Novel nitrogen-containing heterocyclic compounds, pharmaceutical composition, and use thereof

Abstract

This disclosure relates to the compounds disclosed herein and their pharmaceutically acceptable salts; their use in medicine; compositions containing them; methods of their preparation; and intermediates used in such methods. The compounds disclosed herein may be used to treat, prevent, inhibit, and improve conditions such as: atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet'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 fatty liver disease (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), leukoderma, or hidradenitis suppurativa. The compounds disclosed herein may be used to treat, prevent, inhibit, and improve skin or respiratory conditions.

Description

Prior Technology

[0001] This disclosure relates to novel compounds. It also relates to the preparation of such compounds and the intermediates used in their preparation, compositions containing such compounds, and the uses of such compounds, including their use as STAT6 inhibitors.

[0002] STAT6 is a member of the Signal Transducer and Activator of Transcription (STAT) protein 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, facilitating the signal transduction of various cytokines, including IL-2, IL-5, GM-CSF, IL-10, IL-12, IL-23, IL-4, and IL-13. It has been demonstrated that cytokines IL-4 and IL-13 are activated and transduced via STAT6 [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 interleukins is consistent with the efficacy observed with JAK inhibitors, which block the signaling of IL-4 and IL-13, as well as other inflammatory interleukins [Simpson, EL et al. 2020. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 396(10246): 255-266; Guttman-Yassky, E et al. 2021. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet.]. 397(10290): 2151-2168).

[0004] Although known therapeutics are effective for many diseases characterized by inflammatory responses, the need for safe and effective therapeutics that address a wide range of pathogenic mechanisms remains unmet. Summary of the Invention

[0005] This disclosure provides, in part, compounds and their pharmaceutically acceptable salts. Such compounds inhibit STAT6 activity and can be used to treat, prevent, inhibit, and / or improve STAT6-mediated diseases, symptoms, and conditions. Pharmaceutical compositions comprising such compounds or salts, alone or in combination with other therapeutic agents are also provided. This disclosure also provides, in part, methods for preparing such compounds, pharmaceutically acceptable salts, and compositions of this disclosure, as well as methods for using the foregoing. The summary is provided to present some conceptual choices in a simplified form, which will be further described in the embodiments below. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended solely to help define the scope of the claimed subject matter.

[0006] In one state, the compound disclosed herein has Formula I or a pharmaceutically acceptable salt thereof: I The variables are defined in this paper.

[0007] In one state, the compound disclosed herein has formula IA or a pharmaceutically acceptable salt thereof: IA The variables are defined in this paper.

[0008] In one state, the compound disclosed herein has formula IB or a medically acceptable salt thereof: IB The variables are defined in this paper.

[0009] In one embodiment, this disclosure relates to a pharmaceutical composition comprising the compound disclosed herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0010] In another embodiment, this disclosure relates to a treatment for atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease, chronic pruritus, chronic urticaria, and Crohn's disease. Methods for treating diseases (CD), dermatitis, diabetic nephropathy, eosinophilic esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), keloids, non-alcoholic fatty liver disease (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa, comprising administering a therapeutically effective amount of the disclosed compound to an individual in need.

[0011] In another embodiment, this disclosure relates to the compounds disclosed herein or their pharmaceutically acceptable salts, used as medicines; or for the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet's disease, bullous pemphigoid, cancer, chronic obstructive pulmonary disease (COPD), chronic pruritus, chronic urticaria, Crohn's disease (CD), dermatitis, diabetic nephropathy, eosinophilia. It is indicated for the treatment of at least one of the following conditions: bulbar esophagitis, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), arthritis, keloid, non-alcoholic fatty liver disease (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), leukoplakia, or hidradenitis suppurativa; or for the treatment of at least one of the following skin or respiratory conditions.

[0012] It should be understood that the foregoing general description and the following detailed description are merely illustrative and explanatory, and do not limit the disclosures made herein. Implementation

[0013] This disclosure can be more readily understood by referring to the following detailed description and the examples included herein. It should be understood that this disclosure is not limited to a specific synthetic preparation method, which can of course vary. It should also be understood that the terminology used herein is for the purpose of describing a particular state only and is not intended to be limiting.

[0014] In a single-state sample, a compound of formula I or a pharmaceutically acceptable salt thereof: I in X1 is CH, CNH2, or N; X2 is either C or N; X3 is CR13, N, NR13, O, or S; X4 is CH, N, or NR13; X5 is either CR1B or N; X6 is CH or N; X7 is CH, N, or CF; X8 represents CH or N; X9 is either CR1B or N; X10 is either CR1B or N; R1 is -NHR8, -OH, -C2-5 heterocyclic, or -C1-3 alkyl; wherein the -C2-5 heterocyclic of R1 is optionally substituted with one, two, or three -C1-3 alkyl, -C1-3 septoxyalkyl, -C3-5 heterocyclic alkyl, -C3-5 hydroxycyclic alkyl, -C3-5 aminocyclic alkyl, or septoxy group; wherein the -C1-3 alkyl of R1 is optionally substituted with one, two, or three septoxy groups, -NR10AR11, or -NR10R11. R1A is H, halogen, or -CH3; or R1 and R1A form a C5-7 heterocyclic alkyl group fused to ring D or a C5-7 heteroaryl group fused to ring D; wherein the C5-7 heterocyclic alkyl group or the C5-7 heteroaryl group is substituted with a side oxygen group as appropriate; Each R1B is independently H, -CH3, F, Cl, or methoxy; R2 is H, -C1-3 alkyl, -C1-3 alkoxy, -C1-3 fluoroalkyl, or halogen; R3 is a -C1-3 alkyl, -C2-10 heterocyclic, -P(=O)(CH3)2, -S(=O)CH3, -NH-S(=O)2CH3, or -NH-C(=O)-C1-3 alkyl; wherein the -C1-3 alkyl of R3 is optionally substituted with one, two, or three side-oxygen groups, halogens, -C3-6 cycloalkyl groups, -OH, -NR12R12A, or cyano groups; wherein the -C2-10 heterocyclic is optionally substituted with one, two, or three -OH, halogens, -C1-3 hydroxyalkyl groups, -C1-3 alkoxy groups, -C1-3 alkyl groups, -C1-3 fluoroalkyl groups, cyclopropyl groups, or side-oxygen groups; or R2 and R3 form a C3-6 heterocycle fused with ring A, which may be substituted with one, two, or three -C1-3 alkyl, -C2-3 septoxyalkyl, or septoxy groups, depending on the case. R4A is H, -OH, -C1-3 fluoroalkyl, or -C1-3 alkyl; R4B is H or does not exist; or R4A and R4B form a cyclopropyl group; Each R5 group is independently H, halogen, -OH, cyclopropyl, -C1-3 fluoroalkyl, or -C1-3 alkyl; or two R5 groups form a cyclopropyl group; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6 or one of R5 and R6 form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge; or R4B and one R5 form a C3-5 cycloalkyl group fused with ring B; R7 is H, a -C1-3 alkyl group, or a -C1-3 hydroxyalkyl group; R8 is H, -C1-3 alkyl, -SO2CH3, or -C3-4 heterocycle; wherein the -C1-3 alkyl of R8 is substituted with one, two, or three oxy groups, -C3-9 heterocyclic alkyl, -C1-3 alkoxy, cyanoimide, or -NR9R10, depending on the situation; wherein the -C3-4 heterocycle of R8 is substituted with one, two, or three oxy groups, halogen, -C0-1 alkyl-NR10R11, -OH, -C1-3 hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkyl-C1-3 alkyl, depending on the situation, substituted with -NR10R11. Oxygen, -C1-3 side-oxyalkyl, or -C1-3 alkyl substituted; wherein the -C3-9 heterocyclic alkyl of R8 is substituted with one, two, or three -C1-3 alkyl, -OH, -C1-3 hydroxyalkyl, -O-C1-3 hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkyl-C1-3 alkoxy, halogen, -C1-3 fluoroalkyl, -C1-3 fluoroalkoxy, cyano, -C1-3 cyanoalkyl, -C0-1 alkyl-C3-5 heterocyclic alkyl, -O-C3-5 heterocyclic alkyl, or -C0-1 alkyl-NR10R11 as appropriate; R9 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, -methylene-phenyl-NH-C(=O)-NR10R11, or -C3-5 heterocyclic alkyl; wherein the -C1-4 alkyl group of R9 is substituted with one, two, or three -C3-5 cycloalkyl, -C3-5 heterocyclic alkyl, or methoxy groups as appropriate; wherein the -C3-5 cycloalkyl group of R9 is substituted with one or both of -OH or -C1-3 alkyl groups as appropriate; Each R10 is independently H or -C1-4 alkyl; or R10A may be a -C0-1 alkyl-C3-5 heterocyclic alkyl group substituted with a -C1-3 alkyl group, as appropriate; [ ] Each R11 is independently H or -C1-3 alkyl; R12 is H, -C1-3 alkyl, -C1-3 hydroxyalkyl, -(CH2)0-2-C3-5 heterocyclic alkyl, -(CH2)1-2-O-C3-5 heterocyclic alkyl, -methylene-C(=O)-NR10R11 or -methylene-phenyl-NH-C(=O)-NR10R11; wherein the -(CH2)0-2-C3-5 heterocyclic alkyl or -(CH2)1-2-O-C3-5 heterocyclic alkyl of R12 is substituted with -C1-4 alkyl, -C1-3 alkyl-C1-3 alkoxy, -(CH2)0-1-phenyl, halogen, -C1-3 fluoroalkyl or -(CH2)0-1-C3-5 heterocyclic alkyl; wherein the -C1-3 alkyl of R12 is substituted with one, two or three side oxygen groups or NR10R11; R12A is H or -C1-4 alkyl; or R12 and R12A form a C3-10 heterocycle, which may be substituted with one, two, or three -OH, -C1-3 alkyl, syloxy, halogen, -C2-3 syloxyalkyl, -C1-3 alkoxy, -C1-3 hydroxyalkyl, -C1-3 alkyl-C1-3 alkoxy, cyano, -C3-6 cycloalkyl, -S(=O)2CH3, -S(=O)2CH2CH3, -C(=O)-NR10R11, or -NHC(=O)CH3, depending on the situation. R13 is H, -C1-6 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C1-3 alkyl-C1-3 alkoxy, -C1-4 cyanoalkyl, -C3-5 cycloalkyl, -C2-4 syloxyalkyl, or -C3-5 heterocyclic alkyl; wherein the -C1-6 alkyl of R13 is substituted with one, two, or three syloxy groups, fluorine, -NH2, C3-6 cycloalkyl, or methoxy groups as appropriate; wherein the -C3-5 cycloalkyl or -C3-6 cycloalkyl of R13 is substituted with one, two, or three -C1-3 alkyl, -C1-3 fluoroalkyl, or halogen as appropriate; R14 is H; or X4 is NR13, and R13 and R14 form a C4-5 heterocycle fused with ring C; n is 1 or 2; m is 0 or 1; If X3 is CR13 or NR13, then X4 is CH or N; and if X4 is NR13, then X3 is N, O, or S. Each heterocycle independently comprises 1 to 4 heteroatoms, including at least one of N, O, or S.

[0015] In a single-state sample, a compound of formula IA or a pharmaceutically acceptable salt thereof: IA in X1 is CH, CNH2, or N; X2 is either C or N; X3 is CR13, N, NR13, O, or S; X4 is CH, N, or NR13; X5 is CH, CR1B, or N; X6 is CH or N; X7 is CH, N, or CF; X8 represents CH or N; X9 is CH, CR1B, or N; X10 is CH, CR1B, or N; R1 is -NHR8, -OH, -C2-5 heterocyclic, or -C1-3 alkyl; wherein the -C2-5 heterocyclic of R1 is optionally substituted with one, two, or three -C1-3 alkyl, -C1-3 oxyalkyl, -C3-5 heterocyclic alkyl, -C3-5 hydroxycyclic alkyl, -C3-5 aminocyclic alkyl, or oxyalkyl groups; wherein the -C1-3 alkyl of R1 is optionally substituted with one, two, or three oxyalkyl groups or -NR10R11. R1A is H or -CH3; or R1 and R1A form a C6-8 fused heterocyclic alkyl or a C6-8 fused heteroaryl; wherein the C6-8 fused heterocyclic alkyl or the C6-8 fused heteroaryl is substituted with a side oxygen group as appropriate; Each R1B is independently H, -CH3, F, Cl, or methoxy; R2 is H, -C1-3 alkyl, -C1-3 fluoroalkyl, or halogen; R3 is a -C1-3 alkyl, a -C2-10 heterocyclic, or a -NH-C(=O)-C1-3 alkyl; wherein the -C1-3 alkyl group of R3 is substituted with one or more of a side-oxygen group, -OH, -NR12R12A, -C5-8 heterocyclic, or cyano group; wherein the -C2-10 heterocyclic group is substituted with one, two, or three -OH, halogen, -C1-3 hydroxyalkyl, -C1-3 alkyl, cyclopropyl, or side-oxygen group; or R2 and R3 form a C6-10 fused heterocycle, which may be substituted with one, two, or three -C1-3 alkyl, -C2-3 septoxyalkyl, or septoxy groups, depending on the case. R4A is H, -OH, or -C1-3 alkyl; R4B is H or does not exist; Each R5 group is independently H, halogen, -OH, cyclopropyl, or -C1-3 alkyl; or two R5 groups form a cyclopropyl group; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6 or R5 and R6 form C1-3 alkyl bridges or C1-3 heteroalkyl bridges; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, -C1-3 alkyl, -SO2CH3, or -C3-4 heterocycle; wherein the -C1-3 alkyl of R8 is substituted with one, two, or three lateral oxy groups, -C3-7 heterocyclic alkyl, -C3-7 heterocyclic alkyl substituted with methyl, alkoxy, cyanoimide, or -NR9R10, wherein the -C3-4 heterocycle is substituted with one, two, or three lateral oxy groups, halogen, -C0-1 alkyl-NR14R11, -OH, -C1-3 hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkoxy-C1-3 alkyl, -C1-3 lateral oxyalkyl, or -C1-3 alkyl, wherein the substituted lateral oxyalkyl is substituted with -NR10R11, or -C1-3 alkoxy. R9 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocyclic alkyl; wherein the -C1-4 alkyl group of R9 is substituted with one, two, or three cyclopropyl, -C3-5 heterocyclic alkyl, or methoxy groups as appropriate; wherein the -C3-5 cycloalkyl group of R9 is substituted with a -C1-3 alkyl group as appropriate. Each R10 is independently H or -C1-4 alkyl; or If the -C1-3 alkyl group of R8 is substituted with -NR9R10, then the corresponding R9 and R10 may be combined to form a C3-7 heterocyclic alkyl group, which may be substituted with at least one of methoxy, OH, -C1-3 alkyl, halogen, -NH2, -NHCH3 or -N(CH3)2. Each R11 is independently H or -C1-3 alkyl; R12 is H, -C1-3 alkyl, -(CH2)0-1-C3-5 heterocyclic alkyl, or -methylene-phenyl-NH-C-NR10R11; wherein the -(CH2)0-1-C3-5 heterocyclic alkyl is substituted with a -C1-4 alkyl, depending on the case. R12A is H or -C1-4 alkyl; or R12 and R12A form, as appropriate, fused C5-10 heterocyclic alkyl groups substituted with -C1-3 alkyl groups; R13 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C0-1-C3-5 cycloalkyl, -C2-4 syloxyalkyl, or -C3-5 heterocyclic alkyl; wherein the -C1-4 alkyl group of R13 is substituted with one, two, or three cyclopropyl or methoxy groups as appropriate; wherein the -C3-5 cycloalkyl group of R13 is substituted with a -C1-3 alkyl group as appropriate; n is 1 or 2; Each of the individual heterocycles independently comprises one to three heteroatoms, including at least one of N, O, or S; Where at least one of X2 is N or X3 is N, NH or NR13, and X4 is N or NR13; or if X3 is S or O, then X2 is C.

[0016] In a single-state sample, a compound has formula IB or a medically acceptable salt thereof: IB in X1 is CH, CNH2, or N; X2 is either C or N; X3 is CR13, N, NR13, O, or S; X4 is CH, N, or NR13; X5 is CH or N; X6 is CH or N; X7 is CH, N, or CF; X8 represents CH or N; The constraint is that at least one of X2 is N, or X3 is N, NH, or NR13, and X4 is N or NR13; or if X3 is S or O, then X2 is C; R1 is -NHR8, OH, -C2-5 heterocyclic or -C1-3 alkyl; wherein the -C2-5 heterocyclic of R1 is optionally substituted with one or more of -C1-3 alkyl, -C1-3 oxyalkyl, -C3-5 heterocyclic alkyl, -C3-5 hydroxycyclic alkyl, -C3-5 aminocyclic alkyl or oxyalkyl; wherein the -C1-3 alkyl of R1 is optionally substituted with one or more of oxyalkyl or -NR10R11; R2 is H, -C1-3 alkyl, -C1-3 fluoroalkyl, or halogen; R3 is a -C1-3 alkyl, a -C2-10 heterocyclic, or a -NH-C(=O)-C1-3 alkyl; wherein the -C1-3 alkyl group of R3 is substituted with one or more of a side-oxygen group, -OH, -NR12R12A, -C5-8 heterocyclic, or cyano group, depending on the situation; wherein the -C2-10 heterocyclic group is substituted with one or more of a -OH group, halogen, -C1-3 hydroxyalkyl, -C1-3 alkyl, cyclopropyl, or side-oxygen group, depending on the situation; or R2 and R3 form a C6-10 fused heterocyclic alkyl group, which may be substituted, depending on the case, with one or more of -C1-3 alkyl, -C2-3 septoxyalkyl or septoxy groups; R4A is H, -OH, or -C1-3 alkyl; R4B is H or does not exist; Each R5 group is independently H, -OH, halogen, or -C1-3 alkyl; or two R5 groups form a cyclopropyl group; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6 or R5 and R6 form C1-3 alkyl bridges or C1-3 heteroalkyl bridges; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, a -C1-3 alkyl group, or a -C3-4 heterocycle; wherein the -C1-3 alkyl group of R8 is substituted with one or more of a side-oxygen group or -NR9R10, and wherein the -C3-4 heterocycle is substituted with one or more of a side-oxygen group or -C1-3 alkyl group, depending on the situation; R9 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocyclic alkyl; wherein the -C1-4 alkyl group of R9 is substituted with one or more of cyclopropyl, -C3-5 heterocyclic alkyl, or methoxy, as appropriate; wherein the -C3-5 cycloalkyl group of R9 is substituted with a -C1-3 alkyl group, as appropriate. Each R10 is independently H or -C1-4 alkyl; or If the -C1-3 alkyl group of R8 is substituted with -NR9R10, then the corresponding R9 and R10 may be combined to form a C3-6 heterocyclic alkyl group, which may be substituted with at least one of methoxy, OH, -C1-3 alkyl or -N(CH3)2. Each R11 is independently H or -C1-3 alkyl; R12 is H, -C1-3 alkyl, or -methylene-phenyl-NH-C(=O)-NR10R11; Each R13 is independently H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocycloalkyl; wherein the -C1-4 alkyl of R13 is substituted with one or more of cyclopropyl or methoxy, and wherein the -C3-5 cycloalkyl of R13 is substituted with a -C1-3 alkyl, as appropriate. n is 1 or 2; and Each of the individual heterocycles independently comprises one to three heteroatoms, including at least one of N, O, or S.

[0017] In one state, R3 is a -C1-3 alkyl or a -C2-10 heterocycle; the -C2-10 heterocycle is a -C2-5 heteroaryl; the -C1-3 alkyl of R3 is substituted with one, two or three side oxygen groups or -NR12R12A as appropriate; and the -C2-5 heterocycle of R3 is substituted with a -C1-3 alkyl group as appropriate.

[0018] In a single-state sample, the dashed line indicates that the bond is a single bond or a double bond; if the dashed line is a double bond, then R4B does not exist and n is 1.

[0019] In one state, R1 is -NHR8; and R8 is a -C1-3 alkyl group substituted with one, two or three side oxygen groups or -NR9R10.

[0020] In one state, R2 is H; and R3 is a -C1-3 alkyl group substituted with a side oxygen group and -NR12R12A.

[0021] In one state, at least one of X5 is CH; X7 is CH or N; X8 is CH; R1 is -NHR8, -C2-5 heterocyclic or -C1-3 alkyl; R4A is H or -C1-3 alkyl; each R5 is independently H, halogen or -C1-3 alkyl; or two R5 groups form a cyclopropyl group; R6 is H or -C1-3 alkyl; or R7 is H or -C1-3 alkyl.

[0022] In one state, R3 is a -C1-3 alkyl group substituted with a side-oxygen group and -NR12R12A, and R1 is a -NHR8 or a -C1-3 alkyl group substituted with a side-oxygen group and -NR10R11.

[0023] In a single-state sample, R3 can be -C(=O)-NR12R12A and R1 can be -NH-CO-NR10R11.

[0024] In a single-state sample, X3 is CR13 and X4 is CH or N.

[0025] In one state, R1 is -NHR8; wherein R8 is a -C1-3 alkyl or a -C3-4 heterocyclic ring; wherein the -C1-3 alkyl of R8 is substituted with a side oxygen group and -NR9R10; wherein the -C3-4 heterocyclic ring is substituted with one, two or three side oxygen groups or -C1-3 alkyl groups.

[0026] In a single-state sample, X1 is N, X3 is N or NR13, and X4 is N.

[0027] In one state, the -C2-6 heterocycle of R3 is a -C2-10 heterocycle, and R3 is substituted with one, two or three -C1-3 alkyl groups, depending on the situation.

[0028] In one state sample, at least one hydrogen (H) is deuterium (D).

[0029] In a one-state sample, R1 is .

[0030] In a single-state sample, R1A is deuterium; X5, X9 and X10 are each CR1B; and the R1B of each of X5, X9 and X10 is deuterium.

[0031] In one state, the compound is a deuterated compound of any one of examples D1, D2, D6, D31, D33, D128, or D132.

[0032] In one state, a compound or a pharmaceutically acceptable salt thereof, wherein the compound is one of the following: N-(4-(3,3-dimethylureido)benzyl)-1-isopropyl-5-(5-(2-sideoxypyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methamide; 5-(5-(dimethylaminomethido)pyridin-2-yl)-N-(4-(3,3-dimethylureido)benzyl) -1-Isopropyl-4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-carboxylamine; 5-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-carbonyl)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-carboxylamine; 5-(5-(dimethylaminocarboxyl)pyridin-2-yl)-N-( 4-(3,3-dimethylurea)benzyl)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; (S)-5-(5-(dimethylaminocarboxyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; (S)-5-(4-(dimethylaminocarboxyl)pyridine-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; (5-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; or 5-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine.

[0033] In one state, a compound, wherein the compound is one of the following: N-(4-(3,3-dimethylurea)benzyl)-1-isopropyl-5-(5-(2-sideoxypyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methamide; 5-(5-(dimethylaminomethamide)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-isopropyl-4 ,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylamine; 5-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyridine-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylamine; 5-(5-(dimethylaminocarboxyl)pyridine-2-yl)-N-(4-(3,6,7- ... (S)-5-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; (S)-5-(4-(dimethylaminomethyl)benzyl ...benzyl)-1-(4,3-yl)benzyl)-1-(4,3-yl)benzyl)-1-(4,3-yl)benzyl)-1-(4,3-yl)benzyl)-1-(4,3-yl)benzyl)-1-(5-(dimethylaminomethyl)benzyl)benzyl)-1-(4,3-yl)benzyl)-1-(5-(dimethylaminomethyl)benzyl)benzyl)-1-(4,3-yl)benzyl)-1-(5-(dimethylaminomethyl)benzyl)benzyl)-1-(4,3-yl)benzyl)-1-(5-(dimethylaminomethyl)benzyl)benzyl)-1-(4,3-yl)benzyl)-1-(5-(dimethylaminomethyl)benzyl)benzyl)-1-(5-(dimethylaminomethyl)benzyl)benzyl)-1-(5-(dimethylaminomethyl)benzyl)benzyl)-1-(5-(dimethylaminomethyl)benzyl)benzyl)-1-(5-(dimethylaminomethyl)benzyl)benzyl)-1-( 5-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; or 5-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine.

[0034] In a single-state sample, a compound or its pharmaceutically acceptable salt is .

[0035] In a single-state sample, a compound or its pharmaceutically acceptable salt is .

[0036] In a single-state sample, a compound or its pharmaceutically acceptable salt is .

[0037] In a single-state sample, a compound or its pharmaceutically acceptable salt is .

[0038] In a single-state sample, a compound or its pharmaceutically acceptable salt is .

[0039] In a single-state sample, a compound or its pharmaceutically acceptable salt is .

[0040] In a single-state sample, a compound or its pharmaceutically acceptable salt is .

[0041] In one state, the compound is not: rac-(4R,7S)-9-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-methyl-1,4,5,6,7,8-hexahydro-4,7-cycloiminocycloheptano[c]pyrazol-3-methylamine, rac-(R)-N-(4-(3,3-dimethylurea)benzyl)-5-(5-(5-(hydroxy) methyl)-2-side-oxyazolidin-3-yl)pyridin-2-yl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methamide, N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-5-(5-((1S,4S)-6-side-oxy-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-yl)-4,5,6,7-tetrahydro -1H-pyrazolo[4,3-c]pyridine-3-carboxamide, rel-(R or S)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-5-(5-(tetrahydro-2H-piperan-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide, rel-(R or S)-N-(4-(3,3-dimethylureo)benzyl)-1 -Isopropyl-5-(5-(tetrahydro-2H-piperan-2-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-carboxamide or (S)-5-(4-(dimethylaminomethoxy)phenyl)-1-isopropyl-7-methyl-N-(4-(4-methylpyrimidin-2-yl)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-carboxamide.

[0042] In one embodiment, a pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0043] In one embodiment, a method for treating atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet'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), keloid, nonalcoholic fatty liver disease (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa comprises administering to an individual in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0044] In one state, a compound of formula I or a pharmaceutically acceptable salt thereof is used as a drug.

[0045] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof may be used to treat atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet'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), arthritis, keloids, nonalcoholic fatty liver disease (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

[0046] In one state, a compound of formula I or a pharmaceutically acceptable salt thereof may be used to treat at least one of a skin condition or a respiratory condition.

[0047] In one state, the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicine for the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet'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), arthritis, keloids, nonalcoholic fatty liver disease (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

[0048] In one state, a compound or a pharmaceutically acceptable salt thereof may be used to treat at least one of a skin condition or a respiratory condition.

[0049] In one state sample, the compound or its pharmaceutically acceptable salt system is selected from the group consisting of the compounds of Examples 1 and 2 and the compounds listed in Table 2.

[0050] In one of the states, a method for treating atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet'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), keloid, nonalcoholic steatosis (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa comprises administering to an individual in need a therapeutically effective amount of a compound of any of the aforementioned states or a medically acceptable salt thereof. This method can be used to treat atopic dermatitis.

[0051] In one state, a compound or a pharmaceutically acceptable salt thereof, such as any of the aforementioned states, is used as a medicine.

[0052] In one of the aforementioned states, the compound or its pharmaceutically acceptable salt is used to treat atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet'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), arthritis, keloids, nonalcoholic fatty liver disease (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

[0053] In one state sample, the compound or its pharmaceutically acceptable salt, as described in any of the aforementioned states, is used to treat at least one of a skin condition or a respiratory condition.

[0054] In one state, the use of a compound or a pharmaceutically acceptable salt thereof as described in any of the aforementioned states for the manufacture of a medicine for the treatment of atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet'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), arthritis, keloids, non-alcoholic fatty liver disease (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

[0055] In one state sample, the use of a compound or a pharmaceutically acceptable salt thereof as described in any of the aforementioned states sample is for the treatment of at least one of a skin condition or a respiratory condition.

[0056] Each of the states described herein may be combined with any other states described herein that do not contradict the states described herein and their combinations thereof. Furthermore, for any of the states described herein, any compound or its pharmaceutically acceptable salt described in the examples may be claimed alone or grouped together with one or more other compounds or their pharmaceutically acceptable salts in the examples.

[0057] Furthermore, each of the states described herein envisions, within its scope, a medically acceptable salt of the compounds described herein.

[0058] Unless otherwise defined herein, the scientific and technical terms used in connection with this disclosure have the meanings commonly understood by one of ordinary skill in the art.

[0059] The disclosures described herein may be appropriately applied in the absence of any elements not specifically disclosed herein.

[0060] The compounds disclosed herein refer to compounds of formula I and formula IA, wherein a compound of formula I may be a compound of formula IA. Those skilled in the art will understand that the compounds disclosed herein include configurational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., mirror-image and non-mirror-image isomers), such isomers, their tautomers, racemic, non-mirror-image isomers, and other mixtures, if they are present. Those skilled in the art will also understand that the compounds disclosed herein include their solvates, hydrates, isomorphs, polymorphs, esters, salts, prodrugs, and isotopically labeled forms, if they are formable. The compounds disclosed herein may include novel intermediates used in their preparation.

[0061] As used herein, unless otherwise specified, the singular forms “a”, “an”, and “the” include plural references. For example, an “a” substituent includes one or more substituents. Unless otherwise expressly indicated, the term “or” means “and / or”.

[0062] As used herein, the term "about" when used to modify a parameter defined by a numerical value means that the parameter may vary by up to 10% below or above its specified value. For example, a dose of about 5 mg means 5% ± 10%, that is, it may vary between 4.5 mg and 5.5 mg.

[0063] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes both the circumstances under which the event or situation occurs and the circumstances under which it does not occur.

[0064] The terms "substituted as appropriate" and "substituted or unsubstituted" are used interchangeably to indicate that a particular group described may not have non-hydrogen substituents (i.e., unsubstituted), or that the group may have one or more non-hydrogen substituents (i.e., substituted). Unless otherwise stated, the total number of substituents that may be present is equal to the number of H atoms present in the unsubstituted form of the group described. In the case where the substituents present as appropriate are connected by a double bond, such as a side-oxygen (=O) substituent, the group occupies two possible valences, thus reducing the total number of other substituents included by two. In the case where the substituents present as appropriate are independently selected from the list of substitutes, the selected groups may be the same or different. Throughout this disclosure, it should be understood that the number and nature of the substituents selected as appropriate will be limited to the extent that such substitution is chemically significant to a person generally skilled in the art.

[0065] "Halogen" or "halogen group" refers to fluorine, chlorine, bromine, and iodine (F, Cl, Br, I). More specifically, halogen can refer to fluorine and chlorine.

[0066] "Cyano" refers to a substituent that is bonded to a carbon atom of a nitrogen atom by a double bond, i.e., -C≡N. "Cyanoimine" refers to a substituent that is bonded to a carbon atom of a nitrogen atom by a double bond, i.e., -C(R)=NC≡N, where R can be a dimethylamino group, i.e., -C(N(CH3)2)=NC≡N.

[0067] "Hydroxy group" refers to the -OH group.

[0068] "Side oxygen group" refers to the double-bonded oxygen (=O).

[0069] "Alkyl" refers to a saturated monovalent aliphatic hydrocarbon group having a specified number of carbon atoms, including straight-chain or branched-chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms ("C1-12 alkyl"), 1 to 8 carbon atoms ("C1-8 alkyl"), 1 to 6 carbon atoms ("C1-6 alkyl"), 1 to 5 carbon atoms ("C1-5 alkyl"), 1 to 4 carbon atoms ("C1-4 alkyl"), 1 to 3 carbon atoms ("C1-3 alkyl"), or 1 to 2 carbon atoms ("C1-2 alkyl"). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, isobutyl, terbutyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, and similar groups. Alkyl groups may be substituted, unsubstituted, or substituted, as further defined herein. In some cases, substituted alkyl groups are specifically named by reference to the substituent. For example, "haloalkyl" refers to an alkyl group having a specified number of carbon atoms, which is substituted with one or more halogen substituents up to the usable valence.

[0070] "Haloalkyl" refers to an alkyl group containing a specific number of carbon atoms as defined above, wherein at least one hydrogen atom is halogenated. Haloalkyl groups may contain, but are not limited to, 1-6 carbon atoms ("C1-6 haloalkyl"), 1-4 carbon atoms ("C1-4 haloalkyl"), or 1-2 carbon atoms ("C1-2 haloalkyl"). More specifically, fluorinated alkyl groups may be specifically referred to as "fluoroalkyl". Examples of fluoroalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of fully substituted fluoroalkyl groups (also known as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0071] "Hydroxyalkyl" refers to an alkyl group containing a specific number of carbon atoms as defined above, wherein at least one hydrogen atom is replaced by a hydroxyl group (OH), for example, only one hydrogen atom is replaced by a hydroxyl group. Hydroxyalkyl groups may contain, but are not limited to, 1-6 carbon atoms ("C1-6 hydroxyalkyl"), 1-4 carbon atoms ("C1-4 hydroxyalkyl"), or 1-2 carbon atoms ("C1-2 hydroxyalkyl").

[0072] "Cyanoalkyl" refers to an alkyl group containing a specific number of carbon atoms as defined above, wherein at least one hydrogen atom is replaced by a cyano group (-C≡N). A cyanoalkyl group may contain, but is not limited to, 1-6 carbon atoms ("C1-6 cyanoalkyl"), 1-4 carbon atoms ("C1-4 cyanoalkyl"), or 1-2 carbon atoms ("C1-2 cyanoalkyl").

[0073] "Side-oxyalkyl" refers to an alkyl group containing a specific number of carbon atoms as defined above, wherein at least two hydrogen atoms are replaced by side-oxy groups. Side-oxyalkyl groups may contain, but are not limited to, 1-6 carbon atoms ("C1-6 side-oxyalkyl"), 1-4 carbon atoms ("C1-4 side-oxyalkyl"), or 1-2 carbon atoms ("C1-2 side-oxyalkyl").

[0074] "Alkoxy" refers to an alkyl group as defined herein, with a single bond to an oxygen atom. The alkoxy group is bonded to the molecule through an oxygen atom. Alkoxy groups can be described as alkyl-O-. Alkoxy groups may contain, but are not limited to, 1 to 8 carbon atoms ("C1-8 alkoxy"), 1 to 6 carbon atoms ("C1-6 alkoxy"), 1 to 4 carbon atoms ("C1-4 alkoxy"), or 1 to 3 carbon atoms ("C1-3 alkoxy"). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, and similar groups.

[0075] "Lynyl group" refers to a saturated divalent aliphatic hydrocarbon group having a specific number of carbon atoms, including straight-chain or branched-chain groups. Lynyl groups may contain, but are not limited to, 1 to 12 carbon atoms ("C1-12 ynyl group"), 1 to 8 carbon atoms ("C1-8 ynyl group"), 1 to 6 carbon atoms ("C1-6 ynyl group"), 1 to 5 carbon atoms ("C1-5 ynyl group"), 1 to 4 carbon atoms ("C1-4 ynyl group"), 1 to 3 carbon atoms ("C1-3 ynyl group"), or 1 to 2 carbon atoms ("C1-2 ynyl group").

[0076] "Cycloalkyl" refers to a fully or partially saturated hydrocarbon ring system having a specific number of carbon atoms. It can be a monocyclic, bridged, or fused bicyclic or polycyclic ring system, with the carbon atoms of the cycloalkyl ring linked to the base molecule. "Cycloalkyl" can also refer to a fully saturated hydrocarbon ring system. Cycloalkyl groups may contain, but are not limited to, 3 to 12 carbon atoms ("C3-12 cycloalkyl"), 3 to 8 carbon atoms ("C3-8 cycloalkyl"), 3 to 6 carbon atoms ("C3-6 cycloalkyl"), 3 to 5 carbon atoms ("C3-5 cycloalkyl"), or 3 to 4 carbon atoms ("C3-4 cycloalkyl"). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and similar groups. Cycloalkyl groups may be substituted, unsubstituted, or substituted, as further defined herein.

[0077] "Heterocyclic alkyl" refers to a fully or partially saturated ring system containing a specified number of ring atoms and at least one heteroatom selected from N, O, and S as a ring member, wherein the ring S atom is substituted by one or two side oxygen groups (i.e., S(=O)q, where q is 0, 1, or 2), and wherein the heterocyclic alkyl ring is connected to the base molecule via a ring atom (which can be C or N). Heterocyclic alkyl can refer to a fully saturated ring system. Heterocyclic alkyl rings include spirocyclic, bridged, or fused rings with one or more other heterocyclic alkyl rings or carbocyclic rings, wherein such spirocyclic, bridged, or fused rings can themselves be saturated, partially unsaturated, or aromatic to a degree of unsaturation or aromaticity that is chemically significant, limited by the fact that the connection point with the base molecule is an atom of the heterocyclic alkyl portion of the ring system. Heterocyclic alkyl rings may contain 1 to 4 heteroatoms selected from N, O and S(=O)q as ring members, or 1 to 2 cyclic heteroatoms, subject to the restriction that such heterocyclic alkyl rings do not contain two consecutive oxygen or sulfur atoms.

[0078] Heterocyclic alkyl rings may be substituted or unsubstituted, as further defined herein. Such substituents may be present on the heterocycle linked to the base molecule, or on the spirocyclic, bridged, or fused ring linked to it. As defined herein, heterocyclic alkyl rings may include, but are not limited to, 3- to 8-membered heterocyclic groups, such as 4- to 7- or 4- to 6-membered heterocyclic alkyl groups.

[0079] "Aryl" or "aromatic" refers to a monocyclic, bicyclic (e.g., biaryl, fused), or polycyclic ring system containing a specified number of ring atoms, wherein all carbon atoms in the ring are sp2 hybridized and wherein π electrons are conjugated. Aryl groups may contain, but are not limited to, 6 to 20 carbon atoms ("C6-20 aryl"), 6 to 14 carbon atoms ("C6-14 aryl"), 6 to 12 carbon atoms ("C6-12 aryl"), or 6 to 10 carbon atoms ("C6-10 aryl"). Fused aryl groups may include an aromatic ring (e.g., a benzene ring) fused to another aromatic ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracene, phenanthryl, dihydroindenyl, and indenyl. Aryl groups may be substituted, unsubstituted, or substituted, as further defined herein.

[0080] Similarly, "heteroaryl" or "heteroaryl group" refers to a monocyclic, bicyclic (e.g., heterobiaryl, fused), or polycyclic ring system containing a specified number of ring atoms and including at least one heteroatom selected from N, O, and S as a ring member, wherein all carbon atoms in the ring are sp2 hybridized and wherein π electrons are conjugated. Heteroaryl groups may contain, but are not limited to, 5 to 20 ring atoms ("5-20 member heteroaryl"), 5 to 14 ring atoms ("5-14 member heteroaryl"), 5 to 12 ring atoms ("5-12 member heteroaryl"), 5 to 10 ring atoms ("5-10 member heteroaryl"), 5 to 9 ring atoms ("5-9 member heteroaryl"), or 5 to 6 ring atoms ("5-6 member heteroaryl"). The heteroaryl ring is linked to the base molecule via the ring atoms of the heteroaryl ring. Therefore, a 5- or 6-membered heteroaryl ring (alone or in a fused structure) can be linked to the base molecule via a ring C or N atom. Examples of heteroaryl groups include, but are not limited to, pyrrole, furanyl, phenylthio, pyrazolyl, imidazolyl, isozolyl, acezolyl, isothiazolyl, thiazolyl, triazolyl, acediazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridinyl, pyrimidinyl, pyridyl, benzofuranyl, benzophenylthio, indolyl, benzimidazolyl, inzolyl, quinolinyl, isoquinolinyl, purinyl, triazolyl, acediazolyl, acelinyl, quinazolinyl, quinolinyl, and carbazole. Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrroleyl, furanyl, phenylthio, pyrazolyl, imidazolyl, isozolyl, acezolyl, isothiazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyridine, and teradyl rings. Heteroaryl groups may be substituted, unsubstituted, or substituted, as further defined herein.

[0081] "Heterocyclic" or "heterocyclic" refers to a cyclic ring system in which at least one heteroatom selected from N, O, and S is a ring member. The ring system may include heterocyclic alkyl rings or heteroaryl rings. The ring system may include spirocyclic, bridged, or fused rings.

[0082] "Amino" refers to the group -NH2, whether unsubstituted or substituted. When substituted, the term includes groups in the form -NRxRy, where one of Rx and Ry is an alkyl moiety and the other is H, or both Rx and Ry are alkyl moietyes having a specific number of carbon atoms (e.g., -NH(C1-3 alkyl) or -N(C1-3 alkyl)2). The term "aminoheterocyclic alkyl" refers to an amino-substituted heterocyclic alkyl group.

[0083] The term "medically acceptable" means that a substance (such as the compounds described herein) and any salt thereof, or a composition containing the compounds disclosed herein or their salts, is suitable for administration to an individual or patient.

[0084] "Pharmaceutical composition" refers to a mixture of one or more of the compounds disclosed herein or their pharmaceutically acceptable salts, solvates, hydrates or prodrugs as active ingredients and at least one pharmaceutically acceptable excipient.

[0085] As used in this article, "deuterium enrichment factor" refers to the ratio between the abundance of deuterium and the natural abundance of deuterium, each relative to the abundance of hydrogen. The atomic positions designated as having deuterium can typically have at least 1,000 (15% deuterium inclusion), at least 2,000 (30% deuterium inclusion), at least 3,000 (45% deuterium inclusion), at least 3,500 (52.5% deuterium inclusion), at least 3,500 (52.5% deuterium inclusion at each designated deuterium atom), at least 4,000 (60% deuterium inclusion), at least 4,500 (67.5% deuterium inclusion), at least 5,000 (75% deuterium inclusion), at least 5,500 (82.5% deuterium inclusion), at least 6,000 (90% deuterium inclusion), at least 6,333.3 (95% deuterium inclusion), at least 6,466.7 (97% deuterium inclusion), and at least 6,600 (99% deuterium included) or at least 6,633.3 (99.5% deuterium included) deuterium enrichment factor.

[0086] As used herein, "excipient" refers to any component other than the compounds disclosed herein. The selection of excipients will depend to a great extent on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. As used herein, "excipient" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics and absorption delay agents, carriers, diluents, and the like. Examples of excipients include one or more of water, saline, phosphate-buffered saline, dextran, glycerol, ethanol, and the like, and combinations thereof, and isotonics such as sugars, sodium chloride, or polyols such as mannitol or sorbitol may be included in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). Where necessary, pharmaceutical compositions may contain additional excipients such as flavorings, binders / binding agents, lubricants, disintegrants, sweeteners or flavoring agents, colorants or dyes, and the like. 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) and binders (such as sucrose, gelatin, and gum arabic). Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Additionally, lubricants (such as magnesium stearate, sodium lauryl sulfate, and talc) are commonly used for tablet preparation. Similar types of solid compositions can also be used in the form of soft and hard-filled gelatin capsules. Therefore, non-limiting examples of excipients also include lactose or milk candy and high molecular weight polyethylene glycol. When an aqueous suspension or elixir is required for oral administration, the active compound therein can be combined with various sweeteners or flavorings, colorants or dyes, and, if necessary, with emulsifiers or suspending agents and additional excipients (such as water, ethanol, propylene glycol, glycerin, or combinations thereof). Examples of excipients also include pharmaceutically acceptable substances (such as wetting agents) or small amounts of auxiliary substances (such as wetting agents or emulsifiers, preservatives or buffers) that enhance the shelf life or effectiveness of the compound.

[0087] As used herein, the terms “treating,” “treat,” or “treatment” encompass preventive (i.e., preventative) and remissionary treatments, that is, reducing, alleviating, or slowing the progression of a patient’s disease (or condition) or any tissue damage associated with the disease.

[0088] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals. Mammals according to this disclosure include canines, felines, bovines, caprines, equines, sheep, suidae, rodents, rabbits, primates, humans, and the like, and include intrauterine mammals. Humans may be suitable individuals. Human individuals may be of any sex and at any developmental stage.

[0089] As used herein, the phrase "therapeutic effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response sought by researchers, veterinarians, physicians, or other clinicians in a tissue, system, animal, individual, or human, which may include one or more of the following: (1) Disease prevention; for example, preventing disease, condition or symptom in individuals who may be susceptible to disease, condition or symptom but have not yet experienced or shown the pathology or symptoms of disease; (2) Suppressing disease; for example, suppressing the disease, condition, or symptom of an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or ailment (i.e., curbing (or slowing down) the further development of the pathology or symptoms or both); and (3) Improve disease; for example, improve the disease, condition or symptom of an individual who is experiencing or showing the pathology or symptoms of a disease, condition or symptom (i.e., reverse the pathology or symptom or both).

[0090] Salts included in the term "medically acceptable salts" refer to the compounds disclosed herein, which are typically 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 obtain salts suitable for administration to an individual or patient of the compounds disclosed herein.

[0091] In addition, the compounds disclosed herein may also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and may be used as intermediates for one or more of the following: 1) preparing the compounds disclosed herein; 2) purifying the compounds disclosed herein; 3) isolating mirror-image isomers of the compounds disclosed herein; or 4) isolating non-mirror-image isomers of the compounds disclosed herein.

[0092] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to, acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphorsulfonates, citrates, cyclamates, ethanedisulfonates, ethanesulfonates, formates, fumarates, gluconate, glucuronates, glucuronates, hexafluorophosphates, phenacetinates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodates / iodides, hydroxyethanesulfonates, lactates, malates, maleate, malonate, methanesulfonates, methyl sulfates, naphthalenedicarboxylate, 2-naphthalenesulfonate, nicotinate, nitrates, orotates, oxalates, palmitates, dihydroxynaphthalate, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, gluconate, stearates, succinates, tannins, tartrates, toluenesulfonates, trifluoroacetates, 1,5-naphthalenedisulfonic acid, and hydroxynaphthalenecarboxylate. The salt can be a trifluoroacetate or a formate.

[0093] Suitable alkaline salts are formed from bases that produce non-toxic salts. Examples include, but are not limited to, aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, thiamethoxam salts, and zinc salts.

[0094] It can also form half-salts of acids and bases, such as half-sulfates and half-calcium salts.

[0095] 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.

[0096] The pharmaceutically acceptable salts of the compounds disclosed herein can be prepared by methods well known to those skilled in the art, including but not limited to the following procedures: (i) React the disclosed compound with a desired acid or base; (ii) Remove the acid- or base-indestructible protecting group from a suitable precursor of the disclosed compound using the desired acid or base, or open the ring of a suitable cyclic precursor (e.g., lactone or lactamine) using the desired acid or base; or (iii) To convert one salt of the disclosed compound into another salt. This can be achieved by reacting with a suitable acid or base or by a suitable ion exchange procedure.

[0097] These procedures are typically carried out in solution. The resulting salt can be precipitated and collected by filtration, or recovered by evaporating the solvent.

[0098] The compounds disclosed herein and their pharmaceutically acceptable salts may exist in both solvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compounds disclosed herein or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable solvent molecules, such as ethanol. When the solvent is water, the term "hydrate" is used.

[0099] In addition, the compounds disclosed herein may also include other solvates of such compounds, which are not necessarily pharmaceutically acceptable solvates, and may be used as intermediates for one or more of the following: 1) preparing the compounds disclosed herein; 2) purifying the compounds disclosed herein; 3) isolating mirror-image isomers of the compounds disclosed herein; or 4) isolating non-mirror-image isomers of the compounds disclosed herein.

[0100] The currently accepted classification system for organic hydrates defines isolated site hydrates, channel hydrates, or metal ion coordination hydrates. See KR Morris. [Polymorphism in Pharmaceutical Solids] (HG Brittain, ed., Marcel Dekker, 1995). Isolated site hydrates are hydrates in which water molecules are separated from each other by insertion into organic molecules and do not directly contact each other. In channel hydrates, water molecules are located in lattice channels, where these water molecules are adjacent to other water molecules. In metal ion coordination hydrates, water molecules are bonded to metal ions.

[0101] When solvent or water is tightly bound, the complex can have a well-defined stoichiometry independent of humidity. However, when solvent or water is weakly bound, such as in channel solvates and hygroscopic compounds, the water / solvent content can depend on humidity and drying conditions. In these cases, non-stoichiometry becomes the standard.

[0102] Multicomponent complexes (other than salts and solvates) are also included within the scope of this disclosure, wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes cage compounds (drug-body inclusion complexes) and cocrystals. The latter is generally defined as a crystalline complex of neutral molecular components bound together by non-covalent interactions, such as hydrogen-bonded complexes (cocrystals) that can form with neutral molecules or salts. Cocrystals can be prepared by melt crystallization, by recrystallization from an autosolvent, 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).

[0103] The compounds disclosed herein can exist in a continuous solid state 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 exhibits physical properties that vary with temperature, exhibiting either solid or liquid characteristics. Typically, such materials do not provide a unique X-ray diffraction pattern and, when exhibiting solid properties, are more formally described as liquids. Upon heating, a change from solid to liquid properties occurs, characterized by a state transition, typically second-order ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and provides a unique X-ray diffraction pattern with defined peaks. Such materials will also exhibit liquid properties upon sufficient heating, but the change from solid to liquid is characterized by a phase transition, typically first-order ("melting point").

[0104] Under suitable conditions, the compounds disclosed herein can also exist in a mesocrystalline state (mesophase or liquid crystal). The mesocrystalline state lies between a true crystalline state and a true liquid state (melt or solution), and is composed of two-dimensional order at the molecular level. Mesocrystalline phenomena arising from temperature changes are described as "thermotropic," while those arising from the addition of a second component (such as water or another solvent) are described as "lyotropic." Compounds with the potential to form lyotropic mesophases are described as "amphiphilic" and consist of molecules with ionic polar head groups (such as -COO-Na+, -COO-K+, or -SO3-Na+) or nonionic polar head groups (such as -N-N+(CH3)3). For further information, see NH Hartshorne and A. Stuart, Crystals and the Polarizing Microscope, 4th edition (Edward Arnold, 1970).

[0105] The compounds disclosed herein can exist in two or more stereoisomers. Stereoisomers of the compounds may include cis and trans isomers (geometric isomers), optical isomers (such as R and S mirror-image isomers), non-mirror-image isomers, rotational isomers, configurational isomers, and configurational isomers. For example, the compounds disclosed herein containing one or more asymmetric carbon atoms can exist in two or more stereoisomers. When the compounds disclosed herein contain an alkenyl or alkenyl group, geometric cis / trans (or Z / E) isomers are possible. Saturated rings can also exist as cis / trans isomers.

[0106] The pharmaceutically acceptable salts of the compounds disclosed herein may also contain optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine) relative ions.

[0107] Cis / trans isomers can be separated using familiar techniques known to those skilled in the art (such as chromatography and fractional crystallization).

[0108] Conventional techniques for preparing / separating individual mirror-image isomers include palmar synthesis from suitable optically pure precursors or analysis of racemic products (or racemic products of salts or derivatives) using, for example, palmar high-performance liquid chromatography (HPLC). Alternatively, the racemic product (or racemic precursor) can be reacted with a suitable optically active compound (e.g., an alcohol, or, in the case of the disclosed compound containing an acidic or basic moiety, a base or acid, such as 1-phenylethylamine or tartaric acid). The resulting non-mirror-image isomer mixture can be separated by chromatography, fractional crystallization, or by using both techniques, and one or both of the non-mirror-image isomers can be converted to the corresponding pure mirror-image isomers by means well known to those skilled in the art. The palmar compounds (and their palmar precursors) disclosed herein can be obtained in a mirror-image isomer-enriched form using chromatography (typically HPLC). The dissolution is concentrated to obtain a concentrated mixture. Palmar chromatography using subcritical and supercritical fluids can be employed. The palmar chromatographic method that can be used in this disclosure is known in this 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).

[0109] When any racemic compound crystallizes, two different types of crystal systems are possible. The first type is the racemic compound mentioned above (the true racemate), in which a homogeneous form of crystal is produced, containing equimolar amounts of two mirror-image isomers. The second type is a racemic mixture or aggregate, in which two equimolar amounts of crystalline forms are produced, each containing a single mirror-image isomer. Although the two crystalline forms present in a racemic mixture have the same physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures can be separated by known techniques to those skilled in the art, see, for example, E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (Wiley, 1994).

[0110] Tautomerism ("tautomerism") can occur when structural isomers can interconvert via low-energy barriers. This can take the form of proton tautomerism in compounds disclosed herein containing, for example, imine / amino, ketone / enol, or oxime / nitroso, lactamine / lactamine, or so-called valence tautomerism in compounds containing aromatic moieties. Therefore, a single compound can exhibit more than one type of isomerism.

[0111] It must be emphasized that, although for the sake of brevity, the compounds disclosed herein are drawn in a single tautomer form, all possible tautomer forms are included within the scope of this disclosure.

[0112] This disclosure includes all pharmaceutically acceptable isotopically labeled compounds of formula I, wherein one or more atoms have undergone atomic substitutions having the same atomic number but an atomic mass or mass number different from the dominant atomic mass or mass number in nature.

[0113] Examples of isotopes suitable for inclusion in compounds of formula I may include isotopes of hydrogen, such as 2H (D, deuterium) and 3H (T, tritium); isotopes of carbon, such as 11C, 13C and 14C; chlorine, such as 36Cl; fluorine, such as 18F; iodine, such as 123I and 125I; nitrogen, such as 13N and 15N; oxygen, such as 15O, 17O and 18O; phosphorus, such as 32P; and sulfur, such as 35S.

[0114] Certain isotopically labeled Formula I compounds, such as those incorporating radioisotopes, can be used in studies of drug or receptor tissue distribution, either or both. Radioisotopes, such as tritium and 14C, are particularly suitable for this purpose due to their ease of incorporation and readily available detection methods. Substitution with positron-emitting isotopes (such as 11C, 18F, 15O, and 13N) can be used in positron emission tomography (PET) studies to examine receptor occupancy. Substitution with deuterium (i.e., 2H) can provide certain therapeutic advantages resulting from greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, decreased CYP450 inhibition (competitive or time-dependent), or improved therapeutic index or tolerability.

[0115] This disclosure provides deuterium-labeled (or deuterated) compounds and salts, wherein the formulas and variables of such compounds and salts are each and independently as described herein. "Deuteration" means that at least one atom in the compound is deuterium, with an abundance greater than the natural abundance of deuterium (typically about 0.015%). Those skilled in the art will recognize that in compounds containing hydrogen atoms, the hydrogen atom actually represents a mixture of H and D, of which about 0.015% is D. The concentration of deuterium in deuterium-labeled compounds and salts of formula I can be defined by a deuterium enrichment factor. It should be understood that one or more deuterium atoms can exchange with hydrogen under physiological conditions.

[0116] The deuterium compound may be selected from any of the compounds in the examples described in the Examples section.

[0117] One or more hydrogen atoms at certain metabolic sites on a compound of formula I may be deuterated.

[0118] Isotopically labeled compounds of formula I can generally be prepared by means of conventional techniques known to those skilled in the art or by means of methods similar to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents.

[0119] According to this disclosure, pharmaceutically acceptable solvates include solvates in which the crystallizing solvent can be isotopically substituted, such as D2O, d6-acetone, and d6-DMSO.

[0120] The compounds disclosed herein can be administered in prodrug form. Therefore, when administered in vivo or on the body surface, certain derivatives of the disclosed compounds, which may themselves have little or no pharmacological activity, are converted into the disclosed compounds with the desired activity, for example, through hydrolytic cleavage, particularly hydrolytic cleavage promoted by esterases or peptidases. Such derivatives are called "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.)".

[0121] According to this disclosure, the drug can be produced, for example, by replacing appropriate functional groups present in the disclosed compound with certain portions known to those skilled in the art as the "pre-parts," as described in, for example, H. Bundgaard's "Design of Prodrugs" (Elsevier, 1985).

[0122] Therefore, according to this disclosure, the prior drug may be (a) an ester or amide derivative of a carboxylic acid when present in the compound disclosed herein; (b) an ester, carbonate, carbamate, phosphate, or ether derivative of a hydroxyl group when present in the compound disclosed herein; (c) an amide, imine, carbamate, or amine derivative of an amino group when present in the compound disclosed herein; (d) a thiol thioester, thiocarbonate, thiocarbamate, or sulfide derivative of a thiol group when present in the compound disclosed herein; or (e) a carbonyl oxime or imine derivative when present in the compound disclosed herein.

[0123] Based on some specific examples of the drug prior to this disclosure, including: (i) When the compounds disclosed herein contain a carboxylic acid functional group (-COOH), their esters, such as compounds in which the hydrogen of the carboxylic acid functional group is replaced by a C1-8 alkyl group (e.g., ethyl group) or a (-C1-8 alkyl)C(=O)OCH2- group (e.g., tBuC(=O)OCH2- group); (ii) When the compounds disclosed herein contain an alcohol functional group (-OH), their esters, such as compounds in which the hydrogen of the alcohol functional group of the compound is replaced by a -CO (C1-8 alkyl) (e.g., methyl carbonyl) or in compounds in which the alcohol is amino esterified; (iii) When the compounds disclosed herein contain an alcohol functional group (-OH), their ethers, such as compounds in which the hydrogen of the alcohol functional group of the compound is replaced by (C1-8 alkyl)C(=O)OCH2- or -CH2OP(=O)(OH)2; (iv) When the compounds disclosed herein contain an alcohol functional group (-OH), their phosphates, such as compounds in which the hydrogen of the alcohol functional group of the compound is replaced by -P(=O)(OH)2 or -P(=O)(O-Na+)2 or -P(=O)(O-)2Ca2+; (v) When the compounds disclosed herein contain primary or secondary amino functional groups (-NH2 or -NHR, where R ≠ H), their acetylamines, for example, depending on the specific case, are compounds in which one or two hydrogens of the amino functional group are replaced by (C1-10) alkyl, -COCH2NH2 substitution, or the amino group is derivatized by an amino acid; (vi) When the compounds disclosed herein contain primary or secondary amino functional groups (-NH2 or -NHR, where R ≠ H), their amines, for example, depending on the specific case, are compounds in which one or both hydrogens of the amino functional group of the compound are replaced by -CH2OP(=O)(OH)2.

[0124] Some of the compounds disclosed herein can act as prodrugs for other compounds disclosed herein, and the two compounds disclosed herein can also be combined together in prodrug form. In some cases, the prodrugs of the compounds disclosed herein can be generated by internally linking two functional groups in the compounds disclosed herein, for example by forming a lactone.

[0125] This disclosure also includes the active metabolites of the disclosed compounds, i.e., compounds that are typically formed in vivo after drug administration via oxidation or dealkylation. Examples of metabolites according to this disclosure include, but are not limited to: (i) When the compounds disclosed herein contain alkyl groups, their hydroxyalkyl derivatives (-CH → -COH); (ii) When the compounds disclosed herein contain alkoxy groups, their hydroxyl derivatives (-OR → -OH); (iii) When the compounds disclosed herein contain a tertiary amino group, their secondary amino derivatives (-NRR' → -NHR or -NHR'); (iv) When the compounds disclosed herein contain a secondary amine group, their primary derivatives (-NHR→-NH2); (v) When the compounds disclosed herein contain a phenyl moiety, their phenolic derivatives (-Ph → -PhOH); (vi) When the compounds disclosed herein contain an amino group, their carboxylic acid derivatives (-CONH2 → COOH); and (vii) When a compound contains a hydroxyl or carboxylic acid group, it can be metabolized, for example, by conjugation with glucuronic acid to form glucuronic acid. Other conjugation metabolic pathways exist. These pathways are generally referred to as two-phase metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, can also be conjugated.

[0126] Compounds or their pharmaceutically acceptable salts may have the structure of formula I, IA, or IB. Compounds of formula I may have the structure of formula IA or IB. I IA IB

[0127] X1 can be CH, CNH2, or N. X1 can be N.

[0128] X2 can be C or N.

[0129] X3 can be CR13, N, NR13, O, or S. X3 can be CR13. X3 can be N or NR13. X3 can be CR13 or N.

[0130] X4 can be CH, N, or NR13. X4 can be CH, N, or N-cyclopropyl. X4 can be N.

[0131] X5 can be CH, CR1B, or N. X5 can be CH.

[0132] X6 can be CH or N.

[0133] X7 can be CH, N, or CF. X7 can be CH or N. X7 can be CCl.

[0134] X8 can be CH or N. X8 can be CH.

[0135] X9 can be CH, CR1B, or N.

[0136] X10 can be CH, CR1B, or N. At least one of X2 can be N, or X3 can be N, NH, or NR13, and X4 can be N.

[0137] If X3 is S or O, then X2 can be C.

[0138] If X3 is CR13 or NR13, then X4 can be CH or N. If X4 is NR13, then X3 can be N, O, or S.

[0139] A dashed line indicates a single bond (i.e., the dashed line does not exist, leaving only a single bond) or a double bond (i.e., the dashed line exists as a second bond forming a double bond). A dashed line can indicate a single bond. If the dashed line indicates a double bond, then R4B does not exist and n is 1.

[0140] R1 can be -NHR8, -OH, -C2-5 heterocyclic, or -C1-3 alkyl. R1 can be -NHR8, -C2-5 heterocyclic, or -C1-3 alkyl. R1 can be -C2-5 heterocyclic and may be substituted, as appropriate, with one or more, one, two, or three of the following: -C1-3 alkyl, -C1-3 oxyalkyl, -C3-5 heterocyclic alkyl, -C3-5 hydroxycyclic alkyl, -C3-5 aminocyclic alkyl, or oxyalkyl. R1 can be -C2-5 heterocyclic and may be substituted, as appropriate, with one or more, one, two, or three of the following: -C1-3 alkyl, -NR10AR11, or -NR10R11. R1 may be a -C1-3 alkyl group and may be substituted with one or both of a side-oxy group, -NR10AR11, or -NR10R11. R1 may be a -C1-3 alkyl group substituted with one or more, one, two, or three of a side-oxy group or -NR10R11, depending on the situation. R1 may be a -C1-3 alkyl group substituted with a side-oxy group and -NR10R11. R1 may be a -C1-3 alkyl group substituted with a side-oxy group and -NR10AR11. R1 may be -NHR8. Each of the -C2-5 heterocyclic, -C3-5 heterocyclic alkyl, -C3-5 hydroxycyclic alkyl, and -C3-5 aminocyclic alkyl groups may independently include 1 to 4 heteroatoms, including at least one of N, O, or S. The -C2-5 heterocycle of R1 may include 1 to 4 heteroatoms, including at least one of N, O, or S; wherein all of these heteroatoms may be N.

[0141] R1A can be H. R1A can be -CH3. R1A can be H, a halogen, or -CH3. R1A can be H or a halogen, wherein the halogen can be F.

[0142] R1 and R1A can form a C5-7 heterocyclic alkyl group fused to ring D or a C5-7 heteroaryl group fused to ring D. The C5-7 heterocyclic alkyl group or C5-7 heteroaryl group may be substituted with a side-oxygen group, depending on the situation. R1 and R1A can form a C6-8 fused heterocyclic alkyl group, which may be substituted with a side-oxygen group, depending on the situation. R1 and R1A can form a C6-8 fused heteroaryl group, which may be substituted with a side-oxygen group, depending on the situation. Each of the C6-8 fused heterocyclic alkyl group and the C6-8 fused heteroaryl group may independently include one to three heteroatoms, including at least one of N, O, or S.

[0143] Each R1B is independently H, -CH3, F, Cl, or methoxy.

[0144] R2 can be H, -C1-3 alkyl, -C1-3 alkoxy, -C1-3 fluoroalkyl, or halogen. R2 can be H.

[0145] R3 can be a -C1-3 alkyl, a -C2-10 heterocyclic, -P(=O)(CH3)2, -S(=O)CH3, -NH-S(=O)2CH3, or -NH-C(=O)-C1-3 alkyl. R3 can be a -C1-3 alkyl, a -C2-10 heterocyclic, -P(=O)(CH3)2, -S(=O)CH3, or -NH-S(=O)2CH3. R3 can be a -C1-3 alkyl, a -C2-10 heterocyclic, or -NH-C(=O)-C1-3 alkyl. R3 can be a -C1-3 alkyl substituted with one or more, or one, two, or three of the following: a side-oxygen group, -OH, halogen, -C3-6 cycloalkyl, -NR12R12A, -C5-8 heterocyclic, or cyano. R3 can be a -C1-3 alkyl substituted with a side-oxygen group and -NR12R12A. The -C2-10 heterocycle of R3 can be a -C2-10 heterocyclic alkyl or a -C2-10 heteroaryl. The -C2-10 heterocycle of R3 can be a -C2-6 heterocyclic alkyl or a -C2-6 heteroaryl. R3 can be a -C2-10 heterocycle substituted, as appropriate, with one or more, or one, two, or three of the following: -OH, halogen, -C1-3 hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkyl, -C1-3 fluoroalkyl, cyclopropyl, or side-oxygen. R3 can be a -C2-10 heterocyclic alkyl substituted, as appropriate, with one or more, or one, two, or three of the following: -OH, halogen, -C1-3 hydroxyalkyl, -C1-3 alkyl, cyclopropyl, or side-oxygen. R3 can be a -C1-3 alkyl substituted, as appropriate, with one or more, or one, two, or three of the following: side-oxygen or -NR12R12A. R3 may be a -C2-5 heterocycle substituted with a -C1-3 alkyl group, as appropriate. R3 may be a -C2-5 heteroaryl group substituted with one or more, or one, two, or three -C1-3 alkyl groups, as appropriate. Each of the -C2-10 heterocycle, -C5-8 heterocycle, -C2-6 heterocyclic alkyl, -C2-10 heterocyclic alkyl, -C2-10 heteroaryl, -C2-6 heteroaryl, or -C2-5 heterocycle may independently include 1 to 3 heteroatoms, including at least one of N, O, or S. The -C2-10 heterocycle of R3 may include 1 to 3 heteroatoms, including at least one of N, O, or S. The -C2-10 heterocycle of R3 may be a helical, fused, or bridged -C2-10 heterocycle. The C5-8 heterocycle of R3 may include 1 to 4 heteroatoms, including at least one of N, O, or S.

[0146] R2 and R3 may form a C3-6 heterocycle fused to ring A, which may be substituted with one, two, or three -C1-3 alkyl, -C2-3 septoxyalkyl, or septoxy groups, depending on the case. R2 and R3 may form a C3-6 heterocyclic alkyl group fused to ring A, which may be substituted with one or more, or one, two, or three -C1-3 alkyl, -C2-3 septoxyalkyl, or septoxy groups, depending on the case. Each of the C3-6 heterocycle or C3-6 heterocyclic alkyl group may independently include one to three heteroatoms, including at least one of N, O, or S.

[0147] R4A can be H, -OH, -C1-3 fluoroalkyl, or -C1-3 alkyl.

[0148] R4B can be H. R4B may not exist.

[0149] R4A and R4B together can form a cyclopropyl group.

[0150] R4B and an R5 together can form a C3-5 cycloalkyl group fused with ring B.

[0151] Each R5 group can independently be H, -OH, -C3-6 cycloalkyl (e.g., cyclopropyl), halogen, -C1-3 fluoroalkyl, or -C1-3 alkyl. Two R5 groups together can form a cyclopropyl group. If the dashed line indicates the presence of a double bond, then R5 can be H, -C3-6 cycloalkyl (e.g., cyclopropyl), halogen, -C1-3 fluoroalkyl, or -C1-3 alkyl.

[0152] R6 can be H, -OH, or -C1-3 alkyl. R6 can be H or -C1-3 alkyl.

[0153] R4A and R6 together can form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge. An R5 and R6 together can also form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge. A C1-3 heteroalkyl bridge may include one of the heteroatoms N, O, or S.

[0154] R7 can be H, -C1-3 alkyl, or -C1-3 hydroxyalkyl. R7 can be H or -C1-3 alkyl.

[0155] R8 can be H, -C1-3 alkyl, -SO2CH3, or -C3-4 heterocyclic. R8 can be H, -C1-3 alkyl, or -C3-4 heterocyclic. R8 can be a -C1-3 alkyl substituted with one, two, or three oxy groups, a -C3-9 heterocyclic alkyl, a -C3-9 heterocyclic alkyl substituted with a methyl group, a -C1-3 alkoxy group, a cyanoimide, or a -NR9R10 substituted group. R8 can be a -C1-3 alkyl substituted with one or more, one, two, or three of the oxy groups or -NR9R10, depending on the situation. R8 can be a -C1-3 alkyl substituted with one or both of the oxy groups or -NR9R10, depending on the situation. R8 can be a -C1-3 alkyl substituted with both oxy groups and -NR9R10. R8 may be a -C3-4 heterocycle substituted with one, two or three septyl groups, halogens, -C0-1 alkyl-NR10R11, -OH, -C1-3 hydroxyalkyl, -C1-3 alkyl-C1-3 alkoxy, -C1-3 septyl alkyl, -C1-3 alkyl, or -C1-3 alkoxy substituted with -NR10R11, as appropriate. The -C3-9 heterocyclic alkyl group of R8 may be substituted with one, two, or three -C1-3 alkyl, -OH, -C1-3 hydroxyalkyl, -O-C1-3 hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkyl-C1-3 alkoxy, halogen, -C1-3 fluoroalkyl, -C1-3 fluoroalkoxy, cyano, -C1-3 cyanoalkyl, -C0-1 alkyl-C3-5 heterocyclic alkyl, -O-C3-5 heterocyclic alkyl, or -C0-1 alkyl-NR10R11. R8 may be a -C3-4 heterocycle substituted with one or more, or one, two, or three oxy- or -C1-3 alkyl groups, as appropriate. Each of the -C3-4 heterocycle or -C3-9 heterocyclic alkyl group of R8 may independently include one to four heteroatoms, including at least one of N, O, or S. The -C3-4 heterocycle of R8 may include 1 to 4 heteroatoms, including at least one of N or O. The -C3-9 heterocyclic alkyl group of R8 may include 1 to 3 heteroatoms, including at least one of N or O. The -C3-4 heterocycle or -C3-9 heterocyclic alkyl group of R8 may be a bridged, helical, or fused heterocycle.

[0156] R9 may be H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, -methylene-phenyl-NH-C(=O)-NR10R11, or -C3-5 heterocyclic alkyl. R9 may be a -C1-4 alkyl group substituted with one or more, or one, two, or three of -C3-5 cycloalkyl, -C3-5 heterocyclic alkyl, or methoxy, as appropriate. R9 may be a -C3-5 cycloalkyl group of R9 substituted with one or both of -OH or -C1-3 alkyl, as appropriate. R9 may be H or -C1-4 alkyl. Each of the -C3-5 heterocyclic alkyl groups of R9 may independently include one or two heteroatoms, including at least one of N or O.

[0157] Each R10 can be independently H or -C1-4 alkyl. Each R10 can be independently H or -C1-3 alkyl.

[0158] R10A may be a -C0-1 alkyl-C3-5 heterocyclic alkyl group substituted with a -C1-3 alkyl group, as appropriate. The C3-5 heterocyclic alkyl group of R10A may include one N heteroatom.

[0159] If the -C1-3 alkyl group of R8 is substituted with -NR9R10, then the corresponding R9 and R10 can be combined as appropriate to form a C3-9 heterocyclic alkyl group or a C3-9 heterocyclic alkyl group.

[0160] Each R11 can be independently H or -C1-3 alkyl.

[0161] R12 can be H, -C1-3 alkyl, -C1-3 hydroxyalkyl, -(CH2)0-2-C3-5 heterocyclic alkyl, -(CH2)1-2-O-C3-5 heterocyclic alkyl, -methylene-C(=O)-NR10R11, or -methylene-phenyl-NH-C(=O)-NR10R11. The -(CH2)0-2-C3-5 heterocyclic alkyl or -(CH2)1-2-O-C3-5 heterocyclic alkyl of R12 can be substituted with -C1-4 alkyl, -C1-3 alkyl-C1-3 alkoxy, -(CH2)0-1-phenyl, halogen, -C1-3 fluoroalkyl, or -(CH2)0-1-C3-5 heterocyclic alkyl. The -C1-3 alkyl of R12 can be substituted with one, two, or three side oxygen groups or NR10R11. The R12 may independently include one or two heteroatoms, including at least one of N or O.

[0162] R12A can be H. R12A can be a -C1-4 alkyl group.

[0163] R12 and R12A may form a C3-10 heterocycle, depending on the presence of one, two, or three -C1-3 alkyl, -OH, oxy-, halogen, -C2-3 oxyalkyl, -C1-3 alkoxy, -C1-3 hydroxyalkyl, -C1-3 alkyl-C1-3 alkoxy, cyano, -C3-6 cycloalkyl, -S(=O)2CH3, -S(=O)2CH2CH3, -C(=O)-NR10R11, or -NHC(=O)CH3. The C3-10 heterocycle may include one to four heteroatoms, including at least one of N, O, or S. The C3-10 heterocycle may be a bridged, helical, or fused heterocycle.

[0164] R13 can be H, -C1-6 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C1-3 alkyl-C1-3 alkoxy, -C1-4 cyanoalkyl, -C0-1 cycloalkyl-C3-5 cycloalkyl, -C2-4 syloxyalkyl, or -C0-1 cycloalkyl-C3-5 heterocyclic alkyl. R13 can be H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocyclic alkyl. R13 can be H. R13 can be -C0-1-cyclopropyl. The -C1-6 alkyl group of R13 may be substituted with one, two, or three syloxy groups, fluorine, -NH2, C3-6 cycloalkyl, or methoxy groups, as appropriate. The -C3-5 cycloalkyl or -C3-6 cycloalkyl group of R13 may be substituted with one, two or three -C1-3 alkyl, -C1-3 fluoroalkyl or halogen, as appropriate. The -C3-5 heterocycloalkyl group of R13 may include one to three heteroatoms, including at least one of N, O or S.

[0165] R14 can be H.

[0166] X4 can be NR13, and R13 and R14 can form a C4-5 heterocycle that fused with ring C.

[0167] The variable n can be 1 or 2.

[0168] The variable m can be 0 or 1.

[0169] Each heterocycle may independently comprise 1 to 4 heteroatoms, including at least one of N, O, or S.

[0170] At least one hydrogen atom in a compound of formula I may be deuterium.

[0171] The values ​​of A, B, C, and D used to represent the rings in expression I can be used to identify the corresponding rings in expressions IA and IB.

[0172] When defining the number of groups in formula I, IA, or IB, the term "one or more" may, for example, refer to one to four or one to three of the options listed when the term is used independently each time.

[0173] The compound or its pharmaceutically acceptable salt may be N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-5-(5-(2-sideoxypyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methamide.

[0174] The compound or its pharmaceutically acceptable salt may be 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methoxyamine.

[0175] The compound or its pharmaceutically acceptable salt may be 5-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-carbonyl)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methamide.

[0176] The compound or its pharmaceutically acceptable salt may be 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methoxyamine.

[0177] The compound or its pharmaceutically acceptable salt may be (S)-5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methoxyamine.

[0178] The compound or its pharmaceutically acceptable salt may be (S)-5-(4-(dimethylaminomethoxy)phenyl)-1-isopropyl-7-methyl-N-(4-(4-methylpiperazin-1-methoxy)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methoxyamine.

[0179] The compound or its pharmaceutically acceptable salt may be 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methoxyamine.

[0180] Pharmaceutical compositions may contain compounds of formula I. For example, a pharmaceutical composition may contain compounds of formula IA.

[0181] The compositions disclosed herein may be in a variety of forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusionable solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0182] Typical compositions are in injectable or infusionable solution form, such as compositions commonly used for passive immunization of humans with antibodies. One mode of administration is non-enteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). The compound can be administered by intravenous infusion or injection. The compound can be administered by intramuscular or subcutaneous injection.

[0183] Oral administration of solid dosage forms may be presented, for example, as discrete units such as hard or soft capsules, pills, flat capsules, lozenges, or tablets, each containing a predetermined amount of at least one of the disclosed compounds. Oral administration may be in powder or granule form. Oral dosage forms may be sublingual, such as lozenges. In such solid dosage forms, the disclosed compounds are typically combined with one or more adjuvants. Such capsules or tablets may contain controlled-release formulations. In the case of capsules, tablets, and pills, these dosage forms may also contain buffers or may be prepared using enteric coating.

[0184] Oral administration may be in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing an inert diluent (e.g., water) commonly used in this art. Such compositions may also contain one or more of adjuvants, such as wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), or aromatizers.

[0185] This disclosure includes non-enteric dosage forms. "Non-enteric administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable formulations (i.e., sterile injectable aqueous or oil suspensions) can be formulated using one or more of suitable dispersants, wetting agents, or suspending agents according to known techniques.

[0186] This disclosure includes topical dosage forms. "Topical administration" includes, for example, skin and transdermal administration (such as via transdermal patches or iontophoresis devices), intraocular or intranasal administration, or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this disclosure are administered via a transdermal device, administration will be achieved using a reservoir and a patch of the porous membrane type or solid matrix type. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, rice paper capsules, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical excipients include alcohols, water, mineral oils, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. It can be incorporated into penetration enhancers, see, for example, BC Finnin and TM Morgan, J. Pharm. Sci., Vol. 88, pp. 955-958, 1999.

[0187] Formulations suitable for topical administration to the eye include, for example, eye drops, in which the compounds disclosed herein are dissolved or suspended in suitable excipients. Typical formulations suitable for ocular or ear administration may be in the form of micronized suspensions or drops in pH-adjusted isotonic sterile saline. Other formulations suitable for ocular and ear administration include ointments, biodegradable implants (i.e., absorbable gel sponges, collagen) and non-biodegradable implants (i.e., polysiloxane), rice paper encapsulations, lenses, and microparticle or vesicle systems, such as nonionic surfactant vesicles (niosomes) or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose), or heteropolysaccharide polymers (e.g., gellan gum) may be incorporated with preservatives (such as benzalkonium chloride). Such formulations may also be delivered via iontophoresis.

[0188] For intranasal administration, the compounds disclosed herein are preferably delivered in solution or suspension form from a pump-operated spray container squeezed or pumped by the patient, or in aerosol form from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for intranasal administration are typically administered as dry powder (alone, as a mixture, such as a dry blend with lactose, or as mixed component particles, such as mixed with phospholipids (e.g., phosphatidylcholine)) from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, nebulizer, nebulizer (preferably a nebulizer that generates a fine mist using electrohydrodynamics), 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, such as polyglucosamine or cyclodextrin.

[0189] This disclosure includes rectal dosage forms. Such rectal dosage forms may be in the form of, for example, suppositories. Cocoa butter is a traditional suppository base, but various alternatives may be used where appropriate.

[0190] Other excipients and administration methods known in pharmaceutical technology may also be used. The pharmaceutical compositions disclosed herein can be prepared using any of the well-known pharmaceutical techniques, such as efficient dispensing and administration procedures. The above considerations regarding efficient dispensing and administration procedures are well known in this art and described in standard textbooks. Drug dispensing is discussed, for example, by 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; edited by Stahl, P. Heinrich and Camilli G. Wermuth, [Handbook of Pharmaceutical Salts: Properties, Selection, and Use]. New York: Wiley-VCH, 2011; and Brittain, Harry G., eds. [Polymorphism in Pharmaceutical Solids]. New York: Informa Healthcare USA, Inc., 2016.

[0191] Acceptable excipients are non-toxic to individuals at the dosage and concentration used and may contain one or more of the following: 1) buffers, such as phosphates, citrates or other organic acids; 2) salts, such as sodium chloride; 3) antioxidants, such as ascorbic acid or methionine; 4) preservatives, such as octadecyl dimethylbenzyl ammonium chloride, hexahydroxy tetramethylammonium chloride, benzalkonium chloride, benzyl chloride, phenol, butanol or benzyl alcohol; 5) alkyl esters of p-hydroxybenzoate, methylparaben or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol or m-cresol; 6) low molecular weight (less than about 10 residues) peptides; 7) proteins, such as serum albumin. 8) Hydrophilic polymers, such as polyvinylpyrrolidone; 9) Amino acids, such as glycine, glutamic acid, aspartic acid, histamine, 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 ions, such as sodium, metal complexes (e.g., Zn-protein complexes); or 14) Nonionic surfactants, such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamer, or polyethylene glycol (PEG).

[0192] For oral administration, the composition may be provided in tablet or capsule form 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 mg of active ingredient for symptomatic dose adjustment in patients. The drug typically contains 0.01 mg to 500 mg of active ingredient, or 1 mg to 100 mg of active ingredient. During constant-rate infusion, the intravenous dose may range from 0.01 to 10 mg / kg / min.

[0193] Liposomes containing the compounds disclosed herein can be prepared by methods known in this 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 a reverse-phase evaporation method using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derived phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter with defined pore sizes to produce liposomes of the desired diameter.

[0194] The compounds disclosed herein can also be encapsulated in microcapsules prepared by, for example, coagulation techniques or interfacial polymerization (e.g., hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000).

[0195] Sustained-release formulations may be used. Suitable examples of sustained-release formulations include semi-permeable matrices of solid hydrophobic polymers containing the compounds disclosed herein, in the form of molded articles, such as membranes or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and 7-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as degradable lactic acid-glycolic acid copolymers used in leuprolide acetate reservoir suspensions (injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), sucrose isobutyrate acetate, and poly-D-(-)-3-hydroxybutyric acid.

[0196] The preparations used for intravenous administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filter membrane. The compounds disclosed herein are typically placed in containers with sterile dispensing ports, such as intravenous solution bags or vials with stoppers that can be punctured by a hypodermic needle.

[0197] Suitable emulsions can be prepared using commercially available fat emulsions, such as lipid emulsions containing soybean oil, lipid emulsions for intravenous administration (e.g., safflower oil, soybean oil, lecithin, and glycerol contained in water), emulsions containing soybean oil and medium-chain triglycerides, and lipid emulsions containing cottonseed oil. The active ingredient may be soluble in the premixed emulsion composition, or it may be soluble in oils (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and form an emulsion after mixing with phospholipids (e.g., lecithin, soybean phospholipids, or soybean lecithin) and water. It should be understood that other ingredients, such as glycerol or glucose, may be added to adjust the emulsion tension. Suitable emulsions will typically contain up to 20% oil, for example, 5% to 20%. Fat emulsions may contain fat droplets with a diameter of 0.1 to 1.0 micrometers (μm), particularly 0.1 to 0.5 μm, and a pH of 5.5 to 8.0.

[0198] For example, the emulsion composition may be an emulsion composition prepared by mixing the disclosed compound with a lipid emulsion containing soybean oil or its components (soybean oil, lecithin, glycerol and water).

[0199] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Compositions may be administered via oral or nasal inhalation to achieve local or systemic effects. Preferably, compositions in sterile, pharmaceutically acceptable solvents may be nebulized using a gas. Nebulized solutions may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask, diaphragm, or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered from a device that delivers the preparation in a suitable manner, preferably orally or nasally.

[0200] Pharmaceutical intermediates (DPIs) are partially processed materials that must undergo further processing steps before becoming bulk pharmaceutical products. The compounds disclosed herein can be formulated into pharmaceutical intermediate DPIs containing active ingredients in forms with higher free energy than their crystalline forms. One reason for using DPIs is to improve oral absorption properties due to their low solubility, slow dissolution, improved mass transport across the mucous layer near epithelial cells, and in some cases, limitations imposed by biological barriers such as metabolic and transport proteins. Other reasons may include improved solid-state stability and downstream manufacturability. Pharmaceutical intermediates may contain the compounds disclosed herein separated and stabilized in an amorphous state (e.g., amorphous solid dispersions (ASDs)). Many techniques for manufacturing ASDs are known in this art, producing materials suitable for integration into bulk pharmaceutical products, such as spray-dried dispersions (SDDs), melt extrusions (commonly referred to as HMEs), coprecipitates, amorphous drug nanoparticles, and nanoadsorbents. Amorphous solid dispersions may contain the compounds disclosed herein and polymeric excipients. Other excipients and the concentrations of such excipients and the compounds disclosed herein are well known in the art and described in standard textbooks. See, for example, Navnit Shah et al., "Amorphous Solid Dispersions Theory and Practice".

[0201] This disclosure further includes the use of the disclosed compounds as pharmaceuticals (such as unit-dose tablets or unit-dose capsules). This disclosure includes the use of the disclosed compounds in the manufacture of pharmaceuticals (such as unit-dose tablets or unit-dose capsules) for the treatment of one or more of the conditions previously identified in the foregoing sections discussing treatment methods. This disclosure further includes the use of the disclosed compounds as pharmaceuticals or their pharmaceutically acceptable salts, and the use of the disclosed compounds or their pharmaceutically acceptable salts in any treatment method disclosed herein.

[0202] Typically, the compounds disclosed herein are administered in amounts effective in treating the conditions described herein. The compounds disclosed herein may be administered either as the compound itself or as a pharmaceutically acceptable salt. For administration purposes, the compound itself or its pharmaceutically acceptable salt will be referred to simply as the compound disclosed herein.

[0203] The compounds disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition suitable for that route and at a dose effective for the intended treatment. The compounds disclosed herein may be administered orally, rectally, vaginally, non-intestinally, topically, intranasally, or by inhalation.

[0204] The disclosed compounds can be administered orally. Oral administration may involve swallowing, allowing the compounds to enter the gastrointestinal tract, or it may be administered buccally or sublingually, thereby allowing the compounds to enter the bloodstream directly from the oral cavity.

[0205] The compounds disclosed herein can also be administered non-enterally, such as directly into the bloodstream, muscles, or internal organs. Suitable means of administration for non-enteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous administration.

[0206] Suitable devices for non-intestinal administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0207] The disclosed compounds can be administered topically to the skin or mucous membranes, i.e., transdermal or transepidermal. The disclosed compounds can also be administered intranasally or by inhalation. The disclosed compounds can be administered rectally or vaginally. The disclosed compounds can also be administered directly to the eyes or ears.

[0208] The dosing regimens of the disclosed compounds or compositions containing such compounds are based on a variety of factors, including patient type, age, weight, sex, and medical condition; severity of condition; route of administration; and activity of the specific compound used. Therefore, dosing regimens can vary widely. The total daily dose of the disclosed compounds can be from 0.01 to 100 mg / kg (i.e., milligrams of the disclosed compound per kilogram of body weight) for the treatment of the specified conditions discussed herein. The total daily dose of the disclosed compounds can be from 0.1 to 50 mg / kg or from 0.5 to 30 mg / kg. It is not uncommon for the disclosed compounds to be administered repeatedly throughout the day (usually no more than four times). Where necessary, multiple daily doses can often be used to increase the total daily dose.

[0209] The compounds disclosed herein can inhibit the activity of STAT6 and can be used to treat, prevent, inhibit, and improve STAT6-mediated diseases, symptoms, and conditions.

[0210] The compounds disclosed herein may be used to treat or prevent at least one disease or condition associated with an inflammatory condition. These compounds include 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 sinusitis, allergic contact dermatitis, and allergic bronchopulmonary aspergillosis), alopecia (including alopecia areata), Alzheimer's disease, arteritis, asthma, atherosclerosis, autoimmune diseases (including lupus nephritis, autoimmune hepatitis, myasthenia gravis, Guillain-Barré syndrome, and Graves' disease). Diseases including: Behcet'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, diverticulitis, eosinophilic esophagitis (including pediatric eosinophilic esophagitis), ocular diseases or conditions (including ocular autoimmune diseases, keratoconjunctivitis, vernal conjunctivitis, non-infectious uveitis (e.g., uveitis associated with Behcet's disease and lens-induced uveitis), keratitis (e.g., herpetic keratitis and keratoconus), corneal leukoma, ocular pemphigoid, Mooren's ulcer, scleritis, retinitis, retinopathy, Grave's eye disease. ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), bullous keratoconjunctivitis, iridocyclitis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis and ocular neovascularization, fungal keratitis, gout, idiopathic pulmonary fibrosis (IPF), undifferentiated colitis, keloid, mastocytosis, microscopic colitis (such as collagenous colitis or lymphocytic colitis), myositis, nephritis, non-alcoholic fatty liver disease (NASH), pancreatitis, primary biliary cirrhosis, proctitis, nodular prurigo, psoriasis, psoriatic arthritis, primary biliary cirrhosis, sinusitis (including chronic sinusitis with or without nasal polyps), sarcoidosis, scleroderma, sclerosing cholangitis, Sjogren's syndrome Systemic lupus erythematosus (SLE), systemic sclerosis, thyroiditis, ulcerative colitis (UC), vitiligo, vasculitis, Vogt-Koyanagi-Harada syndrome, Wegener's granulomatosis, or hidradenitis suppurativa.A method of treating or preventing one or more symptoms associated with various diseases or conditions comprises administering to a patient a pharmaceutical composition comprising a therapeutically effective amount of the compound disclosed herein.

[0211] The compounds disclosed herein may be used to treat or prevent at least one disease or condition, including atopic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), sinusitis (e.g., chronic sinusitis with or 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 origin), atopic keratoconjunctivitis, chronic induced urticaria, or allergy (e.g., food allergy).

[0212] The compounds disclosed herein can be used to treat or prevent skin conditions such as eczema (e.g., chronic eczema and sweating disorder eczema), chronic pruritus, dermatitis (e.g., atopic dermatitis, irritant contact dermatitis, allergic contact dermatitis, occupational dermatitis, perioral dermatitis, stagnant dermatitis, nummular dermatitis, seborrheic dermatitis, xerotic dermatitis, eyelid dermatitis, diaper dermatitis, and hand dermatitis), vitiligo, alopecia areata, alopecia areata, pruritus (e.g., chronic idiopathic pruritus), nodular prurigo, psoriasis (e.g., plaque psoriasis, guttate psoriasis, reversal psoriasis, pustular psoriasis, nail psoriasis, flexor palmoplantar psoriasis, facial psoriasis, or erythroderma). Symptomatic psoriasis, scleroderma, pemphigus, dermatomyositis, neurodermatitis, skin flushing, cutaneous lupus erythematosus (e.g., acute cutaneous lupus, subacute cutaneous lupus, and chronic cutaneous lupus discoidus), keloids, sunburn, hypertrophic scars, idiopathic thrombocytopenic purpura (ITP), ichthyosis (e.g., ichthyosis vulgaris), epidermal hyperplasia, acne, lichen planus, lichen sclerosus, rosacea, bullous epidermolysis bullosa, trichiasis, keratosis, urticaria (e.g., chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria), molluscum contagiosum, Netherton's syndrome. Sweet's syndrome, pityriasis alba, vulvovaginitis, Sutton's nevus / nevi, post-inflammatory hypopigmentation, senile leukoplakia, chemical / drug-induced leukoplakia, palmoplantar pustulosis, bullous pemphigoid, nodular bullous pemphigoid, bullous pemphigoid, and hidradenitis suppurativa.

[0213] The compounds disclosed herein may be used to treat or prevent respiratory conditions such as rhinitis (e.g., allergic rhinitis and perennial rhinitis), nasal discharge, nasal congestion, nasal inflammation, asthma (e.g., chronic asthma, refractory asthma, late-onset asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), chronic and acute bronchoconstriction, chronic bronchitis, emphysema, allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, acute lung injury (ACI), adult respiratory distress syndrome (ARDS), pulmonary vascular disease (PVD), pulmonary hypertension (PAH), bronchiectasis, sinusitis, sinusitis, allergic fungal sinusitis, chronic sinusitis with nasal polyps, pulmonary sarcoma, and silicosis.

[0214] The compounds disclosed herein may be used to treat or prevent joint diseases such as arthritis (e.g., osteoarthritis, as well as psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, and gouty arthritis), spinal arthropathy (e.g., reactive arthritis (also known as Reiter's Syndrome) and axial spondylitis (including ankylosing spondylitis)), cartilage inflammation, bone degradation, and Still's disease); cardiovascular and metabolic diseases such as diabetes (type 1 and type 2), myocarditis, diabetic neuropathy, atherosclerosis, cachexia, and celiac disease; neuroinflammatory diseases such as lupus (e.g., CNS, generalized and discoid lupus), systemic lupus erythematosus (SLE), diabetic neuropathy, autoimmune encephalitis, Alzheimer's disease, Parkinson's disease, and multiple sclerosis); and cancer.

[0215] The compounds disclosed herein may be used alone or in combination with one or more other therapeutic agents. This disclosure provides any of the uses, methods, or compositions as defined herein, wherein the compounds disclosed herein or their pharmaceutically acceptable salts are used in combination with one or more other therapeutic agents discussed herein.

[0216] "Combination" refers to the administration of two or more compounds in a manner that ensures they are administered close enough in time to affect an individual's treatment. Two or more compounds may be administered simultaneously or sequentially via the same or different routes of administration, at the same or different schedules, with or without specific time constraints depending on the treatment regimen. Simultaneous administration can be achieved by mixing compounds before administration or by administering compounds at the same time but at the same or different sites of administration in separate dosage forms. Examples of "combination" include, but are not limited to, "parallel administration," "co-administration," "simultaneous administration," "sequential administration," and "administered simultaneously."

[0217] The compounds disclosed herein and one or more other therapeutic agents can be administered as a fixed or non-fixed combination of active ingredients. The term "fixed combination" means that the compounds disclosed herein, or their pharmaceutically acceptable salts, and one or more therapeutic agents are administered simultaneously to an individual in a single composition or dose. The term "non-fixed combination" means that the compounds disclosed herein, or their pharmaceutically acceptable salts, and one or more therapeutic agents are formulated into individual compositions or doses such that they can be administered simultaneously or at variable intervals at different times to an individual in need, wherein such administration provides effective levels of two or more compounds in the individual.

[0218] The compounds disclosed herein may be administered in combination with one or more pharmaceutically active agents other than those disclosed herein, such pharmaceutically active agents including pharmaceutically acceptable salts of specifically named pharmaceuticals and pharmaceutically acceptable solvates of such pharmaceuticals and salts.

[0219] This disclosure provides pharmaceutical compositions comprising the compounds disclosed herein or their pharmaceutically acceptable salts, wherein the pharmaceutical composition is administered simultaneously or in combination with pharmaceutical compositions comprising different pharmaceutically active compounds or their pharmaceutically acceptable salts at different times.

[0220] These medications and compounds may be combined with medically acceptable mediators, such as saline, Ringer's solution, dextran solution, and similar formulations. The specific dosing regimen, i.e., dosage, timing, and repetition, will depend on the individual and their medical history.

[0221] Another embodiment of this disclosure provides a kit containing a compound disclosed herein or a pharmaceutical composition containing such a compound. In addition to the compounds disclosed herein or their pharmaceutical compositions, the kit may also include diagnostic agents or therapeutic agents. The kit may also include instructions for use for the diagnostic or therapeutic treatment. The kit may include a compound or its pharmaceutical composition and a diagnostic agent. The kit may include a compound or its pharmaceutical composition and one or more therapeutic agents.

[0222] The kit may be used to perform the treatment methods described herein. The kit may contain a first dosage form containing one or more of the disclosed compounds in an amount sufficient to perform the disclosed methods. The kit may contain one or more of the disclosed compounds in an amount sufficient to perform the disclosed methods, and a container for dosing.

[0223] The compounds disclosed herein can be synthesized via synthetic routes, including those similar to those well-known in chemical techniques, particularly as described herein. Starting materials are generally available from commercial sources or can be prepared using methods familiar to those skilled in the art. Many of the compounds used herein are related to, or may be derived from, compounds that have generated one or more scientific or commercial interests. Therefore, such 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 from other commonly available substances using materials reported in the literature.

[0224] For illustrative purposes, the reaction flow described below provides a potential route for synthesizing the compounds disclosed herein and key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds of this invention. Although specific starting materials and reagents are discussed below, other starting materials and reagents can be substituted to provide a variety of derivatives or one or more of the reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified according to this disclosure using conventional chemical methods well known to those skilled in the art.

[0225] Those familiar with this technique should understand that the experimental conditions described in the following procedure are descriptions of suitable conditions for achieving the transformations shown, and that it may be necessary or desirable to change the exact conditions used to prepare the compound of formula I. It should be further understood that it may be necessary or desirable to perform the transformations in a different order than described in the procedure, or to modify one or more of the transformations, to obtain the desired compound of formula I.

[0226] When preparing compounds of Formula I, it should be noted that some methods used to prepare the compounds described herein may require protection of distal functional groups (e.g., primary amines, secondary amines, carboxyl groups, etc., in precursors of Formula I compounds). The need for such protection will vary depending on the nature of the distal functional group and the conditions of the preparation method. The need for such protection is readily determined by someone skilled in the art. The use of such protection / deprotection methods is also within the skill of this art. For a general description of protecting groups and their uses, see March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th edition.

[0227] For example, if a compound contains amine or carboxylic acid functional groups, these functional groups (if not protected) can interfere with reactions at other sites on the molecule. Therefore, such functional groups can be protected by appropriate protecting groups (PGs) that can be removed in subsequent steps. Suitable protecting groups for amines and carboxylic acids include those commonly used in peptide synthesis (such as N-tertiary butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-pyromethyleneoxycarbonyl (Fmoc) for amines and low-carbon alkyl groups, or benzyl esters for carboxylic acids), which are generally not chemically reactive under the described reaction conditions and can usually be removed without chemically altering other functional groups in the compound of formula I.

[0228] Those skilled in this art will recognize that, in some cases, compounds will be produced as non-mirror image isomers and / or mixtures of mirror image isomers; such compounds can be separated at various stages of the synthetic process using known techniques or combinations of such techniques, such as, but not limited to, crystallization, normal phase chromatography, reverse phase chromatography and palmar chromatography, to obtain the single mirror image isomer disclosed herein; see, for example, E.L. Eliel and S.H. Wilen, "Stereochemistry of Organic Compounds" (Wiley, New York, 1994).

[0229] Unless otherwise specified, the substituents used in the process are as defined above. The separation and purification of the products are carried out using standard procedures known to any chemist.

[0230] Those skilled in the art will understand that the various symbols, superscripts, and subscripts used in the processes, methods, and examples are for convenience of indicating and / or reflecting their order of introduction into the process, and are not intended to necessarily correspond to the symbols, superscripts, or subscripts in the appended claims. The process represents a method that can be used to synthesize the compounds disclosed herein. It does not in any way limit the scope of this disclosure.

[0231] [General Process] [A] Mode The general formula structure of [I] can be prepared as shown in general procedure A. The formula can be synthesized by literature methods or purchased commercially. [AA1] Amines protected by a tributoxycarbonyl (BOC) group can be treated with a standard acidic deprotecting agent, such as hydrochloric acid (HCl), in solvents such as 1,4-diethane (diethane), ethyl acetate (EtOAc), and dichloromethane (DCM) at 10°C to room temperature to obtain the amine of formula [AA1]. [AA2] Amine compounds with the deprotected group. When heated between 80 and 140 °C, standard SNAr conditions can be used, such as N,N-diisopropylethylamine (DIEA), tripotassium phosphate (K3PO4), potassium carbonate (K2CO3), or cesium fluoride (CsF), in 1-pentanol, butyronitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or acetonitrile (ACN) using the formula... [AA3] is a halogenated (e.g., RB=F or Br) aromatic compound treatment formula. The amine of [AA2] is obtained as follows: [AA4]. Mode [AA4] can also be achieved through the use of... [AA2] and [AA3] with copper iodide (I) (CuI), 1,2-dimethylethylenediamine (DMEDA) or trans-N,N'-dimethylcyclohexane-1,2-diamine or Pd catalysts such as methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (RuPhos Pd G3) with 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos), methanesulfonic acid [(di(1-adamantyl)n-butylphosphino)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A Pd G3), [dicyclohexyl(2',6'-diisopropoxy-2-biphenyl)phosphine-κP](methanesulfonate-κO)[2'-(methylamino-κN)-2-biphenyl-κC2]palladium (RuPhos Pd G4) is prepared by reacting a base such as sodium tributoxide (NaOtBu), K2CO3, tripotassium phosphate (K3PO4) or cesium carbonate (Cs2CO3) in a solvent such as dialkyl, dimethylacetamide (DMA), DMF, DMSO, 2-methyl-2-butanol (terpentanol) or toluene, and heating between 80 and 130 °C.

[0232] Mode [AA4], where R3 is a halogen (e.g., F, Br, or I) that can be converted to an amine, urea, or lactamine using the above standard SNAr or cross-coupling conditions, to obtain formula [AA4]. [AA4]. Dang style When R3 in [AA4] is a halogen (e.g., I), the halogen can react with BOC-protected hydrazine under the aforementioned cross-coupling conditions. Subsequently, the protecting group can be removed under standard acidic conditions such as HCl in a solvent such as dialkyl or DCM, and cyclized by reaction with (E)-4-(dimethylamino)but-3-en-2-one in EtOH, thus completing the reaction of the formula... R3 in [AA4] is converted to 5-methyl-1H-pyrazole. For formula [AA4], where R3 is a halogen (e.g., Br, I), which can be obtained by reacting the halogen with nickel(II) glycol dimethyl ether complex (NiCl2. glycol dimethyl ether), 5-methoxypyridine formamidine, and using an activated ester of N-hydroxyphthalimide, tetrabutylammonium iodide, pre-activated zinc (Zn) and trifluoroacetic acid (TFA), in a solvent such as DMA at room temperature to 70°C or under photo-oxidation-reduction conditions, such as hexafluorophosphate [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[2-(2-pyridyl-N)phenyl-C]iridium(III) (Ir(ppy)2(dtbbpy)PF6), nickel(II) glycol dimethyl ether complex (NiBr2.DME), 5-methoxypyridine formamidine, phthalimide and Pyridine reacts with solvents such as DMA and methyl tributyl ether (MTBE) to form carbon-carbon bonds, yielding the formula... [AA4]. Dang style When R3 in [AA4] is a halogen (e.g., Br), the halogen can react with B2Pin2, Pd(dppf)Cl2, and a base such as KOAc in a dialkyl solvent at 85°C to form boronic acid at R3. The boronic acid at R3 can be obtained by reacting with a bromine-substituted 5-membered heterocyclic ring, Pd(dppf)Cl2, and a base such as K3PO4 in a dialkyl solvent at 85°C to obtain the formula... [AA4] The 5-membered heterocyclic ring at R3. (When formula) When R3 in [AA4] is a carboxylic acid, the acid can be further converted by amide coupling with HATU and a base such as DIEA in a solvent such as DMF at 40°C to form an amide on R3. When R3 in [AA4] is tributyl acetate, it can be deprotected under standard acidic conditions such as TFA or HCl in solvents such as dialkylene, H2O, and DCM at room temperature to 40°C, and then further converted under standard amide coupling conditions to form amide at R3. When R3 in [AA4] is methyl propionate, then the formula is... [AA4] can react with 2-bromoacetonitrile in the presence of a base such as bis(trimethylsilyl)aminolithium (LiHMDS) in a solvent such as THF at -78°C. It can be further converted by reacting with sodium borohydride (NaBH4) in a solvent such as THF and H2O at 0°C to room temperature, to achieve the desired effect. A 5-membered endorphin is formed at R3 on [AA4].

[0233] Mode [AA4] esters (e.g., RA = methyl or ethyl) can undergo standard hydrolysis under standard conditions, such as with bases (e.g., lithium hydroxide monohydrate (LiOH), sodium hydroxide (NaOH), 1,5,7-triazabicyclo[4.4.0]dec-5-ene, or potassium trimethylsilane (KOTMS), in solvents such as tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), water (H2O), dialkyl or ACN. The reaction is typically carried out at 0 to 50 °C, preferably at about 23 °C (room temperature), to obtain the [AA4] ester (e.g., RA = methyl or ethyl). [AA5] carboxylic acid. Formula [I] The compound can be obtained by stirring in a standard amide coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) with 2-hydroxypyridine-N-oxide (HOPO), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide (HATU) or other common reagents, in a solvent such as ACN and H2O, DMF or DMSO, and in an organic base such as triethylamine (TEA) or DIEA, at a temperature of 0 to 70°C, preferably at about 23°C (room temperature), to induce oxidation. [AA5] carboxylic acid and formula It is obtained by the amine reaction of [AA6].

[0234] In the formula In [I], when R1 is an amine, it can be reacted with 2,2,2-trichloroethyl chloroformate in pyridine at 0°C to room temperature, followed by further conversion in THF at 40-60°C with a secondary amine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form a urea at R3. In [I], when R1 is phenyl carbamate, it can react with an amine and a base such as TEA in a solvent such as DMF at 40°C, followed by removal of the protecting group under acidic conditions using HCl in a solvent such as dialkylene and DCM at 0°C to room temperature, to form a urea at R3. In [I], when R3 is tributyl acetate, the protecting group can be removed under standard acidic conditions such as HCl in solvents such as H2O and DCM. In [I], when R1 is an amine, it can react with ethyl chloroformate in the presence of a base such as TEA or in a solvent such as DCM at 0°C to room temperature to form amide at R3.

[0235] [General Process] [B] Mode The general formula structure of [I] can be prepared as shown in general procedure B. [BB1] amines can be used in solvents such as water or DMSO under standard SNAr conditions, such as cesium fluoride (CsF) or K3PO4, using formula... [AA3] is treated with halogenated (e.g., RB=F or Cl) aromatic compounds and stirred at 80 to 140 °C to obtain the formula... [AA5]. Formula [I] The compound can be obtained by stirring in a standard amide coupling agent such as EDCI and HOPO, HATU or other common amide coupling agents in a solvent such as ACN and H2O, DMF or DMSO, along with an organic base such as TEA or DIEA, at a temperature of 0 to 70°C, preferably at room temperature, with stirring. [AA5] carboxylic acid and formula [AA6] is obtained through the amine reaction. In formula... In [I], when R6 is hydrogen, it can be oxidized in acetone with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), and subsequently further converted into a methylated product upon reaction with boron trifluoride diethyl ether (BF3OEt2) and dimethyl zinc in solvents such as toluene and THF. In [I], when R3 is tributyl acetate, the protecting group can be removed under standard acidic conditions such as HCl in solvents such as dialkyl, H2O and DCM, and then further converted under standard amide coupling conditions to form amide at R3.

[0236] [General Process] [C] Mode The general formula structure of [II] can be prepared as shown in general procedure C. The formula can be synthesized by literature methods or commercially purchased. [CC1] trifluoromethanesulfonic acid can be used at 85°C with Pd catalysts such as Pd(dppf)Cl2 and bases such as K3PO4, in solvents such as H2O and THF, using the formula... [AA3] is treated with boric acid (e.g., RB = B-(OH)2) to form an aromatic compound. [CC2]. Formula [CC2] Alkenes can be reduced by hydrogenation in EtOH using palladium / carbon (Pd / C), thereby forming the [CC2] alkene. [CC3]. Formula [CC3] esters (e.g., RA=ethyl) can be obtained by undergoing standard hydrolysis under standard conditions using a base such as LiOH in a solvent such as THF, MeOH, and H2O at 0 to 50°C, preferably at room temperature, to obtain the [CC3] ester. [CC4] carboxylic acid. Formula [II] Compounds can be used by making [CC4] carboxylic acid and formula The amine of [AA6] is obtained by stirring in a solvent such as DMSO and an organic base such as DIEA in the presence of standard acetylamine coupling agents such as EDCI and HOPO, at a temperature of 0 to 70°C.

[0237] [General Process] [D] Mode The general formula structure of [III] can be prepared as shown in general procedure D. The formula can be synthesized by literature methods or commercially purchased. [AA1] Amines protected by BOC can be treated in ACN with bromine-substituted alkylamines protected by benzooxycarbonyl (Cbz) in the presence of a base such as Cs2CO3 to obtain the formula... A mixture of N1 and N2 alkylated (e.g., RC = Cbz-protected alkylamine) compounds of [DD1]. Regiomeric isomers can be purified and separated using a silicone column to obtain the formula... [DD2] compound. Formula [DD2] The CBz protecting group can then be removed under reducing conditions such as Pd / C in a solvent such as EtOH with 50-120 psi of hydrogen (H2). The free amine on the N2 of [DD1] can react with DBU in a solvent such as dialkyl at 100°C to form a cyclization compound. [DD2] is a C6-7 heterocycle fused with ring C. (Formula) The cyclized lactamine of [DD2] can be reacted with a base such as K2CO3 or bis(trimethylsilyl)aminopotassium (KHMDS) in THF and an additional solvent such as ACN and DMF, under stirring at 80°C using the formula [DD3] is treated with halogen-substituted aromatic compounds (e.g., RD=Br) to obtain the formula... [DD4]. Formula The BOC-protected amine of [DD4] can be deprotected under acidic conditions such as HCl in solvents such as dialkyl and DCM to form the [DD4] amine. [DD5]amine. Formula The amine [DD5] can be prepared under standard SNAr conditions such as K3PO4 in a solvent such as tripentanol and H2O, under stirring at 100°C using formula... [AA3] is treated with halogen-substituted aromatic compounds (e.g., RB=F) to obtain the formula... [III]. In formula In [III], when R1 is iodine, it can be further reacted with urea in a solvent such as tripentanol at 90°C in the presence of a base such as Cs2CO3 and a palladium catalyst such as ((SP-4-3)-[[5-(diphenylphosphino)-9,9-dimethyl-9H-dibenzopiperan-4-yl]diphenylphosphino-κP](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]-palladium) XantPhos Pd G4, to achieve the desired effect. Urea is formed at R1 of [III].

[0238] To better understand the present invention, the following examples are illustrated. These examples are for illustrative purposes only and should not be construed as limiting the scope of this disclosure in any way.

[0239] [ ] [Example] [ ] The compounds and intermediates described below are named using the nomenclature guidelines provided in ChemDraw version 20.1.1.123. The nomenclature guidelines provided in ChemDraw version 20.1.1.123 are well-known to those skilled in the art and are generally believed to conform to IUPAC (International Union of Pure and Applied Chemistry) recommendations on organic chemistry nomenclature and CAS index rules. Unless otherwise stated, all reactants are commercially available without further purification or prepared using methods known in the literature.

[0240] The following describes the synthesis of various compounds of the present invention. Other compounds within the scope of the present invention can be prepared using the methods described in these examples (alone or in combination with techniques generally known in this art).

[0241] All starting materials used in these preparations and examples are commercially available or can be prepared by methods known in this art or described herein.

[0242] Commercially available solvents and reagents are typically used without further purification. Anhydrous solvents are used where appropriate, typically ACROSEAL™ products from Acros Organics, Aldrich SURE / SEAL™ products from Sigma-Aldrich, or DRISOLV™ products from EMD Chemicals. Commercially available solvents and reagents are used without further purification.

[0243] Experiments are usually conducted in an inert atmosphere (nitrogen or argon), especially when using oxygen- or moisture-sensitive reagents or intermediates.

[0244] Unless otherwise stated, chemical reactions are carried out at room temperature (approximately 23 degrees Celsius).

[0245] In some instances, palmar separation is performed to separate mirror-image or non-mirror-image isomers of certain compounds disclosed herein.

[0246] For the synthetic reference procedures in other examples or methods, the reaction conditions (reaction time and temperature) may be varied. Generally, thin-layer chromatography (TLC) or mass spectrometry (MS) is performed after the reaction, and further processing is carried out as appropriate.

[0247] Commercial benchtop photoreactors, such as the Penn OC photoreactor M2, the Acceled photoreactor M2, and the Lumidox II with a 24-well block, are used with 450 or 445 nanometer (nm) light-emitting diodes (LEDs).

[0248] Purification can vary between experiments: typically, the solvent and solvent ratio used for the dissolution / gradient are selected to provide an appropriate residence time.

[0249] Thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), and high-performance liquid chromatography (HPLC) were used to monitor the reaction progress. TLC was performed on a pre-coated silicone disk with a fluorescence indicator (254 nm excitation wavelength) and visualized under ultraviolet (UV) light.

[0250] LCMS data were acquired using an Agilent 1100 series instrument or similar equipment equipped with a Leap Technologies autosampler, Gemini C18 column, ACN / water gradient, and trifluoroacetic acid (TFA) formic acid or ammonium hydroxide (NH4OH) modifier. The column eluent was analyzed using a Waters ZQ mass spectrometer in positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used.

[0251] High-resolution mass spectrometry (HR / MS) was performed on a Sciex TripleTOF 5600+ liquid chromatography instrument equipped with a DuoSpray ionization source and an Agilent Technologies 1200 binary pump, Agilent 1200 autosampler, Agilent 1200 column compartment, and Agilent 1200 diode array detector. Instrument acquisition and data processing were performed using Sciex Analyst TF version 1.7.1.

[0252] HPLC data were acquired using Agilent 1100 series instruments and similar equipment with acetonitrile (ACN) / water (H2O) gradients and TFA, formic acid, NH4OH, or ammonium bicarbonate (NH4HCO3) modifiers, employing Gemini, Sunfire, Welch Boltimate™, Welch Xtimate, Prep PG-45 MOD10, Boston Prime, Boston Green ODS, Phenomenex Gemini NX, or XBridge C18 columns. Purification was performed by high-performance liquid chromatography (HPLC) and medium-performance liquid chromatography (MPLC) using Isco CombiFIash Companion, AnaLogix InteIIiFIash 280, Biotage SP1, or Biotage Isolera One instruments and pre-filled Isco RediSep or Biotage Snap silica cartridges and similar materials.

[0253] Palmar purification was performed using palmar supercritical fluid chromatography (SFC) with the following Berger or Thar instruments and similar equipment: DAICL CHIRALCEL OD, OJ; DAICL CHIRALPAK AD, AS, IF; Chiral Technologies OJ-H, AD-H, OD-H, IA, IB; Lux Cellulose 1; Lux Cellulose 3; Pirkle Covalent (R,R) Whelk-O1; CHIRALPAK IH; YMC-IB; and Phenomenex Lux Cellulose 1 columns; and mixtures of carbon dioxide (CO2) modified with TFA, formic acid, NH4OH, diethylamine (DEA), ammonia (NH3), or isopropylamine with methanol (MeOH), ethanol (EtOH), isopropanol, or ACN, either alone or using other materials. UV detection was used to trigger the collection of the dissolved fraction.

[0254] Supercritical fluid chromatography (SFC) and reversed-phase liquid chromatography (RPLC) were used to determine the relative purity of 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 alone or using mixtures of TFA, formic acid, NH4OH, DEA, NH3 or isopropylamine-modified CO2 with MeOH, EtOH, isopropanol or ACN.

[0255] Proton nuclear magnetic resonance (¹H NMR) spectra were recorded with reference to residual peaks from the deuterated solvent used, where δ is the chemical shift; d is a doublet; dd is a doublet of a doublet; ddd is a doublet of a doublet of a doublet; dt is a doublet of a triplet; m is a multiplet; s is a singlet; t is a triplet; q is a quartet; quin is a quintet; br s is a broad singlet; MHz is megahertz; ppm is parts per million. The proton nuclear magnetic resonance (¹H NMR) chemical shifts are given as parts per million (ppm, δ) with reference to the tetramethylsilane low-field deuterated solvent and were recorded on a 300, 400, 500, or 600 MHz Varian spectrometer.

[0256] The products are typically dried under vacuum before further reactions or submission for biotesting.

[0257] In the subsequent experimental section, the following abbreviations may be used. ACN is acetonitrile; abs in the structure is absolute and refers to stereochemically confirmed R or S; AcOH is acetic acid; APhos Pd G3 is palladium(II) methanesulfonic acid [4-(di-tertiary butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]; BBr3 is boron tribromide; B2Pin2 is bis(pinacolyl)diboron; BOC is tertiary butoxycarbonyl; Boc2O is di-tertiary butyl dicarbonate; brine is saturated sodium chloride aqueous solution; BINAP is (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; BF3OEt2 is boron trifluoride diethyl ether; ℃ is degrees Celsius; CDCl3 is deuterated chloroform; CD3OD is deuterated methanol; (CD3)2SO is deuterated dimethyl sulfoxide; cataCXium® A is di(1-adamantyl)-n-butylphosphine; cataCXium® A Pd G3 is palladium(II) methanesulfonic acid [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]; CAS is Chemical Abstracts 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 iodide(I); DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM is... Dichloromethane; DCE is 1,2-dichloroethane; DDQ is 2,3-dichloro-5,6-dicyano-p-benzoquinone; DEA is diethylamine; DIEA is N,N-diisopropylethylamine; dimethyl ether is 1,4-dimethyl ether; DMA is dimethylacetamide; DMAP is 4-(dimethylamino)pyridine; DME is dimethyl ether; DMEDA is 1,2-dimethylethylenediamine; DMF is N,N-dimethylmethamide; DMSO is dimethyl sulfoxide; EDCI is 1-(3-dimethylamine) (2-(dimethylamino)methylene)-3-ethylcarbodiimide hydrochloride; ee is an excess of mirror isomer; EtOAc 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 of hexafluorophosphate; HCl is hydrochloric acid; H2 is hydrogen; H2O is water; HOBt is 1-hydroxybenzotriazole hydrate; HOPO is 2-pyridinephenol 1 -Oxides; HPLC is high-performance liquid chromatography; HR / MS is high-resolution mass spectrometry; Hz is Hertz; Ir(ppy)2(dtbbpy)PF6 is hexafluorophosphate [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[2-(2-pyridyl-N)phenyl-C]iridium(III); KHSO4 is potassium hydrogen sulfate; KHMDS is bis(trimethylsilyl)aminopotassium; KOAc is potassium acetate; KOH is potassium hydroxide;KOTMS stands for potassium trimethylsilanolate; K2CO3 stands for potassium carbonate; kg stands for kilogram; K3PO4 stands for tripotassium phosphate; KH2PO4 stands for potassium dihydrogen phosphate; L stands for liter; LC stands for liquid chromatography; LCMS stands for liquid chromatography-mass spectrometry; LDA stands for lithium diisopropylamino; LED stands for light-emitting diode; LiOH stands for lithium hydroxide monohydrate; M stands for molar concentration; LiHMDS stands for bis(trimethylsilyl)aminolithium; MeI stands for iodomethane; MeOH stands for methanol; 4MetBuXPhos Pd G3 is methanesulfonate-based (2-di-tertiary butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); mg is milligram; MgSO4 is magnesium sulfate; MPLC is medium-performance liquid chromatography; MHz is megahertz; min is minute; mL is milliliter; mL / min is milliliters per minute; mmol is millimole; mol is mole; mM is millimole concentration; mm is millimeter; MPa is megapascal; MS is mass spectrometry; MTBE is methyl tributyl ether; m / z is mass-to-charge ratio; N is equivalent (concentration); N2 is nitrogen; NBS is N-bromobutyldiimide; NaBH4 is sodium borohydride; ND is undetermined; N-XantPhos Pd G3 is (2'-amino-2-biphenyl)(methanesulfonate-κO)palladium-4,6-bis(diphenylphosphino)-10H-phenanthracene; NH3 is ammonia; Na2CO3 is sodium carbonate; NaH is sodium hydride; NaHCO3 is sodium bicarbonate; NaI is sodium iodide; NaOCH3 is sodium methoxide; NaOH is sodium hydroxide; Na2SO4 is sodium sulfate; NaOtBu is sodium tributoxide; n-BuLi is n-butyllithium; NH4Cl is ammonium chloride; NH4HCO3 is ammonium bicarbonate; NH4OH is ammonium hydroxide; NMR is nuclear magnetic resonance; NiCl2.ethylene glycol dimethyl ether is nickel(II) glycol dimethyl ether complex; NiBr2.DME is nickel(II) glycol dimethyl ether complex; P(t-Bu)3 Pd G2 is palladium(II) chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]; Pd(dppf)Cl2 is palladium(II) dichloride (1,1'-bis(diphenylphosphino)ferrocene); Pd / C is palladium / carbon; Pd2(dba)3 is palladium(O) diphenylmethyleneacetone; PdCl2(PPh3)2 is palladium(II) dichloride (bis(triphenylphosphine)); Pd(OAc)2 is palladium(II) acetate; Pd(t-Bu3P)2 is palladium(O) diphenyl(tert-butylphosphine); PE is petroleum ether; psi is pounds per square inch; The pyridine is 1-azabicyclo[2.2.2]octane; SFC is supercritical fluid chromatography; SOCl2 is thionyl chloride; TBD is 1,5,7-triazabicyclo[4.4.0]dec-5-ene; TEA is triethylamine; tripentanol is 2-methyl-2-butanol; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin-layer chromatography; trimethylboroxacyclohexane is 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriboroxacyclohexane; µm is micrometer; µmol is micromolar; rac is racemic, referring to the compound containing This includes mixtures of compounds with R and S stereochemistry and represented in the structure as "&1"; rel is relative, referring to stereochemistry as R or S and represented in the structure as "or1", or if the compound has two opposing centers, it is represented by an asterisk in the nomenclature; RhCl(PPh3)3 is triphenylphosphine chloride rhodium(I); rpm is the number of rotations per minute; RPLC is reversed-phase liquid chromatography; Ru / Al2O3 is ruthenium / alumina; RuPhos is 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; RuPhos Pd G3 is palladium(II) of methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]; RuPhos Pd G4 is palladium(II) of [dicyclohexyl(2',6'-diisopropoxy-2-biphenyl)phosphino-κP](methanesulfonic acid-κO)[2'-(methylamino-κN)-2-biphenyl-κC 2]; RuCl(PPh3)3 Ru / SiO2 is ruthenium / silicon dioxide; wt is weight; XPhos Pd G2 is palladium(II) of chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]; XantPhos Pd G4 is (SP-4-3)-[[5-(diphenylphosphino)-9,9-dimethyl-9H-dibenzopiperan-4-yl]diphenylphosphino-κP](methanesulfonate-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]-palladium; and Zn is zinc.

[0258] [preparation] [1] 1-Cyclopropyl-4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride ( [P1]) Step 1. Preparation of 1-cyclopropyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester 3-ethyl ester ( [C1]) and 2-cyclopropyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester ( [C2]) The reaction mixture containing cyclopropylhydrazine monohydrochloride (36.3 mg, 0.334 mmol) and KOAc (36.1 mg, 0.367 mmol) in AcOH (1.0 mL) was heated at 80 °C for 10 min, and then cooled to room temperature. Tributyl 3-(2-ethoxy-2-epoxyacetyl)-4-epoxypiperidine-1-carboxylic acid (CAS: 518990-24-4; 0.100 g, 0.334 mmol) was added to the mixture. The reaction mixture became a viscous yellow oil, which was stirred at 80 °C for 1 hour and 30 min. The reaction mixture was then diluted with saturated aqueous solutions of EtOAc and NaHCO3. The organic layer was separated and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-40% EtOAc:heptane) to obtain the minor first dissolution isomer. [C2]: (11 mg, 27.2% yield) (LC / MS) m / z (M+H)+ = 336.3; followed by the major second dissolution isomer. [C1]: (18 mg, 44.5% yield) (LC / MS) m / z (M+H)+ = 336.3;1H NMR (600 MHz, CDCl3) δ 4.66- 4.54 (m, 2H), 4.36 (q, 2H), 3.71 (s, 2H), 3.40- 3.34 (m, 1H), 2.84- 2.74 (m, 2H), 1.48-1.43 (m, 9H), 1.41- 1.34 (m, 3H), 1.21- 1.18 (m, 2H), 1.07- 1.02 (m, 2H).

[0259] Step 2. Preparation of ethyl 1-cyclopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid hydrochloride ( [P1]) Will A solution of [C1] (0.200 g, 0.596 mmol) was dissolved in DCM (2.0 mL), followed by the addition of dimethyl methacrylate (0.130 g, 3.58 mmol) containing 4 M HCl. The reaction mixture was then stirred at 40 °C for 25 minutes. The reaction mixture was concentrated under vacuum to obtain a white solid. [P1] (0.168 mg, crude material). The solid was used in the next step without further purification. (LC / MS) m / z (M+H)+ = 236.2; 1H NMR (600 MHz, CD3OD) δ 4.41–4.33 (m, 4H), 3.61–3.53 (m, 3H), 3.16 (t, 2H), 1.37 (t, 3H), 1.21–1.16 (m, 2H), 1.15–1.09 (m, 2H).

[0260] [preparation] [2] 1-Isopropyl-4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride ( [P2]) Step 1. Preparation of 1-isopropyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester 3-ethyl ester ( [C3]) and 2-isopropyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester ( [C4]) Tributyl 3-(2-ethoxy-2-epoxyacetyl)-4-epoxypiperidin-1-carboxylic acid (CAS: 518990-24-4, 325 g, 1.09 mol) in EtOH (2.3 L) was added in a single addition of isopropyl hydrazine hydrochloride (120 g, 1.1 mol), followed by dropwise addition of pyridine (103 g, 1.30 mol) to the mixture over 10 minutes at 20–25 °C in an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. The reaction was carried out in two parallel batches, combined, and then concentrated under vacuum. The residue was diluted with EtOAc (5 L) and washed with brine (2 × 5 L), then dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silicone, EtOAc:PE 10–50%) to obtain [C3] and [C4]. [Will] [C3] was dissolved in PE (0.8 L) and then cooled to -20°C. The mixture was stirred for 4 hours, the resulting solid was filtered off and washed with PE (0.1 L). The filter cake was dried under high vacuum to obtain a white solid. [C3] (414 g, 55.9% yield). (LC / MS) m / z (M+H)+ = 338.1; 1H NMR (400 MHz, CDCl3) δ 4.59 (s, 2H), 4.48–4.32 (m, 3H), 3.71 (t, 2H), 2.70 (t, 2H), 1.53–1.45 (m, 15H), 1.39–1.34 (m, 3H). [C4] was dissolved in PE (50 mL) and then cooled to -20°C. The mixture was stirred for 4 hours, the resulting solid was filtered off and washed with PE (20 mL). The filter cake was dried under high vacuum to obtain a white solid. [C4] (11.7 g, 1.58% yield). (LC / MS) m / z (M+H)+ = 338.1; 1H NMR (400 MHz, CDCl3) δ 5.60–5.43 (m, 1H), 4.60 (s, 2H), 4.33 (q, 2H), 3.68 (s, 2H), 2.75 (s, 2H), 1.50–1.44 (m, 15H), 1.38 (m, 3H).

[0261] Step 2. Preparation of ethyl 1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid hydrochloride ( [P2]) At 0℃ [C3] (13.5 g, 40.0 mmol) was added in portions to a mixture in DCM (60 mL) containing 150 mL of dimethyl methacrylate (DMCO). The reaction mixture was stirred at approximately 15 °C for 16 hours and then concentrated under vacuum to obtain a white solid. [P2] (10.5 g, crude material), which was used directly in the next step without further purification. LC / MS m / z (M+H)+ = 238.1; 1H NMR (600 MHz, (CD3)2SO) δ 9.80 (s, 1H), 4.63- 4.51 (m, 1H), 4.28 (q, 2H), 4.18 (s, 2H), 3.36 (s, 2H), 3.02 (t, 2H), 1.38 (d, 6H), 1.29 (t, 3H).

[0262] [ ] [preparation] [3] 5-(tert-butoxycarbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ( [P3]) Step 1. Preparation of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ( [C5]) NaOH (0.542 g, 13.5 mmol) was added to a suspension of 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester (CAS: 518990-23-3; 2.00 g, 6.77 mmol) in MeOH (7.7 mL) and H₂O (7.7 mL). 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 with 1M HCl aqueous solution to a pH of approximately 3. The resulting mixture was filtered, and the solid was further dried under high vacuum and then lyophilized to give a white solid. [C5] (1.60 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 268.1. 1H NMR (400 MHz, (CD3)2SO) δ 13.17 (br s, 2H), 4.48 (s, 2H), 3.58 (t, 2H), 2.65 (t, 2H), 1.41 (s, 9H).

[0263] Step 2. Preparation of 5-(tert-butoxycarbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ( [P3]) At 0℃ [C5] (0.200 g, 0.748 mmol) was added to a suspension in DMF (3.5 mL) with NaH (89.8 mg, 2.24 mmol, 60%) and stirred at 0 °C for 30 min. Iodoethane (0.140 g, 0.898 mmol) in DMF (0.5 mL) was added at 0 °C, followed by stirring at 15 °C for approximately 4 h. Another portion of iodoethane (23.3 mg, 0.150 mmol) in DMF (0.2 mL) was added to the mixture and stirred at 15 °C for 16 h. The reaction solution was quenched with H₂O (10 mL) and then extracted with EtOAc (2 × 20 mL). The aqueous layer was acidified with 1 M HCl aqueous solution to approximately pH 3 and then extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over Na₂SO₄, concentrated under vacuum, and then freeze-dried to obtain a white solid. [P3] (0.173 g, 78.5% yield). (LC / MS) m / z (M+H)+ = 296.1. 1H NMR (400 MHz, (CD3)2SO) δ 12.64 (br s, 1H), 4.45 (s, 2H), 4.07 (q, 2H), 3.60 (t, 2H), 2.74- 2.65 (m, 2H), 1.41 (s, 9H), 1.31 (t, 3H).

[0264] [preparation] [3b] 1-Ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P3b)] Step 1. Preparation of 3-ethyl 1-ethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester. [(C6)] and 2-ethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester [(C7)] Pyridine (129 g, 1.63 mol) was added to a solution of 3-(2-ethoxy-2-epoxyacetyl)-4-epoxypiperidine-1-carboxylic acid tributyl ester (CAS: 518990-24-4; 97.5 g, 326 mmol) and ethylenehydrazine dihydrochloride (56.3 g, 423 mmol) in EtOH (1.6 L). The reaction mixture was stirred at room temperature for 16 hours, followed by vacuum concentration. The residue was purified by column chromatography (silicone, 0-50% THF:PE) to give the first dissolution isomer as a white solid. [C6] (58.0 g); subsequently, a second dissolution isomer in the form of a pale yellow oil was obtained. [C7] (20.6 g, 19.6% yield). [The remaining text appears to be incomplete and requires further context.] [C6] Dilute with EtOAc (200 mL), then stir at 50°C for 30 minutes and cool to 0°C, resulting in the formation of a white solid precipitate. Filter the suspension and wash the filter cake with EtOAc (3 × 10 mL). Collect the filter cake and concentrate under vacuum to obtain a white solid. [C6] (35.4 g, 33.6% yield).

[0265] [C6] [:](LC / MS) m / z (M+H)+ = 324.2; 1H NMR (400 MHz, CDCl3) δ 4.60 (s, 2H), 4.38 (q, 2H), 4.12 (q, 2H), 3.71 (t, 2H), 2.68 (t, 2H), 1.47 (s, 9H), 1.44 - 1.34 (m, 6H).

[0266] [C7] [:](LC / MS) m / z (M+H)+ = 324.3; 1H NMR (400 MHz, CDCl3) δ 4.65 - 4.50 (m, 4H), 4.34 (q, 2H), 3.73 - 3.63 (m, 2H), 2.80 - 2.67 (m, 2H), 1.48 (s, 9H), 1.43 - 1.33 (m, 6H).

[0267] Step 2. Preparation of ethyl 1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid hydrochloride [(P3b)] Towards [C6] (1.00 g, 3.09 mmol) was added to a solution of dimethyl methacrylate (1.13 g, 30.9 mmol) containing 2 M HCl in 10 mL of DCM. The reaction mixture was stirred at room temperature for 2.5 hours, followed by vacuum concentration to give a white solid. [P3b] (0.870 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 224.2. 1H NMR (400 MHz, CD3OD) δ 4.44 - 4.32 (m, 4H), 4.20 (q, 2H), 3.56 (t, 2H), 3.09 (t, 2H), 2.80 - 2.67 (m, 2H), 1.44 (t, 3H), 1.38 (t, 3H).

[0268] [preparation] [4] 1-Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride ( [P4]) Step 1. Preparation of 1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester 3-ethyl ester ( [C8]) 1,4,6,7-Tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester (CAS: 518990-23-3; 2.00 g, 6.77 mmol) was dissolved in DMF (10.0 mL), followed by the addition of K2CO3 (2.81 g, 20.3 mmol) and MeI (0.961 g, 6.77 mmol). The reaction mixture was stirred at room temperature for 3 hours and diluted with EtOAc and H2O. The organic layer was separated and then concentrated under vacuum. The residue was dissolved in DCM and then purified by column chromatography (silicone, 0-40% EtOAc:heptane) to give a clear oil. [C8] (0.825 g, 39.4% yield). (LC / MS) m / z (M+H)+ = 310.3; 1H NMR (600 MHz, CDCl3) δ 4.61 (s, 2H), 4.35 (q, 2H), 4.14 (s, 3H), 3.68 (s, 2H), 2.74 (s, 2H), 1.49 (s, 9H), 1.41- 1.37 (m, 3H).

[0269] Step 2. Preparation of ethyl 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride ( [P4]) At 0℃ [C8] (2.00 g, 6.46 mmol) was dissolved in dimethyl methacrylate (40.0 mL) containing 4 M HCl and then stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to give a yellow solid. [P4] (1.30 g, 81.9% yield). This substance was used in the next step without further purification. (LC / MS) m / z (M+H)+ = 210.3. 1H NMR (400 MHz, CDCl3) δ 10.23 (br s, 1H), 4.50 - 4.32 (m, 4H), 3.86 (s, 3H), 3.55- 3.46 (m, 2H), 3.13 (t, 2H), 1.40 (t, 3H).

[0270] [preparation] [5] 3-Cyclopropyl-5,6,7,8-Tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid ethyl ester hydrochloride ( [P5]) Step 1: Preparation of 1-ethyl 7-(tert-butyl) 3-cyclopropyl-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid ( [C9]) At room temperature under nitrogen atmosphere, K3PO4 (0.984 g, 4.63 mmol) and Pd(dppf)Cl2 (0.226 g, 0.309 mmol) were added to a solution of 1-ethyl 7-(tributyl) 7-bromo-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid (CAS: 2108354-93-2; 0.578 g, 1.54 mmol) in dimethyl ether (8.0 mL) and H2O (1.0 mL). The reaction mixture was stirred at 90 °C for 16 hours. The solution obtained by vacuum concentration was used to obtain a solid, which was then purified by column chromatography (silicone, 0-95% EtOAc:PE) to obtain a yellow gel-like substance. [C9] (0.400 g, 77.2% yield). (LC / MS) m / z (M+H)+ = 336.1. 1H NMR (400 MHz, CD3OD) δ 4.84 (s, 2H), 4.30 (q, 2H), 4.14 - 4.04 (m, 2H), 3.86 (t, 2H), 1.94- 1.86 (m, 1H), 1.53- 1.48 (m, 9H), 1.36 (t, 3H), 1.00- 0.96 (m, 4H).

[0271] Step 2. Preparation of ethyl 3-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate hydrochloride ( [P5]) Towards [C9] (0.300 g, 0.894 mmol) was added to a solution in DCM (5.0 mL) containing dimethyl alkylene (0.261 g, 7.16 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The resulting suspension was concentrated under vacuum to obtain a white solid. [P5] (0.243 g, crude material), which was used directly in the next step without further purification. ¹H NMR (400 MHz, (CD₃)₂SO) δ 10.17 (s, 1H), 4.50 (s, 2H), 4.36 (t, 2H), 4.25 (q, 2H), 3.62–3.57 (m, 2H), 2.13–2.03 (m, 1H), 1.30–1.23 (m, 3H), 1.04–0.98 (m, 2H), 0.97–0.91 (m, 2H).

[0272] [preparation] [6] rac-(R)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride ( [P6]) Step 1: Preparation of rac-(5R)-3-(2-ethoxy-2-epoxyacetyl)-5-methyl-4-epoxypiperidine-1-carboxylic acid tributyl ester ( [C10]) A solution of diisopropylamine (4.2 g, 41 mmol) in THF (19.0 mL) was cooled to -78 °C, followed by the addition of hexane (2.5 g, 39 mmol) containing 2.5 M n-BuLi. After the addition, the reaction mixture was heated to 0 °C and stirred for 15 min. The reaction mixture was then cooled to -78 °C, and a solution of tributyl rac-(R)-3-methyl-4-sideoxypiperidin-1-carboxylic acid (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 approximately 1 hour and 30 min, followed by the addition of diethyl oxalate (4.8 g, 33 mmol) to the reaction solution. The resulting mixture was warmed to room temperature and then stirred for 2 hours. The mixture was neutralized with 1N HCl (80 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (400 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-10% EtOAc:PE) to obtain a yellow oil. [C10] (4.8 g, 47% yield). (LC / MS) m / z (M+H)+ = 314.4. 1H NMR (400 MHz, CDCl3) δ 4.51 - 4.30 (m, 3H), 3.91 - 3.65 (m, 1H), 3.34 - 3.12 (m, 1H), 2.76 - 2.60 (m, 1H), 1.51 - 1.44 (m, 9H), 1.41 - 1.34 (m, 3H), 1.28 - 1.20 (m, 3H).

[0273] Step 2: Preparation of 3-ethyl rac-(R)-7-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester ( [C11]) Towards [C10] (3.55 g, 11.3 mmol) was added to a solution of AcOH (14.2 mL) with hydrazine hydrate (2.09 g, 65 wt%, 27.2 mmol). During the addition, the reaction mixture was exothermic to 65 °C. The reaction mixture was stirred for 1 hour, followed by vacuum concentration. The residue was diluted with H2O, then with a saturated aqueous solution of NaHCO3 (200 mL). The mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under vacuum, and further dried under high vacuum to give a pale yellow solid. [C11] (3.45 g, crude material), which was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 310.40.

[0274] Step 3: Preparation of rac-(R)-1,7-dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester 3-ethyl ester ( [C12]) and rac-(R)-2,7-dimethyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester ( [C13]) Towards [C11] (3.45 g, 11.2 mmol) was added to a solution of Cs₂CO₃ (3.65 g, 11.2 mmol) in DMF (28.6 mL), followed by the addition of 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 EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous solution of NH₄Cl (2 × 100 mL) and H₂O (2 × 100 mL). The organic layers were dried over Na₂SO₄, filtered, and then concentrated under vacuum. The residue was purified by column chromatography (silicone, 10-100% EtOAc:heptane) to obtain [C13] (2.12 g, 58.9% yield) and [C12] (0.999 g, 27.7% yield).

[0275] [C13]:(LC / MS) m / z (M+H)+ = 324.1. 1H NMR (400 MHz, CDCl3) δ 4.74 - 4.41 (m, 2H), 4.38 - 4.27 (m, 2H), 4.17 - 4.10 (m, 3H), 3.98 - 3.65 (m, 1H), 3.36 - 2.88 (m, 2H), 1.48 (s, 9H), 1.38 (t, 3H), 1.26 (d, 3H).

[0276] [C12]: (LC / MS) m / z (M+H)+ = 324.1. 1H NMR (400 MHz, CDCl3) δ 5.18 - 4.87 (m, 1H), 4.43 - 4.30 (m, 2H), 4.27 - 3.99 (m, 2H), 3.85 (s, 3H), 3.23 - 2.87 (m, 2H), 1.51 - 1.43 (m, 9H), 1.41 - 1.33 (m, 3H), 1.24 (d, 3H).

[0277] Step 4: Preparation of rac-(R)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride ( [P6]) At room temperature [C12] (0.536 g, 1.66 mmol) was added to a solution of EtOAc (5.0 mL) containing 1 M HCl in DCM (9.7 mL). The reaction mixture was stirred at room temperature for 16 hours. Another portion of EtOAc (5.0 mL) containing 1 M HCl was added at room temperature, followed by stirring for 1 hour. The reaction mixture was then concentrated under vacuum to obtain a grayish-white solid. [P6] (0.426 g, 99.1% yield). This substance was used in the next step without further purification. (LC / MS) m / z (M+H)+ = 224.2. 1H NMR (400 MHz, CDCl3) δ 10.58 - 10.31 (m, 1H), 10.18 - 9.87 (m, 1H), 4.58 - 4.49 (m, 1H), 4.46 - 4.32 (m, 3H), 3.92 (s, 3H), 3.51 - 3.25 (m, 3H), 1.57 - 1.53 (m, 3H), 1.40 (t, 3H).

[0278] [ ] [preparation] [7] rac-(R)-3,5-dimethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid methyl ester hydrochloride ( [P7]) Step 1. Preparation of methyl 5-methylimidazo[1,5-a]pyridine-1-carboxylate ( [C14]) and ethyl 5-methylimidazo[1,5-a]pyridine-1-carboxylate [(C14a)] Cs₂CO₃ (57.0 g, 175 mmol) and ethyl 2-isocyanate (CAS: 2999-46-4, 26.6 g, 233 mmol) were added to a mixture of 2-chloro-6-methylpyridine (CAS: 38557-71-0, 15.0 g, 117 mmol) in DMF (150.0 mL). 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 vacuum. The brown residue was purified by column chromatography (silicone, 0-100% EtOAC:PE, followed by 2% MeOH:EtOAc). Transesterification occurred during the treatment and purification to produce a light brown solid. [C14] (9.50 g, 42.6% yield) (LC / MS) m / z (M+H)+ = 192.1 and (2:1, A mixture of [C14a:C14] (1.1 g, 4.59% yield) (LC / MS) m / z (M+H)+ = 206.1. [C14] is used for the next step.

[0279] [C14]:1H NMR (400 MHz, (CD3)2SO) δ 9.32 (s, 1H), 8.68 (s, 1H), 7.74 (s, 1H), 3.90 (s, 3H), 2.63 (s, 3H).

[0280] Step 2. Preparation of methyl rac-(R)-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate ( [C15]) The reaction is carried out via flow chemistry. [C14] (2.90 g, 15.2 mmol) was suspended in MeOH (50.0 mL), THF (50.0 mL), and AcOH (0.6 mL), and then heated to 50 °C to dissolve into a solution. The solution was pumped at a flow rate of 0.3 mL / min and the H2 flow rate was 30 mL / min. The solution was passed through a fixed bed (6.350 (1 / 4'') mm) packed with 5.0 mL of granular catalyst 10% Ru / SiO2 (15.3 g, 1.52 mmol) and hydrogenated at 80 °C for 3.3 min under a 2.5 MPa H2 flow. The pale yellow reactant was concentrated under vacuum and then dried under high vacuum to give a light brown oily product. [C15] (2.96 g, crude material). This material was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (s, ¹H), 4.43 (d, ¹H), 4.27 - 4.15 (m, 2H), 3.87 (s, 3H), 3.32 (dd, ¹H), 2.84 (dd, 1H), 2.68 (s, 1H), 1.53 (d, 3H).

[0281] Step 3. Preparation of 1-methyl rac-(R)-5-methyl-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid 7-(tert-butyl) ester ( [C16]) At room temperature [C15] (2.96 g, 15.2 mmol) was added to a solution of Boc2O (4.97 g, 22.8 mmol) and K2CO3 (6.29 g, 45.5 mmol) in ACN (60.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The light brown reaction mixture was filtered and then concentrated under vacuum. The brown residue was purified by column chromatography (silicone; 0-100% EtOAc:PE) to give a grayish-white solid. [C16] (3.02 g, 67.5% yield). (LC / MS) m / z (M+H)+ = 296.1. 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 5.01 - 4.77 (m, 2H), 4.33 - 4.21 (m, 1H), 3.89 (s, 3H), 3.55 - 3.34 (m, 2H), 1.53 - 1.49 (m, 12H).

[0282] Step 4. Preparation of 1-methyl rac-(R)-3-bromo-5-methyl-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid 7-(tert-butyl) ester ( [C17]) At 15℃ [C16] (3.02 g, 10.2 mmol) was added to a solution of NBS (2.73 g, 15.4 mmol) in 50.0 mL of ACN. The reaction mixture was stirred at room temperature for 16 hours. The light brown reaction mixture was concentrated under vacuum. The brown residue was purified by column chromatography (silicone, 0-100% EtOAc:PE) to give an impure light brown solid. [C17]. The solid was ground with EtOAc:PE (1:5). The solid was filtered and then washed with EtOAc:PE (5:1) to obtain a white solid. [C17] (1.32 g, 34.4% yield). (LC / MS) m / z (M+2H)+ = 376.0. 1H NMR (400 MHz, CDCl3) δ 5.62 - 5.23 (m, 1H), 4.54 - 4.22 (m, 3H), 3.93 - 3.86 (m, 3H), 3.48 - 3.16 (m, 1H), 1.51 (s, 9H), 1.43 (d, 3H).

[0283] Step 5. Preparation of 1-methyl rac-(R)-3,5-dimethyl-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid 7-(tert-butyl) ester ( [C18]) At 15°C under nitrogen atmosphere [C17] (1.30 g, 3.47 mmol) and methylboric acid (0.624 g, 10.4 mmol) were added to a solution of dimethyl methacrylate (28.0 mL) and H₂O (7.0 mL), followed by the addition of K₃PO₄ (2.21 g, 10.4 mmol), and then Pd(dppf)Cl₂ (0.519 g, 0.695 mmol). The reaction mixture was heated to 90 °C for 16 hours. The brown reaction mixture was extracted with EtOAc (30 mL). The organic phase was dried over Na₂SO₄ and concentrated under vacuum. The brown residue was purified by column chromatography (silicone, 0-100% EtOAc:PE, followed by 2% MeOH:EtOAc), and then dried under high vacuum to give a light brown solid. [C18] (0.460 g, 42.8%). (LC / MS) m / z (M+H)+ = 310.2. 1H NMR (400 MHz, CDCl3) δ 5.51 - 5.15 (m, 1H), 4.52 - 4.14 (m, 3H), 3.87 (s, 3H), 3.32 - 3.10 (m, 1H), 2.39 (s, 3H), 1.50 (s, 9H), 1.36 (d, 3H).

[0284] Step 6. Preparation of rac-(R)-3,5-dimethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid methyl ester hydrochloride ( [P7]) At room temperature [C18] (140 mg, 0.452 mmol) was added to a solution of dimethyl methacrylate (DCM) in 4.0 mL of 4.0 mL. The reaction mixture was heated to 40 °C and stirred for 2 to 5 hours. The light brown reaction mixture was concentrated under vacuum and further dried under high vacuum to give a light brown solid. [P7] (0.111 g, crude material). The solid was used in the next step without further purification.

[0285] [preparation] [8] (S)-5-(tributoxycarbonyl)-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid [(P8)] [ ] [ ] Step 1. Preparation of rac-(5S)-3-(2-ethoxy-2-epoxyacetyl)-5-methyl-4-epoxypiperidine-1-carboxylic acid tributyl ester [(C19)] [ ] Under nitrogen atmosphere at -65°C, LDA (44.4 g, 0.414 mol, 207 mL) was added to THF (350 mL), followed by dropwise addition of (S)-3-methyl-4-t-oxypiperidine-1-carboxylic acid tributyl ester (CAS: 2092486-33-2; 88.4 g, 0.414 mol) to the THF (350 mL) solution over 1 hour to maintain the internal temperature below -65°C. The reaction mixture was stirred at -65°C for 1 hour, followed by dropwise addition of diethyl oxalate (CAS: 95-92-1; 60.6 g, 0.414 mol) to the THF (350 mL) solution at -65°C. After addition, the reaction mixture was stirred at -65°C for 1 hour, then warmed to -20°C and stirred for 40 minutes. The reaction mixture was quenched with 1M KHSO4 aqueous solution (1415 mL) at 0°C under nitrogen atmosphere, resulting in the formation of a white precipitate. The suspension was filtered, and the filtrate was subsequently extracted with EtOAc (3 × 800 mL). The combined organic layers were washed with brine (800 mL), dried over Na2SO4, filtered, and then concentrated under vacuum to give a yellow oily product. [C19] (129 g, crude material). This oily substance was used directly in the next step without further purification. (LCMS) m / z (M-tert-butyl)+ = 257.9. 1H NMR (400 MHz, (CD3)2SO) δ 12.21 (br s, 1H), 4.47 - 4.17 (m, 3H), 4.06 - 3.47 (m, 2H), 3.29 - 3.17 (m, 1H), 2.59 - 2.53 (m, 1H), 1.45 - 1.37 (m, 9H), 1.28 - 1.21 (m, 3H), 1.18 - 0.95 (m, 3H).

[0286] Step 2. Preparation of concentrated (S)-7-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester 3-ethyl ester [(C20)] [ ] At 0℃, towards [C19] (139 g, 0.443 mol) was added to a suspension in AcOH (552 mL) with hydrazine monohydrate (62.7 g, 1.06 mol), which caused the internal temperature to rise to approximately 30 °C. The reaction mixture was stirred at room temperature under nitrogen for 1 hour, followed by dilution with H2O (500 mL) and saturated NaHCO3 (1000 mL). The diluted suspension was extracted with EtOAc (2 × 800 mL). The combined organic layers were dried over Na2SO4, filtered, and then concentrated under vacuum to obtain a yellow gel. The gel was purified by column chromatography (silicone, (1:1) EtOAc:PE) to obtain a concentrated S-mirror isomer in the form of a yellow gel. [C20] (123 g, 89.7% yield). (LCMS) m / z (M+H)+ = 310.0. 1H NMR (400 MHz, (CD3)2SO) δ 13.71 - 13.28 (m, 1H), 4.63 - 4.18 (m, 4H), 3.86 - 3.59 (m, 1H), 3.12 - 2.80 (m, 2H), 1.40 - 1.38 (m, 9H), 1.30 - 1.24 (m, 3H), 1.17 - 1.13 (m, 3H). The purity of the ligand was determined using the SFC method on a Chiralpak AD-3 100 mm × 4.6 mm × 3 µm column; mobile phase A: CO2 / mobile phase B: EtOH with 0.2% NH3; gradient: 5-40% mobile phase B for 3 minutes, followed by a 1-minute hold at 5% mobile phase B; back pressure: 1500 psi; flow rate: 2.8 mL / min; column temperature: 35 °C. [C20]: Main peak ((SFC-MS) m / z (M-tert-butyl)+ = 254.04, residence time: 2.218 min, 94% ee).

[0287] Step 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)] [ ] Towards [C20] (124 g, 0.400 mol) was dissolved in MeOH (452 ​​mL) and H2O (452 ​​mL) and then NaOH (32.0 g, 0.800 mol) was added, followed by stirring at room temperature for 24 hours. The reaction mixture was diluted with H2O (200 mL) and then cooled to 0 °C. The diluted reaction mixture was then acidified to pH ~3 with 1 M HCl aqueous solution. The acidic reaction mixture was filtered, and the filter cake was collected and lyophilized to give a concentrated S-mirror isomer as a white solid. [P8a] (88.6 g, crude material). The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+ = 282.0. 1H NMR (400 MHz, (CD3)2SO) δ 13.22 (br s, 1H), 4.66 - 4.34 (m, 2H), 3.86 - 3.60 (m, 1H), 3.12 - 2.82 (m, 2H), 1.41 (s, 9H), 1.17 (d, 3H). The purity of the ligand was determined using the SFC method on a Chiralpak IG-3 100 mm × 4.6 mm × 3 µm column; mobile phase A: CO2 / mobile phase B: 50% MeOH with 0.2% NH3; back pressure: 1500 psi; flow rate: 2.8 mL / min; column temperature: 35 °C. [P8a]: Main peak ((SFC-MS) m / z (M-tertiary butyl)+ = 226.03, residence time: 0.784 min, 96% ee)

[0288] Step 4. Preparation of (S)-5-(tert-butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid(+)-bis[(R)-1-phenylethyl]amine salt [(C21)] The reaction was carried out in six batches in parallel, and then combined. The mixture was then reacted at room temperature. [P8a] (0.180 kg, 0.640 mol) was added in a single batch to a mixture of EtOH (3.4 L) containing (+)-bis[(R)-1-phenylethyl]amine (CAS: 23294-41-9; 144 g, 0.640 mol) 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, followed by stirring at room temperature for 20 hours. The white suspension of the first batch was filtered, and the filter cake was then washed with EtOH (3 × 300 mL).

[0289] Collect the filter cake from the first batch, and then mix it with the cake from the first batch. Five other batches of filter cakes from the same reaction of [P8a] (0.180 kg, 0.640 mol) were combined. The combined filter cakes were dried in an oven at 50°C for 18 hours to obtain a white solid. [C21] (1.42 kg, crude material). The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+ = 282.1. 1H NMR (400 MHz, CD3OD) δ 7.46 - 7.36 (m, 6H), 7.29 - 7.23 (m, 4H), 4.76 - 4.53 (m, 2H), 3.95 - 3.86 (m, 2H), 3.83 - 3.70 (m, 1H), 3.25 - 3.18 (m, 1H), 2.99 - 2.89 (m, 1H), 1.52 (dd, 6H), 1.48 (s, 9H), 1.25 (d, 3H). The purity of the piezoresistive material was determined using the SFC method on a Chiralpak IG 50 mm × 4.6 mm × 3 µm column; mobile phase A: CO2 / mobile phase B: MeOH with 0.05% DEA; gradient: 20-40% mobile phase B for 1.5 min, followed by 40% mobile phase B for 1.0 min, then 20% mobile phase B for 0.5 min; flow rate: 4.0 mL / min; back pressure: 1500 psi; column temperature: 35 °C. [C21]: Peak 1 (residence time: 1.019 min, 100% ee).

[0290] Step 5. Preparation of (S)-5-(tert-butoxycarbonyl)-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid [(P8)] [ ] Towards [C21] (48.2 g, 95.1 mmol) was added to a suspension in H2O (482 mL) with 1 M HCl aqueous solution (99 mL) to pH ~1. The reaction mixture was stirred at room temperature for 1 hour, followed by filtration. The filter cake was collected and then lyophilized to give a white solid. [P8] (24.3 g, crude material). The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+ = 282.0. 1H NMR (400 MHz, (CD3)2SO) δ 13.15 (br s, 1H), 4.63 - 4.47 (m, 1H), 4.44 - 4.33 (m, 1H), 3.84 - 3.61 (m, 1H), 3.19 - 3.00 (m, 1H), 2.94 - 2.83 (m, 1H), 1.41 (s, 9H), 1.17 (d, 3H). The purity of the ligand was determined using the SFC method on a Chiralpak IG-3 100 mm × 4.6 mm × 3 µm column; mobile phase A: 50% CO2 / mobile phase B: 50% MeOH with 0.2% NH3; back pressure: 1500 psi; flow rate: 2.8 mL / min; column temperature: 35 °C. [P8]: Peak 1 ((SFC-MS) m / z (M-tert-butyl)+ = 226.00, residence time: 0.757 min, 99% ee). [α]28 D=+11.351 (c= 1.5 (g / L in MeOH).

[0291] [preparation] [9] (S)-1-Isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(P9)] Step 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)] [ ] At 0°C under nitrogen atmosphere, to [P8] 1M LiHMDS (132 mL) was added to a solution of [P8] (12.4 g, 44.1 mmol) in DMF (220 mL). The reaction mixture was warmed to room temperature and stirred for 2 hours, then cooled to 0°C. 2-Iodopropane (11.2 g, 66.1 mmol) was added to the cooled reaction mixture, and the suspension was warmed to room temperature and stirred for 48 hours. The reaction mixture was cooled to 0°C and another portion of 2-iodopropane (1.12 g, 6.61 mmol) was added. The suspension was warmed to room temperature and stirred for 48 hours. The reaction mixture was cooled to 0°C and then quenched with H2O (500 mL). The aqueous phase was washed with EtOAc (2 × 200 mL), and the combined organic layers were discarded. The aqueous layer was acidified with 1M HCl aqueous solution to approximately pH 3, and then extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over Na₂SO₄, and concentrated under vacuum to obtain a yellow solid. [C22] (13.8 g, 96.8% yield). (LCMS) m / z (M+H)+ = 324.0. 1H NMR (400 MHz, (CD3)2SO) δ 12.60 (br s, 1H), 4.99 - 4.73 (m, 1H), 4.57 - 4.41 (m, 1H), 4.19 - 3.86 (m, 2H), 3.17 - 3.00 (m, 2H), 1.42 - 1.36 (m, 15H), 1.17 - 1.08 (m, 3H). The purity of the symmetric phase was determined using the SFC method on a (S,S) Whelk-01 150 mm × 4.6 mm × 3.5 µm column; mobile phase A: CO2 / mobile phase B: MeOH (0.2% isopropylamine); gradient: 10-50% mobile phase B over 6.00 min, followed by a hold at 10% mobile phase B for 2.00 min; back pressure: 2000 psi; flow rate: 1.5 mL / min; column temperature: 35 °C. [C22]: Peak 1 (retention time: 2.352 min, 100% ee). [α]34 D=-100.10 (c= 5.4 (g / L) in ACN).

[0292] Step 2. Preparation of (S)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate salt [(P9)] [ ] Towards [C22] (12.7 g, 39.3 mmol) was added to a solution of dimethyl methacrylate (500 mL) containing 2 M HCl in DCM (40 mL). The reaction mixture was stirred at room temperature for 5 hours, followed by vacuum concentration to give a white solid. [P9] (9.40 g, crude material). The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+ = 224.2. 1H NMR (400 MHz, CD3OD) δ 4.68 - 4.58 (m, 1H), 4.45 (d, 1H), 4.31 (d, 1H), 3.62 - 3.38 (m, 3H), 1.54 (d, 3H), 1.48 (d, 3H), 1.44 (d, 3H). The purity of the piezoresistive material was determined using the SFC method on a Chiralcel OX-3 100 mm × 4.6 mm × 3 µm column; mobile phase A: CO2 / mobile phase B: MeOH containing 0.05% DEA; gradient: 5-40% mobile phase B over 3.0 min, followed by a hold at 40% mobile phase B for 0.9 min, and then a hold at 5% mobile phase B for 0.1 min; back pressure: 100 bar; flow rate: 2.8 mL / min; column temperature: 40 °C. [P9]: Peak 1 (retention time: 3.037 min, 100% ee). [α]33 D=-7.212 (c= 1.5 (g / L) in MeOH).

[0293] [ ] [preparation]

[10] (S)-1-Ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(P10)] Step 1. Preparation of (S)-5-(tert-butoxycarbonyl)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid [(C23)] At 0°C under nitrogen atmosphere, to [P8] 10.0 g (35.5 mmol) of NaH (4.27 g, 107 mmol) was added to a solution of DMF (190 mL). The reaction mixture was stirred at 0 °C for 30 min, followed by the addition of iodoethane (6.65 g, 42.7 mmol) to a solution of DMF (10 mL). The suspension was warmed to room temperature and stirred for 3 h, then quenched with H2O (150 mL). The aqueous phase was extracted with EtOAc (2 × 150 mL), and the combined organic layers were discarded. The aqueous phase was acidified to approximately pH 3 with 1 M HCl aqueous solution, and then extracted again with EtOAc (150 mL × 3). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, and concentrated under vacuum to give a yellow solid. The solid was suspended in a (1:10) EtOAc:PE (25 mL) mixture and stirred at room temperature for 30 min. The suspension was filtered and the filter cake was collected to obtain a white solid. [C23] (8.75 g, crude material). The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+ = 310.0. 1H NMR (400 MHz, (CD3)2SO) δ 12.65 (br s, 1H), 4.85 (dd, 1H), 4.21 - 3.84 (m, 4H), 3.22 - 2.98 (m, 2H), 1.41 (br s, 9H), 1.35 (t, 3H), 1.16 - 1.08 (m, 3H). The palmar purity was determined using a palmar purity HPLC method on a Chiralcel OD-RH 150 mm × 4.6 mm × 5 µm column; mobile phase A: H₂O (1.5 mL TFA) / mobile phase B: ACN (1.5 mL TFA); gradient: 10-80% mobile phase B for 8 min, followed by 10% mobile phase B for 1 min, then held at 10% mobile phase B for 6 min; flow rate: 0.8 mL / min; column temperature: 30 °C. [C23]: Peak 1 (retention time: 9.514 min, 100% ee). [α]34 D=-95.69 (c= 0.4 (g / L) in ACN).

[0294] Step 2. Preparation of (S)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate salt [(P10)] At 0℃, towards [C23] (8.00 g, 25.9 mmol) was mixed with 160 mL of dimethyl methacrylate containing 2 M HCl. The reaction mixture was stirred at room temperature for 4 hours, followed by vacuum concentration to obtain a yellow solid. The solid was dissolved in 40 mL of dimethyl methacrylate containing 2 M HCl and stirred at room temperature for 2 hours, followed by vacuum concentration to obtain a yellow solid. [P10] (7.10 g, crude material). The solid was used directly in the next step without further purification. (LCMS) m / z (M+H)+ = 210.2. 1H NMR (400 MHz, (CD3)2SO) δ 12.97 (br s, 1H), 10.05 (s, 1H), 9.49 (s, 1H), 4.23 - 4.03 (m, 4H), 3.41 - 3.30 (m, 2H), 3.26 - 3.18 (m, 1H), 1.39 - 1.32 (m, 6H). The isocratic purity was determined using the SFC method on a Chiralcel OX-3 100 mm × 4.6 mm, 3 µm column; mobile phase A: CO2 / mobile phase B: MeOH with 0.05% DEA; isocratic purity: 40% mobile phase B; back pressure: 100 bar; flow rate: 2.8 mL / min; column temperature: 40 °C. [P10]: Peak 1 (retention time: 1.631 min, 100% ee). [α]33 D=-1.584 (c= 1.5 (g / L) in MeOH).

[0295] [preparation]

[11] 3-(4-(aminomethyl)phenyl)-1,1-dimethylurea hydrochloride [(P11)] Step 1. Preparation of tert-butyl (4-(3,3-dimethylureo)benzyl)aminoformate [(C24)] [ ] Dimethylaminomethylchlorodimethylamine (14.5 g, 135 mmol) was added dropwise to a solution of tributyl (4-aminobenzyl)aminocarbamate (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) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 50 °C for 16 hours, then diluted with MeOH (150 mL) and concentrated under vacuum to obtain a residue. The residue was suspended in H2O (120 mL) and then rapidly stirred at room temperature for 1 hour. The suspension was filtered, and the filter cake was collected and milled at room temperature with MeOH:EtOAc:MTBE (5 mL:25 mL:250 mL) for 1 hour. The suspension was filtered, and the filter cake was collected and then concentrated under vacuum to obtain a white solid. [C24] (14.6 g, 73.8% yield). (LC / MS) m / z (M+H)+ = 294.1. 1H NMR (400 MHz, (CD3)2SO) δ 8.21 (s, 1H), 7.37 (d, 2H), 7.30 (t, 1H), 7.08 (d, 2H), 4.03 (d, 2H), 2.91 (s, 6H), 1.39 (s, 9H)

[0296] Step 2. Preparation of 3-(4-(aminomethyl)phenyl)-1,1-dimethylurea hydrochloride [(P11)] At 0℃, towards [C24] (23 g, 71 mmol) was added dropwise to a stirred suspension in DCM (130 mL) containing 2 M HCl (270 mL). The reaction mixture was stirred at room temperature for 3 hours, followed by vacuum concentration to obtain a yellow solid. [P11] (15 g, 83.4%). The solid was used directly in the next step without further purification. (LC / MS) m / z (2M+H)+ = 387.1. 1H NMR (400 MHz, (CD3)2SO) δ 8.40 (s, 1H), 8.25 (br s, 2H), 7.53 - 7.47 (m, 2H), 7.35 - 7.29 (m, 2H), 3.91 (q, 2H), 2.92 (s, 6H).

[0297] [preparation]

[12] N-(4-(aminomethyl)phenyl)-4-methylpiperazine-1-methylaminoaminohydrochloride [(P12)] Step 1. Preparation of tributyl (4-(4-methylpiperazine-1-methamido)benzyl)aminoformate [(C25)] Add 1-methylpiperazine (CAS: 109-01-3; 2.8 g, 28 mmol) to a solution of (4-(((tributoxycarbonyl)amino)methyl)phenyl)aminocarbamate (CAS: 1632297-04-2; 8.0 g, 23 mmol) in dimethyl benzoate (120 mL). Stir the reaction mixture overnight at 90 °C. Dilute the suspension with EtOAc (100 mL) and wash with 1M NaOH (2 × 50 mL), followed by washing with brine (50 mL). Dry the organic layer with Na2SO4 and concentrate under vacuum. Grind the residue with PE (2 × 50 mL) for 20 minutes, then filter the suspension. Collect the filter cake to obtain a brown solid. [C25] (7.7 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 349.2. 1H NMR (400 MHz, (CD3)2SO) δ 8.44 (s, 1H), 7.35 (d, 2H), 7.28 (t, 1H), 7.07 (d, 2H), 4.05 - 3.95 (m, 2H), 3.40 (t, 4H), 2.29 (t, 4H), 2.18 (s, 3H), 1.40 - 1.32 (m, 9H).

[0298] Step 2. Preparation of N-(4-(aminomethyl)phenyl)-4-methylpiperazine-1-methylamine hydrochloride [(P12)] [ ] Towards [C25] (7.7 g, 22 mmol) was added to a stirred solution in DCM (20 mL) containing dialkylene (0.050 g, 1.4 mmol) and HCl. The reaction mixture was stirred at 0 °C for 4 hours, then concentrated under vacuum and freeze-dried to obtain a white solid. [P12] (6.9 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 249.1. 1H NMR (400 MHz, (CD3)2SO) δ 11.27 (br s, 1H), 9.08 (s, 1H), 8.36 (br s, 3H), 7.53 - 7.47 (m, 2H), 7.34 - 7.29 (m, 2H), 4.25 (d, 2H), 3.87 (q, 2H), 3.31 - 3.18 (m, 2H), 3.04 - 2.89 (m, 2H), 2.72 (s, 3H).

[0299] [preparation]

[13] (S)-1-Isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P13)] Step 1. Preparation of (S)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P13)] At 0℃ [C22] (0.500 g, 1.55 mmol) was added dropwise to a stirred solution of EtOH (3 mL) with SOCl2 (1.29 g, 10.8 mmol). The reaction mixture was stirred at room temperature for 66 hours, followed by vacuum concentration to obtain a pale yellow solid. [P13] (0.426 g, 95.7% yield). (LC / MS) m / z (M+H)+ = 252.2.

[0300] [preparation]

[14] 1-(1-Methylcyclopropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester [(P14)] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 1-(1-methylcyclopropyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(C26)] [ ] according to [preparation] [2] [step] [1] Using the same procedure, terbutyl 3-(2-ethoxy-2-ethoxyacetyl)-4-ethoxypiperidin-1-carboxylic acid (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) were used. The residue was purified by column chromatography (silicone, 0-30% EtOAc:PE) to obtain a light brown oil. [C26] (0.233 g, 34.6% yield). (LC / MS) m / z (M+H)+ = 350.1. 1H NMR (400 MHz, CDCl3) δ 4.58 (s, 2H), 4.38 (q, 2H), 3.74 - 3.66 (m, 2H), 2.83 - 2.74 (m, 2H), 1.52 (s, 3H), 1.48 (s, 9H), 1.37 (t, 3H), 1.28 - 1.23 (m, 2H), 0.97 - 0.91 (m, 2H).

[0301] Step 2. Preparation of ethyl 1-(1-methylcyclopropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(P14)] [ ] according to [preparation] [5] [step] [2] The same procedure, using [C26] (0.233 g, 0.667 mmol) yielded a pale yellow solid. [P14] (0.191 g, crude material), which was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 250.1. 1H NMR (400 MHz, CD3OD) δ 4.39 - 4.33 (m, 2H), 3.66 (s, 2H), 3.56 (t, 2H), 3.19 (t, 2H), 1.55 (s, 3H), 1.38 (t, 3H), 1.31 - 1.26 (m, 2H), 1.09 - 1.04 (m, 2H).

[0302] [preparation]

[15] 4,5,6,7-Tetrahydrothiopheno[3,2-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P15)] Step 1. Preparation of ethyl 4,5,6,7-tetrahydrothiopheno[3,2-c]pyridine-3-carboxylate hydrochloride [(P15)] The same reaction was carried out in two batches and then combined. The first batch was formed by adding 0.234 g (6.42 mmol) of dialkylene containing HCl to 6,7-dihydrothieno[3,2-c]pyridine-3,5(4H)-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester (CAS: 1363381-39-8; 50.0 mg, 0.161 mmol). The first batch solution was stirred at room temperature for 2 hours, followed by vacuum concentration to give a white solid.

[0303] A second batch of the same reaction was carried out using 3-ethyl 5-(tributyl) 6,7-dihydrothiopheno[3,2-c]pyridine-3,5(4H)-dicarboxylic acid ester (CAS: 1363381-39-8; 0.450 g, 1.45 mmol). The solids from both batches were combined to give a white solid. [P15] (0.339 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 212.0.

[0304] [preparation]

[16] ethyl 1-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-1H-indazole-3-carboxylate [(P16)] [ ] Step 1. Preparation of ethyl 1-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-1H-indazole-3-carboxylate [(P16)] Ethyl 1-methyl-5-sideoxy-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (CAS: 2090404-84-3; 0.500 g, 1.41 mmol) and N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (CAS: 145100-51-2; 0.409 g, 2.12 mmol) in H₂O (1 mL) and THF (10 mL) were supplemented with Pd(dppf)Cl₂ (0.103 g, 0.141 mmol) and K₃PO₄ (0.899 g, 4.23 mmol). The reaction mixture was degassed with nitrogen and stirred at 85 °C for 16 hours, followed by vacuum concentration. The residue was purified by column chromatography (silicone, 0-38% THF:PE) to obtain a pink solid. [P16] (0.470 g, 94.2% yield). (LC / MS) m / z (M+H)+ = 355.0

[0305] [preparation]

[17] 1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P17)] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 1-(2,2,2-trifluoroethyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(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-methylpropyl-1-ylonium [(C28)] [ ] Tributyl 3-(2-ethoxy-2-epoxyacetyl)-4-epoxypiperidine-1-carboxylic acid (CAS: 518990-24-4; 0.450 g, 1.50 mol) was added to a suspension of (2,2,2-trifluoroethyl)hydrazine hydrochloride (CAS: 1081515-82-3; 0.226 g, 1.50 mmol) in EtOH (5 mL) and pyridine (0.476 g, 6.01 mmol). The reaction mixture was stirred at room temperature for 17 hours, and then examined by LCMS. The main isomer of [C27] [LC / MS) m / z (M-tert-butyl)+ = 321.9, residence time 0.87 min] and The minor isomer of [C28] [(LC / MS) m / z (M+H)+ = 378.2, retention time 0.94 min]. The suspension was concentrated under vacuum, then dissolved in DCM and purified by column chromatography (silicone, 0-40% EtOAc:heptane) to obtain a yellow oil. The major isomer of [C27] (dissolved in 30-40% EtOAc:heptane) (0.344 g, 60.7% yield). (LC / MS) m / z (M-tert-butyl)+ = 322.2. 1H NMR (600 MHz, CDCl3) δ 4.69 (q, 2H), 4.62 (br s, 2H), 4.41 (q, 2H), 3.77 - 3.70 (m, 2H), 2.74 - 2.70 (m, 2H), 1.56-1.43 (m, 9H), 1.40 (t, 3H) [ ]

[0306] Step 2. Preparation of ethyl 1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride [(P17)] Towards [C27] (0.344 g, 0.912 mmol) was added to a solution of dimethyl methacrylate (DCM) (5.0 mL) containing 4 M HCl (1.4 mL). The reaction solution was stirred at 40 °C for 24 hours, followed by vacuum concentration to obtain a white solid. [P17] (0.328 g, crude material). (LC / MS) m / z (M+H)+ = 278.2. 1H NMR (600 MHz, (CD3)2SO) δ 9.20 (br s, 1H), 5.31 (q, 2H), 4.32 - 4.22 (m, 4H), 3.39 (t, 2H), 2.99 (t, 2H), 1.29 - 1.26 (m, 3H).

[0307] [preparation]

[18] rac-(R)-1,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester [(P18)] [ ] [ ] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 5-(tri-butyl) pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid. [(C29)] [ ] At 0 °C, hydrazine monohydrate (CAS: 7803-57-8; 14 g, 0.18 mol) was added dropwise to a suspension of rac-(2R)-5-(2-ethoxy-2-ethoxyacetyl)-2-methyl-4-ethoxypiperidin-1-carboxylic acid (CAS: 2386748-67-8; 24 g, 77 mmol) in AcOH (120 mL) via a feeding funnel. The reaction mixture was stirred at room temperature for 1 hour, followed by vacuum concentration. The residue was diluted in EtOAc (200 mL) and then washed with an aqueous solution of NaHCO3. The organic layer was dried over Na2SO4, filtered, and vacuum concentrated to obtain an orange viscous liquid. [C29] (23 g, crude material). The liquid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 310.2. 1H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 5.06 (d, 1H), 4.85 (s, 1H), 4.44 - 4.28 (m, 2H), 4.15 - 4.10 (m, 1H), 2.96 (dd, 1H), 2.67 - 2.58 (m, 1H), 1.48 - 1.46 (m, 9H), 1.44 - 1.32 (m, 3H), 1.10 (d, 3H).

[0308] Step 2. Preparation of 3-ethyl rac-(R)-1,6-dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester [(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-methylpropyl-1-ylonium [(C31)] [ ] At 0℃, towards [C29] (23 g, 74 mmol) was added dropwise to a solution of Cs₂CO₃ (27 g, 82 mmol) and MeI (14 mL) in DMF (200 mL). The reaction mixture was stirred at room temperature for 20 hours, followed by vacuum concentration. The residue was dissolved in MTBE (200 mL) and then washed with H₂O (200 mL). The organic layer was dried over Na₂SO₄, filtered, and vacuum concentrated to form an orange oil. The residue was purified by column chromatography (silicone, 0-100% isopropyl acetate:heptane) to obtain... [C30] (3.0 g, 25% yield) and [C31] (1.6 g, 14% yield).

[0309] [C30] [:](LC / MS) m / z (M+H)+ = 324.2. 1H NMR (400 MHz, CDCl3) δ 5.12 - 4.92 (m, 1H), 4.87 - 4.72 (m, 1H), 4.41 - 4.23 (m, 2H), 4.11 (s, 3H), 4.10 - 4.02 (m, 1H), 2.90 (dd, 1H), 2.59 - 2.48 (m, 1H), 1.48 - 1.44 (m, 9H), 1.39 - 1.34 (m, 3H), 1.09 (d, 3H). [ ]

[0310] [C31] [:](LC / MS) m / z (M+H)+ = 324.2. 1H NMR (400 MHz, CDCl3) δ 5.08 - 4.85 (m, 2H), 4.44 - 4.30 (m, 2H), 4.08 (d, 1H), 3.80 (s, 3H), 2.94 - 2.84 (m, 1H), 2.44 - 2.38 (m, 1H), 1.46 (s, 9H), 1.37 (t, 3H), 1.20 (d, 3H). [, , ]

[0311] Step 3. Preparation of rac-(R)-1,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester [(P18)] Towards [C30] (0.460 g, 1.42 mmol) was added to a solution of EtOAc (5 mL) containing 1 M HCl in DCM (5 mL). The reaction solution was stirred at room temperature for 6 hours, followed by vacuum concentration to obtain a white foamy solution. [P18] (0.325 g, crude material), which was used directly in the next step without further purification. [ ]

[0312] [ ] [Preparation]

[19] 3-(1,1-difluoroethyl)-5,6,7,8-tetrahydroimidazole[1,5-a]pyridine-1-carboxylic acid ethyl ester hydrochloride [(P19)] Step 1. Preparation of 1-ethyl 7-(tert-butyl)-3-(1-ethoxyvinyl)-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid ester. [(C32)] [ ] 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 to a solution of 3-bromo-5,6-dihydroimidazolo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid 7-(tributyl) ester 1-ethyl ester (CAS: 2108354-93-2; 1.50 g, 4.01 mmol) in DCE (30 mL). The reaction mixture was microwaved at 120 °C for 30 min, followed by vacuum concentration. The residue was purified by column chromatography (silicone; 0-27% THF:PE) to obtain an oily product. [C32] (0.960 g, 65.5% yield). (LC / MS) m / z (M+H)+ = 366.1. 1H NMR (400 MHz, CDCl3) δ 5.06 (d, 1H), 4.90 (s, 2H), 4.42 - 4.33 (m, 2H), 4.18 (t, 2H), 3.90 (q, 2H), 3.79 - 3.71 (m, 3H), 1.50 (br s, 9H), 1.44 - 1.33 (m, 6H).

[0313] Step 2. Preparation of 1-ethyl 7-(tert-butyl) 3-acetylated-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid ester. [(C33)] [ ] Towards [C32] (0.660 g, 1.81 mmol) was added to a solution of 2M HCl (0.132 g, 3.61 mmol) in 12 mL of THF. The reaction mixture was stirred in a microwave for 16 hours, followed by vacuum concentration to obtain a clear yellow solution. The residue was poured into saturated NaHCO3 and then extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The brown residue was purified by column chromatography (silicone, 0-20% EtOAc:PE) to obtain a white solid. [C33] (0.440 g, 81.1% yield). (LC / MS) m / z (M+H)+ = 338.3. 1H NMR (400 MHz, CDCl3) δ 4.95 (s, 2H), 4.47 (t, 2H), 4.41 (q, 2H), 3.79 (t, 2H), 2.70 (s, 3H), 1.50 (s, 9H), 1.41 (t, 3H).

[0314] Step 3. Preparation of 1-ethyl 7-(tert-butyl) 3-(1,1-difluoroethyl)-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid ester [(C34)] [ ] Will [C33] (0.435 g, 1.29 mmol) in deoxo-fluor™ solution (CAS: 202289-38-1; 10 mL) was stirred at 40 °C for 72 hours. The reaction mixture was cooled to room temperature and then extracted with DCM (2 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-20% EtOAc:PE) to give a yellow gel. [C34] (0.310 g, 66.9% yield). (LC / MS) m / z (M+H)+ = 360.1. 1H NMR (400 MHz, CDCl3) δ 4.92 (s, 2H), 4.38 (q, 2H), 4.25 (t, 2H), 3.83 (t, 2H), 2.19 (t, 3H), 1.50 (s, 9H), 1.39 (t, 3H).

[0315] Step 4. Preparation of ethyl 3-(1,1-difluoroethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate hydrochloride [(P19)] Towards [C34] (0.310 g, 0.863 mmol) was added to a solution of dimethyl methacrylate (6 mL) containing 2 M HCl in DCM (3 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated under vacuum and further dried under high vacuum to obtain a gel-like product. [P19] (0.255 g, crude material). This gel was used directly in the next step without further purification.

[0316] [preparation]

[20] rac-(R)-7-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P20)] Step 1. Preparation of rac-(5R)-3-(2-ethoxy-2-epoxyacetyl)-5-ethyl-4-epoxypiperidine-1-carboxylic acid tributyl ester [(C35)] [ ] Under nitrogen atmosphere 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. THF (60 mL) containing tributyl 3-ethyl-4-yl-piperidin-1-carboxylate (CAS: 117565-57-8; 9.00 g, 39.6 mmol) was added dropwise to the solution at -78°C, followed by stirring at -78°C for 1 hour. After stirring, diethyl oxalate (5.79 g, 39.6 mmol) was added dropwise to the THF (20 mL) solution at -78°C, followed by stirring at -78°C for 1 hour. The reaction mixture was warmed to room temperature and then stirred for 16 hours. The suspension was cooled to 0°C, quenched with 1 M KHSO4 aqueous solution (150 mL), and filtered. The filtrate was extracted with EtOAc (2 × 200 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum to obtain a yellow gel-like substance. [C35] (13.0 g, crude material). This gel was used directly in the next step without further purification. (LC / MS) m / z (M-tert-butyl)+ = 272.0. 1H NMR (400 MHz, CDCl3) δ 15.42 (br s, 1H), 4.53 - 4.16 (m, 4H), 3.68 - 3.32 (m, 2H), 2.44 - 2.32 (m, 1H), 1.84 - 1.67 (m, 1H), 1.53 - 1.42 (m, 2H), 1.41 - 1.39 (m, 9H), 1.31 (t, 3H), 0.97 (t, 3H).

[0317] Step 2. Preparation of 3-ethyl rac-(R)-7-ethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester [(C36)] [ ] according to [preparation]

[18] [step] [1] uses the same procedure. [C35] (6.00 g, 18.3 mmol) yielded a yellow gel-like substance. [C36] (8.89 g, crude material), which was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 324.1. 1H NMR (400 MHz, CDCl3) δ 8.00 (br s, 1H), 4.93 - 4.44 (m, 2H), 4.37 (q, 2H), 3.83 - 3.68 (m, 1H), 3.57 - 3.41 (m, 1H), 2.88 - 2.71 (m, 1H), 1.84 - 1.70 (m, 1H), 1.62 - 1.51 (m, 2H), 1.50 - 1.48 (m, 9H), 1.38 (t, 3H), 1.05 (t, 3H).

[0318] Step 3. Preparation of rac-(R)-7-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P20)] Towards [C36] (0.400 g, 1.24 mmol) was added to a suspension of dimethyl methacrylate (DCM) (6 mL) and MeOH (2 mL) with 3 mL of 2 M HCl. The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of another 3 mL of DCM containing 2 M HCl. The suspension was stirred at room temperature for 16 hours, followed by vacuum concentration to obtain a yellow solid. [P20] (0.276 g, crude material). The solid was used directly in the next step without further purification. ¹H NMR (400 MHz, (CD3)2SO) δ 9.68 (br s, 2H), 4.37 - 4.11 (m, 4H), 3.52 - 3.44 (m, 1H), 3.14 - 3.06 (m, 1H), 3.05 - 2.94 (m, 1H), 1.99 - 1.85 (m, 1H), 1.67 - 1.53 (m, 1H), 1.29 (t, 3H), 0.94 (t, 3H).

[0319] [preparation] [twenty one ] rac-(R)-7-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(P21)] Step 1. Preparation of rac-(R)-5-(tert-butoxycarbonyl)-7-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid [(C37)] [ ] Towards [C36] (2.00 g, 6.18 mmol) was added to a suspension of MeOH (6.6 mL) and H2O (6.6 mL) with NaOH (0.495 g, 12.4 mmol). The reaction mixture was stirred at 40 °C for 2 hours, then diluted with H2O (20 mL). The diluted reaction mixture was cooled to 0 °C, then acidified with 1 M HCl aqueous solution to approximately pH 3 and filtered. The filter cake was collected to obtain a white solid. [C37] (1.60 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 296.1. 1H NMR (400 MHz, (CD3)2SO) δ 13.15 (br s, 1H), 4.73 - 4.24 (m, 2H), 3.74 - 3.41 (m, 2H), 2.78 - 2.67 (m, 1H), 1.70 (br s, 1H), 1.49 - 1.40 (m, 10H), 1.02 (t, 3H).

[0320] Step 2. Preparation of rac-(R)-5-(tert-butoxycarbonyl)-7-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid [(C38)] [ ] according to [preparation] [3] [step] [2] The same procedure, using [C37] (1.00 g, 3.39 mmol) and MeI (0.577 g, 4.06 mmol) were used to obtain a white solid. [C38] (0.850 g, crude material), which was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 310.1. 1H NMR (400 MHz, (CD3)2SO) δ 12.65 (br s, 1H), 5.01 - 4.75 (m, 1H), 4.34 - 3.88 (m, 2H), 3.79 (s, 3H), 3.07 - 2.67 (m, 2H), 1.63 - 1.50 (m, 1H), 1.43 (s, 9H), 1.36 - 1.23 (m, 1H), 1.08 - 0.95 (m, 3H).

[0321] Step 3. Preparation of rac-(R)-7-ethyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate salt [(P21)] At 0℃, towards [C38] (0.300 g, 0.970 mmol) was added to a solution of dimethyl methacrylate (2 mL) containing HCl in DCM (1 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours, followed by vacuum concentration to obtain a yellow solid. [P21] (0.236 g, crude material). 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).

[0322] [preparation] [twenty two ] 2-Chloro-5-(1-Methyl-1H-imidazol-2-yl)pyridine [(P22)] Step 1. Preparation of 2-chloro-5-(1H-imidazol-2-yl)pyridine [(C39)] [ ] At 0 °C, NaOCH3 (5.50 g, 102 mmol) was added to a solution of 2-chloro-5-ethynylpyridine (CAS: 263012-63-1, 94.0 g, 680 mmol) in MeOH (1.5 L). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of 2,2-dimethoxyethylamine (71.3 g, 678 mmol) and AcOH (81.5 g, 1.36 mol). The reaction mixture was stirred at 50 °C for 1 hour, then cooled to room temperature, followed by the addition of 6M HCl (74.2 g, 2.04 mol). The reaction mixture was stirred at 80 °C for 5 hours, followed by vacuum concentration. The residue was extracted with EtOAc (2 × 500 mL). The aqueous layer was adjusted to pH 10 with a saturated Na2CO3 aqueous solution, which resulted in the formation of a white solid precipitate. The suspension was filtered, and the filter cake was washed with H2O (3 × 100 mL). The filter cake was collected and then freeze-dried to obtain a white solid. [C39] (88.0 g, 72.2% yield). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 180.0. 1H NMR (400 MHz, (CD3)2SO) δ 12.77 (br s, 1H), 8.94 (d, 1H), 8.31 (dd, 1H), 7.62 (d, 1H), 7.22 (s, 2H).

[0323] Step 2. Preparation of 2-chloro-5-(1-methyl-1H-imidazol-2-yl)pyridine [(P22)] At room temperature [C39] (44.0 g, 204 mmol) was added to a solution of DME (440 mL) with KOH (24.0 g, 428 mmol), and the mixture was stirred for 1 hour and 40 minutes. The reaction mixture was cooled to 0°C, and then MeI (57.8 g, 407 mmol) was added, followed by stirring at 0°C for 1 hour. The white suspension was filtered and then concentrated under vacuum. The residue was washed with H2O (300 mL) and stirred for 30 minutes. The reaction mixture was filtered, and the filter cake was concentrated under vacuum to give a white solid. [P22] (34.8 g, 88.8% yield). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 194.0. 1H NMR (400 MHz, (CD3)2SO) δ 8.79–8.76 (m, 1H), 8.20 (dd, 1H), 7.68–7.64 (m, 1H), 7.37 (d, 1H), 7.08 (d, 1H), 3.83 (s, 3H).

[0324] [preparation] [twenty three ] rac-(R)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester trifluoroacetate [(P23)] Step 1. Preparation of 3-ethyl rac-(R)-1-ethyl-7-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester [(C40)] and rac-(R)-2-ethyl-7-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester [(C41)] [ ] Will A suspension of [C10] (1.00 g, 3.19 mmol) and ethylenehydrazine 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. The reaction mixture was concentrated under vacuum and then purified by column chromatography (silicone, 0-40% EtOAc:PE) to obtain a pale yellow solid. [C41] (0.290 g, 26.9% yield) and a pale yellow gelatinous substance. [C40] (0.700 g, 65.0% yield).

[0325] [C40] [:](LC / MS) m / z (M+H)+ = 338.2; 1H NMR (400 MHz, CDCl3) δ 5.20 - 4.88 (m, 1H), 4.44 - 4.32 (m, 2H), 4.29 - 3.97 (m, 4H), 3.16 (d, 1H), 3.00 - 2.88 (m, 1H), 1.52 - 1.44 (m, 12H), 1.38 (t, 3H), 1.25 (d, 3H). [, , ]

[0326] [C41] [:](LC / MS) m / z (M+H)+ = 338.2; 1H NMR (400 MHz, CDCl3) δ 4.75 - 4.46 (m, 4H), 4.33 (q, 2H), 3.96 - 3.64 (m, 1H), 3.36 - 3.08 (m, 1H), 3.00 - 2.91 (m, 1H), 1.50 - 1.44 (m, 9H), 1.39 (q, 6H), 1.26 (d, 3H).

[0327] Step 2. Preparation of rac-(R)-1-ethyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester trifluoroacetate [(P23)] Towards [C40] (0.250 g, 0.741 mmol) was added to a solution of TFA (2 mL) in DCM (4 mL). The reaction mixture was stirred at room temperature for 2 hours, followed by vacuum concentration to obtain a colorless gel. [P23] (0.260 g, crude material), which was used directly in the next step without further purification.

[0328] [ ] [preparation] [twenty four ] rac-(4R,8S)-1-methyl-4,5,6,7,8,9-hexahydro-1H-4,8-cycloiminocyclooctano[c]pyrazole-3-carboxylic acid ethyl ester [(P24)] Step 1. Preparation of rac-(1R,5S)-2-(2-ethoxy-2-ethoxyacetyl)-3-ethoxy-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester [(C42)] [ ] At -78°C, LDA (1.07 g, 10.0 mmol) was added to THF (50 mL). THF (50 mL) containing (1R,5S)-3-sideoxy-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester (CAS: 512822-27-4; 2.00 g, 8.36 mmol) was added dropwise to the solution at -78°C, followed by stirring at -78°C for 1 hour. After stirring, diethyl oxalate (1.28 g, 8.78 mmol) was added dropwise to a solution of THF (20 mL) at -78°C, followed by stirring at -78°C for 30 minutes. The reaction mixture was warmed to room temperature, stirred for 1 hour, and then concentrated under vacuum. The residue was purified by column chromatography (silicone, 2-16% EtOAc:PE) to obtain a pale yellow oil. [C42] (0.750 g, 26.4% yield). (LC / MS) m / z (M+H)+ = 340.1 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).

[0329] Step 2. Preparation of rac-(4R,8S)-1-methyl-4,5,6,7,8,9-hexahydro-1H-4,8-cycloiminocyclooctano[c]pyrazole-3,10-dicarboxylic acid 10-(tertiary butyl) ester 3-ethyl ester [(C43)] and rac-(4R,8S)-2-methyl-4,5,6,7,8,9-hexahydro-2H-4,8-cycloiminocyclooctano[c]pyrazole-3,10-dicarboxylic acid 10-(tributyl) ester 3-ethyl ester [(C44)] [ ] Towards [C42] (0.650 g, 2.17 mmol) was added to a solution of EtOH (20 mL) containing methylhydrazine dihydrochloride (CAS: 55330-60-4; 0.179 g, 2.17 mmol) and pyridine (0.859 g, 10.9 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under vacuum. The residue was purified by column chromatography (silicone, 12-100% EtOAc:PE) to give an oily solution. [C43] (0.390 g, 51.4% yield) and [C44] (0.150 g, 19.8% yield).

[0330] [C43] [:](LC / MS) m / z (M+H)+ = 350.1. 1H NMR (400 MHz, CDCl3) δ 5.68 - 5.53 (m, 1H), 4.79 - 4.57 (m, 1H), 4.46 - 4.28 (m, 2H), 3.80 (s, 3H), 3.11 - 2.95 (m, 1H), 2.43 (d, 1H), 1.89 - 1.69 (m, 4H), 1.63 - 1.55 (m, 1H), 1.50 - 1.41 (m, 10H), 1.40 - 1.34 (m, 3H). [, , ]

[0331] [C44] [:](LC / MS) m / z (M+H)+ = 350.2. 1H NMR (400 MHz, CDCl3) δ 5.68 - 5.48 (m, 1H), 4.78 - 4.53 (m, 1H), 4.45 - 4.19 (m, 2H), 4.15 - 4.07 (m, 3H), 3.19 - 3.00 (m, 1H), 2.63 - 2.52 (m, 1H), 1.90 - 1.58 (m, 5H), 1.44 (s, 10H), 1.38 (t, 3H). [, , ]

[0332] Step 3. Preparation of rac-(4R,8S)-1-methyl-4,5,6,7,8,9-hexahydro-1H-4,8-cycloiminocyclooctano[c]pyrazole-3-carboxylic acid ethyl ester [(P24)] Towards [C43] (0.222 g, 0.636 mmol) was added to a solution of dialkylene containing HCl (0.116 g, 3.18 mmol) in 6 mL of ACN. The reaction mixture was stirred at room temperature for 16 hours, followed by vacuum concentration to obtain a white solid. [P24] (0.150 g, crude material). The solid was used directly in the next step without further purification.

[0333] [Preparation] [P25] 7,7-Difluoro-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P25)] Step 1. Preparation of tert-butyl 3,3-difluoro-4-(pyrrolidin-1-yl)-3,6-dihydropyridine-1(2H)-formate [(C45)] [ ] Pyrrolidine (0.927 g, 13.0 mmol) was added to a solution of 3,3-difluoro-4-dioxypiperidin-1-carboxylic acid tributyl ester (CAS: 1215071-17-2; 3.00 g, 11.8 mmol) in toluene (40 mL). The reaction mixture was heated for 20 hours using a Deans and Stark trap to remove H2O released during the reaction, followed by vacuum concentration to give a brown solid. [C45] (3.42 g, crude material). The solid was used directly in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 4.66 - 4.46 (m, 1H), 4.14 - 4.05 (m, 2H), 3.90 (t, 2H), 3.20 - 3.13 (m, 4H), 1.97 - 1.88 (m, 4H), 1.53 (s, 9H).

[0334] Step 2. Preparation of tert-butyl 5-(2-ethoxy-2-oxyacetyl)-3,3-difluoro-4-(pyrrolidin-1-yl)-3,6-dihydropyridine-1(2H)-formate [(C46)] [ ] Will [C45] (3.42 g, 11.9 mmol) was degassed with nitrogen for 10 min in DCM (50 mL). The reaction mixture was cooled to 0 °C, and then ethylethylenedichloroethylene (1.94 g, 14.2 mmol) was added dropwise over 15 min. The temperature was maintained between 0 and 5 °C throughout the addition. After the addition, TEA (1.80 g, 17.8 mmol) was added dropwise over 5 min. The reaction mixture was warmed to room temperature and stirred for 5 h, then diluted with H2O (300 mL). The diluted reaction mixture was extracted with DCM (3 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-25% EtOAc:PE) to give a yellow solid. [C46] (2.98 g, 64.7% yield). (LC / MS) m / z (M+H)+ = 389.2. 1H NMR (400 MHz, CDCl3) δ 4.41 (s, 2H), 4.30 (q, 2H), 3.89 (t, 2H), 3.49 - 3.41 (m, 4H), 2.00 - 1.94 (m, 4H), 1.48 (s, 9H), 1.35 (t, 3H).

[0335] Step 3. Preparation of 3-ethyl 5-(tert-butyl) 7,7-difluoro-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(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-methylpropyl-1-ylonium [(C48)] [ ] The reaction was carried out in three batches, which were then combined for further purification. At 0°C, after 5 minutes... [C46] (1.09 g, 2.81 mmol) was added dropwise to a solution of EtOH (10 mL) containing methylhydrazine dihydrochloride (CAS: 55330-60-4; 0.402 g, 3.38 mmol), and the reaction mixture was then sealed and stirred at 80 °C for 2 hours to form the first batch.

[0336] use [C46] (0.500 g, 1.29 mmol) was used to carry out a second batch of the same reaction, and with [C46] (0.100 g, 0.257 mmol) was used in a third batch. The batches were combined and subsequently diluted with H2O (60 mL). The diluted reaction mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-15% EtOAc:PE) to give a brown oily substance. [C48] (0.756 g, 50.4% yield) and impurities as residue [C47]. Residue [C47] Purified and lyophilized by reverse-phase HPLC (C18 150 mm × 40 mm × 5 µm column, mobile phase A: H2O (0.05% NH4OH-NH4HCO3) / mobile phase B: ACN, maintained at 32% to 72% mobile phase B for 9 minutes, then at 100% mobile phase B for 2 minutes, flow rate = 60 mL / min) to obtain a colorless oil. [C47] (0.416 g, 27.7% yield).

[0337] [C47]: (LC / MS) m / z (M-tert-butyl)+ = 290.2; 1H NMR (400 MHz, CDCl3) δ 4.69 (br s, 2H), 4.41 (q, 2H), 4.09 - 3.96 (m, 5H), 1.49 (s, 9H), 1.40 (t, 3H).

[0338] [C48]:(LC / MS) m / z (M-tert-butyl)+ = 290.2; 1H NMR (400 MHz, CDCl3) δ 4.73 - 4.63 (m, 2H), 4.37 (q, 2H), 4.23 (s, 3H), 4.06 - 3.95 (m, 2H), 1.49 (s, 9H), 1.40 (t, 3H).

[0339] Step 4. Preparation of ethyl 7,7-difluoro-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride [(P25)] [ ] Towards [C47] (0.416 g, 1.20 mmol) was added to a reaction mixture in DCM (5 mL) along with dialkylene (1.76 g, 48.2 mmol) containing HCl, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then concentrated under vacuum to give a pale yellow solid. [P25] (295 mg, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 246.1. 1H NMR (400 MHz, CD3OD) δ 4.55 (t, 2H), 4.40 (q, 2H), 4.15 - 4.02 (m, 5H), 1.39 (t, 3H).

[0340] [preparation]

[26] rac-(4R,8S)-1-methyl-1,4,5,7,8,9-hexahydro-4,8-cycloiminooxacyclooctano[5,4-c]pyrazole-3-carboxylic acid ethyl ester hydrochloride [(P26)] Step 1. Preparation of rac-(1R,5S)-6-(2-ethoxy-2-epoxyacetyl)-7-epoxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tributyl ester [(C49)] [ ] according to [preparation]

[20] [step] [1] Using the same procedure, tert-butyl 7-sidekto-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (CAS: 280761-97-9; 1.80 g, 7.46 mmol) was used to obtain an orange oil. [C49] (2.50 g, crude material), which was used directly in the next step without further purification.

[0341] Step 2. Preparation of rac-(4R,8S)-1-methyl-1,4,5,7,8,9-hexahydro-4,8-cycloiminooxacyclooctano[5,4-c]pyrazole-3,10-dicarboxylic acid 10-(tertiary butyl) ester 3-ethyl ester [(C50)] and rac-(4R,8S)-2-methyl-2,4,5,7,8,9-hexahydro-4,8-cycloiminooxacyclooctano[5,4-c]pyrazole-3,10-dicarboxylic acid 10-(tributyl) ester 3-ethyl ester [(C51)] [ ] The reaction was carried out in two batches and then combined. A suspension of [C49] (2.50 g, 7.32 mmol) and methylhydrazine dihydrochloride (CAS: 55330-60-4; 0.871 g, 7.32 mmol) in EtOH (40 mL) and pyridine (2.55 g, 32.2 mmol) was stirred at room temperature for 3 hours to form the first batch. The reaction mixture of the first batch was examined by LCMS, showing... The main isomer of [C50] [LC / MS] m / z (M+H)+ = 352.3, residence time was 0.827 min (analytical LC / MS conditions: Chromolith Flash Reverse Phase-18e 25-3 mm column; mobile phase A: 1.5 mL / 4 L TFA / H2O / mobile phase B: 0.75 mL / 4 L TFA / ACN, gradient through 5-95% mobile phase B for 0.7 min, followed by holding at 95% mobile phase B for 0.4 min; flow rate: 1.5 mL / min; column temperature: 50℃)] and The minor isomer of [C51] was [LC / MS] m / z (M+H)+ = 352.3, with a residence time of 0.880 min (analytical LC / MS conditions: Chromolith Flash Reverse Phase-18e 25-3 mm column; mobile phase A: 1.5 mL / 4 L TFA / H2O / mobile phase B: 0.75 mL / 4 L TFA / ACN, gradient through 5-95% mobile phase B for 0.7 min, followed by holding at 95% mobile phase B for 0.4 min; flow rate: 1.5 mL / min; column temperature: 50 °C).

[0342] use [C49] (0.200 g, 0.586 mmol) was used in a second batch of the same reaction. The two batches were combined, concentrated under vacuum, and purified by column chromatography (silicone, 0-50% EtOAc:PE) to obtain a yellow solid. [C50] (0.750 g, 27.0% yield). (LC / MS) m / z (M+H)+ = 352.3. 1H NMR (400 MHz, CDCl3) δ 5.55 - 5.30 (m, 1H), 4.53 - 4.27 (m, 3H), 3.91 - 3.64 (m, 7H), 3.21 - 2.92 (m, 1H), 2.71 - 2.59 (m, 1H), 1.51 - 1.30 (m, 12H).

[0343] Step 3. Preparation of rac-(4R,8S)-1-methyl-1,4,5,7,8,9-hexahydro-4,8-cycloiminooxacyclooctano[5,4-c]pyrazole-3-carboxylic acid ethyl ester hydrochloride [(P26)] Towards [C50] (0.750 g, 2.14 mmol) was added to a solution of dimethyl methacrylate (0.390 g, 10.7 mmol) containing 2 M HCl in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was dissolved in DCM (5 mL) and then concentrated under vacuum (2×) to give a yellow solid. [P26] (0.675 g, crude material). The solid was used directly in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 10.83 (s, 1H), 9.85 (s, 1H), 5.07 (s, 1H), 4.45 - 4.20 (m, 4H), 4.01 - 3.84 (m, 5H), 3.82 - 3.73 (m, 1H), 3.66 - 3.55 (m, 1H), 2.98 - 2.86 (m, 1H), 1.38 (t, 3H).

[0344] [preparation]

[27] 1-Propyl-4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester [(P27)] [ ] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 1-propyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(C52)] and 2-((3-(ethoxycarbonyl)-2-propyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropyl-1-ylonium [(C53)] [ ] K₂CO₃ (0.94 g, 6.7 mmol) was added to a solution of 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester (CAS: 518990-23-3; 0.81 g, 4.7 mmol) and 1-iodopropane (1.0 g, 3.4 mmol) in DMF (13 mL). The reaction mixture was stirred at 100 °C for 4 hours, cooled to room temperature, and diluted with (1:1) EtOAc:H₂O (50 mL). The aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-39% EtOAc:PE) to give a white solid. [C53] (0.48 g, 42% yield) and a white solid. [C52] (0.38 g, 33% yield).

[0345] [C52] [:](LC / MS) m / z (M+H)+ = 338.3; 1H NMR (400 MHz, CDCl3) δ 4.61 (s, 2H), 4.39 (q, 2H), 4.03 (t, 2H), 3.76 - 3.67 (m, 2H), 2.73 - 2.63 (m, 2H), 1.92 - 1.80 (m, 2H), 1.48 (s, 9H), 1.39 (t, 3H), 0.91 (t, 3H).

[0346] [C53] [:](LC / MS) m / z (M+H)+ = 338.3; 1H NMR (400 MHz, CDCl3) δ 4.65 - 4.56 (m, 2H), 4.49 - 4.43 (m, 2H), 4.33 (q, 2H), 3.68 (s, 2H), 2.74 (s, 2H), 1.90 - 1.78 (m, 2H), 1.49 (s, 9H), 1.39 (t, 3H), 0.92 (t, 3H).

[0347] Step 2. Preparation of ethyl 1-propyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(P27)] Towards [C52] (0.370 g, 1.10 mmol) was added to a reaction mixture in DCM (3 mL) containing dimethyl alkylene (0.400 g, 11.0 mmol) and stirred at room temperature for 1 hour and 40 minutes. The reaction mixture was then concentrated under vacuum to give a white solid. [P27] (0.300 g, crude material). The solid was used directly in the next step without further purification. ¹H NMR (400 MHz, (CD₃)₂SO) δ 9.54 (s, 2H), 4.25 (q, 2H), 4.19 (s, 2H), 4.06 (t, 2H), 3.40 - 3.35 (m, 2H), 2.97 (t, 2H), 1.80 - 1.68 (m, 2H), 1.27 (t, 3H), 0.82 (t, 3H).

[0348] [preparation]

[28] 1-(tetrahydro-2H-piperan-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P28)] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 1-(tetrahydro-2H-piperan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(C54)] [ ] according to [preparation] [2] [step] [1] Using the same procedure, tributyl 3-(2-ethoxy-2-epoxyacetyl)-4-epoxypiperidin-1-carboxylic acid (CAS: 518990-24-4; 0.500 g, 1.67 mmol) and (tetrahydro-2H-piperan-4-yl)hydrazine hydrochloride (0.255 g, 1.67 mmol). The residue was purified by column chromatography (silicone, 0-40% THF:PE) to obtain a yellow gel. [C54] (0.492 g, 77.6% yield). (LC / MS) m / z (M+H)+ = 380.3. 1H NMR (400 MHz, CDCl3) δ 4.60 (s, 2H), 4.38 (q, 2H), 4.31 - 4.21 (m, 1H), 4.15 - 4.07 (m, 2H), 3.77 - 3.68 (m, 2H), 3.54 - 3.44 (m, 2H), 2.73 (t, 2H), 2.41 - 2.25 (m, 2H), 1.89 - 1.80 (m, 2H), 1.51 - 1.40 (m, 9H), 1.38 (t, 3H).

[0349] Step 2. Preparation of ethyl 1-(tetrahydro-2H-piperan-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid hydrochloride [(P28)] [ ] Towards [C54] (0.470 g, 1.24 mmol) was added to a solution of dimethyl methacrylate (0.973 g, 26.7 mmol) containing 2 M HCl in 10 mL of DCM. The reaction mixture was stirred at room temperature for 4 hours, followed by vacuum concentration to obtain a yellow solid. [P28] (0.370 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 280.1. 1H NMR (400 MHz, (CD3)2SO) δ 9.37 (s, 1H), 4.56 - 4.45 (m, 1H), 4.33 - 4.19 (m, 4H), 4.03 - 3.93 (m, 2H), 3.52 - 3.41 (m, 4H), 3.04 (t, 2H), 2.07 - 1.92 (m, 2H), 1.86 - 1.77 (m, 2H), 1.29 (t, 3H).

[0350] [preparation]

[29] rac-(R)-1-(secondary butyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P29)] [ ] Step 1. Preparation of 3-ethyl 5-(tertiary butyl) 5-(R)-1-(secondary butyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester [(C55)] [ ] according to [preparation] [2] [step] [1] Using the same procedure, tert-butyl 3-(2-ethoxy-2-ethoxyacetyl)-4-ethoxypiperidin-1-carboxylic acid (CAS: 518990-24-4; 0.400 g, 1.34 mmol) and dibutylhydrazine dihydrochloride (CAS: 1177361-36-2, 0.215 g, 1.34 mmol) was used. The residue was purified by column chromatography (silicone, 50% EtOAc:PE) to obtain a gel-like product. [C55] (0.382 g, 81.3% yield). (LC / MS) m / z (M+H)+ = 352.1. 1H NMR (400 MHz, (CD3)2SO) δ 4.53 - 4.40 (m, 2H), 4.30 - 4.17 (m, 3H), 3.68 - 3.54 (m, 2H), 2.71 (q, 2H), 1.87 - 1.66 (m, 2H), 1.41 (s, 9H), 1.37 (d, 3H), 1.29 (t, 3H), 0.69 (t, 3H).

[0351] Step 2. Preparation of rac-(R)-1-(secondary butyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P29)] [ ] At 0℃, towards [C55] (0.382 g, 1.09 mmol) was added to a solution of dimethyl methacrylate (4 mL) containing HCl in DCM (2 mL). The reaction mixture was stirred at room temperature for 16 hours, followed by vacuum concentration to obtain a solid. [P29] (0.245 g, crude material). The solid was used directly in the next step without further purification.

[0352] [preparation]

[30] rac-(4R,7S)-1-methyl-1,4,5,6,7,8-hexahydro-4,7-cycloiminocycloheptano[c]pyrazole-3-carboxylic acid ethyl ester [(P30)] Step 1. Preparation of rac-(1R,5S)-2-(2-ethoxy-2-ethoxyacetyl)-3-ethoxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [(C56)] [ ] according to [preparation]

[20] [step] [1] The same procedure was followed, using (1R,5S)-8-sideoxy-3-azabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester (CAS: 637301-19-0; 5.10 g, 22.6 mmol), with additional purification. The residue was purified by column chromatography (silicone, 0-10% EtOAc:PE) to obtain a yellow oily substance. [C56] (4.69 g, 63.7% yield).

[0353] Step 2. Preparation of 3-ethyl rac-(4R,7S)-1-methyl-1,4,5,6,7,8-hexahydro-4,7-cycloiminocycloheptano[c]pyrazole-3,9-dicarboxylic acid 9-(tertiary butyl) ester [(C57)] and rac-(4R,7S)-2-methyl-2,4,5,6,7,8-hexahydro-4,7-cycloiminocycloheptano[c]pyrazole-3,9-dicarboxylic acid 9-(tributyl) ester 3-ethyl ester [(C58)] [ ] according to [preparation] [2] [step] [1] uses the same procedure. [C56] (4.69 g, 14.4 mmol) and methylhydrazine sulfate (CAS: 302-15-8, 2.08 g, 14.4 mmol). The reaction mixture was examined by LCMS, and it showed... The main isomer of [C57] [LC / MS] m / z (M+H)+ = 336.2, residence time was 0.846 min (analytical LC / MS conditions: Chromolith Flash Reverse Phase-18e 25-3 mm column; mobile phase A: 1.5 mL / 4 L TFA / H2O / mobile phase B: 0.75 mL / 4 L TFA / ACN, gradient through 5-95% mobile phase B for 0.7 min, then held at 95% mobile phase B for 0.4 min; flow rate: 1.5 mL / min; column temperature: 50℃)] and The minor isomer of [C58] [LC / MS] m / z (M+H)+ = 336.2, retention time was 0.904 min (analytical LC / MS conditions: Chromolith Flash Reverse Phase-18e 25-3 mm column; mobile phase A: 1.5 mL / 4 L TFA / H2O / mobile phase B: 0.75 mL / 4 L TFA / ACN, gradient through 5-95% mobile phase B for 0.7 min, then held at 95% mobile phase B for 0.4 min; flow rate: 1.5 mL / min; column temperature: 50℃)]. Purification was modified. The residue was purified by column chromatography (silicone, 0-50% THF:PE) to obtain a light yellow oil. [C57] (1.40 g, 29.0% yield). ¹H NMR (400 MHz, CDCl3) δ 5.42 - 5.33 (m, 1H), 4.64 - 4.35 (m, 3H), 3.77 (s, 3H), 3.29 - 3.08 (m, 1H), 2.41 - 2.23 (m, 2H), 2.21 - 2.10 (m, 1H), 1.93 - 1.85 (m, 1H), 1.55 - 1.48 (m, 1H), 1.44 - 1.35 (m, 12H).

[0354] Step 3. Preparation of rac-(4R,7S)-1-methyl-1,4,5,6,7,8-hexahydro-4,7-cycloiminocycloheptano[c]pyrazole-3-carboxylic acid ethyl ester [(P30)] [ ] Towards [C57] (0.240 g, 0.716 mmol) was added to a solution of dimethyl methacrylate (3 mL) containing 2 M HCl in 1 mL of DCM. The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated under vacuum to give a gray solid. [P30] (0.168 g, crude material). The solid was used directly in the next step without further purification.

[0355] [preparation]

[31] 1-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester [(P31)] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 1-(cyclopropylmethyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(C59)] and 2-((2-(cyclopropylmethyl)-3-(ethoxycarbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropyl-1-ylonium [(C60)] [ ] according to [preparation] [2] [step] [1] Using the same procedure, tributyl 3-(2-ethoxy-2-ethoxyacetyl)-4-ethoxypiperidin-1-carboxylic acid (CAS: 518990-24-4; 2.00 g, 6.68 mmol) and (cyclopropylmethyl)hydrazine hydrochloride (CAS: 1181457-83-9, 0.655 g, 5.35 mmol). The residue was purified by column chromatography (silicone, 0-60% EtOAc:PE) to obtain an impure, yellow oily substance. [C60] (0.800 g) and a light brown solid. [C59] (0.940 g, 40.3% yield). Further purification was achieved by column chromatography (silicone, 0-10% EtOAc:DCM). [C60] (0.800 g) yielded a gray gel-like substance. [C60] (0.450 g, 19.3% yield).

[0356] [C59]:(LC / MS) m / z (M+H)+ = 350.1; 1H NMR (400 MHz, (CD3)2SO) δ 4.49 (s, 2H), 4.26 (q, 2H), 3.96 (d, 2H), 3.61 (t, 2H), 2.73 (t, 2H), 1.44 - 1.40 (m, 9H), 1.29 (t, 3H), 1.24 - 1.16 (m, 1H), 0.54 - 0.47 (m, 2H), 0.37 - 0.31 (m, 2H).

[0357] [C60]:(LC / MS) m / z (M+H)+ = 350.0; 1H NMR (400 MHz, CDCl3) δ 4.62 (s, 2H), 4.41 - 4.30 (m, 4H), 3.76 - 3.61 (m, 2H), 2.81 - 2.71 (m, 2H), 1.50 - 1.46 (m, 9H), 1.42 - 1.30 (m, 4H), 0.54 - 0.47 (m, 2H), 0.43 - 0.37 (m, 2H).

[0358] Step 2. Preparation of ethyl 1-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(P31)] [ ] Towards [C59] (0.200 g, 0.572 mmol) was added to a solution of dimethyl methacrylate (2.0 mL) containing 2 M HCl in DCM (0.5 mL). The reaction mixture was stirred at 35 °C for 3 hours and then concentrated under vacuum to obtain a gray solid. [P31] (0.143 g, crude material). The solid was used directly in the next step without further purification.

[0359] [preparation]

[32] rac-(R)-1-(1-methoxypropyl-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P32)] [ ] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 5-(R)-1-(1-methoxypropyl-2-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid. [(C61)] and rac-(R)-2-((3-(ethoxycarbonyl)-2-(1-methoxypropyl-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropyl-1-ylonium [(C62)] [ ] The reaction was carried out in two batches, which were then combined for purification. The first batch consisted of a solution of rac-(R)-2-bromo-1-methoxypropane (CAS: 22461-48-9; 0.829 g, 5.42 mmol), 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester (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) stirred at 80 °C for 16 hours.

[0360] A second batch of the same reaction was performed using 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester (CAS: 518990-23-3; 0.100 g, 0.339 mmol). The two batches were combined, diluted with H₂O (20 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-50% EtOAc:PE) to obtain an oily product. [C62] (0.630 g, 56.2% yield) and oily form [C61] (0.430 g, 38.4% yield).

[0361] [C62]:(LC / MS) m / z (M+H)+ = 368.2; 1H NMR (400 MHz, CDCl3) δ 5.72 - 5.60 (m, 1H), 4.68 - 4.55 (m, 2H), 4.33 (q, 2H), 3.85 (t, 1H), 3.74 - 3.63 (m, 2H), 3.55 (dd, 1H), 3.31 (s, 3H), 2.79 - 2.71 (m, 2H), 1.48 (s, 9H), 1.45 - 1.36 (m, 6H).

[0362] [C61]:(LC / MS) m / z (M+H)+ = 368.2; 1H NMR (400 MHz, CDCl3) δ 4.60 (s, 2H), 4.43 - 4.33 (m, 3H), 3.82 - 3.75 (m, 1H), 3.73 - 3.66 (m, 2H), 3.58 (dd, 1H), 3.24 (s, 3H), 2.83 - 2.62 (m, 2H), 1.52 - 1.46 (m, 12H), 1.38 (t, 3H).

[0363] Step 2. Preparation of rac-(R)-1-(1-methoxypropyl-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P32)] [ ] At 0℃, towards [C61] (0.430 g, 1.17 mmol) was added in portions to a suspension in DCM (2 mL) containing dimethyl methacrylate (8 mL). The reaction mixture was stirred at room temperature for 2 hours, followed by vacuum concentration to obtain a yellow solid. [P32] (0.356 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 268.1. 1H NMR (400 MHz, (CD3)2SO) δ 9.28 - 9.05 (m, 2H), 4.66 - 4.55 (m, 1H), 4.36 - 4.13 (m, 4H), 3.67 - 3.57 (m, 1H), 3.55 - 3.51 (m, 1H), 3.48 - 3.38 (m, 2H), 3.18 (s, 3H), 3.08 - 2.86 (m, 2H), 1.36 (d, 3H), 1.29 (t, 3H).

[0364] [preparation]

[33] 1-(oxecyclobutane-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester trifluoroacetate [(P33)] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 1-(oxetane-3-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(C63)] and 2-((3-(ethoxycarbonyl)-2-(oxecyclobutane-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropyl-1-ylonium [(C64)] [ ] The reaction was carried out in two batches, which were then combined for purification. 3-Iodoxetane (CAS: 26272-85-5; 0.748 g, 4.06 mmol) and Cs₂CO₃ (1.32 g, 4.06 mmol) were added to a solution of 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester 3-ethyl ester (CAS: 518990-23-3; 0.600 g, 2.03 mmol) in DMF (10 mL), followed by stirring at 80 °C for 16 hours to form the first batch.

[0365] A second batch of the same reaction was performed using 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester (CAS: 518990-23-3; 0.100 g, 0.339 mmol), and the two batches were then combined and diluted in ice-cold H2O (40 mL). The diluted reaction mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and then concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-80% EtOAc:PE) to give an oily product. [C63] (0.180 g, 25.2% yield) and an oily form [C64] (0.288 g, 40.3% yield).

[0366] [C63](lot number-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).

[0367] [C64]:(LC / MS) m / z (M-tert-butyl)+ = 296.1; 1H NMR (400 MHz, (CD3)2SO) δ 6.08 - 5.95 (m, 1H), 4.97 - 4.84 (m, 4H), 4.56 - 4.50 (m, 2H), 4.28 (q, 2H), 3.62 (t, 2H), 2.70 (t, 2H), 1.42 (s, 9H), 1.30 (t, 3H).

[0368] Step 2. Preparation of 1-(oxetane-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester trifluoroacetate [(P33)] [ ] At 0℃, towards [C63] (0.180 g, 0.512 mmol) was added to a suspension of TFA (3 mL) in DCM (3 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under vacuum to obtain a gel-like product. [P33] (0.187 g, crude material). This gel was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 252.3. 1H NMR (400 MHz, (CD3)2SO) δ 9.18 - 8.94 (m, 2H), 5.69 - 5.58 (m, 1H), 4.98 - 4.82 (m, 4H), 4.37 - 4.23 (m, 4H), 3.44 - 3.35 (m, 2H), 3.04 - 2.91 (m, 2H), 1.35 - 1.26 (m, 3H).

[0369] [preparation]

[34] 1-(cyclobutylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P34)] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 1-(cyclobutylmethyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(C65)] according to [preparation] [2] [step] [1] Using the same procedure, tert-butyl 3-(2-ethoxy-2-ethoxyacetyl)-4-ethoxypiperidine-1-carboxylic acid (CAS: 518990-24-4; 0.400 g, 1.34 mmol) and 1-cyclobutylhydrazine hydrochloride (CAS: 158001-21-9, 0.164 g, 1.34 mmol) was used to obtain a yellow gel-like substance. [C65] (0.280 g, 15.0% yield). (LC / MS) m / z (M+H)+ = 350.2. 1H NMR (400 MHz, (CD3)2SO) δ 4.90 - 4.75 (m, 1H), 4.48 (s, 2H), 4.28 (q, 2H), 3.60 (t, 2H), 2.73 - 2.66 (m, 2H), 2.40 - 2.30 (m, 4H), 1.87 - 1.74 (m, 2H), 1.46 - 1.35 (m, 9H), 1.30 (t, 3H). [ ]

[0370] [ ] Step 2. Preparation of ethyl 1-(cyclobutylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid hydrochloride [(P34)] [ ] Add HCl to 0°C. [C65] (0.280 g, 0.801 mmol) was added to a suspension of dimethyl ether (10 mL) containing DCM (5 mL). The reaction mixture was stirred at room temperature for 3 hours, concentrated under vacuum, and then lyophilized to give a brown solid. [P34] (0.150 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 250.1. 1H NMR (400 MHz, (CD3)2SO) δ 9.37 (s, 2H), 4.94 - 4.80 (m, 1H), 4.29 (q, 2H), 4.21 (s, 2H), 3.42 - 3.36 (m, 2H), 2.95 (t, 2H), 2.48 - 2.44 (m, 1H), 2.41 - 2.31 (m, 2H), 1.87 - 1.75 (m, 2H), 1.30 (t, 3H).

[0371] [preparation]

[35] rac-(R)-1-(1,1,1-trifluoroprop-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester [(P35)] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 5-(R)-1-(1,1,1-trifluoroprop-2-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid. [(C66)] [ ] Pyridine (0.465 g, 5.88 mmol) was added to a solution of tributyl 3-(2-ethoxy-2-yloxyacetyl)-4-yloxypiperidin-1-carboxylic acid (CAS: 518990-24-4; 0.400 g, 1.34 mmol) and (1,1,1-trifluoroprop-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 vacuum. The residue was purified by column chromatography (silicone, 0-25% EtOAc:PE) to give a yellow gel. [C66] (0.415 g, 79.3% yield). (LC / MS) m / z (M+H)+ = 392.2. 1H NMR (400 MHz, (CD3)2SO) δ 5.47 - 5.35 (m, 1H), 4.60 - 4.38 (m, 2H), 4.29 (q, 2H), 3.78 - 3.67 (m, 1H), 3.55 - 3.46 (m, 1H), 2.92 - 2.81 (m, 1H), 2.69 - 2.56 (m, 1H), 1.67 (d, 3H), 1.41 (s, 9H), 1.30 (t, 3H).

[0372] Step 2. Preparation of ethyl rac-(R)-1-(1,1,1-trifluoroprop-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(P35)] [ ] At 0℃, towards [C66] (0.415 g, 1.06 mmol) was added in portions to a suspension in DCM (4 mL) containing dimethyl methacrylate (8 mL). The reaction mixture was stirred at room temperature for 16 hours, followed by vacuum concentration to obtain a yellow solid. [P35] (0.306 g, crude material). The solid was used directly in the next step without further purification.

[0373] [preparation]

[36] 1,7,7-Trimethyl-4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P36)] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 1,7,7-trimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(C67)] and 2-((3-(ethoxycarbonyl)-2,7,7-trimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropyl-1-ylonium [(C68)] [ ] according to [preparation] [2] [step] [1] Using the same procedure, 5-(2-ethoxy-2-ethoxyacetyl)-3,3-dimethyl-4-ethoxypiperidine-1-carboxylic acid tributyl ester (CAS: 2171295-98-8, 1.28 g, 3.91 mmol) and methylhydrazine (CAS: 60-34-4, 1.08 g, 9.38 mmol) was used to obtain a light yellow gel-like substance. [C68] (0.563 g, 42.7% yield) and a light yellow gelatinous substance. [C67] (0.160 g, 12.1% yield).

[0374] [C67] [:](LC / MS) m / z (M+H)+ = 338.2; 1H NMR (400 MHz, CDCl3) δ 4.66 - 4.54 (m, 2H), 4.44 - 4.30 (m, 2H), 4.00 - 3.92 (m, 3H), 3.45 - 3.34 (m, 2H), 1.51 - 1.45 (m, 9H), 1.41 - 1.35 (m, 3H), 1.34 - 1.29 (m, 6H).

[0375] [C68] [:](LC / MS) m / z (M+H)+ = 338.1; 1H NMR (400 MHz, CDCl3) δ 4.66 - 4.56 (m, 2H), 4.38 - 4.26 (m, 2H), 4.16 - 4.05 (m, 3H), 3.45 - 3.32 (m, 2H), 1.49 - 1.46 (m, 9H), 1.37 (t, 3H), 1.28 - 1.24 (m, 6H).

[0376] Step 2. Preparation of ethyl 1,7,7-trimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate hydrochloride [(P36)] [ ] At 0℃, towards [C67] (0.130 g, 0.385 mmol) was added to a suspension in DCM (3 mL) with HCl-containing dimethyl ether (3 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to obtain a yellow solid. [P36] (0.110 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 238.1. 1H NMR (400 MHz, (CD3)2SO) δ 9.58 (s, 2H), 4.27 (q, 2H), 4.18 (s, 2H), 3.98 (s, 3H), 3.21 - 3.16 (m, 2H), 1.42 (s, 6H), 1.31 - 1.22 (m, 3H).

[0377] [preparation]

[37] 1'-Methyl-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-carboxylic acid ethyl ester hydrochloride [(P37)] Step 1. Preparation of 3'-ethyl 5'-(tert-butyl) 1'-methyl-1',4'-dihydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3',5'(6'H)-dicarboxylic acid ester [(C69)] and 2-((3'-(ethoxycarbonyl)-2'-methyl-2',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-5'-carbonyl)oxy)-2-methylpropyl-1-ylonium [(C70)] [ ] according to [preparation] [2] [step] [1] Using the same procedure, 7-(2-ethoxy-2-epoxyacetyl)-8-epoxy-5-azaspiro[2.5]octane-5-carboxylic acid tributyl ester (CAS: 2494304-89-9; 0.620 g, 1.91 mmol) and methylhydrazine sulfate (CAS: 302-15-8, 0.302 g, 2.10 mmol) were used. The purification was modified. The residue was purified by column chromatography (silicone, 0-30% THF:PE) to obtain a white solid. [C70] (0.327 g, 51.2% yield) and a white gel-like substance. [C69] (0.290 g, 45.4% yield).

[0378] [C69] [:](LC / MS) m / z (M+H)+ = 336.3; 1H NMR (400 MHz, CDCl3) δ 4.70 (s, 2H), 4.39 (q, 2H), 3.74 (s, 3H), 3.44 (s, 2H), 1.48 (s, 9H), 1.39 (t, 3H), 1.31 (t, 2H), 1.08 - 0.94 (m, 2H).

[0379] [C70] [:](LC / MS) m / z (M+H)+ = 336.3; 1H NMR (400 MHz, CDCl3) δ 4.75 - 4.65 (m, 2H), 4.34 (q, 2H), 4.08 (s, 3H), 3.53 - 3.47 (m, 2H), 1.48 (s, 9H), 1.39 (t, 3H), 1.12 (q, 2H), 0.97 - 0.86 (m, 2H). [, , ]

[0380] Step 2. Preparation of ethyl 1'-methyl-1',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-pyrazolo[4,3-c]pyridine]-3'-carboxylic acid hydrochloride [(P37)] [ ] At 0℃, towards [C69] (0.272 g, 0.811 mmol) was added to a suspension in DCM (6 mL) containing dimethyl methacrylate (0.591 g, 16.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, followed by vacuum concentration to obtain a white solid. [P37] (0.219 g, crude material). The solid was used directly in the next step without further purification.

[0381] [preparation]

[38] rac-(R)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P38)] Step 1. Preparation of 3-ethyl 5-(tert-butyl) 5-(R)-1-isopropyl-7-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid. [(C71)] and rac-(R)-2-isopropyl-7-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester [(C72)] [ ] according to [preparation] [2] [step] [1] uses the same procedure. [C10] (3.00 g, 9.57 mmol) and isopropyl hydrazine hydrochloride (CAS: 16726-41-3, 1.06 g, 9.57 mmol). Purification was modified. The residue was purified by reverse-phase HPLC (Sunfire C18 150 mm × 40 mm × 5 µm column, mobile phase A: H2O (0.05% NH4OH-NH4HCO3) / mobile phase B: ACN, mobile phase B: after 9.0 min 42 to 82%, 100% mobile phase B held for 2.0 min, flow rate = 30 mL / min), yielding a pale yellow solid. [C71] (1.80 g, 53.5% yield) and a pale yellow solid. [C72] (33.9 mg, 1.01% yield). [ ]

[0382] [C71]:(LC / MS) m / z (M+H)+ = 352.4. 1H NMR (400 MHz, CDCl3) δ 5.05 (dd, 1H), 4.46 - 4.31 (m, 3H), 4.13 (dd, 2H), 3.20 - 3.04 (m, 1H), 2.99 - 2.89 (m, 1H), 1.54 (d, 3H), 1.51 - 1.45 (m, 12H), 1.36 (t, 3H), 1.23 (d, 3H).

[0383] [C72]:(LC / MS) m / z (M+H)+ = 352.4. 1H NMR (400 MHz, CDCl3) δ 5.56 - 5.44 (m, 1H), 4.69 - 4.45 (m, 2H), 4.32 (q, 2H), 3.90 - 3.61 (m, 1H), 3.41 - 3.13 (m, 1H), 3.02 - 2.92 (m, 1H), 1.51 - 1.44 (m, 15H), 1.38 (t, 3H), 1.26 (d, 3H).

[0384] Step 2. Preparation of rac-(R)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P38)] [ ] At 0℃, towards [C71] (0.200 g, 0.569 mmol) was added to a suspension in DCM (1 mL) containing HCl, along with 4 mL of dimethyl methacrylate (DMSO). The reaction mixture was stirred at room temperature for 2 hours, followed by vacuum concentration to obtain a yellow solid. [P38] (0.180 g, crude material). The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 252.1. 1H NMR (400 MHz, (CD3)2SO) δ 9.98 - 9.83 (m, 1H), 9.34 - 9.25 (m, 1H), 4.67 - 4.54 (m, 1H), 4.33 - 4.05 (m, 4H), 3.43 - 3.26 (m, 3H), 1.45 - 1.40 (m, 3H), 1.39 - 1.33 (m, 6H), 1.32 - 1.26 (m, 3H).

[0385] [preparation]

[39] 2-Fluoro-5-(1-Methyl-1H-1,2,4-triazol-5-yl)pyridine [(P39)] [ ] Step 1. Preparation of 2-fluoro-5-(1-methyl-1H-1,2,4-triazol-5-yl)pyridine [(P39)] [ ] Pd(dppf)Cl2 (0.457 g, 0.625 mmol) and K3PO4 (4.97 g, 23.4 mmol) were added to a suspension of (6-fluoropyridin-3-yl)boronic acid (CAS: 351019-18-6; 1.10 g, 7.81 mmol) and 5-bromo-1-methyl-1H-1,2,4-triazole (CAS: 16681-72-4; 1.52 g, 9.37 mmol) in dimethyl ether (10 mL) and H2O (2 mL). The reaction mixture was degassed with nitrogen, stirred at 110 °C for 4 hours, and purified by column chromatography (silicone, 0-40% EtOAc:PE) to obtain a white solid. [P39] (1.20 g, 86.3% yield). (LC / MS) m / z (M+H)+ = 179.1. 1H NMR (400 MHz, (CD3)2SO) δ 8.67 - 8.62 (m, 1H), 8.42 - 8.34 (m, 1H), 8.05 (s, 1H), 7.40 (dd, 1H), 3.97 (s, 3H).

[0386] [preparation]

[40] 2-Fluoro-5-(1-Methyl-1H-imidazol-2-yl)pyridine [(P40)] [ ] Step 1. Preparation of 2-fluoro-5-(1-methyl-1H-imidazol-2-yl)pyridine [(P40)] [ ] Under nitrogen atmosphere, a reaction mixture containing 2-bromo-1-methyl-1H-imidazolium (0.700 g, 4.35 mmol), (6-fluoropyridin-3-yl)boronic acid (1.20 g, 8.70 mmol), and Pd(dppf)Cl2 (0.178 g, 0.217 mmol) suspended in dimethyl ether (10 mL) and H2O (2 mL) was stirred at 90 °C for 1 hour. The reaction mixture was extracted with EtOAc, and the organic layer was subsequently concentrated under vacuum. The residue was dissolved in DCM and then purified by column chromatography (silicone, 0-10% MeOH:DCM) to give an orange oil. [P40] (0.688 g, 89.3% yield). (LC / MS) m / z (M+H)+ = 178.1.

[0387] [preparation]

[41] 2-(4-(aminomethyl)phenyl)pyrimidine-4(3H)-keto hydrochloride [(P41)] Step 1. Preparation of tert-butyl (4-(6-sideoxy-1,6-dihydropyrimidin-2-yl)benzyl)aminocarbamate [(C73)] [ ] Add 2M K3PO4 (0.325 g, 1.53 mmol) to a solution of 2-chloropyrimidin-4-ol (CAS: 55873-09-1; 0.100 g, 0.766 mmol) and tributyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzyl)aminocarbamate (CAS: 330794-35-9; 0.255 g, 0.766 mmol) in THF (7.7 mL). Degas the reaction mixture under nitrogen for 3 min, and then add XPhos Pd G2 (60.3 mg, 0.0766 mmol). Degas the suspension under nitrogen for 3 min, and then stir at 80 °C for 4 h. Dilute the reaction solution with H2O (10 mL) and then extract with MeOH:DCM (1:10, 3 × 5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-100% EtOAc:PE) to obtain a white solid. [C73] (0.115 g, 49.8% yield). (LC / MS) m / z (M+H)+ = 302.1. 1H NMR (400 MHz, (CD3)2SO) δ 12.75 (br s, 1H), 8.16 - 7.92 (m, 3H), 7.51 - 7.44 (m, 1H), 7.36 (d, 2H), 6.36 - 6.24 (m, 1H), 4.18 (d, 2H), 1.39 (s, 9H).

[0388] Step 2. Preparation of 2-(4-(aminomethyl)phenyl)pyrimidine-4(3H)-keto hydrochloride [(P41)] [ ] At 0℃, towards [C73] (0.115 g, 0.382 mmol) was added to a stirred solution of MeOH containing HCl (3 mL) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to give a white solid. [P41] (91.0 mg, crude material). The solid was used directly in the next step without further purification. ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.05 - 10.97 (m, 1H), 10.88 - 10.81 (m, 1H), 8.60 - 8.47 (m, 2H), 8.17 - 8.08 (m, 2H), 7.66 - 7.61 (m, 2H), 7.39 (dd, 1H), 6.40 - 6.36 (m, 1H), 5.46 - 5.42 (m, 1H), 4.10 (q, 2H).

[0389] [preparation]

[42] 6-(4-(aminomethyl)phenyl)pyridine-2(1H)-keto hydrochloride [(P42)] [ ] Step 1. Preparation of tert-butyl (4-(6-sideoxy-1,6-dihydropyridin-2-yl)benzyl)aminocarbamate [(C74)] [ ] Add 2M K3PO4 (0.244 g, 1.15 mmol) to a solution of 6-bromopyridin-2-ol (CAS: 27992-32-1; 0.100 g, 0.575 mmol) and tributyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzyl)carbamate (CAS: 330794-35-9; 0.192 g, 0.575 mmol) in THF (5.7 mL). Degas the reaction mixture under nitrogen for 3 min, then add XPhos Pd G2 (45.2 mg, 0.0575 mmol). Degas the suspension under nitrogen for 3 min and then stir at 80 °C for 4 h. Dilute the reaction solution with H2O (10 mL) and then extract with EtOAc (3 × 5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-100% EtOAc:PE) to obtain a white solid. [C74] (0.110 g, 63.7% yield). (LC / MS) m / z (M+H)+ = 301.1. 1H NMR (400 MHz, (CD3)2SO) δ 11.71 (br s, 1H), 7.73 (d, 2H), 7.58 - 7.51 (m, 1H), 7.49 - 7.44 (m, 1H), 7.33 (d, 2H), 6.71 - 6.57 (m, 1H), 6.37 (d, 1H), 4.18 (d, 2H), 1.41 (s, 9H).

[0390] [ ] Step 2. Preparation of 6-(4-(aminomethyl)phenyl)pyridine-2(1H)-keto hydrochloride [(P42)] [ ] At 0℃, towards [C74] (0.110 g, 0.366 mmol) was added to a stirred solution of MeOH containing HCl (3 mL) in DCM (1 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to give a white solid. [P42] (87.0 mg, crude material). The solid was used directly in the next step without further purification. ¹H NMR (400 MHz, (CD₃)₂SO) δ 8.46–8.36 (m, 3H), 7.84 (d, 2H), 7.61–7.54 (m, 3H), 6.80–6.70 (m, 1H), 6.43 (d, 1H), 4.07 (q, 2H).

[0391] [preparation]

[43] 3-(4-(aminomethyl)phenyl-2,3,5,6-d4)-1,1-dimethylurea hydrochloride [(P43)] [ ] Step 1. Preparation of 3-(4-bromophenyl-2,3,5,6-d4)-1,1-dimethylurea [(C75)] [ ] 4-Bromophenyl-2,3,5,6-d4-amine (CAS: 61357-76-4; 5.50 g, 31.2 mmol) was added to a solution of CDI (6.59 g, 40.6 mmol) in ACN (50 mL) at (-5 to 5) °C. The reaction mixture was stirred at (0 to 5) °C for 3 hours, followed by the slow addition of TEA (6.32 g, 62.5 mmol) and dimethylamine hydrochloride (CAS: 506-59-2; 5.10 g, 62.5 mmol) at (0 to 5) °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The suspension was poured into H2O (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, and concentrated under vacuum. The residue was slurried with MTBE:DCM (10:1, 100 mL) at room temperature for 3 hours and then filtered. The filter cake was vacuum dried and then collected to obtain a white solid. [C75] (6.10 g, 76.2% yield). ¹H NMR (400 MHz, (CD3)2SO) δ 8.40 (s, 1H), 2.91 (s, 6H).

[0392] Step 2. Preparation of tert-butyl (4-(3,3-dimethylurea)2,3,5,6-d4-benzyl)aminoformate [(C76)] [, , ] Will The reaction mixture of [C75] (3.0 g, 12 mmol), [[(tributoxycarbonyl)amino]methyl]trifluoroborate (4.3 g, 18 mmol) and Cs₂CO₃ (7.9 g, 24 mmol) in H₂O (6 mL) and dimethyl ether (40 mL) was degassed and purged three times with nitrogen. Bis(1-adamantyl)-butylphosphine (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 again and purged three times with nitrogen, then stirred at 90 °C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and then poured into H₂O (50 mL) and filtered. The filtrate was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO₄, and concentrated under vacuum. The residue was slurried with DCM (100 mL) at room temperature for 4 hours and then filtered. The filter cake was vacuum dried and then collected to obtain a light yellow solid. [C76] (2.0 g, 30.% yield).

[0393] [ ] Step 3. Preparation of 3-(4-(aminomethyl)phenyl-2,3,5,6-d4)-1,1-dimethylurea hydrochloride [(P43)] Towards [C76] (2.0 g, 6.7 mmol) was added to a solution of dimethyl methacrylate (25 mL) containing 2 M HCl in DCM (30 mL). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under vacuum. The residue was purified by reverse-phase HPLC (Welch Xtimate C18 250 mm × 50 mm × 10 µm column, mobile phase A: H2O containing HCl / mobile phase B: ACN, 0 to 20% mobile phase B for 20 minutes) and then lyophilized to give a white solid. [P43] (1.1 g, 67% yield). ¹H NMR (400 MHz, (CD3)2SO) δ 8.43 (s, ¹H), 8.37 (br s, 2H), 3.90 (q, 2H), 2.92 (s, 6H).

[0394] [ ] [preparation]

[44] rac-(R)-1-isopropyl-7-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P44)] Step 1. Preparation of tert-butyl 3-(2-ethoxy-2-epoxyacetyl)-4-epoxy-5-(trifluoromethyl)-3,4-dihydropyridine-1(2H)-formate [(C77)] [ ] A yellow solution of 1 M LiHMDS in THF (18.4 mL) was diluted with THF (10 mL) and then cooled to -69 °C using a dry ice / acetone bath. After 15 minutes, 20 mL of THF containing tributyl 4-sidekto-5-(trifluoromethyl)-3,4-dihydropyridine-1(2H)-carboxylate (CAS: 1667744-92-4; 4.07 g, 15.4 mmol) was added dropwise to the cooled solution. The acceptor flask was rinsed with THF (2 × 1 mL) and added to the reaction mixture. During the addition, the solution turned brownish-orange. After the addition, the reaction mixture was stirred at -69 °C for 45 minutes.

[0395] A solution of diethyl oxalate (2.52 mL) in THF (5 mL) was added dropwise to the reaction mixture over 8 minutes. The source vial was rinsed with THF (1.5 mL) and then added to the reaction mixture, which turned the solution brownish-orange. The reaction mixture was stirred for another 7 minutes in a dry ice / acetone bath, then removed and replaced with an ice-water bath. The reaction mixture was quenched with 2N HCl aqueous solution (21 mL), which turned the suspension orange. The suspension was diluted with H2O and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with saturated NaHCO3 solution (1 × 20 mL, 2 × 10 mL). The organic layers were set aside. The combined aqueous layers were washed with MTBE (3 × 20 mL). The combined organic layers were set aside. The aqueous layers were acidified to pH 1 with 6N HCl (~6.5 mL). The acidic aqueous layer was extracted with MTBE (2 × 40 mL). The combined organic layers from the acidic aqueous extraction were dried with Na₂SO₄, filtered, and concentrated under vacuum. Further drying under high vacuum yielded an orange-yellow residue. [C77] (1.52 g).

[0396] Combine the set-off organic layers. Dry the combined organic layers with Na₂SO₄, filter, and concentrate under vacuum to obtain a deep orange oil. Dissolve the oil in MTBE (40 mL) and then wash with saturated NaHCO₃ solution (1×32 mL, 1×10 mL). Combine the aqueous layers and acidify with 6N HCl aqueous solution. Extract the acidic aqueous layer with MTBE (30 mL) and then with MTBE (20 mL). Combine the organic layers and then dry with Na₂SO₄, filter, concentrate under vacuum, and further dry under high vacuum to obtain an orange residue. [C77] (1.92 g).

[0397] The two batches of products were combined to form [C77] (3.44 g) was subsequently purified by column chromatography (silicone, 0-85% EtOAc:heptane) to obtain a yellow oily substance. [C77] (2.32 g, 41.3% yield). (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).

[0398] Step 2. Preparation of 3-ethyl 5-(trifluoromethyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(C78)] and 2-((3-(ethoxycarbonyl)-2-isopropyl-7-(trifluoromethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)oxy)-2-methylpropyl-1-ylonium [(C79)] [ ] Towards [C77] (408 mg, 1.12 mmol) was added to a solution of EtOH (4.5 mL) with isopropyl hydrazine hydrochloride (CAS: 16726-41-3; 148 mg, 1.34 mmol) followed by the addition of pyridine (132 mg, 1.67 mmol). The reaction mixture was stirred at 55 °C for 20 hours and then concentrated under vacuum to give a yellow-orange residue. The residue was diluted with EtOAc (20 mL) and washed with NaHCO3 (20 mL). The aqueous layer was back-extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give an orange oil. The oil was dissolved in DCM, pre-adsorbed onto (1:1) silica:diatomaceous earth, and purified by column chromatography (silicone, 0-100% EtOAc:heptan) to give a gel-like product. [C78] (0.315 g, 69.9% yield) and a pale yellow solid. [C79] (7.70 mg, 1.71% yield).

[0399] [C78]:(LC / MS) m / z (M+H)+ = 404.6; 1H NMR (400 MHz, CDCl3) δ 7.67 - 7.46 (m, 1H), 5.02 (s, 2H), 4.73 - 4.63 (m, 1H), 4.39 (q, 2H), 1.55 (s, 9H), 1.50 (d, 6H), 1.39 (t, 3H).

[0400] [C79] [:](LC / MS) m / z (M+H)+ = 404.5; [] 1H NMR (500 MHz, CDCl3) δ 7.63 - 7.33 (m, 1H), 5.51 - 5.49 (m, 1H), 4.97 (s, 2H), 4.35 (q, 2H), 1.55 (s, 9H), 1.48 (d, 6H), 1.39 (t, 3H). [ ]

[0401] Step 3. Preparation of 3-ethyl 5-(trifluoromethyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester (tert-butyl) [(C80)] [ ] Add to the suspension of Pd / C (CAS: 7440-05-3; 83 mg, 5 wt%, 0.039 mmol) in EtOH (0.5 mL) [C78] (0.30 g, 0.75 mmol) was a pale yellow solution in EtOH (1.5 mL). The source vial was rinsed with EtOH (0.5 mL × 2), and the rinse solution was then added to the reaction mixture to bring the total volume of EtOH (3 mL). The reaction mixture was stirred overnight at room temperature in a Hastelloy reactor under H2 gas (50 psi). The suspension was filtered through a pre-filled plastic filter funnel using diatomaceous earth (0.5 g). The filter cake was dissolved with EtOH. The gray filtrate was concentrated under vacuum to give a gray residue.

[0402] The same reaction was repeated. A solution of the crude residue dissolved 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 in a Hastelloy reactor under H2 gas (50 psi). The suspension was filtered through a pre-filled plastic filter funnel using diatomaceous earth (0.5 g). The filter cake was dissolved with EtOH. The gray filtrate was concentrated under vacuum to give a gray solid. The solid was purified by column chromatography (silicone, 0-50% EtOAc:heptane) to give a white solid. [C80] (0.24 g, 78% yield). (LC / MS) m / z (M+H)+ = 406.6; 1H NMR (400 MHz, CDCl3) δ 5.35 - 5.23 (m, 1H), 5.13 - 4.76 (m, 2H), 4.59 - 4.47 (m, 1H), 4.44 - 4.34 (m, 3H), 4.29 - 4.08 (m, 2H), 3.60 - 3.44 (m, 1H), 3.08 (dd, 1H), 1.59 - 1.55 (m, 9H), 1.43 - 1.35 (m, 6H).

[0403] Step 4. Preparation of rac-(R)-1-isopropyl-7-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P44)] [ ] Towards [C80] (0.234 g, 0.577 mmol) was added dropwise with 1.44 mL of dimethyl methacrylate containing 4N HCl. The reaction mixture was stirred at 40 °C for 40 minutes, then concentrated under nitrogen, and further dried under high vacuum to give a white solid. [P44] (0.210 g, crude material). (LC / MS) m / z (M+H)+ = 306.5; 1HNMR (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).

[0404] [preparation]

[45] 1-(6-Fluoropyridin-3-yl)pyrrolidone-2-one [(P45)] Step 1. Preparation of 1-(6-fluoropyridin-3-yl)pyrrolidone-2-one [(P45)] The reaction mixture of 2-fluoro-5-iodopyridine (CAS: 171197-80-1; 2.00 g, 8.97 mmol), pyrrolidone-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 dimethyl ether (40 mL) was heated to 115 °C for 16 hours under nitrogen. The suspension was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-60% EtOAc:PE) to obtain a pale yellow solid. [P45] (1.40 g, 86.6% yield). (LC / MS) m / z (M+H)+ = 181.0; 1H NMR (400 MHz, (CD3)2SO) δ 8.46 - 8.43 (m, 1H), 8.36 - 8.29 (m, 1H), 7.22 (dd, 1H), 3.89 - 3.83 (m, 2H), 2.54 - 2.51 (m, 1H), 2.50 - 2.48 (m, 1H), 2.14 - 2.04 (m, 2H).

[0405] [preparation]

[46] (R)-1-Ethyl-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P46)] [ ] Step 1. Preparation of (R)-1-ethyl-6-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tertiary butyl) ester 3-ethyl ester [(C81)] and (R)-2-ethyl-6-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-(tributyl) ester 3-ethyl ester [(C82)] [ ] The reaction mixture of H₂O (8.8 mL), EtOH (8.8 mL), (2S,5RS)-5-(2-ethoxy-2-epoxyacetyl)-2-methyl-4-epoxypiperidin-1-carboxylic acid tributyl ester (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 LCMS, showing a residence time of 1.69 minutes. [C81](LC / MS) m / z (M+H)+ = 338.3 and the residence time of 1.94 minutes. [C82] (LC / MS) m / z (M+H)+ = 338.3. The reaction mixture was diluted with H2O and extracted with DCM (3×). The combined organic layers were dried over Na2SO4 and then purified by column chromatography (silicone, 0-100% EtOAc:heptane) to give [C81] (1.53 g, 86.0% yield) and [C82] (30.0 mg, 1.70% yield).

[0406] [C81]:1H NMR (400 MHz, (CD3)2SO) δ 4.88 (d, 1H), 4.78 - 4.65 (m, 1H), 4.33 - 4.17 (m, 2H), 4.14 - 3.94 (m, 3H), 2.85 (dd, 1H), 2.68 - 2.60 (m, 1H), 1.42 (s, 9H), 1.33 - 1.26 (m, 6H), 1.03 (d, 3H).

[0407] [C82]:1H NMR (400 MHz, (CD3)2SO) δ 4.91 (d, 1H), 4.78 - 4.63 (m, 1H), 4.54 - 4.36 (m, 2H), 4.35 - 4.15 (m, 2H), 4.09 - 3.96 (m, 2H), 3.38 - 3.26 (m, 1H), 2.82 - 2.65 (m, 2H), 2.56 - 2.51 (m, 1H), 2.47 - 2.36 (m, 1H), 2.28 - 2.12 (m, 2H), 1.35 - 1.27 (m, 6H), 1.10 - 1.06 (m, 3H), 1.04 - 0.99 (m, 3H).

[0408] [ ] Step 2. Preparation of (R)-1-ethyl-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester hydrochloride [(P46)] Towards [C81] (1.00 g, 2.96 mmol) was added to a solution of ACN (10 mL) with 12.1 M HCl (0.216 g, 5.93 mmol). The reaction mixture was stirred at 50 °C for 25 hours and 15 minutes, followed by vacuum concentration. The residue was diluted with ACN and then vacuum concentrated. The residue was diluted with DCM and vacuum concentrated (2×) to obtain a yellow foamy solution. [P46] (0.730 g, crude material). This yellow foam was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 238.2. 1H NMR (600 MHz, (CD3)2SO) δ 9.33 - 9.24 (m, 1H), 9.07 - 8.93 (m, 1H), 4.38 - 4.10 (m, 6H), 3.48 - 3.39 (m, 1H), 3.16 (dd, 1H), 2.71 (dd, 1H), 1.41 - 1.37 (m, 3H), 1.31 (dt, 6H).

[0409] [preparation]

[47] methyl 3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate [(47)] [ ] Step 1. Preparation of methyl 3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate [(P47)] EtOAc (5.0 mL) containing 2 M HCl was added to a solution of 1-methyl 7-(tributyl)-7-methyl 3-methyl-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid (CAS: 1359655-89-2, 0.190 g, 0.643 mmol) in DCM (5.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture became a white suspension, which was concentrated under vacuum to give a white solid. [P47] (0.149 g, crude material). This material was used in the next step without further purification. ¹H NMR (400 MHz, CD3OD) δ 4.80 (s, 2H), 4.51 (t, 2H), 4.00 (s, 3H), 3.84 (t, 2H), 2.71 (s, 3H).

[0410] [preparation]

[48] 3-Isopropyl-5,6,7,8-Tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid ethyl ester hydrochloride [(P48)] Step 1. Preparation of 1-ethyl 7-(tert-butyl) 3-(prop-1-en-2-yl)-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid ester [(C83)] [ ] A solution of 1-ethyl 7-(tributyl) 7-bromo-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid (CAS: 2108354-93-2; 1.00 g, 2.67 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhecyclopentane (CAS: 126726-62-3, 0.808 g, 4.81 mmol), NaHCO3 (0.673 g, 8.02 mmol), cataCXium® A (0.192 g, 0.534 mmol), and Pd(OAc)2 (60.0 mg, 0.267 mmol) in (4:1) DME:H2O (16 mL: 4 mL) was degassed with nitrogen for 5 minutes. The reaction solution was stirred at 90°C for 16 hours and then concentrated under vacuum. The residue was dissolved in DCM (50 mL) and then extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and then concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (silicone, 0-20% EtOAc:PE) to obtain a pale yellow solid. [C83] (0.856 g, 95.5% yield). (LC / MS) m / z (M+H)+ = 336.2.

[0411] Step 2. Preparation of 1-ethyl 7-(tert-butyl) 3-isopropyl-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid ester. [(C84)] [ ] Towards [C83] (0.86 g, 2.5 mmol) was added to a suspension in THF (20 mL) with RuCl(PPh3)3 (0.24 g, 0.25 mmol). The reaction mixture was degassed with hydrogen and then stirred at 60-65 °C for 48 hours under a hydrogen atmosphere (50 psi). The suspension was concentrated under vacuum, and the residue was subsequently purified by column chromatography (silicone, 0-20% THF:PE) to give a brown solid. [C84] (0.67 g, 77% yield). (LC / MS) m / z (M+H)+ = 338.3. 1H NMR (400 MHz, CDCl3) δ 4.87 (s, 2H), 4.36 (q, 2H), 3.92 (t, 2H), 3.82 (t, 2H), 3.03 - 2.89 (m, 1H), 1.50 (s, 9H), 1.43 - 1.32 (m, 9H).

[0412] Step 3. Preparation of ethyl 3-isopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate hydrochloride [(P48)] Towards [C84] (0.67 g, 2.0 mmol) was added to a solution of dimethyl methacrylate (20 mL) containing 2 M HCl in 10 mL of DCM. The reaction solution was stirred at room temperature for 2 hours, then concentrated under vacuum and further dried under high vacuum to obtain a solid. [P48] (0.54 g, crude material). The solid was used directly in the next step without further purification.

[0413] [preparation]

[49] 5,7-Di-tert-butyl-2-(oxetane-3-yloxy)-3-phenyl-2,3-dihydrobenzo[d]azole [(P49)] Step 1. Preparation of 5,7-di-tertiary butyl-2-(oxetane-3-yloxy)-3-phenyl-2,3-dihydrobenzo[d]azole [(P49)] The reaction mixture of 3-hydroxyoxetane (CAS: 7748-36-9; 41 mg, 0.55 mmol) and deoxyazole (CAS: 1207294-92-5; 0.22 g, 0.55 mmol) in MTBE (3 mL) was degassed with nitrogen (2×). The suspension was stirred at room temperature for 5 minutes, followed by the addition of pyridine (43 mg, 0.55 mmol). The reaction mixture was stirred for 30 minutes to obtain... [P49] A solution of 0.21 g (crude substance). This solution was used directly in the next step without further purification.

[0414] [preparation]

[50] rac-(4R)-1-isopropyl-4-methyl-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid methyl ester [(P50)] Step 1. Preparation of methyl 4-chloro-1-isopropyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(C85)] [ ] Cs₂CO₃ (18.5 g, 56.7 mmol) and 2-iodopropane (CAS: 75-30-9; 7.23 g, 42.5 mmol) were added 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). The reaction mixture was stirred at room temperature for 3 hours, diluted with EtOAc (100 mL), and washed with brine (3 × 300 mL). The organic layer was dried over Na₂SO₄ and then concentrated under vacuum. The yellow oil was purified by column chromatography (silicone, 0-37% EtOAc:hexane) to give [C85] (3.30 g, 45.9% yield). (LC / MS) m / z (M+H)+ = 254.0. 1H NMR (400 MHz, (CD3)2SO) δ 8.26 (d, 1H), 7.93 (d, 1H), 5.22 - 5.07 (m, 1H), 3.93 (s, 3H), 1.49 (d, 6H).

[0415] Step 2. Preparation of methyl 1-isopropyl-4-methyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(C86)] [ ] Towards [C85] (2.10 g, 8.28 mmol), trimethylborooxycyclohexane (CAS: 823-96-1; 8.31 g, 33.1 mmol) in dimethyl oxane (60 mL) was mixed with DIEA (4.28 g, 33.1 mmol) and Pd(t-Bu3P)2 (0.635 g, 1.24 mmol). The reaction mixture was degassed with nitrogen and then stirred at 90 °C for 12 hours. The suspension was diluted with EtOAc (100 mL), washed with brine (2 × 150 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-50% EtOAc:hexane) to give an orange gel. [C86] (2.10 g, crude material). This gel was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 234.0. 1H NMR (400 MHz, CDCl3) δ 8.33 (d, 1H), 7.24 (d, 1H), 4.96 - 4.83 (m, 1H), 4.03 (s, 3H), 3.06 (s, 3H), 1.65 - 1.61 (m, 6H).

[0416] [ ] Step 3. Preparation of methyl rac-(4R)-1-isopropyl-4-methyl-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(P50)] The reaction is carried out via 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, with H2 flowing at a rate of 30 mL / min. The solution was hydrogenated at 60 °C by a 2.0 MPa H2 flow through a fixed bed (1 / 4'' mm) packed with 5.0 mL of granular catalyst 5% Ru / Al2O3. The reaction mixture was collected from the reactor outlet to give a black oily product. [P50] (1.85 g, crude material). This oily substance was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 238.2. 1H NMR (400 MHz, (CD3)2SO) δ 4.61 - 4.42 (m, 2H), 4.24 - 4.01 (m, 1H), 3.86 - 3.75 (m, 3H), 3.04 - 2.77 (m, 4H), 1.49 (d, 3H), 1.38 (dd, 6H).

[0417] [preparation]

[51] rac-(4R)-4-ethyl-1-isopropyl-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid methyl ester [(P51)] [ ] Step 1. Preparation of methyl 1-isopropyl-4-vinyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(C87)] [ ] Towards [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) were added to a reaction mixture of dimethyl ether (10.0 mL) and H2O (3.5 mL), followed by the addition of Pd(dppf)Cl2 (0.288 g, 0.394 mmol). The suspension was degassed with nitrogen for 3 minutes and then stirred at 90 °C for 2 hours. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated under vacuum. The yellow gel was purified by column chromatography (silicone, 0-40% EtOAc:hexane) to obtain a pale yellow solid. [C87] (0.700 g, 72.4% yield). (LC / MS) m / z (M+H)+ = 246.1. 1H NMR (400 MHz, (CD3)2SO) δ 8.45 (d, 1H), 8.07 (dd, 1H), 7.79 (d, 1H), 6.51 (dd, 1H), 5.59 (dd, 1H), 5.19 - 5.08 (m, 1H), 3.93 (s, 3H), 1.50 (d, 6H).

[0418] Step 2. Preparation of methyl rac-(4R)-4-ethyl-1-isopropyl-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(P51)] The reaction is carried out via 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, with H2 flowing at a rate of 30 mL / min. The solution was hydrogenated at 60 °C by a 2.0 MPa H2 flow through a fixed bed (1 / 4'' mm) packed with 5.0 mL of granular catalyst 5% Ru / Al2O3. The reaction mixture was collected from the reactor outlet to give a brown oily product. [P51] (0.280 g, crude material). This oily substance was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 252.0. 1H NMR (400 MHz, (CD3)2SO) δ 9.75 (s, 1H), 9.23 (s, 1H), 4.59 - 4.50 (m, 1H), 3.78 (s, 3H), 3.07 - 2.89 (m, 2H), 2.45 - 2.41 (m, 2H), 2.00 - 1.75 (m, 2H), 1.35 (dd, 6H), 1.02 (t, 3H).

[0419] [preparation]

[52] rac-(6R,7R)-1-isopropyl-6,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester [(P52)] [ ] Step 1. Preparation of rac-(R)-2-methyl-4-sideoxy-3,4-dihydropyridine-1(2H)-carboxylic acid methyl ester [(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. The solution was cooled to -78°C, and then toluene (109.0 mL) containing 3M benzoyl chloroformate was added dropwise to obtain a white slurry. 3.4M methyl magnesium bromide solution (55.6 mL) was added dropwise to the suspension. The reaction mixture was stirred at -78°C and slowly warmed to room temperature over 24 hours. The reaction mixture was cooled to 0°C and quenched by fractional addition of 1M HCl aqueous solution. The aqueous mixture was extracted with DCM (3×). The organic layers were combined, dried over Na2SO4, and purified by column chromatography (silicone, 0-50% EtOAc:heptane) to obtain a clear oil. [C88] (51.5 g, 65.5% yield). (LC / MS) m / z (M+H)+ = 246.4. 1H NMR (400 MHz, (CD3)2SO) δ 7.78 (dd, 1H), 7.48 - 7.28 (m, 5H), 5.33 - 5.21 (m, 3H), 4.68 - 4.56 (m, 1H), 2.89 (dd, 1H), 2.24 - 2.14 (m, 1H), 1.15 (d, 3H).

[0420] Step 2. Preparation of rac-(2R,3R)-2,3-dimethyl-4-sideoxy-3,4-dihydropyridine-1(2H)-carboxylic acid methyl ester [(C89)] [ ] Will The reaction mixture of [C88] (10.0 g, 40.8 mmol) in THF (102 mL) was cooled to -78 °C, followed by dropwise addition of THF (42.8 mL) containing 1 M LiHMDS while stirring at -78 °C for 10 min. After stirring for several min, MeI (3.1 mL) was added dropwise to the reaction mixture at -78 °C and then warmed to room temperature for 30 min. The suspension was stirred at room temperature for 9 h and then quenched with brine. The pH of the aqueous layer was adjusted to pH = 1 using 12 M HCl aqueous solution. The reaction mixture was extracted with EtOAc (2×), the organic layer was layered, and then dried with Na2SO4. The mixture was purified by column chromatography (silicone, 0-40% MTBE: heptane) to give a yellow oil. [C89] (7.80 g, 73.6% yield). ¹H NMR (400 MHz, CD3OD) δ 7.84 (dd, ¹H), 7.47 - 7.32 (m, 5H), 5.36 - 5.20 (m, 3H), 4.40 (q, ¹H), 2.27 (q, ¹H), 1.21 (d, 3H), 1.15 (d, 3H).

[0421] Step 3. Preparation of rac-(2R,3R)-2,3-dimethyl-4-sideoxypiperidine-1-carboxylic acid methyl ester [(C90)] [ ] Add the following ingredients to the round-bottom flask in sequence. [C89] (12.8 g, 49.4 mmol), AcOH (82.3 mL), and Zn (12.9 g, 197 mmol) were added, followed by stirring at 60 °C for 5 hours. The reaction mixture was concentrated under vacuum, diluted with saturated NaHCO3, and extracted with DCM (3×). The combined organic layers were purified by column chromatography (silicone, 0-50% EtOAc:heptane) to give a clear oily solution. [C90] (10.1 g, 78.3% yield). 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).

[0422] Step 4. Preparation of rac-(2R,3R,5R)-5-(2-ethoxy-2-epoxyacetyl)-2,3-dimethyl-4-epoxypiperidine-1-carboxylic acid methyl ester [(C91)] [ ] Will 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, followed by the addition of THF (1.89 mL) containing 1 M LiHMDS. The suspension was stirred at room temperature for 17 hours and then quenched with a mixture of 1 M HCl aqueous solution, brine, and DCM. The aqueous layer was extracted with (2:1, MTBE:DCM, 2×). The organic layer was then dried over Na2SO4 and concentrated under vacuum to give a yellow oil. [C91] (0.590 g, crude substance). This oily substance was used directly in the next step without further purification.

[0423] Step 5. Preparation of 3-ethyl 5-phenylmethyl rac-(6R,7R)-1-isopropyl-6,7-dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid ester. [(C92)] [ ] Will 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 h, followed by stirring at room temperature for 24 h. The suspension was diluted with H2O and then extracted with DCM (3×). The organic layer was purified by column chromatography (silicone, 0-60% EtOAc:heptane) to give a clear oil. [C92] (0.322 g, 49.4% yield).

[0424] Step 6. Preparation of ethyl rac-(6R,7R)-1-isopropyl-6,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(P52)] [ ] Add 1 mL of EtOH containing Pd / C (10 wt%, 0.213 g, 2.00 mmol) to the reactor, followed by the addition of... A solution of [C92] (0.800 g, 2.00 mmol) in EtOH (5 mL) was prepared. The suspension was degassed with hydrogen and then stirred at room temperature for 1 hour under a hydrogen atmosphere (120 psi). The reaction mixture was filtered through diatomaceous earth and then washed with tripentalanol. The filtrate was concentrated under vacuum to give a yellow oil. [P52] (0.531 g, crude material). This oily substance was used directly in the next step without further purification. ¹H NMR (400 MHz, (CD₃)₂SO) δ 4.57 - 4.46 (m, 1H), 4.23 (q, 2H), 3.82 - 3.68 (m, 2H), 2.84 - 2.74 (m, 1H), 2.62 - 2.55 (m, 1H), 1.43 (d, 3H), 1.39 - 1.31 (m, 6H), 1.22 - 1.18 (m, 3H), 1.05 - 1.01 (m, 3H).

[0425] [ ] [preparation]

[53] rac-(R)-3-isopropyl-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid ethyl ester hydrochloride [(P53)] [ ] Step 1. Preparation of ethyl 5-methylimidazo[1,5-a]pyridine-1-carboxylate [(C14a)] [ ] Cs₂CO₃ (38.0 g, 117 mmol) and ethyl 2-isocyanate (CAS: 2999-46-4, 17.8 g, 156 mmol) were added to a mixture of 2-chloro-6-methylpyridine (CAS: 38557-71-0, 10.0 g, 77.8 mmol) in DMF (150.0 mL) at 15 °C. The reaction mixture was heated to 85 °C for 16 hours, and then diluted with EtOAc (300 mL). The light brown reaction mixture was filtered, and the filtrate was concentrated under vacuum. The brown residue was diluted with (1:1, EtOAc:THF) and filtered. The filter cake was dissolved in (1:1, H₂O:EtOAc) and subsequently extracted with EtOAc (150 mL). The combined organic phase was dried with Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-100% EtOAC:PE) to obtain a light brown solid. [C14a] (7.71 g, 48.3% yield). (LC / MS) m / z (M+H)+ = 206.1. 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.16 (s, 1H), 7.66 (s, 1H), 4.52 (q, 2H), 2.65 (s, 3H), 1.48 (t, 3H).

[0426] Step 2. Preparation of rac-(R)-5-methyl-5,6,7,8-tetrahydroimidazole[1,5-a]pyridine-1-carboxylic acid ethyl acetate [(C93)] [ ] The reaction is carried out via fluid chemistry. [C14a] (7.71 g, 37.6 mmol) was dissolved in THF (155 mL) and AcOH (40 mL) and then pumped at a flow rate of 0.3 mL / min and H2 at a rate of 30 mL / min. The solution was passed through a fixed bed ((1 / 4'') mm) packed with 5.0 mL of granular catalyst 10% Ru / SiO2 (2.80 g, 2.76 mmol) and hydrogenated at 2.5 MPa for 3.3 min at 80 °C. The H2 flow rate was 100 mL / min. After 10 min, the reaction mixture was collected and then concentrated under vacuum to remove THF. The suspension was stirred for 1–2 hours and then filtered. Vacuum concentration of the filtrate yields a light brown oily substance. [C93] (5.50 g, crude material). This oily substance was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 210.1.

[0427] Step 3. Preparation of 1-ethyl rac-(R)-5-methyl-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid 7-(tert-butyl) ester [(C94)] [ ] At room temperature [C93] (7.50 g, 19.3 mmol) was added to a solution of Boc2O (6.31 g, 28.9 mmol) and K2CO3 (10.7 g, 77.1 mmol) in 100 mL of ACN. The reaction mixture was stirred at room temperature for 16 hours and then diluted with EtOAc (100 mL). The suspension was filtered, and the filtrate was then concentrated under vacuum. The residue was purified by column chromatography (silicone; 0-100% EtOAc:PE) to give a grayish-white solid. [C94] (5.30 g, 93.1% yield). (LC / MS) m / z (M+H)+ = 310.2. 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 4.96 - 4.78 (m, 2H), 4.41 - 4.22 (m, 3H), 3.95 - 3.90 (m, 1H), 3.48 - 3.43 (m, 1H), 1.55 - 1.49 (m, 12H), 1.39 (t, 3H).

[0428] Step 4. Preparation of 1-ethyl rac-(R)-3-bromo-5-methyl-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid 7-(tert-butyl) ester [(C95)] [ ] Towards [C94] (3.20 g, 10.8 mmol) in ACN (30.0 mL) was followed by the addition of NBS (2.89 g, 16.3 mmol) in ACN (20.0 mL). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-40% EtOAc:PE) to give a white solid. [C95] (2.57 g, 64.0% yield). (LC / MS) m / z (M+2H)+ = 390.0. 1H NMR (400 MHz, CDCl3) δ 5.59 - 5.25 (m, 1H), 4.51 - 4.25 (m, 5H), 3.40 - 3.12 (m, 1H), 1.51 (s, 9H), 1.45 - 1.29 (m, 6H).

[0429] [ ] Step 5. Preparation of 1-ethyl rac-(R)-3-isopropyl-5-methyl-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid 7-(tert-butyl) ester [(C96)] [ ] Will A solution of [C95] (1.00 g, 2.58 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaboronium cyclopentane (CAS: 126726-62-3, 0.779 g, 4.64 mmol), NaHCO3 (0.649 g, 7.73 mmol), cataCXium® A (0.185 g, 0.515 mmol), and Pd(OAc)2 (57.8 mg, 0.258 mmol) in (4:1) DME:H2O (16 mL:4 mL) was degassed with nitrogen for 5 minutes. The reaction solution was stirred at 80 °C for 15 hours, then filtered and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-35% EtOAc:PE) to obtain a gel-like solution. [C96] (0.810 g, 90.0% yield). (LC / MS) m / z (M+H)+ = 350.2. 1H NMR (400 MHz, (CD3)2SO) δ 5.49 - 5.38 (m, 2H), 5.26 - 5.05 (m, 1H), 4.79 - 4.65 (m, 1H), 4.58 - 4.36 (m, 1H), 4.33 - 3.97 (m, 4H), 2.10 - 2.06 (m, 3H), 1.43 (s, 9H), 1.31 - 1.24 (m, 3H), 1.23 - 1.16 (m, 3H).

[0430] [ ] Step 6. Preparation of 1-ethyl 7-(tert-butyl) rac-(R)-5-methyl-3-(prop-1-en-2-yl)-5,6-dihydroimidazo[1,5-a]pyridine-1,7(8H)-dicarboxylic acid ester [(C97)] [ ] Towards [C96] (0.810 g, 2.32 mmol) was added to a solution of EtOH with ammonium formate (2.19 g, 34.8 mmol) and Pd / C (0.370 g, 0.348 mmol). The reaction mixture was stirred at 60 °C under argon for 1 hour and then filtered through diatomaceous earth. The filter cake was washed with EtOH (3 × 30 mL). The filtrate was concentrated under vacuum and then dissolved in DCM (50 mL). The solution was washed with brine (3 × 50 mL). The organic layer was concentrated under vacuum to obtain... [C97] (0.715 g, crude material). This crude material was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 352.2.

[0431] [ ] Step 7. Preparation of rac-(R)-3-isopropyl-5-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylic acid ethyl ester hydrochloride [(P53)] [ ] Towards [C97] (0.715 g, 2.03 mmol) was added to a solution of dimethyl methacrylate (20 mL) containing 2 M HCl in 10 mL of DCM. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under vacuum and lyophilized to obtain a gel-like product. [P53] (0.710 g, crude material). This gel was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 252.2.

[0432] Example 1 N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-5-(5-(2-sideoxypyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methylamine [(1)] Step 1. Preparation of ethyl 5-(5-iodopyridin-2-yl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate ( [C98]) Will 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 vacuum and purified by column chromatography (silicone, 0-20% EtOAc:PE) to give a white solid. [C98] (0.61 g, 27.8%). (LC / MS) m / z (M+H)+ = 441.2. 1H NMR (400 MHz, CDCl3) δ 8.32- 8.31 (m, 1H), 7.68 (dd, 1H), 6.58 (d, 1H), 4.60 (s, 2H), 4.52- 4.38 (m, 3H), 4.03 (t, 2H), 2.80 (t, 2H), 1.52 (d, 6H), 1.44-1.40 (m, 3H).

[0433] Step 2. Preparation of ethyl 1-isopropyl-5-(5-(2-sideoxypyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate ( [C99]) Will A mixture of [C98] (0.400 g, 0.909 mmol), pyrrolidone-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 dimethyl ether (10.0 mL) was heated at 120 °C for 16 hours under nitrogen. The reaction mixture was concentrated under vacuum, and the residue was subsequently purified by column chromatography (silicone, 0-30% THF:PE) to give a white solid. [C99] (0.36 g, 99.7% yield). (LC / MS) m / z (M+H)+ = 398.2.

[0434] Step 3. Preparation of 1-isopropyl-5-(5-(2-sideoxypyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ( [C100]) Towards [C99] (0.360 g, 0.906 mmol) was added to a solution of THF (5.00 mL), MeOH (1.25 mL), and H₂O (2.50 mL), followed by stirring at room temperature for 1 hour and 30 minutes. The solution was concentrated under vacuum and then acidified with 2N HCl to pH 5-6. The precipitated grayish-white solid was filtered, washed with H₂O (3 × 50 mL), dried, and then lyophilized to obtain a white solid. [C100] (0.27 g, 80.7%). 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).

[0435] Step 4. Preparation of N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-5-(5-(2-sideoxypyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methamide ( [1]) Will A solution of [C100] (80.0 mg, 0.217 mmol), HOPO (71.0 mg, 0.639 mmol), EDCI (99.6 mg, 0.520 mmol), and DIEA (0.140 g, 1.08 mmol) in DMSO (2.0 mL) was stirred at room temperature for 10 minutes, and then added to the reaction mixture. [P11] (74.6 mg, 0.325 mmol), then heated to 40°C and stirred for 2 hours. The residue was purified by reverse-phase HPLC (C18 150 mm × 30 mm × 5 µm column, mobile phase A: H2O / mobile phase B: ACN (NH4OH-NH4HCO3), for 9 minutes with 18% to 58% mobile phase B, then for 2 minutes with 100% mobile phase B, flow rate: 30 mL / min) and lyophilized to obtain a white solid. [1] (72.2 mg, 61.2% yield). (LC / MS) m / z (M+H)+ = 545.4. 1H NMR (400 MHz, (CD3)2SO) δ 8.33- 8.27 (m, 2H), 8.23 ​​(s, 1H), 7.89 (dd, 1H), 7.42 - 7.37 (m, 2H), 7.20- 7.15 (m, 2H), 6.90 (d, 1H), 4.65 (s, 2H), 4.53- 4.42 (m, 1H), 4.35 (d, 2H), 3.87 (t, 2H), 3.76 (t, 2H), 2.91 (s, 6H), 2.80 (t, 2H), 2.43 (t, 2H), 2.10- 2.00 (m, 2H), 1.39 (d, 6H).

[0436] [Example] [2] 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methoxyamine [2]) Step 1. Preparation of ethyl 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate ( [C101]) Towards [P2] (70.0 g, 256 mmol) and CsF (97.1 g, 639 mmol) in DMSO (0.7 L) were 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. The reaction mixture was diluted with H2O (6 L) and then extracted with MeOH:DCM (1:10, 3×2 L). The combined organic layers were washed with brine (2×3 L), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silicone, 0-100% EtOAc:PE) to give a pale yellow solid. [C101] (72.0 g, 73.1% yield). (LC / MS) m / z (M+H)+ = 386.2. 1H NMR (600 MHz, (CD3)2SO) δ 8.25 (d, 1H), 7.65 (dd, 1H), 6.91 (d, 1H), 4.74 (s, 2H), 4.58-4.47 (m, 1H), 4.30 (q, 2H), 3.96 (t, 2H), 2.97 (s, 6H), 2.83 (t, 2H), 1.38 (d, 6H), 1.32 (t, 3H).

[0437] Step 2. Preparation of 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ( [C102]) The reaction was carried out in two batches, which were then combined for purification. Under nitrogen atmosphere at room temperature, the reaction proceeded... [C101] (42.0 g, 109 mmol) was added to a mixture in ACN (420 mL) with KOTMS (28.0 g, 218 mmol), and then stirred at room temperature for 1 hour to obtain the first batch. The first batch was acidified to pH 5-6 with dimethyl ether (109 mL, 7.95 g, 218 mmol) containing 2M HCl, and then concentrated under vacuum.

[0438] The first batch of residue and its use The second batch of identical reactants of [C101] (43.0 g, 112 mmol) was combined. The combined reaction mixture was diluted with brine (500 mL) and extracted with MeOH:DCM (1:10, 3 × 1 L). The combined organic layers were dried over Na2SO4, filtered, and then concentrated under vacuum to give a white solid. [C102] (66.0 g, 83.7% yield). This substance was used in the next step without further purification. ¹H NMR (600 MHz, (CD3)2SO) δ 8.24 (d, 1H), 7.63 (dd, 1H), 6.92 (d, 1H), 4.70 (s, 2H), 4.54 - 4.37 (m, 1H), 3.94 (t, 2H), 2.97 (s, 6H), 2.79 (t, 2H), 1.37 (t, 6H).

[0439] Step 3. Preparation of 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methamide [(2)] Dissolved in ACN (1.0 mL) and H2O (0.1 mL) [C102] (70 mg, 0.20 mmol) was reacted with HOPO (26 mg, 0.24 mmol) and EDCI (60 mg, 0.31 mmol). The reaction mixture was stirred at 50 °C for 20 minutes and then cooled to room temperature. DIEA (76 mg, 0.59 mmol) was then added to the reaction mixture. [P11] (54 mg, 0.24 mmol). The mixture was stirred at room temperature for 1 hour and 20 minutes. The reactants were concentrated under vacuum, dissolved in DMSO, and acidified with TFA. The acidic residue was purified by reverse-phase HPLC (Sunfire C18 100 mm × 19 mm × 5 µm column, mobile phase A: H2O / mobile phase B: ACN (0.05% TFA), through 15 to 95% mobile phase B for 9.0 min, 95% mobile phase B held for 1.0 min, flow rate: 25 mL / min) to obtain [2] (30 mg, 25% yield). (LC / MS) m / z (M+H)+ = 533.4. 1H NMR (600 MHz, (CD3)2SO) δ = 8.27 (t, 1H), 8.18 - 8.12 (m, 2H), 7.58 (dd, 1H), 7.34 - 7.30 (m, 2H), 7.11 (d, 2H), 6.84 (d, 1H), 4.68 (s, 2H), 4.45- 4.38 (m, 1H), 4.28 (d, 2H), 3.89 (t,2H), 2.93-2.88 (m, 6H), 2.84 (s, 6H), 2.76 (t, 2H), 1.33 (d, 6H).

[0440] [ ] Example 3 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methamide [(3)] Step 1. Preparation of ethyl 5-(5-(dimethylaminomethoxy)pyridin-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 by a method similar to Preparation 1, 0.350 g, 1.35 mmol) was added to a mixture of butyronitrile (5.0 mL) and DIEA (0.697 g, 5.39 mmol), and the reaction mixture was heated at 115 °C for 17 hours. The solution was concentrated under vacuum, then dissolved in DCM and purified by column chromatography (silicone, 0-5% MeOH:DCM) to give a yellow oil. [C103] (0.209 g, 41.7% yield). (LC / MS) m / z (M+H)+ = 372.4. 1H NMR (600 MHz, (CD3)2SO) δ 8.23 ​​(d, 1H), 7.64 (dd, 1H), 6.91 (d, 1H), 4.73 (s, 2H), 4.28 (q, 2H), 4.09 (q, 2H), 3.95 (t, 2H), 2.96 (s, 6H), 2.81 (t, 2H), 1.34-1.28 (m, 6H).

[0441] Step 2. Preparation of 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ( [C104]) At 15℃, containing [C103] (0.250 g, 0.673 mmol) was prepared by adding LiOH (80.6 mg, 3.37 mmol) to 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 vacuum to remove the organic layer, and the aqueous layer was acidified to pH 3 with 2N HCl. The acidic aqueous phase was concentrated under vacuum and then purified by reverse-phase HPLC (C18 150 mm × 30 mm × 5 µm column, mobile phase A: H2O / mobile phase B: ACN (0.05% formic acid), through 0 to 32% mobile phase B for 9 minutes, followed by 100% mobile phase B for 2 minutes, flow rate: 30 mL / min) and lyophilized to obtain a white solid. [C104] (0.150 g, 64.9% yield). (LC / MS) m / z (M+H)+ = 344.3. 1H NMR (400 MHz, CD3OD) δ 8.31 - 8.25 (m, 1H), 7.68 (dd, 1H), 6.91 (d, 1H), 4.77 (s, 2H), 4.15 (q, 2H), 4.06 (t, 2H), 3.09 (s, 6H), 2.86 (t, 2H), 1.40 (t, 3H).

[0442] Step 3. Preparation of 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methamide [(3)] The reaction was carried out in two batches and then combined for purification. [C104] (0.100 g, 0.291 mmol) was added to a solution of DMSO (3.0 mL) with HOPO (97.1 mg, 0.874 mmol), DIEA (0.188 g, 1.46 mmol), and EDCI (0.134 g, 0.699 mmol) to form the first batch. The reaction mixture of the first batch was stirred at 40 °C for 15 minutes, and then added... [P11] (73.6 mg, 0.320 mmol). The first batch of suspension was stirred at 40°C for 2 hours.

[0443] The first batch of reaction mixture and its use The second batch of identical reactants of [C104] (0.563 g, 1.64 mmol) was combined. The combined reactants were purified by reverse-phase HPLC (C18 150 mm × 40 mm × 5 µm column, mobile phase A: H2O / mobile phase B: ACN (NH4OH-NH4HCO3), for 9 min with 3-43% mobile phase B, followed by 2 min with 100% mobile phase B, flow rate: 60 mL / min) and lyophilized to obtain [3] (0.467 g, 46.7% yield). (LC / MS) m / z (M+H)+ = 519.3. 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 1H), 7.62 (dd, 1H), 7.35 (d, 2H), 7.31- 7.27 (m, 2H), 7.09 (t, 1H), 6.77 (d, 1H), 6.31 (s, 1H), 4.75 (s, 2H), 4.55 (d, 2H), 4.15 (t, 2H), 4.03 (q, 2H), 3.08 (s, 6H), 3.03 (s, 6H), 2.81 - 2.74 (m, 2H), 1.40 (t, 3H).

[0444] [ ] [Example] [4] 5-(4-(dimethylaminomethoxy)phenyl)-1-methyl-N-(4-(methylaminomethoxy)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methamide [4]) Step 1. Preparation of ethyl 5-(4-(dimethylaminomethoxy)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate [(C105)] The reaction was carried out in two batches and subsequently combined for purification. The reaction was carried out at room temperature... [P4] (50.0 mg, 0.239 mmol) and 4-bromo-N,N-dimethylbenzamide (CAS: 18469-37-9, 54.5 mg, 0.239 mmol) were added to a solution of dimethyl ether (3.0 mL) with RuPhos (11.2 mg, 0.0239 mmol), RuPhos Pd G3 (20.0 mg, 0.0239 mmol) and NaOtBu (45.9 mg, 0.478 mmol) 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.

[0445] The first batch of reaction mixture and its use [P4] (0.400 g, 1.91 mmol) was combined with a second batch of identical reactants. The combined reactants were purified by HPLC (C18 150 mm × 30 mm × 5 µm column, mobile phase A: H2O / mobile phase B: ACN (0.05% NH4OH-NH4HCO3), for 9 minutes with 6% to 46% mobile phase B, followed by 2 minutes with 100% mobile phase B, flow rate: 30 mL / min) and lyophilized to obtain a white solid. [C105] (50.0 mg, 6.53% yield). (LC / MS) m / z (M+H)+ = 357.2.

[0446] Step 2. Preparation of 5-(4-(dimethylaminomethoxy)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate salt [(C106)] At room temperature [C105] (50.0 mg, 0.140 mmol) was added to a solution of THF (3.0 mL) and H2O (0.5 mL), followed by stirring at 40 °C for 16 hours. The reaction mixture was concentrated under vacuum, washed with H2O (2 × 10 mL), and then acidified with 2 M HCl until pH = 5-6; the resulting solid was filtered to obtain a white solid. [C106] (46.0 mg, 89.8% yield). This substance was used in the next step without further purification. (LC / MS) m / z (M+H)+ = 329.2.

[0447] Step 3. Preparation of 5-(4-(dimethylaminomethoxy)phenyl)-1-methyl-N-(4-(methylaminomethoxy)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methamide ( [4]) Towards [C106] (46.0 mg, 0.140 mmol) was added to a solution of HATU (79.9 mg, 0.210 mmol), DIEA (54.3 mg, 0.420 mmol), and 4-(aminomethyl)-N-methylbenzamide hydrochloride (CAS: 1158467-80-1, 28.1 mg, 0.140 mmol) in DMF (5.0 mL). The reaction mixture was stirred at room temperature for 12 hours. The residue was purified by reverse-phase HPLC (C18 150 mm × 30 mm × 5 µm, mobile phase A: H2O / mobile phase B: ACN (0.05% formic acid), for 9 min with 8% to 33% mobile phase B, followed by 2 min with 100% mobile phase B, flow rate: 30 mL / min) and lyophilized to obtain an impure white solid. [4] (25.0 mg). The solid was purified by reverse-phase HPLC (C18 150 mm × 30 mm × 5 µm, mobile phase A: H2O / mobile phase B: ACN (0.05% NH4OH-NH4HCO3), for 9 min with 4 to 44% mobile phase B, then for 2 min with 100% mobile phase B, flow rate: 30 mL / min) and lyophilized to obtain a white solid. [4] (12.8 mg, 19.3% yield). (LC / MS) m / z (M+H)+ = 475.2. 1H NMR (400 MHz, CD3OD) δ 7.80 - 7.74 (m, 2H), 7.46 - 7.42 (m, 2H), 7.38 - 7.33 (m, 2H), 7.08 - 7.02 (m, 2H), 4.60 (s, 2H), 4.50 (s, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 3.06 (s, 6H), 2.91 (s, 3H), 2.84 (t, 2H).

[0448] [Example] [5] 7-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-methylamine [(5)] Step 1. Preparation of methyl 3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxylate hydrochloride [(C107)] EtOAc (5.0 mL) containing 2 M HCl was added to a solution of 1-methyl 7-(tributyl)-7-methyl-1,7(8H)-dicarboxylic acid (CAS: 1359655-89-2, 0.190 g, 0.643 mmol) in DCM (5.0 mL) at 10 °C. T...

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof: wherein X1 is CH, CNH2, or N; X2 is C or N; X3 is CR13, N, NR13, O, or S; X4 is CH, N, or NR13; X5 is CR1B or N; X6 is CH or N; X7 is CH, N, or CF; X8 is CH or N; X9 is CR1B or N; X10 is CR1B or N; R1 is -NHR8, -OH, -C2-5 heterocyclic, or -C1-3 alkyl; wherein the -C2-5 heterocyclic of R1 is optionally substituted with one, two, or three -C1-3 alkyl, -C1-3 oxoalkyl, -C3-5 heterocyclic alkyl, -C3-5 hydroxycyclic alkyl, -C3-5 aminocyclic alkyl, or oxoalkyl; wherein the -C1-3 alkyl of R1 is optionally substituted with one, two, or three oxoalkyl, -NR10AR11, or -NR10R11; R1A is H, halogen, or -CH3; or R1 and R1A form a C5-7 heterocyclic alkyl fused to ring D or a C5-7 heteroaryl fused to ring D; wherein the C5-7 heterocyclic alkyl or C5-7 heteroaryl is optionally substituted with an oxoalkyl; each R1B is independently H, -CH3, F, Cl, or methoxy. R2 is H, -C1-3 alkyl, -C1-3 alkoxy, -C1-3 fluoroalkyl, or halogen; R3 is a -C1-3 alkyl, -C2-10 heterocyclic, -P(=O)(CH3)2, -S(=O)CH3, -NH-S(=O)2CH3 or -NH-C(=O)-C1-3 alkyl; wherein the -C1-3 alkyl of R3 is substituted with one, two or three septyl groups, halogens, -C3-6 cycloalkyl groups, -OH, -NR12R12A or cyano groups as appropriate; wherein the -C2-10 heterocyclic is substituted with one, two or three -OH, halogens, -C1-3 hydroxyalkyl groups, -C1-3 alkoxy groups, -C1-3 alkyl groups, -C1-3 fluoroalkyl groups, cyclopropyl groups or septyl groups as appropriate; or R2 and R3 form a C3-6 heterocyclic ring fused with ring A, which is substituted with one, two or three -C1-3 alkyl groups, -C2-3 septyl groups or septyl groups as appropriate; R4A is H, -OH, -C1-3 fluoroalkyl, or -C1-3 alkyl; R4B is H or absent; or R4A and R4B form a cyclopropyl group; each R5 is independently H, halogen, -OH, cyclopropyl, -C1-3 fluoroalkyl, or -C1-3 alkyl; or two R5 groups form a cyclopropyl group; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6 or one R5 and R6 form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge; or R4B and one R5 form a C3-5 cycloalkyl group fused with ring B; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, -C1-3 alkyl, -SO2CH3, or -C3-4 heterocyclic.The -C1-3 alkyl group of R8 may be substituted with one, two, or three septyl groups, -C3-9 heterocyclic alkyl groups, -C1-3 alkoxy groups, cyanoimine, or -NR9R10, depending on the situation; the -C3-4 heterocyclic group of R8 may be substituted with one, two, or three septyl groups, halogens, -C0-1 alkyl-NR10R11, -OH, -C1-3 hydroxyalkyl groups, or -C1-3 alkoxy groups, -C1-3 alkyl-C1-3 alkoxy groups, -C1-3 septyl alkyl groups, or - NR10R11, depending on the situation. C1-3 alkyl substitution; wherein the -C3-9 heterocyclic alkyl of R8 is, as appropriate, substituted with one, two or three -C1-3 alkyl, -OH, -C1-3 hydroxyalkyl, -O-C1-3 hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkyl-C1-3 alkoxy, halogen, -C1-3 fluoroalkyl, -C1-3 fluoroalkoxy, cyano, -C1-3 cyanoalkyl, -C0-1 alkyl-C3-5 heterocyclic alkyl, -O-C3-5 heterocyclic alkyl or -C0-1 alkyl-NR10R11; R9 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, -methylene-phenyl-NH-C(=O)-NR10R11, or -C3-5 heterocyclic alkyl; wherein the -C1-4 alkyl of R9 is substituted with one, two, or three -C3-5 cycloalkyl, -C3-5 heterocyclic alkyl, or methoxy, as appropriate; wherein the -C3-5 cycloalkyl of R9 is substituted with one or two -OH or -C1-3 alkyl, as appropriate; each R10 is independently H or -C1-4 alkyl; R10A is -C0-1 alkyl-C3-5 heterocyclic alkyl substituted with -C1-3 alkyl, as appropriate; each R11 is independently H or -C1-3 alkyl; R12 is H, -C1-3 alkyl, -C1-3 hydroxyalkyl, -(CH2)0-2-C3-5 heterocyclic alkyl, -(CH2)1-2-O-C3-5 heterocyclic alkyl, -methylene-C(=O)-NR10R11 or -methylene-phenyl-NH-C(=O)-NR10R11; wherein the -(CH2)0-2-C3-5 heterocyclic alkyl or -(CH2)1-2-O-C3-5 heterocyclic alkyl of R12 is substituted with -C1-4 alkyl, -C1-3 alkyl-C1-3 alkoxy, -(CH2)0-1-phenyl, halogen, -C1-3 fluoroalkyl or -(CH2)0-1-C3-5 heterocyclic alkyl; wherein the -C1-3 alkyl of R12 is substituted with one, two or three side oxygens or NR10R11; R12A is H or -C1-4 alkyl;Alternatively, R12 and R12A may form a C3-10 heterocycle, which may be substituted with one, two, or three -OH, -C1-3 alkyl, syloxy, halogen, -C2-3 syloxyalkyl, -C1-3 alkoxy, -C1-3 hydroxyalkyl, -C1-3 alkyl-C1-3 alkoxy, cyano, -C3-6 cycloalkyl, -S(=O)2CH3, -S(=O)2CH2CH3, -C(=O)-NR10R11, or -NHC(=O)CH3, depending on the situation. R13 is H, -C1-6 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C1-3 alkyl-C1-3 alkoxy, -C1-4 cyanoalkyl, -C0-1 alkyl-C3-5 cycloalkyl, -C2-4 syloxyalkyl, or -C0-1 alkyl-C3-5 heterocyclic alkyl; wherein the -C1-6 alkyl of R13 is substituted with one, two, or three syloxy groups, fluorine, -NH2, C3-6 cycloalkyl, or methoxy groups as appropriate; wherein the -C3-5 cycloalkyl or -C3-6 cycloalkyl of R13 is substituted with one, two, or three -C1-3 alkyl, -C1-3 fluoroalkyl, or halogen as appropriate; R14 is H; or X4 is NR13 and R13 and R14 form a C4-5 heterocycle fused with a cyclic C; n is 1 or 2; m is 0 or 1; If X3 is CR13 or NR13, then X4 is CH or N; and if X4 is NR13, then X3 is N, O, or S; each heterocycle independently comprises one to four heteroatoms, including at least one of N, O, or S.

2. A compound of formula IA, or a pharmaceutically acceptable salt thereof, having the formula IA: IA where X1 is CH, CNH2, or N; X2 is C or N; X3 is CR13, N, NR13, O, or S; X4 is CH, N, or NR13; X5 is CH, CR1B, or N; X6 is CH or N; X7 is CH, N, or CF; X8 is CH or N; X9 is CH, CR1B, or N; X10 is CH, CR1B, or N; R1 is -NHR8, -OH, -C2-5 heterocyclic, or -C1-3 alkyl; wherein the -C2-5 heterocyclic of R1 is optionally substituted with one, two, or three -C1-3 alkyl, -C1-3 oxyalkyl, -C3-5 heterocyclic alkyl, -C3-5 hydroxycyclic alkyl, -C3-5 aminocyclic alkyl, or oxyalkyl groups; wherein the -C1-3 alkyl of R1 is optionally substituted with one, two, or three oxyalkyl groups or -NR10R11; R1A is H or -CH3; or R1 and R1A form a C6-8 fused heterocyclic alkyl or a C6-8 fused heteroaryl group; wherein the C6-8 fused heterocyclic alkyl or the C6-8 fused heteroaryl group is optionally substituted with an oxyalkyl group; each R1B is independently H, -CH3, F, Cl, or methoxy; R2 is H, -C1-3 alkyl, -C1-3 fluoroalkyl, or halogen; R3 is a -C1-3 alkyl, -C2-10 heterocyclic, or -NH-C(=O)-C1-3 alkyl; wherein the -C1-3 alkyl group of R3 is substituted with one or more of a side-oxygen group, -OH, -NR12R12A, -C5-8 heterocyclic, or cyano group; wherein the -C2-10 heterocyclic is substituted with one, two, or three -OH, halogen, -C1-3 hydroxyalkyl, -C1-3 alkyl, cyclopropyl, or side-oxygen group; or R2 and R3 form a C6-10 fused heterocyclic ring, which is substituted with one, two, or three -C1-3 alkyl, -C2-3 side-oxyalkyl, or side-oxygen group; R4A is H, -OH, or -C1-3 alkyl; R4B is H or absent; each R5 is independently H, halogen, -OH, cyclopropyl, or -C1-3 alkyl; or two R5 groups form a cyclopropyl group; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6, or R5 and R6 form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, -C1-3 alkyl, -SO2CH3, or -C3-4 heterocyclic; wherein the -C1-3 alkyl of R8 is substituted with one, two, or three side oxygen groups, -C3-7 heterocyclic alkyl groups, methyl-substituted -C3-7 heterocyclic alkyl groups, alkoxy groups, cyanoimide groups, or -NR9R10 groups, depending on the situation;The -C3-4 heterocyclic ring may be substituted with one, two, or three lateral oxy groups, halogens, -C0-1 alkyl-NR10R11, -OH, -C1-3 hydroxyalkyl, -C1-3 alkoxy, -C1-3 alkoxy-C1-3 alkyl, -C1-3 lateral oxyalkyl, or -C1-3 alkyl, depending on the case; R9 may be H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocyclic alkyl; wherein the -C1-4 alkyl group of R9 may be substituted with one, two, or three cyclopropyl groups, -C3-5 heterocyclic alkyl, or methoxy groups; wherein the -C3-5 cycloalkyl group of R9 may be substituted with a -C1-3 alkyl group. Each R10 is independently H or -C1-4 alkyl; or if the -C1-3 alkyl of R8 is substituted with -NR9R10, then the corresponding R9 and R10 may combine to form a C3-7 heterocyclic alkyl group, which may be substituted with one, two or three methoxy, -OH, -C1-3 alkyl, halogen, -NH2, -NHCH3 or -N(CH3)2; each R11 is independently H or -C1-3 alkyl; R12 is H, -C1-3 alkyl, -(CH2)0-1-C3-5 heterocyclic alkyl or -methylene-phenyl-NH-C(=O)-NR10R11; wherein the -(CH2)0-1-C3-5 heterocyclic alkyl group may be substituted with a -C1-4 alkyl group; R12A is H or -C1-4 alkyl; or R12 and R12A form a fused C5-10 heterocyclic alkyl group substituted with a -C1-3 alkyl group, which may be substituted with a -C1-3 alkyl group. R13 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C0-1-C3-5 cycloalkyl, -C2-4 syloxyalkyl, or -C3-5 heterocyclic alkyl; wherein the -C1-4 alkyl group of R13 is optionally substituted with one, two, or three cyclopropyl or methoxy groups; wherein the -C3-5 cycloalkyl group of R13 is optionally substituted with a -C1-3 alkyl group; n is 1 or 2; wherein each heterocycle independently comprises 1 to 3 heteroatoms, including at least one of N, O, or S; wherein at least one of X2 is N or X3 is N, NH, or NR13, and X4 is N or NR13; or if X3 is S or O, then X2 is C.

3. A compound of formula IB, or a pharmaceutically acceptable salt thereof, having the formula IB: IB where X1 is CH, CNH2, or N; X2 is C or N; X3 is CR13, N, NR13, O, or S; X4 is CH, N, or NR13; X5 is CH or N; X6 is CH or N; X7 is CH, N, or CF; X8 is CH or N; wherein at least one of X2 is N or X3 is N, NH, or NR13, and X4 is N or NR13; or if X3 is S or O, then X2 is C; R1 is -NHR8, -OH, -C2-5 heterocyclic or -C1-3 alkyl; wherein the -C2-5 heterocyclic of R1 is substituted with one or more of -C1-3 alkyl, -C1-3 oxyalkyl, -C3-5 heterocyclic alkyl, -C3-5 hydroxycyclic alkyl, -C3-5 aminocyclic alkyl or oxyalkyl; wherein the -C1-3 alkyl of R1 is substituted with one or more of oxyalkyl or -NR10R11; R2 is H, -C1-3 alkyl, -C1-3 fluoroalkyl or halogen; R3 is a -C1-3 alkyl, a -C2-10 heterocyclic, or a -NH-C(=O)-C1-3 alkyl; wherein the -C1-3 alkyl group of R3 is substituted with one or more of a side-oxy group, -OH, -NR12R12A, -C5-8 heterocyclic, or cyano; wherein the -C2-10 heterocyclic is substituted with one or more of a -OH, halogen, -C1-3 hydroxyalkyl, -C1-3 alkyl, cyclopropyl, or side-oxy group; or R2 and R3 form a C6-10 fused heterocyclic alkyl group, which is substituted with one or more of a -C1-3 alkyl, -C2-3 side-oxyalkyl, or side-oxy group; R4A is H, -OH, or -C1-3 alkyl; R4B is H or absent; each R5 is independently H, -OH, halogen, or -C1-3 alkyl; or the two R5 groups form a cyclopropyl group; R6 is H, -OH, or -C1-3 alkyl; or R4A and R6, or R5 and R6 form a C1-3 alkyl bridge or a C1-3 heteroalkyl bridge; R7 is H, -C1-3 alkyl, or -C1-3 hydroxyalkyl; R8 is H, -C1-3 alkyl, or -C3-4 heterocyclic; wherein the -C1-3 alkyl of R8 is substituted with one or more of a side-oxygen group or -NR9R10; wherein the -C3-4 heterocyclic is substituted with one or more of a side-oxygen group or -C1-3 alkyl; R9 is H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocyclic alkyl; wherein the -C1-4 alkyl of R9 is substituted with one or more of a cyclopropyl group, -C3-5 heterocyclic alkyl, or methoxy group; wherein the -C3-5 cycloalkyl of R9 is substituted with a -C1-3 alkyl group. Each R10 is independently H or -C1-4 alkyl;Alternatively, if the -C1-3 alkyl group of R8 is substituted with -NR9R10, then the corresponding R9 and R10 may combine to form a C3-6 heterocyclic alkyl group, which may be substituted with at least one of methoxy, -OH, -C1-3 alkyl, or -N(CH3)2; each R11 is independently H or -C1-3 alkyl; R12 is H, -C1-3 alkyl, or -methylene-phenyl-NH-C(=O)-NR10R11; each R13 is independently H, -C1-4 alkyl, -C1-4 hydroxyalkyl, -C1-3 fluoroalkyl, -C3-5 cycloalkyl, or -C3-5 heterocyclic alkyl; wherein the -C1-4 alkyl group of R13 may be substituted with one or more of cyclopropyl or methoxy; wherein the -C3-5 cycloalkyl group of R13 may be substituted with -C1-3 alkyl; n is 1 or 2; Each heterocycle independently comprises one to three heteroatoms, including at least one of N, O, or S; wherein at least one of X2 is N, or X3 is N, NH, or NR13, and X4 is N or NR13; or if X3 is S or O, then X2 is C.

4. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3 is a -C1-3 alkyl or a -C2-10 heterocycle; wherein the -C2-10 heterocycle is a -C2-5 heteroaryl; wherein the -C1-3 alkyl group of R3 is substituted with one, two or three side oxygen groups or -NR12R12A as appropriate; wherein the -C2-5 heterocycle of R3 is substituted with a -C1-3 alkyl group as appropriate.

5. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1 is -NHR8; and R8 is a -C1-3 alkyl group substituted with one, two, or three side oxygen groups or -NR9R10.

6. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2 is H; and R3 is a -C1-3 alkyl group substituted with a side oxygen group and -NR12R12A.

7. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein at least one of the following is present: X5 is CH; X7 is CH or N; X8 is CH; R1 is -NHR8, -C2-5 heterocyclic, or -C1-3 alkyl; R4A is H or -C1-3 alkyl; each R5 is independently H, halogen, or -C1-3 alkyl; or the two R5 groups form a cyclopropyl group; R6 is H or -C1-3 alkyl; or R7 is H or -C1-3 alkyl.

8. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3 is a -C1-3 alkyl group substituted with a lateral oxygen group and -NR12R12A, and R1 is -NHR8, or a -C1-3 alkyl group substituted with a lateral oxygen group and -NR10R11.

9. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X3 is CR13 and X4 is CH or N.

10. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1 is -NHR8; wherein R8 is a -C1-3 alkyl or a -C3-4 heterocycle; wherein the -C1-3 alkyl group of R8 is substituted with a side oxygen group and -NR9R10; wherein the -C3-4 heterocycle is substituted with one, two, or three side oxygen groups or -C1-3 alkyl groups.

11. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X1 is N, X3 is N or NR13, and X4 is N.

12. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the -C2-10 heterocycle of R3 is a -C2-5 heterocycle and R3 is substituted with one, two or three -C1-3 alkyl groups, as appropriate.

13. A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein at least one hydrogen atom is deuterium.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R1 is...

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R1A is deuterium; X5, X9 and X10 are each CR1B; and R1B in each of X5, X9 and X10 is deuterium.

16. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is one of the following: N-(4-(3,3-dimethylurea)benzyl)-1-isopropyl-5-(5-(2-sideoxypyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; 5-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; 5-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-carbonyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; 5-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; (S)-5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methoxyamine; (S)-5-(4-(dimethylaminomethoxy)phenyl)-1-isopropyl-7-methyl-N-(4-(4-methylpiperyl-1-methoxyamino)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methamide; or 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methamide.

17. A compound wherein the compound is one of the following: N-(4-(3,3-dimethylurea)benzyl)-1-isopropyl-5-(5-(2-sideoxypyrrolidin-1-yl)pyridin-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; 5-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; 5-(5-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-carbonyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; 5-(5-(dimethylaminomethyl)pyridin-2-yl)-N-(4-(3,3-dimethylurea)benzyl)-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methylamine; (S)-5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-isopropyl-7-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-methoxyamine; (S)-5-(4-(dimethylaminomethoxy)phenyl)-1-isopropyl-7-methyl-N-(4-(4-methylpiperyl-1-methoxyamino)benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methamide; or 5-(5-(dimethylaminomethoxy)pyridin-2-yl)-N-(4-(3,3-dimethylureo)benzyl)-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-methamide.

18. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is [missing information].

19. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is [missing information].

20. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is [missing information].

21. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is [missing information].

22. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is [missing information].

23. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is [missing information].

24. A compound or a pharmaceutically acceptable salt thereof; wherein the compound is [missing information].

25. A pharmaceutical composition comprising a compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

26. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 3 and 16 to 24, used as a medicine.

27. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 3 and 16 to 24, used to treat atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergy, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet'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), arthritis, keloid, nonalcoholic fatty liver disease (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.

28. The compound or its pharmaceutically acceptable salt of any of claims 1 to 3 and 16 to 24, used to treat at least one of skin conditions or respiratory conditions.

29. Use of any compound of claims 1 to 24 or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for treating atopic dermatitis, eosinophilic gastritis, atopic keratoconjunctivitis, allergies, alopecia, Alzheimer's disease, asthma, atherosclerosis, Behcet'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), arthritis, keloids, nonalcoholic fatty liver disease (NASH), primary biliary cirrhosis, nodular prurigo, psoriasis, psoriatic arthritis, sinusitis, scleroderma, systemic lupus erythematosus (SLE), systemic sclerosis, ulcerative colitis (UC), vitiligo, or hidradenitis suppurativa.