Certain chemical entities, compositions and methods

Abstract

Chemical entities are described as inhibitors of tyrosine protein kinase (BTK), pharmaceutical compositions, and methods of treating cancer.

Description

[0001] Cross-references to related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 614,397, filed December 22, 2023, which is incorporated herein by reference in its entirety. Background Technology

[0002] This invention relates to certain compounds, compositions, and methods of treating diseases using said compounds. The compounds of this invention are tyrosine kinase inhibitors. Specifically, the compounds of this invention can be used as inhibitors of Bruton's tyrosine kinase (BTK), including mutant forms of BTK. The invention also contemplates the use of these compounds for treating conditions treatable by inhibiting BTK, such as cancer, lymphoma, leukemia, inflammatory and autoimmune diseases, fibrosis, and other BTK-mediated conditions. Summary of the Invention

[0003] In one aspect, this disclosure provides a compound that can be used to treat BTK-mediated diseases or conditions.

[0004] In some embodiments, the compound is a compound of formula (I): Formula (I), Or its pharmaceutically acceptable salt, wherein Ring A is an optionally substituted arylexyl group, an optionally substituted cycloalkanexyl group, an optionally substituted heteroarylexyl group, or an optionally substituted heterocycloalkanexyl group; X1 is either C-R1 or N; X2 is either C-R2 or N; R1 and R2 are independently hydrogen, cyano, halogroup, hydroxyl, azide, nitro, carboxyl, oxo, sulfinyl, thioalkyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl or optionally substituted formamidinyl. R3 is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycloalkyl group. R4 and R5 are independently hydrogen, halogroup, optionally substituted lower alkyl or optionally substituted cycloalkyl; or R4 and R5 may be linked together with any intercalary atom to form an optionally substituted cycloalkyl or optionally substituted heterocyclic alkyl ring; R6 is hydrogen, an optionally substituted lower alkyl group, or an optionally substituted cycloalkyl group; and R7 is an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

[0005] In some embodiments, the compound of formula (I) is a compound of formula (Ia): Formula (Ia), Or its pharmaceutically acceptable salt.

[0006] In some embodiments, the compound of formula (I) or (Ia) is a compound of formula (Ib): Formula (Ib), Or its pharmaceutically acceptable salt.

[0007] In some embodiments, the compound of formula (I) or (Ia) is a compound of formula (Ic): Formula (Ic), Or its pharmaceutically acceptable salt.

[0008] In some embodiments, the compound of formula (I) or (Ia) is a compound of formula (Id): Formula (Id), Or its pharmaceutically acceptable salt.

[0009] This document considers any combination of the above variable groups. Throughout the specification, those skilled in the art will select groups and their substituents to provide stable moieties and compounds.

[0010] This document also describes pharmaceutical compositions comprising the compounds described herein or their pharmaceutically acceptable salts, tautomers, or solvates, and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical compositions are formulated for administration to mammals via intravenous, subcutaneous, oral, inhalation, nasal, skin, or ocular administration. In some embodiments, the pharmaceutical compositions are formulated for oral administration to mammals. In some embodiments, the pharmaceutical compositions are in the form of tablets, pills, capsules, liquids, suspensions, gels, dispersions, solutions, emulsions, ointments, or lotions. In some embodiments, the pharmaceutical compositions are in the form of tablets, pills, or capsules.

[0011] This article describes compounds of formula (I) or pharmaceutically acceptable salts, tautomers or solvates thereof, which may be used to treat BTK-mediated conditions such as cancer, lymphoma, leukemia, autoimmune diseases, inflammatory conditions or fibrosis.

[0012] Other objectives, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that while the detailed description and specific examples indicate particular embodiments, they are given by way of illustration only, as various changes and modifications from this detailed description within the spirit and scope of this disclosure will become apparent to those skilled in the art.

[0013] Incorporation All publications, patents and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent that each individual publication, patent or patent application is expressly and individually indicated to be incorporated by reference. Detailed Implementation

[0014] As used in this article, the following words and phrases are generally intended to have the meanings stated below, unless otherwise indicated in the context in which they are used.

[0015] The following abbreviations and terms have their meanings as they appear in the text: AcOH = Acetic acid Boc = tert-Butyloxycarbonyl c-=ring DCC = Dicyclohexylcarbodiimide DIEA = N,N-diisopropylethylamine DMAP = 4-Dimethylaminopyridine EDC = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide eq = equivalent Et = Ethyl EtOAc or EA = ethyl acetate EtOH = ethanol g = grams h or hr = hours HBTU = O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate HOBt = Hydroxybenzotriazole HPLC = High-performance liquid chromatography i-=different kg or Kg = kilogram L or l = liter LC / MS = Liquid Chromatography-Mass Spectrometry LRMS = Low Resolution Mass Spectrometry m / z = mass-to-charge ratio Me = methyl MeOH = methanol mg = milligram min = minute mL = milliliter mmol = millimole n- = n- NaOAc = sodium acetate PE = petroleum ether Ph = phenyl Prep = preparative quant. = quantitative RP-HPLC = reversed-phase high performance liquid chromatography rt, r.t. or RT = room temperature s- = sec- = secondary t- = tert- = tertiary THF = tetrahydrofuran TLC = thin-layer chromatography UV = ultraviolet As used herein, when any variable occurs more than once in a chemical formula, its definition at each occurrence is independent of its definition at every other occurrence.

[0016] As used herein, a dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH₂ is attached through the carbon atom.

[0017] As used herein, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl" as defined herein. Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible and / or inherently unstable.

[0018] As used herein, “alkyl” refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (typically from 1 to 20 carbon atoms, e.g., 1 to 8 carbon atoms, such as 1 to 6 carbon atoms). For example, C1-C6 alkyl encompasses straight-chain and branched alkyl groups having 1 to 6 carbon atoms. When naming alkyl residues with a specific number of carbon atoms, it is intended to encompass all straight-chain and branched forms having that number of carbon atoms; thus, for example, “butyl” indicates that it includes n-butyl, sec-butyl, isobutyl, and tert-butyl; “propyl” includes n-propyl and isopropyl. “Lower alkyl” refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, etc. Alkylenes are subsets of alkyl groups, referring to groups that are identical to alkyl groups but have two connecting sites. Alkyl groups typically have 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, or 2 to 6 carbon atoms. For example, C0 alkylene represents a covalent bond, and C1 alkylene is a methylene group.

[0019] As used herein, "alkenyl" refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon double bond, said double bond being obtained by removing a hydrogen molecule from an adjacent carbon atom of a parent alkyl group. The group may be configured in either a cis or trans configuration around the double bond. Typical alkenyl groups include, but are not limited to, vinyl groups; propenyl groups, such as propyl-1-en-1-yl, propyl-1-en-2-yl, propyl-2-en-1-yl (allyl), propyl-2-en-2-yl; butenyl groups, such as buten-1-en-1-yl, buten-1-en-2-yl, 2-methyl-propyl-1-en-1-yl, buten-2-en-1-yl, buten-2-en-2-yl, buten-1,3-dien-1-yl, buten-1,3-dien-2-yl; and so on. In some embodiments, the alkenyl group has from 2 to 20 carbon atoms, while in other embodiments it has from 2 to 6 carbon atoms. "Lower alkenyl" refers to alkenyl groups having 2 to 6 carbons.

[0020] As used herein, "alkynyl" refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon triple bond, which is obtained by removing two hydrogen molecules from adjacent carbon atoms of the parent alkyl group. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and so on. In some embodiments, the alkynyl group has from 2 to 20 carbon atoms, while in other embodiments it has from 3 to 6 carbon atoms. "Lower alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms.

[0021] As used herein, “cycloalkyl” refers to a non-aromatic carbon ring that typically has 3 to 7 cyclic carbon atoms. The ring may be saturated or have one or more carbon-carbon double bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, as well as bridged and caged cyclic groups, such as norbornane.

[0022] As used herein, the term "alkoxy" refers to an alkyl group having a specified number of carbon atoms connected by oxygen bridges, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentylooxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. Alkoxy groups typically have 1 to 7 carbon atoms connected by oxygen bridges. "Lower alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms.

[0023] As used herein, “acyl” refers to the group HC(O)-; (alkyl)-C(O)-; (cycloalkyl)-C(O)-; (aryl)-C(O)-; (heteroaryl)-C(O)-; and (heterocyclic alkyl)-C(O)-, wherein the group is connected to the parent structure via a carbonyl functional group, and wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic alkyl groups are as described herein. An acyl group has a specified number of carbon atoms, wherein the carbon atoms of the ketone group are included in the counted carbon atoms. For example, a C2 acyl group is an acetyl group having the formula CH3(C=O)-.

[0024] As used in this article, "formyl" refers to the group -C(O)H.

[0025] As used herein, "alkoxycarbonyl" refers to a group of the formula (alkoxy) (C=O)- linked by a carbonyl carbon, wherein the alkoxy group has a specified number of carbon atoms. Therefore, C1-C6 alkoxycarbonyl groups are alkoxy groups having 1 to 6 carbon atoms linked by their oxygen to a carbonyl linker.

[0026] As used in this article, "azido" refers to the group -N3.

[0027] As used in this article, "amino" refers to the group -NH2.

[0028] As used herein, “mono- and di(alkyl)amino” refers to secondary alkylamino and tertiary alkylamino groups, wherein the alkyl group is as defined above and has a specified number of carbon atoms. The alkylamino group is bonded at nitrogen. Examples of mono- and dialkylamino groups include ethylamino, dimethylamino, and methyl-propylamino.

[0029] As used in this article, "aminocarbonyl" refers to the group -CONR b R c,in R b H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted alkoxy; and R c It is hydrogen or an optionally substituted C1-C4 alkyl group; or R b and R c Together with the nitrogen they are bound to, they form optionally substituted 4- to 8-membered nitrogen-containing heterocyclic alkyl groups, which optionally contain one or two additional heteroatoms selected from O, N and S in the heterocyclic alkyl ring; Each substituted group is independently substituted by one or more substituents, which are independently: C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halogroup, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl, heterocycloalkyl or heteroaryl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1- C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) or -NHSO2(C1-C4 haloalkyl).

[0030] As used herein, “aryl” refers to: a 6-membered carbon-ring aromatic ring, such as benzene; a bicyclic ring system in which at least one ring is a carbon ring and is aromatic, such as naphthalene, indene, and naphthalene; and a tricyclic ring system in which at least one ring is a carbon ring and is aromatic, such as fluorene.

[0031] For example, aryl groups include 6-membered carbocyclic aromatic rings fused with 4- to 8-membered heterocyclic alkyl rings containing one or more heteroatoms selected from N, O, and S. For such fused bicyclic systems in which only one ring is a carbocyclic aromatic ring, the connecting point can be on either the carbocyclic aromatic ring or the heterocyclic alkyl ring. A divalent group formed from a substituted benzene derivative and having a free valence on the ring atom is called a substituted phenylene group. A divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends with "-" by removing a hydrogen atom from a carbon atom with a free valence is named by adding a "-" to the name of the corresponding monovalent group; for example, a naphthyl group with two connecting points is called a naphthylene group. However, aryl groups do not in any way encompass or overlap with heteroaryl groups, which are defined separately below. Therefore, if one or more carbocyclic aromatic rings are fused with a heterocyclic alkyl aromatic ring, the resulting ring system is a heteroaryl rather than an aryl, as defined herein.

[0032] As used in this article, "aryloxy group" refers to the -O-aryl group.

[0033] As used in this article, "arylalkyl" refers to the group -alkyl-aryl.

[0034] As used in this article, "carbamimidoyl" refers to the group -C(=NH)-NH2.

[0035] As used in this article, "substituted formamidinyl" refers to the group -C(=NR) e )-NR f R g ,in R e It is hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; and R f and R g Independently, it is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl. The condition is R e R f and R g At least one of them is not hydrogen, and the substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl groups refer to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl groups in which one or more (e.g., up to five, e.g., up to three) hydrogen atoms are independently replaced by the following substituents: -R a -OR b Optionally substituted amino groups (including -NR) c COR b -NR c CO2Ra -NR c CONR b R c -NR b C(NR c )NR b R c -NR b C(NCN)NR b R c and -NR c SO2R a ), halogenated groups, cyano groups, nitro groups, oxo groups (as substituents for cycloalkyl, heterocycloalkyl, and heteroaryl groups), and optionally substituted acyl groups (such as -COR). b ), optionally substituted alkoxy carbonyl groups (such as -CO2R) b ), amino carbonyl (such as -CONR) b R c ), -OCOR b -OCO2R a -OCONR b R c -OP(O)(OR) b OR c Thioalkyl (such as SR) b ), sulfinyl groups (such as -SOR) a ) and sulfonyl groups (such as -SO2R) a and -SO2NR b R c ), Where R a The substituted C1-C6 alkyl, substituted aryl, and substituted heteroaryl groups are optional. R b H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R c Hydrogen and optionally substituted C1 - C4 alkyl; or R b and R c and the nitrogen atoms to which they are attached form optionally substituted heterocyclic alkyl groups; and Each optionally substituted group is either unsubstituted or independently substituted by one or more (such as one, two, or three) substituents, which are independently C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halogroup, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OC1-C 4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 phenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) or -NHSO2(C1-C4 haloalkyl).

[0036] As used herein, “halogenated” refers to fluorinated, chloroinated, bromine, and iodinated groups, and the term “halogen” includes fluorine, chlorine, bromine, and iodine.

[0037] As used herein, “haloalkyl” means an alkyl group as defined above that has a specific number of carbon atoms and is substituted with one or more halogen atoms (up to the maximum permissible number of halogen atoms). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

[0038] As used in this article, "hybrid aryl" refers to: A 5- to 7-membered aromatic monocyclic ring containing one or more (e.g., from 1 to 4, or in some embodiments from 1 to 3) heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon; A bicyclic aromatic ring containing one or more (e.g., from 1 to 4, or in some embodiments from 1 to 3) heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon and wherein at least one heteroatom is present in the aromatic ring; and A tricyclic aromatic ring containing one or more (e.g., from 1 to 5, or in some embodiments from 1 to 4) heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon and at least one heteroatom is present in the aromatic ring.

[0039] For example, heteroaryl groups comprise 5- to 7-membered aromatic rings fused to 4- to 8-membered cycloalkyl or heterocycloalkyl rings. In such fused bicyclic heteroaryl ring systems where only one ring contains one or more heteroatoms, the connection point can be on either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrazolinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thiophene, benzothiophene, furanyl, pyrroleyl, benzofuranyl, benzimidazolyl, indolyl, inzolyl, pyridazinyl, triazolyl, quinolinyl, quinoxolinyl, quinazolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl. Divalent groups derived from monovalent heteroaryl groups whose names end with "-" by removing a hydrogen atom from an atom with a free valence are named by adding a "-" to the name of the corresponding monovalent group; for example, a pyridinyl group with two connecting points is a pyridinyl-xylidene group. Heteroaryl groups do not encompass aryl, cycloalkyl, or heterocycloalkyl groups or do not overlap with aryl, cycloalkyl, or heterocycloalkyl groups as defined herein.

[0040] Substituted heteroaryl groups also include those substituted with one or more oxides (-O) - Substituent-substituted ring systems, such as pyridyl N-oxides.

[0041] As used herein, “heterocyclic alkyl” refers to a single non-aromatic ring, typically having 3 to 8 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and combinations containing at least one of the aforementioned heteroatoms. The ring may be saturated or have one or more carbon-carbon double bonds. Suitable heterocyclic alkyl groups include, but are not limited to, pyrrolyl, morpholinyl, piperidinyl, piperazine, azirrocyclobutyl, diazacycloheptyl, diazacyclooctyl, pyrrolyl, morpholinyl, piperidinyl, piperazine, imidazoalkyl, pyrazolyl, dihydrofuranyl, and tetrahydrofuranyl. Substituted heterocyclic alkyl groups may also include those with one or more oxo groups (=O) or oxo groups (-O). - Substituent-substituted ring systems, such as piperidinyl N-oxide, morpholino-N-oxide, 1-oxo-1-thiomorpholino, and 1,1-dioxo-1-thiomorpholino.

[0042] "Heterocyclic alkyl" also includes bicyclic ring systems, wherein one non-aromatic ring (typically having 3 to 7 ring atoms) contains at least 2 carbon atoms in addition to 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and combinations containing at least one of the aforementioned heteroatoms; and the other ring (typically having 3 to 7 ring atoms) optionally contains 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen and is non-aromatic.

[0043] As used herein, “thioalkyl” refers to the following groups: -S- (optionally substituted (C1-C6)alkyl), -S- (optionally substituted cycloalkyl), -S- (optionally substituted aryl), -S- (optionally substituted heteroaryl), and -S- (optionally substituted heterocycloalkyl). Therefore, thioalkyl includes C1-C6 alkylthioalkyl groups.

[0044] As used herein, “sulfinyl” refers to the following groups: -S(O)- (optionally substituted (C1-C6)alkyl), -S(O)- (optionally substituted cycloalkyl), -S(O)- (optionally substituted aryl), -S(O)- (optionally substituted heteroaryl), -S(O)- (optionally substituted heterocycloalkyl); and -S(O)- (optionally substituted amino).

[0045] As used herein, “sulfonyl” refers to the following groups: -S(O2)- (optionally substituted (C1-C6) alkyl), -S(O2)- (optionally substituted cycloalkyl), -S(O2)- (optionally substituted aryl), -S(O2)- (optionally substituted heteroaryl), -S(O2)- (optionally substituted heterocycloalkyl), and -S(O2)- (optionally substituted amino).

[0046] As used herein, “substituted” means that any one or more hydrogen atoms on a specified atom or group are replaced by a substituent selected from the specified group, provided that the normal valence of the specified atom is not exceeded. When the substituent is an oxo group (i.e., =O), then two hydrogen atoms on that atom are replaced. Combinations of substituents and / or variables are permitted only if such combinations produce stable compounds or useful synthetic intermediates. Stable compounds or stable structures are intended to represent compounds that are robust enough to withstand separation from the reaction mixture and subsequent formulation into reagents that are at least practically useful. Unless otherwise stated, substituents are named into the core structure. For example, it should be understood that when (cycloalkyl)alkyl groups are listed as possible substituents, the point of connection between the substituent and the core structure is in the alkyl moiety.

[0047] Unless otherwise explicitly defined, as used herein, the terms “substituted” alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl where one or more (e.g., up to five, e.g., up to three) hydrogen atoms are independently substituted with the following substituents: -R a -OR b Optionally substituted amino groups (including -NR) c COR b -NR c CO2R a -NR c CONR b R c -NR b C(NR c )NR b R c -NR b C(NCN)NR b R c and -NR c SO2R a ), halogenated group, cyano group, azide group, nitro group, oxo group (as a substituent of cycloalkyl or heterocycloalkyl), optionally substituted acyl group (such as -COR) b ), optionally substituted alkoxy carbonyl groups (such as -CO2R) b ), amino carbonyl (such as -CONR) b R c ), -OCOR b -OCO2R a -OCONR b R c -OP(O)(OR) b OR c Thioalkyl (such as SR) b ), sulfinyl groups (such as -SOR) a ) or sulfonyl groups (such as -SO2R) a and -SO2NR b R c ), Where R a The substituted C1-C6 alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted alkenyl, substituted alkynyl, substituted aryl, or substituted heteroaryl; R b It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R c It is hydrogen or an optionally substituted C1-C4 alkyl group; or Rb and R c And the nitrogen atoms to which they are attached form an optionally substituted heterocyclic alkyl group; and Each optionally substituted group is either unsubstituted or independently substituted by one or more (such as one, two, or three) of the following substituents: C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC 1- C4 haloalkyl, halogroup, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxogroup (as a substituent for cycloalkyl or heterocyclic alkyl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl) -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) or -NHSO2(C1-C4 haloalkyl).

[0048] As used herein, “substituted acyl” refers to the group (substituted alkyl)-C(O)-; (substituted cycloalkyl)-C(O)-; (substituted aryl)-C(O)-; (substituted heteroaryl)-C(O)-; and (substituted heterocycloalkyl)-C(O)-, wherein the group is connected to the parent structure via a carbonyl functional group, and wherein the substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl refer to such alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups, respectively, wherein one or more (such as up to five, e.g., up to three) hydrogen atoms are independently -R. a -OR b Optionally substituted amino groups (including -NR) c COR b -NR c CO2R a -NRc CONR b R c -NR b C(NR c )NR b R c -NR b C(NCN)NR b R c and -NR c SO2R a ), halogenated group, cyano group, nitro group, oxo group (as substituents of cycloalkyl or heterocycloalkyl groups), substituted acyl group (e.g., -COR) b ), optionally substituted alkoxy carbonyl groups (such as -CO2R) b ), amino carbonyl (such as -CONR) b R c ), -OCOR b -OCO2R a -OCONR b R c -OP(O)(OR) b OR c Thioalkyl (e.g., SR) b ), sulfinyl (such as -SOR) a ) or sulfonyl (such as -SO2R) a and -SO2NR b R c Substitution of substituents, Where R a It can be an optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl. R b H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R c It is hydrogen or an optionally substituted C1-C4 alkyl group; or R b and R c and the nitrogen atoms to which they are attached form optionally substituted heterocyclic alkyl groups; and Each optionally substituted group is either unsubstituted or independently substituted by one or more (such as one, two, or three) of the following substituents: C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halogroup, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) or -NHSO2(C1-C4 haloalkyl).

[0049] As used herein, “substituted alkoxy” means an alkoxy group in which the alkyl moiety is substituted (i.e., -O-(substituted alkyl)), and “substituted alkyl” means that one or more (e.g., up to five, such as up to three) hydrogen atoms are independently substituted with substituents of the following: -R a -OR b Optionally substituted amino groups (including -NR) c COR b -NR c CO2R a -NR c CONR b R c -NR b C(NR c )NR b R c -NR b C(NCN)NR b R c and -NR cSO2R a ), halogenated group, cyano group, nitro group, oxo group (as substituents of cycloalkyl or heterocycloalkyl groups), optionally substituted acyl group (such as -COR) b ), optionally substituted alkoxy carbonyl groups (such as -CO2R) b ), amino carbonyl (such as -CONR) b R c ), -OCOR b -OCO2R a -OCONR b R c -OP(O)(OR) b OR c Thioalkyl (e.g., SR) b ), sulfinyl (such as -SOR) a ) and sulfonyl groups (such as -SO2R) a and -SO2NR b R c ), Where R a It can be an optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl. R b H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R c It is hydrogen or an optionally substituted C1-C4 alkyl group; or R b and R c and the nitrogen atoms to which they are attached form optionally substituted heterocyclic alkyl groups; and Each optionally substituted group is either unsubstituted or independently substituted by one or more (such as one, two, or three) of the following substituents: C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halogroup, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) or -NHSO2(C1-C4 haloalkyl).

[0050] In some embodiments, the substituted alkoxy group is a "polyalkoxy" or -O-(optionally substituted alkylene)-(optionally substituted alkoxy) group, and includes groups such as -OCH2CH2OCH3, as well as residues of glycol ethers (such as polyethylene glycol), and -O(CH2CH2O). x CH3, where x is an integer from 2 to 20, for example 2-10, or 2-5. Another substituted alkoxy group is a hydroxyalkoxy group or -OCH2(CH2). y OH, where y is an integer from 1 to 10, such as 1 to 4.

[0051] As used herein, “substituted alkoxycarbonyl” refers to a group (substituted alkyl) -OC(O)-, wherein the group is attached to the parent structure via a carbonyl functional group, and wherein substitution means that one or more (e.g., up to five, such as up to three) hydrogen atoms are independently replaced by substituents of the following: -R a -OR b Optionally substituted amino groups (including -NR)c COR b -NR c CO2R a -NR c CONR b R c -NR b C(NR c )NR b R c -NR b C(NCN)NR b R c and -NR c SO2R a ), halogenated group, cyano group, nitro group, oxo group (as substituents of cycloalkyl or heterocycloalkyl groups), optionally substituted acyl group (such as -COR) b ), optionally substituted alkoxy carbonyl groups (such as -CO2R) b ), amino carbonyl (such as -CONR) b R c ), -OCOR b -OCO2R a -OCONR b R c -OP(O)(OR) b OR c Thioalkyl (e.g., SR) b ), sulfinyl (such as -SOR) a ) and sulfonyl groups (such as -SO2R) a and -SO2NR b R c ), Where R a It can be an optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl. R b H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R c It is hydrogen or an optionally substituted C1-C4 alkyl group; or R b and R c and the nitrogen atoms to which they are attached form optionally substituted heterocyclic alkyl groups; and Each optionally substituted group is either unsubstituted or independently substituted by one or more (such as one, two, or three) of the following substituents: C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halogroup, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl or heterocycloalkyl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) or -NHSO2(C1-C4 haloalkyl).

[0052] As used in this article, "substituted amino" refers to the group -NHR d or -NR d R e , where R d The radical is hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted formamidinyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl, and sulfonyl, wherein R e The group is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl, wherein the substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, respectively, wherein one or more (e.g., up to five, e.g., up to three) hydrogen atoms are independently substituted with the following substituents: -R a -OR b Optionally substituted amino groups (including -NR)c COR b -NR c CO2R a -NR c CONR b R c -NR b C(NR c )NR b R c -NR b C(NCN)NR b R c and -NR c SO2R a ), halogenated group, cyano group, nitro group, oxo group (as substituents of cycloalkyl or heterocycloalkyl groups), optionally substituted acyl group (such as -COR) b ), optionally substituted alkoxy carbonyl groups (such as -CO2R) b ), amino carbonyl (such as -CONR) b R c ), -OCOR b -OCO2R a -OCONR b R c -OP(O)(OR) b OR c Thioalkyl (e.g., SR) b ), sulfinyl (such as -SOR) a ) or sulfonyl (such as -SO2R) a and -SO2NR b R c ), Where R a It can be an optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl. R b H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R c It is hydrogen or an optionally substituted C1-C4 alkyl group; or R b and R cAnd the nitrogen to which they are attached forms an optionally substituted heterocyclic alkyl group; and wherein each optionally substituted group is unsubstituted or independently substituted by one or more (such as one, two or three) substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halogroup, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substituent of cycloalkyl or heterocyclic alkyl), -CO2H, -C( -C1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl) or -NHSO2(C1-C4 haloalkyl); and The acyl group, alkoxycarbonyl group, sulfinyl group, and sulfonyl group may be optionally substituted as defined herein.

[0053] The term "substituted amino" also refers to the respective groups as described above -NHR d and NR d R d N-oxides. N-oxides can be prepared by treating the corresponding amino groups with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The reaction conditions used to carry out N-oxidation are well known to those skilled in the art.

[0054] The compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In those cases, a single enantiomer or diastereomer, i.e., the optically active form, can be obtained by asymmetric synthesis or by resolution of the racemate. For example, resolution of the racemate can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral high-performance liquid chromatography (HPLC) column. Furthermore, the compounds include the Z and E forms (or cis and trans forms) of compounds having carbon-carbon double bonds. When the compounds described herein exist in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the compound.

[0055] Compounds of Formula I also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), nonsolventized polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. The terms “crystalline form,” “polymorph,” and “new form” are used interchangeably herein and are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), nonsolventized polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a specific crystalline or amorphous form is mentioned. Similarly, “pharmaceutically acceptable forms” of compounds of Formula I also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), nonsolventized polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of pharmaceutically acceptable salts, as well as mixtures thereof.

[0056] A "solvate" is formed through the interaction of a solvent and a compound. The term "compound" is intended to include solvates of compounds. Similarly, "pharmaceutically acceptable salt" includes solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemihydrates.

[0057] Compounds of Formula I also include other pharmaceutically acceptable forms of the compounds, including chelates, non-covalent complexes, prodrugs, and mixtures thereof.

[0058] A chelate is formed by the coordination of a compound with a metal ion at two (or more) sites. The term "compound" is intended to include chelates of compounds. Similarly, "pharmaceutically acceptable salt" includes chelates of pharmaceutically acceptable salts.

[0059] A “non-covalent complex” is formed through the interaction of a compound with another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also known as ionic bonding). Such non-covalent complexes are included in the term “compound.” Similarly, pharmaceutically acceptable salts include “non-covalent complexes” of pharmaceutically acceptable salts.

[0060] The term "hydrogen bond" refers to the association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom bonded to a second, relatively electronegative atom (also known as a hydrogen bond donor). Suitable hydrogen bond donors and acceptors are well-known in medicinal chemistry.

[0061] "Hydrogen bond acceptor" refers to a group containing oxygen or nitrogen, such as sp. 2 - Hybridized oxygen or nitrogen, ether oxygen, or sulfoxide or N-oxide oxygen.

[0062] The term "hydrogen bond donor" refers to an oxygen, nitrogen, or heteroaryl carbon carrying hydrogen, a group containing a cyclic nitrogen, or a heteroaryl group containing a cyclic nitrogen.

[0063] The compounds disclosed herein can be used in different enriched isotopic forms (e.g., enriched in terms of the content of 2H, 3H, 11C, 13C, and / or 14C). In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve efficacy and increase the duration of drug action.

[0064] Deuterium-substituted compounds can be synthesized using various methods such as those described in the following: Dean, Dennis C., ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [in: Curr., Pharm. Des., 2000;6(10)] 2000, p. 110; George W.; Varma, Rajender S., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0065] "Pharmaceutically acceptable salts" include, but are not limited to, salts formed with inorganic acids, such as hydrochlorides, carbonates, phosphates, hydrogen phosphates, diphosphates, hydrobroms, sulfates, sulfinates, and nitrates; and salts formed with organic acids, such as malates, malonates, maleates, fumarates, tartrates, succinates, citrates, acetates, lactates, gluconates, methanesulfonates, Tris (hydroxymethylaminomethane), p-toluenesulfonates, propionates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, oxalates, bis(hydroxynaphthyl)ates, and alkylates (such as acetates, HOOC-(CH2)). n -COOH, where n is 0-4), etc. Other salts include sulfates, methanesulfonates, bromides, trifluoroacetates, picrates, sorbates, diphenyl glycolates, salicylates, nitrates, phthalates, or morpholines. Pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0066] Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing the acid salt solution. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared according to the conventional procedure for preparing acid addition salts from basic compounds by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic and pharmaceutically acceptable addition salts.

[0067] The term "prodrug" as used herein includes any compound that, upon administration to a subject (e.g., after metabolic processing), is converted to a compound of Formula I. Similarly, "pharmaceuticalally acceptable salt" includes a "prodrug" of a pharmaceutically acceptable salt. Examples of prodrugs include derivatives of compounds of Formula I containing functional groups, such as carboxylic acid groups. Exemplary prodrugs of carboxylic acid groups include, but are not limited to, carboxylic acid esters, such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters (such as ethyl esters), acyloxyalkyl esters (such as neopentyloxymethyl (POM)), glycosides, and ascorbic acid derivatives.

[0068] Other exemplary prodrugs include amides of carboxylic acids. Exemplary amide prodrugs include, for example, metabolically unstable amides formed from amines and carboxylic acids. Exemplary amines include NH2, primary amines, and secondary amines, such as NHR. x and NR x R y , where R x For hydrogen, (C1-C 18 (C3-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl-, (C6-C 14 )aryl (the aryl group is unsubstituted or substituted with residues (C1-C2)-alkyl, (C1-C2)-alkoxy, fluorinated, or chlorolated); heteroaryl-, (C6-C 14 )-aryl-(C1-C4)-alkyl- (wherein the aryl group is unsubstituted or substituted with residues (C1-C2)-alkyl, (C1-C2)-alkoxy, fluorinated or chloro); or heteroaryl-(C1-C4)-alkyl-, and wherein R y With R x The specified meaning (except for hydrogen), or where R x and R yTogether with the nitrogen they bind, they form an optionally substituted 4- to 7-membered heterocyclic alkyl ring, which optionally contains one or two additional heteroatoms selected from nitrogen, oxygen, and sulfur. Discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, the ACS Symposium Series, Volume 14, edited by Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and Design of Prodrugs, edited by H. Bundgaard, Elsevier, 1985.

[0069] As used herein, the terms “group,” “free radical,” or “segment” are synonyms and refer to a molecular functional group or segment that can be attached to a bond or other molecular segment.

[0070] As used herein, the term "leaving group" refers to its conventional meaning in synthetic organic chemistry, namely, an atom or group that can be substituted under nucleophilic substitution conditions. Examples of leaving groups include, but are not limited to, dimethylhydroxyamino (e.g., Weinreb amides), halogens, alkyl or arylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, methylthio, benzenesulfonyloxy, toluenesulfonyloxy, and thiophenoxy), dihalophosphonooxy, optionally substituted benzyloxy, isopropoxy, acyloxy, etc.

[0071] As used herein, the term "protective group" or "protecting group" refers, in its conventional and associated meaning in synthetic chemistry, to a group that selectively blocks one reactive site in a multifunctional compound, thereby enabling the chemical reaction to selectively proceed at another unprotected reactive site. Certain processes of this invention rely on protecting groups to block certain reactive sites present in the reactants. Examples of protecting groups can be found in Wuts et al., Green’s Protective Groups in Organic Synthesis (J. Wiley, 4th edition, 2006).

[0072] As used herein, the term "deprotection" or "deprotecting" refers to the process of removing a protecting group after a selective reaction has been completed. Some protecting groups may be preferred over others due to their convenience or relative ease of removal. Without limitation, deprotecting agents used for protected amino or aniline groups include strong acids such as trifluoroacetic acid (TFA), concentrated HCl, H₂SO₄, or HBr.

[0073] As used herein, “regulation” refers to a change in activity relative to the absence of a chemical entity, as a direct or indirect response to the presence of a chemical entity as described herein. This change may be an increase or decrease in activity and may be due to a direct interaction between the compound and the target, or due to the interaction between the compound and one or more other factors that, in turn, affect the activity of the target. For example, the presence of a chemical entity may increase or decrease target activity, for instance, by directly binding to the target, by (directly or indirectly) increasing or decreasing the target activity of another factor, or by (directly or indirectly) increasing or decreasing the amount of the target present in a cell or organism.

[0074] As used herein, "active agent" refers to a chemical entity that has biological activity. In some embodiments, "active agent" is a compound that has pharmaceutical efficacy. For example, an active agent may be an anticancer therapeutic agent.

[0075] As used in this article, “significant” means any detectable change that is statistically significant in a standard parametric statistical significance test (such as the Student’s T-test) with a p-value less than 0.05.

[0076] As used in this article, a "pharmaceuticalally acceptable" ingredient is one that is suitable for use in humans and / or animals without producing excessive adverse side effects (such as toxicity, irritation, and allergic reactions) commensurate with a reasonable benefit / risk ratio.

[0077] As used herein, the “therapeutic effective amount” of a chemical entity refers to the amount that, when applied to a human or nonhuman subject, effectively provides therapeutic benefits (such as improvement of symptoms, slowing of disease progression, or prevention of disease).

[0078] "Treating" or "treatment" includes administering at least one compound of formula I or a pharmaceutically acceptable salt thereof to a mammalian subject (especially a human subject) to which such administration is required, and includes (i) preventing the development of clinical symptoms of a disease (such as cancer), (ii) causing the clinical symptoms of a disease (such as cancer) to subside, and / or (iii) preventive treatment to prevent the onset of a disease (such as cancer).

[0079] As used in this article, “cancer” refers to all types of cancer, growths, or malignant tumors found in mammals, including carcinomas and sarcomas. Examples of cancers include brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, and medulloblastoma.

[0080] As used herein, "object" refers to a mammal that is or will be the subject of treatment, observation, or experimentation. The methods described herein can be used in human treatment and veterinary applications. In some embodiments, the object is a human being.

[0081] The term "mammal" is intended to have its standard meaning and encompasses, for example, humans, dogs, cats, sheep, and cows.

[0082] As used in this article, the term BTK refers to tyrosine protein kinase (a tyrosine kinase involved in B cell development).

[0083] A. Compounds In one respect, a compound of formula (I) is provided: Formula (I) Or its pharmaceutically acceptable salt, wherein Ring A is an optionally substituted arylexyl group, an optionally substituted cycloalkanexyl group, an optionally substituted heteroarylexyl group, or an optionally substituted heterocycloalkanexyl group; X1 is either C-R1 or N; X2 is either C-R2 or N; R1 and R2 are independently hydrogen, cyano, halogroup, hydroxyl, azide, nitro, carboxyl, oxo, sulfinyl, thioalkyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl or optionally substituted formamidinyl. R3 is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycloalkyl group. R4 and R5 are independently hydrogen, halogroup, optionally substituted lower alkyl or optionally substituted cycloalkyl; or R4 and R5 may be linked together with any intercalary atom to form an optionally substituted cycloalkyl or optionally substituted heterocyclic alkyl ring; R6 is hydrogen, an optionally substituted lower alkyl group, or an optionally substituted cycloalkyl group; and R7 is an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

[0084] In some embodiments, for compounds of formula (I) or their pharmaceutically acceptable salts, R4 is hydrogen, a halogroup, an optionally substituted lower alkyl group, or an optionally substituted cycloalkyl group. In some embodiments, R4 is hydrogen, a halogroup, an optionally substituted lower alkyl group, or a cycloalkyl group. In some embodiments, R4 is hydrogen, a halogroup, or an optionally substituted lower alkyl group. In some embodiments, R4 is hydrogen or a halogroup. In some embodiments, R4 is hydrogen.

[0085] In some embodiments, for compounds of formula (I) or their pharmaceutically acceptable salts, R5 is hydrogen, a halogroup, an optionally substituted lower alkyl group, or an optionally substituted cycloalkyl group. In some embodiments, R5 is hydrogen, a halogroup, an optionally substituted lower alkyl group, or a cycloalkyl group. In some embodiments, R5 is hydrogen, a halogroup, or an optionally substituted lower alkyl group. In some embodiments, R5 is hydrogen or a halogroup. In some embodiments, R5 is hydrogen.

[0086] In some embodiments, for compounds of formula (I) or their pharmaceutically acceptable salts, R4 and R5 are linked with any intercalary atom to form an optionally substituted cycloalkyl or optionally substituted heteroalkyl ring. In some embodiments, R4 and R5 are linked with any intercalary atom to form an optionally substituted C3-C6 cycloalkyl ring or an optionally substituted 4- to 8-membered heteroalkyl ring. In some embodiments, R4 and R5 are linked with any intercalary atom to form an optionally substituted cycloalkyl ring. In some embodiments, R4 and R5 are linked together to form an optionally substituted C3-C6 cycloalkyl ring. In some embodiments, R4 and R5 are linked together to form an optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, R4 and R5 are linked together to form an optionally substituted cyclopropyl. In some embodiments, R4 and R5 are linked with any intercalary atom to form an optionally substituted heteroalkyl ring. In some embodiments, R4 and R5 are linked together with any intercalary atom to form an optionally substituted 4- to 8-membered heterocyclic alkyl ring.

[0087] In some embodiments, for compounds of formula (I) or their pharmaceutically acceptable salts, R6 is hydrogen, an optionally substituted lower alkyl group, or an optionally substituted cycloalkyl group. In some embodiments, R6 is hydrogen, an optionally substituted lower alkyl group, or a cycloalkyl group. In some embodiments, R6 is hydrogen or an optionally substituted lower alkyl group. In some embodiments, R6 is hydrogen, a substituted lower alkyl group, or a lower alkyl group. In some embodiments, R6 is hydrogen. In some embodiments, R6 is hydrogen.

[0088] In some embodiments, the compound of formula (I) is a compound of formula (Ia): Formula (Ia), Or its pharmaceutically acceptable salt.

[0089] In some embodiments, for compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, X1 is C-R1 or N. In some embodiments, X1 is C-R1. In some embodiments, X1 is N.

[0090] In some embodiments, for compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, X2 is C-R2 or N. In some embodiments, X2 is N. In some embodiments, X2 is C-R2.

[0091] In some embodiments, for compounds of formula (I) or (Ia) or their pharmaceutically acceptable salts, X1 is C-R1 and X2 is C-R2. In some embodiments, X1 is C-R1 and X2 is N. In some embodiments, X1 is N and X2 is C-R2.

[0092] In some embodiments, the compound of formula (I) or (Ia) is a compound of formula (Ib): Formula (Ib), Or its pharmaceutically acceptable salt.

[0093] In some embodiments, the compound of formula (I) or (Ia) is a compound of formula (Ic): Formula (Ic), Or its pharmaceutically acceptable salt.

[0094] In some embodiments, the compound of formula (I) or (Ia) is a compound of formula (Id): Formula (Id), Or its pharmaceutically acceptable salt.

[0095] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R1 is hydrogen, cyano, halogroup, hydroxyl, azide, nitro, carboxyl, oxo, sulfinyl, thioalkyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted formamidinyl.

[0096] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R1 is hydrogen, cyano, halogroup, hydroxyl, azide, nitro, carboxyl, oxo, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted formamidinyl.

[0097] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R1 is hydrogen, cyano, halogroup, hydroxyl, azide, nitro, carboxyl, oxo, optionally substituted alkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted formamidinyl.

[0098] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R1 is hydrogen, cyano, halogroup, hydroxyl, carboxyl, oxo, optionally substituted alkoxy, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted amino.

[0099] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R1 is hydrogen, cyano, halogroup, hydroxyl, optionally substituted alkoxy, optionally substituted lower alkyl or optionally substituted amino.

[0100] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, there is an optional substituted cycloalkoxy, an optional substituted heterocycloalkoxy, an optional substituted cycloalkyl, or an optional substituted heterocycloalkyl.

[0101] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, the substituted cycloalkyl or the substituted heterocycloalkyl is optionally substituted.

[0102] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R1 is hydrogen, a halogroup, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted lower alkyl group, or an optionally substituted amino group. In some embodiments, R1 is hydrogen, a halogroup, or an optionally substituted lower alkyl group. In some embodiments, R1 is hydrogen, a halogroup, a substituted lower alkyl group, or a lower alkyl group. In some embodiments, R1 is hydrogen or a halogroup. In some embodiments, R1 is hydrogen or a fluorinated group. In some embodiments, R1 is hydrogen.

[0103] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R2 is hydrogen, cyano, halogroup, hydroxyl, azide, nitro, carboxyl, oxo, sulfinyl, thioalkyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted formamidinyl.

[0104] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R2 is hydrogen, cyano, halogroup, hydroxyl, azide, nitro, carboxyl, oxo, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted formamidinyl.

[0105] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R2 is hydrogen, cyano, halogroup, hydroxyl, azide, nitro, carboxyl, oxo, optionally substituted alkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted formamidinyl.

[0106] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R2 is hydrogen, cyano, halogroup, hydroxyl, carboxyl, oxo, optionally substituted alkoxy, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted amino.

[0107] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R2 is hydrogen, cyano, halogroup, hydroxyl, optionally substituted alkoxy, optionally substituted lower alkyl or optionally substituted amino.

[0108] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R2 is an optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

[0109] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R2 is an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

[0110] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R2 is hydrogen, a halogroup, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted lower alkyl group, or an optionally substituted amino group. In some embodiments, R2 is hydrogen, a halogroup, or an optionally substituted lower alkyl group. In some embodiments, R2 is hydrogen, a halogroup, or a lower alkyl group. In some embodiments, R2 is hydrogen or a halogroup. In some embodiments, R2 is hydrogen or a fluorinated group. In some embodiments, R2 is hydrogen.

[0111] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl.

[0112] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycloalkyl group.

[0113] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, or an optionally substituted heterocyclic alkyl. In some embodiments, R3 is hydrogen, a substituted alkyl, an alkyl group, a substituted cycloalkyl group, a cycloalkyl group, a substituted heterocyclic alkyl group, or a heterocyclic alkyl group. In some embodiments, R3 is hydrogen, a substituted alkyl, an alkyl group, a cycloalkyl group, or a heterocyclic alkyl group.

[0114] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen or an optionally substituted alkyl group.

[0115] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen or an alkyl group optionally substituted with one or more halogroups, hydroxyl groups, or optionally substituted alkoxycarbonyl groups. In some embodiments, R3 is hydrogen or a lower alkyl group optionally substituted with one or more halogroups, hydroxyl groups, or optionally substituted alkoxycarbonyl groups.

[0116] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen or an alkyl group optionally substituted with a halogroup. In some embodiments, R3 is hydrogen or a lower alkyl group optionally substituted with a halogroup.

[0117] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen or an alkyl group optionally substituted with a fluorinated group. In some embodiments, R3 is hydrogen or a lower alkyl group optionally substituted with a fluorinated group.

[0118] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen or an alkyl group optionally substituted with one or more halogroups, hydroxyl groups, carboxyl groups, optionally substituted alkoxycarbonyl groups, or optionally substituted heterocyclic alkyl groups. In some embodiments, R3 is hydrogen or an alkyl group optionally substituted with halogroups, hydroxyl groups, or carboxyl groups. In some embodiments, R3 is hydrogen or an alkyl group optionally substituted with fluorinated groups, hydroxyl groups, or carboxyl groups.

[0119] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is an alkyl group optionally substituted with a heterocyclic alkyl group. In some embodiments, R3 is an alkyl group substituted with a heterocyclic alkyl group, wherein the heterocyclic alkyl group is substituted with one or more alkyl, halogroup, haloalkyl, or acyl groups. In some embodiments, R3 is an alkyl group substituted with a heterocyclic alkyl group, wherein the heterocyclic alkyl group is substituted with a methyl group or -C(O)CH3.

[0120] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen, methyl, , , , , , , , , , , , , , or In some implementations, R3 is hydrogen, methyl, , , or .

[0121] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In some embodiments, R3 is a substituted cycloalkyl, a substituted heterocycloalkyl, or a heterocycloalkyl. In some embodiments, R3 is an optionally substituted (C3-C6)-cycloalkyl or an optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R3 is an optionally substituted (C3-C4)-cycloalkyl or an optionally substituted 3- to 4-membered heterocycloalkyl.

[0122] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is an optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted oxetyl, optionally substituted azacyclobutyl, optionally substituted piperidinyl, or optionally substituted azabicyclo[3.2.1]octyl. In some embodiments, R3 is an optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted oxetyl, or optionally substituted azacyclobutyl.

[0123] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is a cycloalkyl or heterocycloalkyl group optionally substituted with one or more alkyl, halogroup, hydroxyl, or optionally substituted alkoxycarbonyl groups. In some embodiments, R3 is a (C3-C6)-cycloalkyl or a 3- to 6-membered heterocycloalkyl group optionally substituted with one or more alkyl, halogroup, hydroxyl, or optionally substituted alkoxycarbonyl groups. In some embodiments, R3 is a (C3-C4)-cycloalkyl or a 3- to 4-membered heterocycloalkyl group optionally substituted with one or more alkyl, halogroup, hydroxyl, or optionally substituted alkoxycarbonyl groups.

[0124] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is a cycloalkyl or heterocycloalkyl group optionally substituted with one or more halogroups, hydroxyl groups, or optionally substituted alkoxycarbonyl groups. In some embodiments, R3 is a (C3-C6)-cycloalkyl or a 3- to 6-membered heterocycloalkyl group optionally substituted with one or more halogroups, hydroxyl groups, or optionally substituted alkoxycarbonyl groups. In some embodiments, R3 is a (C3-C4)-cycloalkyl or a 3- to 4-membered heterocycloalkyl group optionally substituted with one or more halogroups, hydroxyl groups, or optionally substituted alkoxycarbonyl groups.

[0125] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R3 is cyclopropyl, cyclobutyl, oxetane, azirone, piperidinyl or azibicyclo[3.2.1]octyl, each optionally substituted with one or more alkyl, halogroup, hydroxyl, optionally substituted alkyl or optionally substituted alkoxycarbonyl groups.

[0126] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R3 is cyclopropyl, cyclobutyl, oxetyl, or azirone, each optionally substituted with one or more halogroups, hydroxyl groups, optionally substituted alkyl groups, or optionally substituted alkoxycarbonyl groups.

[0127] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R3 is a cycloalkyl or heterocycloalkyl group optionally substituted with one or more alkyl, halogroup, hydroxyl, or alkoxycarbonyl groups.

[0128] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R3 is a cycloalkyl or heterocycloalkyl group optionally substituted with one or more halogroups, hydroxyl groups or alkoxycarbonyl groups.

[0129] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R3 is cyclopropyl, cyclobutyl, oxetane, azirone, piperidinyl or azibicyclo[3.2.1]octyl, each optionally substituted with one or more alkyl, halogroup, hydroxyl or alkoxycarbonyl groups.

[0130] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R3 is cyclopropyl, cyclobutyl, oxetyl, or azirone, each optionally substituted with one or more halogroups, hydroxyl groups, or alkoxycarbonyl groups.

[0131] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is optionally surrounded by one or more fluorinated groups, hydroxyl groups, methyl groups, or... Substituted cycloalkyl or heterocycloalkyl.

[0132] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is cyclopropyl, cyclobutyl, oxetane, azirone, piperidinyl, or azirbicyclo[3.2.1]octyl, each optionally oxidized by one or more fluorinated groups, hydroxyl groups, methyl groups, or... replace.

[0133] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is cyclopropyl, cyclobutyl, oxetyl, or azirone, each optionally oxidized by one or more fluorinated, hydroxyl, methyl, or... replace.

[0134] In some implementations, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is... , , , , , , , , , or .

[0135] In some implementations, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is... , , , , or .

[0136] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen, methyl, , , , , , , , , , , , , , , , , , , , , , , , , or .

[0137] In some implementations, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is... , , , , , , , , , , , , , , , , , or .

[0138] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R3 is hydrogen, methyl, , , , , , , , , or .

[0139] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R7 is an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclic alkyl. In some embodiments, R7 is an optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. In some embodiments, R7 is an optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted lower alkynyl. In some embodiments, R7 is a lower alkyl, lower alkenyl, or lower alkynyl. In some embodiments, R7 is an optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclic alkyl.

[0140] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R7 is an optionally substituted aryl or optionally substituted heteroaryl.

[0141] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R7 is an optionally substituted phenyl or optionally substituted pyridyl group. In some embodiments, R7 is a substituted phenyl or substituted pyridyl group.

[0142] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R7 is an aryl or heteroaryl group, each optionally substituted with a cyano, halogroup, hydroxyl, alkoxy, cycloalkoxy, or lower alkyl group. In some embodiments, R7 is an aryl or heteroaryl group, each optionally substituted with a halogroup, hydroxyl, alkoxy, or lower alkyl group. In some embodiments, R7 is a C6-aryl or a 5- to 6-membered heteroaryl group, each optionally substituted with a cyano, halogroup, hydroxyl, alkoxy, cycloalkoxy, or lower alkyl group.

[0143] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R7 is phenyl or pyridyl, each optionally substituted with a cyano, halogroup, hydroxyl, alkoxy, cycloalkoxy, or lower alkyl group.

[0144] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R7 is an aryl or heteroaryl group, each optionally substituted with a halogroup and an alkoxy group. In some embodiments, R7 is a C6-aryl or a 5- to 6-membered heteroaryl group, each optionally substituted with a halogroup and an alkoxy group.

[0145] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, R7 is phenyl or pyridyl, each optionally substituted with a halogroup and an alkoxy group.

[0146] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R7 is an aryl or heteroaryl group, each optionally substituted with a fluorinated group, -OCH3, -OCD3, -OCF2H, -OCH2F, or -OCF3. In some embodiments, R7 is an aryl or heteroaryl group, each optionally substituted with a fluorinated group, -OCH3, or -OCD3. In some embodiments, R7 is an aryl or heteroaryl group, each optionally substituted with a fluorinated group or -OCH3.

[0147] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R7 is phenyl or pyridyl, each optionally substituted with a fluorinated group, -OCH3, -OCD3, -OCF2H, -OCH2F, or -OCF3. In some embodiments, R7 is phenyl or pyridyl, each optionally substituted with a fluorinated group, -OCH3, or -OCD3. In some embodiments, R7 is phenyl or pyridyl, each optionally substituted with a fluorinated group or -OCH3.

[0148] In some implementations, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, R7 is... , , or In some implementations, R7 is... .

[0149] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, ring A is an optionally substituted aryl or optionally substituted cycloalkyl group. In some embodiments, ring A is an optionally substituted aryl group. In some embodiments, ring A is an optionally substituted benzyl group. In some embodiments, ring A is an optionally substituted 5- or 6-membered cycloalkyl group. In some embodiments, ring A is an optionally substituted cyclopentylene. In some embodiments, ring A is an optionally substituted cyclohexylene.

[0150] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, ring A is an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycloalkyl group.

[0151] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, ring A is an optionally substituted heteroarylexicon or an optionally substituted heterocycloalkylenexicon. In some embodiments, ring A is an optionally substituted 5- or 6-membered heteroarylexicon or an optionally substituted 5- or 6-membered heterocycloalkylenexicon. In some embodiments, ring A is an optionally substituted 5-membered heteroarylexicon or an optionally substituted 5-membered heterocycloalkylenexicon. In some embodiments, ring A is a 5-membered heteroarylexicon or a 5-membered heterocycloalkylenexicon.

[0152] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, ring A is optionally substituted with a pyrrolidinyl group, optionally substituted with a pyrazolylyl group, optionally substituted with an imidazolylyl group, or optionally substituted with an oxazolylyl group.

[0153] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, ring A is optionally substituted with a pyrrolithoyl group, optionally substituted with a pyrazololithoyl group, optionally substituted with a dihydro-imidazololithoyl group, or optionally substituted with a dihydro-oxazololithoyl group. In some embodiments, ring A is pyrrolithoyl, pyrazololithoyl, dihydro-imidazololithoyl, or dihydro-oxazololithoyl.

[0154] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic) or (Id) or their pharmaceutically acceptable salts, ring A is pyrroleyl, pyrazolyl, 1,3-dihydro-2H-imidazol-2-ketoyl (onylidene), or oxazol-2(3H)-ketoyl.

[0155] In some embodiments, for compounds of formula (I), (Ia), (Ib), (Ic), or (Id) or their pharmaceutically acceptable salts, for , , , , , , or In some implementation schemes, for or .

[0156] In another respect, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 5-Amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(oxetane-3-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, (R)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, 3-(5-amino-4-carbamoyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid methyl ester 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-methyl-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-cyclopropyl-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-carbamoyl-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazol-7-yl)methyl)-2-methoxynicotinamide, N-((4-(5-amino-4-carbamoyl-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxynicotinamide, 5-Amino-3-(7-((2,5-difluorobenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-(1,3-difluoropropane-2-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide, 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(5-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(4-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(4-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrazolo[3,4-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide, (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, (R)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, (S)-5-amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, (R)-5-amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide, (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide, 5-Amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-(3,3-difluorocyclobutyl)-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(oxetane-3-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(oxetane-3-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(oxetane-3-yl)-1H-pyrazol-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide, 5-Amino-1-cyclopropyl-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-cyclopropyl-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-cyclopropyl-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-(1,3-difluoropropane-2-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-(1,3-difluoropropane-2-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrazol-4-carboxamide, 5-Amino-1-(1,3-difluoropropane-2-yl)-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide, (S)-2-(5-amino-4-carbamoyl-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)propionic acid, (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-hydroxypropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-(4-methylpiperazin-1-yl)propane-2-yl)-1H-pyrazole-4-carboxamide, 1-(1-(4-acetylpiperazin-1-yl)propane-2-yl)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-(8-azabicyclo[3.2.1]octane-3-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazole-4-carboxamide, 5-Amino-1-(1-(2,2-difluoroethyl)piperidin-4-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-(methoxy-d3)benzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-(trifluoromethoxy)benzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((2-(difluoromethoxy)-5-fluorobenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,3,3-tetrafluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1,3,3,3-hexafluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazole-4-carboxamide, 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(2-fluorocyclopropyl)-1H-pyrazole-4-carboxamide and 5-Amino-1-(bicyclo[1.1.1]pentan-1-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide, Or its pharmaceutically acceptable salt.

[0157] In another respect, this disclosure provides a compound selected from the compounds set forth in Table 1 below, and a pharmaceutically acceptable salt thereof.

[0158] Table 1. Illustrative Compounds of the Invention Single enantiomer; stereochemical random assignment In some embodiments, the compound of Formula I binds to a kinase selected from BTK mutants (such as BTK C481S). In some embodiments, the compound of Formula I binds to a kinase that is BTK or a BTK C481S mutant, with a Kd less than 50 µM, 25 µM, 10 µM, 5 µM, or 1 µM as measured in an in vitro assay. In some embodiments, the compound of Formula I inhibits a kinase selected from BTK and BTK C481S mutants, with an IC50 value determined in an in vitro kinase assay. 50 The concentrations are 10 µM, 5 µM, 2 µM, 1 µM, 500 nM, 200 nM, 100 nM, or lower. In some embodiments, the compounds of Formula I inhibit the activity of one or more kinases selected from BTK or BTK C481S, as determined in an in vitro kinase assay, with an IC50 value of [value missing] in the in vitro assay. 50 The concentrations are 1 µM, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, or lower. In some embodiments, the compounds of Formula I selectively inhibit the activity of one or more kinases selected from BTK or BTK C481S mutants. In some embodiments, the compounds of Formula I selectively inhibit the activity of one or more kinases selected from BTK or BTK C481S, with an IC50 value of 1 µM, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, or lower. 50 IC50 is selected from the following kinases. 501 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 7, 1 / 10, 1 / 15, 1 / 20, 1 / 25, 1 / 30, 1 / 40, 1 / 50, 1 / 100, 1 / 150, 1 / 200, 1 / 300, 1 / 400, 1 / 500, 1 / 1000, 1 / 2000, or lower: ABL1, AKT1 (PKBα), AURKB (Aurora B), BLK, CDK1 / cyclin B, CHEK1 (CHK1), CSNK1G2 (CK1γ2), EGFR (ErbB1), FGFR1, FGFR2, FGFR3, FGR, FLT3, FRAP1 (mTOR), FYN, IGF1R, IKBKB (IKKβ), INSR, JAK1, JAK2, JAK3, KDR, KIT, LCK, LYN A. MAP2K1 (MEK1), MAP4K5 (KHS1), MAPK1 (ERK2), MAPK14 (p38α), MAPKAPK2, MET (cMet), PDGFRB (PDG FRβ), PIK3CA / PIK3R1 (p110α / p85α), PRKCB2 (PKCβII), PTK2B (FAK2), PTK6 (Brk), RAF1 (cRAF) Y340D Y341D, RET, RPS6KB1 (p70S6K), SRC, SRMS (Srm), and YES1.

[0159] In some embodiments, one or more compounds of Formula I are capable of inhibiting cell proliferation. For example, in some embodiments, one or more compounds of Formula I inhibit the proliferation of tumor cells or tumor cell lines. For example, such cell lines express a kinase, which is BTK or a BTK C481S mutant. In some embodiments, compounds of Formula I inhibit the proliferation of A549, A431, HCC827, or H1975 cells in in vitro models or in vivo models such as xenograft mouse models. In some embodiments, one or more compounds of Formula I can inhibit the proliferation of HCC827 or H1975 cells cultured in vitro, with an IC50 value of [missing information]. 50 Values ​​less than 100 µM, 75 µM, 50 µM, 25 µM, 15 µM, 10 µM, 5 µM, 3 µM, 2 µM, 1 µM or lower.

[0160] B. Preparation method The compounds disclosed herein can be prepared via the following routes. The materials used herein are commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the listed compounds or any particular substituents and are used for illustrative purposes. Although various steps are described and depicted in the schemes, in some cases these steps may be performed in a different order than shown in the schemes. Various modifications can be made to these synthetic reaction schemes, and those skilled in the art will be inspired by the disclosure contained herein. Numbers do not necessarily correspond to the numbers of the claims or other forms.

[0161] Option A In scheme A, boric acid or borate ester A reacts with pyrazolyl halide B in the presence of a base (such as Na₂CO₃, K₂CO₃, Cs₂CO₃) and a Pd catalyst via a Suzuki cross-coupling reaction to generate compound C. This reaction is typically carried out in a suitable solvent (such as 1,4-dioxane, water, tetrahydrofuran, or mixtures thereof) within a temperature range of 25 to 180 °C. The protected amino compound C is then deprotected to the free amine D. The specific reagent used depends on the nature of the protecting group P1, but typical groups include acid-labile groups (such as Boc or silyl ethers), which are deprotected at room temperature in solvents (such as DCM, chloroform, or toluene) with acids (such as HCl, TFA, TsOH, etc.). An amide bond forms with the activated acid E (expressed as an acyl chloride) to generate compound F. Any amide bond formation reaction is suitable for this reaction. For example, the carboxylic acid of E can be activated with oxaloyl chloride, BOP, HATU, HBTU, CDI, etc. Amide bond formation reactions can also occur in the presence of a suitable base. Suitable bases include, but are not limited to, Na₂CO₃, NaHCO₃, K₂CO₃, and Cs₂CO₃. Suitable solvents include, but are not limited to, DMF, DMSO, DMA, NMP, acetonitrile, THF, 1,4-dioxane, water, and combinations thereof. The reaction is typically carried out in the temperature range of 0 to 100 °C. Finally, the hydrolysis of nitrile F yields a compound of formula (I). Suitable reagents for hydrolysis can be acid- or base-catalyzed. Alternatively, treatment of the nitrile with hydrogen peroxide can also lead to the formation of a compound of formula (I). It is noteworthy that the order of steps in scheme A can be reversed, i.e., the amide bond is formed first, followed by the aryl C / C bond.

[0162] C. Pharmaceutical compositions and formulations In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In certain embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers that contain excipients and adjuvants that facilitate the processing of the active compound into a formulation suitable for pharmaceutical manufacturing. A suitable formulation depends on the chosen route of administration. Any pharmaceutically acceptable technique, carrier, and excipient is suitable for formulating the pharmaceutical compositions described herein. Remington: The Science and Practice of Pharmacy 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E. Remington’s Pharmaceutical Sciences Mack Publishing Co., Easton, Pennsylvania 1975; edited by Liberman, HA and Lachman, L. Pharmaceutical Dosage Forms Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins1999).

[0163] This document provides pharmaceutical compositions comprising a compound of Formula I and one or more pharmaceutically acceptable diluents, excipients, or carriers. In some embodiments, the compound is administered as a pharmaceutical composition, wherein the compound of Formula I is mixed with other active ingredients, such as in combination therapy. This document covers the following combination therapy section as well as all combinations of active ingredients described throughout this disclosure. In specific embodiments, the pharmaceutical composition comprises one or more compounds of Formula I.

[0164] As used herein, a pharmaceutical composition refers to a mixture of a compound of Formula I with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In some embodiments, the pharmaceutical composition facilitates the administration of the compound to a living organism. In some embodiments, when implementing the treatment methods or uses provided herein, a therapeutically effective amount of a compound of Formula I provided herein is administered in the form of a pharmaceutical composition to a mammal suffering from a disease or condition to be treated. In a particular embodiment, the mammal is a human. In some embodiments, the therapeutically effective amount may vary depending on the severity of the disease, the age and relative health status of the subject, the potency of the compound used, and other factors. The compounds described herein may be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0165] In one embodiment, one or more compounds of Formula I are formulated in an aqueous solution. In a particular embodiment, the aqueous solution, by way of example only, is selected from physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compounds of Formula I are formulated for transmucosal administration. In a particular embodiment, the transmucosal formulation comprises an exfoliant suitable for penetrating the barrier to be penetrated. In still other embodiments, the compounds described herein are formulated for other parenteral injections, suitable formulations including aqueous or non-aqueous solutions. In a particular embodiment, such solutions comprise physiologically compatible buffers and / or excipients.

[0166] In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein (including those of Formula I) are formulated by combining an active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated into oral dosage forms, including, by way of example only, tablets, powders, pills, sugar-coated pills, capsules, liquids, gels, syrups, elixirs, liquids, suspensions, etc.

[0167] In some embodiments, pharmaceutical formulations for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally milling the resulting mixture, and processing the granular mixture after adding suitable adjuvants (if desired) to obtain tablets or sugar-coated pellet cores. Suitable excipients are in particular fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose formulations, such as: for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In certain embodiments, a disintegrant is optionally added. Disintegrants include, by way of example only, cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginate or salts thereof (such as sodium alginate).

[0168] In one embodiment, dosage forms such as sugar-coated cores and tablets are provided with one or more suitable coatings. In a particular embodiment, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains other ingredients, for example only, such as gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. Dyes and / or pigments may also optionally be added to the coating for identification purposes. Furthermore, dyes and / or pigments are optionally used to characterize different combinations of active compound dosages.

[0169] In some embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-in capsules made of gelatin, and soft-sealable capsules made of gelatin and a plasticizer (such as glycerin or sorbitol). In certain embodiments, push-in capsules contain an active ingredient mixed with one or more fillers. Fillers include, by way of example only, lactose, binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and optionally stabilizers. In other embodiments, soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers are optionally added.

[0170] In other embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated for oral or sublingual administration. Formulations suitable for oral or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus or continuous infusion. In certain embodiments, the injectable formulation is provided in a unit dosage form (e.g., an ampoule) or a multi-dose container. Optionally, a preservative is added to the injectable formulation. In still other embodiments, the pharmaceutical composition of the compounds of Formula I is formulated in a form suitable for parenteral injection, i.e., as a sterile suspension, solution, or emulsion in an oily or aqueous medium. The parenteral injection formulation optionally contains a formulation such as a suspending agent, stabilizer, and / or dispersant. In certain embodiments, the pharmaceutical formulation for parenteral administration comprises an aqueous solution of the active compound in a water-soluble form. In further embodiments, the suspension of the active compound is prepared into a suitable oily injectable suspension. Suitable lipophilic solvents or mediators for the pharmaceutical compositions described herein, by way of example only, include fatty oils such as sesame oil, or synthetic fatty acid esters or liposomes such as ethyl oleate, triglycerides, or liposomes. In certain specific embodiments, the aqueous injectable suspension contains substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for reconstitution with a suitable mediator (such as sterile, pyrogen-free water) prior to use.

[0171] In other embodiments, the compounds of Formula I are applied topically. The compounds described herein are formulated into a variety of topically applicable compositions, such as solutions, suspensions, lotions, gels, pastes, sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonic agents, buffers, and preservatives.

[0172] In other embodiments, the Formula I compound is formulated for transdermal administration. In specific embodiments, the transdermal formulation employs a transdermal delivery device and a transdermal delivery patch, and may be a lipophilic emulsion or buffered aqueous solution, dissolved and / or dispersed in a polymer or binder. In various embodiments, such patches are constructed for continuous, pulsed, or on-demand delivery of pharmaceutical formulations. In further embodiments, transdermal delivery of the Formula I compound is achieved via iontophoresis patches or the like. In some embodiments, the transdermal patch provides controlled delivery of the Formula I compound. In specific embodiments, the absorption rate is slowed by using a rate-controlled membrane or by embedding the compound in a polymer matrix or gel. In alternative embodiments, an absorption enhancer is used to improve absorption. The absorption enhancer or carrier comprises absorbable, pharmaceutically acceptable solvents that facilitate penetration through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage, including a backing member, a reservoir containing the compound (optionally with a carrier), an optional rate-controlled barrier to deliver the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and a means of securing the device to the skin.

[0173] In other embodiments, the compound of Formula I is formulated for inhalation administration. Various forms suitable for inhalation administration include, but are not limited to, aerosols, sprays, or powders. Pharmaceutical compositions of Formula I are conveniently delivered as aerosol sprays from pressurized packaging or nebulizers, using a suitable propellant (such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases). In certain embodiments, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a measured amount. In some embodiments, capsules and cartridges for inhalers or blowpipes, such as gelatin (by way of example only), are formulated to contain a powder mixture of the compound and a suitable powder matrix (such as lactose or starch).

[0174] In other embodiments, the compounds of Formula I are formulated into rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel suppositories, or retention enemas, which contain a conventional suppository base, such as cocoa butter or other glycerides, and a synthetic polymer, such as polyvinylpyrrolidone, PEG, etc. In the suppository form of the composition, a low-melting-point wax (such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter) is first melted.

[0175] In some embodiments, the pharmaceutical composition is formulated in any conventional manner using one or more physiologically acceptable carriers that contain excipients and adjuvants that facilitate the processing of the active compound into a formulation suitable for pharmaceutical manufacturing. A suitable formulation depends on the chosen route of administration. Any pharmaceutically acceptable technique, carrier, and excipient may be used optionally and appropriately. Pharmaceutical compositions comprising compounds of Formula I are manufactured in a conventional manner, for example, by way of conventional mixing, dissolving, granulation, pelleting, grinding, emulsification, encapsulation, embedding, or compression processes, by way of example only.

[0176] The pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent, or excipient, and at least one compound of formula I described herein as an active ingredient. The active ingredient is present in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. Furthermore, the methods and pharmaceutical compositions described herein also include the use of… N- Oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Furthermore, the compounds described herein include unsolvated forms as well as solvated forms that form with pharmaceutically acceptable solvents (such as water, ethanol, etc.). The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally comprise other pharmaceutical or pharmaceutical preparations, carriers, excipients (such as preservatives, stabilizers, wetting agents, or emulsions), solution enhancers, salts for adjusting osmotic pressure, buffers, and / or other substances of therapeutic value.

[0177] Methods of preparing compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, pouches, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles comprising the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein are in the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc.

[0178] In some embodiments, pharmaceutical compositions comprising at least one compound of formula I are illustratively taken in liquid form, wherein the agent is present as a solution, suspension, or both. Typically, when the composition is applied in solution or suspension form, a first portion of the agent is present in solution, while a second portion of the agent is present as particulate matter in a suspension within a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0179] In some embodiments, the useful aqueous suspension contains one or more polymers as suspending agents. Useful polymers include water-soluble polymers (such as cellulose polymers, e.g., hydroxypropyl methylcellulose) and water-insoluble polymers, such as cross-linked carboxyl-containing polymers. Some pharmaceutical compositions described herein contain a mucosal adhesive polymer selected from, for example, carboxymethyl cellulose, carbomer (acrylic polymer), poly(methyl methacrylate), polyacrylamide, polycarbofil, acrylate / butyl acrylate copolymer, sodium alginate, and dextran.

[0180] Useful pharmaceutical compositions may also optionally contain a solubilizer to aid in the dissolution of compounds of formula I. The term "solventizer" generally includes agents that result in the formation of micelle solutions or solutions of the actual reagent. Certain acceptable nonionic surfactants (e.g., polysorbate 80) can be used as solubilizers, as can ophthalmologically acceptable ethylene glycol, polyethylene glycol (e.g., polyethylene glycol 400), and ethylene glycol ethers.

[0181] In addition, useful pharmaceutical compositions optionally comprise one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / glucose, sodium bicarbonate, and ammonium chloride. These acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0182] In addition, useful compositions optionally contain one or more salts in the amount required to bring the osmotic pressure of the composition within an acceptable range. Such salts include those containing sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0183] Other useful pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as phenylmercuric borate and thimerosal; stable chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, hexadecyltrimethylammonium bromide, and hexadecylpyridinium chloride.

[0184] Other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octylphenyl polyol 10 and octylphenyl polyol 40.

[0185] Other useful compositions include one or more antioxidants to enhance chemical stability when needed. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0186] In some embodiments, the aqueous suspension composition is packaged in a single-dose, non-resealable container. Alternatively, a multi-dose, resealable container is used, in which case a preservative is typically included in the composition.

[0187] In alternative embodiments, other delivery systems for hydrophobic drug compounds are employed. Liposomes and emulsions are examples of delivery media or carriers used herein. In some embodiments, organic solvents, such as... N- Methylpyrrolidone. In other embodiments, the compounds described herein are delivered using a sustained-release system, such as a semi-permeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, the sustained-release capsule releases the compound for several weeks to over 100 days. Additional protein stabilization strategies are employed depending on the chemical properties and biological stability of the therapeutic agent.

[0188] In some embodiments, the formulations described herein comprise one or more antioxidants, metal chelators, thiol compounds, and / or other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) about 0.003% to about 0.02% w / v polysorbate 80, (g) about 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations of the above components.

[0189] D. Method of application Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, mucosal, transdermal, vaginal, ocular, nasal, and topical administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0190] In some embodiments, the compounds described herein are administered locally rather than systemically, for example, by direct injection into an organ, typically as a reservoir formulation or a sustained-release formulation. In certain embodiments, long-acting formulations are administered via implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to the organ and selectively absorbed by the organ. In yet another embodiment, the compounds described herein are provided as immediate-release, sustained-release, or intermediate-release formulations. In yet another embodiment, the compounds described herein are administered locally.

[0191] E. Reagent kits / products For use in the therapeutic applications described herein, kits and articles are also provided. In some embodiments, such kits include carriers, packaging, or containers that are divided to contain one or more containers, such as vials, tubes, etc., each containing one of the individual elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. Containers are made of a variety of materials, such as glass or plastic.

[0192] The articles described herein include packaging materials. Packaging materials for packaging pharmaceutical products include, for example, those described in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended administration and mode of treatment. For example, a container may contain one or more of the compounds described herein, optionally in a composition or in combination with another reagent described herein. The container may optionally have a sterile inlet (e.g., the container is an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic needle). Such kits may optionally include compounds with identification descriptions or labels or instructions relating to their use in the methods described herein.

[0193] For example, a kit typically includes one or more additional containers, each containing one or more materials (such as reagents, optionally in concentrated form, and / or devices) required from a commercial and user perspective for using the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carriers, packaging, containers, vials, and / or tube labels listing the contents and / or instructions for use, as well as packaging inserts with instructions for use. A set of instructions for use is also typically included. Labels are optionally on or associated with the containers. For example, a label is on the container when the letters, numbers, or other characters forming the label are affixed, molded, or etched to the container itself; a label is associated with the container when it is present within a container or carrier that also contains the container (e.g., as a packaging insert). Additionally, the label indicates that the contents will be used for a specific therapeutic application. Additionally, the label indicates instructions for use of the contents, such as those described herein. In some embodiments, the pharmaceutical composition is presented in the form of a package or dispenser device containing one or more unit dosage forms of the compounds provided herein. The package may contain, for example, metal or plastic foil, such as blister packs. Alternatively, the packaging or dispenser device may include instructions for use. Alternatively, the packaging or dispenser may include a notification relating to the container, in a form prescribed by a government agency regulating the manufacture, use, or sale of the drug, reflecting that agency's approval of the form for human or veterinary use. For example, such a notification may be a prescription drug label approved by the U.S. Food and Drug Administration, or an approved product insert. In some embodiments, a composition containing the compounds described herein is prepared in a compatible drug carrier, placed in a suitable container, and labeled for the treatment of the indicated condition.

[0194] F. Usage Method The chemical entities described herein can be used to treat or to prepare medicaments for treating various conditions. For example, compounds of Formula I are used as protein kinase inhibitors. In some embodiments, the chemical entities described herein are inhibitors of one or more kinases. For example, compounds of Formula I are inhibitors of BTK or mutants of such kinases (including the BTK C481S mutant). Therefore, without wishing to be bound by any particular theory, compounds of Formula I are particularly useful in treating or alleviating the severity of a disease, condition, or symptom associated with the activation of one or more kinases (such as BTK). When the activation of BTK kinase is associated with a particular disease, condition, or symptom, the disease, condition, or symptom may also be referred to as a "BTK-mediated disease" or disease symptom. Therefore, in another aspect, the present invention provides a method for treating or alleviating the severity of a disease, condition, or symptom, wherein the activation of BTK and / or other kinases is associated with a disease state.

[0195] Kinase inhibition can be determined in vitro, in vivo, or in cell lines. In vitro assays include determinations of phosphorylation activity or ATPase activity inhibition of activated kinases. Alternative in vitro assays quantify the ability of an inhibitor to bind to a kinase. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, separating the inhibitor and the complex, and determining the amount of radiolabeled substance bound. Alternatively, inhibitor binding can be determined by performing a competition experiment in which a novel inhibitor is incubated with a kinase that binds to a known radioligand. At a concentration of 1 μmol, one or more compounds of the present invention exhibit at least about 50%, 60%, 70%, 80%, 90%, or even higher inhibition against kinases including BTK or BTK C481S.

[0196] The chemical entities described herein are typically prepared in essentially pure form by standard chromatography before being formulated into pharmaceutically acceptable forms.

[0197] The compounds described in this article can be used to treat various diseases or conditions mediated by BTK.

[0198] BTK plays a role in B-cell development. BTK is crucial for the proliferation and survival of leukemic B cells, making this kinase a promising target not only for treating inflammatory and autoimmune diseases but also for treating B-cell malignancies such as, but not limited to, lymphomas including non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphomas (including extranodal marginal zone B-cell lymphoma, intranodal marginal zone B-cell lymphoma, and splenic marginal zone B-cell lymphoma), Burkitt lymphoma, lymphoplasmacytic lymphoma (aka Waldenstrom macroglobulinemia), as well as tumors and multiple myeloma.

[0199] BTK is also expressed in specific myeloid cells, including monocytes / macrophages, neutrophils, and mast cells. In these myeloid cells, BTK has been shown to be involved in immune complex-mediated activation of FcyR and FceR, which is thought to contribute to the pathogenesis of rheumatoid arthritis (RA).

[0200] Furthermore, BTK is required for osteoclast maturation, and therefore, inhibiting BTK can prevent bone erosion associated with rheumatoid arthritis (RA). The crucial role of BTK in B cells and myeloid cells makes it an attractive target not only for treating B-cell malignancies but also for treating autoimmune diseases.

[0201] One major limitation of small molecule tyrosine protein kinase (BTK) drugs is the existence of clinically acquired resistance. For example, ibrutinib, an irreversible BTK inhibitor, has been approved for the treatment of CLL, mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM). However, known BTK inhibitors (such as ibrutinib) are also known to have gastrointestinal side effects, which are thought to be caused by secondary EGFR inhibitory activity. Therefore, there is a desire for a BTK inhibitor with higher selectivity for BTK inhibition than for EGFR inhibition to reduce or avoid gastrointestinal side effects. Furthermore, clinically acquired resistance to ibrutinib has been shown to be due to mutations within BTK (such as C481S, C481Y, C481R, and C481F) interfering with drug binding.

[0202] In some implementations, the compounds described herein are highly selective BTK inhibitors.

[0203] In some embodiments, the compounds described herein are highly selective BTK inhibitors that also exhibit high activity against the C481S mutant of BTK. Therefore, in some embodiments described herein, the methods described herein can be used to treat relapsed or refractory diseases, such as relapsed or refractory B-cell malignancies. In specific embodiments, the relapsed or refractory disease has clinically acquired resistance to prior treatment. In some embodiments, the prior treatment is another BTK inhibitor, namely ibrutinib.

[0204] In some implementation schemes, diseases or conditions that can be treated by inhibiting BTK may include: cancer, lymphoma, leukemia, autoimmune diseases, inflammatory conditions, xenoimmune conditions, or fibrosis. Specific conditions that can be treated by inhibiting BTK may include: B-cell malignancies, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma (such as ABC-DLBCL), mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastases, follicular lymphoma, chronic lymphocytic lymphoma, and B-cell prolymphocytes. Leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasmacytoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, intranodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease Diseases including juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, aortitis, temporal arteritis, warm autoimmune hemolytic anemia, and Wegener's granulomatosis. granulomatosis, psoriasis, alopecia universalis, Behcet's diseaseDisease), chronic fatigue, autonomic dysfunction, endometriosis, interstitial cystitis, neurogenic myotonia, scleroderma, vulvar pain, graft-versus-host disease, transplantation, blood transfusion, allergic reaction, allergy, type I hypersensitivity reaction, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis Pleurisy, phlebitis, interstitial pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrotic alveolitis (CFA), obliterative bronchiolitis, bronchiectasis, fatty liver disease, fatty degeneration (such as non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (such as primary biliary cirrhosis (PBC)), cirrhosis, alcoholic liver fibrosis, bile duct injury, biliary fibrosis, cholestasis, or cholangitis. In some implementations, hepatic or liver fibrosis...Fibrosis includes, but is not limited to, liver fibrosis associated with: alcoholism, viral infections (such as hepatitis (e.g., hepatitis C, hepatitis B, or hepatitis D)), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (such as alcohol, drugs, and environmental toxins), renal fibrosis (such as chronic renal fibrosis), kidney diseases associated with injury / fibrosis (such as chronic kidney disease associated with diabetes (e.g., diabetic nephropathy)), lupus, nephrosclerosis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy associated with chronic kidney disease (CKD), renal fibrosis, chronic progressive kidney disease (CPN), and renal fibrosis. Interstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephropathy (PGN), endothelial / thrombotic microangiopathy, HIV-related nephropathy, or fibrosis associated with exposure to toxins, irritants, or chemotherapeutic agents; fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with foregut inflammatory conditions (such as Barrett's esophagus and chronic gastritis), and / or fibrosis associated with hindgut inflammatory conditions (such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohn's disease); age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and neovascular glaucoma.

[0205] In some embodiments, the chemical entities described herein are used to treat B-cell malignancies. In some embodiments, the methods described herein can be used to treat B-cell proliferative disorders, including but not limited to diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, intranodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, and lymphomatoid granulomatosis.

[0206] In some implementations, diseases or conditions that can be treated by inhibiting BTK are immune-mediated diseases, such as: arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Auder's thyroiditis, Graves' disease, Sjögren's syndrome, Guillain-Barré syndrome, acute disseminated encephalomyelitis, and Addison's disease. Oculoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, pulmonary hemorrhage-nephritis syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, aortitis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic dysfunction, endometriosis, interstitial cystitis Neurogenic myotonia, scleroderma and vulvar pain, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, bone Inflammation, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, graft-versus-host disease, transplantation, blood transfusion, allergic reactions, allergies, type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0207] In some implementations, diseases or conditions that can be treated by inhibiting BTK are inflammatory diseases, such as: arthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, and purulent hidradenitis. Inflammation, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

[0208] In some implementations, diseases or conditions that can be treated by inhibiting BTK are autoimmune diseases, such as: lupus and Sjögren's syndrome, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Auder's thyroiditis, Graves' disease, Sjögren's syndrome, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, oculoclonus-myoclonus syndrome, ankylosing spondylitis, and antiphospholipids. Antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, pulmonary hemorrhage-nephritis syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, aortitis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic dysfunction, endometriosis, interstitial cystitis, neurogenic myotonia, scleroderma, and vulvar pain.

[0209] In some implementations, diseases or conditions that can be treated by inhibiting BTK are xenoimmune diseases, such as graft-versus-host disease, transplantation, blood transfusion, allergic reactions, allergies, type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0210] In some implementations, diseases or conditions that can be treated by inhibiting BTK are fibrotic diseases, such as: pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrotic alveolitis (CFA), obliterative bronchiolitis, bronchiectasis, fatty liver disease, steatosis (such as non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (such as primary biliary cirrhosis (PBC), cirrhosis, alcoholic liver fibrosis, bile duct injury, biliary fibrosis, cholestasis, or cholangitis). In some implementations, liver or liver fibrosis includes, but is not limited to, liver fibrosis associated with: alcoholism, viral infections (such as hepatitis (such as hepatitis C, hepatitis B, or hepatitis D)), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (such as alcohol, drugs, and environmental toxins), renal fibrosis (such as chronic renal fibrosis), and injury. Fibrosis-related nephropathy (such as chronic kidney disease associated with diabetes, such as diabetic nephropathy), lupus, nephrotic scleroderma, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy associated with human chronic kidney disease (CKD), renal fibrosis, chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerular nephropathy (PGN), endothelial / thrombotic microangiopathy. Injuries, HIV-related nephropathy, or fibrosis associated with exposure to toxins, irritants, or chemotherapy agents; fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with foregut inflammatory conditions (such as Barrett's esophagus and chronic gastritis), and / or fibrosis associated with hindgut inflammatory conditions (such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohn's disease); age-related macular degeneration; diabetic retinopathy; retinopathy of prematurity; and neovascular glaucoma.

[0211] In some embodiments, the disease or condition treated by the compounds disclosed herein is cancer, lymphoma, leukemia, autoimmune disease, inflammatory condition, or fibrosis. In some embodiments, the disease or condition is selected from: B-cell malignancies, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma (e.g., ABC-DLBCL), mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastases, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, Sjögren's syndrome, and lupus.

[0212] The chemical entities described herein can also be used in combination with other well-known therapeutic agents selected for their specific usefulness against the treated condition. For example, the chemical entities described herein can be used in combination with at least one additional anticancer agent and / or cytotoxic agent. Furthermore, the chemical entities described herein can also be used in combination with other inhibitors of signaling pathways that link cell surface growth factor receptors to portions of nuclear signaling pathways that trigger cell proliferation.

[0213] Known anticancer agents and / or cytotoxic agents that can be used in combination with the chemical entities described herein include: (i) Other antiproliferative / antitumor drugs and combinations thereof, such as those used in medical oncology, including alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolate agents such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytarabine, and hydroxyurea); and antitumor antibiotics (e.g., anthracyclines such as doxorubicin and bleomycin). Doxorubicin, doxorubicin, epirubicin, idarubicin, mitomycin C, styromycin, and styromycin; antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vinorelbine, and vinorelbine, and taxanes such as paclitaxel and taxotere, and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, acridine, topotecan, and camptothecin); (ii) Cell growth inhibitors, such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), anti-androgens (e.g., bicalutamide, flutamide, nilumet, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, voroxyzole, and exemestane), and 5α-reductase inhibitors such as finasteride; (iii) Anti-invasive agents [e.g., c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-Chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazolyl-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 66586661) and bosutinib (SKl-606), as well as metalloproteinase inhibitors such as marimasitol, urokinase plasminogen activator receptor function inhibitors, or antibodies against heparinase-like enzymes; (iv) Growth factor function inhibitors: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux (C225)], and Stem et al. Critical reviews in oncology / haematology, 2005, Vol. 54, Any growth factor antibodies or growth factor receptor antibodies disclosed on pages 11-29); such inhibitors also include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774) and 6-propenyl Amide-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI1033), erbB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors), such as farnesyltransferase inhibitors, such as sorafenib (BAY). 43-9006), tilpifaliben (RI15777) and lonafaliben (SCH66336), inhibitors of cell signaling via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, P13 kinase inhibitors, Plt3 kinase inhibitors, CSF-IR kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (e.g. AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors; (v) Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor (VEGF), such as the anti-VEGF antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vastarani (PTK787), sunitinib (SU1l248), axitinib (AG-013736), pazopanib (GW 786034), and 4-{4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidone-1-ylpropoxy)quinazoline (AZD2l7l; Example 240 in WO 00 / 47212), such as those in international patent applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO Those disclosed in 98 / 13354 and compounds that act through other mechanisms (e.g., linolenic acid, integrin av3 function inhibitors and angiostatin)). (vi) Vascular damaging agents, such as Compressor A4 and compounds disclosed in international patent applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; (vii) Endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan. (viii) Antisense therapies, such as those targeting the targets listed above, such as ISIS 2503 (an anti-ras antisense agent). (ix) Gene therapy approaches, including, for example, methods that replace abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2), GDEPT (gene-guided enzyme prodrug therapy) approaches (such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase), and methods that enhance a subject's tolerance to chemotherapy or radiation therapy (such as gene therapy for multidrug resistance); and (x) Immunotherapy methods, including, for example, in vitro and in vivo methods that enhance the immunogenicity of target tumor cells, such as transfection with cytokines (such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor), methods that reduce T cell energy, methods that use transfected immune cells (such as dendritic cells transfected with cytokines), methods that use tumor cell lines transfected with cytokines, and methods that use anti-idiotype antibodies.

[0214] (xi) Checkpoint inhibitors, including, for example, inhibitors of checkpoint proteins such as PD-1, PD-L1, or TCLA-4. Some examples of checkpoint inhibitors are pembrolizumab, nivoluma, and ipilimumab.

[0215] In some embodiments, at least one chemical entity is administered in combination with one or more agents selected from the following: paclitaxel, bortezomib, dacarbazine, gemcitabine, trastuzumab, bevacizumab, capecitabine, docetaxel, erlotinib, aromatase inhibitors such as AROMASIN™ (exemestane), and estrogen receptor inhibitors such as FASLODEX™ (fulvestrant).

[0216] When the chemical entities described herein are administered to human subjects, the daily dose is typically determined by the prescribing physician, and this dose usually varies based on the individual subject's age, weight, and response, as well as the severity of the subject's symptoms.

[0217] In one exemplary application, an appropriate amount of at least one chemical entity is administered to a mammal undergoing cancer treatment (e.g., breast cancer). Administered typically in doses of about 0.01 mg / kg body weight to about 100 mg / kg body weight daily (administered as a single dose or in multiple doses), such as at least about 0.1 mg / kg body weight daily. Specific therapeutic doses may include, for example, chemical entities from about 0.01 mg to about 1000 mg, such as including, for example, from about 1 mg to 1000 mg. In a unit dose formulation, the amount of at least one chemical entity may vary or be adjusted from about 0.1 mg to 1000 mg, such as from about 1 mg to 300 mg, for example, from 10 mg to 200 mg, depending on the specific application. The amount administered will be based on the specific IC50 of the at least one chemical entity used. 50 Values ​​vary depending on the judgment of the attending clinician, taking into account factors such as health, weight, and age. In the combined use of at least one chemical entity described herein, which is not the sole active ingredient, it is possible to administer a smaller amount of at least one chemical entity and still have therapeutic or preventative effects.

[0218] In some implementations, the pharmaceutical formulation is a unit dosage form. In such dosage forms, the formulation is subdivided into unit doses containing an appropriate amount (e.g., an effective amount to achieve the desired purpose) of the active ingredient.

[0219] The actual dosage used may vary depending on the patient's needs and the severity of the condition being treated. Determining the appropriate dosage for a specific situation is within the scope of skill in the art. Generally, treatment begins with a smaller dose than the optimal dose of at least one chemical entity. This dose is then gradually increased until the optimal effect for that situation is achieved. For convenience, if necessary, the total daily dose may be divided and administered in divided doses within the day.

[0220] The dosage and frequency of administration of at least one chemical entity described herein, as well as (if applicable) other chemotherapeutic agents and / or radiotherapy, will be adjusted based on the judgment of the attending clinician (internist) taking into account factors such as the patient's age, condition and body size, and the severity of the disease being treated.

[0221] Chemotherapy agents and / or radiotherapy may be administered according to treatment regimens well known in the art. It will be apparent to those skilled in the art that the administration of chemotherapy agents and / or radiotherapy may vary depending on the disease being treated and the known effects of the chemotherapy agent and / or radiotherapy on that disease. Furthermore, treatment regimens (e.g., dosage and frequency of administration) may vary based on the knowledge of a skilled clinician, taking into account the observed effects of the administered therapeutic agent (i.e., antitumor agents or radiation) on the subject and the observed response of the disease to the administered therapeutic agent.

[0222] Furthermore, at least one chemical entity described herein generally need not be administered in the same pharmaceutical composition as a chemotherapeutic agent, and may be administered via different routes due to their different physical and chemical properties. For example, a chemical entity / composition may be administered orally to produce and maintain its good blood levels, while a chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the desirability of administration (where possible, in the same pharmaceutical composition) is entirely within the knowledge of a skilled clinician. Initial administration may be performed according to established protocols known in the art, followed by adjustments to the dosage, mode of administration, and frequency of administration by a skilled clinician based on observed effects.

[0223] The specific choice of chemical entity (and, where appropriate, chemotherapeutic agents and / or radiation) will depend on the attending physician’s diagnosis and their judgment of the subject’s condition and the appropriate treatment plan.

[0224] Depending on the nature of the proliferative disease, the condition of the patient, and the actual choice of chemotherapeutic agents and / or radiation to be administered in combination with the described chemical entity / composition (i.e., within a single treatment regimen), the chemical entity described herein (and, where appropriate, chemotherapeutic agents and / or radiation) may be administered concurrently (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially.

[0225] In combined application and use, the chemical entity / composition and chemotherapy agent and / or radiation need not be administered simultaneously or substantially simultaneously, and the initial order of administration of the chemical entity / composition and chemotherapy agent and / or radiation may not be important. Therefore, at least one chemical entity described herein may be administered first, followed by chemotherapy agent and / or radiation; or chemotherapy agent and / or radiation may be administered first, followed by at least one chemical entity described herein. This alternating administration may be repeated during a single treatment regimen. The determination of the order of administration and the number of repetitions of each therapeutic agent during the treatment regimen is entirely within the knowledge of a skilled physician after assessing the disease being treated and the condition of the subject. For example, chemotherapy agent and / or radiation may be administered first, followed by the continuation of the treatment with at least one chemical entity described herein, and then (where deemed advantageous) chemotherapy agent and / or radiation, and so on until the treatment regimen is completed.

[0226] Therefore, based on experience and knowledge, practicing physicians can adjust the various administration regimens of the chemical entities / compositions used for treatment according to the individual patient's needs as treatment progresses.

[0227] When determining the effectiveness of treatment at the administered dose, the attending clinician will consider the patient's overall health and more specific signs, such as the reduction of disease-related symptoms, inhibition of tumor growth, and actual shrinkage or suppression of metastasis of the tumor. Tumor size can be measured using standard methods such as radiological studies (e.g., CAT or MRI scans), and continuous measurements can be used to determine whether tumor growth has been delayed or even reversed. The reduction of disease-related symptoms (such as pain) and improvement in overall condition can also help determine the effectiveness of treatment.

[0228] Example The following examples are provided to more fully describe how the invention is used. These examples are presented for illustrative purposes and are not intended to limit the true scope of the invention.

[0229] When performing the procedures described herein, it should be understood that references to specific buffers, culture media, reagents, cells, culture conditions, etc., are not intended to be limiting, but rather to include all relevant materials that a person skilled in the art would consider of interest or value in the specific context in which the discussion is presented. For example, one buffer system or culture medium can often be substituted for another, and similar (if not exactly identical) results can still be obtained. Those skilled in the art will have sufficient knowledge of these systems and methods to be able to make such substitutions without requiring extensive experimentation, thereby optimally serving the purposes of using the methods and procedures disclosed herein.

[0230] I. Chemical Synthesis Example 1: Preparation of 5-amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide At 0 °C, Tf₂O (1.0 mL, 6.0 mmol, 1.3 equivalence) was added to a solution of 3,3-difluorocyclobutane-1-ol (500.0 mg, 4.6 mmol, 1.0 equivalence) and pyridine (2.5 mL, 32.2 mmol, 7.0 equivalence) in DCM (30 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 3,3-difluorocyclobutyltrifluoromethanesulfonate (500.4 mg, 45.2%), which was used directly in the next step. A solution of 3,3-difluorocyclobutyltrifluoromethanesulfonate (500.0 mg, 2.1 mmol, 1.0 equivalent), 3,5-dibromo-1H-pyrazole-4-carboxylonitrile (523.0 mg, 2.1 mmol, 1.0 equivalent), and Cs₂CO₃ (1.4 g, 4.2 mmol, 2.0 equivalent) in DMF (30 mL) was stirred for 16 hours at room temperature. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC to give 3,5-dibromo-1-(3,3-difluorocyclobutyl)-1H-pyrazole-4-carboxylonitrile (400.3 mg, 56.3%) as a yellow oil. A solution of 3,5-dibromo-1-(3,3-difluorocyclobutyl)-1H-pyrazole-4-carboxynitrile (400.3 mg, 1.2 mmol, 1.0 equivalent) and DMBNH2 (392.1 mg, 2.4 mmol, 2.0 equivalent) in NMP (30 mL) was stirred for 3 hours at 180 °C. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC to give 5-amino-3-bromo-1-(3,3-difluorocyclobutyl)-1H-pyrazole-4-carboxynitrile (150.3 mg, 46.2%). LCMS (M+H +The calculated value of m / z is 277.0, while the actual measured value is 277.1. At 0 °C, NaH (284.4 mg, 7.1 mmol, 1.5 equivalence) was added to a solution of 4-bromo-7-methyl-1H-indazole (1 g, 4.7 mmol, 1.0 equivalence) in THF (50 mL). The reaction mixture was stirred at 0 °C for 0.5 h, and then SEMCl (1.7 mL, 9.5 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 30 / 1, v / v) to give 4-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.4 g, 87.0%) as a colorless oil. LCMS (M+H) + The calculated value of m / z is 341.1, while the actual measured value is 341.2. A solution of 4-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.2 g, 3.5 mmol, 1.0 equivalent), NBS (939.6 mg, 5.3 mmol, 1.5 equivalent), and BPO (169.0 mg, 0.7 mmol, 0.2 equivalent) in CCl4 (50 mL) was stirred for 5 hours at 90 °C. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EtOAc = 30 / 1, v / v) to give 4-bromo-7-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (829 mg, 55.0%) as a yellow oil. LCMS (M+H) + The calculated value of m / z is 421.0, while the actual measured value is 420.8. At 0℃, to NH 3·4-Bromo-7-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (600.0 mg, 1.4 mmol, 1.0 equivalence) was added to a solution of H2O (10.0 mL, 147.1 mmol, 600.0 equivalence) in MeCN (20 mL). The reaction mixture was stirred at room temperature for 1 hour, and then Boc2O (25.1 mL, 108.0 mmol, 77.1 equivalence) and NaHCO3 (5.9 g, 70.0 mmol, 50.0 equivalence) were added. The reaction mixture was stirred at room temperature for another 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reversed-phase HPLC (MeCN / H2O = 4 / 1, v / v) to give tert-butyl ((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)carbamate (154.1 mg, 24.0%), a yellow oil. LCMS (M+H) + The calculated value of m / z is 456.1, while the actual measured value is 455.9. A solution of ((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)carbamate tert-butyl ester (154.1 mg, 0.34 mmol, 1.0 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (112.2 mg, 0.44 mmol, 1.3 equivalent), KOAc (100.0 mg, 1.0 mmol, 3.0 equivalent) and Pd(dppf)Cl2 (25.3 mg, 0.034 mmol, 0.1 equivalent) in dioxane (50 mL) was stirred for 5 hours at 90 °C. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1, v / v) to give tert-butyl carbamate (100.2 mg, 58.0%) as a yellow oil (M+H). + The calculated value of m / z is 504.3, while the actual measured value is 504.2. A solution of ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)carbamate tert-butyl ester (100.2 mg, 0.20 mmol, 1.0 equivalent), 5-amino-3-bromo-1-(3,3-difluorocyclobutyl)-1H-pyrazole-4-carboxynitrile (55.1 mg, 0.20 mmol, 1.0 equivalent), K2CO3 (110.4 mg, 0.80 mmol, 4.0 equivalent) and Pd(dppf)Cl2 (14.3 mg, 0.02 mmol, 0.1 equivalent) in dioxane (5 mL) and water (0.5 mL) was stirred under N2 for 5 hours at 90 °C. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EtOAc = 4 / 1, v / v) to give tert-butyl carbamate (63.2 mg, 80.0%), a yellow oil. + The calculated value of m / z is 574.3, and the actual measured value is also 574.3. TFA (2 mL) was added to a stirred solution of ((4-(5-amino-4-cyano-1-(3,3-difluorocyclobutyl)-1H-pyrazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)carbamate (63.2 mg, 0.20 mmol, 1.0 equivalent) in DCM (10 mL). The reaction mixture was stirred at room temperature for 15 hours. The mixture was concentrated to give 5-amino-3-(7-(aminomethyl)-1H-indazole-4-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazole-4-carboxynitrile (80.0 mg, quantified) as a yellow oil. LCMS (MH) + The calculated value of m / z is 342.1, and the actual measured value is also 342.1. At 0 °C, 5-fluoro-2-methoxybenzoyl chloride (87.7 mg, 0.46 mmol, 2.0 equivalent) in MeCN (3.0 mL) was added to a solution of 5-amino-3-(7-(aminomethyl)-1H-indazol-4-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazole-4-carboxynitrile (80.0 mg, 0.23 mmol, 1.0 equivalent) and NaHCO3 (58.8 mg, 0.70 mmol, 3.0 equivalent) in MeCN (9.0 mL) and H2O (3.0 mL). The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, v / v) to give N-((4-(5-amino-4-cyano-1-(3,3-difluorocyclobutyl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide (10.0 mg, 8.7%) as a pale yellow solid. LCMS (M+H) + The calculated value of m / z is 496.2, while the actual measured value is 496.1. To a solution of N-((4-(5-amino-4-cyano-1-(3,3-difluorocyclobutyl)-1H-pyrazol-3-yl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (10.0 mg, 0.020 mmol, 1.0 equivalent) in DMSO (20 mL), K₂CO₃ (13.9 mg, 0.10 mmol, 5.0 equivalent) and H₂O₂ (30%, 0.2 mL, 0.40 mmol, 20.0 equivalent) were added. The mixture was stirred at 60 °C for 1 hour, then diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reversed-phase HPLC (MeCN / H2O = 1 / 1, v / v) to give 5-amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide (2.0 mg, 19.4%) as a white solid. LCMS (M+H) +The calculated m / z value is 514.2, and the measured value is 514.3. ¹H NMR (DMSO-d⁶, 400 MHz) δ 13.29 (s, ¹H), 8.97 (t, ¹H), 8.06 (s, ¹H), 7.54 (dd, ¹H), 7.32–7.38 (m, 2H), 7.17–7.24 (m, 2H), 6.53 (s, 2H), 4.86–4.92 (m, ¹H), 4.82 (d, 2H), 3.91 (s, 3H), 3.08–3.21 (m, 4H).

[0231] Example 2: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide At 0 °C, NaH (1.6 g, 40.2 mmol, 1.2 equivalent) was added to a solution of 3,5-dibromo-1H-pyrazole-4-carboxynitrile (8.4 g, 33.5 mmol, 1.0 equivalent) in DMF (150 mL). The reaction mixture was stirred at 0 °C for 0.5 h, and then 3-bromocyclobutane-1-one (5.0 g, 33.5 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with water (90 mL) and extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 4 / 1, v / v) to give 3,5-dibromo-1-(3-oxocyclobutyl)-1H-pyrazole-4-carboxynitrile (4.2 g, 53.0%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 317.9, while the actual measured value is 317.8. At 0 °C, NaBH4 (1.0 g, 26.3 mmol, 2.0 equivalent) was added to a solution of 3,5-dibromo-1-(3-oxocyclobutyl)-1H-pyrazole-4-carboxynitrile (4.2 g, 13.2 mmol, 1.0 equivalent) in MeOH (30 mL), and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, v / v) to give 3,5-dibromo-1-(3-hydroxycyclobutyl)-1H-pyrazole-4-carboxynitrile (2.8 g, 55.0%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 319.9, while the actual measured value is 319.8. At 0 °C, DAST (1.7 mL, 12.5 mmol, 2.0 equivalent) was added to a solution of 3,5-dibromo-1-(3-hydroxycyclobutyl)-1H-pyrazole-4-carboxynitrile (2.0 g, 6.2 mmol, 1.0 equivalent) in DCM (30 mL), and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, v / v) to give 3,5-dibromo-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxynitrile (410.2 mg, 20.5%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 321.9, while the actual measured value is 321.8. A solution of 3,5-dibromo-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxynitrile (410.2 mg, 1.3 mmol, 1.0 equivalent) and DMBNH2 (392.1 mg, 2.5 mmol, 2.0 equivalent) in NMP (30 mL) was stirred for 3 hours at 180 °C. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC to give 5-amino-3-bromo-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxynitrile (300.3 mg, 89.2%). LCMS (M+H + The calculated value of m / z is 259.0, while the actual measured value is 259.1. To a solution of 4-bromo-7-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.8 g, 6.70 mmol, 1.0 equivalent) in DMF (40 mL), NaN3 (523.0 mg, 8.0 mmol, 1.2 equivalent) was added. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 7-(azidomethyl)-4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.5 g, quantified) as a yellow oil. LCMS (M+H + The calculated value of m / z is 382.1, and the actual measured value is also 382.1. To a solution of 7-(azidomethyl)-4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.5 g, 6.56 mmol, 1.0 equivalent) in THF (30 ml), PPh3 (2.6 g, 9.84 mmol, 1.5 equivalent) and H2O (1.2 g, 65.6 mmol, 10.0 equivalent) were added. The mixture was stirred at room temperature for 15 hours. The solution of (4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methylamine was used directly in the next step. LCMS (M+H + The calculated value of m / z is 356.1, and the actual measured value is also 356.1. At 0 °C, 5-fluoro-2-methoxybenzoyl chloride (4.1 g, 21.9 mmol, 1.2 equivalent) was added to a solution of (4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methylamine (6.5 g, 18.3 mmol, 1.0 equivalent), NaHCO3 (7.7 g, 91.6 mmol, 5.0 equivalent), and water (20 mL) in THF (60 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 20 / 1, v / v) to give N-((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (6.8 g, 78.1%). LCMS (M+H) + The calculated value of m / z is 508.1, and the actual measured value is also 508.1. A solution of N-((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (2.5 g, 4.9 mmol, 1.0 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (1.6 g, 6.4 mmol, 1.3 equivalent), KOAc (1.4 g, 14.8 mmol, 3.0 equivalent), and Pd(dppf)Cl2 (357.3 mg, 0.49 mmol, 0.1 equivalent) in dioxane (50 mL) was stirred under N2 for 5 hours at 90 °C. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EtOAc = 4 / 1, v / v) to give 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)benzamide (2.6 g, 90.0%) as a yellow oil. LCMS (M+H) + The calculated value of m / z is 556.3, while the actual measured value is 556.2. A solution of 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)benzamide (50.0 mg, 0.090 mmol, 1.0 equivalent), 5-amino-3-bromo-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxynitrile (23.2 mg, 0.090 mmol, 1.0 equivalent), K2CO3 (49.7 mg, 0.36 mmol, 4.0 equivalent), and Pd(dppf)Cl2 (6.5 mg, 0.009 mmol, 0.1 equivalent) in dioxane (5 mL) and water (0.5 mL) was stirred under N2 for 5 hours at 90 °C. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EtOAc = 4 / 1, v / v) to give N-((4-(5-amino-4-cyano-1-(3-fluorocyclobutyl)-1H-pyrazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide (25.2 mg, 45.5%) as a yellow oil. LCMS (M+H) + The calculated value of m / z is 608.3, while the actual measured value is 608.2. A solution of N-((4-(5-amino-4-cyano-1-(3-fluorocyclobutyl)-1H-pyrazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide (25.2 mg, 0.21 mmol, 1.0 equivalent) in TFA (5 mL) was stirred for 1 hour at room temperature. The mixture was concentrated, and the resulting residue was purified by reversed-phase HPLC (MeCN / H2O = 1 / 1, v / v) to give N-((4-(5-amino-4-cyano-1-(3-fluorocyclobutyl)-1H-pyrazole-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide (15.0 mg, 75.0%) as a white solid. LCMS (M+H) + The calculated value of m / z is 478.2, while the actual measured value is 478.1. As described for 5-amino-1-(3,3-difluorocyclobutyl)-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-(3-fluorocyclobutyl)-1H-pyrazole-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-1-(3,3-difluorocyclobutyl)-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated m / z value was 496.2, and the measured value was also 496.2. ¹H NMR (DMSO-d⁶, 400 MHz) δ 13.27 (s, ¹H), 8.97 (t, ¹H), 8.06 (s, ¹H), 7.55 (dd, ¹H), 7.32–7.38 (m, 2H), 7.17–7.23 (m, 2H), 6.44 (s, 2H), 5.29–5.47 (m, ¹H), 5.10–5.15 (m, ¹H), 4.82 (d, 2H), 3.91 (s, 3H), 2.62–2.89 (m, 4H).

[0232] Example 3: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(oxetane-3-yl)-1H-pyrazole-4-carboxamide To a solution of N-((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (2 g, 3.9 mmol, 1.0 equivalent) in DMSO / MeOH (100 mL / 100 mL), DPPP (489.0 mg, 1.2 mmol, 0.4 equivalent), Pd(OAc)₂ (133.0 mg, 0.59 mmol, 0.2 equivalent), and TEA (1.2 g, 11.8 mmol, 3.0 equivalent) were added. The mixture was stirred at 100 °C under CO₂ (1 atm) for 5 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1, v / v) to give methyl 7-((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-carboxylate (1.5 g, 78%) as a yellow solid. The calculated LCMS (M+H+) m / z was 488.2, and the actual value was also 488.2. To a solution of methyl 7-((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-carboxylic acid (1.5 g, 3.1 mmol, 1.0 equivalent) in THF / H₂O (15 ml / 5 mL), LiOH (222.1 mg, 9.3 mmol, 3.0 equivalent) was added. The mixture was stirred at room temperature for 16 hours. Partial solvent was removed under vacuum, and the solution was acidified to pH 5 with concentrated HCl. The precipitate was collected by filtration and dried under vacuum to give 1.5 g, quantified, of 7-((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-carboxylic acid as a white solid. LCMS (M+H) + The calculated value of m / z is 474.2, and the actual measured value is also 474.2. To a solution of 7-((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-carboxylic acid (1.5 g, 3.2 mmol, 1.0 equivalent) in THF (20 mL), malononitrile (628.1 mg, 9.5 mmol, 3.0 equivalent), EDCI (1.2 g, 6.4 mmol, 2.0 equivalent), and HOBT (857.2 mg, 6.4 mmol, 2.0 equivalent) were added. The mixture was cooled to 0 °C, and DIEA (2.8 mL, 16.0 mmol, 5.0 equivalent) was added. The mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 4 / 1, v / v) to give N-((4-(2,2-dicyano-1-hydroxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (1.5 g, 80.2%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 522.2, while the actual measured value is 522.1. Me₂SO₄ (1.6 g, 12.3 mmol, 4.0 equivalent) and DIEA (1.6 g, 12.3 mmol, 4.0 equivalent) were added to a solution of N-((4-(2,2-dicyano-1-hydroxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (1.6 g, 3.1 mmol, 1.0 equivalent) in THF (20 mL). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 4 / 1, v / v) to give N-((4-(2,2-dicyano-1-methoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (1.0 g, 60.2%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 536.2, while the actual measured value is 536.1. At 80 °C, N-((4-(2,2-dicyano-1-methoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (700.0 mg, 1.3 mmol, 1.0 equivalent), TEA (1.8 mL, 13.0 mmol, 10.0 equivalent) and NH 2· NH 2· A solution of H₂O (0.7 mL, 13.0 mmol, 10.0 equivalent) in EtOH (15 mL) was stirred for 2 hours. The mixture was concentrated to give N-((4-(5-amino-4-cyano-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide (750.0 mg, quantified) as a white solid. LCMS (MH + The calculated value of m / z is 534.2, and the actual measured value is also 534.2. A solution of N-((4-(5-amino-4-cyano-1H-pyrazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide (700.0 mg, 1.3 mmol, 1.0 equivalent), 3-iodooxetane (1.1 mL, 13.1 mmol, 10.0 equivalent), and K₂CO₃ (902.0 mg, 6.5 mmol, 5.0 equivalent) in DMF (30 mL) was stirred for 15 hours at 50 °C. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC to give N-((4-(5-amino-4-cyano-1-(oxetane-3-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (125.3 mg, 16.2%) as a yellow solid. LCMS (MH) + The calculated value of m / z is 590.2, and the actual measured value is also 590.2. As described for N-((4-(5-amino-4-cyano-1-(3-fluorocyclobutyl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((4-(5-amino-4-cyano-1-(oxetane-3-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide (120.2 mg) was converted to N-((4-(5-amino-4-cyano-1-(oxetane-3-yl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide (60.0 mg, 64.5%). LCMS (M+H) + The calculated value of m / z is 462.2, while the actual measured value is 462.4. As described for 5-amino-1-(3,3-difluorocyclobutyl)-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-(oxetane-3-yl)-1H-pyrazole-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-(oxetane-3-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated m / z value is 480.2, and the measured value is 480.3. ¹H NMR (DMSO-d⁶, 400 MHz) δ 8.09 (s, ¹H), 7.65 (dd, ¹H), 7.49 (d, ¹H), 7.34 (d, ¹H), 7.23–7.26 (m, ¹H), 7.14–7.19 (m, ¹H), 5.55–5.59 (m, ¹H), 5.17 (t, ²H), 5.01 (t, ²H), 4.96 (s, ²H), 3.94 (s, ³H).

[0233] Example 4: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide To a solution of N-((4-(2,2-dicyano-1-methoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (200.2 mg, 0.37 mmol, 1.0 equivalent) in EtOH (10 mL), (1s,3s)-3-hydrazino-1-methylcyclobutane-1-ol (47.6 mg, 0.41 mmol, 1.1 equivalent) and TEA (379.0 mg, 3.7 mmol, 10.0 equivalent) were added. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, v / v) to give N-((4-(5-amino-4-cyano-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (160.3 mg, 69.2%). LCMS (M+H) + The calculated value of m / z is 620.3, and the actual measured value is also 620.3. As described for 5-amino-3-(7-(aminomethyl)-1H-indazole-4-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-carboxynitrile, N-((4-(5-amino-4-cyano-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((4-(5-amino-4-cyano-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H + The calculated value of m / z is 490.2, while the actual measured value is 490.3. As described for 5-amino-1-(3,3-difluorocyclobutyl)-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzoamide is converted to 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide. LCMS (M+H + The calculated m / z value is 508.2, and the measured value is 508.1. ¹H NMR (400MHz, DMSO-d⁶) δ 13.27 (s, ¹H), 8.97 (t, ¹H), 8.05 (s, ¹H), 7.55 (dd, ¹H), 7.30–7.38 (m, ²H), 7.16–7.23 (m, ²H), 6.38 (s, ²H), 5.18 (s, ¹H), 4.83 (d, ²H), 4.45 (t, ¹H), 3.91 (s, ³H), 2.59 (d, ²H), 2.37 (t, ²H), 1.33 (s, ³H).

[0234] Example 5: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide was prepared as described for 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide. LCMS (M+H +The calculated m / z value is 520.2, and the measured value is 520.1. ¹H NMR (400 MHz, DMSO-d⁶) δ 13.29 (s, ¹H), 8.97 (t, ¹H), 7.99 (s, ¹H), 7.55 (dd, ¹H), 7.35 (ddd, 2H), 7.13–7.18 (m, 2H), 6.73 (s, 2H), 5.35 (dt, ¹H), 4.82 (d, 2H), 3.91 (s, 3H), 1.65 (d, 3H).

[0235] Examples 6 and 7: Preparation of (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide (isomer 1, S) and (R)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide (isomer 2, R) 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide (10 mg, 0.0192 mg) (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide and (R)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide) were separated by chiral column chromatography (column: CHIRALPAKIK, mobile phase: hexane / EtOH / DEA=50 / 50 / 0.1 (V / V / V)) to obtain (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide. The calculated m / z of LCMS (M+H+) is 520.2, while the measured value is 520.1. ¹H NMR (400 MHz, DMSO-d⁶) δ: 13.29 (s, ¹H), 8.97 (t, ¹H), 7.99 (s, ¹H), 7.55 (dd, ¹H), 7.35 (ddd, ²H), 7.13–7.18 (m, ²H), 6.73 (s, ²H), 5.35 (dt, ¹H), 4.82 (d, ²H), 3.91 (s, ³H), 1.65 (d, ³H).

[0236] Example 8: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide At 0 °C, trifluoromethanesulfonic anhydride (108.1 g, 385.7 mmol, 1.1 equivalent) was added to a solution of 1,1,1-trifluoropropane-2-ol (40.0 g, 350.6 mmol, 1.0 equivalent) and pyridine (33.3 g, 420.8 mmol, 1.2 equivalent) in DCM (250 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (150 mL) and extracted with DCM (150 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1,1,1-trifluoropropane-2-yltrifluoromethanesulfonate (47 g, crude) as a brown oil. To a solution of 3,5-dibromo-1H-pyrazole-4-carboxynitrile (16 g, 63.8 mmol, 1.0 equivalent) and Cs₂CO₃ (42.1 g, 127.0 mmol, 2.0 equivalent) in DMF (200 mL), 1,1,1-trifluoropropane-2-yltrifluoromethanesulfonate (47.0 g, 191.1 mmol, 3.0 equivalent) was added. The resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (250 mL x 3). The combined organic layers were washed with brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 20 / 1, v / v) to give 3,5-dibromo-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxynitrile (28.0 g, quantitative) as a white solid. LCMS (M+H) + The calculated value of m / z is 345.9, while the actual measured value is 346.0. To a solution of 3,5-dibromo-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxylonitrile (28.0 g, 80.7 mmol, 1.0 equivalent) in NMP (300 mL), (3,4-dimethylphenyl)methylamine (20.2 g, 121 mmol, 1.5 equivalent) was added. The resulting mixture was stirred at 180 °C for 4 hours. The reaction mixture was diluted with water (250 mL), and the aqueous layer was extracted with EtOAc (250 mL x 3). The combined organic layers were washed with brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-bromo-5-((3,4-dimethylbenzyl)amino)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxylonitrile (31.0 g, 88.1%) as a green solid. LCMS (M+H) + The calculated value of m / z is 433.0, while the actual measured value is 433.1. TFA (150 mL) was added to a solution of 3-bromo-5-((3,4-dimethylbenzyl)amino)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxynitrile (31.0 g, 71.6 mmol, 1.0 equivalent) in DCM (150 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give 5-amino-3-bromo-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxynitrile (17.9 g, 88.4%) as a green solid. LCMS (M+H) +The calculated value of m / z is 283.0, while the actual measured value is 283.1. At room temperature, LiBH4 (700.0 mg, 31.8 mmol, 8.0 equivalent) was added to a solution of methyl 4-bromo-1H-indole-7-carboxylate (1.0 g, 3.9 mmol, 1.0 equivalent) in THF (30 mL), and the mixture was stirred at 50 °C for 15 h. The reaction mixture was diluted with water (50 mL), and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reversed-phase HPLC (MeCN / H2O = 1 / 1, v / v) to give (4-bromo-1H-indole-7-yl)methanol (748.1 mg, 81.0%) as a white solid. The calculated m / z for LCMS (M+H+) was 226.0, and the actual value was 226.1. A solution of (4-bromo-1H-indole-7-yl)methanol (648.2 mg, 2.9 mmol, 1.0 equivalent), DPPA (1.0 mL, 4.3 mmol, 1.5 equivalent), and DBU (0.9 mL, 5.7 mmol, 2.0 equivalent) in THF (50 mL) was stirred for 15 hours at room temperature. The reaction mixture was diluted with water (50 mL), and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reversed-phase HPLC (MeCN / H2O = 7 / 3, v / v) to give 7-(azidomethyl)-4-bromo-1H-indole (511.1 mg, 84.0%) as a yellow oil. LCMS (M+H) + The calculated value of m / z is 251.0, while the actual measured value is 251.1. PPh3 (803.1 mg, 3.0 mmol, 1.5 equivalents) was added to a solution of 7-(azidomethyl)-4-bromo-1H-indole (511.1 mg, 2.0 mmol, 1.0 equivalent) in THF / H2O (30 mL / 1 mL). The mixture was stirred at room temperature for 5 hours. The (4-bromo-1H-indole-7-yl)methylamine solution was used directly in the next step. LCMS (M+H) + The calculated value of m / z is 225.0, while the actual measured value is 225.1. At 0 °C, 5-fluoro-2-methoxybenzoyl chloride (579.7 mg, 3.1 mmol, 1.5 equivalent) was added to a solution of (4-bromo-1H-indol-7-yl)methylamine (457.8 mg, 2.0 mmol, 1.0 equivalent), NaHCO3 (858.7 mg, 10.2 mmol, 5.0 equivalent), and H2O (10 mL) in THF (60 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reversed-phase HPLC (MeCN / H2O = 4 / 1, v / v) to give N-((4-bromo-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (498.5 mg, 65.1%). LCMS (M+H) + The calculated value of m / z is 377.0, while the actual measured value is 377.3. A solution of N-((4-bromo-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (400 mg, 1.0 mmol, 1.0 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (352.0 mg, 1.3 mmol, 1.3 equivalent), KOAc (234.2 mg, 3.0 mmol, 3.0 equivalent), and Pd(dppf)Cl2 (72.6 mg, 0.1 mmol, 0.1 equivalent) in dioxane (10 mL) was stirred for 15 hours at 100 °C. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EtOAc = 4 / 1, v / v) to give 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indol-7-yl)methyl)benzamide (267.3 mg, 59.0%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 425.2, while the actual measured value is 425.5. At 110 °C, 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1H-indol-7-yl)methyl)benzamide (267.3 mg, 0.63 mmol, 1.0 equivalent), 5-amino-3-bromo-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxynitrile (214.2 mg, 0.76 mmol, 1.2 equivalent), Cs2CO3 (411.4 mg, 1.3 mmol, 2.0 equivalent), and Pd(dppf)Cl were added. 2· A solution of DCM (51.3 mg, 0.06 mmol, 0.1 equivalent) in dioxane (5 mL) and H₂O (0.5 mL) was stirred for 5 hours. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, v / v) to give N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (106.2 mg, 32.0%) as a yellow oil. LCMS (M+H) + The calculated value of m / z is 501.2, while the actual measured value is 501.5. As described for 5-amino-1-(3,3-difluorocyclobutyl)-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indole-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) +The calculated m / z value was 519.2, and the measured value was 519.5. ¹H NMR (DMSO-d⁶, 400 MHz) δ 11.30 (s, ¹H), 8.92 (t, ¹H), 7.55 (dd, ¹H), 7.45 (t, ¹H), 7.31–7.38 (m, ¹H), 7.15–7.21 (m, ²H), 7.05 (d, ¹H), 6.77 (s, ²H), 6.33 (t, ¹H), 5.30–5.33 (m, ¹H), 4.80 (d, ²H), 3.89 (s, ³H), 1.62 (d, ³H).

[0237] Example 9: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide was prepared as described for 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide. LCMS (M+H + The calculated m / z value is 506.1, and the measured value is also 506.1. ¹H NMR (400 MHz, DMSO-d⁶) δ 8.04 (s, ¹H), 7.65 (dd, ¹H), 7.48 (d, ¹H), 7.31 (d, ¹H), 7.23–7.26 (m, ¹H), 7.13–7.18 (m, ¹H), 4.96 (s, ²H), 4.58 (s, ²H), 3.94 (s, ³H).

[0238] Example 10: Preparation of methyl 3-(5-amino-4-carbamoyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylate A solution of tert-butyl 3-iodozazecyclobutane-1-carboxylate (11.0 g, 38.9 mmol, 1.0 equivalent) in 4 M HCl-dioxane (100 mL) was stirred for 5 hours at room temperature. The precipitate was filtered and dried to give 7.2 g, 83.7%, 3-iodozazecyclobutane hydrochloride as a white solid. LCMS (M+H) + The calculated value of m / z is 184.0, while the actual measured value is 184.1. At 0 °C, methyl chloroformate (2.0 g, 20.5 mmol, 1.5 equivalent) was added to a solution of 3-iodozacyclobutane hydrochloride (3.0 g, 13.7 mmol, 1.0 equivalent), NaHCO3 (5.8 g, 68.5 mmol, 5.0 equivalent), and H2O (10 mL) in THF (60 mL). The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reversed-phase HPLC (MeCN / H2O = 1 / 1, v / v) to give methyl 3-iodozacyclobutane-1-carboxylate (754.5 mg, 22.9%). LCMS (M+H + The calculated value of m / z is 242.0, while the actual measured value is 242.1. A solution of N-((4-(5-amino-4-cyano-1H-pyrazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide (557.0 mg, 1.0 mmol, 1.0 equivalent), methyl 3-iodozacyclobutane-1-carboxylate (377.2 mg, 1.6 mmol, 1.5 equivalent), and Cs₂CO₃ (509.1 mg, 1.6 mmol, 5.0 equivalent) in DMF (30 mL) was stirred for 15 hours at 50 °C. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC to give methyl 3-(5-amino-4-cyano-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylate (329.3 mg, 49.2%), a yellow solid. LCMS (MH) +The calculated value of m / z is 649.3, while the actual measured value is 649.6. A solution of methyl 3-(5-amino-4-cyano-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-yl)-1H-pyrazole-1-yl)azacyclobutane-1-carboxylate (329.2 mg, 0.51 mmol, 1.0 equivalent) in TFA (2 mL) was stirred for 1 hour at room temperature. The mixture was concentrated to give methyl 3-(5-amino-4-cyano-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazole-1-yl)azacyclobutane-1-carboxylate (368.0 mg, quantified) as a brown solid. LCMS (MH) + The calculated value of m / z is 519.2, while the actual measured value is 519.5. As described with 5-amino-1-(3,3-difluorocyclobutyl)-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazol-4-carboxamide, methyl 3-(5-amino-4-cyano-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylate is converted to methyl 3-(5-amino-4-carbamoyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylate. LCMS (M+H) + The calculated m / z value is 537.2, and the measured value is 537.4. ¹H NMR (DMSO-d⁶, 400 MHz) δ 13.30 (s, ¹H), 8.97 (t, ¹H), 8.06 (s, ¹H), 7.54 (dd, ¹H), 7.32–7.38 (m, 2H), 7.17–7.25 (m, 2H), 6.49 (s, 2H), 5.24–5.26 (m, ¹H), 4.82 (d, 2H), 4.27–4.33 (m, 4H), 3.91 (s, 3H), 3.57 (s, 3H).

[0239] Example 11: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-methyl-1H-pyrazole-4-carboxamide 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared as described for 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide. LCMS (M+H + The calculated value of m / z is 438.2, while the actual measured value is 438.4. 1 H NMR (400 MHz, DMSO) δ 13.42 (d, 1 H), 8.99 (dt, 1 H), 7.93 (d, 1H), 7.49-7.62 (m, 1 H), 7.30-7.45 (m, 2 H), 7.17-7.25 (m, 2 H), 5.93 (d, 2 H), 4.74-4.94 (m, 2 H), 3.91 (d, 3 H), 3.47 (d, 3 H).

[0240] Example 12: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazole-4-carboxamide was prepared as described for p-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide. LCMS (M+H + The calculated value of m / z is 424.1, while the actual measured value is 424.2. 1 H NMR (400 MHz, DMSO) δ 12.41 (s, 1 H), 8.98 (d, 1 H), 7.96 (d,1H), 7.60-7.50 (m, 1 H), 7.34 (d, 2 H), 7.25-7.14 (m, 2 H), 5.93 (s, 1 H), 4.83 (d, 2 H), 3.91 (s, 3 H).

[0241] Example 13: Preparation of 5-amino-1-cyclopropyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide 5-Amino-1-cyclopropyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazole-4-carboxamide was prepared as described for 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide. LCMS (M+H + The calculated value of m / z is 464.2, while the actual measured value is 464.6. 1 H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 8.96 (t, 1H), 7.98 (s, 1 H), 7.54 (dd, 1 H), 7.27-7.41 (m, 2 H), 7.11-7.23 (m, 2 H), 6.38 (s, 2 H), 4.82 (d, 2 H), 3.90 (s, 3 H), 3.37 (dd, 1 H), 0.90-1.11 (m, 4H).

[0242] Example 14: Preparation of N-((4-(5-amino-4-carbamoyl-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazol-7-yl)methyl)-2-methoxynicotinamide As described for N-((4-(5-amino-4-cyano-1-(3,3-difluorocyclobutyl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, (4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methylamine is converted to N-((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-2-methoxynicotinamide. LCMS (M+H + The calculated value of m / z is 491.1, while the actual measured value is 491.2. As described with 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indol-7-yl)methyl)benzamide, N-((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-2-methoxynicotinamide is converted to 2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)nicotinamide. LCMS (M+H + The calculated value of m / z is 539.3, and the actual measured value is also 539.3. As described for N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)nicotinamide is converted to N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-2-methoxynicotinamide. LCMS (M+H + The calculated value of m / z is 615.2, and the actual measured value is also 615.2. As described for N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-2-methoxynicotinamide is converted to N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-2-methoxynicotinamide. LCMS (M+H + The calculated value of m / z is 485.2, while the actual measured value is 485.0. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-2-methoxynicotinamide is converted to N-((4-(5-amino-4-carbamoyl-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-2-methoxynicotinamide. LCMS (M+H) + The calculated m / z value is 503.2, and the measured value is 503.6. ¹H NMR (400 MHz, DMSO) δ 13.29 (s, ¹H), 8.97 (t, ¹H), 8.32 (dd, ¹H), 8.19 (dd, ¹H), 7.99 (d, ¹H), 7.36 (d, ¹H), 7.23 (t, ¹H), 7.10–7.17 (m, ¹H), 6.73 (s, ²H), 5.35 (dt, ¹H), 4.86 (t, ²H), 4.02 (d, ³H), 1.65 (d, ³H).

[0243] Example 15: Preparation of N-((4-(5-amino-4-carbamoyl-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxynicotinamide N-((4-(5-amino-4-carbamoyl-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxynicotinamide was prepared as described for N-((4-(5-amino-4-carbamoyl-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-2-methoxynicotinamide. LCMS (M+H + The calculated m / z value is 521.2, while the actual measured value is 521.4. 1H NMR (400 MHz, DMSO) δ 13.33 (s, 1 H), 9.07(t, 1 H), 8.34 (d, 1 H), 8.06 (dd, 1 H), 7.99 (s, 1 H), 7.36 (d, 1 H), 7.23(d, 1 H), 6.73 (s, 2 H), 5.28-5.42 (m, 1 H), 4.84 (d, 2 H), 4.00 (s, 3 H), 1.65 (d, 3 H).

[0244] Example 16: Preparation of 5-amino-3-(7-((2,5-difluorobenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide 5-Amino-3-(7-(((2,5-difluorobenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide was prepared as described for N-((4-(5-amino-4-carbamoyl-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-3-yl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxynicotinamide. LCMS (M+H + The calculated m / z value is 508.1, while the actual measured value is 508.2. 1 H NMR (400 MHz, DMSO) δ 13.26 (s, 1 H), 9.07 (s,1 H), 7.99 (s, 1 H), 7.48-7.57 (m, 1 H), 7.34-7.46 (m, 3 H), 7.24 (d, 1 H), 6.73 (s, 2 H), 5.36 (dt, 1 H), 4.81 (d, 2 H), 1.65 (d, 3 H).

[0245] Example 17: Preparation of 5-amino-1-(1,3-difluoropropane-2-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide At 0 °C, PPh3 (1.9 g, 7.2 mmol, 1.0 equivalent) and DIAD (1.3 g, 7.2 mmol, 1.2 equivalent) were added dropwise to a stirred solution of 3,5-dibromo-1H-pyrazole-4-carboxynitrile (1.5 g, 6.024 mmol, 1.0 equivalent) and 1,3-difluoropropane-2-ol (694.1 mg, 7.2 mmol, 1.2 equivalent) in THF (35 mL). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The residue was diluted with water (25 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 20 / 1, v / v) to give 3,5-dibromo-1-(1,3-difluoropropane-2-yl)-1H-pyrazole-4-carboxynitrile (2.0 g, quantitative) as a grayish-white solid. 1 H NMR (400 MHz, DMSO) δ 5.08-5.39 (m, 1 H), 4.89 (qd, 2 H), 4.71-4.84 (m, 2 H). As described for 3-bromo-5-((3,4-dimethylbenzyl)amino)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxynitrile, 3,5-dibromo-1-(1,3-difluoropropane-2-yl)-1H-pyrazol-4-carboxynitrile is converted to 3-bromo-1-(1,3-difluoropropane-2-yl)-5-((2,4-dimethoxybenzyl)amino)-1H-pyrazol-4-carboxynitrile. LCMS (M+H) + The calculated value of m / z is 415.1, and the actual measured value is also 415.1. As described for 5-amino-3-bromo-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-4-carboxynitrile, 3-bromo-1-(1,3-difluoropropan-2-yl)-5-((3,4-dimethylbenzyl)amino)-1H-pyrazol-4-carboxynitrile is converted to 5-amino-3-bromo-1-(1,3-difluoropropan-2-yl)-1H-pyrazol-4-carboxynitrile. LCMS (M+H) + The calculated value of m / z is 265.0, while the actual measured value is 265.1. As described for N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)benzamide is converted to N-((4-(5-amino-4-cyano-1-(1,3-difluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 614.2, while the actual measured value is 614.1. As described for N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((4-(5-amino-4-cyano-1-(1,3-difluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((4-(5-amino-4-cyano-1-(1,3-difluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 484.2, while the actual measured value is 484.0. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-(1,3-difluoropropane-2-yl)-1H-pyrazole-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-1-(1,3-difluoropropane-2-yl)-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 502.2, while the actual measured value is 502.3. 1H NMR (400 MHz, DMSO) δ13.29 (d, 1 H), 8.96 (t, 1 H), 8.02 (d, 1 H), 7.55 (dd, 1 H), 7.29-7.42 (m, 2H), 7.14-7.25 (m, 2 H), 6.60 (d, 2 H), 5.19-5.89 (m, 2H), 4.96-5.17 (m, 1H), 4.72-4.90 (m, 4H), 3.90 (s, 3H).

[0246] Example 18: Preparation of 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide was prepared as described for 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide. LCMS (M+H + The calculated value of m / z is 466.2, while the actual measured value is 466.6. 1 H NMR (DMSO-d6, 400 MHz) δ 13.25 (s, 1 H), 8.96 (t, 1H), 8.00 (s, 1 H), 7.54 (dd, 1 H), 7.32-7.38 (m, 2 H), 7.17-7.23 (m, 2 H), 6.37 (s, 2 H), 4.82 (d, 2 H), 4.49-4.52 (m, 1 H), 3.91 (s, 3 H), 1,38 (d, 6H).

[0247] Example 19: Preparation of 5-amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide Add Na₂SO₄ (556.9 g, 3921.6 mmol, 8.0 equivalent), 3-bromo-5-fluoro-2-methylaniline (100.0 g, 490.2 mmol, 1.0 equivalent), and NH₂OH to a solution of trichloroacetaldehyde (86.0 g, 588.2 mmol, 1.2 equivalent) in H₂O (2000 mL) · HCl (121.8 g, 1764.7 mmol, 3.6 equivalents) and HCl (12 M, 82 mL, 980.4 mmol, 2.0 equivalents). The resulting mixture was stirred at 60 °C for 15 hours. The precipitate was collected and dried to give N-(3-bromo-5-fluoro-2-methylphenyl)-2-(hydroxyimino)acetamide (135 g, about 100%) as a brown solid. LCMS (M+H) + The calculated value of m / z is 275.0, while the actual measured value is 275.1. A solution of N-(3-bromo-5-fluoro-2-methylphenyl)-2-(hydroxyimino)acetamide (135.0 g, 490.9 mmol, 1.0 equivalent) in concentrated H₂SO₄ (700 mL) was stirred for 1 hour at 65 °C. The resulting mixture was then poured into ice water. The precipitate was collected and dried to give 135 g, approximately 100%, of 6-bromo-4-fluoro-7-methylindoline-2,3-dione as a brown solid. LCMS (M+H) + The calculated m / z is 257.9, while the actual measured value is 258.0. At room temperature, 30% H₂O₂ (300 mL, 2616.3 mmol, 5.0 equivalent) was added to a solution of 6-bromo-4-fluoro-7-methylindoline-2,3-dione (135.0 g, 523.3 mmol, 1.0 equivalent) and NaOH (209.0 g, 5232.6 mmol, 10.0 equivalent) in water (2500 mL). The resulting mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate was acidified with concentrated HCl. The precipitate was filtered and dried to give 2-amino-4-bromo-6-fluoro-3-methylbenzoic acid (48.4 g, 40%, 3 steps) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 248.0, and the actual measured value is 248.0. A solution of 2-amino-4-bromo-6-fluoro-3-methylbenzoic acid (48.0 g, 193.5 mmol, 1.0 equivalent) in H₂SO₄ (105 mL) and MeOH (1000 mL) was stirred for 15 hours at 80 °C and then concentrated under vacuum. The crude product was diluted with ice-cold H₂O (1000 mL) and extracted with DCM (500 mL x 3). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, v / v) to give 2-amino-4-bromo-6-fluoro-3-methylbenzoate (21.5 g, 42.4%) as a white solid. LCMS (M+H) + The calculated value of m / z is 262.0, and the actual measured value is also 262.0. In an ice bath, Ac₂O (3.5 mL, 38.2 mmol, 2.0 equivalence) was added to a solution of methyl 2-amino-4-bromo-6-fluoro-3-methylbenzoate (5.0 g, 19.1 mmol, 1.0 equivalence) and 2.1 g AcOK (21.0 mmol, 1.1 equivalence) in DCE (100 mL), and the mixture was stirred at room temperature for 0.5 h. 18-crown ether-6 (1.0 g, 3.8 mmol, 0.2 equivalence) and tBuoNO (5.0 mL, 42.0 mmol, 2.2 equivalence) were added to the reaction mixture, and the mixture was stirred again at 80 °C for 15 h. The reaction mixture was quenched with NaHCO₃ (aqueous solution, 200 mL) and extracted with DCM (300 mL x 2). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was ground with DCM (20 mL) to give methyl 4-bromo-6-fluoro-1H-indazole-7-carboxylate (1.9 g, 37%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 273.0, while the actual measured value is 273.1. As described for 4-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole, methyl 4-bromo-6-fluoro-1H-indazole-7-carboxylate is converted to methyl 4-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylate. LCMS (M+H) + The calculated value of m / z is 403.0, while the actual measured value is 403.1. As described for (4-bromo-1H-indol-7-yl)methanol, methyl 4-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylate is converted to (4-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methanol. LCMS (M+H) + The calculated value of m / z is 375.0, while the actual measured value is 375.1. As described for 7-(azidomethyl)-4-bromo-1H-indole, (4-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methanol is converted to 7-(azidomethyl)-4-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole. LCMS (M+H) + The calculated value of m / z is 400.1, and the actual measured value is also 400.1. As described for (4-bromo-1H-indol-7-yl)methylamine, 7-(azidomethyl)-4-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole is converted to (4-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methylamine. LCMS (M+H) + The calculated value of m / z is 374.1, and the actual measured value is also 374.1. As described for N-((4-(5-amino-4-cyano-1-(3,3-difluorocyclobutyl)-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, (4-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methylamine is converted to N-((4-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H + The calculated m / z value is 526.1, while the actual measured value is 526.4. As described for 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole-7-yl)methyl)benzamide, N-((4-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-fluoro-N-((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 574.3, while the actual measured value is 574.0. As described with respect to N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 5-fluoro-N-((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-((2-(trimethylsilyl) Alkyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-2-methoxybenzamide is converted to N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 650.2, while the actual measured value is 650.0. As described with respect to N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy) )methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H + The calculated value of m / z is 520.1, while the actual measured value is 519.9. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-3-yl)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide). LCMS (M+H) + The calculated value of m / z is 538.2, while the actual measured value is 538.3. 1 H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.88 (s,1 H), 8.03 (s, 1 H), 7.50 (dd, 1 H), 7.33 (ddd, 1 H), 7.10-7.19 (m, 2 H),6.65 (s, 2 H), 5.36 (dt, 1 H), 4.82 (d, 2 H), 3.87 (s, 3 H), 1.65 (d, 3 H).

[0248] Example 20: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-pyrazole-4-carboxamide A solution of benzoylhydrazine (5 g, 36.0 mmol, 1 equivalent) and acetone (21 g, 360.0 mmol, 10 equivalent) in hexane (60 mL) was stirred for 2 hours at 85 °C. The mixture was concentrated to give N'-(propane-2-ylidene)benzoylhydrazine (6 g, 94%). LCMS (M+H) + The calculated m / z value is 177.1, while the actual measured value is 177.2. Allyltrimethylsilane (6.2 g, 55.0 mmol, 1 equivalent) was added to a solution of N'-(propane-2-ylidene)benzoylhydrazine (6.5 g, 36.7 mmol, 1 equivalent) and boron trifluoride diethyl ether (7.8 g, 55.0 mmol, 1.5 equivalent) in DCE (70 mL). The mixture was stirred at 85 °C for 1 hour. The mixture was concentrated to give 2,2-difluoro-5-phenyl-3-(propane-2-ylidene)-2,3-dihydro-1,3l4,4,2l4-oxadiazaborane (7 g, 85%). LCMS (M+H) + The calculated value of m / z is 225.1, while the actual measured value is 225.0. Trimethyl(trifluoromethyl)silane (8.9 g, 62.4 mmol, 2.0 equivalent) was added to a solution of 2,2-difluoro-5-phenyl-3-(propane-2-ylidene)-2,3-dihydro-1,3l4,4,2l4-oxadiazaboranecyclopentene (7.0 g, 31.2 mmol, 1.0 equivalent) and NaOAc (10.0 g, 124.8 mmol, 4.0 equivalent) in DMF (150 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 5 / 1, v / v) to give N'-(1,1,1-trifluoro-2-methylpropane-2-yl)benzoylhydrazine (7.0 g, 91%). LCMS (M+H) + The calculated value of m / z is 247.1, while the actual measured value is 247.2. HCl (5 mL) was added to a solution of N'-(1,1,1-trifluoro-2-methylpropane-2-yl)benzoylhydrazine (7.0 g, 31.2 mmol, 1 equivalent) in water (50 mL). The mixture was stirred at 100 °C for 5 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were milled in Et2O to obtain (1,1,1-trifluoro-2-methylpropane-2-yl)hydrazine hydrochloride (3.5 g, 63%). 1 H NMR (400 MHz, DMSO) δ 9.47 (s, 3H), 6.02 (s, 1H), 1.33 (s, 6H). As described for N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-pyrazol-3-yl)-1-(( 2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 646.3, while the actual measured value is 646.7. As described for 5-amino-3-(7-(aminomethyl)-1H-indazol-4-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-carboxynitrile, N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 516.2, while the actual measured value is 516.3. As described for 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-4-yl)-1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-pyrazole-4-carboxamide is converted to 5-amino-3-(4-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 534.2, while the actual measured value is 534.3.1 H NMR (400 MHz, DMSO) δ 13.30 (s, 1 H), 8.97 (t, 1 H), 8.00 (s, 1 H), 7.55 (dd, 1 H), 7.28-7.39 (m, 2 H), 7.19 (dd, 2 H), 6.55 (s, 2 H), 4.82 (d, 2 H), 3.91 (s, 3 H), 1.91 (s, 6 H).

[0249] Example 21: Preparation of 5-amino-3-(5-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide A solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (5.0 g, 19.0 mmol, 1.0 equivalence) in anhydrous THF (60 mL) was cooled to -50 °C under N2, and then a solution of vinyl magnesium bromide in THF (1 M, 61.0 mL, 60.8 mmol, 3.2 equivalence) was added dropwise. The reaction mixture was stirred at -40 °C for 3 h, then quenched with a saturated aqueous solution of NH4Cl (200 mL), acidified with 1 M hydrochloric acid, and extracted with EtOAc (200 mL). The organic layer was washed with brine (150 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, v / v) to give 4-bromo-5-fluoro-1H-indole-7-carboxylic acid (600.0 mg, 13%). LCMS (M+H + The calculated value of m / z is 255.9, and the actual measured value is also 255.9. At 0 °C, LiAlH4 (1.1 mL, 2.5 M, 2.6 mmol, 1.1 equivalence in THF) was added to a solution of 4-bromo-5-fluoro-1H-indole-7-carboxylic acid (600.0 mg, 2.3 mmol, 1.0 equivalence) in THF (15 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into a saturated aqueous solution of ammonium chloride (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1, v / v) to give (4-bromo-5-fluoro-1H-indole-7-yl)methanol (450.1 mg, 79.0%). LCMS (MH + The calculated value of m / z is 242.0, while the actual measured value is 242.1. As described for 7-(azidomethyl)-4-bromo-1H-indole, (4-bromo-5-fluoro-1H-indole-7-yl)methanol is converted to 7-(azidomethyl)-4-bromo-5-fluoro-1H-indole. LCMS (M+H) + The calculated m / z is 269.0, while the actual measured value is 268.9. As described with (4-bromo-1H-indol-7-yl)methylamine, 7-(azidomethyl)-4-bromo-5-fluoro-1H-indole is converted to (4-bromo-5-fluoro-1H-indol-7-yl)methylamine. LCMS (MH + The calculated value of m / z is 241.0, and the actual measured value is also 241.0. As described with N-((4-bromo-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide, (4-bromo-6-fluoro-1H-indol-7-yl)methylamine is converted to N-((4-bromo-5-fluoro-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 395.0, and the actual measured value is also 395.0. As described for 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indol-7-yl)methyl)benzamide, N-((4-bromo-5-fluoro-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-fluoro-N-((5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indol-7-yl)methyl)-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 443.2, and the actual measured value is also 443.2. As described for N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 5-fluoro-N-((5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-7-yl)methyl)-2-methoxybenzamide is converted to N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-5-fluoro-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 519.1, while the actual measured value is 519.0. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-5-fluoro-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-3-(5-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 537.2, and the actual measured value is also 537.2. 1H NMR (DMSO-d6, 400 MHz) δ 11.43 (s, 1 H), 8.96 (t, 1 H), 7.50-7.55 (m, 2 H), 7.32-7.38(m, 1 H), 7.17-7.22 (m, 1 H), 7.01 (d, 1 H), 6.74 (s, 2 H), 6.22 (t, 1 H), 5.32-5.36 (m, 1 H), 4.80 (d, 2 H), 3.90 (s, 3 H), 1.62 (d, 3 H).

[0250] Example 22: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide To a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine (5.0 g, 25.5 mmol, 1.0 equivalent) in EtOAc (80 mL), 3-chloroperoxybenzoic acid (5265 mg, 30.6 mmol, 1.2 equivalent) in EtOAc (40 mL) was slowly added. The reaction mixture was stirred at room temperature for 15 hours. The precipitate was collected and dried to give 4-bromo-1H-pyrrolo[2,3-c]pyridine-6-oxide (4.3 g, 80.1%). LCMS (M+H) + The calculated value of m / z is 213.0, while the actual measured value is 212.9. A solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine-6-oxide (4.3 g, 21.3 mmol, 1.0 equivalent), TEA (3.6 mL, 25.4 mmol), and TMSCN (8.0 g, 81.1 mmol, 4.0 equivalent) in acetonitrile (97 mL) was stirred for 1 hour at 85 °C. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-bromo-1H-pyrrolo[2,3-c]pyridine-7-carboxynitrile (4.2 g, 94%). LCMS (M+H) + The calculated value of m / z is 222.0, while the actual measured value is 221.9. At 0 °C, BH3-THF (1.0 M, 86 mL, 85.9 mmol, 5.0 equivalent in THF) was added to a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine-7-carboxynitrile (3.8 g, 17.2 mmol, 1.0 equivalent) in THF (100 mL). The mixture was stirred at room temperature for 4 hours. After completion, the reaction was quenched with methanol (30 mL) at 0 °C and concentrated under reduced pressure. The residue was used directly for the next step (4.2 g, quantified). LCMS (M+H) + The calculated value of m / z is 238.0, and the actual measured value is also 238.0. A solution of N-((4-bromo-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)boronamine (4.3 g, 18.1 mmol, 1.0 equivalent), NaHCO3 (7.6 g, 90.7 mmol, 5.0 equivalent), and di-tert-butyl dicarbonate (19.8 g, 90.7 mmol, 5.0 equivalent) in THF (75 mL) and H2O (25 mL) was stirred for 5 hours at room temperature. The reaction mixture was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, v / v) to give tert-butyl ((4-bromo-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)carbamate (370 mg, 6%). LCMS (M+H) + The calculated value of m / z is 326.0, while the actual measured value is 325.9. As described for 5-amino-3-(7-(aminomethyl)-1H-indazol-4-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazole-4-carboxynitrile, tert-butyl ((4-bromo-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)carbamate is converted to (4-bromo-1H-pyrrolo[2,3-c]pyridin-7-yl)methylamine. LCMS (M+H + The calculated value of m / z is 226.0, while the actual measured value is 226.2. As described for N-((4-(5-amino-4-cyano-1-(3,3-difluorocyclobutyl)-1H-pyrazol-3-yl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide, (4-bromo-1H-pyrrolo[2,3-c]pyridin-7-yl)methylamine is converted to N-((4-bromo-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H + The calculated value of m / z is 378.0, while the actual measured value is 378.2. As described with 4-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole, N-((4-bromo-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H + The calculated value of m / z is 508.1, while the actual measured value is 508.2. As described for 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyl-2-yl)-1H-indol-7-yl)methyl)benzamide, N-((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)benzamide. LCMS (M+H) + The calculated value of m / z is 556.3, while the actual measured value is 556.1. As described for N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentane-2-yl)-1-((2-(trimethylsilyl)ethyl) The conversion of N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide is shown in the LCMS (M+H) + The calculated m / z value is 632.2, while the actual measured value is 632.0. As described for N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 502.2, while the actual measured value is 501.9. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-3-yl)-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H +The calculated value of m / z is 520.2, while the actual measured value is 520.3. 1 H NMR (400 MHz, DMSO) δ 11.92 (s, 1 H), 9.60 (t, 1 H), 8.19 (s, 1 H), 7.64-7.75 (m, 2 H), 7.31-7.44 (m, 1 H), 7.26 (dd, 1 H), 6.74 (s, 2 H), 6.40-6.50 (m, 1 H), 5.34 (dd, 1 H), 4.98 (d, 2 H), 4.01 (s, 3 H), 1.65 (d, 3 H).

[0251] Example 23: Preparation of 5-amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide was prepared as described for 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated m / z value is 537.2, and the measured value is also 537.2. ¹H NMR (DMSO-d⁶, 400 MHz) δ 11.32 (s, ¹H), 8.85 (t, ¹H), 7.49 (dd, ¹H), 7.46 (t, ¹H), 7.29–7.35 (m, ¹H), 7.15 (dd, ¹H), 6.95 (d, ¹H), 6.75 (s, 2H), 6.35 (t, 1H), 5.30–5.35 (m, ¹H), 4.82 (d, 2H), 3.84 (s, 3H), 1.62 (d, 3H).

[0252] Example 24: Preparation of 5-amino-3-(4-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide A solution of 2-amino-4-bromo-3-methylbenzoic acid (7.0 g, 10.92 mmol, 1.0 equivalent) in H₂SO₄ (15 mL) and MeOH (60 mL) was stirred for 18 hours at 90 °C and then concentrated under vacuum. The crude product was diluted with H₂O (100 mL) and extracted with DCM (150 mL x 3). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue, which was purified by silica gel column chromatography (PE / DCM = 1 / 1, v / v) to give methyl 2-amino-4-bromo-3-methylbenzoate (5.5 g, 74%) as a white solid. LCMS (M+H) + The calculated value of m / z is 244.0, and the actual measured value is also 244.0. At 0 °C, NaNO2 (2.3 g, 33.1 mmol, 1.1 equivalent) was added to a solution of methyl 2-amino-4-bromo-3-methylbenzoate (7.3 g, 30.04 mmol, 1.0 equivalent) in AcOH (80 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with DCM (250 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (PE / DCM = 1 / 3, v / v) to give methyl 4-bromo-1H-indazole-7-carboxylate (3.8 g, 49.8%) as a white solid. LCMS (M+H) + The calculated value of m / z is 255.0, and the actual measured value is 255.0. As described for 4-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole, methyl 4-bromo-1H-indazole-7-carboxylate is converted to methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylate. LCMS (M+H) + The calculated value of m / z is 385.1, while the actual measured value is 385.0. Under N2, potassium salt of ((trifluoro-14-boryl)methyl)carbamate (3.8 g, 16.0 mmol, 1.5 equivalent), Pd(PPh3)2Cl2 (0.75 g, 1.07 mmol, 0.1 equivalent), and Na2CO3 (3.4 g, 32.0 mmol, 3.0 equivalent) were added to a solution of methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylate (4.1 g, 10.6 mmol, 1.0 equivalent) in water (5 mL) and methanol (25 mL). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was then concentrated. The resulting residue was purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give methyl 4-(((tert-butoxycarbonyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylate (2.9 g, 63%) as a colorless oil. LCMS (M+H) + The calculated value of m / z is 436.2, and the actual measured value is also 436.2. As described for methyl 4-(((tert-butoxycarbonyl)amino)methyl)-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylate, the methyl 4-(aminomethyl)-1H-indazole-7-carboxylate is converted to 4-(aminomethyl)-1H-indazole-7-carboxylate. LCMS (M+H) + The calculated value of m / z is 206.1, while the actual measured value is 206.0. To a solution of methyl 4-(aminomethyl)-1H-indazole-7-carboxylate (1.3 g, 6.3 mmol, 1.0 equivalent) in DMF (20 mL), 5-fluoro-2-methoxybenzoic acid (1.1 g, 6.34 mmol, 1.0 equivalent), HATU (2.9 g, 7.6 mmol, 1.2 equivalent), and DIEA (2.5 g, 19.0 mmol, 3.0 equivalent) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, v / v) to give methyl 4-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-7-carboxylate (2.1 g, 91%) as a white oil. LCMS (M+H) +The calculated value of m / z is 358.1, while the actual measured value is 358.2. As described for 4-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole, methyl 4-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-7-carboxylate is converted to methyl 4-((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylate, LCMS (M+H + The calculated value of m / z is 488.2, and the actual measured value is also 488.2. As described for methyl 4-((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-carboxylic acid, the methyl 4-((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylic acid is converted to methyl 4-((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylic acid, LCMS (M+H + The calculated value of m / z is 474.2, and the actual measured value is also 474.2. As described for N-((4-(2,2-dicyano-1-hydroxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 4-((5-fluoro-2-methoxybenzoylamino)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylic acid is converted to N-((7-(2,2-dicyano-1-hydroxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H + The calculated value of m / z is 522.2, and the actual measured value is also 522.2. As described for N-((4-(2,2-dicyano-1-methoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((4-(2,2-dicyano-1-hydroxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((7-(2,2-dicyano-1-methoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-yl)methyl)-5-fluoro-2-methoxybenzamide, LCMS (M+H + The calculated value of m / z is 536.2, and the actual measured value is also 536.2. As described for N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((7-(2,2-dicyano-1-methoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 632.2, while the actual measured value is 632.3. As described for 5-amino-3-(7-(aminomethyl)-1H-indazol-4-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-carboxynitrile, N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H + The calculated value of m / z is 502.2, while the actual measured value is 502.3. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-3-yl)-1H-indazole-4-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-3-(4-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazole-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 520.2, while the actual measured value is 520.4. 1 HNMR (400 MHz, DMSO-d6)δ 12.80 (s, 1 H), 8.92 (t, 1 H), 8.33 (s, 1 H), 7.51 (dd, 1 H), 7.40 (m, 1H), 7.30-7.37 (m, 1 H), 7.11-7.21 (m, 2 H), 6.73 (s, 2 H), 5.34 (m, 1 H), 4.86 (d, 2 H), 3.88 (s, 3 H), 1.68 (d, 3 H).

[0253] Example 25: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide CDI (73 g, 451.2 mmol, 1.2 equivalent) was added to a solution of 3,6-dibromophenyl-1,2-diamine (100 g, 376 mmol, 1.0 equivalent) in DMF (200 mL). The reaction mixture was stirred at 100 °C for 3 h. It was then diluted with water (50 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, v / v) to give 4,7-dibromo-1,3-dihydro-2H-benzo[d]imidazol-2-one (110 g, 100%) as a colorless oil. LCMS (M+H) + The calculated value of m / z is 290.9, while the actual measured value is 291.0. As described for 4,7-dibromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one, 4,7-dibromo-1,3-dihydro-2H-benzo[d]imidazol-2-one is converted to 4,7-dibromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. LCMS (M+H) + The calculated m / z value is 551.0, while the actual measured value is 551.3. As described for 2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4,7-dicarboxylate, 4,7-dibromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one is converted to dimethyl 2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4,7-dicarboxylate. LCMS (M+H + The calculated value of m / z is 511.2, and the actual measured value is also 511.2. As described for methyl 7-(hydroxymethyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylate, 2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4,7-dicarboxylate is converted to dimethyl 7-(hydroxymethyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylate. LCMS (M+H + The calculated m / z value is 483.2, while the actual measured value is 483.1. As described for 7-(azidomethyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylate, methyl 7-(hydroxymethyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylate is converted to methyl 7-(azidomethyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylate. As described for methyl 7-(azidomethyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxylate, methyl 7-(azidomethyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxylate is converted to methyl 7-(aminomethyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxylate. LCMS (M+H + The calculated value of m / z is 482.2, and the actual measured value is also 482.2. As described for methyl 7-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylate, methyl 7-(aminomethyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylate is converted to methyl 7-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylate. LCMS (M+H + The calculated value of m / z is 634.3, and the actual measured value is also 634.3. As described for methyl 7-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylic acid, the methyl 7-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylic acid is converted to methyl 7-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylic acid. LCMS (M+H + The calculated value of m / z is 620.3, while the actual measured value is 620.4. As described for N-((7-(2,2-dicyanoacetyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide, 7-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-carboxylic acid is converted to N-((7-(2,2-dicyanoacetyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (MH + The calculated value of m / z is 666.3, while the actual measured value is 666.2. As described for N-((7-(2,2-dicyano-1-methoxyvinyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((7-(2,2-dicyanoacetyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)) The methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide was converted into N-((7-(2,2-dicyano-1-methoxyvinyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide, a gray solid. LCMS (MH + The calculated value of m / z is 680.3, while the actual measured value is 680.2. As described for N-((7-(2,2-dicyano-1-methoxyvinyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((7-(2,2-dicyano-1-methoxyvinyl)-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((7-(2,2-dicyano-1-methoxyvinyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H +The calculated value of m / z is 422.1, while the actual measured value is 422.4. As described for N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((7-(2,2-dicyano-1-methoxyvinyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 518.1, while the actual measured value is 518.4. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-3- The conversion of 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide is shown in the LCMS (M+H) + The calculated value of m / z is 536.2, while the actual measured value is 536.5. 1 H NMR (400 MHz, DMSO) δ 10.87 (s,1 H), 10.38 (s, 1 H), 8.83 (t, 1 H), 7.52 (dd, 1 H), 7.34 (td, 1 H), 7.18(dd, 1 H), 6.98 (dd, 2 H), 6.71 (s, 2 H), 5.17-5.36 (m, 1 H), 4.55 (d, 2 H), 3.90 (s, 3 H), 1.63 (d, 3 H).

[0254] Example 26: Preparation of 5-amino-3-(4-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide At 0 °C, 40 mL of concentrated HNO3 and 37 mL of concentrated H2SO4 were added to a solution of 2-bromo-5-methylphenol (100.0 g, 135.1 mmol, 1.0 equivalent) in DCM (400 mL). The mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water (300 mL). The mixture was extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 30 / 1, v / v) to give 6-bromo-3-methyl-2-nitrophenol (42.2 g, crude). At room temperature, K₂CO₃ (42.2 g, 305.0 mmol, 3.0 equivalent) and iodomethane (21.6 g, 152.6 mmol, 1.5 equivalent) were added to a solution of 6-bromo-3-methyl-2-nitrophenol (23.6 g, 101.7 mmol, 1.0 equivalent) in DMF (240 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (500 mL). The aqueous layer was extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 200 / 1, v / v) to give 1-bromo-2-methoxy-4-methyl-3-nitrobenzene (17.1 g, 67.9%). LCMS (M+H) + The calculated value of m / z is 246.0, and the actual measured value is also 246.0. As described with 4-bromo-7-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole, 1-bromo-2-methoxy-4-methyl-3-nitrobenzene is converted to 1-bromo-4-(bromomethyl)-2-methoxy-3-nitrobenzene. LCMS (M+H) + The calculated value of m / z is 323.9, while the actual measured value is 324.0. Di-tert-butyl iminodicarboxylate (11.2 g, 51.7 mmol, 1.0 equivalent) was added to a solution of 1-bromo-4-(bromomethyl)-2-methoxy-3-nitrobenzene (16.1 g, 49.2 mmol, 1.0 equivalent) and Cs₂CO₃ (16.8 g, 51.7 mmol, 1.1 equivalent) in DMF (160 mL). The resulting mixture was then stirred at room temperature for 6 hours. The reaction mixture was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc=100 / 1, v / v) to give 1-bromo-4-(di-tert-butyl iminodicarboxylate)-2-methoxy-3-nitrobenzene (17.5 g, 77.1%). LCMS (M+H) + The calculated value of m / z is 461.1, while the actual measured value is 461.0. As described for ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)tert-butyl carbamate, 1-bromo-4-(iminodicarboxylate di-tert-butyl)-2-methoxy-3-nitrobenzene is converted to (tert-butoxycarbonyl)(3-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzyl)tert-butyl carbamate. LCMS (M+H) + The calculated value of m / z is 509.3, while the actual measured value is 509.4. As described for ((4-(5-amino-4-cyano-1-(3,3-difluorocyclobutyl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)tert-butyl carbamate, (tert-butyloxycarbonyl)(3-methoxy-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzyl)tert-butyl carbamate is converted to (4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-3-methoxy-2-nitrobenzyl)(tert-butyloxycarbonyl)tert-butyl carbamate. LCMS (M+H) + The calculated value of m / z is 585.2, and the actual measured value is also 585.2. To a solution of tert-butyl carbamate (4 g, 6.8 mmol, 1 equivalent) in DMF (40 mL), LiCl (870.0 mg, 20.5 mmol, 3.0 equivalent) was added. The resulting mixture was then stirred at 140 °C for 16 hours. The reaction mixture was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, v / v) to give tert-butyl (4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-3-hydroxy-2-nitrobenzyl)carbamate (2.7 g, 83.9%) as a white solid. LCMS (M+H) + The calculated value of m / z is 471.1, while the actual measured value is 471.2. Fe (1.6 g, 28.7 mmol, 5.0 equivalent) was added to a solution of 3-bromo-5-((3,4-dimethylbenzyl)amino)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxynitrile (2.7 g, 5.7 mmol, 1.0 equivalent) and NH4Cl (1.8 g, 34.4 mmol, 6.0 equivalent) in EtOH (30 mL) and water (10 mL). The reaction mixture was stirred at 70 °C for 6 hours. The reaction mixture was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 5 / 1, v / v) to give tert-butyl (2-amino-4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-3-hydroxybenzyl)carbamate (860.1 mg, 34%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 441.2, while the actual measured value is 441.3. At 0 °C, triethylamine (345.1 mg, 3.4 mmol, 3.0 equivalent) and triphosgene (337.0 mg, 1.1 mmol, 1.0 equivalent) were added to a solution of tert-butyl carbamate (2-amino-4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-3-hydroxybenzyl) in THF (20 mL). The resulting mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl ((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-yl)methyl)carbamate (260.0 mg, 50%). LCMS (M+H) + The calculated value of m / z is 467.2, while the actual measured value is 467.3. As described for 5-amino-3-(7-(aminomethyl)-1H-indazol-4-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-carboxynitrile, ((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-yl)methyl)carbamate tert-butyl ester is converted to 5-amino-3-(4-(aminomethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxynitrile. LCMS (M+H) + The calculated value of m / z is 367.1, while the actual measured value is 367.2. As described for N-((4-(5-amino-4-cyano-1-(3,3-difluorocyclobutyl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 5-amino-3-(4-(aminomethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxynitrile is converted to N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) +The calculated value of m / z is 519.1, while the actual measured value is 519.2. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, N-((7-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-3-(4-(((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 537.1, while the actual measured value is 537.4. 1 H NMR (DMSO-d6, 400 MHz) δ8.92 (t, 1 H), 7.52 (d, 1 H), 7.52 (d,1H), 7.32-7.35 (m, 1 H), 7.17-7.20 (m, 1 H), 7.07 (d, 1 H), 6.68 (s, 2 H), 5.30-5.34 (m, 1 H), 4.55 (d, 2 H), 3.91 (s, 3 H), 1.61 (d, 3 H).

[0255] Example 27: Preparation of (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrazolo[3,4-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide At 0 °C, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (19.8 g, 65.7 mmol, 1.5 equivalent) was added to a solution of (R)-1,1,1-trifluoropropane-2-ol (5.0 g, 43.8 mmol, 1.0 equivalent) and TEA (8.8 g, 87.6 mmol, 2.0 equivalent) in DCM (100 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (150 mL) and extracted with DCM (150 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-1,1,1-trifluoropropane-2-yltrifluoromethanesulfonate (15 g, crude) as a brown oil. To a solution of 3,5-dibromo-1H-pyrazole-4-carboxynitrile (4.0 g, 16.0 mmol, 1.0 equivalent) and Cs₂CO₃ (10.4 g, 32.0 mmol, 2.0 equivalent) in DMF (50 mL), (R)-1,1,1-trifluoropropane-2-yltrifluoromethanesulfonate (12.6 g, 32.0 mmol, 2.0 equivalent) was added. The resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 20 / 1, v / v) to give (S)-3,5-dibromo-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxynitrile (6.5 g, quantitative) as a white solid. LCMS (M+H) + The calculated value of m / z is 345.9, while the actual measured value is 346.0. (3,4-Dimethylphenyl)methylamine (4.68 g, 28.1 mmol, 1.5 equivalent) was added to a solution of (S)-3,5-dibromo-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxynitrile (6.5 g, 18.7 mmol, 1.0 equivalent) in NMP (100 mL). The resulting mixture was stirred at 180 °C for 4 hours. The reaction mixture was diluted with water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (S)-3-bromo-5-((3,4-dimethylbenzyl)amino)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxynitrile (4.8 g, 59.1%) as a green solid. LCMS (M+H) + The calculated value of m / z is 433.0, while the actual measured value is 433.1. TFA (20 mL) was added to a solution of (S)-3-bromo-5-((3,4-dimethylbenzyl)amino)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxylonitrile (4.8 g, 12.0 mmol, 1.0 equivalent) in DCM (20 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give (S)-5-amino-3-bromo-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxylonitrile (2.4 g, 76.1%) as a green solid. LCMS (M+H) + The calculated value of m / z is 283.0, while the actual measured value is 283.1. Hydrazine hydrate (80 mL) was added to a solution of 3-bromo-5-fluoroisononoxane (15.0 g, 73.5 mmol, 1.0 equivalent) in DME (50 mL), and the reaction mixture was heated at 110 °C for 15 hours. After the reaction was complete, the solvent was concentrated. The resulting residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, v / v) to give 4-bromo-1H-pyrazolo[3,4-c]pyridine (6.4 g, 43.8%) as a white solid. LCMS (M+H) + The calculated value of m / z is 198.0, while the actual measured value is 198.1. As described for 4-bromo-1H-pyrrolo[2,3-c]pyridine-6-oxide, 4-bromo-1H-pyrazolo[3,4-c]pyridine is converted to 4-bromo-1H-pyrazolo[3,4-c]pyridine-6-oxide. LCMS (M+H + The calculated value of m / z is 216.0, while the actual measured value is 215.9. As described for 4-bromo-1H-pyrrolo[2,3-c]pyridine-7-carboxylonitrile, 4-bromo-1H-pyrazolo[3,4-c]pyridine-6-oxide is converted to 4-bromo-1H-pyrazolo[3,4-c]pyridine-7-carboxylonitrile. LCMS (M+H + The calculated value of m / z is 225.0, while the actual measured value is 225.1. As described for N-((4-bromo-1H-pyrrolo[2,3-c]pyridin-7-yl)methyl)boronamine, 4-bromo-1H-pyrazolo[3,4-c]pyridin-7-carboxynitrile is converted to N-((4-bromo-1H-pyrazolo[3,4-c]pyridin-7-yl)methyl)boronamine. LCMS (M+H + The calculated value of m / z is 239.0, while the actual measured value is 239.1. As described for N-((4-bromo-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide, N-((4-bromo-1H-pyrazolo[3,4-c]pyridin-7-yl)methyl)boronamine is converted to N-((4-bromo-1H-pyrazolo[3,4-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H + The calculated value of m / z is 379.0, while the actual measured value is 379.2. As described for 4-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole, N-((4-bromo-1H-pyrazolo[3,4-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to N-((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H + The calculated value of m / z is 509.1, while the actual measured value is 509.3. As described for ((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl)tert-butyl carbamate, N-((4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)methyl)benzamide. LCMS (M+H) + The calculated value of m / z is 557.3, while the actual measured value is 557.4. As described for ((4-(5-amino-4-cyano-1-(3,3-difluorocyclobutyl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-yl)methyl)tert-butyl carbamate, 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-((2-(trimethylsilyl) The conversion of (S)-N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H + The calculated value of m / z is 633.2, while the actual measured value is 633.5. As described for 5-amino-3-(7-(aminomethyl)-1H-indazol-4-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-carboxynitrile, (S)-N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to (S)-N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H)+ The calculated value of m / z is 503.1, while the actual measured value is 503.2. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, (S)-N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-c]pyridin-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to (S)-5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrazolo[3,4-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide). LCMS (M+H) + The calculated value of m / z is 521.2, and the actual measured value is also 521.2. 1 H NMR (DMSO-d6, 400 MHz) δ 13.94 (brs, 1 H), 9.52 (s, 1 H), 8.49 (s, 2 H), 8.34 (s, 1 H), 8.14 (s, 1 H), 7.67 (dd, 1 H), 7.37-7.43 (m, 1 H), 7.24-7.28 (m, 1 H), 6.66 (s, 2 H), 5.36-5.42 (m, 1 H), 5.04 (d, 2 H), 4.01 (s, 3 H), 1.66 (d, 3 H).

[0256] Example 28: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide A solution of 2-iodopropane (10.1 g, 64.2 mmol, 1.2 equivalents), 5-amino-3-bromo-1H-pyrazole-4-carboxynitrile (10.0 g, 53.5 mmol, 1.0 equivalents), and Cs₂CO₃ (34.9 g, 107.0 mmol, 2.0 equivalents) in DMF (80 mL) was stirred for 16 hours at room temperature. The reaction mixture was diluted with water (130 mL) and extracted with EtOAc (130 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC to give 5-amino-3-bromo-1-isopropyl-1H-pyrazole-4-carboxynitrile (5.2 g, 42.3%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 229.0, while the actual measured value is 229.2. As described for N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)-1H-indole-7-yl)methyl)benzamide is converted to N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 447.2, while the actual measured value is 447.4. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazole-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 465.2, and the actual measured value is also 465.2. 1H NMR (DMSO-d6, 400 MHz) δ 11.25 (s, 1 H), 8.92 (t, 1H), 7.54 (dd, 1 H), 7.43 (t, 1 H), 7.31-7.37 (m, 1 H), 7.13-7.21 (m, 1 H),7.37-7.43 (m, 1 H), 7.03 (d, 1 H), 6.40 (s, 2 H), 6.33-6.35 (m, 1 H), 4.80 (d, 2 H), 4.46-4.54 (m, 1 H), 3.89 (s, 3 H), 1.35 (d, 6 H).

[0257] Example 29: Preparation of 5-amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide was prepared as described for 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated m / z value is 483.2, and the measured value is also 483.2. ¹H NMR (DMSO-d⁶, 400 MHz) δ 11.29 (s, ¹H), 8.85 (t, ¹H), 7.49 (dd, ¹H), 7.44 (t, ¹H), 7.29–7.35 (m, ¹H), 7.13–7.18 (m, ¹H), 6.92 (d, ¹H), 6.38 (s, 2H), 6.34–6.36 (m, ¹H), 4.82 (d, 2H), 4.49–4.52 (m, ¹H), 3.84 (s, 3H), 1.34 (d, 6H).

[0258] Example 30: Preparation of (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide was prepared as described for p-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H + The calculated value of m / z is 519.2, and the actual measured value is also 519.2. 1 H NMR (DMSO-d6, 400 MHz) δ 11.30 (s, 1 H), 8.92 (t, 1 H), 7.55 (dd, 1 H), 7.45 (t, 1 H), 7.31-7.38 (m, 1 H), 7.15-7.21(m, 2 H), 7.05 (d, 1 H), 6.77 (s, 2 H), 6.33 (t, 1 H), 5.30-5.33 (m, 1 H), 4.80 (d, 2 H), 3.89 (s, 3 H), 1.62 (d, 3 H).

[0259] Example 31: Preparation of (S)-5-amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide (S)-5-amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide was prepared as described for p-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H + The calculated value of m / z is 537.2, while the actual measured value is 537.1. 1H NMR (DMSO-d6, 400 MHz) δ 11.32 (s, 1H), 8.85 (t, 1 H), 7.49 (dd, 1 H), 7.46 (t, 1 H), 7.29-7.35 (m, 1 H), 7.15(dd, 1 H), 6.95 (d, 1 H), 6.75 (s, 2 H), 6.35 (t, 1 H), 5.30-5.35 (m, 1 H), 4.82 (d, 2 H), 3.84 (s, 3 H), 1.62 (d, 3 H).

[0260] Example 32: Preparation of (R)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide (10 mg, 0.0192 mmol) was separated by chiral column chromatography (column: CHIRALPAK IK, mobile phase: hexane / EtOH / DEA = 50 / 50 / 0.1 (V / V / V)) to give (R)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated m / z value was 519.2, and the measured value was also 519.2. ¹H NMR (DMSO-d⁶, 400 MHz) δ 11.30 (s, ¹H), 8.92 (t, ¹H), 7.55 (dd, ¹H), 7.45 (t, ¹H), 7.31–7.38 (m, ¹H), 7.15–7.21 (m, ²H), 7.05 (d, ¹H), 6.77 (s, ²H), 6.33 (t, ¹H), 5.30–5.33 (m, ¹H), 4.80 (d, ²H), 3.89 (s, ³H), 1.62 (d, ³H).

[0261] Example 33: Preparation of (S)-2-(5-amino-4-carbamoyl-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)propionic acid At 0 °C, PPh3 (1.7 g, 6.4 mmol, 1.0 equivalent) and DIAD (1.3 g, 6.4 mmol, 1.2 equivalent) were added dropwise to a stirred solution of 5-amino-3-bromo-1H-pyrazole-4-carboxynitrile (1.0 g, 5.3 mmol, 1.0 equivalent) and (R)-2-hydroxypropionate (757.2 mg, 6.4 mmol, 1.2 equivalent) in THF (15 mL). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The resulting residue was diluted with water (25 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, v / v) to give ethyl (S)-2-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)propionate (700.0 mg, 45.6%) as a grayish-white solid. LCMS (M+H) + The calculated value of m / z is 287.0, while the actual measured value is 287.1. As described for N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 5-fluoro-2-methoxy-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane-2-yl)-1H-indole-7-yl)methyl)benzamide is converted to (S)-2-(5-amino-4-cyano-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indole-4-yl)-1H-pyrazol-1-yl)propionic acid. LCMS (M+H) + The calculated value of m / z is 477.2, while the actual measured value is 477.4. As described with 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, (S)-2-(5-amino-4-cyano-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)propionic acid is converted to (S)-2-(5-amino-4-carbamoyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)propionic acid. LCMS (M+H)+ The calculated value of m / z is 495.2, while the actual measured value is 495.3. 1 H NMR (DMSO-d6, 400 MHz) δ 12.88(brs, 1 H), 11.26 (s, 1 H), 8.91 (t, 1 H), 7.54 (dd, 1 H), 7.43 (t, 1 H),7.31-7.37 (m, 1 H), 7.13-7.21 (m, 2 H), 7.03 (d, 1 H), 6.51 (s, 2 H), 6.33-6.35 (m, 1 H), 5.05-5.09 (m, 1 H), 4.80 (d, 2 H), 3.88 (s, 3 H), 1.58 (d, 3H).

[0262] Example 34: Preparation of (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-hydroxypropane-2-yl)-1H-pyrazole-4-carboxamide As described for (4-bromo-1H-indol-7-yl)methanol, ethyl (S)-2-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)propionate is converted to (S)-5-amino-3-bromo-1-(1-hydroxypropane-2-yl)-1H-pyrazol-4-carboxynitrile. LCMS (M+H) + The calculated value of m / z is 247.0, while the actual measured value is 247.1. As described for N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, (4-bromo-1H-indole-7-yl)methanol is converted to (S)-N-((4-(5-amino-4-cyano-1-(1-hydroxypropane-2-yl)-1H-pyrazol-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 463.2, while the actual measured value is 463.4. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, (S)-N-((4-(5-amino-4-cyano-1-(1-hydroxypropane-2-yl)-1H-pyrazole-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to (S)-5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-hydroxypropane-2-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 481.2, and the actual measured value is also 481.2. 1 H NMR (DMSO-d6, 400 MHz) δ11.26 (s, 1 H), 8.92 (t, 1 H), 7.54 (dd, 1 H), 7.43 (t, 1 H), 7.31-7.37 (m, 1H), 7.13-7.21 (m, 2 H), 7.03 (d, 1 H), 6.35-6.37 (m, 1 H), 6.33 (s, 2 H), 4.90-4.92 (m, 1 H), 4.80 (d, 2 H), 4.33-4.36 (m, 1 H), 3.89 (s, 3 H), 3.59-3.68 (m, 2 H), 1.31 (d, 3 H).

[0263] Example 35: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide A solution of 5-amino-3-bromo-1H-pyrazole-4-carboxynitrile (3 g, 16.0 mmol, 1.0 equivalent), tert-butyl 4-((methanesulfonyl)oxy)piperidine-1-carboxylate (6.7 g, 24.1 mmol, 1.5 equivalent), and Cs₂CO₃ (10.5 g, 32.1 mmol, 2.0 equivalent) in DMF (50 mL) was stirred for 5 hours at 30 °C. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1, v / v) to give tert-butyl 4-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.3 g, 22.0%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 368.1, while the actual measured value is 368.2. As described with N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide, tert-butyl 4-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)piperidin-1-carboxylate is converted to tert-butyl 4-(5-amino-4-cyano-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylate. LCMS (M+H) + The calculated value of m / z is 588.3, ​​while the actual measured value is 588.4. As described with 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide, 4-(5-amino-4-cyano-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester is converted to 4-(5-amino-4-carbamoyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester. LCMS (M+H) + The calculated value of m / z is 606.3, while the actual measured value is 606.2. TFA (2 mL) was added to a stirred solution of tert-butyl piperidine-1-carboxylate (100.0 mg, 0.17 mmol, 1.0 equivalent) in DCM (10 mL). The reaction was stirred at room temperature for 0.5 h. The mixture was concentrated and the resulting residue was purified by reversed-phase HPLC (MeCN / H2O = 1 / 1, v / v) to give 5-amino-3-(7-((5-fluoro-2-methoxybenzoamide)methyl)-1H-indol-4-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide. LCMS (MH + The calculated m / z value is 506.2, and the measured value is 506.3. ¹H NMR (DMSO-d⁶, 400 MHz) δ 11.26 (s, ¹H), 8.92 (t, ¹H), 7.55 (dd, ¹H), 7.43 (t, ¹H), 7.31–7.37 (m, ¹H), 7.13–7.21 (m, ²H), 7.03 (d, ¹H), 6.42 (s, ²H), 6.34–6.36 (m, ¹H), 4.80 (d, ²H), 4.18 (brs, ¹H), 3.89 (s, ³H), 3.00–3.03 (m, ²H), 2.54–2.59 (m, ²H), 1.78–1.83 (m, 4H).

[0264] Example 36: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide, tert-butyl 4-(5-amino-4-cyano-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-1-yl)piperidin-1-carboxylate is converted to N-((4-(5-amino-4-cyano-1-(piperidin-4-yl)-1H-pyrazole-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzoamide. LCMS (M+H + The calculated value of m / z is 488.2, while the actual measured value is 488.4. To a solution of N-((4-(5-amino-4-cyano-1-(piperidin-4-yl)-1H-pyrazol-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (200.0 mg, 0.41 mmol, 1.0 equivalent) in MeOH (20 mL), HCHO (1 mL, 37% aqueous solution), NaBH3CN (129.1 mg, 2.0 mmol, 5.0 equivalent), TEA (207.0 mg, 2.0 mmol, 5.0 equivalent), and AcOH (245.9 mg, 4.1 mmol, 10.0 equivalent) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, v / v) to give N-((4-(5-amino-4-cyano-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide (120.0 mg, 43.6%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 502.2, while the actual measured value is 502.3. At 0 °C, NaOH (0.5 M, 19.1 mg, 0.48 mmol, 2.0 equivalent) and H₂O₂ (30%, 0.2 mL, 0.40 mmol, 20.0 equivalent) were added to a solution of N-((4-(5-amino-4-cyano-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-1H-indol-7-yl)-5-fluoro-2-methoxybenzamide (120.0 mg, 0.24 mmol, 1.0 equivalent) in DMSO (20 mL). The mixture was stirred at 35 °C for 1 hour, then diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative HPLC (MeCN / H2O = 1 / 1, v / v) to give 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide (20.7 mg, 16.7%) as a white solid. LCMS (M+H) + The calculated value of m / z is 520.2, while the actual measured value is 520.3. 1H NMR (DMSO-d6, 400 MHz)δ 11.29 (s, 1 H), 8.92 (t, 1 H), 7.55 (dd, 1 H), 7.43 (t, 1 H), 7.31-7.37 (m,1 H), 7.13-7.21 (m, 2 H), 7.03 (d, 1 H), 6.45 (s, 2 H), 6.34-6.36 (m, 1 H), 4.80 (d, 2 H), 4.18 (brs, 1 H), 3.89 (s, 3 H), 3.00-3.03 (m, 2 H), 2.35 (s, 3H), 2.26-2.34 (m, 2 H), 2.02-2.11 (m, 2 H), 1.87–1.90 (m, 2 H).

[0265] Example 37: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-(4-methylpiperazin-1-yl)propane-2-yl)-1H-pyrazole-4-carboxamide At room temperature, DIEA (5.4 mL, 30.4 mmol, 10.0 equivalent) was added to a solution of (S)-2-(5-amino-4-carbamoyl-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)propionic acid (1.5 g, 3.0 mmol, 1.0 equivalent), EDCI (874.2 mg, 4.6 mmol, 1.5 equivalent), N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.2 mmol, 5.0 equivalent), and HOBT (615.3 mg, 4.6 mmol, 1.5 equivalent) in DMF (20 mL). The mixture was stirred at room temperature for 15 hours, diluted with water (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reversed-phase HPLC (MeCN / H2O = 1 / 1, v / v) to give 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-(methoxy(methyl)amino)-1-oxopropane-2-yl)-1H-pyrazole-4-carboxamide (500.1 mg, 31.3%) as a yellow solid. LCMS (M+H + The calculated value of m / z is 538.2, while the actual measured value is 538.5. At -78 °C, LiAlH4 (50.0 mg, 1.3 mmol, 10.0 equivalent) was added to a solution of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-(methoxy(methyl)amino)-1-oxopropane-2-yl)-1H-pyrazole-4-carboxamide (70 mg, 0.13 mmol, 1.0 equivalent) in THF (30 mL) for 15 hours. The reaction mixture was quenched with sodium sulfate decahydrate, filtered, and the filtrate was used directly for the next step. LCMS (M+H) + The calculated value of m / z is 479.2, while the actual measured value is 479.4. As described for N-((4-(5-amino-4-cyano-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-oxypropane-2-yl)-1H-pyrazol-4-carboxamide is converted to 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-(4-methylpiperazin-1-yl)propane-2-yl)-1H-pyrazol-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 563.3, and the actual measured value is also 563.3. 1 H NMR (DMSO-d6, 400 MHz) δ11.26 (s, 1 H), 8.91 (t, 1 H), 7.55 (dd, 1 H), 7.43 (t, 1 H), 7.33-7.35 (m, 1H), 7.13-7.21 (m, 2 H), 7.02 (d, 1 H), 6.42 (s, 2 H), 6.30-6.32 (m, 1 H), 4.80 (d, 2 H), 4.49-4.52 (m, 1 H), 3.89 (s, 3 H), 2.66-2.72 (m, 2 H), 2.54-2.58 (m, 2 H), 2.28-2.40 (m, 6 H), 2.13 (s, 3 H), 1.30 (d, 3 H).

[0266] Example 38: Preparation of 1-(1-(4-acetylpiperazin-1-yl)propane-2-yl)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide 1-(1-(4-acetylpiperazin-1-yl)propan-2-yl)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide was prepared as described for 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-(4-methylpiperazin-1-yl)propan-2-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 591.3, while the actual measured value is 591.4. 1 H NMR (DMSO-d6, 400 MHz) δ11.26 (s, 1 H), 8.91 (t, 1 H), 7.55 (dd, 1 H), 7.43 (t, 1 H), 7.33-7.35 (m, 1H), 7.13-7.21 (m, 2 H), 7.02 (d, 1 H), 6.43 (s, 2 H), 6.30-6.32 (m, 1 H), 4.80 (d, 2 H), 4.51-4.57 (m, 1 H), 3.89 (s, 3 H), 3.38 (brs, 4 H), 2.70-2.76(m, 1 H), 2.56-2.62 (m, 1 H), 2.30-2.42 (m, 4 H), 1.97 (s, 3H), 1.32 (d, 3H).

[0267] Example 39: Preparation of 5-amino-1-(8-azabicyclo[3.2.1]octane-3-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide At 0 °C, PPh3 (3.3 g, 12.83 mmol, 1.2 equivalent) and DIAD (2.59 g, 12.83 mmol, 1.2 equivalent) were added dropwise to a stirred solution of 3,5-dibromo-1H-pyrazole-4-carboxylonitrile (2.0 g, 10.69 mmol, 1.0 equivalent) and (1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.91 g, 12.83 mmol, 1.2 equivalent) in THF (50 mL). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1, v / v) to give 5-amino-1-((1R,5S)-8-azabicyclo[3.2.1]octane-3-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide (450.0 mg, 10.6%). LCMS (M+H + The calculated value of m / z is 396.1, while the actual measured value is 396.2. A solution of 5-amino-1-((1R,5S)-8-azabicyclo[3.2.1]octane-3-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide (450.0 mg, 1.13 mmol, 1.0 equivalent), 5-amino-3-bromo-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxynitrile (578.2 mg, 1.36 mmol, 1.2 equivalent), Cs2CO3 (734.5 mg, 2.26 mmol, 2.0 equivalent) and Pd(dppf)Cl2 (80.4 mg, 0.11 mmol, 0.1 equivalent) in dioxane (15 mL) and water (3 mL) was stirred for 5 hours at 110 °C. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EtOAc=2 / 1, v / v) to give tert-butyl 3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1R,5S)-3-(5-amino-4-cyano-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (450.0 mg, 64.0%). LCMS (M+H) + The calculated value of m / z is 614.3, while the actual measured value is 614.5. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide, (1R,5S)-3-(5-amino-4-carbamoyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl) -1H-pyrazol-1-yl)-8-azabicyclo[3.2.1] tert-butyl octane-8-carboxylate is converted to (1R,5S)-3-(5-amino-4-carbamoyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1] tert-butyl octane-8-carboxylate. LCMS (M+H + The calculated value of m / z is 632.3, while the actual measured value is 632.2. As described for N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1H-indazole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 5-amino-1-((1R,5S)-8-azabicyclo[3.2.1]octane-3-yl)-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indole-4-yl)-1H-pyrazol-4-carboxamide is converted to 5-amino-1-(8-azabicyclo[3.2.1]octane-3-yl)-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indole-4-yl)-1H-pyrazol-4-carboxamide. LCMS (M+H + The calculated value of m / z is 532.2, while the actual measured value is 532.6. 1 H NMR (400 MHz, DMSO) δ 11.25 (s, 1 H), 8.91 (t, 1H), 7.55 (dd, 1 H), 7.43 (s, 1 H), 7.34(td, 1 H), 7.10-7.24 (m, 2 H), 7.02 (d, 1 H), 6.46 (s, 2 H), 6.32 (s, 1 H), 4.80 (d, 2 H), 4.42 (s, 1 H), 3.88 (s, 3 H), 3.46 (s, 2 H), 2.00 (t, 2 H), 1.82 (d, 2 H), 1.71 (s, 4 H).

[0268] Example 40: Preparation of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazole-4-carboxamide A solution of 5-amino-1-((1R,5S)-8-azabicyclo[3.2.1]octane-3-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide (150.0 mg, 0.28 mmol, 1.0 equivalent), TEA (169.7 mg, 1.68 mmol, 6 equivalent), NaBH3CN (88.0 mg, 1.4 mmol, 5.0 equivalent) and AcOH (168.0 mg, 2.8 mmol, 5 equivalent) in MeOH (15 mL) was stirred for 2 hours at 25 °C. The mixture was concentrated, and the resulting residue was purified by preparative HPLC to give 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazole-4-carboxamide (39.0 mg, 25.9%). LCMS (M+H + The calculated value of m / z is 546.3, while the actual measured value is 546.5. 1 H NMR (400 MHz, DMSO) δ11.27 (s, 1 H), 8.92 (t, 1 H), 7.56 (dd, 1 H), 7.43 (s, 1 H), 7.29-7.39 (m, 1H), 7.10-7.24 (m, 2 H), 7.02 (d, 1 H), 6.47 (s, 2 H), 6.34 (d, 1 H), 4.80 (d,2 H), 4.33-4.46 (m, 1 H), 3.89 (s, 3 H), 3.14 (s, 2 H), 2.13-2.26 (m, 5 H),1.95 (s, 2 H), 1.78 (d, 2 H), 1.58 (d, 2 H).

[0269] Example 41: Preparation of 5-amino-1-(1-(2,2-difluoroethyl)piperidin-4-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide At room temperature, 2,2-difluoroethyl trifluoromethanesulfonate (5.5 mg, 0.026 mmol, 1.3 equivalent) was added to a solution of 5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (10.0 mg, 0.020 mmol, 1.0 equivalent) and DIEA (17.8 mg, 0.14 mmol, 7.0 equivalent) in DMF (10 mL). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reversed-phase HPLC (MeCN / H2O = 1 / 1, v / v) to give 5-amino-1-(1-(2,2-difluoroethyl)piperidin-4-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide (2.7 mg, 23.9%) as a white solid. LCMS (M+H) + The calculated value of m / z is 570.2, while the actual measured value is 520.4. 1 H NMR(DMSO-d6, 400 MHz) δ 11.26 (s, 1 H), 8.92 (t, 1 H), 7.55 (dd, 1 H), 7.43 (t, 1 H), 7.31-7.37 (m, 1 H), 7.13-7.21 (m, 2 H), 7.03 (d, 1 H), 6.44 (s, 2 H), 6.34-6.37 (m, 1 H), 5.99-6.27 (m, 1 H), 4.80 (d, 2 H), 4.13-4.15 (m, 1 H), 3.89 (s, 3 H), 2.99-3.03 (m, 2 H), 2.71-2.81 (m, 2 H), 2.29-2.35 (m, 2 H), 1.95-2.02 (m, 2 H), 1.79-1.83 (m, 2 H).

[0270] Example 42: Preparation of 5-amino-1-(1,3-difluoropropane-2-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide 5-Amino-1-(1,3-difluoropropane-2-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide was prepared as described for 5-amino-1-(1,3-difluoropropane-2-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 501.2, while the actual measured value is 501.4. 1 H NMR (DMSO-d6, 400 MHz) δ 11.29 (s, 1 H), 8.91 (t, 1H), 7.55 (dd, 1 H), 7.45 (t, 1 H), 7.32-7.35 (m, 1 H), 7.14-7.21 (m, 2 H),7.05 (d, 1 H), 6.63 (s, 2 H), 6.30-6.35 (m, 1 H), 5.02 (brs, 1 H), 4.72-4.88 (m, 6 H), 3.89 (s, 3 H).

[0271] Example 43: Preparation of 5-amino-3-(7-((5-fluoro-2-(methoxy-d3)benzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide At -70 °C, BBr3 (1 M, 1.1 mL, 1.1 mmol, 10.0 equivalent) was added to a solution of 5-amino-3-(7-((5-fluoro-2-hydroxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide (50 mg, 0.11 mmol, 1.0 equivalent) in DCM (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-amino-3-(7-((5-fluoro-2-hydroxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide (60 mg, 100%) as a yellow solid. LCMS (M+H) + The calculated value of m / z is 451.2, while the actual measured value is 451.3. To a solution of 5-amino-3-(7-((5-fluoro-2-hydroxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide (40 mg, 0.09 mmol, 1.0 equivalent) in MeCN (20 mL), CD3I (20 mg, 0.14 mmol, 1.5 equivalent) and Cs2CO3 (92 mg, 0.28 mmol, 3.0 equivalent) were added. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The resulting residue was purified by preparative HPLC to give 5-amino-3-(7-((5-fluoro-2-(methoxy-d3)benzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide (13 mg, 30%). LCMS (M+H) + The calculated value of m / z is 468.2, while the actual measured value is 468.4. 1 H NMR (DMSO-d6,400 MHz) δ 11.26 (s, 1 H), 8.92 (t, 1 H), 7.55 (dd, 1 H), 7.43 (t, 1 H), 7.34(m, 1 H), 7.18 (dd, 1 H), 7.14 (d, 1 H), 7.03 (d, 1 H), 6.39 (s, 2 H), 6.34 (dd, 1 H), 4.80 (d, 2 H), 4.40-4.57 (m, 1 H), 1.35 (d, 6 H).

[0272] Example 44: Preparation of 5-amino-3-(7-((5-fluoro-2-(trifluoromethoxy)benzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide To a solution of 5-amino-3-(7-(aminomethyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxynitrile (100 mg, 0.32 mmol, 1.0 equivalent) in DCM (4 mL), 5-fluoro-2-(trifluoromethoxy)benzoic acid (86 mg, 0.38 mmol, 1.2 equivalent), HATU (184 mg, 0.48 mmol, 1.5 equivalent), and DIEA (206 mg, 1.6 mmol, 5.0 equivalent) were added. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, v / v) to give N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-(trifluoromethoxy)benzamide (100 mg, 90%) as a white solid. LCMS (M+H) + The calculated value of m / z is 501.2, while the actual measured value is 501.4. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazole-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-(trifluoromethoxy)benzamide is converted to 5-amino-3-(7-((5-fluoro-2-(trifluoromethoxy)benzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated m / z value is 519.2, and the measured value is 519.4. ¹H NMR (DMSO-d⁶, 400 MHz) δ 11.18 (s, ¹H), 9.17 (t, ¹H), 7.54 (m, 2H), 7.43–7.50 (m, ¹H), 7.42 (t, ¹H), 7.16 (d, ¹H), 7.03 (d, ¹H), 6.41 (s, 2H), 6.30–6.38 (m, ¹H), 4.77 (d, 2H), 4.50 (m, ¹H), 1.35 (d, 6H).

[0273] Example 45: Preparation of 5-amino-3-(7-((2-(difluoromethoxy)-5-fluorobenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide As described for N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-(trifluoromethoxy)benzamide, 5-amino-3-(7-(aminomethyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazol-4-carboxynitrile is converted to N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazol-3-yl)-1H-indol-7-yl)methyl)-2-(difluoromethoxy)-5-fluorobenzamide. LCMS (M+H) + The calculated value of m / z is 483.2, while the actual measured value is 483.4. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-isopropyl-1H-pyrazole-3-yl)-1H-indol-7-yl)methyl)-2-(difluoromethoxy)-5-fluorobenzamide is converted to 5-amino-3-(7-((2-(difluoromethoxy)-5-fluorobenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide. LCMS (M+H + The calculated m / z value is 501.2, and the measured value is 501.4. ¹H NMR (DMSO-d⁶, 400 MHz): 11.20 (s, ¹H), 9.02 (t, ¹H), 7.47 (dd, ¹H), 7.37–7.44 (m, ²H), 7.34 (m, ¹H), 7.18 (d, ¹H), 7.14 (s, ¹H), 7.03 (d, ¹H), 6.40 (s, ²H), 6.34 (t, ¹H), 4.77 (d, ²H), 4.44–4.55 (m, ¹H), 1.35 (d, ⁶H).

[0274] Example 46: Preparation of 5-amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide 5-Amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide was prepared as described for 5-amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H + The calculated value of m / z is 513.2, while the actual measured value is 513.4. 1 H NMR (DMSO-d6, 400 MHz) δ 11.30 (s, 1 H), 8.93 (t, 1 H), 7.55 (dd, 1 H), 7.43-7.49 (m, 1 H), 7.30-7.39 (m, 1 H), 7.13-7.23 (m, 2 H), 7.06 (d, 1 H), 6.57 (s, 2 H), 6.36 (dd, 1 H), 4.87 (m, 1 H), 4.80 (d, 2 H), 3.13 (m, 4 H).

[0275] Example 47: Preparation of 5-amino-1-cyclopropyl-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide Under O2 conditions, cyclopropylboronic acid (1.84 g, 10.74 mmol, 2.0 equivalent), Cu(OAc)2 (973 mg, 5.37 mmol, 1.0 equivalent), DMAP (2.62 g, 21.48 mmol, 4.0 equivalent), and pyridine (1.0 g, 13.4 mmol, 2.5 equivalent) were added to a solution of 5-amino-3-bromo-1H-pyrazole-4-carboxynitrile (1.0 g, 5.37 mmol, 1.0 equivalent) in dioxane (50 mL). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The resulting residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1, v / v) to give 5-amino-3-bromo-1-cyclopropyl-1H-pyrazole-4-carboxynitrile (0.25 g, 21%) as a white solid. LCMS (M+H) + The calculated value of m / z is 227.0, while the actual measured value is 227.4. As described for N-((4-(5-amino-4-cyano-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide, 5-amino-3-bromo-1-cyclopropyl-1H-pyrazol-4-carboxynitrile is converted to N-((4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazol-3-yl)-1H-indole-7-yl)methyl)-5-fluoro-2-methoxybenzamide. LCMS (M+H) + The calculated value of m / z is 445.2, while the actual measured value is 445.4. As described for 5-amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide, N-((4-(5-amino-4-cyano-1-cyclopropyl-1H-pyrazole-3-yl)-1H-indol-7-yl)methyl)-5-fluoro-2-methoxybenzamide is converted to 5-amino-1-cyclopropyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide. LCMS (M+H) + The calculated value of m / z is 463.2, while the actual measured value is 463.4. 1 H NMR (DMSO-d6, 400 MHz) δ 11.27 (s, 1 H), 8.91 (t, 1H), 7.55 (dd, 1 H), 7.43 (t, 1 H), 7.28-7.39 (m, 1 H), 7.18 (dd, 1 H), 7.13(d, 1 H), 7.00 (d, 1 H), 6.40 (s, 2 H), 6.27-6.34 (m, 1 H), 4.79 (d, 2 H), 3.88 (s, 3 H), 0.91-1.04 (m, 4 H).

[0276] II. Biological Evaluation Example 1: Inhibitory activity against BTK and BTK C481S.

[0277] Inhibitory activity against BTK and BTK C481S was measured using the ADP-Glo ​​assay. The percentage of inhibition (%) at each compound concentration was calculated relative to the luminescence signal of the largest and smallest control wells contained in each assay plate. The largest control well contained both enzyme and substrate, representing 0% inhibition, and the smallest control well contained only substrate, without enzyme, representing 100% inhibition. The concentrations and % inhibition values ​​of the test compounds were plotted, and the required compound concentration (IC50) for 50% inhibition was determined using a four-parameter logic dose-response equation. 50 Table 2 shows the IC50 values ​​of several compounds in this invention for BTK. 50 The values ​​are defined, and the scales used in Table 2 are as follows: ++ less than 100 nM, and + greater than 100 nM and less than 1000 nM.

[0278] Table 2. IC50 of several illustrative compounds for BTK 50 Table 3 shows the IC50 values ​​of several compounds in this invention for BTK C481S. 50 The values ​​are defined, and the scales used in Table 3 are as follows: ++ less than 100 nM, and + greater than 100 nM and less than 1000 nM.

[0279] Table 3. IC50 of several illustrative compounds to BTK C481S 50 While some embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. For example, for purposes of claim interpretation, the claim...

Claims

1. A compound of formula (I): Equation (I), Or its pharmaceutically acceptable salt, wherein Ring A is an optionally substituted arylexyl group, an optionally substituted cycloalkanexyl group, an optionally substituted heteroarylexyl group, or an optionally substituted heterocycloalkanexyl group; X1 is either C-R1 or N; X2 is either C-R2 or N; R1 and R2 are independently hydrogen, cyano, halogroup, hydroxyl, azide, nitro, carboxyl, oxo, sulfinyl, thioalkyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl or optionally substituted formamidinyl. R3 is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycloalkyl group. R4 and R5 are independently hydrogen, halogroup, optionally substituted lower alkyl or optionally substituted cycloalkyl; or R4 and R5 may be linked together with any intercalary atom to form an optionally substituted cycloalkyl or optionally substituted heterocyclic alkyl ring; R6 is hydrogen, an optionally substituted lower alkyl group, or an optionally substituted cycloalkyl group; and R7 is an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are independently hydrogen, halogroup, optionally substituted lower alkyl group or optionally substituted cycloalkyl group.

3. The compound of claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen, a halogroup or optionally substituted lower alkyl group.

4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen or a halogroup.

5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.

6. The compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen, a halogroup or optionally substituted lower alkyl group.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein R5 is hydrogen or a halogroup.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R5 is hydrogen.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are linked together with any intercalary atom to form an optionally substituted cycloalkyl or optionally substituted heteroalkyl ring.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are connected together with any intercalary atom to form an optionally substituted C3-C6 cycloalkyl ring or an optionally substituted 4- to 8-membered heterocyclic alkyl ring.

11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are linked together with any intercalary atom to form an optionally substituted cycloalkyl ring.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 9-11, wherein R4 and R5 are linked together with any intercalary atom to form an optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein R6 is hydrogen or an optionally substituted lower alkyl group.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, wherein R6 is hydrogen.

15. The compound according to any one of claims 1-14, wherein the compound of formula (I) is a compound of formula (Ia): Formula (Ia), Or its pharmaceutically acceptable salt.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, wherein X1 is N.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, wherein X1 is C-R1.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-17, wherein X2 is C-R2.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-17, wherein X2 is N.

20. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ib), a compound of formula (Ic), or a compound of formula (Id): Or its pharmaceutically acceptable salt.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein R1 is hydrogen, a halogroup, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted lower alkyl group, or an optionally substituted amino group.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-21, wherein R1 is hydrogen, a halogroup or optionally substituted lower alkyl group.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-22, wherein R1 is hydrogen or a halogroup.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-23, wherein R1 is hydrogen or a fluorinated group.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-24, wherein R2 is hydrogen, a halogroup, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted lower alkyl group, or an optionally substituted amino group.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-25, wherein R2 is hydrogen, a halogroup or optionally substituted lower alkyl group.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, wherein R2 is hydrogen or a halogroup.

28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein R2 is hydrogen or a fluorinated group.

29. The compound of any one of claims 1-28 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocycloalkyl group.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-29, wherein R3 is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclic alkyl group.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-30, wherein R3 is hydrogen or an optionally substituted alkyl group.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-31, wherein R3 is hydrogen or an alkyl group optionally substituted with one or more halogroups, hydroxyl groups, carboxyl groups, optionally substituted alkoxycarbonyl groups, or optionally substituted heterocyclic alkyl groups.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-32, wherein R3 is hydrogen or an alkyl group optionally substituted with a halogroup, hydroxyl group or carboxyl group.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-33, wherein R3 is hydrogen or an alkyl group optionally substituted with a fluorinated group, a hydroxyl group or a carboxyl group.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-32, wherein R3 is an alkyl group optionally substituted with a heterocyclic alkyl group.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein R3 is an alkyl group substituted with a heterocyclic alkyl group, said heterocyclic alkyl group being substituted with one or more alkyl groups, halogroups, haloalkyl groups or acyl groups.

37. The compound of claim 35 or claim 36 or a pharmaceutically acceptable salt thereof, wherein R3 is an alkyl group substituted with a heterocyclic alkyl group, said heterocyclic alkyl group being substituted with one or more alkyl or acyl groups.

38. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 35-37, wherein R3 is an alkyl group substituted with a heterocyclic alkyl group, said heterocyclic alkyl group being substituted with a methyl group or -C(O)CH3.

39. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-30, wherein R3 is an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

40. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein R3 is an optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted oxacyclobutane, optionally substituted azacyclobutane, optionally substituted piperidinyl or optionally substituted azabicyclo[3.2.1]octyl.

41. The compound of claim 39 or claim 40 or a pharmaceutically acceptable salt thereof, wherein R3 is a cycloalkyl or heteroalkyl group optionally substituted with one or more alkyl, halogroup, hydroxyl, or optionally substituted alkoxycarbonyl groups.

42. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein R3 is cyclopropyl, cyclobutyl, oxetane, azirone, piperidinyl or azirbicyclo[3.2.1]octyl, each optionally substituted with one or more alkyl, halogroup, hydroxyl, optionally substituted alkyl or optionally substituted alkoxycarbonyl groups.

43. The compound of claim 39 or claim 40 or a pharmaceutically acceptable salt thereof, wherein R3 is a cycloalkyl or heterocycloalkyl group optionally substituted with one or more alkyl, halogroup, hydroxyl, or alkoxycarbonyl groups.

44. The compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein R3 is cyclopropyl, cyclobutyl, oxetane, azirone, piperidinyl or azirbicyclo[3.2.1]octyl, each optionally substituted with one or more alkyl, halogroup, hydroxyl or alkoxycarbonyl groups.

45. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-28, wherein R3 is hydrogen, methyl, , , , , , , , , , , , , , , , , or .

46. ​​The compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof, wherein R3 is... , , , , , , , , , , , , , , , , , or .

47. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-46, wherein R7 is an optionally substituted aryl or optionally substituted heteroaryl.

48. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-47, wherein R7 is an optionally substituted phenyl or optionally substituted pyridyl group.

49. The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein R7 is an aryl or heteroaryl group, each optionally substituted with a cyano, halogroup, hydroxyl, alkoxy, cycloalkoxy, or lower alkyl group.

50. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-49, wherein R7 is phenyl or pyridyl, each optionally substituted with a cyano, halogroup, hydroxyl, alkoxy, cycloalkoxy or lower alkyl group.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R7 is an aryl or heteroaryl group, each optionally substituted with a halogroup and an alkoxy group.

52. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein R7 is phenyl or pyridyl, each optionally substituted with a halogroup and an alkoxy group.

53. The compound of claim 47 or claim 48 or a pharmaceutically acceptable salt thereof, wherein R7 is an aryl or heteroaryl group, each optionally substituted with a fluorinated group, -OCH3, -OCD3, -OCF2H, -OCH2F or -OCF3.

54. The compound of claim 47 or claim 48 or a pharmaceutically acceptable salt thereof, wherein R7 is an aryl or heteroaryl group, each optionally substituted with a fluorinated group, -OCH3 or -OCD3.

55. The compound of claim 47 or claim 48 or a pharmaceutically acceptable salt thereof, wherein R7 is phenyl or pyridyl, each optionally substituted with a fluorinated group or -OCH3.

56. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-55, wherein ring A is an optionally substituted heteroarylexicon or an optionally substituted heterocycloalkanelexicon.

57. The compound of any one of claims 1-56 or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted with a pyrrolidinyl group, optionally substituted with a pyrazolylyl group, optionally substituted with an imidazolidineyl group or optionally substituted with an oxazolidineyl group.

58. The compound of any one of claims 1-57 or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted with a pyrroleyl group, optionally substituted with a pyrazolyl group, optionally substituted with a dihydro-imidazolyl group or optionally substituted with a dihydro-oxazolyl group.

59. The compound of any one of claims 1-58 or a pharmaceutically acceptable salt thereof, wherein ring A is pyrroleyl, pyrazolyl, 1,3-dihydro-2H-imidazol-2-ketoyl or oxazol-2(3H)-ketoyl.

60. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-59, wherein... for , , , , , , or .

61. The compound according to claim 1, wherein the compound is selected from the group consisting of: 5-Amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(oxetane-3-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; (R)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide; 3-(5-amino-4-carbamoyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid methyl ester; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-methyl-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-cyclopropyl-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide; N-((4-(5-amino-4-carbamoyl-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazol-7-yl)methyl)-2-methoxynicotinamide; N-((4-(5-amino-4-carbamoyl-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-3-yl)-1H-indazol-7-yl)methyl)-5-fluoro-2-methoxynicotinamide; 5-Amino-3-(7-((2,5-difluorobenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-(1,3-difluoropropane-2-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide; 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-4-yl)-1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(5-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(4-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indazol-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(4-((5-fluoro-2-methoxybenzoylamino)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrazolo[3,4-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide; (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; (R)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; (S)-5-amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; (R)-5-amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide; (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazole-4-carboxamide; (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-carboxamide; 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-1-(3-fluorocyclobutyl)-1H-pyrazole-4-carboxamide; 5-Amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-(3,3-difluorocyclobutyl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-(3,3-difluorocyclobutyl)-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(oxetane-3-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(oxetane-3-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(oxetane-3-yl)-1H-pyrazol-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide; 5-Amino-1-cyclopropyl-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-cyclopropyl-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-cyclopropyl-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-(1,3-difluoropropane-2-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-(1,3-difluoropropane-2-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrazol-4-carboxamide; 5-Amino-1-(1,3-difluoropropane-2-yl)-3-(6-fluoro-7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide; (S)-2-(5-amino-4-carbamoyl-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazol-1-yl)propionic acid; (S)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-hydroxypropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-(4-methylpiperazin-1-yl)propane-2-yl)-1H-pyrazole-4-carboxamide; 1-(1-(4-acetylpiperazin-1-yl)propane-2-yl)-5-amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-(8-azabicyclo[3.2.1]octane-3-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1H-pyrazole-4-carboxamide; 5-Amino-1-(1-(2,2-difluoroethyl)piperidin-4-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-(methoxy-d3)benzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-(trifluoromethoxy)benzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((2-(difluoromethoxy)-5-fluorobenzoylamino)methyl)-1H-indol-4-yl)-1-isopropyl-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,3,3-tetrafluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1,3,3,3-hexafluoropropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-(((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazole-4-carboxamide; 5-Amino-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1-(2-fluorocyclopropyl)-1H-pyrazole-4-carboxamide; and 5-Amino-1-(bicyclo[1.1.1]pentan-1-yl)-3-(7-((5-fluoro-2-methoxybenzoylamino)methyl)-1H-indol-4-yl)-1H-pyrazole-4-carboxamide; Or its pharmaceutically acceptable salt.

62. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-61.

63. The pharmaceutical composition of claim 62, wherein the composition is formulated in a form selected from tablets, capsules, powders, liquids, suspensions, suppositories and aerosols.

64. A method of treating a disease or condition in a subject in need, comprising administering to said subject a therapeutically effective amount of the compound according to any one of claims 1-61.

65. The method of claim 64, wherein the disease or condition is mediated by BTK.

66. The method of claim 64 or claim 65, wherein the disease or condition is cancer, lymphoma, leukemia, autoimmune disease, inflammatory condition, or fibrosis.

67. The method according to any one of claims 64-66, wherein the disease or condition is selected from: B-cell malignancies, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastases, arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, Sjögren's syndrome, and lupus.

68. The method according to claim 65, wherein the disease or condition is selected from: B-cell malignancies, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastases, follicular lymphoma, chronic lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, intranodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma. Primary exudative lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Auder's thyroiditis, Graves' disease, Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, oculoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, pulmonary hemorrhage-nephritis syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, aortitis, temporal arteritis, and febrile diseases. Autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic dysfunction, endometriosis, interstitial cystitis, neurogenic myotonia, scleroderma, vulvar pain, graft-versus-host disease, transplantation, blood transfusion, allergic reactions, allergy, type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, encephalitis Meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, interstitial pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrotic alveolitis (CFA), obliterative bronchiolitis, bronchiectasis, fatty liver disease, fatty degeneration (e.g., non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC), cirrhosis),Alcoholic liver fibrosis, bile duct injury, bile fibrosis, cholestasis, or cholangitis. In some implementations, liver or liver fibrosis includes, but is not limited to, liver fibrosis associated with: alcoholism, viral infections such as hepatitis (e.g., hepatitis C, hepatitis B, or hepatitis D), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), renal fibrosis (e.g., chronic renal fibrosis), kidney disease associated with injury / fibrosis (e.g., chronic kidney disease associated with diabetes (e.g., diabetic nephropathy)), lupus, nephrosclerosis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy associated with human chronic kidney disease (CKD), and chronic progressive kidney disease (CP). N), renal tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephropathy (PGN), endothelial / thrombotic microangiopathy, H1V-related nephropathy or fibrosis associated with exposure to toxins, irritants, or chemotherapy agents, fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with foregut inflammatory diseases such as Barrett's esophagus and chronic gastritis, and / or fibrosis associated with hindgut inflammatory diseases such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohn's disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and neovascular glaucoma.

69. The method according to claim 64 or claim 65, wherein the disease or condition is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, intranodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis.

70. The method of claim 64 or claim 65, wherein the disease or condition is a B-cell malignancy.

71. The method of claim 70, wherein the B-cell malignancy is a relapsed or refractory B-cell malignancy.

72. The method of claim 71, wherein the B-cell malignancy has relapsed after ibrutinib treatment or is refractory to ibrutinib treatment.

73. The method according to any one of claims 70-72, wherein the disease or condition is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, intranodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis.

74. The method according to any one of claims 64-73, further comprising administering additional anticancer and / or cytotoxic agents.

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