The new regulations contain complex cyclic compounds.

Abstract

This disclosure relates to the compounds of this disclosure and their pharmaceutically acceptable salts; their use in medicine; compositions comprising them; methods for preparing them; and intermediates used in such methods. The compounds of this disclosure may be useful in the treatment, prevention, suppression, and improvement of diseases such as atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa. The compounds of this disclosure may be useful in the treatment, prevention, suppression, and improvement of skin conditions or respiratory conditions.

Description

[Technical Field]

[0001] background This disclosure relates to a novel compound. This disclosure also relates to a method for preparing the compound, intermediates used in the preparation method, compositions comprising the compound, and uses of the compound, including its use as a STAT6 inhibitor. [Background technology]

[0002] STAT6 is a member of the protein signaling and transcriptional activator (STAT) family, which consists of transcription factors that influence cellular 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.

[0003] STAT family proteins are downstream targets of Janus kinase (JAK) family kinases, which are involved in signal transduction from various cytokines, including IL-2, IL-5, GM-CSF, IL-10, IL-12, IL-23, and IL-4 and IL-13. Cytokines IL-4 and IL-13 have been shown to transmit signals 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 the efficacy observed for JAK inhibitors that block IL-4 and IL-13 signaling as well as further inflammatory cytokine signaling [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, randomized, 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, randomized controlled phase 3 trial] trials.Lancet.397(10290):2151~2168]. [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] Despite the effectiveness of known therapies, there remains an unmet need for safe and effective treatments for numerous diseases characterized by inflammatory responses that address a wide range of pathogenic mechanisms. [Means for solving the problem]

[0005] overview This disclosure provides, in part, compounds and pharmaceutically acceptable salts thereof. These compounds may inhibit the activity of STAT6 and may be useful in the treatment, prevention, suppression, and / or improvement of diseases, disorders, and conditions mediated by STAT6. Pharmaceutical compositions comprising the compounds or salts alone or in combination with further therapeutic agents are also provided. This disclosure also provides, in part, methods for preparing the compounds, pharmaceutically acceptable salts, and compositions of this disclosure, as well as methods for using the foregoing. This summary is provided to introduce in a simplified form some of the concepts which will be further described in the detailed description below. This summary is not intended to identify any major or essential features of the claimed subject matter, nor is it intended to be used alone as an aid in determining the scope of the claimed subject matter.

[0006] In one embodiment, the compounds of the present disclosure have formula I or a pharmaceutically acceptable salt thereof:

[0007] [ka] [In the formula, the variable elements are as defined herein.]

[0008] In one embodiment, the compounds of the present disclosure have formula IA or a pharmaceutically acceptable salt thereof:

[0009] [ka] [In the formula, the variable elements are as defined herein.]

[0010] In one embodiment, the compounds of the present disclosure have formula IB or a pharmaceutically acceptable salt thereof:

[0011] [ka] [In the formula, the variable elements are as defined herein.]

[0012] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0013] In another aspect, the present disclosure relates to a method for treating atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa, comprising the step of administering a therapeutically effective amount of the compound of the present disclosure to a subject in need thereof.

[0014] In another aspect, this disclosure is for use as a pharmaceutical agent; or for use in atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), and arthritis. The present disclosure relates to the compounds of this disclosure, or pharmaceutically acceptable salts thereof, for use in the treatment of harm, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, 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 skin condition or respiratory condition.

[0015] It should be understood that the general description above and the detailed description below are illustrative and descriptive only and do not limit the claimed disclosure. [Modes for carrying out the invention]

[0016] Detailed explanation This disclosure can be more readily understood by referring to the detailed description below and the examples included herein. It should be understood that this disclosure is not limited to specific synthetic preparation methods, and these methods may naturally vary. It should also be understood that the terms used herein are intended solely to describe specific embodiments and are not intended to be limiting.

[0017] In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof:

[0018] [ka] [In the formula, X1 is CH, CNH2, or N; X2 is either C or N; X3 is CR 13 , N, NR 13 , O, or S; X4 is CH, N, or NR 13 ; X5 is CR 1B or N; X6 is CH or N; X7 is CH, N, or CF; X8 is CH or N; X9 is CR 1B or N; X 10 is CR 1B or N; R1 is -NHR8, -OH, -C 2~5 heterocyclic ring, or -C 1~3 alkyl; The -C 2~5 heterocyclic ring of R1 may be substituted with one, two, or three -C 1~3 alkyl, -C 1~3 oxoalkyl, -C 3~5 heterocycloalkyl, -C 3~5 hydroxyheterocycloalkyl, -C 3~5 aminoheterocycloalkyl, or oxo; The -C 1~3 alkyl of R1 may be substituted with one, two, or three oxo, -NR 10A R 11 , or -NR 10 R 11 ; R 1A is H, halogen, or -CH3; Or, R1 and R 1A form a C 5~7 heterocycloalkyl fused to the D ring, or a C 5~7 heteroaryl fused to the D ring; The C 5~7 heterocycloalkyl or C 5~7 heteroaryl may be substituted with oxo; Each R 1B is independently H, -CH3, F, Cl, or methoxy; R2 is H, -C 1~3 alkyl, -C1~3 Alkoxy, -C 1~3 It is a fluoroalkyl or halogen; R3 is -C 1~3 Alkyl, -C 2~10 Heterogeneous rings, -P(=O)(CH3)2, -S(=O)CH3, -NH-S(=O)2CH3, or -NH-C(=O)-C 1~3 Alkyl; R3-C 1~3 Alkyls can consist of one, two, or three oxo, halogen, or -C atoms. 3~6 Cycloalkyl, -OH, -NR 12 R 12A , or it may be substituted with cyano;-C 2~10 The heterocycle consists of one, two, or three -OH, halogen, and -C rings. 1~3 Hydroxyalkyl, -C 1~3 Alkoxy, -C 1~3 Alkyl, -C 1~3 It may be substituted with a fluoroalkyl, cyclopropyl, or oxo; or, R2 and R3 are one, two, or three -C 1~3 Alkyl, -C 2~3 A C condensed on the A ring, which may be substituted with an oxoalkyl or oxo alkyl group. 3~6 Forms a complex algebra; R 4A H, -OH, -C 1~3 Fluoroalkyl, or -C 1~3 It is alkyl; R 4B is either H or does not exist; or, R 4A and R 4B It forms cyclopropyl; Each R5 can independently be H, halogen, -OH, cyclopropyl, or -C 1~3 Fluoroalkyl, or -C 1~3 It is alkyl; or, two R5 groups form a cyclopropyl group; R6 is H, -OH, or -C 1~3 Alkyl; or, R 4A and R6, or one R5 and R6, C1~3 form an alkyl bridge or a C 1~3 heteroalkyl bridge; or, R 4B and one R5 form a C 3~5 cycloalkyl fused to the B ring; R7 is H, -C 1~3 alkyl, or -C 1~3 hydroxyalkyl; R8 is H, -C 1~3 alkyl, -SO2CH3, or -C 3~4 heterocycle; the -C 1~3 alkyl of R8 may be substituted with one, two, or three oxo, -C 3~9 heterocycloalkyl, -C 1~3 alkoxy, cyanoimine, or -NR9R 10 ; the -C 3~4 heterocycle of R8 may be substituted with one, two, or three oxo, halogen, -C 0~1 alkylene-NR 10 R 11 , -OH, -C 1~3 hydroxyalkyl, -NR 10 R 11 substituted -C 1~3 alkoxy, -C 1~3 alkyl-C 1~3 alkoxy, -C 1~3 oxoalkyl, or -C 1~3 alkyl; the -C 3~9 heterocycloalkyl of R8 may be substituted with one, two, or three -C 1~3 alkyl, -OH, -C 1~3 hydroxyalkyl, -O-C 1~3 hydroxyalkyl, -C 1~3 alkoxy, -C 1~3 alkyl-C 1~3 alkoxy, halogen, -C 1~3 fluoroalkyl, -C 1~3 fluoroalkoxy, cyano, -C 1~3 cyanoalkyl, -C 0~1 alkylene-C 3~5 heterocycloalkyl, -O-C 3~5heterocycloalkyl, or -C 0~1 alkylene-NR 10 R 11 may be substituted; R9 is H, -C 1~4 alkyl, -C 1~4 hydroxyalkyl, -C 1~3 fluoroalkyl, -C 3~5 cycloalkyl, -methylene-phenylene-NH-C(=O)-NR 10 R 11 or -C 3~5 heterocycloalkyl; the -C of R9 1~4 alkyl may be substituted with one, two, or three -C 3~5 cycloalkyl, -C 3~5 heterocycloalkyl, or methoxy; the -C of R9 3~5 cycloalkyl may be substituted with one or two -OH or -C 1~3 alkyl; each R 10 is independently H or -C 1~4 alkyl; or, R 10A is -C 1~3 alkyl-substituted -C 0~1 alkylene-C 3~5 heterocycloalkyl; each R 11 is independently H or -C 1~3 alkyl; R 12 is H, -C 1~3 alkyl, -C 1~3 hydroxyalkyl, -(CH2) 0~2 -C 3~5 heterocycloalkyl, -(CH2) 1~2 -O-C 3~5 heterocycloalkyl, -methylene-C(=O)-NR 10 R 11 or -methylene-phenylene-NH-C(=O)-NR 10 R 11 and; the -(CH2) of R 12 -C 0~2 -C 3~5Heterocycloalkyl or -(CH2) 1~2 -OC 3~5 Heterocycloalkyl is -C 1~4 Alkyl, -C 1~3 Alkyl-C 1~3 Alkoxy, -(CH2) 0~1 -phenyl, halogen, -C 1~3 Fluoroalkyl, or -(CH2) 0~1 -C 3~5 It may also be substituted with a heterocycloalkyl group; R 12 -C 1~3 Alkyl groups consist of one, two, or three oxo or NR groups. 10 R 11 It may also be replaced with; R 12A is H or -C 1~4 Alkyl; or, R 12 and R 12A This consists of one, two, or three -OH and -C atoms. 1~3 Alkyl, oxo, halogen, -C 2~3 Oxoalkyl, -C 1~3 Alkoxy, -C 1~3 Hydroxyalkyl, -C 1~3 Alkyl-C 1~3 Alkoxy, cyano, -C 3~6 Cycloalkyl, -S(=O)2CH3, -S(=O)2CH2CH3, -C(=O)-NR 10 R 11 C may be substituted with -NHC(=O)CH3. 3~10 Forms a complex algebra; R 13 is H, -C 1~6 Alkyl, -C 1~4 Hydroxyalkyl, -C 1~3 Fluoroalkyl, -C 1~3 Alkyl-C 1~3 Alkoxy, -C 1~4 Cyanoalkyl, -C 3~5 Cycloalkyl, -C 2~4 Oxoalkyl, or -C 3~5 It is heterocycloalkyl; R 13 -C 1~6Alkyl can be 1, 2, or 3 oxo, fluoro, -NH2, C 3~6 It may also be substituted with a cycloalkyl or methoxy group; R 13 -C 3~5 Cycloalkyl or -C 3~6 Cycloalkyls have one, two, or three -C atoms. 1~3 Alkyl, -C 1~3 It may also be substituted with a fluoroalkyl or halogen; R 14 is H; or, X4 is NR 13 And R 13 and R 14 This is a C condensed into a C ring. 4~5 Forms a complex algebra; n is either 1 or 2; m is either 0 or 1; X3 is CR 13 or NR 13 If X4 is CH or N, then X4 is NR 13 If so, X3 is N, O, or S; Each heterocycle independently contains 1 to 4 heteroatoms, each containing at least one N, O, or S atom.

[0019] In one embodiment, a compound of formula IA, or a pharmaceutically acceptable salt thereof:

[0020] [ka] [In the formula, X1 is CH, CNH2, or N; X2 is either C or N; X3 is CR 13 , N, NR 13 It is O, or S; X4 is CH, N, or NR 13 and; X5 is CH, CR 1B , or N; X6 is CH or N; X7 is CH, N, or CF; X8 is CH or N; X9 is CH, CR 1B , or N; X 10 CH, CR 1B , or N; R1 is -NHR8, -OH, -C 2~5 A complex algebra, or -C 1~3 Alkyl; R1-C 2~5 The complex ring has one, two, or three -C elements. 1~3 Alkyl, -C 1~3 Oxoalkyl, -C 3~5 Heterocycloalkyl, -C 3~5 Hydroxyheterocycloalkyl, -C 3~5 It may be substituted with an aminoheterocycloalkyl or oxo; R1's -C 1~3 Alkyl groups consist of one, two, or three oxo or -NR groups. 10 R 11 It may also be replaced with; R 1A is H or -CH3; or, R1 and R 1A is C 6~8 Condensed heterocycloalkyl or C 6~8 Forms a condensed heteroaryl; C 6~8 Condensed heterocycloalkyl or C 6~8 The condensed heteroaryl may be substituted with an oxo; Each R 1B These are independently H, -CH3, F, Cl, or methoxy; R2 is H, -C 1~3 Alkyl, -C 1~3 It is a fluoroalkyl or halogen; R3 is -C 1~3 Alkyl, -C 2~10 A heterogeneous ring, or -NH-C(=O)-C 1~3 Alkyl; R3-C 1~3 Alkyl groups consist of one or more oxo, -OH, and -NR groups. 12 R 12A , -C 5~8 It may be a heterocycle or substituted with a cyano;-C2~10 The heterocycle consists of one, two, or three -OH, halogen, and -C rings. 1~3 Hydroxyalkyl, -C 1~3 It may be substituted with alkyl, cyclopropyl, or oxo; or, R2 and R3 are one, two, or three -C 1~3 Alkyl, -C 2~3 C may be substituted with an oxoalkyl or oxo group. 6~10 Forming a condensed heterocycle; R 4A is H, -OH, or -C 1~3 It is alkyl; R 4B is either H or does not exist; Each R5 can independently be H, halogen, -OH, cyclopropyl, or -C 1~3 It is alkyl; or, two R5 groups form a cyclopropyl group; R6 is H, -OH, or -C 1~3 Alkyl; or, R 4A And R6, or R5 and R6, C 1~3 Alkyl crosslinking or C 1~3 Forming heteroalkyl crosslinks; R7 H, -C 1~3 Alkyl, or -C 1~3 It is a hydroxyalkyl group; R8 H, -C 1~3 Alkyl, -SO2CH3, or -C 3~4 It is a complex algebra; R8 -C 1~3 Alkyl groups consist of one, two, or three oxo, -C 3~7 Heterocycloalkyl, methyl-substituted -C 3~7 Heterocycloalkyl, alkoxy, cyanoimine, or -NR9R 10 It is also fine if it is replaced with -C 3~4 Heterocyclic rings consist of one, two, or three oxo, halogen, and -C atoms. 0~1 Alkilen-NR 14 R 11 -OH, -C 1~3 Hydroxyalkyl, -NR10 R 11 Even if replaced with -C 1~3 Alkoxy, -C 1~3 Alkoxy-C 1~3 Alkyl, -C 1~3 Oxoalkyl, or -C 1~3 It may also be substituted with alkyl groups; R9 is H, -C 1~4 Alkyl, -C 1~4 Hydroxyalkyl, -C 1~3 Fluoroalkyl, -C 3~5 Cycloalkyl, or -C 3~5 It is heterocycloalkyl; R9 -C 1~4 Alkyl is one, two, or three cyclopropyl, -C 3~5 It may be substituted with heterocycloalkyl or methoxy; R9 -C 3~5 Cycloalkyl is -C 1~3 It may also be substituted with alkyl groups; Each R 10 These are independently H or -C 1~4 Alkyl; or, R8 -C 1~3 Alkyl is -NR9R 10 If replaced by the corresponding R9 and R 10 Together, they form at least one methoxy, OH, -C 1~3 C may be substituted with alkyl, halogen, -NH2, -NHCH3, or -N(CH3)2. 3~7 They may form heterocycloalkyl groups; Each R 11 These are independently H or -C 1~3 It is alkyl; R 12 is H, -C 1~3 Alkyl, -(CH2) 0~1 -C 3~5 Heterocycloalkyl, or -methylene-phenylene-NH-C-NR 10 R 11 and ;-(CH2) 0~1 -C 3~5 Heterocycloalkyl is -C 1~4 It may also be substituted with alkyl groups; R 12A is H or -C 1~4 Alkyl; or, R 12 and R 12A is -C 1~3 Condensed C may be substituted with alkyl. 5~10 Forms heterocycloalkyl groups; R 13 is H, -C 1~4 Alkyl, -C 1~4 Hydroxyalkyl, -C 1~3 Fluoroalkyl, -C 0~1 -C 3~5 Cycloalkyl, -C 2~4 Oxoalkyl, or -C 3~5 It is heterocycloalkyl; R 13 -C 1~4 The alkyl group may be substituted with one, two, or three cyclopropyl or methoxy groups; R 13 -C 3~5 Cycloalkyl is -C 1~3 It may also be substituted with alkyl groups; n is either 1 or 2; Each heterocycle independently contains 1 to 3 heteroatoms, each containing at least one N, O, or S; At least one of X2 is N, or X3 is N, NH, or NR 13 And X4 is N or NR 13 [and; or, if X3 is S or O, then X2 is C].

[0021] In one embodiment, a compound of formula IB, or a pharmaceutically acceptable salt thereof:

[0022] [ka] [In the formula, X1 is CH, CNH2, or N; X2 is either C or N; X3 is CR 13 , N, NR 13 It is O, or S; X4 is CH, N, or NR 13 and; X5 is either CH or N; X6 is CH or N; X7 is CH, N, or CF; X8 is either CH or N, However, at least one of X2 is N, or X3 is N, NH, or NR. 13 And X4 is N or NR 13 And; or, if X3 is S or O, then X2 is C; R1 is -NHR8, OH, -C 2~5 A complex algebra, or -C 1~3 Alkyl; R1-C 2~5 A complex algebra has one or more -C 1~3 Alkyl, -C 1~3 Oxoalkyl, -C 3~5 Heterocycloalkyl, -C 3~5 Hydroxyheterocycloalkyl, -C 3~5 It may be substituted with an aminoheterocycloalkyl or oxo; R1's -C 1~3 Alkyl groups consist of one or more oxo or -NR groups. 10 R 11 It may also be replaced with; R2 is H, -C 1~3 Alkyl, -C 1~3 It is a fluoroalkyl or halogen; R3 is -C 1~3 Alkyl, -C 2~10 A heterogeneous ring, or -NH-C(=O)-C 1~3 Alkyl; R3-C 1~3 Alkyl groups consist of one or more oxo, -OH, and -NR groups. 12 R 12A , -C 5~8 It may be a heterocycle or substituted with a cyano;-C 2~10 Heterocycles consist of one or more -OH, halogen, and -C rings. 1~3 Hydroxyalkyl, -C 1~3 It may be substituted with alkyl, cyclopropyl, or oxo; or, R2 and R3 are one or more -C 1~3 Alkyl, -C 2~3 C may be substituted with an oxoalkyl or oxo group. 6~10 Forms condensed heterocycloalkyl groups; R 4A is H, -OH, or -C 1~3 It is alkyl; R 4B is either H or does not exist; Each R5 can independently contain H, -OH, halogen, or -C 1~3 It is alkyl; or, two R5 groups form a cyclopropyl group; R6 is H, -OH, or -C 1~3 Alkyl; or, R 4A And R6, or R5 and R6, C 1~3 Alkyl crosslinking or C 1~3 Forming heteroalkyl crosslinks; R7 H, -C 1~3 Alkyl, or -C 1~3 It is a hydroxyalkyl group; R8 H, -C 1~3 Alkyl, or -C 3~4 It is a complex algebra; R8 -C 1~3 Alkyl is one or more oxo or -NR9R 10 It is also fine if it is replaced with -C 3~4 A heterocycle consists of one or more oxos or -C rings. 1~3 It may also be substituted with alkyl groups; R9 is H, -C 1~4 Alkyl, -C 1~4 Hydroxyalkyl, -C 1~3 Fluoroalkyl, -C 3~5 Cycloalkyl, or -C 3~5 It is heterocycloalkyl; R9 -C 1~4 Alkyl is one or more cyclopropyl, -C 3~5 It may be substituted with heterocycloalkyl or methoxy; R9 -C 3~5 Cycloalkyl is -C 1~3It may also be substituted with alkyl groups; Each R 10 These are independently H or -C 1~4 Alkyl; or, R8 -C 1~3 Alkyl is -NR9R 10 If replaced by the corresponding R9 and R 10 Together, they form at least one methoxy, OH, -C 1~3 C may be substituted with alkyl or -N(CH3)2. 3~6 They may form heterocycloalkyl groups; Each R 11 These are independently H or -C 1~3 It is alkyl; R 12 is H, -C 1~3 Alkyl, or -methylene-phenylene-NH-C(=O)-NR 10 R 11 and; Each R 13 H and -C are independent of each other. 1~4 Alkyl, -C 1~4 Hydroxyalkyl, -C 1~3 Fluoroalkyl, -C 3~5 Cycloalkyl, or -C 3~5 It is heterocycloalkyl; R 13 -C 1~4 The alkyl group may be substituted with one or more cyclopropyl or methoxy groups; R 13 -C 3~5 Cycloalkyl is -C 1~3 It may also be substituted with alkyl groups; n is either 1 or 2; Each heterocycle independently contains 1 to 3 heteroatoms, each containing at least one N, O, or S atom.

[0023] In one embodiment, R3 is -C 1~3 Alkyl or -C 2~10 It is a complex algebra; -C 2~10 The complex algebra is -C 2~5 It is a heteroaryl; R3-C 1~3Alkyl is one, two, or three oxo or -NR 12 R 12A It may be replaced with -C of R3; 2~5 The complex algebra is -C 1~3 It may be substituted with alkyl.

[0024] In one embodiment, a dashed line indicates a bond that is either a single bond or a double bond; if the dashed line is a double bond, R 4B It does not exist, and n is 1.

[0025] In one embodiment, R1 is -NHR8; R8 is one, two, or three oxos or -NR9R 10 -C replaced by 1~3 It is alkyl.

[0026] In one embodiment, R2 is H; R3 is oxo and -NR 12 R 12A -C replaced by 1~3 It is alkyl.

[0027] In one embodiment, X5 is CH; X7 is CH or N; X8 is CH; R1 is -NHR8, -C 2~5 A complex algebra, or -C 1~3 Being alkyl; R 4A is H or -C 1~3 It must be alkyl; each R5 can independently be H, halogen, or -C 1~3 It is alkyl; or two R5 groups form a cyclopropyl group; R6 is H or -C 1~3 Being alkyl; or R7 is H or -C 1~3 At least one of the following conditions is met: it is alkyl.

[0028] In one embodiment, R3 is oxo and -NR 12 R 12A -C replaced by 1~3 It is alkyl, and R1 is -NHR8, or oxo and -NR 10 R 11 -C replaced by 1~3It is alkyl.

[0029] In one embodiment, R3 is -C(=O)-NR 12 R 12A It could be, and R1 is -NH-CO-NR 10 R 11 It is possible.

[0030] In one embodiment, X3 is CR 13 Therefore, X4 is either CH or N.

[0031] In one embodiment, R1 is -NHR8; R8 is -C 1~3 Alkyl or -C 3~4 It is a complex algebra; R8 -C 1~3 Alkyl is oxo and -NR9R 10 It has been replaced with ;-C 3~4 Heterogeneous rings have one, two, or three oxo or -C elements. 1~3 It is substituted with alkyl.

[0032] In one embodiment, X1 is N and X3 is N or NR 13 Therefore, X4 is N.

[0033] In one embodiment, R3's -C 2~6 The complex algebra is -C 2~10 It is a complex ring, and R3 has one, two, or three -C elements. 1~3 It may be substituted with alkyl.

[0034] In one embodiment, at least one hydrogen (H) is deuterium (D).

[0035] In one embodiment, R1 is

[0036] [ka] That is the case.

[0037] In one embodiment, R 1A It is deuterium; X5, X9, and X 10 These are CR 1BX5, X9, and X 10 Each of the R 1B It is deuterium.

[0038] In one embodiment, the compound is a deuterated compound of any of Examples D1, D2, D6, D31, D33, D128, or D132.

[0039] In one embodiment, N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidine-1-yl)pyridine-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(dimethylcarbamoyl)pyridine-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine Zin-3-carboxamide; 5-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyridine-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)pyridine-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)pyridine-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-methylpiper A compound which is one of the following: radin-1-carboxamide)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; or 5-(5-(dimethylcarbamoyl)pyridine-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, or a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidine-1-yl)pyridine-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(dimethylcarbamoyl)pyridine-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)pyridine-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)pyridine-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1,7-dimethyl Tyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;(S)-5-(5-(dimethylcarbamoyl)pyridine-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 A compound that is one of the following: -(4-(4-methylpiperazine-1-carboxamide)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; or 5-(5-(dimethylcarbamoyl)pyridine-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.

[0041] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is

[0042] [ka] That is the case.

[0043] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is

[0044] [ka] That is the case.

[0045] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is

[0046] [ka] That is the case.

[0047] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is

[0048] [ka] That is the case.

[0049] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is

[0050] [ka] That is the case.

[0051] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is

[0052] [ka] That is the case.

[0053] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is

[0054] [ka] That is the case.

[0055] In one embodiment, the compounds are rac-(4R,7S)-9-(5-(dimethylcarbamoyl)pyridine-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-oxoxazolidin N-3-yl)pyridine-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]heptan-2-carbonyl)pyridine-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)pyridine-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-(tetra Anything other than hydro-2H-pyran-2-yl)pyridine-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-methylpyrimidine-2-yl)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide.

[0056] In one embodiment, the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0057] In one embodiment, a method for treating atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa comprises the step of administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0058] In one embodiment, a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a medicine.

[0059] In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof, may be used for the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), joint disorders, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

[0060] In one embodiment, a compound of formula I, or a pharmaceutically acceptable salt thereof, may be for use in the treatment of at least one skin condition or respiratory condition.

[0061] In one embodiment, the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, may be for the manufacture of a medicament for the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), joint disorders, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

[0062] In one embodiment, the use of the compound or a pharmaceutically acceptable salt thereof may be for use in the treatment of at least one skin condition or respiratory condition.

[0063] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compounds of Examples 1 and 2 and the compounds listed in Table 2.

[0064] In one embodiment, a method for treating atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa comprises the step of administering a therapeutically effective amount of any of the compounds of the above embodiment or a pharmaceutically acceptable salt thereof to a subject in need thereof. This method may be used to treat atopic dermatitis.

[0065] In one embodiment, any of the compounds of the above embodiment, or a pharmaceutically acceptable salt thereof, is intended for medicinal use.

[0066] In one embodiment, any of the compounds of the above embodiment, or a pharmaceutically acceptable salt thereof, is for use in the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), joint disorders, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

[0067] In one embodiment, any of the compounds of the above embodiment, or a pharmaceutically acceptable salt thereof, is intended for use in the treatment of at least one skin condition or respiratory condition.

[0068] In one embodiment, the use of any of the compounds in the foregoing embodiment, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), joint disorders, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

[0069] In one embodiment, the use of any of the compounds of the above embodiment, or a pharmaceutically acceptable salt thereof, is for use in the treatment of at least one skin condition or respiratory condition.

[0070] Each embodiment described herein may be combined with any other embodiment described herein that is not inconsistent with that embodiment. Furthermore, for any embodiment described herein, any compound described in the Examples, or a pharmaceutically acceptable salt thereof, may be claimed individually or grouped together with one or more other compounds from the Examples, or a pharmaceutically acceptable salt thereof.

[0071] Furthermore, in each embodiment described herein, pharmaceutically acceptable salts of the compounds described herein are assumed to fall within that range.

[0072] Unless otherwise defined herein, scientific and technical terms used herein have meanings that are commonly understood by those skilled in the art.

[0073] The disclosures described herein can be suitably carried out in the absence of any elements not specifically disclosed herein.

[0074] The compounds of this disclosure mean the compounds of formulas I and IA, where the compound of formula I may specifically be the compound of formula IA. Those skilled in the art will recognize that the compounds of this disclosure include, if possible, conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic mixtures of said isomers, diastereomer mixtures, and other mixtures, tautomers. Furthermore, those skilled in the art will recognize that, if possible, the compounds of this disclosure include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labeled forms. The compounds of this disclosure may include novel intermediates used in their preparation.

[0075] Unless otherwise specified, singular forms such as “a,” “an,” and “the” as used herein include multiple references. For example, a substituent preceded by “a” includes one or more substituents. Unless otherwise explicitly specified, the term “or” means “and / or.”

[0076] As used herein, the term "about" when used to modify numerically defined parameters means that the parameter may vary by at most ±10% from the numerical value stated 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.

[0077] "Optional" or "optionally" means that the event or situation described below may occur but is not necessarily so, and this description includes both cases in which such event or situation occurs and cases in which it does not occur.

[0078] The terms “may be substituted” and “substituted or unsubstituted” are used interchangeably to indicate that a particular group described may have no non-hydrogen substituents (i.e., be unsubstituted) or may have one or more non-hydrogen substituents (i.e., be substituted). Unless otherwise specified, the total number of possible substituents is equal to the number of H atoms present in the unsubstituted form of the group described. If an optional substituent, such as an oxo substituent (=O), is bonded through a double bond, the group occupies two available valences, and therefore the total number of other substituents involved is reduced by two. If each optional substituent is independently selected from a list of options, the selected groups may be the same or different. Throughout this disclosure, it will be understood that the number and nature of optional substituents are limited to such extent that the substitution is chemically reasonable to a person skilled in the art.

[0079] "Halogen" or "halo" refers to fluoro, chloro, bromo, and iodine (F, Cl, Br, I). More specifically, halogen can refer to fluoro and chloro.

[0080] "Cyano" refers to a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, i.e., -C≡N. "Cyanoimine" refers to a substituent having a carbon atom bonded to a nitrogen atom by a double bond and also bonded to a cyano group, i.e., -C(R)=NC≡N (wherein R can be a dimethylamino group, i.e., -C(N(CH3)2)=NC≡N).

[0081] "Hydroxy" refers to the -OH group.

[0082] "Oxo" refers to oxygen (=O) with a double bond.

[0083] "Alkyl" refers to a saturated monovalent aliphatic hydrocarbon group having a specified number of carbon atoms, including a linear or branched group. Alkyl groups have 1 to 12 carbon atoms ("C"). 1~12 Alkyl), 1 to 8 carbon atoms ("C") 1~8 Alkyl), 1 to 6 carbon atoms ("C") 1~6 Alkyl), 1 to 5 carbon atoms ("C") 1~5 Alkyl), 1 to 4 carbon atoms ("C") 1~4 Alkyl), 1 to 3 carbon atoms ("C 1~3 Alkyl), or 1-2 carbon atoms ("C") 1~2Alkyl groups may include, but are not limited to, alkyl groups. 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, and n-octyl. As further specified herein, alkyl groups may be substituted, unsubstituted, or substituted. In some cases, substituted alkyl groups are specifically named in relation to the substituents. For example, “haloalkyl” means an alkyl group having a specified number of carbon atoms substituted with one or more halo substituents up to the available valence.

[0084] "Haloalkyl" means an alkyl group as defined above, containing a specified number of carbon atoms, in which at least one hydrogen atom is replaced by a halogen. Haloalkyl groups contain 1 to 6 carbon atoms ("C"). 1~6 Haloalkyl), 1 to 4 carbon atoms ("C" 1~4 "Haloalkyl"), or 1-2 carbon atoms ("C") 1~2 This may include, but is not limited to, "haloalkyl" compounds. More specifically, fluorinated alkyl groups are sometimes specifically called "fluoroalkyl" compounds. Examples of fluoroalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl compounds. Examples of fully substituted fluoroalkyl groups (also called perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0085] "Hydroxyalkyl" means an alkyl group as defined above, in which at least one hydrogen atom is replaced by hydroxyl (OH), for example, in which only one hydrogen atom is replaced by hydroxyl, and which contains a specified number of carbon atoms. Hydroxyalkyl groups contain 1 to 6 carbon atoms ("C"). 1~6 Hydroxyalkyl), 1 to 4 carbon atoms ("C") 1~4 Hydroxyalkyl), or 1-2 carbon atoms ("C") 1~2It may include, but is not limited to, "hydroxyalkyl" compounds.

[0086] "Cyanoalkyl" means an alkyl group as defined above, containing a specified number of carbon atoms, in which at least one hydrogen atom is replaced by cyano(-C≡N). A cyanoalkyl group contains 1 to 6 carbon atoms ("C 1~6 "Cyanoalkyl"), 1 to 4 carbon atoms ("C") 1~4 "Cyanazole"), or 1-2 carbon atoms ("C") 1~2 It may contain, but is not limited to, "cyanoalkyl" compounds.

[0087] "Oxoalkyl" refers to an alkyl group containing a specified number of carbon atoms, in which at least two hydrogen atoms are replaced by an oxo group. Oxoalkyl groups contain 1 to 6 carbon atoms ("C"). 1~6 Oxoalkyl), 1 to 4 carbon atoms ("C" 1~4 "Oxoalkyl"), or 1-2 carbon atoms ("C") 1~2 It may contain, but is not limited to, "oxoalkyl" (or similar).

[0088] "Alkoxy" means an alkyl group as defined herein, with a single bond to an oxygen atom. The bond site of the alkoxy group to the molecule is through the oxygen atom. The alkoxy group can be represented as alkyl-O-. The alkoxy group has 1 to 8 carbon atoms ("C"). 1~8 Alkoxy), 1 to 6 carbon atoms ("C") 1~6 Alkoxy), 1 to 4 carbon atoms ("C") 1~4 Alkoxy), or 1 to 3 carbon atoms ("C") 1~3 The alkoxy group may include, but is not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, etc.

[0089] "Alkylene" refers to a saturated divalent aliphatic hydrocarbon group having a specified number of carbon atoms, including a linear or branched group. An alkylene group has 1 to 12 carbon atoms ("C"). 1~12 Alkylene), 1 to 8 carbon atoms ("C") 1~8Alkylene), 1 to 6 carbon atoms ("C") 1~6 Alkylene), 1 to 5 carbon atoms ("C" 1~5 Alkylene), 1 to 4 carbon atoms ("C" 1~4 Alkylene), 1 to 3 carbon atoms ("C" 1~3 Alkylene, or 1-2 carbon atoms ("C") 1~2 It may contain, but is not limited to, alkylenes.

[0090] "Cycloalkyl" refers to a complete or partially saturated hydrocarbon ring system having a specified number of carbon atoms, which can be monocyclic, bridged, condensed bicyclic, or polycyclic ring systems connected to a base molecule through the carbon atoms of the cycloalkyl ring. "Cycloalkyl" can also refer to a ring system that is a completely saturated hydrocarbon ring system. Cycloalkyl groups have 3 to 12 carbon atoms ("C"). 3~12 Cycloalkyl), 3 to 8 carbon atoms ("C" 3~8 Cycloalkyl), 3-6 carbon atoms ("C 3~6 Cycloalkyl), 3-5 carbon atoms ("C 3~5 Cycloalkyl, or 3-4 carbon atoms ("C") 3~4 This may include, but is not limited to, cycloalkyl groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantanyl. As further specified herein, cycloalkyl groups may be substituted, unsubstituted, or substituted.

[0091] A "heterocycloalkyl" is defined as a ring containing a specified number of ring atoms, with at least one heteroatom selected from N, O, and S as a ring member, and the ring S atom may be substituted with one or two oxo groups (i.e., S(=O) where q is 0, 1, or 2). q), means a fully or partially saturated ring system in which a heterocycloalkyl ring is connected to a base molecule through a ring atom that can be C or N. Heterocycloalkyl can mean a fully saturated ring system. A heterocycloalkyl ring is a ring of a spirocyclic structure, bridged or fused to one or more other heterocycloalkyl rings or carbocyclic rings, wherein the bridged or fused ring of the spirocyclic structure may itself be saturated to the extent that its unsaturation or aromaticity is chemically reasonable, partially unsaturated or aromatic, provided that the bonding site to the base molecule is an atom of the heterocycloalkyl portion of the ring system. A heterocycloalkyl ring may have N, O, and S(=O) as ring members. q It may contain 1 to 4 heteroatoms selected from, or 1 to 2 ring heteroatoms, provided that the heterocycloalkyl ring does not contain two consecutive oxygen or sulfur atoms.

[0092] As further defined herein, the heterocycloalkyl ring may or may not be substituted. Such substituents may be present on the heterocycle bonded to the base molecule, or on a spirocycle, bridging ring, or fused ring bonded thereto. The heterocycloalkyl ring may, but is not limited to, a 3- to 8-membered heterocyclyl group, such as a 4- to 7-membered or 4- to 6-membered heterocycloalkyl group, according to the definition herein.

[0093] "Aryl" or "aromatic" means that all carbon atoms in the ring are sp. 2 This refers to a hybrid ring system containing a specified number of ring atoms with conjugated π electrons, such as monocyclic, bicyclic (e.g., biaryl, condensed), or polycyclic rings. An aryl group has 6 to 20 carbon atoms ("C"). 6~20 "aryl"), 6 to 14 carbon atoms ("C") 6~14 "aryl"), 6 to 12 carbon atoms ("C") 6~12 "aryl"), or 6 to 10 carbon atoms ("C") 6~10The fused aryl group may include, but is not limited to, an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenantrenyl, indanyl, and indenyl. As further specified herein, the aryl group may be substituted, unsubstituted, or possibly substituted.

[0094] Similarly, "heteroaryl" or "aromatic heterocyclic" means that all carbon atoms in the ring are sp 2A heteroaryl group refers to a monocyclic, bicyclic (e.g., heterobiaryl, condensed), or polycyclic ring system that is hybridized, has conjugated π electrons, contains a specified number of ring atoms, and includes at least one heteroatom selected from N, O, and S as a ring member. A heteroaryl group may, but is not limited to, contain 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"). The heteroaryl ring is bonded to the base molecule through the ring atoms of the aromatic heterocycle. Thus, a 5-membered or 6-membered heteroaryl ring may be bonded to the base molecule through the ring C or N atom, either alone or in a condensed structure. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrididinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthilidinyl, sinnolinyl, quinazolinyl, quinoxalinyl, and carbazolyl. Examples of 5-membered or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl rings, furanyl rings, thiophenyl rings, pyrazolyl rings, imidazolyl rings, isoxazolyl rings, oxazolyl rings, isothiazolyl rings, thiazolyl rings, triazolyl rings, pyridinyl rings, pyrimidinyl rings, pyrazinyl rings, and pyridazinyl rings. As further specified herein, the heteroaryl group may be substituted, unsubstituted, or may be substituted.

[0095] A "heterocyclic ring" or "heterocyclic formula" means a ring system of a ring that contains at least one heteroatom selected from N, O, and S as a ring member. The ring system may include a heterocycloalkyl ring or a heteroaryl ring. The ring system may include a spiro ring, a bridging ring, or a fused ring.

[0096] "Amino" refers to an unsubstituted or substituted -NH2 group. If substituted, the term takes the form -NR. x R y Includes the base of R x and R y Either one part is an alkyl group and the other is H, or R x and R y Both are alkyl moieties, and the alkyl moieties have a specified number of carbon atoms (e.g., -NH(C) 1~3 Alkyl) or -N(C 1~3 Alkyl)2). The term "aminoheterocycloalkyl" refers to a heterocycloalkyl group substituted with an amino group.

[0097] The term "pharmaceutically acceptable" means that a substance (e.g., a compound described herein) or any salt thereof, or a composition comprising a substance or salt of a compound of the Disclosure, is suitable for administration to a subject or patient.

[0098] "Pharmaceutical composition" means a mixture of one or more compounds of the present disclosure, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, as an active ingredient, and at least one pharmaceutically acceptable excipient.

[0099] As used herein, "deuterium enrichment factor" refers to the ratio between the ratio of deuterium to hydrogen and the natural abundance of deuterium. Typically, atomic positions explicitly identified as containing deuterium have the following characteristics: 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 in each explicitly identified deuterium atom), at least 4,000 (60% deuterium incorporation), and at least 4,500 (67.5% It may have a deuterium enrichment factor of at least 5,000 (75% deuterium uptake), at least 5,500 (82.5% deuterium uptake), at least 6,000 (90% deuterium uptake), at least 6,333.3 (95% deuterium uptake), at least 6,466.7 (97% deuterium uptake), at least 6,600 (99% deuterium uptake), or at least 6,633.3 (99.5% deuterium uptake).

[0100] As used herein, “excipient” refers to any component other than the compounds disclosed herein. The choice of excipient largely depends on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the properties of the dosage form. As used herein, “excipient” includes any physiologically compatible solvent, dispersion medium, coating, antimicrobial and antifungal agents, isotonic and absorption retardants, carriers, diluents, etc. Examples of excipients include one or more of water, physiological saline, phosphate buffer solution, glucose, glycerol, ethanol, etc., and combinations thereof, and may also include isotonic agents in the composition, such as sugars, sodium chloride, or polyhydric alcohols such as mannitol or sorbitol. Examples of excipients also include various organic solvents (e.g., hydrates and solvates). If desired, the pharmaceutical composition may also contain further excipients such as flavorings, binders / binding agents, lubricants, disintegrants, sweeteners or flavorings, colorants or pigments. For example, for oral administration, tablets containing various excipients such as citric acid can be used with various disintegrants such as starch, alginic acid, and certain complex silicates, as well as binders such as sucrose, gelatin, and gum arabic. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting. The same solid compositions may be used in soft-filled and hard-filled gelatin capsules. Therefore, non-limiting examples of excipients include lactose and high molecular weight polyethylene glycol. When aqueous suspensions or elixirs are preferred for oral administration, the active compound therein can be combined with various sweeteners or flavorings, colorants or pigments, and optionally emulsifiers or suspending agents, along with further excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.Examples of excipients include pharmaceutically acceptable substances such as wetting agents, or trace amounts of auxiliary substances such as wetting agents, emulsifiers, preservatives, or buffers that improve the shelf life or effectiveness of a compound.

[0101] As used herein, the terms “to treat,” “to treat,” or “treatment” encompass both preventive treatment, i.e., protective treatment, and symptomatic treatment, i.e., treatment to reduce, alleviate, or slow the progression of a patient’s disease (or condition) or any tissue damage associated with the disease.

[0102] As used herein, the terms “subject,” “individual,” or “patient” are interchangeable and mean any animal, including mammals. Mammals as disclosed herein include dogs, cats, cattle, goats, horses, sheep, pigs, rodents, rabbits, primates, and humans, and include mammals in utero. Humans may be preferred subjects. Human subjects may be of any sex and at any developmental stage.

[0103] As used herein, the term “therapeutic dose” means the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician aims to induce a biological or medical response in a tissue, system, animal, individual, or human, which may include one or more of the following: (1) To prevent disease; for example, to prevent disease, condition, or disability in an individual who may be predisposed to disease, condition, or disability but has not yet experienced or presented the pathology or overall symptoms of the disease; (2) inhibiting the disease; for example, inhibiting the disease, condition, or disorder in an individual experiencing or presenting the pathology or overall symptoms of the disease, condition, or disorder (i.e., stopping (or delaying) the further progression of the pathology or overall symptoms or both); and (3) To improve a disease; for example, to improve a disease, condition, or disorder in an individual who is experiencing or presenting with the pathology or overall symptoms of a disease, condition, or disorder (i.e., to improve the pathology or overall symptoms or both).

[0104] The term "pharmaceutically acceptable salt" encompasses salts of the compounds of the disclosed which are generally prepared by reacting a free base or free acid with a suitable organic or inorganic acid or a suitable organic or inorganic base, respectively, to produce a salt of the compounds of the disclosed which is suitable for administration to a subject or patient.

[0105] Furthermore, the compounds of the present disclosure may include other salts of the compounds, which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for one or more of the following: 1) preparing the compounds of the present disclosure; 2) purifying the compounds of the present disclosure; 3) separating enantiomers of the compounds of the present disclosure; or 4) separating diastereomers of the compounds of the present disclosure.

[0106] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipine, aspartate, benzoate, besilate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansilate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, and maleic acid. Examples of salts include, but are not limited to, salts, malonates, mesylates, methylsulfates, naphthylates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, saccharates, stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates, 1,5-naphthalenedisulfonates, and xinofoates. Salts may be trifluoroacetates or formates.

[0107] Suitable basic salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, olamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0108] Hemi salts of acids or bases, such as hemisulfates and hemicalcium salts, can also be formed.

[0109] For a review of suitable salts, see Paulekun, GS 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.

[0110] A pharmaceutically acceptable salt of the compound of this disclosure can be prepared by methods well known to those skilled in the art, including but not limited to the following procedure: (i) A method for reacting a compound of the present disclosure with a desired acid or base; (ii) A method of removing an acid-instability or base-instability protecting group from a suitable precursor of the compound of the Disclosure, or of ring-opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base; or (iii) A method for converting one salt of a compound of the present invention to another salt. This can be achieved by reaction with a suitable acid or base, or by a suitable ion exchange procedure.

[0111] Typically, these procedures are carried out in solution. The resulting salt may be precipitated and filtered, or recovered by evaporation of the solvent.

[0112] The compounds of this disclosure and their pharmaceutically acceptable salts may exist in non-solvated and solvated forms. In this specification, the term “solvate” is used to describe a molecular complex comprising a compound of this disclosure or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term “hydrate” is used when the solvent is water.

[0113] Furthermore, the compounds of the present disclosure may include other solvates of the compounds, which are not necessarily pharmaceutically acceptable solvates, but may be useful as intermediates for one or more of the following: 1) preparing the compounds of the present disclosure; 2) purifying the compounds of the present disclosure; 3) separating enantiomers of the compounds of the present disclosure; or 4) separating diastereomers of the compounds of the present disclosure.

[0114] The currently accepted classification system for organic hydrates defines them as segregated-site hydrates, channel hydrates, or metal-ion coordinated hydrates. See KRMorris' Polymorphism in Pharmaceutical Solids (Ed. HGBrittain, Marcel Dekker, 1995). Segregated-site hydrates are hydrates in which water molecules are segregated from direct contact with each other by the interposition of organic molecules. In channel hydrates, water molecules exist in lattice channels, where they are adjacent to other water molecules. In metal-ion coordinated hydrates, water molecules are bound to metal ions.

[0115] When the solvent or water is tightly bound, the complex can have a distinct stoichiometric composition independent of humidity. However, when the solvent or water is weakly bound, such as in channel solvates and hygroscopic compounds, the water / solvent content can depend on humidity and dry conditions. In these cases, a non-stoichiometric composition is standard.

[0116] Multicomponent complexes (other than salts and solvates) in which a drug and at least one other component are present in stoichiometric or non-stoichiometric amounts are also included within the scope of this disclosure. This type of complex includes clathrates (drug-host inclusion complexes) and cocrystals. Typically, the latter are defined as crystalline complexes of neutral molecular components bonded together through non-covalent interactions; for example, hydrogen-bonded complexes (cocrystals) can be formed by neutral molecules or salts. Cocrystals can be prepared by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. See O. Almarsson and MJ Zaworotko, Chem Commun, 17;1889–1896 (2004). For a general review of multicomponent complexes, see Haleblian, J Pharm Sci, 64(8), 1269–1288 (August 1975).

[0117] The compounds of this disclosure may exist as 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 can exhibit solid or liquid physical properties depending on the temperature. Typically, these materials do not exhibit characteristic X-ray diffraction patterns and, although they exhibit solid properties, are more often described morphologically as liquids. Upon heating, a change in properties occurs from solid to liquid, usually characterized by a phase change, typically a second-order phase change ("glass transition"). The term "crystalline" refers to a solid phase in which the material has an internal structure with regular order at the molecular level and exhibits a characteristic X-ray diffraction pattern with specific peaks. These materials also exhibit liquid properties when sufficiently heated, but the change from solid to liquid is characterized by a phase change, usually a first-order phase change ("melting point").

[0118] Furthermore, the compounds of this disclosure may exist in an intermediate phase state (intermediate phase or liquid crystal) when subjected to suitable conditions. The intermediate phase state is an intermediate between the true crystalline state and the true liquid state (molten or solution), and consists of a two-dimensional order at the molecular level. Liquid crystallinity resulting from a temperature change is described as "thermotropic," and liquid crystallinity 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 a lyotropic intermediate phase are described as "amphiphilic" and ionic (e.g., -COO) - Na + , -COO - K + , or -SO3 - Na + ) or nonionic (e.g., -N - N + It consists of molecules having a polar head group of (CH3)3). For further information, see Crystals and the Polarizing Microscope, 4. th See Edition (Edward Arnold, 1970).

[0119] The compounds of this disclosure may exist as two or more stereoisomers. These stereoisomers may include cis and trans isomers (geometric isomers), optical isomers, such as R and S enantiomers, diastereomers, rotational isomers, atrop isomers, and conformational isomers. For example, a compound of this disclosure containing one or more chiral carbon atoms may exist as two or more stereoisomers. If the compound of this 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.

[0120] Furthermore, pharmaceutically acceptable salts of the compounds of this disclosure may include counterions that are optically active (e.g., d-lactic acid or l-lysine) or racemic (e.g., dl-tartaric acid or dl-arginine).

[0121] The cis / trans isomers can be separated by conventional techniques known to those skilled in the art, such as chromatography and fractional recrystallization.

[0122] Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or separation of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, a racemate (or racemic precursor) can be reacted with a suitable optically active compound, such as an alcohol, or, if the compound of the Disclosure contains an acidic or basic moiety, with an acid or base such as 1-phenylethylamine or tartaric acid. The resulting diastereomer mixture can be separated by techniques using chromatography, fractional crystallization, or both of the aforementioned techniques, and one or both diastereomers can be converted to the corresponding pure enantiomers by means known to those skilled in the art. Chiral compounds of the Disclosure (and their chiral precursors) can be obtained in enantiomerically concentrated forms using chromatography, usually by HPLC concentration of the eluent to obtain the concentrated mixture. Chiral chromatography using subcritical and supercritical fluids can be used. Chiral chromatography methods useful in this 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 the references cited therein).

[0123] When any racemic mixture crystallizes, two different types of crystals can exist. The first type is the racemic compound (true racemic mixture) mentioned above, which produces one homogeneous crystalline form containing equimolar amounts of both enantiomers. The second type is a racemic mixture or racemic aggregate, which produces two crystalline forms, each containing one enantiomer, in equimolar amounts. Both crystalline forms present in a racemic mixture have the same physical properties, although they may have different physical properties compared to a true racemic mixture. Racemic mixtures can be separated by the prior art known to those skilled in the art. See, for example, ELEEliel and SHWilen in Stereochemistry of Organic Compounds (Wiley, 1994).

[0124] When structural isomers are interconvertible across low-energy barriers, tautomerism ("tautomerism") may occur. This can take the form of proton tautomerism in compounds of the disclosure that include, for example, imino / amino, keto / enol, oxime / nitroso, or lactam / lactim groups, or so-called valence tautomerism in compounds that include aromatic moieties. Thus, a single compound may exhibit two or more isomers.

[0125] For the sake of brevity, the compounds disclosed herein are described in a single tautomer form; however, it should be emphasized that all possible tautomer forms are included within the scope of this disclosure.

[0126] This disclosure includes all pharmaceutically acceptable isotope-labeled compounds of formula I in which one or more atoms are substituted with atoms having the same atomic number but a different atomic mass or mass number than the atomic mass or mass number that is dominant in nature.

[0127] Examples of isotopes that are preferably included in the compound of formula I include: 2 H(D, deuterium) and 3 Hydrogen isotopes such as H (tritium), 11 C, 13 C, and 14 Carbon isotopes such as C,36 Chlorine isotopes such as Cl, 18 Fluorine isotopes such as F, 123 I and 125 Iodine isotopes such as I, 13 N and 15 Nitrogen isotopes such as N, 15 O, 17 O, and 18 Oxygen isotopes such as O, 32 Phosphorus isotopes such as P, as well as 35 Examples include, but are not limited to, sulfur isotopes such as 150 (S).

[0128] Certain isotope-labeled compounds of formula I, such as compounds that incorporate radioactive isotopes, are useful in tissue distribution studies for either or both drugs and substrates. Tritium and 14 Radioactive isotopes such as 13C are particularly useful for this purpose because they are easily incorporated and readily available as a detection method. 11 C, 18 F, 15 O, and 13 Substitution with positron-emitting isotopes such as 12N may be useful in positron emission tomography (PET) studies to investigate substrate acceptor occupancy. Deuterium, i.e. 2 H substitution may result in certain therapeutic benefits due to increased metabolic stability, such as an increased in vivo half-life, reduced required dose, reduced CYP450 inhibition (competitive or time-dependent), or improved therapeutic index or tolerability.

[0129] This disclosure provides deuterium-labeled (or deuterated) compounds and salts, the formulas and variability elements of the compounds and salts being independently as described herein. “Deuterated” means that at least one atom in the compound is deuterium in an abundance exceeding the natural abundance of deuterium (typically about 0.015%). Those skilled in the art will recognize that in compounds containing hydrogen atoms, the hydrogen atoms are actually a mixture of H and D, with about 0.015% being D. The concentration of deuterium incorporated into the deuterium-labeled compounds and salts of formula I may be defined by the deuterium concentration factor. It will be understood that one or more deuterium atoms may be exchanged for hydrogen under physiological conditions.

[0130] The deuterium compound may be selected from any one of the compounds specifically illustrated in the Examples section.

[0131] One or more hydrogen atoms at specific metabolic sites in the compound of formula I may be deuterated.

[0132] In general, isotope-labeled compounds of formula I can be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the following examples and preparation examples, using appropriate isotope-labeled reagents instead of conventionally used unlabeled reagents.

[0133] The pharmaceutically acceptable solvates of this disclosure include solvates in which the crystallization solvent, such as D2O, d6-acetone, or d6-DMSO, may be isotope-substituted.

[0134] The compounds of this disclosure may be administered in the form of prodrugs. Therefore, certain derivatives of the compounds of this disclosure, which may themselves have little or no pharmacological activity, may be converted to the compounds of this disclosure having desired activity upon administration into or onto the body, for example, by hydrolytic cleavage, particularly facilitated by esterase or peptidase enzymes. These derivatives are referred to as “prodrugs.” Further information on the use of prodrugs can 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.).

[0135] For example, the prodrugs of the present disclosure may be prepared by substituting appropriate functional groups present in the compounds of the present disclosure with specific parts known to those skilled in the art as "pro-moieties," as described, for example, in H. Bundgaard's "Design of Prodrugs" (Elsevier, 1985).

[0136] Accordingly, the prodrugs of the present disclosure may be (a) ester or amide derivatives of carboxylic acids, if present in the compounds of the present disclosure; (b) ester, carbonate, carbamate, phosphate, or ether derivatives of hydroxyl groups, if present in the compounds of the present disclosure; (c) amide, imine, carbamate, or amine derivatives of amino groups, if present in the compounds of the present disclosure; (d) thioester, thiocarbonate, thiocarbamate, or sulfide derivatives of thiol groups, if present in the compounds of the present disclosure; or (e) oxime or imine derivatives of carbonyl groups, if present in the compounds of the present disclosure.

[0137] Some specific examples of the prodrugs of this disclosure include: (i) If a compound of the present disclosure contains a carboxylic acid functional group (-COOH), then the ester thereof, for example, the hydrogen of the carboxylic acid functional group of the compound is C 1~8 Alkyl (e.g., ethyl) or (-C 1~8 Alkyl)C(=O)OCH2-(for example t Compounds replaced by BuC(=O)OCH2-); (ii) If the compound of the present disclosure contains an alcohol functional group (-OH), then the ester thereof, for example, the hydrogen of the alcohol functional group of the compound is -CO(C 1~8 Compounds in which an alkyl group (e.g., methylcarbonyl) is replaced, or the alcohol is esterified with an amino acid; (iii) If a compound of the present disclosure contains an alcohol functional group (-OH), then the ether, for example, the hydrogen of the alcohol functional group of the compound is (C 1~8 Compounds in which alkyl)C(=O)OCH2- or -CH2OP(=O)(OH)2 are substituted; (iv) If a compound of the present disclosure contains an alcohol functional group (-OH), its phosphate ester, for example, the hydrogen of the alcohol functional group of the compound is -P(=O)(OH)2 or -P(=O)(O - Na + )2 or -P(=O)(O - )2Ca 2+ A compound replaced by; (v) If a compound of the Disclosure contains a primary or secondary amino functional group (-NH2, or -NHR where R≠H), the amide, for example, depending on the compound, may contain one or both hydrogens of the amino functional group (C 1~10 ) Compounds in which the alkanoyl group is replaced with -COCH2NH2, or in which the amino group is derivatized with an amino acid; (vi) If the compound of the present disclosure contains a primary or secondary amino functional group (-NH2, or -NHR where R≠H), the amine thereof, for example, a compound in which one or both hydrogens of the amino functional group of the compound are replaced with -CH2OP(=O)(OH)2, as may be the case.

[0138] Certain compounds of the Disclosure may themselves act as prodrugs of other compounds of the Disclosure, and it is also possible to conjugate two compounds of the Disclosure together in the form of prodrugs. In certain circumstances, prodrugs of the compounds of the Disclosure can be created by internally linking two functional groups in the compounds of the Disclosure, for example, to form a lactone.

[0139] The active metabolites of the compounds disclosed herein, i.e., compounds formed in vivo, often by oxidation or dealkylation, upon administration of the drugs, are also included within the scope of this disclosure. Some examples of metabolites of this disclosure include, but are not limited to, the following: (i) If the compound disclosed herein contains an alkyl group, its hydroxyalkyl derivative (-CH → -COH): (ii) If the compound disclosed herein contains an alkoxy group, its hydroxy derivative (-OR→-OH); (iii) If the compound disclosed herein contains a tertiary amino group, its secondary amino derivative (-NRR' → -NHR or -NHR'); (iv) If the compound disclosed herein contains a secondary amino group, its primary derivative (-NHR→-NH2); (v) If the compound disclosed herein contains a phenyl moiety, its phenol derivative (-Ph→-PhOH); (vi) If the compound disclosed herein contains an amide group, its carboxylic acid derivative (-CONH2→COOH); and (vii) If the compound contains a hydroxyl group or a carboxylic acid group, it may be metabolized to form a glucuronide, for example, by conjugation with glucuronic acid. Other conjugation metabolic pathways also exist. These pathways are often known as phase II metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, can also be conjugated.

[0140] This compound or a pharmaceutically acceptable salt thereof may have the structure of formula I, or formula IA or formula IB. The compound of formula I may have the structure of formula IA or formula IB.

[0141] [ka]

[0142] X1 can be CH, CNH2, or N. X1 can be N.

[0143] X2 can be C or N.

[0144] X3 is CR 13 , N, NR 13 It can be O, or S. X3 is CR 13 It is possible that X3 is N or NR. 13 It is possible. X3 is CR 13 Or it could be N.

[0145] X4 is CH, N, or NR 13 It is possible. X4 can be CH, N, or N-cyclopropyl. X4 can be N.

[0146] X5 is CH, CR 1B , or it could be N. X5 could be CH.

[0147] X6 can be CH or N.

[0148] X7 can be CH, N, or CF. X7 can be CH or N. X7 can be CCl.

[0149] X8 can be CH or N. X8 can be CH.

[0150] X9 is CH, CR 1B It could be N.

[0151] X 10 CH, CR 1B It could be N. At least one of X2 can be N, or X3 can be N, NH, or NR 13 It is possible that X4 is N.

[0152] If X3 is S or O, then X2 can be C.

[0153] X3 is CR 13 or NR 13 If X4 is NR, then X4 can be CH or N. 13 In that case, X3 can be N, O, or S.

[0154] A dashed line indicates a single bond (i.e., no dashed line exists, and only a single bond remains) or a double bond (i.e., the dashed line exists as the second bond constituting a double bond). A dashed line can indicate a single bond. When a dashed line indicates a double bond, R 4B It does not exist, and n is 1.

[0155] R1 is -NHR8, -OH, -C 2~5 A complex algebra, or -C 1~3 It can be alkyl. R1 is -NHR8, -C 2~5 A complex algebra, or -C 1~3 It can be alkyl. R1 is -C 2~5 It can be a complex ring, and has one or more -C elements, or one, two, or three -C elements. 1~3 Alkyl, -C 1~3 Oxoalkyl, -C 3~5 Heterocycloalkyl, -C 3~5 Hydroxyheterocycloalkyl, -C 3~5 It may be substituted with an aminoheterocycloalkyl or oxo molecule. R1 is -C 2~5 It can be a complex ring, and has one or more -C elements, or one, two, or three -C elements. 1~3 It may be substituted with alkyl or oxo. R1 is -C 2~5 It can be a complex ring and may be substituted with oxos. R1 is -C 1~3 It can be alkyl, and have one, two, or three oxo, -NR 10A R 11 , or -NR 10 R 11 It may be replaced with -C. 1~3It can be alkyl, and one or two oxo, -NR 10A R 11 , or -NR 10 R 11 It may be replaced by R1. R1 is one or more oxos or -NRs, or one, two or three oxos or -NRs. 10 R 11 Even if it is replaced with -C 1~3 It can be alkyl. R1 is oxo and -NR 10 R 11 -C replaced by 1~3 It can be alkyl. R1 is oxo and -NR 10A R 11 -C replaced by 1~3 It can be alkyl. R1 can be -NHR8. -C 2~5 Complex algebra, -C 3~5 Heterocycloalkyl, -C 3~5 Hydroxyheterocycloalkyl, and -C 3~5 Each aminoheterocycloalkyl can independently contain 1 to 4 heteroatoms, each containing at least one N, O, or S. R1 -C 2~5 A heterocycle may contain 1 to 4 heteroatoms, each containing at least one N, O, or S atom, and all of these heteroatoms may be N.

[0156] R 1A It can be H. 1A It can be -CH3. 1A R can be H, halogen, or -CH3. 1A can be H or a halogen, and the halogen can be F.

[0157] R1 and R 1A This is a C condensed into a D ring. 5~7 Heterocycloalkyl, or C condensed to a D ring 5~7 It can form heteroaryls. C 5~7 Heterocycloalkyl or C 5~7 The heteroaryl may be substituted with an oxo. R1 and R 1A C may be substituted with an oxo. 6~8Condensed heterocycloalkyls can be formed. R1 and R 1A C may be substituted with an oxo. 6~8 It can form condensed heteroaryls. C 6~8 Condensed heterocycloalkyl and C 6~8 Each condensed heteroaryl can independently contain 1 to 3 heteroatoms, each containing at least one N, O, or S atom.

[0158] Each R 1B These are independently H, -CH3, F, Cl, or methoxy.

[0159] R2 is H, -C 1~3 Alkyl, -C 1~3 Alkoxy, -C 1~3 It can be a fluoroalkyl or halogen. R2 can be H.

[0160] R3 is -C 1~3 Alkyl, -C 2~10 Heterocycle, -P(=O)(CH3)2, -S(=O)CH3, -NH-S(=O)2CH3, or -NH-C(=O)-C 1~3 It can be alkyl. R3 is -C 1~3 Alkyl, -C 2~10 It can be a complex ring, -P(=O)(CH3)2, -S(=O)CH3, or -NH-S(=O)2CH3. R3 is -C 1~3 Alkyl, -C 2~10 Heterogeneous ring, or -NH-C(=O)-C 1~3 It can be alkyl. R3 can be one or more, or one, two or three oxo, -OH, halogen, or -C. 3~6 Cycloalkyl, -NR 12 R 12A , -C 5~8 Heterocyclic rings, or may be substituted with cyano compounds, -C 1~3 It can be alkyl. R3 is oxo and -NR 12 R 12A -C replaced by 1~3 It can be alkyl. R3's -C 2~10 The complex algebra is -C 2~10 Heterocycloalkyl or -C2~10 It can be a heteroaryl. R3 -C 2~10 The complex algebra is -C 2~6 Heterocycloalkyl or -C 2~6 It can be a heteroaryl. R3 has one or more -OH groups, or one, two, or three -OH groups, halogens, and -C groups. 1~3 Hydroxyalkyl, -C 1~3 Alkoxy, -C 1~3 Alkyl, -C 1~3 -C may be substituted with fluoroalkyl, cyclopropyl, or oxo. 2~10 It can be a heterocycle. R3 may have one or more -OH, halogen, or -C groups, or one, two, or three -OH groups. 1~3 Hydroxyalkyl, -C 1~3 -C may be substituted with alkyl, cyclopropyl, or oxo. 2~10 It may be a heterocycloalkyl. R3 may be one or more, or one, two, or three oxos or -NRs. 12 R 12A Even if it is replaced with -C 1~3 It can be alkyl. R3 is -C 1~3 C may be substituted with alkyl. 2~5 It can be a complex algebra. R3 has one or more -C elements, or one, two, or three -C elements. 1~3 It may be substituted with alkyl, -C 2~5 It can be a heteroaryl compound. -C 2~10 Complex algebra, -C 5~8 Complex algebra, -C 2~6 Heterocycloalkyl, -C 2~10 Heterocycloalkyl, -C 2~10 Heteroaryl, -C 2~6 Heteroaryl, or -C 2~5 Each heterocycle can independently contain 1 to 3 heteroatoms, each containing at least one N, O, or S. R3's -C 2~10 The heterocycle may contain 1 to 3 heteroatoms, including at least one N, O, or S. R3 -C 2~10 Heterocycles undergo spiro, condensation, or bridging -C 2~10 It can be a complex algebra. C of R15~8 A heterocycle can contain 1 to 4 heteroatoms, each containing at least one N, O, or S atom.

[0161] R2 and R3 are 1, 2, or 3 -C 1~3 Alkyl, -C 2~3 A C condensed on the A ring, which may be substituted with an oxoalkyl or oxo group. 3~6 They can form a complex ring. R2 and R3 have one or more, or one, two, or three -C elements. 1~3 Alkyl, -C 2~3 A C condensed on the A ring, which may be substituted with an oxoalkyl or oxo group. 3~6 It can form heterocycloalkyl groups. 3~6 Heterogene or C 3~6 Each heterocycloalkyl can independently contain 1 to 3 heteroatoms, each containing at least one N, O, or S atom.

[0162] R 4A H, -OH, -C 1~3 Fluoroalkyl, or -C 1~3 It can be alkyl. 4A is H, -C 1~3 Fluoroalkyl, or -C 1~3 It could be alkyl.

[0163] R 4B It can be H. 4B It is possible that it does not exist.

[0164] R 4A and R 4B These can combine to form a cyclopropyl group.

[0165] R 4B And one R5 together forms a C condensed into ring B. 3~5 It can form cycloalkyl groups.

[0166] Each R5 independently contains H, -OH, and -C. 3~6 Cycloalkyl (e.g., cyclopropyl), halogen, -C 1~3Fluoroalkyl, or -C 1~3 It can be alkyl. Each R5 can independently be H, halogen, or -C 1~3 It can be alkyl. Two R5 groups can combine to form cyclopropyl. When the dashed line represents an existing double bond, R5 is H, -C 3~6 Cycloalkyl (e.g., cyclopropyl), halogen, -C 1~3 Fluoroalkyl, or -C 1~3 It could be alkyl.

[0167] R6 is H, -OH, or -C 1~3 It can be alkyl. R6 is H or -C 1~3 It could be alkyl.

[0168] R 4A And R6 together is C 1~3 Alkyl crosslinking or C 1~3 They can form heteroalkyl crosslinks. One R5 and R6 together form C 1~3 Alkyl crosslinking or C 1~3 It can form heteroalkyl crosslinks. C 1~3 Heteroalkyl crosslinks may contain one heteroatom from among N, O, or S.

[0169] R7 H, -C 1~3 Alkyl, or -C 1~3 It can be a hydroxyalkyl group. R7 is H or -C 1~3 It could be alkyl.

[0170] R8 H, -C 1~3 Alkyl, -SO2CH3, or -C 3~4 It can be a complex algebra. R8 is H, -C 1~3 Alkyl, or -C 3~4 It can be a complex ring. R8 has one, two, or three oxos, -C 3~9 Heterocycloalkyl, methyl-substituted -C 3~9 Heterocycloalkyl, -C 1~3 Alkoxy, cyanoimine, or -NR9R 10 -C was replaced with 1~3It can be alkyl. R8 is one or more, or one, two, or three oxo or -NR9R 10 Even if it is replaced with -C 1~3 It can be alkyl. R8 is one or two oxo or -NR9R 10 Even if it is replaced with -C 1~3 It can be alkyl. R8 is oxo and -NR9R 10 -C replaced by 1~3 It can be alkyl. R8 has one, two, or three oxo, halogen, or -C atoms. 0~1 Alkilen-NR 10 R 11 -OH, -C 1~3 Hydroxyalkyl, -C 1~3 Alkyl-C 1~3 Alkoxy, -C 1~3 Oxoalkyl, -C 1~3 Alkyl, or -NR 10 R 11 Even if replaced with -C 1~3 -C may be substituted with an alkoxy. 3~4 It can be a complex algebra. -C of R8 3~9 Heterocycloalkyls have one, two, or three -C atoms. 1~3 alkyl, -OH, -C 1~3 Hydroxyalkyl, -OC 1~3 Hydroxyalkyl, -C 1~3 Alkoxy, -C 1~3 Alkyl-C 1~3 Alkoxy, halogen, -C 1~3 Fluoroalkyl, -C 1~3 Fluoroalkoxy, cyano, -C 1~3 Cyanoalkyl, -C 0~1 Alkylene-C 3~5 Heterocycloalkyl, -OC 3~5 Heterocycloalkyl, -C 0~1 Alkilen-NR 10 R 11 It may be replaced with R8. R8 is one or more, or one, three, or three oxos or -C 1~3 It may be substituted with alkyl, -C 3~4It can be a complex algebra. -C of R8 3~4 Heterogeneous algebra or -C 3~9 Each heterocycloalkyl can independently contain 1 to 4 heteroatoms, each containing at least one N, O, or S. R8 -C 3~4 The heterocycle may contain 1 to 4 heteroatoms, including at least one N or O. R8 -C 3~9 A heterocycloalkyl group may contain 1 to 3 heteroatoms, including at least one N or O atom. R8 -C 3~4 Heterogeneous algebra or -C 3~9 Heterocycloalkyls can be crosslinked, spiro, or fused heterocycles.

[0171] R9 is H, -C 1~4 Alkyl, -C 1~4 Hydroxyalkyl, -C 1~3 Fluoroalkyl, -C 3~5 Cycloalkyl,-methylene-phenylene-NH-C(=O)-NR 10 R 11 , or -C 3~5 It can be a heterocycloalkyl. R9 may have one or more, or one, two, or three -C atoms. 3~5 Cycloalkyl, -C 3~5 -C may be substituted with heterocycloalkyl or methoxy. 1~4 It can be alkyl. R9 has one or two -OH or -C groups. 1~3 R9's -C may be substituted with alkyl. 3~5 It can be a cycloalkyl. R9 is H or -C 1~4 It can be alkyl. R9 -C 3~5 Each heterocycloalkyl can independently contain one or two heteroatoms, each containing at least one N or O atom.

[0172] Each R 10 H or -C 1~4 It can be alkyl. Each R 10 H or -C 1~3 It could be alkyl.

[0173] R10A is -C 1~3 C may be substituted with alkyl. 0~1 Alkylene-C 3~5 It can be heterocycloalkyl. 10A C 3~5 A heterocycloalkyl group may contain one heteroatom (N).

[0174] R8 -C 1~3 Alkyl is -NR9R 10 If replaced by the corresponding R9 and R 10 They are together C 3~9 Heterocycloalkyl or C 3~9 Heterocycloalkyl groups may be formed.

[0175] Each R 11 H or -C 1~3 It could be alkyl.

[0176] R 12 is H, -C 1~3 Alkyl, -C 1~3 Hydroxyalkyl, -(CH2) 0~2 -C 3~5 Heterocycloalkyl, -(CH2) 1~2 -OC 3~5 Heterocycloalkyl,-methylene-C(=O)-NR 10 R 11 , or -methylene-phenylene-NH-C(=O)-NR 10 R 11 It is possible. R 12 (CH2) 0~2 -C 3~5 Heterocycloalkyl or -(CH2) 1~2 -OC 3~5 Heterocycloalkyl is -C 1~4 Alkyl, -C 1~3 Alkyl-C 1~3 Alkoxy, -(CH2) 0~1 -phenyl, halogen, -C 1~3 Fluoroalkyl, or -(CH2) 0~1 -C 3~5 It may be substituted with a heterocycloalkyl group.12 -C 1~3 Alkyl is one, two, or three oxo or NR 10 R 11 It may be replaced with R. 12 (CH2) 0~2 -C 3~5 Heterocycloalkyl, -(CH2) 1~2 -OC 3~5 Heterocycloalkyl, or -(CH2) 0~1 -C 3~5 Each heterocycloalkyl can independently contain one or two heteroatoms, each containing at least one N or O atom.

[0177] R 12A It can be H. 12A is -C 1~4 It could be alkyl.

[0178] R 12 and R 12A This is one, two, or three -C 1~3 Alkyl, -OH, oxo, halogen, -C 2~3 Oxoalkyl, -C 1~3 Alkoxy, -C 1~3 Hydroxyalkyl, -C 1~3 Alkyl-C 1~3 Alkoxy, cyano, -C 3~6 Cycloalkyl, -S(=O)2CH3, -S(=O)2CH2CH3, -C(=O)-NR 10 R 11 C may be substituted with -NHC(=O)CH3. 3~10 It can form a complex algebra. C 3~10 A heterocycle can contain 1 to 4 heteroatoms, each containing at least one N, O, or S atom. 3~10 A heterocycle can be a bridge, spiro, or fused heterocycle.

[0179] R 13 is H, -C 1~6 Alkyl, -C 1~4 Hydroxyalkyl, -C 1~3 Fluoroalkyl, -C 1~3 Alkyl-C1~3 Alkoxy, -C 1~4 Cyanoalkyl, -C 0~1 Alkylene-C 3~5 Cycloalkyl, -C 2~4 Oxoalkyl, or -C 0~1 Alkylene-C 3~5 It can be heterocycloalkyl. 13 is H, -C 1~4 Alkyl, -C 1~4 Hydroxyalkyl, -C 1~3 Fluoroalkyl, -C 3~5 Cycloalkyl, or -C 3~5 It can be heterocycloalkyl. 13 It can be H. 13 is -C 0~1 - May be cyclopropyl 13 -C 1~6 Alkyl is one, two, or three oxo, fluoro, -NH2, C 3~6 It may be substituted with a cycloalkyl or methoxy compound. 13 -C 3~5 Cycloalkyl or -C 3~6 Cycloalkyls have one, two, or three -C atoms. 1~3 Alkyl, -C 1~3 It may be substituted with a fluoroalkyl or halogen. 13 -C 3~5 A heterocycloalkyl group may contain 1 to 3 heteroatoms, each containing at least one N, O, or S atom.

[0180] R 14 It can be H.

[0181] X4 is NR 13 It could be, R 13 and R 14 This is a C condensed into a C ring. 4~5 It can form a complex algebra.

[0182] The variable n can be 1 or 2.

[0183] The variable m can be 0 or 1.

[0184] Each heterocycle independently contains 1 to 4 heteroatoms, each containing at least one N, O, or S atom.

[0185] At least one hydrogen atom in the compound of formula I can be deuterium.

[0186] The values ​​A, B, C, and D used to indicate rings in formula I can be used to identify the corresponding rings in formulas IA and IB.

[0187] When specifying the number of elements in formulas I, IA, or IB, the term “one or more” refers, for example, independently each time the term is used, to one to four or one to three of the enumerated options.

[0188] The compound or a pharmaceutically acceptable salt thereof may be N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidine-1-yl)pyridine-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide.

[0189] The compound or its pharmaceutically acceptable salt may be 5-(5-(dimethylcarbamoyl)pyridine-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide.

[0190] The compound or its pharmaceutically acceptable salt may be 5-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyridine-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide.

[0191] The compound or its pharmaceutically acceptable salt may be 5-(5-(dimethylcarbamoyl)pyridine-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide.

[0192] The compound or its pharmaceutically acceptable salt may be (S)-5-(5-(dimethylcarbamoyl)pyridine-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.

[0193] The compound or its pharmaceutically acceptable salt may be (S)-5-(4-(dimethylcarbamoyl)phenyl)-1-isopropyl-7-methyl-N-(4-(4-methylpiperazine-1-carboxamide)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide.

[0194] The compound or its pharmaceutically acceptable salt may be 5-(5-(dimethylcarbamoyl)pyridine-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.

[0195] The pharmaceutical composition may contain a compound of formula I. For example, the pharmaceutical composition may contain a compound of formula IA.

[0196] The compositions of this disclosure may be in various forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., solutions for injection and infusion), dispersions, or suspensions, as well as tablets, capsules, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic use.

[0197] Typical compositions are in the form of injectable or infusion solutions, similar to compositions commonly used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). Compounds can be administered by intravenous infusion or intravenous injection. Compounds can be administered by intramuscular or subcutaneous injection.

[0198] Oral administration of solid dosage forms may be presented in individual units such as hard or soft capsules, pills, cachets, licks, or tablets, each containing a predetermined amount of at least one compound of the present disclosure. Oral administration may be in the form of a powder or granules. Oral dosage forms may be sublingual, for example, licks. Typically, these solid dosage forms combine the compounds of the present disclosure with one or more adjuvants. These capsules or tablets may include controlled-release formulations. In the case of capsules, tablets, and pills, the dosage forms may include buffers and may be prepared by enteric coating.

[0199] Oral administration may be in liquid dosage form. Examples of liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, for example, containing an inert diluent commonly used in the art (e.g., water). These compositions may also contain auxiliary agents, such as one or more wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), or fragrances.

[0200] This disclosure includes parenteral dosage forms. Examples of parenteral administration include subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable formulations (i.e., sterile aqueous or oily suspensions for injection) can be formulated using one or more suitable dispersants, lubricants, or suspending agents according to known techniques.

[0201] This disclosure includes topical dosage forms. “Topical administration” includes, for example, skin administration and transdermal administration, such as administration via transdermal patch or ion electrophoresis, intraocular administration, or intranasal or inhalation administration. Transdermal administration compositions include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain compounds that promote the absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this disclosure are administered transdermally, administration is achieved using a reservoir and a porous membrane-type patch or a solid matrix-type patch. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, bandages, foams, films, skin patches, wafers, implants, sponges, fibers, adhesive 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, BCFinnin and TMMorgan, J.Pharm.Sci., vol.88, pp.955-958, 1999.

[0202] Suitable formulations for topical administration to the eye include, for example, eye drops in which the compounds of this disclosure are dissolved or suspended in a suitable excipient. Typical formulations suitable for transocular or transaural administration may be in the form of a finely powdered suspension or solution droplets in isotonic, pH-adjusted sterile saline. Other formulations suitable for transocular or transaural administration include ointments, biodegradable (i.e., absorbent gel sponge, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particulate or vesicle systems such as niosomes or liposomes. Cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gelan gum may be incorporated together with preservatives such as benzalkonium chloride. These formulations may be delivered by iontophoresis.

[0203] For intranasal administration, the compounds of this disclosure are conveniently delivered in the form of a liquid or suspension from a pump spray container squeezed or pumped by the patient, or in the form of an aerosol spray from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder from a dry powder inhaler (alone, as a dry blend with a mixture, e.g., lactose, or as mixed component particles mixed with phospholipids such as phosphatidylcholine), 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 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 contain a bioadhesive, e.g., chitosan or cyclodextrin.

[0204] This disclosure includes rectal dosage forms, which may be, for example, suppositories. Cocoa butter is a traditional suppository base, but various substitutes may be used as appropriate.

[0205] Other excipients and modes of administration known in the pharmaceutical technology field may be used. The pharmaceutical compositions of this disclosure can be prepared by any well-known pharmaceutical technique, for example, an effective formulation and administration procedure. The above considerations regarding effective formulation and administration procedures are well-known in the art and are described in standard textbooks. Drug formulation is described, for example, in 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 Britain, Harry G., Ed., Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare USA, Inc., 2016.

[0206] Acceptable excipients are non-toxic to the subject at the dosage and concentration used and may include one or more of the following: 1) buffers such as phosphoric acid, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, or benzyl alcohol; 5) alkylparabens such as methylparaben or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than approximately 10 residues) polypeptides; 7) serum 1) Proteins such as 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 dextrin; 11) Chelating agents such as EDTA; 12) Sugars such as sucrose, mannitol, trehalose, or sorbitol; 13) Salt-forming counterions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) Nonionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers, or polyethylene glycol (PEG).

[0207] For oral administration, the composition can be given 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, with the dosage adjusted according to the patient's symptoms. Typically, the medicine contains 0.01 mg to 500 mg of the active ingredient or 1 mg to 100 mg of the active ingredient. Intravenous doses may range from 0.01 to 10 mg / kg / min when administered by constant-rate infusion.

[0208] Liposomes containing the compounds of this disclosure can be prepared by methods known in the art (see, for example, Chang, HI; Yeh, MK; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012;7;49~60). Particularly useful liposomes can be produced by reverse-phase evaporation using a lipid composition containing phosphatidylcholine, cholesterol, and PEG-derivativeized phosphatidylethanolamine (PEG-PE). By extruding the liposomes through a filter of a specified pore size, liposomes with a desired diameter can be obtained.

[0209] Furthermore, the compounds of this disclosure can be encapsulated as colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions in microcapsules prepared by, for example, coacervation technology or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively. These technologies are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

[0210] Sustained-release formulations can be used. Preferred examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds of this disclosure, in the form of molded articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and 7-L-ethyl glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, copolymers used in depot suspensions such as leuprolide acetate (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyrate.

[0211] Preparations used for intravenous administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filtration membrane. Generally, the compounds of this disclosure are placed in containers having a sterile access port, such as bags or vials for intravenous solutions with a stopper that can be punctured with a subcutaneous needle.

[0212] Suitable emulsions can be prepared using commercially available lipid emulsions, such as lipid emulsions containing soybean oil, lipid emulsions for intravenous administration (e.g., safflower oil, soybean oil, egg phosphatide, and glycerin in water), emulsions containing soybean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be dissolved in a pre-mixed emulsion composition, or alternatively, it may be dissolved in oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and mixed with phospholipids (e.g., egg phospholipids, soybean phospholipids, or soybean lecithin) and water to form an emulsion. It will be noted that other components, such as glycerol or glucose, may be added to adjust the osmotic pressure of the emulsion. Typically, suitable emulsions contain up to 20%, for example, 5-20%, of oil. The lipid emulsion may contain lipid droplets having a diameter of 0.1 to 1.0 micrometers (μm), particularly 0.1 to 0.5 μm, and may have a pH of 5.5 to 8.0.

[0213] For example, the emulsion composition may be a composition prepared by mixing the compound of the present disclosure with a lipid emulsion containing soybean oil, or its components (soybean oil, egg phospholipid, glycerol, and water).

[0214] Compositions for inhalation or inhalation include pharmaceutically acceptable liquids and suspensions, or mixtures thereof, in aqueous or organic solvents, as well as powders. Liquid or solid compositions may contain the preferred pharmaceutically acceptable excipients described above. Compositions may be administered via mouth or nasal breathing for topical or systemic effects. Compositions in preferably sterile, pharmaceutically acceptable solvents can be sprayed using gas. The sprayed liquid may be inhaled directly from the spraying device, or the spraying device may be attached to a face mask, tent, or intermittent positive pressure breathing apparatus. Liquid, suspension, or powder compositions can be administered from a device that appropriately delivers the formulation, preferably orally or nasally.

[0215] Pharmaceutical intermediates (DPIs) are partially processed materials that require further processing before becoming a pharmaceutical bulk. The compounds of this disclosure can be formulated into pharmaceutical intermediates (DPIs) containing the active ingredient in a form with a higher free energy than the crystalline form. One reason for using DPIs is to improve oral absorption due to low solubility and slow dissolution, to improve mass transport through the mucous layer adjacent to epithelial cells, and, in some cases, to overcome limitations imposed by biological barriers such as metabolism and transporters. Other reasons include improved solid-state stability and downstream manufacturability. Pharmaceutical intermediates may include compounds of this disclosure isolated and stabilized in an amorphous state (e.g., amorphous solid dispersions (ASDs)). Many techniques exist known in the art for producing ASDs that produce materials suitable for incorporation into pharmaceutical bulks, such as spray-dried dispersions (SDDs), melt extrudes (often called HMEs), coprecipitates, amorphous drug nanoparticles, and nanoadsorbents. Amorphous solid dispersions may include compounds of this disclosure and polymer excipients. Other excipients, as well as the concentrations of the excipients and the compounds disclosed herein, are well known in the art and are described in standard textbooks. See, for example, Navnit Shah et al., "Amorphous Solid Dispersions Theory and Practice."

[0216] The Disclosure further includes the use of the compounds of the Disclosure for use as pharmaceuticals (e.g., in the form of tablets or capsules). The Disclosure also includes the use of the compounds of the Disclosure for the manufacture of pharmaceuticals (e.g., in the form of tablets or capsules) for treating one or more conditions already identified in the above section describing treatment methods. The Disclosure further includes the compounds of the Disclosure or pharmaceutically acceptable salts thereof for use as pharmaceuticals, and the compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in any of the treatment methods disclosed herein.

[0217] Typically, the compounds of this disclosure are administered in amounts effective to treat the conditions described herein. The compounds of this disclosure may be administered on their own, or they may be administered as pharmaceutically acceptable salts. For administration and drug-dosing purposes, the compounds themselves, or their pharmaceutically acceptable salts, are simply referred to as the compounds of this disclosure.

[0218] The compounds of this disclosure are administered by any preferred route, in the form of a pharmaceutical composition adapted to that route, and in a dose effective for the intended treatment. The compounds of this disclosure may be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation.

[0219] The compounds of this disclosure may be administered orally. Oral administration may include swallowing, which involves introducing the compound into the gastrointestinal tract, or it may be administered orally or sublingually, which involves introducing the compound directly into the bloodstream through the mouth.

[0220] Furthermore, the compounds of this disclosure may be administered parenterally, for example, directly into the bloodstream, muscle, or internal organs. Preferred means of parenteral administration include intravenous, intraarterial, intraperitoneal, subarachnoid, intraventricular, urethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle syringes (including microneedles), needleless syringes, and injection techniques.

[0221] The compounds of this disclosure may be administered topically to the skin or mucous membranes, i.e., transdermally. They may also be administered intranasally or by inhalation. They may also be administered rectally or vaginally. Furthermore, they may be administered directly to the eyes or ears.

[0222] The administration regimen for the compounds of this disclosure, or compositions containing such compounds, is based on a variety of factors, including the patient's type, age, weight, sex, and medical condition; the severity of the condition; the route of administration; and the activity of the specific compound used. Therefore, the administration regimen can vary considerably. The total daily dose of the compounds of this disclosure may be 0.01 to 100 mg / kg (i.e., mg of the compounds of this disclosure per kg of body weight) for the treatment of the indicated conditions described herein. The total daily dose of the compounds of this disclosure may be 0.1 to 50 mg / kg, or 0.5 to 30 mg / kg. It is not uncommon to repeat the administration of the compounds of this disclosure multiple times a day (usually not more than four times). Typically, multiple doses per day may be used to increase the total daily dose, if desired.

[0223] The compounds of this disclosure may inhibit the activity of STAT6 and may be useful in treating, preventing, suppressing, and improving diseases, disorders, and conditions mediated by STAT6.

[0224] The compounds of this disclosure can be used to treat or prevent at least one disease or condition associated with inflammatory disorders.The compounds disclosed herein are used to treat atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies (including food allergies, latex allergies, pet allergies, mold allergies, insect allergies, pollen allergies, dust allergies, seasonal allergies, ragweed allergies, drug allergies, allergic rhinitis, allergic fungal sinusitis, allergic contact dermatitis, and allergic bronchopulmonary aspergillosis), alopecia (including alopecia areata), Alzheimer's disease, arteritis, asthma, atherosclerosis, and autoimmune disorders. Harm (including lupus nephritis, autoimmune hepatitis, myasthenia gravis, Guillain-Barré syndrome, and Graves' disease), Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritus, chronic urticaria, celiac disease, Crohn's disease (CD), dermatitis (including atopic dermatitis (AD), hand dermatitis, and atopic dermatitis of the hands or feet), diabetic nephropathy, fecal diversion colitis, eosinophilic esophagitis (including pediatric eosinophilic esophagitis), eye disorders or eye conditions (autoimmune diseases of the eye, keratoconjunctivitis, vernal keratoconjunctivitis, non-infectious uveitis (e.g., associated with Behçet's disease) Uveitis and phacoembolic uveitis), keratitis (e.g., herpetic keratitis and keratoconus), corneal exudates, ocular pemphigoid, Mohren's ulcer, scleritis, retinitis, retinopathy, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), vesicles, iridocyclitis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization), fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), atypical colitis, keloids, mastocytosis, microscopic colitis (e.g., collagenous colitis or lymphocytic colitis), myositis, nephritis, non-alcoholic colitis It can be used to treat or prevent at least one disease or condition, including non-alcoholic steatohepatitis (NASH), pancreatitis, primary biliary cirrhosis, proctitis, nodular prurigo, psoriasis, psoriatic arthritis, primary biliary cirrhosis, rhinosinusitis (including chronic rhinosinusitis with or without nasal polyps), sarcoidosis, scleroderma, sclerosing cholangitis, Sjögren'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 for treating or preventing one or more symptoms associated with each disease or condition includes administering to a patient a pharmaceutical composition comprising a therapeutically effective amount of the compound of this disclosure.

[0225] The compounds of this disclosure can be used to treat or prevent at least one disease or condition, including atopic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), rhinosinusitis (e.g., chronic rhinosinusitis with nasal polyps or chronic rhinosinusitis without nasal polyps), chronic urticaria (e.g., chronic induced urticaria or chronic spontaneous urticaria), nodular prurigo, eosinophilic esophagitis, eosinophilic gastritis, bullous pemphigoid, pruritus (e.g., chronic pruritus of unknown cause), atopic keratoconjunctivitis, chronic induced urticaria, or allergy (e.g., food allergy).

[0226] The compounds disclosed herein are used to treat skin conditions such as eczema (e.g., chronic eczema and dyshidrotic eczema), chronic itching, dermatitis (e.g., atopic dermatitis, irritant contact dermatitis, allergic contact dermatitis, occupational dermatitis, perioral dermatitis, stasis dermatitis, nummular dermatitis, seborrheic dermatitis, xerotic dermatitis, blepharitis, diaper dermatitis, and hand dermatitis), vitiligo, alopecia, alopecia areata, pruritus (e.g., chronic idiopathic pruritus), nodular prurigo, psoriasis (e.g., psoriasis vulgaris, guttate psoriasis, psoriasis reversal, pustular psoriasis, onychopsoriasis, flexural psoriasis, palmoplantar psoriasis, facial psoriasis, or erythrodermic psoriasis), scleroderma, pemphigus, dermatomyositis, neurodermatitis, cutaneous flushing, cutaneous lupus erythematosus (e.g., acute cutaneous lupus (acute cutaneous lupus (acute cutaneous ( It can be used to treat or prevent skin lupus, subacute cutaneous lupus, and chronic cutaneous lupus (discoid lupus), keloids, sunburn, hypertrophic scars, idiopathic thrombocytopenic purpura (ITP), ichthyosis (e.g., ichthyosis vulgaris), epidermal hyperplasia, acne, lichen planus, lichen sclerosing, 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 laminecoma, vulvovaginitis, Sutton's nevus, post-inflammatory depigmentation, senile vitiligo, chemical / drug-induced vitiligo, palmoplantar pustulosis, pemphigoid, bullous pemphigoid, and hidradenitis suppurativa.

[0227] The compounds of this disclosure can be used to treat or prevent respiratory conditions, such as rhinitis (e.g., allergic rhinitis and perennial rhinitis), rhinorrhea, nasal congestion, nasal inflammation, asthma (e.g., chronic asthma, refractory asthma, delayed-onset asthma, bronchial asthma, allergic asthma, endogenous asthma, exogenous 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.

[0228] The compounds of this disclosure can be used to treat or prevent joint disorders, such as arthritis (e.g., osteoarthritis, as well as psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, and gouty arthritis), spondyloarthropathy (e.g., reactive arthritis (also known as Reiter's syndrome) and axial spondyloarthritis (including ankylosing spondylitis)), inflammation of cartilage, bone breakdown, and Still's disease; cardiovascular and metabolic disorders, such as diabetes mellitus (type 1 and type 2), myocarditis, diabetic neuropathy, atherosclerosis, cachexia, and celiac spur; neuroinflammatory disorders, such as lupus (e.g., CNS lupus, systemic lupus, and discoid lupus), systemic lupus erythematosus (SLE), diabetic neuropathy, autoimmune encephalitis, Alzheimer's disease, Parkinson's disease, and multiple sclerosis; and cancer.

[0229] The compounds of this disclosure may be used alone or in combination with one or more other therapeutic agents. This disclosure provides any of the uses, methods, or compositions specified herein in which the compounds of this disclosure, or pharmaceutically acceptable salts thereof, are used in combination with one or more other therapeutic agents described herein.

[0230] The administration of two or more compounds "in combination" means administering all compounds close together in time so that they affect the treatment in question. Two or more compounds may be administered simultaneously or sequentially, through the same or different routes of administration, on the same or different administration schedules, with or without specific time constraints, depending on the treatment regimen. Furthermore, simultaneous administration can be achieved by mixing the compounds before administration, or by administering the compounds at the same time, but in the same or different administration sites, as separate dosage forms. Examples of "in combination" include, but are not limited to, "parallel administration," "co-administration," "simultaneous administration," "sequential administration," and "administered at the same time."

[0231] The compounds of the Disclosure and one or more other therapeutic agents may be administered as fixed or non-fixed combinations of active ingredients. The term "fixed combination" means that the compounds of the Disclosure, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents are both administered to a subject simultaneously as a single composition or dosage form. The term "non-fixed combination" means that the compounds of the Disclosure, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents are formulated as separate compositions or dosage forms so that they can be administered simultaneously or at different time points with various time constraints in between to a subject in need, thereby achieving effective levels of two or more compounds in the subject's body.

[0232] The compounds of this disclosure may be administered in combination with one or more pharmaceutically effective agents other than the compounds of this disclosure (including pharmaceutically acceptable salts of the agents specifically mentioned, and pharmaceutically acceptable solvates of the agents and salts).

[0233] This disclosure provides pharmaceutical compositions comprising the compounds of this disclosure or pharmaceutically acceptable salts thereof, which are administered simultaneously or at different time points in combination with pharmaceutical compositions comprising different pharmaceutically effective compounds or pharmaceutically acceptable salts thereof.

[0234] These drugs and compounds can be combined with pharmaceutically acceptable media such as saline, Ringer's solution, and glucose solution. Specific administration regimens, i.e., dosage, timing, and repetitions, depend on the individual and their medical history.

[0235] Another aspect of the present disclosure provides a kit comprising the compound of the present disclosure, or a pharmaceutical composition comprising the compound. The kit may comprise a diagnostic or therapeutic agent in addition to the compound of the present disclosure or its pharmaceutical composition. The kit may also comprise instructions for use in a diagnostic or therapeutic procedure. The kit may comprise the compound of the present disclosure or its pharmaceutical composition, and a diagnostic agent. The kit may comprise the compound of the present disclosure or its pharmaceutical composition, and one or more therapeutic agents.

[0236] The kit may be suitable for use in carrying out the treatment methods described herein. The kit may include a first dosage form containing one or more of the compounds disclosed in an amount sufficient to carry out the method of the disclosure. The kit may include one or more of the compounds disclosed in an amount sufficient to carry out the method of the disclosure, and a container for the dosage form.

[0237] The compounds of this disclosure can be synthesized by synthetic routes involving processes similar to those well known in the chemical art, particularly in light of the descriptions contained herein. The starting materials are generally available from commercial sources or can be prepared using methods well known to those skilled in the art. Many of the compounds used herein relate to or may originate from compounds that have given rise to one or more scientific interests or commercial needs. Thus, these compounds may be one or more of the following: 1) commercially available; 2) reported in the literature; or 3) prepared by those skilled in the art using materials reported in the literature from other generally available substances.

[0238] The synthesis schemes illustrated below illustrate, for illustrative purposes, potential routes for synthesizing the compounds and key intermediates of this disclosure. For a more detailed description of each reaction step, see the Examples section below. Those skilled in the art will recognize that other synthesis routes may be used to synthesize the compounds of the present invention. While specific starting materials and reagents are described below, other starting materials and reagents may be substituted to achieve one or more of the various derivatives or reaction conditions. Furthermore, many of the compounds prepared by the methods described below can be further modified using conventional chemical reactions well known to those skilled in the art in light of this disclosure.

[0239] Those skilled in the art will recognize that the experimental conditions described in the following scheme are illustrative examples of suitable conditions for carrying out the illustrated transformations, and that it may be necessary or desirable to change the exact conditions used for preparing the compounds of formula I. Furthermore, it will be recognized that it may be necessary or desirable to carry out the transformations in a different order than those described in the scheme, or to modify one or more of the transformations, in order to obtain the desired compound of formula I.

[0240] In preparing the compounds of formula I, it should be noted that some preparation methods useful for preparing the compounds described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls, etc., in the precursors of the compounds of formula I). ​​The need for such protection varies depending on the properties of the remote functional groups and the conditions of the preparation method. The need for such protection will be readily determined by those skilled in the art. The use of these protection / deprotection methods is also within the scope of 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.

[0241] For example, if a compound contains an amine or carboxylic acid functional group, if left unprotected, this functional group may interfere with reactions at other parts of the molecule. Therefore, these functional groups may be protected with a suitable protecting group (PG), which may then be removed in a subsequent step. Suitable protecting groups for amines and carboxylic acids include those commonly used in peptide synthesis (e.g., Nt-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids), which are generally non-chemically reactive under the described reaction conditions and can usually be removed without chemically altering other functional groups in the compound of formula I.

[0242] Those skilled in the art will recognize that in some cases the compound is produced as a mixture of diastereomers and / or enantiomers. To obtain a single enantiomer of the present disclosure, these can be separated at various stages of the synthetic scheme using the prior art, or a combination thereof, including but not limited to crystallization, normal-phase chromatography, reverse-phase chromatography, and chiral chromatography. See, for example, "Stereochemistry of Organic Compounds" by ELEEliel and SHWilen (Wiley, New York, 1994).

[0243] Unless otherwise specified, substituents in the scheme are as defined above. Isolation and purification of the product are achieved by standard procedures known to chemists of ordinary skill.

[0244] Those skilled in the art will understand that the various symbols, superscripts, and subscripts used in the schemes, methods, and examples are for convenience of expression 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, and subscripts in the appended claims. The schemes are representative of useful methods for synthesizing the compounds of this disclosure. They are not intended to limit the scope of this disclosure.

[0245] [ka]

[0246] The general structure of formula I can be prepared as shown in general scheme A. A tert-butyloxycarbonyl (BOC) protected amine of formula AA1, synthesized by methods described in the literature or purchased commercially, can be treated with a standard acidic deprotection reagent such as hydrochloric acid (HCl) in a solvent such as 1,4-dioxane (dioxane), ethyl acetate (siRNA), and dichloromethane (DCM) at 10 degrees Celsius to room temperature to obtain a deprotected amine compound of formula AA2. The amine of formula AA2 can be treated with a halogen of formula AA3 (e.g., R B By substitution of F or Br (F) aromatic compounds, standard S compounds such as N,N-diisopropylethylamine (DIEA), tripotassium phosphate (K3PO4), potassium carbonate (K2CO3), or cesium fluoride (CsF) can be used. NFormula AA4 can be obtained by treating the mixture under Ar conditions in 1-pentanol, butyronitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or acetonitrile (ACN) under heating at 80-140°C. Formulas AA2 and AA3, and a combination of copper(I) iodide (CuI), 1,2-dimethylethylenediamine (DMEDA), or trans-N,N'-dimethylcyclohexane-1,2-diamine, or a Pd catalyst, e.g., (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1-biphenyl)]palladium(II) methanesulfonate (RuPhos Pd G3) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1-biphenyl)]palladium(II) (cataCXium(registered trademark)A Pd G3), [Dicyclohexyl(2',6'-diisopropoxy-2-biphenylyl)phosphine-κP](methanesulfonate-κO)[2'-(methylamino-κN)-2-biphenylyl-κC 2 Formula AA4 can also be prepared by reacting palladium (RuPhos Pd G4) with a base such as sodium tert-butoxide (NaOtBu), K2CO3, tripotassium phosphate (K3PO4), or cesium carbonate (Cs2CO3) in a solvent such as dioxane, dimethylacetamide (DMA), DMF, DMSO, 2-methyl-2-butanol (tert-amyl alcohol), or toluene under heating at 80-130°C.

[0247] Formula AA4 can be obtained by converting R3 to an amine, urea, or lactam using the standard SNAr or cross-coupling conditions described above, when R3 is a halogen (e.g., F, Br, or I). In formula AA4, when R3 is a halogen (e.g., I), R3 on formula AA4 can be converted to 5-methyl-1H-pyrazole by reacting the halogen with BOC-protected hydrazine under the cross-coupling conditions described above, then deprotecting in a solvent such as dioxane or DCM under standard acidic conditions such as HCl, and cyclizing by reacting with (E)-4-(dimethylamino)buta-3-en-2-one in EtOH. In formula AA4, when R3 is a halogen (e.g., Br, I), the halogen is reacted with nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl2, Glyme), 5-methoxypicolinimidoamide, and the activated ester of N-hydroxyphthalimide, tetrabutylammonium iodide, pre-activated zinc (Zn), and trifluoroacetic acid (TFA) are reacted in a solvent such as DMA at room temperature to 70°C, or [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[2-(2-pyridinyl-N)phenyl-C]iridium(III) Formula AA4 can be obtained by converting to a carbon-carbon bond under photoredox conditions using hexafluorophosphate (Ir(ppy)2(dtbbpy)PF6), nickel(II) bromide ethylene glycol dimethyl ether complex (NiBr2.DME), 5-methoxypicolinimidoamide, phthalimide, and quinuclidine in solvents such as DMA and methyl tert-butyl ether (MTBE). In formula AA4, if R3 is a halogen (e.g., Br), a boronic acid can be formed at R3 by reacting the halogen with B2Pin2 and Pd(dppf)Cl2 together with a base such as KOAc in a solvent such as dioxane at 85°C. A 5-membered heterocycle can be obtained at R3 of formula AA4 by further reacting the boronic acid at R3 with a bromo-substituted 5-membered heterocycle and Pd(dppf)Cl2 together with a base such as K3PO4 in a solvent such as dioxane at 85°C.In formula AA4, if R3 is a carboxylic acid, an amide can be formed at R3 by further conversion of the acid using amide coupling with a base such as HATU and DIEA in a solvent such as DMF at 40°C. In formula AA4, if R3 is tert-butyl acetate, an amide can be formed at R3 by deprotecting it under standard acidic conditions such as TFA or HCl in a solvent such as dioxane, H2O, and DCM at room temperature to 40°C, and then further conversion under standard amide coupling conditions. In formula AA4, if R3 is methyl propionate, a five-membered lactam can be formed at R3 of formula AA4 by reacting formula AA4 and 2-bromoacetonitrile with a base such as lithium bis(trimethylsilyl)amide (LiHMDS) in a solvent such as THF at -78°C, and then further conversion by reacting this with sodium borohydride (NaBH4) in a solvent such as THF and H2O at 0°C to room temperature.

[0248] Esters of formula AA4 (e.g., R AThe carboxylic acid of formula AA5 can be obtained by subjecting a base (e.g., lithium hydroxide monohydrate (LiOH), sodium hydroxide (NaOH), 1,5,7-triazabicyclo[4.4.0]deca-5-ene, or potassium trimethylsilanolate (KOTMS)) to standard hydrolysis conditions, such as using a solvent like tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), water (H2O), dioxane, or ACN. This reaction is usually carried out at 0 to 50°C, preferably about 23°C (room temperature). Compound I can be obtained by reacting the carboxylic acid of formula AA5 and the amine of formula AA6 with a combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 2-hydroxypyridine-N-oxide (HOPO), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), or other common amide coupling reagents, in a solvent such as a combination of ACN and H2O, DMF, or DMSO, with an organic base such as triethylamine (TEA) or DIEA, under stirring, at a temperature of 0 to 70°C, preferably about 23°C (room temperature).

[0249] In formula I, if R1 is an amine, urea can be formed at R3 by reacting it with 2,2,2-trichloroethyl carbonochloridine in pyridine at 0°C to room temperature, followed by further conversion with a secondary amine and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) in THF at 40-60°C. In formula I, if R1 is phenyl carbamate, urea can be formed at R3 by reacting it with an amine and a base such as TEA in a solvent such as DMF at 40°C, followed by deprotection under acidic conditions with HCl in a solvent such as dioxane and DCM at 0°C to room temperature. In formula I, if R3 is tert-butyl acetate, it can be deprotected under standard acidic conditions such as HCl in a solvent such as H2O and DCM. In formula I, if R1 is an amine, an amide can be formed at R3 by reacting it with ethyl carbonochloridate together with a base such as TEA in a solvent such as DCM at 0°C to room temperature.

[0250] [ka]

[0251] The general structure of formula I can be prepared as shown in general scheme B. The amine of formula BB1 is replaced with the halogen of formula AA3 (e.g., R BFormula AA5 can be obtained by treating a (=F or Cl) substituted aromatic compound in a solvent such as water or DMSO under stirring conditions at 80-140°C using standard SNAr conditions such as cesium fluoride (CsF) or K3PO4. The carboxylic acid of AA5 and the amine of formula AA6 can be reacted with an organic base such as TEA or DIEA under stirring conditions at a temperature of 0-70°C, preferably at room temperature, in a solvent such as In formula I, if R3 is tert-butyl acetate, an amide can be formed at R3 by deprotecting it in a solvent such as dioxane, H2O, and DCM under standard acidic conditions such as HCl, followed by further conversion under standard amide coupling conditions.

[0252] [ka]

[0253] The general structure of formula II can be prepared as shown in general scheme C. Trifluoromethanesulfonic acid of formula CC1, synthesized by the method described in the literature or purchased commercially, is used as a boronic acid of formula AA3 (e.g., R B Formula CC2 can be formed by treating a B-(OH)2)-substituted aromatic compound with a Pd catalyst such as Pd(dppf)Cl2 and a base such as K3PO4 in a solvent such as H2O and THF at 85°C. The alkene of formula CC2 can be reduced to the form of formula CC3 by hydrogenation with palladium-carbon (Pd / C) in EtOH. The ester of formula CC3 (e.g., R AThe carboxylic acid of formula CC4 can be obtained by subjecting ethyl (=ethyl) to a solvent such as THF, MeOH, and H2O at 0-50°C, preferably at room temperature, under standard hydrolysis conditions using a base such as LiOH. The carboxylic acid of CC4 and the amine of formula AA6 can be reacted with an organic base such as DIEA at 0-70°C with stirring, under standard amide coupling reagents such as a combination of EDCI and HOPO, in a solvent such as DMSO, to the compound of formula II. II can be prepared as shown in general scheme C. Trifluoromethanesulfonic acid of formula CC1, synthesized by the methods described in the literature or purchased commercially, is reacted with boronic acid of formula AA3 (e.g., R B Formula CC2 can be formed by treating a B-(OH)2)-substituted aromatic compound with a Pd catalyst such as Pd(dppf)Cl2 and a base such as K3PO4 in a solvent such as H2O and THF at 85°C. The alkene of formula CC2 can be reduced to the form of formula CC3 by hydrogenation with palladium-carbon (Pd / C) in EtOH. The ester of formula CC3 (e.g., R A The carboxylic acid of formula CC4 can be obtained by subjecting ethyl(THF, MeOH, and H2O) to standard hydrolysis conditions using a base such as LiOH, in a solvent such as THF, MeOH, and H2O, at 0-50°C, preferably at room temperature. The carboxylic acid of formula CC4 and the amine of formula AA6 can be reacted with an organic base such as DIEA, in a solvent such as DMSO, under standard amide coupling reagents such as a combination of EDCI and HOPO, at 0-70°C with stirring, to obtain the compound of formula II.

[0254] [ka]

[0255] The general structure of formula III can be prepared as shown in general scheme D. The BOC-protected amine of formula AA1, synthesized by the methods described in the literature or commercially available, is treated in ACN with a bromosubstituted alkylamine protected as benzyloxycarbonyl (Cbz) together with a base such as Cs2CO3 to achieve the N1 and N2 alkylation of formula DD1 (e.g., R C A mixture of compounds (=Cbz-protected alkylamines) can be obtained. By separating the positional isomers by silica gel column purification, the compound of formula DD2 can be obtained. Next, formula DD2 can be subjected to deprotection of the CBz protecting group under reducing conditions such as Pd / C by providing hydrogen (H2) gas at 50-120 pounds per square inch (psi) in a solvent such as EtOH. The free amine at N2 of formula DD1 and DBU can be reacted with a solvent such as dioxane at 100°C to cyclize, thereby condensing the C ring of formula DD2 with C 6~7 A heterocycle can be formed. The cycloadhesive lactam of formula DD2 can be combined with the halogen of formula DD3 (e.g., R D Formula DD4 can be obtained by treating a substituted aromatic compound with a base such as K2CO3, potassium bis(trimethylsilyl)amide (KHMDS), THF, and further solvents such as ACN and DMF, under stirring at 80°C. The BOC-protected amine of formula DD4 can be deprotected under acidic conditions such as HCl in solvents such as dioxane and DCM to form the amine of formula DD5. The amine of formula DD5 can be treated with a halogen (e.g., R) of formula AA3. B=F) Substituting aromatics can be used to obtain formula III by treating with stirring at 100°C in a solvent such as tert-amyl alcohol and H2O using standard SNAr conditions such as K3PO4. If R1 in formula III is iodine, then urea can be formed at R1 in formula III by further reacting it with a base such as Cs2CO3 and a 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 such as tert-amyl alcohol at 90°C.

[0256] To better understand this disclosure, the following examples are provided. These examples are for illustrative purposes only and should not be construed in any way as limiting the scope of this disclosure. [Examples]

[0257] The compounds and intermediates described below have been named using the nomenclature rules presented in ChemDraw version 20.1.1.123. These rules are well known to those skilled in the art and are considered to generally conform to the IUPAC (International Union of Pure and Applied Chemistry) recommendations on organic chemical nomenclature and the CAS index rules. Unless otherwise stated, all reactants are commercially available without further purification or prepared using methods known in the literature.

[0258] The following exemplifies the synthesis of various compounds of the present invention. Further compounds within the scope of the present invention can be prepared by using the methods exemplified in these examples alone or in combination with techniques generally known in the art.

[0259] All starting materials in these preparation examples and examples are commercially available or can be prepared by methods known in the art or specified herein.

[0260] Commercially available solvents and reagents were generally used without further purification. Anhydrous solvents, generally Acros Organics' ACROSEAL® products, Sigma-Aldrich's Aldrich SURE / SEAL® products, or EMD Chemicals' DRISOLV® products were used as needed. Commercially available solvents and reagents were used without further purification.

[0261] Experiments were generally conducted under an inert atmosphere (nitrogen or argon), especially when using oxygen-sensitive or water-sensitive reagents or intermediates.

[0262] Unless otherwise stated, chemical reactions were carried out at room temperature (approximately 23 degrees Celsius).

[0263] In some embodiments, chiral separation was performed to separate enantiomers or diastereomers of specific compounds of the present disclosure.

[0264] In other examples or methods, the reaction conditions (reaction time and reaction temperature) may differ in the synthetic reference procedure. Generally, thin-layer chromatography (TLC) or mass spectrometry (MS) was performed after the reaction, and the results were subjected to work-up as needed.

[0265] Commercial benchtop photoreactors such as the Penn OC photoreactor M2, Acceled photoreactor M2, and Lumidox II with a 24-well block were used in conjunction with 450 or 445 nanometer (nm) light-emitting diodes (LEDs).

[0266] Purification procedures may vary from experiment to experiment. Generally, the solvent and solvent ratio used for the eluent / gradient were selected to obtain an appropriate retention time.

[0267] The reaction progress was monitored using thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), and high-performance liquid chromatography (HPLC). TLC was performed on pre-coated silica gel plates using a fluorescent indicator (excitation wavelength 254 nm) and visualized under ultraviolet (UV) light.

[0268] LCMS data is transferred to Agilent 1100 series instruments using Leap Technologies autosamplers and Gemini C 18 The eluents were obtained using a column, an ACN / water gradient, and trifluoroacetic acid (TFA), formic acid, or ammonium hydroxide (NH4OH) as a modifier, or similar equipment. The column eluents were analyzed by scanning them in both cation and anion modes from 100 to 1200 Da using a Waters ZQ mass spectrometer. Other similar instruments were also used.

[0269] High-resolution mass spectrometry (HR / MS) data was collected on a Sciex TripleTOF 5600+ with a DuoSpray ionization source using a liquid chromatography instrument equipped with an Agilent Technologies 1200 binary pump, Agilent 1200 autosampler, Agilent 1200 column compartment, and Agilent 1200 diode array detector. Acquisition and data processing were performed using Sciex Analyst TF version 1.7.1.

[0270] HPLC data can be transferred to Agilent 1100 series instruments using Gemini, Sunfire, Welch Boltimate®, Welch Xtimate, Prep PG-45 MOD10, Boston Prime, Boston Green ODS, Phenomenex Gemini NX, or XBridge C. 18The samples were obtained using columns, acetonitrile (ACN) / water (H2O) gradients, and combinations of TFA, formic acid, NH4OH, or ammonium bicarbonate (NH4HCO3) modifiers, as well as equivalent equipment. Purification was performed by high-performance liquid chromatography (HPLC) and medium-speed liquid chromatography (MPLC) using instruments such as Isco CombiFIash Companion, AnaLogix InteIIiFIash 280, Biotage SP1, or Biotage Isolera One and pre-filled Isco RediSep or Biotage Snap silica cartridges.

[0271] Chiral purification was performed by chiral supercritical fluid chromatography (SFC) using Berger or Thar apparatus and similar instruments with DAIEL CHIRALCEL OD, OJ; DAIEL 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; as well as with carbon dioxide (CO2) alone or in mixtures of methanol (MeOH), ethanol (EtOH), isopropyl alcohol, or ACN, prepared using TFA, formic acid, NH4OH, diethylamine (DEA), ammonia (NH3), or isopropylamine. Fraction collection was initiated using UV detection.

[0272] Chiral purity was determined using supercritical fluid chromatography (SFC) and reversed-phase liquid chromatography (RPLC) analysis 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 mixtures of CO2 with MeOH, EtOH, isopropyl alcohol, or ACN, either alone or prepared using TFA, formic acid, NH4OH, DEA, NH3, or isopropylamine.

[0273] Proton nuclear magnetic resonance ( 1 The ¹H NMR spectrum was recorded relative to the residual peak from the deuterated solvent used. Here, δ is the chemical shift; d is the doublet; dd is the doublet of doublets; ddd is the doublet of doublets of doublets; dt is the triplet of doublets; m is the multiplet, s is the singlet, t is the triplet, q is the quadruplet; quin is the quintet, br s is the broad singlet; MHz is megahertz, and ppm is parts per million. Proton nuclear magnetic spectroscopy ( 1 The 1H NMR chemical shifts are expressed in parts per million (ppm, δ) relative to the deuterated solvent on the lower magnetic field side of tetramethylsilane and were recorded using 300, 400, 500, or 600 MHz Varian spectrometers.

[0274] Generally, the product was dried under reduced pressure before proceeding to further reactions or before subjecting it to biological testing.

[0275] In the following experimental sections, the following abbreviations may be used: ACN is acetonitrile; abs in the structure refers to the absolute configuration, which is the stereochemical configuration determined as R or S; AcOH is acetic acid; APhos Pd G3 is [4-(di-tert-butylphosphin)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) Methanesulfonate; BBr3 is boron tribromide; B2Pin2 is bis(pinacolato)diborone; BOC is tert-butyloxycarbonyl; Boc2O is di-tert-butyl dicarbonate; Brine is saturated sodium chloride aqueous solution; BINAP is (±)-2,2'-bis(diphenylphosphin)-1,1'-binaphthalene; BF3OEt2 is boron trifluoride diethyl etherate; °C is degrees Celsius; CDCl3 is deuterated chloroform; CD3OD is deuterated methanol; (CD3)2SO is deuterated dimethyl sulfoxide; cataCXium(registered trademark)A is di(1-adamantyl)-n-butylphosphine; cataCXium(registered trademark)A Pd G3 is mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II); CAS is Chemical Abstract Service; CDI is 1,1'-carbonyldiimidazole; CHCl3 is chloroform; CO2 is carbon dioxide; CsHCO3 is cesium bicarbonate; Cs2CO3 is cesium carbonate; CsF is cesium fluoride; CuI is copper(I) iodide; DBU is 1,8-diazabicyclo[5.4.0]undeca-7-ene; DCM DCE is dichloromethane; DCE is 1,2-dichloroethane; DDQ is 2,3-dichloro-5,6-dicyano-p-benzoquinone; DEA is diethylamine; DIEA is N,N-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 enantiomer excess; siRNA is ethyl acetate; EtOH is ethanol; g is grams; g / L is grams per liter; h is hours; HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCl is hydrochloric acid; H2 is 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)PF6 is [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[2-(2-pyridinyl-N)phenyl-C]iridium(III) It is hexafluorophosphate; KHSO4 is potassium bis(trimethylsilyl)amide; 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 monobasic potassium phosphate; 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 concentration; LiHMDS is lithium bis(trimethylsilyl)amide; MeI is iodomethane; MeOH is methanol; 4MetBuXPhosPd G3 is methanesulfonate(2-di-tert-butylphosphin-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); mg is milligrams; MgSO4 is magnesium sulfate; MPLC is medium-speed liquid chromatography; MHz is megahertz; min is minutes; mL is milliliters;mL / min means milliliters per minute; mmol means millimole; mol means mole; mM means millimolar concentration; mm means millimeter; MPa means megapascals; MS means mass spectrometry; MTBE means methyl tert-butyl ether; m / z means mass-to-charge ratio; N means normal (concentration); N2 means nitrogen; NBS means N-bromosuccinimide; NaBH4 means sodium borohydride; ND means undetermined; N-XantPhosPd G3 is (2'-amino-2-biphenylyl)(methanesulfonato-κO)palladium-4,6-bis(diphenylphosphin)-10H-phenoxazine; NH3 is ammonia; Na2CO3 is sodium carbonate; NaH is sodium hydroxide; NaHCO3 is sodium bicarbonate; NaI is sodium iodide; NaOCH3 is sodium methoxide; NaOH is sodium hydroxide; Na2SO4 is sodium sulfate; NaOtBu is sodium tert-butoxide; n-BuLi is n-butyllithium; NH4Cl is ammonium chloride; NH4HCO3 is 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)Cl2 is (1,1'-bis(diphenylphosphine)ferrocene)palladium(II) dichloride; Pd / C is palladium carbon; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(O); PdCl2(PPh3)2 is bis(triphenylphosphine)palladium(II) dichloride; Pd(OAc)2 is palladium(II) acetate; Pd(t-Bu3P)2 is bis(tri-tert-butylphosphine)palladium(O); PE is petroleum ether; psi is pounds per square inch; quinuclidine is 1-azabicyclo[2.2.2]octane;SFC stands for supercritical fluid chromatography; SOCl2 stands for thionyl chloride; TBD stands for 1,5,7-triazabicyclo[4.4.0]deca-5-ene; TEA stands for triethylamine; tert-amyl alcohol stands for 2-methyl-2-butanol; TFA stands for trifluoroacetic acid; THF stands for tetrahydrofuran; TLC stands for thin-layer chromatography; trimethylboroxine stands for 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane; μm stands for micrometer; μmol stands for micromoles; rac stands for racemic mixture, referring to a compound (including mixtures of compounds) having both R and S stereochemical configurations, and is indicated as "&1" in the structure; rel stands for relative configuration, referring to a stereochemical configuration that is either R or S, and is indicated as "or1" in the structure, or as an asterisk in the specified structure if the compound has two chiral centers; RhCl(PPh3)3 stands for tris(triphenylphosphine)rhodium(I) It is a chloride; rpm is revolutions per minute; RPLC is reverse-phase liquid chromatography; Ru / Al2O3 is ruthenium-supported 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](methanesulfonate-κO)[2'-(methylamino-κN)-2-biphenylyl-κC; 2] is palladium; RuCl(PPh3)3Ru / SiO2 is ruthenium-supported 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; Zn is zinc.

[0276] (Preparation Example 1) Ethyl 1-cyclopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P1)

[0277] [ka]

[0278] Process 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 solution 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 minutes and 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 solution became a viscous yellow oily substance, which was stirred at 80°C for 1 hour and 30 minutes. The reaction solution was then diluted with ELISA and saturated NaHCO3 aqueous solution. The organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% Â:heptane) to obtain the first by-eluting isomer C2: (11 mg, yield 27.2%) (LC / MS) m / z (M+H) + = 336.3; Next, the second main eluted isomer C1: (18 mg, yield 44.5%) (LC / MS) m / z (M+H) + = 336.3; 1 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). I obtained it.

[0279] Process 2 Preparation of ethyl 1-cyclopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P1) C1 (0.200 g, 0.596 mmol) was dissolved in DCM (2.0 mL), then 4 M HCl dioxane solution (0.130 g, 3.58 mmol) was added, and the reaction mixture was stirred at 40°C for 25 minutes. The reaction mixture was concentrated under reduced pressure to obtain P1 (0.168 mg, crude product) as a white solid. The solid was used in the next step without further purification. (LC / MS) m / z (M+H) + = 236.2; 1 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).

[0280] (Preparation Example 2) Ethyl 1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P2)

[0281] [ka]

[0282] Process 1 Preparation of 5-(tert-butyl) 3-ethyl 1-isopropyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-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), isopropylhydrazine hydrochloride (120 g, 1.1 mol) was added in one step. Then, pyridine (103 g, 1.30 mol) was added to the mixture over 10 minutes in an ice bath at 20-25°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was carried out twice in parallel, combined, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (5 L), washed with brine (2 x 5 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate:PE 10-50%) to obtain C3 and C4. C3 was dissolved in PE (0.8 L) and cooled to -20°C. The mixture was stirred for 4 hours, the resulting solid was filtered, and washed with PE (0.1 L). The filtered cake was dried under high vacuum to obtain C3 (414 g, yield 55.9%) as a white solid. (LC / MS) m / z (M+H) + = 338.1; 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) and then cooled to -20°C. The mixture was stirred for 4 hours, and the resulting solid was filtered and washed with PE (20 mL). The filtered cake was dried under high vacuum to obtain C4 (11.7 g, yield 1.58%) as a white solid. (LC / MS) m / z (M+H) + = 338.1; 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).

[0283] Process 2 Preparation of ethyl 1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P2) A mixture of C3 (13.5 g, 40.0 mmol) in DCM (60 mL) was gradually added with 4N HCl dioxane solution (150 mL) at 0°C in several portions. The reaction mixture was stirred at approximately 15°C for 16 hours, then concentrated under reduced pressure to obtain P2 (10.5 g, crude product) as a white solid, which was used directly in the next step without further purification. LC / MS m / z (M+H) + = 238.1; 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).

[0284] (Preparation Example 3) 5-(tert-butoxycarbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (P3)

[0285] [ka]

[0286] Process 1 Preparation of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (C5) 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 suspended in MeOH (7.7 mL) and H2O (7.7 mL) to which NaOH (0.542 g, 13.5 mmol) was added. The reaction mixture was stirred at 40 °C for 16 hours. The mixture was diluted with H2O (20 mL), cooled to 0 °C, and acidified to approximately pH 3 with 1 M HCl aqueous solution. The resulting mixture was filtered, and the solid was further dried under high vacuum, followed by lyophilization to obtain C5 (1.60 g, crude product) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 268.1. 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).

[0287] Process 2 Preparation of 5-(tert-butoxycarbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (P3) A suspension of C5 (0.200 g, 0.748 mmol) in DMF (3.5 mL) was mixed with NaH (89.8 mg, 2.24 mmol, 60%) at 0°C and stirred at room temperature for 30 minutes. A solution of iodoethane (0.140 g, 0.898 mmol) in DMF (0.5 mL) was added at 0°C and stirred at 15°C for approximately 4 hours. An additional 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 hours. The reaction mixture was stopped with H2O (10 mL) and then extracted with Depositphotos (2 x 20 mL). The aqueous layer was acidified to approximately pH 3 with 1 M HCl aqueous solution and then extracted with Depositphotos (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2SO4, concentrated under reduced pressure, and then freeze-dried to obtain P3 (0.173 g, yield 78.5%) as a white solid. (LC / MS) m / z (M+H) + = 296.1. 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).

[0288] (Preparation example 3b) Ethyl 1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P3b)

[0289] [ka]

[0290] Process 1 Preparation of 5-(tert-butyl) 3-ethyl 1-ethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-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) Pyridine (129 g, 1.63 mol) was added 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). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% THF:PE) to obtain the first eluted isomer C6 (58.0 g) as a white solid; followed by the second eluted isomer C7 (20.6 g, yield 19.6%) as a light yellow oil. C6 was diluted with ELISA (200 mL), stirred at 50°C for 30 minutes, and then cooled to 0°C to form a white solid precipitate. The suspension was filtered, and the filtered cake was washed with toluene (3 x 10 mL). The filtered cake was collected and concentrated under reduced pressure to obtain C6 (35.4 g, yield 33.6%) as a white solid. C6: (LC / MS) m / z (M+H) + = 324.2; 1 H 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; 1 H 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).

[0291] Process 2 Preparation of ethyl 1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P3b) To a 10 mL solution of C6 (1.00 g, 3.09 mmol) in DCM, 1.13 g, 30.9 mmol of 2 M HCl dioxane solution was added. The reaction mixture was stirred at room temperature for 2.5 hours, then concentrated under reduced pressure to obtain P3b (0.870 g, crude product) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 224.2. 1 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).

[0292] (Preparation Example 4) Ethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P4)

[0293] [ka]

[0294] Process 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), and then K2CO3 (2.81 g, 20.3 mmol) and MeI (0.961 g, 6.77 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours and diluted with HCl and H2O. After separating the organic layer, it was concentrated under reduced pressure. The residue was dissolved in DCM and purified by column chromatography (silica gel, 0-40% HCl:heptane) to obtain C8 (0.825 g, yield 39.4%) as a clear oil. (LC / MS) m / z (M+H) + = 310.3; 1 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).

[0295] Process 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 40.0 mL of 4 M HCl dioxane solution at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain P4 (1.30 g, yield 81.9%) as a yellow solid. This was used in the next step without further purification. (LC / MS) m / z (M+H) + = 210.3. 1 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).

[0296] (Preparation Example 5) Ethyl 3-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P5)

[0297] [ka]

[0298] Process 1 Preparation of 7-(tert-butyl) 1-ethyl 3-cyclopropyl-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (C9) 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) were dissolved in dioxane (8.0 mL) and H2O (1.0 mL). K3PO4 (0.984 g, 4.63 mmol) and Pd(dppf)Cl2 (0.226 g, 0.309 mmol) were added under nitrogen gas at room temperature. The reaction mixture was stirred at 90 °C for 16 hours. The obtained solution was concentrated under reduced pressure to obtain a solid, which was purified by column chromatography (silica gel, 0-95% siRNA:PE) to obtain C9 (0.400 g, yield 77.2%) as a yellow, rubbery substance. (LC / MS) m / z (M+H) + = 336.1. 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).

[0299] Process 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), a 2 M HCl dioxane solution (0.261 g, 7.16 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The resulting suspension was concentrated under reduced pressure to obtain P5 (0.243 g, crude product) as a white solid, which was used directly in the next step without further purification. 1 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).

[0300] (Preparation Example 6) rac-ethyl(R)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P6)

[0301] [ka]

[0302] Process 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, and then a 2.5 M n-BuLi hexane solution (2.5 g, 39 mmol) was added. After the addition, the reaction mixture was raised to 0°C and stirred for 15 minutes. Next, the reaction mixture was 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 hour and 30 minutes, and then diethyl oxalate (4.8 g, 33 mmol) was added to the reaction mixture. The resulting mixture was raised to room temperature and stirred for 2 hours. The mixture was neutralized with 1N HCl (80 mL) and extracted with HCl (2 x 200 mL). The combined organic layer was washed with brine (400 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-10% HCl:PE) to obtain C10 (4.8 g, yield 47%) as a yellow oil. (LC / MS) m / z (M+H) + = 314.4. 1 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).

[0303] Process 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) Hydrazine hydrate (2.09 g, 65 wt%, 27.2 mmol) was added to a solution of C10 (3.55 g, 11.3 mmol) in AcOH (14.2 mL). During the addition, the reaction mixture was exothermic up to 65°C. The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was diluted with H2O, followed by saturated NaHCO3 aqueous solution (200 mL). The mixture was extracted with SiO2 (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and further dried under high vacuum to obtain C11 (3.45 g, crude product) as a pale yellow solid, which was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 310.40.

[0304] Process 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 at room temperature for 16 hours, diluted with H2O (100 mL), and extracted with Depositphotos (3 x 50 mL). The combined organic layers were washed with saturated NH4Cl aqueous solution (2 x 100 mL) and H2O (2 x 100 mL). The organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10-100% Depositphotos:heptane) to obtain C13 (2.12 g, yield 58.9%) and C12 (0.999 g, yield 27.7%). C13: (LC / MS) m / z (M+H) + = 324.1. 1 H 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. 1 H 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).

[0305] Process 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), 5.0 mL of 1 M HCl  (HCl) solution was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. An additional 5.0 mL of 1 M HCl  (HCl) solution was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain P6 (0.426 g, 99.1% yield) as a yellowish-white solid. This was used in the next step without further purification. (LC / MS) m / z (M+H) + = 224.2. 1 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).

[0306] (Preparation Example 7) rac-Methyl (R)-3,5-dimethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P7)

[0307] [Chemical Structure]

[0308] Step 1 Preparation of methyl 5-methylimidazo[1,5-a]pyrazine-1-carboxylate (C14) and ethyl 5-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) were added Cs2CO3 (57.0 g, 175 mmol) and ethyl 2-isocyanoacetate (CAS: 2999-46-4, 26.6 g, 233 mmol). The reaction mixture was heated to 85 °C and stirred for 16 hours. The light brown reaction mixture was filtered, and the solid was washed with MeOH. The filtrate was concentrated under reduced pressure. The brown residue was purified by column chromatography (silica gel, 0 - 100% EtOAC:PE, then 2% MeOH:EtOAc). During workup and purification, an ester exchange reaction occurred, and C14 (9.50 g, yield 42.6%) was obtained as a light brown solid (LC / MS) m / z (M+H) + = 192.1, and a mixture (1.1 g, yield 4.59%) of (2:1, C14a:C14) (LC / MS) m / z (M+H) + = 206.1 was obtained. C14 was carried over to the next step. C14: 1 H 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).

[0309] Process 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 by 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), and then heated to 50°C until dissolved. The solution was pumped at a flow rate of 0.3 mL / min, and H2 was supplied at a flow rate of 30 mL / min. 5.0 mL of the solution was passed through a fixed bed (6.350 (1 / 4'') mm) packed with granular catalyst 10% Ru / SiO2 (15.3 g, 1.52 mmol), and hydrogenated at 80°C for 3.3 minutes by flowing H2 at 2.5 MPa. The light yellow reaction mixture was concentrated under reduced pressure and then dried under high vacuum to obtain C15 (2.96 g, crude product) as a light brown oily substance. This was used in the next step without further purification. 1 H 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).

[0310] Process 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) were added Boc2O (4.97 g, 22.8 mmol) and K2CO3 (6.29 g, 45.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The light brown reaction mixture was filtered and then concentrated under reduced pressure. The brown residue was purified by column chromatography (silica gel; 0 - 100% EtOAc:PE) to give C16 (3.02 g, yield 67.5%) as a pale yellowish white solid. (LC / MS) m / z (M+H) + = 296.1. 1 H 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).

[0311] 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 mixture was stirred at room temperature for 16 h. The light brown reaction mixture was concentrated under reduced pressure. The brown residue was purified by column chromatography (silica gel, 0 - 100% EtOAc:PE) to give impure C17 as a light brown solid. The solid was triturated with EtOAc:PE (1:5). The solid was filtered and then rinsed with EtOAc:PE (5:1) to give C17 (1.32 g, yield 34.4%) as a white solid. (LC / MS) m / z (M+2H) + = 376.0. 1 H 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).

[0312] Process 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), K3PO4 (2.21 g, 10.4 mmol) was added, followed by Pd(dppf)Cl2 (0.519 g, 0.695 mmol) under nitrogen at 15 °C. The reaction mixture was heated at 90 °C for 16 hours. The brown reaction mixture was extracted with SiO4 (30 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The brown residue was purified by column chromatography (silica gel, 0-100% SiO4:PE, then 2% MeOH:SiO4), and then dried under high vacuum to obtain C18 (0.460 g, 42.8%) as a light brown solid. (LC / MS) m / z (M+H) + = 310.2. 1 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).

[0313] Process 6 Preparation of rac-methyl(R)-3,5-dimethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P7) A 2M HCl dioxane solution (8.0 mL) was added to a 4.0 mL solution of C18 (140 mg, 0.452 mmol) in DCM (4.0 mL) at room temperature. The reaction mixture was heated to 40 °C and stirred for 2 to 5 hours. The light brown reaction mixture was concentrated under reduced pressure and then dried under high vacuum to obtain P7 (0.111 g, crude product) as a light brown solid. The solid was used in the next step without further purification.

[0314] (Preparation Example 8) (S)-5-(tert-butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (P8)

[0315] [ka]

[0316] Process 1 Preparation of rac-tert-butyl(5S)-3-(2-ethoxy-2-oxoacetyl)-5-methyl-4-oxopiperidine-1-carboxylate (C19) Under a nitrogen balloon at -65°C, LDA (44.4 g, 0.414 mol, 207 mL) was added to THF (350 mL), and 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 hour to maintain the internal temperature below -65°C. After stirring the reaction mixture at -65°C for 1 hour, a solution of diethyl oxalate (CAS: 95-92-1; 60.6 g, 0.414 mol) in THF (350 mL) was added dropwise at -65°C. After the addition, the reaction mixture was stirred at -65°C for 1 hour, then the temperature was raised to -20°C and stirred for 40 minutes. Under nitrogen gas at 0°C, the reaction was stopped with 1M KHSO4 aqueous solution (1415 mL), which formed a white precipitate. After filtering the suspension, the filtrate was extracted with SiO2 (3 x 800 mL). The combined organic layers were washed with brine (800 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain C19 (129 g, crude product) 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. 1 H 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).

[0317] Process 2 Preparation of concentrated 5-(tert-butyl)3-ethyl(S)-7-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C20) At 0°C, hydrazine monohydrate (62.7 g, 1.06 mol) was added to a suspension of C19 (139 g, 0.443 mol) in AcOH (552 mL), raising the internal temperature to approximately 30°C. The reaction mixture was stirred under nitrogen gas at room temperature for 1 hour, then diluted with H2O (500 mL) and saturated NaHCO3 (1000 mL). The diluted suspension was extracted with SiO2 (2 x 800 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow rubbery substance. The rubbery substance was purified by column chromatography (silica gel, (1:1) SiO2:PE) to obtain concentrated S-enantiomer C20 (123 g, yield 89.7%) as a yellow rubbery substance. (LCMS) m / z (M+H) + = 310.0. 1 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). Chiral purity was determined using SFC analysis with a Chiralpak AD-3 100mm x 4.6mm x 3μm column; mobile phase A: CO2 / mobile phase B: EtOH (containing 0.2% NH3); gradient: mobile phase B 5-40% for 3 minutes, then mobile phase B 5% for 1 minute; back pressure: 1500 psi; flow rate: 2.8 mL / min; column temperature: 35°C. The main peak was C20 ((SFC-MS)), with a retention time of 2.218 minutes at m / z (M-tert-butyl group). + = 254.04, 94% ee) was obtained.

[0318] Process 3 Preparation of concentrated (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 C2O (124 g, 0.400 mol) in MeOH (452 ​​mL) and H2O (452 ​​mL), NaOH (32.0 g, 0.800 mol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with H2O (200 mL), cooled to 0°C, and then acidified to approximately pH 3 with 1 M HCl aqueous solution. After filtering the acidic reaction mixture, the filtered cake was collected and freeze-dried to obtain concentrated S-enantiomer P8a (88.6 g, crude product) as a white solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H) + = 282.0. 1 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). Chiral purity was determined using SFC analysis with a Chiralpak IG-3 100mm x 4.6mm x 3μm column; mobile phase A: CO2 / mobile phase B: 50% MeOH (containing 0.2% NH3); back pressure: 1500 psi; flow rate: 2.8 mL / min; column temperature: 35°C. P8a: Main peak ((SFC-MS) retention time: 0.784 min, m / z (M-tert-butyl group)) + = 226.03, 96% ee) was obtained.

[0319] Process 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 carried out six times in parallel and then combined. To the mixture of P8a (0.180 kg, 0.640 mol) in EtOH (3.4 L), (+)-bis[(R)-1-phenylethyl]amine (CAS: 23294-41-9; 144 g, 0.640 mol) was added in one step at room temperature to form the first batch. The reaction mixture of the first batch was stirred at room temperature for 10 minutes, after which a white precipitate formed. The suspension of the first batch was stirred at 80°C for 1 hour to form a clear solution, and then stirred at room temperature for 20 hours. After filtering the white suspension of the first batch, the filter cake was washed with EtOH (3 x 300 mL).

[0320] After collecting the filtered cake from the first reaction, it was combined with filtered cakes from five further reactions using P8a (0.180 kg, 0.640 mol). The combined filtered cakes were dried in an oven at 50°C for 18 hours to obtain C21 (1.42 kg, crude product) as a white solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H) + = 282.1. 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). Chiral purity was determined using SFC analysis with a Chiralpak IG 50mm x 4.6mm x 3μm column; mobile phase A: CO2 / mobile phase B: MeOH (containing 0.05% DEA); gradient: mobile phase B 20-40% for 1.5 minutes, mobile phase B 40% for 1.0 minute, then mobile phase B 20% for 0.5 minutes; flow rate 4.0 mL / min; back pressure: 1500 psi; column temperature: 35°C, yielding C21: peak 1 (retention time: 1.019 min, 100% ee).

[0321] Process 5 Preparation of (S)-5-(tert-butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (P8) A suspension of C21 (48.2 g, 95.1 mmol) in H2O (482 mL) was mixed with 1 M HCl aqueous solution (99 mL) to adjust the pH to approximately 1. The reaction mixture was stirred at room temperature for 1 hour and then filtered. After collecting the filtered cake, it was freeze-dried to obtain P8 (24.3 g, crude product) as a white solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H) + = 282.0. 1 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). Chiral purity was determined using SFC analysis with a Chiralpak IG-3 100mm x 4.6mm x 3μm column; mobile phase A: 50% CO2 / mobile phase B: 50% MeOH (containing 0.2% NH3); back pressure: 1500 psi; flow rate: 2.8 mL / min; column temperature: 35°C. P8: Peak 1 ((SFC-MS) retention time: 0.757 min at m / z (M-tert-butyl group)) + = 226.00, 99% ee) was obtained. [α] 28 D = +11.351 (c = 1.5(g / L) in MeOH).

[0322] (Preparation Example 9) (S)-1-Isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P9)

[0323] [ka]

[0324] Process 1 Preparation of (S)-5-(tert-butoxycarbonyl)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (C22) Under nitrogen gas at 0°C, 132 mL of 1 M LiHMDS was added to a 220 mL solution of P8 (12.4 g, 44.1 mmol) in DMF. The reaction mixture was heated to room temperature and stirred for 2 hours, then cooled back to 0°C. 11.2 g, 66.1 mmol of 2-iodopropane was added to the cooled reaction mixture, and the suspension was heated to room temperature and stirred for 48 hours. The reaction mixture was cooled back to 0°C, and an additional 1.12 g, 6.61 mmol of 2-iodopropane was added. The suspension was heated to room temperature and stirred for 48 hours. After cooling the reaction mixture back to 0°C, the reaction was stopped with 500 mL of H2O. The aqueous phase was washed with ELISA (2 x 200 mL), and the combined organic layer was discarded. The aqueous layer was acidified to approximately pH 3 with 1 M aqueous HCl and then extracted with ELISA (2 x 200 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain C22 (13.8 g, 96.8% yield) as a yellow solid. (LCMS) m / z (M+H) + = 324.0. 1 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). Chiral purity was determined using SFC analysis on a (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: mobile phase B 10-50% for 6.00 min, then mobile phase B 10% for 2.00 min; back pressure: 2000 psi; flow rate: 1.5 mL / min; column temperature: 35 °C, yielding C22: peak 1 (retention time: 2.352 min, 100% ee). [α] 34 D = -100.10 (c = 5.4 (g / L) in ACN).

[0325] Process 2 Preparation of (S)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P9) A 2M HCl dioxane solution (500mL) was added to a 40mL solution of C22 (12.7g, 39.3 mmol) in DCM. The reaction mixture was stirred at room temperature for 5 hours, then concentrated under reduced pressure to obtain P9 (9.40g, crude product) as a white solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H) + = 224.2. 1 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). Chiral purity was determined using SFC analysis with a Chiralcel OX-3 100mm x 4.6mm x 3μm column; mobile phase A: CO2 / mobile phase B: MeOH (containing 0.05% DEA); gradient: mobile phase B 5-40% for 3.0 min, then mobile phase B 40% for 0.9 min, then mobile phase B 5% for 0.1 min; back pressure: 100 bar; flow rate: 2.8 mL / min; column temperature: 40°C, yielding P9: peak 1 (retention time: 3.037 min, 100% ee). [α] 33D = -7.212 (c = 1.5 g / L in MeOH.

[0326] (Preparation Example 10) (S)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P10)

[0327] [ka]

[0328] Process 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) Under nitrogen gas at 0°C, NaH (4.27 g, 107 mmol) was added to a solution of P8 (10.0 g, 35.5 mmol) in DMF (190 mL). The reaction mixture was stirred at 0°C for 30 minutes, after which a solution of iodoethane (6.65 g, 42.7 mmol) in DMF (10 mL) was added. The suspension was raised to room temperature and stirred for 3 hours, then the reaction was stopped with H2O (150 mL). The aqueous phase was extracted with siRNA (2 x 150 mL), and the combined organic layer was discarded. The aqueous phase was acidified to approximately pH 3 with 1 M HCl aqueous solution, and then extracted again with EtOA (150 mL x 3). The combined organic layer was washed with brine (2 x 100 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain a yellow solid. The solid was suspended in (1:10) siRNA:PE (25 mL) and stirred at room temperature for 30 minutes. The suspension was filtered, and the filtration cake was collected to obtain C23 (8.75 g, crude product) as a white solid. The solid was used directly in the next step without further purification. (LCMS) m / z (M+H) + = 310.0. 1 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). Chiral purity was determined using chiral HPLC analysis with a Chiralcel OD-RH 150 mm x 4.6 mm x 5 μm column; mobile phase A: H2O (TFA 1.5 mL) / mobile phase B: ACN (TFA 1.5 mL); gradient: mobile phase B 10-80% for 8 minutes, then mobile phase B 10% for 1 minute, then mobile phase B 10% for 6 minutes; flow rate: 0.8 mL / min; column temperature: 30°C, yielding C23: peak 1 (retention time: 9.514 min, 100% ee). [α] 34 D = -95.69 (c = 0.4 (g / L) in ACN).

[0329] Process 2 Preparation of (S)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P10) At 0°C, 160 mL of 2 M HCl-dioxane solution was added to C23 (8.00 g, 25.9 mmol). The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure to obtain a yellow solid. The solid was dissolved in 40 mL of 2 M HCl-dioxane solution, stirred at room temperature for 2 hours, and then concentrated under reduced pressure to obtain P10 (7.10 g, crude product) as a yellow solid. The solid was used directly in the next step without further purification. (LC-MS) m / z (M+H) + = 210.2. 1 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). Chiral purity was determined by SFC analysis using a Chiralcel OX-3 100 mm x 4.6 mm, 3 μm column; mobile phase A: CO2 / mobile phase B: MeOH (containing 0.05% DEA); isocratic: mobile phase B 40%; back pressure 100 bar; flow rate: 2.8 mL / min; column temperature: 40°C, yielding P10: peak 1 (retention time: 1.631 min, 100% ee). [α] 33 D = -1.584 (c = 1.5 g / L in MeOH).

[0330] (Preparation Example 11) 3-(4-(aminomethyl)phenyl)-1,1-dimethylurea hydrochloride (P11)

[0331] [ka]

[0332] Process 1 Preparation of tert-butyl (4-(3,3-dimethylureido)benzyl)carbamate (C24) Under nitrogen gas at 0°C, dimethylcarbamate chloride (14.5 g, 135 mmol) was added dropwise 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). The reaction mixture was stirred at 50°C for 16 hours, then diluted with MeOH (150 mL) and concentrated under reduced pressure to obtain the residue. The residue was suspended in H2O (120 mL) and rapidly stirred at room temperature for 1 hour. After filtering the suspension, the filtration cake was collected and triturated with MeOH: Depositphotos:MTBE (5 mL:25 mL:250 mL) at room temperature for 1 hour. The suspension was filtered, and the filtered cake was collected. The mixture was then concentrated under reduced pressure to obtain C24 (14.6 g, 73.8% yield) as a white solid. (LC / MS) m / z (M+H) + = 294.1. 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)

[0333] Process 2 Preparation of 3-(4-(aminomethyl)phenyl)-1,1-dimethylurea hydrochloride (P11) At 0°C, a 23g, 71 mmol C24 suspension in 130 mL of DCM was stirred, to which 270 mL of 2 M HCl dioxane solution was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure to obtain P11 (15g, 83.4%) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (2M+H) + = 387.1. 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).

[0334] (Preparation Example 12) N-(4-(aminomethyl)phenyl)-4-methylpiperazine-1-carboxamide hydrochloride (P12)

[0335] [ka]

[0336] Process 1 Preparation of tert-butyl(4-(4-methylpiperazine-1-carboxamide)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), 1-methylpiperazine (CAS: 109-01-3; 2.8 g, 28 mmol) was added. The reaction mixture was stirred overnight at 90°C. The suspension was diluted with ELISA (100 mL) and washed with 1 M NaOH (2 x 50 mL), then brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was tritulated with PE (2 x 50 mL) for 20 minutes, and the suspension was filtered. The filtered cake was collected to obtain C25 (7.7 g, crude product) as a brown solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 349.2. 1 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).

[0337] Process 2 Preparation of N-(4-(aminomethyl)phenyl)-4-methylpiperazine-1-carboxamide hydrochloride (P12) A stirred solution of C25 (7.7 g, 22 mmol) in DCM (20 mL) was mixed with HCl dioxane solution (0.050 g, 1.4 mmol). The reaction mixture was stirred at 0°C for 4 hours, then concentrated under reduced pressure and freeze-dried to obtain P12 (6.9 g, crude product) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 249.1. 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).

[0338] (Preparation Example 13) Ethyl(S)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P13)

[0339] [ka]

[0340] Process 1 Preparation of ethyl(S)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P13) SOCl2 (1.29 g, 10.8 mmol) was added dropwise at 0°C to a stirred solution of C22 (0.500 g, 1.55 mmol) in EtOH (3 mL). The reaction mixture was stirred at room temperature for 66 hours, then concentrated under reduced pressure to obtain P13 (0.426 g, 95.7% yield) as a bright yellow solid. (LC / MS) m / z (M+H) + = 252.2.

[0341] (Preparation Example 14) Ethyl 1-(1-methylcyclopropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P14)

[0342] [ka]

[0343] Process 1 Preparation of 5-(tert-butyl)3-ethyl 1-(1-methylcyclopropyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C26) Using 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 same procedure as in Step 1 of Preparation Example 2 was followed. The residue was purified by column chromatography (silica gel, 0-30% siRNA:PE) to obtain C26 (0.233 g, yield 34.6%) as a light brown oil. (LC / MS) m / z (M+H) + = 350.1. 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).

[0344] Process 2 Preparation of ethyl 1-(1-methylcyclopropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P14) Using C26 (0.233 g, 0.667 mmol), P14 (0.191 g, crude product) was obtained as a bright yellow solid following the same procedure as in Step 2 of Preparation Example 5, and this was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 250.1. 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).

[0345] (Preparation Example 15) Ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxylate hydrochloride (P15)

[0346] [ka]

[0347] Process 1 Preparation of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxylate hydrochloride (P15) The same reaction was carried out twice and then combined. 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 to HCl dioxane solution (0.234 g, 6.42 mmol) to form the first batch. The first batch solution was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain a white solid.

[0348] The same reaction was carried out a second time using 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 these two reactions were combined to obtain P15 (0.339 g, crude product) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 212.0.

[0349] (Preparation Example 16) Ethyl 1-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-1H-indazole-3-carboxylate (P16)

[0350] [ka]

[0351] Process 1 Preparation of ethyl 1-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-1H-indazole-3-carboxylate (P16) 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-chloropyridine-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (CAS: 145100-51-2; 0.409 g, 2.12 mmol) were suspended in H2O (1 mL) and THF (10 mL) to which Pd(dppf)Cl2 (0.103 g, 0.141 mmol) and K3PO4 (0.899 g, 4.23 mmol) were added. The reaction mixture was degassed with nitrogen gas, stirred at 85°C for 16 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-38% THF:PE) to obtain P16 (0.470 g, 94.2% yield) as a pink solid. (LC / MS) m / z (M+H) + = 355.0

[0352] (Preparation Example 17) Ethyl 1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P17)

[0353] [ka]

[0354] Process 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-methylpropane-1-illium (C28) (2,2,2-trifluoroethyl)hydrazine hydrochloride (CAS: 1081515-82-3; 0.226 g, 1.50 mmol) was suspended in EtOH (5 mL) and pyridine (0.476 g, 6.01 mmol) with 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 hours and then examined by LC / MS. The main isomer was found to be C27[(LC / MS) m / z (M-tert-butyl group)]. + = 321.9 at a retention time of 0.87 minutes, and the subisomer C28[(LC / MS) m / z (M+H) + A value of 378.2 was observed at a retention time of 0.94 minutes. After concentrating the suspension under reduced pressure, it was dissolved in DCM and purified by column chromatography (silica gel, 0-40% HCl:heptane) to obtain the main isomer C27 (eluted with 30-40% HCl:heptane) (0.344 g, yield 60.7%) as a yellow oily substance. (LC / MS) m / z (M-tert-butyl group) + = 322.2. 1 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)

[0355] Process 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), 1.4 mL of 4 M HCl dioxane solution was added. The reaction mixture was stirred at 40°C for 24 hours, then concentrated under reduced pressure to obtain P17 (0.328 g, crude product) as a white solid. (LC / MS) m / z (M+H) + = 278.2. 1 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).

[0356] (Preparation Example 18) rac-ethyl(R)-1,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P18)

[0357] [ka]

[0358] Process 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 0°C, hydrazine monohydrate (CAS: 7803-57-8; 14 g, 0.18 mol) was added dropwise through an additive funnel 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). The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was diluted in ELISA (200 mL) and washed with aqueous NaHCO3 solution. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain C29 (23 g, crude product) 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. 1 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).

[0359] Process 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-methylpropane-1-illium (C31) At 0°C, Cs2CO3 (27g, 82mmol) and MeI (14mL) were added dropwise to a solution of C29 (23g, 74mmol) in DMF (200mL). The reaction mixture was stirred at room temperature for 20 hours and then concentrated under reduced pressure. The residue was dissolved in MTBE (200mL) and washed with H2O (200mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to form an orange oily substance. The residue was purified by column chromatography (silica gel, 0-100% isopropyl acetate:heptane) to obtain C30 (3.0g, yield 25%) and C31 (1.6g, yield 14%). C30: (LC / MS) m / z (M+H) + = 324.2. 1 H 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. 1 H 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).

[0360] Process 3 Preparation of rac-ethyl(R)-1,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P18) A 5 mL solution of C30 (0.460 g, 1.42 mmol) in DCM (5 mL) was mixed with a 5 mL solution of 1 M HCl siRNA. The reaction mixture was stirred at room temperature for 6 hours, then concentrated under reduced pressure to obtain P18 (0.325 g, crude product) as a white foam, which was used directly in the next step without further purification.

[0361] (Preparation Example 19) Ethyl 3-(1,1-difluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P19)

[0362] [ka]

[0363] Process 1 Preparation of 7-(tert-butyl) 1-ethyl 3-(1-ethoxyvinyl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (C32) 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) was dissolved in DCE (30 mL) to which tributyl(1-ethoxyvinyl)tin (CAS: 97674-02-7; 4.45 g, 12.3 mmol) and PdCl2(PPh3)2 (0.422 g, 0.601 mmol) were added. The reaction mixture was stirred in microwave at 120°C for 30 minutes, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; 0-27% THF:PE) to obtain C32 (0.960 g, yield 65.5%) as an oil. (LC / MS) m / z (M+H) + = 366.1. 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).

[0364] Step 2 Preparation of 7-(tert-butyl) 1-ethyl 3-acetyl-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (C33) 2M HCl (0.132 g, 3.61 mmol) was added to a solution of C32 (0.660 g, 1.81 mmol) in THF (12 mL). After stirring the reaction mixture in a microwave for 16 h, the clear yellow solution was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 and then extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The brown residue was purified by column chromatography (silica gel, 0 - 20% EtOAc:PE) to give C33 (0.440 g, yield 81.1%) as a white solid. (LC / MS) m / z (M+H) + = 338.3. 1 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).

[0365] 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-fluor® (CAS: 202289-38-1; 10 mL) was stirred at 40°C for 72 hours. After cooling the reaction mixture to room temperature, it was extracted with DCM (2 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% Â:PE) to obtain C34 (0.310 g, yield 66.9%) as a yellow, rubbery substance. (LC / MS) m / z (M+H) + = 360.1. 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).

[0366] Process 4 Preparation of ethyl 3-(1,1-difluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P19) A 2M HCl dioxane solution (6 mL) was added to a 3 mL solution of C34 (0.310 g, 0.863 mmol) in DCM. The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure and dried under high vacuum to obtain P19 (0.255 g, crude product) as a rubbery substance. The rubbery substance was used directly in the next step without further purification.

[0367] (Preparation Example 20) rac-ethyl(R)-7-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P20)

[0368] [ka]

[0369] Process 1 Preparation of rac-tert-butyl(5R)-3-(2-ethoxy-2-oxoacetyl)-5-ethyl-4-oxopiperidine-1-carboxylate (C35) Under nitrogen gas at -78°C, LDA (4.24 g, 39.6 mmol) was added to THF (25 mL) in a 250 mL three-necked round-bottom flask. A solution of 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 at -78°C, and the mixture was stirred at -78°C for 1 hour. After stirring, a solution of diethyl oxalate (5.79 g, 39.6 mmol) in THF (20 mL) was added dropwise at -78°C, and the mixture was stirred at -78°C for 1 hour. The reaction mixture was raised to room temperature and stirred for 16 hours. After cooling the suspension to 0°C, the reaction was stopped with 1 M KHSO4 aqueous solution (150 mL), and the mixture was filtered. The filtrate was extracted with ELISA (2 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain C35 (13.0 g, crude product) as a yellow, rubbery substance. The rubbery substance was used directly in the next step without further purification. (LC / MS) m / z (M-tert-butyl group) + = 272.0. 1 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).

[0370] Process 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) Using C35 (6.00 g, 18.3 mmol), C36 (8.89 g, crude product) was obtained as a yellow, rubbery substance following the same procedure as in Step 1 of Preparation Example 18, and this was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 324.1. 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).

[0371] Process 3 Preparation of rac-ethyl(R)-7-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P20) A suspension of C36 (0.400 g, 1.24 mmol) in DCM (6 mL) and MeOH (2 mL) was mixed with 2 M HCl dioxane solution (3 mL). The reaction mixture was stirred at room temperature for 2 hours, after which an additional 2 M HCl dioxane solution (3 mL) was added. The suspension was stirred at room temperature for 16 hours, then concentrated under reduced pressure to obtain P20 (0.276 g, crude product) as a yellow solid. The solid was used directly in the next step without further purification. 1 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).

[0372] (Preparation Example 21) rac-(R)-7-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P21)

[0373] [ka]

[0374] Process 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) NaOH (0.495 g, 12.4 mmol) was added to a suspension of C36 (2.00 g, 6.18 mmol) in MeOH (6.6 mL) and H2O (6.6 mL). The reaction mixture was stirred at 40°C for 2 hours, then diluted with H2O (20 mL). After cooling the diluted reaction mixture to 0°C, the pH was acidified to approximately 3 with 1 M HCl aqueous solution, and the mixture was filtered. The filtered cake was collected to obtain C37 (1.60 g, crude product) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 296.1. 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).

[0375] Process 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) Using C37 (1.00 g, 3.39 mmol) and MeI (0.577 g, 4.06 mmol), C38 (0.850 g, crude product) was obtained as a white solid following the same procedure as in step 2 of Preparation Example 3, and this was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 310.1. 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).

[0376] Process 3 Preparation of rac-(R)-7-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P21) At 0°C, 2 mL of HCl dioxane solution was added to a 1 mL solution of C38 (0.300 g, 0.970 mmol) in DCM. The reaction mixture was heated to room temperature and stirred for 16 hours. After concentration under reduced pressure, P21 (0.236 g, crude product) was obtained as a yellow solid. 1 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).

[0377] (Preparation Example 22) 2-Chloro-5-(1-methyl-1H-imidazole-2-yl)pyridine (P22)

[0378] [ka]

[0379] Process 1 Preparation of 2-chloro-5-(1H-imidazole-2-yl)pyridine (C39) At 0°C, 2-chloro-5-ethynylpyridine (CAS: 263012-63-1, 94.0 g, 680 mmol) was dissolved in MeOH (1.5 L) and NaOCH3 (5.50 g, 102 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, after which 2,2-dimethoxyethaneamine (71.3 g, 678 mmol) and AcOH (81.5 g, 1.36 mol) were added. The reaction mixture was stirred at 50°C for 1 hour, then cooled to room temperature, and then 6 M HCl (74.2 g, 2.04 mol) was added. The reaction mixture was stirred at 80°C for 5 hours, and then concentrated under reduced pressure. The residue was extracted with siRNA (2 x 500 mL). The aqueous layer was adjusted to pH=10 with saturated Na2CO3 aqueous solution, thereby forming a white solid precipitate. After filtering the suspension, the filter cake was washed with H2O (3 x 100 mL). After collecting the filtered cake, it was freeze-dried to obtain C39 (88.0 g, 72.2% yield) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 180.0. 1 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).

[0380] Process 2 Preparation of 2-chloro-5-(1-methyl-1H-imidazole-2-yl)pyridine (P22) To a solution of C39 (44.0 g, 204 mmol) in DME (440 mL), KOH (24.0 g, 428 mmol) was added at room temperature, and the mixture was stirred for 1 hour and 40 minutes. After cooling the reaction mixture to 0°C, MeI (57.8 g, 407 mmol) was added, and the mixture was stirred at 0°C for 1 hour. The white suspension was filtered and concentrated under reduced pressure. The residue was washed with H2O (300 mL) and stirred for 30 minutes. The reaction mixture was filtered, and the filtered cake was concentrated under reduced pressure to obtain P22 (34.8 g, yield 88.8%) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 194.0. 1 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).

[0381] (Preparation Example 23) rac-ethyl(R)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate trifluoroacetate (P23)

[0382] [ka]

[0383] Process 1 Preparation of rac-5-(tert-butyl) 3-ethyl(R)-1-ethyl-7-methyl-1,4,6,7-tetrahydro-5H-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 hours. After concentrating the reaction mixture under reduced pressure, it was purified by column chromatography (silica gel, 0-40% siRNA:PE) to obtain C41 (0.290 g, yield 26.9%) as a bright yellow solid and C40 (0.700 g, yield 65.0%) as a bright yellow rubbery substance. C40: (LC / MS) m / z (M+H) + = 338.2; 1 H 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; 1 H 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).

[0384] Process 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), TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain P23 (0.260 g, crude product) as a colorless, rubbery substance, which was used directly in the next step without further purification.

[0385] (Preparation Example 24) rac-ethyl(4R,8S)-1-methyl-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-3-carboxylate(P24)

[0386] [ka]

[0387] Process 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 -78°C, LDA (1.07 g, 10.0 mmol) was added to THF (50 mL). A solution of 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 to the solution at -78°C, and the mixture was stirred at -78°C for 1 hour. After stirring, a solution of diethyl oxalate (1.28 g, 8.78 mmol) in THF (20 mL) was added dropwise at -78°C, and the mixture was then stirred at -78°C for 30 minutes. The reaction mixture was raised to room temperature, stirred for 1 hour, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 2-16% siRNA:PE) to obtain C42 (0.750 g, yield 26.4%) as a bright yellow oil. (LC / MS) m / z (M+H) + = 340.1 1 1H 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).

[0388] Process 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) Methylhydrazine dihydrochloride (CAS: 55330-60-4; 0.179 g, 2.17 mmol) and pyridine (0.859 g, 10.9 mmol) were added to a solution of C42 (0.650 g, 2.17 mmol) in EtOH (20 mL). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 12-100% Â:PE) to obtain C43 (0.390 g, yield 51.4%) as an oil and C44 (0.150 g, yield 19.8%). C43: (LC / MS) m / z (M+H) + = 350.1. 1 H 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. 1 H 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).

[0389] Process 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), HCl dioxane solution (0.116 g, 3.18 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure to obtain P24 (0.150 g, crude product) as a white solid. The solid was used directly in the next step without further purification.

[0390] (Preparation example P25) Ethyl 7,7-difluoro-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P25)

[0391] [ka]

[0392] Process 1 Preparation of tert-butyl 3,3-difluoro-4-(pyrrolidine-1-yl)-3,6-dihydropyridine-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), pyrrolidine (0.927 g, 13.0 mmol) was added. The reaction mixture was heated for 20 hours using a Dean-Stark trap to remove H2O released during the reaction, and then concentrated under reduced pressure to obtain C45 (3.42 g, crude product) as a brown solid. The solid was used directly in the next step without further purification. 1 H 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).

[0393] Process 2 Preparation of tert-butyl 5-(2-ethoxy-2-oxoacetyl)-3,3-difluoro-4-(pyrrolidine-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (C46) A 50 mL solution of C45 (3.42 g, 11.9 mmol) in DCM was degassed with nitrogen gas for 10 minutes. After cooling the reaction mixture to 0°C, ethyl oxalyl chloride (1.94 g, 14.2 mmol) was added dropwise over 15 minutes. The temperature was maintained at (0-5)°C throughout the addition. After the addition, TEA (1.80 g, 17.8 mmol) was added dropwise over 5 minutes. The reaction mixture was heated to room temperature, stirred for 5 hours, and then diluted with H2O (300 mL). The diluted reaction mixture was extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-25% Depositphotos:PE) to obtain C46 (2.98 g, yield 64.7%) as a yellow solid. (LC / MS) m / z (M+H) + = 389.2. 1 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).

[0394] Process 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-methylpropane-1-illium (C48) After carrying out the reaction three times, the mixture was combined for further purification. At 0°C, methylhydrazine dihydrochloride (CAS: 55330-60-4; 0.402 g, 3.38 mmol) was added dropwise over 5 minutes to a solution of C46 (1.09 g, 2.81 mmol) in EtOH (10 mL), then the reaction mixture was sealed and stirred at 80°C for 2 hours to form the first batch.

[0395] The same reaction was carried out a second time using C46 (0.500 g, 1.29 mmol), and a third time using C46 (0.100 g, 0.257 mmol). After combining all the reactions, they were diluted with H2O (60 mL). The diluted reaction mixture was extracted with siRNA (3 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-15% siRNA:PE) to obtain C48 (0.756 g, yield 50.4%) as a brown oily substance and impure C47 as the residue. The residue C47 was analyzed by reverse-phase HPLC (C 18 The solution was purified using a 150 mm x 40 mm x 5 μm column (mobile phase A: H2O (0.05% NH4OH-NH4HCO3) / mobile phase B: ACN, held at 32-72% mobile phase B for 9 minutes, then at 100% mobile phase B for 2 minutes, flow rate = 60 mL / min), and then lyophilized to obtain C47 (0.416 g, yield 27.7%) as a colorless oil. C47: (LC / MS) m / z (M-tert-butyl group) + = 290.2;1 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; 1 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).

[0396] Process 4 Preparation of ethyl 7,7-difluoro-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P25) A reaction mixture of C47 (0.416 g, 1.20 mmol) in DCM (5 mL) was mixed with HCl dioxane solution (1.76 g, 48.2 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure to obtain P25 (295 mg, crude product) as a bright yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 246.1. 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).

[0397] (Preparation Example 26) rac-ethyl(4R,8S)-1-methyl-1,4,5,7,8,9-hexahydro-4,8-epiminooxosino[5,4-c]pyrazole-3-carboxylate hydrochloride (P26)

[0398] [ka]

[0399] Process 1 Preparation of rac-tert-butyl(1R,5S)-6-(2-ethoxy-2-oxoacetyl)-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (C49) Using tert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (CAS:280761-97-9; 1.80 g, 7.46 mmol), C49 (2.50 g, crude product) was obtained as an orange oily substance following the same procedure as in step 1 of Preparation Example 20, and this was used directly in the next step without further purification.

[0400] Process 2 Preparation of rac-10-(tert-butyl) 3-ethyl(4R,8S)-1-methyl-1,4,5,7,8,9-hexahydro-4,8-epiminooxosino[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-epiminooxosino[5,4-c]pyrazole-3,10-dicarboxylate (C51) The reaction was carried out twice and then combined. The 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 hours to form the first batch. The reaction mixture of the first batch was examined by LC-MS and the main isomer was found to be C50 [(LC / MS) m / z (M+H) += 352.3 with a retention time of 0.827 minutes (LC / MS conditions for analysis: Chromolith Flash Reverse Phase-18e 25-3 mm column; mobile phase A: 1.5 mL / 4 L TFA H2O solution / mobile phase B: 0.75 mL / 4 L TFA ACN solution, gradient: mobile phase B 5-95% for 0.7 minutes, then retained at 95% for 0.4 minutes; flow rate: 1.5 mL / min; column temperature: 50°C) and subisomer C51 [(LC / MS) m / z (M+H) + = A reading of 352.3 was obtained with a retention time of 0.880 minutes (Analytical LC-MS conditions: Chromolith Flash Reverse Phase-18e 25-3 mm column; Mobile phase A: 1.5 mL / 4 L TFA H2O solution / Mobile phase B: 0.75 mL / 4 L TFA ACN solution, Gradient: Mobile phase B 5-95% for 0.7 minutes, then retained at 95% for 0.4 minutes; Flow rate: 1.5 mL / min; Column temperature: 50°C).

[0401] The same reaction was carried out a second time using C49 (0.200 g, 0.586 mmol). These two reactions were combined, concentrated under reduced pressure, and purified by column chromatography (silica gel, 0-50% Â:PE) to obtain C50 (0.750 g, yield 27.0%) as a yellow solid. (LC / MS) m / z (M+H) + = 352.3. 1 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).

[0402] Process 3 Preparation of rac-ethyl(4R,8S)-1-methyl-1,4,5,7,8,9-hexahydro-4,8-epiminooxosino[5,4-c]pyrazole-3-carboxylate hydrochloride (P26) To a solution of C50 (0.750 g, 2.14 mmol) in DCM (5 mL), a 2 M HCl dioxane solution (0.390 g, 10.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was dissolved in DCM (5 mL), and then concentrated under reduced pressure (2x) to obtain P26 (0.675 g, crude product) as a yellow solid. The solid was used directly in the next step without further purification. 1 H 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).

[0403] (Preparation Example 27) Ethyl 1-propyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P27)

[0404] [ka]

[0405] Process 1 Preparation of 5-(tert-butyl)3-ethyl 1-propyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-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-methylpropane-1-illium (C53) 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) were dissolved in DMF (13 mL) and K2CO3 (0.94 g, 6.7 mmol) was added. The reaction mixture was stirred at 100 °C for 4 hours, cooled to room temperature, and diluted with (1:1) HCl:H2O (50 mL). The aqueous layer was extracted with HCl (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-39% Â:PE) to obtain 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; 1 H 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; 1 H 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).

[0406] Process 2 Preparation of ethyl 1-propyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P27) A reaction mixture of C52 (0.370 g, 1.10 mmol) in DCM (3 mL) was mixed with 2 M HCl dioxane solution (0.400 g, 11.0 mmol), and the mixture was stirred at room temperature for 1 hour and 40 minutes. The reaction mixture was concentrated under reduced pressure to obtain P27 (0.300 g, crude product) as a white solid. The solid was used directly in the next step without further purification. 1 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).

[0407] (Preparation Example 28) Ethyl 1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P28)

[0408] [ka]

[0409] Process 1 Preparation of 5-(tert-butyl)3-ethyl 1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C54) Using 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 same procedure as in Step 1 of Preparation Example 2 was followed. The residue was purified by column chromatography (silica gel, 0-40% THF:PE) to obtain C54 (0.492 g, yield 77.6%) as a yellow rubbery substance. (LC / MS) m / z (M+H) + = 380.3. 1 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).

[0410] Process 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 10 mL solution of C54 (0.470 g, 1.24 mmol) in DCM, 0.973 g, 26.7 mmol of 2 M HCl dioxane solution was added. The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure to obtain P28 (0.370 g, crude product) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 280.1. 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).

[0411] (Preparation Example 29) rac-ethyl(R)-1-(sec-butyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P29)

[0412] [ka]

[0413] Process 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) Using 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 same procedure as in Step 1 of Preparation Example 2 was followed. The residue was purified by column chromatography (silica gel, 50% siRNA:PE) to obtain C55 (0.382 g, yield 81.3%) as a rubbery substance. (LC / MS) m / z (M+H) + = 352.1. 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).

[0414] Process 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 0°C, HCl dioxane solution (4 mL) was added to a solution of C55 (0.382 g, 1.09 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure to obtain P29 (0.245 g, crude product) as a solid. The solid was used directly in the next step without further purification.

[0415] (Preparation Example 30) rac-ethyl(4R,7S)-1-methyl-1,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-3-carboxylate(P30)

[0416] [ka]

[0417] Process 1 Preparation of rac-tert-butyl(1R,5S)-2-(2-ethoxy-2-oxoacetyl)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (C56) Further purification was performed using tert-butyl(1R,5S)-8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (CAS:637301-19-0; 5.10 g, 22.6 mmol) following the same procedure as in Step 1 of Preparation Example 20. The residue was purified by column chromatography (silica gel, 0-10% siRNA:PE) to obtain C56 (4.69 g, yield 63.7%) as a yellow oil.

[0418] Process 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) Using C56 (4.69 g, 14.4 mmol) and methylhydrazine sulfate (CAS: 302-15-8, 2.08 g, 14.4 mmol), the same procedure as in Step 1 of Preparation Example 2 was followed. The reaction mixture was examined by LC-MS, and the dominant isomer was found to be C57 [(LC / MS) m / z (M+H)]. + = 336.2 with a retention time of 0.846 minutes (LC / MS conditions for analysis: Chromolith Flash Reverse Phase-18e 25-3 mm column; mobile phase A: 1.5 mL / 4 L TFA H2O solution / mobile phase B: 0.75 mL / 4 L TFA ACN solution, gradient: mobile phase B 5-95% for 0.7 minutes, then retained at 95% for 0.4 minutes; flow rate: 1.5 mL / min; column temperature: 50°C) and subisomer C58 [(LC / MS) m / z (M+H) + A reading of 336.2 was obtained with a retention time of 0.904 minutes (Analytical LCMS conditions: Chromolith Flash Reverse Phase-18e 25-3 mm column; mobile phase A: 1.5 mL / 4 L TFA H2O solution / mobile phase B: 0.75 mL / 4 L TFA ACN solution, gradient: mobile phase B 5-95% for 0.7 minutes, then mobile phase B 95% for 0.4 minutes; flow rate: 1.5 mL / min; column temperature: 50°C). The purification method was changed. The residue was purified by column chromatography (silica gel, 0-50% THF:PE) to obtain C57 (1.40 g, yield 29.0%) as a light yellow oily substance. 1 H 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).

[0419] Process 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), 3 mL of 2 M HCl dioxane solution was added. The reaction mixture was stirred at room temperature for 2.5 hours, then concentrated under reduced pressure to obtain P30 (0.168 g, crude product) as a gray solid. The solid was used directly in the next step without further purification.

[0420] (Preparation Example 31) Ethyl 1-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P31)

[0421] [ka]

[0422] Process 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-methylpropane-1-illium (C60) Using 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 same procedure as in Step 1 of Preparation Example 2 was followed. The residue was purified by column chromatography (silica gel, 0-60% siRNA:PE) to obtain impure C60 (0.800 g) as a yellow oily substance and C59 (0.940 g, yield 40.3%) as a light brown solid. C60 (0.800 g) was re-purified by column chromatography (silica gel, 0-10% siRNA:DCM) to obtain C60 (0.450 g, yield 19.3%) as a gray rubbery substance. C59: (LC / MS) m / z (M+H) + = 350.1; 1 H 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; 1 H 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).

[0423] Process 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), 2 M HCl dioxane solution (2.0 mL) was added. The reaction mixture was stirred at 35 °C for 3 hours, then concentrated under reduced pressure to obtain P31 (0.143 g, crude product) as a gray solid. The solid was used directly in the next step without further purification.

[0424] (Preparation Example 32) rac-ethyl(R)-1-(1-methoxypropan-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P32)

[0425] [ka]

[0426] Process 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-illium (C62) After carrying out the reaction twice, the mixture was combined for purification. The first batch was formed by stirring 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) at 80°C for 16 hours.

[0427] The same reaction was carried out a second time using 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). After combining these two reactions, the mixture was diluted with H2O (20 mL) and extracted with siRNA (3 x 10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% siRNA:PE) to obtain C62 (0.630 g, yield 56.2%) as an oil and C61 (0.430 g, yield 38.4%) as an oil. C62: (LC / MS) m / z (M+H) + = 368.2; 1 H 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; 1 H 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).

[0428] Process 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 0°C, HCl dioxane solution (8 mL) was added in several portions to a suspension of C61 (0.430 g, 1.17 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain P32 (0.356 g, crude product) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 268.1. 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).

[0429] (Preparation Example 33) Ethyl 1-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate trifluoroacetate (P33)

[0430] [ka]

[0431] Process 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-methylpropane-1-illium (C64) After carrying out the reaction twice, the mixture was combined for purification. 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) was dissolved in DMF (10 mL) and 3-iodooxetane (CAS: 26272-85-5; 0.748 g, 4.06 mmol) and Cs2CO3 (1.32 g, 4.06 mmol) were added, followed by stirring at 80°C for 16 hours to form the first batch.

[0432] The same reaction was carried out a second time using 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 reactions were then combined and diluted in ice H2O (40 mL). The diluted reaction mixture was extracted with toluene (3 x 10 mL). The combined organic layer was washed with brine (2 x 10 mL) and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-80% toluene:PE) to obtain C63 (0.180 g, yield 25.2%) as an oil and C64 (0.288 g, yield 40.3%) 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; 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).

[0433] Process 2 Preparation of ethyl 1-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate trifluoroacetate (P33) At 0°C, TFA (3 mL) was added to a suspension of C63 (0.180 g, 0.512 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure to obtain P33 (0.187 g, crude product) as a rubbery substance. The rubbery substance was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 252.3. 1 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).

[0434] (Preparation Example 34) Ethyl 1-(cyclobutylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P34)

[0435] [ka]

[0436] Process 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) Using 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), C65 (0.280 g, yield 15.0%) was obtained as a yellow rubbery substance by following the same procedure as in Step 1 of Preparation Example 2. (LC / MS) m / z (M+H) + = 350.2. 1 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).

[0437] Process 2 Preparation of ethyl 1-(cyclobutylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P34) At 0°C, HCl was added to a suspension of C65 (0.280 g, 0.801 mmol) in DCM (5 mL) and dioxane (10 mL). The reaction mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, and then freeze-dried to obtain P34 (0.150 g, crude product) as a brown solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 250.1. 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).

[0438] (Preparation Example 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)

[0439] [ka]

[0440] Process 1 Preparation of rac-5-(tert-butyl)3-ethyl(R)-1-(1,1,1-trifluoropropan-2-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (C66) Pyridine (0.465 g, 5.88 mmol) was added 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). The reaction mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-25% siRNA:PE) to obtain C66 (0.415 g, yield 79.3%) as a yellow, rubbery substance. (LC / MS) m / z (M+H) + = 392.2. 1 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).

[0441] Process 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 0°C, HCl dioxane solution (8 mL) was added in several portions to a suspension of C66 (0.415 g, 1.06 mmol) in DCM (4 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure to obtain P35 (0.306 g, crude product) as a yellow solid. The solid was used directly in the next step without further purification.

[0442] (Preparation Example 36) Ethyl 1,7,7-trimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P36)

[0443] [ka]

[0444] Process 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-methylpropane-1-illium (C68) Using 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), C68 (0.563 g, yield 42.7%) was obtained as a bright yellow rubbery substance and C67 (0.160 g, yield 12.1%) as a bright yellow rubbery substance, following the same procedure as in Step 1 of Preparation Example 2. C67: (LC / MS) m / z (M+H) + = 338.2; 1 H 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; 1 H 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).

[0445] Process 2 Preparation of ethyl 1,7,7-trimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P36) At 0°C, a suspension of C67 (0.130 g, 0.385 mmol) in DCM (3 mL) was added to HCl dioxane solution (3 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain P36 (0.110 g, crude product) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 238.1. 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).

[0446] (Preparation Example 37) Ethyl 1'-methyl-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-carboxylate hydrochloride (P37)

[0447] [ka]

[0448] Process 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-methylpropane-1-illium (C70) Using 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 same procedure as in Step 1 of Preparation Example 2 was followed. The purification method was modified. The residue was purified by column chromatography (silica gel, 0-30% THF:PE) to obtain C70 (0.327 g, yield 51.2%) as a white solid and C69 (0.290 g, yield 45.4%) as a white rubbery substance. C69: (LC / MS) m / z (M+H) + = 336.3; 1 H 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; 1 H 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).

[0449] Process 2 Preparation of ethyl 1'-methyl-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-carboxylate hydrochloride (P37) At 0°C, a suspension of C69 (0.272 g, 0.811 mmol) in DCM (6 mL) was added to HCl dioxane solution (0.591 g, 16.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure to obtain P37 (0.219 g, crude product) as a white solid. The solid was used directly in the next step without further purification.

[0450] (Preparation Example 38) rac-ethyl(R)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P38)

[0451] [ka]

[0452] Process 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) Using C10 (3.00 g, 9.57 mmol) and isopropylhydrazine hydrochloride (CAS: 16726-41-3, 1.06 g, 9.57 mmol), the same procedure as in Step 1 of Preparation Example 2 was followed. The purification method was changed. The residue was subjected to reverse-phase HPLC (Sunfire C 18The samples were purified using a 150mm x 40mm x 5μm column (mobile phase A: H2O (0.05% NH4OH-NH4HCO3) / mobile phase B: ACN, mobile phase B held at 42-82% for 9.0 minutes, mobile phase B held at 100% for 2.0 minutes, flow rate = 30 mL / min) to obtain C71 (1.80 g, yield 53.5%) as a pale yellow solid and C72 (33.9 mg, yield 1.01%) as a pale yellow solid. C71: (LC / MS) m / z (M+H) + = 352.4. 1 H 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. 1 H 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).

[0453] Process 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 0°C, HCl dioxane solution (4 mL) was added to a suspension of C71 (0.200 g, 0.569 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain P38 (0.180 g, crude product) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 252.1. 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).

[0454] (Preparation Example 39) 2-Fluoro-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine (P39)

[0455] [ka]

[0456] Process 1 Preparation of 2-fluoro-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine (P39) (6-Fluoropyridine-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) were suspended in dioxane (10 mL) and H2O (2 mL) to which Pd(dppf)Cl2 (0.457 g, 0.625 mmol) and K3PO4 (4.97 g, 23.4 mmol) were added. After degassing the reaction mixture with nitrogen gas, the mixture was stirred at 110 °C for 4 hours and purified by column chromatography (silica gel, 0-40% siRNA:PE) to obtain P39 (1.20 g, yield 86.3%) as a white solid. (LC / MS) m / z (M+H) + = 179.1. 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).

[0457] (Preparation Example 40) 2-Fluoro-5-(1-methyl-1H-imidazole-2-yl)pyridine (P40)

[0458] [ka]

[0459] Process 1 Preparation of 2-fluoro-5-(1-methyl-1H-imidazole-2-yl)pyridine (P40) Under nitrogen gas, the reaction mixture of 2-bromo-1-methyl-1H-imidazole (0.700 g, 4.35 mmol), (6-fluoropyridine-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 90°C for 1 hour. After extraction of the reaction mixture with ELISA, the organic layer was concentrated under reduced pressure. The residue was dissolved in DCM and purified by column chromatography (silica gel, 0-10% MeOH:DCM) to obtain P40 (0.688 g, yield 89.3%) as an orange oil. (LC / MS) m / z (M+H) + = 178.1.

[0460] (Preparation Example 41) 2-(4-(aminomethyl)phenyl)pyrimidine-4(3H)-one hydrochloride (P41)

[0461] [ka]

[0462] Process 1 Preparation of tert-butyl(4-(6-oxo-1,6-dihydropyrimidine-2-yl)benzyl)carbamate (C73) 2-Chloropyrimidine-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) were dissolved in THF (7.7 mL) and 2M K3PO4 (0.325 g, 1.53 mmol) was added. The reaction mixture was degassed with nitrogen gas for 3 minutes, and then XPhos Pd G2 (60.3 mg, 0.0766 mmol) was added. The suspension was degassed with nitrogen gas for 3 minutes and then stirred at 80°C for 4 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with MeOH:DCM (1:10, 3 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-100% siRNA:PE) to obtain C73 (0.115 g, yield 49.8%) as a white solid. (LC / MS) m / z (M+H) + = 302.1. 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).

[0463] Process 2 Preparation of 2-(4-(aminomethyl)phenyl)pyrimidine-4(3H)-one hydrochloride (P41) At 0°C, a stirred solution of C73 (0.115 g, 0.382 mmol) in DCM (1 mL) was added to HCl MeOH solution (3 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain P41 (91.0 mg, crude product) as a white solid. The solid was used directly in the next step without further purification. 1 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).

[0464] (Preparation Example 42) 6-(4-(aminomethyl)phenyl)pyridine-2(1H)-one hydrochloride (P42)

[0465] [ka]

[0466] Process 1 Preparation of tert-butyl(4-(6-oxo-1,6-dihydropyridine-2-yl)benzyl)carbamate (C74) 6-bromopyridine-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) were dissolved in THF (5.7 mL) and 2 M K3PO4 (0.244 g, 1.15 mmol) was added. The reaction mixture was degassed with nitrogen gas for 3 minutes, and then XPhos Pd G2 (45.2 mg, 0.0575 mmol) was added. The suspension was degassed with nitrogen gas for 3 minutes and then stirred at 80°C for 4 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with siRNA (3 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-100% siRNA:PE) to obtain C74 (0.110 g, yield 63.7%) as a white solid. (LC / MS) m / z (M+H) + = 301.1. 11H 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).

[0467] Process 2 Preparation of 6-(4-(aminomethyl)phenyl)pyridine-2(1H)-one hydrochloride (P42) At 0°C, a stirred solution of C74 (0.110 g, 0.366 mmol) in DCM (1 mL) was added to HCl MeOH solution (3 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure to obtain P42 (87.0 mg, crude product) as a white solid. The solid was used directly in the next step without further purification. 1 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).

[0468] (Preparation Example 43) 3-(4-(aminomethyl)phenyl-2,3,5,6-d4)-1,1-dimethylurea hydrochloride (P43)

[0469] [ka]

[0470] Process 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), 4-bromobenzene-2,3,5,6-d4-amine (CAS: 61357-76-4; 5.50 g, 31.2 mmol) was added at (-5 to 5) °C. The reaction mixture was stirred at (0 to 5) °C for 3 hours, after which TEA (6.32 g, 62.5 mmol) and dimethylamine hydrochloride (CAS: 506-59-2; 5.10 g, 62.5 mmol) were slowly added at (0 to 5) °C. The reaction mixture was raised to room temperature and stirred for 16 hours. The suspension was poured into H2O (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was slurryed with MTBE:DCM (10:1, 100 mL) at room temperature for 3 hours and then filtered. The filtered cake was dried under reduced pressure and collected to obtain C75 (6.10 g, yield 76.2%) as a white solid. 1 1H NMR (400 MHz, (CD3)2SO) δ 8.40 (s, 1H), 2.91 (s, 6H).

[0471] Process 2 Preparation of tert-butyl(4-(3,3-dimethylureido)2,3,5,6-d4-benzyl)carbamate (C76) The 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 three times with nitrogen gas. Bis(1-adamantyl)-butyl-phosphan (0.87 g, 2.4 mmol) and Pd(OAc)2 (0.27 g, 1.2 mmol) were added to the reaction mixture. The suspension was degassed and purged three more times with nitrogen gas, then stirred under nitrogen gas at 90°C for 16 hours. After the reaction mixture was cooled to room temperature, it was poured into H2O (50 mL) and filtered. The filtrate was extracted with SiO2 (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was slurryed in DCM (100 mL) at room temperature for 4 hours and then filtered. The filtered cake was dried under reduced pressure and collected to obtain C76 (2.0 g, yield 30%) as a bright yellow solid.

[0472] Process 3 Preparation of 3-(4-(aminomethyl)phenyl-2,3,5,6-d4)-1,1-dimethylurea hydrochloride (P43) A 25 mL solution of 2 M HCl dioxane was added to a 30 mL solution of C76 (2.0 g, 6.7 mmol) in DCM. The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was analyzed by reverse-phase HPLC (Welch Xtimate C). 18 After purification using a 250 mm x 50 mm x 10 μm column (mobile phase A: H2O containing HCl / mobile phase B: ACN, mobile phase B at 0-20% for 20 minutes), the sample was freeze-dried to obtain P43 (1.1 g, yield 67%) as a white solid. 1 1H NMR (400 MHz, (CD3)2SO) δ 8.43 (s, 1H), 8.37 (br s, 2H), 3.90 (q, 2H), 2.92 (s, 6H).

[0473] (Preparation Example 44) rac-ethyl(R)-1-isopropyl-7-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P44)

[0474] [ka]

[0475] Process 1 Preparation of tert-butyl 3-(2-ethoxy-2-oxoacetyl)-4-oxo-5-(trifluoromethyl)-3,4-dihydropyridine-1(2H)-carboxylate (C77) A yellow 1M LiHMDS THF solution (18.4 mL) was diluted with THF (10 mL) and then cooled to -69°C in a dry ice / acetone bath. To the cooled solution, a THF (20 mL) solution of tert-butyl 4-oxo-5-(trifluoromethyl)-3,4-dihydropyridine-1(2H)-carboxylate (CAS: 1667744-92-4; 4.07 g, 15.4 mmol) was added dropwise over 15 minutes. The substrate flask was rinsed with THF (2 x 1 mL) and added to the reaction mixture. The solution turned brownish-orange during the addition. After the addition, the reaction mixture was stirred at -69°C for 45 minutes.

[0476] A solution of diethyl oxalate (2.52 mL) in THF (5 mL) was added dropwise to the reaction mixture over 8 minutes. After rinsing the source vial with THF (1.5 mL), it was added to the reaction mixture, and the solution turned brownish-orange. The reaction mixture was stirred for a further 7 minutes in a dry ice / acetone bath, then removed and replaced with an ice water bath. The reaction mixture was stopped with 2N HCl aqueous solution (21 mL), and the suspension turned orange. The suspension was diluted with H2O and extracted with HCl (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 layers were acidified to pH=1 with 6N HCl (approximately 6.5 mL). The acidic aqueous layers were extracted with MTBE (2 x 40 mL). The combined organic layers obtained by extraction from the acidic aqueous layer were dried with Na2SO4, filtered, concentrated under reduced pressure, and then dried under high vacuum to obtain C77 (1.52 g) as an orange-yellow residue.

[0477] The reserved organic layers were combined. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a dark orange oily substance. The oily substance 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 6N HCl aqueous solution. The acidic aqueous layers were extracted with MTBE (30 mL), then with MTBE (20 mL). After combining the organic layers, they were dried over Na2SO4, filtered, concentrated under reduced pressure, and further dried under high vacuum to obtain C77 (1.92 g) as an orange residue.

[0478] The products from these two batches were combined to form C77 (3.44 g), which was then purified by column chromatography (silica gel, 0-85% siRNA:heptane) to obtain C77 (2.32 g, yield 41.3%) 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).

[0479] Process 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-methylpropane-1-illium (C79) To a solution of C77 (408 mg, 1.12 mmol) in EtOH (4.5 mL), isopropylhydrazine hydrochloride (CAS: 16726-41-3; 148 mg, 1.34 mmol) was added, followed by pyridine (132 mg, 1.67 mmol). The reaction mixture was stirred at 55°C for 20 hours, then concentrated under reduced pressure to obtain a yellow-orange residue. The residue was diluted with Depositphotos (20 mL) and washed with NaHCO3 (20 mL). The aqueous layer was back-extracted with Depositphotos (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain an orange oily substance. After dissolving the oily substance in DCM, it was pre-adsorbed onto (1:1) silica gel:Celite and purified by column chromatography (silica gel, 0-100% dimethylheptane) to obtain C78 (0.315 g, yield 69.9%) as a rubbery substance and C79 (7.70 mg, yield 1.71%) as a bright yellow solid. C78: (LC / MS) m / z (M+H) + = 404.6; 1 H 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;1 H 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).

[0480] Process 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) A suspension of Pd / C (CAS: 7440-05-3; 83 mg, 5 wt%, 0.039 mmol) in EtOH (0.5 mL) was added to a bright yellow C78 (0.30 g, 0.75 mmol) solution in EtOH (1.5 mL). After rinsing the source vial with EtOH (0.5 mL x 2), the rinse solution was added to the reaction mixture until the total volume of EtOH was (3 mL). The reaction mixture was stirred overnight at room temperature under H2 gas (50 psi) in a Hastelloy reactor. The suspension was filtered through a plastic filtration funnel pre-filled with Celite (0.5 g). The filtration cake was eluted with EtOH. The gray filtrate was concentrated under reduced pressure to obtain a gray residue.

[0481] The same reaction was repeated. A crude residue solution in EtOH (1.5 mL) was added to the reaction mixture of Pd / C (98 mg, 5 wt%, 0.046 mmol) in EtOH (0.5 mL). The reaction mixture was stirred overnight at room temperature under H2 gas (50 psi) in a Hastelloy reactor. The suspension was filtered through a pre-filled plastic filtration funnel containing Celite (0.5 g). The filtration cake was eluted with EtOH. The gray filtrate was concentrated under reduced pressure to obtain a gray solid. The solid was purified by column chromatography (silica gel, 0-50% Depositphotos:heptane) to obtain C80 (0.24 g, yield 78%) as a white solid. (LC / MS) m / z (M+H) + = 406.6; 11H 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).

[0482] Process 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) 1.44 mL of 4N HCl dioxane solution was added dropwise to C80 (0.234 g, 0.577 mmol). The reaction mixture was stirred at 40°C for 40 minutes, then concentrated under nitrogen gas, and subsequently dried under high vacuum to obtain P44 (0.210 g, crude product) as a white solid. (LC / MS) m / z (M+H) + = 306.5; 1 H 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).

[0483] (Preparation Example 45) 1-(6-fluoropyridine-3-yl)pyrrolidine-2-one (P45)

[0484] [ka]

[0485] Process 1 Preparation of 1-(6-fluoropyridine-3-yl)pyrrolidine-2-one (P45) The reaction mixture of 2-fluoro-5-iodopyridine (CAS: 171197-80-1; 2.00 g, 8.97 mmol), pyrrolidine-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 under nitrogen gas at 115 °C for 16 hours. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-60% siRNA:PE) to obtain P45 (1.40 g, yield 86.6%) as a bright yellow solid. (LC / MS) m / z (M+H) + = 181.0; 1 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).

[0486] (Preparation Example 46) Ethyl(R)-1-ethyl-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (P46)

[0487] [ka]

[0488] Process 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) The 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 hours. The yellow slurry was examined by LC / MS and found to have a C81 concentration (LC / MS) m / z (M+H) + = 338.3 with a holding time of 1.69 minutes, and C82 (LC / MS) m / z (M+H) + = A reading of 338.3 was observed at a retention time of 1.94 minutes. The reaction mixture was diluted with H2O and extracted with DCM(3x). The combined organic layers were dried over Na2SO4 and then purified by column chromatography (silica gel, 0-100% Â:heptane) to obtain C81 (1.53 g, yield 86.0%) and C82 (30.0 mg, yield 1.70%). C81: 1 H 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: 1 H 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).

[0489] Process 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), 12.1 M HCl (0.216 g, 5.93 mmol) was added. The reaction mixture was stirred at 50 °C for 25 hours and 15 minutes, then concentrated under reduced pressure. The residue was diluted with ACN and concentrated under reduced pressure. The residue was diluted with DCM and concentrated under reduced pressure (2x) to obtain P46 (0.730 g, crude product) 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. 1 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).

[0490] (Preparation Example 47) Methyl 3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (47)

[0491] [ka]

[0492] Process 1 Preparation of methyl 3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P47) 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) was dissolved in DCM (5.0 mL) and 2 M HCl siRNA solution (5.0 mL) was added at 10°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture became a white suspension, which was concentrated under reduced pressure to obtain P47 (0.149 g, crude product) as a white solid. This was used in the next step without further purification. 1 H 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).

[0493] (Preparation Example 48) Ethyl 3-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P48)

[0494] [ka]

[0495] Process 1 Preparation of 7-(tert-butyl) 1-ethyl 3-(propa-1-en-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (C83) A (4:1) DME:H2O (16 mL:4 mL) 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-(propa-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) was degassed with nitrogen gas for 5 minutes. The reaction mixture was stirred at 90°C for 16 hours, then concentrated under reduced pressure. The residue was dissolved in DCM (50 mL) and extracted with Depositphotos (3 x 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, 0-20% Depositphotos:PE) to obtain C83 (0.856 g, yield 95.5%) as a bright yellow solid. (LC / MS) m / z (M+H) + = 336.2.

[0496] Process 2 Preparation of 7-(tert-butyl) 1-ethyl 3-isopropyl-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (C84) RuCl(PPh3)3 (0.24 g, 0.25 mmol) was added to a THF (20 mL) suspension of C83 (0.86 g, 2.5 mmol). The reaction mixture was degassed with hydrogen gas and then stirred under a hydrogen atmosphere (50 psi) at 60-65°C for 48 hours. After concentrating the suspension under reduced pressure, the residue was purified by column chromatography (silica gel, 0-20% THF:PE) to obtain C84 (0.67 g, 77% yield) as a brown solid. (LC / MS) m / z (M+H) + = 338.3. 1 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).

[0497] Process 3 Preparation of ethyl 3-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P48) To a 10 mL solution of C84 (0.67 g, 2.0 mmol) in DCM, 20 mL of 2 M HCl dioxane solution was added. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure and dried under high vacuum to obtain P48 (0.54 g, crude product) as a solid. The solid was used directly in the next step without further purification.

[0498] (Preparation Example 49) 5,7-di-tert-butyl-2-(oxetane-3-yloxy)-3-phenyl-2,3-dihydrobenzo[d]oxazole (P49)

[0499] [ka]

[0500] Process 1 Preparation of 5,7-di-tert-butyl-2-(oxetane-3-yloxy)-3-phenyl-2,3-dihydrobenzo[d]oxazole (P49) The reaction mixture of 3-hydroxyoxetane (CAS: 7748-36-9; 41 mg, 0.55 mmol) and dexazole (CAS: 1207294-92-5; 0.22 g, 0.55 mmol) in MTBE (3 mL) was degassed with nitrogen gas (2x). After stirring the suspension at room temperature for 5 minutes, pyridine (43 mg, 0.55 mmol) was added. The reaction mixture was stirred for 30 minutes to obtain a solution of P49 (0.21 g, crude product). The solution was used directly in the next step without further purification.

[0501] (Preparation Example 50) rac-methyl(4R)-1-isopropyl-4-methyl-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P50)

[0502] [ka]

[0503] Process 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), Cs2CO3 (18.5 g, 56.7 mmol) and 2-iodopropane (CAS: 75-30-9; 7.23 g, 42.5 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours, diluted with HCl (100 mL), and washed with brine (3 x 300 mL). The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The yellow oily substance was purified by column chromatography (silica gel, 0-37% HCl:hexane) to obtain C85 (3.30 g, yield 45.9%). (LC / MS) m / z (M+H) + = 254.0. 1 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).

[0504] Process 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) and trimethylboroxine (CAS: 823-96-1; 8.31 g, 33.1 mmol) in dioxane (60 mL), DIEA (4.28 g, 33.1 mmol) and Pd(t-Bu3P)2 (0.635 g, 1.24 mmol) were added. The reaction mixture was degassed with nitrogen gas and stirred at 90°C for 12 hours. The suspension was diluted with RINKAN (100 mL), washed with brine (2 x 150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% RINKAN:hexane) to obtain C86 (2.10 g, crude product) as an orange, rubbery substance. The rubbery substance was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 234.0. 1 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).

[0505] Process 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 by flow chemistry. C86 (1.80 g, 7.72 mmol) was dissolved in MeOH (40 mL). The solution was pumped at a flow rate of 0.3 mL / min, and H2 was added at a flow rate of 30 mL / min. 5.0 mL of the solution was passed through a fixed bed (1 / 4'' mm) packed with 5% Ru / Al2O3 granular catalyst, and hydrogenated at 60°C by flowing H2 at 2.0 MPa. The reaction mixture was collected from the reactor output to obtain P50 (1.85 g, crude product) as a black oily substance. The oily substance was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 238.2. 1 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).

[0506] (Preparation Example 51) rac-methyl(4R)-4-ethyl-1-isopropyl-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P51)

[0507] [ka]

[0508] Process 1 Preparation of methyl 1-isopropyl-4-vinyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C87) 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 mixed with Pd(dppf)Cl2 (0.288 g, 0.394 mmol). The suspension was degassed with nitrogen gas for 3 minutes and then stirred at 90°C for 2 hours. After filtering the reaction mixture, the filtrate was washed with HCl (50 mL). The filtrate was concentrated under reduced pressure. The yellow rubbery substance was purified by column chromatography (silica gel, 0-40% HCl:hexane) to obtain C87 (0.700 g, yield 72.4%) as a bright yellow solid. (LC / MS) m / z (M+H) + = 246.1. 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).

[0509] Process 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 by flow chemistry. C87 (0.300 g, 1.22 mmol) was dissolved in MeOH (20 mL). The solution was pumped at a flow rate of 0.3 mL / min, and H2 was added at a flow rate of 30 mL / min. 5.0 mL of the solution was passed through a fixed bed (1 / 4'' mm) packed with 5% Ru / Al2O3 granular catalyst, and hydrogenated at 60°C by flowing H2 at 2.0 MPa. The reaction mixture was collected from the reactor output to obtain P51 (0.280 g, crude product) as a brown oil. The oil was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 252.0. 1 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).

[0510] (Preparation Example 52) rac-ethyl(6R,7R)-1-isopropyl-6,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (P52)

[0511] [ka]

[0512] Process 1 Preparation of rac-benzyl(R)-2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (C88) 4-methoxypyridine (CAS: 620-08-6; 32.6 mL), THF (641.4 mL), and TEA (4.5 mL) were added sequentially to a round-bottom flask. After cooling the solution to -78°C, 109.0 mL of 3 M benzyltoluene chloroformate solution was added dropwise to obtain a white slurry. 55.6 mL of 3.4 M methylmagnesium bromide solution was added dropwise to the suspension. The reaction mixture was stirred at -78°C and slowly heated to room temperature over 24 hours. The reaction mixture was cooled to 0°C, and the reaction was stopped by adding 1 M aqueous HCl in several batches. The aqueous mixture was extracted with DCM (3x). The organic layers were combined, dried over Na2SO4, and purified by column chromatography (silica gel, 0-50% Ã:heptane) to obtain C88 (51.5 g, yield 65.5%) as a clear oil. (LC / MS) m / z (M+H) + = 246.4. 1 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).

[0513] Process 2 Preparation of rac-benzyl(2R,3R)-2,3-dimethyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate(C89) The reaction mixture of C88 (10.0 g, 40.8 mmol) in THF (102 mL) was cooled to -78°C, then 1 M LiHMDS THF solution (42.8 mL) was added dropwise, and the mixture was stirred at -78°C for 10 minutes. After stirring for several minutes, MeI (3.1 mL) was added dropwise to the reaction mixture at -78°C, and then the mixture was raised to room temperature over 30 minutes. The suspension was stirred at room temperature for 9 hours, and then the reaction was stopped with brine. The pH of the aqueous layer was adjusted to pH=1 using 12 M aqueous HCl solution. The reaction mixture was extracted with RINKAN (2x), and the organic layers were combined and dried over Na2SO4. The mixture was purified by column chromatography (silica gel, 0-40% MTBE: heptane) to obtain C89 (7.80 g, yield 73.6%) as a yellow oil. 1 H 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).

[0514] Process 3 Preparation of rac-benzyl(2R,3R)-2,3-dimethyl-4-oxopiperidine-1-carboxylate (C90) C89 (12.8 g, 49.4 mmol), AcOH (82.3 mL), and Zn (12.9 g, 197 mmol) were sequentially added to a round-bottom flask, and the mixture was stirred at 60°C for 5 hours. The reaction mixture was concentrated under reduced pressure, saturated with NaHCO3, and extracted with DCM (3x). The combined organic layer was purified by column chromatography (silica gel, 0-50% Depositphotos:heptane) to obtain C90 (10.1 g, yield 78.3%) as a clear oil. 1 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).

[0515] Process 4 Preparation of rac-benzyl(2R,3R,5R)-5-(2-ethoxy-2-oxoacetyl)-2,3-dimethyl-4-oxopiperidine-1-carboxylate (C91) The reaction mixture of C90 (0.430 g, 1.65 mmol), EtOH (3.29 mL), and diethyl oxalate (0.24 mL) was cooled to -78°C, and then 1.89 mL of 1 M LiHMDS THF solution was added. The suspension was stirred at room temperature for 17 hours, and then the reaction was stopped with a mixture of 1 M aqueous HCl, brine, and DCM. The aqueous layer was extracted with (2:1, MTBE:DCM, 2x). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure to obtain C91 (0.590 g, crude product) as a yellow oil. The oil was used directly in the next step without further purification.

[0516] Process 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) The 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 60°C for 2.5 hours, then stirred at room temperature for 24 hours. The suspension was diluted with H2O and extracted by DCM (3x). The organic layers were combined and purified by column chromatography (silica gel, 0-60% siRNA:heptane) to obtain C92 (0.322 g, yield 49.4%) as a clear oil.

[0517] Process 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) A solution of Pd / C (10% by weight, 0.213 g, 2.00 mmol) in EtOH (1 mL) was added to the reactor, followed by a solution of C92 (0.800 g, 2.00 mmol) in EtOH (5 mL). The suspension was degassed with hydrogen gas and then stirred at room temperature under a hydrogen atmosphere (120 psi) for 1 hour. The reaction mixture was filtered through Celite and washed with tert-amyl alcohol. The filtrate was concentrated under reduced pressure to obtain P52 (0.531 g, crude product) as a yellow oil. The oil was used directly in the next step without further purification. 1 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).

[0518] (Preparation Example 53) rac-ethyl(R)-3-isopropyl-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate hydrochloride (P53)

[0519] [ka]

[0520] Process 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), Cs2CO3 (38.0 g, 117 mmol) and 2-isocyanoethyl acetate (CAS: 2999-46-4, 17.8 g, 156 mmol) were added at 15°C. The reaction mixture was heated at 85°C for 16 hours and then diluted with SiO4 (300 mL). The light brown reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The brown residue was diluted with (1:1, SiO4:THF) and filtered. The filtrate cake was dissolved in (1:1, H2O:SiO4) and extracted with SiO4 (150 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-100% EtOAC:PE) to obtain C14a (7.71 g, yield 48.3%) as a light brown solid. (LC / MS) m / z (M+H) + = 206.1. 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).

[0521] Process 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 by flow chemistry. C14a (7.71 g, 37.6 mmol) was dissolved in THF (155 mL) and AcOH (40 mL), then pumped at a flow rate of 0.3 mL / min, and H2 was added at a flow rate of 30 mL / min. 5.0 mL of the solution was passed through a fixed bed ((1 / 4'') mm) packed with granular catalyst 10% Ru / SiO2 (2.80 g, 2.76 mmol), and hydrogenated at 80°C for 3.3 minutes under a flow of H2 at 2.5 MPa. The H2 flow rate was increased to 100 mL / min. After 10 minutes, the reaction mixture was collected and then concentrated under reduced pressure to remove THF. The suspension was stirred for 1-2 hours and then filtered. The filtrate was concentrated under reduced pressure to obtain C93 (5.50 g, crude product) 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.

[0522] Process 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), Boc2O (6.31 g, 28.9 mmol) and K2CO3 (10.7 g, 77.1 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours, then diluted with SiO2 (100 mL). The suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; 0-100% SiO2:PE) to obtain C94 (5.30 g, yield 93.1%) as a yellowish-white solid. (LC / MS) m / z (M+H) + = 310.2. 1 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).

[0523] Process 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) A solution of C94 (3.20 g, 10.8 mmol) in ACN (30.0 mL) was mixed with a solution of NBS (2.89 g, 16.3 mmol) in ACN (20.0 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% Â:PE) to obtain C95 (2.57 g, yield 64.0%) as a white solid. (LC / MS) m / z (M+2H) + = 390.0. 1 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).

[0524] Process 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 (4:1) DME:H2O (16 mL:4 mL) 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) was degassed with nitrogen gas for 5 minutes. The reaction mixture was stirred at 80°C for 15 hours, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-35% siRNA:PE) to obtain C96 (0.810 g, yield 90.0%) as a rubbery substance. (LC / MS) m / z (M+H)+ = 350.2. 1 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).

[0525] Process 6 Preparation of rac-7-(tert-butyl) 1-ethyl(R)-5-methyl-3-(propa-1-en-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (C97) Ammonium formate (2.19 g, 34.8 mmol) and Pd / C (0.370 g, 0.348 mmol) were added to an EtOH solution of C96 (0.810 g, 2.32 mmol). The reaction mixture was stirred under argon gas at 60°C for 1 hour, and then filtered through Celite. The filtrate cake was washed with EtOH (3 x 30 mL). The filtrate was concentrated under reduced pressure and dissolved in DCM (50 mL). The solution was washed with brine (3 x 50 mL). The organic layer was concentrated under reduced pressure to obtain C97 (0.715 g, crude product). The crude product was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 352.2.

[0526] Process 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 10 mL solution of C97 (0.715 g, 2.03 mmol) in DCM, 20 mL of 2 M HCl dioxane solution was added. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure and freeze-dried to obtain P53 (0.710 g, crude product) as a rubbery substance. The rubbery substance was used directly in the next step without further purification. (LC / MS) m / z (M+H) + = 252.2.

[0527] (Example 1) N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidine-1-yl)pyridine-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(1)

[0528] [ka]

[0529] Process 1 Preparation of ethyl 5-(5-iodopyridine-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 hours. The brown reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, 0-20% siRNA:PE) to obtain C98 (0.61 g, 27.8%) as a white solid. (LC / MS) m / z (M+H) + = 441.2. 1 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).

[0530] Process 2 Preparation of ethyl 1-isopropyl-5-(5-(2-oxopyrrolidine-1-yl)pyridine-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 under nitrogen at 120 °C for 16 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography (silica gel, 0-30% THF:PE) to obtain C99 (0.36 g, 99.7% yield) as a white solid. (LC / MS) m / z (M+H) + = 398.2.

[0531] Process 3 Preparation of 1-isopropyl-5-(5-(2-oxopyrrolidine-1-yl)pyridine-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (C100) 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 prepared by adding LiOH (57.5 mg, 2.40 mmol) and stirring at room temperature for 1 hour and 30 minutes. The solution was concentrated under reduced pressure and then acidified to pH 5-6 with 2N HCl. After filtering the yellowish-white solid precipitate, it was washed with H2O (3 x 50 mL), dried, and then freeze-dried to obtain 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).

[0532] Process 4 Preparation of N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidine-1-yl)pyridine-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (1) A DMSO (2.0 mL) solution of C100 (80.0 mg, 0.217 mmol), HOPO (71.0 mg, 0.639 mol), EDCI (99.6 mg, 0.520 mmol), and DIEA (0.140 g, 1.08 mmol) was stirred at room temperature for 10 minutes. P11 (74.6 mg, 0.325 mmol) was added to the reaction mixture, and the mixture was heated to 40°C and stirred for 2 hours. The residue was analyzed by reverse-phase HPLC (C). 18 The sample was purified using a 150mm x 30mm x 5μm column (mobile phase A: H2O / mobile phase B: ACN(NH4OH-NH4HCO3), held at 18-58% mobile phase B for 9 minutes, then at 100% mobile phase B for 2 minutes, flow rate: 30 mL / min). The sample was then lyophilized to obtain 1 (72.2 mg, yield 61.2%) as a white solid. (LC / MS) m / z (M+H) + = 545.4. 1 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).

[0533] (Example 2) 5-(5-(dimethylcarbamoyl)pyridine-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(2)

[0534] [ka]

[0535] Process 1 Preparation of ethyl 5-(5-(dimethylcarbamoyl)pyridine-2-yl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C101) A mixture of P2 (70.0 g, 256 mmol) and CsF (97.1 g, 639 mmol) in DMSO (0.7 L) was mixed with 6-fluoro-N,N-dimethylnicotinamide (CAS: 1032251-82-3, 57.3 g, 256 mmol). The reaction mixture was stirred at 130 °C for 8 hours. After diluting the reaction mixture with H2O (6 L), it was extracted with MeOH:DCM (1:10, 3 x 2 L). The combined organic layers were washed with brine (2 x 3 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-100% Â:PE) to obtain C101 (72.0 g, yield 73.1%) as a pale yellow solid. (LC / MS) m / z (M+H) + = 386.2. 1 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).

[0536] Process 2 Preparation of 5-(5-(dimethylcarbamoyl)pyridine-2-yl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (C102) After carrying out the reaction twice, the mixture was combined for purification. Under nitrogen at room temperature, KOTMS (28.0 g, 218 mmol) was added to a mixture of C101 (42.0 g, 109 mmol) in ACN (420 mL), and the mixture was stirred at room temperature for 1 hour to obtain the first batch. The first batch was acidified to pH=5-6 with 2 M HCl dioxane solution (109 mL, 7.95 g, 218 mmol), and then concentrated under reduced pressure.

[0537] The residue from the first reaction was combined with the residue from the second reaction using 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 layer was dried over Na2SO4, filtered, and then concentrated under reduced pressure to obtain C102 (66.0 g, yield 83.7%) as a white solid. This was used in the next step without further purification. 1 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).

[0538] Process 3 Preparation of 5-(5-(dimethylcarbamoyl)pyridine-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 a solution of C102 (70 mg, 0.20 mmol) in ACN (1.0 mL) and H2O (0.1 mL), HOPO (26 mg, 0.24 mmol) and EDCI (60 mg, 0.31 mmol) were added. The reaction mixture was stirred at 50°C for 20 minutes, then cooled to room temperature. Next, DIEA (76 mg, 0.59 mmol) and P11 (54 mg, 0.24 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 1 hour and 20 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in DMSO, and acidified with TFA. The acidic residue was analyzed by reverse-phase HPLC (Sunfire C 18 Purification was performed using a 100mm x 19mm x 5μm column, mobile phase A: H2O / mobile phase B: ACN (0.05% TFA), holding at 15-95% mobile phase B for 9.0 minutes, and at 95% mobile phase B for 1.0 minute, flow rate: 25 mL / min, yielding 2 (30 mg, yield 25%). (LC / MS) m / z (M+H) + = 533.4. 1 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).

[0539] (Example 3) 5-(5-(dimethylcarbamoyl)pyridine-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide(3)

[0540] [ka]

[0541] Process 1 Preparation of ethyl 5-(5-(dimethylcarbamoyl)pyridine-2-yl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C103) Ethyl 1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride (prepared using the same method as in Preparation Example 1, 0.350 g, 1.35 mmol) was mixed in butyronitrile (5.0 mL) and DIEA (0.697 g, 5.39 mmol). 6-fluoro-N,N-dimethylnicotinamide (CAS: 1032251-82-3, 0.249 g, 1.48 mmol) was added, and the reaction mixture was heated at 115°C for 17 hours. After concentrating the solution under reduced pressure, it was redissolved in DCM and purified by column chromatography (silica gel, 0-5% MeOH:DCM) to obtain C103 (0.209 g, yield 41.7%) as a yellow oil. (LC / MS) m / z (M+H) + = 372.4. 1 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).

[0542] Process 2 Preparation of 5-(5-(dimethylcarbamoyl)pyridine-2-yl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (C104) LiOH (80.6 mg, 3.37 mmol) was added at 15°C to C103 (0.250 g, 0.673 mmol) in THF (2.0 mL), H2O (2.0 mL), and MeOH (0.2 mL). The reaction mixture was heated to 40°C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the organic layer, and the aqueous layer was acidified to pH=3 with 2N HCl. After concentrating the acidic aqueous phase under reduced pressure, reverse-phase HPLC (C) was performed. 18 The sample was purified using a 150 mm x 30 mm x 5 μm column (mobile phase A: H2O / mobile phase B: ACN (0.05% formic acid), with mobile phase B held at 0-32% for 9 minutes, then at 100% for 2 minutes, flow rate: 30 mL / min). The sample was then lyophilized to obtain C104 (0.150 g, yield 64.9%) as a white solid. (LC / MS) m / z (M+H) + = 344.3. 1 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).

[0543] Process 3 Preparation of 5-(5-(dimethylcarbamoyl)pyridine-2-yl)-N-(4-(3,3-dimethylureido)benzyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide (3) After carrying out the reaction twice, the samples were combined for purification. To a solution of C104 (0.100 g, 0.291 mmol) in DMSO (3.0 mL), HOPO (97.1 mg, 0.874 mmol), DIEA (0.188 g, 1.46 mmol), and EDCI (0.134 g, 0.699 mmol) were added to form the first batch. The reaction mixture of the first batch was stirred at 40°C for 15 minutes, after which P11 (73.6 mg, 0.320 mmol) was added. The suspension of the first batch was stirred at 40°C for 2 hours.

[0544] The reaction mixture from the first reaction was combined with the reaction mixture from the second reaction using C104 (0.563 g, 1.64 mmol). The combined reaction mixture was analyzed using reverse-phase HPLC (C104). 18 The sample was purified using a 150mm x 40mm x 5μm column (mobile phase A: H2O / mobile phase B: ACN(NH4OH-NH4HCO3), held at 3-43% mobile phase B for 9 minutes, then at 100% mobile phase B for 2 minutes, flow rate: 60 mL / min), and lyophilized to obtain 3 (0.467 g, yield 46.7%). (LC / MS) m / z (M+H) + = 519.3. 1 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).

[0545] (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)

[0546] [ka]

[0547] Process 1 Preparation of ethyl 5-(4-(dimethylcarbamoyl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (C105) After carrying out the reaction twice, the samples were 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), RuPhos (11.2 mg, 0.0239 mmol), RuPhos Pd G3 (20.0 mg, 0.0239 mmol), and NaOtBu (45.9 mg, 0.478 mmol) were added at room temperature to form the first batch. The reaction mixture of the first batch was degassed with nitrogen for 1 minute and heated at 115 °C for 20 hours.

[0548] The reaction mixture from the first reaction was combined with the reaction mixture from the second reaction using P4 (0.400 g, 1.91 mmol). The combined reaction mixture was analyzed by HPLC (C). 18 Purification was performed using a 150 mm x 30 mm x 5 μm column (mobile phase A: H2O / mobile phase B: ACN (0.05% NH4OH-NH4HCO3), hol...

Claims

1. Compounds of formula I, or pharmaceutically acceptable salts thereof: 【Chemistry 1】 [In the formula, X １ CH, CNH ２ , or N; X ２ is C or N; X ３ CR １３ , N, NR １３ It is O, or S; X ４ is CH, N, or NR １３ And; X ５ is CR １Ｂ or N; X ６ is CH or N; X ７ is CH, N, or CF; X ８ is CH or N; X ９ CR １Ｂ or N; X １０ CR １Ｂ or N; R １ Ha-NHR ８ -OH, -C ２～５ A complex algebra, or -C １～３ It is alkyl; R １ -C ２～５ The complex ring has one, two, or three -C elements. １～３ Alkyl, -C １～３ Oxoalkyl, -C ３～５ Heterocycloalkyl, -C ３～５ Hydroxyheterocycloalkyl, -C ３～５ It may be substituted with an aminoheterocycloalkyl or oxo; R １ -C １～３ Alkyl is one, two, or three oxo, -NR １０Ａ R １１ , or -NR １０ R １１ It is also fine if it is replaced with; R １Ａ H, halogen, or -CH ３ is; or, R １ and R １Ａ This is a C condensed into a D ring. ５～７ Heterocycloalkyl or C condensed to a D ring ５～７ Forms a heteroaryl; C ５～７ Heterocycloalkyl or C ５～７ Heteroaryls may be substituted with oxo; Each R １Ｂ H and -CH are independent of each other. ３ , F, Cl, or methoxy; R ２ H, -C １～３ Alkyl, -C １～３ Alkoxy, -C １～３ It is a fluoroalkyl or halogen; R ３ Ha-C １～３ Alkyl, -C ２～１０ Heterogeneous ring, -P(=O)(CH ３ ) ２ , -S(=O)CH ３ , -NH-S (=O) ２ CH ３ , or -NH-C(=O)-C １～３ It is alkyl; R ３ -C １～３ Alkyls can consist of one, two, or three oxo, halogen, or -C atoms. ３～６ Cycloalkyl, -OH, -NR １２ R １２Ａ , or it may be substituted with cyano; -C ２～１０ Heterocyclic rings consist of one, two, or three -OH, halogen, and -C rings. １～３ Hydroxyalkyl, -C １～３ Alkoxy, -C １～３ Alkyl, -C １～３ It may be substituted with a fluoroalkyl, cyclopropyl, or oxo; or, R ２ and R ３ This is one, two, or three -C １～３ Alkyl, -C ２～３ A C condensed on the A ring, which may be substituted with an oxoalkyl or oxo group. ３～６ Forming a heterogeneous ring; R ４Ａ H, -OH, -C １～３ Fluoroalkyl, or -C １～３ It is alkyl; R ４Ｂ is either H or does not exist; or, R ４Ａ and R ４Ｂ It forms a cyclopropyl; Each R ５ These are independently H, halogen, -OH, cyclopropyl, and -C １～３ Fluoroalkyl, or -C １～３ Alkyl; or two R ５ The group forms a cyclopropyl group; R ６ is H, -OH, or -C １～３ Alkyl; or, R ４Ａ and R ６ or one R ５ and R ６ is C １～３ alkyl-bridged or C １～３ heteroalkyl-bridged to form; or, R ４Ｂ and one R ５ C is condensed in the B ring. ３～５ Forms a cycloalkyl group; R ７ H, -C １～３ Alkyl, or -C １～３ It is a hydroxyalkyl group; R ８ is H, -C １～３ alkyl, -SO ２ CH ３ or -C ３～４ a heterocyclic ring; R ８ 's -C １～３ alkyl may be substituted with one, two, or three oxo, -C ３～９ heterocycloalkyl, -C １～３ alkoxy, cyanoimine, or -NR ９ R １０ R may be substituted with; R ８ 's -C ３～４ the heterocyclic ring may be substituted with one, two, or three oxo, halogen, -C ０～１ alkylene -NR １０ R １１ OH, -C １～３ hydroxyalkyl, -NR １０ R １１ the -C １～３ alkoxy, -C １～３ alkyl -C １～３ alkoxy, -C １～３ oxoalkyl, or -C １～３ alkyl may be substituted with; R ８ 's -C ３～９ heterocycloalkyl may be substituted with one, two, or three -C １～３ alkyl, -OH, -C １～３ hydroxyalkyl, -O -C １～３ hydroxyalkyl, -C １～３ alkoxy, -C １～３ alkyl -C １～３ alkoxy, halogen, -C １～３ fluoroalkyl, -C １～３ fluoroalkoxy, cyano, -C １～３ cyanoalkyl, -C ０～１ alkylene -C ３～５ heterocycloalkyl, -O -C ３～５ heterocycloalkyl, or -C ０～１ alkylene -NR １０ R １１ and may be substituted with; R ９ H, -C １～４ Alkyl, -C １～４ Hydroxyalkyl, -C １～３ Fluoroalkyl, -C ３～５ Cycloalkyl,-methylene-phenylene-NH-C(=O)-NR １０ R １１ , or -C ３～５ It is heterocycloalkyl; R ９ -C １～４ Alkyl groups have one, two, or three -C atoms. ３～５ Cycloalkyl, -C ３～５ It may be substituted with heterocycloalkyl or methoxy; R ９ -C ３～５ Cycloalkyl groups consist of one or two -OH or -C groups. １～３ It may also be substituted with alkyl; Each R １０ These are independently H or -C １～４ It is alkyl; R １０Ａ is, -C １～３ -C may be substituted with alkyl ０～１ Alkylene-C ３～５ It is heterocycloalkyl; Each R １１ These are independently H or -C １～３ It is alkyl; R １２ H, -C １～３ Alkyl, -C １～３ Hydroxyalkyl, -(CH ２ ) ０～２ -C ３～５ Heterocycloalkyl, -(CH ２ ) １～２ -O-C ３～５ Heterocycloalkyl, -methylene-C(=O)-NR １０ R １１ , or -methylene-phenylene-NH-C(=O)-NR １０ R １１ And; R １２ no- (CH ２ ) ０～２ -C ３～５ Heterocycloalkyl or -(CH ２ ) １～２ -O-C ３～５ Heterocycloalkyl is -C １～４ Alkyl, -C １～３ Alkyl-C １～３ Alkoxy, -(CH ２ ) ０～１ -Phenyl, halogen, -C １～３ Fluoroalkyl, or -(CH ２ ) ０～１ -C ３～５ It may also be substituted with a heterocycloalkyl group; R １２ -C １～３ Alkyl is 1, 2, or 3 oxo or NR １０ R １１ It is also fine if it is replaced with; R １２Ａ is H or -C １～４ Alkyl; or, R １２ and R １２Ａ This consists of one, two, or three -OH and -C atoms. １～３ Alkyl, oxo, halogen, -C ２～３ Oxoalkyl, -C １～３ Alkoxy, -C １～３ Hydroxyalkyl, -C １～３ Alkyl-C １～３ Alkoxy, cyano, -C ３～６ Cycloalkyl, -S (=O) ２ CH ３ , -S (=O) ２ CH ２ CH ３ , -C(=O)-NR １０ R １１ , or -NHC(=O)CH ３ C may be replaced with ３～１０ Forming a heterogeneous ring; R １３ H, -C １～６ Alkyl, -C １～４ Hydroxyalkyl, -C １～３ Fluoroalkyl, -C １～３ Alkyl-C １～３ Alkoxy, -C １～４ Cyanoalkyl, -C ０～１ Alkylene-C ３～５ Cycloalkyl, -C ２～４ Oxoalkyl, or -C ０～１ Alkylene-C ３～５ It is heterocycloalkyl; R １３ -C １～６ Alkyl groups consist of one, two, or three oxo, fluoro, or -NH groups. ２ , C ３～６ It may be substituted with a cycloalkyl or methoxy group; R １３ -C ３～５ Cycloalkyl or -C ３～６ Cycloalkyl groups have one, two, or three -C atoms. １～３ Alkyl, -C １～３ It may also be substituted with a fluoroalkyl or halogen; R １４ is H; or, X ４ NR １３ And R １３ and R １４ This is a C condensed into a C ring. ４～５ Forming a heterogeneous ring; n is either 1 or 2; m is either 0 or 1; X ３ CR １３ Or NR １３ If X ４ is CH or N, X ４ NR １３ If X ３ is N, O, or S; Each heterocycle independently contains 1 to 4 heteroatoms, each containing at least one N, O, or S atom.

2. A compound of formula IA, or a pharmaceutically acceptable salt thereof, which may be the compound described in claim 1: 【Chemistry 2】 [In the formula, X １ CH, CNH ２ , or N; X ２ is C or N; X ３ CR １３ , N, NR １３ It is O, or S; X ４ is CH, N, or NR １３ And; X ５ CH, CR １Ｂ , or N; X ６ is CH or N; X ７ is CH, N, or CF; X ８ is CH or N; X ９ CH, CR １Ｂ , or N; X １０ CH, CR １Ｂ , or N; R １ Ha-NHR ８ -OH, -C ２～５ A complex algebra, or -C １～３ It is alkyl; R １ -C ２～５ The complex ring has one, two, or three -C elements. １～３ Alkyl, -C １～３ Oxoalkyl, -C ３～５ Heterocycloalkyl, -C ３～５ Hydroxyheterocycloalkyl, -C ３～５ It may be substituted with an aminoheterocycloalkyl or oxo; R １ -C １～３ Alkyl groups consist of one, two, or three oxo or -NR groups. １０ R １１ It is also fine if it is replaced with; R １Ａ is H or -CH ３ is; or, R １ and R １Ａ is C ６～８ Condensed heterocycloalkyl or C ６～８ Forms a condensed heteroaryl; C ６～８ Condensed heterocycloalkyl or C ６～８ The condensed heteroaryl may be substituted with an oxo; Each R １Ｂ H and -CH are independent of each other. ３ , F, Cl, or methoxy; R ２ H, -C １～３ Alkyl, -C １～３ It is a fluoroalkyl or halogen; R ３ Ha-C １～３ Alkyl, -C ２～１０ A complex ring, or -NH-C(=O)-C １～３ It is alkyl; R ３ -C １～３ Alkyl groups consist of one or more oxo, -OH, and -NR groups. １２ R １２Ａ , -C ５～８ It may be a heterocycle or substituted with a cyano; -C ２～１０ Heterocyclic rings consist of one, two, or three -OH, halogen, and -C rings. １～３ Hydroxyalkyl, -C １～３ It may be substituted with alkyl, cyclopropyl, or oxo; or, R ２ and R ３ This is one, two, or three -C １～３ Alkyl, -C ２～３ C may be substituted with an oxoalkyl or oxo group. ６～１０ Forming a condensed heterocycle; R ４Ａ is H, -OH, or -C １～３ It is alkyl; R ４Ｂ is either H or does not exist; Each R ５ These are independently H, halogen, -OH, cyclopropyl, or -C １～３ Alkyl; or two R ５ The group forms a cyclopropyl group; R ６ is H, -OH, or -C １～３ Alkyl; or, R ４Ａ and R ６ , or R ５ and R ６ C １～３ Alkyl crosslinking or C １～３ Forming heteroalkyl crosslinks; R ７ H, -C １～３ Alkyl, or -C １～３ It is a hydroxyalkyl group; R ８ H, -C １～３ Alkyl, -SO ２ CH ３ , or -C ３～４ It is a complex algebra; R ８ -C １～３ Alkyl groups consist of one, two, or three oxo, -C ３～７ Heterocycloalkyl, methyl-substituted -C ３～７ Heterocycloalkyl, alkoxy, cyanoimine, or -NR ９ R １０ It may also be replaced with -C ３～４ Heterocyclic rings consist of one, two, or three oxo, halogen, and -C atoms. ０～１ Alkylene-NR １０ R １１ -OH, -C １～３ Hydroxyalkyl, -NR １０ R １１ It may be replaced with -C １～３ Alkoxy, -C １～３ Alkoxy-C １～３ Alkyl, -C １～３ Oxoalkyl, or -C １～３ It may also be substituted with alkyl; R ９ H, -C １～４ Alkyl, -C １～４ Hydroxyalkyl, -C １～３ Fluoroalkyl, -C ３～５ Cycloalkyl, or -C ３～５ It is heterocycloalkyl; R ９ -C １～４ Alkyl is one, two, or three cyclopropyl, -C ３～５ It may be substituted with heterocycloalkyl or methoxy; R ９ -C ３～５ Cycloalkyl is -C １～３ It may also be substituted with alkyl; Each R １０ These are independently H or -C １～４ Alkyl; or, R ８ -C １～３ Alkyl is -NR ９ R １０ If it is replaced with the corresponding R ９ and R １０ These combine to form one, two, or three methoxy, -OH, -C molecules. １～３ Alkyl, halogen, -NH ２ , - NHCH ３ , or -N(CH ３ ) ２ C may be replaced with ３～７ They may also form heterocycloalkyl groups; Each R １１ These are independently H or -C １～３ It is alkyl; R １２ H, -C １～３ Alkyl, -(CH ２ ) ０～１ -C ３～５ Heterocycloalkyl, or -methylene-phenylene-NH-C(=O)-NR １０ R １１ And; - (CH ２ ) ０～１ -C ３～５ Heterocycloalkyl is -C １～４ It may also be substituted with alkyl; R １２Ａ is H or -C １～４ Alkyl; or, R １２ and R １２Ａ is, -C １～３ Condensed C may be substituted with alkyl. ５～１０ Forms heterocycloalkyl groups; R １３ H, -C １～４ Alkyl, -C １～４ Hydroxyalkyl, -C １～３ Fluoroalkyl, -C ０～１ -C ３～５ Cycloalkyl, -C ２～４ Oxoalkyl, or -C ３～５ It is heterocycloalkyl; R １３ -C １～４ The alkyl group may be substituted with one, two, or three cyclopropyl or methoxy groups; R １３ -C ３～５ Cycloalkyl is -C １～３ It may also be substituted with alkyl; n is either 1 or 2; Each heterocycle independently contains 1 to 3 heteroatoms, each containing at least one N, O, or S; X ２ At least one of them is N, or X ３ is N, NH, or NR １３ and X ４ N or NR １３ is; or, X ３ If it is S or O, then X ２ [is C].

3. A compound of formula IB, or a pharmaceutically acceptable salt thereof, which may be the compound described in claim 1 or 2: 【Transformation 3】 [In the formula, X １ CH, CNH ２ , or N; X ２ is C or N; X ３ CR １３ , N, NR １３ It is O, or S; X ４ is CH, N, or NR １３ And; X ５ is CH or N; X ６ is CH or N; X ７ is CH, N, or CF; X ８ is CH or N, However, X ２ At least one of them is N, or X ３ is N, NH, or NR １３ and X ４ N or NR １３ is; or, X ３ If it is S or O, then X ２ is C; R １ Ha-NHR ８ -OH, -C ２～５ A complex algebra, or -C １～３ It is alkyl; R １ -C ２～５ A complex ring has one or more -C １～３ Alkyl, -C １～３ Oxoalkyl, -C ３～５ Heterocycloalkyl, -C ３～５ Hydroxyheterocycloalkyl, -C ３～５ It may be substituted with an aminoheterocycloalkyl or oxo; R １ -C １～３ Alkyl groups consist of one or more oxo or -NR groups. １０ R １１ It is also fine if it is replaced with; R ２ H, -C １～３ Alkyl, -C １～３ It is a fluoroalkyl or halogen; R ３ Ha-C １～３ Alkyl, -C ２～１０ A complex ring, or -NH-C(=O)-C １～３ It is alkyl; R ３ -C １～３ Alkyl groups consist of one or more oxo, -OH, and -NR groups. １２ R １２Ａ , -C ５～８ It may be a heterocycle or substituted with a cyano; -C ２～１０ Heterocyclic rings consist of one or more -OH, halogen, and -C atoms. １～３ Hydroxyalkyl, -C １～３ It may be substituted with alkyl, cyclopropyl, or oxo; or, R ２ and R ３ is one or more -C １～３ Alkyl, -C ２～３ C may be substituted with an oxoalkyl or oxo group. ６～１０ Forms condensed heterocycloalkyl groups; R ４Ａ is H, -OH, or -C １～３ It is alkyl; R ４Ｂ is either H or does not exist; Each R ５ These are independently H, -OH, halogen, or -C １～３ Alkyl; or two R ５ The group forms a cyclopropyl group; R ６ is H, -OH, or -C １～３ Alkyl; or, R ４Ａ and R ６ , or R ５ and R ６ C １～３ Alkyl crosslinking or C １～３ Forming heteroalkyl crosslinks; R ７ H, -C １～３ Alkyl, or -C １～３ It is a hydroxyalkyl group; R ８ H, -C １～３ Alkyl, or -C ３～４ It is a complex algebra; R ８ -C １～３ Alkyl groups consist of one or more oxo or -NR groups. ９ R １０ It may also be replaced with -C ３～４ A heterocycle consists of one or more oxos or -C atoms. １～３ It may also be substituted with alkyl; R ９ H, -C １～４ Alkyl, -C １～４ Hydroxyalkyl, -C １～３ Fluoroalkyl, -C ３～５ Cycloalkyl, or -C ３～５ It is heterocycloalkyl; R ９ -C １～４ Alkyl is one or more cyclopropyl, -C ３～５ It may be substituted with heterocycloalkyl or methoxy; R ９ -C ３～５ Cycloalkyl is -C １～３ It may also be substituted with alkyl; Each R １０ These are independently H or -C １～４ Alkyl; or, R ８ -C １～３ Alkyl is -NR ９ R １０ If it is replaced with the corresponding R ９ and R １０ Together, they form at least one methoxy, -OH, -C １～３ Alkyl, or -N(CH ３ ) ２ C may be replaced with ３～６ They may also form heterocycloalkyl groups; Each R １１ These are independently H or -C １～３ It is alkyl; R １２ H, -C １～３ Alkyl, or -methylene-phenylene-NH-C(=O)-NR １０ R １１ And; Each R １３ H and -C are independent of each other. １～４ Alkyl, -C １～４ Hydroxyalkyl, -C １～３ Fluoroalkyl, -C ３～５ Cycloalkyl, or -C ３～５ It is heterocycloalkyl; R １３ -C １～４ The alkyl group may be substituted with one or more cyclopropyl or methoxy groups; R １３ -C ３～５ Cycloalkyl is -C １～３ It may also be substituted with alkyl; n is either 1 or 2; Each heterocycle independently contains 1 to 3 heteroatoms, each containing at least one N, O, or S; X ２ At least one of them is N, or X ３ is N, NH, or NR １３ and X ４ N or NR １３ is; or, X ３ If it is S or O, then X ２ C is the case.

4. R ３ ga-C １～３ Alkyl or -C ２～１０ It is a complex algebra; -C ２～１０ The complex ring is -C ２～５ It is a heteroaryl; R ３ -C １～３ Oxo or -NR with one, two, or three alkyl groups １２ R １２Ａ It may be replaced with; R ３ -C ２～５ The complex ring is -C １～３ A compound according to any of the claims, which may be substituted with an alkyl group, or a pharmaceutically acceptable salt thereof.

5. R １ ga-NHR ８ And; R ８ However, one, two, or three oxo or -NR ９ R １０ -C replaced by １～３ A compound according to any of the above claims, which is alkyl, or a pharmaceutically acceptable salt thereof.

6. R ２ H is; R ３ However, oxo and -NR １２ R １２Ａ -C replaced by １～３ A compound according to any of the above claims, which is alkyl, or a pharmaceutically acceptable salt thereof.

7. X ５ The condition is CH; X ７ X is either CH or N; ８ The condition is CH; R １ ga-NHR ８ , -C ２～５ A complex algebra, or -C １～３ Being alkyl; R ４Ａ is H or -C １～３ Being alkyl; each R ５ These are independently H, halogen, or -C １～３ Alkyl; or two R ５ The group forms a cyclopropyl group; R ６ is H or -C １～３ Being alkyl; or R ７ is H or -C １～３ A compound according to any of the claims, or a pharmaceutically acceptable salt thereof, satisfying at least one of being alkyl.

8. R ３ However, oxo and -NR １２ R １２Ａ -C replaced by １～３ It is alkyl, R １ ga-NHR ８ , or oxo and -NR １０ R １１ -C replaced by １～３ A compound according to any of the above claims, which is alkyl, or a pharmaceutically acceptable salt thereof.

9. X ３ CR １３ X ４ A compound according to any of the preceding claims, wherein is CH or N, or a pharmaceutically acceptable salt thereof.

10. R １ ga-NHR ８ And; R ８ ga-C １～３ Alkyl or -C ３～４ It is a complex algebra; R ８ -C １～３ Alkyl is oxo and -NR ９ R １０ It is replaced with; -C ３～４ Oxo or -C with one, two, or three heterocycles １～３ A compound according to any of the claims, or a pharmaceutically acceptable salt thereof, which is substituted with an alkyl group.

11. X １ N is X ３ is N or NR １３ X ４ A compound according to any of the above claims, or a pharmaceutically acceptable salt thereof, wherein is N.

12. R ３ -C ２～１０ The complex ring is -C ２～５ It is a complex algebra, R ３ -C with 1, 2, or 3 １～３ A compound according to any of the claims, which may be substituted with an alkyl group, or a pharmaceutically acceptable salt thereof.

13. A compound according to any of the claims, or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen atom is deuterium.

14. R １ but 【Chemistry 4】 The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

15. R １Ａ is deuterium; X ５ , X ９ , and X １０ Each of them is CR １Ｂ X ５ , X ９ , and X １０ Each of the R １Ｂ The compound according to claim 13 or 14, or a pharmaceutically acceptable salt thereof, wherein the compound is deuterium.

16. N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidine-1-yl)pyridine-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(dimethylcarbamoyl)pyridine-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)pyridine-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)pyridine-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)pyridine-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-carboxamide)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; or A compound that is one of the following: 5-(5-(dimethylcarbamoyl)pyridine-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, or a pharmaceutically acceptable salt thereof.

17. N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-oxopyrrolidine-1-yl)pyridine-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 5-(5-(dimethylcarbamoyl)pyridine-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)pyridine-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)pyridine-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)pyridine-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-carboxamide)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; or A compound that is one of the following: 5-(5-(dimethylcarbamoyl)pyridine-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. 【Request Item 18】 【Chemistry 5】 A compound that is a pharmaceutically acceptable salt thereof. 【Request Item 19】 【Chemistry 6】 A compound that is a pharmaceutically acceptable salt thereof. 【Request Item 20】 【Chemistry 7】 A compound that is a pharmaceutically acceptable salt thereof. 【Request Item 21】 【Chemistry 8】 A compound that is a pharmaceutically acceptable salt thereof. 【Request Item 22】 【Chemistry 9】 A compound that is a pharmaceutically acceptable salt thereof. 【Request Item 23】 【Chemistry 10】 A compound that is a pharmaceutically acceptable salt thereof. 【Request Item 24】 【Chemistry 11】 A compound that is a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound according to any of the above 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, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa, comprising the step of administering a therapeutically effective amount of any compound according to claim 1 to 24, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

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

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

29. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), joint disorders, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

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

31. Use of any compound according to claim 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, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behçet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), joint disorders, keloids, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, rhinosinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

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

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