Heteroarene, pharmaceutical composition containing the same, and method of using the same

Abstract

Compounds and pharmaceutically acceptable salts thereof that can be used for the treatment of subjects in need thereof are disclosed. The compounds disclosed herein can be inhibitors of tyrosine- and threonine-specific cdc2 inhibitory kinase (Myt1). Also disclosed are pharmaceutical compositions containing the compound or its pharmaceutically acceptable salt, and methods for their preparation and use.

Description

Technical Field

[0001] The present invention relates to compounds and pharmaceutical compositions in the treatment of diseases or conditions, such as cancer, particularly diseases or conditions (e.g., cancer having CCNE1 amplification / overexpression or FBXW7 mutant cancer) that depend on the activity of membrane-associated tyrosine and threonine-specific cdc2 inhibitory kinase (Myt1), their preparation, and their use.

Background Art

[0002] DNA is constantly exposed to both endogenous assaults (e.g., replication fork stalling, reactive oxygen species) and exogenous assaults (UV, ionizing radiation, chemicals) that can cause DNA damage. As a result, cells have established elaborate mechanisms to counter these harmful events that would otherwise compromise genomic integrity and lead to genomic instability diseases (e.g., cancer). These mechanisms are collectively referred to as DNA damage response (DDR). As one component of the overall DDR, there is the activation of various checkpoint pathways that regulate specific DNA repair mechanisms throughout the various stages of the cell cycle (including the G1, S, G2, and mitotic checkpoints). Most cancer cells have lost the G1 checkpoint due to p53 mutations, so they rely on the G2 checkpoint to repair the necessary DNA damage before proceeding to mitosis and dividing into two daughter cells.

[0003] There is a need for new anticancer treatment approaches, such as those utilizing small molecules, particularly those that enable targeted cancer therapy.

Summary of the Invention

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

Chemical Formula

[0005] In some embodiments, R 5 is N(R 5A ) 2 . In some embodiments, each R 5A is hydrogen.

[0006] In some embodiments, R 1 is as follows.

Chemical formula

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

Chemical formula

[0008] In some embodiments, the compound is a compound of formula (II-A-i).

Chemical formula

[0009] In some embodiments, R 1 is

Chemical formula

[0010] In some embodiments, the compound is a compound of formula (II-B).

Chemical formula

[0011] In some embodiments, the compound is a compound of formula (II-B-i).

Chemical formula

[0012] In some embodiments, A 1 is C. In some embodiments, A 2 is C. In some embodiments, A 2 is N. In some embodiments, A 1 is N.

[0013] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 and R 8 together with the atom to which they are attached form an optionally substituted C 2~12It forms a heteroaryl.

[0014] In some embodiments, R 8 is hydrogen.

[0015] In some embodiments, the compound is a compound of formula (II-B-a). [Chemical formula]

[0016] In some embodiments, the compound is a compound of formula (II-B-b). [Chemical formula]

[0017] In some embodiments, the compound is a compound of formula (II-B-c). [Chemical formula]

[0018] In some embodiments, the compound is a compound of formula (II-B-d). [Chemical formula]

[0019] In some embodiments, the compound is a compound of formula (II-A-a). [Chemical formula]

[0020] In some embodiments, the compound is a compound of formula (II-A-b). [Chemical formula]

[0021] In some embodiments, the compound is a compound of formula (II-A-c). [Chemistry]

[0022] In some embodiments, the compound is a compound of formula (II-A-d). [Chemistry]

[0023] In some embodiments, the compound is a compound of formula (II-C). [Chemistry]

[0024] In some embodiments, the compound is a compound of formula (II-D). [Chemistry]

[0025] In some embodiments, the compound is a compound of formula (II-E). [Chemistry]

[0026] In some embodiments, the compound is a compound of formula (II-F). [Chemistry]

[0027] In some embodiments, R 6 is -C(O)NH(R 6A ). In some embodiments, each R 6A is H.

[0028] In some embodiments, R 2 is H. In some embodiments, R 3 is H. In some embodiments, R2 and R 3 One of them is H and the other is optionally substituted C 1~6 alkyl. In some embodiments, R 2 and R 3 One of them is H and the other is -CH 3 . In some embodiments, R 2 and R 3 are each optionally substituted C 1~6 alkyl. In some embodiments, R 2 and R 3 are each -CH 3 . In some embodiments, R 2 is halogen. In some embodiments, R 2 is Cl. In some embodiments, R 2 is F. In some embodiments, R 3 is halogen. In some embodiments, R 3 is Cl. In some embodiments, R 3 is F.

[0029] In some embodiments, n is 0. In some embodiments, n is 1.

[0030] In some embodiments, R 4 is halogen. In some embodiments, R 4 is F.

[0031] In some embodiments, R 1 is as follows.

Chemical formula

[0032] In some embodiments, R 8 is optionally substituted C 6~10 aryl. In some embodiments, R 8 is optionally substituted phenyl. In some embodiments, R 8 is optionally substituted C 1~9It is a heteroaryl. In some embodiments, R 8 is -L-R 8A is.

[0033] In some embodiments, L is optionally substituted pyrimidinyl. In some embodiments, L is optionally substituted pyridyl. In some embodiments, L is optionally substituted indazolyl. In some embodiments, L is optionally substituted pyrazolyl. In some embodiments, L is optionally substituted imidazolyl. In some embodiments, L is optionally substituted thiazolyl. In some embodiments, L is optionally substituted pyridazinyl. In some embodiments, L is optionally substituted indolyl. In some embodiments, L is optionally substituted furyl.

[0034] In some embodiments, R 8 is optionally substituted bicyclic heteroaryl.

[0035] In some embodiments, -L-R 8A is as follows,

Chemical formula

[0036] In some embodiments, A 3 is N. In some embodiments, A 4 is N. In some embodiments, A 3 is CH. In some embodiments, A 4 is CH.

[0037] In some embodiments, R 8A is -OR 10 is. In some embodiments, R 10 is optionally substituted C 1~6 is aliphatic. In some embodiments, R10 is -CH 3 is. In some embodiments, R 10 is optionally substituted C 2~9 heterocyclyl. In some embodiments, R 10 is optionally substituted C 6~10 aryl.

[0038] In some embodiments, R 8A is -N(R 11 ) 2 is. In some embodiments, one R 11 is H. In some embodiments, one R 11 is optionally substituted C 1~6 alkyl. In some embodiments, each R 11 is H. In some embodiments, two R 11 groups together form an optionally substituted C2-9 heterocyclyl.

[0039] In some embodiments, -L-R 8A is as follows,

Chemical formula

[0040] In some embodiments, -L-R 8A is as follows,

Chemical formula

[0041] In some embodiments, -L-R 8A is as follows,

Chemical formula

[0042] In some embodiments, -L-R 8A is as follows.

Chemical formula

[0043] In some embodiments, -L-R 8A is as follows,

Chemical formula

[0044] In some embodiments, -L-R 8A is as follows,

Chemical formula

[0045] In some embodiments, q is 0. In some embodiments, q is 2.

[0046] In some embodiments, -L-R 8A is as follows, [Chemical formula] wherein R 11 is optionally substituted C 6~10 aryl. In some embodiments, optionally substituted C 6~10 aryl is optionally substituted phenyl.

[0047] In some embodiments, -L-R 8A is as follows, [Chemical formula] wherein R 11 is optionally substituted C 2~9 heterocyclyl.

[0048] In some embodiments, -L-R 8A is as follows, [Chemical formula] wherein R 11 is -S(O) 2 R 11A and is.

[0049] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0050] In some embodiments, each R 14 is, independently, halogen. In some embodiments, each R 14 is F.

[0051] In some embodiments, A 5 is CH. In some embodiments, A 5 is N.

[0052] In some embodiments, -L-R 8A is as follows.

Chemical formula

[0053] In some embodiments, R 8 is optionally substituted C 3~8 cycloalkyl.

[0054] In some embodiments, the compound is selected from the group consisting of Compounds 1-977 and pharmaceutically acceptable salts thereof.

[0055] 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 isotopically enriched with deuterium.

[0056] In yet another aspect, the present invention provides a method of inhibiting Myt1 in a cell expressing Myt1, the method comprising contacting the cell with a compound disclosed herein.

[0057] In some embodiments, the cell overexpresses CCNE1. In some embodiments, the cell is in a subject's body.

[0058] In yet another aspect, the present invention provides a method of treating a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0059] In some embodiments, the subject suffers from a disease or condition having symptoms of cell overproliferation and is in need of treatment therefor. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is a cancer that overexpresses CCNE1.

[0060] In yet another aspect, the present invention provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a Myt1 inhibitor, wherein the cancer has been previously identified as a cancer that overexpresses CCNE1.

[0061] In another aspect, the present invention provides a method of treating cancer in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a Myt1 inhibitor, wherein the cancer is a cancer that overexpresses CCNE1.

[0062] In yet another aspect, the present invention provides a method of inducing cell death in cancer cells that overexpress CCNE1, the method comprising contacting the cells with an effective amount of a Myt1 inhibitor.

[0063] In some embodiments, the cells are in the body of the subject. In some embodiments, the Myt1 inhibitor is a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer that overexpresses CCNE1 is uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, or endometrial cancer.

[0064] In yet another aspect, the present invention provides a method of treating cancer in a subject, the method comprising administering a therapeutically effective amount of a Myt1 inhibitor to a subject in need thereof, wherein the cancer has been previously identified as a cancer having an inactivating mutation in the FBXW7 gene.

[0065] In another aspect, the present invention provides a method of treating cancer in a subject, the method comprising administering a therapeutically effective amount of a Myt1 inhibitor to a subject in need thereof, wherein the cancer has an inactivating mutation in the FBXW7 gene.

[0066] In yet another aspect, the present invention provides a method of inducing cell death in FBXW7 mutant cancer cells, the method comprising contacting the cells with an effective amount of a Myt1 inhibitor.

[0067] 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.

[0068] Abbreviations Abbreviations and terms commonly used in the fields of organic chemistry, medicinal chemistry, pharmacology, and medicine and well known to physicians in these fields are used herein. Representative abbreviations and definitions are provided below. Ac: acetyl [CH 3 C(O)-], ACN: acetonitrile, Ac 2 O: acetic anhydride, AcOH: acetic acid, APC: antigen-presenting cell, Ar: aryl, aq.: aqueous solution, 9-BBN: 9-borabicyclo[3.3.1]nonane, BINAP: (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl), Bn: benzyl, Boc: tert-butyloxycarbonyl, n-BuLi: n-butyllithium, CDI: carbonyldiimidazole, cmpd: compound, conc.: concentrated, DCM: dichloromethane, DIAD: diisopropylazodicarboxylate, DIBAL: diisobutylaluminum hydride, DIPEA: diisopropylethylamine, DMA: dimethylacetamide, DMAP: 4-dimethylaminopyridine, DME: dimethoxyethane, DMF: N,N’-dimethylformamide, DMSO: dimethyl sulfoxide, dppf: 1,1’-bis(diphenylphosphino)ferrocene, dtbpf: 1,1’-bis(di-tert-butylphosphino)ferrocene, EDAC (or EDC): 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide HCl, ESI: electrospray ionization mass spectrometry, Et 2 O: diethyl ether, Et 3 N: triethylamine, Et: ethyl, EtOAc: ethyl acetate, EtOH: ethanol, 3-F-Ph: 3-fluorophenyl, h: hour, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, HCl: hydrochloric acid, Het: heteroaryl, Hex: hexane, HOBt: 1-hydroxybenzotriazole, HPLC: High Performance Liquid Chromatography, IPA: Isopropanol, IPAc: Isopropyl Acetate, LCMS: HPLC with Mass Spectrometry Detection, LiHMDS: Lithium Bis(trimethylsilyl)amide, LG: Leaving Group, M: Molar Concentration, mCPBA: Meta-chloroperoxybenzoic Acid, mmol: Millimole, Me: Methyl, MeCN: Acetonitrile, MeMgBr: Methylmagnesium Bromide, MeMgCl: Methylmagnesium Chloride, MeOH: Methanol, min: Minute, MOM: Methoxymethyl, Ms: Methanesulfonyl, MS: Mass Spectrometry, MTBE: Methyl tert-butyl Ether, MW: Microwave, N: Normal, NaHMDS: Sodium Bis(trimethylsilyl)amide, NaOAc: Sodium Acetate, NaOtBu: Sodium tert-butoxide, NBS: N-Bromosuccinimide, NCS: N-Chlorosuccinimide, NIS: N-Iodosuccinimide, NMO: N-Methylmorpholine N-oxide, NMP: N-Methylpyrrolidinone, NMR: Nuclear Magnetic Resonance Spectroscopy, PdCl 2 (dppf): Dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II), PdCl 2 (dppf).CH 2 Cl 2: Complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane, Pd 2 (dba) 3 : Tris(dibenzylideneacetone)dipalladium, PdCl 2 (PPh 3 ) 2 : Dichlorobis-(triphenylphosphine)palladium, Pd-PEPPSI(trademark)-SIPr: (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride, PG: Protecting group, Ph: Phenyl, PhMe: Toluene, PIV-Cl: Pivaloyl chloride, trimethylacetyl chloride, PPh 3 : Triphenylphosphine, PMB: Para-methoxybenzyl, Reagent alcohol: Mixture of 90% ethanol, 5% isopropanol, and 5% methanol, rt or RT: Room temperature, RBF: Round-bottom flask; RuPhos Pd G1: Chloro-(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II), sat.: Saturated, SEM: [2-(Trimethylsilyl)ethoxy]methyl, SFC: Supercritical fluid chromatography, S N Ar: Aromatic nucleophilic substitution reaction, TBAB: Tetrabutylammonium bromide, TBAF: Tetrabutylammonium fluoride, TBS: tert-Butyldimethylsilyl, tBu: tert-Butyl, Tf: Trifluoromethanesulfonyl, TFA: Trifluoroacetic acid, THF: Tetrahydrofuran, THP: Tetrahydropyran, TLC: Thin layer chromatography, TMAD: Tetramethyl azodicarboxamide, TMS: Trimethylsilyl, TPAP: Tetrapropylammonium perruthenate, Ts: p-Toluenesulfonyl, UPLC: Ultra performance liquid chromatography, Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0069] Definitions As used herein, the term "abnormal" refers to that which is different from normal. When used to describe activity, abnormal refers to activity that is above or below the average of a normal control or normal non-diseased control sample. Abnormal activity can refer to an amount of activity that causes a disease, and in this case, returning the abnormal activity to a normal or non-disease-related amount (e.g., by administering a compound or using a method described herein) results in the alleviation of the disease or one or more disease symptoms.

[0070] As used herein, the term "acyl" represents the group -C(=O)-R, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl. Acyl may be optionally substituted as described herein for each respective R group.

[0071] As used herein, the term "adenocarcinoma" represents a malignant tumor arising from glandular cells present in an organ within an organism. Non-limiting examples of adenocarcinoma include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colorectal cancer.

[0072] As used herein, the term "alkanoyl" refers to a hydrogen or alkyl group attached to a parent molecular group through a carbonyl group, and examples thereof include formyl (i.e., carboxaldehyde group), acetyl, propionyl, butyryl, and isobutyryl. Unsubstituted alkanoyl groups contain 1 to 7 carbons. The alkanoyl group may be unsubstituted or may be substituted as described herein with respect to alkyl groups (e.g., optionally substituted C1-7 alkanoyl). The suffix "-oyl" may be added to another group defined herein, such as aryl, cycloalkyl, and heterocyclyl, to define "aroyl", "cycloalkanoyl", and "(heterocyclyl)oyl". These groups each represent a carbonyl group substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of "aroyl", "cycloalkanoyl", and "(heterocyclyl)oyl" may be optionally substituted as defined with respect to "aryl", "cycloalkyl", or "heterocyclyl", respectively.

[0073] As used herein, the term "alkenyl" refers to an acyclic monovalent straight or branched chain hydrocarbon group containing one, two, or three carbon-carbon double bonds. Non-limiting examples of alkenyl groups include ethenyl, prop-1-enyl, prop-2-enyl, 1-methylethenyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop-1-enyl, 2-methylprop-1-enyl, and 1-methylprop-2-enyl. The alkenyl group may be optionally substituted as defined herein with respect to alkyl.

[0074] As used herein, the term "alkenylene" refers to a divalent alkenyl group. Optionally substituted alkenylene is alkenylene optionally substituted as described herein with respect to alkenyl.

[0075] As used herein, the term "alkoxy" represents a chemical substituent of the formula -OR, where, unless otherwise specified, R in the formula is C 1~6 an alkyl group. In some embodiments, the alkyl group may be further substitutable as defined herein. The term "alkoxy" may be combined with other terms defined herein, such as aryl, cycloalkyl, or heterocyclyl, to define "arylalkoxy", "cycloalkylalkoxy", and "(heterocyclyl)alkoxy" groups. These groups each represent an alkoxy substituted by aryl, cycloalkyl, or heterocyclyl, respectively. Each of "arylalkoxy", "cycloalkylalkoxy", and "(heterocyclyl)alkoxy" may be optionally substituted as defined herein for each individual moiety.

[0076] As used herein, the term "alkoxyalkyl" represents a chemical substituent of the formula -L-OR, where L is C 1~6 an alkylene and R is C 1~6 an alkyl. Optionally substituted alkoxyalkyl is an alkoxyalkyl optionally substituted as described herein for alkyl.

[0077] As used herein, the term "alkyl" refers to an acyclic straight-chain or branched-chain saturated hydrocarbon group, which, when unsubstituted, has 1 to 12 carbons unless otherwise specified. In certain preferred embodiments, unsubstituted alkyl has 1 to 6 carbons. Alkyl groups are, for example, methyl, ethyl, n- and iso-propyl, n-, sec-, iso-, and tert-butyl, neopentyl, etc., and when the valence permits, amino, alkoxy, aryl, aryloxy, azide, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkynyl, halo, heterocyclyl, (heterocyclyl)oxy, heteroaryl, hydroxy, nitro, thiol, silyl, cyano, alkylsulfonyl, alkylsulfinyl, alkylsulfenyl, =O, =S, -C(O)R or -SO 2One, two, or three substituents independently selected from the group consisting of R (wherein R is amino) and =NR' (wherein R' is alkyl, aryl, or heterocyclyl), or in the case of an alkyl group of two or more carbons, optionally substituted with four or more substituents. Each of the substituents may itself be unsubstituted or, where valency permits, substituted with unsubstituted substituent(s) as defined herein for each respective group.

[0078] The term "alkylene" as used herein refers to a divalent alkyl group. Optionally substituted alkylene is alkylene optionally substituted as described herein for alkyl.

[0079] The term "alkylamino" as used herein refers to a group having the formula -N(R N1 ) 2 or -NHR N1 , where R N1 is alkyl as defined herein. The alkyl portion of alkylamino may be optionally substituted as defined for alkyl. Each of the optional substituents of substituted alkylamino may itself be unsubstituted or, where valency permits, substituted with unsubstituted substituent(s) as defined herein for each respective group.

[0080] The term "alkylsulfenyl" as used herein represents a group of the formula -S-(alkyl). Alkylsulfenyl may be optionally substituted as defined for alkyl.

[0081] The term "alkylsulfinyl" as used herein represents a group of the formula -S(O)-(alkyl). Alkylsulfinyl may be optionally substituted as defined for alkyl.

[0082] As used herein, the term "alkylsulfonyl" represents a group of the formula -S(O)2-(alkyl). The alkylsulfonyl may be optionally substituted as defined for alkyl.

[0083] As used herein, the term "alkynyl" represents a monovalent straight-chain or branched-chain hydrocarbon group of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, etc. The alkynyl group may be unsubstituted or may be substituted as defined for alkyl (e.g., optionally substituted alkynyl).

[0084] As used herein, the term "alkynylene" refers to a divalent alkynyl group. Optionally substituted alkynylene is alkynylene optionally substituted as described herein for alkynyl.

[0085] As used herein, the term "amino" represents -N(R N1 ) 2 . When the amino is unsubstituted, both R N1 are H, or when the amino is substituted, each R N1 is independently H, -OH, -NO 2 , -N(R N2 ) 2 , -SO 2 OR N2 , -SO 2 R N2 , -SOR N2 , -C(O)OR N2 , an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, cycloalkyl, cycloalkenyl, heteroalkyl, or heterocyclyl, provided that at least one R N1 is not H, and each R N2is, independently, H, alkyl, or aryl. Each of the substituents may itself be unsubstituted or may be substituted with unsubstituted substituent(s) as defined herein for each respective group. In some embodiments, the amino is unsubstituted amino (i.e., -NH 2 ) or substituted amino (e.g., -NHR N1 ), wherein R N1 is, independently, -OH, SO 2 OR N2 , -SO 2 R N2 , -SOR N2 , -COOR N2 , optionally substituted alkyl, or optionally substituted aryl, and each R N2 can be optionally substituted alkyl or optionally substituted aryl. In some embodiments, the substituted amino may be alkylamino, where the alkyl group is optionally substituted as described herein for alkyl. In some embodiments, the amino group is -NHR N1 , wherein R N1 is optionally substituted alkyl.

[0086] The term "aryl" as used herein represents a monocyclic, bicyclic, or polycyclic carbocyclic system having one or two aromatic rings. The 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, indanyl, indenyl, and the like. The aryl group may be unsubstituted or may be substituted with alkyl, alkenyl, alkynyl, alkoxy, alkylsulfinyl, alkylsulfenyl, alkylsulfonyl, amino, aryl, aryloxy, azide, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkynyl, halo, heteroalkyl, heterocyclyl, (heterocyclyl)oxy, hydroxy, nitro, thiol, silyl, -(CH 2 )n -C(O)OR A 、 -C(O)R, and -SO 2 R (wherein R is amino or alkyl, R A is H or alkyl, and n is 0 or 1) and may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of. Each of the substituents may itself be unsubstituted or may be substituted with an unsubstituted substituent(s) as defined herein for each respective group.

[0087] The term "arylalkyl" as used herein refers to an alkyl group substituted with an aryl group. The aryl and alkyl moieties may each be optionally substituted as individual groups as described herein.

[0088] The term "arylene" as used herein refers to a divalent aryl group. Optionally substituted arylene is arylene optionally substituted as described herein for aryl.

[0089] The term "aryloxy" as used herein refers to a chemical substituent of the formula -OR, wherein R is an aryl group unless otherwise specified. In optionally substituted aryloxy, the aryl group is optionally substituted as described herein for aryl.

[0090] The term "azide" as used herein refers to -N 3 group.

[0091] The term "cancer" as used herein refers to all types of cancer, neoplasm, or malignant tumor found in mammals (e.g., humans).

[0092] As used herein, the term "carbocyclic" refers to an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure in which the ring, which may be aromatic or non-aromatic, is formed of carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl, and certain aryl groups.

[0093] As used herein, the term "carbonyl" refers to the -C(O)- group.

[0094] As used herein, the term "cancer" refers to a malignant neoplasm composed of epithelial cells that tend to invade surrounding tissues and cause metastasis.

[0095] As used herein, the term "cyano" refers to the -CN group.

[0096] As used interchangeably herein, the terms "CCNE1" and "cyclin E1" refer to G1 / S-specific cyclin E1 (gene name: CCNE1). A cell that overexpresses CCNE1 is a cell that exhibits higher activity of CCNE1 than a cell that normally expresses CCNE1. For example, a CCNE1 overexpressing cell is a cell that exhibits at least 3 copy numbers compared to a diploid normal cell with 2 copies. Thus, a cell with a CCNE1 copy number greater than 3 is a cell that overexpresses CCNE1. CCNE1 overexpression can be measured by determining the expression level of the gene product in the cell (e.g., the number of CCNE1 mRNA transcripts or the CCNE1 protein level).

[0097] As used herein, the term "cycloalkenyl", unless otherwise specified, refers to a non-aromatic carbocyclic group having at least one double bond in the ring and having 3 to 10 carbons (e.g., C 3~10refers to (cycloalkenyl). Non-limiting examples of cycloalkenyl include cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, norbornen-1-yl, norbornen-2-yl, norbornen-5-yl, and norbornen-7-yl. The cycloalkenyl group may be unsubstituted or substituted as defined for cycloalkyl (e.g., optionally substituted cycloalkenyl).

[0098] As used herein, the term "cycloalkenylalkyl" represents an alkyl group substituted with a cycloalkenyl group as defined herein. The cycloalkenyl and alkyl moieties may be substituted as individual groups defined herein.

[0099] As used herein, the term "cycloalkenylene" represents a divalent cycloalkenyl group. Optionally substituted cycloalkenylene is cycloalkenylene optionally substituted as described herein for cycloalkyl.

[0100] As used herein, the term "cycloalkoxy" represents a chemical substituent of the formula -OR, wherein, unless otherwise specified, R is a cycloalkyl group. In some embodiments, the cycloalkyl group is further substitutable as defined herein.

[0101] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbons, unless otherwise specified (e.g., C 3~C10(cycloalkyl). The cycloalkyl group may be monocyclic or bicyclic. The bicyclic cycloalkyl group may be of the bicyclo[p.q.0]alkyl type, in which case 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, the bicyclic cycloalkyl group may contain a bridged cycloalkyl structure, such as bicyclo[p.q.r]alkyl, in which case 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. The cycloalkyl group may be a spiro ring group, such as spiro[p.q]alkyl, in which case each of p and q is independently 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 4, 5, 6, 7, 8, or 9. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[2.2.1.]heptyl, 2-bicyclo[2.2.1.]heptyl, 5-bicyclo[2.2.1.]heptyl, 7-bicyclo[2.2.1.]heptyl, and decalinyl. The cycloalkyl group may be unsubstituted or alternatively alkyl, alkenyl, alkynyl, alkoxy, alkylsulfinyl, alkylsulfenyl, alkylsulfonyl, amino, aryl, aryloxy, azide, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkynyl, halo, heteroalkyl, heterocyclyl, (heterocyclyl)oxy, heteroaryl, hydroxy, nitro, thiol, silyl, cyano, =O, =S, -SO 2 R (wherein R is optionally substituted amino), =NR' (wherein R' is H, alkyl, aryl, or heterocyclyl), and -CON(R A ) 2 (wherein R A are independently H or alkyl, or both R A(which, together with the atoms to which they are attached, form a heterocyclyl) and may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of (e.g., optionally substituted cycloalkyl). Each of the substituents may itself be unsubstituted or may be substituted with unsubstituted substituent(s) as defined herein for each respective group.

[0102] As used herein, the term "cycloalkylalkyl" represents an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl moieties may be optionally substituted as the individual groups described herein.

[0103] As used herein, the term "cycloalkylene" represents a divalent cycloalkyl group. Optionally substituted cycloalkylene is cycloalkylene optionally substituted as described herein for cycloalkyl.

[0104] As used herein, the term "cycloalkynyl" refers to a monovalent carbocyclic group having from 8 to 12 carbons and having one or two carbon-carbon triple bonds, unless otherwise specified. Cycloalkynyl may include one exocyclic bond or bridge. Non-limiting examples of cycloalkynyl include cyclooctynyl, cyclononynyl, cyclodecynyl, and cyclodecadienyl. The cycloalkynyl group may be unsubstituted or may be substituted as defined for cycloalkyl (e.g., optionally substituted cycloalkynyl).

[0105] "Disease" or "condition" refers to the condition or health state of a patient that can be treated using the compounds or methods provided herein.

[0106] As used herein, the term "FBXW7" refers to the gene, transcript, or protein of F-box / WD repeat-containing protein 7. An FBXW7 mutant gene (also described herein as an FBXW7 gene having an inactivating mutation) is a gene that cannot produce a functionally active FBXW7 protein in a cell or produces a reduced amount of the FBXW7 protein.

[0107] As used herein, the term "halo" represents a halogen selected from bromine, chlorine, iodine, and fluorine.

[0108] As used herein, the term "heteroalkyl" refers to an alkyl, alkenyl, or alkynyl group interrupted one time, by one or two heteroatoms; two times, each time independently, by one or two heteroatoms; three times, each time independently, by one or two heteroatoms; or four times, each time independently, by one or two heteroatoms. Each heteroatom is independently O, N, or S. In some embodiments, the heteroatom is O or N. No heteroalkyl group contains two consecutive oxygen or sulfur atoms. The heteroalkyl group may be unsubstituted or substituted (e.g., optionally substituted heteroalkyl). When the heteroalkyl is substituted and the substituent is attached to a heteroatom, the substituent is selected according to the nature and valence of the heteroatom. Thus, a substituent attached to a heteroatom is, when the valence permits, =O, -N(R N2 ) 2 , -SO 2 OR N3 , -SO 2 R N2 , -SOR N3 , -COOR N3 , an N-protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, or cyano, selected from the group consisting of (wherein each R N2is, independently, H, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl, each R N3 is, independently, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl or heterocyclyl). Each of these substituents may itself be unsubstituted or may be substituted with unsubstituted substituent(s) as defined herein for each respective group. When a heteroalkyl is substituted and the substituent is attached to a carbon, the substituent is selected from those described for alkyl, provided that the substituent on a carbon atom attached to a heteroatom is not Cl, Br, or I. It should be understood that the carbon atom is found at the end of the heteroalkyl group.

[0109] The term "heteroarylalkyl", as used herein, represents an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl moieties may be optionally substituted as the individual groups described herein.

[0110] The term "heteroarylene", as used herein, represents a divalent heteroaryl. Optionally substituted heteroarylene is heteroarylene optionally substituted as described herein for heteroaryl.

[0111] The term "heteroaryloxy", as used herein, refers to the structure -OR where R is heteroaryl. Heteroaryloxy may be optionally substituted as defined for heterocyclyl.

[0112] As used herein, the term "heterocyclyl", unless otherwise specified, refers to a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused, bridged, and / or spiro-type 3-, 4-, 5-, 6-, 7-, or 8-membered rings and containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, "heterocyclyl", unless otherwise specified, is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridged 5-, 6-, 7-, or 8-membered rings and containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclyl can be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclyl has 0 or 1 double bond, non-aromatic 6- and 7-membered heterocyclyl groups have 0 to 2 double bonds, and non-aromatic 8-membered heterocyclyl groups have 0 to 2 double bonds and / or 0 or 1 carbon-carbon triple bond. Unless otherwise specified, heterocyclyl groups contain 1 to 16 carbon atoms. Certain heterocyclyl groups may contain up to 9 carbon atoms. Examples of non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, and the like. When a heterocyclic ring system has at least one aromatic resonance structure or at least one aromatic tautomer, such a structure is an aromatic heterocyclyl (i.e., heteroaryl).Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl (e.g., 1,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, etc. The term "heterocyclyl" also refers to a heterocyclic compound having a bridged polycyclic structure in which one or more carbon and / or heteroatoms bridge two non-adjacent members of a monocyclic ring, e.g., quinuclidine, tropane, or diazabicyclo[2.2.2]octane. The term "heterocyclyl" includes bicyclic, tricyclic, and tetracyclic groups, where any of the above heterocycles is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocycle. Examples of fused heterocyclyls include 1,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene. The heterocyclyl 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, alkylsulfenyl, alkylsulfonyl, amino, aryl, aryloxy, azide, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkynyl, halo, heteroalkyl, heterocyclyl, (heterocyclyl)oxy, hydroxy, nitro, thiol, silyl, cyano, -C(O)R or -SO. 2 R (wherein R is amino or alkyl), =O, =S, =NR' (wherein R' is H, alkyl, aryl, or heterocyclyl), and may be substituted with one, two, three, four, or five substituents independently selected from the group. Each of the substituents may itself be unsubstituted or may be substituted with an unsubstituted substituent(s) as defined herein for each respective group.

[0113] As used herein, the term "heterocyclylalkyl" represents an alkyl group substituted with a heterocyclyl group, each as defined herein. The heterocyclyl and alkyl moieties may be optionally substituted as individual groups described herein.

[0114] As used herein, the term "heterocyclylene" represents a divalent heterocyclyl. An optionally substituted heterocyclylene is a heterocyclylene optionally substituted as described herein with respect to heterocyclyl.

[0115] As used herein, the term "(heterocyclyl)oxy" represents a chemical substituent of the formula -OR, wherein, unless otherwise specified, R is a heterocyclyl group. (Heterocyclyl)oxy may be optionally substituted as described with respect to heterocyclyl.

[0116] The terms "hydroxyl" and "hydroxy" are used herein interchangeably and represent an -OH group.

[0117] As used herein, the term "isotopically enriched" refers to a pharmaceutically active agent in which the isotopic content of one isotope at a given position within a molecule is at least 100-fold greater than the natural abundance of that isotope. For example, an isotopically enriched composition of deuterium comprises an active agent that includes at least one hydrogen atom position having an abundance of deuterium that is at least 100-fold greater than the natural abundance of deuterium. Preferably, the isotopic enrichment of deuterium is at least 1000-fold greater than the natural abundance of deuterium. More preferably, the isotopic enrichment of deuterium is at least 4000-fold greater (e.g., at least 4750-fold greater, e.g., up to 5000-fold greater) than the natural abundance of deuterium.

[0118] As used herein, the term "leukemia" generally refers to a progressive malignant disease of the hematopoietic organs, typically characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the acute or chronic duration and characteristics of the disease, (2) the type of cells involved: myeloid (myelogenous) of the bone marrow, lymphocytic (lymphoblastic), or monocytic; and (3) the increase or non-increase in the number of abnormal cells in blood leukemia or aleukemia (sub-leukemia).

[0119] As used herein, the term "lymphoma" refers to a cancer that arises from cells of immune origin.

[0120] As used herein, the term "melanoma" is interpreted to mean a tumor that arises from the melanocyte lineage of the skin and other organs.

[0121] As used herein, the term "Myt1" refers to the membrane-associated tyrosine and threonine-specific cdc2 inhibitory kinase (Myt1) (gene name PKMYT1).

[0122] As used herein, the term "Myt1 inhibitor" refers to a compound that reduces the activity of Myt1 such that, regardless of whether in vitro, in cell culture, or in an animal, when contacted with the enzyme Myt1, the measured IC 50 of Myt1 is 10 μM or less (e.g., 5 μM or less, or 1 μM or less). For certain Myt1 inhibitors, the IC 50 of Myt1 can be 100 nM or less (e.g., 10 nM or less, or 3 nM or less), and can be as low as 100 pM or 10 pM. Preferably, the IC 50 of Myt1 is from 1 nM to 1 μM (e.g., from 1 nM to 750 nM, from 1 nM to 500 nM, or from 1 nM to 250 nM). Even more preferably, the IC 50 of Myt1 is less than 20 nM (e.g., from 1 nM to 20 nM).

[0123] As used herein, the term "nitro" refers to -NO2 represents a base.

[0124] As used herein, the term "oxo" represents a divalent oxygen atom (e.g., the structure of oxo may be shown as =O).

[0125] As used herein, the term "Ph" refers to phenyl.

[0126] As used herein, the term "pharmaceutical composition" refers to a composition containing a compound described herein, which is formulated with a pharmaceutically acceptable excipient and can be manufactured or sold by approval of a government regulatory agency as part of a therapeutic regimen for the treatment of mammalian diseases. The pharmaceutical composition can be formulated, for example, for oral administration in unit dosage forms (e.g., tablets, capsules, caplets, gelcaps, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., as a sterile solution free of particulate embolizing substances and in a solvent system suitable for intravenous use), or in any other formulation described herein.

[0127] The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" are used interchangeably herein and refer to any component other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound) and having the properties of being non-toxic and non-inflammatory in a patient. Excipients include, for example, anti-adhesives, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavoring agents, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water of hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methyl cellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0128] The term "pharmaceutically acceptable salt", as used herein, represents salts that have no excessive toxicity, irritation, allergic response, etc., and are suitable for use in contact with human and animal tissues within the scope of sound medical judgment corresponding to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein, or can be prepared separately by reacting the free basic groups with appropriate organic acids. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc.Representative alkali or alkaline earth metal salts include non-toxic ammonium, quaternary ammonium, and amine cations in addition to sodium, lithium, potassium, calcium, magnesium, etc., and these include, but are not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0129] As used herein, the terms "preneoplastic" or "precancerous" refer to a condition that is not malignant but can become malignant.

[0130] As used herein, the term "protecting group" refers to a group that is intended to protect a hydroxy, amino, or carbonyl group from participating in one or more unwanted reactions during chemical synthesis. As used herein, the term "O-protecting group" refers to a group that is intended to protect a hydroxy group or a carbonyl group from participating in one or more unwanted reactions during chemical synthesis. As used herein, the term "N-protecting group" refers to a group that is intended to protect a nitrogen-containing (e.g., amino, amide, heterocyclic N-H, or hydrazine) group from participating in one or more unwanted reactions during chemical synthesis. For commonly used O- and N-protecting groups, reference is made to Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999), which is hereby incorporated by reference herein. Exemplary O- and N-protecting groups include alkanoyl, aroyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, triisopropylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylpehenoxyacetyl, dimethylformamidine, and 4-nitrobenzoyl.

[0131] Exemplary O-protecting groups for protecting carbonyl-containing groups include, but are not limited to, acetals, acylals, 1,3-dithians, 1,3-dioxanes, 1,3-dioxolanes, and 1,3-dithiolanes.

[0132] Other O-protecting groups include, but are not limited to, substituted alkyl, aryl, and arylalkyl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2-trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and diphenylmethylsilyl); carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl).

[0133] 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-containing groups such as benzenesulfonyl, p-toluenesulfonyl, etc.; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydroxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, 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. Useful N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, dimethoxybenzyl, [2-(trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0134] The term "tautomer" often refers to structural isomers that readily interconvert, typically by proton rearrangement. Tautomers are different chemical species that can be distinguished by different spectroscopic features, but generally cannot be isolated individually. Non-limiting examples of tautomers include keto-enol, enamine-imine, amide-imino acid, nitroso-oxime, ketene-enol, and amino acid-carboxylic acid ammonium.

[0135] The term "sarcoma" generally refers to a tumor composed of substances such as embryonic connective tissue and generally consisting of densely packed cells surrounded by fibrils or similar substances.

[0136] The term "subject" as used herein refers to a human or non-human animal (e.g., a mammal) that has or is at risk of having a disease or condition, as determined by a qualified professional (e.g., a physician or a senior nurse) using and / or without using known clinical tests (s) of samples (s) from the subject. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases having symptoms of cell overgrowth, such as cancer.

[0137] "Treatment" and "treating" as used herein refer to the medical management of a subject aimed at improving, alleviating, stabilizing, preventing, or curing a disease or condition. This term includes active treatment (treatment directed at improving a disease or condition), causal treatment (treatment directed at the cause of a related disease or condition), palliative treatment (treatment directed at alleviating the symptoms of a disease or condition), prophylactic treatment (treatment directed at minimizing or partially or completely suppressing the onset of a related disease or condition), and supportive treatment (treatment used to complement another treatment method). BRIEF DESCRIPTION OF THE DRAWINGS

[0138]

Figure 1A

Figure 1B

Figure 2A

Figure 2B

Figure 3A

Figure 3B

Figure 3C

Figure 4A

Figure 4B

Figure 4C

Figure 5

Figure 6

Figure 7

DETAILED DESCRIPTION OF THE INVENTION

[0139] Generally, the present invention provides compounds, pharmaceutical compositions containing them, methods for preparing the compounds, and methods of use. The compounds of the present invention can be Myt1 inhibitors. These compounds can be used to inhibit Myt1 in cells, such as cells in a subject (e.g., cells that overexpress CCNE1 or have an inactivating mutation in the FBXW7 gene). The subject may be in need of treatment for a disease or condition (e.g., a disease or condition having symptoms of cell overproliferation, such as cancer). The Myt1 inhibitory activity of the compounds disclosed herein is useful for the treatment of subjects in need of cancer treatment.

[0140] Myt1 is a cell cycle regulatory kinase that is predominantly localized in the endoplasmic reticulum and Golgi complex and is part of the Wee family of kinases (including Wee1 and Wee1b). It is involved in the negative regulation of the CDK1-cyclin B complex and promotes the progression of cells from the G2 phase to the mitotic (M) phase of the cell cycle. During DNA damage, Myt1 drives the phosphorylation of CDK1 (both Tyr15 and Thr14 of CDK1), thereby, together with Wee1 (which mediates only Tyr15 phosphorylation), maintaining the kinase complex in an inactive state at 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 directly interacts with the CDK1 complex in the cytoplasm, blocks its nuclear translocation, and inhibits cell cycle progression.

[0141] Myt1 is considered a potentially important cancer target as 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 only a minor role in stable cells but has a more prominent role in cells exposed to DNA damage. Furthermore, cells showing high levels of replication stress in addition to defects in G1 checkpoint regulation may be particularly sensitive to loss of Myt1 function. This is because these cells tend to prematurely enter mitosis with damaged genomic material, which leads to mitotic catastrophe.

[0142] Inhibitors of Myt1, a regulator of G2-M transition, may be particularly useful for treating tumors with CCNE1 amplification or loss-of-function mutations in FBXW7 using synthetic lethal therapeutic strategies.

[0143] Cyclin E1 (encoded by the CCNE1 gene) is involved in the cell cycle transition from G1 to S phase. It forms a complex with cyclin-dependent kinase 2 (CDK2) in the late G1 phase of the cell cycle to promote the activation of the E2F transcription factor and the transition to S phase. Cyclin E1 levels are tightly regulated during the normal cell cycle, accumulating at the G1 / S transition and being completely degraded by the end of S phase. The cell cycle-dependent proteasomal degradation of cyclin E1 is mediated by the SCF FBW7 ubiquitin ligase complex. When activated in the late G1 phase, the cyclin E1 / CDK2 complex promotes the transition to S phase through phosphorylation and inactivation of RB1 and subsequent release of the E2F transcription factor. The S phase is promoted by E2F-mediated transcription of many genes involved in DNA replication, including the pre-replication complex subunits ORC1, CDC6, CDT1, and MCM helicase factors.

[0144] 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 is observed in more aggressive subtypes, including uterine carcinosarcoma (UCS; ~40%), uterine serous carcinoma (USC; ~25%), high-grade serous ovarian cancer (HGSOC; ~25%), and triple-negative breast cancer (TNBC; ~8%). Patients with evidence of cyclin E1 overexpression in tumor biopsies by immunohistochemical examination and / or genomic copy number analysis have shorter overall survival compared to patients with normal cyclin E1 levels. HGSOC patients with cyclin E1 overexpression have a low response rate to cisplatin, the current standard treatment.

[0145] SCF FBW7 Defective cell cycle-regulated proteolysis of cyclin E1 by ubiquitin ligase complexes is another mechanism underlying the CCNE1 overexpression observed in tumors. The F-box protein gene FBXW7 is frequently mutated in several cancer types, including endometrial cancer, colorectal cancer, and gastric cancer, with frequencies ranging from 5% to 35% (Figure 2). Similar to CCNE1, driver mutations in FBXW7 are observed in more aggressive subtypes of endometrial cancer, including UCS (~35%) and USC (~25%). FBXW7 has a diverse spectrum of loss-of-function mutations in cancers, including truncating mutations scattered throughout the gene and missense mutations within the WD40 repeats that recognize cyclin E1. FBW7 functions as a homodimer within the SCF complex, and many of the deleterious missense mutations within the WD40 repeats are almost always heterozygous and dominant negative. Notably, several recurrent hotspot missense mutations, including R465, R479, and R505, have been found within the WD40 repeats, all of which are mutations that interfere with cyclin E1 binding and ubiquitination.

[0146] Overexpression of cyclin E1 and / or loss of function of FBXW7 are thought to drive tumorigenesis by inducing genomic instability (e.g., increased origin firing, defects in nucleotide pools, transcription-replication conflicts, and / or fork instability). Overexpression of cyclin E1 has been shown to induce replication stress characterized by delayed or stalled replication forks and loss of heterozygosity at fragile sites. The main mechanism by which overexpression of cyclin E1 causes replication stress is an increase in origin firing in early S phase and subsequent depletion of replication factors including the nucleotide pool. Decrease in overall replication proteins and nucleotides leads to decreased fork progression, causing stalling and subsequent collapse or reversal.

[0147] The compounds of the present invention can be, for example, compounds of formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein, R 1 is [Chemical formula] and n is 0, 1, or 2, R 2 and R 3 each independently is hydrogen, halogen, optionally substituted C 3~4 cycloalkyl, or optionally substituted C 1~6 alkyl, each R 4 is independently halogen, R 5 is hydrogen, halogen, hydroxyl, optionally substituted C 1~6 alkyl, optionally substituted C 1~6 alkoxy, or -N(R 5A ) 2 and each R5A is, 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 wherein, R 6A is hydrogen, optionally substituted C 1~6 alkyl, optionally substituted C 3~8 cycloalkyl, optionally substituted C 2~9 heterocyclyl, optionally substituted C 6~10 aryl, or optionally substituted C 1~9 heteroaryl, R 6B is optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, or -NH(R 6A ), R 6C is optionally substituted C1-6 alkyl, A 1 and each of A 2 is independently 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 heterocyclyl, optionally substituted C 6~10 aryl, optionally substituted C 1~9 heteroaryl, or -OR 10 wherein 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 3~8Cycloalkyl, optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 6~10 Aryl, optionally substituted C 1~9 Heteroaryl, -OR 10 , -N(R 11 ) 2 , or -L-R 8A , or R 7 and R 8 together with the atom to which they are attached form an optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 2~9 Heterocyclyl, 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 Heterocyclyl, optionally substituted C 6~10 Aryl, optionally substituted C 1~9 Heteroaryl, or -OR 10 , and 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 Heterocyclyl, optionally substituted C 6~10 Aryl, optionally substituted C 1~9 Heteroaryl, -OR 10 , -N(R 11 ) 2、 or -L-R 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 heterocyclyl, optionally substituted C 6~10 aryl, optionally substituted C 1~9 heteroaryl, or -OR 10 and alternatively R 8 and R 9 together with the atom to which they are attached form an optionally substituted C 3~8 cycloalkenyl, optionally substituted C 2~9 heterocyclyl, 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 heterocyclyl, optionally substituted C 6~10 aryl, optionally substituted C 1~9 heteroaryl, or -OR 10 and 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, and R 8A is hydrogen, halogen, optionally substituted C 1~6 alkyl, optionally substituted C 2~6Alkenyl, optionally substituted C 2~6 Alkynyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 3~8 Cycloalkenyl, optionally substituted C 2~9 Heterocyclyl, optionally substituted C 6~10 Aryl, optionally substituted C 1~9 Heteroaryl, -OR 10 , or -N(R 11 ) 2 and 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 heterocyclyl, optionally substituted C 6~10 aryl, or optionally substituted C 1~9 heteroaryl and each R 11 is 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 heterocyclyl, optionally substituted C 6~10 aryl, or optionally substituted C 1~9 heteroaryl, -SO2R 11A and two R 11 groups together form an optionally substituted C2-9 heterocyclyl and each R 11A is independently hydrogen, optionally substituted C 1~6Alkyl, 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 Heterocyclyl, optionally substituted C 6~10 Aryl, or optionally substituted C 1~9 is heteroaryl.

[0148] The compounds of the present invention can be, for example, the compounds listed in Table 1 below or pharmaceutically acceptable salts thereof.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-78

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

[0149] The present invention includes, where possible, the individual diastereomers, enantiomers, epimers, and atropisomers of the compounds disclosed herein, as well as mixtures of these diastereomers and / or enantiomers (including racemic mixtures). Although specific stereochemistry is preferred as disclosed herein, other stereoisomers including diastereomers, enantiomers, epimers, atropisomers, and mixtures thereof may also have utility in the treatment of Myt1-mediated diseases. Inactive or less active diastereoisomers and enantiomers may be useful, for example, in scientific studies regarding receptors and mechanisms of activation.

[0150] It is understood that certain molecules may exist in multiple tautomeric forms. The present invention includes all tautomers even if only one tautomer is shown in the examples.

[0151] The present invention also includes pharmaceutically acceptable salts of the compounds, as well as pharmaceutical compositions comprising the compounds and pharmaceutically acceptable carriers. The compounds are particularly useful, for example, in certain types of cancer and for delaying the progression of cancer after it has developed in a patient.

[0152] The compounds disclosed herein can be used in pharmaceutical compositions comprising (a) the compound(s) or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier. The compounds can be used in pharmaceutical compositions comprising one or more other pharmaceutically active ingredients. Also, the compounds can be used in pharmaceutical compositions in which the compounds disclosed herein or a pharmaceutically acceptable salt thereof is the sole active ingredient.

[0153] Optical isomers - Diastereomers - Geometric isomers - Tautomers The compounds disclosed herein can, for example, contain one or more asymmetric centers and can exist as racemates, racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers and / or enantiomers. The present invention includes all such isomeric forms of the compounds disclosed herein. All possible stereoisomers (e.g., enantiomers and / or diastereomers) as pure or partially purified compounds in a mixture (i.e., all possible combinations of asymmetric centers as pure compounds or in a mixture) are intended to be included within the scope of the present invention.

[0154] Some of the compounds described herein can contain bonds with rotational hindrance such that two distinct rotamers or atropisomers can be separated and may be found to have different biological activities that can be advantageous. All possible atropisomers are intended to be included within the scope of the present invention.

[0155] Some of the compounds described herein may contain olefinic double bonds and, unless otherwise specified, are meant to include both E and Z geometric isomers.

[0156] Some of the compounds described herein exist in different states of hydrogen bonding position and are called tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are included in the present invention.

[0157] Compounds disclosed herein having one or more chiral centers can be separated into diastereoisomers, enantiomers, etc. by methods well known in the art.

[0158] Alternatively, enantiomers and other compounds having chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and / or reagents of known configuration.

[0159] Metabolite-prodrug The present invention includes therapeutically active metabolites, where the metabolite itself is within the scope of the claims. The present invention also includes prodrugs, which are compounds that are converted to the compounds described in the claims when administered to a patient or after being administered to a patient. In some cases, the chemical structures described in the claims of the present application may themselves be prodrugs.

[0160] Isotope-enriched derivatives The present invention includes molecules that are isotope-enriched at one or more positions within the molecule. Thus, compounds enriched with deuterium are within the scope of the claims.

[0161] Methods for preparing the compounds of the present invention The compounds of the present invention can be prepared using reactions and techniques known in the art, as well as the reactions and techniques 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 these methods may be interchangeable without affecting the structure of the final product.

[0162] Method A The compounds of the present invention can be prepared as shown in Scheme A and described herein. Known 8-bromoquinolin-7-amine can be converted to 7-aminoquinoline-8-carbonitrile 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 obtain the compounds of the present invention. Depending on the nature of the Ar group, it may be necessary to provide a protecting group prior to the cross-coupling step. If the Ar group has a protecting group, a deprotection step(s) may be required prior to nitrile hydrolysis using an acid, base, and / or fluoride to obtain the compounds of the present invention.

Chemical formula

[0163] Method B The compounds of the present invention can be prepared as shown in Scheme B and described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate and (5-(methoxymethoxy)-2-methylphenyl)boronic acid can be cross-coupled using a metal-mediated step to obtain 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, followed by deprotection under acidic conditions to obtain the compounds of the present invention.

Chemical formula

[0164] Method C The compounds of the present invention can be prepared as shown in Scheme C and as described herein. Commercially available 3-amino-6-chloropicolinic acid can be esterified by treatment with a base (e.g., potassium carbonate) and ethyl iodide to obtain ethyl 3-amino-6-chloropicolinate, which can be brominated with NBS to obtain Intermediate D. This intermediate can be converted to Intermediate E via two steps involving a metal-mediated arylation followed by a transamidation reaction using ammonia. Intermediate E can be arylated using a second metal-mediated cross-coupling step, followed by deprotection with boron tribromide to obtain the compounds of the present invention. Depending on the nature of the aryl group cross-coupled to Intermediate E, a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention.

Chemical Structure

[0165] Method D The compounds of the present invention can be prepared as shown in Scheme D and as described herein. Intermediate E can be arylated using a metal-mediated cross-coupling step, followed by oxidation of the furan ring to obtain Intermediate F. This intermediate can be deprotected with boron tribromide and converted to an amide by using an aromatic amine and an amide bond-forming reagent to obtain the compounds of the present invention.

Chemical Structure

[0166] Method E The compounds of the present invention can be prepared as shown in Scheme E and as described herein. Intermediate D can be arylated with a substituted indazole-4-boronic acid using a metal-mediated cross-coupling step. The resulting ester can be treated with ammonia to convert it to a primary amide, 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 atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention.

Chemical formula

[0167] Method F The compounds of the present invention can be prepared as shown in Scheme F and as described herein. Commercially available quinolinic acid can be esterified under acidic methanol solution, and then converted to methyl 3-chloroquinolate after chlorination with NCS. This ester can be converted to a triflate, which can then be cross-coupled with a boronic acid via a metal-mediated step, and then transamidated to obtain the compounds of the present invention. If the Ar group has a protecting group, a deprotection step(s) may be required to obtain the compounds of the present invention.

Chemical formula

[0168] Method G The compounds of the present invention can be prepared as shown in Scheme G and as described herein. Compound 74 can be reduced under Pd-catalyzed conditions to obtain the compounds of the present invention.

Chemical formula

[0169] Method H The compounds of the present invention can be prepared as shown in Scheme H and as described herein. Commercially available methyl 2,5,6-trichloropyrimidine-4-carboxylate can be arylated with a substituted indazole-4-boronic acid using a metal-mediated cross-coupling step. A second arylation can then be carried out using a metal-mediated cross-coupling step, where hydrolysis of the ester can occur. Amide formation can then be effected with ammonia or its synthetic equivalent to afford the compounds of the present invention.

Chemical formula

[0170] Method I The compounds of the present invention can be prepared as shown in Scheme I and as described herein. Commercially available methyl 2,6-dichloropyrimidine-4-carboxylate can be arylated with a substituted indazole-4-boronic acid using a metal-mediated cross-coupling step. A second arylation can then be carried out using a metal-mediated cross-coupling step, where hydrolysis of the ester can occur. Amide formation can then be effected with ammonia or its synthetic equivalent to afford the compounds of the present invention.

Chemical formula

[0171] Method J 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 (e.g., potassium carbonate) and ethyl iodide to obtain ethyl 5-amino-2-chloroisonicotinate, which can be brominated with NBS to obtain intermediate G. This intermediate can be converted to intermediate H via two steps involving a transamidation reaction with ammonia following a metal-mediated coupling. Intermediate H can be arylated using a metal-mediated cross-coupling step, followed by deprotection with boron tribromide to obtain the compounds of the present invention.

Chemical formula

[0172] Method K The compounds of the present invention can be prepared as shown in Scheme K and described herein. The known 2-amino-5-bromo-3-iodobenzamide can be arylated using a metal-mediated cross-coupling step and then borylated using a second metal-mediated cross-coupling step to obtain intermediate I. This intermediate can be arylated using a metal-mediated cross-coupling step, followed by deprotection with zinc bromide and 1-propanethiol to obtain the compounds of the present invention, although a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention.

Chemical formula

[0173] Method L The compounds of the present invention can be prepared as shown in Scheme L and as described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate can be arylated with a substituted indazole-4-boronic acid using a metal-mediated cross-coupling step. This ester is hydrolyzed with an aqueous NaOH solution and then a primary amide is obtained by forming an amide using NH 4 Cl, HATU, and DIPEA, and a second arylation is carried out using a metal-mediated cross-coupling step to obtain the compounds of the present invention. If the aryl group has a protecting group, a deprotection step using an acid, a base, and / or a fluoride may be required to obtain the compounds of the present invention. If the aryl group has a racemic adduct, a chiral separation step by SFC may be required to obtain the compounds of the present invention. [Chemical formula]

[0174] Method M The compounds of the present invention can be prepared as shown in Scheme M and as described herein. Commercially available ethyl 5-amino-2-chloropyrimidine-4-carboxylate is arylated with phenylboronic acid using a metal-mediated cross-coupling step and then brominated with NBS to obtain Intermediate L. This intermediate is arylated with a substituted N-THP-protected indazole-4-boronic acid pinacol ester, followed by ammonia-mediated transamidation and acidic deprotection of the indazole to obtain the compounds of the present invention. [Chemical formula]

[0175] Method N The compounds of the present invention can be prepared as shown in Scheme N and as described herein. Intermediate G can be arylated with a substituted indazole-4-boronic acid using a metal-mediated cross-coupling step. The resulting ester can be treated with ammonia to convert it to a primary amide and then arylated using a second metal-mediated cross-coupling to obtain the compounds of the present invention.

Chemical formula

[0176] Method O The compounds of the present invention can be prepared as shown in Scheme O and as described herein. The 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 and then a second metal-mediated cross-coupling can be carried out to obtain the compounds of the present invention, although a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention.

Chemical formula

[0177] Method P The compounds of the present invention can be prepared as shown in Scheme P and as described herein. Intermediate K can be arylated with 2-(methylthio)-4-(tributylstannyl)pyrimidine using a metal-mediated cross-coupling step. The resulting methylthioether can be oxidized using an oxidizing agent (e.g., Oxone) to form a methylsulfone to obtain Intermediate N. This intermediate can be subjected to an SNAr reaction with various alcohols that can have other protecting moieties and, after deprotection, the compounds of the present invention can be obtained, although a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention. [Chemical]

[0178] Method Q The compounds of the present invention can be prepared as shown in Scheme Q and as described herein. Intermediate N can be subjected to a SNAr reaction with various amines to obtain the compounds of the present invention, but a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention. [Chemical]

[0179] Method R The compounds of the present invention can be prepared as shown in Scheme R and as described herein. Intermediate K can be arylated with 2-fluoro-6-(tributylstannyl)pyridine using a metal-mediated cross-coupling step to obtain Intermediate O. This intermediate can be subjected to a SNAr reaction with various alcohols to obtain the compounds of the present invention, but a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention. [Chemical]

[0180] Method S The compounds of the present invention can be prepared as shown in Scheme S and as described herein. Intermediate K can be arylated with tributyl(aryl)stannane using a metal-mediated cross-coupling step, where the n-butylated product can be isolated as a by-product to obtain the compounds of the present invention. [Chemical]

[0181] Method T 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 borylated using a metal-mediated cross-coupling step to obtain pinacol (THP)-1H-indazol-4-yl)boronate. These boronates can be subjected to a metal-mediated cross-coupling step with Intermediate P to obtain a THP-protected ester, which can be transamidated with ammonia and deprotected under acidic conditions to obtain the compounds of the present invention, although a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention.

Chemical formula

[0182] Method U The compounds of the present invention can be prepared as shown in Scheme U and described herein. Commercially available 3-amino-5-methylpicolinic acid hydrochloride can be converted to a primary amide by using HATU and an ammonia surrogate. This primary amide can then be brominated to obtain 3-amino-4,6-dibromo-5-methylpicolinamide. This compound can be diarylated using a metal-mediated cross-coupling step with 2-(tributylstannyl)pyridine and pinacol (1H-indazol-4-yl)boronic ester respectively to obtain the compounds of the present invention.

Chemical formula

[0183] Method V The compounds of the present invention can be prepared as shown in Scheme V and as described herein. Intermediate O can be subjected to an SNAr reaction with various amines to obtain the compounds of the present invention, but a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention.

Chemical formula

[0184] Method W The compounds of the present invention can be prepared as shown in Scheme W and as described herein. Intermediate J can be arylated with (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid using a metal-mediated cross-coupling step. Deprotection is carried out under acidic conditions, followed by an SNAr reaction with a substituted 2-halopyrimidine to obtain the compounds of the present invention.

Chemical formula

[0185] Method X The compounds of the present invention can be prepared as shown in Scheme X and as described herein. Intermediate K is protected with di-tert-butyl dicarbonate and aminated with aniline using a metal-mediated cross-coupling step to obtain the compounds of the present invention, but a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention.

Chemical formula

[0186] Method Y The intermediates used in the preparation of the compounds of the present invention can be prepared as shown in Scheme Y and as described herein. Commercially available 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, which can have substituents, can be acylated using an acid chloride or using a carboxylic acid and an amide-forming reagent (e.g., HATU) to obtain a pinacol boronic acid ester, which can be used together with the methods described herein to obtain the compounds of the present invention.

Chemical formula

[0187] Method Z The intermediates used in the preparation of the compounds of the present invention can be prepared as shown in Scheme Z and as described herein. Commercially available 2-bromoaniline, which can have substitutions, can be alkylated using an alkyl halide or a pseudohalide. These alkylated anilines can then be borylated using a metal-mediated cross-coupling step to obtain a pinacol boronic acid ester, which can be used together with the methods described herein to obtain the compounds of the present invention.

Chemical formula

[0188] Method AA The intermediates used in the preparation of the compounds of the present invention can be prepared as shown in Scheme AA and as described herein. Commercially available 2-bromoaniline, which can have substitutions, can be alkylated under a reductive amination reaction using an aldehyde or a ketone. These alkylated anilines can then be borylated using a metal-mediated cross-coupling step to obtain a pinacol boronic acid ester, which can be used together with the methods described herein to obtain the compounds of the present invention.

Chemical formula

[0189] Method AB The compounds of the present invention can be prepared as shown in Scheme AB and as described herein. Commercially available 5-bromo-6-fluoroindoline-2,3-dione is arylated with (2-hydroxyphenyl)boronic acid using a metal-mediated cross-coupling step and then cyclized using a base such as potassium tert-butoxide to obtain 1H-benzo[f]indole-2,3-dione. This compound can then be hydrolyzed and oxidized in a one-pot procedure using NaOH and H 2 O 2 followed by conversion to a primary amide using standard amide coupling reagents (e.g., HATU and ammonium chloride). This carboxamide can then be brominated with a brominating reagent (e.g., NBS) and subsequently arylated with (5-methyl-1H-indazol-4-yl)boronic acid using a metal-mediated cross-coupling step to obtain the compounds of the present invention.

Chemical Structure

[0190] Method AC The compounds of the present invention can be prepared as shown in Scheme AC and as described herein. Intermediate J can be arylated with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline which can have substituents using a metal-mediated cross-coupling step and then sulfonylated using sulfonyl chloride to obtain the compounds of the present invention.

Chemical Structure

[0191] Method AD The compounds of the present invention can be prepared as shown in Scheme AD and as described herein. 5-Amino-2-chloro-6-(1H-indazol-4-yl)pyrimidine-4-carboxamide having a substitution on the indazole moiety is arylated with a borylated or stannylated substituted aniline using a metal-mediated cross-coupling step, followed by N-arylation under acidic SNAr conditions to obtain the compounds of the present invention.

Chemical Structure

[0192] Method AE The intermediates used in the preparation of the compounds of the present invention can be prepared as shown in Scheme AE and as described herein. Commercially available 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline which can have a substitution is acylated using an acid chloride or using a carboxylic acid and an amide-forming reagent (e.g., HATU) to obtain an amide, which is then reduced using a reducing reagent (e.g., borane) to obtain a pinacol boronic acid ester, which can be used together with the methods described herein to obtain the compounds of the present invention.

Chemical Structure

[0193] Method AF The compounds of the present invention can be prepared as shown in Scheme AF and as described herein. Intermediate J is arylated with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline which can have a substituent using a metal-mediated cross-coupling step, followed by acylation using an acid chloride or a carboxylic acid and an amide-forming reagent (e.g., HATU) to obtain the compounds of the present invention.

Chemical Structure

[0194] Method AG 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 is protected with 2,5-hexanedione under acidic conditions and subsequently cross-coupled with Intermediate V under metal-mediated steps to obtain protected 7-aminobenzofuro[3,2-b]pyridine-6-carbonitrile. This intermediate is hydrolyzed to a carboxamide under basic conditions, deprotected using hydroxylamine, brominated with a brominating reagent (e.g., NBS), and subsequently arylated with (5-methyl-1H-indazol-4-yl)boronic acid using a metal-mediated cross-coupling step to obtain the compounds of the present invention.

Chemical Structure

[0195] Method AH The intermediates used in the preparation of the compounds of the present invention can be prepared as shown in Scheme AH and described herein. Commercially available 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, which can have substituents, is reductively aminated with a ketone or aldehyde using a reducing agent (e.g., sodium cyanoborohydride) to obtain a pinacol boronic acid ester, which can be used together with the methods described herein to obtain the compounds of the present invention.

Chemical Structure

[0196] Method AI The compounds of the present invention can be prepared as shown in Scheme AI and described herein. Commercially available methyl 2,6-dichloropyrimidine-4-carboxylate can be arylated with an N-THP protected pinacol indazole-4-boronic ester having substituents using a metal-mediated cross-coupling step. A 3-(2-amino-pyridyl) group (which may have substituents) can be incorporated using a second metal-mediated cross-coupling step. This primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia is carried out, and then the THP group is cleaved under acidic conditions to obtain the compounds of the present invention. [Chemical formula]

[0197] Method AJ The compounds of the present invention can be prepared as shown in Scheme AJ and described herein. Commercially available ethyl 2,6-dichloro-5-fluoropyrimidine-4-carboxylate can be arylated with an N-THP protected pinacol indazole-4-boronic ester having substituents using a metal-mediated cross-coupling step. A 3-(2-amino-pyridyl) group (which may have substituents) can be incorporated using a second metal-mediated cross-coupling step. This primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia is carried out, and then the THP group is cleaved under acidic conditions to obtain the compounds of the present invention. [Chemical formula]

[0198] Method AK The compounds of the present invention can be prepared as shown in Scheme AK and as described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate can be arylated with an N-THP protected pinacol indazole-4-boronic ester having substituents using a metal-mediated cross-coupling step. A second metal-mediated cross-coupling step can be used to incorporate a 3-(2-amino-pyridyl) group (which may have substituents). This primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia is carried out, and then the THP group is cleaved under acidic conditions to obtain the compounds of the present invention.

Chemical formula

[0199] Method AL The compounds of the present invention can be prepared as shown in Scheme AL and as described herein. Intermediate J can be arylated with a suitable boronic acid or ester, or with a suitable tributylstannane using a metal-mediated cross-coupling step to incorporate a 3-(2-fluoro-pyridyl) group which may have substituents. These 2-fluoropyridines are then subjected to an SNAr reaction with a primary amine to obtain the compounds of the present invention.

Chemical formula

[0200] Method AM The intermediates used in the preparation of the compounds of the present invention can be prepared as shown in Scheme AM and described herein. Commercially available 2-bromo-1-iodobenzene, which can have substituents, can be N-arylated with commercially available arylamines or heteroarylamines using a metal-mediated cross-coupling step. These secondary anilines can then be borated using a metal-mediated cross-coupling step to obtain pinacol boronic acid esters, which can be used together with the methods described herein to obtain the compounds of the present invention.

Chemical formula

[0201] Method AN The compounds of the present invention can be prepared as shown in Scheme AN and described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate can be arylated with an N-THP-protected pinacol indazole-4-boronate having substituents using a metal-mediated cross-coupling step. A second metal-mediated cross-coupling step can be used to incorporate a 3-(4-amino-pyridyl) group (which may have substituents). These 2-fluoropyridines can then be subjected to SNAr reaction conditions with a primary amine, followed by transamidation with ammonia and deprotection under acidic conditions to obtain the compounds of the present invention.

Chemical formula

[0202] Method AO The compounds of the present invention can be prepared as shown in Scheme AO and described herein. Intermediate J can be stannylated with bis(tributyltin) using a metal-mediated cross-coupling step to obtain Intermediate X. A second metal-mediated cross-coupling step can be used to incorporate an aryl group or heteroaryl group with or without substituents to obtain the compounds of the present invention.

Chem.

[0203] Method AP The compounds of the present invention can be prepared as shown in Scheme AP and described herein. Intermediate J is first borylated with bis(pinacolato)diboron using a metal-mediated cross-coupling step, and then arylated using a second metal-mediated cross-coupling step to incorporate an aryl or heteroaryl group with or without substituents to obtain the compounds of the present invention.

Chem.

[0204] Method AQ The compounds of the present invention can be prepared as shown in Scheme AQ and described herein. An SNAr reaction using an alcohol and a base (e.g., NaH) can be carried out on Intermediate Z. The resulting intermediate can be hydrolyzed using a Ghaffar-Parkins catalyst to form a primary amide to obtain the compounds of the present invention, but a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention.

Chem.

[0205] Method AR The compounds of the present invention can be prepared as shown in Scheme AR and described herein. An SNAr reaction using an amine can be carried out on Intermediate Z. The resulting intermediate can be hydrolyzed using a Ghaffar-Parkins catalyst to form a primary amide to obtain the compounds of the present invention, but a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention.

Chem.

[0206] Method AS The compounds of the present invention can be prepared as shown in Scheme AS and described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate can be arylated with an N-THP protected pinacol indazole-4-boronate having substituents using a metal-mediated cross-coupling step. A second metal-mediated cross-coupling step can be used to incorporate a 3-(2-amino-phenyl) group (which may have substituents). This primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia is carried out, and then the THP group is cleaved under acidic conditions to obtain the compounds of the present invention. [Chemical formula]

[0207] Method AT The compounds of the present invention can be prepared as shown in Scheme AT and described herein. Commercially available ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate can be arylated with an N-THP protected pinacol indazole-4-boronate having substituents using a metal-mediated cross-coupling step. This chloropyrimidine can be stannylated with bis(tributyltin) using a metal-mediated cross-coupling step. A third metal-mediated cross-coupling step can be used to cross-couple an aryl group or a heteroaryl group which may have substituents. Transamidation with ammonia is carried out, and then the THP group is cleaved under acidic conditions to obtain the compounds of the present invention. [Chemical formula]

[0208] Method AU The compounds of the present invention can be prepared as shown in Scheme AU and as described herein. Stannylated N-THP protected 5-amino-6-(1H-indazol-4-yl)pyrimidine-4-carboxamide having a substituent on the indazole moiety can be arylated with 3-bromopyridine using a metal-mediated cross-coupling step to incorporate a 3-(2-amino-pyridyl) group which may have a substituent. This primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia is carried out, and then the THP group is cleaved under acidic conditions to obtain the compounds of the present invention.

Chemical Structure

[0209] Method AV The compounds of the present invention can be prepared as shown in Scheme AV and as described herein. Stannylated N-THP protected 5-amino-6-(1H-indazol-4-yl)pyrimidine-4-carboxamide having a substituent on the indazole moiety can be arylated with 2-bromoaniline using a metal-mediated cross-coupling step to incorporate a 3-(2-aminophenyl) group which may have a substituent. This primary amine can then be N-arylated using a metal-mediated cross-coupling step. Transamidation with ammonia is carried out, and then the THP group is cleaved under acidic conditions to obtain the compounds of the present invention.

Chemical Structure

[0210] Method AW The compounds of the present invention can be prepared as shown in Scheme AW and as described herein. Commercially available 2-halogeno-3-bromopyridines having substituents can be reacted with primary amines under SNAr reaction conditions. These 2-amino-3-bromopyridines can then be cross-coupled, using a metal-mediated cross-coupling step, with stannylated N-THP protected 5-amino-6-(1H-indazol-4-yl)pyrimidine-4-carboxamide having a substituent on the indazole moiety. Transamidation with ammonia can be carried out, and then the THP group can be cleaved under acidic conditions to obtain the compounds of the present invention.

Chemical formula

[0211] Method AX The compounds of the present invention can be prepared as shown in Scheme AX and as described herein. N-alkylated or N-protected 3-amino-4-bromopyrazoles can first be reacted with a ketone under reductive amination conditions, followed by borylation with bis(pinacolato)diboron using a metal-mediated cross-coupling step to obtain 4-borylated pyrazoles. These pyrazoles can be subjected to a second metal-mediated cross-coupling step with 4-chloropyrimidine (e.g., intermediate AB), and then to transamidation with ammonia and cleavage of the THP group under acidic conditions to obtain the compounds of the present invention.

Chemical formula

[0212] Method AY The compounds of the present invention can be prepared as shown in Scheme AY and as described herein. N-alkylated 3-amino-4-bromopyrazoles can first be borylated with bis(pinacolato)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 is carried out, and then the THP group is cleaved under acidic conditions to obtain the compounds of the present invention.

Chemical formula

[0213] Method AZ The compounds of the present invention can be prepared as shown in Scheme AZ and as described herein. Intermediate BT can be arylated using a metal-mediated cross-coupling step to incorporate a 3-(2-amino-pyridyl) group which may have substituents. This primary amine can then be N-arylated with a heteroaryl halide using a metal-mediated cross-coupling step. Transamidation with ammonia is carried out, and then the THP group is cleaved under acidic conditions to obtain the compounds of the present invention.

Chemical formula

[0214] Method BA 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)pyrimidine-4-carboxylate having a substituent on the indazole moiety can be arylated using a metal-mediated cross-coupling step. These arylation intermediates can be subjected to transamidation with ammonia and then to cleavage of the THP group under acidic conditions to obtain the compounds of the present invention.

Chemical formula

[0215] Method BB 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)pyrimidine-4-carboxylate having a substituent on the indazole moiety can be arylated using a metal-mediated cross-coupling step via a one-pot borylation / Suzuki cross-coupling step. This primary amine can then be N-arylated with a heteroaryl halide using a metal-mediated cross-coupling step. Transamidation with ammonia is carried out, and then the THP group is cleaved under acidic conditions to obtain the compounds of the present invention.

Chemical formula

[0216] Method BC The compounds of the present invention and synthetic routes for accessing them are described with the following exemplary compounds.

[0217] Method BD The compounds of the present invention can be prepared as shown in Scheme BD and as described herein. Intermediate D can be arylated with (3-methoxy-2,6-dimethylphenyl)boronic acid using a metal-mediated cross-coupling step, followed by a transamidation reaction using ammonia, and then deprotected with boron tribromide to obtain Intermediate CO. This intermediate can be arylated using a second metal-mediated cross-coupling step to obtain the compounds of the present invention. Depending on the nature of the aryl group cross-coupled to Intermediate CO, a mixture of atropisomers may be obtained. In such cases, it may be necessary to isolate the desired atropisomer to obtain the compounds of the present invention.

Chemical formula

[0218] Treatment method The compounds of the present invention can be used for the treatment of diseases or conditions that depend on the activity of Myt1 (gene name PKMYT1) (for example, cancers that overexpress CCNE1, or cancers that have inactivating mutations in the FBXW7 gene).

[0219] The disease or condition may have a symptom of excessive cell proliferation. For example, the disease or condition may be cancer (for example, cancer that overexpresses CCNE1, or cancer that has an inactivating mutation in the FBXW7 gene).

[0220] Examples of cancers with a high incidence of CCNE1 overexpression include, for example, uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, and endometrial cancer.

[0221] Examples of cancers with a deficiency in FBXW7 include, for example, uterine cancer, colorectal cancer, breast cancer, lung cancer, and esophageal cancer.

[0222] The compounds of the present invention can be administered by a route selected from the group consisting of oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, intratumoral, and topical administration.

[0223] Pharmaceutical composition The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for in vivo administration. Pharmaceutical compositions typically contain a compound described herein and a pharmaceutically acceptable excipient. Certain pharmaceutical compositions may contain one or more additional pharmaceutically active agents described herein.

[0224] The compounds described herein can also be used in the form of free bases, salts, zwitterions, solvates, or prodrugs or pharmaceutical compositions thereof. All forms are within the scope of the present invention. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof can be administered to patients in various forms depending on the selected route of administration, as would be understood by one of ordinary skill in the art. The compounds used in the methods described herein can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions are formulated accordingly. Parenteral administration includes modes of administration by intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical routes. Parenteral administration can be by continuous infusion over a selected period.

[0225] When used in humans, the compounds of the present invention can be administered alone or as a mixture with a pharmaceutical carrier selected with respect to the intended route of administration and standard pharmaceutical practice. Accordingly, pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries that facilitate processing of the compounds of the present invention into pharmaceutically usable preparations.

[0226] The present invention also includes a pharmaceutical composition which can contain one or more pharmaceutically acceptable carriers. When preparing the pharmaceutical composition of the present invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or enclosed in a carrier such as in the form of a capsule, sachet, paper, or other container. The excipient, when functioning as a diluent, can be a solid, semi-solid, or liquid material (e.g., standard physiological saline) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can be varied according to the intended route of administration. The resulting composition can contain additional agents, such as preservatives.

[0227] The excipient or carrier is selected based on the mode of administration and the route of administration. For suitable pharmaceutical carriers and pharmaceutical necessities for use in pharmaceutical formulations, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and USP / NF (United States Pharmacopeia and the National Formulary), which are well-known in the art. Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can additionally contain lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoate; sweetening agents; and flavoring additives. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

[0228] These pharmaceutical compositions can be manufactured by conventional methods, for example, by conventional mixing, dissolving, granulating, sugar coating, trituration, emulsifying, encapsulating, entrapping, 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 Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988 - 1999, Marcel Dekker, New York. Appropriate formulations depend on the chosen route of administration. The formulation and preparation of such compositions are well known to those skilled in the pharmaceutical arts. When preparing a formulation, the active compound can be milled to provide an appropriate particle size before combining it with other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by milling, for example, to about 40 mesh to provide a substantially uniform distribution in the formulation.

[0229] Dosage The dosage of the compounds, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof, used in the methods described herein can vary depending on a number of factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health status, and weight of the recipient; the nature and extent of the symptoms; the frequency of treatment; and the type of concomitant therapy, if any; as well as the clearance rate of the compound in the animal being treated. One of ordinary skill in the art can determine an appropriate dosage based on the above factors. The compounds used in the methods described herein can be initially administered at an appropriate dosage that can be adjusted in response to the clinical response as needed. Generally, an appropriate daily dosage of the compounds of the present invention is the amount of the compound that is the lowest effective dosage to produce a therapeutic effect. Such effective dosages generally depend on the above factors.

[0230] The compounds of the present invention can be administered to a patient either as a single dose or as multiple doses. When multiple doses are administered, the doses can be spaced apart from each other, for example, by 1 to 24 hours, 1 to 7 days, 1 to 4 weeks, or 1 to 12 months. The compounds can be administered according to a schedule or without an accompanying predetermined schedule. The active compound can be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times a day, every 2, 3, 4, 5, or 6 days, 1, 2, 3, 4, 5, 6, or 7 times a week, 1, 2, 3, 4, 5, or 6 times a month, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times a year. It should be understood that for any particular subject, it may be necessary to adjust the specific dosing regimen over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0231] Ultimately, the attending physician determines the appropriate amount and dosing regimen, but the effective amount of the compounds of the present invention can be, for example, a total daily dosage of 0.05 mg to 3000 mg of any of the compounds described herein. Alternatively, the dosage can be calculated using the patient's body weight. Such dosage ranges can include, for example, 10 to 1000 mg (e.g., 50 to 800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

[0232] In the method of the present invention, the period during which multiple doses of the compound of the present invention are administered to a patient can be changed. For example, in some embodiments, the dose of the compound of the present invention is administered to the patient over a period of 1 to 7 days, 1 to 12 weeks, or 1 to 3 months. In some embodiments, the compound is administered to the patient over a period of, for example, 4 to 11 months, or 1 to 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 the compound administered may be changed during the period of administration. If the compound is administered daily, the administration may be carried out 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day.

[0233] Formulation Using any of the methods described herein, a compound identified as being capable of treating any of the conditions described herein can be administered to a patient or animal in unit dosage form, together with a pharmaceutically acceptable diluent, carrier, or excipient. Such chemical substances for use in such therapies can be produced and isolated by any standard technique known to those skilled in pharmaceutical chemistry. Conventional pharmaceutical services can be utilized to provide a suitable formulation or composition for administering the identified compound to a patient suffering from a disease or condition. Administration may be initiated before the patient exhibits symptoms.

[0234] Exemplary routes of administration of the compounds used in the present invention (e.g., the compounds of the present invention) or pharmaceutical compositions thereof include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intrathecal, intraperitoneal, intranasal, inhalation, and topical administration. The compound is preferably administered together with a pharmaceutically acceptable carrier. The pharmaceutical formulations of the compounds described herein formulated for the treatment of the disorders described herein are also part of the present invention.

[0235] Formulations for oral administration The pharmaceutical compositions contemplated by the present invention include those formulated for oral administration ("oral dosage forms"). Oral dosage forms can be, for example, tablets, capsules, liquid solutions or suspensions, powders, or in the form of liquid or solid crystals, containing the active ingredient(s) together with pharmaceutically acceptable excipients that are non-toxic in the mixture. These excipients can be, for example, inert diluents or fillers (such as sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate), granulating and disintegrating agents (such as cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid), binders (such as sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, polyvinylpyrrolidone, or polyethylene glycol), and lubricants, fluidizing agents, and anti-adhesive agents (such as magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be coloring agents, flavoring agents, plasticizers, wetting agents, buffering agents, and the like.

[0236] Also, formulations for oral administration can be presented as chewable tablets, as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets can be prepared in a conventional manner using the components described above for tablets and capsules, for example, using a mixer, a fluid bed apparatus, or a spray drying apparatus.

[0237] Oral use controlled release compositions can be constructed to release the active pharmaceutical substance by controlling the dissolution and / or diffusion of the active drug substance. Any of a number of strategies can be implemented to obtain controlled release and target plasma concentration versus time profiles. In one example, controlled release is obtained by appropriate selection of 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, microparticles, nanoparticles, patches, and liposomes. In some embodiments, the composition includes a biodegradable, pH, and / or temperature sensitive polymer coating.

[0238] Dissolution or diffusion controlled release can be achieved by appropriate coating of tablets, capsules, pellets, or granule formulations of the compound, or by incorporating the compound into an appropriate matrix. Controlled release coatings can include one or more of the coating substances described above, and / or, for example, shellac, beeswax, glyceryl wax, candelilla wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxy methacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled release matrix formulations, the matrix material can include, for example, hydrated methyl cellulose, carnauba wax, and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbon.

[0239] When the compounds and compositions of the present invention are incorporable for oral administration, liquid forms include aqueous solutions, properly flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0240] Formulations for parenteral administration The compounds described herein for use in the methods of the present invention are administrable in pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulations as described herein. Also, the pharmaceutical formulations may be administered parenterally (intravenously, intramuscularly, subcutaneously, etc.) in dosage forms or formulations containing conventional non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration may include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. For example, to prepare such compositions, the compounds of the present invention may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents, water, water adjusted to an appropriate pH by the addition of a suitable amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution may be used. Also, the aqueous formulations may contain one or more preservatives, such as methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), which is incorporated herein by reference.

[0241] The parenteral formulations can be any of five general types of preparations specified by the USP-NF as being suitable for parenteral administration. (1) Drug injection: A liquid preparation that is a drug substance (e.g., a compound of the present invention), or a solution thereof; (2) Injectable drug: A drug substance (e.g., a compound of the present invention) that is a dry solid to be mixed with a suitable sterile vehicle for parenteral administration as a drug injection; (3) Emulsion for drug injection: A liquid preparation of a drug substance (e.g., a compound of the present invention) dissolved or dispersed in a suitable emulsion medium; (4) Suspension for drug injection: A liquid preparation of a drug substance (e.g., a compound of the present invention) suspended in a suitable liquid medium; (5) Drug for suspension for injection: A drug substance (e.g., a compound of the present invention) that is a dry solid to be mixed with a suitable sterile vehicle for parenteral administration as a suspension for drug injection.

[0242] Formulations for parenteral administration include solutions of compounds prepared in water appropriately mixed with a surfactant, e.g., hydroxypropylcellulose. Dispersions can also be prepared in those mixtures, with or without glycerol, liquid polyethylene glycol, DMSO, and alcohol, and in oils. These formulations may contain preservatives to prevent the growth of microorganisms under normal storage and use conditions. Conventional procedures and components for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and The United States Pharmacopeia: The National Formulary (USP 36 NF31) published in 2013.

[0243] Formulations for parenteral administration may contain, for example, excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, plant-derived oils, or hydrogenated naphthalene. Biocompatible and biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compound. Other potentially useful parenteral delivery systems for the compound include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain, for example, lactose, or may be an aqueous solution containing, for example, polyoxyethylene-9-lauryl ether, glycolic acid, and deoxycholic acid, or may be in the form of a nasal spray or an oily solution for administration as a gel.

[0244] Parenteral formulations can be formulated for immediate release or sustained / prolonged release of the compound. Exemplary formulations for parenteral release of the compound include aqueous solutions, powders for solution preparation, cosolvent solutions, oil / water emulsions, suspensions, oil-based solutions, liposomes, microparticles, and polymeric gels.

[0245] Combination The compounds of the present invention can be administered to a subject, for example, in combination with one or more of the following additional agents. (a) Cytotoxic agents, (b) Antimetabolites, (c) Alkylating agents, (d) Anthracyclines, (e) Antibiotics, (f) Mitotic inhibitors, (g) Hormonal therapy agents, (h) Signal transduction inhibitors, (i) Gene expression modulators, (j) Apoptosis-inducing factors, (k) Angiogenesis inhibitors, (l) Immunotherapy agents, (m) DNA damage repair inhibitors, Or Combinations thereof.

[0246] Cytotoxic agents include, for example, actinomycin D, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, amphotericin, amsacrine, arsenic trioxide, asparaginase, azacitidine, azathioprine, Bacillus Calmette-Guérin (BCG), bendamustine, bexarotene, bevacizumab, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carfilzomib, carmustine, cetuximab, cisplatin, chlorambucil, cladribine, clofarabine, colchicine, crisantaspase, cyclophosphamide, cyclosporine, cytarabine, cytochalasin B, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, 1-dehydrotestosterone, denileukin, dexamethasone, dexrazoxane, dihydroxyanthracenedione, disulfiram, docetaxel, doxorubicin, emetine, epirubicin, erlotinib, epigallocatechin gallate, epoetin alfa, estramustine, ethidium bromide, etoposide, everolimus, filgrastim, finasteride, floxuridine, fludarabine, fluorouracil (5-FU), fulvestrant, ganciclovir, geldanamycin, gemcitabine, glucocorticoid, gramicidin D, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, irinotecan, interferon, interferon alfa 2a, interferon alfa 2b, ixabepilone, lactate dehydrogenase A (LDH-A), lenalidomide, letrozole, leucovorin, levamisole, lidocaine, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, methoxsalen, methopterin, metronidazole, mitramycin, mitomycin C, mitoxantrone, nandrolone, nelarabine, nilotinib, nolatrexed, oprelvekin, oxaliplatin, paclitaxel, pemetrexed, pentostatin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, procaine, procarbazine, propranolol, promycin,It may be quinacrine, radicicol, radioisotope, larotrectinib, rapamycin, rasburicase, salinosporamide A, sargramostim, sunitinib, temozolomide, teniposide, tetracaine, 6-thioguanine, thiotepa, topotecan, tamoxifen, trastuzumab, treosulfan, tretinoin, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, zoledronate, or a combination thereof.

[0247] The antimetabolite may be, for example, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil, decarbazine, cladribine, pemetrexed, gemcitabine, capecitabine, hydroxyurea, mercaptopurine, fludarabine, pralatrexate, clofarabine, cytarabine, decitabine, floxuridine, nelarabine, trimetrexate, thioguanine, pentostatin, or a combination thereof.

[0248] The alkylating agent may be, for example, mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiammineplatinum (II) (DDP) cisplatin, altretamine, cyclophosphamide, ifosfamide, hexamethylmelamine, altretamine, procarbazine, dacarbazine, temozolomide, streptozocin, carboplatin, cisplatin, oxaliplatin, uramustine, bendamustine, trabectedin, semustine, or a combination thereof.

[0249] The anthracycline may be, for example, daunorubicin, doxorubicin, aclarubicin, aldoxorubicin, amrubicin, annamycin, carubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, or a combination thereof.

[0250] Antibiotics can be, for example, dactinomycin, bleomycin, mitomycin, anthramycin (AMC), ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, piperacillin, pivampicillin, pivmecillinam, ticarcillin, aztreonam, imipenem, doripenem, ertapenem, meropenem, cephalosporin, clarithromycin, dirithromycin, roxithromycin, telithromycin, lincomycin, pristinamycin, quinupristin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, tobramycin, streptomycin, sulfamethizole, sulfamethoxazole, sulfisoxazole, demeclocycline, minocycline, oxytetracycline, tetracycline, penicillin, amoxicillin, cephalexin, erythromycin, clarithromycin, azithromycin, ciprofloxacin, levofloxacin, ofloxacin, doxycycline, clindamycin, metronidazole, tigecycline, chloramphenicol, metronidazole, tinidazole, nitrofurantoin, vancomycin, teicoplanin, telavancin, linezolid, cycloserine, rifamycin, polymyxin B, bacitracin, viomycin, capreomycin, quinolone, daunorubicin, doxorubicin, 4'-deoxydoxorubicin, epirubicin, idarubicin, plicamycin, mitomycin C, mitoxantrone, or a combination thereof.

[0251] Mitotic inhibitors can be, for example, vincristine, vinblastine, vinorelbine, docetaxel, estramustine, ixabepilone, paclitaxel, maytansinoid, dolastatin, cryptophycin, or a combination thereof.

[0252] Signal transduction inhibitors can be, for example, imatinib, trastuzumab, erlotinib, sorafenib, sunitinib, temsirolimus, vemurafenib, lapatinib, bortezomib, cetuximab, panitumumab, matuzumab, gefitinib, STI 571, rapamycin, flavopiridol, imatinib mesylate, batatinib, semaxinib, motesanib, axitinib, afatinib, bosutinib, crizotinib, cabozantinib, dasatinib, enzotrectinib, pazopanib, lapatinib, vandetanib, or combinations thereof.

[0253] Gene expression modulators can be, for example, siRNA, shRNA, antisense oligonucleotides, HDAC inhibitors, or combinations thereof. HDAC inhibitors can be, for example, trichostatin A, trapoxin B, valproic acid, vorinostat, belinostat, LAQ824, panobinostat, entinostat, tacedinaline, mocetinostat, givinostat, resminostat, abexinostat, xeno stat, roslinostat, pracinostat, CHR-3996, butyric acid, phenylbutyric acid, 4SC202, romidepsin, suberoylanilide hydroxamic acid, cambinol, EX-527, nicotinamide, or combinations thereof. Antisense oligonucleotides can be, for example, custirsen, apatorasen, AZD9150, trabadersen, EZN-2968, LErafAON-ETU, or combinations thereof. siRNA can be, for example, ALN-VSP, CALAA-01, Atu-027, SPC2996, or combinations thereof.

[0254] The hormonal therapeutic agent can be, for example, a luteinizing hormone-releasing hormone (LHRH) antagonist. The hormonal therapeutic agent can be, for example, Pharmagon, leuprorelin, goserelin, buserelin, flutamide, bicalutamide, ketoconazole, aminoglutethimide, prednisone, hydroxy-progesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, raloxifene, droloxifene, iodoxyfene, 4-hydroxy tamoxifen, trioxifene, keoxifene, LY117018, onapristone, citrate tamoxifen, megestrol acetate, exemestane, fadrozole, vorozole, letrozole, anastrozole, nilutamide, tripterelin, histrelin, abiraterone, medroxyprogesterone acetate, diethylstilbestrol, Premarin, fluoxymesterone, tretinoin, fenretinide, troxacitabine, or a combination thereof.

[0255] The apoptosis-inducing factor can be, for example, recombinant human TNF-related apoptosis-inducing ligand (TRAIL), camptothecin, bortezomib, etoposide, tamoxifen, or a combination thereof.

[0256] The angiogenesis inhibitor can be, for example, sorafenib, sunitinib, pazopanib, everolimus, or a combination thereof.

[0257] An immunotherapeutic agent can be, for example, a monoclonal antibody, a cancer vaccine (e.g., a dendritic cell (DC) vaccine), an oncolytic virus, a cytokine, adoptive T cell therapy, Bacillus Calmette-Guérin (BCG), GM-CSF, thalidomide, lenalidomide, pomalidomide, imiquimod, or a combination thereof. The monoclonal antibody can be, for example, anti-CTLA4, anti-PD1, anti-PD-L1, anti-LAG3, anti-KIR, or a combination thereof. The monoclonal antibody can be, for example, alemtuzumab, trastuzumab, ibritumomab tiuxetan, brentuximab vedotin, trastuzumab, ado-trastuzumab emtansine, blinatumomab, bevacizumab, cetuximab, pertuzumab, panitumumab, ramucirumab, obinutuzumab, ofatumumab, rituximab, pertuzumab, tositumomab, gemtuzumab ozogamicin, tositumomab, or a combination thereof. The cancer vaccine can be, for example, Sipuleucel-T, BioVaxID™, NeuVax™, DCVax®, SuVaxM, CIMAvax™, Provenge®, hsp110 chaperone complex vaccine, CDX-1401, MIS416, CDX-110, GVAX Pancreas, HyperAcute™ Pancreas, GTOP-99 (MyVax™), or Imprime PGG®. The oncolytic virus can be, for example, talimogene laherparepvec. The cytokine can be, for example, IL-2, IFNα, or a combination thereof. The adoptive T cell therapy agent can be, for example, tisagenlecleucel, axicabtagene ciloleucel, or a combination thereof.

[0258] The DNA damage repair inhibitor can be, for example, a PARP inhibitor, a cell checkpoint kinase inhibitor, or a combination thereof. The PARP inhibitor can be, for example, olaparib, rucaparib, veliparib (ABT-888), niraparib (ZL-2306), iniparib (BSI-201), talazoparib (BMN 673), 2X-121, CEP-9722, KU-0059436 (AZD2281), PF-01367338, or a combination thereof. The cell checkpoint kinase inhibitor can be, for example, MK-1775 or AZD1775, AZD7762, LY2606368, PF-0477736, AZD0156, GDC-0575, ARRY-575, CCT245737, PNT-737, or a combination thereof.

Example

[0259] The following examples are intended to illustrate the present invention. They are not intended to limit the present invention in any way.

[0260] Typically, reactions were carried out under a nitrogen atmosphere at room temperature (rt or RT) using a dry solvent (Sure / Seal™) unless otherwise stated in the following examples. Reactions were monitored by TLC or by injection of a small aliquot in a Waters® Acquity-H UPLC® Class system (using an Acquity® UPLC® HSS C18 2.1×30 mm column; elution with a gradient of acetonitrile in water (both containing 0.1% formic acid) (15% - 98% over 1.86 minutes)). Purification by preparative HPLC was carried out on a Teledyne Isco Combi Flash® EZ Prep system (using either a Phenomenex® Gemini® 5μm NX-C18, 110Å, 150×21.2 mm column (flow rate 40 mL / min, 12 minutes (<100 mg or multiple injections of <100 mg)) or an HP C18 RediSep® Rf Gold column (>100 mg), eluting with an appropriate gradient of acetonitrile in water (both containing 0.1% formic acid)). The gradient was selected based on the retention times observed by reaction monitoring in a Waters® Acquity-H UPLC® Class system (see above). Fractions containing the desired compound were combined and finally lyophilized. Purification by silica gel chromatography was carried out on a Teledyne Isco Combi Flash® Rf system using a RediSep® Rf silica gel column of appropriate size. The purity of the final compound was evaluated by injection of a small aliquot in a Waters® Acquity-H UPLC® Class system (using an Acquity® UPLC® BEH C18 2.1×50 mm column; elution with a gradient of acetonitrile in water (both containing 0.1% formic acid) (2% - 98%; 7 minutes)).

[0261] Example 1. Preparation of Compounds Intermediate

Chemical Structure

[0262]

Chemical Structure

[0263]

Chemical Structure

[0264] To a solution of 2.5-amino-2-chloro-6-[5-(methoxymethoxy)-2-methyl-phenyl]pyrimidine-4-carboxylic acid (520 mg, 1.61 mmol) in DMF (20 mL) were added HATU (780 mg, 2.05 mmol), a 0.5 M solution of ammonia in dioxane (10 mL, 5 mmol), and triethylamine (330 μL, 2.37 mmol). The mixture was stirred at 50 °C for 1 hour. The mixture was concentrated to a small volume in vacuo, then diluted with water, stirred at room temperature for 20 minutes, and filtered. The solid was washed with water and dried in vacuo to give 5-amino-2-chloro-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-4-carboxamide (420 mg, 81% yield).

[0265] [Chemical formula] To a solution of 3-amino-6-chloro-pyridine-2-carboxylic acid (60.0 g, 347.7 mmol) in DMF (650 mL) were added K 2 CO 3 (50.6 g, 366.11 mmol), iodoethane (31 mL, 385.60 mmol), and tetrabutylammonium iodide (579 mg, 1.74 mmol). The mixture was stirred at room temperature overnight, then transferred to a 4 L conical flask and cooled in an ice bath. The mixture was diluted with water (2 L) and stirred for 90 minutes. The solid was collected by filtration, washed with water, and dried in vacuo to give ethyl 3-amino-6-chloro-pyridine-2-carboxylate (61.5 g, 88% yield). MS: [M+H]+: 201.1.

[0266] To a solution of ethyl 3-amino-6-chloro-pyridine-2-carboxylate (13.08 g, 65.2 mmol) in DMF (130 mL) was added NBS (15.0 g, 84.3 mmol). The mixture was stirred at room temperature overnight. The mixture was cooled in an ice bath and water (260 mL) was added dropwise. The solid was collected by filtration on a Buchner funnel. This solid was Na 2 S 2 O 3A 20 wt% aqueous solution (60 mL) and saturated NaHCO 3 was suspended in an aqueous solution (130 mL) and stirred at room temperature for about 30 minutes. The solid was collected by filtration on a Buchner funnel, washed with water, and then dried in vacuo to obtain ethyl 3-amino-4-bromo-6-chloro-pyridine-2-carboxylate (13.68 g, yield 75%). MS: [M+H] + : 278.9. 1 H NMR (400 MHz, chloroform-d) δ 7.54 (s, 1H), 6.36 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).

[0267]

Chemical formula

[0268]

Chemical Structure

[0269] Step 2. Potassium permanganate (1.34 g, 8.49 mmol) was added in one portion to a suspension of 3 - amino - 6 - (2 - furyl) - 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 room temperature. After 75 minutes, the mixture was filtered through Celite® and washed with MeOH and concentrated. The residue was purified by 10 - 80% reverse - phase flash chromatography (MeCN in water, both containing 0.1% formic acid) to obtain 5 - amino - 6 - carbamoyl - 4 - (3 - methoxy - 2,6 - dimethyl - phenyl)pyridine - 2 - carboxylic acid (140 mg, yield 26%). MS: [M + H]+: 316.3.

[0270]

Chemical Structure

[0271]

Chemical formula

[0272] Step 2. A 7N solution of 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 at 130 °C for 4 hours. After cooling to room temperature, the solution was concentrated to dryness. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in hexane (0 - 100%)) to give 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% yield). MS: [M+H] + : 306.2.

[0273]

Chemical formula

[0274] Step 2. In a pressure vessel, 2-amino-5-bromo-3'-(methoxymethoxy)-2',6'-dimethyl-[1,1'-biphenyl]-3-carboxamide (0.1 g, 0.264 mmol), dioxane (3 mL), Cs 2 CO 3 (0.215 g, 0.659 mmol), and bis(pinacolato)diboron (0.133 g, 0.527 mmol) were charged. The vessel was purged with N 2 gas for 10 minutes, and then PdCl2(dppf) (0.038 g, 0.0527 mmol) was added. The vessel was sealed, and the reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by silica gel chromatography (eluted with 35% EtOAc in hexane) to obtain 2-amino-3'-(methoxymethoxy)-2',6'-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-3-carboxamide (0.08 g, 71%). MS: [M+H] + : 427.2.4

[0275]

Chemical formula

[0276] Step 2. To a suspension of ethyl 5-amino-2-chloro-6-(5-methyl-1H-indazol-4-yl)pyrimidine-4-carboxylate (3.86 g, 11.64 mmol) in THF (17 mL) and MeOH (17 mL) was added 4 M aqueous sodium hydroxide solution (28 mL, 112 mmol). After stirring for 70 minutes, the pH was adjusted to 4 - 5 with 3 N aqueous HCl and diluted with water (50 mL). The resulting suspension was stirred at 0 °C for 2 hours, and the solid was collected by filtration and washed with water. The solid was air-dried overnight to give 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.

[0277] Step 3. To the pressure vessel, 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) were added. DMF (27 mL) was added, and then DIPEA (9.2 mL, 52.82 mmol) was added. The vessel was sealed and stirred at 80 °C for 75 minutes. Water was slowly added to the cooled reaction mixture with stirring. The precipitate was collected by filtration, washed with water, and air-dried overnight to obtain 5-amino-2-chloro-6-(5-methyl-1H-indazol-4-yl)pyrimidine-4-carboxamide (2.19 g, yield 84%). MS: [M+H] + : 303.0; 1 H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.23 (s, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 6.50 (brs, 2H), 2.20 (s, 3H).

[0278]

Chemical Structure

[0279] Step 2. A 7N ammonia solution (27.9 mmol) in MeOH (300 mL, 2.1 mol) of ethyl 3-amino-6-chloro-4-(5-methyl-1H-indazol-4-yl)pyridine-2-carboxylate (9.24 g, 27.9 mmol) was heated in a pressure vessel at 100 °C overnight. The mixture was cooled to room temperature, concentrated to dryness, co-evaporated with DCM / MeOH, and then co-evaporated with DCM / heptane and dried under vacuum to obtain 3-amino-6-chloro-4-(5-methyl-1H-indazol-4-yl)pyridine-2-carboxamide (8.35 g, yield 99%). MS: [M+H] + : 302.0

[0280]

Chemical formula

[0281]

Chemical Structure

[0282]

Chemical Structure

[0283] Step 2. 3-Amino-4-(5-methyl-1H-indazol-4-yl)-6-(2-(methylthio)pyrimidin-4-yl)picolylamide (0.28 g, 0.7161 mmol) and THF (3 mL) were added to a pressure vessel. This solution was added dropwise to a stirred solution of water (1 mL) and oxone (0.88 g, 2.864 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (30 mL) and then extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. The residue was triturated with n-pentane to give 3-amino-4-(5-methyl-1H-indazol-4-yl)-6-(2-(methylsulfonyl)pyrimidin-4-yl)picolylamide (0.2 g, 66% yield). MS: [M+H] + : 424.5.

[0284]

Chem.

[0285]

Chem.

[0286] Step 2. A mixture of 5-bromo-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.7 g, 11.7 mmol) and vinylboronic acid pinacol ester (3 mL, 17.7 mmol) in dioxane (37 mL) and 2M aqueous solution of Na 2 CO 3 (8.8 mL, 17.6 mmol) was degassed under a nitrogen atmosphere, and then Pd(PPh 3 ) 4 (677 mg, 0.586 mmol) was added. The mixture was degassed again and heated at 100 °C for 18 hours. After cooling to room temperature, the mixture was diluted with EtOAc and water and filtered through Celite®. The layers were separated, and the organic layer was washed with brine, dried over MgSO 4It was dried, filtered, and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 45%)) to give 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-vinyl-1H-indazole (2.5 g, 81%). MS: [M+H] + : 263.1.

[0287] 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) was added OsO 4 (4% in water, 6 mL, 0.944 mmol) and NaIO 4 (10 g, 46.7 mmol). The reaction mixture was stirred at room temperature for 18 h. EtOAc (120 mL) and water (120 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (120 mL). The combined organic layers were washed with brine, dried over MgSO 4 and filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 45%)) to give 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carbaldehyde (1.1 g, 44% yield) as a colorless oil. MS: [M-THP+H] + : 181.0.

[0288] Step 4. To a solution of 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carbaldehyde (1.1 g, 4.16 mmol) in DCM (40 mL) at room temperature was added XtalFluor-E (2.0 g, 8.73 mmol), followed by triethylamine hydrofluoride (1.4 mL, 8.59 mmol). The reaction was stirred at room temperature for 18 h. Saturated aqueous NaHCO 3 was added dropwise to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO 4It was dried, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with a gradient of EtOAc in heptane (0 - 40%)), and 4-chloro-5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.69 g, yield 58%) was obtained. MS: [M-THP+H] + : 203.0.

[0289] 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) were added bis(pinacolato)diboron (443 mg, 1.75 mmol), KOAc (260 mg, 2.62 mmol), tricyclohexylphosphine (61 mg, 0.218 mmol), and Pd 2 (dba) 3 (40 mg, 0.044 mmol). The mixture was degassed, backfilled with argon (3 cycles), and heated at 100 °C for 3 h. After cooling to room temperature, water (40 mL) and EtOAc (35 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were washed with brine, dried over MgSO 4 and filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with a gradient of EtOAc in heptane (0 - 40%)), and 5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was obtained. MS: [M+H] + : 379.2 [M+1]+.

[0290]

Chemical Structure

[0291] Step 2. To a suspension of ethyl 5-amino-[2,3'-bipyridine]-6-carboxylate (730 mg, 3.0 mmol) in water (20 mL) was added sulfuric acid (0.32 mL, 6.0 mmol) at 5 °C. A solution of bromine (0.19 mL, 3.71 mmol) in acetic acid (2 mL, 34.94 mmol) was added dropwise and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (40 mL) and neutralized by adding solid NaHCO 3 (a very exothermic quench). The mixture was extracted with DCM (3 × 30 mL). The combined organic layers were washed with saturated NaHCO 3Washed sequentially with aqueous solution, water, and brine, and dried over MgSO 4 and filtered and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (30 - 100%)) to give ethyl 5 - amino - 4 - bromo - [2,3’ - bipyridine] - 6 - carboxylate (0.66 g, yield 75%). MS: [M + H] + : 322.0 / 324.0.

[0292]

Chemical Structure

[0293] Step 2. A 1 M THF solution of borane (15 mL, 15 mmol) was added to a solution of N-(2-bromophenyl)-2,2,2-trifluoro-acetamide (2.04 g, 7.61 mmol) in THF (5 mL). The mixture was stirred overnight under reflux. MeOH (5 mL) was added dropwise to the cooled reaction mixture, and the mixture was stirred at room temperature for 2 hours and then concentrated. The residue was purified by silica gel chromatography (eluted with a gradient of EtOAc in heptane (0 - 50%)) to obtain 2-bromo-N-(2,2,2-trifluoroethyl)aniline (463 mg, yield 24%). 1 H NMR (400 MHz, chloroform-d) δ 7.46 (dd, J = 7.9, 1.5 Hz, 1H), 7.21 (ddd, J = 8.6, 7.4, 1.5 Hz, 1H), 6.80 - 6.73 (m, 1H), 6.68 (td, J = 7.6, 1.4 Hz, 1H), 4.68 (bRs, 1H), 3.83 (qd, J = 8.8, 7.0 Hz, 2H).

[0294] Step 3. Dioxane (8 mL) was added to a MW vial charged with 2-bromo-N-(2,2,2-trifluoroethyl)aniline (463 mg, 1.82 mmol), bis(pinacolato)diboron (555 mg, 2.19 mmol) and KOAc (533 mg, 5.43 mmol), and N 2 was bubbled into the solution, and Pd(dppf)Cl 2 -DCM (157 mg, 192.25 μmol) was added. N 2 was bubbled into the solution again, the vial was capped and transferred to a preheated (100 °C) heat block for 1 hour. The cooled reaction mixture was diluted with DCM and adsorbed onto silica gel. The residue was purified by silica gel chromatography (eluted with a gradient of EtOAc in heptane (0 - 100%)) to obtain 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)aniline (265 mg, yield 48%). MS: [M + H] + : 302.0.

[0295]

Chemical Structure

[0296]

Chemical formula

[0297]

Chemical Structure

[0298]

Chemical Structure

[0299] Step 2. - A solution of 3-bromo-4-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (2.5 g, 8.2 mmol) in THF (8 mL) was added dropwise to a solution of n-BuLi (6.6 mL, 16.5 mmol) in THF (34 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 20 min. Tributylstannyl chloride (2.5 mL, 9.216 mmol) was added to the reaction mixture. The mixture was stirred at -78 °C for 40 min and at room temperature for 1.5 h. Water (40 mL) was added and the volatiles were removed in vacuo. The mixture was extracted with DCM (2 × 40 mL). The combined organic layers were washed with brine, dried over MgSO 4 and filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 30%)) to afford 3-(tributylstannyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (1.5 g, 35% yield). MS: [M+H] + : 516.2.1 H-NMR (400 MHz, CDCl3): δ 8.41 (d; J = 4.66 Hz; 1H); 7.28 (d; J = 8.40 Hz; 1H); 7.07 (dd; J = 8.39; 4.66 Hz; 1H); 5.20 (s; 2H); 3.73 (t; J = 8.31 Hz; 2H); 1.51 - 1.57 (m; 8H); 1.25 - 1.34 (m; 8H); 1.07 - 1.14 (m; 8H); 0.95 (t; J = 8.26 Hz; 2H); 0.87 (t; J = 7.31 Hz; 12H); 0.00 (s; 9H).

[0300]

Chem.

[0301] Step 2. A 2 M solution of lithium diisopropylamide 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) at -78 °C under an inert atmosphere. The mixture was stirred at -78 °C for 4 h. Iodomethane (750 μL, 12.05 mmol) was added slowly. The mixture was stirred at -78 °C for 30 min and then warmed to room temperature. The mixture was quenched with saturated NH 4 Cl aqueous solution. The mixture was extracted with EtOAc (3 times). The combined organic layers were washed with brine and Na 2 SO 4It was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with a gradient of EtOAc in heptane (0 - 15%)), and 4-bromo-6-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (750 mg, yield 72%) was obtained. MS: [M - TFP + H] + : 229.0 / 231.0.

[0302] Step 3. To a flask were added 4-bromo-6-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (800 mg, 2.55 mmol), KOAc (765 mg, 7.79 mmol), bis(pinacolato)diboron (750 mg, 2.95 mmol), and dioxane (10 mL). The mixture was degassed with nitrogen for 5 minutes, and Pd(dppf)Cl 2 -DCM (125 mg, 153.00 μmol) was added. The resulting mixture was degassed again with nitrogen for 2 minutes and stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite® and the filter cake was washed with ethyl acetate. The filtrate was evaporated and the crude product was purified by silica gel chromatography (eluted with a gradient of EtOAc in heptane (0 - 20%)), and 6-fluoro-5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (720 mg, yield 78%) was obtained. MS: [M + H] + : 361.3.

[0303]

Chemical Structure

[0304]

Chemical formula

[0305]

Chemical formula

[0306] Step 2. To a solution of 2-bromo-6-fluoropyridin-3-ol (15.0 g, 36.1 mmol) in DMF (300 mL) at room temperature were added bis(tert-butyl) (4-bromo-2-cyano-3-fluorophenyl)carbamate (7.6 g, 39.6 mmol) and K 2 CO 3 (6.0 g, 43.4 mmol). The reaction mixture was degassed (3 cycles of vacuum / nitrogen atmosphere), stirred at room temperature for 30 min, then heated to 40 °C for 18 h. After cooling to room temperature, the mixture was poured into a 1:1 water / saturated NaHCO 3 aqueous solution. The mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with water (2 times), brine, dried over MgSO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in hexanes (5 - 55%)) to give 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 (400 MHz, CDCl3): δ 7.90 (d; J = 8.68 Hz; 1H); 7.16 (d; J = 8.67 Hz; 1H); 6.87 - 6.91 (m; 1H); 6.79 - 6.82 (m; 1H); 1.48 (s; 18H).

[0307] Step 3. In a sealed tube, bis(tert-butyl) (4-bromo-3-((2-bromopyridin-3-yl)oxy)-2-cyanophenyl) carbamate (7.95 g, 13.5 mmol), bis(pinacolato) diboron (3.78 g, 14.9 mmol), KOAc (4.0 g, 40.3 mmol), Pd(dppf)Cl 2 -DCM (2.2 g, 2.7 mmol), and dioxane (80 mL) were charged. The reaction mixture was degassed (3 cycles of vacuum / nitrogen gas) and stirred at 110 °C for 8 hours. After cooling to room temperature, the reaction mixture was diluted with water and EtOAc and filtered through Celite®. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 and filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in hexane (5 - 35%)) to give bis(tert-butyl) (6-cyano-2-fluorobenzo[f] [3,2-b] iridin-7-yl) carbamate (3.2 g, 55% yield). MS: [M - Boc + H] + : 328.1; 1H-NMR (400 MHz, CDCl3): δ 8.34 (d; J = 8.34 Hz; 1H); 8.09 (t; J = 7.53 Hz; 1H); 7.37 (d; J = 8.38 Hz; 1H); 7.15 (d; J = 8.88 Hz; 1H); 1.46 (s; 18H).

[0308] Step 4. A solution of bis(tert-butyl) (6-cyano-2-fluorobenzo[f] [3,2-b] iridin-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 co-evaporated with n-heptane (3 times), and dried under high vacuum to give 1.6 g of 7-amino-2-fluorobenzo[f] [3,2-b] pyridine-6-carbonitrile, which was used in the next step without further purification. MS: [M+H] + : 228.0.

[0309] Step 5. To a solution of 7-amino-2-fluorobenzo[f] [3,2-b] pyridine-6-carbonitrile (1.9 g, 8.4 mmol) in DMF (20 mL) at room temperature was added NBS (1.5 g, 8.4 mmol). The reaction mixture was stirred at room temperature for 1 h, then diluted with 20 wt% Na 2 S 2 O 3 aqueous solution (80 mL). The mixture was gently stirred at room temperature 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-fluorobenzo[f] [3,2-b] pyridine-6-carbonitrile (2.3 g, 89% yield). MS: [M+H] + : 305.9 / 307.9; 1 1H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.37 (m; 1H); 7.18 (d; J = 8.70 Hz; 1H); 7.01 (s; 1H).

[0310] Step 6. 7-Amino-8-bromo-2-fluorobenzo[f] [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), K 3 PO 4 of 2M aqueous solution (9.3 mL, 18.6 mmol), Pd 2 (dba) 3(570 mg, 0.622 mmol), a mixture of tri-tert-butylphosphonium tetrafluoroborate (360 mg, 1.241 mmol), and dioxane (38 mL) was degassed (3 cycles of vacuum / nitrogen atmosphere). The mixture was heated to reflux for 2 hours, cooled to room temperature, poured into a mixture of water (50 mL) and EtOAc (70 mL), and filtered through Celite®. The layers were separated, and the aqueous layer was extracted with EtOAc (70 mL). The combined organic layers were washed with water and brine, dried over MgSO 4 and filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in hexane (30 - 100%)), and 7-amino-2-fluoro-8-(5-methyl-1H-indazol-4-yl)benzofuro[3,2-b]pyridine-6-carbonitrile (1.2 g, 57% yield) was obtained. MS: [M+H] + : 358.1.

[0311]

Chemical formula

[0312]

Chemical formula

[0313]

Chemical formula

[0314] Step 2. A round-bottom flask (250 mL) equipped with a condenser was flame-dried and magnesium (1.24 g, 51.0 mmol) was added. The flask was flame-dried again and iodine (104 mg, 408 μmol) was added. The flask was degassed (3 cycles of vacuum / argon atmosphere), and degassed Et 2 O (62 mL) was added, and then iodomethane-d3 (3.18 mL, 51.0 mmol) was added dropwise. After adding a few drops of iodomethane-d3, the mixture was sonicated for 5 minutes. The color of the reaction changed from orange to yellow, then to milky white, and finally to a turbid metallic color (high exotherm was observed and the suspension refluxed without external heating). After adding iodomethane-d3, the reaction mixture became even more metallic in color. This was stirred at room temperature for 1.5 hours.

[0315] A clear solution of zinc chloride (0.5 M in THF, 51.0 mL, 25.5 mmol) was charged into a flame-dried three-necked flask. The Grignard suspension was added dropwise thereto by syringe (exotherm was observed) and the mixture became milky white. After adding the Grignard reagent, the formation of a white precipitate was observed. The reaction mixture was stirred at room temperature for 40 minutes and then used in the next step. The supernatant was used directly in the next step.

[0316] Step 3. A three-necked flask (250 mL) equipped with a condenser was flame-dried. 4-Bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.00 g, 12.7 mmol), tri-tert-butylphosphonium tetrafluoroborate (735 mg, 2.5 mmol), and Pd 2 (dba )3(1.16 g, 1.27 mmol) was charged into a flask. The mixture was degassed (3 cycles of vacuum / argon atmosphere). The light to the flask was blocked, and a solution of dimethyl-d6 zinc (70 mL, 25.5 mmol) prepared in the previous step was added dropwise by syringe. After the addition, the mixture was heated at 70 °C for 2 hours. After cooling to room temperature, the mixture was diluted with saturated NH 4 Cl aqueous solution (100 mL) and EtOAc (150 mL) and filtered through Celite®. The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over MgSO 4 4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of 15% EtOAc - hexane in hexane (0 - 70%)) to obtain 4-chloro-5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.9 g, yield 90%). MS: [M+H] + : 254.1; 1 H-NMR (400 MHz, CDCl3): δ 8.04 (s; 1H); 7.40 (d; J = 8.51 Hz; 1H); 7.25 (d, J = 8.50 Hz, 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; 4.34 Hz; 1H); 1.67 - 1.76 (m; 3H).

[0317]

Chemical Structure

[0318]

Chemical formula

[0319]

Chem.

[0320] Step 2. Ethyl 5-amino-2-chloro-6-(5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidine-4-carboxylate (270 mg, 0.645 mmol) was placed in a microwave reaction vial, and ammonia solution (7N in MeOH, 9.21 mL, 64.5 mmol) was added. The reaction mixture was heated at 80 °C for 1.5 h. After cooling to room temperature, the volatiles were removed in vacuo and placed under high vacuum to give 5-amino-2-chloro-6-(5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidine-4-carboxamide (250 mg, yield 99%). MS: [M+H] + : 390.1.

[0321] Step 3. To a solution of 5-amino-2-chloro-6-(5-(methyl-d3)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrimidine-4-carboxamide (130 mg, 0.33 mmol) in MeOH (1.7 mL) was added HCl (4M in dioxane, 4.2 mL, 16.8 mmol). The reaction mixture was stirred for 18 h. The volatiles were removed in vacuo to give 5-amino-2-chloro-6-(5-(methyl-d3)-1H-indazol-4-yl)pyrimidine-4-carboxamide (100 mg, yield 99%). MS: [M+H] + : 306.0. 1 1H-NMR (400 MHz, DMSO): δ 7.80 (s, 1H); 7.70 (s, 2H); 7.60 (s, 1H); 7.50 (d, J = 8.4 Hz, 1H); 7.41 (s, 1H); 7.26 (d, J = 8.4 Hz, 1H).

[0322]

Chemical formula

[0323] [Chemical formula] To a flame-dried MW vessel were charged Pd 2 (dba) 3 (388 mg, 0.424 mmol), tri-tert-butylphosphonium tetrafluoroborate (246 mg, 0.847 mmol), 2-(3-methoxy-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.67 g, 6.4 mmol), and ethyl 5-amino-2,6-dichloropyrimidine-4-carboxylate (1.0 g, 4.2 mmol). Dioxane (8 mL) and water (2 mL) were added, and then K 3 PO 4 (1.8 g, 8.5 mmol) was added. The mixture was degassed, the vessel was sealed, and the mixture was stirred at 100 °C for 10 hours. The cooled reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was concentrated to dryness, diluted with water, and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over MgSO 4 and filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in hexane (0 - 20%)) to give ethyl 5-amino-2-chloro-6-(3-methoxy-2,6-dimethylphenyl)pyrimidine-4-carboxylate (330 mg, 23% yield). MS: [M+H] +: 336.1. 1 1H NMR (CDCl3, 400 MHz): δH 1.45 (3H, t, J = 7.1 Hz), 1.92 (3H, s), 1.98 (3H, s), 3.82 (3H, s), 4.48 (2H, q, J = 7.1 Hz), 5.62 (2H, s), 6.85 (1H, d, J = 8.4 Hz), 7.10 (1H, d, J = 8.4 Hz).

[0324]

Chem.

[0325]

Chem.

[0326]

Chem.

[0327]

Chemical Structure

[0328]

Chemical Structure

[0329]

Chemical Structure

[0330]

Chemical Structure

[0331]

Chemical Structure

[0332] Step 2. To a solution of 2,4-difluoro-5-methyl-aniline (19.42 g, 135.7 mmol) in DCM (250 mL) at 0 °C was added NBS (24.8 g, 139.3 mmol) portionwise over 5 - 10 minutes. The reaction mixture was stirred at 0 °C for 5 minutes and then the ice bath was removed. The reaction was stirred for 15 minutes and then concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 25%)) to give 2-bromo-4,6-difluoro-3-methyl-aniline (18.1 g, 60% yield). MS: [M+H]+: 221.9.

[0333] Step 3. An RBF was charged with ice-cold water (80 mL) and sulfuric acid (18 M, 70 mL) and cooled in an ice bath. 2-Bromo-4,6-difluoro-3-methyl-aniline (16.44 g, 74.04 mmol) in ACN (120 mL) was added dropwise via an addition funnel. The resulting suspension was stirred at 0 °C for 15 minutes. Sodium nitrite (10.22 g, 148.1 mmol) in water (80 mL) was added dropwise. After stirring for 30 minutes, a solution of potassium iodide (49.17 g, 296.2 mmol) in water (130 mL) was added dropwise via an addition funnel. After addition, the ice bath was removed and the mixture was stirred overnight. The mixture was placed in an ice bath and quenched by slowly adding 20% Na 2 S 2 O 3 aqueous solution (250 mL) (via an addition funnel). EtOAc (250 mL) was added to the mixture and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with 20% Na 2 S 2 O 3 aqueous solution (2 × 250 mL), water, and brine, dried over a 2 SO 4 and filtered and concentrated. The residue was purified by silica gel chromatography (eluting with heptane) to give 3-bromo-1,5-difluoro-2-iodo-4-methyl-benzene (20.19 g, 82% yield).

[0334] Step 4. 2-Bromo-1,5-difluoro-2-iodo-4-methyl-benzene (20.5 g, 61.58 mmol) in THF (120 mL) at -78 °C was added dropwise with a 2.5 M solution of n-butyllithium in hexane (27 mL, 67.5 mmol). The reaction mixture was stirred at -78 °C for 35 minutes. Dry DMF (6.0 mL, 77.49 mmol) was added dropwise and the mixture was stirred at -78 °C for 1 hour. The reaction mixture was quenched with 1 N aqueous HCl (150 mL). Water was added to the mixture and the aqueous layer was extracted with EtOAc (3 times). The combined organic layers were successively washed with water and brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAC in heptane (0 - 20%)) to give 2-bromo-4,6-difluoro-3-methyl-benzaldehyde (8.09 g, 56% yield). 1 1H NMR (400 MHz, chloroform-d) δ 10.33 (d, J = 1.5 Hz, 1H), 6.90 (dd, J = 10.3, 9.3 Hz, 1H), 2.36 (dd, J = 2.6, 1.1 Hz, 3H).

[0335] Step 5. Hydrazine hydrate (20 mL, 411.5 mmol) was added to a mixture of 2-bromo-4,6-difluoro-3-methyl-benzaldehyde (8.09 g, 34.42 mmol) in DMSO (45 mL). The mixture was stirred at 130 °C for 1 hour under an open atmosphere. The mixture was cooled to room temperature and water (100 mL) was added dropwise with stirring until a white precipitate was observed. After stirring for an additional 30 minutes, the suspension was filtered, the solid was washed several times with water, air-dried, and then dried in vacuo to give 4-bromo-6-fluoro-5-methyl-1H-indazole (6.26 g, 79% yield). MS: [M + H]+: 230.9

[0336] Step 6. 4,4-Dihydro-2H-pyran (5.07 mL, 55.8 mmol) was added 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). The mixture was heated to reflux for 2.5 h. The cooled reaction mixture was diluted with saturated NaHCO 3 aqueous solution, and the layers were separated. The aqueous layer was extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried over Na 2 SO 4 and filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 30%)) to give 4-bromo-6-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (6.51 g, 76% yield). MS: [M+H]+: 314.9; 1 H NMR (400 MHz, chloroform-d) δ 7.95 (d, J = 0.9 Hz, 1H), 7.25 - 7.20 (m, 1H), 5.61 (dd, J = 9.1, 2.8 Hz, 1H), 3.99 (dtd, J = 11.4, 3.6, 1.5 Hz, 1H), 3.76 - 3.68 (m, 1H), 2.54 - 2.43 (m, 1H), 2.41 (d, J = 2.6 Hz, 3H), 2.19 - 2.02 (m, 2H), 1.82 - 1.62 (m, 3H).

[0337] Step 7. To an RBF were charged 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(pinacolato)diboron (6.90 g, 27.2 mmol), and dioxane (150 mL). The mixture was degassed with nitrogen for 5 min, and Pd(dppf)Cl 2-DCM (1.2 g, 1.47 mmol) was added. The resulting mixture was degassed again with nitrogen for 2 minutes and stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite® and the Celite® cake was washed with ethyl acetate. The filtrate was evaporated and the residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 20%)) to give 6-fluoro-5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (5.1 g, 60% yield). MS: [M+H]+: 361.3.

[0338]

Chem.

[0339]

Chem.

[0340]

Chem.

[0341]

Chem.

[0342]

Chemical formula

[0343] Step 2. To RBF, 2-bromo-5,6-difluoro-3-methyl-benzaldehyde (10.4 g, 44.3 mmol) and DMSO (100 mL) were added. The solution was 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 1 h, the mixture was acidified to pH 5 with concentrated HCl, and the solid was filtered. The filter cake was successively washed with water and heptane and dried under high vacuum overnight to give 4-bromo-7-fluoro-5-methyl-1H-indazole (8.9 g, yield 87%). MS: [M+H]+: 228.9 / 230.9.

[0344] 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 at reflux for 3 h. The mixture was filtered, and the volatiles were removed under vacuum. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 10%)) to give 4-bromo-7-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (6.0 g, yield 60%). MS: [M-THP+H]+: 228.5 / 230.5. 11H NMR (chloroform-d) δ: 7.99 (d, J = 1.9 Hz, 1H), 6.96 (d, J = 12.1 Hz, 1H), 5.80 (dd, J = 10.0, 2.6 Hz, 1H), 4.02 (ddt, J = 11.8, 4.1, 2.1 Hz, 1H), 3.72 (td, J = 11.3, 2.7 Hz, 1H), 2.64 - 2.48 (m, 1H), 2.44 (s, 3H), 2.17 - 2.10 (m, 1H), 2.07 (dt, J = 12.9, 3.0 Hz, 1H), 1.80 - 1.65 (m, 2H), 1.65 - 1.54 (m, 1H)

[0345] Step 4. A solution of 4-bromo-7-fluoro-5-methyl-1-tetrahydropyran-2-yl-indazole (7.83 g, 25.0 mmol) in dioxane (50 mL) was charged into a pressure vessel. Bis(pinacolato)diboron (7.62 g, 30.0 mmol) was added, followed by KOAc (7.36 g, 75.0 mmol) and Pd(dppf)Cl 2 -DCM (1.02 g, 1.3 mmol) was added. The vessel was flushed with N 2 and sealed, and stirred at 100 °C for 4 hours. The cooled reaction mixture was filtered through Celite® (rinsed with EtOAc) and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 20%)) to give 7-fluoro-5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (8.12 g, 90% yield). MS: [M + H]+: 361.0.

[0346]

Chemical Structure

[0347]

Chemical formula

[0348]

Chemical formula

[0349]

Chemical formula

[0350]

Chemical formula

[0351]

Chemical formula

[0352]

Chemical formula

[0353] Step 2. To a solution of ethyl 5-amino-2-(2-amino-3-pyridyl)-6-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)pyrimidine-4-carboxylate (120 mg, 253.4 μmol) in MeOH (1 mL), add 7N ammonia solution in MeOH (1.5 mL, 10.5 mmol). Stir the mixture in a sealed vial at 80 °C for 2 hours. Remove the volatiles in vacuo to obtain 5-amino-2-(2-amino-3-pyridyl)-6-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)pyrimidine-4-carboxamide (110 mg, 247.48 μmol, 98% yield). MS: [M+H]+: 464.3.

[0354] [Chemical formula] Step 1. To a solution of 2-bromo-5-fluoroaniline (2.00 g, 10.3 mmol) in DCM (20 mL) at room temperature, add thietan-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). Stir the reaction mixture at room temperature for 3 days. Slowly pour the reaction mixture into saturated NaHCO 3 aqueous solution. Separate the layers and extract the aqueous layer with DCM. Wash the combined organic layers with brine, dry over MgSO 4It was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with a gradient of 15% EtOAc in hexane / hexane (0 - 100%)), and N-(2-bromo-5-fluorophenyl)thietan-3-amine (1.27 g, yield 47%) was obtained. MS: [M+H]+: 261.9 / 263.9.

[0355] Step 2. To a solution of N-(2-bromo-5-fluorophenyl)thietan-3-amine (1.33 g, 5.07 mmol) in EtOAc (13.0 mL) were added sodium tungstate dihydrate (83.7 mg, 254 μmol) and tetrabutylammonium hydrogensulfate (138 mg, 406 μmol). 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 room temperature for 3 hours. Additional hydrogen peroxide (1.5 mL) was added, and the mixture was stirred for an additional 1 hour. The reaction mixture was diluted with EtOAc and 10% NaHSO 3 aqueous solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 and filtered and concentrated. The residue was purified by silica gel chromatography (eluted with a gradient of EtOAc in hexane (50 - 60%)), and 3-((2-bromo-5-fluorophenyl)amino)thietane 1,1-dioxide (1.1 g, yield 74%) was obtained. MS: [M+H]+: 294.0 / 296.0. 1 1H-NMR (400 MHz, CDCl 3 ): δ 7.43 (dd; J = 8.74; 5.87 Hz; 1H); 6.47 (td; J = 8.36; 2.76 Hz; 1H); 6.18 (dd; J = 10.44; 2.76 Hz; 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).

[0356] Step 3.3-((2-Bromo-5-fluorophenyl)amino)thietane 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 charged into a microwave reaction vial and capped. The mixture was degassed (3 cycles of vacuum / argon atmosphere). MeOH (1.50 mL) and ethylene glycol (500 μL) were added, and the reaction mixture was heated at 60 °C for 18 h. The mixture was filtered through Celite® and washed with EtOAc. The volatiles were removed in vacuo to afford crude (2-((1,1-dioxidothietan-3-yl)amino)-4-fluorophenyl)boronic acid, which was used in the next step without further purification.

[0357]

Chem.

[0358] Step 2. To a solution of N-(3-bromo-5-fluoropyridin-2-yl)-2,2,2-trifluoroacetamide (500 mg, 1.74 mmol) in THF (10 mL) was added a 2 M solution of BH3-DMS in THF (1.74 mL, 3.48 mmol). The reaction mixture was heated at 60 °C for 24 h. The cooled reaction mixture was diluted with water and extracted with EtOAc (2 times). The combined organic extracts were dried over MgSO 4 and filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in hexane (0 - 90%)) to afford 3-bromo-5-fluoro-N-(2,2,2-trifluoroethyl)pyridin-2-amine (400 mg, 84% yield). MS: [M+H]+: 272.6 / 274.4.

[0359]

Chemical Structure

[0360]

Chemical Structure

[0361]

Chemical formula

[0362]

Chemical formula

[0363] Step 2. A mixture of 3-(benzyloxy)-1-methylcyclobutan-1-ol (120 mg, 624 μmol) and 10 wt.% palladium on carbon (60 mg, 567 μmol) in MeOH (5.7 mL) was stirred under a hydrogen atmosphere for 16 h. The reaction mixture was filtered through Celite® and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in hexane (0 - 40%)) to give 1-methylcyclobutane-1,3-diol (30 mg, 47% yield).

[0364] Step 3. To 3-bromo-2,5-difluoropyridine (43 μL, 401 μmol) and 1-methylcyclobutane-1,3-diol (45.0 mg, 441 μmol) in dry THF (1 mL), sodium hydride (60%, 19 mg, 481 μmol) was added. The mixture was heated to 50 °C for 2 h. The cooled reaction mixture was quenched with saturated NaHCO 3 aqueous solution, and the aqueous layer was extracted with DCM (2 times). The organic layers were combined, washed with brine, and Na 2 SO 4It was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with a gradient of EtOAc in hexane (0 - 100%)), and 3-((3-bromo-5-fluoropyridin-2-yl)oxy)-1-methylcyclobutan-1-ol (50 mg, yield 45%) was obtained. MS: [M+H]+: 276.1.

[0365]

Chem.

[0366]

Chem.

[0367]

Chemical formula

[0368] Step 2. To an RBF were charged 4-bromo-1-methyl-N-tetrahydropyran-4-yl-pyrazol-3-amine (622 mg, 2.39 mmol), potassium 2-ethylhexanoate (959 mg, 5.26 mmol), bis(pinacolato)diboron (729 mg, 2.87 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (57 mg, 119.6 μmol), and IPAc (12 mL). The mixture was heated at 40 °C for 10 minutes under N 2Stir below, then add XPhos Pd(allyl)Cl (79 mg, 119.6 μmol) under N 2 under. The mixture was stirred at 40 °C for 24 h. The reaction mixture was diluted with EtOAc and water. The aqueous layer was cut, and the organic layer was washed with brine, dried over MgSO 4 and filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (50 - 100%)), to give 1-methyl-N-tetrahydropyran-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-amine (785 mg, 50% yield).

[0369]

Chemical formula

[0370]

Chemical formula

[0371] Step 2. To a solution of (6-amino-5-bromo-2-pyridyl)methanol (1.94 g, 9.55 mmol) in DCM (40 mL) was added manganese(IV) oxide (activated) (10 g, 115.03 mmol) in one portion. The mixture was stirred at room temperature for 3 h and then filtered. The filtrate was concentrated in vacuo to give 6-amino-5-bromo-pyridine-2-carbaldehyde (1.5 g, 78% yield).

[0372] Step 3. To a solution of triethylamine hydrofluoride (7.22 mL, 44.32 mmol) in DCM (120 mL) was added XtalFluor-E (9.89 g, 43.19 mmol), and then 6-amino-5-bromo-pyridine-2-carbaldehyde (4.3 g, 21.39 mmol) was added. The mixture was stirred at room temperature for 2 h and then quenched by adding saturated NaHCO 3 aqueous solution, diluted with water, and extracted with DCM (3 × 100 mL). The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAC in heptane (0 - 30%)) to give 3-bromo-6-(difluoromethyl)pyridin-2-amine (2.1 g, 44% yield). 1H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.38 (t, J = 55.6 Hz, 1H), 5.08 (s, 2H).

[0373]

Chemical Structure

[0374]

Chemical Structure

[0375]

Chemical formula

[0376]

Chem.

[0377]

Chem.

[0378] 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 diphenylphosphoryl azide (950 μL, 4.23 mmol) in tert-BuOH (21 mL) was heated to reflux for 16 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of MeOH in DCM (0 - 10%)), and 1,5-dimethyl-2-oxa-4-azabicyclo[3.1.1]heptan-3-one (450 mg, 75% yield) was obtained. MS: [M + H]+: 142.0.

[0379] Step 3. A mixture of 1,5-dimethyl-2-oxa-4-azabicyclo[3.1.1]heptan-3-one (450 mg, 3.19 mmol), 4 M aqueous solution of KOH (4.78 mL, 19.1 mmol) in isopropanol (16 mL) was heated at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was acidified by adding aqueous HCl and concentrated to dryness in vacuo. The residue was triturated with EtOAc and the filtrate was concentrated to dryness to give 3-amino-1,3-dimethylcyclobutan-1-ol (367 mg, yield 99%).

[0380]

Chem.

[0381] Step 2. To a solution of 2-fluoro-N-(1-(trifluoromethyl)cyclopropyl)pyridin-2-amine (180 mg, 818 μmol) in DCM (2 mL) and MeOH (2 mL) were added benzyltrimethylammonium tribromide (351 mg, 899 μmol) and calcium carbonate (100 mg, 981 μmol). The reaction mixture was stirred at room temperature for 18 h, filtered through Celite®, and the filter cake was washed with DCM. The filtrate was concentrated, and the residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in hexanes (20 - 60%)) to afford 3-bromo-5-fluoro-N-(1-(trifluoromethyl)cyclopropyl)pyridin-2-amine (145 mg, 59% yield). MS: [M+H]+: 299.0.

[0382] Step 3. 3-Bromo-5-fluoro-N-(1-(trifluoromethyl)cyclopropyl)pyridin-2-amine (13.8 mg, 46.3 μmol), bis(pinacolato)diboron (23.5 mg, 92.5 μmol), PdCl 2 (dppf)·DCM (3.8 mg, 4.63 μmol), and potassium acetate (13.8 mg, 139 μmol) were placed in a microwave vial. The reaction mixture was then heated to 90 °C for 16 h. The reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was concentrated to dryness to afford (5-fluoro-2-((1-(trifluoromethyl)cyclopropyl)amino)pyridin-3-yl)boronic acid, which was used in the next step without further purification.

[0383]

Chemical formula

[0384]

Chemical Structure

[0385]

Chemical Structure

[0386] Step 2. To a solution of 2-amino-3-bromopyridine (308 mg, 1.78 mmol) in DCM (9 mL) was added 2,2-difluoro-1-(pyridin-3-yl)ethan-1-one (420 mg, 2.67 mmol), and then titanium(IV) chloride (1 M in toluene, 2.14 mL, 2.14 mmol) was added under argon. The resulting mixture was stirred at room temperature for 6 h. Then sodium triacetoxyborohydride (755 mg, 3.56 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was filtered through Celite® and washed with EtOAc. Volatiles were removed under vacuum and the residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in hexanes (0 - 100%)) to afford 3-bromo-N-(2,2-difluoro-1-(pyridin-3-yl)ethyl)pyridin-2-amine (290 mg, 52% yield). MS: [M+H]+: 315.9.

[0387] Step 3.3 - Bromo - N-(2,2 - difluoro - 1-(pyridin - 3 - yl)ethyl)pyridin - 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 charged into a microwave reaction vial and capped. The mixture was degassed (3 cycles of vacuum / Ar). MeOH (562 μL) and ethylene glycol (187 μL) were added. This was heated at 60 °C for 18 h. The mixture was filtered through Celite® and washed with MeOH. Volatiles were removed in vacuo, and crude (2 - ((2,2 - difluoro - 1-(pyridin - 3 - yl)ethyl)amino)pyridin - 3 - yl)boronic acid was used in the next step without further purification.

[0388]

Chemical Structure

[0389]

Chemical Structure

[0390] Step 2. To a MW vial charged with bis(pinacolato)diboron (602 mg, 2.37 mmol), 3-bromo-N-(2,2,2-trifluoroethyl)pyridin-2-amine (503 mg, 1.97 mmol), potassium acetate (600 mg, 6.11 mmol), and Pd(dppf)Cl 2 -DCM (166 mg, 203.3 μmol), dioxane (8 mL) was added. N 2 was bubbled through the solution, the vial was capped and 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 in heptane (0 - 60%)) to afford 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)pyridin-2-amine (260 mg, 44% yield). MS: [M+H]+: 304.0

[0391]

Chemical Structure

[0392] Step 2. To a solution of 4-bromo-5-fluoro-1-tetrahydropyran-2-yl-indazole (1.66 g, 5.55 mmol) in THF (16 mL) in a dry-ice / acetone bath was added dropwise a 2.5 M solution of n-butyllithium in hexane (3.4 mL, 8.5 mmol). The mixture was stirred at -78 °C for 55 minutes, then trimethyl borate (1.89 mL, 16.65 mmol) was added dropwise. The mixture was stirred at -78 °C for 90 minutes and then quenched with saturated aqueous NH 4 Cl. The mixture was extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 100%)) to afford (5-fluoro-1-tetrahydropyran-2-yl-indazol-4-yl)boronic acid (756 mg, 52% yield). MS: [M+H]+: 265.0.

[0393]

Chemical Structure

[0394] Step 3. To a suspension of magnesium (675 mg, 27.8 mmol) in ether (27.50 mL) was added molecular iodine (60 mg, 236.4 μmol). The mixture was stirred at room temperature for 10 minutes, then trideutero(iodo)methane (1.8 mL, 28.93 mmol) was added dropwise. After adding a few drops of iodomethane-d3, the mixture was sonicated for 5 minutes. The color of the reaction changed from orange to yellow, then to milky white, and finally to a turbid metallic color (high exotherm was observed and the suspension refluxed without any external heating). After adding iodomethane-d3, the mixture was stirred at room temperature for 1 hour 30 minutes. This solution was added dropwise at room temperature to a 0.5 M solution of ZnCl2 in THF (55 mL, 27.5 mmol). After addition, the mixture was stirred at room temperature for 20 minutes. This solution was added to a mixture of 3-bromo-6-iodo-pyridin-2-amine (1500 mg, 5.02 mmol) and Pd(PPh 3 ) 4 (576 mg, 498.5 μmol). The mixture was stirred at 60 °C for 1 hour under N 2 . The reaction was quenched with dilute aqueous HCl and water and extracted with EtOAC (2 × 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 in heptane (0 - 60%)) to give 3-bromo-6-(trideuteriomethyl)pyridin-2-amine (600 mg, 63% yield). 1 1H NMR (400 MHz, chloroform-d) δ 7.47 (d, J = 7.8 Hz, 1H), 6.36 (d, J = 7.9 Hz, 1H), 4.95 (s, 2H).

[0395] Step 4. To a solution of 3-bromo-6-(trideuteriomethyl)pyridin-2-amine (272 mg, 1.43 mmol) in dioxane (10 mL) were added potassium acetate (354 mg, 3.61 mmol), Pd(dppf)Cl 2 (65 mg, 88.8 μmol), and bis(pinacolato)diboron (460 mg, 1.81 mmol). The mixture was degassed under vacuum and N2 Backfill with N 2 Stir at 110 °C for 1 hour to obtain a solution of 6-(methyl-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, which was used directly in the arylation reaction.

[0396]

Chemical Structure

[0397]

Chemical Structure

[0398]

Chemical formula

[0399] [Chemical] Step 1. 3-Bromo-2,5-difluoro-pyridine (4.5 g, 23.2 mmol) and K 2 CO 3 (8.10 g, 58.6 mmol) in DMSO (20 mL) was added (1S,3S)-3-amino-1-methylcyclobutan-1-ol hydrochloride (3.30 g, 24.0 mmol) at room temperature. 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 MgSO 4 and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 65%)) to give (1S,3S)-3-((3-bromo-5-fluoropyridin-2-yl)amino)-1-methylcyclobutan-1-ol (5.8 g, 91% yield). MS: [M+H]+: 275.0 / 277.0.

[0400] Step 2. Into an oven-dried three-necked RBF equipped with a condenser was charged (1S,3S)-3-((3-bromo-5-fluoropyridin-2-yl)amino)-1-methylcyclobutan-1-ol (39.8 g, 144.7 mmol), bis(pinacolato)diboron (47.55 g, 187.3 mmol), and potassium acetate (35.5 g, 361.7 mmol). Dioxane (600 mL) was added and N 2 was bubbled through the mixture. Pd(dppf)Cl 2 -DCM (4.87 g, 5.96 mmol) was added and N 2 was bubbled through the mixture and the mixture was stirred at 110 °C for 90 min. The cooled reaction mixture was diluted with water (600 mL), filtered through Celite® and washed with EtOAc (600 mL in total). The layers were separated and the aqueous layer was extracted with EtOAc (300 mL). The combined organic extracts were washed with brine and Na 2 SO 4It was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with a gradient of EtOAc in heptane (25 - 100%)). The solid was triturated in heptane at 50 °C to obtain (1s,3s)-3-((5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)-1-methylcyclobutan-1-ol (25.09 g, yield 54%). MS: [M+H]+: 323.3. 1 1H NMR (400 MHz, chloroform-d) δ 8.00 (dd, J = 3.3, 0.8 Hz, 1H), 7.56 (dd, J = 8.3, 3.2 Hz, 1H), 6.25 (d, J = 6.8 Hz, 1H), 4.03 (h, J = 7.7 Hz, 1H), 2.62 (ddt, J = 9.5, 7.6, 2.4 Hz, 2H), 2.13 (s, 1H), 2.06 - 1.97 (m, 2H), 1.44 (s, 3H), 1.34 (s, 12H).

[0401]

Chemical Structure

[0402]

Chem.

[0403]

Chem.

[0404]

Chem.

[0405]

Chem.

[0406] Step 2. 2-Bromo-7-fluoro-5-nitro-1H-indazole (1.2 g, 4.62 mmol) and ammonium chloride (1.48 g, 27.7 mmol) were stirred in a mixture of water (10 mL), methanol (10 mL), and THF (10 mL). Iron powder (1.03 g, 18.5 mmol) was added and the reaction was heated to 80 °C for 1 hour with stirring. The reaction was cooled to ambient temperature and filtered through Celite® using EtOAc as the eluent. The filtrate was adsorbed onto silica gel and the residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (2 - 80%)) to give 4-bromo-7-fluoro-1H-indazol-5-amine (720 mg, 68% yield). MS: [M+H]+: 231.9.

[0407] Step 3. 4-Bromo-7-fluoro-1H-indazol-5-amine (1.0 g, 4.35 mmol) was sonicated until dissolved in concentrated HCl (7 mL) and then cooled with stirring in an ice bath. To this stirred solution was added a solution of sodium nitrite (360 mg, 5.22 mmol) in water (7 mL). The mixture was stirred at 0 °C for 15 minutes and then slowly added to a stirred suspension of copper(I) chloride (887 mg, 8.69 mmol) in water (20 mL) at 60 °C. When the addition was complete, the reaction was stirred at 60 °C for a further 30 minutes and then cooled in an ice bath. Potassium carbonate was added slowly with stirring until gas evolution ceased. Then ammonium hydroxide (28 - 30%, 10 mL, 25.7 mmol) was added and the product was extracted into EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and adsorbed onto silica gel. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (2 - 80%)) to give 4-bromo-5-chloro-7-fluoro-1H-indazole (730 mg, 67% yield). MS: [M+H]+: 251.3.

[0408] Step 4. A solution of 4,4-dihydro-2H-pyran (550 μL, 5.85 mmol) and p-toluenesulfonic acid monohydrate (56.5 mg, 293 μmol) in DCM (1.5 mL) was added to a stirred solution of 4-bromo-5-chloro-7-fluoro-1H-indazole (730 mg, 2.93 mmol) in DCM (7.6 mL). The mixture was stirred at room temperature overnight and adsorbed directly onto silica gel. The residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (2 - 60%)) to give 4-bromo-5-chloro-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (480 mg, 49% yield). MS: [M-THP+H]+: 251.3.

[0409] Step 5. 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 dry THF (6.00 mL) was cooled to -78 °C under nitrogen. 1.7 M tert-butyllithium in pentane (1.23 mL, 2.10 mmol) was added dropwise. The mixture was stirred at -78 °C for 30 minutes. Another portion of 1.7 M tert-butyllithium in pentane (1.23 mL, 2.10 mmol) was added and the mixture was stirred at -78 °C for a further 30 minutes. Again, 1.7 M tert-butyllithium in pentane (1.23 mL, 2.10 mmol) was added and the mixture was stirred at -78 °C for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organics were 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 in DCM (1 - 40%)) to give (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.

[0410]

Chemical formula

[0411]

Chemical Structure

[0412]

Chemical Structure

[0413] Step 2. Into a 150 mL pressure vessel were charged ethyl 3-amino-6-chloro-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxylate (1.45 g, 4.32 mmol) and 7N ammonia solution in MeOH (50 mL, 350 mmol). The vessel was sealed and stirred at 70 °C overnight. The mixture was cooled to room temperature and then concentrated to dryness. The residue was purified by flash silica gel chromatography (eluting with 0 - 50% EtOAc / hexane) to give 3-amino-6-chloro-4-(3-methoxy-2,6-dimethyl-phenyl)pyridine-2-carboxamide (1.13 g, 86% yield). MS: [M+H] + : 306.2.

[0414] Step 3. 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) was added 1M BBr 3A solution (9.3 mL, 9.3 mmol) was added. The mixture was stirred at room temperature for 20 minutes. Silica was added to the mixture and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography (eluting with a gradient of MeOH in DCM (0 - 10%)) to give 3-amino-6-chloro-4-(3-hydroxy-2,6-dimethyl-phenyl)pyridine-2-carboxamide (906 mg, 99% yield). MS: [M+H] + : 292.2.

[0415]

Chemical formula

[0416] Step 2. To a stirred solution of 2-methoxybutyl methanesulfonate (0.32 g, 1.75 mmol) in DMF (3.5 mL) was added K 2 CO 3(0.727 g, 5.27 mmol) and 3-bromophenol (0.272 g, 1.575 mmol) were added. 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 × 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 in hexane (0 - 100%)), and 1-bromo-3-(2-methoxybutoxy)benzene (0.4 g, 83%) was obtained. 1 1H NMR (400 MHz, DMSO-d6) δ 7.19 - 7.11 (m, 3H), 6.89 (d, J = 8 Hz, 1H), 3.99 (d, J = 4.8 Hz, 2H), 3.51 (s, 4H), 1.75 - 1.62 (m, 2H), 1.02 (t, J = 7.6 Hz, 3H).

[0417] Step 3. A solution of 1-bromo-3-(2-methoxybutoxy)benzene (0.4 g, 1.54 mmol), bis(pinacolato)diboron (0.588 g, 2.31 mmol), and KOAc (0.452 g, 4.62 mmol) in dioxane (10 mL) was purged with N 2 2 gas for 15 min. PdCl 2 (dppf)-DCM (0.125 g, 0.154 mmol) was added and the mixture was stirred at 100 °C for 5 h. The cooled reaction mixture was poured into water and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 2-(3-(2-methoxybutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.3 g, 63%), which was used in the next step without purification. MS: [M + H] + : 307.2.

[0418] Compound

Chemical Structure

[0419] Step 2. To a suspension of 7-amino-6-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-8-carbonitrile (10.0 mg, 31 μmol) in DCM (1 mL) was added a 4M HCl solution in dioxane (47 μL, 188 μmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo to obtain 7-amino-6-(5-hydroxy-2-methyl-phenyl)quinoline-8-carbonitrile (9 mg, yield 99%). MS: [M+H] + : 276.1.

[0420] Step 3. To a microwave vial containing 7-amino-6-(5-hydroxy-2-methyl-phenyl)quinoline-8-carbonitrile (9 mg, 33 μmol) in methanol (500 μL) was added a 4M solution of NaOH (100 μL, 400 μmol). The vial was sealed and the mixture was heated at 130 °C for 30 minutes. The reaction mixture was purified by preparative HPLC (eluted with ACN / water / 0.1% formic acid) to obtain 7-amino-6-(5-hydroxy-2-methyl-phenyl)quinoline-8-carboxamide (0.4 mg, yield 4%). MS: [M+H] + : 294.1; 1 H NMR (400 MHz, chloroform-d) δ 8.67 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 8.9 Hz, 1H), 6.83 - 6.69 (m, 3H), 5.88 (s, 2H), 2.21 (s, 3H).

[0421] [Chemical] Step 1. To a solution of intermediate C (26 mg, 80.56 μmol) in dioxane (2 mL) were added sodium carbonate (2 M, 160 μL), phenylboronic acid (18 mg, 147.6 μmol), and Pd(dppf)Cl 2 (6 mg, 8.2 μmol). The mixture was degassed under vacuum and backfilled with N 2 and then stirred at 120 °C for 5 h. The volatiles were removed under vacuum, and the residue was purified using flash silica gel chromatography (eluting with 0 - 50% EtOAc / hexane) to give 5-amino-6-[5-(methoxymethoxy)-2-methyl-phenyl]-2-phenyl-pyrimidine-4-carboxamide (18 mg, 49.40 μmol, 61.32% yield). MS: [M+H] + : 365.2; 1 H NMR (400 MHz, 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).

[0422] Step 2. To a solution of 5-amino-6-[5-(methoxymethoxy)-2-methyl-phenyl]-2-phenyl-pyrimidine-4-carboxamide (18 mg, 49.4 μmol) in DCM (1 mL) was added a 4 M HCl solution in dioxane (200 μL, 0.8 mmol). The mixture was stirred at room temperature for 1 h, and the volatiles were removed under vacuum. The residue was dissolved in water and acetonitrile and then lyophilized to give 5-amino-6-(5-hydroxy-2-methylphenyl)-2-phenylpyrimidine-4-carboxamide hydrochloride (17 mg, 96% yield). MS: [M+H] + : 321.2; 11H NMR (400 MHz, DMSO-d6) δ 9.57 (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 = 8.4 Hz, 1H), 6.78 (dd, J = 8.3, 2.6 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 6.49 (s, 2H), 2.00 (s, 3H).

[0423]

Chem.

[0424] Step 2. To a solution of 5-amino-6-[5-(methoxymethoxy)-2-methyl-phenyl]-2-thiazol-2-yl-pyrimidine-4-carboxamide (52 mg, 140.0 μmol) in DCM (1 mL) was added 4M HCl solution in dioxane (0.35 mL, 1.4 mmol). The mixture was stirred at room temperature for 1 h. The volatiles were removed under vacuum and the residue was purified by preparative HPLC on a C18 column (eluting with ACN / water / 0.1% formic acid) to give 5-amino-6-(5-hydroxy-2-methyl-phenyl)-2-thiazol-2-yl-pyrimidine-4-carboxamide (25 mg, 55% yield). MS: [M+H] + : 328.2;1 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.90 (dd, J = 6.9, 2.9 Hz, 2H), 7.76 (d, J = 3.2 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.93 - 6.47 (m, 4H), 2.00 (s, 3H).

[0425]

Chemical formula

[0426] Step 2. To ethyl 4-hydroxy-3-iodoquinoline-2-carboxylate (800 mg, 2.33 mmol) in pyridine (5 mL) at 0 °C, a 1 M solution of trifluoromethylsulfonyl trifluoromethanesulfonate in DCM (3.5 mL, 3.5 mmol) was added and the mixture was stirred at room temperature 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 in heptane (0 - 100%)) to obtain ethyl 3-iodo-4-(trifluoromethylsulfonyloxy)quinoline-2-carboxylate (1.0 g, yield 90%). MS: [M+H] + : 476.1.

[0427] Step 3. [5-(Methoxymethoxy)-2-methyl-phenyl]boronic acid (453.7 mg, 2.31 mmol), K 2 CO 3 (1.02 g, 7.37 mmol), Pd(PPh 3 ) 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 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (eluting with a gradient of EtOAc in heptane (0 - 100%)) to give ethyl 3-iodo-4-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-2-carboxylate (450 mg, 45% yield). MS: [M+H] + : 478.2.

[0428] Step 4. Iron(III) chloride (7.0 mg, 41.9 μmol) and copper(I) iodide (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 2 M solution of ammonia in EtOH (576 μL, 1.152 mmol) and sodium hydroxide (16.8 mg, 419.03 μmol) were sequentially added to the reaction mixture. The reaction tube was sealed and then heated at 90 °C for 16 hours. The cooled reaction mixture was extracted with EtOAc and concentrated in vacuo to give the crude mixture 3-amino-4-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-2-carboxamide (10.6 mg, 15% yield). MS: [M+H] + : 338.4.

[0429] Step 5. 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) was added a 4 M HCl solution in dioxane (47 μL, 188 μmol). The mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo, and the residue was purified by preparative HPLC on a C18 column (eluting with ACN / water / 0.1% formic acid) to give 3-amino-4-(5-hydroxy-2-methyl-phenyl)quinoline-2-carboxamide (4 mg, 44% yield). MS: [M+H] +: 294.3; 1 1H NMR (400 MHz, chloroform-d) δ 8.34 (s, 1H), 7.90 (ddd, J = 8.4, 1.4, 0.7 Hz, 1H), 7.45 - 7.25 (m, 3H), 7.09 (ddd, J = 8.4, 1.5, 0.7 Hz, 1H), 6.88 (dd, J = 8.3, 2.8 Hz, 1H), 6.63 (d, J = 2.7 Hz, 1H), 5.78 (s, 2H), 5.53 (s, 1H), 1.98 (s, 3H).

[0430]

Chemical formula

[0431] To a solution of 2-amino-4-(3-methoxy-2,6-dimethyl-phenyl)-6-thiazol-2-yl-pyridine-2-carboxamide (35 mg, 98.75 μmol) in DCE (1 mL) was added a 1 M solution of BBr3 in DCM (300 μL, 300 μmol). The mixture was stirred at 45 °C for 0.5 h and the volatiles were removed in vacuo. The residue was treated with MeOH and concentrated to dryness again. The residue was purified by preparative HPLC on a C18 column (eluting with ACN / water / 0.1% formic acid) to give 3-amino-4-(3-hydroxy-2,6-dimethyl-phenyl)-6-thiazol-2-yl-pyridine-2-carboxamide (20 mg, 60% yield). MS: [M+H] + : 341.2; 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.86 (d, J = 3.1 Hz, 1H), 7.80 (d, J = 3.2 Hz, 1H), 7.69 (d, J = 3.2 Hz, 1H), 7.66 (d, J = 3.1 Hz, 1H), 7.62 (s, 1H), 7.10 - 6.84 (m, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.52 (s, 2H), 1.84 s, 3H), 1.77 (s, 3H).

[0432]

Chemical formula

[0433] 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) was added a solution of 1M BBr 3 in DCM (400 μL, 400 μmol). The mixture was stirred at 45 °C for 0.5 hour. Volatiles were removed in vacuo, the residue was treated with MeOH and concentrated to dryness again. The residue was purified by preparative HPLC on a C18 column (eluting with ACN / water 10 mM ammonium bicarbonate) to give 3 - amino - 6-(3,5 - difluorophenyl)-4-(3 - hydroxy - 2,6 - dimethylphenyl)pyridine - 2 - carboxamide (32 mg, 64% yield). MS: [M + H] + : 370.2; 1 1H NMR (400 MHz, DMSO - d6) δ 9.26 (s, 1H), 8.40 (d, J = 2.7 Hz, 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 = 8.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.15 (bs, 2H), 1.84 (s, 3H), 1.78 (s, 3H).

[0434]

Chemical Structure

[0435] Step 2. 5-Amino-2-(4,4-difluorocyclohex-1-en-1-yl)-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-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 under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite® and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluting with 2% methanol in dichloromethane) to give 5-amino-2-(4,4-difluorocyclohexyl)-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-4-carboxamide (0.19 g, yield 68%). MS: [M+H] + : 407.3.

[0436] 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 4M HCl solution in dioxane (2 mL) was added at -10 °C. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC C18 column (eluted with ACN / water / 0.1% formic acid) to obtain 5-amino-2-(4,4-difluorocyclohexyl)-6-(5-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (0.11 g, yield 65%). MS: [M+H] + : 363.3; 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.18 (s, 1H), 7.77 (s, 1H), 7.16 (d, J = 8 Hz, 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).

[0437]

Chemical Structure

[0438] Step 2. 5-Amino-2-(3,6-dihydro-2H-pyran-4-yl)-6-(5-(methoxymethoxy)-2-methylphenyl)pyrimidine-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 under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through Celite® and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluted with 35% EtOAc in hexane) to obtain 5-amino-6-(5-(methoxymethoxy)-2-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide (0.16 g, yield 53%). LCMS: MS: [M+H] + : 373.3.

[0439] 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 4M HCl solution in dioxane (1.6 mL) was added at -10 °C. The reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC C18 column (eluted with ACN / water / 0.1% formic acid) to obtain 5-amino-6-(5-hydroxy-2-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide (0.015 g, yield 11%). MS: [M+H] + : 328.6; 11H NMR (400 MHz, DMSO-d6) δ 9.44 (bs, 1H), 8.20 (s, 1H), 7.76 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 2 Hz, 1H), 6.67 (d, J = 2 Hz, 1H), 6.22 (bs, 2H), 3.93 (d, J = 10.8 Hz, 1H), 3.47 - 3.42 (m, 3H), 2.99 - 2.92 (m, 1H), 2.00 (s, 3H), 1.89 - 1.76 (m, 4H).

[0440]

Chem.

Chem.

[0441]

Chemical Structure

[0442] 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 hours. The solid was filtered, and the filtrate was concentrated to obtain methyl 3-chloro-4-hydroxy-quinoline-2-carboxylate (376 mg, yield 92%). MS: [M+H] + : 238.1.

[0443] Step 3. To a solution of methyl 3-chloro-4-hydroxy-quinoline-2-carboxylate (376 mg, 1.58 mmol) in pyridine (10 mL) at 0 °C was added trifluoromethylsulfonyl trifluoromethanesulfonate (1 M in DCM, 2.1 mL, 2.1 mmol), and the reaction mixture was stirred from 0 °C to room temperature for 17 h. The solvent was removed under reduced pressure, and the residue was purified by flash silica gel chromatography (eluting with 5 - 95% EtOAc / hexane) to give methyl 3-chloro-4-(trifluoromethylsulfonyloxy)quinoline-2-carboxylate (182 mg, 31% yield). MS: [M+H] + : 370.0.

[0444] Step 4. [5-(Methoxymethoxy)-2-methyl-phenyl]boronic acid (106.14 mg, 541.52 μmol), potassium carbonate (238 mg, 1.72 mmol), Pd(PPh 3 ) 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 N 2 2 and then stirred under reflux for 3 h. The solvent was removed under reduced pressure, and the residue was purified by flash silica gel chromatography (eluting with 5 - 95% EtOAc / hexane) to give methyl 3-chloro-4-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-2-carboxylate (91 mg, 50% yield). MS: [M+H] + : 372.1.

[0445] Step 5. Methyl 3-chloro-4-[5-(methoxymethoxy)-2-methyl-phenyl]quinoline-2-carboxylate (90 mg, 242.06 μmol) and MeOH (3.5 mL) were charged into an MW vial. 7N ammonia solution in MeOH (3.5 mL, 24.5 mmol) was added, the container was sealed, and the mixture was stirred at 110 °C for 3 hours. The solvent was removed under reduced pressure. The solid was suspended in DCM (1 mL), treated with 4M HCl solution in dioxane (380 μL, 1.52 mmol), and the mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo, and the residue was purified by preparative HPLC on a C18 column (eluted with ACN / water / 0.1% formic acid) to give 3-chloro-4-(5-hydroxy-2-methyl-phenyl)quinoline-2-carboxamide (3 mg, 4% yield). MS: [M+H] + : 313.1. 1 H NMR (400 MHz, chloroform-d) δ 8.11 (ddd, J = 8.5, 1.3, 0.7 Hz, 1H), 7.73 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.56 - 7.43 (m, 2H), 7.32 (ddd, J = 8.5, 1.4, 0.7 Hz, 1H), 6.90 (dd, J = 8.3, 2.7 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), 5.68 (s, 1H), 4.95 (s, 1H), 1.85 (s, 3H).

[0446]

Chemical Structure

[0447]

Chemical Structure

[0448] Step 2. A solution of methyl 2,5-dichloro-6-(5-methyl-1H-indazol-4-yl)pyrimidine-4-carboxylate (103 mg, 305.5 μmol), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (68 mg, 333.2 μmol), and Pd(dppf)Cl 2 -DCM (28 mg, 34.3 μmol) in dioxane (1 mL) and 2 M aqueous solution of potassium carbonate (460 μL, 0.92 mmol) was degassed by bubbling with N 2 . Then the reaction mixture was stirred at 100 °C for 4 h, cooled to room temperature, acidified with 1 N aqueous HCl, and extracted with CHCl 3 / iPrOH 4:1 (3 times). The combined organic extracts were concentrated and dried in vacuo. The residue was dissolved in DMF (1 mL), then treated with ammonium chloride (81 mg, 1.52 mmol) and HATU (148 mg, 389.24 μmol). DIPEA (320 μL, 1.84 mmol) was added and the solution was stirred at room temperature for 3 h. The crude reaction mixture was filtered and the filtrate was purified by preparative HPLC on a C18 column (eluting with ACN / water / 0.1% formic acid) to give 5-chloro-6-(5-methyl-1H-indazol-4-yl)-2-phenyl-pyrimidine-4-carboxamide (23 mg, yield 21%). MS: [M+H] + : 364.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.42 (s, 1H), 8.40 - 8.38 (m, 1H), 8.38 - 8.33 (m, 1H), 8.13 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.60 - 7.48 (m, 3H), 7.39 (d, J = 8.6 Hz, 1H), 2.27 (s, 3H).

[0449]

Chemical Structure

[0450] Step 2. A solution of 2-chloro-6-(5-methyl-1H-indazol-4-yl)pyrimidine-4-carboxylic acid (208 mg, 720.5 μmol), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (177 mg, 867.3 μmol), and Pd(dppf)Cl 2 -DCM (65 mg, 79.6 μmol) in dioxane (2 mL) and 2M aqueous potassium carbonate (1.08 mL, 2.16 mmol) was degassed by bubbling with N 2 . The reaction mixture was stirred at 100 °C for 2 h 20 min, then cooled to room temperature, acidified with 1N aqueous HCl, and extracted with CHCl 3 / iPrOH 4:1. The combined organic extracts were dried over MgSO 4It was dried, filtered, concentrated, and dried in vacuo to obtain crude 6-(5-methyl-1H-indazol-4-yl)-2-phenyl-pyrimidine-4-carboxylic acid (335 mg). A solution containing this 238 mg of crude solid in DMF (2 mL) was treated with ammonium chloride (201 mg, 3.76 mmol) and HATU (350 mg, 920.5 μmol), and then DIPEA (760 μL, 4.35 mmol) was added. The mixture was stirred at room temperature for 1 hour. The crude reaction mixture was filtered, and the filtrate was purified by preparative HPLC (Phenomenex® Gemini®) (eluting with a gradient of acetonitrile in water (both containing 0.1% formic acid)) to obtain 6-(5-methyl-1H-indazol-4-yl)-2-phenyl-pyrimidine-4-carboxamide (15 mg, yield 6%). MS: [M+H] + : 330.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.73 (s, 1H), 8.69 (dd, J = 7.5, 2.4 Hz, 2H), 8.10 (s, 1H), 8.05 (d, J = 1.2 Hz, 1H), 7.96 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.61 - 7.51 (m, 3H), 7.40 (d, J = 8.5 Hz, 1H), 2.50 (s, 3H).

[0451]

Chemical Structure

[0452] Step 2. 1 M boron tribromide solution (1.2 mL, 1.2 mmol) in DCM was added to a solution of 3-amino-2-(3-methoxy-2,6-dimethyl-phenyl)-6-pyridazin-4-yl-pyridine-4-carboxamide (130 mg, 372.1 μmol) in DCM (1.5 mL). After 30 minutes, the volatiles were removed and the residue was taken up in MeOH. The MeOH was evaporated to dryness. The residue was taken up in MeOH and 1 mL of Et 3 N was added. The mixture was evaporated to dryness. The residue was dissolved in 10% MeOH / DCM and adsorbed onto silica gel. The residue was purified by silica gel chromatography (eluting with a gradient of MeOH in DCM (0 - 10%)) to give 3-amino-2-(3-hydroxy-2,6-dimethyl-phenyl)-6-pyridazin-4-yl-pyridine-4-carboxamide (76 mg, 55% yield). MS: [M+H]+: 336.3. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (dd, J = 2.5, 1.1 Hz, 1H), 9.32 (dd, J = 5.9, 1.1 Hz, 1H), 8.53 (s, 1H), 8.41 (dd, J = 5.9, 2.4 Hz, 1H), 8.34 (s, 1H), 7.84 - 7.71 (m, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 1.83 (s, 3H), 1.76 (s, 3H).

[0453]

Chemical Structure

Claims

1. A compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof. [Wherein, R １ is 【Chemical 2】 is, n is 0, 1, or 2, R ２ and R ３ each independently is hydrogen, halogen, optionally substituted C ３～４ cycloalkyl, or optionally substituted C １～６ alkyl, Each R ４ is independently a halogen, R ５ is hydrogen, halogen, hydroxyl, optionally substituted C １～６ alkyl, optionally substituted C １～６ alkoxy, or -N(R ５Ａ ) ２ and Each R ５Ａ is, 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 and R ６Ａ is hydrogen, optionally substituted C １～６ alkyl, optionally substituted C ３～８ cycloalkyl, optionally substituted C ２～９ heterocyclyl, optionally substituted C ６～１０ aryl, or optionally substituted C １～９ heteroaryl, and R ６Ｂ is optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, or -NH(R ６Ａ ) and R ６Ｃ is optionally substituted C1-6 alkyl, A １ and A ２ each of which is independently 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 heterocyclyl, optionally substituted C ６～１０ aryl, optionally substituted C １～９ heteroaryl, or -OR １０ wherein 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 heterocyclyl, optionally substituted C ６～１０ aryl, optionally substituted C １～９ heteroaryl, -OR １０ , -N(R １１ ), or -L-R ２ wherein, or R ８Ａ and R ７ together with the atom to which they are attached form an optionally substituted C ８ cycloalkenyl, optionally substituted C ３～８ heterocyclyl, optionally substituted C ２～９ aryl, or optionally substituted C ６～１０ heteroaryl, and R ２～１２ is absent, hydrogen, halogen, optionally substituted C ９ alkyl, optionally substituted C １～６ alkenyl, optionally substituted C ２～６ alkynyl, optionally substituted C ２～６ cycloalkyl, optionally substituted C ３～８ cycloalkenyl, optionally substituted C ３～８ wherein, and R ２～９ heterocyclyl, optionally substituted C ６～１０ aryl, optionally substituted C １～９ heteroaryl, or -OR １０ wherein 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 heterocyclyl, optionally substituted C ６～１０ aryl, optionally substituted C １～９ heteroaryl, -OR １０ , -N(R １１ ), or -L-R ２ wherein R ８Ａ is absent, hydrogen, halogen, optionally substituted C ９ alkyl, optionally substituted C １～６ alkenyl, optionally substituted C ２～６ alkynyl, optionally substituted C ２～６ cycloalkyl, optionally substituted C ３～８ cycloalkenyl, optionally substituted C ３～８ heterocyclyl, optionally substituted C ２～９ aryl, optionally substituted C ６～１０ heteroaryl, or -OR １～９ wherein R １０ is absent, hydrogen, halogen, optionally substituted C ８ alkyl, optionally substituted C ９ and R ３～８ together with the atom to which they are attached form an optionally substituted C ２～９ cycloalkenyl, optionally substituted C ６～１０ heterocyclyl, optionally substituted C １～１２ aryl, or optionally substituted C ７ heteroaryl, and R １～６ is absent, hydrogen, halogen, optionally substituted C ２～６ alkyl, optionally substituted C ２～６ alkenyl, optionally substituted C ３～８ alkynyl, optionally substituted C ３～８ cycloalkyl, optionally substituted C ２～９ heterocyclyl, optionally substituted C ６～１０ aryl, optionally substituted C １～９ heteroaryl, or -OR １０ and is L is 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, and 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 heterocyclyl, optionally substituted C ６～１０ aryl, optionally substituted C １～９ heteroaryl, -OR １０ or -N(R １１ ) ２ and 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 heterocyclyl, optionally substituted C ６～１０ aryl, or optionally substituted C １～９ heteroaryl, and Each R １１ is, 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 heterocyclyl, optionally substituted C ６～１０ aryl, or optionally substituted C １～９ heteroaryl, -SO2R １１Ａ wherein, or two R １１ groups together form an optionally substituted C2-9 heterocyclyl, Each R １１Ａ is, 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 heterocyclyl, optionally substituted C ６～１０ aryl, or optionally substituted C １～９ heteroaryl.]

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

3. Each R ５Ａ The compound according to claim 1 or 2, wherein R is hydrogen, or a pharmaceutically acceptable salt thereof.

4. R １ is [Chemical Formula 3] The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A). 【Chemical 4】

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A-i). 【Chemical Formula 5】

7. R １ is 【Chemical Formula 6】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-B). 【Chemical Formula 7】

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-B-i). 【Chemical Formula 8】

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

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

12. R ７ and R ８ together with the atoms to which they are attached, optionally substituted C ２～１２ heteroaryl, the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

13. A ２ The compound according to any one of claims 1 to 12, wherein A is C, or a pharmaceutically acceptable salt thereof.

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

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

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

17. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-B-a). 【Chemical Formula 9】

18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-B-b). 【Chemical Formula 10】

19. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-B-c). 【Chemical Formula 11】

20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-B-d). 【Chemical 12】

21. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A-a). 【Chemical 13】

22. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A-b). 【Chemical 14】

23. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A-c). 【Chemical 15】

24. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A-d). 【Chemical 16】

25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-C). 【Chemical 17】

26. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-D). 【Chemical 18】

27. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-E). 【Chemical 19】

28. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-F). 【Chemical 20】

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

30. Each R ６Ａ The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R is H.

31. R ２ The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R is H.

32. R ３ The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R is H.

33. R ２ and R ３ wherein one of them is H and the other is optionally substituted C １～６ alkyl, the compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.

34. R ２ and R ３ one of which is H and the other is -CH ３ as described in claim 33, or a pharmaceutically acceptable salt thereof.

35. R ２ and R ３ are each optionally substituted C １～６ alkyl, a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.

36. R ２ and R ３ each being -CH ３ The compound according to claim 35, or a pharmaceutically acceptable salt thereof, wherein R and R are each -CH

37. R ２ The compound according to any one of claims 1 to 30 and 32, or a pharmaceutically acceptable salt thereof, wherein R is a halogen.

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

39. R ２ The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein R is F.

40. R ３ The compound according to any one of claims 1 to 31 and 37 to 39, or a pharmaceutically acceptable salt thereof, wherein R is a halogen.

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

42. R ３ The compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein R is F.

43. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein n is 0.

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

45. R ４ The compound according to any one of claims 1 to 42 and 44, or a pharmaceutically acceptable salt thereof, wherein R is halogen.

46. R ４ The compound according to claim 45, or a pharmaceutically acceptable salt thereof, wherein R is F.

47. R １ The compound according to any one of claims 1 to 3, 7 to 20, 25 to 31, 33, 34, and 43, or a pharmaceutically acceptable salt thereof, wherein R is as defined below. 【Chemical 21】

48. R ８ is optionally substituted C ６～１０ aryl, a compound according to any one of claims 1 to 11, 13, and 15 to 47, or a pharmaceutically acceptable salt thereof.

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

50. R ８ is optionally substituted C １～９ The compound according to any one of claims 1 to 11, 13, and 15 to 47, or a pharmaceutically acceptable salt thereof, wherein is a heteroaryl.

51. R ８ is -L-R ８Ａ The compound according to any one of claims 1 to 11, 13, and 15 to 47, wherein

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

53. The compound according to claim 51, or a pharmaceutically acceptable salt thereof, wherein L is optionally substituted pyridyl.

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

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

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

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

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

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

60. The compound according to claim 51, or a pharmaceutically acceptable salt thereof, wherein L is optionally substituted furyl.

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

62. L-R ８Ａ The compound according to claim 51, or a pharmaceutically acceptable salt thereof, wherein [the relevant condition] is as follows. 【Chemical 22】 [wherein each of A ３ and A ４ is independently N or CH.]

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

64. A ４ The compound according to claim 62 or 63, or a pharmaceutically acceptable salt thereof, wherein A is N.

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

66. A ４ The compound according to any one of claims 62, 63, and 65, wherein A is CH, or a pharmaceutically acceptable salt thereof.

67. R ８Ａ is - OR １０ The compound according to any one of claims 62 to 66, or a pharmaceutically acceptable salt thereof.

68. R １０ is optionally substituted C １～６ alkyl, the compound according to claim 67, or a pharmaceutically acceptable salt thereof.

69. R １０ is -CH ３ The compound according to claim 67, or a pharmaceutically acceptable salt thereof, wherein R is -CH.

70. R １０ is optionally substituted C ２～９ heterocyclyl, the compound according to claim 67, or a pharmaceutically acceptable salt thereof.

71. R １０ is optionally substituted C ６～１０ aryl, the compound according to claim 67, or a pharmaceutically acceptable salt thereof.

72. R ８Ａ is -N(R １１ ) ２ is a compound according to any one of claims 62 to 66, or a pharmaceutically acceptable salt thereof.

73. One R １１ The compound according to claim 72, or a pharmaceutically acceptable salt thereof, wherein R is H.

74. One R １１ is optionally substituted C １～６ alkyl, the compound according to claim 72, or a pharmaceutically acceptable salt thereof.

75. Each R １１ The compound according to claim 72, or a pharmaceutically acceptable salt thereof, wherein each R is H.

76. Two Rs １１ The compound according to claim 72, or a pharmaceutically acceptable salt thereof, wherein two R groups are joined together to form an optionally substituted C2-9 heterocyclyl.

77. L-R ８Ａ The compound according to claim 51, or a pharmaceutically acceptable salt thereof, wherein [the relevant condition] is as follows. 【Chemical 23】 [Wherein, each R １４ is independently cyano, halogen, optionally substituted C １～６ alkyl, -S(O) ２ R １４Ａ , or optionally substituted C １～８ heteroalkyl, and R １４Ａ is optionally substituted C １～６ alkyl, and A ５ is N or CH, p is 0, 1, 2, 3, or 4. ]

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

79. L-R ８Ａ The compound according to claim 78, or a pharmaceutically acceptable salt thereof, wherein [description is here]. 【Chemical 24】 [wherein each of R １５ , R １６ , R １７ , R １８ , and R １９ is independently cyano, hydrogen, halogen, -CH ３ , -CF ３ , or -OCH ３ .]

80. L-R ８Ａ The compound according to claim 79, or a pharmaceutically acceptable salt thereof, wherein [the relevant condition] is as follows. 【Chemical 25】

81. R １１ is optionally substituted C １～９ heteroaryl, the compound according to claim 77, or a pharmaceutically acceptable salt thereof.

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

83. The compound according to claim 82, or a pharmaceutically acceptable salt thereof, wherein the 6-membered heteroaryl ring contains exactly two nitrogens.

84. R １１ The compound according to claim 83, or a pharmaceutically acceptable salt thereof, wherein R is as defined below. 【Chemical 26】 [Wherein, each R １１Ｂ is independently halogen or optionally substituted C １～６ alkyl, q is 0, 1, 2, or 3. ]

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

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

87. R １１ is optionally substituted C ６～１０ aryl, the compound according to claim 77, or a pharmaceutically acceptable salt thereof.

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

89. R １１ is optionally substituted C ２～９ heterocyclyl, the compound according to claim 87, or a pharmaceutically acceptable salt thereof.

90. R １１ is - S(O) ２ R １１Ａ The compound according to claim 77, wherein

91. The compound according to any one of claims 77 to 90, or a pharmaceutically acceptable salt thereof, wherein p is 0.

92. The compound according to any one of claims 77 to 90, or a pharmaceutically acceptable salt thereof, wherein p is 1.

93. The compound according to any one of claims 77 to 90, or a pharmaceutically acceptable salt thereof, wherein p is 2.

94. Each R １４ is independently halogen, a compound according to any one of claims 77 to 90, 92, and 93, or a pharmaceutically acceptable salt thereof.

95. Each R １４ The compound according to claim 94, or a pharmaceutically acceptable salt thereof, wherein each R is F.

96. A ５ The compound according to any one of claims 77 to 95, or a pharmaceutically acceptable salt thereof, wherein A is CH.

97. A ５ The compound according to any one of claims 77 to 95, wherein A is N, or a pharmaceutically acceptable salt thereof.

98. -L-R ８Ａ The compound according to any one of claims 77 to 90, 92, and 94 to 97, or a pharmaceutically acceptable salt thereof, wherein [the relevant condition] is as follows. 【Chemical 27】

99. R ８ is optionally substituted C ３～８ cycloalkyl, a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof.

100. A compound selected from the group consisting of Compounds 1 to 977 and a pharmaceutically acceptable salt 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 according to claim 101, wherein the composition is isotopically enriched with deuterium.

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

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

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

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

110. The method according to 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 according to claim 105, 106, 109, or 110, wherein the cells are in the body of the subject.

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