Nitrogen-containing heteroaryl compounds for the treatment of chronic diseases

Abstract

The disclosure relates to compounds of the disclosure and pharmaceutically acceptable salts thereof to their use in medicine; to compositions containing them; to processes for their preparation; and to intermediates used in such processes. The compounds of the disclosure may be useful in the treatment, prevention, suppression, and amelioration of disease(s) such as allergy, alopecia, Alzheimer's disease, asthma, atherosclerosis, Bechet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritis, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic kidney disease, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IFF), keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, prurigo nodularis, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa. The compounds of the disclosure may be useful in the treatment, prevention, suppression and amelioration of a dermatological condition or a respiratory condition. Formula (I): (I).

Description

[0001] PC073074A Novel Nitrogen-Containing Heteroaryl Compounds Background The present disclosure relates to novel compounds. The disclosure also relates to the preparation of the compounds and intermediates used in the preparation, compositions containing the compounds, and uses of the compounds including their use as a STAT6 inhibitor. STAT6 is a member of the Signal Transducer and Activator of Transcription (STAT) family of proteins consisting of transcription factors that impact cell processes including differentiation, survival, and proliferation and functional activation [Levy, DE and Darnell, JE. STATs: transcriptional control and biological impact.2002. Nat Rev Mol Cell Biol.3(9):651–62]. The STAT family consists of seven members: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. STAT family proteins are downstream targets of the Janus kinase (JAK) family kinases, which contribute to signal transduction from a variety of cytokines including IL-2, IL-5, GM-CSF, IL-10, IL-12, IL-23, as well as IL-4 and IL-13. Cytokines IL-4 and IL-13 have been demonstrated to signal through STAT6 activation [Kaplan, MH et al.1996. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity.4: 313-319]. The pathogenic activity of IL-4 and IL-13 cytokines is consistent with efficacy that has been observed with JAK inhibitors, which block signaling of IL-4 and IL-13 as well as signaling of additional inflammatory cytokines [Simpson, EL et al.2020. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet.396(10246): 255-266; Guttman-Yassky, E et al.2021. Once-daily upadacitinib versus placebo in adolescents and adults with moderate- to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet.397(10290): 2151-2168]. Despite the effectiveness of known therapeutics, an unmet need remains for safe and effective therapeutics for numerous diseases characterized by inflammatory responses, that address a broad range of pathogenic mechanisms. Brief Summary The present disclosure provides, in part, compounds and pharmaceutically acceptable salts thereof. Such compounds may inhibit the activity of STAT6 and may be useful in the treatment, prevention, suppression, and / or amelioration of disease(s), disorders and conditions mediated by STAT6. Also provided are pharmaceutical compositions, comprising the compounds or salts, alone or in combination with additional therapeutic agents. The present disclosure also provides, in part, methods for preparing such compounds, pharmaceutically acceptable salts and compositions of the disclosure, and methods of using the foregoing. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter. In an aspect, a compound of the disclosure has the Formula I or a pharmaceutically acceptable salt thereof: I where the variables are defined herein. In an aspect, the disclosure relates to a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In another aspect, the disclosure relates to a method for treating allergy, alopecia, Alzheimer’s disease, asthma, atherosclerosis, Bechet’s disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritis, chronic urticaria, Crohn’s disease (CD), dermatitis, diabetic kidney disease, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, prurigo nodularis, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the disclosure. In another aspect, the disclosure relates to the compound of the disclosure or a pharmaceutically acceptable salt thereof for use as a medicament; or for use in the treatment of allergy, alopecia, Alzheimer’s disease, asthma, atherosclerosis, Bechet’s disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritis, chronic urticaria, Crohn’s disease (CD), dermatitis, diabetic kidney disease, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), a joint disorder, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, prurigo nodularis, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa; or for use in the treatment of at least one of a dermatological condition or a respiratory condition. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed. Detailed Description The present disclosure may be understood more readily by reference to the following detailed description and the Examples included herein. It is to be understood that this disclosure is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific aspects only and is not intended to be limiting. In an aspect, a compound of Formula I or a pharmaceutically acceptable salt thereof: I wherein X1is CH, N, or CF; X2is CH, CCH3, C(CH2CH3), C-cyclopropyl, N, CF, or CCl; X3is CR6or NR6; X4is C or N; X5is C or N; X6is CH or N; X7is CH, N, or CF; X8is CH or N; X9is CH or N; X10is CH or N; R1is -NHR9, -OH, -C3-4heteroaryl optionally substituted with -C1-3alkyl, or -C1-4alkyl optionally substituted with one, two, or three of oxo, -NR10R11, or -C3-5heterocycloalkyl optionally substituted with R1A, wherein R1Ais -OH; R2is H or -CH3; or R1and R2form a C6-8fused heterocycloalkyl or a C6-8fused heteroaryl; wherein the C6-8fused heterocycloalkyl is optionally substituted with oxo, -C1-3alkyl, -NR10R11, or -OH; wherein the C6-8fused heteroaryl is optionally substituted with -C1-3alkyl, -NR10R11, or -OH; R3is -C1-3alkyl, -C2-5heteroaryl, -C3-5cycloalkyl, -NH-C(=O)-C1-3alkyl, or -C2-5heterocycloalkyl, wherein R3is optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, oxo, -NR7R8, or cyano; R4is H, -C1-3alkyl, -C1-3fluoroalkyl, or halogen; or R3and R4form a fused C6-10heterocycloalkyl optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, -NR7R8, cyano, or oxo; R5is H, -C1-3alkyl, or -C1-3hydroxyalkyl; R6is H, -C3-5cycloalkyl, alkoxyalkyl, or -C1-3alkyl optionally substituted with -OH; R7is H or -C1-3alkyl; R8is -C1-3alkyl; or R7and R8form a fused C5-10heterocycloalkyl optionally substituted with -C1-3alkyl; R9 is H, -SO2CH3, or -C1-3 alkyl optionally substituted with one, two, or three of oxo, -C3-7 heterocycloalkyl, alkoxy, cyanoimine, or -NR12R13; wherein the -C3-7heterocycloalkyl is optionally substituted with one, two, or three of halogen, oxo, -C0-1alkylene-NR14R15, -OH, -C1-3hydroxyalkyl, -C1-3 alkoxy optionally substituted with -NR14R15, -C1-3 alkoxy-C1-3 alkyl, or a -C1-3 alkyl optionally substituted with oxo; R10is H, -C3-5cycloalkyl optionally substituted with -OH, or -C1-3alkyl optionally substituted with one, two, or three of a -C3-5heteroaryl, -C3-5cycloalkyl, cyano, -OH, or -C1-3alkoxy; R11is H or -C1-3alkyl; or R10and R11form a C3-4heterocycloalkyl optionally substituted with -OH; R12is H or -C1-3alkyl optionally substituted with one, two, or three -OH; R13is H or -C1-3alkyl; or R12and R13form a C3-8heterocycloalkyl, wherein the C3-8heterocycloalkyl is optionally substituted with one, two, or three of halogen, oxo, -C0-1alkylene-NR14R15, -OH, -C1-3hydroxyalkyl, -C0-3alkylene-C1-3alkoxy, or -C1-3alkyl; R14is each independently H, -C2-4oxoalkyl, -C1-4alkyl, or cyclopropyl optionally substituted with methyl; and R15is each independently H or -C1-3alkyl; wherein no more than 2 of X6, X7, and X8are N. In an aspect, a compound of Formula I or a pharmaceutically acceptable salt thereof: I wherein X1is CH, N, or CF; X2is CH, CCH3, N, CF, or CCl; X3is CR6or NR6; X4is C or N; X5is C or N; X6is CH or N; X7is CH, N, or CF; X8is CH or N; X9is CH or N; X10is CH; R1is -NHR9, -OH, -C3-4heteroaryl optionally substituted with -C1-3alkyl, or -C1-3alkyl optionally substituted with one, two, or three of oxo, -NR10R11, or -C3-5heterocycloalkyl optionally substituted with R1A, wherein R1Ais -OH; R2is H; or R1and R2form a C6-8fused heterocycloalkyl or a C6-8heteroaryl; R3is -C1-3alkyl, -C2-5heteroaryl, -C3-5cycloalkyl, -NH-C(=O)-C1-3alkyl, or -C2-5heterocycloalkyl, wherein R3is optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, oxo, -NR7R8, or cyano; R4is H, -C1-3alkyl, -C1-3fluoroalkyl, or halogen; or R3and R4form a fused C6-10heterocycloalkyl optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, -NR7R8, cyano, or oxo; R5is H or -C1-3alkyl optionally substituted with -OH; R6is H, -C3-5cycloalkyl, alkoxyalkyl, or -C1-3alkyl optionally substituted with -OH; R7is H or -C1-3alkyl; R8is -C1-3alkyl; or R7and R8form a fused C6-10heterocycloalkyl; R9is H, -SO2CH3, or -C1-3alkyl optionally substituted with one, two, or three of oxo, -C3-7heterocycloalkyl, alkoxy, cyanoimine, or -NR12R13; wherein the -C3-7heterocycloalkyl is optionally substituted with one, two, or three of halogen, oxo, -C0-1-NR14R15, -OH, -C1-3 hydroxyalkyl, -C1-3alkoxy optionally substituted with -NR14R15, -C1-3alkoxy-C1-3alkyl, or a -C1-3alkyl optionally substituted with oxo; R10is H, -C3-5cycloalkyl optionally substituted with -OH, or -C1-3alkyl optionally substituted with a -C3-5heteroaryl, cyclopropyl, cyano, -OH, or -C1-3alkoxy; R11is H or -C1-3alkyl; or R10and R11form a -C3-4heterocycloalkyl optionally substituted with -OH; R12is -C1-3alkyl optionally substituted with one, two, or three of -OH; R13is H or -C1-3alkyl; R14is each independently H, -C1-4alkyl, or cyclopropyl optionally substituted with methyl; and R15is each independently H or -C1-3alkyl. In an aspect, R1 is -NHR9, -C(=O)-NR10R11, -OH, -C(=O)-C1-3 alkyl, or -C3-4 heteroaryl; wherein the -C3-4heteroaryl is optionally substituted with -C1-3alkyl. In an aspect, R1is -NHR9or -C1-3alkyl. In an aspect, R1 is -C1-3 alkyl substituted with one, two, or three of oxo, -C3-5 heterocycloalkyl optionally substituted with R1A, or -NR10R11, wherein R1Ais -OH. In an aspect, R1is -C(=O)-NR10R11and R10is H or -C1-3alkyl optionally substituted with a cyclopropyl, cyano, or -C1-3alkoxy. In an aspect, R1is -NHR9and R9is H or -C1-3alkyl substituted with one, two, or three of oxo, -C3-5heterocycloalkyl, methoxy, or -NR12R13. In an aspect, R1is -NHR9and R9is H, -SO2CH3, -C(=O)-NR12R13, -C(=O)-C1-3alkoxy, or -C(N(CH3)2)-cyanoimine. In an aspect, R1is -NHR9and R9is -SO2CH3, -C(=O)-NR12R13, -C(=O)-C1-3alkoxy, or -C(N(CH3)2)-cyanoimine. In an aspect, R2is H. In an aspect, R3is -C(=O)-NR7R8. In an aspect, R3is -C3-5heteroaryl, -C3-5cycloalkyl, or -C3-5heterocycloalkyl and wherein R3is optionally substituted with one of -C1-3alkyl, oxo, or -NR7R8.In an aspect, R3is -C(=O)-NR7R8, -C1-3cyanoalkyl, -C3-5cycloalkyl-cyano; -C3-5heterocycloalkyl, -C2-5heteroaryl, or -NH-C(=O)-C1-3alkyl; wherein the -C3-5heterocycloalkyl is optionally substituted with one, two, or three of -C1-3alkyl or oxo; and wherein the -C2-5heteroaryl is optionally substituted with one, two, or three of -C1-3alkyl or oxo. In an aspect, R3is -C3-5heteroaryl optionally substituted with one of -C1-3alkyl or oxo. In an aspect, R7is -C1-3alkyl. In an aspect, R7and R8form a fused C5-7heterocycloalkyl optionally substituted with -C1-3alkyl; wherein the C5-7heterocycloalkyl includes 2 to 3 heteroatoms of at least one of N or S. In an aspect, R4is H or -C1-3alkyl. In an aspect, R4is H and R6is -C3-5cycloalkyl or -C1-3alkyl. In an aspect, R3and R4form a fused C7-9heterocycloalkyl optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, or oxo; and wherein the fused C7-9heterocycloalkyl contains 1 to 2 heteroatoms of at least one of N or O. In an aspect, R5is H or -C1-3alkyl. In an aspect, R6is H, -C1-3alkyl, -C3-5cycloalkyl, -C1-3hydroxyalkyl, or -C1-3alkoxy-C1-3alkyl. In an aspect, R10is H, -C1-3alkylene-C1-3alkoxy, -C1-3hydroxyalkyl, -C1-3alkylene-C3-5heteroaryl, -C0-3alkylene-C3-5cycloalkyl, or -C1-3cyanoalkyl. In an aspect, X7is CH or CF. In an aspect, at least one of: the -C3-4heteroaryl of R1contains 1 to 2 heteroatoms of N; the -C3-5 heterocycloalkyl of R1 contains 1 to 2 heteroatoms of N; R1 and R2 form the C6-8 fused heterocycloalkyl or the C6-8fused heteroaryl and the C6-8fused heterocycloalkyl or the C6-8fused heteroaryl include 1 to 2 heteroatoms of N; the -C2-5heteroaryl of R3includes 2 to 3 heteroatoms of at least one of N or O; the -C2-5 heterocycloalkyl of R3 includes 1 to 2 heteroatoms of N; R3and R4form the fused C6-10heterocycloalkyl contains 1 to 2 heteroatoms of at least one of N or O; R7and R8form the fused C5-10heterocycloalkyl and the C5-10heterocycloalkyl includes 2 to 3 heteroatoms of at least one of N or S; the -C3-7heterocycloalkyl of R9includes 1 to 2 heteroatoms of N; the -C3-5heteroaryl of R10includes 1 to 2 heteroatoms of N; R10and R11form the C3-4heterocycloalkyl and the C3-4heterocycloalkyl includes 1 or 2 heteroatoms of N; R12and R13form the C3-8heterocycloalkyl and the C3-8heterocycloalkyl includes 1 to 3 heteroatoms of at least one of N or O. In an aspect, at least one hydrogen is deuterium. In an aspect, X6is CH and the hydrogen is deuterium. In an aspect, the compound has the formula Ia or a pharmaceutically acceptable salt thereof: In an aspect, the compound has the formula D1: or a pharmaceutically acceptable salt thereof; wherein X6and X7are each independently N or CY5, wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10are each independently H or D; and at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10is D. In an aspect, the compound has the formula D2 or D3: or a pharmaceutically acceptable salt thereof; wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10are each independently H or D and wherein at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10is D. In an aspect, the compound is one of N-({4-[(dimethylcarbamoyl)amino]phenyl}methyl)- 5-[5-(dimethylcarbamoyl)pyridin-2-yl]-1-methyl-1H-indazole-3-carboxamide; 5-(4- (dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1H-indazole-3- carboxamide; 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1H- pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-(3,3-dimethylureido)benzyl)-1-methyl-5-(4-(1- methyl-1H-imidazol-2-yl)phenyl)-1H-indazole-3-carboxamide; and 5-(5- (dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-N-(4-(4-methylpiperazine-1-carboxamido)benzyl)-1H- indazole-3-carboxamide. In an aspect, the compound is one of N-({4-[(dimethylcarbamoyl)amino]phenyl}methyl)- 5-[5-(dimethylcarbamoyl)pyridin-2-yl]-1-methyl-1H-indazole-3-carboxamide; 5-(4- (dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1H-indazole-3- carboxamide; 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1H- pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-(3,3-dimethylureido)benzyl)-1-methyl-5-(4-(1- methyl-1H-imidazol-2-yl)phenyl)-1H-indazole-3-carboxamide; and 5-(5- (dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-N-(4-(4-methylpiperazine-1-carboxamido)benzyl)-1H- indazole-3-carboxamide. In an aspect, the compound is in the form of a solvate or a hydrate. In an aspect, a pharmaceutical composition comprises the compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In an aspect, a method for treating allergy, alopecia, Alzheimer’s disease, asthma, atherosclerosis, Bechet’s disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritis, chronic urticaria, Crohn’s disease (CD), dermatitis, diabetic kidney disease, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, prurigo nodularis, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa comprising administering to a subject in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof. In an aspect, the compound a pharmaceutically acceptable salt thereof is for use as a medicament. In an aspect, the compound or a pharmaceutically acceptable salt thereof for use in the treatment of allergy, alopecia, Alzheimer’s disease, asthma, atherosclerosis, Bechet’s disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritis, chronic urticaria, Crohn’s disease (CD), dermatitis, diabetic kidney disease, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), a joint disorder, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, prurigo nodularis, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa. In an aspect, the compound or a pharmaceutically acceptable salt thereof for use in the treatment of at least one of a dermatological condition or a respiratory condition. In an aspect, use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of allergy, alopecia, Alzheimer’s disease, asthma, atherosclerosis, Bechet’s disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritis, chronic urticaria, Crohn’s disease (CD), dermatitis, diabetic kidney disease, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), a joint disorder, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, prurigo nodularis, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa. In an aspect, use of the compound a pharmaceutically acceptable salt thereof for use in the treatment of at least one of a dermatological condition or a respiratory condition. In an aspect, the compound is that of Formula I with the proviso that it is not 5-(4-(1,4- dimethyl-1H-imidazol-2-yl)phenyl)-1-methyl-N-(4-(methylcarbamoyl)benzyl)-1H-indazole-3- carboxamide. Each of the aspects described herein may be combined with any other aspect(s) described herein not inconsistent with the aspect(s) with which it is combined. In addition, any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of the Examples, or pharmaceutically acceptable salts thereof, for any of the aspect(s) described herein. Furthermore, each of the aspects described herein envisions within its scope pharmaceutically acceptable salts of the compounds described herein. Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure have the meanings that are commonly understood by those of ordinary skill in the art. The disclosure described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. The compound(s) of the disclosure refers to the compounds of Formula I. One of ordinary skill in the art will appreciate that the compounds of the disclosure include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate that the compounds of the disclosure include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labelled versions thereof, where they may be formed. Compounds of the disclosure can include novel intermediates used in the preparation thereof. As used herein, the singular form “a”, “an”, and “the” include plural references unless indicated otherwise. For example, “a” substituent includes one or more substituents. The term “or” means “and / or” unless clearly indicated otherwise. As used herein, the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5% ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg. “Optional" or "optionally" means that the subsequently described event or circumstance may, but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not. The terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or the group may have one or more non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Where an optional substituent is attached via a double bond, such as an oxo (=O) substituent, the group occupies two available valences, so the total number of other substituents that are included is reduced by two. In the case where optional substituents are selected independently from a list of alternatives, the selected groups may be the same or different. Throughout the disclosure, it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense to one of ordinary skill in the art. “Halogen” or “halo” refers to fluoro, chloro, bromo, and iodo (F, Cl, Br, I). “Cyano” refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., -C≡N. “Hydroxy” refers to an -OH group. “Oxo” refers to a double bonded oxygen (=O). "Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms (“C1-12alkyl”), 1 to 8 carbon atoms (“C1-8alkyl”), 1 to 6 carbon atoms (“C1-6alkyl”), 1 to 5 carbon atoms (“C1-5alkyl”), 1 to 4 carbon atoms (“C1-4alkyl”), 1 to 3 carbon atoms (“C1-3alkyl”), or 1 to 2 carbon atoms (“C1-2alkyl”). Examples include, but are not limited to, methyl, ethyl, n‑propyl, isopropyl, n‑butyl, sec- butyl, isobutyl, tert‑butyl, n‑pentyl, isopentyl, neopentyl, n‑hexyl, n‑heptyl, n‑octyl, and the like. Alkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example, “haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number. “Haloalkyl” refers to an alkyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen. Haloalkyl groups man contain, but are not limited to, 1-6 carbon atoms (“C1-6haloalkyl”), 1-4 carbon atoms (“C1-4haloalkyl”), or 1-2 carbon atoms (“C1-2haloalkyl”). More specifically, fluorinated alkyl groups may be specifically referred to as “fluoroalkyl.” Examples of fluoroalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of fully substituted fluoroalkyl groups (also referred to as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5). “Alkoxy” refers to an alkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as alkyl-O-. Alkoxy groups may contain, but are not limited to, 1 to 8 carbon atoms (“C1-8alkoxy”), 1 to 6 carbon atoms (“C1-6alkoxy”), 1 to 4 carbon atoms (“C1-4alkoxy”), or 1 to 3 carbon atoms (“C1-3alkoxy”). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, and the like. “Haloalkoxy” refers to an alkoxyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen.Haloalkoxy groups may contain, but are not limited to, 1-6 carbon atoms, (“C1-6 haloalkoxy”), 1-4carbon atoms (“C1-4haloalkoxy”), or 1-2 carbon atoms (“C1-2haloalkoxy”). More specifically, fluorinated alkoxyl groups may be specifically referred to as “fluoroalkoxy.” “Alkoxyalkyl” refers to an alkyl group, as defined herein, that is substituted by an alkoxy group, as defined herein. Examples include, but are not limited to, CH3OCH2- and CH3CH2OCH2-. "Alkylene" refers to a saturated, divalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkylene groups may contain, but are not limited to, 1 to 12 carbon atoms (“C1-12alkylene”), 1 to 8 carbon atoms (“C1-8alkylene”), 1 to 6 carbon atoms (“C1-6alkylene”), 1 to 5 carbon atoms (“C1-5alkylene”), 1 to 4 carbon atoms (“C1-4alkylene”), 1 to 3 carbon atoms (“C1-3alkylene”), or 1 to 2 carbon atoms (“C1-2alkylene”). “Cycloalkyl” refers to a fully or partially saturated hydrocarbon ring system that has the specified number of carbon atoms, which may be a monocyclic, bridged or fused bicyclic, or polycyclic ring system that is connected to the base molecule through a carbon atom of the cycloalkyl ring. “Cycloalkyl” can refer to the ring system being a fully saturated hydrocarbon ring system. Cycloalkyl groups may contain, but are not limited to, 3 to 12 carbon atoms (“C3-12cycloalkyl”), 3 to 8 carbon atoms (“C3-8cycloalkyl”), 3 to 6 carbon atoms (“C3-6cycloalkyl”), 3 to 5 carbon atoms (“C3-5cycloalkyl”) or 3 to 4 carbon atoms (“C3-4cycloalkyl”). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantanyl, and the like. Cycloalkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. “Heterocycloalkyl” refers to a fully or partially saturated ring system containing the specified number of ring atoms and containing at least one heteroatom selected from N, O and S as a ring member, where ring S atoms are optionally substituted by one or two oxo groups (i.e., S(O)q, where q is 0, 1 or 2) and where the heterocycloalkyl ring is connected to the base molecule via a ring atom, which may be C or N. The heterocycloalkyl can refer to the ring system being fully saturated. Heterocycloalkyl rings include rings which are spirocyclic, bridged, or fused to one or more other heterocycloalkyl or carbocyclic rings, where such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated, or aromatic to the extent unsaturation or aromaticity makes chemical sense, provided the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system. Heterocycloalkyl rings may contain 1 to 4 heteroatoms selected from N, O, and S(O)qas ring members, or 1 to 2 ring heteroatoms, provided that such heterocycloalkyl rings do not contain two contiguous oxygen or sulfur atoms. Heterocycloalkyl rings may be optionally substituted or unsubstituted, as further defined herein. Such substituents may be present on the heterocyclic ring attached to the base molecule, or on a spirocyclic, bridged or fused ring attached thereto. Heterocycloalkyl rings may include, but are not limited to, 3-8 membered heterocyclyl groups, for example 4-7 or 4-6 membered heterocycloalkyl groups, in accordance with the definition herein. “Aryl” or “aromatic” refers to monocyclic, bicyclic (e.g., biaryl, fused), or polycyclic ring systems that contain the specified number of ring atoms, in which all carbon atoms in the ring are of sp2hybridization and in which the pi electrons are in conjugation. Aryl groups may contain, but are not limited to, 6 to 20 carbon atoms ("C6-20aryl"), 6 to 14 carbon atoms ("C6-14aryl"), 6 to 12 carbon atoms ("C6-12aryl"), or 6 to 10 carbon atoms ("C6-10aryl"). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. Similarly, “heteroaryl” or “heteroaromatic” refer to monocyclic, bicyclic (e.g., heterobiaryl, fused), or polycyclic ring systems that contain the specified number of ring atoms and include at least one heteroatom selected from N, O, and S as a ring member in a ring in which all carbon atoms in the ring are of sp2hybridization and in which the pi electrons are in conjugation. Heteroaryl groups may contain, but are not limited to, 5 to 20 ring atoms (“5-20 membered heteroaryl”), 5 to 14 ring atoms (“5-14 membered heteroaryl”), 5 to 12 ring atoms (“5-12 membered heteroaryl”), 5 to 10 ring atoms (“5-10 membered heteroaryl”), 5 to 9 ring atoms (“5- 9 membered heteroaryl”), or 5 to 6 ring atoms (“5-6 membered heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring. Thus, either 5- or 6- membered heteroaryl rings, alone or in a fused structure, may be attached to the base molecule via a ring C or N atom. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl and carbazolyl. Examples of 5- or 6- membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl rings. Heteroaryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. “Amino” refers to a group -NH2, which is unsubstituted. Where the amino is described as substituted or optionally substituted, the term includes groups of the form -NRxRy, where each of Rxand Ryis defined as further described herein. For example, “alkylamino” refers to a group -NRxRy, wherein one of Rxand Ryis an alkyl moiety and the other is H, and “dialkylamino” refers to -NRxRywherein both of Rxand Ryare alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., -NH(C1-4 alkyl) or -N(C1-4 alkyl)2). “Aminoalkyl” refers to an alkyl group, as defined above, that is substituted by 1, 2, or 3 amino groups, as defined herein. The term “pharmaceutically acceptable” means the substance (e.g., the compounds described herein) and any salt thereof, or composition containing the substance or salt of the compounds of the disclosure is suitable for administration to a subject or patient. A “pharmaceutical composition” refers to a mixture of one or more of the compounds of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable excipient. “Deuterium enrichment factor” as used herein means the ratio between the deuterium abundance and the natural abundance of deuterium, each relative to hydrogen abundance. An atomic position designated as having deuterium typically can have a deuterium enrichment factor of, at least 1,000 (15% deuterium incorporation), at least 2,000 (30% deuterium incorporation), at least 3,000 (45% deuterium incorporation), at least 3,500 (52.5% deuterium incorporation), at least 3,500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4,000 (60% deuterium incorporation), at least 4,500 (67.5% deuterium incorporation), at least 5,000 (75% deuterium incorporation), at least 5,500 (82.5% deuterium incorporation), at least 6,000 (90% deuterium incorporation), at least 6,333.3 (95% deuterium incorporation), at least 6,466.7 (97% deuterium incorporation), at least 6,600 (99% deuterium incorporation), or at least 6,633.3 (99.5% deuterium incorporation). “Excipient” as used herein describes any ingredient other than the compound(s) of the disclosure. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. As used herein, “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugar, sodium chloride, or polyalcohol such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof. Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound. The term “treating”, “treat”, or “treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease. As used herein, the term, “subject”, “individual”, or “patient,” used interchangeably, refers to any animal, including mammals. Mammals according to the disclosure include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans, and the like, and encompass mammals in utero. Humans can be suitable subjects. Human subjects may be of any gender and at any stage of development. As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following: (1) preventing the disease; for example, preventing a disease, condition, or disorder in an individual that may be predisposed to the disease, condition, or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition, or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., arresting (or slowing) further development of the pathology or symptomatology or both); and (3) ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., reversing the pathology or symptomatology or both). Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this disclosure, which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compound of the disclosure that is suitable for administration to a subject or patient. In addition, the compound of the disclosure may also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparing a compound of the disclosure; 2) purifying the compound of the disclosure; 3) separating enantiomers of the compound of the disclosure; or 4) separating diastereomers of the compound of the disclosure. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphathalenedisulfonic acid and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see Paulekun, G. S. et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem.2007; 50(26), 6665-6672. Pharmaceutically acceptable salts of the compounds of the disclosure may be prepared by methods well known to one skilled in the art, including but not limited to the following procedures (i) by reacting a compound of the disclosure with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the disclosure or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of a compound of the disclosure to another. This may be accomplished by reaction with an appropriate acid or base or by means of a suitable ion exchange procedure. These procedures are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The compounds of the disclosure, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water. In addition, the compounds of the disclosure may also include other solvates of such compounds which are not necessarily pharmaceutically acceptable solvates, which may be useful as intermediates for one or more of the following: 1) preparing the compounds of the disclosure; 2) purifying the compounds of the disclosure; 3) separating enantiomers of the compounds of the disclosure; or 4) separating diastereomers of the compounds of the disclosure. A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion. When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. Also included within the scope of the disclosure are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug- host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, for example, hydrogen bonded complex (cocrystal) may be formed with either a neutral molecule or with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see Chem Commun, 17;1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64(8), 1269-1288, by Haleblian (August 1975). The compounds of the disclosure may exist in a continuum of solid states ranging from amorphous to crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’). The compounds of the disclosure may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) and consists of two dimensional order on the molecular level. Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COO-Na+, -COO-K+, or -SO3-Na+) or non-ionic (such as -N-N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970). Compounds of the disclosure may exist as two or more stereoisomers. Stereoisomers of the compounds may include cis and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the disclosure containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where a compound of the disclosure contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may also exist for saturated rings. The pharmaceutically acceptable salts of the compounds of the disclosure may also contain a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl- tartrate or dl-arginine). Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the disclosure contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, or by using both of said techniques, and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the disclosure (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in the present disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp.223-249 and references cited therein). When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994). Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) may occur. This may take the form of proton tautomerism in the compounds of the disclosure containing, for example, an imino / amino, keto / enol, or oxime / nitroso group, lactam / lactim or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. It must be emphasized that while, for conciseness, the compounds of the disclosure have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the disclosure. The present disclosure includes all pharmaceutically acceptable isotopically-labeled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of Formula I may include isotopes of hydrogen, such as2H (D, deuterium) and3H (T, tritium), carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labelled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in one or both of drug or substrate tissue distribution studies. The radioactive isotopes, such as, tritium and14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with positron emitting isotopes, such as,11C,18F,15O and13N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Substitution with deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability. The disclosure provides deuterium-labeled (or deuterated) compounds and salts, where the formula and variables of such compounds and salts are each and independently as described herein. “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance that is greater than the natural abundance of deuterium (typically approximately 0.015%). A skilled artisan recognized that in chemical compounds with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of the deuterium incorporated into the deuterium-labeled compounds and salt of Formula I may be defined by the deuterium enrichment factor. It is understood that one or more deuterium may exchange with hydrogen under physiological conditions. The deuterium compound can be selected from any one of the compounds of Examples 1 to 99 or in the deuterated analogs D1-D3 specifically illustrated in the Examples section. One or more hydrogen atoms on certain metabolic sites on the compounds of Formula I can be deuterated. Isotopically-labeled compounds of Formula I may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, d6- DMSO. A compound of the disclosure may be administered in the form of a prodrug. Thus, certain derivatives of a compound of the disclosure which may have little or no pharmacological activity themselves may, when administered into or onto the body, be converted into a compound of the disclosure having the desired activity, for example by hydrolytic cleavage, particularly hydrolytic cleavage promoted by an esterase or peptidase enzyme. Such derivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘The Expanding Role of Prodrugs in Contemporary Drug Design and Development, Nature Reviews Drug Discovery, 17, 559-587 (2018) (J. Rautio et al.). Prodrugs in accordance with the disclosure may, for example, be produced by replacing appropriate functionalities present in the compounds of the disclosure with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in ‘Design of Prodrugs’ by H. Bundgaard (Elsevier, 1985). Thus, a prodrug in accordance with the disclosure may be (a) an ester or amide derivative of a carboxylic acid when present in a compound of the disclosure; (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group when present in a compound of the disclosure; (c) an amide, imine, carbamate or amine derivative of an amino group when present in a compound of the disclosure; (d) a thioester, thiocarbonate, thiocarbamate or sulfide derivatives of a thiol group when present in a compound of the disclosure; or (e) an oxime or imine derivative of a carbonyl group when present in a compound of the disclosure. Some specific examples of prodrugs in accordance with the disclosure include: (i) when a compound of the disclosure contains a carboxylic acid functionality (- COOH), an ester thereof, such as a compound wherein the hydrogen of the carboxylic acid functionality of the compound is replaced by -C1-8alkyl (e.g., ethyl) or (-C1-8alkyl)C(=O)OCH2- (e.g.,tBuC(=O)OCH2-); (ii) when a compound of the disclosure contains an alcohol functionality (-OH), an ester thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by –CO(C1-8alkyl) (e.g., methylcarbonyl) or the alcohol is esterified with an amino acid; (iii) when a compound of the disclosure contains an alcohol functionality (-OH), an ether thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by (C1-8alkyl)C(=O)OCH2- or –CH2OP(=O)(OH)2; (iv) when a compound of the disclosure contains an alcohol functionality (-OH), a phosphate thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by –P(=O)(OH)2or –P(=O)(O-Na+)2or –P(=O)(O-)2Ca2+; (v) when a compound of the disclosure contains a primary or secondary amino functionality (-NH2or -NHR where R ≠ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound is / are replaced by (C1-10)alkanoyl, –COCH2NH2or the amino group is derivatized with an amino acid; (vi) when a compound of the disclosure contains a primary or secondary amino functionality (-NH2or -NHR where R ≠ H), an amine thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound is / are replaced by –CH2OP(=O)(OH)2. Certain compounds of the disclosure may themselves act as prodrugs of other compounds the disclosure it is also possible for two compounds of the disclosure to be joined together in the form of a prodrug. In certain circumstances, a prodrug of a compound of the disclosure may be created by internally linking two functional groups in a compound of the disclosure, for instance by forming a lactone. Also included within the scope of the disclosure are active metabolites of compounds of the disclosure, that is, compounds formed in vivo upon administration of the drug, often by oxidation or dealkylation. Some examples of metabolites in accordance with the disclosure include, but are not limited to, (i) where the compound of the disclosure contains an alkyl group, a hydroxyalkyl derivative thereof (-CH ^ -COH): (ii) where the compound of the disclosure contains an alkoxy group, a hydroxy derivative thereof (-OR ^ -OH); (iii) where the compound of the disclosure contains a tertiary amino group, asecondary amino derivative thereof (-NRR’^ -NHR or –NHR’);(iv) where the compound of the disclosure contains a secondary amino group, a primary derivative thereof (-NHR ^ -NH2); (v) where the compound of the disclosure contains a phenyl moiety, a phenol derivative thereof (-Ph ^ -PhOH); (vi) where the compound of the disclosure contains an amide group, a carboxylic acid derivative thereof (-CONH2^ COOH); and (vii) where the compound contains a hydroxy or carboxylic acid group, the compound may be metabolized by conjugation, for example, with glucuronic acid to form a glucuronide. Other routes of conjugative metabolism exist. These pathways are frequently known as Phase 2 metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, may also be subject to conjugation. The compound of Formula I or a pharmaceutically acceptable salt thereof can have the structure: I X1can be CH. X1can be N. X1can be CF. X2 can be CH. X2 can be CCH3. X2 can be N. X2 can be CF. X2 can be CCl. X2 can be C(CH2CH3). X2can be C-cyclopropyl. X3can be CR6. X3can be NR6. X4can be C. X4can be N. X5can be C. X5can be N. X6can be CH. X6can be N. X7can be CH. X7can be N. X7can be CF. X8can be CH. X8can be N. X9can be CH. X9can be N. X10can be CH. X10can be N. R1can be -NHR9. R1can be -OH. R1can be -C3-4heteroaryl optionally substituted with -C1-3alkyl. R1can be -C1-3alkyl optionally substituted with one, two, or three of oxo, - NR10R11, or -C3-5heterocycloalkyl optionally substituted with R1A, wherein R1Ais -OH. R1can be -C1-3alkyl optionally substituted with one or two of oxo, -NR10R11, or -C3-5heterocycloalkyl optionally substituted with R1A, wherein R1Ais -OH. R1 can be -C1-3 alkyl optionally substituted with oxo. R1can be -C1-3alkyl substituted with oxo and -NR10R11,for example, R1can be -C(=O)- NR10R11. R1can be -C1-3alkyl substituted with oxo and -C3-5heterocycloalkyl optionally substituted with -OH. R1 can be -C3-4 heteroaryl optionally substituted with methyl. R1 can be -C1-3alkyl optionally substituted with oxo and -NHR10,for example, R1can be -C(=O)-NHR10. R1can be -C(=O)-C1-3alkyl. The -C3-4heteroaryl of R1can contain 1 to 2 heteroatoms of N. The -C3-5heterocycloalkyl of R1can contain 1 to 2 heteroatoms of N. R2can be H. R2can be -CH3. R1and R2can form a C6-8fused heterocycloalkyl that is optionally substituted with oxo. R1and R2can form a C6-8fused heterocycloalkyl that is optionally substituted with oxo, -C1-3alkyl, -NR10R11, or -OH. R1and R2can form a C6-8heteroaryl. R1and R2can form a C6-8fused heteroaryl is optionally substituted with -C1-3alkyl, -NR10R11, or -OH. The C6-8fused heterocycloalkyl or the C6-8fused heteroaryl or R1and R2can include 1 to 2 heteroatoms of N. R3can be -C1-3alkyl. R3can be -C2-5heteroaryl. R3can be -C3-5cycloalkyl. R3can be -NH-C(=O)-C1-3alkyl. R3can be -C2-5heterocycloalkyl. R3can be substituted with one, two, or three, specifically, one or two of -C1-3alkyl, oxo, -NR7R8, or cyano. R3can be substituted with one, two, or three, specifically, one or two of -C1-3alkyl, -C2-3oxoalkyl, oxo, -NR7R8, or cyano. R3can be -C3-5heteroaryl, -C3-5cycloalkyl, or -C3-5heterocycloalkyl and R3can be optionally substituted with one of -C1-3alkyl, oxo, or -NR7R8. R3can be -C1-3alkyl substituted with oxo and -NR7R8. R3can be -C1-3alkyl substituted with cyano. R3can be -C3-5heteroaryl optionally substituted with one of -C1-3alkyl or oxo. R3can be -C3-5cycloalkyl substituted with one of cyano, -C1-3alkyl, or oxo. R3can be -C2-5heterocycloalkyl substituted with one of -C1-3alkyl or oxo. R3can be -C3-5heteroaryl, -C3-5cycloalkyl, or -C3-5heterocycloalkyl and R3can optionally be substituted with one of -C1-3alkyl, oxo, or -NR7R8. R3can be -C(=O)-NR7R8, -C1-3cyanoalkyl, -C3-5cycloalkyl-cyano; -C3-5heterocycloalkyl, -C2-5heteroaryl, or -NH-C(=O)-C1-3alkyl; where the -C3-5heterocycloalkyl can optionally be substituted with one, two, or three of -C1-3alkyl or oxo; and where the -C2-5heteroaryl can optionally be substituted with one, two, or three of -C1-3 alkyl or oxo. R3can be -C3-5heteroaryl optionally substituted with one of -C1-3alkyl or oxo. The - C2-5heteroaryl of R3can include 2 to 3 heteroatoms of at least one of N or O. The -C2-5heterocycloalkyl of R3can include 1 to 2 heteroatoms of N. R4can be H. R4can be -C1-3alkyl. R4can be -C1-3haloalkyl, for example, -C1-3fluoroalkyl. R4can be halogen. R3and R4can form a fused C6-10heterocycloalkyl optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, -NR7R8, cyano, or oxo. R3and R4can form a fused C7-9heterocycloalkyl optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, or oxo. The formed heterocycloalkyl of R3and R4can include 1 to 2 heteroatoms of at least one of N or O. R5can be H. R5can be -C1-3alkyl optionally substituted with -OH. R6 can be H. R6 can be -C3-5 cycloalkyl. R6 can be alkoxyalkyl (for example, -C1-3 alkoxy- C1-3alkyl) . R6can be -C1-3alkyl optionally substituted with -OH (for example, -C1-3hydroxyalkyl) or alkoxy (for example, -C1-3alkoxy-C1-3alkyl). R6can be -C1-3alkyl. R6can be methyl. R7 can be H. R7 can be -C1-3 alkyl. R8can be -C1-3alkyl. R7and R8can form a fused C5-10heterocycloalkyl that can be optionally substituted with -C1-3alkyl. R7and R8can form a fused C6-10heterocycloalkyl that can be optionally substituted with -C1-3alkyl. R7and R8can form a fused C5-7heterocycloalkyl that can be optionally substituted with -C1-3alkyl. The formed heterocycloalkyl of R7and R8can include 2 to 3 heteroatoms of at least one of N or S. R9can be H. R9can be -SO2CH3. R9can be -C1-3alkyl optionally substituted with one, two, or three of oxo, -C3-7heterocycloalkyl, alkoxy, cyanoimine, or -NR12R13. The -C3-7heterocycloalkyl can be substituted with one, two, or three of halogen, oxo, -C0-1alkylene- NR14R15, -OH, -C1-3hydroxyalkyl, -C1-3alkoxy optionally substituted with -NR14R15, -C1-3alkoxy- C1-3alkyl, or a -C1-3alkyl optionally substituted with oxo. R9can be -C1-3alkyl substituted with cyanoimine and NR12R13. R9can be -C1-3alkyl substituted with one, two, or three of oxo, -C3-5heterocycloalkyl, methoxy, and NR12R13. R9can be H, -SO2CH3, -C(=O)-NR12R13, -C(=O)-C1-3alkoxy, or -C(N(CH3)2)-cyanoimine. R9can be -SO2CH3, -C(=O)-NR12R13, -C(=O)-C1-3alkoxy, or -C(N(CH3)2)-cyanoimine. The -C3-7heterocycloalkyl of R9can include 1 to 2 heteroatoms of N. The -C3-5heterocycloalkyl or the -C3-5heteroaryl of R10can include 1 to 2 heteroatoms of N. R10can be H. R10can be -C3-5cycloalkyl optionally substituted with -OH. R10can be -C3-5heterocycloalkyl optionally substituted with -OH. R10can be -C1-3alkyl optionally substituted with a -C3-5heteroaryl, cyclopropyl, cyano, -OH, or -C1-3alkoxy. R10can be -C1-3alkyl optionally substituted with a cyclopropyl, cyano, or -C1-3alkoxy. R10can be -C1-3alkoxy. R10can be H, -C1-3alkylene-C1-3alkoxy, -C1-3hydroxyalkyl, -C1-3alkylene-C3-5heteroaryl, -C0-3alkylene-C3-5cycloalkyl, or -C1-3cyanoalkyl; wherein the -C3-5cycloalkyl is optionally substituted with -OH. The -C3-5heterocycloalkyl and the -C3-5heteroaryl can include 1 to 2 heteroatoms of N. R11can be H. R11can be -C1-3alkyl. R10can be H and R11can be -C1-3alkyl, for example, methyl. R10and R11can be methyl. R10and R11can form a C3-4heterocycloalkyl optionally substituted with -OH. The C3-4heterocycloalkyl of R10and R11can include 1 or 2 heteroatoms of N. R12can be H. R12can be -C1-3alkyl optionally substituted with one, two, or three -OH. R13can be H. R13can be -C1-3alkyl. R12and R13can form a C3-8heterocycloalkyl, wherein the C3-8heterocycloalkyl can optionally be substituted with one, two, or three of halogen, oxo, -C0-1alkylene-NR14R15, -OH, - C1-3hydroxyalkyl, -C0-3alkylene-C1-3alkoxy, or -C1-3alkyl. The C3-8heterocycloalkyl can include 1 to 3 heteroatoms of at least one of N or O. R14can each independently be H. R14can each independently be -C2-4oxoalkyl. R14can each independently be -C1-4 alkyl or -C1-3 alkyl. R14 can each independently be cyclopropyl optionally substituted with methyl. R15can each independently be H. R15can each independently be -C1-3alkyl. In an aspect, no more than 2 of X6, X7, and X8 are N. The heteroatoms can each independently be N, S, or O. The heteroatoms can each independently be N or O. The heteroatoms can be N. At least one hydrogen can be deuterium. For example, X6can be CH and the hydrogen can be deuterium and / or the compound of Formula I can have the formula Ia, where the D is deuterium. The compound can have any one of the formulas illustrated in the example section. For example, the compound or a pharmaceutically acceptable salt thereof can be one of N-({4- [(dimethylcarbamoyl)amino]phenyl}methyl)-5-[5-(dimethylcarbamoyl)pyridin-2-yl]-1-methyl-1H- indazole-3-carboxamide; 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1- methyl-1H-indazole-3-carboxamide; 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(3,3- dimethylureido)benzyl)-1-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; and N-(4-(3,3- dimethylureido)benzyl)-1-methyl-5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-1H-indazole-3- carboxamide. The compound can be that of Formula I with the proviso that it is not 5-(4-(1,4- dimethyl-1H-imidazol-2-yl)phenyl)-1-methyl-N-(4-(methylcarbamoyl)benzyl)-1H-indazole-3- carboxamide. A pharmaceutical composition can comprise a compound of Formula I. The compositions of the disclosure may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application. Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). The compound can be administered by intravenous infusion or injection. The compound can be administered by intramuscular or subcutaneous injection. Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the disclosure. The oral administration may be in a powder or granule form. The oral dosage form can be sub-lingual, for example, a lozenge. In such solid dosage forms, the compounds of the disclosure are ordinarily combined with one or more adjuvants. Such capsules or tablets may comprise a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings. Oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as one or more of wetting, emulsifying, suspending, flavoring (e.g., sweetening), or perfuming agents. The disclosure comprises a parenteral dosage form. “Parenteral administration” includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using one or more of suitable dispersing, wetting agents, or suspending agents. The disclosure comprises a topical dosage form. “Topical administration” includes, for example, dermal and transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the disclosure are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sci., vol.88, pp.955-958, 1999. Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of the disclosure is dissolved or suspended in a suitable excipient. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. For intranasal administration, the compounds of the disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The disclosure comprises a rectal dosage form. Such rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Other excipients and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the disclosure may be prepared by any of the well- known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005; Stahl, P. Heinrich and Camilli G. Wermuth, Eds. Handbook of Pharmaceutical Salts: Properties, Selection, and Use. New York: Wiley-VCH, 2011; and Brittain, Harry G., Ed. Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare USA, Inc., 2016. Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counter-ions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG). For oral administration, the compositions may be provided in the form of tablets or capsules containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, or 500 milligrams (mg) of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains 0.01 mg to 500 mg of the active ingredient, or 1 mg to 100 mg of active ingredient. Intravenous doses may be in the range of 0.01 to 10 mg / kg / minute during a constant rate infusion. Liposome containing compounds of the disclosure may be prepared by methods known in the art (See, for example, Chang, H.I.; Yeh, M.K.; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49- 60). Particularly useful liposomes may be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Compounds of the disclosure may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000). Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a compound of the disclosure, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate) or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid. The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Compounds of the disclosure are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. Suitable emulsions may be prepared using commercially available fat emulsions, such as a lipid emulsion comprising soybean oil, a fat emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soya bean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion may comprise fat droplets having a diameter of 0.1 to 1.0 micrometers (μm), particularly 0.1 to 0.5 μm, and have a pH of 5.5 to 8.0. For example, the emulsion compositions may be those prepared by mixing a compound of the disclosure with a lipid emulsion comprising soybean oil or the components thereof (soybean oil, egg phospholipids, glycerol and water). Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. The compositions can be administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably, orally or nasally, from devices which deliver the formulation in an appropriate manner. A drug product intermediate (DPI) is a partly processed material that must undergo further processing steps before it becomes bulk drug product. Compounds of the disclosure may be formulated into drug product intermediate DPI containing the active ingredient in a higher free energy form than the crystalline form. One reason to use a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, improved mass transport through the mucus layer adjacent to the epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid state stability and downstream manufacturability. The drug product intermediate can contain a compound of the disclosure isolated and stabilized in the amorphous state (for example, amorphous solid dispersions (ASDs)). There are many techniques known in the art to manufacture ASD’s that produce material suitable for integration into a bulk drug product, for example, spray dried dispersions (SDD’s), melt extrudates (often referred to as HME’s), co- precipitates, amorphous drug nanoparticles, and nano-adsorbates. Amorphous solid dispersions can comprise a compound of the disclosure and a polymer excipient. Other excipients as well as concentrations of said excipients and the compound of the disclosure are well known in the art and are described in standard textbooks. See, for example, “Amorphous Solid Dispersions Theory and Practice” by Navnit Shah et al. This disclosure further comprises use of a compound of the disclosure for use as a medicament (such as a unit dosage tablet or unit dosage capsule). This disclosure comprises the use of a compound of the disclosure for the manufacture of a medicament (such as a unit dosage tablet or unit dosage capsule) to treat one or more of the conditions previously identified in the above sections discussing methods of treatment. This disclosure further comprises a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use as a medicament and a compound the disclosure, or a pharmaceutically acceptable salt therefore, for use in any method of treatment herein disclosed. Typically, a compound of the disclosure is administered in an amount effective to treat a condition as described herein. The compounds of the disclosure may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the disclosure. The compounds of the disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds of the disclosure may be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation. The compounds of the disclosure may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth. The compounds of the disclosure may also be administered parenterally, for example, directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques. The compounds of the disclosure may be administered topically to the skin or mucosa, that is, dermally or transdermally. The compounds of the disclosure may also be administered intranasally or by inhalation. The compounds of the disclosure may be administered rectally or vaginally. The compounds of the disclosure may also be administered directly to the eye or ear. The dosage regimen for the compounds of the disclosure or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. The total daily dose of a compound of the disclosure can be 0.01 to 100 mg / kg (i.e., mg compound of the disclosure per kg body weight) for the treatment of the indicated conditions discussed herein. The total daily dose of the compound of the disclosure can be 0.1 to 50 mg / kg, or 0.5 to 30 mg / kg. It is not uncommon that the administration of the compounds of the disclosure will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired. The compounds of the disclosure may inhibit the activity of STAT6 and may be useful in the treatment, prevention, suppression, and amelioration of disease(s) or diseases, disorders, and conditions mediated by STAT6. The compounds of the disclosure may be used to treat or prevent at least one disease or condition relating to an inflammatory disorder. The compounds of the disclosure may be used to treat or prevent at least one disease or condition including allergy (including food allergy, latex allergy, pet allergy, mold allergy, insect allergy, pollen allergy, dust allergy, seasonal allergy, ragweed allergy, drug allergy, allergic rhinitis, allergic rhinitis, allergic fungal rhinosinusitis, allergic contact dermatitis, and allergic bronchopulmonary aspergillosis), alopecia (including alopecia areata), Alzheimer’s disease, arteritis, asthma, atherosclerosis, autoimmune disorders (including lupus nephritis, autoimmune hepatitis, myasthenia gravis, Guillain-Barre syndrome, and Graves' disease) Bechet’s disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritis, chronic urticaria, celiac disease, Crohn’s disease (CD), dermatitis (including atopic dermatitis (AD), hand dermatitis, and hand or foot atopic dermatitis), diabetic kidney disease, diversion colitis, eosinophilic esophagitis (including pediatric eosinophilic esophagitis), eye disorders or conditions (including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, non-infectious uveitis (e.g. uveitis associated with Bechet’s disease and lens-induced uveitis), keratitis (e.g. herpetic keratitis and conical keratitis), keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, retinitis, retinopathy, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization), fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), indeterminate colitis, keloids, mastocytosis, microscopic colitis (such as collagenous colitis or lymphocytic colitis), myositis, nephritis, non-alcoholic steatohepatitis (NASH), pancreatitis, primary biliary cirrhosis, proctitis, prurigo nodularis, psoriasis, psoriatic arthritis, primary biliary cirrhosis, rhinosinusitis (including chronic rhinosinusitis with nasal polyps), sarcoidosis, scleroderma, sclerosing cholangitis, Sjogren's syndrome, systemic lupus erythematosus (SLE), systemic sclerosis, thyroiditis, ulcerative colitis (UC), vitiligo, vasculitis, Vogt-Koyanagi-Harada syndrome, Wegener's granulomatosis, or hidradenitis suppurativa. A method of treating or preventing one or one or more symptoms associated with the respective disease or condition comprises administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of the disclosure to a patient. The compounds of the disclosure may be used to treat or prevent dermatological conditions, such as eczema (e.g. chronic and dyshidrotic eczema), chronic itch, dermatitis (e.g. atopic, irritant contact, allergic contact, occupational, perioral, stasis, nummular, seborrheic, xerotic, eyelid, diaper, and hand dermatitis), vitiligo, alopecia, alopecia areata, pruritis (e.g. chronic idiopathic pruritus), prurigo nodularis, psoriasis (e.g. plaque, guttate, inverse, pustular, nail, flexural palmoplantar, facial or erythrodermic psoriasis), scleroderma, pemphigus, dermatomyositis, neurodermatitis, skin flushing, cutaneous lupus erythematosus (e.g. acute cutaneous lupus (acute skin lupus), subacute cutaneous lupus (subacute lupus), and chronic cutaneous lupus (discoid lupus)), keloid, sunburn, hypertrophic scar, idiopathic thrombocytopenic purpura (ITP), ichthyosis (e.g. ichthyosis vulgaris), epidermal hyperplasia, acne, lichen planus, lichen sclerosis, rosacea, epidermolysis bullosa, intertrigo, keratosis pilaris, urticaria (e.g. chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria), molluscum contagiosum, Netherton syndrome, Sweet's syndrome, pityriasis alba, vulvovaginitis, Sutton's nevus / nevi, post inflammatory hypopigmentation, senile leukoderma, chemical / drug-induced leukoderma, palmoplantar pustulosis, pemphigoid, pemphigoid nodularis, bullous pemphigoid, and hidradenitis suppurativa. The compounds of the disclosure may be used to treat or prevent respiratory conditions, such as rhinitis (e.g. allergic and perennial rhinitis), rhinorrhea, nasal congestion, nasal inflammation, asthma (e.g. chronic asthma, inveterate asthma, late asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), chronic and acute bronchoconstriction, chronic bronchitis, emphysema, allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, acute lung injury (ACI), adult respiratory distress syndrome (ARDS), pulmonary vascular disease (PVD), pulmonary arterial hypertension (PAH), bronchiectasis, sinusitis, rhinosinusitis, allergic fungal rhinosinusitis, chronic rhinosinusitis with nasal polyps, pulmonary sarcoidosis, and silicosis. The compounds of the disclosure may be used to treat or prevent joint disorders, such as arthritis (e.g. osteoarthritis, as well as psoriatic, rheumatoid, juvenile, and gouty arthritis), spondyloarthropathy (e.g. reactive arthritis (also known as Reiter's Syndrome) and axial spondyloarthritis (including ankylosing spondylitis)), cartilage inflammation, bone degradation, and Still's disease; cardiovascular and metabolic disorders, such as diabetes (type 1 and type 2), myocarditis, diabetic neuropathy, atherosclerosis, cachexia, and celiac sprue; neuroinflammatory disorders, such as lupus (e.g. CNS, systemic and discoid lupus), systemic lupus erythematosus (SLE), diabetic neuropathy, autoimmune encephalitis, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis; and cancer. The compound of the disclosure may be used alone, or in combination with one or more other therapeutic agents. The disclosure provides any of the uses, methods or compositions as defined herein wherein the compound of the disclosure, or pharmaceutically acceptable salt thereof, is used in combination with one or more other therapeutic agent discussed herein. The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compound at the same point in time but as separate dosage forms at the same or different site of administration. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”. A compound of the disclosure and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients. The term "fixed combination" means a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage. The term "non-fixed combination" means that a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject. The compounds of the disclosure can be administered in combination with one or more pharmaceutically active agents other than the compounds of the disclosure including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts. The present disclosure can provide a pharmaceutical composition comprising the compound of the disclosure or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with a pharmaceutical composition comprising a different pharmaceutically active compound or a pharmaceutically acceptable salt thereof simultaneously or at different times. These agents and compounds may be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual’s medical history. Another aspect of the disclosure provides kits comprising the compound of the disclosure or pharmaceutical compositions comprising the compound . A kit may include, in addition to the compound of the disclosure or pharmaceutical composition thereof, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. The kit can include the compound or a pharmaceutical composition thereof and a diagnostic agent. The kit can include the compound or a pharmaceutical composition thereof and one or more therapeutic agents. The kits can be suitable for use in performing the methods of treatment described herein. The kit can contain a first dosage form comprising one or more of the compounds of the disclosure in quantities sufficient to carry out the methods of the disclosure. The kit can comprise one or more compounds of the disclosure in quantities sufficient to carry out the methods of the disclosure and a container for the dosage and a container for the dosage. Compounds of the present disclosure may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art. Many of the compounds used herein, are related to, or may be derived from compounds in which one or more of the scientific interest or commercial need has occurred. Accordingly, such compounds may be one or more of 1) commercially available; 2) reported in the literature or 3) prepared from other commonly available substances by one skilled in the art using materials which have been reported in the literature. For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are discussed below, other starting materials and reagents may be substituted to provide one or more of a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below may be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of Formula I. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of Formula I. In the preparation of compounds of Formula I it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., a primary amine, secondary amine, carboxyl, etc. in a precursor of a compound of Formula I). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition. For example, if a compound contains amine or carboxylic acid functionality, such functionality may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group (PG) that may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids) that are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of Formula I. One skilled in the art will recognize that, in some cases, the compounds will be generated as a mixture of diastereomers and / or enantiomers; these may be separated at various stages of the synthetic scheme using conventional techniques or a combination of such techniques, such as, but not limited to, crystallization, normal-phase chromatography, reversed- phase chromatography and chiral chromatography, to afford the single enantiomers of the disclosure; for example, see “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994). Unless otherwise indicated, the substituents in the schemes are defined as above. Isolation and purification of the products are accomplished by standard procedures, which are known to a chemist of ordinary skill. It will be understood by one skilled in the art that the various symbols, superscripts, and subscripts used in the schemes, methods, and examples are used for the convenience of representation and / or to reflect the order in which they are introduced in the schemes and are not intended to necessarily correspond to the symbols, superscripts or subscripts in the appended claims. The schemes are representative of methods useful in synthesizing the compounds of the present disclosure. They are not to constrain the scope of the disclosure in any way. Formula I can be prepared as shown in General Scheme A. A halogen (e.g., Br)- substituted carboxylic acid of Formula AA1, synthesized either by literature methods or purchased commercially, can be treated with an amine AA2 using standard amide coupling reagents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 2-(3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU), 1-hydroxybenzotriazole-hydrate (HOBt), propylphosphonic anhydride (T3P), or other common reagents in a solvent such as dichloromethane (DCM) or dimethylformamide (DMF) with an organic base such as N,N-diisopropylethylamine (DIPEA) or triethylamine (TEA) stirred at a temperature of 0 degrees Celsius (°C) to reflux to afford an amide of Formula AA3. In select cases where X3in Formula AA3 is an unalkylated amine, the amine can react with a halogen (e.g., Br-) substituted alkyl chain under basic conditions like with cesium carbonate (Cs2CO3) in a solvent such as DMF heated from 50-100 °C to form the alkylated compound such as Formula AA3. Formula I can be obtained by a Suzuki cross-coupling between the boronic ester or boronic acid of Formula AA4 and the halogenated aryl compound AA3 using a base such as Cs2CO3, potassium bicarbonate (KHCO3), tribasic potassium phosphate (K3PO4), and a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) or mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2’-amino-1,1’-biphenyl)]palladium(II) (cataCXium®A Pd G3) in solvents such as 1,4-dioxane or water at a temperature of 50 to 100 °C. In certain cases, when X3of Formula I is an unalkylated nitrogen, the amine can be ethylated with ethyl iodide (EtI) and a base like Cs2CO3in a solvent such as DMF to form the alkylated Formula I. In cases when R3of Formula I is an ester, the ester can be hydrolyzed to an acid under standard hydrolysis conditions, then the acid can react with an amine under standard amide coupling conditions to form an amide compound such as Formula I. Scheme B For certain examples, Formula I can be prepared as shown in General Scheme B. The halogen (e.g., Br)-substituted such as Formula AA3 can be reacted with bis(pinacolato)diboron in a solvent such as 1,4-dioxane or dimethyl sulfoxide (DMSO) in the presence of a base such as potassium acetate (KOAc) and catalyst such as Pd(dppf)Cl2at a temperature of 60 to 110 °C for about 12 to 24 hours to afford a boronic ester compound such as Formula BB1. Formula I can be obtained by a Suzuki cross-coupling between a compound of Formula BB1 and a halogenated aryl compound BB2 using a base such as K3PO4, KHCO3, or Cs2CO3and a catalyst such as Pd(dppf)Cl2or cataCXium®A Pd G3 in a solvent such as tert-amyl alcohol, 1,4- dioxane, or water at a temperature of 50 to 110 °C. In some instances, when X3of Formula I is an unalkylated nitrogen atom, it can be alkylated in the presence of an alkyl halide, base, and solvent, such as using EtI with potassium carbonate (K2CO3) in a solvent such as DMSO to obtain compounds of Formula I. Scheme C Formula I can be prepared as shown in General Scheme C. A halogen (e.g., Br, Cl)- substituted Formula such as CC1 can react with bis(pinacolato)diboron in a solvent such as 1,4- dioxane or DMSO in the presence of a base such as KOAc and a catalyst such as Pd(dppf)Cl2at a temperature of 60 to 100 °C for about 12 to 24 hours to afford the boronic ester such as of Formula CC2. Formula CC3 can be obtained by a Suzuki cross-coupling between the boronic ester such as Formula CC2 and the halogenated aryl compound such as BB2 using a base such as K3PO4or Cs2CO3and a catalyst such as Pd(dppf)Cl2or chloro(2- dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) (XPhos Pd G2) in a solvent such as 1,4-dioxane, tetrahydrofuran (THF), or water at a temperature of 50 to 90 °C. Treatment of the ester of Formula CC3 with a base such as lithium hydroxide monohydrate (LiOH), potassium trimethylsilanolate (KOTMS), or sodium hydroxide (NaOH) in solvents like acetonitrile (MeCN), methanol (MeOH), tetrahydrofuran (THF), or water from 0 °C to room temperature followed by a pH adjustment which can form the acid such as Formula CC4. Formula CC4 can be treated with an amine AA2 using standard amide coupling reagents such as EDCI, HATU, T3P or other common reagents in a solvent such as DCM or DMF with an organic base such as DIPEA or TEA present at a temperature of 0 °C to reflux to afford Formula I. Scheme D Formula I can be prepared as shown in alternative General Scheme D. A halogen (e.g., Br)-substituted compound such as Formula AA1, synthesized either by literature methods or purchased commercially, can be reacted with the boronic acid or boronic ester such as Formula AA4 under standard Suzuki coupling conditions using a base such as K3PO4or Cs2CO3and catalyst Pd(dppf)Cl2in a solvent such as 1,4-dioxane or water at a temperature of 50 to 100 °C to give Formula CC4. Formula CC4 can react with the amine of Formula AA2 under standard amide coupling conditions in EDCI with HOBt, HATU, T3P, or other common reagents in a solvent such as DCM or DMF with an organic base such as DIPEA or TEA present at a temperature of 0 °C to reflux can afford an amide compound of Formula I. In the case where R1is an acid, amine or an ester, it can be further converted to an amide, urea or guanidine using standard coupling to afford compound of Formula I. Scheme E Formula I can be prepared according to the synthetic route shown in General Scheme E. A halogen (e.g., Br, Cl)-substituted compound such as Formula CC1, synthesized either by literature methods or purchased commercially, can react with a boronic acid or trimethyltin such as Formula EE1 in solvents such as water, THF, toluene, or 1,4-dioxane in the presence of a base such as K3PO4and a catalyst like Pd(dppf)Cl2or tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4). The reactions can be conducted under nitrogen and heated at a temperature of 60 to 100 °C for about 12 to 24 hours to afford Formula CC3. In some instances, when X3in Formula CC3 is a carbon, Formula CC3 can react with a halogenating reagent in the presence of a solvent to produce halo-substituted Formula CC3. For example, N-iodosuccinimide (NIS) in MeCN heated at 30-50 °C can be used to form iodo- Formula CC3, which can then undergo further reaction under standard Suzuki coupling conditions to produce compounds of Formula CC3. The ester group can be hydrolyzed under standard hydrolysis conditions by utilizing a base such as LiOH or NaOH in solvents such as MeOH, THF, or water and heated at 30 to 50 °C then stirred from 1 to 16 hours to provide the carboxylic acid of Formula CC4. Formula CC4 can react with the amine of Formula AA2 through the standard amide coupling reagents such as EDCI with 2-pyridinol 1-oxide (HOPO), HATU, T3P, or other common reagents in solvents such as DCM, DMF, or DMSO with a base such as DIPEA or TEA at a temperature from 0 °C to reflux to result in Formula I. Scheme F Formula I can be prepared as shown in General Scheme F. A halogen (e.g., Br)- substituted compound such as Formula AA1 can react with bis(pinacolato)diboron in a solvent such as toluene in the presence of a base such as KOAc and catalysts such as di(1- adamantyl)-n-butylphosphine (cataCXium®A) or palladium(II) acetate (Pd(OAc)2) at a temperature of 60 to 100 °C for about 12 to 24 hours to afford boronic ester of Formula FF1. The boronic ester of Formula FF1 can react in a Suzuki cross-coupling with the halogenated aryl Formula BB2 using a base such as K3PO4and a catalyst such as cataCXium®A Pd G3 in a solvent such as tert-amyl alcohol or water at a temperature of 50 to 100 °C for 12 to 24 hours to provide Formula CC4. The acid of Formula CC4 can be treated with an amine AA2 using standard amide coupling reagents such as EDCI, HATU, T3P, or other common reagents in a solvent such as DCM or DMF with an organic base such as DIPEA or TEA present at a temperature of 0 °C to reflux to afford Formula I. In order that this disclosure may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the disclosure in any manner. EXAMPLES The compounds and intermediates described below were named using the naming convention provided with ChemDraw version 20.1.1.123. The naming convention provided with ChemDraw version 20.1.1.123 is well known by those skilled in the art and it is believed that the naming convention generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules. Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature. The following illustrate the synthesis of various compounds of the present disclosure. Additional compounds within the scope of this disclosure may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art. All starting materials in these Preparations and Examples are either commercially available or can be prepared by methods known in the art or as described herein. Reactions were performed in air or, when oxygen-or moisture-sensitive reagents or intermediates were employed, under an inert atmosphere (nitrogen or argon). Unless otherwise noted, chemical reactions were performed at room temperature (about 15 to 25 °C). Unless noted otherwise, all reactants were obtained commercially and used without further purification, or were prepared using methods known in the literature. In the examples, proton nuclear magnetic resonance (1H NMR) spectra were recorded at 400 MHz or 600 MHz, where δ is chemical shift; br is broad; CDCl3is deuterated chloroform; (CD3)2SO is deuterated dimethyl sulfoxide; CD3OD is deuterated methanol; d is doublet; dd is doublet of doublets; ddd is doublet of doublet of doublets; dt is doublet of triplets; s is singlet; t is triplet; m is multiplet; MHz is megahertz; ppm is parts per million; q is quartet. Preparation P1 5-Chloro-1-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (P1) Step 1. Preparation of 5-chloro-1-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (P1) The reaction was conducted in two batches then combined for purification. At 0 degrees Celsius (°C) under nitrogen, to a suspension of sodium hydride (NaH) (19.0 grams (g), 475 millimole (mmol)) in dimethylformamide (DMF) (335 milliliter (mL)) was added 5-chloro-1H- pyrazolo[3,4-c]pyridine-3-carboxylic acid (CAS: 1260664-22-9, 33.5 g, 169 mmol) and then stirred for 30 minutes at 0 °C before methyl iodide (MeI) (32.5 g, 229 mmol) in DMF (15 mL) was added to form the first batch. The first batch was stirred at room temperature for 2 hours then cooled to 0 °C before the reaction was quenched with cold water (200 mL) dropwise. A second batch of the same reaction was conducted with 5-chloro-1H-pyrazolo[3,4- c]pyridine-3-carboxylic acid (CAS: 1260664-22-9, 77.0 g, 390 mmol). The batches were combined then extracted with methyl tert-butyl ether (TBME) (800 mL x 2). The aqueous layer was diluted with water (8 liters (L)) then acidified with 6 normal (N) hydrochloric acid (HCl) to pH~4 which caused solid to precipitate. The solid was filtered then washed with water (500 mL x 3). The filter cake was collected, diluted with acetonitrile (MeCN) (~500 mL), concentrated in vacuo, and then lyophilized. The beige solid was triturated with (200 mL: 100 mL: 200 mL) methanol (MeOH): ethyl acetate (EtOAc): TBME for 1 hour. The solid was filtered and then dried under high vacuum to provide P1 (84.0 g, 71.0% yield) as a beige solid. The solid was used directly in the next step without further purification. Liquid chromatography mass spectrometry (LC / MS) m / z (M+H)+= 212.1.1H NMR (400 MHz, (CD3)2SO) δ 13.44 (s, 1H), 9.17 (d, 1H), 7.96 (d, 1H), 4.30 (s, 3H). Preparation P2 5-Bromo-7-chloro-1-methyl-1H-indazole-3-carboxylic acid (P2) Step 1. Preparation of 7-chloro-1-methyl-1H-indazole-3-carboxylic acid (C1) At 0 °C under nitrogen, to a suspension of NaH (1.02 g, 25.4 mmol) in DMF (24 mL) was added 7-chloro-1H-indazole-3-carboxylic acid (CAS: 129295-32-5, 2.00 g, 10.2 mmol), then stirred for 30 minutes at 0 °C before MeI (1.88 g, 13.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then quenched with water (20 mL). The aqueous phase was extracted with EtOAc (15 mL x 2) then acidified with 1M HCl to pH<4. The acidic aqueous phase was extracted with EtOAc: tetrahydrofuran (THF) (15 mL x 3). The combined organic phase was diluted with EtOAc and then stirred at room temperature for 30 minutes. The solid was filtered to provide C1 (1.70 g, 79.3% yield) as a brown solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M)+= 210.7.1H NMR (400 MHz, (CD3)2SO) δ 13.21 (br s, 1H), 8.07 (d, 1H), 7.55 (d, 1H), 7.28 (t, 1H), 4.41 (s, 3H). Step 2. Preparation of 5-bromo-7-chloro-1-methyl-1H-indazole-3-carboxylic acid (P2) To C1 (1.00 g, 4.75 mmol) dissolved in acetic acid (AcOH) (10 mL) and water (1 mL) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (2.04 g, 7.12 mmol) at room temperature. The reaction mixture was warmed to 60 °C and stirred for 16 hours. Another portion of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (1.36 g, 4.75 mmol) was added and then stirred at 60 °C for 16 hours then filtered. The filter cake was washed with water, then collected and lyophilized. The solid was triturated with EtOAc then stirred at room temperature for 30 minutes before the mixture was filtered to provide P2 (0.900 g, 65.5% yield) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 290.9.1H NMR (400 MHz, (CD3)2SO) δ 13.42 (br s, 1H), 8.20 (d, 1H), 7.79 (d, 1H), 4.40 (s, 3H). Preparation P3 5-Bromo-7-fluoro-1-methyl-1H-indazole-3-carboxylic acid (P3) Step 1. Preparation of 5-bromo-7-fluoro-1-methyl-1H-indazole-3-carboxylic acid (P3) To a solution of 5-bromo-7-fluoro-1H-indazole-3-carboxylic acid (CAS: 1360953-31-6, 0.110 g, 0.425 mmol) in THF (2 mL) was added 1 molar (M) lithium bis(trimethylsilyl)amide (LiHMDS) (0.156 g, 0.934 mmol) in one portion at room temperature. The clear solution was stirred at room temperature for 4 hours before neat dimethyl sulfate (0.134 g, 1.06 mmol) was added. After the addition, the reaction mixture was stirred at room temperature for 20 hours. Precipitate formed in the first 10 minutes of the stirring. Another portion of 1M LiHMDS (50.1 milligrams (mg), 0.300 mmol) was added to the reaction mixture and then stirred for 4 hours at room temperature. An additional portion of dimethyl sulfate (0.05 mL) was added then the reaction mixture was stirred for an hour at room temperature. The reaction mixture was diluted with brine (5 mL) then acidified with 1M HCl (2 mL) before heptane (5 mL) was added. The mixture was stirred for 30 minutes then the solid was filtered. The filter cake was washed with water and heptane then the solid was collected and dried in a vacuum oven at 45 °C for 18 hours to provide P3 (83.0 mg, 72.0% yield) as a solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+2H)+= 275.0.1H NMR (400 MHz, (CD3)2SO) δ 13.38 (s, 1H), 8.05 (d, 1H), 7.63 (dd, 1H), 4.27 (s, 3H). Preparation P4 Methyl 5-bromo-1-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (P4) Step 1. Preparation of methyl 5-bromo-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (C2) To a mixture of 5-chloro-3-iodo-1H-pyrazolo[3,4-c]pyridine (CAS: 1260666-29-2, 40.0 g, 143 mmol) in MeOH (500 mL) and DMF (500 mL) were added 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (xantphos) (4.14 g, 7.16 mmol), palladium(II) acetate (Pd(OAc)2) (1.61 g, 7.16 mmol) and triethylamine (TEA) (57.9 g, 573 mmol) at room temperature. The reaction mixture was stirred at 80 °C under carbon monoxide (CO) at 45 pound per square inch (psi) for 16 hours. The mixture was concentrated in vacuo and diluted with water (2 L). A brown solid precipitated from the solution which was filtered. The filter cake was collected then triturated with (100 mL: 50 mL: 100 mL: 1 L) dichloromethane (DCM) / MeOH / TBME / EtOAc for 3 hours. The mixture was filtered, and the filter cake was lyophilized to give C2 (32.0 g, >99% yield) as a white solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 14.69 (s, 1H), 9.01 (s, 1H), 7.95 (s, 1H), 3.94 (s, 3H). Step 3. Preparation of methyl 5-bromo-1-cyclopropyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (P4) The mixture of C2 (1.00 g, 4.73 mmol), cyclopropylboronic acid (1.22 g, 14.2 mmol), copper(II) acetate (Cu(OAc)2) (0.901 g, 4.96 mmol), 2,2’-bipyridyl (0.775 g, 4.96 mmol) and sodium carbonate (Na2CO3) (1.10 g, 10.4 mmol) in dichloroethane (DCE) (30 mL) was stirred at 75 °C under oxygen for 32 hours. The green-blue reaction mixture was filtered. The filtrate was concentrated in vacuo then the residue was purified by column chromatography (silica, petroleum ether: EtOAc, 0-100% EtOAc) to provide P4 (0.650 g, 54.7% yield) as an off-white solid. (LC / MS) m / z (M+H)+= 252.0.1H NMR (400 MHz, CDCl3) δ 8.95 (d, 1H), 8.08 (d, 1H), 4.04 (s, 3H), 3.86-3.77 (m, 1H), 1.41-1.24 (m, 4H). Preparation P5 5-Bromo-1-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (P5) Step 1. Preparation of methyl 5-bromo-1-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (P5) A mixture of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (CAS: 916325- 84-3, 1.74 g, 6.79 mmol), cyclopropylboronic acid (1.75 g, 20.4 mmol), Cu(OAc)2(1.30 g, 7.14 mmol), 2,2’-bipyridyl (1.11 g, 7.14 mmol), and Na2CO3 (1.58 g, 14.9 mmol) in DCE (40 mL) was heated to 70 °C under oxygen for 16 hours. The green-blue reaction mixture was filtered. The filtrate was concentrated in vacuo and then the residue was purified by column chromatography (silica, EtOAc: petroleum ether, 0-100% EtOAc) to provide an impure P5 (1.30 g) as a light brown solid. The solid was repurified by column chromatography (silica, EtOAc: petroleum ether, 0-100% EtOAc) to provide P5 (0.650 g, 32.3% yield) as an off-white solid. (LC / MS) m / z (M+2H)+= 298.0.1H NMR (400 MHz, (CD3)2SO) δ 8.81 (d, 1H), 8.63 (d, 1H), 4.18-4.10 (m, 1H), 3.97 (s, 3H), 1.33-1.19 (m, 4H). Preparation P6 Methyl 5-bromo-1-cyclopropyl-7-fluoro-1H-indazole-3-carboxylate (P6) Step 1. Preparation of methyl 5-bromo-7-fluoro-1H-indazole-3-carboxylate (C3) To a mixture of 5-bromo-7-fluoro-1H-indazole-3-carboxylic acid (CAS: 1360953-31-6, 0.540 g, 2.08 mmol) in MeOH (10 mL) was added thionyl chloride (SOCl2) (372 mg, 3.13 mmol) dropwise. The reaction mixture was heated to 60 °C for 16 hours then concentrated in vacuo to provide C3 (536 mg, 94.6% yield) as a yellow solid. The solid was used directly into the next step without further purification. Step 2. Preparation of methyl 5-bromo-1-cyclopropyl-7-fluoro-1H-indazole-3-carboxylate (P6) A mixture of C3 (0.536 g, 1.96 mmol), cyclopropylboronic acid (506 mg, 5.89 mmol),Cu(OAc)2 (374 mg, 2.06 mmol), 2,2’-bipyridyl (322 mg, 2.06 mmol), and Na2CO3 (458 mg, 4.32mmol) in DCE (20 mL) was heated to 75 °C under oxygen for 16 hours. The green-blue reaction mixture was filtered. The filtrate was concentrated in vacuo then the residue was purified by column chromatography (silica, EtOAc: petroleum ether, 0-11% EtOAc) to provide P6 (415 mg, 67.5% yield) as a white solid.1H NMR (400 MHz, (CD3)2SO) δ 8.08 (d, 1H), 7.70 (dd, 1H), 4.19- 4.09 (m, 1H), 3.97 (s, 3H), 1.34-1.16 (m, 4H). Preparation P7 and P8 Ethyl 7-bromo-3-isopropylimidazo[1,5-a]pyridine-1-carboxylate (P7) and ethyl 7-chloro-3- isopropylimidazo[1,5-a]pyridine-1-carboxylate (P8) Step 1. Preparation of ethyl 2-amino-2-(4-bromopyridin-2-yl)acetate (C4) To a solution of ethyl (Z)-2-(4-bromopyridin-2-yl)-2-(hydroxyimino)acetate (CAS: 2768546-00-3, 5.60 g, 21.6 mmol), which was prepared by a known literature procedure, in AcOH (30 mL) was added zinc (Zn) (3.40 g, 52.0 mmol) at 0 °C for 10 minutes. The yellow reaction mixture was stirred at room temperature for 16 hours then filtered. The filter cake was washed with EtOAc (20 mL) then with 1M HCl. The organic phase was concentrated in vacuo to provide C4 (5.31 g, > 99% yield) as a brown gum. The gum was used directly in the next step without further purification. Step 2. Preparation of ethyl 2-(4-bromopyridin-2-yl)-2-isobutyramidoacetate (C5) At 0 °C, to a solution of C4 (0.500 g, 1.93 mmol) in DCM (30 mL) was added sodium bicarbonate (NaHCO3) (0.811 g, 9.65 mmol) and then isobutyryl chloride (247 mg, 2.32 mmol). The reaction mixture was stirred at 0 °C for 15 minutes then warmed to room temperature and stirred for 2 hours. The reaction mixture was extracted with DCM (50 mL x 3). The combined organic layer was washed with water (50 mL) then brine (50 mL), dried over sodium sulfate (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc: petroleum ether, 0-18% EtOAc) to provide C5 (334 mg, 52.6% yield) as a yellow solid. (LC / MS) m / z (M)+= 329.0. Step 3. Preparation of ethyl 7-bromo-3-isopropylimidazo[1,5-a]pyridine-1-carboxylate (P7) and ethyl 7-chloro-3-isopropylimidazo[1,5-a]pyridine-1-carboxylate (P8) The brown solution of C5 ( 2.06 g, 6.26 mmol) in phosphorus oxychloride (POCl3) (15 mL) was heated to 90 °C and stirred for 16 hours. According to LCMS, the reaction contained 13% conversion to P7 (LC / MS) m / z (M+2H)+= 313.1 and 82% conversion to P8 (LC / MS) m / z (M+H)+= 267.1. The mixture was concentrated in vacuo then diluted with DCM (50 mL). The solution was washed with saturated aqueous NaHCO3, dried over magnesium sulfate (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase high- performance liquid chromatography (HPLC) (C18150 millimeter (mm) x 40 mm x 5 micrometer (µm), water (0.05% ammonium hydroxide (NH4OH)-ammonium bicarbonate (NH4HCO3) / MeCN)), 25 to 65% MeCN over 9 minutes, then hold at 100% MeCN for 2 minutes, flow rate= 60 milliliter per minute (mL / min)) then lyophilized to provide P8 (1.10 g, 65.9% yield) as a white solid. (LC / MS) m / z (M+H)+= 267.1.1H NMR (400 MHz, (CDCl3) δ 8.16 (s, 1H), 7.83 (d, 1H), 6.72 (d, 1H), 4.46 (q, 2H), 3.39-3.21 (m, 1H), 1.50-1.40 (m, 9H). Preparation P9 3-(4-(Aminomethyl)phenyl)-1,1-dimethylurea hydrochloride (P9) Step 1. Preparation of tert-butyl (4-(3,3-dimethylureido)benzyl)carbamate (C6) At 0 °C under nitrogen, to a solution of tert-butyl (4-aminobenzyl)carbamate (CAS:94838-55-8, 15.0 g, 67.5 mmol) in DCM (150 mL), TEA (20.5 g, 202 mmol) and 4- dimethylaminopyridine (DMAP) (0.824 g, 6.75 mmol) was added dimethylcarbamic chloride (14.5 g, 135 mmol) dropwise. The mixture was heated to 50 °C and stirred for 16 hours. The reaction mixture was diluted with MeOH (150 mL) then concentrated in vacuo. The residue was suspended in water (120 mL) then rapidly stirred at room temperature for 1 hour. The mixture was filtered then the filter cake was collected and triturated with (5 mL: 25 mL: 250 mL) MeOH: EtOAc: TBME at room temperature for 1 hour. The mixture was filtered, and the filter cake was concentrated in vacuo to provide C6 (14.6 g, 73.8% yield) as a white solid. (LC / MS) m / z (M+H)+= 294.1.1H NMR (400 MHz, (CD3)2SO) δ 8.21 (s, 1H), 7.37 (d, 2H), 7.30 (t, 1H), 7.08 (d, 2H), 4.03 (d, 2H), 2.91 (s, 6H), 1.39 (s, 9H) Step 2. Preparation of 3-(4-(aminomethyl)phenyl)-1,1-dimethylurea hydrochloride (P9) To a stirred solution of C6 (1.00 g, 3.07 mmol) in DCM (10 mL) was added 2M HCl in 1,4-dioxane (20 mL). The reaction mixture was stirred at room temperature for 1 hour then concentrated in vacuo to provide P9 (0.700 g, >99% yield) as a yellow solid. The solid was used directly in the next step without additional purification.1H NMR (400 MHz, (CD3)2SO) δ 8.41 (s, 1H), 8.32 (br s, 2H), 7.53-7.47 (m, 2H), 7.34-7.30 (m, 2H), 3.91 (q, 2H), 2.92 (s, 6H). Preparation P10 2-Chloro-5-(1-methyl-1H-imidazol-2-yl)pyridine (P10) MeOH, NaOCH o30 C- room temperature MeI N 2,2-dimethoxyethanamine DME, KOH AcOH, 50oC room Cl HCl, 80oC P10Step 1. Preparation of 2-chloro-5-(1H-imidazol-2-yl)pyridine (C7) At 0 °C, to a solution of 2-chloro-5-ethynylpyridine (CAS: 263012-63-1, 94.0 g, 680. mmol) in MeOH (1.5 L) was added NaOCH3(5.50 g, 102 mmol). The reaction was stirred at room temperature for 1 hour before 2,2-dimethoxyethanamine (71.3 g, 678 mmol) and AcOH(81.5 g, 1.36 mol) were added. The reaction was stirred at 50°C for 1 hour then cooled to roomtemperature before 6M HCl (74.2 g, 2.04 mol) was added. The reaction was stirred at 80 °C for 5 hours then concentrated in vacuo. The residue was extracted with EtOAc (500 mL x 2). The aqueous layer was adjusted to pH=10 with saturated aqueous Na2CO3solution. White solid precipitated out of solution which was filtered then washed with water (100 mL x 3). The filter cake was lyophilized to provide C7 (88.0 g, 72.2% yield) as a white solid. The solid was used directly in the next step without additional purification. (LC / MS) m / z (M+H)+= 180.0.1H NMR (400 MHz, (CD3)2SO) δ 12.77 (br s, 1H), 8.94 (d, 1H), 8.31 (dd, 1H), 7.62 (d, 1H), 7.22 (s, 2H). Step 2. Preparation of 2-chloro-5-(1-methyl-1H-imidazol-2-yl)pyridine (P10) To a solution of C7 (44.0 g, 204 mmol) in DME (440 mL) was added potassium hydroxide (KOH) (24.0 g, 428 mmol) at room temperature then stirred for 1 hour and 40 minutes. The reaction mixture was cooled to 0 °C before MeI (57.8 g, 407 mmol) was added then stirred at 0 °C for 1 hour. The white suspension was filtrated then concentrated in vacuo. The residue was washed with water (300 mL) and stirred for 30 minutes. The mixture was filtered, and the filter cake was concentrated in vacuo to provide P10 (34.8 g, 88.8% yield) as a white solid. The solid was used directly in the next step without additional purification. (LC / MS) m / z (M+H)+= 194.0.1H NMR (400 MHz, (CD3)2SO) δ 8.79-8.76 (m, 1H), 8.20 (dd, 1H), 7.68- 7.64 (m, 1H), 7.37 (d, 1H), 7.08 (d, 1H), 3.83 (s, 3H). Preparation P11 2-(4-Chlorophenyl)-1,5-dimethyl-1H-imidazole (P11) Step 1. Preparation of 2-(4-chlorophenyl)-1,5-dimethyl-1H-imidazole (P11) A mixture of 2-bromo-1,5-dimethyl-1H-imidazole (CAS: 235426-31-0, 1.00 g, 5.71 mmol), (4-chlorophenyl)boronic acid (CAS: 1679-18-1, 1.34 g, 8.57 mmol), potassium carbonate (K2CO3) (2.37 g, 17.1 mmol) and [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2-DCM) (233 mg, 286 mmol) in (4:1) 1,4-dioxane (15 mL) and water (3.8 mL) was purged with nitrogen for 5 minutes. The reaction mixture was heated to 90 °C and stirred for 3 hours then cooled to room temperature. The mixture was diluted with EtOAc (50 mL) then washed with brine (15 mL). The organic layer was dried with Na2SO4, filtered then concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc: heptane, 0-100% EtOAc) to provide P11 (0.550 g, 46.6% yield) as a yellow-orange solid. (LC / MS) m / z (M+H)+= 207.2.1H NMR (600 MHz, (CD3)2SO) δ 7.66 (dt, 2H), 7.54 (dt, 2H), 6.79-6.77 (m, 1H), 3.59 (s, 3H), 2.23 (d, 3H). Preparation P12 2-(4-Chlorophenyl)-1,4-dimethyl-1H-imidazole (P12) Step 1. Preparation of 2-(4-chlorophenyl)-1,4-dimethyl-1H-imidazole (P12) The same procedure was followed from Preparation P11, step 1 with 2-bromo-1,4- dimethyl-1H-imidazole (CAS: 235426-30-9, 1.00 g, 5.71 mmol) to provide P12 (0.785 g, 66.5% yield) as an orange oil. (LC / MS) m / z (M+H)+= 207.2.1H NMR (600 MHz, (CD3)2SO) δ 7.71-7.65 (m, 2H), 7.52-7.48 (m, 2H), 6.95 (s, 1H), 3.68 (s, 3H), 2.12-2.10 (m, 3H). Preparation P13 6-Chloro-2-methyl-3-(1-methyl-1H-imidazol-2-yl)pyridine (P13) 1,4-dioxane, water, 90oCP13 Step 1. Preparation of 6-chloro-2-methyl-3-(1-methyl-1H-imidazol-2-yl)pyridine (P13) The same procedure was followed from Preparation P11, step 1 with 2-bromo-1- methyl-1H-imidazole (CAS: 16681-59-7, 705 mg, 4.38 mmol) and (6-chloro-2-methylpyridin-3- yl)boronic acid (CAS: 913836-15-4, 0.500 g, 2.92 mmol) to provide crude P13 (236 mg) as a green gum. The crude gum was used directly in the next step without additional purification. (LC / MS) m / z (M+H)+= 208.1. Preparation P14 1-(6-Chloropyridin-3-yl)-3-methylimidazolidin-2-one (P14) room temperature- 110 oCStep 1. Preparation of 1-(6-chloropyridin-3-yl)-3-methylimidazolidin-2-one (P14) A mixture of 1-methylimidazolidin-2-one (CAS: 694-32-6, 0.450 g, 4.49 mmol), 2-chloro- 5-iodopyridine (CAS: 69045-79-0, 1.13 g, 4.72 mmol) and copper(I) iodide (CuI) (89.9 mg, 0.472 mmol) in 1,4-dioxane (15 mL) was backfilled with nitrogen twice before 1,2- dimethylethylenediamine (DMEDA) (41.6 mg, 0.472 mmol) was added. The reaction mixture was heated to 85 °C and stirred for 2 hours then the temperature was increased to 110 °C and stirred for 20 hours. The reaction mixture was cooled to room temperature and stirred for ~72 hours. The temperature was increased to 110 °C and stirred for 2 hours then cooled to room temperature and stirred for an additional 24 hours. The mixture was filtered through Celite, rinsed with EtOAc and then the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc: heptane, 30-100% EtOAc) then concentrated in vacuo to provide P14 (121 mg, 12.7% yield) as a solid. (LC / MS) m / z (M+H)+= 212.2. Preparation P15 7-(Aminomethyl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride (P15) Step 1. Preparation of tert-butyl ((2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)methyl)carbamate (C8) The reaction was conducted in two batches then combined for purification. To a solution of 7-bromo-3,4-dihydroquinazolin-2(1H)-one (CAS: 1246765-38-7, 0.100 g, 0.440 mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (CAS: 1314538-55-0, 157 mg, 0.661 mmol) and Na2CO3(117 mg, 1.10 mmol) in (3:1) 1,4-dioxane (2.4 mL) and water (0.8 mL) was added mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2’-amino-1,1’- biphenyl)]palladium(II) (cataCXium®A Pd G3) (16.0 mg, 0.0220 mmol) at room temperature to form the first batch. The first batch was purged with nitrogen then heated to 90 °C and stirred for 6 hours. A second batch of the same reaction was conducted with 7-bromo-3,4- dihydroquinazolin-2(1H)-one (CAS: 1246765-38-7, 50.0 mg, 0.220 mmol). The batches were combined then filtered through Celite. The filter cake was washed with EtOAc (10 mL x 2) and collected to provide C8 (45.0 mg) as a white solid. Solid precipitated out in the filtrate which was concentrated in vacuo then diluted with EtOAc. The mixture was filtered then washed with EtOAc (5 mL x 2) to provide C8 (55.0 mg) as a yellow solid. The solids were combined to provide C8 (0.100 g, 54.7% yield) as a solid. The solid was used directly in the next step without additional purification. (LC / MS) m / z (M+H)+= 278.1. Step 2. Preparation of 7-(aminomethyl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride (P15) The same procedure was followed from Preparation P9, step 2 with C8 (45.0 mg, 0.162 mmol) to provide P15 (36.0 mg, >99% yield) as a light-yellow solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 9.12 (s, 1H), 8.21 (br s, 2H), 7.24-7.16 (m, 2H), 6.87 (br s, 1H), 6.78 (d, 1H), 4.30 (s, 2H), 3.88 (q, 2H). Preparation P16 (4-Bromophenyl)(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone (P16) 0oC- room temperature Step 1. Preparation of (4-bromophenyl)(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methanone (P16) At 0 °C under nitrogen, to a stirred solution of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (CAS: 147740-02-1, 0.200 g, 1.04 mmol) and 4-bromobenzoic acid (CAS: 586- 76-5, 0.208 g, 1.04 mmol) in DMF (5.0 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)- 1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU)(394 mg, 1.04 mmol) and N,N- diisopropylethylamine (DIPEA) (1.07 g, 8.29 mmol). The reaction was stirred at room temperature for 16 hours. The yellow mixture was diluted with DCM (15 mL) then washed with saturated NaHCO3(15 mL x 2) and brine (10 mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, MeOH: DCM, 0-10% MeOH) to provide P16 (0.390 g, >99% yield) as brown solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M)+= 303.0. Preparation P17 3-(5-(Aminomethyl)pyridin-2-yl)-1,1-dimethylurea hydrochloride (P17) Step 1. Preparation of tert-butyl ((6-(3,3-dimethylureido)pyridin-3-yl)methyl)carbamate (C9) The same procedure was followed from Preparation P9, step 1 with tert-butyl ((6- aminopyridin-3-yl)methyl)carbamate (CAS: 400720-77-6, 0.140 g, 0.627 mmol). The work-up and purification was altered. The reaction mixture was diluted with water (15 mL) and extracted with DCM (20 mL). The organic layer was concentrated in vacuo then the residue was purified by column chromatography (silica, EtOAc: petroleum ether, 0-60% EtOAc) to provide C9 (0.160 g, 37.9% yield) as a yellow gum. (LC / MS) m / z (M+H)+= 295.1. Step 2. Preparation of 3-(5-(aminomethyl)pyridin-2-yl)-1,1-dimethylurea hydrochloride (P17) The same procedure was followed from Preparation P9, step 2 with C9 (0.160 g, 0.544 mmol) to provide P17 (0.106 g, >99% yield) as a white solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 10.42 (br s, 1H), 8.56 (br s, 2H), 8.43-8.40 (m, 1H), 8.23 (d, 1H), 7.96 (d, 1H), 4.06 (q, 2H), 3.03 (s, 6H). Preparation P18 N-(4-(Aminomethyl)phenyl)-4-methylpiperazine-1-carboxamide hydrochloride (P18) Step 1. Preparation of tert-butyl (4-(4-methylpiperazine-1-carboxamido)benzyl)carbamate (C10) To a solution of phenyl (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamate (CAS: 1632297-04-1, 4.00 g, 11.7 mmol) in 1,4-dioxane (60 mL) was added 1-methylpiperazine (CAS: 109-01-3, 1.40 g, 14.0 mmol). The reaction mixture was heated to 90 °C and stirred for 1 hour. The mixture was dissolved in EtOAc (80 mL) then washed with 1M sodium hydroxide (NaOH) (40 mL x 2) and brine (40 mL). The organic phase was dried with Na2SO4then concentrated in vacuo. The residue was triturated with (1:10) EtOAc: petroleum ether (40mL) then filtered. The filter cake was collected to provide C10 (4.00 g, 98.3% yield) as a white solid. (LC / MS) m / z (M+H)+= 349.2.1H NMR (400 MHz, (CD3)2SO) δ 8.44 (s, 1H), 7.35 (d, 2H), 7.30 (t, 1H), 7.06 (d, 2H), 4.01 (d, 2H), 3.40 (t, 4H), 2.28 (t, 4H), 2.17 (s, 3H), 1.37 (s, 9H). Step 2. Preparation of N-(4-(aminomethyl)phenyl)-4-methylpiperazine-1-carboxamide hydrochloride (P18) The same procedure was followed from Preparation P9, step 2 with C10 (4.00 g, 11.5 mmol). An additional work-up was conducted with the crude residue. The residue was suspended in (10:1:1) THF: DCM: MeOH (20 mL) then stirred for 2 hours at room temperature. The mixture was filtered then the filter cake was collected and dried by high vacuum to provide P18 (3.50 g, 94.9% yield) as a pink solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 249.1.1H NMR (400 MHz, (CD3)2SO) δ 11.14 (br s, 1H), 9.04 (s, 1H), 8.31 (br s, 2H), 7.55-7.49 (m, 2H), 7.38-7.32 (m, 2H), 4.35-4.20 (m, 2H), 3.96- 3.88 (m, 2H), 3.46-3.37 (m, 2H), 3.29-3.22 (m, 2H), 3.00 (br s, 2H), 2.76 (s, 3H). Preparation P19 N,N-Dimethyl-6-(trimethylstannyl)nicotinamide (P19) Step 1. Preparation of N,N-dimethyl-6-(trimethylstannyl)nicotinamide (P19) Under nitrogen, a mixture of 6-chloro-N,N-dimethylnicotinamide (CAS: 54864-83-4, 1.00 g, 5.42 mmol), hexamethylditin (1.95 g, 5.96 mmol), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) (0.313 g, 0.271 mmol) in toluene (20 mL) was stirred at 80 °C for 16 hours then an additional 5 hours at 100 °C to provide P19 (1.70 g, >99% yield) as a solution. The solution was used directly in the next step. (LC / MS) m / z (M+H)+= 314.9. Preparation P20 and P21 Ethyl 2-(4-bromopyridin-2-yl)-2-propionamidoacetate (P20) and ethyl 7-bromo-3- ethylimidazo[1,5-a]pyridine-1-carboxylate (P21) Step 1. Preparation of ethyl 2-(4-bromopyridin-2-yl)-2-propionamidoacetate (P20) and ethyl 7- bromo-3-ethylimidazo[1,5-a]pyridine-1-carboxylate (P21) At 0 °C, to a solution of C4 (1.50 g, 5.79 mmol) in DCM (60 mL) was added NaHCO3(2.43 g, 28.9 mmol) then propionyl chloride (0.803 g, 8.68 mmol). The reaction mixture was stirred at 0 °C for 15 minutes then stirred at room temperature for 2.5 hours. According to LCMS, the reaction had 19% conversion to P20 (LC / MS) m / z (M)+= 315.2 and 57% conversion to P21 (LC / MS) m / z (M+2H)+ = 299.1 with 12% of C4 still remaining (LC / MS) m / z (M)+ = 259.1. The reaction mixture was extracted with DCM (100 mL x 3). The combined organic layer was washed with water (50 mL) then brine (50 mL), dried over sodium sulfate (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc: petroleum ether, 36% EtOAc) to provide P20 (0.573 g, 31.4% yield) as a brown gum. (LC / MS) m / z (M)+ = 315.1.1H NMR (400 MHz, (CDCl3)) δ 8.36 (d, 1H), 7.68 (d, 1H), 7.43 (dd, 1H), 7.10 (d, 1H), 5.63 (d, 1H), 4.28-4.12 (m, 2H), 2.44-2.23 (m, 2H), 1.20 (dt, 6H). An impure P21 was also isolated, and which was washed with EtOAc (5 mL) to provide P21 (0.290 g, 16.9% yield) as a white solid. (LC / MS) m / z (M)+= 297.1.1H NMR (400 MHz, (CDCl3)) δ 8.37 (dd, 1H), 7.72 (dd, 1H), 6.87-6.83 (m, 1H), 4.46 (q, 2H), 3.03 (q, 2H), 1.47-1.39 (m, 6H). P21 was used directly in the next step and P20 was discarded. Preparation P22 (S)-N-(4-(Aminomethyl)phenyl)-3-(dimethylamino)pyrrolidine-1-carboxamide hydrochloride Step 1. Preparation of tert-butyl (S)-(4-(3-(dimethylamino)pyrrolidine-1- carboxamido)benzyl)carbamate (C11) The same procedure was followed from Preparation P18, step 1 with phenyl (4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamate (CAS: 1632297-04-1, 0.500 g, 1.46 mmol) and (S)-N,N-dimethylpyrrolidin-3-amine (CAS: 132883-44-4, 0.200 g, 1.75 mmol) to provide C11 (0.410 g, 77.5% yield) as a red solid. (LC / MS) m / z (M+H)+= 363.2.1H NMR (400 MHz, (CD3)2SO) δ 8.06 (s, 1H), 7.40 (d, 2H), 7.28 (t, 1H), 7.07 (d, 2H), 4.02 (d, 2H), 3.65-3.49 (m, 2H), 3.31-3.22 (m, 1H), 3.06 (t, 1H), 2.70-2.50 (m, 1H), 2.16 (s, 6H), 2.08-1.97 (m, 1H), 1.75- 1.60 (m, 1H), 1.38 (s, 9H). Step 2. Preparation of (S)-N-(4-(aminomethyl)phenyl)-3-(dimethylamino)pyrrolidine-1- carboxamide hydrochloride (P22) The same procedure was followed from Preparation P9, step 2 with C11 (0.410 g, 1.13 mmol) to provide P22 (0.390 g, >99% yield) as a red solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 7.50-7.44 (m, 2H), 7.33- 7.29 (m, 2H), 3.92-3.89 (m, 2H), 3.88-3.80 (m, 2H), 3.67-3.32 (m, 3H), 2.79 (s, 6H), 2.41-2.31 (m, 1H), 2.16-2.03 (m, 1H). Preparation P23 N-(4-(Aminomethyl)phenyl)-3-(dimethylamino)azetidine-1-carboxamide hydrochloride (P23) Step 1. Preparation of tert-butyl (4-(3-(dimethylamino)azetidine-1- carboxamido)benzyl)carbamate (C12) The same procedure was followed from Preparation P18, step 1 with phenyl (4-(((tert- butoxycarbonyl)amino)methyl)phenyl)carbamate (CAS: 1632297-04-1, 0.500 g, 1.46 mmol) and 3-(dimethylamino)azetidine dihydrochloride (CAS: 124668-49-1, 0.303 g, 1.75 mmol) to provide C12 (0.450 g, 88.4% yield) as a white solid. (LC / MS) m / z (M+H)+= 349.2.1H NMR (400 MHz, (CD3)2SO) δ 8.35 (s, 1H), 7.42-7.34 (m, 2H), 7.28 (t, 1H), 7.07 (d, 2H), 4.02 (d, 2H), 3.92 (t, 2H), 3.70 (dd, 2H), 2.99 (tt, 1H), 2.06 (s, 6H), 1.37 (s, 9H). Step 2. Preparation of N-(4-(aminomethyl)phenyl)-3-(dimethylamino)azetidine-1-carboxamide hydrochloride (P23) The same procedure was followed from Preparation P9, step 2 with C12 (0.450 g, 1.29 mmol) to provide P23 (0.420 g, >99% yield) as a yellow solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 11.72 (s, 1H), 8.86 (s, 1H), 8.30 (br s, 3H), 7.53-7.48 (m, 2H), 7.33-7.28 (m, 2H), 4.21-4.09 (m, 4H), 4.08-3.99 (m, 1H), 3.87 (q, 2H), 2.67 (br s, 6H). Preparation P24 Methyl 5-bromo-7-chloro-1-ethyl-1H-indazole-3-carboxylate (P24) Step 1. Preparation of methyl 5-bromo-7-chloro-1H-indazole-3-carboxylate (C13) The following reaction was conducted in two batches and then combined for purification. To a solution of methyl 7-chloro-1H-indazole-3-carboxylate (CAS: 885278-56-8; 66.61 g, 316.26 mmol) in MeCN (1.4 L) was added NBS (N-bromosuccinimide) (141.0 g, 791.0 mmol) portion wise to form the first batch. The first batch was heated to 60 °C and stirred for 16 hours then filtered. The filter cake from the first batch was washed with EtOAc (50 mL) then dried. A second batch of the same reaction was conducted with methyl 7-chloro-1H-indazole- 3-carboxylate (CAS: 885278-56-8; 75.00 g, 356.10 mmol). The solids from both batches were combined then stirred in EtOAc (300 mL) and filtered. The filter cake was dried and collected to provide C13 (89.92 g, 46.19% yield) as a white solid. H NMR (400 MHz, (CD3)2SO) δ 14.71 (br s, 1H), 8.18 (d, 1H), 7.84-7.80 (m, 1H), 3.96 (s, 3H). Step 2. Preparation of 5-bromo-7-chloro-1H-indazole-3-carboxylic acid (C14) To a solution of C13 (89.9 g, 311 mmol) in THF (350 mL), water (300 mL), and MeOH (300 mL) was added NaOH (33.1 g, 826 mmol) dropwise at room temperature. After the addition, the reaction mixture was heated to 50 °C and stirred for 16 hours then concentrated in vacuo. The reaction mixture was diluted with water (1000 mL), extracted with EtOAc (200 mL). Solid precipitated in the aqueous layer. The mixture was filtered, and the filter cake was lyophilized to provide C14 (85.6 g, >99% yield) as a white solid. The solid was used directly in the next step without additional purification.1H NMR (400 MHz, (CD3)2SO) δ 8.31 (d, 1H), 7.45 (d, 1H). Step 3. Preparation of 5-bromo-7-chloro-1-ethyl-1H-indazole-3-carboxylic acid (C15) At 0°C, to a stirred mixture of C14 (2.00 g, 7.26 mmol) in DMF (20 mL) was added 1M LiHMDS (3.64 g, 21.8 mmol) followed by MeI (6.20 g, 43.7 mmol) dropwise. The reaction mixture was stirred from 0 °C to room temperature for about 3.5 hours. The reaction mixture was quenched with water (100 mL) then EtOAc (100 mL) was added. The suspension was filtered, and the filter cake was collected to provide C15 (1.18 g, 52.3% yield) as a white solid.1H NMR (400 MHz, (CD3)2SO) δ 8.47 (d, 1H), 7.55 (d, 1H), 4.66 (q, 2H), 1.37 (t, 3H). Step 4. Preparation of methyl 5-bromo-7-chloro-1-ethyl-1H-indazole-3-carboxylate (P24) To a suspension of C15 (1.18 g, 3.80 mmol) in MeOH (10 mL) was added SOCl2(thionyl chloride) (678 mg, 5.70 mmol) dropwise. The reaction mixture was warmed to 60 °C and stirred for 16 hours then concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc: petroleum ether, 0-43% EtOAc) and then dried over under vacuo to provide P24 (0.890 g, 73.8% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.34 (d, 1H), 7.54 (d, 1H), 4.88 (q, 2H), 4.04 (s, 3H), 1.55 (t, 3H) Example 1 5-[5-(Dimethylcarbamoyl)pyridin-2-yl]-1-methyl-N-{[4-(methylcarbamoyl)phenyl]methyl}-1H- indazole-3-carboxamide (1) Step 1. Preparation of 5-bromo-1-methyl-N-(4-(methylcarbamoyl)benzyl)-1H-indazole-3- carboxamide (C16) To a solution of 5-bromo-1-methyl-1H-indazole-3-carboxylic acid (CAS: 1363380-96-4; 15.0 g, 58.8 mmol) in DMF (294.0 mL) was added 4-(aminomethyl)-N-methylbenzamide (CAS: 164648-64-0; 11.8 g, 58.8 mmol), HATU (23.4 g, 61.6 mmol), and DIPEA (34.1 g, 264 mmol). The reaction mixture was stirred at room temperature for about 18 hours. The reaction solution was quenched with ice water (300 mL) and the resulting white solid was filtered then washed with water (300 mL). The filter cake was lyophilized to provide C16 (21.2 g, 89.9% yield) as a white solid. Liquid chromatography mass spectrometry (LC / MS) m / z (M+H)+= 401.1.1H NMR (400 MHz, (CD3)2SO) δ 9.11 (t, 1H), 8.38 (br d, 1H), 8.31 (d, 1H), 7.78 (dd, 3H), 7.61 (dd, 1H), 7.40 (d, 2H), 4.52 (d, 2H), 4.15 (s, 3H), 2.77 (d, 3H). Step 2: Preparation of 1-methyl-N-(4-(methylcarbamoyl)benzyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazole-3-carboxamide (C17) To a solution of C16 (4.00 g, 9.97 mmol) in 1,4-dioxane (40.0 mL) was added bis(pinacolato)diboron (B2Pin2) (3.29 g, 13.0 mmol) and potassium acetate (KOAc) (1.96 g, 19.9 mmol). The reaction was purged with argon for a few minutes, then [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (0.73 g, 1.0 mmol) was added. The reaction mixture was heated at around 100 °C for about 16 hours. The solution was cooled to room temperature, filtered, and concentrated in vacuo to give the crude mixture. The residue was purified by chromatography (silica, EtOAc: petroleum ether, 0-100% EtOAc) to provide C17 (2.7 g, 60.4% yield) as a yellow solid. LC / MS m / z (M+H)+= 449.2.1H NMR (400 MHz, (CD3)2SO) δ 9.11-9.04 (m, 1H), 8.65-8.60 (m, 1H), 8.42-8.34 (m, 1H), 7.80 (d, 2H), 7.67- 7.75 (m, 2H), 7.39-7.46 (m, 2H), 4.54 (d, 2H), 4.17-4.11 (m, 3H), 2.78 (d, 3 H), 1.27-1.37 (m, 12H). Step 3: Preparation of 5-[5-(dimethylcarbamoyl)pyridine-2-yl]-1-methyl-N-{[4- (methylcarbamoyl)phenyl]methyl}-1H-indazole-3-carboxamide (1) To a mixture of C17 (566 mg, 1.26 mmol), 6-chloro-N,N-dimethylnicotinamide (CAS: 54864-83-4; 0.270 g, 1.46 mmol) and tribasic potassium phosphate (K3PO4) (858 mg, 4.04 mmol) was added tert-amyl alcohol (5.4 mL) and water (1.1 mL). The reaction mixture was purged with nitrogen for a few minutes, then cataCXium A Pd G3 (85 mg, 0.12 mmol) was added. The reaction was heated at around 90 °C for about 16 hours. The reaction mixture was cooled to room temperature and diluted with 20% MeOH in EtOAc (200 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (silica, MeOH: DCM, 0-20% MeOH) to provide 1 (346 mg, 58.4% yield) as a white solid. LC / MS m / z (M+H)+= 471.4.1H NMR (600 MHz, (CD3)2SO) δ 9.10 (t, 1H), 8.94 (d, 1H), 8.73 (d, 1H), 8.38 (d, 1H), 8.26 (dd, 1H), 8.08 (d, 1H), 7.95 (dd, 1H), 7.87 (d, 1H), 7.79 (d, 2H), 7.43 (d, 2H), 4.56 (d, 2H), 4.19 (s, 3H), 3.02 (d, 6H), 2.77 (d, 3H). Example 2 1-Methyl-N-(4-(methylcarbamoyl)benzyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)-1H-indazole-3- carboxamide (2) Step 1. Preparation of 1-methyl-N-(4-(methylcarbamoyl)benzyl)-5-(4-(2-oxopyrrolidin-1- yl)phenyl)-1H-indazole-3-carboxamide (2) To a mixture of C16 (0.070 g, 0.17 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)pyrrolidin-2-one (CAS: 1003309-09-8, 0.050 g, 0.17 mmol) and K3PO4(92 mg, 0.44 mmol) was added 1,4-dioxane (1.0 mL) and water (0.25 mL). The reaction mixture was purged with nitrogen for a few minutes, then Pd(dppf)Cl2(13 mg, 0.017 mmol) was added. The reaction was heated at around 90 °C for about 16 hours, filtered through Celite or diatomaceous earth, and concentrated in vacuo. The residue was dissolved in dimethyl sulfoxide (DMSO) (1 mL) and purified by reverse phase HPLC (Boston Prime C18150 mm x 30 mm x 5 µm, water (0.05% NH4OH-NH4HCO3) / MeCN, 18 to 58% MeCN over 10 minutes, 100% MeCN hold for 2.5 minutes, flow rate= 30 (mL / min)) and lyophilized to provide 2 (0.010 g, 12% yield) as a white solid. LC / MS m / z (M+H)+= 482.2.1H NMR (400 MHz, (CD3)2SO) δ 9.10-9.06 (m, 1H), 8.38 (s, 2H), 7.86-7.76 (m, 6H), 7.75 (m, 2H), 7.42 (d, 2H), 4.57-4.52 (m, 2H), 4.18 (s, 3H), 3.89 (t, 2H), 2.77 (d, 3H), 2.54 (d, 2H), 2.14-2.05 (m, 2H). Example 3 N-({4-[(Dimethylcarbamoyl)amino]phenyl}methyl)-5-[5-(dimethylcarbamoyl)pyridin-2-yl]-1- methyl-1H-indazole-3-carboxamide (3) Step 1. Preparation of methyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazole-3-carboxylate (C18) To a solution of methyl-5-bromo-1-methyl-1H-indazole-3-carboxylate (CAS: 1363381- 41-2; 26 g, 97 mmol) in 1,4-dioxane (310.0 mL) was added B2Pin2(29.7 g, 117 mmol) and KOAc (28.7 g, 293 mmol). The reaction was purged with nitrogen for a few minutes before Pd(dppf)Cl2(7.96 g, 9.75 mmol) was added. The reaction mixture was heated at around 90 °C for about 16 hours. The solution was cooled to room temperature, filtered, and concentrated in vacuo to give the crude mixture. The residue was purified by chromatography (silica, EtOAc: petroleum ether, 0-50% EtOAc) to provide C18 (56 g, 99% yield) as a yellow solid. LC / MS m / z (M+H)+= 317.3.1H NMR (400 MHz, (CD3)2SO) δ 8.47 (s, 1H), 7.81-7.77 (m, 1H), 7.76-7.72 (m, 1H), 4.17 (s, 3H), 3.96-3.93 (m, 3H), 1.37-1.31 (m, 12H). Step 2. Preparation of methyl-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-methyl-1H-indazole-3- carboxylate (C19) To a mixture of C18 (1.1 g, 3.4 mmol), 6-chloro-N,N-dimethylnicotinamide (CAS: 54864- 83-4; 0.600 g, 3.25 mmol), and K3PO4(1.72 g, 8.12 mmol) was added 1,4-dioxane (10.0 mL) and water (2.5 mL). The reaction mixture was purged with nitrogen for a few minutes, then Pd(dppf)Cl2(238 mg, 0.325 mmol) was added. The reaction was heated at around 90 °C for about 3 hours, filtered through Celite, and concentrated in vacuo. The residue was purified by chromatography (silica, MeOH: DCM, 0-10% MeOH) to provide C19 (1.1 g, 99% yield) as a yellow solid. LC / MS m / z (M+H)+= 339.1.1H NMR (400 MHz, (CD3)2SO) δ 8.83 (dd, 1H), 8.77 (dd, 1H), 8.30 (dd, 1H), 8.14 (dd, 1H), 7.96 (ddd, 2H), 4.22 (s, 3H), 3.98 (s, 3H), 3.07-2.99 (m, 6H). Step 3: Preparation of 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-methyl-1H-indazole-3-carboxylic acid (C20) To a solution of C19 (1.1 g, 3.2 mmol) in MeOH (5.0 mL) and THF (5.0 mL) was added lithium hydroxide monohydrate (LiOH) (0.27 g, 6.5 mmol) in water (2.5 mL) at 0 °C. The reaction was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, and the residue was diluted with water (10 mL), and the pH was adjusted to 4 to 5 with 1M HCl. The resulting suspension was filtered to collect the solids. The solids were dried to give a crude compound (0.59 g, 56% yield) as a gray solid. About (50 mg) of residue was dissolved in DMF (1.5 mL) and purified by reverse phase HPLC (Boston Prime C18150 mm x 30 mm x 5 µm, water (0.05% NH4OH-NH4HCO3) / MeCN, 0 to 23% over 10 minutes, 30 mL / min) and lyophilized to provide C20 (10 mg, 20% yield) as a white solid. LC / MS m / z (M+H)+= 325.2.1H NMR (400 MHz, (CD3)2SO) δ 8.95 (s, 1H), 8.73 (d, 1H), 8.20 (d, 1H), 8.06 (d, 1H), 7.94 (dd, 1H), 7.78 (d, 1H), 4.13 (s, 3H), 3.02 (br s, 6H). Step 4: Preparation of N-({4-[(dimethylcarbamoyl)amino]phenyl}methyl)-5-[5- (dimethylcarbamoyl)pyridin-2-yl]-1-methyl-1H-indazole-3-carboxamide (3) To a solution of C20 (0.10 g, 0.31 mmol) in DMF (2.0 mL) was added HATU (0.12 g, 0.32 mmol) and then DIPEA (139 mg, 1.08 mmol) and 3-(4-(aminomethyl)phenyl)-1,1- dimethylurea hydrochloride, P9, (CAS: 903556-27-4, 71 mg, 0.31 mmol) at 0 °C. The reaction mixture was stirred at around 20 °C for about 3 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (Boston Prime C18150 mm x 30 mm x 5 µm, water (0.05% NH4OH-NH4HCO3) / MeCN, 20 to 40% MeCN over 10 minutes, 100% MeCN hold for 2.5 minutes, flow rate= 30 mL / min) and lyophilized to provide 3 (45 mg, 29% yield) as a white solid. (LC / MS) m / z (M+H)+= 500.4.1H NMR (400 MHz, (CD3)2SO) δ 8.94-8.99 (m, 1H), 8.91 (t, 1H), 8.74 (d, 1H), 8.26 (dd, 1H), 8.24 (s, 1H), 8.09 (d, 1H), 7.95 (dd, 1H), 7.86 (d, 1H), 7.40 (m, 2H), 7.23 (m, 2H), 4.44 (br d, 2H), 4.18 (s, 3H), 2.96-3.09 (m, 6H), 2.91 (s, 6H). Example 4 5-(4-(Dimethylcarbamoyl)phenyl)-1-methyl-N-(4-(methylcarbamoyl)benzyl)-1H-indazole-3- carboxamide (4) Step 1. Preparation of 5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-1H-indazole-3-carboxylic acid (C21) To a mixture of 5-bromo-1-methyl-1H-indazole-3-carboxylic acid (CAS: 1363380-96-4, 14.5 g, 56.8 mmol), (4-(dimethylcarbamoyl)phenyl)boronic acid (CAS: 405520-68-5; 13.2 g, 68.2 mmol), and K3PO4(30.2 g, 142 mmol) was added 1,4-dioxane (200.0 mL) and water (50.0 mL). The reaction mixture was purged with nitrogen for a few minutes, then Pd(dppf)Cl2(4.16 g, 5.68 mmol) was added. The reaction was heated at around 90 °C for about 16 hours, filtered and concentrated in vacuo. The residue was washed with EtOAc (200 mL) and then the filtrate was discarded. The solid was diluted with water (200 mL) and then the pH of the aqueous phase was adjusted to 2-3 using 1M HCl. The acidic aqueous phase was extracted with EtOAc: THF (1:1, 100 mL x 6). The combined organic layer was filtered over Celite or diatomaceous earth and concentrated in vacuo. The residue was recrystallized using EtOAc: THF (1:1, 80 mL) to provide compound C21 (123 g, 67.1%) as a light pink solid. LC / MS m / z (M+H)+= 324.1.1H NMR (400MHz, (CD3)2SO) δ 8.34-8.28 (m, 1H), 7.92-7.82 (m, 2H), 7.82-7.73 (m, 2H), 7.56-7.50 (m, 2H), 4.22-4.15 (m, 3H), 3.05-2.93 (m, 6H). Step 2: 5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-N-(4-(methylcarbamoyl)benzyl)-1H-indazole- 3-carboxamide (4) To a stirred solution of C21 (0.030 g, 93 micromoles (μmol)),^4-(aminomethyl)-N- methylbenzamide (CAS: 164648-64-0; 18.3 mg, 111 μmol),^1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (28.5 mg, 148 μmol),^1-hydroxybenzotriazole-hydrate (HOBt) (21.3 mg, 139 μmol) in^DMF (0.464 mL) was added DIPEA (47.9 mg, 371 μmol). The reaction mixture was stirred at room temperature for 16 hours, then diluted with EtOAc (4.0 mL). The organic layer was washed sequentially with saturated aqueous NaHCO3(3 mL), water (2 mL), and brine (2 mL). The organic layer was concentrated, diluted with DMSO (0.9 mL) and purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% trifluoroacetic acid (TFA) / MeCN), 15 to 40% MeCN over 8.5 minutes, then hold at 95% MeCN for 1.5 minutes, flow rate= 25 mL / min) to provide 4 (0.010 g, 24% yield) as a white solid. LC / MS m / z (M+H)+= 470.4.1H NMR (600 MHz, (CD3)2SO) δ 9.07 (t,^1H), 8.43 (s, 1H), 8.38 (q,^1H), 7.85 (q, 2H), 7.77 (t,^4H), 7.52 (d,^2H), 7.42 (d,^2H), 4.55 (d,^2H), 4.18 (s, 3H), 3.05-2.94 (m, 6H), 2.77 (d,^3H). Example 5 7-(4-(Dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-3-methylimidazo[1,5- a]pyridine-1-carboxamide (5) Step 1. Preparation of methyl 7-(4-(dimethylcarbamoyl)phenyl)-3-methylimidazo[1,5-a]pyridine- 1-carboxylate (C22) To a suspension of methyl 7-bromo-3-methylimidazo[1,5-a]pyridine-1-carboxylate (CAS: 2091549-14-1; 0.468 g, 1.74 mmol) and (4-(dimethylcarbamoyl)phenyl)boronic acid (CAS: 405520-68-5; 0.437 g, 2.26 mmol) in water (3.0 mL) and THF (15.0 mL) was added Pd(dppf)Cl2(0.127 g, 0.174 mmol) and K3PO4(1.11 g, 5.22 mmol). The mixture was purged with nitrogen and stirred at 90 °C for 16 hours then extracted with DCM (50 mL x 3). The combined organic layers were washed with water (50 mL) then brine (50 mL), dried over Na2SO4and concentrated in vacuo to give a residue. The residue was purified by chromatography (silica; MeOH: EtOAc at 4:96) to provide C22 (0.425 g, 72.3% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 338.3.1H NMR (400 MHz, CD3OD) δ 8.35-8.26 (m, 2H), 7.89-7.83 (m, 2H), 7.58 (d, 2H), 7.34-7.29 (m, 1H), 3.96 (s, 3H), 3.10 (d, 6H), 2.72-2.70 (m, 3H). Step 2. Preparation of 7-(4-(dimethylcarbamoyl)phenyl)-3-methylimidazo[1,5-a]pyridine-1- carboxylic acid hydrochloride (C23) To a solution of C22 (0.110 g, 0.326 mmol) in THF (5.0 mL), MeOH (0.5 mL) and water (1.0 mL) was added LiOH (41.0 mg, 0.978 mmol) at room temperature then stirred at 40 °C for 16 hours. The reaction mixture was acidified with aqueous 2M HCl until pH = 5-6 and then concentrated in vacuo to provide C23 (107 mg, >95% yield) as a yellow solid. This was used in the next step without further purification. Step 3. Preparation of 7-(4-(dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-3- methylimidazo[1,5-a]pyridine-1-carboxamide (5) To a solution of C23 (0.100 g, 0.309 mmol) in DMSO (3.0 mL) was added 2-pyridinol 1- oxide (HOPO) (101 mg, 0.912 mmol), EDCI (142 mg, 0.742 mmol), DIPEA (160 mg, 1.24 mmol). The reaction was stirred at room temperature for 5 minutes then 3-(4- (aminomethyl)phenyl)-1,1-dimethylurea hydrochloride, P9, (CAS: 903556-27-4, 89.6 mg, 0.464 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours then purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm, water (NH4OH-NH4HCO3) / MeCN, 10 to 50% MeCN over 9 minutes, 100% MeCN hold for 2 minutes, flow rate= 30 mL / min) and lyophilized to provide 5 (72.5 mg, 47.1% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 499.4.1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 8.17 (d, 1H), 7.87-7.82 (m, 2H), 7.58-7.54 (m, 2H), 7.37-7.28 (m, 4H), 7.22 (dd, 1H), 4.57 (s, 2H), 3.09 (d, 6H), 3.00 (s, 6H), 2.67 (s, 3H). Example 6 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-N-(4-(4-methylpiperazine-1-carboxamido)benzyl)- 1H-indazole-3-carboxamide (6) Step 1: Preparation of 5-bromo-1-ethyl-1H-indazole-3-carboxylic acid sodium salt (C24) To a solution of NaH (10.4 g, 259 mmol) in DMF (305.0 mL) was added 5-bromo-1H- indazole-3-carboxylic acid (CAS: 1077-94-7; 25.0 g, 104 mmol) at 0 °C then stirred at 0 °C for 30 minutes. Ethyl iodide (EtI) (21.0 g, 135 mmol) was added at 0 °C then the reaction mixture was warmed to 15 °C and stirred for 5 hours. The mixture was cooled down with an ice water bath and quenched with ice water (300 mL) dropwise. After the addition, the quenched reaction was stirred at 10 °C for 30 minutes then filtered. The filter cake was washed with water (100 mL x 2) then the solid was collected and dried further to provide C24 (28.0 g, 92.4% yield) as a gray solid. This was used in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 8.42 (d, 1H), 7.58 (d, 1H), 7.41 (dd, 1H), 4.40 (q, 2H), 1.35 (t, 3H). Step 2: Preparation of ethyl 5-bromo-1-ethyl-1H-indazole-3-carboxylate (C25) To a mixture of C24 (5.00 g, 17.1 mmol) in ethanol (EtOH) (50.0 mL) was added concentrated sulfuric acid (1.0 mL) then heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated in vacuo then diluted with saturated NaHCO3(100 mL) and stirred for 5 minutes at room temperature. The reaction was extracted with EtOAc (100 mL x 3) then the combined organic layer was washed with brine, dried over Na2SO4and filtered. The filtrate was concentrated in vacuo to provide C25 (4.70 g, 92.4% yield) as a yellow solid. This was used in the next step without further purification. Step 3: Preparation of ethyl 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole- 3-carboxylate (C26) A mixture of C25 (9.30 g, 31.3 mmol), B2Pin2(11.9 g, 46.9 mmol), KOAc (7.68 g, 78.2 mmol) and Pd(dppf)Cl2(2.29 g, 3.13 mmol) in 1,4-dioxane (200.0 mL) was purged with nitrogen 3 times then heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated in vacuo then the residue was purified by chromatography (silica; EtOAc: petroleum ether, 0-15% EtOAc) to provide C26 (8.00 g, 74.3% yield) as an off-white solid. (LC / MS) m / z (M+H)+= 344.9.1H NMR (400 MHz, (CDCl3) δ 8.75-8.73 (m, 1H), 7.84 (dd, 1H), 7.44 (dd, 1H), 4.57-4.50 (m, 4H), 1.54 (t, 3H), 1.49 (t, 3H), 1.37 (s, 12H). Step 4: Preparation of ethyl 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-1H-indazole-3- carboxylate (C27) To a stirred solution of C26 (5.50 g, 16.0 mmol) and 6-chloro-N,N-dimethylnicotinamide (CAS: 54864-83-4; 2.95 g, 16.0 mmol) in THF (160.0 mL) was added 2M K3PO4(6.78 g, 32.0 mmol). The reaction was degassed with nitrogen for 3 minutes, then chloro(2- dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) (XPhos Pd G2) (1.26 g, 1.60 mmol) was added. The reaction mixture was degassed again with nitrogen for 3 minutes, then heated to 80 °C for 13 hours. The mixture was diluted with water (200 mL) then extracted with EtOAc (100 mL x 3). The combined organic layers were dried with Na2SO4,filtered and concentrated in vacuo. The residue was purified by chromatography (silica; EtOAc: petroleum ether, 0-100% EtOAc) to provide C27 (4.70 g, 80.3% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 367.1.1H NMR (400 MHz, (CD3)2SO) δ 8.85-8.83 (m, 1H), 8.77-8.75 (m, 1H), 8.28 (dd, 1H), 8.11 (d, 1H), 8.00-7.95 (m, 2H), 4.61 (q, 2H), 4.44 (q, 2H), 3.03 (d, 6H), 1.48 (t, 3H), 1.41 (t, 3H). Step 5: Preparation of 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-1H-indazole-3-carboxylic acid hydrochloride (C28) The reaction was conducted in two batches then combined for purification. To a mixture of C27 (0.500 g, 1.36 mmol) in MeCN (5.0 mL) was added potassium trimethylsilanolate (KOTMS) (315 mg, 2.46 mmol) at room temperature then stirred for 2 hours to form the first batch. A second batch of the same reaction was conducted with C27 (50.0 mg, 0.136 mmol). The batches were combined then acidified with 0.2M HCl in 1,4-dioxane (1.0 mL) to pH=5~6.The reaction mixture was concentrated in vacuo to provide C28 (0.720 g, >95% yield) as a white solid. This was used in the next step without further purification. (LC / MS) m / z (M+H)+= 339.1.1H NMR (400 MHz, (CD3)2SO) δ 8.98 (s, 1H), 8.71 (d, 1H), 8.14 (dd, 1H), 8.02 (d, 1H), 7.92 (dd, 1H), 7.75 (d, 1H), 4.47 (q, 2H), 3.01 (s, 6H), 1.43 (t, 3H). Step 6: Preparation of 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-N-(4-(4-methylpiperazine-1- carboxamido)benzyl)-1H-indazole-3-carboxamide (6) To a stirred solution of C28 (0.470 g, 0.889 mmol) and P18 (285 mg, 0.887 mmol) in DMF (4.4 mL) under nitrogen was added HATU (355 mg, 0.933 mmol) and DIPEA (517 mg, 4.00 mmol) at 0 °C. The reaction was warmed to room temperature then stirred for 1 hour. The solution was purified by reverse phase HPLC (Welch Xtimate C18150 mm x 25 mm x 5 µm, water (NH4OH-NH4HCO3) / MeCN, 25 to 45% MeCN over 11 minutes, 100% MeCN hold for 2 minutes, flow rate= 60 mL / min) and lyophilized to provide 6 (0.330 g, 65.4% yield) as a white solid. (LC / MS) m / z (M+H)+= 569.4.1H NMR (400 MHz, (CD3)2SO) δ 8.98-8.95 (m, 1H), 8.88 (t, 1H), 8.75-8.72 (m, 1H), 8.47 (s, 1H), 8.25 (dd, 1H), 8.10-8.06 (m, 1H), 7.95 (dd, 1H), 7.92-7.88 (m, 1H), 7.42-7.38 (m, 2H), 7.24 (d, 2H), 4.57 (q, 2H), 4.44 (d, 2H), 3.42 (t, 4H), 3.05-3.00 (m, 6H), 2.30 (t, 4H), 2.19 (s, 3H), 1.49 (t, 3H). Example 7 5-(4-(Dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1H-indazole-3- carboxamide (7) Step 1. Preparation of 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1- methyl-1H-indazole-3-carboxamide (7) To a stirred solution of C21 (1.50 g, 4.64 mmol) in DMF (23 mL) was added HATU (1.85 g, 4.87 mmol). The reaction mixture was stirred at 0oC for 15 minutes. To the suspension was added 3-(4-(aminomethyl)phenyl)-1,1-dimethylurea hydrochloride, P9, (CAS: 903556-27-4, 1.07 g, 4.64 mmol) and DIPEA (2.10 g, 16.2 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours then poured into ice-water (30 mL) slowly which caused precipitate to form. The suspension was filtered. The filter cake was collected and lyophilized to provide a yellow solid. The solid was suspended in EtOH (25 mL) and heated to 80oC then cooled to 50oC and stirred at 50oC for 1 hour. The suspension was slowly cooled to room temperature then stirred at room temperature overnight and filtered. The filter cake was rinsed with the filtrate then rinsed with cold EtOH. The filter cake was collected to provide 7 (1.60 g, 69.2% yield) as a white solid. LC / MS m / z (M+H)+= 499.3.1H NMR (400 MHz, (CD3)2SO) δ 8.88 (t, 1H), 8.45 – 8.43 (m, 1H), 8.23 (s, 1H), 7.88 – 7.80 (m, 2H), 7.77 (d, 2H), 7.54 – 7.49 (m, 2H), 7.42 – 7.37 (m, 2H), 7.24 – 7.19 (m, 2H), 4.42 (d, 2H), 4.16 (s, 3H), 3.03 – 2.95 (m, 6H), 2.90 (s, 6H). Example 10 N-(4-(3,3-Dimethylureido)benzyl)-1-methyl-5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-1H- indazole-3-carboxamide (10) Step 1. Preparation of 5-bromo-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1H-indazole-3- carboxamide (D1) To a solution of 5-bromo-1-methyl-1H-indazole-3-carboxylic acid (CAS: 1363380-96-4, 5.00 g, 19.6 mmol) in DMF (50 mL) was added HATU (7.83 g, 20.6 mmol). The reaction mixture was stirred at 0oC for 15 minutes. To the suspension was added 3-(4-(aminomethyl)phenyl)- 1,1-dimethylurea hydrochloride, P9, (CAS: 903556-27-4, 4.50 g, 19.6 mmol) and DIPEA (8.87 g, 68.6 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours then poured into ice-water (100 mL) slowly which caused precipitate to form. The suspension was filtered. The filter cake was collected and lyophilized to provide D1 (7.82 g, 92.7% yield) as a light-yellow solid. The solid was used directly in the next step without further purification. LC / MS m / z (M+2H)+= 432.0.1H NMR (400 MHz, (CD3)2SO) δ 8.89 (t, 1H), 8.32 (d, 1H), 8.22 (s, 1H), 7.73 (d, 1H), 7.58 (dd, 1H), 7.42 – 7.37 (m, 2H), 7.23 – 7.18 (m, 2H), 4.41 (d, 2H), 4.12 (s, 3H), 2.90 (s, 6H). Step 2. Preparation of N-(4-(3,3-dimethylureido)benzyl)-1-methyl-5-(4-(1-methyl-1H-imidazol-2- yl)phenyl)-1H-indazole-3-carboxamide (10) The same reaction was conducted in two batches then combined for further purification. To a solution of D1 (1.50 g, 3.49 mmol) and 1-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-1H-imidazole (CAS: 1394374-23-2, 1.39 g, 4.88 mmol) in 1,4-dioxane (15.0 mL) and water (3.7 mL) was added K3PO4(1.85 g, 8.71 mmol). The reaction mixture was degassed with nitrogen for 3 minutes then Pd(dppf)Cl2(255 mg, 0.349 mmol) was added to form the first batch. The reaction mixture of the first batch was degassed with nitrogen for 3 minutes then was stirred at 80 °C for about 2 hours. The suspension was filtered through Celite or diatomaceous earth and concentrated in vacuo. The black gum was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 µm, water / MeCN, (0.05% NH4OH-NH4HCO3), 18 to 58% MeCN over 9 minutes, 100% MeCN for 2 minutes, flow rate= 60 (mL / min)) and lyophilized to provide a yellow solid. The second batch of the same reaction was conducted with D1 (1.00 g, 2.32 mmol). The two batches were combined then diluted with MeOH: DCM (1:10, 30 mL). To the solution was added silica shells-SH (1.3 g) then stirred at 50°C for 30 minutes and concentrated in vacuo to give a yellow solid. The solid was suspended in EtOH (12 mL). The mixture was heated to 80oC then cooled to 50oC and stirred at 50oC for 1 hour. The suspension was cooled to room temperature slowly and stirred overnight. The mixture was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 µm, water / MeCN, (0.05% NH4OH-NH4HCO3), 18 to 58% MeCN over 9 minutes, 100% MeCN for 2 minutes, flow rate= 60 (mL / min)) and lyophilized. The suspension was filtered, and the filter cake was washed with the filtrate then EtOH. The filter cake was dried with a flow of nitrogen over top then collected to provide 10 (0.760 g, 25.8% yield) as a white solid. LC / MS m / z (M+H)+= 508.5.1H NMR (400 MHz, (CD3)2SO) δ 8.89 (t, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 7.88 – 7.77 (m, 6H), 7.41 (d, 2H), 7.28 (s, 1H), 7.23 (d, 2H), 7.01 (s, 1H), 4.44 (d, 2H), 4.16 (s, 3H), 3.81 (s, 3H), 2.90 (s, 6H). Example 15 1-Methyl-5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-N-(4-(methylcarbamoyl)benzyl)-1H-indazole- Step 1. Preparation of 1-methyl-5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-N-(4- (methylcarbamoyl)benzyl)-1H-indazole-3-carboxamide (15) 00804066-0088-001 A mixture of C16 (0.076 g, 0.19 mmol), (4-(1-methyl-1H-imidazol-2-yl)phenyl)boronic acid (CAS: 1310383-27-7, 0.042 g, 0.21 mmol), K3PO4(0.12 g, 0.57 mmol) and cataCXium®A Pd G3 (2.8 mg, 3.8 µmol) in tert-amyl alcohol (1.0 mL) and water (0.3 mL) was degassed with nitrogen for a few minutes then heated to 75 °C. To the reaction mixture was added DMF (1.0 mL) and stirred for 14 hours. The suspension was concentrated in vacuo then suspended in DMSO and filtered. The filtrate was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water / MeCN (0.05% TFA), 5 to 95% MeCN over 8.54 minutes, 95% MeCN hold for 1.46 minutes, flow rate= 25 mL / min) to provide 15 (15 mg, 17% yield). LC / MS m / z (M+H)+= 479.4.1H NMR (600 MHz, (CD3)2SO) δ 9.12 (t, 1H), 8.52 – 8.50 (m, 1H), 8.40 – 8.36 (m, 1H), 8.03 – 8.00 (m, 2H), 7.92 – 7.89 (m, 3H), 7.85 – 7.76 (m, 3H), 7.42 (d, 2H), 4.54 (d, 2H), 4.19 (s, 3H), 3.92 (s, 3H), 2.76 (d, 3H). Example 17 5-(4-(Dimethylcarbamoyl)phenyl)-1-ethyl-N-(4-(methylcarbamoyl)benzyl)-1H-indazole-3- carboxamide (17) Step 1. Preparation of 5-bromo-N-(4-(methylcarbamoyl)benzyl)-1H-indazole-3-carboxamide (C29) To a mixture of 4-(aminomethyl)-N-methylbenzamide (CAS: 164648-64-0, 0.954 g, 5.81 mmol), 5-bromo-1H-indazole-3-carboxylic acid (CAS: 1077-94-7, 1.40 g, 5.81 mmol) and HOBt (0.889 g, 5.81 mmol) in DMF (19 mL) was added TEA (1.17 g, 11.6 mmol) then EDCI (1.22 g, 6.39 mmol). The reaction mixture was stirred at room temperature for 66 hours then water (40 mL) was added slowly and stirred for 3 hours. The mixture was filtered and rinsed with water (3 x 4 mL). The filter cake was collected then dried by high vacuum to provide C29 (1.57 g, 69.9% yield) as a white solid. The solid was used in the next step without further purification. (LC / MS) m / z (M+2H)+= 389.1.1H NMR (400 MHz, (CD3)2SO) δ 13.87 (br s, 1H), 9.12 (t, 1H), 8.38-8.33 (m, 1H), 8.31 (d, 1H), 7.81-7.75 (m, 2H), 7.63 (d, 1H), 7.54 (dd, 1H), 7.43-7.38 (m, 2H), 4.53 (d, 2H), 2.77 (d, 3H). Step 2. Preparation of 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(methylcarbamoyl)benzyl)-1H- indazole-3-carboxamide (C30) A mixture of C29 (0.100 g, 0.258 mmol) and (4-(dimethylcarbamoyl)phenyl)boronic acid (CAS: 405520-68-5, 54.8 mg, 0.284 mmol), K3PO4(103 mg, 1.03 mmol) in (2:1) 1,4-dioxane (1.15 mL): water (0.57 mL) was degassed with nitrogen for 5 minutes before cataCXium®A Pd G3 (9.40 mg, 0.0129 mmol) was added. The reaction mixture was degassed with nitrogen for 5 minutes then the creamy-white suspension was heated to 100 °C for 16 hours and stirred at room temperature for 48 hours. The mixture was concentrated in vacuo then dissolved in MeOH: DCM. The mixture was pre-absorbed onto 1 g (1:1) silica gel: Celite then purified by column chromatography (silica gel; MeOH: DCM, 0-50% MeOH) and dried further by high vacuum at 40 °C for 2 hours to provide C30 (99.0 mg, 84.2% yield) as a light-yellow solid gum. (LC / MS) m / z (M+H)+= 456.2.1H NMR (400 MHz, (CD3)2SO) δ 13.73 (s, 1H), 9.10 (t, 1H), 8.47- 8.44 (m, 1H), 8.37 (q, 1H), 7.84-7.72 (m, 6H), 7.56-7.51 (m, 2H), 7.45 (d, 2H), 4.57 (d, 2H), 3.01 (br s, 6H), 2.78 (d, 3H). Step 3. Preparation for 5-(4-(dimethylcarbamoyl)phenyl)-1-ethyl-N-(4- (methylcarbamoyl)benzyl)-1H-indazole-3-carboxamide (17) To a solution of C30 (0.030 g, 0.066 mmol) in DMF (0.22 mL) was added EtI (15 mg, 0.099 mmol) and cesium carbonate (Cs2CO3) (24 mg, 0.072 mmol). The reaction mixture was stirred at room temperature for 4 hours then diluted with DCM (2 mL) and filtered. The filter cake was washed with DCM then the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc then heptane was added and concentrated in vacuo (3x). The resultant solid was dried further under high vacuum then purified by reverse phase HPLC (Xbridge C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 5 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) and lyophilized to provide 17 (21 mg, 66% yield). (LC / MS) m / z (M+H)+= 484.4.1H NMR (600 MHz, (CD3)2SO) δ 8.97 (t, 1H), 8.39-8.36 (m, 1H), 8.34-8.29 (m, 1H), 7.86-7.82 (m, 1H), 7.78-7.67 (m, 5H), 7.48-7.44 (m, 2H), 7.39-7.35 (m, 2H), 4.53-4.46 (m, 4H), 2.92 (br d, 6H), 2.73-2.69 (m, 3H), 1.45-1.39 (m, 3H). Example 25 7-(4-(Dimethylcarbamoyl)phenyl)-N-(4-(methylcarbamoyl)benzyl)imidazo[1,5-a]pyridine-1- carboxamide (25) Step 1. Preparation of 7-bromo-N-(4-(methylcarbamoyl)benzyl)imidazo[1,5-a]pyridine-1- carboxamide (C31) The same procedure was followed from Example 1, step 1 with 7-bromoimidazo[1,5- a]pyridine-1-carboxylic acid (CAS: 1379306-59-8, 0.060 g, 0.25 mmol) to provide C31 (0.080 g, 83% yield) as a light yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+22H)+= 408.9. Step 2. Preparation of 7-(4-(dimethylcarbamoyl)phenyl)-N-(4- (methylcarbamoyl)benzyl)imidazo[1,5-a]pyridine-1-carboxamide (25) To a suspension of C31 (50 mg, 0.13 mmol) and (4-(dimethylcarbamoyl)phenyl)boronic acid (CAS: 405520-68-5; 0.030 g, 0.15 mmol) in (4:1) 1,4-dioxane (0.8 mL): water (0.2 mL) was added K3PO4(68 mg, 0.32 mmol). The mixture was degassed with nitrogen for 3 minutes before Pd(dppf)Cl2-DCM (10 mg, 0.013 mmol) was added. The reaction mixture was stirred at 90 °C for 3 hours then filtered through Celite. The filter cake was washed with EtOAc then the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC (Boston Prime C18150 mm x 30 mm x 5 µm, water (0.05% NH4OH) / MeCN, 20 to 40% MeCN over 10 minutes, 100% MeCN hold for 2 minutes, flow rate= 35 mL / min) and lyophilized to provide 25 (0.020 g, 34% yield). (LC / MS) m / z (M+H)+= 456.1.1H NMR (400 MHz, (CD3)2SO) δ 8.76 (t, 1H), 8.59-8.55 (m, 1H), 8.49 (s, 1H), 8.40-8.31 (m, 2H), 7.84-7.79 (m, 2H), 7.78-7.74 (m, 2H), 7.55- 7.50 (m, 2H), 7.39 (d, 2H), 7.30 (dd, 1H), 4.52 (d, 2H), 2.97 (d, 6H), 2.75 (d, 3H). Example 49 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-7-fluoro-N-(4-(methylcarbamoyl)benzyl)-1H- Step 1. Preparation of 5-bromo-7-fluoro-N-(4-(methylcarbamoyl)benzyl)-1H-indazole-3- carboxamide (C32) To a solution of 4-(aminomethyl)-N-methylbenzamide (CAS: 164648-64-0, 85.4 mg, 0.425 mmol) and DIPEA (99.8 mg, 0.772 mmol) in MeCN (1.93 mL) was added 5-bromo-7- fluoro-1H-indazole-3-carboxylic acid (CAS: 959236-59-0, 0.100 g, 0.386 mmol), HOPO (51.5 mg, 0.463 mmol) and EDCI (111 mg, 0.579 mmol). The reaction was stirred at room temperature overnight then diluted with water (4 mL) and stirred for 5 minutes. The mixture was filtered and rinsed with minimal MeCN. The filter cake was collected to provide C32 (101 mg, 64.6% yield) as a solid. The solid was used in the next step without further purification. (LC / MS) m / z (M+2H)+= 407.4. Step 2. Preparation of 7-fluoro-N-(4-(methylcarbamoyl)benzyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazole-3-carboxamide (C33) and 5-(5-(dimethylcarbamoyl)pyridin-2-yl)- 7-fluoro-N-(4-(methylcarbamoyl)benzyl)-1H-indazole-3-carboxamide (C34) A mixture of C32 (0.050 g, 0.12 mmol), B2Pin2(47 mg, 0.19 mmol) and KOAc (48 mg, 0.49 mmol) in 1,4-dioxane (1.2 mL) was bubbled with nitrogen. To the mixture was added Pd(dppf)Cl2-DCM (0.010 g, 0.012 mmol) then the reaction mixture was bubbled with nitrogen again for 5 minutes. The reaction was heated to 110 °C and stirred overnight then cooled to room temperature to provide C33 (56 mg, >99% yield) as a crude mixture. (LC / MS) m / z (M+H)+= 453.4. To the crude mixture was added 6-chloro-N,N-dimethylnicotinamide (27 mg, 0.15 mmol), K3PO4(79 mg, 0.37 mmol), water (0.30 mL) and an additional portion of Pd(dppf)Cl2-DCM (0.010 g, 0.012 mmol) under nitrogen. The reaction mixture was heated to 110 °C for 2 hours then the mixture was cooled to room temperature. The reaction mixture was diluted with water then extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, MeOH: DCM, 1-20% MeOH) to provide C34 (8.5 mg, 15% yield) as a gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 475.4. Step 3: Preparation of 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-7-fluoro-N-(4- (methylcarbamoyl)benzyl)-1H-indazole-3-carboxamide (49) To a solution of C34 (8.5 mg, 0.018 mmol) in DMSO (0.18 mL) was added K2CO3(7.4 mg, 0.054 mmol) then EtI (3.4 mg, 0.021 mmol). The reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature then concentrated to about half the volume by stream of nitrogen. The mixture was filtered then purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 5 to 95% MeCN over 4 minutes, 95% MeCN hold 1 minute, flow rate= 2 mL / min) and lyophilized to provide 49 (11 mg, >99% yield). (LC / MS) m / z (M+H)+= 503.5. Example 50 N-(4-(3,3-Bis(hydroxymethyl)ureido)benzyl)-5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-1H- indazole-3-carboxamide (50) Step 1. Preparation of N-(4-aminobenzyl)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-methyl-1H- indazole-3-carboxamide (C35) To a suspension of C21 (0.309 g, 0.953 mmol) in MeCN (4.3 mL) and water (0.5 mL) was added HOPO (0.127 g, 1.14 mmol) followed by EDCI (0.274 g, 1.43 mmol). The reaction mixture was stirred at room temperature for 15 minutes before 4-aminobenzylamine (CAS: 4403-71-8, 0.128 g, 1.05 mmol) was added. The reaction mixture was stirred at room temperature overnight then concentrated in vacuo. To the residue was water (~10 mL) which caused yellow solid to precipitate. The mixture was diluted with DCM then washed with additional water and brine. The aqueous layer was back extracted with DCM (2x) then with 10% 2-butanol in DCM (1x). The combined organic layer was concentrated under a stream of nitrogen then dried further under high vacuum. The residue was purified by supercritical fluid chromatography (SFC) (Princeton Propyl-pyridyl-Urea 250 mm x 30 mm x 5 µm, carbon dioxide (CO2): MeOH (70: 30)% at 35 °C, 100 bar, 80 mL / min) then dried further under high vacuum to provide an impure C35 (0.222 g). Further purification was conducted in two batches. In the first batch, an impure C35 (20.0 mg, 0.0467 mmol) was suspended in heptane then heated to 45 °C and stirred for 2 hours. The solution of the first batch was allowed to cool to room temperature while slowly stirring then the mixture was filtered, the solid was collected and dried under high vacuum. The second batch was repurified under the same purification conditions as batch 1. The second batch of impure C35 (0.202 g, 0.471 mmol) was suspended in heptane then heated to 45 °C and stirred for 2 hours. The solution of the second batch was allowed to cool to room temperature while slowly stirring then the mixture was filtered, the solid was collected and dried under high vacuum. The solids from batch 1 and 2 were combined to provide C35 (0.127 g, 31.4% yield). (LC / MS) m / z (M+H)+= 429.4.1H NMR (400 MHz, (CDCl3) δ 8.95 (s, 1H), 8.77 (s, 1H), 8.34 (t, 1H), 7.99 (d, 1H), 7.89 (d, 1H), 7.57-7.46 (m, 1H), 7.39-7.28 (m, 1H), 7.24-7.07 (m, 2H), 6.75 (d, 2H), 4.72-4.53 (m, 2H), 4.13-4.04 (m, 3H), 3.12 (d, 6H). Step 2. Preparation of N-(4-(3,3-bis(hydroxymethyl)ureido)benzyl)-5-(4- (dimethylcarbamoyl)phenyl)-1-methyl-1H-indazole-3-carboxamide (50) Under nitrogen, a mixture of C35 (0.100 g, 0.234 mmol) and 1,1’-carbonyldiimidazole (CDI) (46.0 mg, 0.281 mmol) were suspended in MeCN (4 mL) and stirred at room temperature for 30 minutes. The reaction mixture was heated to 60 °C and stirred for 30 minutes before DMF (2 mL) was added. The reaction mixture was stirred for an additional 20 minutes at room temperature before 2-aminopropane-1,3-diol (CAS: 534-03-2, 21.0 mg, 0.234 mmol) was added. The mixture was stirred at room temperature overnight then the reaction was heated to 60 °C and stirred for 3 hours. The reaction was cooled to room temperature then filtered. The filter cake was washed with minimal MeCN. The filtrate was concentrated in vacuo then diluted with water and extracted with EtOAc (2x). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 15 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide 50 (7.80 mg, 6.14% yield). (LC / MS) m / z (M+H)+= 545.4.1H NMR (600 MHz, (CD3)2SO) δ 8.81 (t, 1H), 8.51 (s, 1H), 8.39- 8.37 (m, 1H), 7.80-7.75 (m, 2H), 7.72-7.69 (m, 2H), 7.48-7.44 (m, 2H), 7.26-7.23 (m, 2H), 7.18- 7.14 (m, 2H), 5.94 (d, 1H), 4.67 (td, 2H), 4.35 (d, 2H), 4.10 (s, 3H), 3.55-3.50 (m, 1H), 3.44-3.39 (m, 4H), 2.93 (d, 6H) Example 51 5-(4-(Dimethylcarbamoyl)phenyl)-N-(4-((2-methoxyethyl)carbamoyl)benzyl)-1-methyl-1H- indazole-3-carboxamide (51) Step 1. Preparation of methyl 4-((5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-1H-indazole-3- carboxamido)methyl)benzoate (C36) A mixture of C21 (0.150 g, 0.464 mmol), HOPO (0.155 g, 1.39 mmol) and EDCI (0.213 g, 1.11 mmol) in DMSO (8 mL) was stirred at room temperature for 20 minutes then methyl 4- (aminomethyl)benzoate (CAS: 18469-52-8, 92.0 mg, 0.557 mmol) and DIPEA (0.240 g, 1.86 mmol) were added. The light brown reaction mixture was stirred at 30 °C for 16 hours then poured into water (30 mL). The precipitated off-white solid was collected by filtration to provide C36 (0.195 g, 89.3% yield) as a grey-white solid. The material was used in the next step without further purification. Step 2. Preparation of 4-((5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-1H-indazole-3- carboxamido)methyl)benzoic acid (C37) A mixture of C36 (0.190 g, 0.404 mmol) and LiOH (33.9 mg, 0.808 mmol) in THF (6.0 mL), MeOH (2.0 mL) and water (2.0 mL) was stirred at 30 °C for 16 hours. The reaction mixture was concentrated in vacuo then the residue was diluted with water (10 mL) and extracted with EtOAc (5 mL). The pH of the aqueous layer was adjusted to 4~5 by 2M HCl. Precipitate formed which was collected by filtration and washed with water (5 mL). The solid was lyophilized to provide C37 (55.0 mg) as an off-white solid. The aqueous phase was also lyophilized to provide C37 (0.201 g) as a light brown solid. The solids were combined to provide C37 (0.256 g, >99% yield) as a solid. The solids were used in the next step without additional purification. (LC / MS) m / z (M+H)+= 457.1.1H NMR (400 MHz, (CD3)2SO) δ 9.05 (t, 1H), 8.46-8.42 (m, 1H), 7.93-7.80 (m, 4H), 7.78-7.72 (m, 2H), 7.54-7.49 (m, 2H), 7.40 (d, 2H), 4.55 (d, 2H), 4.17 (s, 3H), 2.98 (br s, 6H). Step 3. Preparation of 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-((2- methoxyethyl)carbamoyl)benzyl)-1-methyl-1H-indazole-3-carboxamide (51) To 2-methoxyethan-1-amine (15 mg, 0.20 mmol) was added a solution of C37 (27 mg, 0.060 mmol) in DMF (0.25 mL) followed a solution of HATU (34 mg, 0.090 mmol) in DMF (0.25 mL) then TEA (36 mg, 0.36 mmol). The reaction was shaken at room temperature for 16 hours then diluted with DCM (4 mL) and washed with water (2 mL). The organic layer was concentrated in vacuo to give a residue that was dissolved in DMSO (1 mL), filtered and purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 25 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide 51 (20.4 mg, 67.1% yield). (LC / MS) m / z (M+H)+= 514.3 Example 61 5-(4-(Dimethylcarbamoyl)phenyl)-1-(2-hydroxyethyl)-N-(4-(methylcarbamoyl)benzyl)-1H- indazole-3-carboxamide hydrochloride (61) Step 1. Preparation of rac-(R)-5-bromo-N-(4-(methylcarbamoyl)benzyl)-1-(2-((tetrahydro-2H- pyran-2-yl)oxy)ethyl)-1H-indazole-3-carboxamide (C38) A mixture of C29 (80.0 mg, 0.207 mmol), rac-(R)-2-(2-bromoethoxy)tetrahydro-2H-pyran (CAS: 17739-45-6, 47.5 mg, 0.227 mmol) and Cs2CO3 (74.0 mg, 0.227 mmol) in DMF (0.69 mL) was heated to 80 °C for 2.5 hours. The mixture was diluted with water and stirred for 10 minutes. EtOAc was added and stirred for 5 minutes. During the stir white precipitate formed. The mixture was filtered, and the filter cake was dried by passing nitrogen overtop for 10 minutes to provide C38 (21.5 mg) as a white solid. The organic layer was extracted from the filtrate and the aqueous layer was back extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated in vacuo then dried further under high vacuum to provide C38 (112 mg) as a gum. The two batches were combined then purified by column chromatography (silica, EtOAc: heptane, 0-100% EtOAc then MeOH: DCM, 0-50% MeOH) to provide C38 (92.1 mg, 86.5% yield) as a white solid.1H NMR (400 MHz, (CDCl3) δ 8.56 (d, 1H), 7.77-7.71 (m, 2H), 7.52-7.42 (m, 4H), 7.36 (t, 1H), 6.12 (s, 1H), 4.71 (d, 2H), 4.56 (t, 2H), 4.49-4.44 (m, 1H), 4.17-4.09 (m, 1H), 3.87-3.77 (m, 1H), 3.49-3.32 (m, 2H), 3.01 (d, 3H), 1.56-1.30 (m, 6H), Step 2. Preparation rac-(R)-5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(methylcarbamoyl)benzyl)-1- (2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-indazole-3-carboxamide (C39) A mixture of C38 (0.040 g, 0.078 mmol) and (4-(dimethylcarbamoyl)phenyl)boronic acid (CAS: 405520-68-5, 16 mg, 0.085 mmol), K3PO4(49 mg, 0.23 mmol) in (2:1) 1,4-dioxane (0.41 mL): water (0.10 mL) was degassed with nitrogen for 5 minutes before cataCXium A Pd G3 (2.8 mg, 0.0039 mmol) was added. The reaction was degassed with nitrogen for 5 minutes then the off-white suspension was heated to 90 °C for 16 hours. The mixture was diluted with EtOAc and water then filtered and rinsed with EtOAc and water. The aqueous layer was back extracted with EtOAc (2 x 5 mL). The combined organic layer was washed with brine (1x), dried withNa2SO4, filtered and concentrated in vacuo to provide C39 (0.050 g, >99% yield) as a light tan solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 584.5.1H NMR (400 MHz, (CDCl3) δ 8.62-8.61 (m, 1H), 7.77-7.67 (m, 5H), 7.62 (d, 1H), 7.53-7.39 (m, 5H), 6.16-6.09 (m, 1H), 4.74 (d, 2H), 4.61 (t, 2H), 4.50 (t, 1H), 4.21-4.13 (m, 1H), 3.90-3.82 (m, 1H), 3.70 (s, 6H), 3.54-3.46 (m, 1H), 3.41-3.33 (m, 1H), 3.01 (d, 3H), 1.62- 1.32 (m, 6H). Step 3: Preparation of 5-(4-(dimethylcarbamoyl)phenyl)-1-(2-hydroxyethyl)-N-(4- (methylcarbamoyl)benzyl)-1H-indazole-3-carboxamide hydrochloride (61) The same procedure was followed from Preparation P9, step 2 with C39 (45.0 mg, 0.0771 mmol). Additional purification was conducted. The residue was purified by reverse phase HPLC (XBridge C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 10 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide 61 (20.5 mg, 53.2% yield). (LC / MS) m / z (M+H)+= 500.4.1H NMR (600 MHz, (CD3)2SO) δ 9.00 (t, 1H), 8.40-8.38 (m, 1H), 8.34 (q, 1H), 7.83 (d, 1H), 7.78-7.70 (m, 5H), 7.50-7.46 (m, 2H), 7.39 (d, 2H), 4.92 (td, 1H), 4.54-4.50 (m, 4H), 3.86 (q, 2H), 2.99-2.92 (m, 6H), 2.73 (d, 3H) Example 75 rac-(R)-5-(4-(Dimethylcarbamoyl)phenyl)-1-methyl-N-(4-(3-methylpyrrolidin-1-yl)benzyl)-1H- indazole-3-carboxamide (75) Step 1. Preparation of rac-(R)-5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-N-(4-(3- methylpyrrolidin-1-yl)benzyl)-1H-indazole-3-carboxamide (75) A suspension of C35 (0.050 g, 0.12 mmol) and triphosgene (12 mg, 0.041 mmol) in THF (2 mL) was stirred at room temperature for 30 minutes before DMAP (43 mg, 0.35 mmol) and rac-(R)-3-methylpyrrolidine (CAS: 120986-93-7, 0.030 mL, 0.29 mmol) were added. The reaction mixture was stirred for 15 minutes at room temperature then diluted with water. The mixture was extracted with EtOAc (2x). The combined organic layer was dried over MgSO4which was filtered then concentrated in vacuo. The residue was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 5 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide 75 (26 mg, 41% yield). (LC / MS) m / z (M+H)+= 539.6.1H NMR (600 MHz, (CD3)2SO) δ 8.86 (t, 1H), 8.45-8.41 (m, 1H), 8.01 (s, 1H), 7.85-7.79 (m, 2H), 7.76-7.73 (m, 2H), 7.52-7.48 (m, 2H), 7.43-7.39 (m, 2H), 7.21-7.17 (m, 2H), 4.40 (d, 2H), 4.14 (s, 3H), 3.53 (dd, 1H), 3.47-3.43 (m, 1H), 3.30-3.24 (m, 1H), 2.97 (d, 6H), 2.86 (t, 1H), 2.25-2.17 (m, 1H), 1.99-1.91 (m, 1H), 1.50-1.41 (m, 1H), 1.00 (d, 3H). Example 76 5-(4-(2,3-Dihydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)phenyl)-1-methyl-N-(4- (methylcarbamoyl)benzyl)-1H-indazole-3-carboxamide (76) Step 1: Preparation of methyl 4-(1-methyl-3-((4-(methylcarbamoyl)benzyl)carbamoyl)-1H- indazol-5-yl)benzoate benzoate (C40) To a stirred solution of C16 (1.00 g, 2.49 mmol) and (4- (methoxycarbonyl)phenyl)boronic acid (CAS: 99768-12-4, 471 mg, 2.62 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added K3PO4(1.32 g, 6.23 mmol). The reaction mixture was degassed with nitrogen for 3 minutes before Pd(dppf)Cl2(182 mg, 0.249 mmol) was added. The reaction mixture was degassed with nitrogen for 3 minutes then heated to 80 °C for 2 hrs. The reaction mixture was filtered then the filter cake was dissolved in (1:10) MeOH: DCM (50 mL) and washed with water. The organic layer was filtered through Celite then washed with EtOAc (20 mL) and (1:10) MeOH: DCM (20 mL). The filtrate was concentrated in vacuo to provide C40 (0.860 g) as a brown solid. The filtrate of the reaction mixture was washed with water (20 mL) then filtered through Celite. The filter cake was washed with (1:10) MeOH: DCM (20 mL). The organic layer was washed with brine (20 mL) then dried with Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica, MeOH: DCM, 0-9% MeOH) to provide C40 (0.100 g) as a brown solid. The two batches of solids were combined to form C40 (0.960 g, 84.4% yield) as a brown solid. (LC / MS) m / z (M+H)+= 457.0.1H NMR (400 MHz, (CD3)2SO) δ 9.10 (t, 1H), 8.48 (s, 1H), 8.38 (q, 1H), 8.08-8.04 (m, 2H), 7.92-7.84 (m, 4H), 7.78 (d, 2H), 7.42 (d, 2H), 4.54 (d, 2H), 4.18 (s, 3H), 3.88 (s, 3H), 2.76 (d, 3H). Step 2. Preparation of 4-(1-methyl-3-((4-(methylcarbamoyl)benzyl)carbamoyl)-1H-indazol-5- yl)benzoic acid (C41) At 0 °C, to a stirred solution of C40 (4.10 g, 8.98 mmol) in THF (41 mL) and MeOH (41 mL) was added LiOH (1.13 g, 26.9 mmol) in water (41 mL). The reaction mixture was stirred at room temperature for 40 hours then diluted with water (50 mL). The mixture was concentrated in vacuo then treated with 1M HCl to pH~4 which caused precipitate to form. The reaction was set aside for 10 minutes then filtered. The filter cake was collected then lyophilized to provide C41 (3.93 g, 98.9% yield) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 443.2.1H NMR (400 MHz, (CD3)2SO) δ 12.95 (br s, 1H), 9.09 (t, 1H), 8.48-8.45 (m, 1H), 8.39-8.34 (m, 1H), 8.06-8.01 (m, 2H), 7.90-7.81 (m, 4H), 7.80-7.75 (m, 2H), 7.41 (d, 2H), 4.53 (d, 2H), 4.18 (s, 3H), 2.76 (d, 3H). Step 3. Preparation of 5-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carbonyl)phenyl)-1-methyl- N-(4-(methylcarbamoyl)benzyl)-1H-indazole-3-carboxamide (76) To a stock solution of C41 (0.541 g, 1.22 mmol) and HATU (0.701 g, 1.84 mmol) in DMF (11.4 mL) was added DIPEA (0.639 g, 4.94 mmol) to form a gray slurry. The reaction mixture was stirred at room temperature for 15 minutes then a portion of the stock solution (0.100 mL) was added to the 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (3.0 mg, 0.025 mmol). The reaction mixture was stirred at room temperature for 18 hours then concentrated by Evaporex. To the residue was added MeOH (0.400 mL) then the mixture shook at room temperature for 20 minutes. The mixture was filtered then rinsed with MeOH (0.200 mL) twice. The solution was concentrated by Evaporex then dissolved in DMSO (0.150 mL) and purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 25 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide 76 (1.5 mg, 27.8% yield). (LC / MS) m / z (M+H)+= 545.3. Example 88 3-Cyclopropyl-7-(4-(dimethylcarbamoyl)phenyl)-N-(4-(methylcarbamoyl)benzyl)imidazo[1,5- a]pyridine-1-carboxamide (88) Step 1. Preparation of ethyl 7-(4-(dimethylcarbamoyl)phenyl)imidazo[1,5-a]pyridine-1- carboxylate (C42) The same procedure was followed from Example 5, step 1 with ethyl 7- bromoimidazo[1,5-a]pyridine-1-carboxylate (CAS: 1363381-07-0, 1.94 g, 7.21 mmol). The purification was altered. The residue was purified by column chromatography (silica, MeOH: DCM, 0-3%) to provide C42 (2.16 g, 88.8% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 338.1. Step 2. Preparation of ethyl 7-(4-(dimethylcarbamoyl)phenyl)-3-iodoimidazo[1,5-a]pyridine-1- carboxylate (C43) To a solution of C42 (2.16 g, 6.40 mmol) in MeCN (40 mL) was added N- iodosuccinimide (NIS) (2.16 g, 9.60 mmol). The mixture was stirred at 50 °C for 12 hours. The reaction mixture was extracted by DCM (50 mL x 3). The combined organic layers were washed with water (50 mL) then brine (50 mL), dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica; EtOAc, 100%) to provide C43 (2.00 g, 67.4% yield) as a light brown solid.1H NMR (400 MHz, (CDCl3) δ 8.42-8.38 (m, 1H), 8.08 (dd, 1H), 7.75-7.69 (m, 2H), 7.58-7.52 (m, 2H), 7.19 (dd, 1H), 4.48 (q, 2H), 3.07 (d, 6H), 1.46 (t, 3H). Step 3. Preparation of ethyl 3-cyclopropyl-7-(4-(dimethylcarbamoyl)phenyl)imidazo[1,5- a]pyridine-1-carboxylate (C44) The reaction was conducted in two batches then combined for purification. To a suspension of C43 (0.700 g, 1.51 mmol) and cyclopropylboronic acid (0.389 g, 4.53 mmol) in DME (20 mL) was added Pd(dppf)Cl2(0.111 g, 0.151 mmol) and K2CO3(0.626 g, 4.53 mmol) to form the first batch. The first batch was purged under nitrogen and stirred at 100 °C for 16 hours. A second batch of the same reaction was conducted with C43 (50.0 mg, 0.108 mmol). The batches were combined then purified with column chromatography (silica; EtOAc: MeOH=10:1) to provide C44 (0.140 g, 22.9% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 378.2. Step 4. Preparation of 3-cyclopropyl-7-(4-(dimethylcarbamoyl)phenyl)imidazo[1,5-a]pyridine-1- carboxylic acid (C45) The same procedure was followed from Example 5, step 2 with C44 (0.140 g, 0.371 mmol) to provide C45 (0.130 g, >99% yield) as a yellow solid. The solid was used directly in the next step without additional purification. (LC / MS) m / z (M+H)+= 350.1. Step 5. Preparation of 3-cyclopropyl-7-(4-(dimethylcarbamoyl)phenyl)-N-(4- (methylcarbamoyl)benzyl)imidazo[1,5-a]pyridine-1-carboxamide (88) To a stirred mixture of C45^(65 mg, 0.19 mmol),^4-(aminomethyl)-N-methylbenzamide (CAS: 164648-64-0; 48 mg, 0.24 mmol),^EDCI (52 mg, 0.28 mmol),^HOBt (38 mg, 0.28 mmol) in^DMF (2 mL) was added DIPEA (120 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 16 hours then heated to 50 °C and stirred for 32 hours. The reaction was purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm, water (0.05% formic acid) / MeCN, 8 to 48% MeCN over 9 minutes, then hold at 100% MeCN for 2 minutes, flow rate= 30 mL / min) and lyophilized to provide 88 (8.1 mg, 8.7% yield) as a yellow solid. LC / MS m / z (M+H)+= 496.2.1H NMR (400 MHz, (CD3OD) δ 8.49-8.41 (m, 2H), 7.87 (d, 2H), 7.78 (d, 2H), 7.57 (d, 2H), 7.47 (d, 2H), 7.26 (dd, 1H), 4.66 (s, 2H), 3.10 (d, 6H), 2.90 (s, 3H), 2.33-2.25 (m, 1H), 1.21-1.06 (m, 4H). Example 99 (Z)-N-(4-(2-Cyano-3,3-dimethylguanidino)benzyl)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1- methyl-1H-indazole-3-carboxamide (99) Step 1. Preparation of N-(4-aminobenzyl)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-methyl-1H- indazole-3-carboxamide (C46) To a suspension of C20 (1.00 g, 3.08 mmol) in DCM (15 mL) was added 4- aminobenzylamine (CAS: 4403-71-8, 0.539 g, 4.41 mmol), HATU (2.34 g, 6.17 mmol), and TEA (0.653 g, 6.46 mmol). The reaction mixture was stirred at room temperature for 2 hours then was diluted with DCM and washed with water. The organic layer was dried with Na2SO4, filtered then concentrated in vacuo. The residue was purified by medium pressure liquid chromatography (MPLC) (silica, MeOH: DCM, 0-10% MeOH) to provide C46 (1.38 g, >99% yield) as a yellow foam. The yellow foam was used directly in the next step without additional purification. (LC / MS) m / z (M+H)+= 429.6. Step 2. Preparation of methyl (E)-N'-(4-((5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-methyl-1H- indazole-3-carboxamido)methyl)phenyl)-N-cyanocarbamimidothioate (C47) To a solution of C46 (0.100 g, 0.233 mmol) and dimethyl cyanocarbonimidodithioate (68.3 mg, 0.467 mmol) in DMF (2.5 mL) was added cesium fluoride (CsF) (70.9 mg, 0.467 mmol). The reaction mixture was stirred at 100 °C for 16 hours then an additional portion of dimethyl cyanocarbonimidodithioate (68.3 mg, 0.467 mmol) and CsF (70.9 mg, 0.467 mmol) were added. The reaction was stirred at 100 °C for 16 hours to provide C47 (123 mg, >99% yield) as a mixture in DMF (2.5 mL). The crude mixture was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 527.2. Step 3. Preparation of (Z)-N-(4-(2-cyano-3,3-dimethylguanidino)benzyl)-5-(5- (dimethylcarbamoyl)pyridin-2-yl)-1-methyl-1H-indazole-3-carboxamide (99) The reaction was conducted in two batches then combined for purification. To a reaction mixture of C47 (123 mg, 0.234 mmol) in DMF (2.5 mL) was added dimethylamine hydrochloride (38.1 mg, 0.467 mmol) in EtOH (2.5 mL) then CsF (71.0 mg, 0.467 mmol) was added to form the first batch. The first batch was stirred at 100 °C for 16 hours. A second batch of the same reaction was conducted with C47 (25.0 mg, 0.0475 mmol). The batches were combined then diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was wash with saturated Na2CO3then brine. The organic layer was dried over Na2SO4and concentrated in vacuo. The residue was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 µm, water (0.05% formic acid) / MeCN, 9 to 49% MeCN over 9 minutes, 100% MeCN hold for 2 minutes, flow rate= 60 mL / min) then concentrated in vacuo and lyophilized to provide 99 (1.47 mg, 1.00% yield). (LC / MS) m / z (M+H)+= 524.3.1H NMR (400 MHz, (CD3)2SO) δ 9.08 (s, 1H), 9.00-8.95 (m, 1H), 8.89 (t, 1H), 8.74 (d, 1H), 8.31-8.20 (m, 1H), 8.09 (d, 1H), 7.96 (dd, 1H), 7.87 (d, 1H), 7.41 (d, 1H), 7.36-7.29 (m, 1H), 7.24 (d, 1H), 7.01 (d, 1H), 4.46 (dd, 2H), 4.19 (d, 3H), 3.03 (br s, 6H), 2.95 (d, 6H). Example 103 5-(4-(6,7-Dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)phenyl)-N-(4-(3,3- dimethylureido)benzyl)-1-methyl-1H-indazole-3-carboxamide (103) Step 1: Preparation of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3- carboxylic acid (C48) To a suspension of 5-bromo-1-methyl-1H-indazole-3-carboxylic acid (CAS: 1363380-96- 4, 5.00 g, 19.6 mmol) and B2Pin2(5.97 g, 23.5 mmol) in toluene (75 mL) was added KOAc (4.81 g, 49.0 mmol). The reaction mixture was charged with nitrogen 3 times before di(1-adamantyl)- n-butylphosphine (cataCXium®A) (703 mg, 1.96 mmol) and Pd(OAc)2(0.220 g, 0.980 mmol) were added. The mixture was charged with nitrogen 3 times then stirred at 85 °C (internal temperature) for 20 hours. The mixture was filtered and washed with EtOAc (50 mL). The filter cake was concentrated in vacuo then poured into water (60 mL) and stirred for 10 minutes at room temperature. The mixture was filtered, and the filter cake was concentrated in vacuo to provide C48 (2.70 g, 45.6% yield) as a white solid. The aqueous layer was filtered and washed with EtOAc (50 mL). The filter cake was concentrated in vacuo to provide C48 (1.21 g, 20.4% yield) as a white solid. The solid was used directly in the next step without additional purification. (LC / MS) m / z (M+H)+= 303.1.1H NMR (400 MHz, (CD3)2SO) δ 8.55 (s, 1H), 7.76- 7.63 (m, 2H), 4.13 (s, 3H), 1.32 (s, 12H). Step 2: Preparation of 5-(4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)phenyl)-1-methyl- 1H-indazole-3-carboxylic acid (C49) To a stirred solution of P16 (0.390 g, 1.03 mmol) and C48 (0.296 g, 0.980 mmol) in tert- amyl alcohol (6.0 mL) and water (1.5 mL) was added K3PO4(3.39 g, 16.0 mmol). The reaction was degassed with nitrogen for 3 minutes then cataCXium®A Pd G3 (57.1 mg, 0.0784 mmol) was added. The reaction mixture was degassed with nitrogen for 3 minutes then heated to 95 °C for 16 hours. The solution was concentrated in vacuo then the residue was diluted by water (10 mL) and extracted with DCM (15mL x 3). The aqueous layer was adjusted to pH=3 then filtered. The filter cake was concentrated in vacuo then diluted with (1:10) MeOH: DCM (30 mL). The mixture was filtered then the filtrate was concentrated in vacuo to provide C49 (0.270 g, 65.8% yield) as yellow solid. (LC / MS) m / z (M+H)+= 399.1. Step 3: Preparation of 5-(4-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)phenyl)-N-(4-(3,3- dimethylureido)benzyl)-1-methyl-1H-indazole-3-carboxamide (103) At 0 °C under nitrogen, to a stirred solution of 3-(4-(aminomethyl)phenyl)-1,1- dimethylurea hydrochloride, P9, (CAS: 903556-27-4, 40.4 mg, 0.176 mmol) and C49 (70.0 mg, 0.176 mmol) in DMF (1.0 mL) was added HATU (66.8 mg, 0.176 mmol) and DIPEA (182 mg, 1.41 mmol). The reaction mixture was stirred at room temperature for 16 hours then was purified by reverse phase HPLC (Boston Prime C18150 mm x 30 mm x 5 µm, water (0.05% NH4OH-NH4HCO3) / MeCN, 16 to 46% MeCN over 8 minutes, 100% MeCN hold for 3 minutes, flow rate= 50 mL / min) and lyophilized to provide 103 (29.5 mg, 29.5% yield). (LC / MS) m / z (M+H)+= 574.4.1H NMR (400 MHz, (CD3)2SO) δ 8.87 (t, 1H), 8.47 (q, 2H), 8.22 (s, 1H), 7.86- 7.80 (m, 4H), 7.78-7.70 (m, 3H), 7.42-7.36 (m, 2H), 7.35-7.28 (m, 1H), 7.24-7.19 (m, 2H), 4.97- 4.82 (m, 4H), 4.42 (d, 2H), 4.17 (s, 3H), 2.89 (s, 6H). Example 176 N-((6-(3,3-Dimethylureido)pyridin-3-yl)methyl)-1-methyl-5-(4-(1-methyl-1H-imidazol-2- yl)phenyl)-1H-indazole-3-carboxamide (176) Step 1. Preparation of 1-methyl-5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-1H-indazole-3- carboxylic acid (C50) To a stirred solution of 1-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-1H-imidazole (CAS: 1394374-23-2, 20.1 g, 70.8 mmol) and 5-bromo-1-methyl-1H- indazole-3-carboxylic acid (CAS: 1363380-96-4, 14.0 g, 54.9 mmol) in tert-amyl alcohol (336 mL) and water (84 mL) was added K3PO4(44.4 g, 209 mmol). The reaction mixture was degassed with nitrogen for 3 minutes before cataCXium®A Pd G3 (2.84 g, 3.90 mmol) was added. The reaction mixture was degassed with nitrogen for 3 minutes again then heated to 110 °C for 16 hours. The reaction mixture was cooled to room temperature then another portion of 1-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole (CAS: 1394374-23-2, 5.20 g, 18.3 mmol) and cataCXium A Pd G3 (3.02 g, 4.15 mmol) were added. The mixture was degassed with nitrogen for 3 minutes then heated to 110 °C for 16 hours. The mixture was cooled down to room temperature and solid precipitated. The mixture was filtered and the filtered cake was washed with DCM. The filter cake was diluted with water (300 mL) then acidified with 1M HCl until pH=4 which caused some light-yellow precipitate to form. The mixture was filtered then lyophilized and triturated with THF (200 mL). The mixture was stirred at room temperature for 2 hours then was filtered. The filter cake was dissolved in (1:1) MeOH: DCM (500 mL) then NH4OH (10 mL) was added. To the solution was added Silicagel-SH (30 g) then the mixture was stirred at 50 °C for 2 hours, filtered and the filtrate was concentrated in vacuo. The residue was diluted with water (100 mL) and acidified with 1 M HCl till pH=6. The mixture was filtered then lyophilized to provide C50 (10.4 g, 57.0% yield) as a light-yellow solid. (LC / MS) m / z (M+H)+= 333.2.1H NMR (400 MHz, (CD3)2SO) δ13.12 (br s, 1H), 8.37-8.36 (m, 1H), 7.96-7.85 (m, 6H), 7.60-7.59 (m, 1H), 7.46-7.43 (m, 1H), 4.20 (s, 3H), 3.88 (s, 3H). Step 2. Preparation of N-((6-(3,3-dimethylureido)pyridin-3-yl)methyl)-1-methyl-5-(4-(1-methyl- 1H-imidazol-2-yl)phenyl)-1H-indazole-3-carboxamide (176) At 0 °C under nitrogen, to a stirred solution of C50 (80 mg, 0.24 mmol) and HATU (91 mg, 0.24 mmol) in DMF (2.0 mL) was added P17 (47 mg, 0.24 mmol) and DIPEA (93 mg, 0.72 mmol). The reaction mixture was stirred at room temperature for 2 hours then diluted with water (6.0 mL) and filtered. The filter cake was dissolved in DMSO (2.5 mL) and purified by reverse phase HPLC (Boston Prime C18150 mm x 30 mm x 5 µm, water (0.05% NH4OH-NH4HCO3) / MeCN, 28 to 48% MeCN over 11 minutes, 100% MeCN hold for 2 minutes, flow rate= 35 mL / min) then lyophilized to provide 176 (25 mg, 20% yield) as a white solid. (LC / MS) m / z (M+H)+= 509.3.1H NMR (400 MHz, (CD3)2SO) δ 9.01 (t, 1H), 8.80 (s, 1H), 8.47-8.44 (m, 1H), 8.23 (d, 1H), 7.89-7.73 (m, 7H), 7.69 (dd, 1H), 7.28 (d, 1H), 7.00 (d, 1H), 4.44 (d, 2H), 4.17 (s, 3H), 3.81 (s, 3H), 2.92 (s, 6H). Example 183 7-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-3-isopropylimidazo[1,5- a]pyridine-1-carboxamide (183) Step 1. Preparation of ethyl 7-(5-(dimethylcarbamoyl)pyridin-2-yl)-3-isopropylimidazo[1,5- a]pyridine-1-carboxylate (C51) To a solution of P8 (0.200 g, 0.750 mmol), P19 (0.469 g, 1.50 mmol) in toluene (5 mL) was added Pd(PPh3)4(86.6 mg, 0.0750 mmol). The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica, EtOAc: petroleum ether, 0-100%) to provide C50 (215 mg, 75.4% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 381.3. Step 2. Preparation of 7-(5-(dimethylcarbamoyl)pyridin-2-yl)-3-isopropylimidazo[1,5-a]pyridine- 1-carboxylic acid (C52) The same procedure was followed from Example 5, step 2 with C51 (215 mg, 0.565 mmol). Additional purification occurred. The residue was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 µm, water (0.05% formic acid) / MeCN, 0 to 40% MeCN over 9 minutes, 100% MeCN hold for 2 minutes, flow rate= 60 mL / min) and lyophilized to provide C52 (59.0 mg, 29.6% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 353.3. Step 3. Preparation of 7-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-3- isopropylimidazo[1,5-a]pyridine-1-carboxamide (183) The same procedure was followed from Example 5, step 3 with C52 (59 mg, 0.17 mmol). The residue was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 µm, water (NH4OH-NH4HCO3) / MeCN, 6 to 46% MeCN over 9 minutes, 100% MeCN hold for 2 minutes, flow rate= 60 mL / min) and lyophilized to provide 183 (33 mg, 38% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 528.5.1H NMR (400 MHz, (CD3OD) δ 8.87-8.84 (m, 1H), 8.74 (d, 1H), 8.29 (d, 1H), 8.08 (d, 1H), 7.97 (dd, 1H), 7.62 (dd, 1H), 7.38-7.27 (m, 4H), 4.57 (s, 2H), 3.54- 3.43 (m, 1H), 3.12 (d, 6H), 3.00 (s, 6H), 1.43 (d, 6H). Example 187 N-(4-((5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-1-methyl-1H-indazole-3- carboxamido)methyl)phenyl)-6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide (187) Step 1. Preparation of 2,2,2-trichloroethyl (4-((5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-methyl- 1H-indazole-3-carboxamido)methyl)phenyl)carbamate (C53) A solution of C46 (0.500 g, 1.17 mmol) in DCM (6 mL) was cooled with an ice bath before pyridine (0.196 g, 2.47 mmol) was added, followed by the dropwise addition of the solution of 2,2,2-trichloroethoxycarbonylchloride (0.309 g, 1.46 mmol) in DCM (1 mL). The reaction mixture was stirred for 30 minutes at 0 °C then was warmed to room temperature and concentrated in vacuo. The residue was dissolved in MeOH and DCM and purified by MPLC (silica, MeOH: DCM, 0-10% MeOH) to provide C53 (0.462 g, 65.6% yield) as a white foam. (LC / MS) m / z (M+H)+= 605.5.1H NMR (500 MHz, (CDCl3)) δ 8.93-8.92 (m, 1H), 8.78-8.75 (m, 1H), 8.33 (dd, 1H), 8.02-7.93 (m, 2H), 7.54 (d, 1H), 7.44-7.34 (m, 4H), 7.23-7.20 (m, 1H), 7.09- 7.03 (m, 1H), 4.85-4.76 (m, 2H), 4.65 (d, 2H), 4.12-4.09 (m, 3H), 3.12 (d, 6H). Step 2. Preparation of N-(4-((5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-methyl-1H-indazole-3- carboxamido)methyl)phenyl)-6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide (187) To 6-methyl-3,6-diazabicyclo[3.1.1]heptane (1.5 mg, 0.10 mmol) was added a solution of the C53 (0.030 g, 0.050 mmol) in THF (0.7 mL) followed by a solution of 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU) (0.030 g, 0.20 mmol) in THF (0.1 mL). The reaction mixture was heated to 60 °C for 16 hours then concentrated in vacuo. The residue was suspended in DMSO (1 mL) then filtered and purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 5 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide 187 (11 mg, 39% yield). (LC / MS) m / z (M+H)+= 567.4. Example 192 5-(4-(Dimethylcarbamoyl)phenyl)-1-methyl-N-(3-methyl-4-(methylcarbamoyl)benzyl)-1H- indazole-3-carboxamide (192) Step 1. Preparation of ethyl 4-((5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-1H-indazole-3- carboxamido)methyl)-2-methylbenzoate (C54) To ethyl 4-(aminomethyl)-2-methylbenzoate (CAS: 91358-21-6, 19.3 mg, 0.100 mmol) was added a solution of C21 (32.3 mg, 0.100 mmol) in DMF (0.5 mL). After the addition, a solution of HATU (57.0 mg, 0.150 mmol) in DMF (0.5 mL) was added then a portion of TEA (40.5 mg, 0.400 mmol). The reaction mixture was stirred at room temperature for 16 hours then diluted with DCM (4 mL) and washed with water (2 mL). The organic layer was concentrated in vacuo to provide C54 (49.9 mg, >99% yield) as a residue. The residue was used directly in the next step without further purification. Step 2. Preparation of 5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-N-(3-methyl-4- (methylcarbamoyl)benzyl)-1H-indazole-3-carboxamide (192) To C54 (0.05 g, 0.1 mmol) in MeOH (1.0 mL) was added methylamine in water (40% weight (wt), 0.8 g, 10 mmol). The reaction mixture was heated to 80 °C and stirred for 24 hours then concentrated in vacuo. The residue was dissolved in 1 mL DMSO, filtered then purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 25 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide 192 (0.8 mg, 0.003% yield). (LC / MS) m / z (M+H)+= 484.5. Example 195 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-1,7-diethyl-N-(4-(4-methylpiperazine-1- carboxamido)benzyl)-1H-indazole-3-carboxamide (195) Step 1. Preparation of methyl 7-chloro-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-1H- indazole-3-carboxylate (C55) The same procedure was followed from Example 183, step 1 with P24 (0.350 g, 1.10 mmol) to provide C55 (0.180 g, 42.2% yield) as a yellow gum. (LC / MS) m / z (M+H)+= 387.0. Step 6. Preparation of methyl 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-7-vinyl-1H-indazole- 3-carboxylate (C56) To a solution of C55 (0.180 g, 0.465 mmol) and potassium vinyltrifluoroborate (93.5 mg, 0.698 mmol) in (4:1) 1,4-dioxane: water (5 mL) was added K3PO4(0.296 g, 1.40 mmol) then Pd(dppf)Cl2-DCM (34.7 mg, 0.0465 mmol). The reaction mixture was stirred at 90 °C for 2 hours under nitrogen then the heat was increased to 100oC and stirred for 25 hours. The reaction mixture was diluted with EtOAc (10 mL) then washed with brine (5 mL). The aqueous layer was separated, and the organic layer was concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc: petroleum ether, 0-100% EtOAc) to provide C56 (75.0 mg, 42.6% yield) as a yellow gum. Step 7. Preparation of methyl 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1,7-diethyl-1H-indazole-3- carboxylate (C57) To a 75 mL of hydrogenation vessel equipped with a magnetic stirrer was added C56 (75.0 mg, 0.198 mmol) in THF (20 mL) then tris(triphenylphosphine)rhodium(I) chloride (27.5 mg, 0.0297 mmol). The black reaction mixture was stirred at 50oC for 24 hours under hydrogen gas at 50 psi. The suspension was concentrated in vacuo to provide C57 (75.0 mg,>99% yield) as a brown mixture. The crude mixture was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 381.2. Step 8. Preparation of 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1,7-diethyl-1H-indazole-3- carboxylic acid (C58) The same procedure was followed from Example 5, step 2 with C57 (65.0 mg, 0.171 mmol). Additional purification occurred. The residue was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 µm, water (0.05% formic acid) / MeCN, 9 to 49% MeCN over 9 minutes, 100% MeCN hold for 2 minutes, flow rate= 60 mL / min) and lyophilized to provide C58 (10.0 mg, 15.9% yield) as a white solid. Step 9. Preparation of 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1,7-diethyl-N-(4-(4- methylpiperazine-1-carboxamido)benzyl)-1H-indazole-3-carboxamide (195) The same procedure was followed from Example 5, step 3 with C58 (10.0 mg, 0.0273 mmol). The residue was purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm, water (0.05% formic acid) / MeCN, 12 to 52% MeCN over 9 minutes, 100% MeCN hold for 2 minutes, 30 mL / min) and lyophilized to provide an impure 195 (15 mg) as a yellow solid. The solid was purified again by reverse phase HPLC (C18150 mm x 30 mm x 5 µm, water (0.05% NH4OH- NH4HCO3) / MeCN, 20 to 60% MeCN over 9 minutes, 100% MeCN hold for 2 minutes, flow rate= 30 mL / min) and lyophilized to provide 195 (9.20 mg, 57.5% yield) as a white solid. (LC / MS) m / z (M+H)+= 597.3.1H NMR (400 MHz, (CDCl3)) δ 8.83 (d, 1H), 8.75 (dd, 1H), 8.10- 8.08 (m, 1H), 7.97-7.94 (m, 1H), 7.83 (dd, 1H), 7.34 (s, 4H), 4.68-4.53 (m, 4H), 3.54 (t, 4H), 3.17-3.06 (m, 8H), 2.48 (t, 4H), 2.35 (s, 3H), 1.52 (t, 3H), 1.43 (t, 3H). Examples 7-195 The compounds in Table 1 can be prepared using similar chemistry from the Examples described above by utilizing, for example, an amide coupling reaction, a borylation reaction, and a Suzuki coupling reaction in either order from compounds that are commercially available or that can be synthesized by literature methods to form the resultant compounds of the disclosure.

[0002] Table 1 Method of LC / MS Ex. synthesisStructureIUPACm / z tingName(M++; Star H) ; 1 materials H NMR 5-(5- O (dimethylca NH rbamoyl)pyr NH idin-2-yl)-1- Ex.103, O methyl-N- 8 CAS: O N N NH (4-(3- 1363380- methylureid 486.4 96-4 o)benzyl)- N 1H- N indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph H enyl)-N-(4- O N (3,3- N dimethylure O O ido)benzyl)- 9 Ex.4jN NH , P1 1-methyl- 500.3 N 1H- N N pyrazolo[3, 4- c]pyridine- 3- carboxamid e 5-(5- (dimethylca H rbamoyl)pyr O N N imidin-2-yl)- Ex.3, O N-(4-(3,3- CA N N NH O 11 S: dimethylure 1363381- 5 N ido)benzyl)- 01.5 41-2 N 1-methyl- N 1H- indazole-3- carboxamid e 5-(4- O (dimethylca NH rbamoyl)ph N enyl)-1- Ex.4, O H methyl-N- CAS: O N NH (4-(3- 1363380- methylureid 485.4 96-4 o)benzyl)- N 1H- N indazole-3- carboxamid e 1-methyl-N- (4- O (methylcarb O amoyl)benz Ex.1, N N O H yl)-5-(4-(2- CAS: NH oxopyridin- 1363380- 1(2H)- 492.5 96-4 N yl)phenyl)- N 1H- indazole-3- carboxamid e 1-methyl-N- (4- O (methylcarb O amoyl)benz Ex.1, N N O H yl)-5-(4-(2- CAS: NH oxopiperidi 1363380- n-1- 496.5 96-4 N yl)phenyl)- N 1H- indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph O enyl)-1- methyl-N- O Ex.4, N (4- O H CAS:NNH(methylcarb 916326- amoyl)benz 471.4 80-2 yl)-1H- N N pyrazolo[3, N 4- b]pyridine- 3- carboxamid e 484.4;1H NMR (600 MHz, (CD3)2SO ) δ 8.97 (t, 1H), 8.39-8.36 5-(4- (m, 1H), O (dimethylca 8.34-8.29 O rbamoyl)ph (m, 1H), N Ex.17, O H enyl)-1- 7.86-7.82 CAS: N NH ethyl-N-(4- (m, 1H), 1077-94- (methylcarb 7.78-7.67 7 N amoyl)benz (m, 5H), N yl)-1H- 7.48-7.44 indazole-3- (m, 2H), carboxamid 7.39-7.35 e (m, 2H), 4.53-4.46 (m, 4H), 2.92 (br d, 6H), 2.73-2.69 (m, 3H), 1.45-1.39 (m, 3H). 5-(4- Ex.17 O (dimethylca substitute rbamoyl)ph O 2- N enyl)-1- O iodopropNNHHisopropyl-N- ane in (4- (methylcar 498.4 step 2, b N CAS: amoyl)benz N 1077-94- yl)-1H- 7 indazole-3- carboxamid e

[0003] 456.3;1H NMR (400MHz, (CD3)2SO ) δ 9.12- 9.03 (m, 1H), 8.48-8.40 (m, 1H), N-(4- 7.94-7.89 O carbamoylb (m, 1H), O enzyl)-5-(4- 7.88-7.81 Ex.4, NH O2(dimethylca (m, 4H), CAS: N NH rbamoyl)ph 7.79-7.73 1363380- enyl)-1- (m, 2H), 96-4 N methyl-1H- 7.54-7.48 N indazole-3- (m, 2H), carboxamid e 7.45-7.37 (m, 2H), 7.34-7.26 (m, 1H), 4.58-4.49 (m, 2H), 4.22-4.13 (m, 3H), 3.03-2.94 (m, 6H). 484.3;1H NMR (400MHz, (CD3)2SO ) δ 9.09- 9.03 (m, 1H), 8.45-8.37 (m, 2H), 5-(4- 7.89-7.81 O (dimethylca (m, 2H), rbamoyl)ph O 7.81-7.74 Ex.51, NH enyl)-N-(4- O (m, 4H), CAS: N NH (ethylcarba 7.54-7.49 1363380- moyl)benzyl (m, 2H), 96-4 )-1-methyl- N 7.44-7.38 1H- N (m, 2H), indazole-3- carboxamid e 4.56-4.51 (m, 2H), 4.20-4.15 (m, 3H), 3.30-3.22 (m, 2H), 3.03-2.94 (m, 6H), 1.16-1.04 (m, 3H). 486.3;1H NMR (400MHz, (CD3)2SO ) δ 9.61- 9.54 (m, 1H), 8.93-8.87 (m, 1H), 8.45-8.41 methyl (4- (m, 1H), H ((5-(4- 7.88-7.81 O N (dimethylca O (m, 2H), Ex.4, rbamoyl)ph 7.79-7.74 CAS:NONH O enyl)-1- (m, 2H), 1363380- methyl-1H- 7.55-7.50 96-4 N indazole-3- (m, 2H), N carboxamid o)methyl)ph enyl)carba 7.42-7.35 mate (m, 2H), 7.30-7.24 (m, 2H), 4.44-4.40 (m, 2H), 4.17-4.15 (m, 3H), 3.65-3.62 (m, 3H), 3.02-2.96 (m, 6H). 1-methyl-5- (4-(1- methyl-1H- O imidazol-2- yl)phenyl)- N Ex.5e,g, N N-(4- O H CAS: N NH (methylcarb 916326- amoyl)benz 480.4 80-2yl)-1H- N pyrazolo[3, NN4- b]pyridine- 3- carboxamid e 7-(4- (dimethylca rbamoyl)ph O enyl)-3- O methyl-N- Ex.5, N O H (4- CAS: N NH (methylcarb 2091549- amoyl)benz 470.4 14-1 N yl)imidazo[1 N ,5- a]pyridine- 1- carboxamid e 472.3;1H NMR (400 MHz, (CD3)2SO ) δ 9.35 (d, 1H), 5-(5- 9.09-9.14 (dimethylca (m, 1H), O rbamoyl)pyr 9.00 (s, imidin-2-yl) Ex.76iO - 2H), , N H 1-methyl-N- 8.52-8.58 CAS: N NONH(4- (m, 1H), 1363380- (methylcarb 8.34-8.40 96-4 N N amoyl)benz (m, 1H), N yl)-1H- 7.87-7.92 indazole-3- (m, 1H), carboxamid 7.79 (d, e 2H), 7.44 (d, 2H), 4.56 (d, 2H), 4.20 (s, 3H), 3.05 (s, 6H), 2.77 (d, 3H).

[0004] 456.1;1H NMR (400 MHz, (CD3)2SO ) δ 8.76 (t, 1H), 8.59-8.55 (m, 1H), 7-(4- 8.49 (s, (dimethylca 1H), O rbamoyl)ph 8.40-8.31 enyl)-N-( Ex.25, O 4- (m, 2H), N (methylcarb O 7.84-7.79 CAS: H N NH amoyl)benz (m, 2H), 1379306- yl)imidazo[1 7.78-7.74 59-8 ,5- N (m, 2H), N a]pyridine- 7.55-7.50 1- (m, 2H), carboxamid 7.39 (d, e 2H), 7.30 (dd, 1H), 4.52 (d, 2H), 2.97 (d, 6H), 2.75 (d, 3H). 1-methyl-5- (4-(1- O methyl-1H- 1,2,4- N Ex.1, N N triazol-5- O H CAS: N NH yl)phenyl)- 1363380- N-(4- 480.5 96-4 (methylcarb N amoyl)benz N yl)-1H- indazole-3- carboxamid e 1-methyl-5- (4-(5- O methyl-1H- pyrazol-1- Ex.1, N N O H yl)phenyl)- CAS:NNH N-(4- 1363380- (methylcarb 479.5 96-4 N amoyl)benz N yl)-1H- indazole-3- carboxamid e 5-(4-(1- ethyl-1H- O imidazol-2- N yl)phenyl)- Ex.1, N 1-methyl-N- CAS: N O H NH (4- 1363380- (methylcarb 493.5 96-4 N amoyl)benz N yl)-1H- indazole-3- carboxamid e 1- O cyclopropyl- Ex.17 5-(4- substitute O N (dimethylca bromocyc O H N NH rbamoyl)ph lopropan enyl)-N-(4- e in step (methylcarb 496.4 2, CAS: N amoyl)benz 1077-94- N yl)-1H- 7 indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph H enyl)-1- O N O methyl-N- Ex.187, O (4- CAS: N NH N (pyrrolidine- 1363380- 1- 525.6 96-4 N carboxamid N o)benzyl)- 1H- indazole-3- carboxamid e N-(4-(1H- pyrazol-5- yl)benzyl)- HN N5-(4- O (dimethylca O rbamoyl)ph Ex. 4j,e, N NH enyl)-1- P1 methyl-1H- 480.4 N pyrazolo[3, NN4- c]pyridine- 3- carboxamid e 5-(4- (dimethylca Ex.17 O rbamoyl)ph substitute enyl)-6- O methyl N fluoro-1- O H iodide in N NH methyl-N- step 2, (4- 488.4 CAS (methylcarb N 1360928- amoyl)benz 47-7F N yl)-1H- indazole-3- carboxamid e N-((1H- N indazol-5- NHyl)methyl)- Ex.4,O5-(4- CAS: O (dimethylca N NH 1363380- rbamoyl)ph 453.4 96-4 enyl)-1- N methyl-1H- N indazole-3- carboxamid e N-(4- ((cycloprop O ylmethyl)car Ex.51, O bamoyl)ben CAS: NH O zyl)-5-(4- 1363380- N NH (dimethylca 96-4 rbamoyl)ph 510.3 N enyl)-1- N methyl-1H- indazole-3- carboxamid e 5-(4- (dimethylca O rbamoyl)ph O O S enyl)-1- Ex.4, O H methyl-N CAS: N NH - N (4- 1363380- (methylsulfo 506.4 96-4 N namido)ben N zyl)-1H- indazole-3- carboxamid e N-(4-(1H- pyrazol-1- O yl)benzyl)- Ex.4, O H 5-(4- N N N CAS: N (dimethylca 1363380- rbamoyl)ph 479.4 96-4 N enyl)-1- N methyl-1H- indazole-3- carboxamid e N-(4-(1H- pyrazol-5- O yl)benzyl)- Ex.4, O H 5-(4- N N N CAS: N (dimethylca 1363380- H rbamoyl)ph 479.3 96-4 N enyl)-1- N methyl-1H- indazole-3- carboxamid e 5-(4-(1- cyanocyclo O propyl)phen yl)-1- Ex.1, N O H methyl-N- CAS: NH (4- 1363380- (methylcarb 464.3 96-4NN amoyl)benz N yl)-1H- indazole-3- carboxamid e 1-methyl-N- O (4- (methylcarb O Ex.1, N amoyl)benz O H CAS: N NH yl)-5-(4- 1363380- (oxazol-2- 466.2 96-4 yl)phenyl)- N 1H- N indazole-3- carboxamid e 6-(4- (dimethylca O rbamoyl)ph enyl)-N-(4- Ex.2d,f, O N (methylcarb CAS N O H NH amoyl)benz 1159827- yl)imidazo[1 456.2 21-0N,5- N a]pyridine- 3- carboxamid e 7-fluoro-1- methyl-5-(4- N (1-methyl- O 1H- NO HN imidazol-2- Ex. 25,N H yl)phenyl)- P3N-(4- 497.4 N (methylcarb N amoyl)benz F yl)-1H- indazole-3- carboxamid e 1-methyl-5- (5-(1- O methyl-1H- N imidazol-2- Ex.1, O HN yl)pyridin-2- CAS: N N NH yl)-N-(4- 1363380- (methylcarb 480.4 96-4 N amoyl)benz N yl)-1H- indazole-3- carboxamid e 7-chloro-1- methyl-5-(4- N (1-methyl- O 1H- NO HN imidazol-2- N Ex. 25,H yl)phenyl)- P2N-(4- 513.3 N (methylcarb N amoyl)benz Cl yl)-1H- indazole-3- carboxamid e 5-(4-(1,5- dimethyl- O 1H- N imidazol-2- Ex.1, yl)phenyl) O N - CAS: N NH H 1-methyl-N- 1363380- (4- 493.4 96-4 (methylcarb N amoyl)benz N yl)-1H- indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)-2- O O fluoropheny NO HN l)-7-fluoro- Ex. 25,N 1-methyl-N- H P3(4- 506.3 N F (methylcarb N amoyl)benz F yl)-1H- indazole-3- carboxamid e 5-(4- (dimethylca Ex.17 rbamoyl)ph O O substitute enyl)-7- methyl NOH N fluoro-1- N iodide in H methyl-N- step 2, (4- 488.4 N CAS (methylcarb N 1360953- amoyl)benz 31-6F yl)-1H- indazole-3- carboxamid e 5-(5- (dimethylca rbamoyl)pyr O O idin-2-yl)-7- OHN N N fluoro-1- Ex. 1bN , H methyl-N- P3 (4- 489.3 N (methylcarb N amoyl)benz F yl)-1H- indazole-3- carboxamid e 7-chloro-5- (5- (dimethylca O O rbamoyl)pyr N NO HN idin-2-yl)-1- Ex. 1bN , methyl-N- H P2(4- 505.3 N (methylcarb N amoyl)benz Cl yl)-1H- indazole-3- carboxamid e 5-(5- O (dimethylca rbamoyl)pyr O N idin-2-yl)-1- Ex.49, O H ethyl-7- CAS N N NH fluoro-N-(4- 1360953- (methylcarb 503.5 31-6 N amoyl)benz N yl)-1H- F indazole-3- carboxamid e

[0005] 545.4;1H NMR (600 MHz, (CD3)2SO ) δ 8.81 (t, 1H), 8.51 (s, 1H), 8.39-8.37 N-(4-(3- (m, 1H), (1,3- 7.80-7.75 dihydroxypr (m, 2H), H O N opan-2- 7.72-7.69 Ex.50,Oyl)ureido)be (m, 2H), O CAS: N NH HN nzyl)-5-(4- 7.48-7.44 1363380- OH (dimethylca (m, 2H), 96-4 N rbamoyl)ph 7.26-7.23 OH N enyl)-1- (m, 2H), methyl-1H- 7.18-7.14 indazole-3- (m, 2H), carboxamid 5.94 (d, e 1H), 4.67 (td, 2H), 4.35 (d, 2H), 4.10 (s, 3H), 3.55-3.50 (m, 1H), 3.44-3.39 (m, 4H), 2.93 (d, 6H) 5-(4- (dimethylca O rbamoyl)ph enyl)-N-(4- O Ex.51, NH ((2- O CAS: N NH methoxyeth 1363380- yl)carbamo 514.3 96-4 yl)benzyl NO)- 1-methyl- N 1H- indazole-3- carboxamid e 5-(4- Ex.17b(dimethylca substitute O O rbamoyl)ph with H enyl)-1,7- methyl NON N dimethyl-N- iodide in H (4- ep 2, (met 484.4 st N hylcarb CAS N amoyl)benz 1360962- yl)-1H- 29-3 indazole-3- carboxamid e 1-methyl-5- (4-(1- methyl-1H- O imidazol-2- yl)phenyl)- N N N-(4-Ex. 5a,g,eO H , N NH (methylcarb P1 amoyl)benz 480.4 yl)-1H- N N pyrazolo[3, N 4- c]pyridine- 3- carboxamid e 5-(4-(1H- pyrazol-1- N O yl)phenyl)- Ex.2a, N O H 1-methyl-N- N CAS: N (4- H 1363380- (methylcarb 465.5 96-4 N amoyl)benz N yl)-1H- indazole-3- carboxamid e (S)-5-(4- (dimethylca O rbamoyl)ph enyl)-1- O Ex.192, H N methyl-N- O abs H CAS: N NH (1-(4- 1363380- (methylcarb 484.5 96-4 amoyl)phen N yl)ethyl)- N 1H- indazole-3- carboxamid e N-(4- ((cyanomet O hyl)carbam O oyl)benzyl)- Ex.51, NH O 5-(4- CAS: N NH (dimethylca 1363380- rbamoy 495.3 N l)ph 96-4 N enyl)-1- N methyl-1H- indazole-3- carboxamid e 5-(4- O (dimethylca rbamoyl)ph O N Ex.15, enyl)-7- O H CAS N NH fluoro-N-(4-1360953- (methylcarb 474.4 31-6 N amoyl)benz N yl)-1H- H indazole-3- F carboxamid e 439.2;1H NMR (400 MHz, (CD3)2SO ) δ 9.10 (t, 1H), 5-(5- 8.90 (s, (cyanometh 1H), 8.66 N O yl)pyridin-2- (d, 1H), yl)-1- 8.38 (br Ex.1b, N O H methyl-N- d, 1H), CAS: N NH (4- 8.23 (dd, 1363380- (methylcarb 1H), 8.07 96-4 N amoyl)benz (d, 1H), N yl)-1H- 7.84-7.92 indazole-3- (m, 2H), carboxamid 7.79 (m, e 2H), 7.43 (m, 2H), 4.56 (d, 2H), 4.19 (s, 3H), 4.16 (s, 2H), 2.77 (d, 3H). 465.2;1H NMR (400 MHz, (CD3)2SO ) δ 9.09 (t, 1H), 5-(5-(1- 8.89 (s, cyanocyclo 1H), 8.68 O propyl)pyrid (d, 1H), in-2-yl)-1- 8.38 (br Ex.1b, N d, 1H), O H methyl-N- CAS: NH (4- 8.23 (dd, 1363380- (methylcarb 1H), 8.03 96-4 N N (d, 1H), N amoyl)benz 7.88-7.77 N yl)-1H- indazole-3- (m, 4H), carboxamid 7.43 (d, e 2H), 4.55 (d, 2H), 4.18 (s, 3H), 2.77 (d, 3H), 1.90-1.79 (m, 2H), 1.72-1.62 (m, 2H). 1-methyl-5- (4-(4- O methyl-4H- 1,2,4- N N Ex.1, N triazol-3- O H CAS: N NH yl)phenyl)- 1363380- N-(4- 480.5 96-4 (methylcarb N amoyl)benz N yl)-1H- indazole-3- carboxamid e

[0006] 500.4;1H NMR (600 MHz, (CD3)2SO ) δ 9.00 (t, 1H), 5-(4- 8.40-8.38 O (dimethylca (m, 1H), rbamoyl 8.34 (q, O )ph N enyl)-1 1H), 7.83 Ex.61,NOH-(2- hydroxyeth (d, 1H), NH CAS: yl)-N-(4- 7.78-7.70 1077-94- (m, 5H), 7 N (methylcarb 7.50-7.4 N amoyl)benz 6 yl)-1H- (m, 2H), indazole-3- 7.39 (d, OHcarboxamid 2H), 4.92 e (td, 1H), 4.54-4.50 (m, 4H), 3.86 (q, 2H), 2.99-2.92 (m, 6H), 2.73 (d, 3H) N-(4-((2- (1H- O imidazol-1- yl)ethyl)car O Ex.51, NH bamoyl)ben O CAS: N NH zyl)-5-(4- 1363380- (dimethylca 550.5 96-4 rbamoyl)ph N N enyl)-1- N N methyl-1H- indazole-3- carboxamid e 1-(2- hydroxyeth O yl)-5-(4-(1- N methyl-1H- N Ex.61, N O imidazol-2- NH H CAS: yl)phenyl)- 1077-94- N-(4- 509.4 7 N (methylcarb N amoyl)benz yl)-1H- OH indazole-3- carboxamid e 1-methyl-5- (6-methyl-5- O (1-methyl- 1H- N Ex.1, N imidazol-2- O H CAS: N NH yl)pyridin-2- 1363380- yl)-N-(4- 494.5 96-4 N (methylcarb N amoyl)benz N yl)-1H- indazole-3- carboxamid e 5-(5- (dimethylca O rbamoyl)-6- O methylpyridi Ex.1,Nn-2-yl)-1- O H CAS: N N NH methyl-N- 1363380- (4- 485.4 96-4 (methylcarb N amoyl)benz N yl)-1H- indazole-3- carboxamid e

[0007] 526.5;1H NMR (400 MHz, (CD3)2SO ) δ 9.08 (t, 1H), 8.45 (s, rac-(R)-5- 1H), (4- 7.89-7.82 (dimethylca (m, 2H), &1OH rbamoyl)ph 7.77 (d, enyl)- 2H), O N-(4- Ex.51, N 7.55-7.38 H (3- CAS: O N N hydroxypyrr (m, 6H), 1363380- O olidine-1- 5.05-4.87 96-4 carbonyl)be (m, 1H), N N nzyl)-1- 4.55 (br methyl-1H- d, 2H), indazole-3- 4.31 (br carboxamid s, 1H), e 4.19 (s, 3H), 3.63-3.42 (m, 3H), 3.31-3.09 (m, 1H), 2.99 (br s, 6H), 1.98-1.73 (m, 2H). 484.5;1H NMR (400 MHz, (CD3)2SO ) δ 9.08 (t, 1H), N-(4- 8.45 (s, O (dimethylca 1H), O rbamoyl)be 7.90-7.81 Ex.51,Nnzyl)-5-(4- (m, 2H), O CAS: N NH (dimethylca 7.77 (m, 1363380- rbamoyl)ph 2H), 7.52 96-4 enyl)-1- (m, 2H), N methyl-1H- 7.42 (m, N indazole-3- 2H), 7.37 carboxamid (m, 2H), e 4.54 (br d, 2H), 4.19 (s, 3H), 2.99 (br s, 9H), 2.91 (br s, 3H). 526.1;1H NMR (400 MHz, (CD3)2SO ) δ 9.10- 9.03 (m, 5-(4- 1H), (dimethylca 8.51-8.41 rbamoyl) (m, 2H), O ph enyl)-N-(4- 7.88-7.73 O (((1s,3s)-3 (m, 6H), Ex.51, NH - O hy 7.55-7.38 CAS: N NH &1 droxycycl (m, 4 1363380- obutyl)carb H), 5.11-5.03 96-4 &1 amoyl)benz N HO yl)-1- (m, 1H) , N methyl-1H- 4.58-4.49 indazole-3- (m, 2H), carboxamid 4.22-4.14 e (m, 3H), 3.94-3.78 (m, 2H) , 3.28 (s, 2H), 3.05-2.93 (m, 6H), 1.96-1.84 (m, 2H). 500.1;1H NMR (400 MHz, (CD3)2SO ) δ 9.07 (t, 1H), 5-(4- 8.47-8.32 O (dimethylca (m, 2H), rbamoyl)ph 7.89-7.74 O Ex.51, NH enyl)-N-(4- (m, 6H), O CAS: N NH ((2- 7.54-7.40 1363380- hydroxyeth (m, 4H), 96-4 yl)carbamo 4.76-4.68 N HO yl)benzyl)- (m, 1H), N 1-methyl- 4.59-4.51 1H- (m, 2H), indazole-3- 4.22-4.15 carboxamid (m, 3H), e 3.53-3.45 (m, 2H), 3.33-3.27 (m, 2H), 3.06-2.93 (m, 6H). 5-(1-acetyl- 1,2,3,4- O tetrahydroq O uinolin-6- Ex.1, N yl)-1- N O H CAS: NH methyl-N- 1363380- (4- 496.3 96-4 (methylcarb N amoyl)benz N yl)-1H- indazole-3- carboxamid e 457.4; 1H NMR (400 MHz, (CD3)2SO ) δ 10.26 5-(5- (s, 1H), acetamidop 9.06 (t, yridi 1H), 8.83 O n-2-yl)- 1-m (s, 1H), O ethyl-N- (4- 8.80 (d, Ex.1b, N HN O H (methylcar 1H), 8.38 N NH b CAS: amoyl)benz (br d, 1363380- yl)-1H- 1H), 8.18 96-4 N indazole-3- (ddd, N carboxamid 2H), 7.96 e (d, 1H), 7.84-7.77 (m, 3H), 7.43 (d, 2H), 4.55 (d, 2H), 4.17 (s, 3H), 2.77 (d, 3H), 2.11 (s, 3H). 5-(4- (dimethylca OH rbamoyl)ph O enyl)-N-(4- N (4-hydroxy- Ex.187, O NH 4- CAS: O methylpiper 1363380- N NH idine-1- 569.5 96-4 carboxamid N o)benzyl)-1- N methyl-1H- indazole-3- carboxamid e 1-methyl-5- (4-methyl-5- O oxo-2,3,4,5- tetrahydrob O Ex.1, N enzo[f][1,4] N O H CAS: NH oxazepin-8- 1363380- yl)-N-(4- 498.2 96-4O (methylcarb N amoyl)benz N yl)-1H- indazole-3- carboxamid e N-((1H- indazol-6- O yl)methyl)- Ex.4e, O H 5-(4- N N CAS: (dimethylca N 1363380- N rbamoyl)ph 453.2 96-4 N H enyl)-1- N methyl-1H- indazole-3- carboxamid e

[0008] 539.6;1H NMR (600 MHz, (CD3)2SO ) δ 8.86 (t, 1H), 8.45-8.41 (m, 1H), 8.01 (s, 1H), 7.85-7.79 (m, 2H), rac-(R)-5- 7.76-7.73 (4- (m, 2H), (dimethylca 7.52-7.48 H rbamoyl)ph (m, 2H), O N enyl)-1- 7.43-7.39 O Ex.75, methyl-N- (m, 2H), O CAS: N NH N (4-(3- 7.21-7.17 1363380- methylpyrro (m, 2H), 96-4 &1 lidine-1- 4.40 (d, N carboxamid 2H), 4.14 N o)benzyl)- (s, 3H), 1H- 3.53 (dd, indazole-3- 1H), carboxamid 3.47-3.43 e (m, 1H), 3.30-3.24 (m, 1H), 2.97 (d, 6H), 2.86 (t, 1H), 2.25-2.17 (m, 1H), 1.99-1.91 (m, 1H), 1.50-1.41 (m, 1H), 1.00 (d, 3H). 5-(4-(2,3- dihydro-1H- pyrrolo[3,4- c]pyridine- 2- Ex.76, carbonyl)ph CAS: enyl)-1- 1363380- methyl-N- 545.3 96-4 (4- (methylcarb amoyl)benz yl)-1H- indazole-3- carboxamid e 5-(4-(6,7- dihydro-5H- pyrrolo[3,4- b]pyridine- 6- Ex.76, carbonyl)ph CAS: enyl)-1- 1363380- methyl-N- 545.3 96-4 (4- (methylcarb amoyl)benz yl)-1H- indazole-3- carboxamid e 7-fluoro-1- methyl-5-(5- (1-methyl- 1H- imidazol-2- Ex. 1b, yl)pyridin-2- P3 yl)-N-(4- 498.3 (methylcarb amoyl)benz yl)-1H- indazole-3- carboxamid e 7-chloro-1- methyl-5-(5- (1-methyl- 1H- imidazol-2- Ex. 1b, yl)pyridin-2- P2 yl)-N-(4- 514.3 (methylcarb amoyl)benz yl)-1H- indazole-3- carboxamid e

[0009] 483.1;1H NMR (400MHz, (CD3)2SO ) δ 8.97- 8.93 (m, 1H), 8.89-8.83 5-(4- (m, 1H), (dimethylca 8.45-8.41 rbam (m, 1H), H oyl)ph N eny 7.88-7.80 O l)-1- methyl-N- (m, 2H), Ex.4e, NH 7.79-7.73 O ((2-oxo- CAS: (m, 2H), O 1,2,3,4- 1363380- N NH tetrahydroq 7.55-7.49 96-4 uinazolin-6- (m, 2H), N yl)methyl)- 7.14-7.09 N 1H- (m, 1H), indazole-3- 7.09-7.05 carboxamid (m, 1H), e 6.77-6.67 (m, 2H), 4.42-4.35 (m, 2H), 4.28 (s, 2H), 4.19-4.13 (m, 3H), 3.04-2.93 (m, 6H). 5-(4- (dimethylca rbamoyl)ph Ex.4, enyl)-N-(4- CAS: hydroxyben 1363380- zyl)-1- 429.4 96-4 methyl-1H- indazole-3- carboxamid e 1-methyl-N- (4- (methylcarb amoyl)benz Ex.1, yl)-5-(5-(2- CAS: oxopyrrolidi 1363380- n-1- 483.4 96-4 yl)pyridin-2- yl)-1H- indazole-3- carboxamid e 5-(1- acetylindoli n-5-yl)-1- Ex.1, methyl-N- CAS: (4- 1363380- (methylcarb 482.3 96-4 amoyl)benz yl)-1H- indazole-3- carboxamid e 481.2;1H NMR (400 MHz, (CD3)2SO ) δ 9.44 1-methyl-5- (d, 1H), (5-(1- 9.28-9.21 methyl-1H- (m, 2H), imidazol-2- 9.07 (s, O yl)114yridin 1H), 8.38 N e-2-yl)-N- (br d, Ex.1b, N H (4- 1H), CAS N O N NH (methylcarb 8.27-8.24 916326- amoyl)benz (m, 2H), 81-3 N yl)-1H- 7.82-7.78 NNpyrazolo[3, (m, 2H), 4- 7.47-7.42 b]pyridine- (m, 2H), 3- 7.37 (s, carboxamid 1H), 7.08 e (s, 1H), 4.57 (d, 2H), 4.21 (s, 3H), 3.87 (s, 3H), 2.77 (d, 3H). 5-(4- (dimethylca rbamoyl)ph enyl)-1- methyl-N- (4-(3- Ex. 4j,e, methylureid P1 o)benzyl)- 486.4 1H- pyrazolo[3, 4- c]pyridine- 3- carboxamid e 5-(5- (dimethylca H rbamoyl)pyr O N H N imidin-2-yl)- Ex.1, O 1-methyl-N- CAS: N N NH O (4-(3- 1363380- 487.4 N methylureid 96-4 N o)benzyl)- N 1H- indazole-3- carboxamid e 472.2;1H NMR (400 MHz, (CD3)2SO ) δ 9.30 (d, 1H), 5-(5- 9.13 (t, (dimethylca 1H), 9.01 rbamoyl)pyr (d, 1H), azin-2-yl)-1- 8.90 (d, Ex.1, methyl-N- 1H), 8.37 CAS: (4- (br d,1363380- (methylcarb 1H), 8.32 96-4 amoyl)benz (dd, 1H), yl)-1H- 7.94 (d, indazole-3- 1H), 7.79 carboxamid (m, 2H), e 7.43 (m, 2H), 4.56 (d, 2H), 4.21 (s, 3H), 3.07 (s, 6H), 2.77 (d, 3H).

[0010] 496.2;1H NMR (400 MHz, CD3OD) 3- δ 8.49- cyclopropyl- 8.41 (m, 7-(4- 2H), 7.87 (dimethylca (d, 2H), rbamoyl)ph 7.78 (d, Ex.88, enyl)-N-(4- 2H), 7.57 CAS: (methylcarb (d, 2H), 1363381- amoyl)benz 7.47 (d, 07-0 yl)imidazo[1 2H), 7.26 ,5- (dd, 1H), a]pyridine- 4.66 (s, 1- 2H), 3.10 carboxamid (d, 6H), e 2.90 (s, 3H), 2.33-2.25 (m, 1H), 1.21-1.06 (m, 4H). 525.2;1H NMR (400 MHz, CD3OD) 3- δ 8.46- cyclopropyl- 8.40 (m, 7-(4- 2H), (dimethylca 7.88-7.84 rbamoyl)ph (m, 2H), Ex.88, enyl)-N-(4- 7.56-7.54 CAS: (3,3- (m, 2H), 1363381- dimethylure 7.31 (q, 07-0 ido)benzyl)i 4H), midazo[1,5- 7.26-7.22 a]pyridine- (m, 1H), 1- 4.55 (s, carboxamid 2H), 3.10 e (d, 6H), 3.00 (s, 6H), 2.30-2.22 (m, 1H), 1.17-1.04 (m, 4H) 1- cyclopropyl- 5-(4- H (dimethylca O N rbamoyl)ph N enyl)-N-(4- O N NH O (3,3- Ex.4, P4 dimethylure ido)be 526.2 N nzyl)- NN1H- pyrazolo[3, 4- c]pyridine- 3- carboxamid e 497.3;1H NMR (400 MHz, CD3OD) δ 8.88 (s, 1- 1H), 8.72 cyclopropyl- (s, 1H), 5-(5- 8.26-8.21 (dimethylca (m, 1H), 8.06-7.94 Ex.183, rbamoyl)pyr idin-2-yl)-N- (m, 2H), CAS: 7.90-7.84 2851974- (4- (methy (m, 1H), 84-4 lcarb amoyl)benz 7.79 (d, yl)-1H- 2H), 7.50 indazole-3- (d, 2H), carboxamid 4.69 (s, e 2H), 3.88-3.81 (m, 1H), 3.13 (d, 6H), 2.90 (s, 3H), 1.35-1.20 (m, 4H). 1- cyclopropyl- H N 5-(5- O N (dimethylca Ex.183, O rbamoyl)pyr N N NH O CAS: idin-2-yl)-N- 2851974- (4-(3,3- 526.2 N 84-4 dimethylure N ido)benzyl)- 1H- indazole-3- carboxamid e 494.2;1H NMR (400 MHz, (CD3)2SO ) δ 9.01 (t, 1H), 1-methyl-5- 8.80 (s, (4-(1- 1H), methyl-1H- 8.47-8.44 imidazol-2- (m, 1H), Ex.176, yl)phenyl)- 8.23 (d, CAS: N-(4-(3- 1H), 1363380- methylureid 7.89-7.73 96-4 o)benzyl)- (m, 7H), 1H- 7.69 (dd, indazole-3- 1H), 7.28 carboxamid (d, 1H), e 7.00 (d, 1H), 4.44 (d, 2H), 4.17 (s, 3H), 3.81 (s, 3H), 2.92 (s, 6H). 1-methyl-5- (4-(1- methyl-1H- imidazol-2- yl)phenyl)- N-(4-(3- methylureid Ex.2, P1 o)benzyl)- 495.3 1H- pyrazolo[3, 4- c]pyridine- 3- carboxamid e N-(4-(3,3- dimethylure ido)benzyl)- 1-methyl-5- (4-(1- methyl-1H- imidazol-2- Ex.2, P1 yl)phenyl)- 509.3 1H- pyrazolo[3, 4- c]pyridine- 3- carboxamid e N-(4-(3,3- dimethylure ido)benzyl)- 1-methyl-5- Ex.1k, (5-(1- CAS: methyl-1H- 1363380- imidazol-2- 509.4 96-4 yl)pyridin-2- yl)-1H- indazole-3- carboxamid e 498.3;1H NMR (400 MHz, CD3OD) 1- δ 9.25 (d, cyclopropyl- 1H), 9.08 5-(5- (d, 1H), (dimethylca 8.72 (d, rbamoyl)pyr 1H), 8.00 idin-2-yl)-N- (d, 1H), (4- 7.94 (dd,Ex. 183,(methylcarb 1H), 7.77 P5amoyl)benz (d, 2H), yl)-1H- 7.47 (d, pyrazolo[3, 2H), 4.65 4- (s, 2H), b]pyridine- 4.07-4.00 3- (m, 1H), carboxamid 3.11 (d, e 6H), 2.89 (s, 3H), 1.39-1.33 (m, 2H), 1.21-1.14 (m, 2H). 1-methyl-5- (5-(3- O methyl-2- NOoxoimidazol Ex.1, N idin-1- N O H CAS: N NH yl)pyridin-2- 1363380- yl)-N-(4- 498.4 96-4 (methylcarb N amoyl)benz N yl)-1H- indazole-3- carboxamid e 524.3;1H NMR (400 MHz, (CD3)2SO ) δ 9.08 (s, 1H), 9.00-8.95 (m, 1H), 8.89 (t, (Z)-N-(4-(2- 1H), 8.74 cyano-3,3- (d, 1H), H dimethylgu 8.31-8.20 O N N anidino)ben (m, 1H), Ex.99, zyl)-5-(5- 8.09 (d, CAS:N NONH N (dimethylca 1H), 7.96 1363381- N rbamoyl)pyr (dd, 1H), 41-2 N idin-2-yl)-1- 7.87 (d, N methyl-1H- 1H), 7.41 indazole-3- (d, 1H), carboxamid 7.36-7.29 e (m, 1H), 7.24 (d, 1H), 7.01 (d, 1H), 4.46 (dd, 2H), 4.19 (d, 3H), 3.03 (br s, 6H), 2.95 (d, 6H). 5-(4-(1,4- dimethyl- O 1H- imidazol-2- N Ex.1, N yl)phenyl)- O H CAS: N NH 1-methyl-N- 1363380- (4- 493.4 96-4 (methylcarb N amoyl)benz N yl)-1H- indazole-3- carboxamid e 471.3;1H NMR (400 MHz, 7-(5- CD3OD) (dimethylca δ 8.80 (s, rbamoy 1H), 8.73 Ex.88 l)pyr O idi (s, 1H), substitute n-2-yl)-3- 8.17 (d, with O methyl-N- N (4 1H), 8.06 methylbo O H - N N NH (methylcar (d, 1H), ronic acid b amoy 7.95 (d, to step 3, l)benz yl)imidaz 1H), 7.78 CAS: N o[1 N (d, 2H), 1363381- ,5- a]pyridi 7.62 (d, 07-0 ne- 1- 1H), 7.48 carboxamid (d, 2H), e 4.67 (s, 2H), 3.11 (d, 6H), 2.90 (s, 3H), 2.68 (s, 3H) 512.4;1H NMR (400 MHz, (CD3)2SO ) δ 8.95 (d, 1H), N-(4-(3,3- 8.90-8.85 dimethylure (m, 2H), ido)benzyl)- 8.25-8.18 1-methy (m, 3H), H l-5- Ex.3c, N 8.02 (d NO HN N, CAS:N(5-(2- O oxopyrrolidi 1H), 7.82 1363381- O n- (d, 1H), 41-2N 1- N yl)pyridin-2- 7.40 (d, yl)-1H- 2H), 7.22 indazole-3- (d, 2H), carboxamid 4.43 (d, e 2H), 4.16 (s, 3H), 3.92 (t, 2H), 2.90 (s, 6H), 2.57-2.50 (m, 2H), 2.17-2.05 (m, 2H). 574.4;1H NMR (400 MHz, (CD3)2SO ) δ 8.87 5-(4-(6,7- (t, 1H), dihydro-5H- 8.47 (q, pyrrolo[3,4- 2H), 8.22 b]pyridine- (s, 1H), H 7.86-7.80 ON6- N carbonyl) (m, Ex.103, ph O N eny 4H),7.78- CAS:NNH O l)-N-(4- 7.70 (m, 1363380- (3,3- dime 3H), 96-4 N thylure i 7.42-7.36 N do)benzyl)- 1-methyl- (m, 2H), 1H- 7.35-7.28 indazole-3- (m, 1H), carboxamid 7.24-7.19 e (m, 2H), 4.97-4.82 (m, 4H), 4.42 (d, 2H), 4.17 (s, 3H), 2.89 (s, 6H).

[0011] 575.3;1H NMR (400 MHz, (CD3)2SO ) δ 9.38 5-(4-(6,7- (s, 1H), dihydro-5H- 9.06 (t, pyrrolo[3,4- 1H), 8.58 b]pyridine- (s, 1H), 6- 8.51-8.44 H carbonyl)ph (m, 1H), ONNenyl)-N-(4- 8.25-8.19 O (3,3- (m, 3H),Ex. 76,NNNH O dimethylure 7.88-7.68 P1ido)benzyl)- (m, 3H), N N 1-methyl- 7.43-7.37 N 1H- (m, 2H), pyrazolo[3, 7.36-7.26 4- (m, 1H), c]pyridine- 7.25-7.20 3- (m, 2H), carboxamid 4.97-4.82 e (m, 4H), 4.45 (d, 2H), 4.31-4.28 (m, 3H), 2.90 (d, 6H)

[0012] 575.3;1H NMR (400 MHz, (CD3)2SO ) δ 9.02- 8.90 (m, 3H), 5-(5-(6,7- 8.51-8.41 dihydro-5H- (m, 1H), pyrrolo[3,4- 8.31-8.26 b]pyridine- (m, 1H), H N 6- 8.24-8.11 O Ex.103,Ncarbonyl)py (m, 3H), O CAS:NNN NH O ridin-2-yl)- 7.88-7.84 1363380- N-(4-(3,3- (m, 1H), 96-4 N dimethylure 7.74-7.70 N ido)benzyl)- (m, 1H), 1-methyl- 7.40 (d, 1H- 2H), indazole-3- 7.37-7.29 carboxamid (m, 1H), e 7.23 (d, 2H), 4.49-4.87 (m, 4H), 4.45 (d, 2H), 4.18 (s, 3H), 2.90 (s, 6H)

[0013] 514.3;1H NMR (400 MHz, (CD3)2SO ) δ 8.96- 8.94 (m, 1H), 8.83 (t, 1H), 5-(5- 8.73 (dd, ( 1H), H dimethylca O r 8.25-8.20 N bamoyl)pyr N idin-2-yl)-N- (m, 2H), Ex.1b, O (4-(3, 8.07 (dd, CAS: N N NH O 3- dim 1H), 7.94 1077-94- ethylure ido)ben (dd, 1H), 7Nzyl)- 1-ethyl 7.89 (d, N -1H- indazole-3- 1H), carboxamid 7.42-7.38 e (m, 2H), 7.26-7.21 (m, 2H), 4.56 (q, 2H), 4.44 (d, 2H), 3.02 (br s, 6H), 2.90 (s, 6H), 1.48 (t, 3H)

[0014] 514.3;1H NMR (400 MHz, (CD3)2SO ) δ 9.41 (d, 1H), 5-(4- 9.02 (t, (dimethylca 1H), 8.55 rbamoyl)ph (d, 1H), H enyl)-N-(4- 8.23 (s, Ex.25, O N N (3,3- 1H), P1 O dim substitute O ethylure 8.18-8.12 N NH ido)benzyl)- (m, 2H), with ethyl 1-ethyl-1H- 7.55-7.50 iodide in N N pyrazolo[3, (m, 2H), step 4 N 4- 7.42-7.37 c]pyridine- (m, 2H), 3- 7.25-7.21 carboxamid (m, 2H), e 4.68 (q, 2H), 4.44 (d, 2H), 3.03-2.95 (m, 6H), 2.90 (s, 6H), 1.54 (t, 3H). 527.4;1H NMR (400 MHz, CD3OD) 1- δ 9.31 (d, cyclopropyl- 1H), 9.16 5-(5- (d, 1H), (dimethylca 8.80-8.71 H O N rbamoyl)pyr (m, 1H), N idin-2-yl)-N- 8.07 (d, O N NH O (4-(3,3- 1H), 7.99Ex. 183,dimethylure (dd, 1H), P5N N ido)benzyl)- 7.37-7.28 NN1H- (m, 4H), pyrazolo[3, 4.62-4.50 4- (m, 2H), b]pyridine- 4.11-4.03 3- (m, 1H), carboxamid 3.13 (d, e 6H), 3.00 (s, 6H), 1.43-1.32 (m, 2H), 1.27-1.16 (m, 2H). 1-methyl-5- (5-(1- H methyl-1H- N N H imidazol-2- Ex.1bN , yl)pyridin-2- CAS: NNONH O yl)-N-(4-(3- 1363380- methylureid 495.2 96-4No)benzyl)- N 1H- indazole-3- carboxamid e N-(4-(3,3- dimethylure H N N ido)benzyl)- Ex.2,N5-(4-(1- O CAS: N NH O methyl-1H- 1077-94- imidazol-2- 494.4 7Nyl)phenyl)- N 1H- H indazole-3- carboxamid e 486.3;1H NMR (400 MHz, (CD3)2SO ) δ 13.71 (s, 1H), 8.97-8.94 (m, 1H), 5-(5- 8.91 (t, (dimethylca 1H), H N rbamoyl)pyr 8.73-8.71 O N Ex.1, idin-2-yl)-N- (m, 1H), O CAS: N N NH O (4-(3,3- 8.25-8.18 1077-94- dimethylure (m, 2H), 7Nido)benzyl)- 8.05 (d, N 1H- 1H), 7.94 H indazole-3- (dd, 1H), carboxamid 7.72 (d, e 1H), 7.43-7.36 (m, 2H), 7.25-7.20 (m, 2H), 4.45 (d, 2H), 3.02 (s, 6H), 2.90 (s, 6H). N-(4-(1H- N imidazol-2- yl)benzyl)- O Ex.4e, N 5-(4- CAS:NOH NH (dimethylca 1363380- rbamoyl)ph 479.4 96-4 enyl)-1- N methyl-1H- N indazole-3- carboxamid e 480.3;1H NMR (400 MHz, (CD3)2SO ) δ 8.87 (t, 1H), 8.48-8.44 1-methyl-5- (m, O (4-(1- 2H),7.87- NH2methyl-1H- 7.84 (m, NH 76, im 2H), Ex.1 N idazol-2- CAS: yl 7.83-7.80 N O )phenyl)- NH (m, 4 380- N-(4 H), 1363 - 7.36-7.31 96-4 ureidobenz yl)- (m, 2H), N 1H- i 7.29-7.25 N ndazole-3- carboxamid (m, 1H), e 7.25-7.20 (m, 2H), 7.01 (d, 1H), 5.78 (s, 2H), 4.42 (d, 2H), 4.17 (s, 3H), 3.81 (s, 3H).

[0015] 472.4;1H NMR (400 MHz, (CD3)2SO ) δ 8.98- 8.93 (m, 1H), 8.89 (t, 1H), 5-(5- 8.74-8.71 O (dimethy (m, 1H), NH lca 2 rbamoyl)pyr 8.46 (s, NH idin-2-yl 1H), 8.25 Ex.103, O )-1- m (dd, 1H), CAS: O ethyl-N- N N NH 8.08 (d, 1363380- (4- 1H), 7.94 96-4 ureidobenz (dd, 1H), N yl)-1H- indazo 7.85 (d, N le-3- carboxamid 1H), e 7.37-7.30 (m, 2H), 7.24-7.18 (m, 2H), 5.78 (s, 2H), 4.42 (d, 2H), 4.17 (s, 3H), 3.07-2.96 (m, 6H). 500.3;1H NMR (400 MHz, CD3OD) 7-(5- δ 8.86 (s, (dimethylca 1H), Ex.88 rbamoyl)pyr 8.76-8.73 substitute H idin-2-yl)-N- (m, 1H), N with O N (4-(3,3- 8.21 (d, methylbo O dimethylure 1H), 8.10 N N NH O ronic acid ido)benzyl)- (d, 1H), in step 3, 3- 7.98 (dd, CAS: N methylimida 1H), N 1363381- zo[1,5- 7.69-7.64 07-0 a]pyridine- (m, 1H), 1- 7.38-7.29 carboxamid (m, 4H), e 4.58 (s, 2H), 3.12 (d, 6H), 3.00 (s, 6H), 2.70 (s, 3H). 531.3;1H NMR (400 N-(4- MHz, carbamoylb (CD3)2SO enzyl)-5-(4- ) δ 9.08 O (6,7- (t, 1H), dihydro-5 Ex.103,OH- 8.50-8.42 NH2pyrrolo[3,4- (m, 2H), CAS:ONHb]pyridine- 7. 1363380-NN96-7.68 6- (m, 10H), 96-4 N carbonyl)ph 7.42 (d, N enyl)-1- 2H), methyl-1H- 7.39-7.25 indazole-3- (m, 2H), carboxamid 4.98-4.79 e (m, 4H), 4.55 (d, 2H), 4.19 (s, 3H). 523.3;1H NMR (400 MHz, (CD3)2SO ) δ 9.04- 9.02 (m, 1H), 8.99-8.96 (m, 1H), N-(4-(3,3- 8.88 (t, dimethylure 1H), ido)be 8.30-8.18 H nzyl)- N N 1-eth (m, 3H), N yl-5- Ex.1b, ( 8.12 (d, O 5-(1- CAS:NNNH O methyl-1H- 1H), 7.90 1077-94- imidazol-2- (d, 1H), 7 N yl)pyridin-2- 7.43-7.38 N yl)-1H- (m, 2H), indazole-3- 7.36-7.34 carboxamid (m, 1H), e 7.24 (d, 2H), 7.06 (d, 1H), 4.56 (q, 2H), 4.44 (d, 2H), 3.85 (s, 3H), 2.91-2.90 (m, 6H), 1.48 (t, 3H). 523.3;1H NMR (400 MHz, (CD3)2SO ) δ 9.42 (d, 1H), N-(4-(3,3- 9.03 (t, dimethylure 1H), 8.57 ido)benzyl)- (d, 1H), H 1-ethyl-5- 8.26-8.16 Ex.2c, N N (4-(1- (m, 3H), N P1 methyl-1H- 7.86-7.81 substitute N O NH O imidazol-2- (m, 2H), with ethyl yl)phenyl)- 7.42-7.38 iodide in N 1H- (m, 2H), step 4NNpyrazolo[3, 7.30-7.27 4- (m, 1H), c]pyridine- 7.26-7.21 3- (m, 2H), carboxamid 7.01 (d, e 1H), 4.69 (q, 2H), 4.45 (d, 2H), 3.82 (s, 3H), 2.90 (s, 6H), 1.54 (t, 3H). 5-(4-(5,6- dihydro-4H- pyrrolo[3,4- d]thiazole- O O 5- Ex.76, NO Hcarbonyl)ph CAS:NN enyl)-1- H 1363380- methyl-N- 551.2 S 96-4 N N (4- N (methylcarb amoyl)benz yl)-1H- indazole-3- carboxamid e 7-chloro-5- (4- (dimethylca O O rbamoyl)ph OHN N enyl)-1-Ex. 25,N methyl-N- H P2(4- 504.3 N (methylcarb N amoyl)benz Cl yl)-1H- indazole-3- carboxamid e 515.4;1H NMR (400 MHz, CD3OD) 1- δ 8.73- cyclopropyl- 8.68 (m, O 5-(5- 2H), ( 8.08-7.93 O dimethylca N rbamoyl) (m, 3H), O H pyr 7.80-7.76Ex. 183,N N NHidin-2-yl)-7- (m, 2H), P6fluoro-N-(4- (m 7.49 (d, N ethylcarb amoyl)ben 2H), 4.68 N z yl)- (s, 2H), F 1H- indazole-3- 4.12-4.04 carboxamid (m, 1H), e 3.12 (d, 6H), 2.90 (s, 3H), 1.43-1.37 (m, 2H), 1.24-1.18 (m, 2H).

[0016] 532.4;1H NMR (400 MHz, (CD3)2SO ) δ 9.10 N-(4- (t, 1H), carbamoylb 9.00-8.90 enzyl)-5-(5- (m, 2H), (6, 8.48 (dd, O 7- dihy 1H), O dro-5H- Ex.103, NH 8.23-8.26 CAS: O2pyrrolo[3,4- N N NH b]pyridine- (m, 1H), 1363380- 6- 8.21-8.10 96-4 carbonyl)p (m, 2H), N N y N ridin-2-yl)-1- 7.95-7.80 methyl-1H- (m, 4H), indazole-3- 7.72 (d, carboxamid 1H), 7.43 e (d, 2H), 7.37-7.28 (m, 2H), 4.97-4.85 (m, 4H), 4.56 (d, 2H), 4.19 (s, 3H). 485.4;1H NMR (600 MHz, (CD3)2SO ) δ 9.05 (t, 1H), 8.95-8.92 5-(5- (m, 1H), (di 8.73 (d, O methylca rbamoyl)pyr 1H), 8.37 O idin-2 (q, 1H), Ex.176,N-yl)-1- O H ethyl-N- 8.24 (d, CAS: N NH (4- 1 1077-94- (methylcarb H), 8.08 amoyl)ben (d, 1H), 7 N z N yl)-1H- 7.95 (dd, N indazole-3- 1H), 7.91 carboxamid (d, 1H), e 7.79 (d, 2H), 7.43 (d, 2H), 4.60-4.53 (m, 4H), 3.01 (d, 6H), 2.76 (d, 3H), 1.49 (t, 3H). 486.2;1H NMR (400 MHz, (CD3)2SO ) δ 9.36- 9.33 (m, 5-(5- 1H), 9.09 (dimethylca (t, 1H), O rbamoyl)pyr 8.99 (s, O imidin-2-yl)- 2H), 8.53 Ex.1b,N(dd, 1H), O H 1-ethyl-N- CAS:N N NH(4- 8.40-8.34 1077-94- (methylcarb (m, 1H), 7 N N amoyl)benz 7.92 (d, N yl)-1H- 1H), indazole-3- 7.81-7.77 carboxamid (m, 2H), e 7.44 (d, 2H), 4.61-4.54 (m, 4H), 3.04 (s, 6H), 2.76 (d, 3H), 1.50 (t, 3H). 548.6;1H NMR (400 MHz, (CD3)2SO ) δ 9.08 1-methyl-5- (t, 1H), (4-(1- 8.45-8.43 methyl- (m, 1H), 1,4,5,6- 8.38 (q, tetrahydrop 1H), O O yrrolo[3,4- 7.89-7.84 Ex.76, NO Hc]pyrazole- (m, 2H), CAS:NN 5- 7.82-7.76 H 1363380-Ncarbo (m, 4H), N N nyl)ph 96-4 N enyl)-N-(4- 7.72-7.68 (methylcarb (m, 2H), amoyl)benz 7.42 (d, yl)-1H- 2H), 7.22 indazole-3- (d, 1H), carboxamid 4.73 (d, e 2H), 4.61-4.52 (m, 4H), 4.18 (s, 3H), 3.75 (d, 3H), 2.76 (d, 3H). 5-(4- (dimethylca rbamoyl)ph O N enyl)-1- methyl-N- Ex.187, O NH (4- CAS: NON (piperidine- 1363380-H1- 539.5 96-4 carboxamid N N o)benzyl)- 1H- indazole-3- carboxamid e (R)-N-(4- ((5-(4- (dimethylca rbamoyl)ph O N O enyl)-1- abs methyl-1H- Ex.187h, O NH N indazole-3- CAS: O H N NH carboxamid 1363380- o)methyl)ph 596.3 96-4 N enyl)-6-oxa- N 2,9- diazaspiro[ 4.5]decane- 2- carboxamid e rac-(R)-5- (4- (dimethylca rbamoyl)ph O N &1 enyl)-N-(4- Ex.187, O NH OH (3- CAS:O(hydroxyme 1363380- NNHthyl)piperidi 569.5 96-4 ne-1- N carboxamid N o)benzyl)-1- methyl-1H- indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph O NNenyl)-1- methyl-N- Ex.187, O NH (4-(4- CAS: 1363380- NONHmethylpiper azine-1- 554.5 96-4 carboxamid N N o)benzyl)- 1H- indazole-3- carboxamid e (R)-5-(4- (dimethylca rbamoyl)ph O abs enyl)-1- N methyl-N- Ex.187, O NH (4-(2- CAS: methylpyrr 1363380- NOo NHlidine-1- 539.5 96-4 carboxamid N o)benzyl)- N 1H- indazole-3- carboxamid e rac-(R)-5- (4- (dimethylca O rbamoyl)ph N&1enyl)-N-(4- Ex.187, O NH O (3- CAS: (methoxym NO1363380-NHethyl)pyrroli 569.5 96-4 dine-1- N carboxamid N o)benzyl)-1- methyl-1H- indazole-3- carboxamid e

[0017] 5-(4- (dimethylca rbamoyl)ph enyl)-1- O NNHmethyl-N- Ex.187, O NH (4-(3-oxo- O CAS: 1,4- O 1363380- N NH diazepane- 568.5 96-4 1- N carboxamid N o)benzyl)- 1H- indazole-3- carboxamid e (R)-5-(4- O (dimethylca rbamoyl)ph O abs N enyl)-N-(4- Ex.187, (3- NH CAS: O methoxypip 1363380- eridine-1- 56 NO9.5 NH96-4 carboxamid o)benzyl)-1- N methyl-1H- N indazole-3- carboxamid e 5-(4- (dimethylca O N rbamoyl)ph N &1 enyl)-N-(4- Ex.187, NH (3,4- O CAS:Odimethylpip 1363380- NNHerazine-1- 568.5 96-4 carboxamid N o)benzyl)-1- N methyl-1H- indazole-3- carboxamid e N-(4-((5-(4- (dimethylca rbamoyl)ph O O enyl)-1- N methyl-1H- Ex.187, O NH indazole-3- CAS: O carboxamid 1363380- N NH o)methyl)ph 553.5 96-4 enyl)-2-oxa- N 6- N azaspiro[3. 3]heptane- 6- carboxamid e N-(4-((5-(4- (dimethylca ON Orbamoyl)ph enyl)-1- Ex.187, O NH methyl-1H- CAS:Oindazole-3- 1363380- NNHcarboxamid 541.5 96-4 o)methyl)ph N enyl)morph N oline-4- carboxamid e (S)-5-(4- (dimethylca rbamoyl)ph O Nabs OHenyl)-N-(4- (3-hydroxy- Ex.187, O NH 3- CAS: NO1363380-NHmethylpyrro lidine-1- 555.5 96-4 N carboxamid N o)benzyl)-1- methyl-1H- indazole-3- carboxamid e 5-(4- (dimethylca O O rbamoyl)ph N enyl)-N-(4- Ex.187, O NH (4- CAS:Omethoxypip 1363380- NNHeridine-1- 569.5 96-4 carboxamid N o)benzyl)-1- N methyl-1H- indazole-3- carboxamid e (S)-5-(4- OH (dimethylca rbamoyl)ph abs enyl)-N-(4- O N (2- Ex.187, (hydroxyme CAS: O NH thyl)pyrrolidi 1363380- ne-1- 555.5 NO96-4NHcarboxamid o)benzyl)-1- N methyl-1H- N indazole-3- carboxamid e N-(4-(3- amino-3- methylazeti O NNHdine-1- 2 carboxamid Ex.187h, O NH o)benzyl)-5- CAS: O N NH (4- 1363380- (dimethylca 540.5 96-4 N rbamoyl)ph N enyl)-1- methyl-1H- indazole-3- carboxamid e 5-(4- (dimethylca O rbamoyl)ph O enyl)-N-(4- N (3- Ex.187, O NH (methoxym CAS: O ethyl)azetidi 1363380- N NH ne-1- 555.4 96-4 carboxamid N o)benzyl)-1- N methyl-1H- indazole-3- carboxamid e (S)-N-(4-(3- (dimethyla mino)pyrroli absN dine-1- O N carboxamid Ex.187, NH o)benzyl)-5- CAS: O (4- 1363380- NONH(dimethylca 568.5 96-4 rbamoyl)ph N enyl)-1- N methyl-1H- indazole-3- carboxamid e (S)-5-(4- (dimethylca O rbamoyl)ph Nabsenyl)-N-(4- Ex.187, O NH OH (3- CAS:Ohydroxypip 1363380- NNHeridine-1- 555.5 96-4 carboxamid N o)benzyl)-1- N methyl-1H- indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph O NNHenyl)-1- methyl-N- Ex.187h, O NH (4- CAS: O (piperazine- 1363380- N NH 1- 540.5 96-4 carboxamid N N o)benzyl)- 1H- indazole-3- carboxamid e N-(4-(3- (dimethyla mino)azetid O ine-1- NNcarboxamid Ex.187, O NH o)benzyl)-5- CAS: N O (4- 1363380- NH (dimethylca 554.5 96-4 rbamoyl)ph N N enyl)-1- methyl-1H- indazole-3- carboxamid e (R)-5-(4- (dimethylca abs OH rbamoyl)ph O N enyl)-N-(4- Ex.187, (3- O NH CAS: hydroxypyrr O 1363380- N NH olidine-1- 541.5 96-4 carboxamid N o)benzyl)-1- N methyl-1H- indazole-3- carboxamid e (R)-N-(4- ((5-(4- OH (dimethylca abs rbamoyl)ph O enyl)-1- N O Ex.187, methyl-1H- NH CAS: O indazole-3- 1363380- O carboxamid 571.5 N NH 96-4 o)methyl)ph enyl)-2- N (hydroxyme N thyl)morpho line-4- carboxamid e (S)-N-(4- ((5-(4- OH (dimethylca abs rbamoyl)ph O enyl)-1- N O Ex.187, methyl-1H- CAS: O NH indazole-3- 1363380- O carboxamid 571.5 N NH 96-4 o)methyl)ph enyl)-2- N (hydroxyme N thyl)morpho line-4- carboxamid e 5-(4- (dimethylca O N rbamoyl)ph enyl)-N-(4- NH Ex.187, (3-(2- O CAS:OOH hydroxyeth 1363380- NNHyl)-3- 529.5 96-4 methylureid N o)benzyl)-1- N methyl-1H- indazole-3- carboxamid e (S)-5-(4- (dimethylca O rbamoyl)ph N enyl)-1- NH abs methyl-N- Ex.187, O (4-(2- CAS: NOmethylpy 1363380-NHrro lidine-1- 539.5 96-4 carboxamid N o)benzyl)- N 1H- indazole-3- carboxamid e N-(4-((5-(4- (dimethylca rbamoyl)ph O N enyl)-1- O methyl-1H- Ex.187, O NH indazole-3- CAS: NOcarboxamid 1363380-NHo)methyl)ph 567.5 96-4 N enyl)-2-oxa- N 6- azaspiro[3. 4]octane-6- carboxamid e (S)-N-(4-(3- acetamidop H N yrrolidine-1- abs O carboxamid Ex.187,N Oo)benzyl)-5- O NH CAS: (4- 1363380- N O (dimethylca 582.5 NH 96-4 rbamoyl)ph N enyl)-1- N methyl-1H- indazole-3- carboxamid e N-(4-(3- aminoazeti O dine-1- NNH2carboxamid NH Ex.187h, O o)benzyl)-5- CAS: N O (4- 1363380- NH (dimethylca 526.5 96-4 rbamoyl)ph N enyl)-1- N methyl-1H- indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph enyl)-1- O NH N methyl-N- Ex.187h, (4-(3- O NH CAS: (methylami O 1363380- N NH no)azetidin 540.5 96-4 e-1- N carboxamid N o)benzyl)- 1H- indazole-3- carboxamid e rac-N-(4- ((3R,4R)-3- amino-4- &1O methoxypyr O rolidine-1- N &1 Ex.187h, NH carboxamid NH2CAS: O o)benzyl)-5- 1363380- O (4- 570.5 N NH 96-4 (dimethylca rbamoyl)ph N N enyl)-1- methyl-1H- indazole-3- carboxamid e N-(4- ((3R,4R)-3- amino-4- absO methoxypyr O rolidine-1- N abs Ex.187h, NH carboxamid NH2CAS: O o)benzyl)-5- 1363380- O (4- 570.5 N NH 96-4 (dimethylca rbamoyl)ph N enyl)-1- N methyl-1H- indazole-3- carboxamid e rac-N-(4- ((3R,4S)-3- (dimethyla &1F mino)-4- O fluoropyrroli N &1 dine-1- Ex.187, N O NH carboxamid CAS: O o)benzyl)-5- 1363380- N NH (4- 586.5 96-4 (dimethylca N rbamoyl)ph N enyl)-1- methyl-1H- indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph O N enyl)-N-(4- N H (3- Ex.187h, O NH O (methoxym CAS: O ethyl)pipera 1363380- N NH zine-1- 584.5 96-4 N carboxamid N o)benzyl)-1- methyl-1H- indazole-3- carboxamid e N-(4-(3- (dimethyla mino)-3- O methylazeti N N dine-1- Ex.187, O NH carboxamid CAS: O o)benzyl)-5- N NH 1363380- (4- 568.5 96-4 (dimethylca N rbamoyl)ph N enyl)-1- methyl-1H- indazole-3- carboxamid e N-(4-(3- (dimethyla mino)pyrroli O N dine-1- N carboxamid Ex.187, O NH o)benzyl)-5- CAS: O N NH (4- 1363380- (dimethylca 568.5 96-4 N rbamoyl)ph N enyl)-1- methyl-1H- indazole-3- carboxamid e N-(4-(1- amino-3- azabicyclo[ O 3.1.0]hexan N e-3- N Ex.187h, O NH H2carboxamid CAS: O o)benzyl)-5- N NH 1363380- (4- 552.6 96-4 (dimethylca N rbamoyl)ph N enyl)-1- methyl-1H- indazole-3- carboxamid e N-(4-(3- ((dimethyla mino)methy N l)azetidine- O 1- N Ex.187, carboxamid N CAS: O H o)benzyl)-5- 1363380- O N (4- NH 568.5 96-4 (dimethylca N rbamoyl)ph N enyl)-1- methyl-1H- indazole-3- carboxamid e N-(4-(3- (dimethyla mino)-3- O methylpyrro N N lidine-1- Ex.187, O NH carboxamid CAS: O o)benzyl)-5- N NH 1363380- (4- 582.5 96-4 (dimethylca N rbamoyl)ph N enyl)-1- methyl-1H- indazole-3- carboxamid e N-(4-(3- ((dimethyla mino)methy O l)pyrrolidine N -1- Ex.187, O NH N carboxamid CAS: O o)benzyl)-5- N NH 1363380- (4- 582.5 96-4 (dimethylca N rbamoyl)ph N enyl)-1- methyl-1H- indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph enyl)-1- O methyl-N- NN(4-(4- Ex.187, meth CAS: O NH yl-4,7- diazaspiro[ 1363380- O N NH 2.5]octane- 580.5 96-4 7- N carboxamid N o)benzyl)- 1H- indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph O F enyl)-N-(4- N (3-fluoro-3- Ex.187h, O NH HN ((methylami CAS: O no)methyl)a 1363380- N NH zetidine-1- 572.5 96-4 carboxamid N N o)benzyl)-1- methyl-1H- indazole-3- carboxamid e N-(4-(3- (dimethyla mino)piperi O dine-1- N carboxamid Ex.187, O NH N o)benzyl)-5- CAS: O 1363380- N (4- NH (dimethylca 582.5 96-4 N rbamoyl)ph N enyl)-1- methyl-1H- indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph H O N enyl)-N-(4- N (3- Ex.187h, O NH (ethylamino CAS:O)azetidine- 1363380- NNH1- 554.5 96-4 carboxamid N N o)benzyl)-1- methyl-1H- indazole-3- carboxamid e 555.5;1H NMR (400 MHz, (CD3)2SO ) δ 8.97- 8.90 (m, 2H), 8.73-8.71 (m, 1H), 5-(5- 8.46 (s, (dimethylca 1H), 8.25 rbamoyl)pyr (dd, 1H), O NNidin-2-yl)-1- 8.08 (d, methyl-N- Ex.103, O NH 1H), 7.94 (4-(4- (dd, 1H), CAS: 63380-NOmethylpiper 7.85 (d, 13N NHazine-1- 1H), 96-4 carboxamid N 7.40-7.35 N o)benzyl)- (m, 2H), 1H- 7.24-7.19 indazole-3- (m, 2H), carboxamid 4.42 (d, e 2H), 4.16 (s, 3H), 3.40 (t, 4H), 3.01 (d, 6H), 2.28 (t, 4H), 2.17 (s, 3H). 1-methyl-5- (4-(1- methyl-1H- imidazol-2- H N N N yl)phenyl)- Ex.176f, N O N-(4-(4- CAS: N NH O methylpiper 1363380- azine-1- 563.5 96-4 N N carboxamid o)benzyl)- 1H- indazole-3- carboxamid e 5-(4- (dimethylca rbamoyl)ph enyl)-1- methyl-N- H (4-(4- O N N N methylpiper O O azine-1- j N NH Ex.4, P1 carboxamid 555.5 N o)benzyl)- N N 1H- pyrazolo[3, 4- c]pyridine- 3- carboxamid e

[0018] 494.4;1H NMR (400 MHz, (CD3)2SO ) δ 12.45 (br s, N-(4-(1H- 1H), 9.43 imidazol-2- (d, 1H), yl)benzyl)- 9.15 (t, N 5-(4- 1H), 8.57 Ex.4e, (di (d, 1H), O methylca P1 N 8.1 O H rbamoyl)ph 9-8.14 substitute N NH enyl)-1- (m, 2H), with ethyl ethyl-1H- 7.92-7.88 iodide in (m, 2H), N pyrazolo[3, step 4 N 7.57-7.50 N 4- c]pyridine- (m, 2H), 3- 7.45 (d, carboxamid 2H), e 7.28-6.92 (m, 2H), 4.71 (q, 2H), 4.56 (d, 2H), 3.00 (br s, 6H), 1.56 (t, 3H).

[0019] 578.3;1H NMR (400 MHz, (CD3)2SO ) δ 9.03 (dd, 1H), 9.00-8.95 (m, 1H), 8.88 (t, 1H), 8.47 1-ethyl-5- (s, 1H), (5-(1- 8.28 (dd, methyl-1H- 1H), 8.21 O imidazol-2- (dd, 1H), N N yl)pyridin-2- 8.14-8.10 Ex.1b, N NH yl)-N-(4-(4- (m, 1H), CAS: N O meth 7.92-7.88 N NH ylpiper 1077-94- azine-1- (m, 1H), 7 carboxamid 7.42-7.37 N o)ben (m, 2H), N zyl)- 1H- 7.35 (d, indazole-3- 1H), carboxamid 7.26-7.22 e (m, 2H), 7.06 (d, 1H), 4.57 (q, 2H), 4.44 (d, 2H), 3.86 (s, 3H), 3.41 (t, 4H), 2.29 (t, 4H), 2.18 (s, 3H), 1.49 (t, 3H).

[0020] 494.4;1H NMR (400 MHz, (CD3)2SO ) δ 12.45 (s, 1H), 9.02 (t, 1H), 8.98-8.96 (m, 1H), N-(4-(1H- 8.74 (dd, N imidazol-2- 1H), 8.25 yl)benzyl)- (dd, 1H), O Ex.6, N 5-(5- 8.08 (dd, CAS:N NOH NH (dimethylca 1H), 7.95 1077-94- rbamoyl)pyr (dd, 1H), 7Nidin-2-yl)-1- 7.93-7.92 N ethyl-1H- (m, 1H), indazole-3- 7.91-7.88 carboxamid (m, 2H), e 7.46-7.42 (m, 2H), 7.23-7.21 (m, 1H), 7.00-6.98 (m, 1H), 4.65-4.48 (m, 4H), 3.07-2.93 (m, 6H), 1.50 (t, 3H). 508.4;1H NMR (400 MHz, CD3OD) N-(4-(3,3- δ 8.44 (s, dimethylure 1H), 8.17 ido)benzyl)- (d, 1H), H N N 3-methyl-7- 7.89 (d, N Ex.176, (4-(1- 2H), 7.76 O CAS: N NH O methyl-1H- (d, 2H), 2091549- imidazol-2- 7.33 (q, 14-1 N yl)phenyl)im 4H), N idazo[1,5- 7.27-7.19 a]pyridine- (m, 2H), 1- 7.07 (s, carboxamid 1H), 4.57 e (s, 2H), 3.82 (s, 3H), 3.00 (s, 6H), 2.66 (s, 3H). 509.3;1H NMR (400 MHz, (CD3)2SO ) δ 9.01 (t, 1H), N-((6-(3,3- 8.80 (s, dimethylure 1H), ido)pyridin- 8.47-4.45 3- (m, 1H), N H NNyl 8.24 (d, N )methyl)- Ex.176,O1-methyl-5- 1H), CAS: NNHO (4-(1- 7.86-7.84 1363380- methyl-1H- (m, 2H), 96-4 N imidazol-2- 7.81 (s, N yl)phenyl)- 4H), 7.75 1H- (d, 1H), indazole-3- 7.69 (dd, carboxamid 1H), 7.28 e (d, 1H), 7.00 (d, 1H), 4.44 (d, 2H), 4.17 (s, 3H), 3.81 (s, 3H), 2.92 (s, 6H) 5-(4- (dimethylca rbamoyl)ph enyl)-1- ONethyl-N-(4- N Ex.176, (4- P1 O NH methylpiper substitute O azine-1- N NH with ethyl carboxamid 569.4 iodide in o)benzyl)- N step 4 N 1H- N pyrazolo[3, 4- c]pyridine- 3- carboxamid e (S)-N-(4-(3- (dimethyla absN mino)pyrroli O dine-1- N carboxamid Ex.6, NH o)benzyl)-5- CAS: O 1077-94-N NO(5- NH (dimethylca 583.4 7 rbamoyl)pyr N idin-2-yl)-1- N ethyl-1H- indazole-3- carboxamid e 569.4;1H NMR (400 MHz, (CD3)2SO ) δ 8.97- 8.94 (m, 1H), 8.89 (t, 1H), 8.75-8.72 (m, 1H), 8.40 (s, N-(4-(3- 1H), 8.24 (dimethyla (dd, 1H), mino)azetid ON8.08 (d, N ine-1- 1H), 7.95 carboxamid (dd, 1H), Ex.6, O NH o)benzyl)-5- 7.90 (d, CAS: 94-N NO(5- 1H), 1077- NH (dimethylca 7.46-7.40 7 rbamoyl)pyr N (m, 2H), N idin-2-yl)-1- 7.27-7.22 ethyl-1H- (m, 2H), indazole-3- 4.56 (q, carboxamid 2H), 4.44 e (d, 2H), 3.96-3.90 (m, 2H), 3.71 (dd, 2H), 3.09-2.95 (m, 7H), 2.07 (s, 6H), 1.48 (t, 3H). N-(4-((5-(5- (dimethylca rbamoyl)pyr idin-2-yl)-1- O N methyl-1H- Ex.187, O NH N indazole-3- CAS: carb 1363381-N NOoxamid NH o)methyl)ph 609.5 41-2 enyl)-8- N methyl-2,8- N diazaspiro[ 4.5]decane- 2- carboxamid e N-(4-((5-(5- (dimethylca rbamoyl)pyr O idin-2-yl)-1- N methyl-1H- Ex.187, O NH N indazole-3- CAS: carboxami 1363381-N NOd NH o)methyl)ph 609.5 41-2 enyl)-7- N methyl-2,7- N diazaspiro[ 4.5]decane- 2- carboxamid e 5-(5- (dimethylca rbamoyl)pyr idin-2-yl)-1- ON Nmethyl-N- (4-(3- Ex.187, O NH methyl-3,8- CAS: 1363381-N NOdiazabicycl NH o[3.2.1]octa 581.5 41-2 ne-8- N N carboxamid o)benzyl)- 1H- indazole-3- carboxamid e 528.5;1H NMR (400 MHz, CD3OD) δ 8.87- 7-(5- 8.84 (m, (dimethylca 1H), 8.74 rbamoyl)pyr (d, 1H), H N idin-2-yl)-N- 8.29 (d, O N (4-(3,3- 1H), 8.08 O N N NH O dimethylure (d, 1H),Ex. 183,ido)benzyl)- 7.97 (dd, P83- 1H), 7.62 N N isopropylimi (dd, 1H), dazo[1,5- 7.38-7.27 a]pyridine- (m, 4H), 1- 4.57 (s, carboxamid 2H), e 3.54-3.43 (m, 1H), 3.12 (d, 6H), 3.00 (s, 6H), 1.43 (d, 6H). N-(4-((5-(5- (dimethylca rbamoyl)pyr idin-2-yl)-1- O O methyl-1H- NNindazole-3- Ex.187, O NH carboxamid CAS: o)m 1363381-N NOethyl)ph NH enyl)-9- 597.5 41-2 methyl-3- N N oxa-7,9- diazabicycl o[3.3.1]non ane-7- carboxamid e

[0021] 5-(5- (dimethylca rbamoyl)pyr idin-2-yl)-1- ON Nmethyl-N- (4-(9- Ex.187, O NH methyl-3,9- CAS: 1363381-N NOdiazabicycl NH o[3.3.1]non 595.5 41-2 ane-3- N N carboxamid o)benzyl)- 1H- indazole-3- carboxamid e N-(4-((5-(5- (dimethylca rbamoyl)pyr idin-2-yl)-1- O NNmethyl-1H- Ex.187, O NH indazole-3- CAS: carboxamid 1363381-N NONH o)methyl)ph 567.5 41-2 enyl)-3- N methyl-3,6- N diazabicycl o[3.1.1]hept ane-6- carboxamid e N-(4-((5-(5- (dimethylca rbamoyl)pyr ONidin-2-yl)-1- N methyl-1H- Ex.187, O NH indazole-3- CAS:Ocarboxamid 1363381-N NNH o)methyl)ph 567.4 41-2 enyl)-6- N methyl-3,6- N diazabicycl o[3.1.1]hept ane-3- carboxamid e N-(4-((5-(5- (dimethylca rbamoyl)pyr N idin-2-yl)-1- methyl-1H- O indazole-3- NOEx.187, carboxamid CAS: O NH o)methyl)ph 1363381- enyl)-2- 611.5 41-2N NONH methyl-6- oxa-2,9- N diazaspiro[ N 4.5]decane- 9- carboxamid e N-(4-((5-(5- (dimethylca rbamoyl)pyr idin-2-yl)-1- O NOmethyl-1H- indazole-3- Ex.187, O NH N carboxamid CAS: 63381-NOo)methyl)ph 13NNH enyl)-9- 611.5 41-2Nmethyl-6- N oxa-2,9- diazaspiro[ 4.5]decane- 2- carboxamid e N-(4-((5-(5- (dimethylca rbamoyl)pyr O idin-2-yl)-1- N methyl-1H- Ex.187, O NH N indazole-3- CAS: 1363381-N NOcarboxamid NH o)methyl)ph 595.5 41-2 enyl)-7- N methyl-2,7- N diazaspiro[ 4.4]nonane- 2- carboxamid e rac-(R)-N- (4-((5-(5- (dimethylca rbamoyl)pyr ONidin-2-yl)-1- N &1 methy Ex.187, O l-1H- NH indazole-3- CAS: NNONH carboxamid 1363381- o)methyl)ph 595.5 41-2Nenyl)octahy N dro-2H- pyrido[1,2- a]pyrazine- 2- carboxamid e 5-(4- (dimethylca O rbamoyl)ph O enyl)-1- Ex.192,NON methyl-N- CAS: NH H (3-methyl-4- 1363380- (methylcarb 484.5 96-4Namoyl)benz N yl)-1H- indazole-3- carboxamid e

[0022] 514.3;1H NMR (400 MHz, CD3OD) δ 8.80 (s, 1H), 8.71 (s, 1H), 7-(5- 8.17 (d, (dimethylca 1H), 8.04 rbamoyl)pyr (d,1H), idin-2-yl) O H -N- N 7.94 (4-(3,3- N N (d,1H),Ex. 183,NOdimethylure NH O 7.57 ido)benzyl)- P21(d,1H), 3- NN7.32 (q, ethylimidaz 4H), o[1,5- 4.62-4.52 a]pyridine- (m, 2H), 1- 3.36-3.25 carboxamid (m, 3H), e 3.15-3.05 (m, 6H), 3.04-2.96 (m, 8H), 1.40 (t, 3H).

[0023] 583.3;1H NMR (400 MHz, CD3OD) δ 8.90 – 7-(5- 8.88 (m, (dimethylca 1H), 8.75 rbamoyl)pyr (dd, 1H), 8.33 H idin-2-yl)-3- (d, O isopro 1H), 8.10 NNN pyl-N- (4-( (d, 1H),Ex. 183,N NO4- NHO methylpiper 7.98 (dd, 1H), 7. P8azine-1- 65 NNcarboxamid (dd, 1H), o)benzyl)imi 7.35 – dazo[1,5- 7.32 (m, a]pyridine- 4H), 4.58 1- (s, 2H), carboxamid 3.58 – e 3.47 (m, 5H), 3.12 (d, 6H), 2.47 (t, 4H), 2.32 (s, 3H), 1.45 (d, 6H).

[0024] 597.3;1H NMR (400 MHz, (CDCl3)) δ 8.83 (d, 1H), 8.75 (dd, 1H), 8.10 – 5-(5- 8.08 (m, (dimethylca 1H), 7.97 O rbamoyl)pyr NN– 7.94 idin-2-yl)- (m, 1H), N 1,7-diethyl- O H 7.83 (dd, N-(4-(4- 195Ex. 195,N NO1H), 7.34 NHmethylpiper P24(s, 4H), azine-1- 4.68 – N carboxamid 4.53 (m, N o)benzyl)- 4H), 3.54 1H- (t, 4H), indazole-3- 3.17 – carboxamid 3.06 (m, e 8H), 2.48 (t, 4H), 2.35 (s, 3H), 1.52 (t, 3H), 1.43 (t, 3H).aSuzuki method 1: A mixture of chloro-intermediate (1.0 eq), boronic acid or boronate ester intermediate (1.1 eq), K3PO4(3.0 eq) and cataCXium®A Pd G3 (0.05 eq) in (4:1) tert-amyl alcohol: water was purged with nitrogen for a few minutes then heated to 85 °C and stirred for 3 hours. The reaction was cooled to room temperature then filtered through Celite. The solid was dissolved in DMSO then purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 20 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide the target product.bSuzuki method 2: A mixture of the boronate ester or bromo intermediate (1.0 eq), aryl chloride or aryl bromide intermediate (1.5 eq), 2M K2CO3(aqueous) (5.0 eq) and Pd(dppf)Cl2or Pd(dppf)Cl2-DCM (0.10 eq) in 1,4-dioxane (0.04M) was degassed with nitrogen for 5 minutes. The reaction was heated to 85 °C and stirred for 6 hours. The mixture diluted with EtOAc then washed with brine. The organic layer was dried over MgSO4 then concentrated in vacuo. The residue was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 5 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min).cSuzuki method 3: To a stirred solution of the aryl chloride intermediate (1.0 eq) and the boronate ester intermediate (1.5 eq) in (1: 0.02) THF: water was added K3PO4(2.5 eq) and XPhos Pd G2 (0.1 eq). The reaction was degassed with nitrogen again for 3 minutes then heated at 80 °C and stirred for 1 hour. The suspension was diluted with EtOAc then concentrated in vacuo. The residue was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 µm, water (NH4OH-NH4HCO3) / MeCN, 16 to 56% MeCN over 9 minutes, 100% MeCN hold for 5 minutes, flow rate= 60 mL / min) and lyophilized to provide the desired target.dSuzuki Coupling method 5: A solution of the chloro or bromo intermediate (1.0 eq) in 1,4- dioxane (0.22M) was sparged with argon for 15 minutes. A solution of boronate ester intermediate (1.0 eq) in 1,4-dioxane (0.22M) was sparged with argon for 15 minutes then added to the reaction. After the addition, a solution of 2M K2CO3(aqueous) (2.0 eq) was sparged with argon for 15 minutes then added to the reaction. To the mixture was added bis(tri-tert- butylphosphine)palladium(0), 20.9% palladium (0.20 eq). The reaction was heated to 100 °C for 1 hour. The mixture diluted with (1:1) water: brine then EtOAc was added and was centrifugedfor ~ 1 minute. The organic layer was dried with Na2SO4 then filtered and concentrated withnitrogen blowdown. The residue was dissolved in DMSO, filtered then purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 25 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide the desired target.eAmide coupling 1: To the acid intermediate (1.0 eq), amine intermediate (1.0 eq) and HATU (1.5 eq) in DMF (0.10M) was added DIPEA (5.0 eq). The reactions were stirred at room temperature for overnight then diluted with water and stirred for 15 minutes. The mixture was filtered then rinsed with water (2x) to provide the desired target. The filtrate was dissolved in DMSO then filtered and purified by reverse phase HPLC (XBridge C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 15 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide the desired target.fAmide coupling 2: To the solution of carboxylic acid intermediate (1.0 eq) in MeCN (0.21 M) was added HOPO (1.2 eq) and EDCI (1.6 eq). The reaction was stirred at room temperature for 20 minutes. Following the stir, DIPEA (4.0 eq) and the amine intermediate (1.5 eq) were added. The mixture was stirred at room temperature for 4.5 hours then heated to 40 °C and stirred overnight. The reaction was cooled to room temperature then water was added. The solution was concentrated in vacuo then cooled in an ice bath. The mixture was filtered then rinsed with EtOAc and water. The solid was dissolved in DMSO and a minimal amount of TFA was added. The solution was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 5 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide the desired target.gHydrolysis 1: To the ester intermediate (1.0 eq) in MeOH (0.13M) was added 1M NaOH (3.2 eq). The reaction was stirred at 75 °C for 4 hours then cooled to room temperature before potassium bisulfate (KHSO4) was added. The reaction was stirred at room temperature overnight. The mixture was filtered then concentrated in vacuo and azeotroped with MeCN to provide the target intermediate.hThe synthesis from Example 187 was followed utilizing tert-butyloxycarbonyl (BOC)-protected amines. The BOC-protected amine intermediate formed was deprotected under standard acidic conditions. To the BOC-protected amine intermediate (1.0 eq) was added a 20% TFA (52 eq) in DCM (0.06M). The reaction was shaken for 16 hours then concentrated in vacuo. The residue was dissolved in DMSO then filtered and purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm, water (0.05% TFA) / MeCN, 5 to 95% MeCN over 9 minutes, 95% MeCN hold for 1 minute, flow rate= 25 mL / min) to provide the desired target.iThe same synthesis was used for example (24) as example (76); however, the advanced intermediate C12 was used instead of C11.jSuzuki method 1: A mixture of chloro-intermediate (1.0 eq), boronic acid intermediate (2.0 eq) and K3PO4(3.0 eq) in (4:1) DMF: water was degassed with nitrogen for 3 minutes then cataCXium®A Pd G3 (0.1 eq) was added. The reaction was degassed again with nitrogen for 3 minutes then heated to 110 °C for 48 hours. The mixture was cooled to room temperature then diluted with water and extracted with EtOAc (3x). The aqueous layer was filtered then the filtrate was concentrated in vacuo. The solid was diluted with water and acidified with 6N HCl to pH~3. The mixture was filtered and washed with water (3x) then MeOH (2x). The solid was collected then concentrated in vacuo. The white solid was triturated with (20:5:1) MeOH: DCM: DMF for 1 hour. The mixture was filtered, washed with MeOH (2x) then collected and lyophilized. The white solid was dissolved in (1:2) MeOH: DCM and palladium removal silicone was added. The mixture was warmed to 50 °C and stirred for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to remove most the solvent then filtered again. The filter cake was collected, dried further to provide the target intermediate.kSuzuki method 6: A mixture of the boronate ester (1.0 eq) and an aryl chloride intermediate (1.0 eq) in (4:1) 1,4-dioxane: water was degassed with nitrogen for 3 minutes before K3PO4(2.5 eq) and Pd(dppf)Cl2(0.10 eq) were added. The reaction was degassed with nitrogen again for 3 minutes then heated to 80 °C and stirred for 16 hours. The mixture was filtered and concentrated in vacuo. The residue was dissolved in DMSO and MeOH then purified by reverse phase HPLC (Welch Xtimate C18150 mm x 25 mm x 5 µm, water (0.05% formic acid) / MeCN, 11 to 33% MeCN over 11 minutes, 95% MeCN hold for 2 minutes, flow rate= 60 mL / min) and lyophilized. The white solid was added to MeOH: DCM and heated to 50 °C until the solid dissolved then 3-mercaptopropyltrimethoxysilane modified silica gel (1:1) was added. The mixture was heated at 50 °C for 0.5 hours then filtered and washed with MeOH: DCM (5x). The filtrate was concentrated in vacuo and lyophilized to provide the desired target intermediate. Pharmacology Assays STAT6 Reporter Luciferase Assay Pharmacological measurements of STAT6 transcriptional activity through the IL13-IL13 receptor / IL4 receptor pathway were made with a stably transfected HaCaT keratinocyte cell line, which expresses NanoLuc luciferase reporter gene under the transcriptional control of the STAT6 responsive promoter for IL-13Ra2. The readout of the STAT6 activity utilized Promega Nano-Glo Luciferase assay kit. The reporter cells were cultured in a growth media comprised of DMEM High Glucose, no calcium and no glutamine, 10% heat inactivated fetal bovine serum (HI FBS), 1% 100x Glutamax, and 100 U / mL Penicillin-Streptomycin (units of penicillin in 1 mL of streptomycin). Seven thousand cells were plated in 25 microliter (µL) per well in a 384-well, white bottom, tissue culture plate. Cells were cultured overnight at 37 ºC. The next day, test compounds (solubilized and serially diluted in DMSO, in an 11 point, 4-fold dilution series in duplicate) were spotted, 60 nanoliters (nL) per well, into a 384 well v-bottom polypropylene plate. Thirty µL per well of 37 °C dosing media (Dulbecco's modified eagle medium (DMEM) High Glucose, no calcium and no glutamine with 2% HI FBS) was added to the compound plate. Growth media was removed from the cell plate, and the cells were washed with DPBS. Twenty µL per well of compounds diluted in dosing media were transferred from the compound plate to the cell plate and the compounds were further diluted with an additional 15 µL of dosing media in the cell plate: the cell plate was incubated for two hours at 37 ºC. After two hours, STAT6 activity was stimulated with the addition of 5 µL per well of IL-13 (R&D Systems) in dosing media with a final concentration of 0.12 nM IL13. Cells were incubated at 37 ºC for 4 hours to allow for reporter gene expression, then all media was removed from the plate. The cell plates were treated with assay buffer and Luciferase substrate from Nano-Glo Luciferase Assay Kit for 15 min and then measured for luminescence on an EnVision 2105 multilabel reader (PerkinElmer). EC50(half maximal effective concentration) values were determined from this data using a 4-parameter fit algorithm and are provided in Table 2, where the EC50values are the statistical mean values of n number of samples as denoted by n(EC50). Human Whole Blood (HWB) CCL17 TR-FRET Assay The IC50(half-maximal concentration required for inhibition) of compounds for the inhibition of CCL17 secretion in peripheral human whole blood, stimulated through the IL-13-IL- 13 receptor / IL-4 receptor pathway was evaluated with a TR-FRET sandwich ELISA CCL17 (TARC) Assay Kit (Bioauxilium). Test compounds (solubilized and serially diluted in DMSO, in an 11 point, 3-fold dilution series in duplicate) were spotted, 80 nL per well, into a 384 well v-bottom polypropylene plate. Human whole blood was collected from a peripheral vein, 714 units of sodium heparin was added for every 50 mL of blood collected. Sixty µL per well of blood was added to the compound plate. The blood plate was incubated for two hours at 37 °C. After two hours, CCL17 production was stimulated with the addition of 20 µL per well of IL13 (R&D Systems) in HBSS with calcium and magnesium, with a final concentration of 10 ng / mL IL13. The plate containing blood, compound, and IL-13 was incubated at 37 °C for 48 hours, to allow for CCL17 production. After 48 hours, the plate was centrifuged at 1,500 revolutions per minute (RPM) for 7 minutes, with no braking. The CCL17 TR-FRET Assay Kit detection reagent was prepared according to kit instructions and 4 µL per well of the antibody cocktail was added to a 384-well white low volume non-binding coated plate (Corning). Sixteen µL of serum from the centrifuged blood plate was transferred to the detection plate containing the TR-FRET antibody cocktail. The plate was centrifuged briefly, then covered and incubated 16 hours at room temperature. The plate was then read on an EnVision 2105 multilabel reader (PerkinElmer) with settings for TR-FRET Ratio = 10,000 X (fluorescence intensity 665 nm / fluorescence intensity 615 nm). IC50values were determined from this data using a 4-parameter fit algorithm and are shown in Table 2, where the EC50 values are the statistical mean values of n number of samples as denoted by n(IC50). Table 2 Ex. Reportern HWB CCL17 n EC50 (µM)(EC50) IC50(µM) (IC50) 1 0.075 5 0.722 10 2 0.058 1 - - 3 0.006 18 0.083 36 4 0.027 4 0.935 11 5 0.005 2 0.041 4 6 0.004 3 0.046 3 7 0.003 4 0.177 5 8 0.016 5 0.265 4 9 0.008 3 0.145 6 10 0.002 18 0.095 17 11 0.011 2 0.101 3 12 0.005 9 0.120 23 13 0.018 3 0.446 5 14 0.046 3 1.754 4 15 0.018 3 0.705 8 16 0.127 4 1.038 3 17 0.020 3 0.978 4 18 0.013 2 0.806 4 19 0.028 3 0.442 2 20 0.042 2 1.846 1 21 0.008 3 0.681 2 22 0.037 4 0.862 4 23 0.123 2 1.973 2 24 0.050 2 0.686 1 25 0.090 3 0.999 3 26 0.014 2 1.597 3 27 0.014 2 1.858 3 0.035 2 2.387 3 0.011 3 - - 0.005 5 0.453 3 0.028 2 2.793 1 0.096 2 5.602 2 0.080 4 2.421 1 0.068 2 3.210 1 0.067 5 7.387 1 0.091 4 8.223 1 0.046 3 11.005 1 0.051 2 7.889 1 0.050 2 3.695 1 0.089 2 1.715 2 0.015 2 0.719 3 0.031 4 0.402 4 0.019 3 1.399 3 0.058 4 1.733 3 0.031 3 1.836 3 0.021 4 0.415 10 0.032 4 0.872 3 0.032 4 1.449 3 0.049 2 1.002 3 0.085 2 0.739 4 0.094 3 1.947 1 0.031 3 1.825 4 0.098 4 1.290 8 0.020 3 2.258 2 0.061 2 1.730 1 0.076 2 1.526 1 0.127 3 1.755 3 0.114 2 2.106 1 1.759 3 0.519 1 0.150 3 0.656 5 0.282 2 1.961 4 0.418 5 6.645 5 0.187 2 2.141 3 0.242 2 5.678 3 1.646 4 5.251 3 1.835 2 13.588 2 2.350 2 >30 1 0.423 2 3.104 2 0.130 2 2.209 2 0.013 4 0.735 1 0.234 2 0.901 3 0.003 2 0.182 2 0.154 3 2.883 4 0.102 4 7.342 3 0.006 4 1.743 4 0.011 2 1.015 4 0.013 3 0.664 3 0.013 2 0.496 3 0.015 4 0.734 3 0.049 2 1.024 1 0.050 2 5.249 1 0.081 3 0.755 3 0.045 2 1.621 2 0.075 2 0.747 2 0.032 3 0.108 3 0.020 2 0.098 2 1.094 3 14.884 2 0.011 1 0.462 2 0.003 1 0.054 2 0.007 1 0.133 2 0.020 3 0.571 4 0.003 3 0.074 3 0.004 2 0.158 2 0.013 2 0.079 3 0.003 2 0.124 3 0.004 2 0.049 4 0.128 2 0.676 2 0.597 3 > 28.977 2 0.021 2 0.183 1 >10 2 >30 1 0.107 2 0.573 2 0.003 2 0.027 2 0.002 2 0.090 2 0.004 2 0.104 2 0.005 2 0.159 3 0.003 4 0.048 4 0.005 3 0.054 3 0.009 2 0.064 2 0.008 2 0.055 3 0.023 2 0.174 2 0.129 2 0.171 2 0.004 2 0.487 2 0.014 2 0.180 2 0.048 2 0.132 2 0.033 4 0.059 2 0.010 2 0.261 2 0.002 3 0.032 3 0.003 3 0.054 2 0.014 2 1.625 2 0.016 3 2.342 3 0.023 3 0.611 3 0.029 2 >30.000 1 0.030 2 0.752 2 0.036 2 0.469 3 0.040 2 1.435 2 0.002 2 0.372 2 0.003 2 0.054 2 0.003 2 0.174 2 0.004 2 0.175 2 0.004 2 0.454 2 0.004 2 0.298 2 0.005 2 0.051 2 0.006 2 - - 0.006 3 0.367 2 0.007 1 0.249 2 0.007 2 0.352 2 0.007 2 0.256 2 0.007 2 0.505 2 0.007 2 0.365 3 0.008 2 0.179 2 0.009 2 0.168 2 0.009 2 0.295 3 0.009 2 0.153 2 0.010 3 0.191 2 0.010 2 0.410 2 0.012 2 0.090 2 0.012 2 >30.000 1 0.012 2 0.264 2 0.012 2 0.164 2 0.014 2 1.505 2 0.014 2 0.745 2 0.015 2 0.605 2 0.019 2 0.177 2 0.020 2 0.541 2 0.012 2 0.058 2 0.010 2 0.130 2 0.012 2 0.253 2 0.013 2 0.179 2 0.016 2 0.485 2 0.018 2 0.468 2 0.010 2 0.286 1 0.014 2 0.426 2 0.015 2 0.545 2 0.016 2 0.304 2 0.013 2 0.856 2 0.018 2 0.312 1 0.008 2 - - 0.016 2 - - 0.010 2 0.104 2 0.004 2 0.267 2 0.016 2 0.132 2 0.013 2 0.274 2 0.002 2 0.024 3 0.007 2 0.118 2 0.006 2 0.134 2 0.015 2 2.485 4 0.005 1 0.096 1 0.005 1 0.062 1 0.005 2 0.057 2 0.026 2 0.207 1 0.035 2 0.524 1 0.037 2 0.641 1 0.004 1 0.019 1 0.055 2 0.229 2 0.019 2 0.197 2 0.025 2 0.225 2 0.090 2 0.707 2 0.033 2 0.220 2 0.003 2 0.048 2 190 0.038 2 0.353 2 191 0.007 2 0.200 2 192 0.174 4 5.176 1 193 0.009 2 0.036 2 194 0.005 2 0.058 2 195 0.006 2 0.286 1 Prophetic Deuterated Analogs General methods / reviews of obtaining metabolite profile and identifying metabolites of a compound are described in: Dalvie, et al., “Assessment of Three Human in Vitro Systems in the Generation of Major Human Excretory and Circulating Metabolites,” Chemical Research in Toxicology, 2009, 22, 2, 357-368, tx8004357 (acs.org); King, R., “Biotransformations in Drug Metabolism,” Ch.3, Drug Metabolism Handbook Introduction, https: / / doi.org / 10.1002 / 9781119851042.ch3; Wu, Y., et al, “Metabolite Identification in the Preclinical and Clinical Phase of Drug Development,” Current Drug Metabolism, 2021, 22, 11, 838-857, 10.2174 / 1389200222666211006104502; Godzien, J., et al, “Chapter Fifteen - Metabolite Annotation and Identification”. Numerous publicly available and commercially available software tools are available to aid in the predictions of metabolic pathways and metabolites of compounds. Examples of such tools include, BioTransofrmer 3.0 (biotransformer.ca / new), which predicts the metabolic biotransformations of small molecules using a database of known metabolic reactions; MetaSite (moldiscovery.com / software / metasite / ), which predicts metabolic transformations related to cytochrome P450 and flavin-containing monooxygenase mediated reactions in phase I metabolism; and Lhasa Meteor Nexus (lhasalimited.org / products / meteor-nexus.htm) offers prediction of metabolic pathways and metabolite structures using a range of machine learning models, which covers phase I and phase II biotransformations of small molecules. Predicted deuterated analogs in the examples may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, increased STAT6 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability. A person with ordinary skill may make additional deuterated analogs of the disclosed compounds with different combinations of deuterium replacing hydrogen. Such additional deuterated analogs may provide similar therapeutic advantages that may be achieved by the deuterated analogs as illustrated below. In the examples, the “Yi” is used to indicate the order of the sites most likely to be metabolized based on MetaSite predictions for the respective compound, where i=1 indicates the most likely, i=2 indicates the second most likely site and so on. It is noted that where Yiis indicated as being deuterated, D, each Yiindependently can be D as long as at least one Yiis D. For example, if Y1is deuterated and there are two Y1groups in the compound, then one or both groups can be deuterated as long as at least one Y1group is deuterated. These examples are not intended to be limited to the specific compounds or locations of deuteration. Example D1 Formula D1 is the generic formula of deuterated Examples 3 and 5, wherein X7is N or CY5and Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10are each independently H or D. Table 3 shows some examples of deuterated compounds based on the most likely metabolized sites that can be applied to the compounds predicted by MetaSite. Table 3 Deuteration ExampleY1 Y2 Y3 Y4 Y5 Y6 Y7 Y8 Y9 Y10D1A D H H H H H H H H H D1B D D H H H H H H H H D1C D D D H H H H H H H D1D D H D H H H H H H H D1E D H H D H H H H H H D1F D H H H D H H H H H D1G D H H H H D H H H H D1H D H H H H H D H H H D1I D H H H H H H D H H D1J D H H H H H H H D H D1K D H H H H H H H H D D1L D D D D H H H H H H D1M H D D H H H H H H H D1N H D H D H H H H H H D1O H D H H D H H H H H D1P H D H H H D H H H H D1Q H D H H H H D H H H D1R H D H H H H H D H H D1S H D H H H H H H D H D1T H D H H H H H H H D D1U D H D D H H H H H H D1V D D H D H H H H H H Example D2 Formula D2 is the generic formula of deuterated Example 9, wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10are each independently H or D. Table 4 shows some examples of deuterated compounds based on the most likely metabolized sites that can be applied to the compounds predicted by MetaSite. Y Y49Y1YH1Y2Y2O Y10NY1N Y O Y1N 5YOY8NH 2 Y2Y Y 94Y1Y1Y2Y Y102Y N 5 N Y7Y3Y6Y3 Y3D2 Table 4 Deuteration ExampleY1 Y2 Y3 Y4 Y5 Y6 Y7 Y8 Y9 Y10D2A D H H H H H H H H H D2B D D H H H H H H H H D2C D D D H H H H H H H D2D D H D H H H H H H H D2E D H H D H H H H H H D2F D H H H D H H H H H D2G D H H H H D H H H H D2H D H H H H H D H H H D2I D H H H H H H D H H D2J D H H H H H H H D H D2K D H H H H H H H H D D2L D D D D H H H H H H D2M H D D H H H H H H H D2N H D H D H H H H H H D2O H D H H D H H H H H D2P H D H H H D H H H H D2Q H D H H H H D H H H D2R H D H H H H H D H H D2S H D H H H H H H D H D2T H D H H H H H H H D D2U D H D D H H H H H H D2V D D H D H H H H H H Example D3 Formula D3 is the generic formula of deuterated Example 8, wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10are each independently H or D. Table 5 shows some examples of deuterated compounds based on the most likely metabolized sites that can be applied to the compounds predicted by MetaSite. Table 5 Deuteration ExampleY1 Y2 Y3 Y4 Y5 Y6 Y7 Y8 Y9 Y10D3A D H H H H H H H H H D3B D D H H H H H H H H D3C D D D H H H H H H H D3D D H D H H H H H H H D3E D H H D H H H H H H D3F D H H H D H H H H H D3G D H H H H D H H H H D3H D H H H H H D H H H D3I D H H H H H H D H H D3J D H H H H H H H D H D3K D H H H H H H H H D D3L D D D D H H H H H H D3M H D D H H H H H H H D3N H D H D H H H H H H D3O H D H H D H H H H H D3P H D H H H D H H H H D3Q H D H H H H D H H H D3R H D H H H H H D H H D3S H D H H H H H H D H D3T H D H H H H H H H D D3U D H D D H H H H H H D3V D D H D H H H H H H It will be apparent to those skilled in the art that various modifications and variations may be made in the present disclosure without departing from the scope or spirit of the disclosure. Other aspects of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims. All references cited herein, including patents, patent applications, papers, textbooks, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entireties. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

Claims

CLAIMS We claim:

1. A compound of Formula I or a pharmaceutically acceptable salt thereof:I wherein X1is CH, N, or CF; X2is CH, CCH3, C(CH2CH3), C-cyclopropyl, N, CF, or CCl; X3is CR6or NR6; X4 is C or N; X5is C or N; X6is CH or N; X7is CH, N, or CF; X8is CH or N; X9is CH or N; X10is CH or N; R1is -NHR9, -OH, -C3-4heteroaryl optionally substituted with -C1-3alkyl, or -C1-4alkyl optionally substituted with one, two, or three of oxo, -NR10R11, or -C3-5heterocycloalkyl optionally substituted with R1A, wherein R1Ais -OH; R2is H or -CH3; or R1and R2form a C6-8fused heterocycloalkyl or a C6-8fused heteroaryl; wherein the C6-8fused heterocycloalkyl is optionally substituted with oxo, -C1-3alkyl, -NR10R11, or -OH; wherein the C6-8fused heteroaryl is optionally substituted with -C1-3alkyl, -NR10R11, or -OH; R3is -C1-3alkyl, -C2-5heteroaryl, -C3-5cycloalkyl, -NH-C(=O)-C1-3alkyl, or -C2-5heterocycloalkyl, wherein R3is optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, oxo, -NR7R8, or cyano; R4is H, -C1-3alkyl, -C1-3fluoroalkyl, or halogen; or R3and R4form a fused C6-10heterocycloalkyl optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, -NR7R8, cyano, or oxo; R5is H, -C1-3alkyl, or -C1-3hydroxyalkyl; R6is H, -C3-5cycloalkyl, alkoxyalkyl, or -C1-3alkyl optionally substituted with -OH; R7is H or -C1-3alkyl;R8is -C1-3alkyl; or R7and R8form a fused C5-10heterocycloalkyl optionally substituted with -C1-3alkyl; R9is H, -SO2CH3, or -C1-3alkyl optionally substituted with one, two, or three of oxo, -C3-7heterocycloalkyl, alkoxy, cyanoimine, or -NR12R13; wherein the -C3-7heterocycloalkyl is optionally substituted with one, two, or three of halogen, oxo, -C0-1alkylene-NR14R15, -OH, -C1-3hydroxyalkyl, -C1-3alkoxy optionally substituted with -NR14R15, -C1-3alkoxy-C1-3alkyl, or a -C1-3alkyl optionally substituted with oxo; R10is H, -C3-5cycloalkyl optionally substituted with -OH, or -C1-3alkyl optionally substituted with one, two, or three of a -C3-5heteroaryl, -C3-5cycloalkyl, cyano, -OH, or -C1-3alkoxy; R11is H or -C1-3alkyl; or R10and R11form a C3-4heterocycloalkyl optionally substituted with -OH; R12is H or -C1-3alkyl optionally substituted with one, two, or three -OH; R13is H or -C1-3alkyl; or R12and R13form a C3-8heterocycloalkyl, wherein the C3-8heterocycloalkyl is optionally substituted with one, two, or three of halogen, oxo, -C0-1alkylene-NR14R15, -OH, -C1-3hydroxyalkyl, -C0-3alkylene-C1-3alkoxy, or -C1-3alkyl; R14is each independently H, -C2-4oxoalkyl, -C1-4alkyl, or cyclopropyl optionally substituted with methyl; and R15is each independently H or -C1-3alkyl; wherein no more than 2 of X6, X7, and X8are N.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1is -NHR9, -C(=O)-NR10R11, -OH, -C(=O)-C1-3alkyl, or -C3-4heteroaryl; wherein the -C3-4heteroaryl is optionally substituted with -C1-3alkyl.

3. A compound of Formula I or a pharmaceutically acceptable salt thereof:I wherein X1is CH, N, or CF; X2is CH, CCH3, N, CF, or CCl;X3is CR6or NR6; X4is C or N; X5is C or N; X6is CH or N; X7is CH, N, or CF; X8is CH or N; X9is CH or N; X10is CH; R1is -NHR9, -OH, -C3-4heteroaryl optionally substituted with -C1-3alkyl, or -C1-3alkyl optionally substituted with one, two, or three of oxo, -NR10R11, or -C3-5heterocycloalkyl optionally substituted with R1A, wherein R1Ais -OH; R2is H; or R1and R2form a C6-8fused heterocycloalkyl or a C6-8heteroaryl; R3is -C1-3alkyl, -C2-5heteroaryl, -C3-5cycloalkyl, -NH-C(=O)-C1-3alkyl, or -C2-5heterocycloalkyl, wherein R3is optionally substituted with one, two, or three of -C1-3alkyl, oxo, -NR7R8, or cyano; R4is H, -C1-3alkyl, -C1-3fluoroalkyl, or halogen; or R3and R4form a fused C6-10heterocycloalkyl optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, or oxo; R5is H or -C1-3alkyl optionally substituted with -OH; R6is H, -C3-5cycloalkyl, alkoxyalkyl, or -C1-3alkyl optionally substituted with -OH; R7is H or -C1-3alkyl; R8is -C1-3alkyl; or R7and R8form a fused C6-10heterocycloalkyl; R9is H, -SO2CH3, or -C1-3alkyl optionally substituted with one, two, or three of oxo, -C3-7heterocycloalkyl, alkoxy, cyanoimine, or -NR12R13; wherein the -C3-7heterocycloalkyl is optionally substituted with one, two, or three of halogen, oxo, -C0-1-NR14R15, -OH, -C1-3hydroxyalkyl, -C1-3alkoxy optionally substituted with -NR14R15, -C1-3alkoxy-C1-3alkyl, or a -C1-3alkyl optionally substituted with oxo; R10is H, -C3-5cycloalkyl optionally substituted with -OH, or -C1-3alkyl optionally substituted with a -C3-5 heteroaryl, cyclopropyl, cyano, -OH, or -C1-3 alkoxy; R11is H or -C1-3alkyl; or R10and R11form a -C3-4heterocycloalkyl optionally substituted with -OH; R12 is -C1-3 alkyl optionally substituted with one, two, or three -OH; R13is H or -C1-3alkyl; R14is each independently H, -C1-4alkyl, or cyclopropyl optionally substituted with methyl; andR15is each independently H or -C1-3alkyl.

4. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R1is -NHR9or the optionally substituted -C1-3alkyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R1is -C1-3alkyl substituted with one, two, or three of oxo, -NR10R11, or -C3-5heterocycloalkyl optionally substituted with R1A, wherein R1Ais -OH.

6. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R1is -C(=O)-NR10R11and R10is H or -C1-3alkyl optionally substituted with a cyclopropyl, cyano, or -C1-3alkoxy.

7. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R1is -NHR9and R9is H or -C1-3alkyl substituted with one, two, or three of oxo, -C3-5heterocycloalkyl, methoxy, or -NR12R13.

8. The compound of claim or a pharmaceutically acceptable salt thereof 4, wherein R1is -NHR9and R9is H, -SO2CH3, -C(=O)-NR12R13, -C(=O)-C1-3alkoxy, or -C(N(CH3)2)- cyanoimine.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R1is -NHR9and R9is -SO2CH3, -C(=O)-NR12R13, -C(=O)-C1-3alkoxy, or -C(N(CH3)2)- cyanoimine.

10. The compound of any of claim 1, 2, and 4 to 9 or a pharmaceutically acceptable salt thereof, wherein R2is H.

11. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R3is -C(=O)-NR7R8.

12. The compound of any of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R3is -C3-5heteroaryl, -C3-5cycloalkyl, or -C3-5heterocycloalkyl and R3is optionally substituted with one of -C1-3alkyl, oxo, or -NR7R8.

13. The compound of any of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R3is -C(=O)-NR7R8, -C1-3cyanoalkyl, -C3-5cycloalkyl-cyano; -C3-5heterocycloalkyl, -C2-5heteroaryl, or -NH-C(=O)-C1-3alkyl; wherein the -C3-5heterocycloalkyl is optionally substituted with one, two, or three of -C1-3alkyl or oxo; and wherein the -C2-5heteroaryl is optionally substituted with one, two, or three of -C1-3alkyl or oxo.

14. The compound of any of claims 1 to 10, 12, and 13 or a pharmaceutically acceptable salt thereof, wherein R3is -C3-5heteroaryl optionally substituted with one of -C1-3alkyl or oxo.

15. The compound of any of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R7is -C1-3alkyl.

16. The compound of any of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R7and R8form a fused C5-7heterocycloalkyl optionally substituted with -C1-3alkyl; wherein the C5-7heterocycloalkyl includes 2 to 3 heteroatoms of at least one of N or S.

17. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R4is H or -C1-3alkyl.

18. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R4is H and R6is -C3-5cycloalkyl or -C1-3alkyl.

19. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R3and R4form a fused C7-9heterocycloalkyl optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, or oxo; and wherein the fused C7-9heterocycloalkyl contains 1 to 2 heteroatoms of at least one of N or O.

20. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R5is H or -C1-3alkyl.

21. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R6is H, -C1-3alkyl, -C3-5cycloalkyl, -C1-3hydroxyalkyl, or -C1-3alkoxy-C1-3alkyl.

22. The compound of any of claims 1, 2, and 4 to 21 or a pharmaceutically acceptable salt thereof, wherein R10is H, -C1-3alkylene-C1-3alkoxy, -C1-3hydroxyalkyl, -C1-3alkylene-C3-5heteroaryl, -C0-3alkylene-C3-5cycloalkyl, or -C1-3cyanoalkyl.

23. The compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein X7is CH or CF.

24. The compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein at least one of: the -C3-4heteroaryl of R1contains 1 to 2 heteroatoms of N; the -C3-5heterocycloalkyl of R1contains 1 to 2 heteroatoms of N;R1and R2form the C6-8fused heterocycloalkyl or the C6-8fused heteroaryl and the C6-8fused heterocycloalkyl or the C6-8fused heteroaryl include 1 to 2 heteroatoms of N; the -C2-5heteroaryl of R3includes 2 to 3 heteroatoms of at least one of N or O; the -C2-5heterocycloalkyl of R3includes 1 to 2 heteroatoms of N; R3and R4form the fused C6-10heterocycloalkyl contains 1 to 2 heteroatoms of at least one of N or O; R7and R8form the fused C5-10heterocycloalkyl and the C5-10heterocycloalkyl includes 2 to 3 heteroatoms of at least one of N or S; the -C3-7heterocycloalkyl of R9includes 1 to 2 heteroatoms of N; the -C3-5heteroaryl of R10includes 1 to 2 heteroatoms of N; R10and R11form the C3-4heterocycloalkyl and the C3-4heterocycloalkyl includes 1 or 2 heteroatoms of N; R12and R13form the C3-8heterocycloalkyl and the C3-8heterocycloalkyl includes 1 to 3 heteroatoms of at least one of N or O.

25. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen is deuterium.

26. The compound of any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein X6is CH and the hydrogen is deuterium.

27. The compound of any of the preceding claims , wherein the compound has the formula Ia:or a pharmaceutically acceptable salt thereof.

28. The compound of any of the preceding claims, wherein the compound has the formula D1:or a pharmaceutically acceptable salt thereof; wherein X6and X7are each independently N or CY5, wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10are each independently H or D; and at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10is D.

29. The compound of any of the preceding claims, wherein the compound has the formula D2 or D3:or a pharmaceutically acceptable salt thereof; wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10are each independently H or D and wherein at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10is D.

30. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is one of N-({4-[(dimethylcarbamoyl)amino]phenyl}methyl)-5-[5-(dimethylcarbamoyl)pyridin-2-yl]- 1-methyl-1H-indazole-3-carboxamide; 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1H- indazole-3-carboxamide; 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1H- pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-(3,3-dimethylureido)benzyl)-1-methyl-5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-1H- indazole-3-carboxamide; and 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-N-(4-(4-methylpiperazine-1- carboxamido)benzyl)-1H-indazole-3-carboxamide.

31. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen is deuterium.

32. A compound; wherein the compound is one of N-({4-[(dimethylcarbamoyl)amino]phenyl}methyl)-5-[5-(dimethylcarbamoyl)pyridin-2-yl]- 1-methyl-1H-indazole-3-carboxamide; 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1H- indazole-3-carboxamide; 5-(4-(dimethylcarbamoyl)phenyl)-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1H- pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-(3,3-dimethylureido)benzyl)-1-methyl-5-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-1H- indazole-3-carboxamide; and 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-N-(4-(4-methylpiperazine-1- carboxamido)benzyl)-1H-indazole-3-carboxamide.

33. The compound of claim 32, wherein at least one hydrogen is deuterium.

34. A pharmaceutical composition comprising the compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

35. A method for treating allergy, alopecia, Alzheimer’s disease, asthma, atherosclerosis, Bechet’s disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritis, chronic urticaria, Crohn’s disease (CD), dermatitis, diabetic kidney disease, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, prurigo nodularis,psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

36. A compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 33 for use as a medicament.

37. A compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 33 for use in the treatment of allergy, alopecia, Alzheimer’s disease, asthma, atherosclerosis, Bechet’s disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritis, chronic urticaria, Crohn’s disease (CD), dermatitis, diabetic kidney disease, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), a joint disorder, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, prurigo nodularis, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

38. A compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 33 for use in the treatment of at least one of a dermatological condition or a respiratory condition.

39. Use of a compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 33 for the manufacture of a medicament for the treatment of allergy, alopecia, Alzheimer’s disease, asthma, atherosclerosis, Bechet’s disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritis, chronic urticaria, Crohn’s disease (CD), dermatitis, diabetic kidney disease, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), a joint disorder, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, prurigo nodularis, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

40. Use of a compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 33 for use in the treatment of at least one of a dermatological condition or a respiratory condition.

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