.3 mmol). The reaction mixture was slowly heated and stirred at rt for 4 h. The reaction mixture was diluted with water and hexane-EtOAc (1:1). The layers were partitioned and the aqueous layer was extracted with hexane-EtOAc (1:1). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 2-bromo-3-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (2.5 g, 57% yield). MS: [M+H] + :304.1 / 306.1. 1 H-NMR (400MHz, CDCl3): δ8.04 (dd; J=4.61; 1.60Hz; 1H); 7.45 (dd; J=8.11; 1.60Hz; 1H); 7.20 (dd ; J=8.14; 4.63Hz; 1H); 5.32 (s; 2H); 3.80 (t; J=8.36Hz; 2H); 0.95 (t; J=8.34Hz; 2H); 0.00 (s; 9H).

[0828] Step 2. Add dropwise a solution of 3-bromo-4-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (2.5 g, 8.2 mmol) in THF (8 mL) to a solution of n-BuLi (6.6 mL, 16.5 mmol) in THF (34 mL) at -78 °C. Stir the reaction mixture at -78 °C for 20 min. Add tributyltin chloride (2.5 mL, 9.216 mmol) to the reaction mixture. Stir the mixture at -78 °C for 40 min and then at rt for 1.5 h. Add water (40 mL) and remove volatiles under vacuum. Extract the mixture with DCM (2 x 40 mL). Wash the combined organic layers with brine, dry over MgSO4, filter, and concentrate. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 3-(tributyltinyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (1.5 g, 35% yield). MS: [M+H] + :516.2. 1H-NMR (400MHz, CDCl3): δ8.41 (d; J=4.66Hz; 1H); 7.28 (d; J=8.40Hz; 1H); 7.07 (dd; J=8.39; 4.66Hz; 1H); 5.20 (s; 2H); 3.73 (t; J=8. 31Hz; 2H); 1.51-1.57 (m; 8H); 1.25-1.34 (m; 8H); 1.07-1.14 (m; 8H); 0.95 (t; J=8.26Hz; 2H); 0.87 (t; J=7.31Hz; 12H); 0.00 (s; 9H).

[0829]

[0830] Intermediate W(6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole)

[0831] Step 1. 3,4-Dihydro-2H-pyran (15.93 g, 189.35 mmol, 17.2 mL) was added to a solution of 4-bromo-6-fluoro-1H-indazole (20 g, 93.01 mmol) and p-toluenesulfonic acid (800 mg, 4.65 mmol) in EtOAc (100 mL). The mixture was stirred under reflux for 3 h. Volatile substances were removed under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 10%) in heptane to provide 4-bromo-6-fluoro-1-tetrahydropyran-2-yl-indazole (23.9 g, 86% yield). MS: [M+H] + :299.0 / 301.0.

[0832] Step 2. Under an inert atmosphere, a 2M solution of lithium diisopropylaminotrimethylammonium in THF / hexane / ethylbenzene (5.5 mL, 11.0 mmol) was added dropwise to 4-bromo-6-fluoro-1-tetrahydropyran-2-yl-indazole (1 g, 3.34 mmol) in THF (15 mL). The mixture was stirred at -78 °C for 4 h. Iodomethane (750 μL, 12.05 mmol) was slowly added. The mixture was stirred at -78 °C for 30 min, and then heated to rt. The mixture was quenched with a saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 15%) in heptane to provide 4-bromo-6-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (750 mg, 72% yield). MS: [M-TFP+H] + :229.0 / 231.0.

[0833] Step 3. In a flask, add 4-bromo-6-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (800 mg, 2.55 mmol), KOAc (765 mg, 7.79 mmol), bis(pinacol)diboron (750 mg, 2.95 mmol), and dioxane (10 mL). Degas the mixture with nitrogen for 5 min, and add Pd(dppf)Cl2·DCM (125 mg, 153.00 μmol). Degas the resulting mixture again with nitrogen for 2 min, and stir at 100 °C for 16 h. Cool the reaction mixture to rt, and pass it through Celite. TM The filter cake was washed with ethyl acetate. The filtrate was evaporated and the crude product was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 20%) in heptane to provide 6-fluoro-5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indazole (720 mg, 78% yield). MS: [M+H] + :361.3.

[0834]

[0835] Intermediate X (5-amino-6-(5-methyl-1H-indazol-4-yl)-2-(tributyltinyl)pyrimidin-4-carboxamide)

[0836] Tributyltinyl stanane (430 μL, 852.43 μmol) and PdCl2 (dtbpf) (43 mg, 66.1 μmol) were added to a solution of intermediate J (200 mg, 660.7 μmol) in dioxane (6 mL). The mixture was degassed under vacuum, backfilled with N2, and stirred under reflux for 18 h under N2. The cooled reaction mixture was diluted with water and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed successively with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (50 to 100%) in heptane to provide 5-amino-6-(5-methyl-1H-indazol-4-yl)-2-tributyltinyl-pyrimidin-4-carboxamide (85 mg, 23% yield). 1H NMR (400MHz, chloroform-d) δ11.53(s,1H),8.17(d,J=4.9Hz,1H),7.70(d,J=0.9Hz,1H),7.42(dd,J=8.6,1.0Hz,1H),7.29(d,J=8.6Hz,1H) ,6.30(d,J=4.9Hz,1H),5.72(s,2H),2.27(s,3H),1.71–1.50(m,6H),1.34–1.27(m,6H),1.16–1.07(m,6H),0.84(t,J=7.3Hz,9H).

[0837]

[0838] Intermediate Y (N-(2-bromo-5-fluorophenyl)pyridazine-4-amine)

[0839] To a solution of 1-bromo-4-fluoro-2-iodobenzene (570 mg, 1.89 mmol) in DMF (8 mL), pyridazin-4-amine (200 mg, 2.10 mmol), cesium carbonate (930 mg, 2.85 mmol), Xantphos (16 mg, 27.7 μmol), and Pd(OAc)₂ (41 mg, 182.6 μmol) were added. The mixture was degassed under vacuum, backfilled with N₂, and stirred at 110 °C for 2 h. Volatiles were removed under vacuum, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (20 to 100%) in heptane to provide N-(2-bromo-5-fluoro-phenyl)pyridazin-4-amine (300 mg, 59% yield). MS: [M+H] + :268.1.

[0840]

[0841] Intermediate Z (7-amino-2-fluoro-8-(5-methyl-1H-indazol-4-yl)benzofurano[3,2-b]pyridine-6-carboxynitrile)

[0842] Step 1. Di-tert-butyl carbonate (23 g, 105.4 mmol) and DMAP (1 g, 8.19 mmol) were added to a solution of 6-amino-3-bromo-2-fluorobenzonitrile (10 g, 42.0 mmol) in THF (100 mL) under reflux. The reaction mixture was heated to reflux for 3 h. After cooling to reflux, volatiles were removed under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (10 to 30%) in hexane to provide bis(tert-butyl)(4-bromo-2-cyano-3-fluorophenyl)carbamate (15.0 g, 86% yield). MS: [M+Na] +:437.0 / 439.0; 1 H-NMR (400MHz, CDCl3): δ7.77-7.81 (m; 1H); 7.02 (d; J=8.65Hz; 1H); 1.46 (s; 18H).

[0843] Step 2. Under reflux, bis(tert-butyl)(4-bromo-2-cyano-3-fluorophenyl)carbamate (7.6 g, 39.6 mmol) and K₂CO₃ (6.0 g, 43.4 mmol) were added to a solution of 2-bromo-6-fluoropyridin-3-ol (15.0 g, 36.1 mmol) in DMF (300 mL). The reaction mixture was degassed (3 cycles of vacuum / nitrogen atmosphere), stirred under reflux for 30 min, and then heated to 40 °C for 18 h. After cooling to reflux, the mixture was poured into a 1:1 water / saturated NaHCO₃ aqueous solution. The mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with water (2 x) and brine, dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (5 to 55%) in hexane to provide 7.95 g of bis(tert-butyl)(4-bromo-3-((2-bromo-6-fluoropyridin-3-yl)oxy)-2-cyanophenyl)carbamate (7.95 g, 38% yield). MS: [M-Boc+H] + :487.9; 1H-NMR (400MHz, CDCl3): δ7.90 (d; J=8.68Hz; 1H); 7.16 (d; J=8.67Hz; 1H); 6.87-6.91 (m; 1H); 6.79-6.82 (m; 1H); 1.48 (s; 18H).

[0844] Step 3. Add bis(tert-butyl)(4-bromo-3-((2-bromopyridin-3-yl)oxy)-2-cyanophenyl)carbamate (7.95 g, 13.5 mmol), bis(pinacol)diboron (3.78 g, 14.9 mmol), KOAc (4.0 g, 40.3 mmol), Pd(dppf)Cl2·DCM (2.2 g, 2.7 mmol), and dioxane (80 mL) to a sealed tube. Degas the reaction mixture (3 cycles of vacuum / nitrogen gas) and stir at 110 °C for 8 h. After cooling to rt, dilute the reaction mixture with water and EtOAc and pass it through Celite. TMFiltration. The layers were partitioned and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (5 to 35%) in hexane to provide bis(tert-butyl)(6-cyano-2-fluorobenzofurano[3,2-b]pyridin-7-yl)carbamate (3.2 g, 55% yield). MS: [M-Boc+H] + :328.1; 1H-NMR (400MHz, CDCl3): δ8.34 (d; J=8.34Hz; 1H); 8.09 (t; J=7.53Hz; 1H); 7.37 (d; J=8.38Hz; 1H); 7.15 (d; J=8.88Hz; 1H); 1.46 (s; 18H).

[0845] Step 4. A solution of bis(tert-butyl)(6-cyano-2-fluorobenzofurano[3,2-b]pyridin-7-yl)carbamate (2.9 g, 6.8 mmol) in acetic acid (58 mL) was heated to reflux for 35 h. The solvent was removed under vacuum, and the solution was co-evaporated with n-heptane (3x) and dried under high vacuum to obtain 1.6 g of 7-amino-2-fluorobenzofurano[3,2-b]pyridin-6-carboxynitrile, which could be used unchanged in subsequent steps without further purification. MS: [M+H] + :228.0.

[0846] Step 5. NBS (1.5 g, 8.4 mmol) was added to a solution of 7-amino-2-fluorobenzofurano[3,2-b]pyridine-6-carboxylonitrile (1.9 g, 8.4 mmol) in DMF (20 mL) under reflux. The reaction mixture was stirred under reflux for 1 h and then diluted with 20% (w) Na₂S₂O₃ aqueous solution (80 mL). The mixture was gently stirred under reflux and the solid was collected by filtration. The filter cake was washed with water and (1:1) n-heptane-MTBE (30 mL). The solid was dried under high vacuum to give 7-amino-8-bromo-2-fluorobenzofurano[3,2-b]pyridine-6-carboxylonitrile (2.3 g, 89% yield). MS: [M+H] + 305.9 / 307.9; 1 H NMR (400MHz, DMSO-d6) δ 8.31-8.37 (m; 1H); 7.18 (d; J = 8.70Hz; 1H); 7.01 (s; 1H).

[0847] Step 6. Degas a mixture of 7-amino-8-bromo-2-fluorobenzofurano[3,2-b]pyridine-6-carboxamide (1.9 g, 3.2 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (2.2 g, 12.5 mmol), 2M K3PO4 aqueous solution (9.3 mL, 18.6 mmol), Pd2(dba)3 (570 mg, 0.622 mmol), tri-tert-butylphosphine tetrafluoroborate (360 mg, 1.241 mmol), and dioxane (38 mL) (3 cycles under vacuum / nitrogen atmosphere). The mixture was heated to reflux for 2 h, cooled to rt, poured into a mixture of water (50 mL) and EtOAc (70 mL), and passed through Celite. TM Filtration. The layers were partitioned and the aqueous layer extracted with EtOAc (70 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (30 to 100%) in hexane to provide 7-amino-2-fluoro-8-(5-methyl-1H-indazol-4-yl)benzofurano[3,2-b]pyridin-6-carboxynitrile (1.2 g, 57% yield). MS: [M+H] + :358.1.

[0848]

[0849] Intermediate AA (5-bromo-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine)

[0850] To a solution of 1-bromo-4-fluoro-2-iodobenzene (570 mg, 1.89 mmol) in DMF (8 mL), pyridazin-4-amine (200 mg, 2.10 mmol), cesium carbonate (930 mg, 2.85 mmol), Xantphos (16 mg, 27.7 μmol), and Pd(OAc)₂ (41 mg, 182.6 μmol) were added. The mixture was degassed under vacuum, backfilled with N₂, and stirred at 110 °C for 2 h. Volatiles were removed under vacuum, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (20 to 100%) in heptane to provide N-(2-bromo-5-fluoro-phenyl)pyridazin-4-amine (300 mg, 59% yield). MS: [M+H] + :268.1.

[0851]

[0852] Intermediate AB (ethyl 5-amino-2-chloro-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidin-4-carboxylate)

[0853] A mixture of ethyl 5-amino-2,6-dichloropyrimidin-4-carboxylate (10 g, 42.36 mmol), 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)inazole (16 g, 46.75 mmol), Pd(dtbpf)Cl2 (2.75 g, 4.22 mmol), and an aqueous solution of 2MK3PO4 (34 mL, 68 mmol) in dioxane (200 mL) was bubbled through N2 and then heated at 80 °C for 5 h. The cooled reaction mixture was poured into water and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 70%) in heptane to provide ethyl 5-amino-2-chloro-6-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)pyrimidine-4-carboxylate (13.1 g, 74% yield). MS: [M+H] + :416.3.

[0854]

[0855] Intermediate AC (4-chloro-5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole)

[0856] Step 1. To a suspension of 5-bromo-4-chloro-1H-indazole (6.8 g, 29.4 mmol) in DCM (170 mL), p-toluenesulfonic acid monohydrate (559 mg, 2.9 mmol) and 3,4-dihydro-2H-pyran (8 mL, 87.7 mmol) were added at rt. The mixture was stirred at rt for 18 h. A saturated aqueous solution of NaHCO3 was slowly added. The layers were partitioned and the organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in hexane to provide 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (9.0 g, 97% yield). 1 H-NMR (400MHz, DMSO): δ8.18 (s; 1H); 7.69-7.70 (m; 2H); 5.88 (dd; J=9.44; 2.35Hz; 1H); 3.83-3.86 (m ; 1H); 3.68-3.76 (m; 1H); 2.28-2.37 (m; 1H); 1.94-2.02 (m; 2H); 1.70-1.74 (m; 1H); 1.42-1.60 (m; 2H).

[0857] Step 2. Dry a 250 mL round-bottom flask equipped with a condenser with a flame and add magnesium (1.24 g, 51.0 mmol). Dry the flask again with a flame and add iodine (104 mg, 408 μmol). Degas the flask (3 cycles under vacuum / argon atmosphere), then add degassed Et₂O (62 mL), followed by dropwise addition of iodomethane-d₃ (3.18 mL, 51.0 mmol). After adding a few drops of iodomethane-d₃, sonicate the mixture for 5 min. The color of the reactants changes from orange to yellow, then to milky white, and finally to a cloudy metallic color (high exothermic reaction was observed, and the suspension refluxed without external heat). After adding iodomethane-d₃, the reaction mixture becomes more metallic. Stir at rt for 1.5 h.

[0858] A clear zinc chloride solution (0.5 M in THF, 51.0 mL, 25.5 mmol) was transferred into a flame-dried three-necked flask. Grignard suspension was added dropwise using a syringe (exothermic reaction was observed), and the mixture turned milky white. Upon addition of the Grignard reagent, a white precipitate was observed to form. The reaction mixture was stirred at rt for 40 min and then used for the next step. The supernatant was used directly for the next step.

[0859] Step 3. Dry the three-necked flask (250 mL) equipped with a condenser with a flame. Add 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.00 g, 12.7 mmol), tri-tert-butylphosphine tetrafluoroborate (735 mg, 2.5 mmol), and Pd2(dba)3 (1.16 g, 1.27 mmol) to the flask. Degas the mixture (3 cycles under vacuum / argon atmosphere). Protect the flask from light and add the dimethyl-d6 zinc solution (70 mL, 25.5 mmol) prepared in the previous step dropwise using a syringe. After addition, heat the mixture to 70 °C for 2 h. After cooling to rt, dilute the mixture with saturated NH4Cl aqueous solution (100 mL) and EtOAc (150 mL) and pass through a Celite precipitate solution. TM Filtration. The layers were partitioned and the aqueous layer extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a 15% EtOAc-hexane (0 to 70%) gradient in hexane to provide 4-chloro-5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.9 g, 90% yield). MS: [M+H] + :254.1; 1H-NMR (400MHz, CDCl3): δ8.04 (s; 1H); 7.40 (d; J = 8.51Hz; 1H); 7.25 (d, J = 8.50Hz, 1H), 5.67-5.70 (m; 1H); 3.98-4.03 (m; 1H); 3.70-3.75 (m; 1H); 2.50-2.58 (m; 1H); 2.14-2.16 (m; 1H); 2.07 (dd; J=14.39; 4.34Hz; 1H); 1.67-1.76 (m; 3H).

[0860]

[0861] Intermediate AD((5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid)

[0862] Intermediate AC (5.00 g, 19.7 mmol), tetrahydroxydiboron (5.30 g, 59.1 mmol), potassium acetate (5.80 g, 59.1 mmol), and chlorine (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (774 mg, 985 μmol) were loaded into an RBF equipped with a condenser. The mixture was degassed (3 cycles of vacuum / argon gas). MeOH (60 mL) and ethylene glycol (20 mL) were added, and the mixture was stirred at 60 °C for 3 h. The mixture was then analyzed by Celite. TM The mixture was filtered, and the filter cake was washed with MeOH. Volatiles were removed under vacuum, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 60%) in hexane to provide (5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (3.26 g, 63% yield). MS: [M+H] + :264.1.

[0863]

[0864] Intermediate AE (5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole)

[0865] 4-Chloro-1-tetrahydropyran-2-yl-5-(trideuterylmethyl)indazole (7.15 g, 28.2 mmol), XPhos (0.675 g, 1.42 mmol), bis(pinacol)diboron (8.60 g, 33.86 mmol), and potassium 2-ethylhexanoate (11.70 g, 64.2 mmol) were loaded into an RBF container. IPAc (145 mL) was added, the container was capped, and air was replaced with N2 (3 cycles of vacuum / N2). The mixture was stirred at 50 °C for 5 min, and then XPhos Pd(allyl)Cl (0.925 g, 1.40 mmol) was added. The mixture was stirred at 50 °C under N2 for 18 h. The reaction mixture was cooled to rt and diluted with 100 mL EtOAc and 50 mL water. The aqueous layer was collected, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (20 to 100%) in heptane to provide 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-5-(trideutermethyl)indazole (9.54 g, 98% yield). MS: [M+H] + :346.3.

[0866]

[0867] Intermediate AF (5-amino-2-chloro-6-(5-(methyl-d3)-1H-indazol-4-yl)pyrimidin-4-carboxamide)

[0868] Step 1. Ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate ( 300mg, 1.27mmol ), (5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid ( 368mg, 1.4mmol ), Pd(dtbpf)Cl2(84.1mg, 0.127mmol) 2M K3PO4 aqueous solution (1.02 mL, 2.04 mmol) and Dioxane (4.20 mL) Place in a round-bottom flask. Purge the mixture with nitrogen gas for 10 min, and heat to 80 °C under nitrogen for 5 h. Concentrate the cooled reaction mixture and purify the residue by silica gel chromatography, eluting with a gradient of EtOAc (10 to 60%) in hexane to provide 5-amino-2-chloro-6-(5-(methyl-d3)-1H-indazol-4-yl)pyrimidine-4-carboxamide (310 mg, 58% yield). MS: [M+H] + :419.1; 1H-NMR (400MHz, CDCl3): δ7.61-7.71 (m; 2H); 7.36 (dd; J=8.64; 5.91Hz; 1H); 5.66-5.76 (m; 3H); 4.51 (q; J=7.11Hz; 2H); 3.96-4.09 (m; 1H); 3.71-3.80 (m; 1H); 2.47-2.58 (m; 1H); 2.08-2.16 (m; 2H); 1.66-1.78 (m; 3H); 1.48 (t; J=7.11Hz; 3H).

[0869] Step 2. Ethyl 5-amino-2-chloro-6-(5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)pyrimidin-4-carboxylate (270 mg, 0.645 mmol) was placed in a microwave-safe reaction vial, and ammonia solution (7N in MeOH, 9.21 mL, 64.5 mmol) was added. The reaction mixture was heated to 80 °C for 1.5 h. After cooling to rt, the volatiles were removed under vacuum and the mixture was placed under high vacuum to give 5-amino-2-chloro-6-(5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl)pyrimidin-4-carboxamide (250 mg, 99% yield). MS: [M+H] + :390.1.

[0870] Step 3. To a solution of 5-amino-2-chloro-6-(5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidin-4-carboxamide (130 mg, 0.33 mmol) in MeOH (1.7 mL), HCl (4 M in dioxane, 4.2 mL, 16.8 mmol) was added. The reaction mixture was stirred for 18 h. The volatiles were removed under vacuum to give 5-amino-2-chloro-6-(5-(methyl-d3)-1H-indazol-4-yl)pyrimidin-4-carboxamide (100 mg, 99% yield). MS: [M+H] + :306.0. 1 H-NMR (400MHz, DMSO): δ7.80 (s, 1H); 7.70 (s, 2H); 7.60 (s, 1H); 7.50 (d, J = 8.4Hz, 1H); 7.41 (s, 1H); 7.26 (d, J = 8.4Hz, 1H).

[0871]

[0872] Intermediate AF (5-amino-2-chloro-6-(3-fluoro-5-methyl-1H-indazol-4-yl)pyrimidin-4-carboxamide)

[0873] Using a syringe pump, a solution of SelectFluor (1.76 g, 4.97 mmol) in DMF (5 mL) was added to a solution of intermediate J (500 mg, 1.65 mmol) in DMF (5 mL) over 10 h at 50 °C. The reaction mixture was stirred at 50 °C for 10 h, then diluted with water and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to provide 5-amino-2-chloro-6-(3-fluoro-5-methyl-1H-indazol-4-yl)pyrimidine-4-carboxamide (20 mg, 4% yield).

[0874]

[0875] Intermediate AG (ethyl 5-amino-2-chloro-6-(3-methoxy-2,6-dimethylphenyl)pyrimidine-4-carboxylate)

[0876] Pd2(dba)3 (388 mg, 0.424 mmol), tri-tert-butylphosphine tetrafluoroborate (246 mg, 0.847 mmol), 2-(3-methoxy-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.67 g, 6.4 mmol), and ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate (1.0 g, 4.2 mmol) were charged into a flame-dried MW container. Dioxane (8 mL) and water (2 mL) were added, followed by K3PO4 (1.8 g, 8.5 mmol). The mixture was degassed, the container was sealed, and the mixture was stirred at 100 °C for 10 h. The cooled reaction mixture was diluted with EtOAc and passed through Celite. TM Filtration. The filtrate was concentrated to dryness, diluted with water, and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 20%) in hexane to provide ethyl 5-amino-2-chloro-6-(3-methoxy-2,6-dimethylphenyl)pyrimidine-4-carboxylate (330 mg, 23% yield). MS: [M+H] + :336.1. 1 HNMR(CDCl3,400MHz):δH 1.45(3H,t,J=7.1Hz), 1.92(3H,s), 1.98(3H,s), 3.82(3H,s), 4.48(2H,q,J=7.1Hz), 5.62(2H,s), 6.85(1H,d,J=8.4Hz), 7.10(1H,d,J=8.4Hz).

[0877]

[0878] Intermediate AH (N-(2,2-difluoroethyl)-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine-2-amine)

[0879] Step 1. Add DMF (6 mL) to a MW vial containing 3-bromo-2,5-difluoropyridine (622 mg, 3.21 mmol) and 2,2-difluoroethylamine (321 mg, 3.96 mmol), followed by K₂CO₃ (884 mg, 6.40 mmol). Cap the vial, transfer it to a preheated (120 °C) heating block, and stir overnight. Add more 2,2-difluoroethylamine (1.27 g, 15.60 mmol, 1.1 mL) and stir the mixture overnight at 120 °C. Add more 2,2-difluoroethylamine (1.27 g, 15.60 mmol, 1.1 mL) and stir the mixture at 120 °C for another 3 days. Pour the cooled reaction mixture into water and extract with EtOAc (3X). Wash the combined organic layers with saturated NH₄Cl aqueous solution and brine, dry over Na₂SO₄, filter, and concentrate. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 3-bromo-N-(2,2-difluoroethyl)-5-fluoro-pyridin-2-amine (333 mg, 41% yield). MS: [M+H] + :255.0 / 257.0.

[0880] Step 2. Add dioxane (6 mL) to a MW vial containing bis(pinacol)diboron (403 mg, 1.59 mmol), 3-bromo-N-(2,2-difluoroethyl)-5-fluoro-pyridin-2-amine (333 mg, 1.31 mmol), KOAc (388 mg, 3.95 mmol), and Pd(dppf)Cl2·DCM (114 mg, 139.6 μmol). Bubble the solution through with N2, cap the vial, and transfer it to a preheated (100 °C) heating block for 2.5 h. The cooled reaction mixture was adsorbed onto silica, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 50%) in heptane to provide N-(2,2-difluoroethyl)-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-amine (301 mg, 76% yield). MS: [M+H] + :303.2.

[0881]

[0882] Intermediate AI (4-bromo-N-(2,2,2-trifluoroethyl)pyrimidin-5-amine)

[0883] THF (2 mL) and 4-amino-5-bromopyrimidine (200 mg, 1.15 mmol) were charged into a flame-dried MW tube. The reaction mixture was heated to 80 °C, and phenylsilane (355 μL, 2.87 mmol) was added, followed by TFA (106 μL, 1.38 mmol). The reaction mixture was maintained at 80 °C for 6 h. After cooling to rt, volatiles were removed under vacuum. The residue was dissolved in EtOAc and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 90%) in hexane to provide 4-bromo-N-(2,2,2-trifluoroethyl)pyrimidine-5-amine (230 mg, 56% yield). MS: [M+H] + :255.8.

[0884]

[0885] Intermediate AJ (4-bromo-N-(2,2,2-trifluoroethyl)pyrimidin-5-amine)

[0886] TFA (3 mL) was added to a solution of 3-amino-4-bromobenzonitrile (269 μL, 1.02 mmol) and 1,1,1-trifluoroacetone (145 μL, 1.62 mmol) in DCM (3 mL), followed by sodium cyanoborohydride (128 mg, 2.03 mmol). The reaction mixture was stirred at rt for 18 h and then concentrated to dryness. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 90%) in hexane to provide 4-bromo-3-((1,1,1-trifluoroprop-2-yl)amino)benzonitrile (190 mg, 64% yield). MS: [M+H] + :294.9.

[0887]

[0888] Intermediate AK (N-(2-bromo-6-methylphenyl)pyrimidin-2-amine)

[0889] Trifluoroethanol (3 mL) and TFA (374 μL, 4.85 mmol) were added to a MW vial containing 2-bromo-6-methyl-aniline (301 mg, 1.62 mmol) and 2-fluoropyrimidine (198 mg, 2.02 mmol). The vial was capped and microwaved at 80 °C for 60 min. More 2-fluoropyrimidine (138 mg, 1.41 mmol) was added. The vial was capped and microwaved at 80 °C for 20 min. The cooled reaction mixture was concentrated. The residue was dissolved in DCM and washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM (3X), and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 60%) in heptane to provide N-(2-bromo-6-methyl-phenyl)pyrimidin-2-amine (230 mg, 54% yield). MS: [M+H] + :264.0.

[0890]

[0891] Intermediate AL (5-amino-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(tributyltinyl)-pyrimidin-4-carboxylic acid ethyl ester)

[0892] Intermediate AB (500 mg, 1.20 mmol), dioxane (7 mL), bis(tributyltin) (1.2 mL, 2.38 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (85.1 mg, 120.2 μmol) were charged into a MW container. The container was flushed with N2, sealed, and stirred overnight at 110 °C. Volatiles were removed under vacuum, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 40%) in heptane to provide ethyl 5-amino-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(tributyltinalkyl)pyrimidin-4-carboxylate (464 mg, 58% yield). MS: [M+H] + :670.3.

[0893]

[0894] Intermediate AM (5-amino-2-(2-amino-6-chloropyridin-3-yl)-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidin-4-carboxylic acid ethyl ester)

[0895] To a solution of intermediate AL (4.2 g, 6.26 mmol) in DMF (50 mL), 6-chloro-3-iodopyridin-2-amine (2 g, 7.86 mmol), CuI (242 mg, 1.27 mmol), bis(tri-tert-butylphosphine)palladium(0) (350 mg, 684.9 μmol), and LiCl (570 mg, 13.5 mmol) were added. The mixture was degassed under vacuum, backfilled with N2, and stirred at 110 °C for 1 h under nitrogen. Volatiles were removed under vacuum, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (20 to 80%) in heptane to provide ethyl 5-amino-2-(2-amino-6-chloro-3-pyridyl)-6-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)pyrimidin-4-carboxylate (1.62 g, 51% yield). MS:[M+H] + :508.3.

[0896]

[0897] Intermediate AN (5-amino-2-(2-amino-6-cyanopyridin-3-yl)-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidin-4-carboxylic acid ethyl ester)

[0898] Zinc cyanide (170 mg, 1.45 mmol) and bis(tri-tert-butylphosphine)palladium (0) (150 mg, 129.8 μmol) were added to a solution of intermediate AM (340 mg, 669.3 μmol) in DMF (5 mL). The mixture was degassed under vacuum, backfilled with N2, and stirred at 120 °C for 18 h under N2. Volatiles were removed under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (40 to 100%) in heptane to provide ethyl 5-amino-2-(2-amino-6-cyano-3-pyridyl)-6-(5-methyl-1-tetrahydropyran-2-yl-indazole-4-yl)pyrimidine-4-carboxylate (248 mg, 74% yield). MS: [M+H] + :499.3.

[0899]

[0900] Intermediate AO (6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole)

[0901] Step 1. Add concentrated hydrochloric acid (12.5 mL) to a solution of 1,5-difluoro-2-methyl-4-nitrobenzene (25.14 g, 145.2 mmol) in reagent alcohol (150 mL) and water (150 mL), which is a 36% (w / w) aqueous solution. Heat the mixture at 80 °C and slowly add iron powder (28.6 g, 512.1 mmol) in portions over 35 minutes. Stir the mixture at the same temperature for 30 minutes. Basicilate the cooled reaction mixture to approximately pH 8 with a saturated aqueous solution of NaHCO3 and dilute with EtOAc (300 mL). Filter the layers and wash the solids with portions of EtOAc and water. Separate the layers from the filtrate and extract the aqueous layer with EtOAc (2X). The combined organic layers were washed with brine, dried over Na2SO4, filtered through a silica gel pad, washed with EtOAc, and concentrated under reduced pressure to give 2,4-difluoro-5-methylaniline (19.98 g, 96% yield). MS: [M+H]+: 144.1.

[0902] Step 2. NBS (24.8 g, 139.3 mmol) was added fractionally to a solution of 2,4-difluoro-5-methylaniline (19.42 g, 135.7 mmol) in DCM (250 mL) at 0 °C for 5–10 min. The reaction mixture was stirred at 0 °C for 5 min, then removed from the ice bath. The reaction mixture was stirred for 15 min, then concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 25%) in heptane to provide 2-bromo-4,6-difluoro-3-methylaniline (18.1 g, 60% yield). MS: [M+H]+: 221.9.

[0903] Step 3. Add ice water (80 mL) and sulfuric acid (18 M, 70 mL) to an RBF container and cool in an ice bath. Add 2-bromo-4,6-difluoro-3-methylaniline (16.44 g, 74.04 mmol) dropwise to ACN (120 mL) using a feeding funnel. Stir the resulting suspension at 0 °C for 15 min. Add sodium nitrite (10.22 g, 148.1 mmol) dropwise to water (80 mL). After stirring for 30 min, add potassium iodide (49.17 g, 296.2 mmol) dropwise to water (130 mL) using a feeding funnel. After addition, remove the ice bath and stir the mixture overnight. Place the mixture in an ice bath and slowly add (using a feeding funnel) 20% Na₂S₂O₃ aqueous solution (250 mL) to quench the reaction. Add EtOAc (250 mL) to the mixture and separate the layers. Extract the aqueous layer with EtOAc. The combined organic extracts were washed with 20% Na₂S₂O₃ solution (2 x 250 mL), water, and brine, dried over Na₂SO₄, filtered, and concentrated. The residues were purified by silica gel chromatography, eluted with heptane to provide 3-bromo-1,5-difluoro-2-iodo-4-methylbenzene (20.19 g, 82% yield).

[0904] Step 4. Add dropwise a solution of 2.5 M n-butyllithium in hexane (27 mL, 67.5 mmol) to a solution of 20.5 g (61.58 mmol) of 3-bromo-1,5-difluoro-2-iodo-4-methylbenzene in THF (120 mL) at -78 °C. Stir the reaction mixture at -78 °C for 35 min. Add dropwise anhydrous DMF (6.0 mL, 77.49 mmol) and stir the mixture at -78 °C for 1 h. Quench the reaction mixture with 1 N HCl aqueous solution (150 mL). Add water to the mixture and extract the aqueous layer with EtOAc (3X). Wash the combined organic layers successively with water and brine, dry over Na2SO4, filter, and concentrate. The residue was purified by silica gel chromatography and eluted with a gradient of EtOAc (0 to 20%) in heptane to provide 2-bromo-4,6-difluoro-3-methylbenzaldehyde (8.09 g, 56% yield). 1 ¹H NMR (400MHz, chloroform-d) δ 10.33 (d, J = 1.5Hz, 1H), 6.90 (dd, J = 10.3, 9.3Hz, 1H), 2.36 (dd, J = 2.6, 1.1Hz, 3H).

[0905] Step 5. Add hydrazine hydrate (20 mL, 411.5 mmol) to a mixture of 2-bromo-4,6-difluoro-3-methylbenzaldehyde (8.09 g, 34.42 mmol) in DMSO (45 mL). Stir the mixture at 130 °C for 1 h under an open atmosphere. Cool the mixture to rt and add water (100 mL) dropwise with stirring until a white precipitate is observed. After stirring for another 30 min, filter the suspension and wash the solid with water in batches, air dry, and then dry under vacuum to produce 4-bromo-6-fluoro-5-methyl-1H-indazole (6.26 g, 79% yield). MS: [M+H]+: 230.9

[0906] Step 6. Add 3,4-dihydro-2H-pyran (5.07 mL, 55.8 mmol) to a solution of 4-bromo-6-fluoro-5-methyl-1H-indazole (6.26 g, 27.3 mmol) and p-toluenesulfonic acid (239 mg, 1.39 mmol) in EtOAc (100 mL). Heat the mixture under reflux for 2.5 h. Dilute the cooled reaction mixture with a saturated aqueous solution of NaHCO3 and separate the layers. Extract the aqueous layer with EtOAc (2X). Wash the combined organic layers with brine, dry over Na2SO4, filter, and concentrate under vacuum. Purify the residue by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 4-bromo-6-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (6.51 g, 76% yield). MS: [M+H]+: 314.9; 1 ¹H NMR (400MHz, chloroform-d) δ 7.95 (d, J = 0.9Hz, 1H), 7.25–7.20 (m, 1H), 5.61 (dd, J = 9.1, 2.8Hz, 1H), 3.99 (dtd, J = 11.4, 3.6, 1.5Hz, 1H), 3.76–3.68 (m, 1H), 2.54–2.43 (m, 1H), 2.41 (d, J = 2.6Hz, 3H), 2.19–2.02 (m, 2H), 1.82–1.62 (m, 3H).

[0907] Step 7. 4-Bromo-6-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (7.4 g, 23.6 mmol), potassium acetate (7.1 g, 72.4 mmol), bis(pinacol)diboron (6.90 g, 27.2 mmol), and dioxane (150 mL) were charged into an RBF container. The mixture was degassed with nitrogen for 5 min, and Pd(dppf)Cl2·DCM (1.2 g, 1.47 mmol) was added to the reaction mixture. The resulting mixture was again degassed with nitrogen for 2 min, and stirred at 100 °C for 16 h. The reaction mixture was cooled to rt and passed through a Celite filter.TM Filter and wash Celite with ethyl acetate TM Cake. The filtrate was evaporated and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 20%) in heptane to provide 6-fluoro-5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indazole (5.1 g, 60% yield). MS: [M+H]+: 361.3.

[0908]

[0909] Intermediate AP (4-bromo-N-(2,2,2-trifluoroethyl)pyrimidin-5-amine)

[0910] Sodium cyanoborohydride (292 mg, 4.65 mmol) was added to a solution of 5-amino-4-bromo-2-fluorobenzonitrile (269 μL, 2.33 mmol) in DCM (4 mL) at 0 °C, followed by slow addition of TFA (4.00 mL). The resulting bubbling mixture was stirred at 0 °C. 1,1,1-trifluoroacetone (333 μL, 3.72 mmol) was slowly added, and the mixture was stirred overnight at rt. The reaction mixture was concentrated, carefully diluted to an alkaline pH with saturated aqueous NaHCO3 solution, and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 90%) in hexane to provide 4-bromo-2-fluoro-5-((1,1,1-trifluoroprop-2-yl)amino)benzonitrile (550 mg, 76% yield). MS:[M+H]+:313.0.

[0911]

[0912] Intermediate AQ (3-bromo-6-fluoropyridine-2-amine)

[0913] A solution of 3-bromo-2,6-difluoropyridine (1.0 g, 5.2 mmol) and 7N ammonia in MeOH (3.7 mL, 25.9 mmol) was loaded into a 20 mL MW container. The container was sealed and heated overnight at 65 °C. The reaction mixture was concentrated and the residue was redissolved in EtOAc and saturated NaHCO3 aqueous solution. The aqueous layer was collected and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 3-bromo-6-fluoropyridine-2-amine (554 mg, 56% yield). MS: [M+H]+: 191.0 / 193.0; 1¹H NMR (chloroform-d) δ: 7.67 (ddd, J = 8.0, 7.2, 0.7 Hz, 1H), 6.17 (ddd, J = 8.3, 2.8, 0.7 Hz, 1H), 4.96 (br s, 2H).

[0914]

[0915] Intermediate AR (N-(2-bromo-6-fluorophenyl)pyrimidin-2-amine)

[0916] TFA (617 μL, 8.01 mmol) was added to a mixture of 2-bromo-6-fluoro-aniline (507 mg, 2.67 mmol) and 2-chloropyrimidine (611 mg, 5.34 mmol) in trifluoroethanol (5 mL). The vial was capped, transferred to a preheated (100 °C) heating block, and stirred for 8 h. The cooled reaction mixture was diluted with saturated aqueous NaHCO3 solution and extracted with DCM (3x). The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 60%) in heptane to provide N-(2-bromo-6-fluoro-phenyl)pyrimidine-2-amine (137 mg, 19% yield). MS: [M+H]+: 268.0.

[0917]

[0918] Intermediate AS[(1s,3s)-3-((3-bromo-6-chloropyridin-2-yl)amino)-1-methylcyclobut-1-ol]

[0919] (1s,3s)-3-amino-1-methylcyclobut-1-ol hydrochloride (350 mg, 2.54 mmol) was added to a solution of 3-bromo-6-chloro-2-fluoropyridine (530 mg, 2.52 mmol) and K₂CO₃ (870 mg, 6.29 mmol) in DMSO (2 mL) under reflux. The mixture was stirred under reflux for 2 h, then poured into water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over MgSO₄ and concentrated. The residue was purified by silica gel chromatography, eluting with an EtOAc (0 to 65%) gradient in heptane to provide (1s,3s)-3-((3-bromo-6-chloropyridin-2-yl)amino)-1-methylcyclobut-1-ol (540 mg, 74% yield). MS: [M+H]+: 293.0.

[0920]

[0921] Intermediate AT(7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole)

[0922] Step 1. Charge 2,2,6,6-Tetramethylpiperidine (7.20 mL, 42.7 mmol) and THF (60 mL) into an RBF container. Cool the mixture to -20 °C and treat it with a solution of 2.5 M n-butyllithium in hexane (17 mL, 42.5 mmol). Stir the mixture at 0 °C for 30 min, then cool it to -78 °C and treat it with 1-bromo-4,5-difluoro-2-methylbenzene (8.03 g, 38.8 mmol) dissolved in THF (35 mL), keeping the internal temperature below -60 °C. Stir the mixture at -78 °C for 1 h and then treat it with dimethylformamide diluted in THF (6 mL) (3.3 mL, 42.6 mmol). After the addition, remove the cooling bath and heat the mixture to -20 °C. Quench the reaction mixture with 70 mL of 10% HCl aqueous solution and then dilute with 50 mL of EtOAc. Withdraw the aqueous layer and extract it with 50 mL of EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 2-bromo-5,6-difluoro-3-methylbenzaldehyde (9.18 g, 99% yield). 1 H NMR (chloroform-d) δ: 10.35 (dd, J = 1.8, 1.0 Hz, 1H), 7.31 (dd, J = 10.4, 7.9 Hz, 1H), 2.43 (d, J = 1.1 Hz, 3H).

[0923] Step 2. 2-Bromo-5,6-difluoro-3-methylbenzaldehyde (10.4 g, 44.3 mmol) and DMSO (100 mL) were charged into an RBF container. The solution was then treated with hydrazine hydrate (26 mL, 535 mmol). The mixture was stirred at 120 °C for 8 h. The cooled reaction mixture was slowly added to 900 mL of rapidly stirred water. After stirring for one hour, the mixture was acidified to pH 5 with concentrated HCl and the solid was filtered. The filter cake was washed successively with water and heptane and dried overnight under high vacuum to provide 4-bromo-7-fluoro-5-methyl-1H-indazole (8.9 g, 87% yield). MS: [M+H]+: 228.9 / 230.9.

[0924] Step 3. 3,4-Dihydro-2H-pyran (6 mL, 66.1 mmol) was added to a solution of 4-bromo-7-fluoro-5-methyl-1H-indazole (7.35 g, 32.1 mmol) and p-toluenesulfonic acid (553 mg, 3.2 mmol) in EtOAc (120 mL), and the mixture was stirred under reflux for 3 h. The mixture was filtered and volatiles were removed under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 10%) in heptane to provide 4-bromo-7-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (6.0 g, 60% yield). MS: [M-THP+H]+: 228.5 / 230.5. 1 H NMR (chloroform-d) δ: 7.99 (d, J = 1.9Hz, 1H), 6.96 (d, J = 12.1Hz, 1H), 5.80 (dd, J = 10.0, 2.6Hz, 1H), 4.02 (ddt, J = 11.8, 4.1, 2.1Hz, 1H), 3.72 (td, J =11.3,2.7Hz,1H),2.64–2.48(m,1H),2.44(s,3H),2.17–2.10(m,1H),2.07(dt,J=12.9,3.0Hz,1H),1.80–1.65(m,2H),1.65–1.54(m,1H)

[0925] Step 4. Place a solution of 4-bromo-7-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (7.83 g, 25.0 mmol) in dioxane (50 mL) into a pressure vessel. Add bis(pinacol)diboron (7.62 g, 30.0 mmol), followed by KOAc (7.36 g, 75.0 mmol) and Pd(dppf)Cl2·DCM (1.02 g, 1.3 mmol). Rinse the vessel with N2, seal, and stir at 100 °C for 4 h. (By Celite) TM The cooled reaction mixture was filtered (washed with EtOAc) and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 20%) in heptane to provide 7-fluoro-5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indazole (8.12 g, 90% yield). MS: [M+H]+: 361.0.

[0926]

[0927] Intermediate AU (N-(2-bromo-6-methylphenyl)-4-methylpyrimidin-2-amine)

[0928] Trifluoroethanol (5 mL) and TFA (640 μL, 8.31 mmol) were added to a microwave vial containing 2-bromo-6-methylaniline (515 mg, 2.77 mmol) and 2-chloro-4-methylpyrimidine (702 mg, 5.46 mmol). The vial was capped and microwave-treated at 100 °C for 2 h. The reaction mixture was concentrated and then diluted with DCM and a saturated aqueous solution of NaHCO3. The layers were separated and the aqueous layer was extracted with DCM (3X). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 60%) in heptane to provide N-(2-bromo-6-methylphenyl)-4-methylpyrimidine-2-amine (175 mg, 23% yield). MS: [M+H]+: 280.0.

[0929]

[0930] Intermediate AV (N-(2-bromo-6-fluorophenyl)-4-methylpyrimidin-2-amine)

[0931] Trifluoroethanol (5 mL) and TFA (625 μL, 8.11 mmol) were added to a microwave vial containing 2-bromo-6-fluoroaniline (513 mg, 2.70 mmol) and 2-chloro-4-methylpyrimidine (708 mg, 5.51 mmol). The vial was capped and microwave-treated at 100 °C for 2 h. The reaction mixture was concentrated and then diluted with DCM and saturated NaHCO3 aqueous solution. The layers were separated and the aqueous layer was extracted with DCM (3X). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 60%) in heptane to provide N-(2-bromo-6-fluoro-phenyl)-4-methylpyrimidine-2-amine (152 mg, 20% yield). MS: [M+H]+: 284.0.

[0932]

[0933] Intermediate AW(2-((2-bromophenyl)((tert-butyldimethylsilyl)oxy)methyl)pyridine)

[0934] To a solution of (2-bromophenyl)-(2-pyridyl)methanol (1.5 g, 5.7 mmol) and imidazole (775 mg, 11.4 mmol) in DMF (20 mL), tert-butyldimethylchlorosilane (1.25 g, 8.3 mmol) was added. After stirring for 18 h, water was added and the mixture was extracted with ether. The mixture was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 50%) in heptane to provide 2-((2-bromophenyl)((tert-butyldimethylsilyl)oxy)methyl)pyridine (1.65 g, 77% yield). MS: [M+H]+: 378.2.

[0935]

[0936] Intermediate AX ((1-(2-bromophenyl)ethoxy)(tert-butyl)dimethylsilane)

[0937] To a solution of 1-(2-bromophenyl)ethanol (2.5 g, 12.4 mmol) and imidazole (1.35 g, 19.8 mmol) in DMF (30 mL), tert-butyldimethylchlorosilane (1.5 g, 10.0 mmol) was added. After stirring for 18 h, water was added and the mixture was extracted with ether. The mixture was washed with brine and dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 15%) in heptane to provide 1-(2-bromophenyl)ethoxy-tert-butyl-dimethylsilane (2.2 g, 88% yield). ¹H NMR (400MHz, chloroform-d) δ 7.60 (dd, J = 7.8, 1.8Hz, 1H), 7.45 (dd, J = 8.0, 1.3Hz, 1H), 7.30 (td, J = 7.5, 1.3Hz, 1H), 7.06 (ddd, J = 7.9, 7.3, 1.8Hz, 1H), 5.15 (q, J = 6.2Hz, 1H), 1.37 (d, J = 6.2Hz, 3H), 0.89 (s, 9H), 0.05 (s, 3H), -0.05 (s, 3H).

[0938]

[0939] Intermediate AY (3-iodo-4-(pyrimidin-2-ylamino)benzonitrile)

[0940] DMF (10 mL) was added to a MW vial containing 4-amino-3-iodobenzonitrile (996 mg, 4.1 mmol), 2-fluoropyrimidine (710 mg, 7.2 mmol), and K₂CO₃ (1.73 g, 12.5 mmol). The vial was capped, transferred to a preheated (110 °C) heating block, and stirred overnight. The reaction mixture was cooled to rt, diluted with water, and stirred. The solid was collected by filtration, washed with water, and dried to give 3-iodo-4-(pyrimidin-2-ylamino)benzonitrile (1.09 g, 83% yield). MS: [M+H]+: 323.1.

[0941]

[0942] Intermediate AZ((1s,3s)-3-((3-bromo-6-fluoropyridin-2-yl)amino)-1-methylcyclobut-1-ol)

[0943] (1S,3S)-3-amino-1-methylcyclobut-1-ol hydrochloride (142 mg, 1.03 mmol) was added to a solution of 3-bromo-2,6-difluoropyridine (200 mg, 1.0 mmol) and K₂CO₃ (360 mg, 2.6 mmol) in DMSO (1 mL) under reflux. The mixture was stirred under reflux for 2 h, then poured into water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over MgSO₄ and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 65%) in heptane to provide (1S,3S)-3-((3-bromo-6-fluoropyridin-2-yl)amino)-1-methylcyclobut-1-ol (197 mg, 69% yield).

[0944]

[0945] Intermediate BA (5-amino-2-(2-aminopyridin-3-yl)-6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidin-4-carboxamide)

[0946] Step 1. In a MW vial, intermediate AB (250 mg, 601.2 μmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)pyridine-2-amine (170 mg, 772.5 μmol), and Pd(dppf)Cl2·DCM (20 mg, 30.7 μmol) were added. Dioxane (3 mL) and 2MK2CO3 aqueous solution (750 μL, 1.5 mmol) were added. The vial was rinsed with N2, sealed, and stirred at 110 °C for 90 min. The reaction mixture was diluted with EtOAc and water and passed through a Celite tube. TMFilter with a pad. Collect the aqueous layer and wash the organic layer with brine, dry with MgSO4, filter, and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of EtOAc (50 to 100%) in heptane to provide ethyl 5-amino-2-(2-amino-3-pyridyl)-6-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)pyrimidine-4-carboxylate (217 mg, 76% yield). MS: [M+H]+: 474.2.

[0947] Step 2. To a solution of 7N ammonia in MeOH (1.5 mL, 10.5 mmol) in 1 mL of 5-amino-2-(2-amino-3-pyridyl)-6-(5-methyl-1-tetrahydropyran-2-yl-indazole-4-yl)pyrimidine-4-carboxylate (120 mg, 253.4 μmol), add 7N ammonia in MeOH. Stir the mixture in a sealed vial at 80 °C for 2 h. Remove volatiles under vacuum to provide 5-amino-2-(2-amino-3-pyridyl)-6-(5-methyl-1-tetrahydropyran-2-yl-indazole-4-yl)pyrimidine-4-carboxamide (110 mg, 247.48 μmol, 98% yield). MS: [M+H]+: 464.3.

[0948]

[0949] Intermediate BB((2-((1,1-sulfur dioxide heterocyclic butyl-3-yl)amino)-4-fluorophenyl)boronic acid)

[0950] Step 1. Add thiocyclic butyronitrile-3-one (1.86 g, 20.6 mmol), sodium triacetoxyborohydride (4.37 g, 20.6 mmol), and acetic acid (1.77 mL, 30.9 mmol) to a solution of 2-bromo-5-fluoroaniline (2.00 g, 10.3 mmol) in DCM (20 mL) at rt. Stir the reaction mixture at rt for 3 days. Slowly pour the reaction mixture into a saturated aqueous solution of NaHCO3. Distribute the layers and extract the aqueous layer with DCM. Wash the combined organic layers with brine, dry over MgSO4, filter, and concentrate. Purify the residue by silica gel chromatography, eluting with a 15% EtOAc / hexane (0 to 100%) gradient in hexane to provide N-(2-bromo-5-fluorophenyl)thiocyclic butyronitrile-3-amine (1.27 g, 47% yield). MS: [M+H]+: 261.9 / 263.9.

[0951] Step 2. Sodium tungstate dihydrate (83.7 mg, 254 μmol) and tetrabutylammonium hydrogen sulfate (138 mg, 406 μmol) were added to a solution of N-(2-bromo-5-fluorophenyl)thione-3-amine (1.33 g, 5.07 mmol) in EtOAc (13.0 mL). The reaction mixture was cooled to 0 °C and hydrogen peroxide (3.89 mL, 38.1 mmol) was added dropwise. The reaction mixture was stirred at rt for 3 h. Additional hydrogen peroxide (1.5 mL) was added and the mixture was stirred for another 1 h. The reaction mixture was diluted with EtOAc and a 10% aqueous solution of NaHSO3. The layers were partitioned and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (50 to 60%) in hexane to provide 1,1-dioxide of 3-((2-bromo-5-fluorophenyl)amino)thione-butane (1.1 g, 74% yield). MS: [M+H]+: 294.0 / 296.0. 1 H-NMR (400MHz, CDCl3): δ7.43 (dd; J=8.74; 5.87Hz; 1H); 6.47 (td; J=8.36; 2.76Hz; 1H); 6.18 (dd; J =10.44; 2.76Hz; 1H); 4.82-4.85 (m; 1H); 4.57-4.63 (m; 2H); 4.23-4.29 (m; 1H); 4.00-4.05 (m; 2H).

[0952] Step 3. 3-((2-bromo-5-fluorophenyl)amino)thione-butane 1,1-dioxide (125 mg, 425 μmol), Xphos Pd G3 (18.0 mg, 21.2 μmol), potassium acetate (125 mg, 1.27 mmol), and tetrahydroxydiboron (114 mg, 1.27 mmol) were placed in a microwave-safe reaction flask and capped. The mixture was degassed (3 cycles under vacuum / argon atmosphere). MeOH (1.50 mL) and ethylene glycol (500 μL) were added, and the reaction mixture was heated to 60 °C for 18 h. The reaction mixture was then analyzed using Celite. TM The mixture was filtered and washed with EtOAc. The volatiles were removed under vacuum to obtain crude (2-((1,1-sulfur dioxide heterocyclic butyl-3-yl)amino)-4-fluorophenyl)boronic acid, which could be used as is in subsequent steps without further purification.

[0953]

[0954] Intermediate BC (3-bromo-5-fluoro-N-(2,2,2-trifluoroethyl)pyridine-2-amine)

[0955] Step 1. THF (3.0 mL), DMF (500 μL), and 2-amino-3-bromo-5-fluoropyridine (200 mg, 1.05 mmol) were loaded into a flame-dried microwave-safe tube. The reaction mixture was heated at 80 °C, and phenylsilane (323 μL, 2.62 mmol) was added, followed by TFA (96 μL, 1.26 mmol). The reaction mixture was maintained at 80 °C for 18 h. After cooling to rt, the volatiles were removed under vacuum. The residue was dissolved in EtOAc and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 90%) in hexane to provide N-(3-bromo-5-fluoropyridine-2-yl)-2,2,2-trifluoroacetamide (250 mg, 83% yield). MS: [M+H]+: 286.6.

[0956] Step 2. Add a solution of 2M BH3·DMS in THF (1.74 mL, 3.48 mmol) to a solution of N-(3-bromo-5-fluoropyridin-2-yl)-2,2,2-trifluoroacetamide (500 mg, 1.74 mmol) in THF (10 mL). Heat the reaction mixture to 60 °C for 24 h. Dilute the cooled reaction mixture with water and extract with EtOAc (2X). Dry the combined organic extracts over MgSO4, filter, and concentrate to dryness. Purify the residue by silica gel chromatography, eluting with a gradient of EtOAc (0 to 90%) in hexane to provide 3-bromo-5-fluoro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (400 mg, 84% yield). MS: [M+H]+: 272.6 / 274.4.

[0957]

[0958] Intermediate BD (N-(2-bromo-5-(methylsulfonyl)phenyl)tetrahydro-2H-pyran-4-amine)

[0959] Tetrahydropyran-4-one (700 mg, 7.00 mmol) and THF (10 mL) were loaded into an RBF container. Concentrated sulfuric acid (2.25 mL) was added, followed by 2-bromo-5-methylsulfonyl-aniline (250 mg, 1.00 mmol). The mixture was stirred at rt for 1 h, then cooled to 0 °C and treated with sodium borohydride (265 mg, 7.00 mmol). The mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and alkalized with 1 N KOH aqueous solution. The aqueous layer was collected and extracted with EtOAc (2X). The combined organic layers were washed with 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 to provide N-(2-bromo-5-methylsulfonyl-phenyl)tetrahydropyran-4-amine (89 mg, 27% yield). MS:[M+H]+:334.1 / 336.1.

[0960]

[0961] Intermediate BE (6-chloro-4-iodo-N-(tetrahydro-2H-pyran-4-yl)pyridin-3-amine)

[0962] In a 4 mL vial, 6-chloro-4-iodo-pyridin-3-amine (100 mg, 393.0 μmol), EtOAc (1.2 mL), tetrahydropyran-4-one (47 μL, 507.1 μmol), and TFA (62.00 μL, 804.8 μmol) were added. Sodium triacetoxyborohydride (106 mg, 500.1 μmol) was added, and the mixture was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc and water and neutralized with a saturated aqueous solution of NaHCO3. The aqueous layer was collected, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 50%) in heptane to provide 6-chloro-4-iodo-N-tetrahydropyran-4-ylpyridin-3-amine (86 mg, 65% yield). MS:[M+H]+:339.1 / 341.0.

[0963]

[0964] Intermediate BF (6-chloro-N-(3,3-difluorocyclobutyl)-4-iodopyridin-3-amine)

[0965] In a 4 mL vial, 6-chloro-4-iodopyridin-3-amine (100 mg, 393.0 μmol), EtOAc (1.2 mL), 3,3-difluorocyclobutanone (54.19 mg, 510.89 μmol), and TFA (62.00 μL, 804.8 μmol) were added. Sodium triacetoxyborohydride (106 mg, 500.1 μmol) was added, and the mixture was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc and water and neutralized with a saturated aqueous solution of NaHCO3. The aqueous layer was collected, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 50%) in heptane to provide 6-chloro-N-(3,3-difluorocyclobutyl)-4-iodopyridin-3-amine (53 mg, 39% yield). MS:[M+H]+:345.0 / 347.0.

[0966]

[0967] Intermediate BG(3-((3-bromo-5-fluoropyridin-2-yl)oxy)-1-methylcyclobut-1-ol)

[0968] Step 1. 3-(benzyloxy)cyclobutanone (500 mg, 2.75 mmol) and anhydrous toluene (13.8 mL) were charged into an RBF container. Methyl magnesium bromide (3 M in Et₂O, 1.10 mL, 3.30 mmol) was slowly added to the reaction mixture under a nitrogen atmosphere at -78 °C. After 2 h, MeOH was added, followed by celite reaction. TM The slurry was filtered and washed with EtOAc. The mixture was concentrated and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 40%) in hexane to provide 3-(benzyloxy)-1-methylcyclobut-1-ol (270 mg, 51% yield). MS: [M-OH]+: 175.2.

[0969] Step 2. A mixture of 3-(benzyloxy)-1-methylcyclobut-1-ol (120 mg, 624 μmol) and 10 wt% palladium on carbon (60 mg, 567 μmol) in MeOH (5.7 mL) was stirred for 16 h under a hydrogen atmosphere. (The mixture was then processed by Celite.) TM The reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 40%) in hexane to provide 1-methylcyclobut-1,3-diol (30 mg, 47% yield).

[0970] Step 3. Sodium hydride (60%, 19 mg, 481 μmol) was added to a solution of 3-bromo-2,5-difluoropyridine (43 μL, 401 μmol) and 1-methylcyclobutane-1,3-diol (45.0 mg, 441 μmol) in anhydrous THF (1 mL). The mixture was heated to 50 °C for 2 h. The cooled reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and the aqueous layer was extracted with DCM (2X). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in hexane to provide 3-((3-bromo-5-fluoropyridin-2-yl)oxy)-1-methylcyclobutane-1-ol (50 mg, 45% yield). MS: [M+H]+: 276.1.

[0971]

[0972] Intermediate BH (4-bromo-6-fluoro-N-(tetrahydro-2H-pyran-4-yl)pyridin-3-amine)

[0973] 4-Bromo-6-fluoro-pyridin-3-amine (150 mg, 785.3 μmol), EtOAc (1.2 mL), tetrahydropyran-4-one (94 μL, 1.01 mmol), and TFA (124 μL, 1.61 mmol) were loaded into a 4 mL vial. Sodium triacetoxyborohydride (212 mg, 1.00 mmol) was added, and the mixture was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc and water and neutralized with a saturated aqueous solution of NaHCO3. The aqueous layer was collected, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 4-bromo-6-fluoro-N-tetrahydropyran-4-yl-pyridin-3-amine (198 mg, 92% yield). MS: [M+H]+: 275.1 / 277.1.

[0974]

[0975] Intermediate BI (4-bromo-N-(3,3-difluorocyclobutyl)-6-fluoropyridine-3-amine)

[0976] 4-Bromo-6-fluoro-pyridine-3-amine (150 mg, 785.3 μmol), EtOAc (1.2 mL), 3,3-difluorocyclobutanone (108 mg, 1.01 mmol), and TFA (124 μL, 1.61 mmol) were loaded into a 4 mL vial. Sodium triacetoxyborohydride (212 mg, 1.00 mmol) was added, and the mixture was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc and water and neutralized with a saturated aqueous solution of NaHCO3. The aqueous layer was collected, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 4-bromo-N-(3,3-difluorocyclobutyl)-6-fluoropyridine-3-amine (146 mg, 66% yield). MS: [M+H]+: 281.0 / 283.0.

[0977]

[0978] Intermediate BJ (1-methyl-N-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-3-amine)

[0979] Step 1. 4-Bromo-1-methyl-N-tetrahydropyran-4-yl-pyrazole-3-amine (500 mg, 2.84 mmol), IPAc (10 mL), tetrahydropyran-4-one (340 μL, 3.67 mmol), and TFA (445 μL, 5.78 mmol) were charged into an RBF. The mixture was treated with sodium triacetoxyborohydride (789 mg, 3.72 mmol) and stirred at rt for 90 min. The reaction mixture was diluted with EtOAc and water and neutralized with a saturated aqueous solution of NaHCO3. The aqueous layer was collected and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (50 to 100%) in heptane to provide 4-bromo-1-methyl-N-tetrahydropyran-4-yl-pyrazole-3-amine (622 mg, 84% yield). MS: [M+H]+: 259.9 / 261.9.

[0980] Step 2. 4-Bromo-1-methyl-N-tetrahydropyran-4-ylpyrazol-3-amine (622 mg, 2.39 mmol), potassium 2-ethylhexanoate (959 mg, 5.26 mmol), bis(pinacol)diboron (729 mg, 2.87 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (57 mg, 119.6 μmol), and IPAc (12 mL) were charged into an RBF container. The mixture was stirred at 40 °C for 10 min under N2, and then XPhos Pd(allyl)Cl (79 mg, 119.6 μmol) was added under N2. The mixture was stirred at 40 °C for 24 h. The reaction mixture was diluted with EtOAc and water. The aqueous layer was collected and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography and eluted with a gradient of EtOAc (50 to 100%) in heptane to provide 1-methyl-N-tetrahydropyran-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrazol-3-amine (785 mg, 50% yield).

[0981]

[0982] Intermediate BK (2-chloro-3-(difluoromethyl)pyrazine)

[0983] XtalFluor-E (2.18 g, 9.52 mmol) was added to a solution of triethylamine trihydrofluoride (2.1 mL, 12.88 mmol) in DCM (10 mL), followed by the addition of 3-chloropyrazine-2-carboxaldehyde (890 mg, 6.33 mmol). The mixture was stirred at rt for 2 h, then quenched by the addition of a saturated aqueous solution of NaHCO3, diluted with water, and extracted with DCM (3 x 20 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 2-chloro-3-(difluoromethyl)pyrazine (700 mg, 67% yield). 1 ¹H NMR (400 MHz, chloroform-d) δ 8.59 (d, J = 2.4 Hz, 1H), 8.52 (dt, J = 2.2, 1.0 Hz, 1H), 6.89 (m, 1H).

[0984]

[0985] Intermediate BL (3-bromo-6-(difluoromethyl)pyridine-2-amine)

[0986] Step 1. LiBH4 (250 mg, 11.5 mmol) was added to a solution of methyl 6-amino-5-bromo-pyridin-2-carboxylate (2.5 g, 10.8 mmol) in THF (25 mL). The mixture was stirred at rt for 18 h. The reactants were quenched with water and the mixture was diluted with water, then extracted with CHCl3 / IPA (4:1) (4 x 30 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated to dryness to provide (6-amino-5-bromo-2-pyridyl)methanol (2.0 g, 91% yield) as a white solid, which was ready for use without purification.

[0987] Step 2. Activated manganese oxide (IV) (10 g, 115.03 mmol) was added in a single batch to a solution of (6-amino-5-bromo-2-pyridyl)methanol (1.94 g, 9.55 mmol) in DCM (40 mL). The mixture was stirred at rt for 3 h and then filtered. The filtrate was concentrated to dryness to provide 6-amino-5-bromo-pyridyl-2-carboxaldehyde (1.5 g, 78% yield).

[0988] Step 3. XtalFluor-E (9.89 g, 43.19 mmol) was added to a solution of triethylamine trihydrofluorate (7.22 mL, 44.32 mmol) in DCM (120 mL), followed by 6-amino-5-bromo-pyridine-2-carboxaldehyde (4.3 g, 21.39 mmol). The mixture was stirred at rt for 2 h, then quenched by adding a saturated aqueous solution of NaHCO3, diluted with water, and extracted with DCM (3 x 100 mL). The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 3-bromo-6-(difluoromethyl)pyridine-2-amine (2.1 g, 44% yield). ¹H NMR (400MHz, chloroform-d) δ 7.74 (d, J = 7.8Hz, ¹H), 6.82 (d, J = 7.9Hz, ¹H), 6.38 (t, J = 55.6Hz, ¹H), 5.08 (s, 2H).

[0989]

[0990] Intermediate BM ((3,4-dihydro-2H-benzo[b][1,4]oxazine-5-yl)boronic acid)

[0991] Add 5-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (150 mg, 0.666 mmol), bis(neopentylethylene glycol)diboron (317 mg, 1.33 mmol), potassium acetate (198 mg, 2.0 mmol), and PdCl2(dppf) (48.7 mg, 0.067 mmol) and dioxane (5 mL) to a vial equipped with a stir bar. Degas the mixture with nitrogen for 5 min, seal the vial, and heat to 80 °C with stirring for 18 h. Cool the reaction mixture to ambient temperature and remove the solvent under vacuum. Absorb the residue in DMSO and purify by reversed-phase rapid chromatography (C18 silica gel with water / ACN: 10%–100%) to provide (3,4-dihydro-2H-benzo[b][1,4]oxazine-5-yl)boronic acid (100 mg, 84% yield). MS:[M+H]+:180.0.

[0992]

[0993] Intermediate BN (4-iodo-N-(tetrahydro-2H-pyran-4-yl)isothiazolyl-3-amine)

[0994] Step 1. Add isothiazol-5-amine hydrochloride (100 mg, 0.695 mmol), tetrahydro-4H-pyran-4-one (57 μL, 0.835 mmol), sodium triacetoxyborohydride (220 mg, 1.04 mmol), TFA (107 μL, 1.39 mmol), and isopropyl acetate (3.3 mL) to a vial equipped with a stir bar. Sonicate the mixture for 2 min and stir at ambient temperature for 16 h. Dilute the reactants with EtOAc and add triethylamine (500 μL, 3.55 mmol). Adsorb the mixture directly onto silica gel. Purify the residue by silica gel chromatography, eluting with a gradient of i-PrOH (1 to 30%) in DCM to provide N-(tetrahydro-2H-pyran-4-yl)isothiazol-5-amine, which is absorbed in DMF (3 mL) and N-iodosuccinimide (192 mg, 835 μmol) is added. The reactants were stirred at room temperature for 30 min, diluted with EtOAc, and adsorbed onto silica gel. The residues were purified by silica gel chromatography, eluting with a gradient of EtOAc (2 to 80%) in DCM to provide 4-iodo-N-(tetrahydro-2H-pyran-4-yl)isothiazolyl-5-amine (55.0 mg, 25% yield). MS: [M+H]+: 310.9.

[0995]

[0996] Intermediate BO (3-bromo-5-fluoro-N-(2-(trifluoromethyl)tetrahydro-2H-pyran-4-yl)pyridin-2-amine)

[0997] To a solution of 3-bromo-5-fluoro-pyridin-2-amine (231 mg, 1.21 mmol) in EtOAc (5 mL), 2-(trifluoromethyl)tetrahydropyran-4-one (256 mg, 1.52 mmol) and TFA (186 μL, 2.41 mmol) were added. Sodium triacetoxyborohydride (384 mg, 1.81 mmol) was added, and the mixture was stirred at rt for 4 days. A saturated aqueous solution of NaHCO3 was slowly added, and the mixture was stirred vigorously. The layers were separated, and the aqueous layer was extracted with EtOAc (2X). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 70%) in heptane to provide 3-bromo-5-fluoro-N-[2-(trifluoromethyl)tetrahydropyran-4-yl]pyridin-2-amine (179 mg, 43% yield). MS:[M+H]+:344.9.

[0998]

[0999] Intermediate BP (ethyl 5-amino-2-chloro-6-(7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidin-4-carboxylate)

[1000] Ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate (4.57 g, 19.4 mmol) and a 0.225 M dioxane solution of intermediate AT (80 mL, 18 mmol) were charged into a pressure vessel. 2 M K₃PO₄ aqueous solution (20 mL, 40 mmol) was added, followed by Pd(dtbpf)Cl₂ (631 mg, 968 μmol). The vessel was flushed with N₂, sealed, and stirred at 85 °C for 1 h. The cooled reaction mixture was diluted with water and EtOAc and passed through a Celite tube. TM Filtration. The filtrate was further diluted with EtOAc and water, then saturated with NaCl. The aqueous layer was collected and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (20 to 50%) in heptane to provide ethyl 5-amino-2-chloro-6-(7-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)pyrimidine-4-carboxylate (5.15 g, 61% yield). MS: [M+H]+: 434.0 / 436.0.

[1001]

[1002] Intermediate BQ (3-amino-1,3-dimethylcyclobutanol)

[1003] Step 1. 1-Methyl-3-oxocyclobutanecarboxylic acid (1.0 g, 7.8 mmol) and anhydrous THF (16 mL) were charged into an RBF container under an inert atmosphere. The mixture was cooled to 0 °C and methyl magnesium bromide (1.4 M in THF, 12.3 mL, 17.2 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. The reaction mixture was acidified to pH 1–2 with 1 N HCl aqueous solution and EtOAc (10 mL) was added. The layers were partitioned and the aqueous phase was extracted twice with EtOAc (10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of MeOH (1–8%) in DCM to provide 3-hydroxy-1,3-dimethylcyclobutane-1-carboxylic acid (610 mg, 54% yield). 1 H-NMR (400MHz, CDCl3): δ2.66 (dm, J=13.5Hz, 2H); 2.06 (dm, J=13.5Hz, 2H); 1.53 (s, 3H); 1.39 (s, 3H).

[1004] Step 2. A solution of triethylamine (590 μL, 4.23 mmol), 3-hydroxy-1,3-dimethylcyclobutane-1-carboxylic acid (610 mg, 4.23 mmol), and diphenylphosphoazide (950 μL, 4.23 mmol) in tert-BuOH (21 mL) was heated to reflux for 16 h. After cooling to rt, the mixture was diluted with water and extracted with EtOAc (3X). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of MeOH (0 to 10%) in DCM to provide 1,5-dimethyl-2-oxa-4-azabicyclo[3.1.1]hepta-3-one (450 mg, 75% yield). MS: [M+H]+: 142.0.

[1005] Step 3. A mixture of 1,5-dimethyl-2-oxa-4-azabicyclo[3.1.1]hepta-3-one (450 mg, 3.19 mmol), 4 MkOH aqueous solution (4.78 mL, 19.1 mmol), and isopropanol (16 mL) was heated to 100 °C for 16 h. After cooling to rt, the reaction mixture was acidified by adding aqueous HCl and concentrated to dryness under vacuum. The residue was ground together with EtOAc and the filtrate was concentrated to dryness to provide 3-amino-1,3-dimethylcyclobut-1-ol (367 mg, 99% yield).

[1006]

[1007] Intermediate BR (5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-N-(1-(trifluoromethyl)cyclopropyl)pyridine-2-amine)

[1008] Step 1. 2-Bromo-5-fluoropyridine (500 mg, 2.84 mmol), 1-(trifluoromethyl)cyclopropylamine hydrochloride (551 mg, 3.41 mmol), Pd2(dba)3 (260 mg, 284 μmol), rac-Binap (354 mg, 568 μmol), sodium tert-butoxide (828 mg, 8.52 mmol), and THF (14 mL) were placed in a microwave-safe reaction flask. The reaction mixture was degassed and heated to 50 °C for 16 h. The reaction mixture was diluted with EtOAc and purified via Celite. TM The filtrate was filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in hexane to provide 5-fluoro-N-(1-(trifluoromethyl)cyclopropyl)pyridine-2-amine (280 mg, 45% yield). MS: [M+H]+: 221.1.

[1009] Step 2. Benzyltrimethylammonium tribromide (351 mg, 899 μmol) and calcium carbonate (100 mg, 981 μmol) were added to a solution of 5-fluoro-N-(1-(trifluoromethyl)cyclopropyl)pyridine-2-amine (180 mg, 818 μmol) in DCM (2 mL) and MeOH (2 mL). The reaction mixture was stirred at rt for 18 h and then analyzed by Celite. TM The filter cake was filtered and washed with DCM. The filtrate was concentrated and the residue purified by silica gel chromatography, eluting with a gradient of EtOAc (20 to 60%) in hexane to provide 3-bromo-5-fluoro-N-(1-(trifluoromethyl)cyclopropyl)pyridine-2-amine (145 mg, 59% yield). MS: [M+H]+: 299.0.

[1010] Step 3. The 3-bromo-5-fluoro-N-(1-(trifluoromethyl)cyclopropyl)pyridine-2-amine (13.8 mg, 46.3 μmol), bis(pinacol)diboron (23.5 mg, 92.5 μmol), PdCl2(dppf)·DCM (3.8 mg, 4.63 μmol), and potassium acetate (13.8 mg, 139 μmol) from the degassed DMF were placed into a microwave-safe vial. The reaction mixture was then heated to 90 °C for 16 h. The reaction mixture was diluted with EtOAc and purified by Celite. TM Filtration. The filtrate was concentrated to dryness to obtain (5-fluoro-2-((1-(trifluoromethyl)cyclopropyl)amino)pyridin-3-yl)boronic acid, which can be used as is in subsequent steps without further purification.

[1011]

[1012] Intermediate BS (N-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine-2-amine)

[1013] 3-Bromo-N-cyclopropyl-pyridine-2-amine (127 mg, 596.0 μmol) in dioxane (3 mL) was placed in a MW vial. Nitrogen gas was bubbled through the solution and bis(pinacol)diboron (194 mg, 764.0 μmol), KOAc (150 mg, 1.53 mmol), and Pd(dppf)Cl2·DCM (27 mg, 33.1 μmol) were added. The vial was rinsed with N2, sealed, and stirred at 110 °C for 1 h to provide N-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine-2-amine as a solution in dioxane, which could be used as is in subsequent steps.

[1014]

[1015] Intermediate BT (ethyl 3-amino-6-chloro-2-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)isonicotinic acid)

[1016] Ethyl 3-amino-2-bromo-6-chloroisonicotinic acid (2.0 g, 7.16 mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-indazole (2.57 g, 7.51 mmol), potassium carbonate (2.47 g, 17.9 mmol), PdCl2 (dppf) (534 mg, 0.716 mmol), dioxane (40 mL), and water (10 mL) were added to a flask equipped with a stir bar. The mixture was degassed with nitrogen for 5 min, and the flask was fitted with a reflux condenser and heated to 100 °C with stirring for 3 h. The reaction mixture was cooled to rt and analyzed by Celite. TM Filtration was performed with EtOAc as the eluent, and the residue was adsorbed onto silica gel. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (1 to 40%) in DCM to provide ethyl-3-amino-6-chloro-2-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-yl) (1.7 g, 57% yield). MS: [M+H]+: 415.3.

[1017]

[1018] Intermediate BU((2-((2,2-difluoro-1-(pyridin-3-yl)ethyl)amino)pyridin-3-yl)boronic acid)

[1019] Step 1. Selectfluor (7.75 g, 21.9 mmol) was added to a solution of 4,4,4-trifluoro-1-(pyridin-3-yl)butane-1,3-dione (2.0 g, 8.75 mmol) in acetonitrile (88 mL). The resulting mixture was heated to reflux for 3 h. Water (18 μL) was then added and reflux was maintained for another 15 min. The reaction mixture was cooled to rt and triethylamine (6.1 mL) was added. It was stirred at rt for 16 h. Volatiles were removed under vacuum and the residue was purified by silica gel chromatography, eluting with an EtOAc gradient (0 to 100%) in hexane to provide 2,2-difluoro-1-(pyridin-3-yl)ethyl-1-one (960 mg, 70% yield).

[1020] Step 2. Under argon atmosphere, 2,2-difluoro-1-(pyridin-3-yl)ethyl-1-one (420 mg, 2.67 mmol) was added to a solution of 2-amino-3-bromopyridine (308 mg, 1.78 mmol) in DCM (9 mL), followed by titanium chloride (IV) (1 M in toluene, 2.14 mL, 2.14 mmol). The resulting mixture was then stirred at rt for 6 h. Sodium triacetoxyborohydride (755 mg, 3.56 mmol) was then added, and the mixture was stirred at rt for 16 h. (By Celite) TM The mixture was filtered and washed with EtOAc. Volatiles were removed under vacuum, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in hexane to provide 3-bromo-N-(2,2-difluoro-1-(pyridin-3-yl)ethyl)pyridine-2-amine (290 mg, 52% yield). MS: [M+H]+: 315.9.

[1021] Step 3. 3-Bromo-N-(2,2-difluoro-1-(pyridin-3-yl)ethyl)pyridine-2-amine (50.0 mg, 159 μmol), XPhos Pd G3 (6.74 mg, 7.96 μmol), potassium acetate (46.9 mg, 478 μmol), and tetrahydroxydiboron (42.8 mg, 478 μmol) were placed in a microwave-safe reaction flask and capped. The mixture was degassed (3 cycles of vacuum / Ar). MeOH (562 μL) and ethylene glycol (187 μL) were added. The mixture was heated to 60 °C for 18 h. The mixture was then passed through diatomaceous earth. TM The mixture was filtered and washed with MeOH. Volatile substances were removed under vacuum and the crude (2-((2,2-difluoro-1-(pyridin-3-yl)ethyl)amino)pyridin-3-yl)boronic acid was ready for use in subsequent steps without further purification.

[1022]

[1023] Intermediate BV (N-(6-chloro-4-iodopyridin-3-yl)-3-fluoropyridin-2-amine)

[1024] 6-Chloro-4-iodopyridin-3-amine (100 mg, 393.0 μmol), 2,3-difluoropyridine (45 mg, 393.0 μmol), and DMF (4 mL) were loaded into an RBF container. Sodium hydride (60% dispersed in mineral oil) (79 mg, 1.96 mmol) was added, and the mixture was stirred overnight at rt. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and diluted with EtOAc and water. The aqueous layer was collected, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 30%) in heptane to provide 6-chloro-N-(3-fluoro-2-pyridyl)-4-iodopyridin-3-amine (86 mg, 63% yield). MS: [M+H]+: 350.0 / 351.9.

[1025]

[1026] Intermediate BW(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-N-(2,2,2-trifluoroethyl)pyridine-2-amine)

[1027] Step 1. Add TFA (392 μL, 5.09 mmol) to a MW vial containing 3-bromo-2-fluoropyridine (299 mg, 1.70 mmol) and 2,2,2-trifluoroethylamine (675 μL, 8.52 mmol) in trifluoroethanol (3 mL). Cap the vial and stir at 120 °C for 18 h. Cool the cooled reaction mixture with saturated NaHCO3 aqueous solution and extract with DCM (3X). Adsorb the combined organic extracts onto silica. Purify the residue by silica gel chromatography, eluting with an EtOAc (0 to 100%) gradient in heptane to provide 3-bromo-N-(2,2,2-trifluoroethyl)pyridine-2-amine (390 mg, 2.38 mmol, 90% yield). MS: [M+H]+: 255.0 / 257.0.

[1028] Step 2. Dioxane (8 mL) was added to a MW vial containing bis(pinacol)diboron (602 mg, 2.37 mmol), 3-bromo-N-(2,2,2-trifluoroethyl)pyridine-2-amine (503 mg, 1.97 mmol), potassium acetate (600 mg, 6.11 mmol), and Pd(dppf)Cl2·DCM (166 mg, 203.3 μmol). The solution was bubbled through with N2, the vial was capped, and the mixture was stirred at 100 °C for 2.5 h. The cooled reaction mixture was adsorbed onto silica using DCM. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 60%) in heptane to provide 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-N-(2,2,2-trifluoroethyl)pyridine-2-amine (260 mg, 44% yield). MS:[M+H]+:304.0

[1029]

[1030] Intermediate BX ((5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid)

[1031] Step 1. To a suspension of 4-bromo-5-fluoro-1H-indazole (2.0 g, 9.30 mmol) in MeCN (30 mL), p-toluenesulfonic acid (160.17 mg, 930.1 μmol) was added, followed by 3,4-dihydropyran (2.55 mL, 28.1 mmol). The resulting solution was stirred at rt for 45 min. The mixture was concentrated and partitioned between saturated NaHCO3 aqueous solution and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2X). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 50%) in DCM to provide 4-bromo-5-fluoro-1-tetrahydropyran-2-yl-indazole (1.66 g, 60% yield). MS: [M+H]+: 214.9 / 216.9.

[1032] Step 2. In a dry ice / acetone bath, a solution of 2.5 M n-butyllithium in hexane (3.4 mL, 8.5 mmol) was added dropwise to a solution of 4-bromo-5-fluoro-1-tetrahydropyran-2-yl-indazole (1.66 g, 5.55 mmol) in THF (16 mL). The mixture was stirred at -78 °C for 55 min, and then trimethyl borate (1.89 mL, 16.65 mmol) was added dropwise. The mixture was stirred at -78 °C for 90 min, and then quenched with a saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (3X). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in heptane to provide (5-fluoro-1-tetrahydropyran-2-yl-indazole-4-yl)boronic acid (756 mg, 52% yield). MS:[M+H]+:265.0.

[1033]

[1034] Intermediate BY (6-(methyl-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine-2-amine)

[1035] Step 3. Add molecular iodine (60 mg, 236.4 μmol) to a suspension of magnesium (675 mg, 27.8 mmol) in diethyl ether (27.50 mL). Stir the mixture at rest for 10 min, then add trideuterium (iodo)methane (1.8 mL, 28.93 mmol) dropwise. After a few drops of iodomethane-d3, sonicate the mixture for 5 min. The color of the reactant changes from orange to yellow, then to milky white, and finally to a turbid metallic color (high exothermic reaction was observed, and the suspension refluxed without any external heat). After adding iodomethane-d3, stir the mixture at rest for 1 h 30. Add this solution dropwise at rest to a solution of 0.5 M ZnCl2 in THF (55 mL, 27.5 mmol). After addition, stir the mixture at rest for 20 min. This solution was added to a mixture of 3-bromo-6-iodopyridine-2-amine (1500 mg, 5.02 mmol) and Pd(PPh3)4 (576 mg, 498.5 μmol). The mixture was stirred at 60 °C for 1 h under N2. The reaction mixture was quenched with dilute aqueous HCl and water and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 60%) in heptane to provide 3-bromo-6-(trideuterylmethyl)pyridine-2-amine (600 mg, 63% yield). 1¹H NMR (400MHz, chloroform-d) δ 7.47 (d, J = 7.8Hz, 1H), 6.36 (d, J = 7.9Hz, 1H), 4.95 (s, 2H).

[1036] Step 4. To a solution of 3-bromo-6-(trideuterylmethyl)pyridin-2-amine (272 mg, 1.43 mmol) in dioxane (10 mL), potassium acetate (354 mg, 3.61 mmol), Pd(dppf)Cl2 (65 mg, 88.8 μmol), and bis(pinacol)diboron (460 mg, 1.81 mmol) were added. The mixture was degassed under vacuum, backfilled with N2, and stirred at 110 °C for 1 h under N2 to provide a solution of 6-(methyl-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-amine, which was used as is for arylation.

[1037]

[1038] Intermediate BZ (3-bromo-6-iodopyridin-2-amine)

[1039] A MW container containing a solution (5 mL, 35 mmol) of 3-bromo-2-fluoro-6-iodopyridine (2.0 g, 6.63 mmol) and 7N ammonia in MeOH was sealed and stirred overnight at 60 °C. The solvent was evaporated and the residue was absorbed into EtOAc, washed with a saturated aqueous solution of NaHCO3, then washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 20%) in heptane to provide 3-bromo-6-iodopyridine-2-amine (1.32 g, 67% yield). MS: [M+H]+: 298.8 / 300.8.

[1040]

[1041] Intermediate CA (3-amino-6-chloro-2-(5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)isonicotinic acid ethyl ester)

[1042] Ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate (13.0 g, 55.07 mmol), dioxane (280 mL), 2MK3PO4 aqueous solution (44 mL, 88 mmol), and Pd(dppf)Cl2·DCM (4.50 g, 5.51 mmol) were charged into an RBF containing intermediate AE (19.71 g, 57.09 mmol). The mixture was bubbled with N2 for 10 min, followed by condensation. Three vacuum / nitrogen cycles were performed, and the mixture was stirred at 85 °C for 3 h. The cooled reaction mixture was concentrated into a slurry, diluted with EtOAc and water, and passed through a Celite precipitate. TM Filter the mixture. Withdraw the aqueous layer from the filtrate and extract twice with EtOAc. Wash the combined organic layers with brine, dry over MgSO4, filter, and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of EtOAc (10 to 60%) in heptane to provide ethyl 5-amino-2-chloro-6-[1-tetrahydropyran-2-yl-5-(trideuterylmethyl)indazole-4-yl]pyrimidine-4-carboxylate (13.7 g, 59% yield). MS: [M+H]+: 419.0 / 420.9.

[1043]

[1044] Intermediate CB (6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine-2-amine)

[1045] Intermediate AQ (22.5 g, 117.8 mmol), XPhos (555 mg, 1.16 mmol), bis(pinacol)diboron (35 g, 137.8 mmol), and potassium 2-ethylhexanoate (43.2 g, 237.0 mmol) were loaded into an RBF container. Isopropyl acetate (650 mL) was added, and nitrogen gas was bubbled through for 5 min while maintaining a positive nitrogen pressure. The thick suspension was stirred at 50 °C for 5–10 min, and then XPhos Pd(allyl)Cl (776 mg, 1.18 mmol) was added. The suspension was stirred at 50 °C under nitrogen for 4 h. The cooled reaction mixture was diluted with water and EtOAc. The layers were separated, and the organic layer was washed successively with water and brine, dried over Na2SO4, filtered, and adsorbed onto silica. The residue was purified by silica gel chromatography, eluted with a gradient of EtOAc (0 to 30%) in heptane to provide 6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-amine (22.2 g, 79% yield). MS: [M+H]+: 239.3.

[1046]

[1047] Intermediate CD((1s,3s)-3-((5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)amino)-1-methylcyclobut-1-ol)

[1048] Step 1. Under reflux, (1s,3s)-3-amino-1-methylcyclobut-1-ol hydrochloride (3.30 g, 24.0 mmol) was added to a solution of 3-bromo-2,5-difluoropyridine (4.5 g, 23.2 mmol) and K₂CO₃ (8.10 g, 58.6 mmol) in DMSO (20 mL). The mixture was stirred at 100 °C for 18 h. The cooled reaction mixture was poured into water and extracted with ether. The organic layer was separated, washed with water and brine, dried over MgSO₄ and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 65%) in heptane to provide (1s,3s)-3-((3-bromo-5-fluoropyridin-2-yl)amino)-1-methylcyclobut-1-ol (5.8 g, 91% yield). MS: [M+H]+: 275.0 / 277.0.

[1049] Step 2. In an oven-dried three-necked RBF with a condenser, (1s,3s)-3-((3-bromo-5-fluoropyridin-2-yl)amino)-1-methylcyclobut-1-ol (39.8 g, 144.7 mmol), bis(pinacol)diboron (47.55 g, 187.3 mmol), and potassium acetate (35.5 g, 361.7 mmol) were charged. Dioxane (600 mL) was added and the mixture was bubbled through with N2. Pd(dppf)Cl2·DCM (4.87 g, 5.96 mmol) was added, and the mixture was bubbled through with N2 and stirred at 110 °C for 90 min. The cooled reaction mixture was diluted with water (600 mL) and purified by Celite. TM Filter and wash with EtOAc (600 mL total). Separate the layers and extract the aqueous layer with EtOAc (300 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of EtOAc (25 to 100%) in heptane. Grind the solid in heptane at 50 °C to provide (1s,3s)-3-((5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)amino)-1-methylcyclobut-1-ol (25.09 g, 54% yield). MS: [M+H]+: 323.3. 1¹H NMR (400MHz, chloroform-d) δ 8.00 (dd, J = 3.3, 0.8Hz, 1H), 7.56 (dd, J = 8.3, 3.2Hz, 1H), 6.25 (d, J = 6.8Hz, 1H), 4.03 (h, J = 7.7Hz, 1H), 2.62 (ddt, J = 9.5, 7.6, 2.4Hz, 2H), 2.13 (s, 1H), 2.06–1.97 (m, 2H), 1.44 (s, 3H), 1.34 (s, 12H).

[1050]

[1051] Intermediate CE (3-bromo-6-cyclopropylpyridine-2-amine)

[1052] To a mixture of intermediate BZ (1.0 g, 3.35 mmol) and Pd(PPh3)4 (384 mg, 332.3 μmol) in THF (20 mL), a solution of 0.5 M cyclopropyl zinc bromide in THF (26 mL, 13 mmol) was added dropwise. The mixture was stirred at 60 °C for 1 h under N2. The cooled reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 40%) in heptane to provide 3-bromo-6-cyclopropyl-pyridin-2-amine (460 mg, 65% yield). MS: [M+H]+: 213.0 / 215.0. 1 ¹H NMR (400MHz, chloroform-d) δ 7.43 (d, J = 7.9Hz, 1H), 6.37 (d, J = 7.9Hz, 1H), 4.74 (s, 2H), 1.90–1.71 (m, 1H), 0.96–0.80 (m, 4H).

[1053]

[1054] Intermediate CF (3-bromo-6-ethylpyridine-2-amine)

[1055] 3-Bromo-6-iodopyridin-2-amine (400 mg, 1.34 mmol) was dissolved in THF (6.7 mL) in flame-dried RBF. The mixture was degassed under nitrogen for 10 min, and Pd(PPh3)4 (156 mg, 134 μmol) was added under rt, followed by dropwise addition of a solution of 2 M diethylzinc in hexane (1.34 mL, 2.68 mmol). The mixture was stirred under nitrogen at 60 °C for 1 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 40%) in heptane to provide 3-bromo-6-ethylpyridin-2-amine (53 mg, 20%). MS: [M+H]+: 201.0 / 203.0.

[1056]

[1057] Intermediate CG (3-fluoro-N-(4-iodopyridin-3-yl)pyridin-2-amine)

[1058] 2,3-Difluoropyridine (212 mg, 1.77 mmol) and 3-amino-4-iodopyridine (400 mg, 1.82 mmol) were dissolved in DMF (6.2 mL). Sodium hydride (60% dispersed in mineral oil, 197 mg, 4.91 mmol) was added fractionally at rt, and the mixture was stirred at rt for 1 h. MeOH (1 mL) and silica were added, and the mixture was concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (5 to 100%) in heptane to provide 3-fluoro-N-(4-iodopyridin-3-yl)pyridine-2-amine (300 mg, 78% yield). MS: [M+H]+: 315.9.

[1059]

[1060] Intermediate CH(N-(4-iodopyridin-3-yl)pyrimidin-2-amine)

[1061] 2-Chloroprene (187 μL, 1.81 mmol) and 3-amino-4-iodopyridine (400 mg, 1.82 mmol) were dissolved in DMF (6.2 mL). Sodium hydride (60% dispersed in mineral oil, 197 mg, 4.91 mmol) was added fractionally at rt, and the mixture was stirred at rt for 1 h. MeOH (1 mL) and silica were added, and the mixture was concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (5 to 100%) in heptane to provide N-(4-iodopyridin-3-yl)pyrimidin-2-amine (270 mg, 74% yield). MS: [M+H]+: 299.3.

[1062]

[1063] Intermediate CI ((5-chloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid)

[1064] Step 1. Dissolve 1.2 g (5.47 mmol) of 4-bromo-7-fluoro-1H-indazole in 7.5 mL of concentrated sulfuric acid and cool with stirring in an ice bath. Add 2.4 mL of concentrated nitric acid dropwise and stir the reaction mixture for 1 h. Pour the mixture into ice water, collect the precipitate by vacuum filtration, and dry it under vacuum to give 1.22 g (86% yield) of 4-bromo-7-fluoro-5-nitro-1H-indazole. MS: [M+H]+: 260.0.

[1065] Step 2. In a mixture of water (10 mL), methanol (10 mL), and THF (10 mL), stir 1.2 g (4.62 mmol) of 4-bromo-7-fluoro-5-nitro-1H-indazole and 1.48 g (27.7 mmol) of ammonium chloride. Add 1.03 g (18.5 mmol) of iron powder and heat the reaction mixture to 80 °C with stirring for 1 h. Cool the reaction mixture to ambient temperature and pass it through a Celite tube. TM Filtration was performed, with EtOAc as the eluent. The filtrate was adsorbed onto silica gel and the residue was purified by silica gel chromatography, followed by gradient elution with EtOAc (2 to 80%) in heptane to provide 4-bromo-7-fluoro-1H-indazole-5-amine (720 mg, 68% yield). MS: [M+H]+: 231.9.

[1066] Step 3. Sonicate 4-bromo-7-fluoro-1H-indazole-5-amine (1.0 g, 4.35 mmol) in concentrated HCl (7 mL) until dissolved, then cool with stirring in an ice bath. Add a solution of sodium nitrite (360 mg, 522 mmol) in water (7 mL) to this stirred solution. Stir the mixture at 0 °C for 15 min, then slowly add it to a stirred suspension of copper chloride (I) (887 mg, 8.69 mmol) in water (20 mL) at 60 °C. After the addition is complete, stir the reaction mixture at 60 °C for another 30 min, then cool in an ice bath. Slowly add potassium carbonate with stirring until gas escaping stops. Then add ammonium hydroxide (28-30%, 10 mL, 257 mmol) and extract the product into EtOAc. Wash the organic layer with water and brine, dry with sodium sulfate, filter, and adsorb onto silica gel. The residue was purified by silica gel chromatography, eluted with a gradient of EtOAc (2 to 80%) in heptane to provide 4-bromo-5-chloro-7-fluoro-1H-indazole (730 mg, 67% yield). MS: [M+H]+: 251.3.

[1067] Step 4. To a stirred solution of 4-bromo-5-chloro-7-fluoro-1H-indazole (730 mg, 2.93 mmol) in DCM (7.6 mL), add a solution of 3,4-dihydro-2H-pyran (550 μL, 5.85 mmol) and p-toluenesulfonic acid monohydrate (56.5 mg, 293 μmol) in DCM (1.5 mL). Stir the mixture overnight at room temperature and adsorb directly onto silica gel. Purify the residue by silica gel chromatography, eluting with a gradient of EtOAc (2 to 60%) in heptane to provide 4-bromo-5-chloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (480 mg, 49% yield). MS: [M-THP+H]+: 251.3.

[1068] Step 5. Cool a stirred solution of 4-bromo-5-chloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (350 mg, 1.05 mmol) and triisopropyl borate (737 μL, 3.15 mmol) in anhydrous THF (6.00 mL) to -78 °C under nitrogen. Add dropwise a solution of 1.7 M tert-butyllithium in pentane (1.23 mL, 2.10 mmol). Stir the mixture at -78 °C for 30 min. Add another portion of 1.7 M tert-butyllithium in pentane (1.23 mL, 2.10 mmol), and stir the mixture at -78 °C for another 30 min. Add yet another portion of 1.7 M tert-butyllithium in pentane (1.23 mL, 2.10 mmol), and stir the mixture at -78 °C for 30 min. The reactants were quenched with a saturated ammonium chloride aqueous solution and extracted with EtOAc. The combined organic matter was washed with brine, dried over sodium sulfate, filtered, and adsorbed onto silica gel. The residue was purified by silica gel chromatography, eluting with a gradient of i-PrOH (1 to 40%) in DCM to provide (5-chloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (125 mg, 40% yield). MS: [M-THP+H]+: 215.2.

[1069]

[1070] Intermediate CM (3-((3-bromopyridin-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxynitrile)

[1071] To a solution of 3-bromo-2-iodopyridine (400 mg, 1.41 mmol) in toluene (15 mL), 3-aminobicyclo[1.1.1]pentane-1-carboxylonitrile hydrochloride (230 mg, 1.59 mmol), Pd(OAc)₂ (30 mg, 133.6 μmol), cesium carbonate (1.1 g, 3.38 mmol), and rac-BINAP (172 mg, 276.2 μmol) were added. The mixture was degassed under vacuum, backfilled with N₂, and stirred at 110 °C for 2 h. The cooled reaction mixture was concentrated, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 50%) in heptane to provide 3-[(3-bromo-2-pyridyl)amino]bicyclo[1.1.1]pentane-1-carboxylonitrile (115 mg, 31% yield). 1 ¹H NMR (400MHz, chloroform-d) δ 8.03 (dd, J = 4.8, 1.6 Hz, 1H), 7.58 (dd, J = 7.7, 1.6 Hz, 1H), 6.52 (dd, J = 7.7, 4.8 Hz, 1H), 2.63 (s, 6H).

[1072]

[1073] Intermediate CN(6-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyridine-2-amine)

[1074] Potassium acetate (283 mg, 2.88 mmol), Pd(dppf)Cl2 (55 mg, 75.2 μmol), and bis(pinacol)diboron (370 mg, 1.46 mmol) were added to a solution of intermediate BL (256 mg, 1.15 mmol) in dioxane (10 mL). The mixture was degassed under vacuum, backfilled with N2, and stirred at 110 °C for 1 h under N2 to provide a solution of 6-(trifluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)pyridine-2-amine, which was used as is for arylation.

[1075]

[1076] Intermediate CO (3-amino-6-chloro-4-(3-hydroxy-2,6-dimethylphenyl)pyridinecarboxamide)

[1077] Step 1. To a solution of intermediate D (6.0 g, 21.5 mmol) in toluene (100 mL), add 2-(3-methoxy-2,6-dimethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (6.00 g, 22.9 mmol), 2M Na₂CO₃ aqueous solution (21 mL, 42 mmol), 1M tri-tert-butylphosphine solution in toluene (4.2 mL, 4.20 mmol), and Pd₂(dba)₃ (1.95 g, 2.13 mmol). Degas the mixture under vacuum, then backfill with N₂, and stir at 90 °C for 2 h. Volatile substances were removed under vacuum, and the residue was purified by rapid silica gel chromatography, eluting with EtOAc / hexane 0–30% to provide ethyl 3-amino-6-chloro-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxylate (4.56 g, 63% yield). MS: [M+H] + :335.2.

[1078] Step 2. In a 150 mL pressure vessel, add ethyl 3-amino-6-chloro-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxylate (1.45 g, 4.32 mmol) and a solution of 7N ammonia in MeOH (50 mL, 350 mmol). Seal the vessel and stir overnight at 70 °C. Cool the mixture to rt and then concentrate to dryness. Purify the residue by rapid silica gel chromatography, eluting with EtOAc / hexane 0-50% to provide 3-amino-6-chloro-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxamide (1.13 g, 86% yield). MS: [M+H] + :306.2.

[1079] Step 3. Add a solution of 1 M BBr3 in DCM (9.3 mL, 9.3 mmol) to a solution of 3-amino-6-chloro-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxamide (950 mg, 3.11 mmol) in DCM (12 mL). Stir the mixture at rt for 20 min. Add silica to the mixture and remove volatiles under vacuum. Purify the residue by silica gel chromatography, eluting with a MeOH gradient (0 to 10%) in DCM to provide 3-amino-6-chloro-4-(3-hydroxy-2,6-dimethyl-phenyl)pyridine-2-carboxamide (906 mg, 99% yield). MS: [M+H] + :292.2.

[1080]

[1081] Intermediate CP (2-(3-(2-methoxybutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane)

[1082] Step 1. Et3N (0.389 g, 3.846 mmol) was added to a solution of 2-methoxybut-1-ol (0.2 g, 1.92 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred for 10 min, and methanesulfonyl chloride (0.262 g, 2.3 mmol) was added. The mixture was stirred at rt for 2 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated to provide 2-methoxybutyrate methanesulfonate (0.320 g, 91% yield), which could be used in the next step without purification. 1 H NMR (400MHz, DMSO-d6) δ4.35-4.18(m,2H),3.47(s,3H),3.42-3.40(m,1s),3.1(s,3H),1.66-1.59(m,2H),1.01-0.99(m,3H).

[1083] Step 2. K₂CO₃ (0.727 g, 5.27 mmol) and 3-bromophenol (0.272 g, 1.575 mmol) were added to a stirred solution of 2-methoxybutyl methanesulfonate (0.32 g, 1.75 mmol) in DMF (3.5 mL). The resulting mixture was heated at 80 °C for 16 h. The cooled reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to %) in hexane to provide 1-bromo-3-(2-methoxybutoxy)benzene (0.4 g, 83%). 1 H NMR (400MHz, DMSO-d6) δ7.19–7.11(m,3H),6.89(d,J=8Hz,1H),3.99(d,J=4.8Hz,2H),3.51(s,4H),1.75-1.62(m,2H),1.02(t,J=7.6Hz,3H).

[1084] Step 3. Purge a solution of 1-bromo-3-(2-methoxybutoxy)benzene (0.4 g, 1.54 mmol), bis(pinacol)diborane (0.588 g, 2.31 mmol), and KOAc (0.452 g, 4.62 mmol) in dioxane (10 mL) with N2 gas for 15 min. Add PdCl2 (dppf)·DCM (0.125 g, 0.154 mmol) and stir the mixture at 100 °C for 5 h. Pour the cooled reaction mixture into water and extract with ethyl acetate (3 x 10 mL). Dry the combined organic layers over sodium sulfate and concentrate to give 2-(3-(2-methoxybutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (0.3 g, 63%), which can be used in the next step without purification. MS: [M+H] + :307.2.

[1085] Compound

[1086]

[1087] Compound 1 (7-amino-6-(5-hydroxy-2-methylphenyl)quinoline-8-carboxamide)

[1088] Step 1. A mixture of [5-(methoxymethoxy)-2-methyl-phenyl]boronic acid (13 mg, 66 μmol), potassium carbonate (29 mg, 211 μmol), Pd(PPh3)4 (7.0 mg, 6 μmol), and intermediate A (15 mg, 60 μmol) in toluene and water (0.5 mL) was degassed and stirred under reflux for 5 h. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC, eluting with ACN / water / 0.1% formic acid to provide 7-amino-6-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-8-carboxynitrile (11 mg, 57% yield). MS: [M+H] + 320.2

[1089] Step 2. To a suspension of 7-amino-6-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-8-carboxynitrile (10.0 mg, 31 μmol) in DCM (1 mL), add a solution of 4 M HCl in dioxane (47 μL, 188 μmol). Stir the mixture at rt for 3 h. Remove the solvent under vacuum to provide 7-amino-6-(5-hydroxy-2-methyl-phenyl)quinoline-8-carboxynitrile (9 mg, 99% yield). MS: [M+H] + :276.1.

[1090] Step 3. Add 100 μL (400 μmol) of 4M NaOH solution to a microwave-safe container containing 9 mg (33 μmol) of 7-amino-6-(5-hydroxy-2-methyl-phenyl)quinoline-8-carboxynitrile in methanol (500 μL). Seal the container and heat the mixture at 130 °C for 30 min. Purify the reaction mixture by preparative HPLC, eluting with ACN / water / 0.1% formic acid to provide 7-amino-6-(5-hydroxy-2-methyl-phenyl)quinoline-8-carboxamide (0.4 mg, 4% yield). MS: [M+H] + 294.1; 1 ¹H NMR (400MHz, chloroform-d) δ 8.67 (d, J = 2.4Hz, 1H), 7.88 (d, J = 2.4Hz, 1H), 7.58 (d, J = 9.0Hz, 1H), 7.16 (d, J = 8.1Hz, 2H), 6.91 (d, J = 8.9Hz, 1H), 6.83–6.69 (m, 3H), 5.88 (s, 2H), 2.21 (s, 3H).

[1091]

[1092] Compound 2 (5-amino-6-(5-hydroxy-2-methylphenyl)-2-phenylpyrimidine-4-carboxamide)

[1093] Step 1. Sodium carbonate (2M, 160μL), phenylboronic acid (18mg, 147.6μmol), and Pd(dppf)Cl2 (6mg, 8.2μmol) were added to a solution of intermediate C (26mg, 80.56μmol) in dioxane (2mL). The mixture was degassed under vacuum, backfilled with N2, and stirred at 120°C for 5h. Volatiles were removed under vacuum, and the residue was purified by rapid silica gel chromatography, eluting with EtOAc / hexane 0-50% to provide 5-amino-6-[5-(methoxymethoxy)-2-methyl-phenyl]-2-phenyl-pyrimidine-4-carboxamide (18mg, 49.40μmol, yield 61.32%). MS: [M+H] + 365.2; 1 ¹H NMR (400MHz, chloroform-d) δ 8.42–8.24 (m, 2H), 8.11 (d, J = 4.5 Hz, 1H), 7.45–7.31 (m, 3H), 7.31–7.21 (m, 1H), 7.12–7.00 (m, 2H), 5.94 (s, 2H), 5.75 (d, J = 4.6 Hz, 1H), 5.16 (s, 2H), 3.47 (s, 3H), 2.17 (s, 3H).

[1094] Step 2. To a solution of 5-amino-6-[5-(methoxymethoxy)-2-methyl-phenyl]-2-phenylpyrimidine-4-carboxamide (18 mg, 49.4 μmol) in DCM (1 mL), a solution of 4 M HCl in dioxane (200 μL, 0.8 mmol) was added. The mixture was stirred at rt for 1 h and volatiles were removed under vacuum. The residue was dissolved in water and acetonitrile and then lyophilized to provide 5-amino-6-(5-hydroxy-2-methylphenyl)-2-phenylpyrimidine-4-carboxamide hydrochloride (17 mg, 96% yield). MS: [M+H] + 321.2; 1 H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.50(s,1H),8.44–8.29(m,2H),7.79(s,1H),7.52–7.31(m,3H) ,7.14(d,J=8.4Hz,1H),6.78(dd,J=8.3,2.6Hz,1H),6.69(d,J=2.6Hz,1H),6.49(s,2H),2.00(s,3H).

[1095]

[1096] Compound 3 (5-amino-6-(5-hydroxy-2-methylphenyl)-2-(thiazolyl-2-yl)pyrimidine-4-carboxamide)

[1097] Step 1. A solution of tributyl(thiazol-2-yl)stanane (140 μL, 445 μmol), intermediate C (70 mg, 217 μmol), copper iodide (I) (5 mg, 26 μmol), lithium chloride (13 mg, 307 μmol), and Pd(dppf)Cl2 (16 mg, 22 μmol) in DMF (2 mL) was degassed under vacuum and then backfilled with N2. The solution was then stirred at 110 °C for 2 h. Volatiles were removed under vacuum, and the residue was purified by rapid silica gel chromatography, eluting with MeOH / DCM 0-10% to provide 5-amino-6-[5-(methoxymethoxy)-2-methyl-phenyl]-2-thiazol-2-yl-pyrimidine-4-carboxamide (52 mg, 65% yield). MS: [M+H] + :372.2.

[1098] Step 2. To a solution of 5-amino-6-[5-(methoxymethoxy)-2-methyl-phenyl]-2-thiazolyl-2-ylpyrimidine-4-carboxamide (52 mg, 140.0 μmol) in DCM (1 mL), a solution of 4 M HCl in dioxane (0.35 mL, 1.4 mmol) was added. The mixture was stirred at rt for 1 h. Volatiles were removed under vacuum, and the residue was purified by preparative HPLC C18 column, eluting with ACN / water / 0.1% formic acid to provide 5-amino-6-(5-hydroxy-2-methyl-phenyl)-2-thiazolyl-2-ylpyrimidine-4-carboxamide (25 mg, 55% yield). MS: [M+H] + 328.2; 1 H NMR (400MHz, DMSO-d6) δ9.47 (s, 1H), 8.11 (d, J = 2.6Hz, 1H), 7.90 (dd, J = 6.9, 2.9Hz ,2H),7.76(d,J=3.2Hz,1H),7.15(d,J=8.3Hz,1H),6.93–6.47(m,4H),2.00(s,3H).

[1099]

[1100] Compound 10 (3-amino-4-(5-hydroxy-2-methylphenyl)quinoline-2-carboxamide)

[1101] Step 1. A suspension of ethyl 4-oxo-1H-quinoline-2-carboxylate (1.07 g, 4.92 mmol) and NIS (1.22 g, 5.41 mmol) in ACN (10 mL) and acetic acid (0.5 mL) was stirred at 90 °C for 17 h. The solid was filtered to provide ethyl 4-hydroxy-3-iodo-quinoline-2-carboxylate (962 mg, 57% yield). MS: [M+H] + :344.0.

[1102] Step 2. At 0 °C, a solution of 1 M trifluoromethanesulfonyl trifluoromethanesulfonate in DCM (3.5 mL, 3.5 mmol) was added to ethyl 4-hydroxy-3-iodo-quinoline-2-carboxylate (800 mg, 2.33 mmol) in pyridine (5 mL), and the mixture was stirred at rt for 17 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in heptane to provide ethyl 3-iodo-4-(trifluoromethanesulfonyloxy)quinoline-2-carboxylate (1.0 g, 90% yield). MS: [M+H] + :476.1.

[1103] Step 3. [5-(methoxymethoxy)-2-methyl-phenyl]boronic acid (453.7 mg, 2.31 mmol), K₂CO₃ (1.02 g, 7.37 mmol), Pd(PPh₃)₄ (243 mg, 210.5 μmol), and ethyl 3-iodo-4-(trifluoromethylsulfonyloxy)quinoline-2-carboxylate (1.0 g, 2.10 mmol) in toluene (10 mL) and water (2.5 mL) were degassed and stirred under reflux for 5 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in heptane to provide ethyl 3-iodo-4-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-2-carboxylate (450 mg, 45% yield). MS: [M+H] + :478.2.

[1104] Step 4. Ferric chloride (III) (7.0 mg, 41.9 μmol) and copper iodide (I) (8.0 mg, 41.9 μmol) were added to a solution of ethyl 3-iodo-4-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-2-carboxylate (100 mg, 209.5 μmol) in EtOH (10 mL). A solution of 2M ammonia in EtOH (576 μL, 1.152 mmol) and sodium hydroxide (16.8 mg, 419.03 μmol) were added sequentially to the reaction mixture. The reaction tube was sealed and heated at 90 °C for 16 h. The cooled reaction mixture was extracted with EtOAc and concentrated under vacuum to give a crude mixture of 3-amino-4-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-2-carboxamide (10.6 mg, 15% yield). MS: [M+H] + :338.4.

[1105] Step 5. Add a solution of 4M HCl in dioxane (47 μL, 188 μmol) to a suspension of 3-amino-4-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-2-carboxamide (10.6 mg, 31.3 μmol) in DCM (1 mL). Stir the mixture at rt for 3 h. Remove volatiles under vacuum and purify the residue by preparative HPLC C18 column, eluting with ACN / water / 0.1% formic acid to provide 3-amino-4-(5-hydroxy-2-methyl-phenyl)quinoline-2-carboxamide (4 mg, 44% yield). MS: [M+H] + 294.3; 1¹H NMR (400MHz, chloroform-d) δ 8.34 (s, 1H), 7.90 (ddd, J = 8.4, 1.4, 0.7Hz, 1H), 7.45–7.25 (m, 3H), 7.09 (ddd, J = 8.4, 1.5, 0.7Hz, 1H), 6.88 (dd, J = 8.3, 2.8Hz, 1H), 6.63 (d, J = 2.7Hz, 1H), 5.78 (s, 2H), 5.53 (s, 1H), 1.98 (s, 3H).

[1106]

[1107] Compound 13 (3-amino-4-(3-hydroxy-2,6-dimethylphenyl)-6-(thiazolyl-2-yl)pyridinecarboxamide)

[1108] Step 1. A solution of tributyl(thiazol-2-yl)stanane (119.00 mg, 318.04 μmol), intermediate E (50 mg, 163.5 μmol), copper iodide (I) (4 mg, 21.0 μmol), lithium chloride (12 mg, 283.09 μmol), and Pd(dppf)Cl2 (13 mg, 17.8 μmol) in DMF (1 mL) was degassed under vacuum and then backfilled with N2. The solution was then stirred at 110 °C for 1 h. Volatiles were removed under vacuum, and the residue was purified by rapid silica gel chromatography, eluting with EtOAc / hexane 0-50% to provide 3-amino-4-(3-methoxy-2,6-dimethyl-phenyl)-6-thiazol-2-yl-pyrimidine-2-carboxamide (35 mg, 60% yield). MS: [M+H] + :355.2.

[1109] Step 2. To a solution of 3-amino-4-(3-methoxy-2,6-dimethyl-phenyl)-6-thiazolyl-2-ylpyridin-2-carboxamide (35 mg, 98.75 μmol) in DCE (1 mL), add 1 MBBr3 in DCM (300 μL, 300 μmol). Stir the mixture at 45 °C for 0.5 h and remove volatiles under vacuum. Treat the residue with MeOH and concentrate again to dryness. Purify the residue by preparative HPLC C18 column, eluting with ACN / water / 0.1% formic acid to provide 3-amino-4-(3-hydroxy-2,6-dimethyl-phenyl)-6-thiazolyl-2-ylpyridin-2-carboxamide (20 mg, 60% yield). MS: [M+H] + 341.2; 1H NMR (400MHz, DMSO-d6) δ9.31(s,1H),7.86(d,J=3.1Hz,1H),7.80(d,J=3.2Hz,1H),7.69(d,J=3.2Hz,1H),7.66 (d,J=3.1Hz,1H),7.62(s,1H),7.10–6.84(m,1H),6.78(d,J=8.2Hz,1H),6.52(s,2H),1.84s,3H),1.77(s,3H).

[1110]

[1111] Compound 16 (3-amino-6-(3,5-difluorophenyl)-4-(3-hydroxy-2,6-dimethylphenyl)pyridinecarboxamide)

[1112] Step 1. To a solution of intermediate E (50 mg, 163.5 μmol) in dioxane (1 mL), add 2 M Na₂CO₃ aqueous solution (200 μL, 400 μmol), (3,5-difluorophenyl)boric acid (35 mg, 221.6 μmol), and Pd(dppf)Cl₂ (10 mg, 13.7 μmol). Degas the mixture under vacuum, backfill with N₂, and then stir at 120 °C for 1 h. Remove volatiles under vacuum and purify the residue using rapid silica gel chromatography, eluting with EtOAc / hexane 20–100% to provide 3-amino-6-(3,5-difluorophenyl)-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxamide (52 mg, 83% yield) as a grayish-white solid. MS: [M+H] + :384.2.

[1113] Step 2. To a solution of 3-amino-6-(3,5-difluorophenyl)-4-(3-methoxy-2,6-dimethylphenyl)pyridine-2-carboxamide (52 mg, 135.63 μmol) in DCE (1.2 mL), a solution of 1 M BBr3 in DCM (400 μL, 400 μmol) was added. The mixture was stirred at 45 °C for 0.5 h. Volatiles were removed under vacuum, and the residue was treated with MeOH and concentrated again to dryness. The residue was purified by preparative HPLC C18 column elution with ACN / water and 10 mM ammonium bicarbonate to provide 3-amino-6-(3,5-difluorophenyl)-4-(3-hydroxy-2,6-dimethylphenyl)pyridine-2-carboxamide (32 mg, 64% yield). MS: [M+H] + 370.2; 1H NMR(400MHz, DMSO-d6)δ9.26(s,1H),8.40(d,J=2.7Hz,1H),8.07–7.82(m,2H),7.72(s,1H),7.48(d,J=2.7 Hz,1H),7.07(m,1H),6.96(d,J=8.2Hz,1H),6.77(d,J=8.2Hz,1H),6.15(bs,2H),1.84(s,3H),1.78(s,3H).

[1114]

[1115] Compound 41 (5-amino-2-(4,4-difluorocyclohexyl)-6-(5-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide)

[1116] Step 1. In a MW vial, intermediate B (0.3 g, 0.925 mmol), dioxane-water 9:1 (5 mL), (4,4-difluorocyclohexyl-1-en-1-yl)boronic acid (0.31 g, 1.85 mmol), and Cs₂CO₃ (0.9 g, 2.77 mmol) were charged. The reaction mixture was purged with N₂ gas for 10 min. Then XPos-Pd-G₃ (0.078 g, 0.092 mmol) was added, and the reaction mixture was heated in MW at 140 °C for 2.5 h. The cooled reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography and eluted with ethyl acetate in 20% hexane to provide 5-amino-2-(4,4-difluorocyclohex-1-en-1-yl)-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-4-carboxamide (0.28 g, 64% yield). MS: [M+H] + :405.3.

[1117] Step 2. 5-Amino-2-(4,4-difluorocyclohexyl-1-en-1-yl)-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidin-4-carboxamide (0.28 g, 0.692 mmol) was dissolved in MeOH (5 mL) and treated with 10% Pd / C (0.28 g). The reaction mixture was stirred for 3 h under a hydrogen atmosphere. (The solution was obtained via Celite.) TM The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography, eluting with methanol in 2% dichloromethane to provide 5-amino-2-(4,4-difluorocyclohexyl)-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-4-carboxamide (0.19 g, 68% yield). MS: [M+H] + :407.3.

[1118] Step 3. 5-Amino-2-(4,4-difluorocyclohexyl)-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-4-carboxamide (0.19 g, 0.586 mmol) was dissolved in dichloromethane (5 mL), and a solution of 4 M HCl in dioxane (2 mL) was added at -10 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC C18 column elution with ACN / water / 0.1% formic acid to provide 5-amino-2-(4,4-difluorocyclohexyl)-6-(5-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (0.11 g, 65% yield). MS: [M+H] + 363.3; 1 H NMR (400MHz, DMSO-d6) δ9.43(s,1H),8.18(s,1H),7.77(s,1H),7.16(d,J=8Hz,1H),6.80(d,J=8 Hz,1H),6.66(s,1H),6.22(bs,2H),2.90(bs,1H),2.05-0.03(m,4H),1.99(s,3H),1.88(bs,4H).

[1119]

[1120] Compound 44 (5-amino-6-(5-hydroxy-2-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide)

[1121] Step 1. In a MW vial, intermediate B (0.3 g, 0.925 mmol), dioxane-water 9:1 (5 mL), Cs₂CO₃ (0.909 g, 2.78 mmol), and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (0.39 g, 1.85 mmol) were charged. The reaction mixture was purged with N₂ gas for 10 min. Xphos Pd G₃ (0.078 g, 0.0929 mmol) was added, and the reaction mixture was stirred at 140 °C for 2.5 h. The cooled reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography and eluted with ethyl acetate in 35% hexane to provide 5-amino-2-(3,6-dihydro-2H-pyran-4-yl)-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-4-carboxamide (0.3 g, 87% yield). MS: [M+H] + :371.3.

[1122] Step 2. 5-Amino-2-(3,6-dihydro-2H-pyran-4-yl)-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidin-4-carboxamide (0.3 g, 0.8077 mmol) was dissolved in MeOH (10 mL) and treated with 10% Pd / C (0.3 g). The reaction mixture was stirred for 16 h under a hydrogen atmosphere. (The solution was obtained by Celite...) TM The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography, eluting with EtOAc in 35% hexane to provide 5-amino-6-(5-(methoxymethoxy)-2-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide (0.16 g, 53% yield). LCMS:MS:[M+H] + :373.3.

[1123] Step 3. 5-Amino-6-(5-(methoxymethoxy)-2-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide (0.16 g, 0.429 mmol) was dissolved in dichloromethane (2 mL), and a solution of 4M HCl in dioxane (1.6 mL) was added at -10 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC C18 column elution with ACN / water / 0.1% formic acid to provide 5-amino-6-(5-hydroxy-2-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide (0.015 g, 11% yield). MS: [M+H] + 328.6; 1 H NMR (400MHz, DMSO-d6) δ9.44(bs,1H),8.20(s,1H),7.76(s,1H),7.17(d,J=8.4Hz,1H),6.81(d,J=2Hz,1H),6.67(d,J= 2Hz, 1H), 6.22 (bs, 2H), 3.93 (d, J = 10.8Hz, 1H), 3.47-3.42 (m, 3H), 2.99-2.92 (m, 1H), 2.00 (s, 3H), 1.89-1.76 (m, 4H).

[1124]

[1125] Compound 53 (5-amino-6-carbamoyl-4-(3-hydroxy-2,6-dimethylphenyl)pyridinecarboxylic acid)

[1126] A solution of 1 M BBr3 in DCM (200 μL, 0.2 mmol) was added to a solution of intermediate F (12 mg, 38.06 μmol) in DCM (200 μL). The solution was stirred for 135 min, then concentrated and co-evaporated with MeOH (2X). The residue was purified by preparative HPLC C18 column elution with ACN / water / 0.1% formic acid to provide 5-amino-6-carbamoyl-4-(3-hydroxy-2,6-dimethyl-phenyl)pyridine-2-carboxylic acid (5 mg, 44% yield). MS: [M+H] + 302.2; 1 H NMR (400MHz, DMSO-d6) δ9.36 (br s, 1H), 8.88 (br s, 1H), 7.55 (s, 1H), 6.99 (d, J = 8.2Hz, 1H), 6.81 (d, J = 8.2Hz, 1H), 1.83 (s, 3H), 1.76 (s, 3H).

[1127]

[1128] Compound 69 (3-amino-4-(5-methyl-1H-indazol-4-yl)-6-(pyridazin-4-yl)pyridinecarboxamide)

[1129] A solution of intermediate K (100 mg, 347.6 μmol), tributyl(pyridazin-4-yl)stanane (128 mg, 347.6 μmol), copper iodide (I) (8.4 mg, 43.9 μmol), LiCl (30.4 mg, 717.5 μmol), and Pd(dppf)Cl2·DCM (26.6 mg, 33.8 μmol) in DMF (3 mL) was degassed under vacuum, backfilled with N2, and stirred at 130 °C for 2 h. The solution was filtered and then purified by preparative HPLC using a C18 column, eluting with ACN / water / 0.1% formic acid to provide 3-amino-4-(1H-indazol-4-yl)-6-pyridazin-4-yl-pyridine-2-carboxamide (12 mg, 10% yield). MS: [M+H] + :332.3; 1H NMR (400MHz, DMSO-d6) δ13.26(s,1H),10.07(dd,J=2.5,1.2Hz,1H),9.15(dd,J=5.5,1.2Hz,1H),8.52(d,J=2.6Hz,1H),8.37(d d,J=5.5,2.5Hz,1H),8.13(s,1H),7.86(s,1H),7.69–7.54(m,2H),7.57–7.38(m,1H),7.20(dd,J=7.0,0.8Hz,1H),6.98(s,1H).

[1130]

[1131] Compound 73 (3-chloro-4-(5-hydroxy-2-methylphenyl)quinoline-2-carboxamide)

[1132] Step 1. Concentrated sulfuric acid (141 μL, 2.64 mmol) was added to a suspension of 4-oxo-1H-quinoline-2-carboxylic acid (5.00 g, 26.43 mmol) in MeOH (10 mL). The reaction mixture was stirred under reflux for 72 h. The pH was adjusted to 4 and MeOH was removed under reduced pressure. The residue was purified by rapid silica gel chromatography, eluting with MeOH / DCM 0–20% to provide methyl 4-oxo-1H-quinoline-2-carboxylic acid (350 mg, 7% yield). MS: [M+H] + :204.2.

[1133] Step 2. A suspension of methyl 4-oxo-1H-quinoline-2-carboxylate (350 mg, 1.72 mmol) and NCS (253 mg, 1.89 mmol) dissolved in ACN (10 mL) and acetic acid (0.5 mL) was stirred at 90 °C for 17 h. The solid was filtered and the filtrate was concentrated to provide methyl 3-chloro-4-hydroxy-quinoline-2-carboxylate (376 mg, 92% yield). MS: [M+H] + :238.1.

[1134] Step 3. Add trifluoromethanesulfonyl trifluoromethanesulfonate (1M in DCM, 2.1 mL, 2.1 mmol) to a solution of methyl 3-chloro-4-hydroxy-quinoline-2-carboxylate (376 mg, 1.58 mmol) in pyridine (10 mL) at 0 °C and stir the reaction mixture from 0 °C to rt for 17 h. Remove the solvent under reduced pressure and purify the residue using rapid silica gel chromatography, eluting with EtOAc / hexane 5–95% to provide methyl 3-chloro-4-(trifluoromethanesulfonyloxy)quinoline-2-carboxylate (182 mg, 31% yield). MS: [M+H] + :370.0.

[1135] Step 4. [5-(methoxymethoxy)-2-methyl-phenyl]boronic acid (106.14 mg, 541.52 μmol), potassium carbonate (238 mg, 1.72 mmol), Pd(PPh3)4 (57 mg, 49.23 μmol), and methyl 3-chloro-4-(trifluoromethylsulfonyloxy)quinoline-2-carboxylate (182 mg, 492.3 μmol) in toluene (3 mL) and water (0.8 mL) were degassed under N2, followed by stirring under reflux for 3 h. The solvent was removed under reduced pressure, and the residue was purified by rapid silica gel chromatography, eluting with EtOAc / hexane 5–95% to provide methyl 3-chloro-4-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-2-carboxylate (91 mg, 50% yield). MS: [M+H] + :372.1.

[1136] Step 5. In a MW vial, methyl 3-chloro-4-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-2-carboxylate (90 mg, 242.06 μmol) and MeOH (3.5 mL) were loaded. A solution of 7N ammonia in MeOH (3.5 mL, 24.5 mmol) was added, the container was sealed, and the mixture was stirred at 110 °C for 3 h. The solvent was removed under reduced pressure. The solid was suspended in DCM (1 mL) and then treated with a solution of 4M HCl in dioxane (380 μL, 1.52 mmol), and the mixture was stirred at rt for 2 h. Volatiles were removed under vacuum, and the residue was purified by preparative HPLC C18 column, eluting with ACN / water / 0.1% formic acid to provide 3-chloro-4-(5-hydroxy-2-methyl-phenyl)quinoline-2-carboxamide (3 mg, 4% yield). MS: [M+H] + :313.1. 1 ¹H NMR (400MHz, chloroform-d) δ 8.11 (ddd, J = 8.5, 1.3, 0.7Hz, 1H), 7.73 (ddd, J = 8.4, 6.9, 1.4Hz, 1H), 7.56–7.43 (m, 2H), 7.32 (ddd, J = 8.5, 1.4, 0.7Hz, 1H), 6.90 (dd, J = 8.3, 2.7Hz, 1H), 6.59 (d, J = 2.7Hz, 1H), 5.68 (s, 1H), 4.95 (s, 1H), 1.85 (s, 3H).

[1137]

[1138] Compound 74 (4-(5-hydroxy-2-methylphenyl)quinoline-2-carboxamide)

[1139] In a sealed tube, a mixture of cesium carbonate (21.0 mg, 63.95 μmol), (2,4-dimethoxyphenyl)methylamine (6.6 mg, 39.65 μmol), and tri-tert-butylphosphine Pd2(dba)3-tetrafluoroborate (molar ratio: 1 / 1.2) (3.9 mg, 3.2 μmol) was added to a solution of compound 73 (10.0 mg, 31.97 μmol) in DMF (2 mL). The mixture was degassed under vacuum, backfilled with N2, and stirred at 120 °C for 17 h. Volatiles were removed under vacuum, and the residue was purified by preparative HPLC C18 column, eluting with ACN / water / 0.1% formic acid to provide 4-(5-hydroxy-2-methyl-phenyl)quinoline-2-carboxamide (3.1 mg, 35% yield). MS: [M+H] + :279.1. 1 ¹H NMR (400MHz, chloroform-d) δ 8.22–8.04 (m, 3H), 7.81–7.69 (m, 1H), 7.66–7.41 (m, 2H), 7.21–7.14 (m, 1H), 6.87 (dd, J = 8.3, 2.7Hz, 1H), 6.70 (d, J = 2.7Hz, 1H), 5.68 (s, 1H), 1.89 (s, 3H).

[1140]

[1141] Compound 75 (5-chloro-6-(5-methyl-1H-indazol-4-yl)-2-phenylpyrimidine-4-carboxamide)

[1142] Step 1. A mixture of methyl 2,5,6-trichloropyrimidin-4-carboxylate (1.00 g, 4.14 mmol), (5-methyl-1H-indazole-4-yl)boronic acid (771 mg, 4.38 mmol), and sodium carbonate (880 mg, 8.30 mmol) in dioxane (10 mL) and water (1.5 mL) was bubbled through N2, followed by the addition of Pd(PPh3)4 (240 mg, 207.7 μmol). The mixture was stirred at 80 °C for 2.5 h under N2. The cooled reaction mixture was filtered, the filtrate was diluted with water, and extracted with EtOAc(3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and adsorbed onto silica. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc (0 to 100%) in heptane to give methyl 2,5-dichloro-6-(5-methyl-1H-indazol-4-yl)pyrimidin-4-carboxylate (268 mg, 19% yield). MS: [M+H] + :337.0.

[1143] Step 2. Degassing was performed by bubbling N2 through a solution of methyl 2,5-dichloro-6-(5-methyl-1H-indazol-4-yl)pyrimidin-4-carboxylate (103 mg, 305.5 μmol), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborane (68 mg, 333.2 μmol), and Pd(dppf)Cl2·DCM (28 mg, 34.3 μmol) in dioxane (1 mL) and 2M potassium ...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in R 1 yes: n is 0, 1, or 2; R 2 and R 3 are each independently hydrogen, halogen, optionally substituted C 3-4 Cycloalkyl or optionally substituted C 1-6 alkyl; Each R 4 are independently halogen; R 5 is hydrogen, halogen, hydroxy, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, or -N(R 5A )2; Each R 5A are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C3-8 cycloalkyl; R 6 is -C(O)NH(R 6A ),-SO2R 6B , or -C(O)R 6C ; R 6A is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, or optionally substituted C 1-9 heteroaryl; R 6B is an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, or -NH(R 6A ); R 6C is an optionally substituted C1-6 alkyl group; A 1 and A 2 each independently is N or C; R 7 is absent, hydrogen, halogen, optionally substituted C 1-6 Alkyl, 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 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -OR 10 ; R 8 is hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -OR 10 、-N(R 11 )2, or -LR 8A ; or R 7 and R 8 Combined with the atoms to which they are attached to form an optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, or optionally substituted C 2-12 heteroaryl; and R 9 is absent, hydrogen, halogen, optionally substituted C 1-6 Alkyl, 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 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl or -OR 10 ; or R 8 is hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-8 Alkynyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -OR 10 、-N(R 11 )2, or -LR 8A ; and R 9 is absent, hydrogen, halogen, optionally substituted C 1-6 Alkyl, 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 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -OR 10 ; or R 8 and R 9 Combined with the atoms to which they are attached to form an optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, or optionally substituted C 1-12 heteroaryl; and R 7 is absent, hydrogen, halogen, optionally substituted C 1-6 Alkyl, 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 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl or -OR 10 ; L 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 Cycloalkylene; R 8A is hydrogen, halogen, optionally substituted C 1-6 Alkyl, 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 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -OR 10 or -N(R 11 )2; R 10 is hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-8 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 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl or optionally substituted C 1-9 heteroaryl; Each R 11 are independently hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted acyl, optionally substituted C 1-8 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 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, or optionally substituted C 1-9 Heteroaryl, -SO2R 11A , or two R 11 The groups combine to form an optionally substituted C2-9 heterocyclic group; and Each R 11A are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-8 Heteroalkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 3-8 Cycloalkenyl, optionally substituted C 2-9 Heterocyclic group, optionally substituted C 6-10 Aryl, or optionally substituted C 1-9 Heteroaryl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is N(R 5A )2.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein each R 5A It's all hydrogen.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 yes 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-A):

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-Ai):

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 yes 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-B):

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-Bi):

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein A 1 It is C.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 7 It's hydrogen.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 7 and R 8 Combined with the atoms to which they are attached to form an optionally substituted C 2-12 Heteroaryl.

13. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, wherein A 2 It is C.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 8 It's hydrogen.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein A 2 It is N.

16. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9 and 13 to 15, wherein A 1 It is N.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-Ba):

18. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has formula (II-Bb):

19. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has formula (II-Bc):

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-Bd):

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-Aa):

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-Ab):

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-Ac):

24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-Ad):

25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-C):

26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-D):

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II-E):

28. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the compound has formula (II-F):

29. A compound as described in any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 6 is -C(O)NH(R 6A ).

30. A compound as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each R 6A All are H.

31. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R 2 It's H.

32. A compound as described in any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 3 It's H.

33. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 One of them is H, and the other is an optionally substituted C 1-6 alkyl.

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 One of them is H, and the other is -CH3.

35. A compound as described in any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each is an optionally substituted C 1-6 alkyl.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein X is R 2 and R 3 Each is -CH3.

37. A compound as described in any one of claims 1 to 30 and 32, or a pharmaceutically acceptable salt thereof, wherein R 2 It's a halogen.

38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein R 2 It is Cl.

39. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein R 2 It's F.

40. A compound as described in any one of claims 1 to 31 and 37 to 39, or a pharmaceutically acceptable salt thereof, wherein R 3 It's a halogen.

41. The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein R 3 It is Cl.

42. The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein R 3 It's F.

43. A compound as described in any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein n is 0.

44. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein n is 1.

45. A compound as described in any one of claims 1 to 42 and 44, or a pharmaceutically acceptable salt thereof, wherein R 4 It's a halogen.

46. ​​The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein R 4 It's F.

47. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, 7 to 20, 25 to 31, 33, 34 and 43, wherein R 1 yes:

48. A compound as described in any one of claims 1 to 11, 13 and 15 to 47, or a pharmaceutically acceptable salt thereof, wherein R 8 is an optionally substituted C 6-10 Aryl.

49. The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein R 8 is optionally substituted phenyl.

50. A compound as described in any one of claims 1 to 11, 13 and 15 to 47, or a pharmaceutically acceptable salt thereof, wherein R 8 is an optionally substituted C 1-9 Heteroaryl.

51. A compound as described in any one of claims 1 to 11, 13 and 15 to 47, wherein R 8 Yes -LR 8A .

52. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein L is an optionally substituted pyrimidinyl.

53. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein L is an optionally substituted pyridinyl.

54. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein L is optionally substituted indazolyl.

55. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein L is optionally substituted pyrazolyl.

56. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein L is an optionally substituted imidazolyl.

57. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein L is an optionally substituted thiazolyl.

58. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein L is an optionally substituted pyridazinyl.

59. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein L is an optionally substituted indolyl.

60. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein L is an optionally substituted furanyl.

61. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 8 is an optionally substituted bicyclic heteroaryl.

62. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein -LR 8A yes: Among them A 3 and A 4 are each independently N or CH.

63. The compound of claim 62 or a pharmaceutically acceptable salt thereof, wherein A 3 It is N.

64. A compound as described in claim 62 or 63, or a pharmaceutically acceptable salt thereof, wherein A 4 It is N.

65. The compound of claim 62 or 64, or a pharmaceutically acceptable salt thereof, wherein A 3 It is CH.

66. A compound as described in any one of claims 62, 63 and 65, or a pharmaceutically acceptable salt thereof, wherein A 4 It is CH.

67. A compound as described in any one of claims 62 to 66, or a pharmaceutically acceptable salt thereof, wherein R 8A Yes-OR 10 .

68. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 10 is an optionally substituted C 1-6 alkyl.

69. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 10 It is -CH3.

70. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 10 is an optionally substituted C 2-9 Heterocyclic group.

71. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 10 is an optionally substituted C 6-10 Aryl.

72. A compound as described in any one of claims 62 to 66, or a pharmaceutically acceptable salt thereof, wherein R 8A Yes-N(R 11 )2.

73. The compound of claim 72 or a pharmaceutically acceptable salt thereof, wherein one R 11 It's H.

74. The compound of claim 72 or a pharmaceutically acceptable salt thereof, wherein one R 11 is an optionally substituted C 1-6 alkyl.

75. The compound of claim 72 or a pharmaceutically acceptable salt thereof, wherein each R 11 All are H.

76. The compound of claim 72 or a pharmaceutically acceptable salt thereof, wherein two R 11 The groups are combined to form an optionally substituted C2-9 heterocyclic group.

77. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein -LR 8A yes: Each R 14 are independently cyano, halogen, optionally substituted C 1-6 Alkyl, -S(O)2R 14A or optionally substituted C 1-8 heteroalkyl; R 14A is an optionally substituted C 1-6 alkyl; A 5 is N or CH; and p is 0, 1, 2, 3 or 4.

78. The compound of claim 77 or a pharmaceutically acceptable salt thereof, wherein R 11 is an optionally substituted acyl group.

79. The compound of claim 78 or a pharmaceutically acceptable salt thereof, wherein -LR 8A yes: Where R 15 , R 16 , R 17 , R 18 and R 19 Each is independently cyano, hydrogen, halogen, -CH3, -CF3 or -OCH3.

80. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein -LR 8A yes 81. The compound of claim 77 or a pharmaceutically acceptable salt thereof, wherein R 11 is an optionally substituted C 1-9 Heteroaryl.

82. The compound of claim 81 or a pharmaceutically acceptable salt thereof, wherein the optionally substituted C 1-9 Heteroaryl is a 6-membered heteroaromatic ring containing at least one nitrogen.

83. The compound of claim 82, or a pharmaceutically acceptable salt thereof, wherein the 6-membered heteroaromatic ring contains exactly 2 nitrogens.

84. The compound of claim 83 or a pharmaceutically acceptable salt thereof, wherein R 11 yes: Each R 11B is independently halogen or optionally substituted C 1-6 Alkyl; and q is 0, 1, 2 or 3.

85. The compound of claim 84, or a pharmaceutically acceptable salt thereof, wherein q is 0.

86. The compound of claim 84 or a pharmaceutically acceptable salt thereof, wherein q is 2.

87. The compound of claim 77 or a pharmaceutically acceptable salt thereof, wherein R 11 is an optionally substituted C 6-10 Aryl.

88. The compound of claim 87, wherein R 11 is optionally substituted phenyl.

89. The compound of claim 87 or a pharmaceutically acceptable salt thereof, wherein R 11 is an optionally substituted C 2-9 Heterocyclic group.

90. The compound of claim 77, wherein R 11 Yes-S(O)2R 11A .

91. A compound as described in any one of claims 77 to 90, or a pharmaceutically acceptable salt thereof, wherein p is 0.

92. A compound as described in any one of claims 77 to 90, or a pharmaceutically acceptable salt thereof, wherein p is 1.

93. A compound as described in any one of claims 77 to 90, or a pharmaceutically acceptable salt thereof, wherein p is 2.

94. A compound as described in any one of claims 77 to 90, 92 and 93, or a pharmaceutically acceptable salt thereof, wherein each R 14 are independently halogen.

95. The compound of claim 94 or a pharmaceutically acceptable salt thereof, wherein each R 14 All F.

96. A compound as described in any one of claims 77 to 95, or a pharmaceutically acceptable salt thereof, wherein A 5 It is CH.

97. A compound as described in any one of claims 77 to 95, or a pharmaceutically acceptable salt thereof, wherein A 5 It is N.

98. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 77 to 90, 92 and 94 to 97, wherein -LR 8A yes:

99. A compound as described in any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R 8 is an optionally substituted C 3-8 Cycloalkyl.

100. A compound selected from the group consisting of compounds 1 to 977 and pharmaceutically acceptable salts thereof.

101. A pharmaceutical composition comprising a compound according to any one of claims 1 to 100 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

102. The pharmaceutical composition of claim 101, wherein the composition is isotopically deuterium enriched.

103. A method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 100 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 101 or 102, wherein the cancer has been previously identified as a cancer that overexpresses CCNE1.

104. A method for treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 100 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 101 or 102, wherein the cancer is a cancer that overexpresses CCNE1.

105. A method of inducing cell death in a cancer cell overexpressing CCNE1, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 100 or a pharmaceutically acceptable salt thereof.

106. The method of any one of claims 103 to 105, wherein the cancer is uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, or endometrial cancer.

107. A method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 100 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 101 or 102, wherein the cancer has been previously identified as a cancer having an inactivating mutation in the FBXW7 gene.

108. A method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 100 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 101 or 102, wherein the cancer has an inactivating mutation in the FBXW7 gene.

109. A method of inducing cell death in a FBXW7 mutated cancer cell, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 100, or a pharmaceutically acceptable salt thereof.

110. The method of any one of claims 107 to 109, wherein the cancer is uterine cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

111. The method of claim 105, 106, 109 or 110, wherein the cell is in a subject.

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