N-substituted dioxocyclobutenylamino-3-hydroxypyridinecarboxamide as a CCR6 inhibitor

Abstract

This invention relates to N-substituted dioxocyclobutenylamino-3-hydroxypyridine carboxamide compounds of formulas (IIA) and (IIB) that inhibit CC chemokine receptor 6 (CCR6), or pharmaceutically acceptable salts thereof; pharmaceutical compositions containing these compounds; and the use of these compounds for the treatment or prevention of diseases, conditions, or ailments that are improved by inhibiting CCR6.

Description

[0001] This application is a divisional application of Chinese patent application 201980058547.8, filed on September 18, 2019, entitled "N-substituted dioxocyclobutenylamino-3-hydroxy-pyridinecarboxamide as a CCR6 inhibitor". Technical Field

[0002] This invention relates to N-substituted dioxocyclobutenylamino-3-hydroxypyridinecarboxamide compounds that inhibit CC chemokine receptor 6 (CCR6), pharmaceutical compositions containing these compounds, and the use of these compounds for the treatment or prevention of diseases, conditions, or ailments that are improved by inhibiting CCR6. Background Technology

[0003] Chemokine receptors are a subfamily of seven transmembrane proteins on the cell surface. They can be functionally divided into two main classes: G protein-coupled chemokine receptors (which mediate leukocyte transport) and "atypical chemokine receptors" (which can signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients) [Bachelerie, 2014; Murphy, 2002]. Chemokines are natural ligands of chemokine receptors and are low-molecular-weight proteins that stimulate leukocyte recruitment. Based on the presence and relative position of the NH2-terminal Cys residues, chemokines are structurally classified into CC, CXC, CX3C, and C chemokines [White, 2013]. In humans, chemokines and chemokine receptors form a pharmacologically complex system. In many cases, the recognition of a single chemokine by different receptors and the binding of different chemokines to the same receptor lead to different signal transduction and transport responses [Kufareva, 2016]. Physiologically, members of the chemokine family induce the recruitment of well-defined subsets of leukocytes and play important roles in development, immunity, and autoimmune diseases.

[0004] CC chemokine receptor 6 (CCR6) is expressed on a variety of key immune cells, including immature dendritic cells, B cells, memory T cells (including all Th17 cells), neutrophils, and a subset of Tregs. CCR6 is the only known receptor for the chemokine CCL20 (also known as LARC or MIP-3a). CCL20 is produced by synovial cells, colonic epithelial cells, various skin cells (e.g., keratinocytes and dermal fibroblasts), and alveolar epithelial cells. The ligand-receptor pair CCL20-CCR6 is responsible for the migration of immature dendritic cells and effector / memory T cells to the skin and mucosal surfaces in homeostatic and inflammatory conditions, as well as in autoimmune diseases such as psoriasis and inflammatory bowel disease. [Liao, 1999; Schuttyser, 2003].

[0005] CCL20 is an inducible chemokine that is highly upregulated in inflammatory lesions of various autoimmune diseases, including psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis, and rheumatoid arthritis. Increased numbers of CCR6-positive T cells and dendritic cells were found in lesions co-localized with CCL20 expression. These T cell-dendritic cell clusters, maintained through CCR6-CCL20 interactions, are crucial for disease development and maintenance. In mice, both CCR6 knockout and neutralizing anti-CCL20 antibodies were protective in an IL-23-induced skin inflammation model, suggesting that blocking CCR6-CCL20-mediated immune cell recruitment offers an attractive mechanism for novel small-molecule therapies in autoimmune and inflammatory diseases. [Homey, 2000; Kim, 2014; Kwon, 2002; Shen, 2010].

[0006] Type 1 CXC chemokine receptors (CXCR1) and type 2 CXC chemokine receptors (CXCR2) are chemokine receptors expressed on neutrophils. Both receptors bind to the chemokine IL-8 (CXCL8) with high affinity. In contrast, CXCL1 (GROα) and CXCL2 (GROβ) are specific ligands of CXCR2 with 90% sequence homology. In clinical studies, dual CXCR1 / 2 antagonists (such as navarixin) have shown a reversible decrease in the absolute neutrophil count in patients [Hastrup, 2015]. Patients with decreased neutrophil counts may have an increased risk of infection. Therefore, CCR6 antagonists with reduced CXCR2 receptor antagonistic potency may offer improved safety compared to non-discriminating antagonists. Human genetic evidence and gene knockout studies in mice have shown that neutrophil extravasation from the bone marrow depends on CXCR2 function and is mediated by the CXCR2-specific ligands CXCL1 (GROα) and CXCL2 (GROβ) [Auer, 2014; Eash, 2010]. Therefore, to understand the pharmacology of CXCR2 inhibitors on bone marrow neutrophil migration, it is important to use the relevant CXCR2 ligands (CXCL1 or CXCL2) in primary human neutrophil analysis systems.

[0007] Auer, PL et al., Nature Genetics (2014) 46, 629-634.

[0008] Bachelerie, F. et al., Pharmacol. Rev. (2014) 66, 1-79.

[0009] Eash, KJ et al., J. Clin. Invest. (2010) 120, 2423-2431.

[0010] Hastrup, N. et al., Cytokine (2015) 72, 197-203.

[0011] Homey, B. et al., J. Immunol. (2000) 164, 6621-6632.

[0012] Kim, T.-G. et al., J. Invest. Dermatol. (2014) 134, 1462-1465.

[0013] Kufareva, I. Curr. Opin. Pharmacol. (2016) 30, 27-37.

[0014] Kwon, JH et al., Gut (2002) 51, 818-826.

[0015] Liao, F. et al., J. Immunol. (1999) 162, 186-194.

[0016] Murphy, PM Pharmacol. Rev. (2002) 54, 227-229.

[0017] Schutyser, E.; Struyf, S.; Van Damme, J. Cytokine Growth Factor Rev. (2003) 14, 409-426.

[0018] Shen, H.; Goodall, JC; Gaston, JSHJRheumatol. (2010) 37, 2096-2099.

[0019] White, GE; Iqbal, AJ; Greaves, DR Pharmacol. Rev. (2013) 65, 47-89. Invention Overview

[0020] This invention provides compounds of formulas (IA) and (IB), or pharmaceutically acceptable salts or hydrates thereof, that inhibit CCR6 and are used in humans for the treatment or prevention of conditions improved by inhibiting CCR6.

[0021]

[0022] in

[0023] R1 and R2 are independently H or (C1-C6) alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally one or two other heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted by one, two, or three (C1-C4) alkyl groups.

[0024] R3 is H, (C1-C6)alkyl, (C1-C4)alkylcarbonyl, -C(=O)CH=CHCO2H, -SO2NH2, -CH2OC(=O)(C1-C4)alkyl, -CH2OP(=O)(OH)2 or -C(=O)NR A R B The (C1-C4) alkyl carbonyl group is optionally substituted with -CO2H or -NH2, the -CH2OC(=O) (C1-C4) alkyl group is optionally substituted with -NH2, and R A and R B Independently H or (C1-C6) alkyl;

[0025] A is

[0026]

[0027] R4 is H, (C1-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C4)alkyl, or halo(C1-C4)alkyl;

[0028] R5 and R6 are independently H, deuterium, (C2-C4) alkenyl, (C1-C4) alkoxy, (C1-C4) alkyl, or (C1-C4) alkyl-d. 1-9 (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C4)alkyl, cyano, halogen, halo(C1-C4)alkoxy, halo(C1-C4)alkyl or hydroxy(C1-C4)alkyl;

[0029] B is

[0030]

[0031] R7 represents -F, -CN, (C1-C3)alkyl, (C1-C3)alkyl-d 1-7 Or halogenated (C1-C3) alkyl;

[0032] R8 is independently deuterium, -F, -Cl, -Br or -I each time it appears, or two R8s attached to the same carbon atom form a (C3-C5) cycloalkyl group;

[0033] n can be 0, 1, 2, 3, or 4;

[0034] R9 is independently deuterium, -F, -Cl, -Br or -I each time it appears, or two R9s attached to the same carbon atom form a (C3-C5) cycloalkyl group;

[0035] m is 1, 2, 3, or 4; and

[0036] X is O, S, or NR C , where R C It is H or (C1-C4) alkyl.

[0037] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA) or a pharmaceutically acceptable salt or hydrate thereof.

[0038] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IB) or a pharmaceutically acceptable salt or hydrate thereof.

[0039] In another embodiment, the present invention provides the use of a compound of formula (IA) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating a disease, condition or ailment that is improved by inhibiting CCR6 in humans.

[0040] In another embodiment, the present invention provides the use of a compound of formula (IB) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating a disease, condition or ailment that is improved by inhibiting CCR6 in humans.

[0041] In another embodiment, the present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt or hydrate thereof, which is used as a medicine.

[0042] In another embodiment, the present invention provides a compound of formula (IB) or a pharmaceutically acceptable salt or hydrate thereof, which is used as a medicine.

[0043] In another embodiment, the present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt or hydrate thereof for use in humans to treat or prevent diseases, conditions or ailments that are improved by inhibiting CCR6.

[0044] In another embodiment, the present invention provides a compound of formula (IB) or a pharmaceutically acceptable salt or hydrate thereof for use in humans to treat or prevent diseases, conditions or ailments that are improved by inhibiting CCR6.

[0045] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (IA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0046] In another embodiment, the present invention provides a pharmaceutical composition comprising an IB compound or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0047] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound of formula (IA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0048] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (IB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0049] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating or preventing diseases, conditions or ailments that are improved by inhibiting CCR6 in humans.

[0050] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising an inclusive (IB) compound or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating or preventing diseases, conditions or ailments that are improved by inhibiting CCR6 in humans.

[0051] In another embodiment, the present invention provides a pharmaceutical combination comprising a compound of formula (IA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0052] In another embodiment, the present invention provides a pharmaceutical combination comprising an IB compound or its pharmaceutically acceptable salt or hydrate and at least one anti-inflammatory agent.

[0053] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering a therapeutically effective amount of a combination of pharmaceuticals to a human requiring such treatment, said combination of pharmaceuticals comprising a compound of formula (IA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0054] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising a compound of formula (IB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0055] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating or preventing diseases, conditions or ailments that are improved by inhibiting CCR6 in humans.

[0056] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising an IB compound or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating or preventing diseases, conditions or ailments in humans that are improved by inhibiting CCR6. Attached Figure Description

[0057] Figure 1 X-ray structure of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate (ORTEP drawing).

[0058] Figure 2 X-ray structure of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate (ORTEP drawing).

[0059] Figure 3 X-ray structure (ORTEP drawing) of crystalline (S)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylic acid ((1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl) methylamine salt (Example 36F).

[0060] Figure 4 Powder X-ray diffraction analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0061] Figure 5 Differential scanning calorimetry analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0062] Figure 6 Thermogravimetric analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0063] Figure 7 Powder X-ray diffraction analysis of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0064] Figure 8 Differential scanning calorimetry analysis of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0065] Figure 9 Thermogravimetric analysis of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0066] Figure 10 X-ray structure of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate (ORTEP drawing).

[0067] Figure 11 X-ray structure of the unit cell of (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate (ORTEP drawing).

[0068] Figure 12 Powder X-ray diffraction analysis of the crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate. Invention Details

[0069] In another embodiment, the present invention provides compounds of formulas (IA) and (IB) or their pharmaceutically acceptable salts or hydrates.

[0070]

[0071] R1 and R2 are independently (C1-C6) alkyl groups, or R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally one or two other heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with a (C1-C4) alkyl group; R3 is H, (C1-C6) alkyl, (C1-C4) alkyl carbonyl, -C(=O)CH=CHCO2H, -SO2NH2, -CH2OC(=O)(C1-C4) alkyl, -CH2OP(=O)(OH)2, or -C(=O)NR A R B The (C1-C4) alkyl carbonyl group is optionally substituted with -CO2H or -NH2, the -CH2OC(=O) (C1-C4) alkyl group is optionally substituted with -NH2, and R A and R B Independently, it is H or (C1-C6) alkyl; A is R4 is a (C1-C4)alkyl; R5 and R6 are independently H, deuterium, (C1-C4)alkoxy, (C1-C4)alkyl, or (C1-C4)alkyl-d. 1-9 (C3-C4)cycloalkyl, cyano, halogen, halo(C1-C4)alkoxy, halo(C1-C4)alkyl, or hydroxy(C1-C4)alkyl; B is... R7 is a (C1-C3) alkyl or (C1-C3) alkyl-d 1-7R8 is deuterium, or two R8s attached to the same carbon atom form a (C3-C5) cycloalkyl group; n is 0 or 2; R9 is F each time it appears; m is 1, 2, 3 or 4; and X is O.

[0072] In another embodiment, the invention provides compounds of formulas (IA) and (IB) or their pharmaceutically acceptable salts or hydrates, wherein R1 and R2 are independently (C1-C6) alkyl groups, or R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally one or two other heteroatoms selected from O, N, and S, said heterocycle optionally substituted with a (C1-C4) alkyl group; R3 is H; A is R4 is a (C1-C4)alkyl; R5 and R6 are independently H, deuterium, (C1-C4)alkoxy, (C1-C4)alkyl, or (C1-C4)alkyl-d. 1-9 (C3-C4)cycloalkyl, cyano, halogen, halo(C1-C4)alkoxy, halo(C1-C4)alkyl, or hydroxy(C1-C4)alkyl; B is... R7 is a (C1-C3) alkyl or (C1-C3) alkyl-d 1-7 R8 is deuterium, or two R8s attached to the same carbon atom form a (C3-C5) cycloalkyl group; n is 0 or 2; R9 is F each time it appears; m is 2; and X is O.

[0073] In another embodiment, the invention provides compounds of formulas (IA) and (IB) or their pharmaceutically acceptable salts or hydrates, wherein R1 and R2 are independently methyl, ethyl, or isopropyl, or R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or piperazine, wherein the piperazine is substituted with a methyl group; R3 is H; A is R4 is methyl; R5 is methyl, methyl-d3, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is H or methyl; B is... R7 is methyl; R8 is deuterium, or two R8s attached to the same carbon atom form a cyclopropyl group; n is 0 or 2; R9 is F each time it appears; m is 2; and X is O.

[0074] In another embodiment, the present invention provides compounds of formulas (IA) and (IB) or their pharmaceutically acceptable salts or hydrates, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; and A is... R4 is methyl; R5 is methyl, methyl-d3, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; B is... R7 is methyl; R8 is deuterium, or two R8s attached to the same carbon atom form a cyclopropyl group; n is 0 or 2; R9 is F each time it appears; m is 2; and X is O.

[0075] In another embodiment, the present invention provides compounds of formulas (IA) and (IB) or their pharmaceutically acceptable salts or hydrates, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; and A is... R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; B is... R7 is a methyl group; and n is 0.

[0076] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof.

[0077]

[0078] R1 and R2 are independently (C1-C6) alkyl groups, or R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally one or two other heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with a (C1-C4) alkyl group; R3 is H, (C1-C6) alkyl, (C1-C4) alkyl carbonyl, -C(=O)CH=CHCO2H, -SO2NH2, -CH2OC(=O)(C1-C4) alkyl, -CH2OP(=O)(OH)2, or -C(=O)NR A R B The (C1-C4) alkyl carbonyl group is optionally substituted with -CO2H or -NH2, the -CH2OC(=O) (C1-C4) alkyl group is optionally substituted with -NH2, and R A and R B R4 is independently H or (C1-C6)alkyl; R5 and R6 are independently H, deuterium, (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)alkyl-d 1-9 (C3-C4)cycloalkyl, cyano, halogen, halo(C1-C4)alkoxy, or halo(C1-C4)alkyl; B is... R7 is a (C1-C3) alkyl or (C1-C3) alkyl-d 1-7 R8 is deuterium, or two R8s attached to the same carbon atom form a (C3-C5) cycloalkyl group; n is 0 or 2; R9 is F each time it appears; m is 2; and X is O.

[0079] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is a methyl group.

[0080] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; B is... R7 is a methyl group.

[0081] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is a methyl group; and n is 0.

[0082] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, methyl-d3, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; B is R7 is a methyl group; and n is 0.

[0083] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, methyl-d3, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0084] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0085] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, methyl-d3, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is methyl; R8 is deuterium; and n is 0 or 2.

[0086] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; B is... R7 is a methyl group; and n is 0.

[0087] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0088] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0089] In another embodiment, the compound of formula (IIA) is (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or its pharmaceutically acceptable salt or hydrate.

[0090] In another embodiment, the compound of formula (IIA) is (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide.

[0091] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, which is used as a medicine.

[0092] In another embodiment, the present invention provides a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof for use in humans to treat or prevent diseases, conditions or ailments that are improved by inhibiting CCR6.

[0093] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof.

[0094] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof.

[0095] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof.

[0096] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof.

[0097] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof.

[0098] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human in need of such treatment a therapeutically effective amount of (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof.

[0099] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a prodrug of (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide.

[0100] In another embodiment, the present invention provides the use of a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating a disease, condition or ailment that is improved by inhibiting CCR6 in humans.

[0101] In another embodiment, the present invention provides the use of a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating a disease, condition or ailment that is improved in humans by inhibiting T cell chemotaxis.

[0102] In another embodiment, the present invention provides the use of a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating inflammatory diseases, conditions or ailments in humans.

[0103] In another embodiment, the present invention provides the use of a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0104] In another embodiment, the present invention provides the use of a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans.

[0105] In another embodiment, the present invention provides the use of (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or its pharmaceutically acceptable salt or hydrate in the preparation of a medicament for the treatment of rheumatoid arthritis in humans.

[0106] In another embodiment, the present invention provides the use of (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide, or a pharmaceutically acceptable salt or hydrate thereof, in the preparation of a medicament for the treatment of rheumatoid arthritis in humans.

[0107] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0108] In another embodiment, the present invention provides a pharmaceutical composition comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0109] In another embodiment, the present invention provides a pharmaceutical composition comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide prodrug or its pharmaceutically acceptable salt or hydrate and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0110] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0111] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0112] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0113] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human in need of such treatment, said pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0114] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0115] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0116] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human in need of such treatment, said pharmaceutical composition comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide prodrug or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0117] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating, in humans, a disease, condition or ailment that is improved by inhibiting CCR6.

[0118] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating, in humans, a disease, condition or ailment that is improved by inhibiting T cell chemotaxis.

[0119] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating an inflammatory disease, condition or ailment in humans.

[0120] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating an autoimmune disease, condition or ailment in humans.

[0121] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

[0122] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0123] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0124] In another embodiment, the present invention provides a pharmaceutical combination comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0125] In another embodiment, the present invention provides a pharmaceutical combination comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0126] In another embodiment, the present invention provides a pharmaceutical combination comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide prodrug or its pharmaceutically acceptable salt or hydrate and at least one anti-inflammatory agent.

[0127] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering a therapeutically effective amount of a combination of pharmaceuticals to a human requiring such treatment, said combination of pharmaceuticals comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0128] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0129] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a combination of pharmaceuticals to a human requiring such treatment, said combination of pharmaceuticals comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0130] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a combination of pharmaceuticals to a human requiring such treatment, said combination of pharmaceuticals comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0131] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a combination of pharmaceuticals to a human requiring such treatment, said combination of pharmaceuticals comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0132] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0133] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising a prodrug of (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0134] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting CCR6.

[0135] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting T cell chemotaxis.

[0136] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating inflammatory diseases, conditions or ailments in humans.

[0137] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0138] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

[0139] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0140] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0141] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide.

[0142] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0143] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern including diffraction peaks at 18.7±0.2, 19.1±0.2, and 20.2±0.2°2θ.

[0144] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising the following diffraction peaks: 17.6±0.2, 18.4±0.2, 18.7±0.2, 19.1±0.2, and 20.2±0.2°2θ.

[0145] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising the following diffraction peaks: 11.4±0.2, 15.5±0.2, 17.6±0.2, 18.4±0.2, 18.7±0.2, 19.1±0.2, 20.2±0.2, and 24.3±0.2°2θ.

[0146] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising the following diffraction peaks: 11.4±0.2, 12.4±0.2, 15.5±0.2, 17.6±0.2, 18.4±0.2, 18.7±0.2, 19.1±0.2, 20.2±0.2, 24.3±0.2, 26.8±0.2, and 30.5±0.2°2θ.

[0147] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks selected from the following: 11.4±0.2, 12.4±0.2, 15.5±0.2, 17.6±0.2, 18.4±0.2, 18.7±0.2, 19.1±0.2, 20.2±0.2, 24.3±0.2, 26.8±0.2, and 30.5±0.2°2θ.

[0148] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 7.

[0149] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 7.

[0150] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate, which has the following properties: Figure 4 The X-ray powder diffraction pattern shown is shown.

[0151] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate, which has the following properties: Figure 5 The differential scanning calorimetry analysis shown is illustrated.

[0152] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate, which has the following properties: Figure 6 The thermogravimetric analysis shown.

[0153] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate, which is used as a pharmaceutical.

[0154] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate for use in humans to treat or prevent diseases, conditions, or ailments that are improved by inhibiting CCR6.

[0155] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human in need of such treatment a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0156] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T cell chemotaxis, comprising administering to a human in need of such treatment a therapeutically effective amount of crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0157] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering to a human in need of such treatment a therapeutically effective amount of crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0158] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering to a human in need of such treatment a therapeutically effective amount of crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0159] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0160] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human in need of such treatment a therapeutically effective amount of crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0161] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting CCR6.

[0162] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting T cell chemotaxis.

[0163] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of a medicament for treating inflammatory diseases, conditions or ailments in humans.

[0164] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0165] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of medicaments for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans.

[0166] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0167] In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0168] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0169] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human in need of such treatment, said pharmaceutical composition comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0170] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0171] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human in need of such treatment, said pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0172] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0173] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0174] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting CCR6.

[0175] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting T-cell chemotaxis.

[0176] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating inflammatory diseases, conditions or ailments in humans.

[0177] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating human autoimmune diseases, conditions or symptoms.

[0178] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

[0179] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0180] In another embodiment, the present invention provides a pharmaceutical combination comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0181] In another embodiment, the present invention provides a pharmaceutical combination comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0182] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering a therapeutically effective amount of a pharmaceutical combination to a human requiring such treatment, the pharmaceutical combination comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0183] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering a therapeutically effective amount of a pharmaceutical combination to a human requiring such treatment, the pharmaceutical combination comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0184] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0185] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a combination of drugs to a human in need of such treatment, the combination of drugs comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0186] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a combination of drugs to a human requiring such treatment, the combination of drugs comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0187] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising crystal (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0188] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting CCR6.

[0189] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis.

[0190] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating inflammatory diseases, conditions, or ailments in humans.

[0191] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0192] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans.

[0193] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0194] In another embodiment, the present invention provides a crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate.

[0195] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5-calcium salt monohydrate having an X-ray powder diffraction pattern comprising the following diffraction peaks: 7.8±0.2, 10.3±0.2, and 10.7±0.2°2θ.

[0196] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate having an X-ray powder diffraction pattern comprising the following diffraction peaks: 7.8±0.2, 10.3±0.2, 10.7±0.2, 15.5±0.2, and 18.4±0.2°2θ.

[0197] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate having an X-ray powder diffraction pattern comprising the following diffraction peaks: 7.7±0.2, 7.8±0.2, 10.3±0.2, 10.7±0.2, 15.5±0.2, 17.0±0.2, 18.4±0.2, 20.8±0.2, and 21.0±0.2°2θ.

[0198] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5° calcium salt monohydrate, having an X-ray powder diffraction pattern comprising the following diffraction peaks: 7.7±0.2, 7.8±0.2, 10.3±0.2, 10.7±0.2, 15.5±0.2, 17.0±0.2, 18.4±0.2, 20.5±0.2, 20.8±0.2, 21.0±0.2, 24.0±0.2, and 25.6±0.2°2θ.

[0199] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazole-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate, having an X-ray powder diffraction pattern containing the following diffraction peaks: 7.7±0.2, 7.8±0.2, 10.3±0.2. 10.7±0.2, 11.9±0.2, 13.6±0.2, 15.5±0.2, 16.6±0.2, 17.0±0.2, 18.4±0.2, 20.5±0.2, 20.8±0.2, 21.0±0.2, 22.3±0.2, 24.0±0.2, 24.9±0.2, 25.6±0.2, 26.1±0.2, 31.3±0.2 and 31.4±0.2°2θ.

[0200] In another embodiment, the present invention provides a crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 10.

[0201] In another embodiment, the present invention provides a crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 10.

[0202] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate, which has the following properties: Figure 12 The X-ray powder diffraction pattern shown is shown.

[0203] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate, which is used as a pharmaceutical.

[0204] In another embodiment, the present invention provides crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate for use in humans to treat or prevent diseases, conditions, or ailments that are improved by inhibiting CCR6.

[0205] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human in need of such treatment a therapeutically effective amount of crystalline ((R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate.

[0206] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T cell chemotaxis, comprising administering to a human in need of such treatment a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate.

[0207] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate.

[0208] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate.

[0209] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate.

[0210] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate.

[0211] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting CCR6.

[0212] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting T cell chemotaxis.

[0213] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate in the preparation of a medicament for treating inflammatory diseases, conditions, or ailments in humans.

[0214] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0215] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate in the preparation of medicaments for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans.

[0216] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0217] In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0218] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0219] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0220] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0221] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0222] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0223] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0224] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting CCR6.

[0225] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting T cell chemotaxis.

[0226] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating inflammatory diseases, conditions or ailments in humans.

[0227] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating human autoimmune diseases, conditions or symptoms.

[0228] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

[0229] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0230] In another embodiment, the present invention provides a pharmaceutical composition comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent.

[0231] In another embodiment, the present invention provides a pharmaceutical composition comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent.

[0232] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent.

[0233] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent.

[0234] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent.

[0235] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent.

[0236] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical combination to a human requiring such treatment, said pharmaceutical combination comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent.

[0237] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent.

[0238] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating, in humans, diseases, or ailments that are improved by inhibiting CCR6.

[0239] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting T cell chemotaxis.

[0240] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating inflammatory diseases, conditions, or ailments in humans.

[0241] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0242] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans.

[0243] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0244] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide.

[0245] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0246] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising the following diffraction peaks: 18.5±0.2, 18.8±0.2, and 19.2±0.2°2θ.

[0247] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising the following diffraction peaks: 8.4±0.2, 11.5±0.2, 12.5±0.2, 18.5±0.2, 18.8±0.2, and 19.2±0.2°2θ.

[0248] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising the following diffraction peaks: 8.4±0.2, 9.3±0.2, 11.5±0.2, 12.5±0.2, 18.5±0.2, 18.8±0.2, 19.2±0.2, and 20.4±0.2°2θ.

[0249] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks selected from the following: 8.4±0.2, 9.3±0.2, 11.5±0.2, 12.5±0.2, 18.5±0.2, 18.8±0.2, 19.2±0.2, 20.4±0.2, 24.5±0.2, 25.1±0.2, and 26.7±0.2°2θ.

[0250] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 8.

[0251] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 8.

[0252] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate, which has the following properties: Figure 7 The X-ray powder diffraction pattern shown is shown.

[0253] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate, which has the following properties: Figure 8 The differential scanning calorimetry analysis shown is illustrated.

[0254] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate, which has the following properties: Figure 9 The thermogravimetric analysis shown.

[0255] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate, which is used as a pharmaceutical.

[0256] In another embodiment, the present invention provides crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate for use in humans to treat or prevent diseases, conditions, or ailments that are improved by inhibiting CCR6.

[0257] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human in need of such treatment a therapeutically effective amount of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0258] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T cell chemotaxis, comprising administering to a human in need of such treatment a therapeutically effective amount of crystal (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0259] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of crystalline (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0260] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering to a human in need of such treatment a therapeutically effective amount of crystal (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0261] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0262] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human in need of such treatment a therapeutically effective amount of crystalline (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate.

[0263] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting CCR6.

[0264] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis.

[0265] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of a medicament for treating inflammatory diseases, conditions, or ailments in humans.

[0266] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0267] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of medicaments for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans.

[0268] In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0269] In another embodiment, the present invention provides a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0270] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human in need of such treatment, said pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0271] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition comprising crystal (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0272] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising crystalline (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0273] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human in need of such treatment, said pharmaceutical composition comprising crystalline (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0274] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising crystal (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0275] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising crystal (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0276] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting CCR6.

[0277] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting T-cell chemotaxis.

[0278] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating inflammatory diseases, conditions or ailments in humans.

[0279] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent, or carrier in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0280] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

[0281] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0282] In another embodiment, the present invention provides a pharmaceutical combination comprising (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0283] In another embodiment, the present invention provides a pharmaceutical combination comprising (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0284] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering a therapeutically effective amount of a combination of drugs to a human requiring such treatment, the combination of drugs comprising crystal (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0285] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising crystal (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0286] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a combination of pharmaceuticals to a human requiring such treatment, the combination of pharmaceuticals comprising crystal (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0287] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a combination of drugs to a human in need of such treatment, the combination of drugs comprising crystal (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0288] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical combination to a human requiring such treatment, said pharmaceutical combination comprising crystal (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0289] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising crystal (R)-4-((2-((((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent.

[0290] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting CCR6.

[0291] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis.

[0292] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating inflammatory diseases, conditions, or ailments in humans.

[0293] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0294] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans.

[0295] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate and at least one anti-inflammatory agent in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0296] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0297]

[0298] R1 and R2 are independently (C1-C6) alkyl groups, or R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally one or two other heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with a (C1-C4) alkyl group; R3 is H, (C1-C6) alkyl, (C1-C4) alkyl carbonyl, -C(=O)CH=CHCO2H, -SO2NH2, -CH2OC(=O)(C1-C4) alkyl, -CH2OP(=O)(OH)2, or -C(=O)NR A R B The (C1-C4) alkyl carbonyl group is optionally substituted with -CO2H or -NH2, the -CH2OC(=O) (C1-C4) alkyl group is optionally substituted with -NH2, and R A and R B R4 is independently H or (C1-C6)alkyl; R5 and R6 are independently H, deuterium, (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)alkyl-d 1-9 (C3-C4)cycloalkyl, cyano, halogen, halo(C1-C4)alkoxy, or halo(C1-C4)alkyl; B is... R7 is a (C1-C3) alkyl or (C1-C3) alkyl-d 1-7 R8 is deuterium, or two R8s attached to the same carbon atom form a (C3-C5) cycloalkyl group; n is 0 or 2; R9 is F each time it appears; m is 2; and X is O.

[0299] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is a methyl group.

[0300] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is a methyl group.

[0301] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is a methyl group; and n is 0.

[0302] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, methyl-d3, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; B is... R7 is a methyl group; and n is 0.

[0303] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, methyl-d3, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0304] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0305] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, methyl-d3, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is methyl; R8 is deuterium; and n is 0 or 2.

[0306] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is a methyl group; and n is 0.

[0307] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0308] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H; and B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0309] In another embodiment, the compound of formula (IIA) is (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or its pharmaceutically acceptable salt or hydrate.

[0310] In another embodiment, the compound of formula (IIA) is (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide.

[0311] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof, which is used as a medicine.

[0312] In another embodiment, the present invention provides a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof for use in humans to treat or prevent diseases, conditions or ailments that are improved by inhibiting CCR6.

[0313] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0314] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0315] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0316] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0317] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0318] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human in need of such treatment a therapeutically effective amount of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof.

[0319] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of a prodrug of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide.

[0320] In another embodiment, the present invention provides the use of a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating a disease, condition or ailment that is improved by inhibiting CCR6 in humans.

[0321] In another embodiment, the present invention provides the use of a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating a disease, condition or ailment that is improved in humans by inhibiting T cell chemotaxis.

[0322] In another embodiment, the present invention provides the use of a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating inflammatory diseases, conditions or ailments in humans.

[0323] In another embodiment, the present invention provides the use of a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0324] In another embodiment, the present invention provides the use of a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans.

[0325] In another embodiment, the present invention provides the use of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for the treatment of rheumatoid arthritis in humans.

[0326] In another embodiment, the present invention provides the use of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide, or a pharmaceutically acceptable salt or hydrate thereof, in the preparation of a medicament for the treatment of rheumatoid arthritis in humans.

[0327] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0328] In another embodiment, the present invention provides a pharmaceutical composition comprising (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0329] In another embodiment, the present invention provides a pharmaceutical composition comprising a prodrug of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0330] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0331] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0332] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0333] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human in need of such treatment, said pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0334] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0335] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or agent.

[0336] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising a prodrug or a pharmaceutically acceptable salt or hydrate of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0337] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating, in humans, a disease, condition or ailment that is improved by inhibiting CCR6.

[0338] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating, in humans, a disease, condition or ailment that is improved by inhibiting T cell chemotaxis.

[0339] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating an inflammatory disease, condition or ailment in humans.

[0340] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating an autoimmune disease, condition or ailment in humans.

[0341] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

[0342] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0343] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a prodrug of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0344] In another embodiment, the present invention provides a pharmaceutical combination comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0345] In another embodiment, the present invention provides a pharmaceutical combination comprising (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0346] In another embodiment, the present invention provides a pharmaceutical combination comprising a prodrug or a pharmaceutically acceptable salt or hydrate of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide and at least one anti-inflammatory agent.

[0347] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0348] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0349] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a combination of pharmaceuticals to a human requiring such treatment, said combination of pharmaceuticals comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0350] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a combination of pharmaceuticals to a human requiring such treatment, said combination of pharmaceuticals comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0351] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0352] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0353] In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of drugs, said combination of drugs comprising a prodrug or a pharmaceutically acceptable salt or hydrate of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide and at least one anti-inflammatory agent.

[0354] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting CCR6.

[0355] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting T cell chemotaxis.

[0356] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the preparation of a medicament for treating inflammatory diseases, conditions, or ailments in humans.

[0357] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating human autoimmune diseases, conditions, or ailments.

[0358] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

[0359] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0360] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent in the preparation of a medicament for treating rheumatoid arthritis in humans.

[0361] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof.

[0362]

[0363] Wherein Y is O or S; R1 and R2 are independently (C1-C6)alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally one or two other heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with a (C1-C4)alkyl; R3 is H, (C1-C6)alkyl, (C1-C4)alkylcarbonyl, -C(=O)CH=CHCO2H, -SO2NH2, -CH2OC(=O)(C1-C4)alkyl, -CH2OP(=O)(OH)2, or -C(=O)NR A R B The (C1-C4) alkyl carbonyl group is optionally substituted with -CO2H or -NH2, the -CH2OC(=O) (C1-C4) alkyl group is optionally substituted with -NH2, and R A and R B R5 and R6 are independently H or (C1-C6) alkyl; R6 are independently H, deuterium, (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)alkyl-d 1-9 (C3-C4)cycloalkyl, cyano, halogen, halo(C1-C4)alkoxy, or halo(C1-C4)alkyl; B is... R7 is a (C1-C3) alkyl or (C1-C3) alkyl-d 1-7 R8 is deuterium, or two R8s attached to the same carbon atom form a (C3-C5) cycloalkyl group; n is 0 or 2; R9 is F each time it appears; m is 2; and X is O.

[0364] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group.

[0365] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group.

[0366] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group.

[0367] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group.

[0368] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group.

[0369] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7 is a methyl group.

[0370] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group; and n is 0.

[0371] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0372] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0373] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group; and n is 0.

[0374] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0375] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7 is a methyl group; and n is 0.

[0376] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0377] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0378] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0379] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0380] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0381] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0382] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group; and n is 0.

[0383] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0384] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0385] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group; and n is 0.

[0386] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0387] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7 is a methyl group; and n is 0.

[0388] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is methyl; R9 is F; m is 2; and X is O.

[0389] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0390] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0391] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is methyl; R9 is F; m is 2; and X is O.

[0392] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0393] In another embodiment, the present invention provides a compound of formula (IIIA) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7 is methyl; R9 is F; m is 2; and X is O.

[0394] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0395]

[0396] Wherein Y is O or S; R1 and R2 are independently (C1-C6)alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally one or two other heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with a (C1-C4)alkyl; R3 is H, (C1-C6)alkyl, (C1-C4)alkylcarbonyl, -C(=O)CH=CHCO2H, -SO2NH2, -CH2OC(=O)(C1-C4)alkyl, -CH2OP(=O)(OH)2, or -C(=O)NR A R B The (C1-C4) alkyl carbonyl group is optionally substituted with -CO2H or -NH2, the -CH2OC(=O) (C1-C4) alkyl group is optionally substituted with -NH2, and R A and R B R5 and R6 are independently H or (C1-C6) alkyl; R6 are independently H, deuterium, (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C4)alkyl-d 1-9 (C3-C4)cycloalkyl, cyano, halogen, halo(C1-C4)alkoxy, or halo(C1-C4)alkyl; B is... R7 is a (C1-C3) alkyl or (C1-C3) alkyl-d 1-7 R8 is deuterium, or two R8s attached to the same carbon atom form a (C3-C5) cycloalkyl group; n is 0 or 2; R9 is F each time it appears; m is 2; and X is O.

[0397] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is... R7 is a methyl group.

[0398] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group.

[0399] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group.

[0400] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group.

[0401] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group.

[0402] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7 is a methyl group.

[0403] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is... R7 is a methyl group; and n is 0.

[0404] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0405] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0406] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group; and n is 0.

[0407] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0408] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7 is a methyl group; and n is 0.

[0409] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0410] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0411] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0412] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0413] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0414] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7 is a methyl group; two R8s attached to the same carbon atom form a cyclopropyl group; and n is 0 or 2.

[0415] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is... R7 is a methyl group; and n is 0.

[0416] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0417] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0418] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is a methyl group; and n is 0.

[0419] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is a methyl group; and n is 0.

[0420] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7 is a methyl group; and n is 0.

[0421] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0422] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0423] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0424] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7 is methyl; R9 is F; m is 2; and X is O.

[0425] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is... R7 is methyl; R9 is F; m is 2; and X is O.

[0426] In another embodiment, the present invention provides a compound of formula (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, wherein Y is O or S; R1 and R2 together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7 is methyl; R9 is F; m is 2; and X is O.

[0427] In another embodiment, the present invention provides a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, which is used as a medicine.

[0428] In another embodiment, the present invention provides a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof for use in humans to treat or prevent diseases, conditions or ailments that are improved by inhibiting CCR6.

[0429] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0430] In another embodiment, the present invention provides a method for treating or preventing a disease, condition, or ailment in humans that is improved by inhibiting T-cell chemotaxis, comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0431] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0432] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0433] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0434] In another embodiment, the present invention provides the use of compounds of formula (IIIA) or (IIIB) or their pharmaceutically acceptable salts or hydrates in the preparation of medicaments for treating diseases, conditions or ailments in humans that are improved by inhibiting CCR6.

[0435] In another embodiment, the present invention provides the use of compounds of formula (IIIA) or (IIIB) or their pharmaceutically acceptable salts or hydrates in the preparation of medicaments for treating diseases, conditions or ailments in humans that are improved by inhibiting T cell chemotaxis.

[0436] In another embodiment, the present invention provides the use of compounds of formula (IIIA) or (IIIB) or their pharmaceutically acceptable salts or hydrates in the preparation of medicaments for treating inflammatory diseases, conditions or ailments in humans.

[0437] In another embodiment, the present invention provides the use of compounds of formula (IIIA) or (IIIB) or their pharmaceutically acceptable salts or hydrates in the preparation of medicaments for treating human autoimmune diseases, conditions or ailments.

[0438] In another embodiment, the present invention provides the use of compounds of formula (IIIA) or (IIIB) or their pharmaceutically acceptable salts or hydrates in the preparation of medicaments for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

[0439] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0440] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0441] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0442] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0443] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0444] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering a therapeutically effective amount of a pharmaceutical composition to a human requiring such treatment, said pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0445] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating, in humans, a disease, condition or ailment that is improved by inhibiting CCR6.

[0446] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating, in humans, a disease, condition or ailment that is improved by inhibiting T cell chemotaxis.

[0447] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating an inflammatory disease, condition or ailment in humans.

[0448] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating an autoimmune disease, condition or ailment in humans.

[0449] In another embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable excipient, diluent or carrier in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

[0450] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0451] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting CCR6, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0452] In another embodiment, the present invention provides a method for treating or preventing diseases, conditions, or ailments in humans that are improved by inhibiting T-cell chemotaxis, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0453] In another embodiment, the present invention provides a method for treating or preventing inflammatory diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0454] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases, conditions, or ailments in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0455] In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a combination of pharmaceuticals, said combination of pharmaceuticals comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent.

[0456] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting CCR6.

[0457] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating, in humans, a disease, condition, or ailment that is improved by inhibiting T cell chemotaxis.

[0458] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating inflammatory diseases, conditions or ailments in humans.

[0459] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating an autoimmune disease, condition or ailment in humans.

[0460] In another embodiment, the present invention provides the use of a pharmaceutical combination comprising a compound of formula (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof and at least one anti-inflammatory agent in the preparation of a medicament for treating psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

[0461] In another embodiment, the present invention provides a method for treating or preventing immune disorders in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0462] In another embodiment, the present invention provides a method for treating or preventing autoimmune diseases in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0463] In another embodiment, the present invention provides a method for treating or preventing neurodegenerative or neuroinflammatory conditions in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0464] In another embodiment, the present invention provides a method for treating or preventing the following diseases in humans: rheumatoid arthritis, juvenile arthritis, Still's disease, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, pauciarticular rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatoid arthritis, enteropathic spondylitis, and juvenile idiopathic arthritis. Arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis caused by inflammatory diseases, the method comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0465] In another embodiment, the present invention provides a method for treating or preventing the following diseases in humans: lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, lupus nephritis, Sjögren's syndrome, scleroderma (systemic sclerosis), Raynaud's phenomenon juvenile scleroderma, polymyositis, dermatomyositis, polymyositis-dermatomyositis, mixed connective tissue disease, sarcoidosis, fibromyalgia, vasculitis microscopic polyangiitis, vasculitis, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome), granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), polyarteritis nodosa, and Henoch-Schönlein purpura. purpura), idiopathic thrombocytopenic thrombotic purpura, juvenile vasculitis, polyarteritis nodossa (also known as panarteritis nodosa, periarteritis nodosa, Kussmaul disease, Kussmaul-Maier disease, or PAN), serum sickness, myasthenia gravis, Takayasu's sarteritis, Behçet's syndrome ( The method comprises administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof. The methods include administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0466] In another embodiment, the present invention provides a method for treating or preventing the following diseases in humans: inflammatory bowel disease, Crohn's disease, ulcerative colitis, steatorrhea, celiac disease, proctitis, eosinophilic gastroenteritis, autoimmune atrophic gastritis of pernicious anemia, or mastocytosis, said method comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0467] In another embodiment, the present invention provides a method for treating or preventing psoriasis, atopic dermatitis, eczema dermatitis, dermatitis, pruritus, alopecia, autoimmune alopecia, vitiligo, epidermal hyperplasia, juvenile dermatomyositis, or dermatomyositis. In some other embodiments, psoriasis is plaque psoriasis, guttate psoriasis, psoriatic epidermal hyperplasia, inverse psoriasis, pustular psoriasis, or erythrodermic psoriasis in humans, the method comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0468] In another embodiment, the present invention provides a method for treating or preventing the following diseases in humans: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, autoimmune hepatitis, chronic active hepatitis, or primary biliary sclerosis, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0469] In another embodiment, the present invention provides a method for treating or preventing human diseases including multiple sclerosis, amyotrophic lateral sclerosis, Guillain-Barré disease, autoimmune encephalomyelitis, Alzheimer's disease, major depressive disorder, traumatic brain injury, epilepsy, Parkinson's disease, or bipolar disorder, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0470] In another embodiment, the present invention provides a method for treating or preventing the following diseases in humans: Graves' disease, non-infectious uveitis, dry eye syndrome, sympathetic ophthalmia, Cogan's syndrome, keratoconjunctivitis, vernal conjunctivitis, uveitis (including uveitis associated with Behcet's disease and lenticulopneumonia), keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, corneal leukoma, ocular pemphigoid. Premphigus), keratotic ulcers, scleritis, keratoconjunctivitis sicca (dry eye syndrome), phlyctenules, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis, ocular neovascularization, or proliferative diabetic retinopathy, the method comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0471] In another embodiment, the present invention provides a method for treating or preventing asthma, allergies, chronic obstructive pulmonary disease or acute respiratory disease in humans, comprising administering to a human requiring such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof.

[0472] In another embodiment, the present invention provides a method for treating or preventing the following diseases: gastrointestinal / digestive tract cancer, colon cancer, liver cancer, skin cancer (including mast cell carcinoma and squamous cell carcinoma), breast and breast cancer, ovarian cancer, prostate cancer, leukemia, diffuse large B-cell lymphoma, cutaneous T-cell lymphoma, non-Hodgkin's lymphoma, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, multiple myeloma, myeloproliferation, glioblastoma, oligodendroglioma, pancreatic cancer, brain tumor or glioma (including astrocytoma). In some other embodiments, the leukemia is acute myeloid leukemia, T-cell acute lymphoblastic leukemia, or adult T-cell leukemia in humans, and the method includes administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0473] In another embodiment, the present invention provides a method for treating or preventing type 1 diabetes, type 2 diabetes, or juvenile diabetes in humans, comprising administering to a human in need of such treatment a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof.

[0474] definition

[0475] As used throughout this specification and the appended claims, the following terms have the following meanings.

[0476] As used herein, the term “(C2-C4)alkenyl” refers to a straight-chain or branched hydrocarbon containing 2 to 4 carbons and a carbon-carbon double bond. Representative examples of (C2-C4)alkenyl include, but are not limited to, vinyl, 2-propenyl, 2-methyl-2-propenyl, and 3-butenyl.

[0477] As used herein, the term “(C1-C4)alkoxy” means an alkyl group as defined herein that is attached to a parent molecule via an oxygen atom. Representative examples of (C1-C4)alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0478] As used herein, the term "(C1-C3)alkyl" refers to a straight-chain or branched hydrocarbon containing 1 to 3 carbon atoms. Representative examples of (C1-C3)alkyl include methyl, ethyl, n-propyl, and isopropyl.

[0479] As used herein, the term "(C1-C3)alkyl-d" 1-7 "This refers to straight-chain or branched hydrocarbons containing 1 to 3 carbon atoms, in which one to seven hydrogen atoms have been deuterated (...") 2 H or D) substitution. (C1-C3)alkyl-d 1-7 Representative examples include methyl-d3, ethyl-d5, and ethyl-2,2,2-d3.

[0480] As used herein, the term “(C1-C4)alkyl” refers to a straight-chain or branched hydrocarbon containing 1 to 4 carbon atoms. Representative examples of (C1-C4)alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0481] As used herein, the term "(C1-C4)alkyl-d" 1-9 "Refers to straight-chain or branched hydrocarbons containing 1 to 4 carbon atoms, of which one to nine hydrogen atoms have been deuterated ( 2 H or D) substitution. (C1-C4)alkyl-d 1-9Representative examples include methyl-d3, ethyl-d5, and ethyl-2,2,2-d3.

[0482] As used herein, the term “(C1-C6)alkyl” means a straight-chain or branched hydrocarbon containing 1 to 6 carbon atoms. Representative examples of (C1-C6)alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0483] As used herein, the term “(C1-C4)alkylcarbonyl” means a (C1-C4)alkyl group as defined herein that is attached to a parent molecule via a carbonyl group. Representative examples of (C1-C4)alkylcarbonyl groups include, but are not limited to, acetyl, 1-oxopropyl, and 2,2-dimethyl-1-oxopropyl.

[0484] As used in this article, the term "carbonyl" refers to the -C(=O)- group.

[0485] As used in this article, the term "cyano" refers to the -CN group.

[0486] As used herein, the term "(C3-C4)cycloalkyl" refers to a saturated cycloalkyl group containing 3 to 4 carbons, and examples of (C3-C4)cycloalkyl include cyclopropyl and cyclobutyl. The (C3-C4)cycloalkyl groups of the present invention are optionally substituted with 1, 2, or 3 substituents that are independently (C1-C4)alkyl, CN, halogen, or OH.

[0487] As used herein, the term “(C3-C4)cycloalkyl (C1-C4)alkyl” means a (C3-C4)cycloalkyl group as defined herein that is attached to a parent molecule via a (C1-C4)alkyl group. Representative examples of (C3-C4)cycloalkyl (C1-C4)alkyl groups include cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopropylpropyl, 3-cyclopropylpropyl, cyclobutylmethyl, 2-cyclobutylethyl, 2-cyclobutylpropyl, and 3-cyclobutylpropyl.

[0488] As used herein, the term "(C3-C5)cycloalkyl" refers to a saturated cycloalkyl group containing 3 to 5 carbons, and examples of (C3-C5)cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl. The (C3-C5)cycloalkyl groups of the present invention are optionally substituted with one, two, or three substituents that are independently (C1-C4) alkyl, CN, halogen, or OH.

[0489] As used in this article, the term “halogenated” or “halogen” refers to -Cl, -Br, -I, or -F.

[0490] As used herein, the term "halo(C1-C4)alkoxy" means at least one halogen as defined herein, which is attached to a parent molecule via a (C1-C4)alkoxy group. Representative examples of halo(C1-C4)alkoxy groups include, but are not limited to, chloromethoxy, difluoromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

[0491] As used herein, the term “halo(C1-C3)alkoxy” means at least one halogen as defined herein, which is attached to a parent molecule moiety via a (C1-C3)alkoxy group. Representative examples of halo(C1-C3)alkyl groups include, but are not limited to, chloromethyl, difluoromethyl, 2-fluoroethyl, trifluoromethyl, and pentafluoroethyl.

[0492] As used herein, the term "halogenated (C1-C4)alkyl" means at least one halogen as defined herein, which is attached to a parent molecule via a (C1-C4)alkyl group. Representative examples of halogenated (C1-C4)alkyl groups include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, and pentafluoroethyl.

[0493] As used herein, the term "heterocycle" means a 4-, 5-, or 6-membered ring containing one N heteroatom and optionally one or two other heteroatoms selected from O, N, and S. Representative examples of heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, imidazolyl, morpholino, oxadiazolyl, oxazolyl, piperazine, piperidinyl, pyrazolyl, pyrrolidinyl, thiadiazolyl, thiazolyl, and thiomorpholino. The heterocyclic groups of the present invention are optionally substituted with one, two, or three (C1-C4) alkyl groups.

[0494] As used herein, the term "hydroxy(C1-C4)alkyl" means at least one hydroxyl group, as defined herein, attached to a parent molecule moiety via a (C1-C4)alkyl group. Representative examples of hydroxy(C1-C4)alkyl groups include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,4-dihydroxybutyl, and 2,3-dihydroxypropyl.

[0495] In another embodiment, the present invention provides a pharmaceutical combination for topical administration comprising a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof, in combination with another agent for treating the diseases, conditions, and / or symptoms described herein. Suitable agents that can be used in combination with the compounds of the present invention for topical administration include, but are not limited to: another compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof; PDE4 isoenzyme inhibitors, including but not limited to ampremilast, roflumilast, rolipram, piclamilast, crisaborole, PF-07038124, PF-07091905, etc. PF-07090414, PF-07062087, PF-07062077 and PF-07057566; corticosteroids, including but not limited to fluocinonide, desoximetasone, mometasone, triamcinolone, betamethasone, alclometasone, desonide, hydrocortisone, LEO-134 310A and mapracorat; calcineurin inhibitors, including but not limited to tacrolimus, pimecrolimus, and cyclosporine; JAK inhibitors, including but not limited to tofacitinib, JTE-052, baricitinib, upadacitinib, PF-04965842, PF-06651600, and PF-06700841; TYK inhibitors, including but not limited to PF-068. 26647 and BMS-986165; ITK inhibitors, including but not limited to JTE-051; SYK inhibitors, including but not limited to fostamatinib, cerdulatinib, entospletinib, TAK-659, ASN-002 and GS-9876; tyrosine kinase inhibitors, including but not limited to cerdulatinib; IRAK4 inhibitors, including but not limited to 1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidone-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide;Anti-inflammatory agents, including but not limited to WBI-1001 and MRX-6; retinoic acid derivatives, including but not limited to alitretinoin; selective hepatic X receptor (LXR) agonists, including but not limited to VTP-38543; H4 receptor antagonists, including but not limited to ZPL-389; NKI receptor antagonists, including but not limited to aprepitant and tripiditant; CRTH2 receptor antagonists, including but not limited to fevipiprant and OC-459; rennet inhibitors, including but not limited to SUN 13834; GATA-3 inhibitors, including but not limited to SB-011; and RORC2 inverse agonists, including but not limited to PF-06763809, ESR-114, VTP-43742, ARN6039, TAK-828, RTA-1701, BOS-172767, AUR-101, and JTE-451.

[0496] In another embodiment, the present invention provides a pharmaceutical combination for oral administration comprising a compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof, in combination with another pharmaceutical agent for treating the diseases, conditions, and / or ailments described herein. Suitable pharmaceutical agents that can be used in combination with the compounds of the present invention for oral administration include, but are not limited to: another compound of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof; oral anti-inflammatory agents, including but not limited to aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamic acid, droxicam, diclofenac, sulfinpyrazone, and piroxicam. Pharmaceutically acceptable salts or prodrugs thereof; oral retinoic acid derivatives, including but not limited to avitamin A; oral selective hepatic X receptor (LXR) agonists, including but not limited to VTP-38543; oral H4 receptor antagonists, including but not limited to ZPL-389; oral NKI receptor antagonists, including but not limited to aprepitant and tripipitant; oral CRTH2 receptor antagonists, including but not limited to fevipiprant and OC-459; oral rennet inhibitors, including but not limited to SUN 13834; oral GATA-3 inhibitors, including but not limited to SB-011; oral RORC2 inverse agonists, including but not limited to ESR-114, VTP-43742, ARN6039, TAK-828, RTA-1701, BOS-172767, AUR-101, and JTE-451; oral JAK inhibitors, including but not limited to tofacitinib, JTE-052, baricitinib, utpatinib, PF-04965842, PF-06651600, and PF-06700841; oral TYK inhibitors, including but not limited to PF-06826647 and BMS- 986165; oral ITK inhibitors, including but not limited to JTE-051; oral SYK inhibitors, including but not limited to fortenatinib, cerdulatinib, entospletinib, TAK-659, ASN-002 and GS-9876; oral S1P receptor modulators, including but not limited to ozanimod and etrasimod; and oral IRAK4 inhibitors, including but not limited to 1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidone-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide and BAY 1830839.

[0497] In another embodiment, the present invention provides a pharmaceutical combination for injection administration comprising a compound of formula (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB) or a pharmaceutically acceptable salt or hydrate thereof, in combination with another pharmaceutical agent for treating the diseases, conditions and / or ailments described herein. Suitable agents that can be used in combination with the compounds of the present invention for injection administration include, but are not limited to: TNFα inhibitors, including but not limited to infliximab, adalimumab, golimumab, and certolizumab pegol; anti-MAdCAM, including but not limited to SHP647; anti-IL-12P40, including but not limited to ustekinumab; anti-IL-23P19, including but not limited to risankizumab, mirikizumab, brazikumab, guselkumab, and tidrakizumab; anti-IL-17, including but not limited to secukinumab, brodalumab, and ixekizumab; and integrin inhibitors, including but not limited to natalizumab, vedolizumab, and etrolizumab.

[0498] Combination therapy includes the simultaneous or sequential administration of two or more therapeutic agents. The agents may be administered in any order. Alternatively, multiple therapeutic agents may be combined into a single composition that can be administered to a patient. For example, a single pharmaceutical composition may comprise a compound according to formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt, hydrate, ester, or prodrug thereof; another therapeutic agent or a pharmaceutically acceptable salt, hydrate, ester, or prodrug thereof; and at least one pharmaceutically acceptable excipient or carrier.

[0499] As used herein, the term "pharmaceutically acceptable salt" or "salt" refers to a salt known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977), which is incorporated herein by reference. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include nitrates, bisulfates, borates, formates, butyrates, valerates, 3-phenylpropionates, camphorates, adipates, benzoates, benzenesulfonates, oleates, palmitates, stearates, laurates, lactates, fumarates, ascorbic acid salts, aspartates, nicotinates, p-toluenesulfonates, camphorsulfonates, methanesulfonates, 2-hydroxyethanesulfonates, gluconates, gluconoses, lactobionates, glycerophosphates, pectates, lauryl sulfates, metal salts (such as sodium, potassium, magnesium, or calcium salts) or amino salts (such as ammonium salts or triethylamine salts), all of which can be prepared using conventional methods.

[0500] Base addition salts can be prepared in situ during the final separation and purification of the compounds of the present invention by reacting the hydroxyl group at the 3-position of the N,N-dimethylpyridine carboxamide group with a suitable base (such as a pharmaceutically acceptable hydroxide, carbonate, or bicarbonate of a metal cation) or with ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to: alkali metal or alkaline earth metal-based cations, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts; and non-toxic quaternary ammonium and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium, etc. Other representative organic amines suitable for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, etc.

[0501] This invention also includes pharmaceutically acceptable salts of the prodrugs of the compounds of this invention. Representative examples include, but are not limited to, the compounds shown below, wherein R + The compounds include lithium, sodium, potassium, ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium, among which R... 2+ It contains calcium, magnesium, aluminum, etc.

[0502]

[0503] The compounds of this invention can be isolated and used in their own pharmaceutically acceptable salt form (including salts of prodrugs). According to the invention, compounds having multiple basic nitrogen atoms can form salts with acids of varying equivalence (“eq.”) numbers. Compounds having multiple acidic groups can form base addition salts with base adduct molecules or positive counterions of varying equivalence (“eq.”) numbers. Those skilled in the art will understand that all such salts are within the scope of this invention.

[0504] When prepared by synthetic or metabolic processes, this invention covers compounds of formulas (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB). Preparation of the compounds of this invention by metabolic processes includes those processes that occur in humans or animals (in vivo) or in vitro.

[0505] This invention also covers pharmaceutically active metabolites formed by in vivo biotransformation of compounds of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB). As used herein, the term pharmaceutically active metabolite means a compound formed by in vivo biotransformation of compounds of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB). A detailed discussion of biotransformation is provided in (Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 7th Edition, MacMillan Publishing Company, New York, NY, (1985)).

[0506] When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be used in its pure form or in a pharmaceutically acceptable form as a salt, ester, amide, or prodrug (where such forms are available). Alternatively, the compound may be administered as a pharmaceutical composition comprising a combination of the compound of interest and one or more pharmaceutically acceptable carriers. The phrase "therapeutically effective amount" for a compound of the present invention means an adequate amount of the compound for treating the disease, condition, or ailment indicated herein, given a reasonable benefit / risk ratio applicable to any medical treatment. The specific therapeutically effective dose level for any particular patient will depend on a number of factors, including the condition being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and rate of excretion of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors known in the medical field.

[0507] Pharmaceutical compositions or preparations

[0508] In another embodiment, the present invention provides a pharmaceutical composition or formulation comprising a therapeutically effective amount of the compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical compositions or formulations of the present invention can be administered topically, orally, parenterally, intracranially, vaginally, intraperitoneally, sublingually, as an oral spray, as a nasal spray, as a suppository, rectally, or in liposome form to humans and other mammals.

[0509] Typical pharmaceutical compositions or formulations are prepared by mixing the compounds of the present invention with a carrier, diluent, or excipient. Suitable carriers, diluents, and excipients include substances such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc. The specific carrier, diluent, or excipient used will depend on the manner and purpose of applying the compounds of the present invention. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and mixtures thereof. Formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, flow aids, processing aids, colorants, sweeteners, flavoring agents, and other known additives for providing optimal performance of the drug (i.e., the compounds of the present invention or their pharmaceutical compositions) or for assisting in the preparation of the drug (i.e., for the preparation of the drug).

[0510] Formulations can be prepared using conventional dissolution and mixing procedures. For example, the active pharmaceutical ingredient (i.e., the compound of the present invention or a stable form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more excipients described above. The dissolution rate of poorly water-soluble compounds can be enhanced by using spray-dried dispersions, such as those described by Takeuchi, H., et al. in “Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent deposition method and disintegrants” J. Pharm. Pharmacol., 39, 769-773 (1987) and EP0901786 B1 (US2002 / 009494), which are incorporated herein by reference. The compounds of the present invention are generally formulated into pharmaceutical dosage forms to provide a drug with easily controllable dosage and a refined and easy-to-use product for the patient.

[0511] Depending on the method of administration, pharmaceutical compositions or formulations for delivery can be packaged in various ways. Generally, dispensing articles include containers that store pharmaceutical formulations in a suitable form. Suitable containers include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. Containers may also include tamper-proof assemblies to prevent accidental contact with the contents. Additionally, the container is labeled with a description of its contents. The label may also include appropriate warnings.

[0512] The term "pharmaceutically acceptable carrier" refers to a carrier medium that provides an effective amount of an active agent as defined herein, without interfering with the effectiveness of the active agent's biological activity, and is sufficiently non-toxic to the host or patient. Representative carriers include water, oils (vegetable and mineral oils), cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickeners, penetration enhancers, etc. Further information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams and Wilkins (2005), which is incorporated herein by reference. Other examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; astragalus powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; diols, such as propylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions; and other non-toxic and compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, release agents, coating agents, sweeteners, flavoring agents, and aroma agents, preservatives, and antioxidants, which may also be present in the composition at the discretion of the formulator.

[0513] The term "pharmaceutically acceptable topical carrier" refers to a pharmaceutically acceptable carrier as described above, suitable for topical application. Examples of pharmaceutically acceptable topical carriers are inactive liquid or cream carriers that, when applied to the skin, nails, hair, claws, or hooves, suspend or dissolve the active agent and possess non-toxic and non-inflammatory properties. This term is particularly intended to also cover carrier substances approved for use in topical cosmetics.

[0514] The term "topical administration" refers to the application of a drug to the outer surface of the skin, nails, hair, claws, or hooves, allowing the drug to cross the outer surface of the skin, nails, hair, claws, or hooves and enter the underlying tissues. Topical administration includes applying a composition to intact skin, nails, hair, claws, or hooves, or to broken, untreated, or exposed wounds of the skin, nails, hair, claws, or hooves. Topical administration of a drug can result in limited distribution of the drug to the skin and surrounding tissues, or systemic distribution of the drug when it is removed from the treatment area via the bloodstream.

[0515] Dosage forms for topical or transdermal administration of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is blended under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers (as needed). Volatile compounds may require blending with specific formulations or encapsulation materials to ensure appropriate dose delivery. Additionally, compounds of this invention with poor human skin permeability may require one or more permeation enhancers, while compounds rapidly absorbed through the skin may require absorption blockers or absorption barriers.

[0516] In addition to the active compounds of this invention, ointments, pastes, creams, lotions, gels, powders, and solutions for topical administration may contain pharmaceutically acceptable excipients, such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragali, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, zinc oxide, preservatives, antioxidants, fragrances, emulsifiers, dyes, inert fillers, anti-irritants, thickeners, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, emollients, colorants, preservatives, buffers, penetration enhancers, or mixtures thereof. Topical excipients should not interfere with the effectiveness of the bioactivity of the active agent and should not be harmful to epithelial cells or their function.

[0517] The term "permeability enhancer" or "permeation enhancer" refers to an increase in the permeability of a drug to the skin, nails, hair, claws, or hooves, thereby increasing the rate at which the drug permeates through the skin, nails, hair, claws, or hooves. The permeation enhancement achieved by using such enhancers can be observed, for example, by measuring the diffusion rate of a drug through the skin, nails, hair, claws, or hooves of an animal or human using a diffusion cell device. A diffusion cell is described by Merritt et al., *Diffusion Apparatus for Skin Penetration*, *J. of Controlled Release*, 1 (1984), pp. 161-162. The term "permeability enhancer" or "permeation enhancer" means, alone or in combination, a substance or mixture of substances used to increase the permeability of a drug to the skin, nails, hair, or hooves.

[0518] The term "transdermal delivery" refers to the diffusion of a drug across the barriers of skin, nails, hair, claws, or hooves caused by the local administration or other application of a composition. The stratum corneum acts as a barrier, and very few drugs can penetrate unbroken skin. In contrast, many solutes can permeate the epidermis and dermis, and therefore drug absorption is more readily achieved through abrasion or exfoliation of the stratum corneum to expose the epidermis, such as skin, nails, hair, claws, or hooves. Transdermal delivery includes injection or other delivery via any part of the skin, nails, hair, claws, or hooves or mucous membranes, as well as absorption or permeation via the remaining parts. Absorption via unbroken skin, nails, hair, claws, or hooves can be enhanced by placing the active agent in a suitable pharmaceutically acceptable carrier prior to application to the skin, nails, hair, claws, or hooves. Passive local administration can consist of the direct application of the active agent in combination with an emollient or penetration enhancer to the treatment site. As used herein, transdermal delivery is intended to include delivery via permeation or through the body membrane (i.e., skin, nails, hair, claws, or hooves).

[0519] In addition to the compounds of this invention, powders and sprays may contain lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Sprays may also contain conventional propellants, such as chlorofluorocarbons.

[0520] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert carrier (such as sodium citrate or calcium phosphate) and / or the following substances: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) humectants, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0521] Similar solid compositions can also be used as fillers in soft and hard-filled gelatin capsules that use lactose (or milk sugar) and high molecular weight polyethylene glycol.

[0522] Solid dosage forms such as tablets, lozenges, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the field of pharmaceutical formulation. They may optionally contain light-blocking agents and may also have compositions that allow for the delayed release of the active ingredient only or preferably in certain portions of the intestine. Examples of usable encapsulating components include polymers and waxes.

[0523] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as (e.g.) water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitol fatty acid esters; and mixtures thereof.

[0524] In addition to inert diluents, oral compositions may also contain excipients such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatizers.

[0525] As used herein, the term "parenteral" refers to a mode of administration that includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injection and infusion. Pharmaceutical compositions of the present invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or loading agents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Appropriate flowability can be maintained, for example, by using coatings (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0526] Injectable reservoir formulations are prepared by forming a microencapsulated matrix of the drug within a biodegradable polymer, such as polylactide-polyglycolide. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable reservoir formulations are also prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0527] Injectable formulations can be sterilized, for example, by filtration via a bacterial-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be immediately dissolved or dispersed in sterile water or other sterile injectable media before use.

[0528] Injectable formulations (e.g., sterile injectable aqueous or oily suspensions) can be formulated using suitable dispersants or wetting agents and suspending agents. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable carriers and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solution are acceptable. Furthermore, sterile non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids (such as oleic acid) are used in the preparation of injections.

[0529] Pharmaceutical compositions or formulations for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compound of the invention with a suitable non-irritating carrier (such as cocoa butter, polyethylene glycol or suppository wax) that is solid at ambient temperature but liquid at body temperature, and thus melts and releases the active compound in the rectal or vaginal cavity.

[0530] The compounds of this invention can also be administered in liposome form. Liposomes are typically derived from phospholipids or other lipid substances and are formed from monolayers or multilayers of hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes can be used. In addition to the compounds of this invention, the compositions of this invention in liposome form may contain stabilizers, preservatives, etc. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholine (lecithin), used alone or in combination. Methods for forming liposomes are known in the art. See, for example, Prescott, ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY, (1976), page 33 and effusive.

[0531] The pharmaceutical compositions or formulations of the present invention may also contain excipients, such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). Isotonic agents, such as sugars and sodium chloride, may also be required. Prolonged absorption of injectable drug forms can be achieved by using substances that delay absorption (e.g., aluminum monostearate and gelatin).

[0532] The pharmaceutical compositions or formulations of the present invention may be suspensions. In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, tragali, and mixtures thereof.

[0533] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of active compound that effectively achieves the desired therapeutic response for a specific patient, composition, and administration route. The selected dosage level will depend on the activity of the specific compound, the route of administration, the severity of the condition being treated, and the patient's condition and prior medical history. However, within the scope of the art, the compound dosage is started at a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is achieved.

[0534] The total daily dose range of the compounds of the present invention administered to humans or lower animals can be from about 0.0001 to about 15 mg / kg / day. For oral administration, a more preferred dose range is from about 0.01 to about 5 mg / kg / day. For topical administration, a more preferred dose range is from 0.001 mg / kg / day to about 5 mg / kg / day. As needed, for the purpose of administration, the effective daily dose can be divided into multiple doses, for example, two to four individual doses per day.

[0535] The pharmaceutical compositions also comprise solvates and hydrates of the compounds of the present invention. The term "solvate" refers to a molecular complex of a compound represented by formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB) (including its pharmaceutically acceptable salts or hydrates) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field that are known to be harmless to the recipient, such as water, ethanol, ethylene glycol, (S)-propylene glycol, (R)-propylene glycol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water. The solvates and / or hydrates are preferably present in crystalline form. Other solvents may be used as intermediate solvents in the preparation of more desired solvates. Intermediate solvents include, but are not limited to, methanol, methyl tert-butyl ether, ethyl acetate, methyl acetate, 1,4-butynediol, etc.

[0536] The compounds of the present invention can exist in more than one crystalline form. Polymorphs of compounds of formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), and their salts (including solvates and hydrates), form part of the present invention and can be prepared by crystallizing the compounds of the present invention under different conditions. For example, different solvents or mixtures of different solvents are used for recrystallization; crystallization is performed at different temperatures; and various cooling modes are used, ranging from very rapid cooling to very slow cooling during crystallization. Polymorphs can also be obtained by heating or melting the compounds of the present invention, followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid-state probe nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, differential scanning calorimetry, powder X-ray diffraction, or other such techniques.

[0537] This invention also includes isotopically labeled compounds that are identical to those described by formulas (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB), but in fact have one or more atoms replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14C 15 N、 18 O、 17 O、 35 S, 36 Cl、 125 I, 129 I and 18 F. Certain isotopically labeled compounds of the present invention (e.g., those doped with substances such as...) 3 H and 14 Compounds containing radioactive isotopes of C are used for drug and / or substrate tissue distribution analysis. Tritium (i.e., 3 H) and carbon-14 (i.e., H) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, isotopes such as deuterium (i.e., 2 Substitution of H) with a heavier isotope can yield certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and is therefore preferred in some cases. The isotopically labeled compounds of the present invention can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents by performing the operations disclosed in the routes described below and / or the examples.

[0538] Specifically, the present invention includes deuterated compounds of formulas (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB). Any of the hydrogen atoms contained in the compounds of the present invention (including pyridine hydrogen as shown below) may be deuterated.

[0539]

[0540] Representative examples of the deuterated compounds of the present invention include, but are not limited to, Examples 39 and 40.

[0541] All of the listed U.S. patents and publications (including all technical publications referenced in the embodiments) are incorporated herein by reference in their entirety.

[0542] The compounds of the present invention, or their pharmaceutically acceptable salts or hydrates thereof, can be prepared by the methods described below, as well as synthetic methods known in the field of organic chemistry, or modifications and derivations common to those skilled in the art. The raw materials used herein are commercially available or can be prepared by conventional methods known in the art, such as those disclosed in standard reference books (including the Compendium of Organic Synthetic Methods, Volumes I-VI, published by Wiley-Interscience). Preferred methods include, but are not limited to, those described below.

[0543] During any of the following synthetic sequences, it may be necessary and / or required to protect sensitive or reactive groups on any of the molecules in question. This can be achieved by conventional protecting groups as described in the following literature: TWGreene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; TWGreene and PGMWuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991; and TWGreene and PGMWuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0544] The compounds of the present invention can be prepared as single enantiomers or as mixtures of single enantiomers comprising racemic mixtures. Methods for preferentially obtaining single enantiomers from mixtures of single enantiomers or racemic mixtures are well known to those skilled in the art of organic chemistry. Such methods include, but are not limited to, preferential crystallization of diastereomer salts (e.g., tartrates or camphor sulfonates); covalent derivatization with a chiral racemic reagent, followed by separation of the resulting diastereomers by conventional methods (e.g., crystallization, chromatographic separation, or distillation) and chemical conversion to a racemic compound; or high-pressure / medium-pressure liquid chromatography or supercritical fluid chromatography using a chiral stationary phase. These techniques can be performed on the final compounds of the present invention or on any intermediates of the compounds of the present invention bearing a stereoisomeric source center. Furthermore, to facilitate separation by any of the methods described above, the compounds of the present invention or any intermediates of the compounds of the present invention bearing a stereoisomeric source center can be briefly reacted with a chiral reagent, separated, and then converted to a racemic compound by standard synthetic techniques.

[0545] Depending on the configuration of the substituents surrounding the chiral carbon atom, the stereoisomers are named (R) or (S). As used herein, the terms (R) and (S) refer to the configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45:13-30. Specifically, “A” and “B” in formulas (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB) are...

[0546] The stereochemistry at the junction can be independently (R) or (S). The enantiomers of the invention indicated by (R), (S), or * are substantially free of other enantiomers. "Substantially free" means an enantiomer excess of more than about 90%, preferably more than about 95%, and more preferably more than about 99%. In the case of an enantiomer excess, the term "about" means ±1.0%. Depending on the configuration of the substituents surrounding the chiral carbon atom, the symbol * designates the chiral carbon atom as having (R) or (S) stereochemistry.

[0547] The compounds of the present invention, without specified (R), (S), or *, may exist as racemates (i.e., 50% (R) and 50% (S)) or as a mixture of two enantiomers in excess of one of them. For example, an enantiomeric mixture may contain 51% (R) enantiomers and 49% (S) enantiomers, or vice versa, or any combination of (R) and (S) other than a racemate mixture of 50% (R) and 50% (S). The present invention includes racemates and enantiomeric mixtures of the compounds of the present invention.

[0548] The compounds of the present invention can exist in separable, different stable conformations. The separation of different conformational isomers is allowed due to restricted rotation around asymmetric single bonds, for example, due to torsional asymmetry caused by steric hindrance or ring stress. The compounds of the present invention further include conformational isomers of compounds of formulas (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), and mixtures thereof.

[0549] Tautomers may be present in the compounds of the present invention, and are particularly included within the scope of the present invention. As used herein, the term "tautomer" refers to a proton transfer from one atom of a molecule to another atom of the same molecule, wherein two or more structurally different compounds are in equilibrium with each other. The compounds of the present invention may exist as tautomers. Because the transfer of a proton from one atom of the same molecule to another results in two or more different compounds in equilibrium with each other, the present invention covers tautomers. In particular, the bis(amino)cyclobut-3-ene-1,2-dione moiety in the compounds of the present invention may be tautomerized as shown below and is included within the scope of the present invention.

[0550]

[0551] The compounds of the present invention or their pharmaceutically acceptable salts can be prepared according to the reaction routes and examples disclosed below. Unless otherwise indicated, R1, R2, R3, R4, R5, R6, R7, R8, R9, m, n, A, B, X, R in the route are not intended to be used. A R B and R CAs defined in formulas (IA) and (IB) in the overview section above. Those skilled in the art will understand that the various symbols, superscripts, and subscripts used in the routes, methods, and examples are for convenience and / or to reflect their order of introduction in the route, and are not intended to correspond necessarily to the symbols, superscripts, or subscripts in the appended claims. The routes represent methods for synthesizing the compounds of the invention. They do not limit the scope of the invention in any way. The separation and purification of products are achieved through standard practices known to those skilled in the art.

[0552] Route A

[0553]

[0554] Compounds of formula (IA) and (IB) can be prepared as described in route A. Nucleophilic aromatic substitution between aminopyridine A-1 (prepared as described in route B) and a commercially available 3,4-diethoxycyclobut-3-ene-1,2-dione (A-2) yields compound A-3. A second nucleophilic aromatic substitution between A-3 and amine A-4 (prepared as described in route CG) yields compound A-5.

[0555] Route B

[0556]

[0557] The compound of formula A-1 used in route A can be prepared as described in route B. Under basic conditions, amidation of commercially available 4-chloro-3-methoxypyridinecarboxyl chloride (B-1) with a commercially available amine B-2 provides a compound of formula B-3. Buchwald coupling of B-3 with tert-butyl carbamate yields a compound of formula B-4, which can be subjected to acidic conditions to remove the Boc group, providing a compound of formula B-5. Demethylation of B-5 produces a compound of formula A-1.

[0558] Route C

[0559]

[0560] The compound of formula A-4 used in route A can be prepared as described in route C, wherein the amine is enantiomerically enriched. A titanium ethoxide (IV)-mediated condensation of an aldehyde C-2 (obtainable commercially or by reducing a corresponding nitrile C-1, which is commercially available or prepared by methods known in the art) with (S)-2-methylpropane-2-sulfinamide (C-3) provides the compound of formula C-4. Metallization of a heteroaryl halide C-5 (where X is iodine or bromine) provides a highly diastereoselective addition to C-4 to give a sulfonamide of formula C-6 as the major diastereomer. Subsequently, the chiral auxiliary is removed under acidic conditions to produce the compound of formula A-4. The absolute stereochemistry of amine A-4 can be established by methods known to those skilled in the art (including Mosher amide analysis and single-crystal X-ray crystallization) or by methods similar to those used for known compounds.

[0561] Route D

[0562]

[0563] The compound of formula A-4 used in route A can be prepared as described in route D, wherein the amine is a racemic mixture or a diastereomeric mixture. The carboxylic acid of formula D-1 (commercially available or prepared as described below) can be converted to the corresponding Weinreb amide D-2 by HATU-mediated condensation with methoxymethylamine. Metallation of the heteroaryl halide C-5 (where X is iodine or bromine) followed by reaction with D-2 yields the ketone of formula D-3. Reductive amination of D-3 with ammonia in methanol yields the compound of formula A-4 as a racemic mixture or a diastereomeric mixture.

[0564] Route E

[0565]

[0566]

[0567] Alternatively, as described in route E, compound A-4 can be prepared from 3-halo-1-alkylpyrazole E-1 (R4 = alkyl and X = bromine or iodine), where variable A in formula (IA) or (IB) is defined as a substituted pyrazole. Metallization of E-1 followed by addition to sulfinamide C-4 or Weinreb amide D-2 yields addition products of formula E-2 or E-4, respectively. An R5 substituent can be introduced via electrophilic aromatic substitution or by reaction with NIS followed by metal-mediated cross-coupling of the resulting iodide to provide compounds E-3 or E-5. The chiral auxiliary of E-3 can then be removed under acidic conditions to provide compound A-4. Reductive ammoniation of E-5 with ammonia in methanol yields compound A-4.

[0568] Route F

[0569]

[0570] The compound of formula A-4 used in route A can be prepared as described in route F, wherein variable B of formula (IA) or (IB) is defined as 5-methylspiro[2,3]hex-5-yl. Commercially available spiro[2,3]hexane-5-carboxylic acid (F-1) can be converted to the corresponding Weinreb amide F-2 by HATU-mediated condensation with methoxymethylamine. Metallization of the heteroaryl halide C-5 (where X is iodine or bromine) followed by reaction with F-2 yields the ketone of formula F-3. F-3 is then alkylated with an alkyl halide (such as iodomethane or iodoethane) and a suitable base, followed by reductive amination with ammonia in methanol to give the compound of formula A-4 as a racemic mixture.

[0571] Route G

[0572]

[0573] Compound A-4, used in route A, can be prepared as described in route G, wherein variable A of formula (IA) or (IB) is defined as a 2,5-disubstituted oxazole. A commercially available carboxylic acid of formula G-1, or prepared by methods known in the art, can be condensed with methoxymethylamine in the presence of HATU to provide a Weinreb amide of formula G-2. Compound G-2 can be reacted with a Grignard reagent (such as isopropyl magnesium bromide or cyclopentyl magnesium bromide) to provide a ketone of formula G-3, wherein R and R' are methyl groups, or R and R' together with the carbon atom to which they are attached form a C-1 group. 3-5 Cycloalkyl ring. G-3 is then alkylated with an alkyl halide (such as iodomethane or iodoethane) and a suitable base, followed by reductive amination with ammonia in methanol to give compound A-4 as a racemic mixture.

[0574] Route H

[0575]

[0576] The specific carboxylic acid D-1 used in route D can be prepared as described in route H, wherein variable B of formula (IA) or (IB) is defined as (S) or (R)-4,4-difluoro-2-methyltetrahydrofuran-2-yl. Allylation of commercially available ethyl 2-oxopropionate (H-1) with allyltrimethylsilane via titanium chloride (IV)-mediated allylation yields ethyl 2-hydroxy-2-methylpent-4-enoate (H-2). Epoxidation of the terminal olefin of H-2 with 3-chloroperbenzoic acid, followed by magnesium bromide-mediated intramolecular cyclization, provides ethyl 4-hydroxy-2-methyltetrahydrofuran-2-carboxylate (H-4). The secondary alcohol is then oxidized with pyridinium chlorochromate, followed by fluorination with diethylaminosulfur trifluoride, to give ethyl 4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate (H-6). Ester H-6 was transesterified to obtain benzyl ester H-7, which was then resolved by chiral HPLC. The ester was subsequently saponified to obtain a single enantiomer H-8, which can be used in route D. The absolute stereochemistry of H-8 was established by single-crystal X-ray crystallization (see [link to original text]). Figure 3 ).

[0577] Route I

[0578]

[0579] 1,4-Disubstituted-3-iodopyrazole, which can be used in the synthetic methods described in Routes C, D, and F, can be prepared as described in Route I. A commercially available 4-substituted pyrazole (I-1) is provided by NIS iodination, yielding compound I-2. I-2 is then N-alkylated with an alkyl halide (e.g., iodomethane, iodoethane), followed by separation of positional isomers by chromatography to give compound C-5, which can be used in the synthetic methods described in the above routes.

[0580] Route J

[0581]

[0582] Alternatively, the 1,4-disubstituted-3-iodopyrazole, which can be used in the synthetic methods described in routes C, D, and F, can be prepared as described in route J. The 1,4-disubstituted-3-aminopyrazole (J-1) can be converted to the C-5 compound via the Sandmeyer reaction using sodium nitrite and potassium iodide. The C-5 compound can also be prepared by direct iodination of a commercially available 1,4-disubstituted pyrazole J-2 using NIS.

[0583] Route K

[0584]

[0585] In another variant, the 1,4-disubstituted 3-iodopyrazole used in routes CD and F can be prepared as described in route K, especially with R4=R5=methyl. The 3-iodo-1-methyl-1H-pyrazole (K-1) can be regioselectively formylated with a Vilsmeier reagent to give 3-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde (K-2), which can then be reduced (TFA, triethylsilane) to give 3-iodo-1,4-dimethyl-1H-pyrazole (K-3).

[0586] Route L

[0587]

[0588] The 2,5-disubstituted 4-bromothiazole used in routes CD and F can be prepared as described in route L. Commercially available 2,5-disubstituted thiazole L-1 can be obtained by NBS bromination to yield compound C-5.

[0589] Route M

[0590]

[0591] Alternatively, compounds of formulas (IA) and (IB) can be prepared as described in route M. Esterification of commercially available 4-chloro-3-methoxypyridinecarboxyl chloride (B-1) under basic conditions provides tert-butyl 4-chloro-3-methoxypyridinecarboxylate (M-1). Buchwald coupling between M-1 and commercially available 3-amino-4-ethoxycyclobut-3-ene-1,2-dione (M-2), followed by nucleophilic aromatic substitution with amine A-4, yields compound M-4. Ester hydrolysis under acidic conditions, followed by HATU-mediated amidation with amine B-2 and O-demethylation with magnesium bromide, yields compound A-5.

[0592] Route N

[0593]

[0594] Compounds of formulas (IA) and (IB) can be prepared as described in route N, wherein R3 is -CH2OP(O)(OH)2. Compound A-5 is alkylated with a commercially available di-tert-butyl (chloromethyl) phosphate under basic conditions to provide N-1. Subsequently, the tert-butyl ester protecting group is cleaved under acidic or neutral conditions to give compound N-2. Example

[0595] The invention will be more readily understood by referring to the following examples, which are for illustrative purposes only and are not intended to limit the invention. The synthesis of various compounds according to the invention is described below. Other compounds within the scope of the invention can be prepared using the methods (alone or in combination with techniques generally known in the art) described in these examples and routes.

[0596] Experiments are typically conducted under an inert atmosphere (nitrogen or argon), especially when using reagents or intermediates sensitive to oxygen or moisture. Commercially available solvents and reagents are usually used without further purification, including anhydrous solvents where appropriate. Mass spectrometry data are reported by liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI), or gas chromatography-mass spectrometry (GCMS). Chemical shifts in nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, δ) with reference to residual peaks from the deuterated solvent used. Coupling constants (J values) are reported in Hertz. For the synthetic reference operation in other examples, reaction conditions (reaction time and temperature) may vary. Generally, thin-layer chromatography or mass spectrometry is performed after the reaction, with post-processing where appropriate. Purification may vary for each experiment: generally, the solvent and solvent ratio used for the eluent / gradient are selected to provide suitable Rf's or retention time (RetT).

[0597] The compounds of this invention are named by Chemdraw Professional version 16.0 or given names consistent with Chemdraw nomenclature.

[0598] The following abbreviations are used in this document: DCM: dichloromethane; DAST: (diethylamino)sulfur trifluoride; DEA: diethylamine; DIPEA: diisopropylethylamine; DMF: dimethylformamide; EtOAc: ethyl acetate; EtOH: ethanol; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; IPA: isopropanol; HPLC: high-performance liquid chromatography; LHMDS: lithium hexamethyldisilamide. hexamethyldisilazide; MeOH: methanol; MTBE: methyl tert-butyl ether; NMM: N-methylmorpholine; NIS: N-iodosuccinimide; PCC: pyridinium chlorochromate; PE: petroleum ether; SFC: supercritical fluid chromatography; TBAI: tetrabutylammonium iodide; TEA: triethylamine; TFA: trifluoroacetic acid; and THF: tetrahydrofuran.

[0599] The following SFC method has been used. SFC Method A: Chiral Tech OD-H 250mm×4.6mm×5μm, 5 to 60% 0.2% NH4 +

[0600] (7N in MeOH) / EtOH, 3.0 mL / min. SFC Method B: Chiralpak AD-3 50 mm × 3 mm × 3 μm, 5 to 40% 0.05%

[0601] DEA / EtOH, 2.5 mL / min, 40 °C. SFC method C: Chiralcel OD 250 mm × 4.6 mm × 5 μm, 5 to 60% 0.2% NH4 +

[0602] (7M in MeOH) / EtOH, 3.0 mL / min. SFC method D: Chiralpak AD-3 150 mm × 4.6 mm × 3 μm, 5 to 40%

[0603] 0.05% DEA / EtOH, 2.5 mL / min, 40 °C. SFC method E: Chiralcel OJ-H 150 mm × 4.6 mm × 5 μm, 5 to 40%

[0604] 0.05% DEA / EtOH, 2.5 mL / min, 40 °C. SFC method F: Chiralcel OD-3 100 mm × 4.6 mm × 3 μm, 5 to 40%

[0605] 0.05% DEA / EtOH, 2.8 mL / min, 40 °C. SFC Method G: Chiralpak AD-3 150 mm × 4.6 mm × 3 μm, 5 to 40%

[0606] SFC Method H: Chiralcel OD-3 150×4.6mm I.D. 3μm, 5 to 40% 0.05% DEA / EtOH, 2.5mL / min, 40℃. SFC Method I: REGIS(s,s)WHELK-O1 250mm×30mm×5μm 40% 0.05% DEA / EtOH, 2.5mL / min, 35℃. SFC Method J: Chiralpak AS-3 150×4.6mm×3μm, 5 to 40% 0.05% DEA / EtOH, 2.5mL / min, 35℃. SFC Method K: Chiralpak AS-3 100×4.6mm×3μm, 5 to 40% 0.05% DEA / EtOH, 2.8mL / min, 40℃. SFC Method L: Lux Amylose W-1, 250mm × 4.6mm, 5μm, 5 to 60% 0.2% NH3 / EtOH, 3mL / min. SFC Method M: Lux Cellulose, 150mm × 4.6mm, 3μm, 5 to 40% MeOH, 2mL / min. SFC Method N: Chiralpak AD-3, 150mm × 4.6mm × 3μm, 5 to 40% 0.1% ethanolamine / EtOH, 2.5mL / min.

[0607] The following HPLC method was used. HPLC Method A: Chiralcel OD-RH, 150 mm × 4.6 mm × 5 μm, 10 to 80%

[0608] MeCN / 0.069% TFA / H2O, 0.8 mL / min, 30 °C. HPLC Method B: Chiralpak AS-RH, 150 mm × 4.6 mm × 5 μm, 10 to 80% MeCN / 0.069% TFA / H2O, 0.8 mL / min, 30 °C.

[0609] Example 1

[0610] (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide

[0611]

[0612] Step 1A. 1-Methylcyclopentane-1-carboxynitrile

[0613] Cyclopentaneformonitrile (26.67 g, 280.3 mmol) in a 1 M THF solution (280 mL, 280 mmol) at -70 °C was added dropwise over 15 min. After stirring for 30 min, methyl iodide (59.7 g, 26.2 mL, 420 mmol) was added dropwise, and the reaction mixture was heated to ambient temperature and stirred for 16 h. The resulting yellow solution was cooled to 0 °C and quenched with 200 mL of saturated NH4Cl aqueous solution and 100 mL of water. The mixture was extracted with MTBE (2.5 L × 2), and the combined organic extracts were washed with brine (1 L), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The crude product was purified twice by silica gel column chromatography (100% petroleum ether) to give 60 g (65%) of the title compound as a yellow oil. 1 H NMR (400MHz, CDCl3) δ2.20-2.10(m,2H),1.90-1.70(m,4H),1.65-1.55(m,2H),1.41(s,3H).

[0614] Step 1B. 1-Methylcyclopentane-1-carboxaldehyde

[0615] 1-Methylcyclopentane-1-carboxynitrile (30 g, 275 mmol) was added dropwise to a solution of DCM (30 mL) in DCM at -65 °C (824 mL, 824 mmol, 1 M in toluene). The mixture was stirred at the same temperature for 30 min. The reactants were quenched at -40 °C with saturated aqueous NH4Cl solution (1 L) and stirred vigorously at 25 °C for 10 min. The mixture was diluted with DCM (1 L), filtered, and the solid was washed with DCM (500 mL × 3). The combined filtrates were washed with brine (1 L), dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound as a solution in DCM / toluene (3 / 2, 2 L). The solution was used directly without further purification (assuming quantitative yield). 1 H NMR (400MHz, CDCl3) δ9.59 (s, 1H), 2.15-2.01 (m, 2H), 1.80-1.75 (m, 4H), 1.55-1.45 (m, 2H), 1.25 (s, 3H).

[0616] Step 1: C.(S,E)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide

[0617] Titanium ethoxide (IV) (163 g, 717 mmol) was added to a solution of 1-methylcyclopentane-1-carboxaldehyde (30.8 g, 275 mmol) in DCM / toluene (3 / 2, 2.0 L) at 20 °C. The reaction mixture was stirred for 20 min, followed by the addition of (S)-2-methylpropane-2-sulfinamide (33.3 g, 275 mmol). The mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with water (250 mL). The mixture was filtered and the solid was washed with THF (3 L × 3). The combined organic layers were concentrated under vacuum. The crude product was purified by silica gel column chromatography (100% petroleum ether) to give 44.89 g (38%) of the title compound as a pale yellow oil. LCMS m / z 216.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.94(s,1H),1.93-1.85(m,2H),1.80-1.60(m,4H),1.55-1.45(m,2H),1.21(s,3H),1.20(s,9H).

[0618] Step 1D. 3-Iodo-1,4-Dimethyl-1H-pyrazole

[0619] Pathway A

[0620] 3-Iodo-1,4-Dimethyl-1H-pyrazole. Sodium nitrite (1.22 g, 17 mmol) in water (1.78 mL) was added to a solution of 1,4-dimethyl-1H-pyrazole-3-amine (1.0 g, 8.6 mmol) in concentrated HCl (7.15 mL) at 0 °C over 5 min. Then, potassium iodide (3.57 g, 21.5 mmol) in water (3.6 mL) was added dropwise over 5 min. The mixture was stirred at 0 °C for 30 min, then heated to ambient temperature and stirred for 2 h. The reaction mixture was diluted with THF (8 mL) and water (8 mL) and extracted with EtOAc (30 mL × 4). The combined organic extracts were washed with saturated Na₂S₂O₃ aqueous solution (30 mL × 2), followed by washing with water (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (0 to 60% EtOAc / heptane) to give 988 mg (52%) of the title compound as a white solid. LCMS m / z 223.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.05(s,1H),3.87(s,3H),1.98(s,3H).

[0621] Pathway B

[0622] Step 1. 3-Iodo-1-methyl-1H-pyrazole-4-carboxaldehyde. POCl3 (45.0 mL, 481 mmol) was added to a solution of 3-iodo-1-methyl-1H-pyrazole (25 g, 120.2 mmol) in DMF (150 mL) at 0 °C. After 10 min, the reaction mixture was heated to 65 °C for 18 h. A solution of NaH2PO4 (50 g in 200 mL) was slowly added to the reaction mixture, ensuring the temperature was maintained between 25-35 °C and the pH did not exceed 4. After the addition, the reaction mixture was stirred at room temperature for 45 min, followed by the cautious addition of saturated Na2CO3 to make it alkaline. The aqueous mixture was extracted with EtOAc. The organic layer was washed with brine, dried, and filtered. The filtrate was concentrated. Recrystallization from EtOAc / heptane yielded a yellow oily substance to give 28.4 g (88%) of the title compound as a brown solid. 1 H NMR (400MHz, CDCl3) δ9.67 (s, 1H), 7.84 (s, 1H), 4.00 (s, 4H).

[0623] Step 2.3-Iodo-1,4-Dimethyl-1H-pyrazole. Triethylsilane (5.08 mL, 0.32 mmol) and TFA (1.36 mL, 0.18 mmol) were added to a mixture of 3-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde (1.0 g, 0.042 mmol) and chlorobenzene (10 mL). The mixture was heated to 50 °C overnight. The reaction mixture was cooled to room temperature and a saturated aqueous solution of NaHCO3 was added. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc / heptane) to give 0.64 g (68%) of the title compound. 1 H NMR (400MHz, CDCl3) δ7.08 (s, 1H), 3.90 (s, 3H), 2.01 (s, 3H).

[0624] Pathway C

[0625] Step 1: 3-Iodo-4-methyl-1H-pyrazole. NIS (2196.0 g, 9.76 mol) was added in portions to a solution of 4-methyl-1H-pyrazole (800.0 g, 9.76 mol) in DMF (5 L), maintaining the temperature below 25 °C. The mixture was stirred at 25 °C for 20 h. The two batches were combined. The combined mixture was poured into water (20 L) and then extracted with MTBE (5 L × 5). The combined organic layers were washed with brine (5 L × 3), dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum, and the residue was ground with petroleum ether / EtOAc (5 L, 10:1). The suspension was stirred at 16 °C for 2 h and then filtered. The resulting solid was dried under vacuum to give 1280.0 g (32%) of the title compound as a pale yellow solid. 1 H NMR (CDCl3, 400MHz) δ7.42 (s, 1H), 2.07 (s, 3H).

[0626] Step 2.3 - Iodo-1,4-Dimethyl-1H-pyrazole. At 0°C, a mixture of 3-iodo-4-methyl-1H-pyrazole (710.0 g, 3.41 mol) in anhydrous THF (1.5 L) was added dropwise to a suspension of mineral oil (165.0 g, 4.12 mol) containing 60% NaH in anhydrous THF (4.5 L). The mixture was stirred at 10°C for 1 h. Iodomethane (496.0 g, 3.49 mol) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 20°C for 16 h. The reactants were quenched with water (4.5 L) and extracted with EtOAc (2.5 L × 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 10:1 to 1:1) to obtain two fractions. The first fraction (150 g) was diluted with petroleum ether (200 mL) and stirred at 10 °C for 30 min. The suspension was filtered. The solid was washed with petroleum ether (100 mL) and dried under vacuum to give 100.0 g of the title compound as a white solid. The filtrate was concentrated under vacuum and combined with the second fraction (1300 g), and purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give the remaining desired compound (500.0 g). This compound was diluted with petroleum ether (800 mL) and stirred at 10 °C for 30 min. The suspension was filtered. The filter cake was washed with petroleum ether (500 mL) and dried under vacuum to give 440.0 g of the title compound as a white solid. The total yield was 540 g (35.6%). LCMS m / z 222.8 [M+H] + . 1 H NMR (CDCl3, 400MHz) δ7.04 (s, 1H), 3.86 (s, 3H), 1.97 (s, 3H).

[0627] Step 1: E.(S)-N-((R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide

[0628] After 1 hour, 50 mL of THF containing 3-iodo-1,4-dimethyl-1H-pyrazole (33 g, 148.6 mmol) was added to a solution of 1.0 MiPrMgCl·LiCl in THF (189 mL, 189 mmol), and the internal temperature was maintained at 0–5 °C under nitrogen. After 1 hour, 50 mL of THF containing (S,E)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (20 g, 92.85 mmol) was added, and the mixture was stirred at 25 °C for 18 hours. The reaction mixture was cooled to 0 °C, and 10% acetic acid was added. The organic layer was separated and partially concentrated. MTBE and water were added. The mixture was stirred for 10 minutes, and the layers were separated. The organic layer was concentrated to obtain the title compound (66% purity) for use in subsequent steps without further purification.

[0629] Step 1: F.(R)-(1,4-dimethyl-1H-pyrazole-3-yl)(1-methylcyclopentyl)methylamine

[0630] Crude (S)-N-((R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide (231 g) was suspended in MTBE (300 mL), cooled to 10 °C, and concentrated HCl (38.4 mL, 2 eq) was added. The mixture was stirred at 10–20 °C for 1 h and then diluted with water (300 mL). The layers were separated and the organic layer was discarded. The aqueous layer was alkalized to pH 11–13 with 20% NaOH and extracted with MTBE (2 × 300 mL). The combined organic layers were concentrated to give 120 g of the title compound as an oil. The absolute stereochemistry of the title compound was determined based on open transition state analysis as described in the literature (Robak, MT; Herbage, MAEllman, JAChem. Rev. 2010, 110, 3600), and was clearly confirmed by Mosher amide analysis.

[0631] Step 1: G.(R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine L-pyroglutamate

[0632] L-pyroglutamic acid (77.7 g, 0.6 mol) was added to a solution of (R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine (100 g, 0.48 mol) in THF (1.3 L) at 10–20 °C. The mixture was heated to 50 °C and stirred for 2 h, followed by cooling to 25 °C over 18 h. The solid was filtered and washed with THF (890 mL). The solid was dried under vacuum at 45 °C for 6 h to give 259.6 g (88%) of the title compound. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.58 (br.s., ¹H), 7.40 (s, ¹H), 3.93 (s, ¹H), 3.87–3.84 (m, ¹H), 3.77 (s, ³H), 2.27–2.14 (m, ¹H), 2.12–2.02 (m, 2H), 1.98 (s, ³H), 1.96–1.84 (m, ¹H), 1.70–1.48 (m, 6H), 1.42–1.31 (m, ¹H), 1.08–1.02 (m, ¹H), 0.97 (s, ³H). Chiral SFC (SFC method M) RT = 3.81 min, 99% ee.

[0633] Step 1: H.4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide

[0634] 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide was prepared as described in WO / 2010 / 131145.

[0635] Step 1I.(R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide

[0636] A mixture of 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide (180 g, 590 mmol), (R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine L-pyroglutamate (209 g, 625 mmol), EtOH (1 L), and DIPEA (205 mL, 1180 mmol) was stirred for 2 h at 20–30 °C. HOAc (23.8 mL, 416 mmol) was added to adjust the pH to 6–7. The reaction mixture was then concentrated to approximately half its volume under reduced pressure. The mixture was diluted with water (3.2 L) and stirred for 1.5 h. The resulting solid was filtered, washed with water, and then dried under vacuum at 40–50 °C for 20 h to provide 256 g (93%) of the title compound as a yellow solid. LCMS m / z 467.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.59(br.s.,1H),9.92(br.s.,1H),9.16(s,1H),8.03-8.00(m,2H),7.43(s,1H),5.33(d,J=10.0Hz,1H ),3.80(s,3H),3.18(s,3H),3.05(s,3H),2.00(s,3H),1.80-1.50(m,6H),1.20-1.15(m,1H),1.14-1.09(m,1H),1.08(s,3H).[α] 20 D = -78.4 (c = 1.0, MeOH). Chiral SFC (SFC method N) RT = 4.77 min, 98.5% ee. Absolute configuration was established by single-crystal X-ray analysis ( Figure 1 ).

[0637] Example 2

[0638] (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide

[0639]

[0640] The title compound was prepared using (R)-2-methylpropane-2-sulfinamide in a manner similar to that of Example 1. LCMS m / z 467.4 [M+H]+. 1H NMR(400 MHz, DMSO-d6)δ9.18(br.s.,1H),8.12-7.85(m,2H),7.43(s,1H),5.34(d,J=10.0 Hz,1H),3.80(s,3H),3.15(br.s.,3H),3.05(br.s.,3H),1.98(s,3H),1 .74-1.52(m,6H),1.41-1.27(m,1H),1.23-1.15(m,1H),1.08(s,3H).[α] 29 D = +88.49 (c = 0.5, MeOH). Chiral SFC (SFC method F) RT = 5.45 min, 100% ee.

[0641] Example 3

[0642] (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpyridinecarboxamide

[0643]

[0644] Step 3A. 4-Chloro-3-methoxypyridinecarboxyl chloride

[0645] Oxaloyl chloride (8.46 g, 5.71 mL, 66.6 mmol) was added dropwise to a solution of 4-chloro-3-methoxypyridinecarboxylic acid (5.0 g, 30 mmol) in DCM (59 mL). The resulting mixture was heated to ambient temperature and stirred for 2 h. The reaction mixture was concentrated under vacuum to give 5.49 g (100%) of the title compound as a pale yellow solid. The crude product was used directly in the next step without further purification. 1 HNMR (400 MHz, CDCl3) δ8.43 (d, J = 5.1 Hz, 1H), 7.71-7.51 (m, 1H), 4.01 (s, 3H).

[0646] Step 3B. 4-Chloro-N-isopropyl-3-methoxy-N-methylpyridinecarboxamide

[0647] Et3N (172 g, 1.7 mol) was added to a solution of 4-chloro-3-methoxypyridinecarboxyl chloride (175 g, 0.85 mol) in DCM (500 mL) at 0 °C. N-methylpropyl-2-amine (62 g, 0.85 mol) was then added, maintaining the internal temperature below 10 °C. The mixture was stirred at 15 °C for 16 h. Water (500 mL) was added, and the organic layer was separated. The aqueous layer was extracted with DCM (200 mL × 2). The combined organic extracts were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give 153 g (74%) of the title compound as a brown oil. The crude product was used directly without further purification.

[0648] Step 3: C. (2-(isopropyl(methyl)carbamoyl)-3-methoxypyridin-4-yl)tert-butyl carbamate

[0649] NH₂Boc (88.5 g, 0.76 mol) and K₂CO₃ (130 g, 0.95 mol) were added to a solution of 4-chloro-N-isopropyl-3-methoxy-N-methylpyridinecarboxamide (153 g, 0.63 mol) in dioxane (1 L). The mixture was sprayed with N₂ and Pd(OAc)₂ (11.3 g, 0.05 mol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (xantphos) (36.4 g, 0.063 mol) was added. The mixture was heated to 120 °C and stirred for 16 h. The reaction mixture was cooled to 20 °C and filtered through diatomaceous earth. The filtrate was concentrated under vacuum. The residue was partitioned between EtOAc (500 mL) and water (500 mL). The organic layer was separated, washed with brine (500 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum and the crude product was purified by silica gel column chromatography (50 to 66% EtOAc / petroleum ether) to give 160 g (78%) of the title compound as a yellow solid. 1 HNMR(400 MHz, CDCl3)δ8.24-8.20(m,1H),8.07-8.04(m,1H),7.24(s,1H),5.03-5.00(m,0.4H),3.90(s,3H),3. 66-3.63(m,0.6H),2.98(s,1.7H),2.69(s,1.3H),1.54(s,9H),1.25-1.20(m,3H),1.16-1.13(m,3H).

[0650] Step 3D. 4-Amino-N-isopropyl-3-methoxy-N-methylpyridinecarboxamide

[0651] HCl / EtOAc (4.0 M, 750 mL) was added to a solution of (160 g, 0.50 mol) of tert-butyl (2-(isopropyl(methyl)carbamoyl)-3-methoxypyridin-4-yl)carbamate in EtOAc (320 mL). The mixture was stirred at 20 °C for 4 h. The reactants were concentrated under vacuum to give 150 g (>100%) of the title compound as a brown solid. The crude material was used directly without further purification.

[0652] Step 3E. 4-Amino-3-hydroxy-N-isopropyl-N-methylpyridinecarboxamide

[0653] TBAI (168 g, 0.47 mol) was added to a solution of 4-amino-N-isopropyl-3-methoxy-N-methylpyridinecarboxamide (150 g, 0.67 mol) in DCM (1.5 L). The mixture was cooled to 0 °C and BBr3 (420 g, 1.68 mol) was added dropwise to a solution of DCM (500 mL), keeping the internal temperature below 10 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (2.5 L) and the pH was adjusted to 6–7. The organic layer was separated and washed with water (500 mL). The combined aqueous layers were back-extracted with DCM (1 L × 2). The combined organic extracts were concentrated under vacuum, and the residue was treated with DCM:MeOH = 10:1 (2 L) for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was treated with DCM:MeOH = 10:1 (600 mL) for 1 h, and the mixture was filtered. The filtrate was concentrated under vacuum to obtain 140 g (99%) of the title compound as a pink solid. The crude material was used directly without further purification.

[0654] Step 3F. 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpyridinecarboxamide

[0655] DIPEA (147 g, 1.14 mol) and 3,4-diethoxycyclobut-3-ene-1,2-dione (159 g, 0.94 mol) were added to a solution of 4-amino-3-hydroxy-N-isopropyl-N-methylpyridinecarboxamide (140 g, 0.67 mol) in EtOH (1.4 L). The mixture was heated to 35 °C and stirred for 16 h. The reaction mixture was filtered and the filtrate was stored for later use. The filter cake was dissolved in water (500 mL) and the pH was adjusted to 6 with HCl (1.0 M aqueous solution), and extracted with DCM (500 mL × 2). The combined DCM was washed with brine (1 L), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was ground with MTBE (500 mL) for 2 h, followed by filtration to give 73 g (33%) of the title compound as a yellow solid. The mother liquor was combined with the earlier separated filtrate and concentrated under vacuum. The residue was purified by silica gel column chromatography (25 to 50% EtOAc / petroleum ether) to give an additional 30 g (13%) of the title compound as a yellow solid. LCMS m / z 334.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ13.30(s,1H),8.09(s,1H),8.01-7.90(m,2H),5.85-5.80(m,0.5H),4.95- 4.88(m,2.5H),3.50-3.31(m,1.5H),3.03-2.95(m,1.5H),1.55-1.50(m,6H),1.42-1.32(m,3H).

[0656] Step 3G.(S)-N-((R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide

[0657] A dried round-bottom flask was filled with i-PrMgCl·LiCl (67 mL, 87.1 mmol, 1.3 M solution in THF). The solution was cooled to 0 °C, and then 3-iodo-1,4-dimethyl-1H-pyrazole (15.5 g, 69.7 mmol) was added dropwise to a solution of 90 mL THF via an addition funnel over 15 min. The mixture was heated to ambient temperature and stirred for 1 h. The mixture was then cooled back to 0 °C, and (S,E)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (Preparation Step 1C) (10.0 g, 46.4 mmol) was added dropwise over 5 min. The mixture was heated to ambient temperature and stirred for 18 h. The reaction mixture was slowly poured into a saturated aqueous solution of NH4Cl at 0 °C (300 mL). The mixture was then extracted with EtOAc (350 mL × 2). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude oil was dissolved in MTBE (50 mL) and heptane (100 mL) to obtain a homogeneous solution, which was then concentrated under vacuum to obtain a solid. The solid was suspended in heptane (50 mL) and then concentrated under vacuum. This process was repeated twice, and the heptane (50 mL) containing the final suspension was cooled to 0 °C to allow for the formation of more solid. The suspension was filtered to give 11.5 g (80%) of the title compound as a white solid. LCMS m / z 312.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ7.34(s,1H),4.37(d,J=6.5Hz,1H),4.10(d,J=6.4Hz,1H),3.72(s,3H) ,1.96(s,3H),1.72-1.51(m,6H),1.44-1.35(m,1H),1.16-1.03(m,1H),1.01(d,J=1.8Hz,12H).

[0658] Step 3H.(R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine hydrochloride

[0659] HCl (50 mL, 200 mmol, 4.0 M in 1,4-dioxane) was added to a solution of (S)-N-((R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide (28.7 g, 92.14 mmol) in MeOH (150 mL) at 5 °C. After stirring at 20 °C for 3 h, the solution was concentrated under vacuum to give the title compound as a single HCl salt (assuming quantitative yield). The crude product was used directly without further purification. LCMS m / z 191.2 [M-NH2] + .1 H NMR (400MHz, CD3OD) δ7.39(s,1H),4.25(s,1H),3.86(s,3H),2.07(s,3H),1.75-1.54(m,7H),1.21-1.20(m,1H),1.14(s,3H).

[0660] Step 3I.(R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpyridinecarboxamide

[0661] DIEA (3.10 g, 4.31 mL, 24.0 mmol) was added to a solution of (R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine hydrochloride (3.50 g, 14.36 mmol) in EtOH (50 mL) at 10 °C. After stirring for 20 min, a yellow suspension of 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpyridinecarboxamide (4.0 g, 12.0 mmol) in EtOH (100 mL) was added, and the resulting brown solution was stirred at the same temperature for 16 h. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (80% to 100% EtOAc / petroleum ether). The crude product was azeotropically reacted with EtOH (50 mL × 2), and the resulting yellow suspension was concentrated to approximately 30 mL. Add an additional 10 mL of EtOH and stir the suspension at 15 °C for 20 min. Filter the mixture and wash the filter cake with 10 mL of EtOH. Collect and dry the filter cake to give 2.62 g (44%) of the title compound as a pale yellow solid. LCMS m / z 495.5 [M+H] + . 1 HNMR(400MHz, DMSO-d6)δ11.35(s,0.3H),10.85(s,0.7H),9.88(s,1H),9.11(d,J=9.8Hz,1H),8.05-7.90(m,2H),7.43(s,1H),5.33(d,J=10.0Hz, 1H),4.81(s,0.3H),4.20(s,0.7H),3.80(s,3H),2.88(s,3H),1.98(s,3H ),1.75-1.51(m,6H),1.36-1.32(m,1H),1.25-1.10(m,7H),1.08(s,3H). [α] 20 D= -49.8 (c = 0.26, MeOH). Chiral SFC conditions (SFC method D) RT = 4.62 min, 100% ee.

[0662] Example 4

[0663] (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpyridinecarboxamide

[0664]

[0665] Step 4A. 4-Chloro-N-ethyl-3-methoxy-N-methylpyridinecarboxamide

[0666] N-methylethylamine (138 g, 233 mmol) and triethylamine (32.3 mL, 233 mmol) were added to a solution of 4-chloro-3-methoxypyridinecarboxyl chloride (Preparation Step 3A) (32 g, 155 mmol) in DCM (150 mL). The mixture was stirred at ambient temperature for 48 h and then concentrated. The residue was purified by silica gel column chromatography (0 to 100% EtOAc / petroleum ether) to give 22 g (62%) of the title compound as a yellow oil. 1 H NMR (400MHz, CDCl3) δ8.25 (dd, J=5.3, 6.8Hz, 1H), 7.35 (d, J=5.3Hz, 1H), 3.94 (d, J=1. 8Hz,3H),3.66-3.55(m,1H),3.23-3.12(m,1H),3.12-2.72(m,3H),1.35-1.05(m,3H).

[0667] Step 4B. (2-(ethyl(methyl)carbamoyl)-3-methoxypyridin-4-yl)tert-butyl carbamate

[0668] NH₂Boc (21.8 g, 186 mmol) and K₂CO₃ (25.7 g, 186 mmol) were added to a solution of 4-chloro-N-ethyl-3-methoxy-N-methylpyridinecarboxamide (21.3 g, 93 mmol) in dioxane (120 mL). The mixture was protected under N₂ and Pd(OAc)₂ (1.05 g, 4.7 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (2.7 g, 4.7 mmol) was added. The mixture was heated to 120 °C and stirred for 16 h. The reaction mixture was cooled to 20 °C and filtered through diatomaceous earth. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 100% EtOAc / petroleum ether) to give 24 g (83%) of the title compound as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.25(ddd,J=5.5,3.8,0.6Hz,1H),8.09(dd,J=5.5,1.6Hz,1H),7.26(d,J=5.6Hz,1H),3.92(d,J=1.0Hz,3H),3.64 (q,J=7.2Hz,1H),3.18(q,J=7.1Hz,1H),3.13(s,1.5H),2.86(s,1.5H),1.56(s,9H),1.28(t,J=7.2Hz,1.5H),1.13(t,J=7.1Hz,1.5H).

[0669] Step 4C. 4-Amino-N-ethyl-3-methoxy-N-methylpyridinecarboxamide

[0670] A solution of HCl / EtOAc (4.0 M, 40 mL) was added to tert-butyl 2-(ethyl(methyl)carbamoyl)-3-methoxypyridin-4-yl)carbamate (16 g, 51.7 mmol), and the mixture was stirred at 20 °C for 18 h. The mixture was concentrated under vacuum to give 12.71 g (100%) of the title compound as a yellow solid. 1 H NMR (400MHz, CD3OD) δ8.00 (dd, J=6.9, 1.5Hz, 1H), 7.02 (dd, J=6.8, 0.7Hz, 1H), 3.86 ( d,J=2.7Hz,3H),3.35-3.28(m,2H),3.16(s,1.5H),3.00(s,1.5),1.33-1.17(m,3H).

[0671] Step 4D. 4-Amino-N-ethyl-3-hydroxy-N-methylpyridinecarboxamide

[0672] TBAI (5.7 g, 15.5 mmol) was added to a solution of 4-amino-N-ethyl-3-methoxy-N-methylpyridinecarboxamide (5 g, 24 mmol) in DCM (100 mL). The mixture was cooled to 0 °C, and BBr3 (23.9 g, 95.6 mmol) was added dropwise to a solution of DCM (100 mL), maintaining the internal temperature below 10 °C. The reaction mixture was stirred at 10 °C for 15 h. The reaction mixture was quenched with an aqueous solution of NaOH / MeOH (200 mL MeOH, 11.5 g NaOH, 50 mL water) while maintaining the internal temperature at 0 °C. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (3 to 9% MeOH / DCM) to give 3.1 g (78%) of the title compound as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.81(d,J=6.3Hz,1H),7.39(br.s.,3H),6.85(d,J=6.2Hz,1H),3.52-3.18(m,2H),2.91(br.s.,3H),1.37-0.80(m,3H).

[0673] Step 4: E.4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpyridinecarboxamide

[0674] K₂CO₃ (4.96 g, 35.9 mmol) and 3,4-diethoxycyclobut-3-ene-1,2-dione (9.17 g, 53.9 mmol) were added to a solution of 4-amino-N-ethyl-3-hydroxy-N-methylpyridinecarboxamide (7.01 g, 35.9 mmol) in EtOH (150 mL). The mixture was heated to 50 °C and stirred for 16 h. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (10 to 100% DCM / petroleum ether, 0 to 20% MeOH / DCM) to give 4.77 g (42%) of the title compound as a brown oil. 1 H NMR (400MHz, CDCl3) δ13.62(br s,0.5H),13.50(br s,0.5H),8.07(d,J=5.2Hz,1H),7.94(s,1H),7.88(s,1H),4.90(q,J=7.1Hz,2H),4.16(br s,1H),3.62(br s,3H),3.14(br s,1H),1.55(t,J=7.1Hz,3H),1.45-1.20(m,3H).

[0675] Step 4F.(R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpyridinecarboxamide

[0676] A solution of 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpyridinecarboxamide (5.92 g, 18.54 mmol) in EtOH (140 mL) was added to EtOH (50 mL) containing (R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine L-pyroglutamate (Preparation Step 1G) (7.48 g, 22.2 mmol) and DIPEA (4.79 g, 37.1 mmol). The reaction mixture was stirred at room temperature for 16 h, and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc, 1:5 to 0:1) to give 4.4 g (49%) of the title compound as a yellow solid. LCMS m / z 481.1 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.22(br.s.,1H),7.94(br.s.,1H),7.28(s,1H),5.44(s,1H),3.83(s,3H),3.65(br.s., [α] 26 D = -77.88 (c = 0.5, MeOH). Chiral SFC (SFC method F) RT = 3.52 min, 99% ee.

[0677] Example 5

[0678] (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpyridinecarboxamide

[0679]

[0680] The title compound was prepared in a manner similar to that of Example 4 using (S)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine (Example 2). LCMS m / z 481.4 [M+H]+ . 1 H NMR(400MHz,DMSO-d6)δ11.70(br.s.,1H),9.90(br.s.,1H),9.15(br.s.,1H),8.00(br.s.,2H),7.43(s,1H),5.34(d,J=10.0Hz,1H),3.80(s, 3H),3.54(br.s.,2H),3.17(br.s.,1H),3.02(br.s.,2H),1.98(s,3H), 1.75-1.52(m,6H),1.40-1.28(m,1H),1.25-1.10(4H),1.08(s,3H).[α] 29 D = +80.8 (c = 0.5, MeOH). Chiral SFC (SFC method K) RT = 3.11 min, 99% ee.

[0681] Example 6

[0682] (R)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2-(morpholin-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione

[0683]

[0684] Step 6A. tert-butyl 4-chloro-3-methoxypyridinecarboxylate

[0685] A solution of 4-chloro-3-methoxypyridinecarboxyl chloride (Preparation Step 3A) (5.49 g, 26.7 mmol) in DCM (26.7 mL) was added dropwise to a solution of pyridine (7.91 g, 8.05 mL, 100 mmol) at 0 °C and t-BuOH (7.90 g, 10.1 mL, 107 mmol) in DCM (32 mL). The reaction mixture was stirred at 0 °C for 15 min, heated to ambient temperature, and then heated under reflux for 4 h. The solvent was removed under vacuum, and the residue was dissolved in EtOAc. The solution was washed with 1 N NaOH aqueous solution and brine, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 20% EtOAc / DCM) to give 3.10 g (48%) of the title compound in liquid form. LCMS m / z 188.1 [M-tBu] + . 1 H NMR (400MHz, CDCl3) δ8.30 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 5.1 Hz, 1H), 3.98 (s, 3H), 1.65 (s, 9H).

[0686] Step 6B. 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-methoxypyridinecarboxylic acid tert-butyl ester

[0687] At 25°C, tert-butyl 4-chloro-3-methoxypyridinecarboxylate (97.2 g, 0.4 mol) was added to a mixture of 3-amino-4-ethoxycyclobut-3-ene-1,2-dione (169.2 g, 1.2 mol) and Na₂CO₃ (67.84 g, 0.64 mol) in THF (1.8 L). The mixture was degassed and purged three times with N₂. tBuXPhos-Pd-G₃ (15.9 g, 0.02 mol) and tBuXPhos (8.48 g, 0.02 mol) were added. The reaction mixture was degassed and purged three times with N₂. The reaction mixture was heated to 80°C and stirred for 16 hours. The mixture was cooled to 25°C and then filtered through diatomaceous earth. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 50% DCM / petroleum ether, followed by 0 to 2.5% THF / DCM). The resulting oil was ground with heptane (250 mL) and stirred at 25 °C for 3 h. The mixture was filtered to give 84.7 g of the title compound as a 60% pale yellow solid. LCMS m / z 349.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.38 (d, J = 5.4Hz, 1H), 7.93 (br s, 2H), 4.95 (q, J = 7.1Hz, 2H), 4.01 (s, 3H), 1.68 (s, 9H), 1.59 (t, J = 7.2Hz, 3H).

[0688] Step 6 C.(R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-methoxypyridinecarboxylic acid tert-butyl ester

[0689] DIEA (6.0 g, 46.4 mmol) was added to a solution of (R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine hydrochloride (preparation step 3H) (4.70 g, 19.3 mmol) in EtOH (70 mL). The mixture was stirred for 10 min, followed by the addition of 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-methoxypyridinecarboxylate tert-butyl ester (4.0 g, 11.5 mmol). The resulting mixture was stirred at 20 °C for 70 h and then concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 80% EtOAc / petroleum ether) to give 5.85 g (100%) of the title compound as a yellow solid. LCMS m / z 510.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.97(s,1H),9.06-9.02(m,1H),8.20-8.18(m,1H),8.09-8.07(m,1H),7.44(s,1H),5.36-5.33 (m,1H),3.84(s,3H),3.80(s,3H),1.98(s,3H),1.72-1.53(m,15H),1.35-1.30(m,1H),1.24-1.15(m,1H),1.09(s,3H).

[0690] Step 6: D.(R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-methoxypyridinecarboxylic acid

[0691] TFA (25 g, 16.3 mL, 219.3 mmol) was added to a solution of (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-methoxypyridinecarboxylate (6.60 g, 13.0 mmol) in DCM (50 mL). The resulting solution was stirred at ambient temperature for 44 h. The mixture was concentrated under vacuum, and the pH was adjusted to approximately 8 using a saturated aqueous solution of NaHCO3. The mixture was extracted with DCM (20 mL). The aqueous layer was acidified to approximately pH 3 with a 1 N aqueous solution of HCl, followed by extraction with DCM (100 mL × 5). The combined organic extracts were concentrated under vacuum to give 5.8 g (99%) of the title compound as a yellow solid. LCMS m / z 454.4 [M+H] + .

[0692] Step 6 E.(R)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-methoxy-2-(morpholin-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione

[0693] At 0 °C, HATU (377 mg, 0.99 mmol) was added to a solution of (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-methoxypyridinecarboxylic acid (300 mg, 0.66 mmol), morpholine (57.6 mg, 0.66 mmol), and TEA (134 mg, 1.32 mmol) in DCM (5 mL). The resulting mixture was stirred at 25 °C for 16 h and then concentrated under vacuum. The residue was dissolved in EtOAc (10 mL) and washed with saturated KHCO2 aqueous solution (10 mL). The aqueous layer was extracted with EtOAc (40 mL × 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound as a yellow solid. The crude product was used directly without further purification (assuming quantitative yield). LCMS m / z 523.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.28-8.26(m,1H),8.21-8.19(m,1H),7.29(s,1H),5.45(s,1H),3.94(s,3H),3.90-3.75 (m,5H),3.68-3.64(m,2H),3.01-2.96(m,4H),2.09(s,3H),1.90-1.65(m,7H),1.50-1.42(m,1H),1.18(s,3H).

[0694] Step 6F.(R)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2-(morpholin-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione

[0695] MgBr2 (634 mg, 3.44 mmol) was added to a solution of (R)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-methoxy-2-(morpholin-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione (600 mg, 1.15 mmol) in 1,4-dioxane (5 mL). The mixture was heated at 120 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified using preparative HPLC (Agela Durashell C18 150 mm × 25 mm × 5 μm, 30 to 50% MeCN / 0.225% formic acid in water, 25 mL / min, 11 min) to give 66 mg (11%) of the title compound as a yellow solid. LCMS m / z 509.4 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.22 (d, J = 5.5Hz, 1H), 7.91 (br s,1H),7.28(s,1H),5.44(s,1H),3.90-3.70(m,11H),2.09(s,3H),1.9 0-1.65(m,6H),1.50-1.43(m,1H),1.35-1.26(m,1H),1.17(s,3H).[α] 20 D = -65.6 (c = 0.17, MeOH). Chiral SFC conditions (SFC method K) RT = 3.47 min, 100% ee.

[0696] Example 7

[0697] (R)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2-(4-methylpiperazin-1-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione

[0698]

[0699] The title compound was prepared using 1-methylpiperazine following a procedure similar to that used in the preparation of (R)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2-(morpholin-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione (Example 6), yielding 19.7 mg (9%) of the title compound as a yellow solid. LCMS m / z 522.5 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.35(s,1H),8.24(d,J=5.6Hz,1H),7.90(d,J=5.6Hz,1H),7.28(s,1H),5.44(s,1H),3.92(br s,4H),3.82(s,3H),2.80(br s,4H),2.53(s,3H),2.09(s,3H),1.90-1.65(m,6H),1.51-1.42(m,1H),1.35-1.25(m,1H),1.17(s,3H). Chiral SFC (SFC method F) RT = 3.66 min, 98.6%ee.

[0700] Example 8

[0701] (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide

[0702]

[0703] Step 8A. (R)-2-methyl-N-((R)-(1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)propane-2-sulfinamide

[0704] Add 4.35 g (20.9 mmol) of 3-iodo-1-methyl-1H-pyrazole to a solution of i-PrMgCl·LiCl (20.1 mL, 26.2 mmol, in 1.3 M THF) at -30 °C to a solution of 20 mL THF. Stir at 30–40 °C to obtain a yellow solution for 2 h. Cool the reaction mixture to -30 °C and add dropwise (S,E)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (Preparation Step 1C) (3.0 g, 13.93 mmol) to a solution of 5 mL THF. Heat the reaction mixture to 30 °C and stir for 16 h. Slowly pour the reaction mixture into a saturated aqueous solution of NH4Cl at 5 °C (100 mL) and dilute with water (20 mL). Then extract the mixture with EtOAc (50 mL × 2). Dry the combined organic extracts in Na2SO4, filter, and concentrate under vacuum. The residue was purified by silica gel column chromatography (0 to 80% EtOAc in petroleum ether) to give 3.48 g (84%) of the title compound as a yellow oil. LCMS m / z 297.9 [M+H] + . 1H NMR(400MHz, CDCl3) δ7.26(d,J=2.1Hz,1H),6.08(d,J=2.2Hz,1H),4.34(d,J=3.4Hz,1H),3.86(s,3H), 3.59-3.55(m,1H),1.80-1.55(m,6H),1.50-1.43(s,1H),1.18(s,9H),1.18-1.12(m,1H),0.98(s,3H).

[0705] Step 8B. (R)-(1-methyl-1H-pyrazole-3-yl)(1-methylcyclopentyl)methylamine

[0706] HCl (80 mL, 4.0 M solution in MeOH) was added to a solution of (R)-2-methyl-N-((R)-(1-methyl-1H-pyrazole-3-yl)(1-methylcyclopentyl)methyl)propane-2-sulfinamide (6.59 g, 22.15 mmol) in 50 mL of MeOH. The resulting solution was stirred at ambient temperature for 3 h and then concentrated under vacuum. The title compound was isolated as a single HCl salt (assuming quantitative yield) and used directly without further purification. LCMS m / z 193.8 [M+H] + . 1 ¹H NMR (400 MHz, CD₃OD) δ 7.63 (d, J = 2.3 Hz, 1H), 6.33 (d, J = 2.3 Hz, 1H), 4.25 (s, 1H), 3.92 (s, 3H), 1.85–1.65 (m, 6H), 1.60–1.55 (m, 1H), 1.31–1.25 (m, 1H), 1.05 (s, 3H). The absolute stereochemistry of the title compound was determined by a method similar to that used in Preparation Example 1F.

[0707] Step 8 C.(R)-((1-methyl-1H-pyrazole-3-yl)(1-methylcyclopentyl)methyl)tert-butyl carbamate

[0708] TEA (9.25 mL, 66.5 mmol) and (Boc)₂O (7.25 g, 33.2 mmol) were added to a solution of (R)-(1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine (5.09 g, 22.2 mmol) in MeOH (150 mL) at 15 °C. The mixture was stirred for 16 h. The reactants were concentrated under vacuum, and the residue was purified by silica gel column chromatography (0 to 20% EtOAc / petroleum ether) to give 5.72 g (88%) of the title compound as a pale yellow oil. LCMS m / z 176.8 [M-BocNH] + . 1HNMR (400MHz, CDCl3) δ7.24(d,J=2.2Hz,1H),6.07(d,J=2.2Hz,1H),5.39-5.30(m,1H),4.67( d,J=9.5Hz,1H),3.87(s,3H),1.79-1.61(m,6H),1.44(s,9H),1.38-1.17(m,2H),0.94(s,3H).

[0709] Step 8: D.(R)-((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)tert-butyl carbamate

[0710] NCS (3.12 g, 23.4 mmol) was added in portions to a solution of (R)-((1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)carbamate (5.72 g, 19.5 mmol) in DMF (100 mL). The mixture was heated at 50 °C for 16 h. After cooling to ambient temperature, the reaction mixture was poured into a 3% LiCl aqueous solution (150 mL) and then extracted with EtOAc (70 mL × 2). The combined organic extracts were concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 15% EtOAc / petroleum ether) to give 6.0 g (94%) of the title compound as a pale yellow oil. LCMS m / z 210.7 [M-BocNH] + . 1 H NMR (400MHz, CDCl3) δ7.25 (s, 1H), 5.32-5.29 (m, 1H), 4.79 (d, J = 9.7Hz, 1H), 3.82 (s, 3 H),1.80-1.55(m,6H),1.42(s,9H),1.40-1.30(m,1H),1.21-1.12(m,1H),1.00(s,3H).

[0711] Step 8: E.(R)-(4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine

[0712] HCl (150 mL, 600 mmol, 4.0 M in MeOH) was added to a mixture of (R)-((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)carbamate tert-butyl ester (6.0 g, 18.3 mmol) in MeOH (20 mL) at 15 °C. The mixture was stirred for 5 h and then concentrated under vacuum. The title compound was isolated as a single HCl salt (assuming quantitative yield) and used directly without further purification. LCMS m / z 228.0 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.77(s,1H),4.32(s,1H),3.92(s,3H),1.90-1.55(m,7H),1.30-1.22(m,1H),1.15(s,3H).

[0713] Step 8F.(R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide

[0714] DIEA (5.0 g, 38.7 mmol) was added to a suspension of (R)-(4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine (5.90 g, 22.3 mmol) in EtOH (100 mL). The mixture was stirred for 30 min, followed by the addition of 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide (Preparation step 1H) (5.0 g, 16.4 mmol). The resulting mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered and the solid was washed with EtOH (10 mL × 3). The solid was suspended in water (30 mL) and heated at 50 °C for 3 h. The suspension was filtered. The solid was washed with water (10 mL × 3) and dried to give 5.24 g (66%) of the title compound as a yellow solid. LCMS m / z487.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.67(br s,1H),9.95(br s,1H),9.18(s,1H),8.01(s,2H),7.95(s,1H),5.44(d,J=10.0Hz,1H),3.86(s,3H),3.18(br s,3H),3.05(brs,3H),1.78-1.58(m,6H),1.39-1.31(m,1H),1.21-1.10(m,1H),1.07(s,3H).[α] 24 D =-145.151 (c=0.50, MeOH). Chiral SFC (SFC method F) RT=3.85min, 100% ee. Absolute configuration was established by single-crystal X-ray analysis ( Figure 2 ).

[0715] Example 9

[0716] (S)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide

[0717]

[0718] The title compound was prepared using (R)-2-methylpropane-2-sulfinamide in a manner similar to that of Example 8. LCMS m / z 487.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.68(br.s.,1H),9.92(br.s.,1H),9.16(br.s.,1H),8.02-7.98(m,2H),7.94(s,1H),5.37(d,J=10.2Hz [α] 20 D = +107.3 [c = 1, MeOH). Chiral SFC (SFC method L) RT = 6.28 min, 98% ee.

[0719] Example 10

[0720] (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpyridinecarboxamide

[0721]

[0722] The title compound was prepared by means of 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpyridinecarboxamide (Preparation Step 3F) and (R)-(4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine (Preparation Step 8E) following the same procedure as in Preparation Example 8. Yellow solid, 64 mg (41%). LCMS m / z 515.3 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.21 (d, J = 5.1Hz, 1H), 7.93 (br s,1H),7.64(s,1H),5.55(s,1H),4.70-4.55(m,0.4H),4.40-4.20(m,0.6H),3.88(s,3H) ,3.01(s,3H),1.95-1.62(m,6H),1.51-1.42(m,1H),1.35-1.20(m,7H),1.18(s,3H).[α] 20 D = -75.5 (c = 0.23, MeOH). Chiral SFC (SFC method B) RT = 1.59 min, 100% ee.

[0723] Example 11

[0724] (R)-3-hydroxy-N-isopropyl-4-((2-(((4-methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-methylpyridinecarboxamide

[0725]

[0726] Step 11A. 3-Iodo-4-methoxy-1-methyl-1H-pyrazole

[0727] NIS (4.41 g, 19.6 mmol) was added to a solution of 4-methoxy-1-methyl-1H-pyrazole (2.20 g, 19.6 mmol) in DMF (20 mL). The reaction mixture was stirred at ambient temperature for 18 h. The mixture was diluted with water (100 mL) and brine (20 mL) and extracted with EtOAc (50 mL × 5). The combined organic extracts were concentrated under vacuum. The residue was purified by silica gel column chromatography (0 to 16% EtOAc / petroleum ether) to give 310 mg (7%) of the title compound as a brown solid. LCMS m / z 238.8 [M+H] + . 1 H NMR (400MHz, CDCl3) δ6.91 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H).

[0728] Step 11B. (R)-N-((R)-(4-methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide

[0729] Add i-PrMgCl·LiCl (3 mL, 3.90 mmol, 1.3 M solution in THF) to a solution of 3-iodo-4-methoxy-1-methyl-1H-pyrazole (399 mg, 1.68 mmol) in freshly distilled THF (4 mL) at -40 °C. Stir the resulting mixture at ambient temperature for 2 h, then cool to -40 °C. Add (S,E)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (Preparation Step 1C) (250 mg, 1.16 mmol) to a solution of freshly distilled THF (1 mL). Heat the reaction mixture to ambient temperature and stir for 16 h. Quench the reaction mixture at 0 °C with saturated NH4Cl aqueous solution (1 mL) and extract with EtOAc. Concentrate the combined organic extracts under vacuum. The residue was purified by silica gel column chromatography (0 to 100% EtOAc / petroleum ether) to give 150 mg of the title compound as a 33% yellow oil. LCMS m / z 327.9 [M+H] + . 1 HNMR(400MHz, CDCl3)δ6.95(s,1H),4.31-4.29(m,1H),4.15-4.13(m,1H),3.77(s,3H),3.69 (s,3H),1.80-1.70(m,2H),1.70-1.55(m,4H),1.50-1.42(m,2H),1.11(s,9H),1.02(s,3H).

[0730] Step 11 C.(R)-(4-methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine

[0731] HCl (2.5 mL, 4.0 M in 1,4-dioxane) was added to a solution of (R)-N-((R)-(4-methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide (150 mg, 0.458 mmol) in MeOH (15 mL). The resulting solution was stirred for 4 h, followed by vacuum concentration. The title compound was isolated as a single HCl salt (assuming quantitative yield) and used directly without further purification. LCMS m / z 207.3 [M-NH2] + . 1¹H NMR (400 MHz, CD₃OD) δ 7.40 (s, ¹H), 4.19 (s, ¹H), 3.82 (s, ³H), 3.75 (s, ³H), 1.80–1.61 (m, ⁶H), 1.51–1.45 (m, ¹H), 1.25–1.15 (m, ¹H), 1.09 (s, ³H). The absolute stereochemistry of the title compound was determined by a method similar to that used in Preparation Example 1F.

[0732] Step 11 D.(R)-3-hydroxy-N-isopropyl-4-((2-(((4-methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-methylpyridinecarboxamide

[0733] DIEA (11.8 g, 91.5 mmol) was added to a suspension of (R)-(4-methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methylamine (2.43 g, 9.35 mmol) in EtOH (60 mL) at 5 °C. After stirring for 10 min, 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpyridinecarboxamide (Preparation step 3F) (3.05 mg, 9.15 mmol) was added. The resulting solution was stirred for 3 days. The mixture was concentrated under vacuum. T...

Claims

1. A compound of formula (IIA) or (IIB) or a pharmaceutically acceptable salt thereof, in R1 and R2 are each independently -(C1-C6)alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form a 6-membered heterocycle containing one N heteroatom and optionally one or two other heteroatoms selected from O and N, wherein the 6-membered heterocycle is optionally substituted by one, two or three (C1-C4)alkyl groups. R3 is H; R4and R5are each independently -(Ci-C4)alkyl or -(Ci-C4)alkyl-d 1-9 ; R6 is H or deuterium; B is R7 is a -(C1-C3)alkyl or -(C1-C3)alkyl-d 1-7 ; R8 is independently deuterium each time it appears; and n is 0 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIA).

3. The compound of claim 1 or its pharmaceutically acceptable salt, wherein R1 and R2 are each independently -(C1-C6)alkyl.

4. The compound of claim 1 or its pharmaceutically acceptable salt, wherein R4 and R5 are each independently -(C1-C6)alkyl, and R6 is H.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide monohydrate having an X-ray powder diffraction pattern comprising the diffraction peaks listed in the table below:

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpyridinecarboxamide 0.5 calcium salt monohydrate having an X-ray powder diffraction pattern comprising the diffraction peaks listed in the table below:

7. Use of a compound in the preparation of a medicament for treating a ailment, wherein the compound is a compound of formula (IIA) or (IIB) or a pharmaceutically acceptable salt thereof. in R1 and R2 are each independently -(C1-C6) alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form a 6-membered heterocycle containing one N heteroatom and optionally one or two other heteroatoms selected from O and N, wherein the 6-membered heterocycle is optionally substituted by one, two or three (C1-C4) alkyl groups. R3 is H; R4 and R5 are each independently -(C1-C4)alkyl or -(C1-C4)alkyl-d 1-9 ; R6 is H or deuterium; and B is R7 is a -(C1-C3)alkyl or -(C1-C3)alkyl-d 1-7 ; R8 is independently deuterium each time it appears; and n is 0 or 2, The condition mentioned is selected from psoriasis, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis.

8. The use of claim 7, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

9. The use of claim 7, wherein the drug is formulated as a tablet.

10. The use of claim 7, wherein the drug is formulated as a capsule.

11. The use of claim 7, wherein the drug is for oral administration.

12. The use of claim 7, wherein the drug is administered once daily.

13. The use of claim 7, wherein the condition is ulcerative colitis.

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