Novel nitrogen-containing heterocyclic compounds

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 atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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. The compounds of the disclosure may be useful in the treatment, prevention, suppression and amelioration of a dermatological condition or a respiratory condition.

Description

[0001] PC073111A Novel Nitrogen-Containing Heterocyclic 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, 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, a compound of the disclosure has the Formula IA or a pharmaceutically acceptable salt thereof: where the variables are defined herein. In an aspect, a compound of the disclosure has the Formula IB or a pharmaceutically acceptable IB 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 atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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 atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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 X1is CH, CNH2, or N; X2is C or N; X3is CR13, N, NR13, O, or S; X4is CH, N, or NR13; X5is CR1Bor N; X6is CH or N; X7is CH, N, or CF; X8is CH or N; X9is CR1Bor N; X10is CR1Bor N; R1is -NHR8, -OH, -C2-5heterocycle, or -C1-3alkyl; wherein the -C2-5heterocycle of R1is optionally substituted with one, two, or three of -C1-3 alkyl, -C1-3 oxoalkyl, -C3-5 heterocycloalkyl, - C3-5 hydroxyheterocycloalkyl, -C3-5 aminoheterocycloalkyl, or oxo; wherein the -C1-3 alkyl of R1 is optionally substituted with one, two, or three of oxo, -NR10AR11, or -NR10R11; R1A is H, halogen, or -CH3; or R1 and R1A form a C5-7 heterocycloalkyl fused to Ring D or a C5-7 heteroaryl fused to Ring D; wherein the C5-7 heterocycloalkyl or the C5-7 heteroaryl is optionally substituted with oxo; each R1B independently is H, -CH3, F, Cl, or methoxy; R2 is H, -C1-3 alkyl, -C1-3 alkoxy, -C1-3 fluoroalkyl, or halogen; R3 is -C1-3 alkyl, -C2-10 heterocycle, -P(=O)(CH3)2, -S(=O)CH3, -NH-S(=O)2CH3, or -NH- C(=O)-C1-3 alkyl; wherein the -C1-3 alkyl of R3 is optionally substituted with one, two, or three of oxo, halogen, -C3-6 cycloalkyl, -OH, -NR12R12A, or cyano; wherein the -C2-10 heterocycle is optionally substituted with one, two, or three of -OH, halogen, -C1-3 hydroxyalkyl, -C1-3 alkoxy, - C1-3 alkyl, -C1-3 fluoroalkyl, cyclopropyl, or oxo; or R2 and R3 form a C3-6 heterocycle fused to Ring A optionally substituted with one, two, or three of -C1-3 alkyl, -C2-3 oxoalkyl, or oxo; R4A is H, -OH, -C1-3 fluoroalkyl, or -C1-3 alkyl; R4Bis H or is absent; or R4Aand R4Bform cyclopropyl; each R5independently is H, halogen, -OH, cyclopropyl, -C1-3fluoroalkyl, or -C1-3alkyl; or two R5groups form cyclopropyl; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6 or one R5 and R6 form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge; or R4B and one R5 form a C3-5 cycloalkyl fused to Ring B; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, -C1-3 alkyl, -SO2CH3, or a -C3-4 heterocycle; wherein the -C1-3 alkyl of R8 is optionally substituted with one, two, or three of oxo, -C3-9 heterocycloalkyl, -C1-3 alkoxy, cyanoimine, or -NR9R10; wherein the -C3-4 heterocycle of R8 is optionally substituted with one, two, or three of oxo, halogen, -C0-1 alkylene-NR10R11, -OH, -C1-3 hydroxyalkyl, -C1-3 alkoxy optionally substituted with -NR10R11, -C1-3 alkyl-C1-3 alkoxy, -C1-3 oxoalkyl, or -C1-3 alkyl; wherein the -C3-9 heterocycloalkyl of R8 is optionally substituted with one, two, or three of -C1-3 alkyl, -OH, -C1-3 hydroxyalkyl, -O-C1-3 hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkyl-C1-3 alkoxy, halogen, -C1-3 fluoroalkyl, -C1-3 fluoroalkoxy, cyano, -C1-3 cyanoalkyl, -C0-1 alkylene-C3-5 heterocycloalkyl, -O-C3-5 heterocycloalkyl, or -C0-1 alkylene-NR10R11; R9 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, -methylene- phenylene-NH-C(=O)-NR10R11, or -C3-5 heterocycloalkyl; wherein the -C1-4 alkyl of R9 is optionally substituted with one, two, or three of -C3-5 cycloalkyl, -C3-5 heterocycloalkyl, or methoxy; wherein the -C3-5 cycloalkyl of R9 is optionally substituted with one or two of -OH or -C1-3 alkyl; each R10 independently is H or -C1-4 alkyl; or R10Ais -C0-1alkylene-C3-5heterocycloalkyl optionally substituted with -C1-3alkyl; each R11independently is H or -C1-3alkyl; R12is H, -C1-3alkyl, -C1-3hydroxyalkyl, -(CH2)0-2-C3-5heterocycloalkyl, -(CH2)1-2-O-C3-5heterocycloalkyl, -methylene-C(=O)-NR10R11, or -methylene-phenylene-NH-C(=O)-NR10R11; wherein the -(CH2)0-2-C3-5heterocycloalkyl or the -(CH2)1-2-O-C3-5heterocycloalkyl of R12is optionally substituted with -C1-4alkyl, -C1-3alkyl-C1-3alkoxy, -(CH2)0-1-phenyl, halogen, -C1-3fluoroalkyl, or -(CH2)0-1-C3-5heterocycloalkyl; wherein the -C1-3alkyl of R12is optionally substituted with one, two, or three of oxo or NR10R11; R12Ais H or -C1-4alkyl; or R12and R12Aform a C3-10heterocycle optionally substituted with one, two, or three of - OH, -C1-3alkyl, oxo, halogen, -C2-3oxoalkyl, -C1-3alkoxy, -C1-3hydroxyalkyl, -C1-3alkyl-C1-3alkoxy, cyano, -C3-6cycloalkyl, -S(=O)2CH3, -S(=O)2CH2CH3, -C(=O)-NR10R11, or -NHC(=O)CH3; R13is H, -C1-6alkyl, -C1-4hydroxyalkyl, -C1-3fluoroalkyl, -C1-3alkyl-C1-3alkoxy, -C1-4cyanoalkyl, -C3-5cycloalkyl, -C2-4oxoalkyl, or -C3-5heterocycloalkyl; wherein the -C1-6alkyl of R13is optionally substituted with one, two, or three of oxo, fluoro, -NH2, C3-6cycloalkyl, or methoxy; wherein the -C3-5cycloalkyl or the -C3-6cycloalkyl of R13is optionally substituted with one, two, or three of -C1-3alkyl, -C1-3fluoroalkyl, or halogen; R14is H; or X4is NR13and R13and R14form a C4-5heterocycle fused to Ring C; n is 1 or 2; m is 0 or 1; wherein if X3 is CR13 or NR13 then X4 is CH or N, and if X4 is NR13 then X3 is N, O, or S; wherein the respective heterocycles each independently include 1 to 4 heteroatoms including at least one of N, O, or S. In an aspect, a compound of Formula IA or a pharmaceutically acceptable salt thereof: IA wherein X1 is CH, CNH2, or N; X2 is C or N; X3 is CR13, N, NR13, O, or S; X4 is CH, N, or NR13; X5 is CH, CR1B, or N; X6 is CH or N; X7 is CH, N, or CF; X8 is CH or N; X9is CH, CR1B, or N; X10is CH, CR1B, or N; R1is -NHR8, -OH, -C2-5heterocycle, or -C1-3alkyl; wherein the -C2-5heterocycle of R1is optionally substituted with one, two, or three of -C1-3alkyl, -C1-3oxoalkyl, -C3-5heterocycloalkyl, - C3-5hydroxyheterocycloalkyl, -C3-5aminoheterocycloalkyl, or oxo; wherein the -C1-3alkyl of R1is optionally substituted with one, two, or three of oxo or -NR10R11; R1Ais H or -CH3; or R1and R1Aform a C6-8fused heterocycloalkyl or a C6-8fused heteroaryl; wherein the C6-8fused heterocycloalkyl or the C6-8fused heteroaryl is optionally substituted with oxo; each R1Bindependently is H, -CH3, F, Cl, or methoxy; R2is H, -C1-3alkyl, -C1-3fluoroalkyl, or halogen; R3is -C1-3alkyl, -C2-10heterocycle, or -NH-C(=O)-C1-3alkyl; wherein the -C1-3alkyl of R3is optionally substituted with one or more of oxo, -OH, -NR12R12A, -C5-8heterocycle, or cyano; wherein the -C2-10heterocycle is optionally substituted with one, two, or three of -OH, halogen, - C1-3hydroxyalkyl, -C1-3alkyl, cyclopropyl, or oxo; or R2 and R3 form a C6-10 fused heterocycle optionally substituted with one, two, or three of -C1-3 alkyl, -C2-3 oxoalkyl, or oxo; R4A is H, -OH, or -C1-3 alkyl; R4B is H or is absent; each R5 independently is H, halogen, -OH, cyclopropyl, or -C1-3 alkyl; or two R5 groups form cyclopropyl; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6 or R5 and R6 form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, -C1-3 alkyl, -SO2CH3, or a -C3-4 heterocycle; wherein the -C1-3 alkyl of R8 is optionally substituted with one, two, or three of oxo, -C3-7 heterocycloalkyl, -C3-7 heterocycloalkyl substituted with methyl, alkoxy, cyanoimine, or -NR9R10; wherein the -C3-4 heterocycle is optionally substituted with one, two, or three of oxo, halogen, -C0-1 alkylene-NR14R11, -OH, -C1-3 hydroxyalkyl, -C1-3 alkoxy optionally substituted with -NR10R11, -C1-3 alkoxy-C1-3 alkyl, -C1-3 oxoalkyl, or -C1-3 alkyl; R9 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocycloalkyl; wherein the -C1-4 alkyl of R9 is optionally substituted with one, two, or three of cyclopropyl, -C3-5 heterocycloalkyl, or methoxy; wherein the -C3-5 cycloalkyl of R9 is optionally substituted with -C1-3 alkyl; each R10independently is H or -C1-4alkyl; or if the -C1-3alkyl of R8is substituted with -NR9R10, then the corresponding R9and R10are optionally combined to form a C3-7heterocycloalkyl optionally substituted with at least one of methoxy, OH, -C1-3alkyl, halogen, -NH2, -NHCH3, or -N(CH3)2; each R11independently is H or -C1-3alkyl; R12is H, -C1-3alkyl, -(CH2)0-1-C3-5heterocycloalkyl, or -methylene-phenylene-NH-C- NR10R11; wherein the -(CH2)0-1-C3-5heterocycloalkyl is optionally substituted with -C1-4alkyl; R12Ais H or -C1-4alkyl; or R12and R12Aform a fused C5-10heterocycloalkyl optionally substituted with -C1-3alkyl; R13is H, -C1-4alkyl, -C1-4hydroxyalkyl, -C1-3fluoroalkyl, -C0-1-C3-5cycloalkyl, -C2-4oxoalkyl, or -C3-5heterocycloalkyl; wherein the -C1-4alkyl of R13is optionally substituted with one, two, or three of cyclopropyl or methoxy; wherein the -C3-5cycloalkyl of R13is optionally substituted with -C1-3alkyl; n is 1 or 2; wherein the respective heterocycles each independently include 1 to 3 heteroatoms including at least one of N, O, or S; wherein at least one of X2 is N or X3 is N, NH, or NR13, and X4 is N or NR13; or if X3 is S or O, then X2 is C. In an aspect, a compound has the Formula IB or a pharmaceutically acceptable salt thereof: IB wherein X1 is CH, CNH2, or N; X2 is C or N; X3 is CR13, N, NR13, O, or S; X4 is CH, N, or NR13; X5 is CH or N; X6 is CH or N; X7 is CH, N, or CF; X8 is CH or N; with the proviso that at least one of X2 is N or X3 is N, NH, or NR13, and X4 is N or N R13; or if X3 is S or O, then X2 is C; R1 is -NHR8, OH, -C2-5 heterocycle, or -C1-3 alkyl; wherein the -C2-5 heterocycle of R1 is optionally substituted with one or more of -C1-3 alkyl, -C1-3 oxoalkyl, -C3-5 heterocycloalkyl, -C3-5 hydroxyheterocycloalkyl, -C3-5aminoheterocycloalkyl, or oxo; wherein the -C1-3alkyl of R1is optionally substituted with one or more of oxo or -NR10R11; R2is H, -C1-3alkyl, -C1-3fluoroalkyl, or halogen; R3is -C1-3alkyl, -C2-10heterocycle, or -NH-C(=O)-C1-3alkyl; wherein the -C1-3alkyl of R3is optionally substituted with one or more of oxo, -OH, -NR12R12A, -C5-8heterocycle, or cyano; wherein the -C2-10heterocycle is optionally substituted with one or more of -OH, halogen, -C1-3hydroxyalkyl, -C1-3alkyl, cyclopropyl, or oxo; or R2and R3form a C6-10fused heterocycloalkyl optionally substituted with one or more of - C1-3alkyl, -C2-3oxoalkyl, or oxo; R4Ais H, -OH, or -C1-3alkyl; R4Bis H or is absent; each R5independently is H, -OH, halogen, or -C1-3alkyl; or two R5groups form cyclopropyl; R6is H, -OH, or -C1-3alkyl; or R4Aand R6or R5and R6form a C1-3alkyl bridge or a C1-3heteroalkyl bridge; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, -C1-3 alkyl, or a -C3-4 heterocycle; wherein the -C1-3 alkyl of R8 is optionally substituted with one or more of oxo or -NR9R10; wherein the -C3-4 heterocycle is optionally substituted with one or more of oxo or -C1-3 alkyl; R9 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocycloalkyl; wherein the -C1-4 alkyl of R9 is optionally substituted with one or more of cyclopropyl, -C3-5 heterocycloalkyl, or methoxy; wherein the -C3-5 cycloalkyl of R9 is optionally substituted with -C1-3 alkyl; each R10 independently is H or -C1-4 alkyl; or if the -C1-3 alkyl of R8 is substituted with -NR9R10, then the corresponding R9 and R10 are optionally combined to form a C3-6 heterocycloalkyl optionally substituted with at least one of methoxy, OH, -C1-3 alkyl, or -N(CH3)2; each R11 independently is H or -C1-3 alkyl; R12 is H, -C1-3 alkyl, or -methylene-phenylene-NH-C(=O)-NR10R11; each R13 independently is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocycloalkyl; wherein the -C1-4 alkyl of R13 is optionally substituted with one or more of cyclopropyl or methoxy; wherein the -C3-5 cycloalkyl of R13 is optionally substituted with -C1-3 alkyl; n is 1 or 2; and wherein the respective heterocycles each independently include 1 to 3 heteroatoms including at least one of N, O, or S. In an aspect, R3is -C1-3alkyl or -C2-10heterocycle; the -C2-10heterocycle is -C2-5heteroaryl; the -C1-3alkyl of R3is optionally substituted with one, two, or three of oxo or - NR12R12A; and the -C2-5heterocycle of R3is optionally substituted with -C1-3alkyl. In an aspect, the dashed line refers to the bond being a single bond or a double bond; if the dashed line is a double bond, then R4Bis absent and n is 1. In an aspect, R1is -NHR8; and R8is -C1-3alkyl substituted with one, two, or three of oxo or -NR9R10. In an aspect, R2is H; and R3is -C1-3alkyl substituted with oxo and -NR12R12A. In an aspect, at least one of X5is CH; X7is CH or N; X8is CH; R1is -NHR8, -C2-5heterocycle, or -C1-3alkyl; R4Ais H or -C1-3alkyl; each R5independently is H, halogen, or -C1-3alkyl; or the two R5groups form cyclopropyl; R6is H or -C1-3alkyl; or R7is H or -C1-3alkyl. In an aspect, R3is -C1-3alkyl substituted with oxo and -NR12R12Aand R1is -NHR8or -C1-3alkyl substituted with oxo and -NR10R11. In an aspect, R3 can be -C(=O)-NR12R12Aand R1 can be -NH-CO-NR10R11. In an aspect, X3is CR13and X4is CH or N. In an aspect, R1is -NHR8; wherein R8is -C1-3alkyl or a -C3-4heterocycle; wherein the - C1-3alkyl of R8is substituted with oxo and -NR9R10; wherein the -C3-4heterocycle is substituted with one, two, or three of oxo or -C1-3 alkyl. In an aspect, X1 is N, X3 is N or NR13, and X4 is N. In an aspect, the -C2-6 heterocycle of R3 is a -C2-10 heterocycle and R3 is optionally substituted with one, two, or three of -C1-3 alkyl. In an aspect, at least one hydrogen (H) is deuterium (D). In an aspect, R1 is . In an aspect, R1Ais deuterium; X5, X9, and X10are each CR1B; and the R1Bof each of X5, X9, and X10 is deuterium. In an aspect, the compound is a deuterated compound of any of Examples D1, D2, D6, D31, D33, D128, or D132. In an aspect, a compound or a pharmaceutically acceptable salt thereof wherein the compound is one of: N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidin-1- yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5- (Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carbonyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N- (4-(3,3-dimethylureido)benzyl)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxamide; (S)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1- isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; (S)-5-(4- (dimethylcarbamoyl)phenyl)-1-isopropyl-7-methyl-N-(4-(4-methylpiperazine-1- carboxamido)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; or 5-(5- (dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-(2,2,2-trifluoroethyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide. In an aspect, a compound wherein the compound is one of: N-(4-(3,3- dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3- dimethylureido)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxamide; 5-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyridin-2-yl)-N-(4-(3,3- dimethylureido)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxamide; 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1,7- dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;(S)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-7-methyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; (S)-5-(4-(dimethylcarbamoyl)phenyl)-1- isopropyl-7-methyl-N-(4-(4-methylpiperazine-1-carboxamido)benzyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxamide; or 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3- dimethylureido)benzyl)-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxamide. In an aspect, a compound or a pharmaceutically acceptable salt thereof is . In an aspect, a compound or a pharmaceutically acceptable salt thereof is ○ . In an aspect, a compound or a pharmaceutically acceptable salt thereof is . In an aspect, a compound or a pharmaceutically acceptable salt thereof is . In an aspect, a compound or a pharmaceutically acceptable salt thereof is . In an aspect, a compound or a pharmaceutically acceptable salt thereof is . In an aspect, a compound or a pharmaceutically acceptable salt thereof is . In an aspect, the compound is other than the following: rac-(4R,7S)-9-(5- (dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-methyl-1,4,5,6,7,8- hexahydro-4,7-epiminocyclohepta[c]pyrazole-3-carboxamide, rac-(R)-N-(4-(3,3- dimethylureido)benzyl)-5-(5-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)pyridin-2-yl)-1-isopropyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, N-(4-(3,3-dimethylureido)benzyl)- 1-isopropyl-5-(5-((1S,4S)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, rel-(R or S)-N-(4-(3,3- dimethylureido)benzyl)-1-isopropyl-5-(5-(tetrahydro-2H-pyran-2-yl)pyridin-2-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, rel-(R or S)-N-(4-(3,3- dimethylureido)benzyl)-1-isopropyl-5-(5-(tetrahydro-2H-pyran-2-yl)pyridin-2-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, or (S)-5-(4-(dimethylcarbamoyl)phenyl)- 1-isopropyl-7-methyl-N-(4-(4-methylpyrimidin-2-yl)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxamide. In an aspect, a pharmaceutical composition comprises the compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In an aspect, a method for treating atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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 comprises administering to a subject in need thereof a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In an aspect, a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament. In an aspect, a compound of Formula I, or a pharmaceutically acceptable salt thereof, can be for use in the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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, a compound of Formula I, or a pharmaceutically acceptable salt thereof, can be for use in the treatment of at least one of a dermatological condition or a respiratory condition. In an aspect, use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, can be for the manufacture of a medicament for the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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 a compound, or a pharmaceutically acceptable salt thereof, can be for use in the treatment of at least one of a dermatological condition or a respiratory condition. In an aspect, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compounds of Examples 1 and 2 and those listed in Table 2. In an aspect, a method for treating atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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 comprises administering to a subject in need thereof a therapeutically effective amount of the compound of the any of the preceding aspects, or a pharmaceutically acceptable salt thereof. The method can be for treating atopic dermatitis. The method can be for treating In an aspect, a compound according to any of the preceding aspects, or a pharmaceutically acceptable salt thereof, is for use as a medicament. In an aspect, a compound according to any of the preceding aspects, or a pharmaceutically acceptable salt thereof, is for use in the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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, a compound according to any of the preceding aspects, or a pharmaceutically acceptable salt thereof, is for use in the treatment of at least one of a dermatological condition or a respiratory condition. In an aspect, a use of a compound according to any of the preceding aspects, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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, a use of a compound according to any of the preceding aspects, or a pharmaceutically acceptable salt thereof, is for use in the treatment of at least one of a dermatological condition or a respiratory condition. 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 and Formula IA, where a compound of Formula I can be a compound specifically of Formula IA. 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). More specifically, halogen can refer to fluoro and chloro. “Cyano” refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., -C≡N. “Cyanoimine” refers to a substituent having a carbon atom joined to a nitrogen atom by a double bond and that is bound to a cyano group, i.e., -C(R)=N-C≡N, where R can be a dimethylamino group, i.e., -C(N(CH3)2)=N-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 (“C1-6 haloalkyl”), 1-4 carbon atoms (“C1-4 haloalkyl”), or 1-2 carbon atoms (“C1-2 haloalkyl”). 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). “Hydroxyalkyl” 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 hydroxy (OH), for example, only one hydrogen atom is replaced by hydroxy. Hydroxyalkyl groups man contain, but are not limited to, 1-6 carbon atoms (“C1-6 hydroxyalkyl”), 1-4 carbon atoms (“C1-4 hydroxyalkyl”), or 1-2 carbon atoms (“C1-2 hydroxyalkyl”). “Cyanoalkyl” 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 cyano (-C≡N). Cyanoalkyl groups man contain, but are not limited to, 1-6 carbon atoms (“C1-6 cyanoalkyl”), 1-4 carbon atoms (“C1-4 cyanoalkyl”), or 1-2 carbon atoms (“C1-2 cyanoalkyl”). “Oxoalkyl” refers to an alkyl group as defined above containing the specified number of carbon atoms wherein at least two hydrogen atoms have been replaced by an oxo group. Oxoalkyl groups man contain, but are not limited to, 1-6 carbon atoms (“C1-6 oxoalkyl”), 1-4 carbon atoms (“C1-4 oxoalkyl”), or 1-2 carbon atoms (“C1-2 oxoalkyl”). “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. "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)q as 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. “Heterocycle” or “heterocyclic” refers to a cyclic ring system that includes at least one heteroatom selected from N, O, and S as a ring member in the ring system. The ring system can include heterocycloalkyl or heteroaryl rings. The ring system can include spirocyclic rings, bridged rings, or fused rings. “Amino” refers to a group -NH2, which is unsubstituted or substituted. When substituted, the term includes groups of the form -NRxRy, one of Rx and Ry is an alkyl moiety and the other is H, or both of Rx and Ry are alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., -NH(C1-3 alkyl) or -N(C1-3 alkyl)2). The term “aminoheterocycloalkyl” refers to a heterocycloalkyl substituted with an amino group. 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. The salt can be a trifluoroacetate salt or a formate salt. 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, i.e.,2H, 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 the examples 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)2 or –P(=O)(O-Na+)2 or –P(=O)(O-)2Ca2+; (v) when a compound of the disclosure contains a primary or secondary amino functionality (-NH2 or -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, –COCH2NH2 or the amino group is derivatized with an amino acid; (vi) when a compound of the disclosure contains a primary or secondary amino functionality (-NH2 or -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, a secondary 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 or a pharmaceutically acceptable salt thereof can have the structure of Formula I or Formula IA or Formula IB. The compound of Formula I can have the structure of Formula IA or Formula IB. IB X1can be CH, CNH2, or N. X1can be N. X2can be C or N. X3can be CR13, N, NR13, O, or S. X3can be CR13. X3can be N or NR13. X3can be CR13or N. X4 can be CH, N, or NR13. X4 can be CH, N, or N-cyclopropyl. X4 can be N. X5 can be CH, CR1B, or N. X5 can be CH. X6 can be CH or N. X7 can be CH, N, or CF. X7 can be CH or N. X7 can be CCl. X8can be CH or N. X8can be CH. X9can be CH, CR1B, or N. X10can be CH, CR1B, or N. At least one of X2can be N or X3can be N, NH, or NR13, and X4can be N. If X3 is S or O, then X2 can be C. If X3 is CR13 or NR13, then X4 can be CH or N. If X4 is NR13, then X3 can be N, O, or S. The dashed line refers to the bond being a single bond (i.e., the dashed line is not present leaving only the single bond) or a double bond (i.e., the dashed line is present as a second bond making the double bond). The dashed line can refer to the bond being a single bond. If the dashed line refers to the bond being a double bond, then R4B is absent and n is 1. R1 can be -NHR8, -OH, -C2-5 heterocycle, or -C1-3 alkyl. R1 can be -NHR8, -C2-5 heterocycle, or -C1-3 alkyl. R1 can be -C2-5 heterocycle and can optionally be substituted with one or more or one, two, or three of -C1-3 alkyl, -C1-3 oxoalkyl, -C3-5 heterocycloalkyl, -C3-5 hydroxyheterocycloalkyl, -C3-5 aminoheterocycloalkyl, or oxo. R1 can be -C2-5 heterocycle and can optionally be substituted with one or more or one, two, or three of -C1-3 alkyl or oxo. R1 can be -C2-5 heterocycle and can optionally be substituted with oxo. R1 can be -C1-3 alkyl and can be substituted with one, two, or three of oxo, -NR10AR11, or -NR10R11. R1 can be -C1-3 alkyl and can be substituted with one or two of oxo, -NR10AR11, or -NR10R11. R1 can be -C1-3 alkyl optionally substituted with one or more or one, two, or three of oxo or -NR10R11. R1 can be -C1-3 alkyl substituted with oxo and -NR10R11. R1 can be -C1-3 alkyl substituted with oxo and -NR10AR11. R1 can be -NHR8. Each of the -C2-5 heterocycle, -C3-5 heterocycloalkyl, -C3-5 hydroxyheterocycloalkyl, and the -C3-5 aminoheterocycloalkyl independently can include 1 to 4 heteroatoms including at least one of N, O, or S. The -C2-5 heterocycle of R1 can include 1 to 4 heteroatoms including at least one of N, O, or S; where the heteroatoms can all be N. R1Acan be H. R1Acan be -CH3. R1Acan be H, halogen, or -CH3. R1Acan be H or halogen, where the halogen can be F. R1and R1Acan form a C5-7heterocycloalkyl fused to Ring D or a C5-7heteroaryl fused to Ring D. The C5-7heterocycloalkyl or the C5-7heteroaryl can optionally be substituted with oxo. R1and R1Acan form a C6-8fused heterocycloalkyl that is optionally substituted with oxo. R1and R1Acan form a C6-8fused heteroaryl that is optionally substituted with oxo. Each of the C6-8fused heterocycloalkyl and the can C6-8fused heteroaryl independently can include 1 to 3 heteroatoms including at least one of N, O, or S. Each R1Bindependently is H, -CH3, F, Cl, or methoxy. R2can be H, -C1-3alkyl, -C1-3alkoxy, -C1-3fluoroalkyl, or halogen. R2can be H. R3can be -C1-3alkyl, -C2-10heterocycle, -P(=O)(CH3)2, -S(=O)CH3, -NH-S(=O)2CH3, or -NH-C(=O)-C1-3alkyl. R3can be -C1-3alkyl, -C2-10heterocycle, -P(=O)(CH3)2, -S(=O)CH3, or -NH-S(=O)2CH3. R3can be -C1-3alkyl, -C2-10heterocycle, or -NH-C(=O)-C1-3alkyl. R3can be - C1-3alkyl optionally substituted with one or more or one, two, or three of oxo, -OH, halogen, -C3-6cycloalkyl, -NR12R12A, -C5-8heterocycle, or cyano. R3can be -C1-3alkyl substituted with oxo and -NR12R12A. The -C2-10heterocycle of R3can be -C2-10heterocycloalkyl or -C2-10heteroaryl. The -C2-10heterocycle of R3can be -C2-6heterocycloalkyl or -C2-6heteroaryl. R3can be -C2-10heterocycle optionally substituted with one or more or one, two, or three of -OH, halogen, -C1-3hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkyl, -C1-3 fluoroalkyl, cyclopropyl, or oxo. R3 can be -C2-10 heterocycloalkyl optionally substituted with one or more or one, two, or three of -OH, halogen, - C1-3 hydroxyalkyl, -C1-3 alkyl, cyclopropyl, or oxo. R3 can be -C1-3 alkyl optionally substituted with one or more or one, two, or three of oxo or -NR12R12A. R3 can be -C2-5 heterocycle optionally substituted with -C1-3 alkyl. R3 can be -C2-5 heteroaryl optionally substituted with one or more or one, two, or three -C1-3 alkyl. Each of the -C2-10 heterocycle, -C5-8 heterocycle, -C2-6 heterocycloalkyl, -C2-10 heterocycloalkyl, -C2-10 heteroaryl, -C2-6 heteroaryl, or -C2-5 heterocycle independently can include 1 to 3 heteroatoms including at least one of N, O, or S. The -C2-10 heterocycle of R3 can include 1 to 3 heteroatoms including at least one of N, O, or S. The -C2-10 heterocycle of R3 can be a spiro, fused, or bridged -C2-10 heterocycle. The C5-8 heterocycle of R3 can include 1 to 4 heteroatoms including at least one of N, O, or S. R2 and R3 can form a C3-6 heterocycle fused to Ring A optionally substituted with one, two, or three of -C1-3 alkyl, -C2-3 oxoalkyl, or oxo. R2 and R3 can form a C3-6 heterocycloalkyl fused to Ring A optionally substituted with one or more or one, two, or three of -C1-3 alkyl, -C2-3 oxoalkyl, or oxo. Each of the C3-6 heterocycle or the C3-6 heterocycloalkyl independently can include 1 to 3 heteroatoms including at least one of N, O, or S. R4A can be H, -OH, -C1-3 fluoroalkyl, or -C1-3 alkyl. R4A can be H, -C1-3 fluoroalkyl, or -C1-3 alkyl. R4B can be H. R4B can be absent. R4Aand R4Btaken together can form cyclopropyl. R4Band one R5taken together can form a C3-5cycloalkyl fused to Ring B. Each R5independently can be H, -OH, -C3-6cycloalkyl (e.g., cyclopropyl), halogen, -C1-3fluoroalkyl, or -C1-3alkyl. Each R5independently can be H, halogen, or -C1-3alkyl. The two R5groups taken together can form cyclopropyl. If the dashed line represents a double bond being present, then R5can be H, -C3-6cycloalkyl (e.g., cyclopropyl), halogen, -C1-3fluoroalkyl, or -C1-3alkyl. R6can be H, -OH, or -C1-3alkyl. R6can be H or -C1-3alkyl. R4Aand R6taken together can form a C1-3alkyl bridge or a C1-3heteroalkyl bridge. One R5and R6taken together can form a C1-3alkyl bridge or a C1-3heteroalkyl bridge. The C1-3heteroalkyl bridge can include one heteroatom of N, O, or S. R7can be H, -C1-3alkyl, or -C1-3hydroxyalkyl. R7can be H or -C1-3alkyl. R8can be H, -C1-3alkyl, -SO2CH3, or a -C3-4heterocycle. R8can be H, -C1-3alkyl, or a -C3-4heterocycle. R8can be -C1-3alkyl substituted with one, two, or three of oxo, -C3-9heterocycloalkyl, -C3-9heterocycloalkyl substituted with methyl, -C1-3alkoxy, cyanoimine, or -NR9R10. R8can be -C1-3alkyl optionally substituted with one or more or one, two, or three of oxo or -NR9R10. R8can be -C1-3alkyl optionally substituted with one or two of oxo or -NR9R10. R8can be -C1-3alkyl substituted with oxo and -NR9R10. R8can be -C3-4heterocycle optionally substituted with one, two, or three of oxo, halogen, -C0-1alkylene-NR10R11, -OH, -C1-3hydroxyalkyl, -C1-3 alkyl-C1-3 alkoxy, -C1-3 oxoalkyl, -C1-3 alkyl, or -C1-3 alkoxy optionally substituted with -NR10R11. The -C3-9 heterocycloalkyl of R8 can be substituted with one, two, or three of -C1-3 alkyl, -OH, -C1-3 hydroxyalkyl, -O-C1-3 hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkyl-C1-3 alkoxy, halogen, -C1-3 fluoroalkyl, -C1-3 fluoroalkoxy, cyano, -C1-3 cyanoalkyl, -C0-1 alkylene-C3-5 heterocycloalkyl, -O-C3-5 heterocycloalkyl, -C0-1 alkylene-NR10R11. R8 can be -C3-4 heterocycle optionally substituted with one or more or one, two, or three of oxo or -C1-3 alkyl. Each of the - C3-4 heterocycle or the -C3-9 heterocycloalkyl of R8 independently can include 1 to 4 heteroatoms including at least one of N, O, or S. The -C3-4 heterocycle of R8 can include 1 to 4 heteroatoms including at least one of N or O. The -C3-9 heterocycloalkyl of R8 can include 1 to 3 heteroatoms including at least one of N or O. The -C3-4 heterocycle or the -C3-9 heterocycloalkyl of R8 can be a bridged, spiro, or fused heterocycle. R9 can be H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, -methylene- phenylene-NH-C(=O)-NR10R11, or -C3-5 heterocycloalkyl. R9 can be the -C1-4 alkyl optionally substituted with one or more or one, two, or three of -C3-5 cycloalkyl, -C3-5 heterocycloalkyl, or methoxy. R9 can be -C3-5 cycloalkyl of R9 optionally substituted with one or two of -OH or -C1-3 alkyl. R9 can be H or -C1-4 alkyl. Each of the -C3-5 heterocycloalkyl of R9 independently can include 1 to 2 heteroatoms including at least one of N or O. Each R10 independently can be H or -C1-4 alkyl. Each R10 independently can be H or -C1-3 alkyl. R10Acan be -C0-1alkylene-C3-5heterocycloalkyl optionally substituted with -C1-3alkyl. The C3-5heterocycloalkyl of R10Acan include 1 heteroatom of N. If the -C1-3alkyl of R8is substituted with -NR9R10, then the corresponding R9and R10can optionally be combined to form the C3-9heterocycloalkyl or the C3-9heterocycloalkyl. Each R11independently can be H or -C1-3alkyl. R12can be H, -C1-3alkyl, -C1-3hydroxyalkyl, -(CH2)0-2-C3-5heterocycloalkyl, -(CH2)1-2-O- C3-5heterocycloalkyl, -methylene-C(=O)-NR10R11, or -methylene-phenylene-NH-C(=O)-NR10R11. The -(CH2)0-2-C3-5heterocycloalkyl or the -(CH2)1-2-O-C3-5heterocycloalkyl of R12can be substituted with -C1-4alkyl, -C1-3alkyl-C1-3alkoxy, -(CH2)0-1-phenyl, halogen, -C1-3fluoroalkyl, or - (CH2)0-1-C3-5heterocycloalkyl. The -C1-3alkyl of R12can be substituted with one, two, or three of oxo or NR10R11. Each of the -(CH2)0-2-C3-5heterocycloalkyl, the -(CH2)1-2-O-C3-5heterocycloalkyl, or the -(CH2)0-1-C3-5heterocycloalkyl of R12independently can include 1 to 2 heteroatoms including at least one of N or O. R12Acan be H. R12Acan be -C1-4alkyl. R12and R12Acan form a C3-10heterocycle optionally substituted with one, two, or three of -C1-3alkyl, -OH, oxo, halogen, -C2-3oxoalkyl, -C1-3alkoxy, -C1-3hydroxyalkyl, -C1-3alkyl-C1-3alkoxy, cyano, -C3-6cycloalkyl, -S(=O)2CH3, -S(=O)2CH2CH3, -C(=O)-NR10R11, or -NHC(=O)CH3. The C3-10heterocycle can include 1 to 4 heteroatoms including at least one of N, O, or S. The C3-10 heterocycle can be a bridged, spiro, or fused heterocycle. R13 can be H, -C1-6 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C1-3 alkyl-C1-3 alkoxy, -C1-4 cyanoalkyl, -C0-1 alkylene-C3-5 cycloalkyl, -C2-4 oxoalkyl, or -C0-1 alkylene-C3-5 heterocycloalkyl. R13 can be H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocycloalkyl. R13 can be H. R13 can be -C0-1-cyclopropyl. The -C1-6 alkyl of R13 can optionally be substituted with one, two, or three of oxo, fluoro, -NH2, C3-6 cycloalkyl, or methoxy. The -C3-5 cycloalkyl or the -C3-6 cycloalkyl of R13 can optionally be substituted with one, two, or three of - C1-3 alkyl, -C1-3 fluoroalkyl, or halogen. The -C3-5 heterocycloalkyl of R13 can include 1 to 3 heteroatoms including at least one of N, O, or S. R14 can be H. X4 can be NR13 and R13 and R14 can form a C4-5 heterocycle fused to Ring C. The variable n can be 1 or 2. The variable m can be 0 or 1. The respective heterocycles can each independently include 1 to 4 heteroatoms including at least one of N, O, or S. At least one hydrogen of the compound of Formula I can be deuterium. The A, B, C, and D values used to denote the rings in Formula I can be used to identify the corresponding rings of Formula IA and Formula IB. The term “one or more of” when defining the number of groups in Formula I, IA, or IB can, for example, refer to one to four, or one to three of the listed options each time independently that the term is used. The compound or a pharmaceutically acceptable salt thereof can be N-(4-(3,3- dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxamide. The compound or a pharmaceutically acceptable salt thereof can be 5-(5- (Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide. The compound or a pharmaceutically acceptable salt thereof can be 5-(5-(6,7-dihydro- 5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide. The compound or a pharmaceutically acceptable salt thereof can be 5-(5- (Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1,7-dimethyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide. The compound or a pharmaceutically acceptable salt thereof can be(S)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-7-methyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide. The compound or a pharmaceutically acceptable salt thereof can be (S)-5-(4- (dimethylcarbamoyl)phenyl)-1-isopropyl-7-methyl-N-(4-(4-methylpiperazine-1- carboxamido)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide. The compound or a pharmaceutically acceptable salt thereof can be 5-(5- (dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-(2,2,2-trifluoroethyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide. A pharmaceutical composition can comprise a compound of Formula I. For example, the pharmaceutical composition can comprise a compound of Formula IA. 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 atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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 or without 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 at least one disease or condition including atopic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), rhinosinusitis (for example, chronic rhinosinusitis with nasal polyps or chronic rhinosinusitis without nasal polyps), chronic urticaria (for example, chronic inducible urticaria or chronic spontaneous urticaria), prurigo nodularis, eosinophilic esophagitis, eosinophilic gastritis, bullous pemphigoid, pruritis (for example, chronic pruritis of unknown origin), atopic keratoconjunctivitis, chronic inducible urticaria, or allergy (for example, food allergy). 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. General Scheme A The general structure of Formula I can be prepared as shown in General Scheme A. The tert-butyloxycarbonyl (BOC) protected amine of Formula AA1, synthesized by literature methods or purchased commercially, can be treated with standard acidic deprotection reagents such as hydrochloric acid (HCl) in solvents like 1,4-dioxane (dioxane), ethyl acetate (EtOAc) and dichloromethane (DCM) from 10 degrees Celsius (°C) to room temperature to afford the deprotected amine compound of Formula AA2. The amine of Formula AA2 can be treated with a halogen (e.g., RB= F or Br)-substituted aromatic of Formula AA3 using standard SNAr conditions such as N,N-diisopropylethylamine (DIEA), tripotassium phosphate (K3PO4), potassium carbonate (K2CO3), or cesium fluoride (CsF) in 1-pentanol, butyronitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or acetonitrile (ACN) when heated between 80 to 140 °C to afford Formula AA4. The Formula AA4 can also be prepared by reacting Formula AA2 and AA3 with copper(I) iodide (CuI), 1,2-dimethylethylenediamine (DMEDA), or trans-N,N′-dimethylcyclohexane-1,2-diamine or Pd catalyst such as (2- dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (RuPhos Pd G3) with 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) (cataCXium®A Pd G3), [dicyclohexyl(2′,6′-diisopropoxy-2-biphenylyl)phosphine- κP](methanesulfonatato-κO)[2′-(methylamino-κN)-2-biphenylyl-κC2]palladium (RuPhos Pd G4) with a base such as sodium tert-butoxide (NaOtBu), K2CO3, tripotassium phosphate (K3PO4) or cesium carbonate (Cs2CO3) in a solvent like dioxane, dimethylacetamide (DMA), DMF, DMSO, 2-methyl-2-butanol (tert-amyl alcohol) or toluene and heated between 80 to 130 °C. Formula AA4, where R3 is a halogen (e.g., F, Br, or I), can be converted to an amine, urea, or lactam using standard SNAr or cross coupling conditions described above to afford Formula AA4. When R3 is a halogen (e.g. I) on Formula AA4, the halogen can react with a BOC-protected hydrazine with the cross coupling conditions described above then can be deprotected under standard acidic conditions such as HCl in a solvent like dioxane or DCM and cyclized by reacting with (E)-4-(dimethylamino)but-3-en-2-one in EtOH to converted R3to a 5- methyl-1H-pyrazole on Formula AA4. For Formula AA4, where R3is a halogen (e.g., Br, I), can be converted to a carbon-carbon bond by reacting the halogen with nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl2.glyme), 5-methoxypicolinimidamide, and using activated ester of N-hydroxyphthalimide, tetrabutylammonium iodide, preactivated zinc (Zn) and trifluoroacetic acid (TFA) in a solvent like DMA from room temperature to 70oC or under photoredox conditions such as [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[2-(2- pyridinyl-N)phenyl-C]iridium(III) hexafluorophosphate (Ir(ppy)2(dtbbpy)PF6), nickel(II) bromide ethylene glycol dimethyl ether complex (NiBr2.DME), 5-methoxypicolinimidamide, phthalimide and quinuclidine in a solvent such as DMA and methyl tertiary-butyl ether (MTBE) to afford Formula AA4. When R3 is a halogen (e.g. Br) on Formula AA4, the halogen can react with B2Pin2 and Pd(dppf)Cl2 with a base like KOAc in a solvent like dioxane at 85oC to form boronic acid at R3. The boronic acid at R3 can react further by reacting with bromo-substituted 5- membered ring heterocycle, Pd(dppf)Cl2 and with a base like K3PO4 in solvents like dioxane at 85oC to give a 5-membered ring heterocycle at R3 on Formula AA4. When R3 is a carboxylic acid on Formula AA4, the acid can be transformed further via amide coupling with HATU and a base like DIEA in a solvent like DMF at 40oC to form the amide on R3. When R3 is a tert-butyl acetate on Formula AA4, it can be deprotected under standard acidic conditions such as TFA or HCl in a solvent like dioxane, H2O, and DCM from room temperature to 40oC, then transformed further under standard amide coupling conditions to form an amide at R3. When R3 is a methyl propionate on Formula AA4 then Formula AA4 can react with 2-bromoacetonitrile with a base like lithium bis(trimethylsilyl)amide (LiHMDS) in a solvent like THF at -78oC which can be transformed further by reacting with sodium borohydride (NaBH4) in solvents like THF and H2O at 0oC to room temperature to form a 5-membered lactam at R3 on Formula AA4. The ester (e.g., RA= methyl or ethyl) of Formula AA4 can undergo standard hydrolysis conditions such as utilizing a base (e.g., lithium hydroxide monohydrate (LiOH), sodium hydroxide (NaOH), 1,5,7-triazabicyclo[4.4.0]dec-5-ene, or potassium trimethylsilanolate (KOTMS) in solvents like tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), water (H2O), dioxane, or ACN. The reaction can typically occur at 0 to 50oC, preferably at about 23oC (room temperature), to afford the carboxylic acid of Formula AA5. The compound of Formula I can be obtained by reacting the carboxylic acid of AA5 with the amine of Formula AA6 under standard amide coupling reagents like 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) with 2-hydroxypyridine-N-oxide (HOPO), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), or other common reagents in solvents such as ACN and H2O, DMF, or DMSO along with an organic base such as triethylamine (TEA) or DIEA stirred at a temperature of 0 to 70 °C, preferably at about 23oC (room temperature). In Formula I, when R1is an amine, it can react with 2,2,2-trichloroethyl carbonochloridate in pyridine from 0oC to room temperature, then transform further with a secondary amine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in THF from 40-60oC to form a urea at R3. In Formula I, when R1is phenyl carbamate, it can react with an amine and a base like TEA in a solvent like DMF from 40oC, then deprotected under acidic conditions with HCl in a solvent like dioxane and DCM from 0oC to room temperature to form a urea at R3. In Formula I, when R3 is a tert-butyl acetate, it can be deprotected under standard acidic conditions, such as HCl in a solvent like H2O and DCM. In Formula I, when R1 is an amine, it can react with ethyl carbonochloridate with a base like TEA in a solvent like DCM from 0oC to room temperature to form an amide at R3.

[0002] General Scheme B structure I can as B. The amine of Formula BB1 can be treated with a halogen (e.g., RB= F or Cl)-substituted aromatic of Formula AA3 using standard SNAr conditions such as cesium fluoride (CsF) or K3PO4in a solvent like water or DMSO and stirred at 80 to 140 °C to afford Formula AA5. The compound of Formula I can be obtained by reacting the carboxylic acid of AA5 with the amine of Formula AA6 under standard amide coupling reagents like EDCI with HOPO, HATU, or other common amide coupling reagents in solvents such as ACN and H2O, DMF, or DMSO along with an organic base such as TEA or DIEA stirred at a temperature of 0 to 70 °C, preferably at room temperature. In Formula I, when R6is a hydrogen, can be oxidized with 2,3-dichloro-5,6- dicyano-p-benzoquinone (DDQ) in acetone and then further transformed to methylate when reacted with boron trifluoride diethyl etherate (BF3OEt2) and dimethylzinc in solvents like toluene and THF. In Formula I, when R3is a tert-butyl acetate, can be deprotected under standard acidic conditions, such as HCl in a solvent like dioxane, H2O, and DCM, then transformed further under standard amide coupling conditions to form an amide at R3.

[0003] General Scheme C The general structure of Formula II can be prepared as shown in General Scheme C. The trifluoromethanesulfonic acid of Formula CC1, synthesized by literature methods or purchased commercially, can be treated with a boronic acid (e.g. RB= B-(OH)2)-substituted aromatic of Formula AA3 using with a Pd catalyst such as Pd(dppf)Cl2 and a base like K3PO4 in solvents such as H2O and THF at 85oC to form Formula CC2. The alkene of Formula CC2 can undergo hydrogenation with palladium on carbon (Pd / C) in EtOH to reduce the alkene to form Formula CC3. The ester (e.g., RA= ethyl) of Formula CC3 can undergo standard hydrolysis conditions by utilizing a base like LiOH in solvents like THF, MeOH and H2O from 0 to 50oC, preferably at room temperature, to afford the carboxylic acid of Formula CC4. The compound of Formula II can be obtained by reacting the carboxylic acid of CC4 with the amine of Formula AA6 under standard amide coupling reagents like EDCI with HOPO in solvents such as DMSO along with an organic base such as DIEA stirred at 0 to 70 °C.II can be prepared as shown in General Scheme C. The trifluoromethanesulfonic acid of Formula CC1, synthesized by literature methods or purchased commercially, can be treated with a boronic acid (e.g. RB= B- (OH)2)-substituted aromatic of Formula AA3 using with a Pd catalyst such as Pd(dppf)Cl2and a base like K3PO4in solvents such as H2O and THF at 85oC to form Formula CC2. The alkene of Formula CC2 can undergo hydrogenation with palladium on carbon (Pd / C) in EtOH to reduce the alkene to form Formula CC3. The ester (e.g., RA= ethyl) of Formula CC3 can undergo standard hydrolysis conditions by utilizing a base like LiOH in solvents like THF, MeOH and H2O from 0 to 50oC, preferably at room temperature, to afford the carboxylic acid of Formula CC4. The compound of Formula II can be obtained by reacting the carboxylic acid of CC4 with the amine of Formula AA6 under standard amide coupling reagents like EDCI with HOPO in solvents such as DMSO along with an organic base such as DIEA stirred at 0 to 70 °C. General Scheme D The general structure of Formula III can be prepared as shown in General Scheme D. The BOC protected amine of Formula AA1, synthesized by literature methods or purchased commercially, which can be treated with bromo substituted alkyl amine protected as benzyloxy carbonyl (Cbz) with a base like Cs2CO3 in ACN to give mixture of N1 and N2-alkylated (e.g. RC= Cbz protected alkyl amine) compounds of Formula DD1. The regioisomers can be separated by silica gel column purification to provide compounds of Formula DD2. Formula DD2 can then undergo deprotection of the CBz protecting group with reducing conditions such as Pd / C in a solvent like EtOH at 50-120 pounds per square inch (psi) of hydrogen (H2) gas. The free amine on the N2 of Formula DD1 can be reacted with DBU in a solvent like dioxane at 100 °C to cyclize to form a C6-7 heterocycle fused to Ring C of Formula DD2. The cyclized lactam of Formula DD2 can be treated with a halogen (e.g., RD= Br)-substituted aromatic of Formula DD3 with bases such as K2CO3, potassium bis(trimethylsilyl)amide (KHMDS) in THF with additional solvents such as ACN and DMF with stirring at 80oC to afford Formula DD4. The BOC protected amine of Formula DD4 can be deprotected under acidic conditions such as HCl in solvents like dioxane and DCM to form the amine of Formula DD5. The amine of Formula DD5 can be treated with a halogen (e.g., RB= F)-substituted aromatic of Formula AA3 using standard SNAr conditions such as K3PO4in a solvent like tert-amyl alcohol and H2O with stirring at 100 °C to afford Formula III. In Formula III, when R1 is an iodine, can react further with an urea with a base like Cs2CO3 and palladium catalyst such as ((SP-4-3)-[[5-(diphenylphosphino)-9,9- dimethyl-9H-xanthen-4-yl]diphenylphosphine-κP](methanesulfonato-κO)[2′-(methylamino- κN)[1,1′-biphenyl]-2-yl-κC]- palladium) XantPhos Pd G4 in a solvent like tert-amyl alcohol at 90 °C to form an urea at R1 in Formula III. In order that this disclosure may be better understood, the following examples are set forth. These examples are for the purpose 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 illustrates the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention 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. Commercial solvents and reagents were generally used without further purification. Anhydrous solvents were employed where appropriate, generally ACROSEALTMproducts from Acros Organics, Aldrich SURE / SEAL™ from Sigma- Aldrich, or DRISOLVTMproducts from EMD Chemicals. Commercial solvents and reagents were used without further purification. Experiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were employed. Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius). In some examples, chiral separations were carried out to separate enantiomers or diastereomers of certain compounds of the disclosure. For syntheses referencing procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. In general, reactions were followed by thin-layer chromatography (TLC) or mass spectrometry (MS) and subjected to work-up when appropriate. Commercial benchtop photoreactors such as the Penn OC Photoreactor M2, Acceled Photoreactor M2 and Lumidox II with 24-well block were utilized with 450 or 445 nanometer (nm) light-emitting diode (LED). Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents / gradients were chosen to provide appropriate retention times. Reaction progress was monitored using thin layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS) and high-performance liquid chromatography (HPLC), analyses. TLC was performed on pre-coated silica gel plates with a fluorescence indicator (254 nm excitation wavelength) and visualized under ultraviolet (UV) light. LCMS data were acquired on an Agilent 1100 Series instrument with a Leap Technologies autosampler, Gemini C18 columns, ACN / water gradients, and either trifluoroacetic acid (TFA), formic acid, or ammonium hydroxide (NH4OH) modifiers or similar equipment. The column eluent was analyzed using Waters ZQ mass spectrometer scanning in both positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used. High resolution mass spectrometry (HR / MS) was gathered on Sciex TripleTOF 5600+ with DuoSpray ionization source with the liquid chromatography instrument with an Agilent Technologies, 1200 binary pump, Agilent 1200 autosampler, Agilent 1200 column compartment, and Agilent 1200 diode array detector. The instrument acquisition and data handling were done with Sciex Analyst TF version 1.7.1. HPLC data were acquired on an Agilent 1100 Series instrument using Gemini, Sunfire, Welch BoltimateTM, Welch Xtimate, Prep PG-45 MOD10, Boston Prime, Boston Green ODS, Phenomenex Gemini NX or XBridge C18columns with acetonitrile (ACN) / water (H2O) gradients, and either TFA, formic acid, NH4OH, or ammonium bicarbonate (NH4HCO3) modifiers and comparable equipment. Purifications were performed by high performance liquid chromatography (HPLC) and medium performance liquid chromatography (MPLC) using Isco CombiFIash Companion, AnaLogix InteIIiFIash 280, Biotage SP1, or Biotage Isolera One instruments and pre-packed Isco RediSep or Biotage Snap silica cartridges and the like. Chiral purifications were performed by chiral supercritical fluid chromatography (SFC) using Berger or Thar instruments and similar instruments with DAICEL CHIRALCEL OD, OJ; DAICEL CHIRALPAK AD, AS, IF; Chiral Technologies OJ-H, AD-H, OD-H, IA, IB; Lux Cellulose 1; Lux Cellulose 3; Pirkle Covalent (R,R) Whelk-O1; CHIRALPAK IH; YMC-IB; and Phenomenex Lux Cellulose 1 columns; and carbon dioxide (CO2) mixtures with methanol (MeOH), ethanol (EtOH), isopropyl alcohol, or ACN, alone or modified using TFA, formic acid, NH4OH, diethylamine (DEA), ammonia (NH3) or isopropylamine. UV detection was used to trigger fraction collection. The chiral purity was determined using supercritical fluid chromatography (SFC) and reverse-phase liquid chromatography (RPLC) analytical method with Chiralpak AD-3, IG-3, IF, AS-3, IB-N; Chiralcel OJ-, OD-3; Chiral Technologies OJ-H, AD-H, OD-H, IA, IB, IH; Lux Cellulose 1; IM-3; Lux Cellulose 3; Phenomenex Kinetex and Regis (R,R) Whelk-01 columns; and CO2 mixtures with MeOH, EtOH, isopropyl alcohol, or ACN, alone or modified using TFA, formic acid, NH4OH, DEA, NH3, or isopropylamine. Proton nuclear magnetic resonance (1H NMR) spectra were recorded, referenced to residual peaks from the deuterated solvents employed, where δ is chemical shift; d is doublet; dd is doublet of doublets; ddd is doublet of doublet of doublets; dt is doublet of triplets, m is multiplet, s is singlet, t is triplet, q, quartet; quin, quintet, br s, broad singlet; MHz is megahertz, ppm is parts per million. Proton nuclear magnetic spectroscopy (1H NMR) chemical shifts are given in parts per million (ppm, δ) referenced to the deuterated solvent downfield from tetramethylsilane and were recorded on 300, 400, 500, or 600 MHz Varian spectrometers. Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing. In the experimental sections that follow the following abbreviations may be used. ACN is acetonitrile; abs in the structures is absolute and refers to the stereochemistry being confirmed as R or S; AcOH is acetic acid; APhos Pd G3 is [4-(di-tert-butylphosphino)-N,N-dimethylaniline- 2-(2′-aminobiphenyl)]palladium(II) methanesulfonate; BBr3 is boron tribromide; B2Pin2 is bis(pinacolato)diboron; BOC is tert-butyloxycarbonyl; Boc2O is di-tert-butyl dicarbonate; brine is a saturated sodium chloride water solution; BINAP is (±)-2,2′-bis(diphenylphosphino)-1,1′- binaphthalene; BF3OEt2is boron trifluoride diethyl etherate; °C is degrees Celsius; CDCl3is deuterated chloroform; CD3OD is deuterated methanol; (CD3)2SO is deuterated dimethyl sulfoxide; cataCXium® A is di(1-adamantyl)-n-butylphosphine; cataCXium®A Pd G3 is mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II); CAS is Chemical Abstracts Service; CDI is 1,1′-carbonyldiimidazole; CHCl3is chloroform; CO2is carbon dioxide; CsHCO3is cesium hydrogencarbonate; Cs2CO3is cesium carbonate; CsF is cesium fluoride; CuI is copper(I) iodide; DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM is dichloromethane; DCE is 1,2-dichloroethane; DDQ is 2,3-dichloro-5,6-dicyano-p-benzoquinone; DEA is diethylamine; DIEA is Ν,Ν-diisopropylethylamine; dioxane is 1,4-dioxane; DMA is dimethylacetamide; DMAP is 4-(dimethylamino)pyridine; DME is dimethyl ether; DMEDA is 1,2- dimethylethylenediamine; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ee is enantiomeric excess; EtOAc is ethyl acetate; EtOH is ethanol; g is gram; g / L is grams per liter; h is hour; HATU is 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; HCI is hydrochloric acid; H2is hydrogen; H2O is water; HOBt is 1-hydroxybenzotriazole hydrate; HOPO is 2-pyridinol 1-oxide; HPLC is high performance liquid chromatography; HR / MS is high resolution mass spectrometry; Hz is hertz; Ir(ppy)2(dtbbpy)PF6is [4,4′-bis(1,1-dimethylethyl)- 2,2′-bipyridine-N1,N1′]bis[2-(2-pyridinyl-N)phenyl-C]iridium(III) hexafluorophosphate; KHSO4is potassium bisulfate; KHMDS is potassium bis(trimethylsilyl)amide; KOAc is potassium acetate; KOH is potassium hydroxide; KOTMS is potassium trimethylsilanolate; K2CO3 is potassium carbonate; kg is kilogram; K3PO4 is tripotassium phosphate; KH2PO4 is potassium phosphate monobasic; L is liter; LC is liquid chromatography; LCMS is liquid chromatography mass spectrometry; LDA is lithium diisopropylamide; LED is light-emitting diode; LiOH is lithium hydroxide monohydrate; M is molar; LiHMDS is lithium bis(trimethylsilyl)amide; MeI is iodomethane; MeOH is methanol; 4MetBuXPhos Pd G3 is methanesulfonato (2-di-tert- butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II); mg is milligram; MgSO4 is magnesium sulfate; MPLC is medium performance liquid chromatography; MHz is megahertz; min is minute; mL is milliliter; mL / min is milliliter per minute; mmol is millimole; mol is mole; mM is millimolar; mm is millimeter; MPa is megapascal; MS is mass spectrometry; MTBE is methyl tertiary-butyl ether; m / z is mass-to-charge ratio; N is normal (concentration); N2 is nitrogen; NBS is N-bromosuccinimide; NaBH4 is sodium borohydride; ND is not determined; N-XantPhos Pd G3 is (2′-amino-2- biphenylyl)(methanesulfonato-κO)palladium - 4,6-bis(diphenylphosphino)-10H-phenoxazine; NH3is ammonia; Na2CO3is sodium carbonate; NaH is sodium hydride; NaHCO3is sodium bicarbonate; NaI is sodium iodide; NaOCH3is sodium methoxide; NaOH is sodium hydroxide; Na2SO4is sodium sulfate; NaOtBu is sodium tert-butoxide; n-BuLi is n-butyllithium; NH4Cl is ammonium chloride; NH4HCO3is ammonium bicarbonate; NH4OH is ammonium hydroxide; NMR is nuclear magnetic resonance; NiCl2.glyme is nickel(II) chloride ethylene glycol dimethyl ether complex; NiBr2.DME is nickel(II) bromide ethylene glycol dimethyl ether complex; P(t- Bu)3Pd G2 is chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II); Pd(dppf)Cl2is (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; Pd / C is palladium on carbon; Pd2(dba)3is tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2is bis(triphenylphosphine)palladium(II) dichloride; Pd(OAc)2is palladium(II) acetate; Pd(t-Bu3P)2is bis(tri-tert-butylphosphine)palladium(0); PE is petroleum ether; psi is pounds per square inch; quinuclidine is 1-azabicyclo[2.2.2]octane; SFC is super critical fluid chromatography; SOCl2is thionyl chloride; TBD is 1,5,7-triazabicyclo[4.4.0]dec-5-ene; TEA is triethylamine; tert-amyl alcohol is 2-methyl-2-butanol; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin- layer chromatography; trimethylboroxine is 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane; µm is micrometer; µmol is micromole; rac is racemic referring to the compound including a mixture of compounds having both R and S stereochemistry and is denoted in the structures as “&1”; rel is relative referring to the stereochemistry being either R or S and is denoted in the structures as “or1” or as an asterisk in the named structure if there are two chiral centers in the compound; RhCl(PPh3)3 is tris(triphenylphosphine)rhodium(I) chloride; rpm is revolutions per minute; RPLC is reverse-phase liquid chromatography; Ru / Al2O3is ruthenium on aluminum oxide; RuPhos is 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl; RuPhos Pd G3 is (2- dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; RuPhos Pd G4 is [dicyclohexyl(2′,6′-diisopropoxy-2-biphenylyl)phosphine- κP](methanesulfonatato-κO)[2′-(methylamino-κN)-2-biphenylyl-κC2]palladium; RuCl(PPh3)3 Ru / SiO2 is ruthenium on silica; wt is weight; XPhos Pd G2 is chloro(2-dicyclohexylphosphino- 2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); XantPhos Pd G4 is (SP-4-3)-[[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine- κP](methanesulfonato-κO)[2′-(methylamino-κN)[1,1′-biphenyl]-2-yl-κC]- palladium; and Zn is zinc. Preparation 1 Ethyl 1-cyclopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P1) Step 1. Preparation of 5-(tert-butyl) 3-ethyl 1-cyclopropyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-3,5-dicarboxylate (C1) and 5-(tert-butyl) 3-ethyl 2-cyclopropyl-2,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C2) A reaction containing cyclopropylhydrazine monohydrochloride (36.3 mg, 0.334 mmol) and KOAc (36.1 mg, 0.367 mmol) in AcOH (1.0 mL) was heated at 80 °C for 10 min then cooled to room temperature. tert-butyl 3-(2-ethoxy-2-oxoacetyl)-4-oxopiperidine-1-carboxylate (CAS: 518990-24-4; 0.100 g, 0.334 mmol) was added to the mixture. The reaction turned into a viscous yellow oil, which was stirred at 80 °C for 1 h and 30 min. The reaction was then diluted with EtOAc and saturated aqueous NaHCO3. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-40% EtOAc: heptane) to provide minor first eluting isomer C2: (11 mg, 27.2% yield) (LC / MS) m / z (M+H)+= 336.3; followed by major second eluting isomer C1: (18 mg, 44.5% yield) (LC / MS) m / z (M+H)+= 336.3;1H NMR (600 MHz, CDCl3) δ 4.66- 4.54 (m, 2H), 4.36 (q, 2H), 3.71 (s, 2H), 3.40- 3.34 (m, 1H), 2.84- 2.74 (m, 2H), 1.48-1.43 (m, 9H), 1.41- 1.34 (m, 3H), 1.21- 1.18 (m, 2H), 1.07- 1.02 (m, 2H). Step 2. Preparation of ethyl 1-cyclopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate hydrochloride (P1) A solution of C1 (0.200 g, 0.596 mmol) was dissolved in DCM (2.0 mL), then 4M HCl in dioxane (0.130 g, 3.58 mmol) was added, then the reaction was stirred at 40 °C for 25 min. The reaction was concentrated in vacuo to provide P1 (0.168 mg, crude) as a white solid. The solid was used in the next step without further purification. (LC / MS) m / z (M+H)+= 236.2;1H NMR (600 MHz, CD3OD) δ 4.41– 4.33 (m, 4H), 3.61- 3.53 (m, 3H), 3.16 (t, 2H), 1.37 (t, 3H), 1.21 – 1.16 (m, 2H), 1.15 – 1.09 (m, 2H). Preparation 2 Ethyl 1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P2) c]pyridine-3,5-dicarboxylate (C3) and 5-(tert-butyl) 3-ethyl 2-isopropyl-2,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C4) To a solution of tert-butyl 3-(2-ethoxy-2-oxoacetyl)-4-oxopiperidine-1-carboxylate (CAS: 518990-24-4, 325 g, 1.09 mol) in EtOH (2.3 L) was added isopropylhydrazine hydrochloride (120 g, 1.1 mol) in one portion then pyridine (103 g, 1.30 mol) was added dropwise into the mixture for 10 min at 20- 25 °C with ice water bath. The reaction mixture was stirred for 2 h at room temperature. The reaction was carried out in two batches in parallel, were combined, and then concentrated in vacuo. The residue was diluted with EtOAc (5 L) and washed with brine (2 x 5 L) then dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc: PE from 10-50%) to provide C3 and C4. C3 was dissolved in PE (0.8 L) and then cooled to -20 °C. The mixture was stirred for 4 h, resulting solids were filtered, and washed with PE (0.1 L). The filter cake was dried under high vacuum to obtain C3 (414 g, 55.9% yield) as a white solid. (LC / MS) m / z (M+H)+= 338.1;1H NMR (400 MHz, CDCl3) δ 4.59 (s, 2H), 4.48- 4.32 (m, 3H), 3.71 (t, 2H), 2.70 (t, 2H), 1.53 – 1.45 (m, 15H), 1.39-1.34 (m, 3H). C4 was dissolved in PE (50 mL) then cooled to -20 °C. The mixture was stirred for 4 h, resulting solids were filtered, and washed with PE (20 mL). The filter cake was dried under high vacuum to provide C4 (11.7 g, 1.58% yield) as a white solid. (LC / MS) m / z (M+H)+= 338.1;1H NMR (400 MHz, CDCl3) δ 5.60- 5.43 (m, 1H), 4.60 (s, 2H), 4.33 (q, 2H), 3.68 (s, 2H), 2.75 (s, 2H), 1.50- 1.44 (m, 15H), 1.38 (m, 3H). Step 2. Preparation of ethyl 1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate hydrochloride (P2) To a mixture of C3 (13.5 g, 40.0 mmol) in DCM (60 mL) was added 4N HCl in dioxane (150 mL) in batches at 0 °C. The reaction was stirred at about 15 °C for 16 h and then concentrated in vacuo to provide P2 (10.5 g, crude) as a white solid, used directly in the next step without further purification. LC / MS m / z (M+H)+= 238.1;1H NMR (600 MHz, (CD3)2SO) δ 9.80 (s, 1H), 4.63- 4.51 (m, 1H), 4.28 (q, 2H), 4.18 (s, 2H), 3.36 (s, 2H), 3.02 (t, 2H), 1.38 (d, 6H), 1.29 (t, 3H). Preparation 3 5-(tert-Butoxycarbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (P3) - 3- carboxylic acid (C5) To a suspension of 5-(tert-butyl) 3-ethyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine- 3,5-dicarboxylate (CAS: 518990-23-3; 2.00 g, 6.77 mmol) in MeOH (7.7 mL) and H2O (7.7 mL) was added NaOH (0.542 g, 13.5 mmol). The reaction mixture was stirred at 40 °C for 16 h. The mixture was diluted with H2O (20 mL), cooled to 0 °C and acidified with 1M aqueous HCl to pH of about 3. The resulting mixture was filtered, the solid was dried further under a high vacuum and then lyophilized to provide C5 (1.60 g, crude) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 268.1.1H NMR (400 MHz, (CD3)2SO) δ 13.17 (br s, 2H), 4.48 (s, 2H), 3.58 (t, 2H), 2.65 (t, 2H), 1.41 (s, 9H). Step 2. Preparation of 5-(tert-butoxycarbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxylic acid (P3) To the suspension of C5 (0.200 g, 0.748 mmol) in DMF (3.5 mL) was added NaH (89.8 mg, 2.24 mmol, 60%) at 0 °C and stirred for 30 min at 0 °C. A solution of iodoethane (0.140 g, 0.898 mmol) in DMF (0.5 mL) was added at 0 °C then stirred at 15 °C for about 4 h. An additional portion of the solution of iodoethane (23.3 mg, 0.150 mmol) in DMF (0.2 mL) was added to the mixture and stirred at 15 °C for 16 h. The reaction solution was quenched with H2O (10 mL) and then extracted with EtOAc (2 x 20 mL). The aqueous layer was acidified with 1M aqueous HCl to pH ~3 and then extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2SO4,concentrated in vacuo and then lyophilized to provide P3 (0.173 g, 78.5% yield) as a white solid. (LC / MS) m / z (M+H)+= 296.1.1H NMR (400 MHz, (CD3)2SO) δ 12.64 (br s, 1H), 4.45 (s, 2H), 4.07 (q, 2H), 3.60 (t, 2H), 2.74- 2.65 (m, 2H), 1.41 (s, 9H), 1.31 (t, 3H). Preparation 3b Ethyl 1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P3b) c]pyridine-3,5-dicarboxylate (C6) and 5-(tert-butyl) 3-ethyl 2-ethyl-2,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C7) To a solution of tert-butyl 3-(2-ethoxy-2-oxoacetyl)-4-oxopiperidine-1-carboxylate (CAS: 518990-24-4; 97.5 g, 326 mmol) and ethylhydrazine dihydrochloride (56.3 g, 423 mmol) in EtOH (1.6 L) was added pyridine (129 g, 1.63 mol). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-50% THF: PE) to provide the first eluting isomer C6 (58.0 g) as a white solid; followed by the second eluting isomer C7 (20.6 g, 19.6% yield) as a light-yellow oil. C6 was diluted with EtOAc (200 mL) then stirred at 50oC for 30 min and cooled to 0oC which caused white solid precipitate to form. The suspension was filtered, and the filter cake was washed with EtOAc (3 x 10 mL). The filter cake was collected and concentrated in vacuo to provide C6 (35.4 g, 33.6% yield) as a white solid. C6: (LC / MS) m / z (M+H)+= 324.2;1H NMR (400 MHz, CDCl3) δ 4.60 (s, 2H), 4.38 (q, 2H), 4.12 (q, 2H), 3.71 (t, 2H), 2.68 (t, 2H), 1.47 (s, 9H), 1.44 – 1.34 (m, 6H). C7: (LC / MS) m / z (M+H)+= 324.3;1H NMR (400 MHz, CDCl3) δ 4.65 – 4.50 (m, 4H), 4.34 (q, 2H), 3.73 – 3.63 (m, 2H), 2.80 – 2.67 (m, 2H), 1.48 (s, 9H), 1.43 – 1.33 (m, 6H). Step 2. Preparation of ethyl 1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P3b) To a solution of C6 (1.00 g, 3.09 mmol) in DCM (10 mL) was added 2M HCl in dioxane (1.13 g, 30.9 mmol). The reaction mixture was stirred at room temperature for 2.5 h then concentrated in vacuo to provide P3b (0.870 g, crude) as a white solid. The solid was used directly in the nest step without further purification. (LC / MS) m / z (M+H)+= 224.2.1H NMR (400 MHz, CD3OD) δ 4.44 – 4.32 (m, 4H), 4.20 (q, 2H), 3.56 (t, 2H), 3.09 (t, 2H), 2.80 – 2.67 (m, 2H), 1.44 (t, 3H), 1.38 (t, 3H). Preparation 4 Ethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P4) Step 1. Preparation of 5-(tert-butyl) 3-ethyl 1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-3,5-dicarboxylate (C8) 5-(tert-Butyl) 3-ethyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (CAS: 518990-23-3; 2.00 g, 6.77 mmol) was dissolved in DMF (10.0 mL) then K2CO3(2.81 g, 20.3 mmol) and MeI (0.961 g, 6.77 mmol) were added. The reaction was stirred at room temperature for 3 h and diluted with EtOAc and H2O. The organic layer was separated and then concentrated in vacuo. The residue was dissolved in DCM and then purified by column chromatography (silica gel, 0-40% EtOAc: heptane) to provide C8 (0.825 g, 39.4% yield) as a clear oil. (LC / MS) m / z (M+H)+= 310.3;1H NMR (600 MHz, CDCl3) δ 4.61 (s, 2H), 4.35 (q, 2H), 4.14 (s, 3H), 3.68 (s, 2H), 2.74 (s, 2H), 1.49 (s, 9H), 1.41- 1.37 (m, 3H). Step 2. Preparation of ethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate hydrochloride (P4) C8 (2.00 g, 6.46 mmol) was dissolved in 4M HCl in dioxane (40.0 mL) at 0 °C and then stirred at room temperature for 16 h. The reaction was concentrated in vacuo to provide P4 (1.30 g, 81.9% yield) as a yellow solid. This was used in the next step without further purification. (LC / MS) m / z (M+H)+= 210.3.1H NMR (400 MHz, CDCl3) δ 10.23 (br s, 1H), 4.50 – 4.32 (m, 4H), 3.86 (s, 3H), 3.55- 3.46 (m, 2H), 3.13 (t, 2H), 1.40 (t, 3H). Preparation 5 3- 5,6,7,8- [1,5-a] 1- (P5) Step 1: Preparation of 7-(tert-butyl) 1-ethyl 3-cyclopropyl-5,6-dihydroimidazo[1,5-a]pyrazine- 1,7(8H)-dicarboxylate (C9) To a solution of 7-(tert-butyl) 1-ethyl 3-bromo-5,6-dihydroimidazo[1,5-a]pyrazine- 1,7(8H)-dicarboxylate (CAS: 2108354-93-2; 0.578 g, 1.54 mmol) and cyclopropylboronic acid (CAS: 411235-57-9, 0.398 g, 4.63 mmol) in dioxane (8.0 mL) and H2O (1.0 mL) was added K3PO4 (0.984 g, 4.63 mmol) and Pd(dppf)Cl2 (0.226 g, 0.309 mmol) at room temperature under nitrogen gas. The reaction was stirred at 90 °C for 16 h. The resulting solution was concentrated in vacuo to give a solid that was purified by column chromatography (silica gel, 0- 95% EtOAc: PE) to provide C9 (0.400 g, 77.2% yield) as a yellow gum. (LC / MS) m / z (M+H)+= 336.1.1H NMR (400 MHz, CD3OD) δ 4.84 (s, 2H), 4.30 (q, 2H), 4.14 – 4.04 (m, 2H), 3.86 (t, 2H), 1.94- 1.86 (m, 1H), 1.53- 1.48 (m, 9H), 1.36 (t, 3H), 1.00- 0.96 (m, 4H). Step 2. Preparation of ethyl 3-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1- carboxylate hydrochloride (P5) To a solution of C9 (0.300 g, 0.894 mmol) in DCM (5.0 mL) was added 2M HCl in dioxane (0.261 g, 7.16 mmol) and reaction stirred at room temperature for 16 h. The resulting suspension was concentrated in vacuo to provide P5 (0.243 g, crude) as a white solid, used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 10.17 (s, 1H), 4.50 (s, 2H), 4.36 (t, 2H), 4.25 (q, 2H), 3.62- 3.57 (m, 2H), 2.13- 2.03 (m, 1H), 1.30-1.23 (m, 3H), 1.04 – 0.98 (m, 2H), 0.97 – 0.91 (m, 2H). Preparation 6 rac-Ethyl (R)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P6) Step 1: Preparation of rac-tert-butyl (5R)-3-(2-ethoxy-2-oxoacetyl)-5-methyl-4-oxopiperidine-1- carboxylate (C10) A solution of diisopropylamine (4.2 g, 41 mmol) in THF (19.0 mL) was cooled to –78 °C before 2.5M n-BuLi in hexane (2.5 g, 39 mmol) was added. After the addition, the reaction mixture was warmed to 0 °C and stirred for 15 min. The reaction was then cooled to –78 °C and a solution of rac-tert-butyl (R)-3-methyl-4-oxopiperidine-1-carboxylate (CAS:181269-69-2, 7.0 g, 33 mmol) in THF (81.0 mL) was slowly added while maintaining the temperature below -67 °C. The mixture was stirred at -78 °C for about 1 h and 30 min before diethyl oxalate (4.8 g, 33 mmol) was added to the reaction solution. The resulting mixture was allowed to warm to room temperature and then stirred for 2 h. The mixture was neutralized with 1N HCl (80 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (400 mL), dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-10% EtOAc: PE) to provide C10 (4.8 g, 47% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 314.4.1H NMR (400 MHz, CDCl3) δ 4.51 – 4.30 (m, 3H), 3.91 – 3.65 (m, 1H), 3.34 – 3.12 (m, 1H), 2.76 – 2.60 (m, 1H), 1.51 – 1.44 (m, 9H), 1.41 – 1.34 (m, 3H), 1.28 – 1.20 (m, 3H). Step 2: Preparation of rac-5-(tert-butyl) 3-ethyl (R)-7-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-3,5-dicarboxylate (C11) To a solution of C10 (3.55 g, 11.3 mmol) in AcOH (14.2 mL), hydrazine hydrate was added (2.09 g, 65% wt, 27.2 mmol). During the addition, the reaction mixture became exothermic to 65 °C. The reaction mixture was stirred for 1 h then concentrated in vacuo. The residue was diluted with H2O followed by saturated aqueous NaHCO3(200 mL). The mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried with Na2SO4, filtered, concentrated in vacuo, and dried further under a high vacuum to provide C11 (3.45 g, crude) as a pale-yellow solid, used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 310.40. Step 3: Preparation of rac-5-(tert-butyl) 3-ethyl (R)-1,7-dimethyl-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C12) and rac-5-(tert-butyl) 3-ethyl (R)-2,7-dimethyl- 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C13) To a solution of C11 (3.45 g, 11.2 mmol) in DMF (28.6 mL), Cs2CO3 (3.65 g, 11.2 mmol) was added, followed by MeI (4.80 g, 33.5 mmol). The reaction mixture was stirred for 16 h at room temperature, diluted with H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with saturated aqueous NH4Cl (2 x 100 mL) and H2O (2 x 100 mL). The organic layer was dried over Na2SO4, filtered, and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 10-100% EtOAc: heptane) to provide C13 (2.12 g, 58.9% yield) and C12 (0.999 g, 27.7% yield). C13: (LC / MS) m / z (M+H)+= 324.1.1H NMR (400 MHz, CDCl3) δ 4.74 – 4.41 (m, 2H), 4.38 – 4.27 (m, 2H), 4.17 – 4.10 (m, 3H), 3.98 – 3.65 (m, 1H), 3.36 – 2.88 (m, 2H), 1.48 (s, 9H), 1.38 (t, 3H), 1.26 (d, 3H). C12: (LC / MS) m / z (M+H)+= 324.1.1H NMR (400 MHz, CDCl3) δ 5.18 – 4.87 (m, 1H), 4.43 – 4.30 (m, 2H), 4.27 – 3.99 (m, 2H), 3.85 (s, 3H), 3.23 – 2.87 (m, 2H), 1.51 – 1.43 (m, 9H), 1.41 – 1.33 (m, 3H), 1.24 (d, 3H). Step 4: Preparation of rac-ethyl (R)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine- 3-carboxylate hydrochloride (P6) To a solution of C12 (0.536 g, 1.66 mmol) in DCM (9.7 mL) was added 1M HCl in EtOAc (5.0 mL) at room temperature. The reaction was stirred at room temperature for 16 h. An additional portion of 1M HCl in EtOAc (5.0 mL) was added at room temperature then stirred for 1 h. The reaction was concentrated in vacuo to provide P6 (0.426 g, 99.1% yield) as an off- white solid. This was used in the next step without further purification. (LC / MS) m / z (M+H)+= 224.2.1H NMR (400 MHz, CDCl3) δ 10.58 – 10.31 (m, 1H), 10.18 – 9.87 (m, 1H), 4.58 – 4.49 (m, 1H), 4.46 – 4.32 (m, 3H), 3.92 (s, 3H), 3.51 – 3.25 (m, 3H), 1.57 – 1.53 (m, 3H), 1.40 (t, 3H). Preparation 7 rac-Methyl (R)-3,5-dimethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P7) methylimidazo[1,5-a]pyrazine-1-carboxylate (C14a) To a mixture of 2-chloro-6-methylpyrazine (CAS: 38557-71-0, 15.0 g, 117 mmol) in DMF (150.0 mL) was added Cs2CO3 (57.0 g, 175 mmol) and ethyl 2-isocyanoacetate (CAS: 2999-46- 4, 26.6 g, 233 mmol). The reaction was heated to 85 °C and stirred for 16 h. The light brown reaction mixture was filtered then the solid was washed with MeOH. The filtrate was concentrated in vacuo. The brown residue was purified by column chromatography (silica gel, 0-100% EtOAC: PE then 2% MeOH: EtOAc). Transesterification occurred during workup and purification to generate C14 (9.50 g, 42.6% yield) as a light brown solid (LC / MS) m / z (M+H)+= 192.1 and a mixture of (2:1, C14a:C14) ( 1.1 g, 4.59% yield) (LC / MS) m / z (M+H)+= 206.1. C14 was brought forward to the next step. C14:1H NMR (400 MHz, (CD3)2SO) δ 9.32 (s, 1H), 8.68 (s, 1H), 7.74 (s, 1H), 3.90 (s, 3H), 2.63 (s, 3H). Step 2. Preparation of rac-methyl (R)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1- carboxylate (C15) The reaction was carried out via flow chemistry. C14 (2.90 g, 15.2 mmol) was suspended in MeOH (50.0 mL), THF (50.0 mL) and AcOH (0.6 mL) then heated to 50 °C to dissolve to a solution. The solution was pumped with a flow rate of 0.3 mL / min and the H2 had a rate of 30 mL / min. The solution passed through the fixed bed (6.350 (1 / 4’’) mm) packed with granular catalyst 10% Ru / SiO2 (15.3 g, 1.52 mmol) with a 5.0 mL volume and was hydrogenated for 3.3 min at 80 °C via flow at 2.5 MPa H2. The light-yellow reaction was concentrated in vacuo then dried in high vacuum to provide C15 (2.96 g, crude) as a light brown oil. This was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 4.43 (d, 1H), 4.27 – 4.15 (m, 2H), 3.87 (s, 3H), 3.32 (dd, 1H), 2.84 (dd, 1H), 2.68 (s, 1H), 1.53 (d, 3H). Step 3. Preparation of rac-7-(tert-butyl) 1-methyl (R)-5-methyl-5,6-dihydroimidazo[1,5- a]pyrazine-1,7(8H)-dicarboxylate (C16) To a solution of C15 (2.96 g, 15.2 mmol) in ACN (60.0 mL) was added Boc2O (4.97 g, 22.8 mmol) and K2CO3 (6.29 g, 45.5 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The light brown reaction mixture was filtered then concentrated in vacuo. The brown residue was purified by column chromatography (silica gel; 0-100% EtOAc: PE) to provide C16 (3.02 g, 67.5% yield) as an off-white solid. (LC / MS) m / z (M+H)+= 296.1.1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 5.01 – 4.77 (m, 2H), 4.33 – 4.21 (m, 1H), 3.89 (s, 3H), 3.55 – 3.34 (m, 2H), 1.53 – 1.49 (m, 12H). Step 4. Preparation of rac-7-(tert-butyl) 1-methyl (R)-3-bromo-5-methyl-5,6-dihydroimidazo[1,5- a]pyrazine-1,7(8H)-dicarboxylate (C17) To a solution of C16 (3.02 g, 10.2 mmol) in ACN (50.0 mL) was added NBS (2.73 g, 15.4 mmol) at 15 °C. The reaction was stirred at room temperature for 16 h. The light brown reaction mixture was concentrated in vacuo. The brown residue was purified by column chromatography (silica gel, 0-100% EtOAc: PE) which gave an impure C17 as a light brown solid. The solid was triturated with EtOAc: PE (1:5). The solid was filtered then rinsed with EtOAc: PE (5:1) to provide C17 (1.32 g, 34.4% yield) as a white solid. (LC / MS) m / z (M+2H)+= 376.0.1H NMR (400 MHz, CDCl3) δ 5.62 – 5.23 (m, 1H), 4.54 – 4.22 (m, 3H), 3.93 – 3.86 (m, 3H), 3.48 – 3.16 (m, 1H), 1.51 (s, 9H), 1.43 (d, 3H). Step 5. Preparation of rac-7-(tert-butyl) 1-methyl (R)-3,5-dimethyl-5,6-dihydroimidazo[1,5- a]pyrazine-1,7(8H)-dicarboxylate (C18) To a solution of C17 (1.30 g, 3.47 mmol) and methylboronic acid (0.624 g, 10.4 mmol) in dioxane (28.0 mL) and H2O (7.0 mL) was added K3PO4(2.21 g, 10.4 mmol) then Pd(dppf)Cl2(0.519 g, 0.695 mmol) at 15 °C under nitrogen. The reaction was heated to 90 °C for 16 h. The brown reaction mixture was extracted with EtOAc (30 mL). The organic phase was dried over Na2SO4and concentrated in vacuo. The brown residue was purified by column chromatography (silica gel, 0-100% EtOAc: PE then 2% MeOH: EtOAc) then dried by high vacuum to provide C18 (0.460 g, 42.8%) as a light brown solid. (LC / MS) m / z (M+H)+= 310.2.1H NMR (400 MHz, CDCl3) δ 5.51 – 5.15 (m, 1H), 4.52 – 4.14 (m, 3H), 3.87 (s, 3H), 3.32 - 3.10 (m, 1H), 2.39 (s, 3H), 1.50 (s, 9H), 1.36 (d, 3H). Step 6. Preparation of rac-methyl (R)-3,5-dimethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1- carboxylate hydrochloride (P7) To a solution of C18 (140 mg, 0.452 mmol) in DCM (4.0 mL) was added 2M HCl in dioxane (8.0 mL) at room temperature. The reaction was heated to 40 °C and stirred for 2 to 5 h. The light brown reaction mixture was concentrated in vacuo and dried further under high vacuum to provide P7 (0.111 g, crude) as a light brown solid. The solid was used in the next step without further purification. Preparation 8 (S)-5-(tert-Butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (P8) Step 1. Preparation of rac-tert-butyl (5S)-3-(2-ethoxy-2-oxoacetyl)-5-methyl-4-oxopiperidine-1- carboxylate (C19) Under a nitrogen balloon at -65oC, LDA (44.4 g, 0.414 mol, 207 mL) was added to THF (350 mL) then a solution of tert-butyl (S)-3-methyl-4-oxopiperidine-1-carboxylate (CAS: 2092486-33-2; 88.4 g, 0.414 mol) in THF (350 mL) was added dropwise over 1 h to keep the inner temperature below -65oC. The reaction mixture was stirred at -65oC for 1 h before a solution of diethyl oxalate (CAS: 95-92-1; 60.6 g, 0.414 mol) in THF (350 mL) was added dropwise at -65oC. After the addition, the reaction mixture was stirred at -65oC for 1 h, then warmed to -20oC and stirred for 40 min. At 0oC under nitrogen gas, the reaction mixture was quenched with 1M aqueous KHSO4solution (1415 mL), which caused a white precipitate to form. The suspension was filtered, and then the filtrate was extracted with EtOAc (3 x 800 mL). The combined organic layer was washed with brine (800 mL), dried over Na2SO4, filtered then concentrated in vacuo to provide C19 (129 g, crude) as a yellow oil. The oil was used directly in the next step without further purification. (LCMS) m / z (M-tert-butyl group)+= 257.9.^1H NMR (400 MHz, (CD3)2SO) δ 12.21 (br s, 1H), 4.47 – 4.17 (m, 3H), 4.06 – 3.47 (m, 2H), 3.29 – 3.17 (m, 1H), 2.59 - 2.53 (m, 1H), 1.45 – 1.37 (m, 9H), 1.28 – 1.21 (m, 3H), 1.18 – 0.95 (m, 3H). Step 2. Preparation of enriched 5-(tert-butyl) 3-ethyl (S)-7-methyl-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C20) At 0oC, to a suspension of C19 (139 g, 0.443 mol) in AcOH (552 mL) was added hydrazine monohydrate (62.7 g, 1.06 mol) which caused the internal temperature to increase to ~30oC. The reaction mixture was stirred at room temperature under nitrogen gas for 1 h then was diluted with H2O (500 mL) and saturated NaHCO3 (1000 mL). The diluted suspension was extracted with EtOAc (2 x 800 mL). The combined organic layer wasdried over Na2SO4, filteredthen concentrated in vacuo to give a yellow gum. The gum was purified by column chromatography (silica gel, (1:1) EtOAc: PE) to give the enriched S-enantiomer C20 (123 g, 89.7% yield) as a yellow gum. (LCMS) m / z (M+H)+= 310.0.1H NMR (400 MHz, (CD3)2SO) δ 13.71 – 13.28 (m, 1H), 4.63 – 4.18 (m, 4H), 3.86 - 3.59 (m, 1H), 3.12 – 2.80 (m, 2H), 1.40 – 1.38 (m, 9H), 1.30 – 1.24 (m, 3H), 1.17 – 1.13 (m, 3H). The chiral purity was determined using SFC analytical method on Chiralpak AD-3100 mm x 4.6 mm x 3 µm column; Mobile phase A: CO2 / Mobile phase B: EtOH with 0.2% of NH3; gradient: 5-40% of Mobile Phase B over 3 min then held at 5% of Mobile phase B for 1 min; backpressure: 1500 psi; flow rate: 2.8 mL / min; column temperature: 35oC to provide C20: major peak ((SFC-MS) m / z (M-tert-butyl group)+= 254.04 at retention time: 2.218 min, 94% ee). Step 3. Preparation of enriched (S)-5-(tert-butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylic acid (P8a) To a solution of C20 (124 g, 0.400 mol) in MeOH (452 mL) and H2O (452 mL) was added NaOH (32.0 g, 0.800 mol) then stirred at room temperature for 24 h. The reaction mixture was diluted with H2O (200 mL) then cooled to 0oC before the diluted reaction was acidified to pH~3 with 1M aqueous HCl solution. The acidic reaction mixture was filtered then the filter cake was collected and lyophilized to give the enriched S-enantiomer P8a (88.6. g,crude) as a white solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+= 282.0.1H NMR (400 MHz, (CD3)2SO) δ 13.22 (br s, 1H), 4.66 – 4.34 (m, 2H), 3.86 – 3.60 (m, 1H), 3.12 – 2.82 (m, 2H), 1.41 (s, 9H), 1.17 (d, 3H). The chiral purity was determined using SFC analytical method on Chiralpak IG-3100 mm x 4.6 mm x 3 µm column; Mobile phase A: CO2 / Mobile phase B: 50% MeOH with 0.2% of NH3; backpressure: 1500 psi; flow rate: 2.8 mL / min; column temperature: 35oC to provide P8a: major peak ((SFC-MS) m / z (M-tert-butyl group)+= 226.03 at retention time: 0.784 min, 96% ee) Step 4. Preparation of (S)-5-(tert-butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxylic acid (+)-bis[(R)-1-phenylethyl]amine salt (C21) The reaction was conducted in six batches in parallel then combined. To a mixture of P8a (0.180 kg, 0.640 mol) in EtOH (3.4 L) was added (+)-bis[(R)-1-phenylethyl]amine (CAS: 23294-41-9; 144 g, 0.640 mol) in one portion at room temperature to form the first batch. The reaction mixture of the first batch was stirred at room temperature for 10 min then white precipitate formed. The suspension of the first batch was stirred at 80oC for 1 h to form a clear solution then stirred at room temperature for 20 h. The white suspension of the first batch was filtered then the filter cake was washed with EtOH (3 x 300 mL). The filter cake from the first batch was collected then combined with the filter cakes from the additional five batches of the same reaction utilizing P8a (0.180 kg, 0.640 mol). The combined filter cake was dried in an oven at 50 °C for 18 h to provide C21 (1.42 kg, crude) as a white solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+= 282.1.1H NMR (400 MHz, CD3OD) δ 7.46 – 7.36 (m, 6H), 7.29 – 7.23 (m, 4H), 4.76 – 4.53 (m, 2H), 3.95 – 3.86 (m, 2H), 3.83 – 3.70 (m, 1H), 3.25 – 3.18 (m, 1H), 2.99 – 2.89 (m, 1H), 1.52 (dd, 6H), 1.48 (s, 9H), 1.25 (d, 3H). The chiral purity was determined using SFC analytical method on Chiralpak IG 50 mm x 4.6 mm x 3 µm column; Mobile phase A: CO2 / Mobile phase B: MeOH with 0.05% of DEA; gradient: 20-40% of Mobile phase B over 1.5 min and hold 40% of Mobile phase B for 1.0 min then 20% of Mobile Phase B for 0.5 min; flow rate of 4.0 mL / min; backpressure: 1500 psi; column temperature: 35 °C to provide C21: peak 1 (retention time: 1.019 min, 100% ee).Step 5. Preparation of (S)-5-(tert-butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxylic acid (P8) To a suspension of C21 (48.2 g, 95.1 mmol) in H2O (482 mL) was added 1M aqueous HCl solution (99 mL) to pH~1. The reaction mixture was stirred at room temperature for 1 h then filtered. The filter cake was collected then lyophilized to give P8 (24.3 g, crude) as a white solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+= 282.0.1H NMR (400 MHz, (CD3)2SO) δ 13.15 (br s, 1H), 4.63 – 4.47 (m, 1H), 4.44 – 4.33 (m, 1H), 3.84 – 3.61 (m, 1H), 3.19 – 3.00 (m, 1H), 2.94 – 2.83 (m, 1H), 1.41 (s, 9H), 1.17 (d, 3H). The chiral purity was determined using SFC analytical method on Chiralpak IG-3100 mm x 4.6 mm x 3 µm column; Mobile phase A: 50% of CO2 / Mobile phase B: 50% of MeOH with 0.2% NH3; backpressure: 1500 psi; flow rate: 2.8 mL / min; column temperature: 35oC to provide P8: peak 1 ((SFC-MS) m / z (M-tert-butyl group)+= 226.00 at retention time: 0.757 min, 99% ee).[α]28D=+11.351 (c= 1.5 (g / L in MeOH). Preparation 9 (S)-1-Isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid hydrochloride (P9) Step 1. -5- -1- 7- 4,5,6,7- 1H- pyrazolo[4,3-c]pyridine-3-carboxylic acid (C22) At 0oC under nitrogen gas, to a solution of P8 (12.4 g, 44.1 mmol) in DMF (220 mL) was added 1M LiHMDS (132 mL). The reaction mixture was warmed to room temperature and stirred for 2 h before cooling the reaction mixture again to 0oC. To the cooled reaction mixture was added 2-iodopropane (11.2 g, 66.1 mmol) then the suspension was warmed to room temperature and stirred for 48 h. The reaction mixture was cooled to 0oC and another portion of 2-iodopropane (1.12 g, 6.61 mmol) was added. The suspension was warmed to room temperature and stirred for 48 h. The reaction mixture was cooled to 0oC then quenched with H2O (500 mL). The aqueous phase was washed with EtOAc (2 x 200 mL) then the combined organic layer was discarded. The aqueous layer was acidified with 1M aqueous HCl to pH~3 then extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with brine (2 x 300 mL), dried over Na2SO4 and concentrated in vacuo to give C22 (13.8 g, 96.8% yield) as a yellow solid. (LCMS) m / z (M+H)+= 324.0.1H NMR (400 MHz, (CD3)2SO) δ 12.60 (br s, 1H), 4.99 – 4.73 (m, 1H), 4.57 – 4.41 (m, 1H), 4.19 – 3.86 (m, 2H), 3.17 – 3.00 (m, 2H), 1.42 – 1.36 (m, 15H), 1.17 – 1.08 (m, 3H). The chiral purity was determined using SFC analytical method on (S,S) Whelk-01, 150 mm x 4.6 mm x 3.5 µm column; Mobile phase A: CO2 / Mobile phase B: MeOH (0.2% isopropylamine); gradient: 10-50% of Mobile phase B in 6.00 min then held at 10% of Mobile phase B for 2.00 min; backpressure: 2000 psi; flow rate: 1.5 mL / min; column temperature: 35oC to provide C22: peak 1 (retention time: 2.352 min, 100% ee). [α]34D=-100.10 (c= 5.4 (g / L) in ACN). Step 2. Preparation of (S)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylic acid hydrochloride (P9) To a solution of C22 (12.7 g, 39.3 mmol) in DCM (40 mL) was added 2M HCl in dioxane (500 mL). The reaction mixture was stirred at room temperature for 5 h then was concentrated in vacuo to provide P9 (9.40 g, crude) as a white solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+= 224.2.1H NMR (400 MHz, CD3OD) δ 4.68 – 4.58 (m, 1H), 4.45 (d, 1H), 4.31 (d, 1H), 3.62 – 3.38 (m, 3H), 1.54 (d, 3H), 1.48 (d, 3H), 1.44 (d, 3H). The chiral purity was determined using SFC analytical method on Chiralcel OX-3 100 mm x 4.6 mm x 3 µm column; Mobile phase A: CO2 / Mobile phase B: MeOH containing 0.05% of DEA; gradient: 5-40% of Mobile Phase B in 3.0 min then held at 40% of Mobile phase B for 0.9 min then held at 5% of Mobile phase B for 0.1 min; backpressure: 100 bar; flow rate: 2.8 mL / min; column temperature: 40oC to provide P9: peak 1 (retention time: 3.037 min, 100% ee).[α]33D=-7.212 (c= 1.5 (g / L) in MeOH). Preparation 10 (S)-1-Ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid hydrochloride (P10) Step 1. Preparation of (S)-5-(tert-butoxycarbonyl)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylic acid (C23) At 0oC under nitrogen gas, to a solution of P8 (10.0 g, 35.5 mmol) in DMF (190 mL) was added NaH (4.27 g, 107 mmol). The reaction mixture was stirred 0oC for 30 min then a solution of iodoethane (6.65 g, 42.7 mmol) in DMF (10 mL) was added. The suspension was warmed to room temperature and stirred for 3 h then quenched with H2O (150 mL). The aqueous phase was extracted with EtOAc (2 x 150 mL) then the combined organic layer was discarded. The aqueous phase was acidified with 1M aqueous HCl to pH~3 then extracted again with EtOAc (150 mL x3). The combined organic layer was washed with brine (2 x 100 mL), dried over Na2SO4and concentrated in vacuo to give a yellow solid. The solid was suspended in (1:10) EtOAc: PE (25 mL) and stirred at room temperature for 30 min. The suspension was filtered, and the filter cake was collected to provide C23 (8.75 g, crude) as a white solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+= 310.0.1H NMR (400 MHz, (CD3)2SO) δ 12.65 (br s, 1H), 4.85 (dd, 1H), 4.21 – 3.84 (m, 4H), 3.22 – 2.98 (m, 2H), 1.41 (br s, 9H), 1.35 (t, 3H), 1.16 – 1.08 (m, 3H). The chiral purity was determined using Chiral HPLC analytical method on Chiralcel OD-RH 150 mm x 4.6 mm x 5 µm column; Mobile phase A: H2O (1.5 mL TFA) / Mobile phase B: ACN (1.5 mL TFA); gradient: 10-80% of Mobile phase B over 8 min then 10% of Mobile phase B in 1 min then a hold at 10% of Mobile phase B for 6 min, flow rate: 0.8 mL / min; column temperature: 30oC to provide C23: peak 1 (retention time: 9.514 min, 100% ee). [α]34D=-95.69 (c= 0.4 (g / L) in ACN). Step 2. Preparation of (S)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylic acid hydrochloride (P10) At 0oC, to C23 (8.00 g, 25.9 mmol) was added 2M HCl in dioxane (160 mL). The reaction mixture was stirred at room temperature for 4 h then was concentrated in vacuo to provide a yellow solid. The solid was dissolved in 2M HCl in dioxane (40 mL) and stirred at room temperature for 2 h then was concentrated in vacuo to provide P10 (7.10 g, crude) as a yellow solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+= 210.2.1H NMR (400 MHz, (CD3)2SO) δ 12.97 (br s, 1H), 10.05 (s, 1H), 9.49 (s, 1H), 4.23 – 4.03 (m, 4H), 3.41 – 3.30 (m, 2H), 3.26 – 3.18 (m, 1H), 1.39 – 1.32 (m, 6H). The chiral purity was determined using SFC analytical method on Chiralcel OX-3100 mm x 4.6 mm, 3 µm column; Mobile phase A: CO2 / Mobile phase B: MeOH with 0.05% of DEA; Isocratic: 40% of Mobile phase B; backpressure: 100 bar; flow rate: 2.8 mL / min; column temperature: 40oC to provide P10: peak 1 (retention time: 1.631 min, 100% ee). [α]33D=-1.584 (c= 1.5 (g / L) in MeOH). Preparation 11 3-(4-(Aminomethyl)phenyl)-1,1-dimethylurea hydrochloride (P11) Step 1. Preparation of tert-butyl (4-(3,3-dimethylureido)benzyl)carbamate (C24) At 0 °C under nitrogen gas, 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 DMAP (0.824 g, 6.75 mmol) was added dimethylcarbamic chloride (14.5 g, 135 mmol) dropwise. The reaction mixture was stirred at 50 °C for 16 h then was diluted with MeOH (150 mL) and concentrated in vacuo to give a residue. The residue was suspended in H2O (120 mL) then rapidly stirred at room temperature for 1 h. The suspension was filtered then the filter cake was collected and triturated with MeOH: EtOAc: MTBE (5 mL: 25 mL: 250 mL) at room temperature for 1 h. The suspension was filtered, and the filter cake was collected then concentrated in vacuo to provide C24 (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 (P11) At 0oC, to a stirred suspension of C24 (23 g, 71 mmol) in DCM (130 mL) was added 2M HCl in dioxane (270 mL) dropwise. The reaction mixture was stirred at room temperature for 3 h then was concentrated in vacuo to provide P11 (15 g, 83.4%) as a yellow solid. The solid was used directly in the next step without additional purification. (LC / MS) m / z (2M+H)+= 387.1.1H NMR (400 MHz, (CD3)2SO) δ 8.40 (s, 1H), 8.25 (br s, 2H), 7.53 - 7.47 (m, 2H), 7.35 - 7.29 (m, 2H), 3.91 (q, 2H), 2.92 (s, 6H). Preparation 12 N-(4-(Aminomethyl)phenyl)-4-methylpiperazine-1-carboxamide hydrochloride (P12) Step 1. Preparation of tert-butyl (4-(4-methylpiperazine-1-carboxamido)benzyl)carbamate (C25) To a solution of phenyl (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)carbamate (CAS: 1632297-04-2; 8.0 g, 23 mmol) in dioxane (120 mL) was added 1-methylpiperazine (CAS: 109- 01-3; 2.8 g, 28 mmol). The reaction mixture was stirred at 90oC overnight. The suspension was diluted with EtOAc (100 mL) and washed with 1M NaOH (2 x 50 mL) then brine (50 mL). The organic layer was dried with Na2SO4and concentrated in vacuo. The residue was triturated with PE (2 x 50 mL) over 20 min then the suspension was filtered. The filter cake was collected to provide C25 (7.7 g, crude) as a brown solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 349.2.1H NMR (400 MHz, (CD3)2SO) δ 8.44 (s, 1H), 7.35 (d, 2H), 7.28 (t, 1H), 7.07 (d, 2H), 4.05 – 3.95 (m, 2H), 3.40 (t, 4H), 2.29 (t, 4H), 2.18 (s, 3H), 1.40 – 1.32 (m, 9H). Step 2. Preparation of N-(4-(aminomethyl)phenyl)-4-methylpiperazine-1-carboxamide hydrochloride (P12) To a stirred solution of C25 (7.7 g, 22 mmol) in DCM (20 mL) was added HCl in dioxane (0.050 g, 1.4 mmol). The reaction mixture was stirred at 0oC for 4 h then concentrated in vacuo and lyophilized to provide P12 (6.9 g, crude) as a white 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 11.27 (br s, 1H), 9.08 (s, 1H), 8.36 (br s, 3H), 7.53 – 7.47 (m, 2H), 7.34 – 7.29 (m, 2H), 4.25 (d, 2H), 3.87 (q, 2H), 3.31 – 3.18 (m, 2H), 3.04 – 2.89 (m, 2H), 2.72 (s, 3H). Preparation 13 Ethyl (S)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate Step 1. Preparation of ethyl (S)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxylate hydrochloride (P13) To a stirred solution of C22 (0.500 g, 1.55 mmol) in EtOH (3 mL) was added SOCl2(1.29 g, 10.8 mmol) dropwise at 0oC. The reaction mixture was stirred at room temperature for 66 h then concentrated in vacuo to provide P13 (0.426 g, 95.7% yield) as a light-yellow solid. (LC / MS) m / z (M+H)+= 252.2. Preparation 14 Ethyl 1-(1-methylcyclopropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P14) Step pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C26) The same procedure was followed from Preparation 2, step 1 with tert-butyl 3-(2- ethoxy-2-oxoacetyl)-4-oxopiperidine-1-carboxylate (CAS: 518990-24-4; 0.577 g, 1.93 mmol) and (1-methylcyclopropyl)hydrazine hydrochloride (CAS: 2737246-42-1, 0.166 g, 1.93 mmol). The residue was purified by column chromatography (silica gel, 0-30% EtOAc: PE) to provide C26 (0.233 g, 34.6% yield) as a light-brown oil. (LC / MS) m / z (M+H)+= 350.1.1H NMR (400 MHz, CDCl3) δ 4.58 (s, 2H), 4.38 (q, 2H), 3.74 – 3.66 (m, 2H), 2.83 – 2.74 (m, 2H), 1.52 (s, 3H), 1.48 (s, 9H), 1.37 (t, 3H), 1.28 – 1.23 (m, 2H), 0.97 – 0.91 (m, 2H). Step 2. Preparation of ethyl 1-(1-methylcyclopropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxylate (P14) The same procedure was followed from Preparation 5, step 2 with C26 (0.233 g, 0.667 mmol) to provide P14 (0.191 g, crude) as a light-yellow solid, which was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 250.1.1H NMR (400 MHz, CD3OD) δ 4.39 – 4.33 (m, 2H), 3.66 (s, 2H), 3.56 (t, 2H), 3.19 (t, 2H), 1.55 (s, 3H), 1.38 (t, 3H), 1.31 – 1.26 (m, 2H), 1.09 – 1.04 (m, 2H). Preparation 15 Ethyl 4,5,6,7- (P15) Step 1. Preparation of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxylate hydrochloride (P15) The same reaction was conducted in two batches then combined. To 5-(tert-butyl) 3- ethyl 6,7-dihydrothieno[3,2-c]pyridine-3,5(4H)-dicarboxylate (CAS: 1363381-39-8; 50.0 mg, 0.161 mmol) was added HCl in dioxane (0.234 g, 6.42 mmol) to form the first batch. The solution of the first batch was stirred at room temperature for 2 h then concentrated in vacuo to provide a white solid. A second batch of the same reaction was conducted with 5-(tert-butyl) 3-ethyl 6,7- dihydrothieno[3,2-c]pyridine-3,5(4H)-dicarboxylate (CAS: 1363381-39-8; 0.450 g, 1.45 mmol). The solids from the two batches were combined to provide P15 (0.339 g, crude) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 212.0. Preparation 16 Ethyl 1-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-1H-indazole-3-carboxylate (P16) Step 1. Preparation of ethyl 1-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-1H-indazole- 3-carboxylate (P16) To a suspension of ethyl 1-methyl-5-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (CAS: 2090404-84-3; 0.500 g, 1.41 mmol) and N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (CAS: 145100-51-2; 0.409 g, 2.12 mmol) in H2O (1 mL) and THF (10 mL) was added Pd(dppf)Cl2(0.103 g, 0.141 mmol) and K3PO4(0.899 g, 4.23 mmol). The reaction mixture was degassed with nitrogen gas and stirred at 85oC for 16 h then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0- 38% THF: PE) to provide P16 (0.470 g, 94.2% yield) as a pink solid. (LC / MS) m / z (M+H)+= 355.0 Preparation 17 Ethyl 1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate Step 1. Preparation of 5-(tert-butyl) 3-ethyl 1-(2,2,2-trifluoroethyl)-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C27) and 2-((3-(ethoxycarbonyl)-2-(2,2,2- trifluoroethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropan-1- ylium (C28) To a suspension of (2,2,2-trifluoroethyl)hydrazine hydrochloride (CAS: 1081515-82-3; 0.226 g, 1.50 mmol) in EtOH (5 mL) and pyridine (0.476 g, 6.01 mmol) was added tert-butyl 3- (2-ethoxy-2-oxoacetyl)-4-oxopiperidine-1-carboxylate (CAS: 518990-24-4; 0.450 g, 1.50 mol). The reaction mixture was stirred at room temperature for 17 h then was checked by LCMS which showed the major isomer of C27 [LC / MS) m / z (M-tert-butyl group)+= 321.9 at 0.87 min retention time] and the minor isomer of C28 [(LC / MS) m / z (M+H)+= 378.2 at 0.94 min retention time]. The suspension was concentrated in vacuo then dissolved in DCM and purified by column chromatography (silica gel, 0-40% EtOAc: heptane) to provide the major isomer of C27 (eluted at 30-40% EtOAc: heptane) (0.344 g, 60.7% yield) as a yellow oil. (LC / MS) m / z (M-tert- butyl group)+= 322.2.1H NMR (600 MHz, CDCl3) δ 4.69 (q, 2H), 4.62 (br s, 2H), 4.41 (q, 2H), 3.77 – 3.70 (m, 2H), 2.74 – 2.70 (m, 2H), 1.56-1.43 (m, 9H), 1.40 (t, 3H) Step 2. Preparation of ethyl 1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxylate hydrochloride (P17) To a solution of C27 (0.344 g, 0.912 mmol) in DCM (5.0 mL) was added 4M HCl in dioxane (1.4 mL). The reaction solution was stirred at 40oC for 24 h then concentrated in vacuo to provide P17 (0.328 g, crude) as a white solid. (LC / MS) m / z (M+H)+= 278.2.1H NMR (600 MHz, (CD3)2SO) δ 9.20 (br s, 1H), 5.31 (q, 2H), 4.32 – 4.22 (m, 4H), 3.39 (t, 2H), 2.99 (t, 2H), 1.29 – 1.26 (m, 3H). Preparation 18 rac- - 1H- 3- Step 1. Preparation of rac-5-(tert-butyl) 3-ethyl (R)-6-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-3,5-dicarboxylate (C29) At 0oC, to a suspension of rac-tert-butyl (2R)-5-(2-ethoxy-2-oxoacetyl)-2-methyl-4- oxopiperidine-1-carboxylate (CAS: 2386748-67-8; 24 g, 77 mmol) in AcOH (120 mL) was added hydrazine monohydrate (CAS: 7803-57-8; 14 g, 0.18 mol) dropwise via addition funnel. The reaction was stirred at room temperature for 1 h then concentrated in vacuo. The residue was diluted in EtOAc (200 mL) then washed with aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide C29 (23 g, crude) as an orange viscous liquid. The liquid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 310.2.1H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 5.06 (d, 1H), 4.85 (s, 1H), 4.44 – 4.28 (m, 2H), 4.15 – 4.10 (m, 1H), 2.96 (dd, 1H), 2.67 – 2.58 (m, 1H), 1.48 – 1.46 (m, 9H), 1.44 – 1.32 (m, 3H), 1.10 (d, 3H). Step 2. Preparation of rac-5-(tert-butyl) 3-ethyl (R)-1,6-dimethyl-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C30) and rac-(R)-2-((3-(ethoxycarbonyl)-2,6-dimethyl- 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropan-1-ylium (C31) At 0oC, to a solution C29 (23 g, 74 mmol) in DMF (200 mL) was added Cs2CO3 (27 g, 82 mmol) and MeI (14 mL) dropwise. The reaction mixture was stirred at room temperature for 20 h then concentrated in vacuo. The residue was dissolved in MTBE (200 mL) then wash with H2O (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to form an orange oil. The residue was purified by column chromatography (silica gel, 0-100% isopropyl acetate: heptane) to provide C30 (3.0 g, 25% yield) and C31 (1.6 g, 14% yield). C30: (LC / MS) m / z (M+H)+= 324.2.1H NMR (400 MHz, CDCl3) δ 5.12 – 4.92 (m, 1H), 4.87 – 4.72 (m, 1H), 4.41 – 4.23 (m, 2H), 4.11 (s, 3H), 4.10 – 4.02 (m, 1H), 2.90 (dd, 1H), 2.59 – 2.48 (m, 1H), 1.48 – 1.44 (m, 9H), 1.39 – 1.34 (m, 3H), 1.09 (d, 3H). C31: (LC / MS) m / z (M+H)+= 324.2.1H NMR (400 MHz, CDCl3) δ 5.08 – 4.85 (m, 2H), 4.44 – 4.30 (m, 2H), 4.08 (d, 1H), 3.80 (s, 3H), 2.94 – 2.84 (m, 1H), 2.44 – 2.38 (m, 1H), 1.46 (s, 9H), 1.37 (t, 3H), 1.20 (d, 3H). Step 3. Preparation of rac-ethyl (R)-1,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine- 3-carboxylate (P18) To a solution of C30 (0.460 g, 1.42 mmol) in DCM (5 mL) was added 1M HCl in EtOAc (5 mL). The reaction solution was stirred at room temperature for 6 h then concentrated in vacuo to provide P18 (0.325 g, crude) as a white foam, which was used directly in the next step without further purification. Preparation 19 Ethyl 3- - 1- Step 1. Preparation of 7-(tert-butyl) 1-ethyl 3-(1-ethoxyvinyl)-5,6-dihydroimidazo[1,5-a]pyrazine- 1,7(8H)-dicarboxylate (C32) To a solution of 7-(tert-butyl) 1-ethyl 3-bromo-5,6-dihydroimidazo[1,5-a]pyrazine- 1,7(8H)-dicarboxylate (CAS: 2108354-93-2; 1.50 g, 4.01 mmol) in DCE (30 mL) was added tributyl(1-ethoxyvinyl)tin (CAS: 97674-02-7; 4.45 g, 12.3 mmol) and PdCl2(PPh3)2 (0.422 g, 0.601 mmol). The reaction mixture was stirred in a microwave at 120oC for 30 min then was concentrated in vacuo. The residue was purified by column chromatography (silica gel; 0-27% THF: PE) to provide C32 (0.960 g, 65.5% yield) as an oil. (LC / MS) m / z (M+H)+= 366.1.1H NMR (400 MHz, CDCl3) δ 5.06 (d, 1H), 4.90 (s, 2H), 4.42 – 4.33 (m, 2H), 4.18 (t, 2H), 3.90 (q, 2H), 3.79 – 3.71 (m, 3H), 1.50 (br s, 9H), 1.44 – 1.33 (m, 6H). Step 2. Preparation of 7-(tert-butyl) 1-ethyl 3-acetyl-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)- dicarboxylate (C33) To a solution of C32 (0.660 g, 1.81 mmol) in THF (12 mL) was added 2M HCl (0.132 g, 3.61 mmol). The reaction mixture was stirred in the microwave for 16 h then the clear yellow solution was concentrated in vacuo. The residue was poured into saturated NaHCO3 then extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The brown residue was purified by column chromatography (silica gel, 0-20% EtOAc: PE) to provide C33 (0.440 g, 81.1% yield) as a white solid. (LC / MS) m / z (M+H)+= 338.3.1H NMR (400 MHz, CDCl3) δ 4.95 (s, 2H), 4.47 (t, 2H), 4.41 (q, 2H), 3.79 (t, 2H), 2.70 (s, 3H), 1.50 (s, 9H), 1.41 (t, 3H). Step 3. Preparation of 7-(tert-butyl) 1-ethyl 3-(1,1-difluoroethyl)-5,6-dihydroimidazo[1,5- a]pyrazine-1,7(8H)-dicarboxylate (C34) A solution of C33 (0.435 g, 1.29 mmol) in deoxo-fluorTMsolution (CAS: 202289-38-1; 10 mL) was stirred at 40oC for 72 h. The reaction mixture was cooled to room temperature then extracted with DCM (2 x 20 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0- 20% EtOAc: PE) to provide C34 (0.310 g, 66.9% yield) as a yellow gum. (LC / MS) m / z (M+H)+= 360.1.1H NMR (400 MHz, CDCl3) δ 4.92 (s, 2H), 4.38 (q, 2H), 4.25 (t, 2H), 3.83 (t, 2H), 2.19 (t, 3H), 1.50 (s, 9H), 1.39 (t, 3H). Step 4. Preparation of ethyl 3-(1,1-difluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1- carboxylate hydrochloride (P19) To a solution of C34 (0.310 g, 0.863 mmol) in DCM (3 mL) was added 2M HCl in dioxane (6 mL). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo and dried further by high vacuo to provide P19 (0.255 g, crude) as a gum. The gum was used directly in the next step without further purification. Preparation 20 rac-Ethyl (R)-7-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P20) - - carboxylate (C35) At -78oC under nitrogen gas in a 250 mL three-neck round bottom flask, LDA (4.24 g, 39.6 mmol) was added to THF (25 mL). To the solution at -78oC, tert-butyl 3-ethyl-4- oxopiperidine-1-carboxylate (CAS: 117565-57-8; 9.00 g, 39.6 mmol) in THF (60 mL) was added dropwise then stirred at -78oC for 1 h. After the stir, a solution of diethyl oxalate (5.79 g, 39.6 mmol) in THF (20 mL) was added dropwise at -78oC then stirred at -78oC for 1 h. The reaction mixture warmed to room temperature then stirred for 16 h. The suspension was cooled to 0oC then quenched with 1M aqueous KHSO4 (150 mL) and filtered. The filtrate was extracted with EtOAc (2 x 200 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide C35 (13.0 g, crude) as a yellow gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M-tert-butyl group)+= 272.0.1H NMR (400 MHz, CDCl3) δ 15.42 (br s, 1H), 4.53 – 4.16 (m, 4H), 3.68 – 3.32 (m, 2H), 2.44 – 2.32 (m, 1H), 1.84 – 1.67 (m, 1H), 1.53 – 1.42 (m, 2H), 1.41 – 1.39 (m, 9H), 1.31 (t, 3H), 0.97 (t, 3H). Step 2. Preparation of rac-5-(tert-butyl) 3-ethyl (R)-7-ethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-3,5-dicarboxylate (C36) The same procedure was followed from Preparation 18, step 1 with C35 (6.00 g, 18.3 mmol) to provide C36 (8.89 g, crude) as a yellow gum, which was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 324.1.1H NMR (400 MHz, CDCl3) δ 8.00 (br s, 1H), 4.93 – 4.44 (m, 2H), 4.37 (q, 2H), 3.83 – 3.68 (m, 1H), 3.57 – 3.41 (m, 1H), 2.88 – 2.71 (m, 1H), 1.84 – 1.70 (m, 1H), 1.62 – 1.51 (m, 2H), 1.50 – 1.48 (m, 9H), 1.38 (t, 3H), 1.05 (t, 3H). Step 3. Preparation of rac-ethyl (R)-7-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate hydrochloride (P20) To a suspension of C36 (0.400 g, 1.24 mmol) in DCM (6 mL) and MeOH (2 mL) was added 2M HCl in dioxane (3 mL). The reaction mixture was stirred at room temperature for 2 h then an additional portion of 2M HCl in dioxane (3 mL) was added. The suspension was stirred for 16 h at room temperature then concentrated in vacuo to provide P20 (0.276 g, crude) as a yellow solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 9.68 (br s, 2H), 4.37 – 4.11 (m, 4H), 3.52 – 3.44 (m, 1H), 3.14 – 3.06 (m, 1H), 3.05 – 2.94 (m, 1H), 1.99 – 1.85 (m, 1H), 1.67 – 1.53 (m, 1H), 1.29 (t, 3H), 0.94 (t, 3H). Preparation 21 rac-(R)-7-Ethyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid hydrochloride (P21) Step 1. Preparation of rac-(R)-5-(tert-butoxycarbonyl)-7-ethyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylic acid (C37) To a suspension of C36 (2.00 g, 6.18 mmol) in MeOH (6.6 mL) and H2O (6.6 mL) was added NaOH (0.495 g, 12.4 mmol). The reaction mixture was stirred at 40oC for 2 h then was diluted with H2O (20 mL). The diluted reaction mixture was cooled to 0oC then acidified with 1M aqueous HCl to pH~3 and filtered. The filter cake was collected to provide C37 (1.60 g, crude) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 296.1.1H NMR (400 MHz, (CD3)2SO) δ 13.15 (br s, 1H), 4.73 – 4.24 (m, 2H), 3.74 - 3.41 (m, 2H), 2.78 – 2.67 (m, 1H), 1.70 (br s, 1H), 1.49 – 1.40 (m, 10H), 1.02 (t, 3H). Step 2. Preparation of rac-(R)-5-(tert-butoxycarbonyl)-7-ethyl-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylic acid (C38) The same procedure was followed from Preparation 3, step 2 with C37 (1.00 g, 3.39 mmol) and MeI (0.577 g, 4.06 mmol) to provide C38 (0.850 g, crude) as a white solid, which was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 310.1.1H NMR (400 MHz, (CD3)2SO) δ 12.65 (br s, 1H), 5.01 – 4.75 (m, 1H), 4.34 – 3.88 (m, 2H), 3.79 (s, 3H), 3.07 – 2.67 (m, 2H), 1.63 – 1.50 (m, 1H), 1.43 (s, 9H), 1.36 – 1.23 (m, 1H), 1.08 – 0.95 (m, 3H). Step 3. Preparation of rac-(R)-7-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylic acid hydrochloride (P21) At 0oC, to a solution of C38 (0.300 g, 0.970 mmol) in DCM (1 mL) was added HCl in dioxane (2 mL). The reaction mixture was warmed to room temperature and stirred for 16 h then concentrated in vacuo to provide P21 (0.236 g, crude) as a yellow solid.1H NMR (400 MHz, (CD3)2SO) δ 12.97 (br s, 1H), 9.70 (br s, 1H), 9.13 (br s, 1H), 4.27 – 4.03 (m, 2H), 3.86 (s, 3H), 3.32 – 3.08 (m, 3H), 1.81 – 1.66 (m, 2H), 0.97 (t, 3H). Preparation 22 2-Chloro-5-(1-methyl-1H-imidazol-2-yl)pyridine (P22) Step 1. Preparation of 2-chloro-5-(1H-imidazol-2-yl)pyridine (C39) 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 h 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 h then cooled to room temperature before 6M HCl (74.2 g, 2.04 mol) was added. The reaction was stirred at 80 °C for 5 h then concentrated in vacuo. The residue was extracted with EtOAc (2 x 500 mL). The aqueous layer was adjusted to pH=10 with saturated aqueous Na2CO3 solution which caused white solid precipitate to form. The suspension was filtered then the filter cake was washed with H2O (3 x 100 mL). The filter cake was collected then lyophilized to provide C39 (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 (P22) To a solution of C39 (44.0 g, 204 mmol) in DME (440 mL) was added KOH (24.0 g, 428 mmol) at room temperature then stirred for 1 h and 40 min. The reaction mixture was cooled to 0 °C before MeI (57.8 g, 407 mmol) was added then stirred at 0 °C for 1 h. The white suspension was filtrated then concentrated in vacuo. The residue was washed with H2O (300 mL) and stirred for 30 min. The reaction mixture was filtered, and the filter cake was concentrated in vacuo to provide P22 (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 23 rac-Ethyl (R)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate trifluoroacetate (P23) Step pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C40) and rac-5-(tert-butyl) 3-ethyl (R)-2-ethyl-7- methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C41) A suspension of C10 (1.00 g, 3.19 mmol) and ethylhydrazine dihydrochloride (CAS: 49540-34-3; 0.425 g, 3.19 mmol) in EtOH (20 mL) and pyridine (1.11 g, 14.0 mmol) was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo then purified by column chromatography (silica gel, 0-40% EtOAc: PE) to provide C41 (0.290 g, 26.9% yield) as a light-yellow solid and C40 (0.700 g, 65.0% yield) as a light-yellow gum. C40: (LC / MS) m / z (M+H)+= 338.2;1H NMR (400 MHz, CDCl3) δ 5.20 – 4.88 (m, 1H), 4.44 – 4.32 (m, 2H), 4.29 – 3.97 (m, 4H), 3.16 (d, 1H), 3.00 – 2.88 (m, 1H), 1.52 – 1.44 (m, 12H), 1.38 (t, 3H), 1.25 (d, 3H). C41: (LC / MS) m / z (M+H)+= 338.2;1H NMR (400 MHz, CDCl3) δ 4.75 – 4.46 (m, 4H), 4.33 (q, 2H), 3.96 – 3.64 (m, 1H), 3.36 – 3.08 (m, 1H), 3.00 – 2.91 (m, 1H), 1.50 – 1.44 (m, 9H), 1.39 (q, 6H), 1.26 (d, 3H). Step 2. Preparation of rac-ethyl (R)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxylate trifluoroacetate (P23) To a solution of C40 (0.250 g, 0.741 mmol) in DCM (4 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo to provide P23 (0.260 g, crude) as a colorless gum, which was used directly in the next step without further purification. Preparation 24 rac-Ethyl (4R,8S)-1-methyl-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-3- Step 1. Preparation of rac-tert-butyl (1R,5S)-2-(2-ethoxy-2-oxoacetyl)-3-oxo-9- azabicyclo[3.3.1]nonane-9-carboxylate (C42) At -78oC, LDA (1.07 g, 10.0 mmol) was added to THF (50 mL). To the solution at -78oC, tert-butyl (1R,5S)-3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (CAS: 512822-27-4; 2.00 g, 8.36 mmol) in THF (50 mL) was added dropwise and then stirred at -78oC for 1 h. After the stir, a solution of diethyl oxalate (1.28 g, 8.78 mmol) in THF (20 mL) was added dropwise at -78oC and then stirred at -78oC for 30 min. The reaction mixture was warmed to room temperature, stirred for 1 h, and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2-16% EtOAc: PE) to provide C42 (0.750 g, 26.4% yield) as a light yellow oil. (LC / MS) m / z (M+H)+= 340.11H NMR (400 MHz, CDCl3) δ 5.49 (d, 1H), 4.77 – 4.48 (m, 2H), 4.36 (q, 2H), 2.98 – 2.81 (m, 1H), 2.44 – 2.31 (m, 1H), 1.86 – 1.72 (m, 3H), 1.69 – 1.58 (m, 3H), 1.50 – 1.42 (m, 9H), 1.39 (t, 3H). Step 2. Preparation of rac-10-(tert-butyl) 3-ethyl (4R,8S)-1-methyl-4,5,6,7,8,9-hexahydro-1H- 4,8-epiminocycloocta[c]pyrazole-3,10-dicarboxylate (C43) and rac-10-(tert-butyl) 3-ethyl (4R,8S)-2-methyl-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-3,10-dicarboxylate (C44) To a solution of C42 (0.650 g, 2.17 mmol) in EtOH (20 mL) was added methylhydrazine dihydrochloride (CAS: 55330-60-4; 0.179 g, 2.17 mmol) and pyridine (0.859 g, 10.9 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 12-100% EtOAc: PE) to provide C43 (0.390 g, 51.4% yield) as an oil and C44 (0.150 g, 19.8% yield). C43: (LC / MS) m / z (M+H)+= 350.1.1H NMR (400 MHz, CDCl3) δ 5.68 – 5.53 (m, 1H), 4.79 – 4.57 (m, 1H), 4.46 – 4.28 (m, 2H), 3.80 (s, 3H), 3.11 – 2.95 (m, 1H), 2.43 (d, 1H), 1.89 – 1.69 (m, 4H), 1.63 – 1.55 (m, 1H), 1.50 – 1.41 (m, 10H), 1.40 – 1.34 (m, 3H). C44: (LC / MS) m / z (M+H)+ = 350.2.1H NMR (400 MHz, CDCl3) δ 5.68 – 5.48 (m, 1H), 4.78 – 4.53 (m, 1H), 4.45 – 4.19 (m, 2H), 4.15 – 4.07 (m, 3H), 3.19 – 3.00 (m, 1H), 2.63 – 2.52 (m, 1H), 1.90 – 1.58 (m, 5H), 1.44 (s, 10H), 1.38 (t, 3H). Step 3. Preparation of rac-ethyl (4R,8S)-1-methyl-4,5,6,7,8,9-hexahydro-1H-4,8- epiminocycloocta[c]pyrazole-3-carboxylate (P24) To a solution of C43 (0.222 g, 0.636 mmol) in ACN (6 mL) was added HCl in dioxane (0.116 g, 3.18 mmol). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo to provide P24 (0.150 g, crude) as a white solid. The solid was used directly in the next step without further purification. Preparation P25 Ethyl 7,7-difluoro-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P25) Step 1. - 1(2H)- carboxylate (C45) To a solution of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (CAS:1215071-17- 2; 3.00 g, 11.8 mmol) in toluene (40 mL) was added pyrrolidine (0.927 g, 13.0 mmol). The reaction mixture was heated for 20 h using a Deans and Stark trap to remove the H2O liberated during the reaction, then concentrated in vacuo to provide C45 (3.42 g, crude) as a brown solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, CDCl3) δ 4.66 – 4.46 (m, 1H), 4.14 – 4.05 (m, 2H), 3.90 (t, 2H), 3.20 – 3.13 (m, 4H), 1.97 – 1.88 (m, 4H), 1.53 (s, 9H). Step 2. Preparation of tert-butyl 5-(2-ethoxy-2-oxoacetyl)-3,3-difluoro-4-(pyrrolidin-1-yl)-3,6- dihydropyridine-1(2H)-carboxylate (C46) A solution of C45 (3.42 g, 11.9 mmol) in DCM (50 mL) was degassed with nitrogen gas for 10 min. The reaction mixture was cooled to 0oC before ethyl oxalyl chloride (1.94 g, 14.2 mmol) was added dropwise over 15 min. The temperature was maintained between (0-5)oC throughout the addition. Following the addition, TEA (1.80 g, 17.8 mmol) was added dropwise over 5 min. The reaction mixture was warmed to room temperature and stirred for 5 h, then diluted with H2O (300 mL). The diluted reaction mixture was extracted with DCM (3 x 100 mL). The combined organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-25% EtOAc: PE) to provide C46 (2.98 g, 64.7% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 389.2.1H NMR (400 MHz, CDCl3) δ 4.41 (s, 2H), 4.30 (q, 2H), 3.89 (t, 2H), 3.49 – 3.41 (m, 4H), 2.00 – 1.94 (m, 4H), 1.48 (s, 9H), 1.35 (t, 3H). Step 3. Preparation of 5-(tert-butyl) 3-ethyl 7,7-difluoro-1-methyl-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C47) and 2-((3-(ethoxycarbonyl)-7,7-difluoro-2- methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropan-1-ylium (C48) The reaction was conducted in three batches and then combined for further purification. At 0oC, to a solution of C46 (1.09 g, 2.81 mmol) in EtOH (10 mL) was added methylhydrazine dihydrochloride (CAS: 55330-60-4; 0.402 g, 3.38 mmol) dropwise over 5 min then the reaction was sealed and stirred at 80oC for 2 h to form the first batch. The second batch of the same reaction was conducted with C46 (0.500 g, 1.29 mmol), and the third batch was conducted with C46 (0.100 g, 0.257 mmol). The batches were combined and then diluted with H2O (60 mL). The diluted reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-15% EtOAc: PE) to provide C48 (0.756 g, 50.4% yield) as brown oil and an impure C47 as a residue. The residue, C47, was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 µm column, Mobile Phase A: H2O (0.05% NH4OH-NH4HCO3) / Mobile Phase B: ACN, 32 to 72% of Mobile Phase B over 9 min, 100% of Mobile Phase B hold 2 min, flow rate= 60 mL / min) and lyophilized to provide C47 (0.416 g, 27.7% yield) as a colorless oil. C47: (LC / MS) m / z (M-tert-butyl group)+= 290.2;1H NMR (400 MHz, CDCl3) δ 4.69 (br s, 2H), 4.41 (q, 2H), 4.09 – 3.96 (m, 5H), 1.49 (s, 9H), 1.40 (t, 3H). C48: (LC / MS) m / z (M-tert-butyl group)+= 290.2;^1H NMR (400 MHz, CDCl3) δ 4.73 – 4.63 (m, 2H), 4.37 (q, 2H), 4.23 (s, 3H), 4.06 – 3.95 (m, 2H), 1.49 (s, 9H), 1.40 (t, 3H). Step 4. Preparation of ethyl 7,7-difluoro-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine- 3-carboxylate hydrochloride (P25) To a reaction mixture of C47 (0.416 g, 1.20 mmol) in DCM (5 mL) was added HCl in dioxane (1.76 g, 48.2 mmol) and then stirred at room temperature for 2.5 h. The reaction mixture was concentrated in vacuo to provide P25 (295 mg, crude) as a light-yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 246.1.1H NMR (400 MHz, CD3OD) δ 4.55 (t, 2H), 4.40 (q, 2H), 4.15 – 4.02 (m, 5H), 1.39 (t, 3H). Preparation 26 rac-Ethyl (4R,8S)-1-methyl-1,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-3- carboxylate hydrochloride (P26) rac- - - oxo- oxa- azabicyclo[3.3.1]nonane-9-carboxylate (C49) The same procedure was followed from Preparation 20, step 1 with tert-butyl 7-oxo-3- oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (CAS: 280761-97-9; 1.80 g, 7.46 mmol) to provide C49 (2.50 g, crude) as an orange oil, which was used directly in the next step without further purification. Step 2. Preparation of rac-10-(tert-butyl) 3-ethyl (4R,8S)-1-methyl-1,4,5,7,8,9-hexahydro-4,8- epiminooxocino[5,4-c]pyrazole-3,10-dicarboxylate (C50) and rac-10-(tert-butyl) 3-ethyl (4R,8S)- 2-methyl-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-3,10-dicarboxylate (C51) The reaction was conducted in two batches and then combined. A suspension of C49 (2.50 g, 7.32 mmol) and methylhydrazine dihydrochloride (CAS: 55330-60-4; 0.871 g, 7.32 mmol) in EtOH (40 mL) and pyridine (2.55 g, 32.2 mmol) was stirred at room temperature for 3 h to form the first batch. The reaction mixture of the first batch was checked by LCMS, which showed the major isomer of C50 [LC / MS) m / z (M+H)+= 352.3 at 0.827 min retention time (analytical LCMS conditions: Chromolith Flash Reverse Phase-18e 25-3mm column; Mobile Phase A: 1.5 mL / 4 L TFA in H2O / Mobile Phase B: 0.75 mL / 4 L TFA in ACN, gradient 5-95% of Mobile Phase B over 0.7 min then held at 95% of Mobile Phase B for 0.4 min; flow rate: 1.5 mL / min column temperature: 50oC)] and the minor isomer of C51 [LC / MS) m / z (M+H)+= 352.3 at 0.880 min retention time (analytical LCMS conditions: Chromolith Flash Reverse Phase-18e 25-3mm column; Mobile Phase A: 1.5 mL / 4 L TFA in H2O / Mobile Phase B: 0.75 mL / 4 L TFA in ACN, gradient 5-95% of Mobile Phase B over 0.7 min then held at 95% of Mobile Phase B for 0.4 min; flow rate: 1.5 mL / min column temperature: 50oC)]. The second batch of the same reaction was conducted with C49 (0.200 g, 0.586 mmol). The two batches were combined, concentrated in vacuo, and purified by column chromatography (silica gel, 0-50% EtOAc: PE) to provide C50 (0.750 g, 27.0% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 352.3.1H NMR (400 MHz, CDCl3) δ 5.55 – 5.30 (m, 1H), 4.53 – 4.27 (m, 3H), 3.91 – 3.64 (m, 7H), 3.21 – 2.92 (m, 1H), 2.71 – 2.59 (m, 1H), 1.51 – 1.30 (m, 12H). Step 3. Preparation of rac-ethyl (4R,8S)-1-methyl-1,4,5,7,8,9-hexahydro-4,8- epiminooxocino[5,4-c]pyrazole-3-carboxylate hydrochloride (P26) To a solution of C50 (0.750 g, 2.14 mmol) in DCM (5 mL) was added 2M HCl in dioxane (0.390 g, 10.7 mmol). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in DCM (5 mL) and then concentrated in vacuo (2x) to provide P26 (0.675 g, crude) as a yellow solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, CDCl3) δ 10.83 (s, 1H), 9.85 (s, 1H), 5.07 (s, 1H), 4.45 – 4.20 (m, 4H), 4.01 – 3.84 (m, 5H), 3.82 – 3.73 (m, 1H), 3.66 – 3.55 (m, 1H), 2.98 – 2.86 (m, 1H), 1.38 (t, 3H). Preparation 27 Ethyl 1-propyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P27) c]pyridine-3,5-dicarboxylate (C52) and 2-((3-(ethoxycarbonyl)-2-propyl-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropan-1-ylium (C53) To a solution of 5-(tert-butyl) 3-ethyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5- dicarboxylate (CAS: 518990-23-3; 0.81 g, 4.7 mmol) and 1-iodopropane (1.0 g, 3.4 mmol) in DMF (13 mL) was added K2CO3(0.94 g, 6.7 mmol). The reaction mixture was stirred at 100oC for 4 h, cooled to room temperature, and diluted with (1:1) EtOAc: H2O (50 mL). The aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-39% EtOAc: PE) to provide C53 (0.48 g, 42% yield) as a white solid and C52 (0.38 g, 33% yield) as a white solid. C52: (LC / MS) m / z (M+H)+= 338.3;1H NMR (400 MHz, CDCl3) δ 4.61 (s, 2H), 4.39 (q, 2H), 4.03 (t, 2H), 3.76 – 3.67 (m, 2H), 2.73 – 2.63 (m, 2H), 1.92 – 1.80 (m, 2H), 1.48 (s, 9H), 1.39 (t, 3H), 0.91 (t, 3H). C53: (LC / MS) m / z (M+H)+= 338.3;1H NMR (400 MHz, CDCl3) δ 4.65 – 4.56 (m, 2H), 4.49 – 4.43 (m, 2H), 4.33 (q, 2H), 3.68 (s, 2H), 2.74 (s, 2H), 1.90 – 1.78 (m, 2H), 1.49 (s, 9H), 1.39 (t, 3H), 0.92 (t, 3H). Step 2. Preparation of ethyl 1-propyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate (P27) To a reaction mixture of C52 (0.370 g, 1.10 mmol) in DCM (3 mL) was added 2M HCl in dioxane (0.400 g, 11.0 mmol) and then stirred at room temperature for 1 h and 40 min. The reaction mixture was concentrated in vacuo to provide P27 (0.300 g, crude) as a white solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 9.54 (s, 2H), 4.25 (q, 2H), 4.19 (s, 2H), 4.06 (t, 2H), 3.40 – 3.35 (m, 2H), 2.97 (t, 2H), 1.80 – 1.68 (m, 2H), 1.27 (t, 3H), 0.82 (t, 3H). Preparation 28 Ethyl 1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P28) Step 1. tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C54) The same procedure was followed from Preparation 2, step 1 with tert-butyl 3-(2- ethoxy-2-oxoacetyl)-4-oxopiperidine-1-carboxylate (CAS: 518990-24-4; 0.500 g, 1.67 mmol) and (tetrahydro-2H-pyran-4-yl)hydrazine hydrochloride (0.255 g, 1.67 mmol). The residue was purified by column chromatography (silica gel, 0-40% THF: PE) to provide C54 (0.492 g, 77.6% yield) as a yellow gum. (LC / MS) m / z (M+H)+= 380.3.1H NMR (400 MHz, CDCl3) δ 4.60 (s, 2H), 4.38 (q, 2H), 4.31 – 4.21 (m, 1H), 4.15 – 4.07 (m, 2H), 3.77 – 3.68 (m, 2H), 3.54 – 3.44 (m, 2H), 2.73 (t, 2H), 2.41 – 2.25 (m, 2H), 1.89 – 1.80 (m, 2H), 1.51 – 1.40 (m, 9H), 1.38 (t, 3H). Step 2. Preparation of ethyl 1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxylate hydrochloride (P28) To a solution of C54 (0.470 g, 1.24 mmol) in DCM (10 mL) was added 2M HCl in dioxane (0.973 g, 26.7 mmol). The reaction mixture was stirred at room temperature for 4 h then concentrated in vacuo to provide P28 (0.370 g, crude) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 280.1.1H NMR (400 MHz, (CD3)2SO) δ 9.37 (s, 1H), 4.56 – 4.45 (m, 1H), 4.33 – 4.19 (m, 4H), 4.03 – 3.93 (m, 2H), 3.52 – 3.41 (m, 4H), 3.04 (t, 2H), 2.07 – 1.92 (m, 2H), 1.86 – 1.77 (m, 2H), 1.29 (t, 3H). Preparation 29 rac-Ethyl (R)-1-(sec-butyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate Step 1. Preparation of rac-5-(tert-butyl) 3-ethyl (R)-1-(sec-butyl)-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C55) The same procedure was followed from Preparation 2, step 1 with tert-butyl 3-(2- ethoxy-2-oxoacetyl)-4-oxopiperidine-1-carboxylate (CAS: 518990-24-4; 0.400 g, 1.34 mmol) and sec-butylhydrazine dihydrochloride (CAS: 1177361-36-2, 0.215 g, 1.34 mmol). The residue was purified by column chromatography (silica gel, 50% EtOAc: PE) to provide C55 (0.382 g, 81.3% yield) as a gum. (LC / MS) m / z (M+H)+= 352.1.1H NMR (400 MHz, (CD3)2SO) δ 4.53 – 4.40 (m, 2H), 4.30 – 4.17 (m, 3H), 3.68 – 3.54 (m, 2H), 2.71 (q, 2H), 1.87 – 1.66 (m, 2H), 1.41 (s, 9H), 1.37 (d, 3H), 1.29 (t, 3H), 0.69 (t, 3H). Step 2. Preparation of rac-ethyl (R)-1-(sec-butyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine- 3-carboxylate hydrochloride (P29) At 0oC, to a solution of C55 (0.382 g, 1.09 mmol) in DCM (2 mL) was added HCl in dioxane (4 mL). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo to provide P29 (0.245 g, crude) as a solid. The solid was used directly in the next step without further purification. Preparation 30 rac-Ethyl (4R,7S)-1-methyl-1,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-3- carboxylate (P30) Step 1. Preparation of rac-tert-butyl (1R,5S)-2-(2-ethoxy-2-oxoacetyl)-3-oxo-8- azabicyclo[3.2.1]octane-8-carboxylate (C56) The same procedure was followed from Preparation 20, step 1, with tert-butyl (1R,5S)- 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (CAS: 637301-19-0; 5.10 g, 22.6 mmol), with an additional purification added. The residue was purified by column chromatography (silica gel, 0- 10% EtOAc: PE) to provide C56 (4.69 g, 63.7% yield) as a yellow oil. Step 2. Preparation of rac-9-(tert-butyl) 3-ethyl (4R,7S)-1-methyl-1,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-3,9-dicarboxylate (C57) and rac-9-(tert-butyl) 3-ethyl (4R,7S)-2- methyl-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-3,9-dicarboxylate (C58) The same procedure was followed from Preparation 2, step 1 with C56 (4.69 g, 14.4 mmol) and methylhydrazine sulfate (CAS: 302-15-8, 2.08 g, 14.4 mmol). The reaction mixture was checked by LCMS, which showed the major isomer of C57 [LC / MS) m / z (M+H)+= 336.2 at 0.846 min retention time (analytical LCMS conditions: Chromolith Flash Reverse Phase-18e 25- 3mm column; Mobile Phase A: 1.5 mL / 4 L TFA in H2O / Mobile Phase B: 0.75 mL / 4 L TFA in ACN, gradient 5-95% of Mobile Phase B over 0.7 min then held at 95% of Mobile Phase B for 0.4 min; flow rate: 1.5 mL / min; column temperature: 50oC)] and the minor isomer of C58 [LC / MS) m / z (M+H)+= 336.2 at 0.904 min retention time (analytical LCMS conditions: Chromolith Flash Reverse Phase-18e 25-3mm column; Mobile Phase A: 1.5 mL / 4 L TFA in H2O / Mobile Phase B: 0.75 mL / 4 L TFA in ACN, gradient 5-95% of Mobile Phase B over 0.7 min then held at 95% of Mobile Phase B for 0.4 min; flow rate: 1.5 mL / min; column temperature: 50oC)]. The purification was altered. The residue was purified by column chromatography (silica gel, 0-50% THF: PE) to provide C57 (1.40 g, 29.0% yield) as a light- yellow oil.1H NMR (400 MHz, CDCl3) δ 5.42 – 5.33 (m, 1H), 4.64 – 4.35 (m, 3H), 3.77 (s, 3H), 3.29 – 3.08 (m, 1H), 2.41 – 2.23 (m, 2H), 2.21 – 2.10 (m, 1H), 1.93 – 1.85 (m, 1H), 1.55 – 1.48 (m, 1H), 1.44 – 1.35 (m, 12H). Step 3. Preparation of ethyl 1-methyl-1,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole- 3-carboxylate (P30) To a solution of C57 (0.240 g, 0.716 mmol) in DCM (1 mL), 2M HCl in dioxane (3 mL) was added. The reaction mixture was stirred at room temperature for 2.5 h and then concentrated in vacuo to provide P30 (0.168 g, crude) as a grey solid. The solid was used directly in the next step without further purification. Preparation 31 Ethyl 1-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P31) Step 1. Preparation of 5-(tert-butyl) 3-ethyl 1-(cyclopropylmethyl)-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C59) and 2-((2-(cyclopropylmethyl)-3- (ethoxycarbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2- methylpropan-1-ylium (C60) The same procedure was followed from Preparation 2, step 1 with tert-butyl 3-(2- ethoxy-2-oxoacetyl)-4-oxopiperidine-1-carboxylate (CAS: 518990-24-4; 2.00 g, 6.68 mmol) and (cyclopropylmethyl)hydrazine hydrochloride (CAS: 1181457-83-9, 0.655 g, 5.35 mmol). The residue was purified by column chromatography (silica gel, 0-60% EtOAc: PE) to provide an impure C60 (0.800 g) as a yellow oil and C59 (0.940 g, 40.3% yield) as a light-brown solid. C60 (0.800 g) was repurified by column chromatography (silica gel, 0-10% EtOAc: DCM) to provide C60 (0.450 g, 19.3% yield) as a grey gum. C59: (LC / MS) m / z (M+H)+= 350.1;1H NMR (400 MHz, (CD3)2SO) δ 4.49 (s, 2H), 4.26 (q, 2H), 3.96 (d, 2H), 3.61 (t, 2H), 2.73 (t, 2H), 1.44 – 1.40 (m, 9H), 1.29 (t, 3H), 1.24 – 1.16 (m, 1H), 0.54 – 0.47 (m, 2H), 0.37 – 0.31 (m, 2H). C60: (LC / MS) m / z (M+H)+= 350.0;1H NMR (400 MHz, CDCl3) δ 4.62 (s, 2H), 4.41 – 4.30 (m, 4H), 3.76 – 3.61 (m, 2H), 2.81 – 2.71 (m, 2H), 1.50 – 1.46 (m, 9H), 1.42 - 1.30 (m, 4H), 0.54 – 0.47 (m, 2H), 0.43 – 0.37 (m, 2H). Step 2. Preparation of ethyl 1-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxylate (P31) To a solution of C59 (0.200 g, 0.572 mmol) in DCM (0.5 mL), 2M HCl in dioxane (2.0 mL) was added. The reaction mixture was stirred at 35oC for 3 h and then concentrated in vacuo to provide P31 (0.143 g, crude) as a grey solid. The solid was used directly in the next step without further purification. Preparation 32 rac-Ethyl (R)-1-(1-methoxypropan-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate hydrochloride (P32) Step 1. Preparation of rac-5-(tert-butyl) 3-ethyl (R)-1-(1-methoxypropan-2-yl)-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C61) and rac-(R)-2-((3-(ethoxycarbonyl)-2-(1- methoxypropan-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2- methylpropan-1-ylium (C62) The reaction was conducted in two batches then combined for purification. A solution of rac-(R)-2-bromo-1-methoxypropane (CAS: 22461-48-9; 0.829 g, 5.42 mmol), 5-(tert-butyl) 3- ethyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (CAS: 518990-23-3; 0.800 g, 2.71 mmol), Cs2CO3(1.77 g, 5.42 mmol) and NaI (40.6 mg, 0.271 mmol) in DMF (13.5 mL) was stirred at 80oC for 16 h to form the first batch. The second batch of the same reaction was conducted with 5-(tert-butyl) 3-ethyl 1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (CAS: 518990-23-3; 0.100 g, 0.339 mmol). The two batches were combined then diluted with H2O (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was dried Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-50% EtOAc: PE) to provide C62 (0.630 g, 56.2% yield) as an oil and C61 (0.430 g, 38.4% yield) as an oil. C62: (LC / MS) m / z (M+H)+= 368.2;1H NMR (400 MHz, CDCl3) δ 5.72 – 5.60 (m, 1H), 4.68 – 4.55 (m, 2H), 4.33 (q, 2H), 3.85 (t, 1H), 3.74 – 3.63 (m, 2H), 3.55 (dd, 1H), 3.31 (s, 3H), 2.79 – 2.71 (m, 2H), 1.48 (s, 9H), 1.45 – 1.36 (m, 6H). C61: (LC / MS) m / z (M+H)+= 368.2;1H NMR (400 MHz, CDCl3) δ 4.60 (s, 2H), 4.43 – 4.33 (m, 3H), 3.82 – 3.75 (m, 1H), 3.73 – 3.66 (m, 2H), 3.58 (dd, 1H), 3.24 (s, 3H), 2.83 – 2.62 (m, 2H), 1.52 – 1.46 (m, 12H), 1.38 (t, 3H). Step 2. Preparation of rac-ethyl (R)-1-(1-methoxypropan-2-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P32) At 0oC, to a suspension of C61 (0.430 g, 1.17 mmol) in DCM (2 mL) was added HCl in dioxane (8 mL) in batches. The reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo to provide P32 (0.356 g, crude) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 268.1.1H NMR (400 MHz, (CD3)2SO) δ 9.28 – 9.05 (m, 2H), 4.66 – 4.55 (m, 1H), 4.36 – 4.13 (m, 4H), 3.67 – 3.57 (m, 1H), 3.55 – 3.51 (m, 1H), 3.48 – 3.38 (m, 2H), 3.18 (s, 3H), 3.08 – 2.86 (m, 2H), 1.36 (d, 3H), 1.29 (t, 3H). Preparation 33 Ethyl 1-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate trifluoroacetate (P33) Step 1. Preparation of 5-(tert-butyl) 3-ethyl 1-(oxetan-3-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-3,5-dicarboxylate (C63) and 2-((3-(ethoxycarbonyl)-2-(oxetan-3-yl)-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropan-1-ylium (C64) The reaction was conducted in two batches then combined for purification. To a solution of 5-(tert-butyl) 3-ethyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (CAS: 518990-23-3; 0.600 g, 2.03 mmol) in DMF (10 mL) was added 3-iodooxetane (CAS: 26272-85- 5; 0.748 g, 4.06 mmol) and Cs2CO3(1.32 g, 4.06 mmol) then stirred at 80oC for 16 h to form the first batch. The second batch of the same reaction conducted with 5-(tert-butyl) 3-ethyl 1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (CAS: 518990-23-3; 0.100 g, 0.339 mmol) then the two batches were combined then diluted in ice H2O (40 mL). The diluted reaction mixture was extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine (2 x 10 mL) then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-80% EtOAc: PE) to provide C63 (0.180 g, 25.2% yield) as an oil and C64 (0.288 g, 40.3% yield) as an oil. C63 (Lot-001): (LC / MS) m / z (M+H)+= 352.1;1H NMR (400 MHz, (CD3)2SO) δ 5.61 – 5.51 (m, 1H), 4.89 (d, 4H), 4.49 (s, 2H), 4.33 – 4.24 (m, 2H), 3.58 (t, 2H), 2.68 (t, 2H), 1.41 (s, 9H), 1.31 (t, 3H). C64: (LC / MS) m / z (M-tert-butyl group)+= 296.1;1H NMR (400 MHz, (CD3)2SO) δ 6.08 – 5.95 (m, 1H), 4.97 – 4.84 (m, 4H), 4.56 – 4.50 (m, 2H), 4.28 (q, 2H), 3.62 (t, 2H), 2.70 (t, 2H), 1.42 (s, 9H), 1.30 (t, 3H). Step 2. Preparation of ethyl 1-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate trifluoroacetate (P33) At 0oC, to a suspension of C63 (0.180 g, 0.512 mmol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo to provide P33 (0.187 g, crude) as a gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 252.3.1H NMR (400 MHz, (CD3)2SO) δ 9.18 – 8.94 (m, 2H), 5.69 – 5.58 (m, 1H), 4.98 – 4.82 (m, 4H), 4.37 – 4.23 (m, 4H), 3.44 – 3.35 (m, 2H), 3.04 – 2.91 (m, 2H), 1.35 – 1.26 (m, 3H). Preparation 34 Ethyl 1-(cyclobutylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P34) Step 1. Preparation of 5-(tert-butyl) 3-ethyl 1-(cyclobutylmethyl)-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C65) The same procedure was followed from Preparation 2, step 1 with tert-butyl 3-(2- ethoxy-2-oxoacetyl)-4-oxopiperidine-1-carboxylate (CAS: 518990-24-4; 0.400 g, 1.34 mmol) and 1-cyclobutylhydrazine hydrochloride (CAS: 158001-21-9, 0.164 g, 1.34 mmol) to provide C65 (0.280 g, 15.0% yield) as a yellow gum. (LC / MS) m / z (M+H)+= 350.2.1H NMR (400 MHz, (CD3)2SO) δ 4.90 – 4.75 (m, 1H), 4.48 (s, 2H), 4.28 (q, 2H), 3.60 (t, 2H), 2.73 – 2.66 (m, 2H), 2.40 – 2.30 (m, 4H), 1.87 – 1.74 (m, 2H), 1.46 – 1.35 (m, 9H), 1.30 (t, 3H). Step 2. Preparation of ethyl 1-(cyclobutylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine- 3-carboxylate hydrochloride (P34) At 0oC, HCl was added to a suspension of C65 (0.280 g, 0.801 mmol) in DCM (5 mL) in dioxane (10 mL). The reaction mixture was stirred at room temperature for 3 h, concentrated in vacuo, and then lyophilized to provide P34 (0.150 g, crude) as a brown solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 250.1.1H NMR (400 MHz, (CD3)2SO) δ 9.37 (s, 2H), 4.94 – 4.80 (m, 1H), 4.29 (q, 2H), 4.21 (s, 2H), 3.42 – 3.36 (m, 2H), 2.95 (t, 2H), 2.48 – 2.44 (m, 1H), 2.41 – 2.31 (m, 2H), 1.87 – 1.75 (m, 2H), 1.30 (t, 3H). Preparation 35 rac-Ethyl (R)-1-(1,1,1-trifluoropropan-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate (P35) Step 1. - - tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C66) To a solution of tert-butyl 3-(2-ethoxy-2-oxoacetyl)-4-oxopiperidine-1-carboxylate (CAS: 518990-24-4; 0.400 g, 1.34 mmol) and (1,1,1-trifluoropropan-2-yl)hydrazine hydrochloride (CAS: 1453472-98-4; 0.269 g, 1.34 mmol) in EtOH (7 mL) was added pyridine (0.465 g, 5.88 mmol). The reaction mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-25% EtOAc: PE) to provide C66 (0.415 g, 79.3% yield) as a yellow gum. (LC / MS) m / z (M+H)+= 392.2.1H NMR (400 MHz, (CD3)2SO) δ 5.47 – 5.35 (m, 1H), 4.60 – 4.38 (m, 2H), 4.29 (q, 2H), 3.78 – 3.67 (m, 1H), 3.55 – 3.46 (m, 1H), 2.92 – 2.81 (m, 1H), 2.69 – 2.56 (m, 1H), 1.67 (d, 3H), 1.41 (s, 9H), 1.30 (t, 3H). Step 2. Preparation of rac-ethyl (R)-1-(1,1,1-trifluoropropan-2-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylate (P35) At 0oC, to a suspension of C66 (0.415 g, 1.06 mmol) in DCM (4 mL) was added HCl in dioxane (8 mL) in batches. The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo to provide P35 (0.306 g, crude) as a yellow solid. The solid was used directly in the next step without further purification. Preparation 36 Step 1. Preparation of 5-(tert-butyl) 3-ethyl 1,7,7-trimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-3,5-dicarboxylate (C67) and 2-((3-(ethoxycarbonyl)-2,7,7-trimethyl-4,5,6,7-tetrahydro- 2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropan-1-ylium (C68) The same procedure was followed from Preparation 2, step 1 with tert-butyl 5-(2- ethoxy-2-oxoacetyl)-3,3-dimethyl-4-oxopiperidine-1-carboxylate (CAS: 2171295-98-8, 1.28 g, 3.91 mmol) and methylhydrazine (CAS: 60-34-4, 1.08 g, 9.38 mmol) to provide C68 (0.563 g, 42.7% yield) as a light-yellow gum and C67 (0.160 g, 12.1% yield) as a light-yellow gum. C67: (LC / MS) m / z (M+H)+= 338.2;1H NMR (400 MHz, CDCl3) δ 4.66 – 4.54 (m, 2H), 4.44 – 4.30 (m, 2H), 4.00 – 3.92 (m, 3H), 3.45 – 3.34 (m, 2H), 1.51 – 1.45 (m, 9H), 1.41 – 1.35 (m, 3H), 1.34 – 1.29 (m, 6H). C68: (LC / MS) m / z (M+H)+= 338.1;1H NMR (400 MHz, CDCl3) δ 4.66 – 4.56 (m, 2H), 4.38 – 4.26 (m, 2H), 4.16 – 4.05 (m, 3H), 3.45 – 3.32 (m, 2H), 1.49 – 1.46 (m, 9H), 1.37 (t, 3H), 1.28 – 1.24 (m, 6H). Step 2. Preparation of ethyl 1,7,7-trimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate hydrochloride (P36) At 0oC, to a suspension of C67 (0.130 g, 0.385 mmol) in DCM (3 mL) was added HCl in dioxane (3 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to provide P36 (0.110 g, crude) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 238.1.1H NMR (400 MHz, (CD3)2SO) δ 9.58 (s, 2H), 4.27 (q, 2H), 4.18 (s, 2H), 3.98 (s, 3H), 3.21 – 3.16 (m, 2H), 1.42 (s, 6H), 1.31 – 1.22 (m, 3H). Preparation 37 Ethyl 1'-methyl-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'- (P37) Step 1. Preparation of 5'-(tert-butyl) 3'-ethyl 1'-methyl-1',4'-dihydrospiro[cyclopropane-1,7'- pyrazolo[4,3-c]pyridine]-3',5'(6'H)-dicarboxylate (C69) and 2-((3'-(ethoxycarbonyl)-2'-methyl- 2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)oxy)-2- methylpropan-1-ylium (C70) The same procedure was followed from Preparation 2, step 1 with tert-butyl 7-(2- ethoxy-2-oxoacetyl)-8-oxo-5-azaspiro[2.5]octane-5-carboxylate (CAS: 2494304-89-9; 0.620 g, 1.91 mmol) and methylhydrazine sulfate (CAS: 302-15-8, 0.302 g, 2.10 mmol). The purification was altered. The residue was purified by column chromatography (silica gel, 0-30% THF: PE) to provide C70 (0.327 g, 51.2% yield) as a white solid and C69 (0.290 g, 45.4% yield) as a white gum. C69: (LC / MS) m / z (M+H)+= 336.3;1H NMR (400 MHz, CDCl3) δ 4.70 (s, 2H), 4.39 (q, 2H), 3.74 (s, 3H), 3.44 (s, 2H), 1.48 (s, 9H), 1.39 (t, 3H), 1.31 (t, 2H), 1.08 – 0.94 (m, 2H). C70: (LC / MS) m / z (M+H)+= 336.3;1H NMR (400 MHz, CDCl3) δ 4.75 – 4.65 (m, 2H), 4.34 (q, 2H), 4.08 (s, 3H), 3.53 – 3.47 (m, 2H), 1.48 (s, 9H), 1.39 (t, 3H), 1.12 (q, 2H), 0.97 – 0.86 (m, 2H). Step 2. Preparation of ethyl 1'-methyl-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3- c]pyridine]-3'-carboxylate hydrochloride (P37) At 0oC, to a suspension of C69 (0.272 g, 0.811 mmol) in DCM (6 mL) was added HCl in dioxane (0.591 g, 16.2 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated in vacuo to provide P37 (0.219 g, crude) as a white solid. The solid was used directly in the next step without further purification. Preparation 38 rac-Ethyl (R)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P38) Step 1. Preparation of rac-5-(tert-butyl) 3-ethyl (R)-1-isopropyl-7-methyl-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C71) and rac-5-(tert-butyl) 3-ethyl (R)-2-isopropyl-7- methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C72) The same procedure was followed from Preparation 2, step 1 with C10 (3.00 g, 9.57 mmol) and isopropylhydrazine hydrochloride (CAS: 16726-41-3, 1.06 g, 9.57 mmol). The purification was altered. The residue was purified by reverse phase HPLC (Sunfire C18150 mm x 40 mm x 5 µm column, Mobile Phase A: H2O (0.05% NH4OH-NH4HCO3) / Mobile Phase B: ACN, Mobile Phase B: 42 to 82% over 9.0 min, 100% of Mobile Phase B hold 2.0 min, flow rate= 30 mL / min) to provide C71 (1.80 g, 53.5% yield) as a pale yellow solid and C72 (33.9 mg, 1.01% yield) as a pale yellow solid. C71: (LC / MS) m / z (M+H)+= 352.4.1H NMR (400 MHz, CDCl3) δ 5.05 (dd, 1H), 4.46 – 4.31 (m, 3H), 4.13 (dd, 2H), 3.20 – 3.04 (m, 1H), 2.99 – 2.89 (m, 1H), 1.54 (d, 3H), 1.51 – 1.45 (m, 12H), 1.36 (t, 3H), 1.23 (d, 3H). C72: (LC / MS) m / z (M+H)+= 352.4.1H NMR (400 MHz, CDCl3) δ 5.56 – 5.44 (m, 1H), 4.69 – 4.45 (m, 2H), 4.32 (q, 2H), 3.90 – 3.61 (m, 1H), 3.41 – 3.13 (m, 1H), 3.02 – 2.92 (m, 1H), 1.51 – 1.44 (m, 15H), 1.38 (t, 3H), 1.26 (d, 3H). Step 2. Preparation of rac-ethyl (R)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridine-3-carboxylate hydrochloride (P38) At 0oC, to a suspension of C71 (0.200 g, 0.569 mmol) in DCM (1 mL) was added HCl in dioxane (4 mL). The reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo to provide P38 (0.180 g, crude) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 252.1.1H NMR (400 MHz, (CD3)2SO) δ 9.98 – 9.83 (m, 1H), 9.34 – 9.25 (m, 1H), 4.67 – 4.54 (m, 1H), 4.33 – 4.05 (m, 4H), 3.43 – 3.26 (m, 3H), 1.45 – 1.40 (m, 3H), 1.39 – 1.33 (m, 6H), 1.32 – 1.26 (m, 3H). Preparation 39 2-Fluoro-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine (P39) Step 1. Preparation of 2-fluoro-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine (P39) To a suspension of (6-fluoropyridin-3-yl)boronic acid (CAS: 351019-18-6; 1.10 g, 7.81 mmol) and 5-bromo-1-methyl-1H-1,2,4-triazole (CAS: 16681-72-4; 1.52 g, 9.37 mmol) in dioxane (10 mL) and H2O (2 mL) was added Pd(dppf)Cl2 (0.457 g, 0.625 mmol) and K3PO4 (4.97 g, 23.4 mmol). The reaction mixture was degassed with nitrogen gas, then stirred at 110oC for 4 h and purified by column chromatography (silica gel, 0-40% EtOAc: PE) to provide P39 (1.20 g, 86.3% yield) as a white solid. (LC / MS) m / z (M+H)+= 179.1.1H NMR (400 MHz, (CD3)2SO) δ 8.67 – 8.62 (m, 1H), 8.42 – 8.34 (m, 1H), 8.05 (s, 1H), 7.40 (dd, 1H), 3.97 (s, 3H). Preparation 40 2-Fluoro-5- 1H-imidazol-2- Step 1. Preparation of 2-fluoro-5-(1-methyl-1H-imidazol-2-yl)pyridine (P40) Under nitrogen gas, the reaction mixture of 2-bromo-1-methyl-1H-imidazole (0.700 g, 4.35 mmol), (6-fluoropyridin-3-yl)boronic acid (1.20 g, 8.70 mmol) and Pd(dppf)Cl2 (0.178 g, 0.217 mmol) suspended in dioxane (10 mL) and H2O (2 mL) was stirred at 90oC for 1 h. The reaction mixture was extracted with EtOAc, and then the organic layer was concentrated in vacuo. The residue was dissolved in DCM and then purified by column chromatography (silica gel, 0-10% MeOH: DCM) to provide P40 (0.688 g, 89.3% yield) as an orange oil. (LC / MS) m / z (M+H)+= 178.1. Preparation 41 2-(4-(Aminomethyl)phenyl)pyrimidin-4(3H)-one hydrochloride (P41) To a solution of 2-chloropyrimidin-4-ol (CAS: 55873-09-1; 0.100 g, 0.766 mmol) and tert- butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (CAS: 330794-35-9; 0.255 g, 0.766 mmol) in THF (7.7 mL) was added 2M K3PO4(0.325 g, 1.53 mmol). The reaction mixture was degassed with nitrogen gas for 3 min, and then XPhos Pd G2 (60.3 mg, 0.0766 mmol) was added. The suspension was degassed with nitrogen gas for 3 min and then stirred at 80oC for 4 h. The reaction solution was diluted with H2O (10 mL) and then extracted with MeOH: DCM (1:10, 3 x 5 mL). The combined organic layer was dried with Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100% EtOAc: PE) to provide C73 (0.115 g, 49.8% yield) as a white solid. (LC / MS) m / z (M+H)+= 302.1.1H NMR (400 MHz, (CD3)2SO) δ 12.75 (br s, 1H), 8.16 – 7.92 (m, 3H), 7.51 – 7.44 (m, 1H), 7.36 (d, 2H), 6.36 – 6.24 (m, 1H), 4.18 (d, 2H), 1.39 (s, 9H). Step 2. Preparation of 2-(4-(aminomethyl)phenyl)pyrimidin-4(3H)-one hydrochloride (P41) At 0oC, to a stirred solution of C73 (0.115 g, 0.382 mmol) in DCM (1 mL) was added HCl in MeOH (3 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to provide P41 (91.0 mg, crude) as a white solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 11.05 – 10.97 (m, 1H), 10.88 – 10.81 (m, 1H), 8.60 - 8.47 (m, 2H), 8.17 – 8.08 (m, 2H), 7.66 – 7.61 (m, 2H), 7.39 (dd, 1H), 6.40 – 6.36 (m, 1H), 5.46 – 5.42 (m, 1H), 4.10 (q, 2H). Preparation 42 - Step 1. Preparation of tert-butyl (4-(6-oxo-1,6-dihydropyridin-2-yl)benzyl)carbamate (C74) To a solution of 6-bromopyridin-2-ol (CAS: 27992-32-1; 0.100 g, 0.575 mmol) and tert- butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (CAS: 330794-35-9; 0.192 g, 0.575 mmol) in THF (5.7 mL) was added 2M K3PO4 (0.244 g, 1.15 mmol). The reaction mixture was degassed with nitrogen gas for 3 min, then XPhos Pd G2 (45.2 mg, 0.0575 mmol) was added. The suspension was degassed with nitrogen gas for 3 min and then stirred at 80oC for 4 h. The reaction solution was diluted with H2O (10 mL) and then extracted with EtOAc (3 x 5 mL). The combined organic layer was dried with Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100% EtOAc: PE) to provide C74 (0.110 g, 63.7% yield) as a white solid. (LC / MS) m / z (M+H)+= 301.1.1H NMR (400 MHz, (CD3)2SO) δ 11.71 (br s, 1H), 7.73 (d, 2H), 7.58 – 7.51 (m, 1H), 7.49 – 7.44 (m, 1H), 7.33 (d, 2H), 6.71 – 6.57 (m, 1H), 6.37 (d, 1H), 4.18 (d, 2H), 1.41 (s, 9H). Step 2. Preparation of 6-(4-(aminomethyl)phenyl)pyridin-2(1H)-one hydrochloride (P42) At 0oC, to a stirred solution of C74 (0.110 g, 0.366 mmol) in DCM (1 mL) was added HCl in MeOH (3 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to provide P42 (87.0 mg, crude) as a white solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 8.46 – 8.36 (m, 3H), 7.84 (d, 2H), 7.61 – 7.54 (m, 3H), 6.80 – 6.70 (m, 1H), 6.43 (d, 1H), 4.07 (q, 2H). Preparation 43 3-(4- dimethylurea hydrochloride (P43) Step 1. Preparation of 3-(4-bromophenyl-2,3,5,6-d4)-1,1-dimethylurea (C75) To a solution of CDI (6.59 g, 40.6 mmol) in ACN (50 mL) was added 4-bromobenzen- 2,3,5,6-d4-amine (CAS: 61357-76-4; 5.50 g, 31.2 mmol) at (-5 to 5) °C. The reaction mixture was stirred from (0 to 5) °C for 3 h before TEA (6.32 g, 62.5 mmol) and dimethylamine hydrochloride (CAS: 506-59-2; 5.10 g, 62.5 mmol) were added slowly at (0 to 5) °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The suspension was poured into H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (200 mL), dried over MgSO4, and concentrated in vacuo. The residue was slurried with MTBE: DCM (10:1, 100 mL) at room temperature for 3 h and then filtered. The filter cake was dried in vacuo and then collected to provide C75 (6.10 g, 76.2% yield) as a white solid.1H NMR (400 MHz, (CD3)2SO) δ 8.40 (s, 1H), 2.91 (s, 6H). Step 2. Preparation of tert-butyl (4-(3,3-dimethylureido)2,3,5,6-d4-benzyl)carbamate (C76) A reaction mixture of C75 (3.0 g, 12 mmol), potassium [[(tert- butoxycarbonyl)amino]methyl]trifluoroborate (4.3 g, 18 mmol) and Cs2CO3(7.9 g, 24 mmol) in H2O (6 mL) and dioxane (40 mL) was degassed and purged with nitrogen gas 3 times. To the reaction mixture were added bis(1-adamantyl)-butyl-phosphane (0.87 g, 2.4 mmol) and Pd(OAc)2 (0.27 g, 1.2 mmol). The suspension was degassed and purged with nitrogen gas 3 times again, then stirred at 90 °C for 16 h under nitrogen gas. The reaction mixture was cooled to room temperature and then poured into H2O (50 mL) and filtered. The filtrate was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was slurried with DCM (100 mL) at room temperature for 4 h and then filtered. The filter cake was dried in vacuo and then collected to provide C76 (2.0 g, 30.% yield) as a light-yellow solid. Step 3. Preparation of 3-(4-(aminomethyl)phenyl-2,3,5,6-d4)-1,1-dimethylurea hydrochloride (P43) To a solution of C76 (2.0 g, 6.7 mmol) in DCM (30 mL) was added 2M HCl in dioxane (25 mL). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was purified by reverse phase HPLC (Welch Xtimate C18250 mm x 50 mm x 10 µm column, Mobile Phase A: H2O with HCl / Mobile Phase B: ACN, 0 to 20% of Mobile Phase B over 20 min) then lyophilized to provide P43 (1.1 g, 67% yield) as a white solid.1H NMR (400 MHz, (CD3)2SO) δ 8.43 (s, 1H), 8.37 (br s, 2H), 3.90 (q, 2H), 2.92 (s, 6H). Preparation 44 rac-Ethyl (R)-1-isopropyl-7-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate hydrochloride (P44) Step 1. Preparation of tert-butyl 3-(2-ethoxy-2-oxoacetyl)-4-oxo-5-(trifluoromethyl)-3,4- dihydropyridine-1(2H)-carboxylate (C77) A yellow solution of 1M LiHMDS in THF (18.4 mL) was diluted with THF (10 mL) then cooled to -69oC with a dry ice / acetone bath. To the cooled solution was added tert-butyl 4-oxo- 5-(trifluoromethyl)-3,4-dihydropyridine-1(2H)-carboxylate (CAS: 1667744-92-4; 4.07 g, 15.4 mmol) in THF (20 mL) dropwise over 15 min. The substrate flask was rinsed with THF (2 x 1 mL) and added to the reaction mixture. During the addition, the solution became a brownish- orange color. The reaction was stirred at -69oC for 45 min after the addition. A solution of diethyl oxalate (2.52 mL) in THF (5 mL) was added dropwise to the reaction mixture over 8 min. The source vial was rinsed with THF (1.5 mL), which was then added to the reaction mixture, which changed the solution to a brownish-orange color. The reaction mixture was stirred in the dry ice / acetone bath for another 7 min, then removed and replaced with an ice water bath. The reaction mixture was quenched with aqueous 2N HCl (21 mL), which changed the color of the suspension to an orange color. The suspension was diluted with H2O and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with saturated NaHCO3 solution (1 x 20 mL, 2 x 10 mL). The organic layers were set aside. The aqueous layers were combined and washed with MTBE (3 x 20 mL). The combined organic layers were set aside. The aqueous layer was acidified with 6N HCl (~6.5 mL) to pH=1. The acidic aqueous layer was extracted with MTBE (2 x 40 mL). The combined organic layer from the acidic aqueous layer extraction was dried with Na2SO4, filtered, and concentrated in vacuo, then dried further by high vacuum to provide C77 (1.52 g) as an orange-yellow residue. The organic layers that were set aside were combined. The combined organic layer was dried with Na2SO4, filtered, and concentrated in vacuo to give a deep orange oil. The oil was dissolved in MTBE (40 mL) and then washed with saturated NaHCO3 solution (1 x 32 mL, 1 x 10 mL). The aqueous layers were combined and acidified with aqueous 6N HCl. The acidic aqueous layer was extracted with MTBE (30 mL) and then MTBE (20 mL). The organic layers were combined and then dried with Na2SO4, filtered, concentrated in vacuo, and dried further by high vacuum to provide C77 (1.92 g) as an orange residue. The two batches of products were combined to form C77 (3.44 g) and then purified by column chromatography (silica gel, 0-85% EtOAc: heptane) to provide C77 (2.32 g, 41.3% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 366.5.1H NMR (400 MHz, CDCl3) δ 15.18 (s, 1H), 8.28 (s, 1H), 5.03 (s, 2H), 4.38 (q, 2H), 1.58 (s, 9H), 1.40 (t, 3H). Step 2. Preparation of 5-(tert-butyl) 3-ethyl 1-isopropyl-7-(trifluoromethyl)-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C78) and 2-((3-(ethoxycarbonyl)-2-isopropyl-7- (trifluoromethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropan- 1-ylium (C79) To a solution of C77 (408 mg, 1.12 mmol) in EtOH (4.5 mL) was added isopropylhydrazine hydrochloride (CAS: 16726-41-3; 148 mg, 1.34 mmol) and then pyridine (132 mg, 1.67 mmol). The reaction mixture was stirred at 55oC for 20 h and then concentrated in vacuo to give a yellow-orange residue. The residue was diluted with EtOAc (20 mL) and washed with NaHCO3(20 mL). The aqueous layer was back-extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to give an orange oil. The oil was dissolved in DCM then preabsorbed on (1:1) silica gel: Celite and purified by column chromatography (silica gel, 0-100% EtOAc: heptane) to provide C78 (0.315 g, 69.9% yield) as a gum and C79 (7.70 mg, 1.71% yield) as a light-yellow solid. C78: (LC / MS) m / z (M+H)+= 404.6;1H NMR (400 MHz, CDCl3) δ 7.67 – 7.46 (m, 1H), 5.02 (s, 2H), 4.73 – 4.63 (m, 1H), 4.39 (q, 2H), 1.55 (s, 9H), 1.50 (d, 6H), 1.39 (t, 3H). C79: (LC / MS) m / z (M+H)+= 404.5;1H NMR (500 MHz, CDCl3) δ 7.63 – 7.33 (m, 1H), 5.51 – 5.49 (m, 1H), 4.97 (s, 2H), 4.35 (q, 2H), 1.55 (s, 9H), 1.48 (d, 6H), 1.39 (t, 3H). Step 3. Preparation of rac-5-(tert-butyl) 3-ethyl (R)-1-isopropyl-7-(trifluoromethyl)-1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C80) To a suspension of Pd / C (CAS: 7440-05-3; 83 mg, 5% wt, 0.039 mmol) in EtOH (0.5 mL) was added a light-yellow solution of C78 (0.30 g, 0.75 mmol) in EtOH (1.5 mL). The source vial was rinsed with EtOH (0.5 mL x 2), and then the rinses were added to the reaction mixture for a total volume of EtOH (3 mL). The reaction mixture was stirred at room temperature overnight in a Hastelloy reactor at H2 gas (50 psi). The suspension was filtered through Celite (0.5 g) with a prepacked plastic filter funnel. The filter cake was eluted with EtOH. The grey filtrate was concentrated in vacuo to give a grey residue. The same reaction was set up again. To a reaction mixture of Pd / C (98 mg, 5 wt%, 0.046 mmol) in EtOH (0.5 mL) was added the solution of the crude residue dissolved in EtOH (1.5 mL). The reaction mixture was stirred at room temperature overnight in a Hastelloy reactor at H2gas (50 psi). The suspension was filtered through Celite (0.5 g) with a prepacked plastic filter funnel. The filter cake was eluted with EtOH. The grey filtrate was concentrated in vacuo to provide a grey solid. The solid was purified by column chromatography (silica gel, 0-50% EtOAc: heptane) to provide C80 (0.24 g, 78% yield) as a white solid. (LC / MS) m / z (M+H)+= 406.6;1H NMR (400 MHz, CDCl3) δ 5.35 – 5.23 (m, 1H), 5.13 – 4.76 (m, 2H), 4.59 – 4.47 (m, 1H), 4.44 – 4.34 (m, 3H), 4.29 – 4.08 (m, 2H), 3.60 – 3.44 (m, 1H), 3.08 (dd, 1H), 1.59 – 1.55 (m, 9H), 1.43 – 1.35 (m, 6H). Step 4. Preparation of rac-ethyl (R)-1-isopropyl-7-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P44) To C80 (0.234 g, 0.577 mmol) was added 4N HCl in dioxane (1.44 mL) dropwise. The reaction mixture was stirred at 40oC for 40 min then concentrated under nitrogen gas then dried further under high vacuum to provide P44 (0.210 g, crude) as a white solid. (LC / MS) m / z (M+H)+= 306.5;1H NMR (400 MHz, (CD3)2SO) δ 10.41 (br s, 1H), 8.55 (br s, 1H), 4.91 – 4.80 (m, 1H), 4.76 – 4.65 (m, 1H), 4.40 – 4.20 (m, 3H), 3.92 (d, 1H), 3.74 – 3.64 (m, 1H), 3.55 – 3.45 (m, 1H), 1.44 (d, 3H), 1.36 (d, 3H), 1.30 (t, 3H). Preparation 45 1-(6-Fluoropyridin-3-yl)pyrrolidin-2-one (P45) Step 1. Preparation of 1-(6-fluoropyridin-3-yl)pyrrolidin-2-one (P45) A reaction mixture of 2-fluoro-5-iodopyridine (CAS: 171197-80-1; 2.00 g, 8.97 mmol), pyrrolidin-2-one (CAS: 616-45-5; 0.763 g, 8.97 mmol), K2CO3(3.72 g, 26.9 mmol), DMEDA (0.158 g, 1.79 mmol) and CuI (0.342 g, 1.79 mmol) in dioxane (40 mL) was heated to 115 °C for 16 h under nitrogen gas. The suspension was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-60% EtOAc: PE) to provide P45 (1.40 g, 86.6% yield) as a light-yellow solid. (LC / MS) m / z (M+H)+= 181.0;1H NMR (400 MHz, (CD3)2SO) δ 8.46 – 8.43 (m, 1H), 8.36 – 8.29 (m, 1H), 7.22 (dd, 1H), 3.89 – 3.83 (m, 2H), 2.54 – 2.51 (m, 1H), 2.50 – 2.48 (m, 1H), 2.14 – 2.04 (m, 2H). Preparation 46 Ethyl (R)-1-ethyl-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P46) Step 1. Preparation of 5-(tert-butyl) 3-ethyl (R)-1-ethyl-6-methyl-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C81) and 5-(tert-butyl) 3-ethyl (R)-2-ethyl-6-methyl- 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C82) A reaction mixture of H2O (8.8 mL), EtOH (8.8 mL), tert-butyl (2S,5RS)-5-(2-ethoxy-2- oxoacetyl)-2-methyl-4-oxopiperidine-1-carboxylate (CAS: 2171296-27-6; 1.65 g, 5.27 mmol), ethylhydrazine oxalate (0.949 g, 6.32 mmol) and KH2PO4(1.00 g, 7.37 mmol) was stirred at room temperature for 2 h. The yellow slurry was checked by LCMS, which showed C81 (LC / MS) m / z (M+H)+= 338.3 at 1.69 min retention time and C82 (LC / MS) m / z (M+H)+= 338.3 at 1.94 min retention time. The reaction mixture was diluted with H2O and extracted with DCM (3x). The combined organic layer was dried with Na2SO4and then purified by column chromatography (silica gel, 0-100% EtOAc: heptane) to provide C81 (1.53 g, 86.0% yield) and C82 (30.0 mg, 1.70% yield). C81:1H NMR (400 MHz, (CD3)2SO) δ 4.88 (d, 1H), 4.78 – 4.65 (m, 1H), 4.33 – 4.17 (m, 2H), 4.14 – 3.94 (m, 3H), 2.85 (dd, 1H), 2.68 – 2.60 (m, 1H), 1.42 (s, 9H), 1.33 – 1.26 (m, 6H), 1.03 (d, 3H). C82:1H NMR (400 MHz, (CD3)2SO) δ 4.91 (d, 1H), 4.78 – 4.63 (m, 1H), 4.54 – 4.36 (m, 2H), 4.35 – 4.15 (m, 2H), 4.09 – 3.96 (m, 2H), 3.38 – 3.26 (m, 1H), 2.82 – 2.65 (m, 2H), 2.56 – 2.51 (m, 1H), 2.47 - 2.36 (m, 1H), 2.28 – 2.12 (m, 2H), 1.35 – 1.27 (m, 6H), 1.10 – 1.06 (m, 3H), 1.04 – 0.99 (m, 3H). Step 2. Preparation of ethyl (R)-1-ethyl-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine- 3-carboxylate hydrochloride (P46) To a solution of C81 (1.00 g, 2.96 mmol) in ACN (10 mL) was added 12.1M HCl (0.216 g, 5.93 mmol). The reaction mixture was stirred at 50 °C for 25 h and 15 min, then concentrated in vacuo. The residue was diluted with ACN and then concentrated in vacuo. The residue was diluted with DCM and concentrated in vacuo (2x) to provide P46 (0.730 g, crude) as a yellow foam. The yellow foam was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 238.2.1H NMR (600 MHz, (CD3)2SO) δ 9.33 – 9.24 (m, 1H), 9.07 – 8.93 (m, 1H), 4.38 – 4.10 (m, 6H), 3.48 – 3.39 (m, 1H), 3.16 (dd, 1H), 2.71 (dd, 1H), 1.41 – 1.37 (m, 3H), 1.31 (dt, 6H). Preparation 47 Methyl 3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (47) Step 1. Preparation of methyl 3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P47) To a solution of 7-(tert-butyl) 1-methyl 3-methyl-5,6-dihydroimidazo[1,5-a]pyrazine- 1,7(8H)-dicarboxylate (CAS: 1359655-89-2, 0.190 g, 0.643 mmol) in DCM (5.0 mL) was added 2M HCl in EtOAc (5.0 mL) at 10 °C.^The reaction mixture was stirred at room temperature for 16 h. The reaction mixture became a white suspension concentrated in vacuo to provide the P47 (0.149 g, crude) as a white solid. This was used in the next step without further purification.1H NMR (400 MHz, CD3OD) δ 4.80 (s, 2H), 4.51 (t, 2H), 4.00 (s, 3H), 3.84 (t, 2H), 2.71 (s, 3H). Preparation 48 Ethyl 3-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P48) en- - a]pyrazine-1,7(8H)-dicarboxylate (C83) A solution of 7-(tert-butyl) 1-ethyl 3-bromo-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)- dicarboxylate (CAS: 2108354-93-2; 1.00 g, 2.67 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)- 1,3,2-dioxaborolane (CAS: 126726-62-3, 0.808 g, 4.81 mmol), NaHCO3 (0.673 g, 8.02 mmol), cataCXium® A (0.192 g, 0.534 mmol) and Pd(OAc)2 (60.0 mg, 0.267 mmol) in (4:1) DME: H2O (16 mL: 4 mL) was degassed with nitrogen gas for 5 min. The reaction solution was stirred at 90oC for 16 h and then concentrated in vacuo. The residue was dissolved in DCM (50 mL) and then extracted with EtOAc (3 x 50 mL). The combined organic layer was dried with Na2SO4, filtered, and then concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, 0-20% EtOAc: PE) to provide C83 (0.856 g, 95.5% yield) as a light- yellow solid. (LC / MS) m / z (M+H)+= 336.2. Step 2. Preparation of 7-(tert-butyl) 1-ethyl 3-isopropyl-5,6-dihydroimidazo[1,5-a]pyrazine- 1,7(8H)-dicarboxylate (C84) To the suspension of C83 (0.86 g, 2.5 mmol) in THF (20 mL) was added RuCl(PPh3)3(0.24 g, 0.25 mmol). The reaction mixture was degassed with hydrogen gas and then stirred under a hydrogen atmosphere (50 psi) from 60-65oC for 48 h. The suspension was concentrated in vacuo, and then the residue was purified by column chromatography (silica gel, 0-20% THF: PE) to provide C84 (0.67 g, 77% yield) as a brown solid. (LC / MS) m / z (M+H)+= 338.3.1H NMR (400 MHz, CDCl3) δ 4.87 (s, 2H), 4.36 (q, 2H), 3.92 (t, 2H), 3.82 (t, 2H), 3.03 – 2.89 (m, 1H), 1.50 (s, 9H), 1.43 – 1.32 (m, 9H). Step 3. Preparation of ethyl 3-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P48) To a solution of C84 (0.67 g, 2.0 mmol) in DCM (10 mL) was added 2M HCl in dioxane (20 mL). The reaction solution was stirred at room temperature for 2 h then was concentrated in vacuo and was dried further by high vacuo to provide P48 (0.54 g, crude) as a solid. The solid was used directly in the next step without further purification. Preparation 49 5,7-Di-tert-butyl-2-(oxetan-3-yloxy)-3-phenyl-2,3-dihydrobenzo[d]oxazole (P49) Step 1. Preparation - [d]oxazole (P49) A reaction mixture of 3-hydroxyoxetane (CAS: 7748-36-9; 41 mg, 0.55 mmol) and deoxazole (CAS: 1207294-92-5; 0.22 g, 0.55 mmol) in MTBE (3 mL) was degassed with nitrogen gas (2x). The suspension was stirred at room temperature for 5 min before adding pyridine (43 mg, 0.55 mmol). The reaction mixture was stirred for 30 min to provide a solution of P49 (0.21 g, crude). The solution was used directly in the next step without further purification. Preparation 50 rac-Methyl (4R)-1-isopropyl-4-methyl-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine-3- Step 1. Preparation of methyl 4-chloro-1-isopropyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C85) To a solution of methyl 4-chloro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (CAS: 1658466-48-8; 6.00 g, 28.3 mmol) in DMF (120 mL) was added Cs2CO3 (18.5 g, 56.7 mmol) and 2-iodopropane (CAS: 75-30-9; 7.23 g, 42.5 mmol). The reaction mixture was stirred at room temperature for 3 h, diluted with EtOAc (100 mL), and washed with brine (3 x 300 mL). The organic layer was dried with Na2SO4 and then concentrated in vacuo. The yellow oil was purified by column chromatography (silica gel, 0-37% EtOAc: hexane) to provide C85 (3.30 g, 45.9% yield). (LC / MS) m / z (M+H)+= 254.0.1H NMR (400 MHz, (CD3)2SO) δ 8.26 (d, 1H), 7.93 (d, 1H), 5.22 – 5.07 (m, 1H), 3.93 (s, 3H), 1.49 (d, 6H). Step 2. Preparation of methyl 1-isopropyl-4-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C86) To a solution of C85 (2.10 g, 8.28 mmol), trimethylboroxine (CAS: 823-96-1; 8.31 g, 33.1 mmol) in dioxane (60 mL) was added DIEA (4.28 g, 33.1 mmol) and Pd(t-Bu3P)2 (0.635 g, 1.24 mmol). The reaction mixture was degassed with nitrogen gas and then stirred at 90oC for 12 h. The suspension was diluted with EtOAc (100 mL), washed with brine (2 x 150 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-50% EtOAc: hexane) to provide C86 (2.10 g, crude) as an orange gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 234.0.1H NMR (400 MHz, CDCl3) δ 8.33 (d, 1H), 7.24 (d, 1H), 4.96 – 4.83 (m, 1H), 4.03 (s, 3H), 3.06 (s, 3H), 1.65 – 1.61 (m, 6H). Step 3. Preparation of rac-methyl (4R)-1-isopropyl-4-methyl-3a,4,5,6,7,7a-hexahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylate (P50) The reaction was carried out via flow chemistry. C86 (1.80 g, 7.72 mmol) was dissolved in MeOH (40 mL). The solution was pumped with a flow rate of 0.3 mL / min, and the H2 had a 30 mL / min rate. The solution passed through the fixed bed (1 / 4’’ mm) packed with granular catalyst 5% Ru / Al2O3 with a 5.0 mL volume and was hydrogenated at 60 °C via flow at 2.0 MPa H2. The reaction mixture was collected from the reactor output to provide P50 (1.85 g, crude) as a black oil. The oil was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 238.2.1H NMR (400 MHz, (CD3)2SO) δ 4.61 – 4.42 (m, 2H), 4.24 – 4.01 (m, 1H), 3.86 – 3.75 (m, 3H), 3.04 – 2.77 (m, 4H), 1.49 (d, 3H), 1.38 (dd, 6H). Preparation 51 rac-Methyl (4R)-4-ethyl-1-isopropyl-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine-3- Step 1. Preparation of methyl 1-isopropyl-4-vinyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C87) To a reaction mixture of C85 (1.00 g, 3.94 mmol), potassium vinyltrifluoroborate (CAS: 13682-77-4; 0.792 g, 5.91 mmol) and K3PO4 (2.09 g, 9.85 mmol) in dioxane (10.0 mL) and H2O (3.5 mL) was added Pd(dppf)Cl2 (0.288 g, 0.394 mmol). The suspension was degassed with nitrogen gas for 3 min and then stirred at 90oC for 2 h. The reaction mixture was filtered, and then the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated in vacuo. The yellow gum was purified by column chromatography (silica gel, 0-40% EtOAc: hexane) to provide C87 (0.700 g, 72.4% yield) as a light yellow solid. (LC / MS) m / z (M+H)+= 246.1.1H NMR (400 MHz, (CD3)2SO) δ 8.45 (d, 1H), 8.07 (dd, 1H), 7.79 (d, 1H), 6.51 (dd, 1H), 5.59 (dd, 1H), 5.19 – 5.08 (m, 1H), 3.93 (s, 3H), 1.50 (d, 6H). Step 2. Preparation of rac-methyl (4R)-4-ethyl-1-isopropyl-3a,4,5,6,7,7a-hexahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylate (P51) The reaction was carried out via flow chemistry. C87 (0.300 g, 1.22 mmol) was dissolved in MeOH (20 mL). The solution was pumped with a flow rate of 0.3 mL / min, and the H2 had a 30 mL / min rate. The solution passed through the fixed bed (1 / 4’’ mm) packed with granular catalyst 5% Ru / Al2O3 with a 5.0 mL volume and was hydrogenated at 60 °C via flow at 2.0 MPa H2. The reaction mixture was collected from the reactor output to provide P51 (0.280 g, crude) as a brown oil. The oil was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 252.0.1H NMR (400 MHz, (CD3)2SO) δ 9.75 (s, 1H), 9.23 (s, 1H), 4.59 – 4.50 (m, 1H), 3.78 (s, 3H), 3.07 – 2.89 (m, 2H), 2.45 – 2.41 (m, 2H), 2.00 – 1.75 (m, 2H), 1.35 (dd, 6H), 1.02 (t, 3H). Preparation 52 rac-Ethyl (6R,7R)-1-isopropyl-6,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxylate (P52) Step 1. Preparation of rac-benzyl (R)-2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (C88) To a round bottom flask was added 4-methoxypyridine (CAS: 620-08-6; 32.6 mL), THF (641.4 mL), and TEA (4.5 mL) sequentially. The solution was cooled to -78oC, and then 3M benzyl chloroformate in toluene (109.0 mL) was added dropwise to give a white slurry.3.4M methylmagnesium bromide solution (55.6 mL) dropwise was added to the suspension. The reaction mixture was stirred at -78oC and slowly warmed to room temperature over 24 h. The reaction mixture was cooled to 0oC and quenched via a portion-wise addition of 1M aqueous HCl. The aqueous mixture was extracted with DCM (3x). The organic layer was combined, then dried with Na2SO4and purified by column chromatography (silica gel, 0-50% EtOAc: heptane) to provide C88 (51.5 g, 65.5% yield) as a clear oil. (LC / MS) m / z (M+H)+= 246.4.1H NMR (400 MHz, (CD3)2SO) δ 7.78 (dd, 1H), 7.48 – 7.28 (m, 5H), 5.33 – 5.21 (m, 3H), 4.68 – 4.56 (m, 1H), 2.89 (dd, 1H), 2.24 – 2.14 (m, 1H), 1.15 (d, 3H). Step 2. Preparation of rac-benzyl (2R,3R)-2,3-dimethyl-4-oxo-3,4-dihydropyridine-1(2H)- carboxylate (C89) A reaction mixture of C88 (10.0 g, 40.8 mmol) in THF (102 mL) was cooled to -78oC, then 1M LiHMDS in THF (42.8 mL) was added dropwise and stirred at -78oC for 10 min. After stirring for a few min, MeI (3.1 mL) was added dropwise at -78oC to the reaction mixture and then warmed to room temperature over 30 min. The suspension was stirred at room temperature for 9 h and then quenched with brine. The pH of the aqueous layer was adjusted to pH = 1 using 12M aqueous HCl. The reaction mixture was extracted with EtOAc (2x), and the organic layers were combined and then dried with Na2SO4. The mixture was purified by column chromatography (silica gel, 0-40% MTBE: heptane) to provide C89 (7.80 g, 73.6% yield) as a yellow oil.1H NMR (400 MHz, CD3OD) δ 7.84 (dd, 1H), 7.47 – 7.32 (m, 5H), 5.36 – 5.20 (m, 3H), 4.40 (q, 1H), 2.27 (q, 1H), 1.21 (d, 3H), 1.15 (d, 3H). Step 3. Preparation of rac-benzyl (2R,3R)-2,3-dimethyl-4-oxopiperidine-1-carboxylate (C90) To a round bottom flask was added C89 (12.8 g, 49.4 mmol), AcOH (82.3 mL), and Zn (12.9 g, 197 mmol) sequentially, then stirred at 60oC for 5 h. The reaction mixture was concentrated in vacuo, then saturated NaHCO3 and extracted with DCM (3x). The combined organic layer was purified by column chromatography (silica gel, 0-50% EtOAc: heptane) to provide C90 (10.1 g, 78.3% yield) as a clear oil.1H NMR (400 MHz, (CD3)2SO) δ 7.44 – 7.28 (m, 5H), 5.17 – 5.06 (m, 2H), 4.13 (dd, 1H), 4.07 – 3.96 (m, 1H), 3.53 – 3.41 (m, 1H), 2.57 – 2.44 (m, 2H), 2.33 – 2.23 (m, 1H), 1.21 (d, 3H), 1.05 (d, 3H). Step 4. Preparation of rac-benzyl (2R,3R,5R)-5-(2-ethoxy-2-oxoacetyl)-2,3-dimethyl-4- oxopiperidine-1-carboxylate (C91) A reaction mixture of C90 (0.430 g, 1.65 mmol), EtOH (3.29 mL), and diethyl oxalate (0.24 mL) was cooled to -78oC, then 1M LiHMDS in THF (1.89 mL) was added. The suspension was stirred at room temperature for 17 h and then quenched with a mixture of 1M aqueous HCl, brine, and DCM. The aqueous layer was extracted with (2:1, MTBE: DCM, 2x). The organic layers were combined and then dried with Na2SO4and concentrated in vacuo to provide C91 (0.590 g, crude) as a yellow oil. The oil was used directly in the next step without further purification. Step 5. Preparation of rac-5-benzyl 3-ethyl (6R,7R)-1-isopropyl-6,7-dimethyl-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C92) A reaction mixture of C91 (0.590 g, 1.63 mmol), KHPO4(0.311 g, 2.29 mmol) and isopropylhydrazine HCl (217 mg, 1.96 mmol) in EtOH (2.7 mL) and H2O (2.7 mL) was stirred at 60oC for 2.5 h then stirred at room temperature for 24 h. The suspension was diluted with H2O and then extracted with DCM (3x). The organic layers were combined and then purified with column chromatography (silica gel, 0-60% EtOAc: heptane) to provide C92 (0.322 g, 49.4% yield) as a clear oil. Step 6. Preparation of rac-ethyl (6R,7R)-1-isopropyl-6,7-dimethyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylate (P52) In a reactor was added Pd / C (10 wt%, 0.213 g, 2.00 mmol) in EtOH (1 mL), then added solution of C92 (0.800 g, 2.00 mmol) in EtOH (5 mL). The suspension was degassed with hydrogen gas and then stirred under a hydrogen atmosphere (120 psi) at room temperature for 1 h. The reaction mixture was filtered through Celite and then washed with tert-amyl alcohol. The filtrate was concentrated in vacuo to provide P52 (0.531 g, crude) as a yellow oil. The oil was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) δ 4.57 – 4.46 (m, 1H), 4.23 (q, 2H), 3.82 – 3.68 (m, 2H), 2.84 – 2.74 (m, 1H), 2.62 – 2.55 (m, 1H), 1.43 (d, 3H), 1.39 – 1.31 (m, 6H), 1.22 – 1.18 (m, 3H), 1.05 – 1.01 (m, 3H). Preparation 53 rac-Ethyl (R)-3-isopropyl-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate Step 1. Preparation of ethyl 5-methylimidazo[1,5-a]pyrazine-1-carboxylate (C14a) To a mixture of 2-chloro-6-methylpyrazine (CAS: 38557-71-0, 10.0 g, 77.8 mmol) in DMF (150.0 mL) was added Cs2CO3 (38.0 g, 117 mmol) and ethyl 2-isocyanoacetate (CAS: 2999-46-4, 17.8 g, 156 mmol) at 15 °C. The reaction was heated to 85 °C for 16 h, then diluted with EtOAc (300 mL). The light brown reaction mixture was filtered, and the filtrate was concentrated in vacuo. The brown residue was diluted with (1:1, EtOAc: THF) and filtered. The filter cake was dissolved in (1:1, H2O: EtOAc) and then extracted with EtOAc (150 mL). The combined organic phase was dried with Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100% EtOAC: PE) to provide C14a (7.71 g, 48.3% yield) as a light-brown solid. (LC / MS) m / z (M+H)+= 206.1.1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.16 (s, 1H), 7.66 (s, 1H), 4.52 (q, 2H), 2.65 (s, 3H), 1.48 (t, 3H). Step 2. Preparation of rac-ethyl (R)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1- carboxylate acetate (C93) The reaction was carried out via flow chemistry. C14a (7.71 g, 37.6 mmol) was dissolved in THF (155 mL) and AcOH (40 mL) and then was pumped with a flow rate of 0.3 mL / min, and the H2 had a rate of 30 mL / min. The solution passed through the fixed bed ((1 / 4’’) mm) packed with granular catalyst 10% Ru / SiO2 (2.80 g, 2.76 mmol) with a 5.0 mL volume and was hydrogenated for 3.3 min at 80 °C via flow at 2.5 MPa H2. The flow rate of H2 was 100 mL / min. The reaction mixture was collected after 10 min and then concentrated in vacuo to remove THF. The suspension was stirred for 1-2 h and then filtered. The filtrate was concentrated in vacuo to provide C93 (5.50 g, crude) as a light-brown oil. The oil was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 210.1. Step 3. Preparation of rac-7-(tert-butyl) 1-ethyl (R)-5-methyl-5,6-dihydroimidazo[1,5-a]pyrazine- 1,7(8H)-dicarboxylate (C94) To a solution of C93 (7.50 g, 19.3 mmol) in ACN (100 mL) was added Boc2O (6.31 g, 28.9 mmol) and K2CO3(10.7 g, 77.1 mmol) at room temperature. The reaction was stirred at room temperature for 16 h and then diluted with EtOAc (100 mL). The suspension was filtered then the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel; 0-100% EtOAc: PE) to provide C94 (5.30 g, 93.1% yield) as an off- white solid. (LC / MS) m / z (M+H)+= 310.2.1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 4.96 – 4.78 (m, 2H), 4.41 – 4.22 (m, 3H), 3.95 – 3.90 (m, 1H), 3.48 – 3.43 (m, 1H), 1.55 – 1.49 (m, 12H), 1.39 (t, 3H). Step 4. Preparation of rac-7-(tert-butyl) 1-ethyl (R)-3-bromo-5-methyl-5,6-dihydroimidazo[1,5- a]pyrazine-1,7(8H)-dicarboxylate (C95) To a solution of C94 (3.20 g, 10.8 mmol) in ACN (30.0 mL) was added a solution of NBS (2.89 g, 16.3 mmol) in ACN (20.0mL). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-40% EtOAc: PE) to provide C95 (2.57 g, 64.0% yield) as a white solid. (LC / MS) m / z (M+2H)+= 390.0.1H NMR (400 MHz, CDCl3) δ 5.59 – 5.25 (m, 1H), 4.51 – 4.25 (m, 5H), 3.40 – 3.12 (m, 1H), 1.51 (s, 9H), 1.45 – 1.29 (m, 6H). Step 5. Preparation of rac-7-(tert-butyl) 1-ethyl (R)-3-isopropyl-5-methyl-5,6-dihydroimidazo[1,5- a]pyrazine-1,7(8H)-dicarboxylate (C96) A solution of C95 (1.00 g, 2.58 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2- dioxaborolane (CAS: 126726-62-3, 0.779 g, 4.64 mmol), NaHCO3 (0.649 g, 7.73 mmol), cataCXium® A (0.185 g, 0.515 mmol) and Pd(OAc)2(57.8 mg, 0.258 mmol) in (4:1) DME: H2O (16 mL: 4 mL) was degassed with nitrogen gas for 5 min. The reaction solution was stirred at 80oC for 15 h, then filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-35% EtOAc: PE) to provide C96 (0.810 g, 90.0% yield) as a gum. (LC / MS) m / z (M+H)+= 350.2.1H NMR (400 MHz, (CD3)2SO) δ 5.49 – 5.38 (m, 2H), 5.26 – 5.05 (m, 1H), 4.79 – 4.65 (m, 1H), 4.58 – 4.36 (m, 1H), 4.33 – 3.97 (m, 4H), 2.10 – 2.06 (m, 3H), 1.43 (s, 9H), 1.31 – 1.24 (m, 3H), 1.23 – 1.16 (m, 3H). Step 6. Preparation of rac-7-(tert-butyl) 1-ethyl (R)-5-methyl-3-(prop-1-en-2-yl)-5,6- dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (C97) To a solution of C96 (0.810 g, 2.32 mmol) in EtOH were added ammonium formate (2.19 g, 34.8 mmol) and Pd / C (0.370 g, 0.348 mmol). The reaction mixture was stirred at 60oC under argon gas for 1 h and then filtered through celite. The filter cake was washed with EtOH (3 x 30 mL). The filtrate was concentrated in vacuo and then dissolved in DCM (50 mL). The solution was washed with brine (3 x 50 mL). The organic layer was concentrated in vacuo to provide C97 (0.715 g, crude). The crude was used directly into the next step without further purification. (LC / MS) m / z (M+H)+= 352.2. Step 7. Preparation of rac-ethyl (R)-3-isopropyl-5-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazine-1-carboxylate hydrochloride (P53) To a solution of C97 (0.715 g, 2.03 mmol) in DCM (10 mL) was added 2M HCl in dioxane (20 mL). The reaction mixture was stirred for 2 h at room temperature, then concentrated in vacuo and lyophilized to provide P53 (0.710 g, crude) as a gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 252.2. Example 1 N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7- 1H- 3-carboxamide Step 1. Preparation of ethyl 5-(5-iodopyridin-2-yl)-1-isopropyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylate (C98) A mixture of P2 (1.36 g, 4.98 mmol), 2-fluoro-5-iodopyridine (CAS: 171197-80-1, 1.22 g, 5.48 mmol), and DIEA (1.93 g, 14.9 mmol) in DMF (25.0 mL) was stirred at 130 °C for 16 h. The brown reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel, 0- 20% EtOAc: PE) to provide C98 (0.61 g, 27.8%) as a white solid. (LC / MS) m / z (M+H)+= 441.2.1H NMR (400 MHz, CDCl3) δ 8.32- 8.31 (m, 1H), 7.68 (dd, 1H), 6.58 (d, 1H), 4.60 (s, 2H), 4.52- 4.38 (m, 3H), 4.03 (t, 2H), 2.80 (t, 2H), 1.52 (d, 6H), 1.44-1.40 (m, 3H). Step 2. Preparation of ethyl 1-isopropyl-5-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C99) A mixture of C98 (0.400 g, 0.909 mmol), pyrrolidine-2-one (0.116 g, 1.36 mmol), CuI (34.6 mg, 0.182 mmol), DMEDA (16.0 mg, 0.182 mmol) and K2CO3(0.377 g, 2.73 mmol) in dioxane (10.0 mL) was heated at 120 °C for 16 h under nitrogen. The reaction was concentrated in vacuo, and then the residue was purified by column chromatography (silica gel, 0-30% THF:PE) to provide C99 (0.36 g, 99.7% yield) as a white solid. (LC / MS) m / z (M+H)+= 398.2. Step 3. Preparation of 1-isopropyl-5-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylic acid (C100) To a solution of C99 (0.360 g, 0.906 mmol) in THF (5.00 mL), MeOH (1.25 mL) and H2O (2.50 mL) was added LiOH (57.5 mg, 2.40 mmol) then stirred at room temperature for 1 h and 30 min. The solution was concentrated in vacuo and then acidified to pH=5-6 with 2N HCl. An off-white solid precipitated was filtered, then washed with H2O (3 x 50 mL), dried, then lyophilized to provide C100 (0.27 g, 80.7%) as a white solid.1H NMR (400 MHz, CD3OD) δ 8.29 (d, 1H), 7.82 (dd, 1H), 6.91 (d, 1H), 4.67 (s, 2H), 4.60- 6.45 (m, 1H), 3.96 (t, 2H), 3.88- 3.83 (m, 2H), 2.86 (t, 2H), 2.60- 2.52 (m, 2H), 2.24 – 2.13 (m, 2H), 1.47 (d, 6H). Step 4. Preparation of N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidin-1- yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (1) A solution of C100 (80.0 mg, 0.217 mmol), HOPO (71.0 mg, 0.639 mmol), EDCI (99.6 mg, 0.520 mmol) and DIEA (0.140 g, 1.08 mmol) in DMSO (2.0 mL) were stirred at room temperature for 10 min. to the reaction mixture was added P11 (74.6 mg, 0.325 mmol) then heated to 40 °C and stirred for 2 h. The residue was purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm column, Mobile Phase A: H2O / Mobile Phase B: ACN (NH4OH-NH4HCO3), 18 to 58% of Mobile Phase B over 9 min, 100% of Mobile Phase B hold 2 min, flow rate: 30 mL / min) and lyophilized to provide 1 (72.2 mg, 61.2% yield) as a white solid. (LC / MS) m / z (M+H)+= 545.4.1H NMR (400 MHz, (CD3)2SO) δ 8.33- 8.27 (m, 2H), 8.23 (s, 1H), 7.89 (dd, 1H), 7.42 – 7.37 (m, 2H), 7.20- 7.15 (m, 2H), 6.90 (d, 1H), 4.65 (s, 2H), 4.53- 4.42 (m, 1H), 4.35 (d, 2H), 3.87 (t, 2H), 3.76 (t, 2H), 2.91 (s, 6H), 2.80 (t, 2H), 2.43 (t, 2H), 2.10- 2.00 (m, 2H), 1.39 (d, 6H). Example 2 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (2) Step 1. Preparation of ethyl 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-isopropyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C101) To a mixture of P2 (70.0 g, 256 mmol) and CsF (97.1 g, 639 mmol) in DMSO (0.7 L) was added 6-fluoro-N,N-dimethylnicotinamide (CAS: 1032251-82-3, 57.3 g, 256 mmol). The reaction was stirred at 130 °C for 8 h. The reaction was diluted with H2O (6 L) and then extracted with MeOH: DCM (1:10, 3 x 2 L). The combined organic layer was washed with brine (2 x 3 L), dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100% EtOAc: PE) to provide C101 (72.0 g, 73.1% yield) as a pale yellow solid. (LC / MS) m / z (M+H)+= 386.2.1H NMR (600 MHz, (CD3)2SO) δ 8.25 (d, 1H), 7.65 (dd, 1H), 6.91 (d, 1H), 4.74 (s, 2H), 4.58-4.47 (m, 1H), 4.30 (q, 2H), 3.96 (t, 2H), 2.97 (s, 6H), 2.83 (t, 2H), 1.38 (d, 6H), 1.32 (t, 3H). Step 2. Preparation of 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-isopropyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylic acid (C102) The reaction was conducted in two batches then combined for purification. At room temperature under nitrogen, a mixture of C101 (42.0 g, 109 mmol) in ACN (420 mL) was added KOTMS (28.0 g, 218 mmol) then stirred at room temperature for 1 h to afford the first batch. The first batch was acidified with 2M HCl in dioxane (109 mL, 7.95 g, 218 mmol) to pH= 5-6 then concentrated in vacuo. The first batch's residue was combined with the second batch of the same reaction utilizing C101 (43.0 g, 112 mmol). The combined reaction mixture was diluted with brine (500 mL) and extracted with MeOH: DCM (1:10, 3 x 1 L). The combined organic layers were dried with Na2SO4, filtered, and then concentrated in vacuo to provide C102 (66.0 g, 83.7% yield) as a white solid. This was used in the next step without further purification.1H NMR (600 MHz, (CD3)2SO) δ 8.24 (d, 1H), 7.63 (dd, 1H), 6.92 (d, 1H), 4.70 (s, 2H), 4.54 – 4.37 (m, 1H), 3.94 (t, 2H), 2.97 (s, 6H), 2.79 (t, 2H), 1.37 (t, 6H). Step 3. Preparation of 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1- isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (2) To C102 (70 mg, 0.20 mmol) dissolved in ACN (1.0 mL) and H2O (0.1 mL) was added HOPO (26 mg, 0.24 mmol) and EDCI (60 mg, 0.31 mmol). The reaction was stirred for 20 min at 50 °C and then cooled to room temperature before DIEA (76 mg, 0.59 mmol) and P11 (54 mg, 0.24 mmol) were added to the reaction. The mixture was stirred at room temperature for 1 h and 20 min. The reaction was concentrated in vacuo, dissolved in DMSO, and acidified by TFA. The acidic residue was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm column, Mobile Phase A: H2O / Mobile Phase B: ACN (0.05% TFA), 15 to 95% of Mobile Phase B over 9.0 min, 95% of Mobile Phase B hold 1.0 min, flow rate: 25 mL / min) to provide 2 (30 mg, 25% yield). (LC / MS) m / z (M+H)+= 533.4.^1H NMR (600 MHz, (CD3)2SO) δ = 8.27 (t, 1H), 8.18 – 8.12 (m, 2H), 7.58 (dd, 1H), 7.34 – 7.30 (m, 2H), 7.11 (d, 2H), 6.84 (d, 1H), 4.68 (s, 2H), 4.45- 4.38 (m, 1H), 4.28 (d, 2H), 3.89 (t, 2H), 2.93-2.88 (m, 6H), 2.84 (s, 6H), 2.76 (t, 2H), 1.33 (d, 6H).^^^^ Example 3 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-ethyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (3) Step 1. Preparation of ethyl 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylate (C103) To a mixture of ethyl 1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (prepared using similar methods to Preparation 1, 0.350 g, 1.35 mmol) in butyronitrile (5.0 mL) and DIEA (0.697 g, 5.39 mmol) was added 6-fluoro-N,N- dimethylnicotinamide (CAS: 1032251-82-3, 0.249 g, 1.48 mmol) and reaction heated at 115 °C for 17 h. The solution was concentrated in vacuo, then redissolved in DCM, and purified by column chromatography (silica gel, 0-5% MeOH: DCM) to provide C103 (0.209 g, 41.7% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 372.4.^1H NMR (600 MHz, (CD3)2SO) δ 8.23 (d, 1H), 7.64 (dd, 1H), 6.91 (d, 1H), 4.73 (s, 2H), 4.28 (q, 2H), 4.09 (q, 2H), 3.95 (t, 2H), 2.96 (s, 6H), 2.81 (t, 2H), 1.34-1.28 (m, 6H). Step 2. Preparation of 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1-ethyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylic acid (C104) To C103 (0.250 g, 0.673 mmol) in THF (2.0 mL), H2O (2.0 mL), MeOH (0.2 mL) was added LiOH (80.6 mg, 3.37 mmol) at 15 °C. The reaction was heated to 40 °C and stirred for 1 h. The reaction was concentrated in vacuo to remove the organic layer, and the aqueous layer was acidified to pH= 3 by 2N HCl. The acidic aqueous phase was concentrated in vacuo then purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm column, Mobile Phase A: H2O / Mobile Phase B: ACN (0.05% formic acid), 0 to 32% of Mobile Phase B over 9 min, 100% then Mobile Phase B hold 2 min, flow rate: 30 mL / min) and lyophilized to provide C104 (0.150 g, 64.9% yield) as a white solid. (LC / MS) m / z (M+H)+= 344.3.1H NMR (400 MHz, CD3OD) δ 8.31 – 8.25 (m, 1H), 7.68 (dd, 1H), 6.91 (d, 1H), 4.77 (s, 2H), 4.15 (q, 2H), 4.06 (t, 2H), 3.09 (s, 6H), 2.86 (t, 2H), 1.40 (t, 3H). Step 3. Preparation of 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1- ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (3) The reaction was conducted in two batches and then combined for purification. To a solution of C104 (0.100 g, 0.291 mmol) in DMSO (3.0 mL) was added HOPO (97.1 mg, 0.874 mmol), DIEA (0.188 g, 1.46 mmol), and EDCI (0.134 g, 0.699 mmol) to form the first batch. The reaction mixture of the first batch was stirred at 40 °C for 15 min before P11 (73.6 mg, 0.320 mmol) was added. The suspension of the first batch was stirred at 40 °C for 2 h. The reaction mixture of the first batch was combined with a second batch of the same reaction utilizing C104 (0.563 g, 1.64 mmol). The combined reaction was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 µm column, Mobile Phase A: H2O / Mobile Phase B: ACN (NH4OH-NH4HCO3), 3 to 43% of Mobile Phase B over 9 min, 100% of Mobile Phase B hold 2 min, flow rate: 60 mL / min) and lyophilized to provide 3 (0.467 g, 46.7% yield). (LC / MS) m / z (M+H)+= 519.3.^1H NMR (400 MHz, CDCl3) δ 8.32 (d, 1H), 7.62 (dd, 1H), 7.35 (d, 2H), 7.31- 7.27 (m, 2H), 7.09 (t, 1H), 6.77 (d, 1H), 6.31 (s, 1H), 4.75 (s, 2H), 4.55 (d, 2H), 4.15 (t, 2H), 4.03 (q, 2H), 3.08 (s, 6H), 3.03 (s, 6H), 2.81 – 2.74 (m, 2H), 1.40 (t, 3H). Example 4 5-(4-(Dimethylcarbamoyl)phenyl)-1-methyl-N-(4-(methylcarbamoyl)benzyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridine-3-carboxamide (4) Step 1. Preparation of ethyl 5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylate (C105) The reaction was conducted in two batches and then combined for purification. To a solution of^P4 (50.0 mg, 0.239 mmol)^and 4-bromo-N,N-dimethylbenzamide (CAS: 18469-37-9, 54.5 mg, 0.239 mmol) in dioxane (3.0 mL) was added RuPhos (11.2 mg, 0.0239 mmol), RuPhos Pd G3 (20.0 mg, 0.0239 mmol) and NaOtBu (45.9 mg, 0.478 mmol) at room temperature to form the first batch. The reaction mixture of the first batch was degassed with nitrogen for 1 min and heated at 115 °C for 20 h. The first batch's reaction mixture was combined with the second batch of the same reaction utilizing P4 (0.400 g, 1.91 mmol). The combined reaction was purified by HPLC (C18150 mm x 30 mm x 5 µm column, Mobile Phase A: H2O / Mobile Phase B: ACN (0.05% NH4OH- NH4HCO3), 6 to 46% of Mobile Phase B over 9 min, 100% of Mobile Phase B hold 2 min, flow rate: 30 mL / min) and lyophilized to provide C105 (50.0 mg, 6.53% yield) as a white solid. (LC / MS) m / z (M+H)+= 357.2. Step 2. Preparation of 5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-c]pyridine-3-carboxylic acid hydrochloride (C106) To a solution of^C105 (50.0 mg, 0.140 mmol) in THF (3.0 mL) and H2O (0.5 mL)^was added LiOH (17.7 mg, 0.421 mmol) at room temperature and then stirred at 40 °C for 16 h. The reaction was concentrated in vacuo, washed with H2O (2 x 10 mL), and then acidified with 2M HCl until pH= 5-6; the resulting solid was filtered to provide C106 (46.0 mg, 89.8% yield) as a white solid. This was used in the next step without further purification. (LC / MS) m / z (M+H)+= 329.2. Step 3. Preparation of 5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-N-(4- (methylcarbamoyl)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (4) To a solution of^C106 (46.0 mg, 0.140 mmol) in DMF (5.0 mL) was added HATU (79.9 mg, 0.210 mmol), DIEA (54.3 mg, 0.420 mmol), and 4-(aminomethyl)-N-methylbenzamide hydrochloride (CAS: 1158467-80-1, 28.1 mg, 0.140 mmol). The reaction was stirred at room temperature for 12 h. The residue was purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm, Mobile Phase A: H2O / Mobile Phase B: ACN (0.05% formic acid), 8 to 33% of Mobile Phase B over 9 min, 100% of Mobile Phase B hold 2 min, flow rate: 30 mL / min) and lyophilized to provide an impure 4 (25.0 mg) as a white solid. The solid was re-purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm, Mobile Phase A: H2O / Mobile Phase B: ACN (0.05% NH4OH-NH4HCO3), 4 to 44% of Mobile Phase B over 9 min, 100% of Mobile Phase B hold 2 min, flow rate: 30 mL / min) and lyophilized to provide 4 (12.8 mg, 19.3% yield) as a white solid. (LC / MS) m / z (M+H)+= 475.2.^1H NMR (400 MHz, CD3OD) δ 7.80 – 7.74 (m, 2H), 7.46 – 7.42 (m, 2H), 7.38 – 7.33 (m, 2H), 7.08 – 7.02 (m, 2H), 4.60 (s, 2H), 4.50 (s, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 3.06 (s, 6H), 2.91 (s, 3H), 2.84 (t, 2H). Example 5 7-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-3-methyl-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (5) Step 1. Preparation of methyl 3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (C107) To a solution of 7-(tert-butyl) 1-methyl 3-methyl-5,6-dihydroimidazo[1,5-a]pyrazine- 1,7(8H)-dicarboxylate (CAS: 1359655-89-2, 0.190 g, 0.643 mmol) in DCM (5.0 mL) was added 2M HCl in EtOAc (5.0 mL) at 10 °C.^The reaction mixture was stirred at room temperature for 16 h. The resulting white suspension was concentrated in vacuo to provide the C107 (0.149 g, crude) as a white solid. This was used in the next step without further purification.1H NMR (400 MHz, CD3OD) δ 4.80 (s, 2H), 4.51 (t, 2H), 4.00 (s, 3H), 3.84 (t, 2H), 2.71 (s, 3H). Step 2. Preparation of methyl 7-(5-(tert-butoxycarbonyl)pyridin-2-yl)-3-methyl-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (C108) A mixture of C107 (90.0 mg, 0.388 mmol),^tert-butyl 6-fluoronicotinate (CAS: 676560-01- 3, 152 mg, 0.777 mmol), and DIEA (251 mg, 1.94 mmol) in DMF (4.0 mL) was stirred at 120 °C for 5 h. The light brown reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, 0-100% EtOAc: PE) to provide C108 (87.0 mg, 60.0% yield) as an off-white solid. (LC / MS) m / z (M+H)+= 373.1.1H NMR (400 MHz, CDCl3) δ 8.80- 8.78 (m, 1H), 8.08 (dd, 1H), 6.75 (d, 1H), 5.00 (s, 2H), 4.31 (t, 2H), 4.02 (t, 2H), 3.93 (s, 3H), 2.43 (s, 3H), 1.58 (s, 9H). Step 3. Preparation of 6-(1-(methoxycarbonyl)-3-methyl-5,6-dihydroimidazo[1,5-a]pyrazin- 7(8H)-yl)nicotinic acid hydrochloride (C109) To a solution of C108 (87.0 mg, 0.234 mmol) in DCM (2.0 mL) and 2M HCl in dioxane (2.0 mL) was added H2O (0.1 mL), then the reaction was stirred for 6 h at room temperature.^The light-yellow reaction was concentrated in vacuo and then dried under high vacuum for 3 h to provide C109 (73.9 mg, crude) as a light brown residue. This was used in the next step without further purification. (LC / MS) m / z (M+H)+= 317.1.^ Step 4. Preparation of methyl 7-(5-(dimethylcarbamoyl)pyridin-2-yl)-3-methyl-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (C110) To a solution of C109 (73.0 mg, 0.231 mmol) in DMF (5.0 mL) was added HATU (0.132 g, 0.346 mmol), DIEA (0.149 g, 1.15 mmol), and dimethylamine hydrochloride (CAS: 506-59-2; 28.2 mg, 0.346 mmol) at room temperature. The mixture was stirred at room temperature for 4 h, then heated to 30 °C and stirred for 16 h. The reaction mixture was concentrated in vacuo then the residue was purified by column chromatography (silica gel, 0-100% PE: EtOAc to 3.3% MeOH: DCM to provide C110 (71.0 mg, 78.9% yield) as an off-white solid. Step 5. Preparation of 7-(5-(dimethylcarbamoyl)pyridin-2-yl)-3-methyl-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (C111) To a solution of^C110 (71.0 mg, 0.207 mmol) in THF (5.0 mL), MeOH (0.5 mL), H2O (1.0 mL) was added LiOH (15.5 mg, 0.369 mmol) at room temperature.^The reaction was stirred at 40 °C for 4 h and then acidified with formic acid to pH= 5. The resulting mixture was concentrated in vacuo and then purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm column, Mobile Phase A: H2O / Mobile Phase B: ACN (0.05% formic acid), 0 to 16% of Mobile Phase B over 9 min, 100% of Mobile Phase B hold 2 min, flow rate: 30 mL / min) and lyophilized to provide C111 (41.0 mg, 60.2% yield) as a white solid. (LC / MS) m / z (M+H)+= 330.1.^ Step 6. Preparation of 7-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-3- methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (5) A mixture of C111 (40.0 mg, 0.121 mmol), HOPO (40.5 mg, 0.364 mmol), EDCI (55.9 mg, 0.291 mmol), and DIEA (78.5 mg, 0.607 mmol) in DMSO (2.0 mL) was stirred at room temperature for 20 min. P11 (30.7 mg, 0.134 mmol) was added, and the light brown reaction mixture was stirred at 30 °C for 3 h and 30 min. The residue was purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm column, Mobile Phase A: H2O / Mobile Phase B: ACN (0.05% formic acid), 0 to 36% of Mobile Phase B over 9 min, 100% of Mobile Phase B hold 2 min, flow rate: 30 mL / min) and lyophilized to provide 5 (28.4 mg, 46.4% yield) as a white solid. (LC / MS) m / z (M+H)+= 505.4.^1H NMR (400 MHz, (CD3)2SO) δ 8.29- 8.26 (m, 1H), 8.21- 8.15 (m, 2H), 7.69 (dd, 1H), 7.40– 7.35 (m, 2H), 7.17- 7.13 (m, 2H), 6.95 (d, 1H), 5.02 (s, 2H), 4.32 (d, 2H), 4.09– 3.98 (m, 4H), 2.97 (s, 6H), 2.90 (s, 6H), 2.28 (s, 3H). Example 6 rac-(R)-5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1,7-dimethyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (6) Step 1: Preparation of rac-ethyl (R)-5-(5-(tert-butoxycarbonyl)pyridin-2-yl)-1,7-dimethyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C112) To a solution of P6 (0.426 g, 1.64 mmol), tert-butyl 6-fluoronicotinate (CAS: 676560-01- 3, 0.356 g, 1.80 mmol) in DMSO (3.4 mL) was added DIEA (1.06 g, 8.20 mmol). The reaction mixture was stirred at 60 °C for 16 h, poured into H2O (60 mL), and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, 0-100% EtOAc: heptane) to provide C112 (0.566 g, 86.2% yield) as a white crystal solid. (LC / MS) m / z (M+H)+= 401.40.1H NMR (400 MHz, CDCl3) δ 8.77 (dd, 1H), 8.01 (dd, 1H), 6.69 (dd, 1H), 4.95 (d, 1H), 4.72 (dd, 1H), 4.50 – 4.36 (m, 3H), 3.89 (s, 3H), 3.46 (dd, 1H), 3.13- 3.05 (m, 1H), 1.57 (s, 9H), 1.43 (t, 3H), 1.28 (d, 3H). Step 2: Preparation of rac-(R)-6-(3-(ethoxycarbonyl)-1,7-dimethyl-1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-5-yl)nicotinic acid (C113) TFA (2.81 g, 24.7 mmol) was added to a stirred solution of C112 (0.353 g, 0.881 mmol) in DCM (8.0 mL). The reaction was stirred at room temperature for 4 h and then concentrated in vacuo. The resulting gum was sonicated with heptane to yield a solid. The solvent was concentrated in vacuo then the white solid was dissolved in EtOAc and concentrated in vacuo to provide C113 (0.304 g, crude) as an off-white solid. This was used in the next step without further purification. (LC / MS) m / z (M+H)+= 345.40. Step 3: Preparation of rac-ethyl (R)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1,7-dimethyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C114) A mixture of C113 (0.304 g, 0.883 mmol), dimethylamine hydrochloride (CAS: 506-59-2; 86.4 mg, 1.06 mmol), HATU (0.369 g, 0.971 mmol), and DIEA (0.342 g, 2.65 mmol) in DMF (1.2 mL) was stirred at room temperature for 4 h. The reaction mixture was quenched with H2O (30 mL) and extracted with MeOH in DCM (1:9; 4 x 100 mL). The combined organic layer was dried over Na2SO4and then concentrated in vacuo. The residue was purified twice by column chromatography. The first purification was by column chromatography (silica gel, 0-100% EtOAc: heptane), and the second purification was by column chromatography (silica gel, 0-15% MeOH: DCM) to provide C114 (0.208 g, 63.4% yield) as a white solid. (LC / MS) m / z (M+H)+= 372.40.1H NMR (400 MHz, CDCl3) δ 8.32-8.30 (m, 1H), 7.65 (dd, 1H), 6.74 (d, 1H), 4.92 (d, 1H), 4.58 (dd, 1H), 4.46 – 4.35 (m, 3H), 3.90- 3.86 (m, 3H), 3.74 – 3.64 (m, 1H), 3.46 (dd, 1H), 3.09 (s, 6H), 1.44 – 1.38 (m, 3H), 1.29 (d, 3H). Step 4: Preparation of rac-(R)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-1,7-dimethyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (C115) A flask was charged with C114 (0.106 g, 0.285 mmol), EtOH (2.3 mL), H2O (0.9 mL), and LiOH (85.5 mg, 1.14 mmol) and then heated to 50 °C. The reaction mixture became a solution and was stirred at 50 °C for 1 h and 40 min. The reaction was acidified with 12.1M HCl (0.123 g, 3.37 mmol) then concentrated in vacuo and dried further under high vacuum to provide C115 (0.110 g, crude) as a white solid. This was used in the next step without further purification. (LC / MS) m / z (M+H)+= 344.40. Step 5: Preparation of rac-(R)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3- dimethylureido)benzyl)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxamide (6) To a solution of C115 (0.110 g, 0.348 mmol) in ACN (1.7 mL) was added HOPO (46.4 mg, 0.417 mmol) and EDCI (0.233 g, 1.22 mmol). The reaction was heated to 50 °C and stirred for 2 h and 20 min. The solution was cooled to room temperature, and DIEA (0.180 g, 1.39 mmol) was added to give a clear yellow solution. P11 (87.9 mg, 0.383 mmol) was added to the reaction and stirred for 1 h at room temperature. The reaction was concentrated in vacuo to give an oil, then dissolved in DCM for purification by column chromatography (silica gel, 0-20% MeOH: DCM) to give an impure 6 (65.0 mg) as a yellow oil. The yellow oil was purified again by reverse phase HPLC (Prep PG-45 MOD10 column, Mobile Phase A: H2O with 2% ACN / Mobile Phase B: ACN, 5 to 60% of Mobile Phase B over 20 min, 95% of Mobile Phase B hold 5 min, flow rate: 30 mL / min) to provide 6 (34.6 mg, 19.2% yield). (LC / MS) m / z (M+H)+= 519.2.1H NMR (400 MHz, CDCl3) δ 8.31 (d, 1H), 7.62 (dd, 1H), 7.37 – 7.32 (m, 2H), 7.28 – 7.24 (m, 2H), 7.08 (t, 1H), 6.76 (d, 1H), 6.39 (s, 1H), 4.93 (d, 1H), 4.65 – 4.43 (m, 5H), 3.79 (s, 3H), 3.47 (dd, 1H), 3.08 (s, 6H), 3.02 (s, 6H), 1.28 (d, 3H). Examples 7 and 8 rel-(R or S)-5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1,7- dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (7) and (8) Step 1. Preparation of rel-(R or S)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3- dimethylureido)benzyl)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxamide (7) and (8) Chiral SFC purification of compound 6 (44 mg, 0.085 mmol) [Column: Phenomenex Cellulose-1250 mm x 10 mm x 5 µm; Mobile phase: 60% CO2 / 40% (1:1 MeOH / ACN); flow rate: 25 mL / min; backpressure: 100 bar; column temperature: 40oC] provided the first eluting isomer as 7 (4.887 min, 22 mg, 50% yield, 100% ee): (LC / MS) m / z (M+H)+= 519.3 and the second eluting isomer as 8 (5.377 min, 22 mg, 50% yield, 100% ee): (LC / MS) m / z (M+H)+= 519.4. Example 9 rac-(R)-7-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-3,5-dimethyl- 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide formate (9)

[0004] Step 1: Preparation of rac-methyl (R)-7-(5-(tert-butoxycarbonyl)pyridin-2-yl)-3,5-dimethyl- 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (C116) A mixture of P7 (0.111 g, 0.452 mmol), tert-butyl 6-fluoronicotinate (CAS: 676560-01-3, 0.223 g, 1.13 mmol), and DIEA (0.292 g, 2.26 mmol) in DMF (5.0 mL) was stirred at 140 °C for 2 h. The light brown reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100% EtOAc: PE then 2% MeOH: EtOAc) to provide C116 (45.0 mg, 25.7% yield) as a light brown solid. (LC / MS) m / z (M+H)+= 387.1. Step 2. Preparation of rac-(R)-6-(1-(methoxycarbonyl)-3,5-dimethyl-5,6-dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)nicotinic acid hydrochloride (C117) To a solution of C116 (45.0 mg, 0.116 mmol) in DCM (3.0 mL) and 2M HCl in dioxane (10.0 mL) was added H2O (0.02 mL) at room temperature. The reaction was stirred at 40 °C for 2 h and then concentrated in vacuo to provide C117 (42.7 mg, crude) as an off-white solid. This was used in the next step without further purification. (LC / MS) m / z (M+H)+= 331.1. Step 3. Preparation of rac-methyl (R)-7-(5-(dimethylcarbamoyl)pyridin-2-yl)-3,5-dimethyl- 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (C118) The reaction was conducted in three batches and then combined for purification. To a solution of C117 (53.0 mg, 0.144 mmol) in DMF (3.0 mL) was added HATU (82.4 mg, 0.217 mmol), DIEA (93.4 mg, 0.722 mmol) and dimethylamine hydrochloride (CAS: 506-59-2; 17.7 mg, 0.217 mmol) at room temperature and then heated to 40 °C and stirred for 16 h. The light brown reaction of the first batch was combined with the second batch of the same reaction utilizing C117 (42.0 mg, 0.116 mmol) and the third batch of the same reaction utilizing C117 (70.0 mg, 0.191 mmol). The combined reaction was concentrated in vacuo then purified by column chromatography (silica gel; 0-100% EtOAc: PE then 2.5% MeOH: EtOAc) to provide C118 (75.0 mg, 41.9% yield) as a light brown solid. (LC / MS) m / z (M+H)+= 358.1. Step 4. Preparation of rac-(R)-7-(5-(dimethylcarbamoyl)pyridin-2-yl)-3,5-dimethyl-5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (C119) The reaction was conducted in two batches and then combined for purification. To a solution of C118 (75.0 mg, 0.210 mmol) in THF (4.0 mL), MeOH (1.0 mL), and H2O (2.0 mL) was added LiOH (17.6 mg, 0.420 mmol) at room temperature, which was then heated at 40 °C for 2 h. Another portion of LiOH (8.8 mg, 0.21 mmol) was added and stirred at 40 °C for 3 h. The reaction of the first batch was combined with the second batch of the same reaction utilizing C118 (33.0 mg, 0.0923 mmol), then acidified with formic acid to pH=~5 and concentrated in vacuo. The residue was purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm column, Mobile Phase A: H2O / Mobile Phase B: ACN (0.05% formic acid), 0 to 25% of Mobile Phase B over 9 min, 100% of Mobile Phase B hold 2 min, flow rate: 30 mL / min) and lyophilized to provide C119 (59.0 mg, 56.7% yield) as a light brown solid. (LC / MS) m / z (M+H)+= 344.1. Step 5. Preparation of rac-(R)-7-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3- dimethylureido)benzyl)-3,5-dimethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide formate (9) A mixture of C119 (59.0 mg, 0.172 mmol), HOPO (57.3 mg, 0.515 mmol), EDCI (79.1 mg, 0.412 mmol) and DIEA (111 mg, 0.859 mmol) in DMSO (3.0 mL) was stirred for 30 min at 40 °C, then P11 (59.2 mg, 0.258 mmol) was added at room temperature. The light brown reaction mixture was stirred at 40 °C for 3 h and 30 min then the residue was purified by reverse phase HPLC (C18150 mm x 30 mm x 5 µm column, Mobile Phase A: H2O / Mobile Phase B: ACN (0.05% formic acid), 0 to 39% of Mobile Phase B over 9 min, 100% of Mobile Phase B hold 2 min, flow rate: 30 mL / min) and lyophilized to provide 9 (58.2 mg, 43.2% yield) as a white solid. (LC / MS) m / z (M+H)+= 519.5.1H NMR (400 MHz, CD3OD) δ 8.31 (d, 1H), 7.74 (dd, 1H), 7.36-7.30 (m, 2H), 7.26 (d, 2H), 6.93 (d, 1H), 5.39 (d, 1H), 4.67- 4.41 (m, 5H), 3.41 (dd, 1H), 3.10 (s, 6H), 3.04- 2.99 (m, 6H), 2.41 (s, 3H), 1.40 (d, 3H). Example 10 1-Cyclopropyl-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide trifluoroacetate (10)

[0005] Step 1. Preparation of ethyl 1-cyclopropyl-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C120) To a solution of P1 (0.070 g, 0.26 mmol) in 1-pentanol (1 mL) and DIEA (0.20 g, 1.5 mmol) was added 6-fluoro-N,N-dimethylnicotinamide (CAS: 1032251-82-3; 65 mg, 0.39 mmol). The reaction mixture was heated at 105oC for 24 h, then the temperature was increased to 115oC and stirred for 23 h. The reaction mixture was concentrated in vacuo and then dissolved with DCM. The solution was purified by column chromatography (silica gel, 0-5% MeOH: DCM) to provide C120 (0.10 g, crude) as a yellow oil. The oil was used directly in the next step without further purification. Step 2. Preparation of 1-cyclopropyl-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (C121) To a solution of C120 (99 mg, 0.26 mmol) in ACN (1 mL) and H2O (93 µL) was added TBD (0.11 g, 0.77 mmol) and then stirred for 40 min at room temperature followed by 40oC for 2 h. The reaction was then cooled to room temperature, and 12.1M HCl (24 mg, 0.65 mmol) was added. The acidic reaction mixture was concentrated in vacuo to provide C121 (0.090 g, crude) as a yellow oil. The oil was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 356.2. Step 3. Preparation of 1-cyclopropyl-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3- dimethylureido)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide trifluoroacetate (10) To a solution of C121 (0.090 g, 0.25 mmol) in ACN (1.0 mL) and H2O (0.2 mL) was added HOPO (34 mg, 0.30 mmol) and EDCI (78 mg, 0.41 mmol). To the reaction mixture was added an additional portion of EDCI (78 mg, 0.41 mmol) and then was stirred at room temperature for 20 min before DIEA (98 mg, 0.76 mmol) and P11 (0.070 g, 0.30 mmol) were added. The suspension was stirred at room temperature for 30 min and then was concentrated in vacuo. The residue was diluted with DMSO then acidified with TFA and purified with reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm column, Mobile Phase A: H2O (0.05% TFA) / Mobile Phase B: ACN (0.05% TFA), 5 to 95% of Mobile Phase B over 9 min, 95% of Mobile Phase B hold 1 min, flow rate= 25 mL / min) and lyophilized to provide 10 (24 mg, 18% yield). (LC / MS) m / z (M+H)+= 531.5.1H NMR (600 MHz, (CD3)2SO) δ 8.46 (t, 1H), 8.22-8.21 (m, 2H), 7.68 (dd, 1H), 7.40 – 7.34 (m, 2H), 7.15 (d, 2H), 6.96 (d, 1H), 4.75 (s, 2H), 4.32 (d, 2H), 3.96 (t, 2H), 3.56 (tt, 1H), 2.97 (s, 6H), 2.91-2.86 (m, 8H), 1.12-1.05 (m, 2H), 1.01 – 0.95 (m, 2H). Example 12 N-(4-(3,3-Dimethylureido)benzyl)-1-methyl-5-(5-(1-methyl-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (12) Step 1. Preparation of ethyl 1-methyl-5-(5-(1-methyl-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C122) and pentyl 1-methyl-5-(5-(1-methyl- 1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C123) To a suspension of P4 (0.60 g, 2.4 mmol) in 1-pentanol (5 mL) was added DIEA (1.9 g, 15 mmol) and P40 (0.47 g, 2.7 mmol), then heated at 125oC for 20 h. The reaction mixture was checked by LCMS which showed 30% of C122 (LC / MS) m / z (M+H)+= 367.3 and 32% of C123 at (LC / MS) m / z (M+H)+= 409.3 was formed due to transesterification with 1-pentanol. The suspension was concentrated in vacuo then dissolved in DCM and heptane. The solution was purified by column chromatography (silica gel, 0-10% MeOH: DCM) to form a mixture of C122 and C123 (1.1 g, crude) as a brown oil. The brown oil was used directly in the next step without further purification. Step 2. Preparation of 1-methyl-5-(5-(1-methyl-1H-imidazol-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (C124) To a reaction mixture of C122 and C123 (0.80 g, 2.2 mmol) in EtOH (6 mL) and H2O (4 mL) was added NaOH (0.35 g, 8.7 mmol) then stirred at 40oC for 50 min. The suspension was concentrated in vacuo and acidified with 12.1M HCl (0.40 g, 11 mmol) to pH~1. The acidic reaction mixture was extracted with DCM then the organic layer was concentrated in vacuo to form C124 (0.30 g, crude) as a brown oil. The oil was used directly in the next step without further purification. Step 3. Preparation of N-(4-(3,3-dimethylureido)benzyl)-1-methyl-5-(5-(1-methyl-1H-imidazol-2- yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (12) To a reaction mixture of C124 (0.30 g, 0.89 mmol) in ACN (3.0 mL) and H2O (0.5 mL) was added HOPO (0.12 g, 1.1 mmol) and EDCI (0.27 g, 1.4 mmol). The suspension was stirred at room temperature for 35 min before adding DIEA (0.34 g, 2.7 mmol) and P11 (0.24 g, 1.1 mmol). The reaction mixture was stirred at room temperature for 30 min and then was concentrated in vacuo. The residue was split into two portions for purification. The first portion of the residue was diluted with DMSO and then purified with reverse- phase HPLC (Sunfire C18100 mm x 19 mm x 5 µm column, Mobile Phase A: H2O (0.05% TFA) / Mobile Phase B: ACN (0.05% TFA), 5 to 95% of Mobile Phase B over 9 min, 95% of Mobile Phase B hold 1 min, flow rate = 25 mL / min) and lyophilized to provide 12 (8.5 mg). The second portion of the residue was diluted with DCM and then purified by column chromatography (silica gel, 0-5% MeOH: DCM) to provide an impure residue. The impure residue was diluted with MeOH then purified by SFC (Princeton Methanesulfamide Column 250 mm x 30 mm x 5 µm, 70% CO2 / 30% MeOH (0.2% 7N NH3 in MeOH), backpressure= 100 bar, temperature= 40oC, flow rate= 80 mL / min) to provide 12 (62 mg) as a tan solid. The two purified batches were combined to form 12 (0.070 g, 15% yield) as a solid. (LC / MS) m / z (M+H)+= 514.4.1H NMR (600 MHz, (CD3)2SO) δ 8.47 (t, 1H), 8.43 (d, 1H), 8.22 (s, 1H), 7.84 (dd, 1H), 7.42 – 7.34 (m, 2H), 7.22 (s, 1H), 7.16 (d, 2H), 7.01 – 6.93 (m, 2H), 4.77 (s, 2H), 4.32 (d, 2H), 3.96 (t, 2H), 3.76 (s, 3H), 3.71 (s, 3H), 2.90 (s, 6H), 2.80 (t, 2H).

[0006] Example 18 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-4,5,6,7-tetrahydro-1H...

Claims

CLAIMS We claim:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:I wherein X1is CH, CNH2, or N; X2is C or N; X3is CR13, N, NR13, O, or S; X4is CH, N, or NR13; X5is CR1Bor N; X6is CH or N; X7is CH, N, or CF; X8is CH or N; X9is CR1Bor N; X10is CR1Bor N; R1is -NHR8, -OH, -C2-5heterocycle, or -C1-3alkyl; wherein the -C2-5heterocycle of R1is optionally substituted with one, two, or three of -C1-3 alkyl, -C1-3 oxoalkyl, -C3-5 heterocycloalkyl, - C3-5 hydroxyheterocycloalkyl, -C3-5 aminoheterocycloalkyl, or oxo; wherein the -C1-3 alkyl of R1 is optionally substituted with one, two, or three of oxo, -NR10A R11, or -NR10R11; R1A is H, halogen, or -CH3; or R1 and R1A form a C5-7 heterocycloalkyl fused to Ring D or a C5-7 heteroaryl fused to Ring D; wherein the C5-7 heterocycloalkyl or the C5-7 heteroaryl is optionally substituted with oxo; each R1B independently is H, -CH3 , F, Cl, or methoxy; R2 is H, -C1-3 alkyl, -C1-3 alkoxy, -C1-3 fluoroalkyl, or halogen; R3 is -C1-3 alkyl, -C2-10 heterocycle, -P(=O)(CH3)2, -S(=O)CH3, -NH-S(=O)2CH3, or -NH- C(=O)-C1-3 alkyl; wherein the -C1-3 alkyl of R3 is optionally substituted with one, two, or three of oxo, halogen, -C3-6 cycloalkyl, -OH, -NR12R12A, or cyano; wherein the -C2-10 heterocycle isoptionally substituted with one, two, or three of -OH, halogen, -C1-3hydroxyalkyl, -C1-3alkoxy, - C1-3alkyl, -C1-3fluoroalkyl, cyclopropyl, or oxo; or R2and R3form a C3-6heterocycle fused to Ring A optionally substituted with one, two, or three of -C1-3alkyl, -C2-3oxoalkyl, or oxo; R4A is H, -OH, -C1-3 fluoroalkyl, or -C1-3 alkyl; R4B is H or is absent; or R4A and R4B form cyclopropyl; each R5 independently is H, halogen, -OH, cyclopropyl, -C1-3 fluoroalkyl, or -C1-3 alkyl; or two R5 groups form cyclopropyl; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6 or one R5 and R6 form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge; or R4B and one R5 form a C3-5 cycloalkyl fused to Ring B; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, -C1-3 alkyl, -SO2CH3, or a -C3-4 heterocycle; wherein the -C1-3 alkyl of R8 is optionally substituted with one, two, or three of oxo, -C3-9 heterocycloalkyl, -C1-3 alkoxy, cyanoimine, or -NR9R10; wherein the -C3-4 heterocycle of R8 is optionally substituted with one, two, or three of oxo, halogen, -C0-1 alkylene-NR10R11, -OH, -C1-3 hydroxyalkyl, -C1-3 alkoxy optionally substituted with -NR10R11, -C1-3 alkyl-C1-3 alkoxy, -C1-3 oxoalkyl, or -C1-3 alkyl; wherein the -C3-9 heterocycloalkyl of R8 is optionally substituted with one, two, or three of -C1-3 alkyl, - OH, -C1-3 hydroxyalkyl, -O-C1-3 hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkyl-C1-3 alkoxy, halogen, -C1-3 fluoroalkyl, -C1-3 fluoroalkoxy, cyano, -C1-3 cyanoalkyl, -C0-1 alkylene-C3-5 heterocycloalkyl, -O- C3-5 heterocycloalkyl, or -C0-1 alkylene-NR10R11; R9 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, -methylene- phenylene-NH-C(=O)-NR10R11, or -C3-5heterocycloalkyl; wherein the -C1-4alkyl of R9is optionally substituted with one, two, or three of -C3-5cycloalkyl, -C3-5heterocycloalkyl, or methoxy; wherein the -C3-5cycloalkyl of R9is optionally substituted with one or two of -OH or - C1-3alkyl; each R10independently is H or -C1-4alkyl; R10Ais -C0-1alkylene-C3-5heterocycloalkyl optionally substituted with -C1-3alkyl; each R11independently is H or -C1-3alkyl; R12is H, -C1-3alkyl, -C1-3hydroxyalkyl, -(CH2)0-2-C3-5heterocycloalkyl, -(CH2)1-2-O-C3-5heterocycloalkyl, -methylene-C(=O)-NR10R11, or -methylene-phenylene-NH-C(=O)-NR10R11; wherein the -(CH2)0-2-C3-5heterocycloalkyl or the -(CH2)1-2-O-C3-5heterocycloalkyl of R12is optionally substituted with -C1-4alkyl, -C1-3alkyl-C1-3alkoxy, -(CH2)0-1-phenyl, halogen, -C1-3fluoroalkyl, or -(CH2)0-1-C3-5heterocycloalkyl; wherein the -C1-3alkyl of R12is optionally substituted with one, two, or three of oxo or NR10R11; R12Ais H or -C1-4alkyl; orR12and R12Aform a C3-10heterocycle optionally substituted with one, two, or three of - OH, -C1-3alkyl, oxo, halogen, -C2-3oxoalkyl, -C1-3alkoxy, -C1-3hydroxyalkyl, -C1-3alkyl-C1-3alkoxy, cyano, -C3-6cycloalkyl, -S(=O)2CH3, -S(=O)2CH2CH3, -C(=O)-NR10R11, or -NHC(=O)CH3; R13is H, -C1-6alkyl, -C1-4hydroxyalkyl, -C1-3fluoroalkyl, -C1-3alkyl-C1-3alkoxy, -C1-4cyanoalkyl, -C0-1 alkylene-C3-5 cycloalkyl, -C2-4 oxoalkyl, or -C0-1 alkylene-C3-5 heterocycloalkyl; wherein the -C1-6 alkyl of R13 is optionally substituted with one, two, or three of oxo, fluoro, -NH2, C3-6 cycloalkyl, or methoxy; wherein the -C3-5 cycloalkyl or the -C3-6 cycloalkyl of R13 is optionally substituted with one, two, or three of -C1-3 alkyl, -C1-3 fluoroalkyl, or halogen; R14 is H; or X4 is NR13 and R13 and R14 form a C4-5 heterocycle fused to Ring C; n is 1 or 2; m is 0 or 1; wherein if X3 is CR13 or NR13 then X4 is CH or N, and if X4 is NR13 then X3 is N, O, or S; wherein the respective heterocycles each independently include 1 to 4 heteroatoms including at least one of N, O, or S.

2. A compound of Formula IA, or a pharmaceutically acceptable salt thereof, that is optionally a compound of Claim 1:IA wherein X1is CH, CNH2, or N; X2is C or N; X3is CR13, N, NR13, O, or S; X4is CH, N, or NR13; X5 is CH, CR1B, or N; X6 is CH or N; X7 is CH, N, or CF; X8 is CH or N; X9 is CH, CR1B, or N; X10 is CH, CR1B, or N;R1is -NHR8, -OH, -C2-5heterocycle, or -C1-3alkyl; wherein the -C2-5heterocycle of R1is optionally substituted with one, two, or three of -C1-3alkyl, -C1-3oxoalkyl, -C3-5heterocycloalkyl, - C3-5hydroxyheterocycloalkyl, -C3-5aminoheterocycloalkyl, or oxo; wherein the -C1-3alkyl of R1is optionally substituted with one, two, or three of oxo or -NR10R11; R1A is H or -CH3; or R1 and R1A form a C6-8 fused heterocycloalkyl or a C6-8 fused heteroaryl; wherein the C6-8 fused heterocycloalkyl or the C6-8 fused heteroaryl is optionally substituted with oxo; each R1B independently is H, -CH3 , F, Cl, or methoxy; R2 is H, -C1-3 alkyl, -C1-3 fluoroalkyl, or halogen; R3 is -C1-3 alkyl, -C2-10 heterocycle, or -NH-C(=O)-C1-3 alkyl; wherein the -C1-3 alkyl of R3 is optionally substituted with one or more of oxo, -OH, -NR12R12A, -C5-8 heterocycle, or cyano; wherein the -C2-10 heterocycle is optionally substituted with one, two, or three of -OH, halogen, - C1-3 hydroxyalkyl, -C1-3 alkyl, cyclopropyl, or oxo; or R2 and R3 form a C6-10 fused heterocycle optionally substituted with one, two, or three of -C1-3 alkyl, -C2-3 oxoalkyl, or oxo; R4A is H, -OH, or -C1-3 alkyl; R4B is H or is absent; each R5 independently is H, halogen, -OH, cyclopropyl, or -C1-3 alkyl; or two R5 groups form cyclopropyl; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6 or R5 and R6 form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, -C1-3 alkyl, -SO2CH3, or a -C3-4 heterocycle; wherein the -C1-3 alkyl of R8 is optionally substituted with one, two, or three of oxo, -C3-7heterocycloalkyl, -C3-7heterocycloalkyl substituted with methyl, alkoxy, cyanoimine, or -NR9R10; wherein the -C3-4heterocycle is optionally substituted with one, two, or three of oxo, halogen, -C0-1alkylene-NR10R11, -OH, -C1-3hydroxyalkyl, -C1-3alkoxy optionally substituted with -NR10R11, -C1-3alkoxy-C1-3alkyl, -C1-3oxoalkyl, or -C1-3alkyl; R9is H, -C1-4alkyl, -C1-4hydroxyalkyl, -C1-3fluoroalkyl, -C3-5cycloalkyl, or -C3-5heterocycloalkyl; wherein the -C1-4alkyl of R9is optionally substituted with one, two, or three of cyclopropyl, -C3-5heterocycloalkyl, or methoxy; wherein the -C3-5cycloalkyl of R9is optionally substituted with -C1-3alkyl; each R10independently is H or -C1-4alkyl; or if the -C1-3alkyl of R8is substituted with -NR9R10, then the corresponding R9and R10are optionally combined to form a C3-7heterocycloalkyl optionally substituted with one, two, or three of methoxy, -OH, -C1-3alkyl, halogen, -NH2, -NHCH3, or -N(CH3)2; each R11independently is H or -C1-3alkyl;R12is H, -C1-3alkyl, -(CH2)0-1-C3-5heterocycloalkyl, or -methylene-phenylene-NH-C(=O)- NR10R11; wherein the -(CH2)0-1-C3-5heterocycloalkyl is optionally substituted with -C1-4alkyl; R12Ais H or -C1-4alkyl; or R12and R12Aform a fused C5-10heterocycloalkyl optionally substituted with -C1-3alkyl; R13 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C0-1-C3-5 cycloalkyl, -C2-4 oxoalkyl, or -C3-5 heterocycloalkyl; wherein the -C1-4 alkyl of R13 is optionally substituted with one, two, or three of cyclopropyl or methoxy; wherein the -C3-5 cycloalkyl of R13 is optionally substituted with -C1-3 alkyl; n is 1 or 2; wherein the respective heterocycles each independently include 1 to 3 heteroatoms including at least one of N, O, or S; wherein at least one of X2 is N or X3 is N, NH, or NR13, and X4 is N or NR13; or if X3 is S or O, then X2 is C.

3. A compound of Formula IB or a pharmaceutically acceptable salt thereof, that is optionally a compound of Claim 1 or Claim 2:IB wherein X1is CH, CNH2, or N; X2is C or N; X3is CR13, N, NR13, O, or S; X4is CH, N, or NR13; X5is CH or N; X6is CH or N; X7 is CH, N, or CF; X8 is CH or N; with the proviso that at least one of X2 is N or X3 is N, NH, or NR13, and X4 is N or N R13; or if X3 is S or O, then X2 is C; R1 is -NHR8, -OH, -C2-5 heterocycle, or -C1-3 alkyl; wherein the -C2-5 heterocycle of R1 is optionally substituted with one or more of -C1-3 alkyl, -C1-3 oxoalkyl, -C3-5 heterocycloalkyl, -C3-5hydroxyheterocycloalkyl, -C3-5aminoheterocycloalkyl, or oxo; wherein the -C1-3alkyl of R1is optionally substituted with one or more of oxo or -NR10R11; R2is H, -C1-3alkyl, -C1-3fluoroalkyl, or halogen; R3is -C1-3alkyl, -C2-10heterocycle, or -NH-C(=O)-C1-3alkyl; wherein the -C1-3alkyl of R3is optionally substituted with one or more of oxo, -OH, -NR12R12A, -C5-8 heterocycle, or cyano; wherein the -C2-10 heterocycle is optionally substituted with one or more of -OH, halogen, -C1-3 hydroxyalkyl, -C1-3 alkyl, cyclopropyl, or oxo; or R2 and R3 form a C6-10 fused heterocycloalkyl optionally substituted with one or more of - C1-3 alkyl, -C2-3 oxoalkyl, or oxo; R4A is H, -OH, or -C1-3 alkyl; R4B is H or is absent; each R5 independently is H, -OH, halogen, or -C1-3 alkyl; or two R5 groups form cyclopropyl; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6 or R5 and R6 form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, -C1-3 alkyl, or a -C3-4 heterocycle; wherein the -C1-3 alkyl of R8 is optionally substituted with one or more of oxo or -NR9R10; wherein the -C3-4 heterocycle is optionally substituted with one or more of oxo or -C1-3 alkyl; R9 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocycloalkyl; wherein the -C1-4 alkyl of R9 is optionally substituted with one or more of cyclopropyl, -C3-5 heterocycloalkyl, or methoxy; wherein the -C3-5 cycloalkyl of R9 is optionally substituted with -C1-3 alkyl; each R10independently is H or -C1-4alkyl; or if the -C1-3alkyl of R8is substituted with -NR9R10, then the corresponding R9and R10are optionally combined to form a C3-6heterocycloalkyl optionally substituted with at least one of methoxy, -OH, -C1-3alkyl, or -N(CH3)2; each R11independently is H or -C1-3alkyl; R12is H, -C1-3alkyl, or -methylene-phenylene-NH-C(=O)-NR10R11; each R13independently is H, -C1-4alkyl, -C1-4hydroxyalkyl, -C1-3fluoroalkyl, -C3-5cycloalkyl, or -C3-5heterocycloalkyl; wherein the -C1-4alkyl of R13is optionally substituted with one or more of cyclopropyl or methoxy; wherein the -C3-5cycloalkyl of R13is optionally substituted with -C1-3alkyl; n is 1 or 2; wherein the respective heterocycles each independently include 1 to 3 heteroatoms including at least one of N, O, or S; wherein at least one of X2is N or X3is N, NH, or NR13, and X4is N or NR13; or if X3is S or O, then X2is C.

4. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3is -C1-3alkyl or -C2-10heterocycle; wherein the -C2-10heterocycle is -C2-5heteroaryl; wherein the -C1-3alkyl of R3is optionally substituted with one, two, or three of oxo or -NR12R12A; wherein the -C2-5heterocycle of R3is optionally substituted with -C1-3alkyl.

5. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is -NHR8; and R8 is -C1-3 alkyl substituted with one, two, or three of oxo or -NR9R10.

6. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is H; and R3 is -C1-3 alkyl substituted with oxo and -NR12R12A.

7. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one of: X5 is CH; X7 is CH or N; X8 is CH; R1 is -NHR8, -C2-5 heterocycle, or -C1-3 alkyl; R4A is H or -C1-3 alkyl; each R5 independently is H, halogen, or -C1-3 alkyl; or the two R5 groups form cyclopropyl; R6 is H or -C1-3 alkyl; or R7 is H or -C1-3 alkyl.

8. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is -C1-3 alkyl substituted with oxo and -NR12R12A and R1 is -NHR8 or -C1-3 alkyl substituted with oxo and -NR10R11.

9. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3 is CR13 and X4 is CH or N.

10. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is -NHR8; wherein R8 is -C1-3 alkyl or a -C3-4 heterocycle; wherein the -C1-3 alkyl of R8 is substituted with oxo and -NR9R10; wherein the -C3-4 heterocycle is substituted with one, two, or three of oxo or -C1-3 alkyl.

11. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1is N, X3is N or NR13, and X4is N.

12. The compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the -C2-10heterocycle of R3is a -C2-5heterocycle and R3is optionally substituted with one, two, or three of -C1-3alkyl.

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

14. The compound of Claim 13, or a pharmaceutically acceptable salt thereof, .

15. The compound of Claim 13 or 14, or a pharmaceutically acceptable salt thereof, wherein R1Ais deuterium; X5, X9, and X10are each CR1B; and the R1Bof each of X5, X9, and X10is deuterium.

16. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is one of: N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyridin-2-yl)-N-(4-(3,3- dimethylureido)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxamide; 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1,7-dimethyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; (S)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl- 7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;(S)-5-(4-(dimethylcarbamoyl)phenyl)-1-isopropyl-7-methyl-N-(4-(4-methylpiperazine-1- carboxamido)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; or 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-(2,2,2- trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide.

17. A compound, wherein the compound is one of : N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyridin-2-yl)-N-(4-(3,3- dimethylureido)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3- carboxamide; 5-(5-(Dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1,7-dimethyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;(S)-5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl- 7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; (S)-5-(4-(dimethylcarbamoyl)phenyl)-1-isopropyl-7-methyl-N-(4-(4-methylpiperazine-1- carboxamido)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; or 5-(5-(dimethylcarbamoyl)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-(2,2,2- trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide.

18. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is.

19. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is ○ .

20. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is.

21. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is.

22. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is.

23. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is.

24. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is.

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

26. A method for treating atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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 24, or a pharmaceutically acceptable salt thereof.

27. A method for treating at least one of a dermatological condition or a respiratory condition comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

28. A compound according to any of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use as a medicament.

29. A compound according to any of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, 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.

30. A compound according to any of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment of at least one of a dermatological condition or a respiratory condition.

31. Use of a compound according to any of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergy, alopecia, Alzheimer’s disease, asthma, atherosclerosis, Bechet’s disease, bullous pemphigoid, cancer, chronicobstructive 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.

32. Use of a compound according to any of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment of at least one of a dermatological condition or a respiratory condition.

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