OA20305A - N-substituted-dioxocyclobutenylamino-3hydroxy-picolinamides useful as CCR6 Inhibitors. - Google Patents

N-substituted-dioxocyclobutenylamino-3hydroxy-picolinamides useful as CCR6 Inhibitors. Download PDF

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Publication number
OA20305A
OA20305A OA1202100114 OA20305A OA 20305 A OA20305 A OA 20305A OA 1202100114 OA1202100114 OA 1202100114 OA 20305 A OA20305 A OA 20305A
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OAPI
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methyl
amino
another embodiment
pharmaceutically acceptable
présent invention
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OA1202100114
Inventor
John Isidro Trujillo
Daniel Wei-Shung Kung
Atli Thorarensen
Mark Edward SCHNUTE
Rayomand Jal Unwalla
Andrew Christopher Flick
Brian Stephen Gerstenberger
Vincent Michael Lombardo
James John Mousseau
Philippe Marcel Nuhant
Jr. Ralph Pelton Robinson
Daniel Copley Schmitt
Huixian Wu
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Pfizer Inc.
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Publication of OA20305A publication Critical patent/OA20305A/en

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Abstract

The present invention relates to N-substituteddioxocyclobutenylamino-3-hydroxy-picolinamide compounds of Formulae (IA and 1B)

Description

N-SUBSTITUTED-DIOXOCYCLOBUTENYLAMINO-3-HYDROXY-PICOLINAMIDES USEFUL AS CCR6 INHIBITORS
FIELD OFTHE INVENTION
The présent invention relates to N-substituted-dioxocyclobutenylamino-3-hydroxypicolinamide compounds that inhibit CC chemokine receptor 6 (CCR6), pharmaceutical compositions containing these compounds, and the use of these compounds for treating or preventing diseases, conditions, or disorders ameliorated by inhibition of CCR6.
BACKGROUND OFTHE INVENTION
Chemokine receptors are a large subfamily of cell surface seven transmembrane proteins. They can be divided by function into two main groups: G protein-coupled chemokine receptors, which médiate leukocyte trafficking, and atypical chemokine receptors, which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [Bachelerie, 2014; Murphy, 2002], Chemokines, the natural ligands for chemokine receptors are low-molecular-weight proteins that stimulate recruitment of leukocytes. Based on the presence and the relative position of the NH2-terminal Cys residues, chemokines are structurally grouped into the CC, CXC, CX3C and C chemokines [White, 2013]. In humans, chemokines and chemokine receptors form a pharmacologically complex System. In many cases, récognition of a single chemokine by different receptors, as well as binding of different chemokines to the same receptor, leads to different signaling and trafficking responses [Kufareva, 2016]. Physiologically, members of the chemokine family induce recruitment of well-defined leukocyte subsets and play an important rôle in development, immunity and autoimmune diseases.
CC chemokine receptor 6 (CCR6) is expressed on a variety of key immune cells including immature dendritic cells, B cells, memory T cells (including ail Th17 cells), neutrophils, and a subset of Tregs. CCR6 is the only known receptor for chemokine CCL20 (alternatively named LARC or MIP-3a). CCL20 is produced by synoviocytes, colonie épithélial cells, various skin cells (e.g.,kératinocytes and dermal fibroblasts), and alveolar épithélial cells. The ligand-receptor pair CCL20-CCR6 is responsible for the migration of immature dendritic cells and effector/memory Tcells to the skin and mucosal surfaces under homeostatic and inflammatory conditions, as well as in autoimmune diseases such as psoriasis and inflammatory bowel diseases. [Liao, 1999; Schutyser, 2003].
CCL20 is an inducible chemokine that is highly upregulated in inflammatory lésions in various autoimmune diseases including psoriasis, ulcerative colitis, Crohn’s disease, psoriatic arthritis and rheumatoid arthritis. Increased amounts of CCR6 positive T cells and dendritic cells were found in lésions co-localizing with CCL20 expression. These T cell-dendritic cell clusters maintained by CCR6-CCL20 interaction are crucial for disease initiation and maintenance. In mice, both CCR6 knock-out and neutralizing anti-CCL20 antibody were protective in an IL-23 induced skin inflammation model, suggesting that blocking CCR6-CCL20 mediated immune cell recruitment présents an attractive mechanism for novel small molécule therapy in autoimmune and inflammatory diseases. [Homey , 2000; Kim, 2014; Kwon, 2002; Shen, 2010].
C-X-C chemokine receptor type 1 (CXCR1) and C-X-C chemokine receptor type 2 (CXCR2) are chemokine receptors expressed on neutrophils. Both receptors bind the chemokine IL-8 (CXCL8) with high affinity. In contrast, CXCL1 (GRO alpha) and CXCL2 (GRO beta) are spécifie ligands for CXCR2 with 90% sequence homology. In clinical studies, CXCR1/2 dual antagonists such as Navarixin hâve shown a réversible décliné in the absolute neutrophil count in patients [Hastrup, 2015]. Patients with reduced neutrophil counts may be subject to increased risk of infections. Therefore, CCR6 antagonists with reduced potency for antagonism of the CXCR2 receptor may offer an improved safety profile compared to non-discriminating antagonists. Human genetic evidence and knock-out studies in mice suggest the egress of neutrophils from the bone marrow is dépendent on CXCR2 function and mediated by CXCR2 spécifie ligands CXCL1 (GRO alpha) and CXCL2 (GRO beta) [Auer, 2014; Eash, 2010]. Thus to understand the pharmacology of CXCR2 inhibitors on bone marrow neutrophil mobilization, it is important to use the relevant CXCR2 ligand (CXCL1 or CXCL2) in a primary human neutrophil assay System.
Auer, P. L. et. al. Nature Genetics (2014) 46, 629-634.
Bachelerie, F. et. al. Pharmacol. Rev. (2014) 66, 1-79.
Eash, K. J. et. al. J. Clin. Invest. (2010) 120, 2423-2431.
Hastrup, N. et. al. Cytokine (2015) 72, 197-203.
Homey, B. et. al. J. Immunol. (2000) 164, 6621-6632.
Kim, T.-G. et. al. J. Invest. Dermatol. (2014) 134, 1462-1465.
Kufareva, I. Curr. Opin. Pharmacol. (2016) 30, 27-37.
Kwon, J. H. et. al. Gut (2002) 51,818-826.
Liao, F. et. al. J. Immunol. (1999) 162, 186-194.
Murphy, P. M. Pharmacol. Rev. (2002) 54, 227-229.
Schutyser, E.; Struyf, S.; Van Damme, J. Cytokine Growth Factor Rev. (2003) 14, 409-426.
Shen, H.; Goodall, J. C.; Gaston, J. S. H. J. Rheumatol. (2010) 37, 2096-2099.
White, G. E.; Iqbal, A. J.;Greaves, D. R. Pharmacol. Rev. (2013) 65, 47-89.
SUMMARY OF THE INVENTION
The présent invention provides compounds of Formulae (IA) and (IB) that inhibit CCR6 and are useful for treating or preventing disorders ameliorated by inhibition of CCR6 in humans
Formula (IA)
Formula (IB) or a pharmaceutically acceptable sait or hydrate thereof, wherein
Ri and R2 are independently H or (Ci-C6)alkyl, or Ri and R2 taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally 1 or 2 additional heteroatoms selected from the group consisting of O, N, and S, wherein the heterocycle is optionally substituted with 1,2, or 3 (CiC4)alkyl groups;
R3 is H, (Ci-C6)alkyl, (Ci-C4)alkylcarbonyl, -C(=O)CH=CHCO2H, -SO2NH2,
-CH2OC(=O)(Ci-C4)alkyl, -CH2OP(=O)(OH)2, or -C(=O)NRaRb, wherein the (Ci-C4)alkylcarbonyl is optionally substituted with -CO2H or -NH2, wherein the -CH2OC(=O)(Ci-C4)alkyl is optionally substituted with -NH2, and wherein Ra and RB are independently H or (Ci-Ce)alkyl;
A is
R4 is H, (Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C4) alkyl, or halo(Ci-C4)alkyl;
R5 and R6 are independently H, deuterium, (C2-C4)alkenyl, (Ci-C4)alkoxy, (Ci-C4)alkyl, (Ci-C4)alkyl-di-9, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C4)alkyl, cyano, halogen, halo(Ci-C4)alkoxy, halo(Ci-C4)alkyl, or hydroxy(Ci-C4)alkyl;
B is /R8)n (R8)n
R? is -F, -CN, (Ci-Cs)alkyl, (Ci-C3)alkyl-di-7, or halo(Ci-C3)alkyl;
Rs at each occurance is independently deuterium, -F, -Cl, -Br, or -I, or two RsS attached to the same carbon atom form a (Cs-Csjcycloalkyl group;
n is 0, 1,2, 3, or 4;
R9 at each occurance is independently deuterium, -F, -Cl, -Br, or -I, or two RgS attached to the same carbon atom form a (Cs-Csjcycloalkyl group;
m is 1,2, 3, or 4; and
X is O, S, or NRc, wherein Rc is H or (Ci-C4)alkyl.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IA), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides the use of a compound of Formula (IA), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a compound of Formula (IB), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides a compound of Formula (IA), or a pharmaceutically acceptable sait or hydrate thereof, for use as a médicament.
In another embodiment, the présent invention provides a compound of Formula (IB), or a pharmaceutically acceptable sait or hydrate thereof, for use as a médicament.
In another embodiment, the présent invention provides a compound of Formula (IA), or a pharmaceutically acceptable sait or hydrate thereof, for use in treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides a compound of Formula (IB), or a pharmaceutically acceptable sait or hydrate thereof, for use in treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides a pharmaceutical composition comprising a compound of Formula (IA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a pharmaceutical composition comprising a compound of Formula (IB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides a pharmaceutical combination comprising a compound of Formula (IA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a pharmaceutical combination comprising a compound of Formula (IB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-ray structure (ORTEP drawing) of crystalline (/7)-4-((2-(((1,4-dimethyl1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocycIobut-1-en-1-yl)amino)-3hydroxy-/V,A/-dimethylpicolinamide monohydrate.
Figure 2 is an X-ray structure (ORTEP drawing) of crystalline (/7)-4-((2-(((4-chloro-1methyl-1/-/-pyrazoi-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)3-hydroxy-/V,A/-dimethylpicolinamide monohydrate.
Figure 3 is an X-ray structure (ORTEP drawing) of crystalline (S)-4,4-difluoro-2methyltetrahydrofuran-2-carboxylic acid ((1 R,4aS,10aR)-7-isopropyl-1,4a-dimethyl1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methanamine sait (Example 36F).
Figure 4 is a powder X-ray diffraction analysis of crystalline (/7)-4-((2-(((1,4-dimethyi-1/7pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide monohydrate.
Figure 5 is a differential scanning calorimeter analysis for crystalline (R)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide monohydrate.
Figure 6 is a thermogravimetric analysis for crystalline (/7)-4-((2-(((1,4-dimethyl-1/7pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyΛ/,/V-dimethylpicolinamide monohydrate.
Figure 7 is a powder X-ray diffraction analysis of crystalline (/7)-4-((2-(((4-chloro-1methyl-1 H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)3-hydroxy-A/,A/-dimethylpicolinamide monohydrate.
Figure 8 is a differential scanning calorimeter analysis for crystalline (/7)-4-((2-(((4chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate.
Figure 9 is a thermogravimetric analysis for crystalline (/7)-4-((2-(((4-chloro-1 -methyl-1 Hpyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/./V-dimethylpicolinamide monohydrate.
Figure 10 is an X-ray structure (ORTEP drawing) of crystalline (/7)-4-((2-(((1,4-dimethyl1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-A/,A/-dimethylpicolinamide, 0.5 calcium sait,monohydrate.
Figure 11 is an X-ray structure (ORTEP drawing) for the unit ceil of crystalline (/7)-4-((2(((1,4-dimethyl-1 H-pyrazol-3-yl) (1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-/V,/V-dimethylpicoIinamide, 0.5 calcium sait,monohydrate.
Figure 12 is a powder X-ray diffraction analysis of crystalline (/7)-4-((2-(((1,4-dimethyl1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-/V,/V-dimethylpicolinamide, 0.5 calcium sait,monohydrate.
DETAILED DESCRIPTION
In another embodiment, the présent invention provides compounds of Formulae (IA) and
Formula (IB)
Formula (IA) or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 are independently (Ci-C6)alkyl or Ri and R2 taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally 1 or 2 additional heteroatoms selected from the group consisting of O, N, and S, optionally substituted with (Ci-C4)alkyl; R3 is H, (Ci-C6)alkyl, (Ci-C4)alkylcarbonyl, -C(=O)CH=CHCO2H, -SO2NH2, -CH2OC(=O)(Ci-C4)alkyl, -CH2OP(=O)(OH)2, or -C(=O)NRARB, wherein the (Ci-C4)alkylcarbonyl is optionally substituted with -CO2H or -NH2, wherein the -CH2OC(=O)(Ci-C4)alkyl is optionally substituted with -NH2, and wherein RA and Rb are independently H or (Ci-C6)alkyl; A is
R4 is (Ci-C4)alkyl; R5 and Re are independently
H, deuterium, (Ci-C4)alkoxy, (Ci-C4)alkyl, (Ci-C4)alkyl-di.9, (C3-C4)cycloalkyl, cyano, halogen, halo(Ci-C4)alkoxy, halo(Ci-C4)alkyl, or hydroxy(Ci-C4)alkyl; B is
Ci-C3)alkyl-c/i-7; Rs is deuterium or two R3s attached to the same carbon atom form a (Cs-Csjcycloalkyl group; n is 0 or 2; Rg at each occurance is F; m is 1,2, 3, or 4; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IA) and (IB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 are independently (Ci-Ce)alkyl or Ri and R2 taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally 1 or 2 additional heteroatoms selected from the group consisting of O, N, and S, optionally substituted with (Ci-C4)alkyl; R3 is H; A is
R4 is (Ci-C4)alkyl; R5 and Re are independently
H, deuterium, (Ci-C4)alkoxy, (Ci-C4)alkyl, (Ci-C4)alkyl-di-9, (C3-C4)cycloalkyl, cyano, halogen, halo(Ci-C4)alkoxy, halo(Ci-C4)alkyl, or hydroxy(Ci-C4)alkyl; B is
Ci-C3)alkyl-di-7,; Rs is deuterium or two R8s attached to the same carbon atom form a (C3-C5)cycloalkyl group; n is 0 or 2; Rg at each occurance is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IA) and (IB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 are independently methyl, ethyl, or isopropyl, or Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or piperazine wherein the piperazine is substituted with methyl; 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
two Ras attachée! to the same carbon atom form cyclopropyl; n is 0 or 2; Rg at each occurance is
F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IA) and (IB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri is methyl; Ra is methyl, ethyl, or isopropyl; R3 is H; A is
; R4 is methyl; R5 is methyl, methyl-d3, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; Re is H; B is
two RgS attached to the same carbon atom form cyclopropyl; n is 0 or 2; R9 at each occurance is
F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IA) and (IB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; A is
; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; Re is H; B is
R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (I1A)
Formula (IIA) or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 are independently (Ci-C6)alkyl or Ri and R2 taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally 1 or 2 additionai heteroatoms selected from the group consisting of O, N, and S, optionally substituted with (Ci-C4)alkyl; R3 is H, (Ci-C6)alkyl, (C1-C4)alkylcarbonyl, -C(=O)CH=CHCO2H, -SO2NH2, CH2OC(=O)(Ci-C4)alkyl, -CH2OP(=O)(OH)2, or -C(=O)NRaRb, wherein the (Ci-C4)alkylcarbonyl is optionally substituted with -CO2H or -NH2, wherein the -CH2OC(=O)(Ci-C4)alkyl is optionally substituted with -NH2, and wherein Ra and Rb are independently H or (Ci-Ce)alkyl; R4 is (CiC4)alkyl; R5 and R6 are independently H, deuterium, (Ci-C4)alkoxy, (Ci-C4)alkyl, (Ci-C4)alkyl-di-9, (C3-C4)cycloalkyl, cyano, halogen, halo(Ci-C4)alkoxy, or halo(Ci-C4)alkyl; B is
Ci-CsJalkyl-di.?; Rs is deuterium or two R8s attached to the same carbon atom form a (C3-C5)cycloalkyl group; n is 0 or 2; R9 at each occurance is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; Re is H; B is
R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; Re is H; B is
R/Ά r ; R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIA), or a pharrnaceutically acceptable sait or hydrate thereof, wherein Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; Re is H; B is
JR8)n
RyYL i ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIA), or a pharrnaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, methyl-d3, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; Re is H; B is
RyYk । ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIA), or a pharrnaceutically acceptable sait or hydrate thereof, wherein Ri 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; R8 is H; B is (Ra)n\r—I
R —
Τ' ; R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is 0 or 2.
In another embodiment, the présent invention provides compounds of Formula (IIA), or a pharrnaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; Re is H; B is
or 2.
R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is
In another embodiment, the présent invention provides compounds of Formula (IIA), or a pharrnaceutically acceptable sait or hydrate thereof, wherein Ri 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; B is (RX
P
Ά ; R7 is methyl; Rs is deuterium; and n is 0 or 2.
In another embodiment, the présent invention provides compounds of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form 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 (R8A
Ry/P । ; R? is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; Re is H; B is (Rg)m । ; R7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form 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 (Rg)m .A
T ; r7 js methyl; Rg is F; m is 2; and X is O.
In another embodiment the compound of Formula (HA) is (R)-4-((2-(((1,4-Dimethyl-1/7pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment the compound of Formula (HA) is (R)-4-((2-(((1,4-Dimethyl-1Hpyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide.
In another embodiment, the présent invention provides a compound of Formula (IlA), or a pharmaceutically acceptable sait or hydrate thereof, for use as a médicament.
In another embodiment, the présent invention provides a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, for use in treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing inflammatory diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing autoimmune diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of (F?)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3yl) (1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,/Vdimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of F 15 such treatment, a therapeutically effective amount of a prodrug of (fî)-4-((2-(((1,4-Dimethyl-1Hpyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicoünamide.
In another embodiment, the présent invention provides the use of a compound of
Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a 10 médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a compound of
Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a 20 médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of (R)-4-((2-(((1,4Dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate 25 thereof, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a prodrug of (R)-4-((2(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical composition comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a pharmaceutical composition comprising (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,420305 dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/v,/\/-dimethylpicohnamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a pharmaceutical composition comprising a prodrug of (/7)-4-((2-(((1,4-Dimethyl-1 /-/-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/Vdimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (HA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (HA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (HA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising ~ 17 a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of 5 such treatment, a therapeutically effective amount of a pharmaceutical composition comprising (F?)-4-((2-(((1,4-Dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a prodrug of (F?)-4-((2-(((1,4-DimethyI-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an infiammatory disease, condition, or disorder in 30 a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or 5 hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising (/7)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(110 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a prodrug of (/7)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/Vdimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical combination comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a pharmaceutical combination comprising (R)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,425 dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a pharmaceutical combination comprising a prodrug of (/7)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/30 dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective w 19 amount of a pharmaceutical combination comprising a compound of Formula (I IA), or a pharrnaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a 5 human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IIA), or a pharrnaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease, condition, or disorder in a human comprising administering 10 to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IIA), or a pharrnaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disease, condition, or disorder in a human comprising administering 15 to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IlA), or a pharrnaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic 20 arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IIA), or a pharrnaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or 25 preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising (/7)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, or a pharrnaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a prodrug of (R)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,420305 dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or 5 hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament 15 for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIA), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising (F?)-4-((2-(((1,4-Dimethyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating rheumatoid arthritis in 30 a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a prodrug of (/7)-4-((2-(((1,4-Dimethyl-1/-/-pyrazol-3-yl)(1methylcycIopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,A/dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides crystalline (F?)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-15 yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((1,4dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,410 dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 18.7 ± 0.2, 19.1 ± 0.2, and 20.2 ± 0.2 degrees two thêta.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-115 yl)amino)-3-hydroxy-/\/,/\/-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 17.6 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 19.1 ± 0.2, and 20.2 ± 0.2 degrees two thêta.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-120 yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising 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 degrees two thêta.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocycIobut-1-en-125 yl)amino)-3-hydroxy-/\/,/\/-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising 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 degrees two thêta.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-130 yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks selected from the group consisting of 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 degrees two thêta.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/\/,/\/-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 7.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 7.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,410 dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,/\/-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern as depicted in Figure 4.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-115 yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide monohydrate having a differential scanning calorimeter analysis as depicted in Figure 5.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate having a thermogravimetric 20 analysis as depicted in Figure 6.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate for use as a médicament.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,425 dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate for use in treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human 30 comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/\/dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1 5 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,/Vdimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing inflammatory diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-410 ((2-(((1,4-dimethyl-1 /7-pyrazol-3-yl) (1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-
-yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing autoimmune diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-415 ((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-
-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of 20 such treatment, a therapeutically effective amount of crystalline (/7)-4-((2-(((1,4-dimethyl-1Hpyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyN,/\/-dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of 25 such treatment, a therapeutically effective amount of crystalline (/7)-4-((2-(((1,4-dimethyl-1Hpyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy/V,/V-dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-130 yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide monohydrate, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-120305
yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide monohydrate, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of crystalline (R)-4-((25 (((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of crystalline (R)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methy!)amino)-3,4-dioxocyclobut-1-en-110 yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide monohydrate, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of crystalline (R)-4-((2(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,/\/-dimethylpicolinamide monohydrate, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of crystalline (R)-4-((2(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide monohydrate, in the manufacture of a 20 médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,A/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, 25 diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H30 pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a
human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate, and at least one pharmaceutically 5 acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(110 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disease, condition, or disorder in a human comprising administering 15 to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,425 dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising 30 crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/-dimethylpicormamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(120305 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/Vdimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (/?)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (F?)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient,
diluent, or carrier, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1 5 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,A/- dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/715 pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyΛ/,/V-dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically 20 effective amount of a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or 25 preventing an inflammatory disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(120305
methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/\/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic 5 arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate, and at least 15 one anti-inflammatory agent.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/Vdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1 -yl)amino)-3-hydroxy-/V,A/25 dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(130 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcycIopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/- dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1 15 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-120 yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 7.8 ± 0.2, 10.3 ± 0.2, and 10.7 ± 0.2 25 degrees two thêta.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 7.8 ± 0.2, 10.3 ± 0.2, 10.7 ± 0.2, 15.5 ± 30 0.2, and 18.4 ± 0.2 degrees two thêta.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate having an X-ray ~ 30 powder diffraction pattern comprising 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 degrees two thêta.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-15 yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate having an X-ray powder diffraction pattern comprising 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, degrees two thêta.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,410 dimethyI-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide, 0.5 calcium sait, monohydrate having an X-ray powder diffraction pattern comprising 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, 15 degrees two thêta.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,/\/-dimethylpicolinamide, 0.5 calcium sait, monohydrate having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 10.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1 /7-pyrazol-3-yl) (1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 10.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,425 dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate having an X-ray powder diffraction pattern as depicted in Figure 12.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-130 yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide, 0.5 calcium sait, monohydrate for use as a médicament.
In another embodiment, the présent invention provides crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,/\/-dimethylpicolinamide, 0.5 calcium sait, monohydrate for use in
treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human 5 comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline ((/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide, 0.5 calcium sait, monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/\/dimethylpicolinamide, 0.5 calcium sait, monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing inflammatory diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing autoimmune diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1-yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4-((2-(((1,4-dimethyl-1/7pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy30 A/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4-((2-(((1,4-dimethyl-1/720305
pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-15 yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide, 0.5 calcium sait, monohydrate, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-110 yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-115 yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-120 yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-125 yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-130 yl)amino)-3-hydroxy-/\/,A/-dimethylpicolinarnide, 0.5 calcium sait, monohydrate, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/\/20305 dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (7)-4-((2-(((1,4-dimethyl-17pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy/\/,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-115 yl)amino)-3-hydroxy-A/,/\/-dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical 20 composition comprising crystalline (7)-4-((2-(((1,4-dimethyl-17-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,A/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (7)-4-((2-(((1,4-dimethyl-17-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/\/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or 5 preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1 /7-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1 -yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating 15 diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1 H-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1 -yl)amino)-3-hydroxy-/\/,/\/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically 20 acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/\/25 dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1 /7-pyrazol-3-yl)(1 30 methylcycIopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-/V,A/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically 5 acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(110 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-/V,/Vdimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical combination 15 comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(ΙΣΟ methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,A/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective 25 amount of a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/7pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or 30 preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-120305 yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease, condition, or disorder in a human comprising administering 5 to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/\/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,420 dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising 25 crystalline (fî)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/-/-pyrazoi-3-yl)(130 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1 /-/-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent, 5 in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/\/10 dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/-/-pyrazoI-3-yl)(115 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-/V,/Vdimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical 20 combination comprising crystalline (/7)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide, 0.5 calcium sait, monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((4-chloro-1methyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)3-hydroxy-A/,A/-dimethylpicolinamide.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((4-chloro-1methyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yI)amino)3-hydroxy-/V,A/-dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((4-chloro-15 methyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)3-hydroxy-A/,A/-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 18.5 ± 0.2, 18.8 ± 0.2, and 19.2 ± 0.2 degrees two thêta.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((4-chloro-1methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)10 3-hydroxy-A/,/V-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising 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 degrees two thêta.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((4-chloro-1methyl-1 /-/-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)15 3-hydroxy-N,/V-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising 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 degrees two thêta.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((4-chloro-1methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)20 S-hydroxy-N./V-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks selected from the group consisting of 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 degrees two thêta.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((4-chloro-125 methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)3-hydroxy-A/,A/-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising 3 to 10 diffraction peaks listed in Table 8.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((4-chloro-1methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)30 3-hydroxy-A/,/V-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising the diffraction peaks listed in Table 8.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((4-chloro-1methyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)20305
3-hydroxy-A/,A/-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern as depicted in Figure 7.
In another embodiment, the présent invention provides crystalline (F?)-4-((2-(((4-chloro-1methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)5 3-hydroxy-/V,A/-dimethylpicolinamide monohydrate having a differential scanning calorimeter analysis as depicted in Figure 8.
In another embodiment, the présent invention provides crystalline (F?)-4-((2-(((4-chloro-1methyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)3-hydroxy-/V,/V-dimethylpicolinamide monohydrate having a thermogravimetric analysis as depicted in Figure 9.
In another embodiment, the présent invention provides crystalline (R)-4-((2-(((4-chloro-1methyl-1/7-pyrazol-3-yl)(1-methylcyclopenty!)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)3-hydroxy-/V,/V-dimethylpicolinamide monohydrate for use as a médicament.
In another embodiment, the présent invention provides crystalline (F?)-4-((2-(((4-chloro-115 methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)3-hydroxy-/V,/V-dimethylpicolinamide monohydrate for use in treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human 20 comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides a method for treating or 25 preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing inflammatory diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (F?)-4((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1 -en-1 -yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing autoimmune diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4((2-(((4-chIoro-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut5 1 -en-1 -yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4-((2-(((4-chloro-1-methyl10 1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-/V,/V-dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of crystalline (/7)-4-((2-(((4-chloro-1-methyl15 1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-/V,/V-dimethylpicolinamide monohydrate.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1en-1-yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide monohydrate, in the manufacture of a 20 médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1en-1-yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide monohydrate, in the manufacture of a 25 médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1en-1-yl)arnino)-3-hydroxy-/V,/V-dimethyipicolinamide monohydrate, in the manufacture of a 30 médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of crystalline (/7)-4-((2(((4-chloro-1-methyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1en-1-yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide monohydrate, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of crystalline (R)-4-((2(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1en-1-yl)amino)-3-hydroxy-A/,/\/-dimethylpicolinamide monohydrate, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of crystalline (R)-4-((2(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-320 hydroxy-/V,A/-dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1 methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)3-hydroxy-A/,A/-dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/20305 dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disease, condition, or disorder in a human comprising administering 5 to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/\/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)15 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising 20 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-A/,/V-dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(125 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical 30 composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (fî)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, 5 diluent, or carrier, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1 -yl)amino)-3-hydroxy-/V,A/- dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(115 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating rheumatoid arthritis in a 25 human.
In another embodiment, the présent invention provides a pharmaceutical combination comprising crystalline (/7)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyI)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1 -methyl-1/-/-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl5 l/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-/V,/V-dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically 10 effective amount 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,/V-dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease, condition, or disorder in a human comprising administering 15 to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1methy!cyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or 20 preventing an autoimmune disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (fî)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)30 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,/Vdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1 -yI)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (R)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/\/25 dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (fî)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(130 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising crystalline (F?)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides compounds of Formula (IIB)
Formula (IIB) or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 are independently (Ci-C6)alkyl or Ri and R2 taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally 1 or 2 additional heteroatoms selected from the group consisting of O, N, and S, optionally substituted with (Ci-C4)alkyl; R3 is H, (Ci-Ce)alkyl, (Ci-C4)alkylcarbonyl, -C(=O)CH=CHCO2H, -SO2NH2, -CH2OC(=O)(Ci-C4)alkyl, -CH2OP(=O)(OH)2, or -C(=O)NRaRb, wherein the (Ci-C4)alkylcarbonyl is optionally substituted with -CO2H or -NH2, wherein the -CH2OC(=O)(Ci-C4)alkyl is optionally substituted with -NH2, and wherein RA and Rb are independently H or (Ci-C6)alkyl; R4 is (Ci-C4)alkyl; R5 and R6 are independently H, deuterium, (Ci-C4)alkoxy, (Ci-C4)alkyl, (Ci-C4)alkyl-di-9, (C3-C4)cycloalkyl, cyano, halogen, halo(Ci-C4)alkoxy, or halo(Ci-C4)alkyl; B is (R8)nx ~ (R9’+
R A , or 7 g ; R7 is (Ci-C3)alkyl or
Ci-C3)alkyl-di-7; R3 is deuterium or two Rgs attached to the same carbon atom form a (C3-C5)cycloalkyl group; n is 0 or 2; R9 at each occurance is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri 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; B is
; R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form 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.
In another embodiment, the présent invention provides compounds of Formula (IlB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R4 is methyl; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; Re is H; B is
AR8)n
R 'Ί 7 + ; R? is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form 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
ARsin
R —!i 7 + ; r7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri 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; Re is H; B is (R8)n^q
R — 7 ; R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form 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 (R8)n~
R7 ; R7 is methyl; two R8s attachée) to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri 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; R8 is H; B is (R8)nx
R j 7 V ; R7 is methyl; R8 is deuterium; and n is 0 or 2.
In another embodiment, the présent invention provides compounds of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form 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 (R8)nx r7XL
T ; r7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri 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; B is (Rg)m
7 ; R7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form 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 (Rs)m
r7 ; R7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment the compound of Formula (ΙΙΑ) is (S)-4-((2-(((1,4-dimethyl-1Hpyrazol-3-yl)(Tmethylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyΛ/,/V-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment the compound of Formula (ΙΙΑ) is (S)-4-((2-(((1,4-dimethyl-1H5 pyrazol-3-yl)(1-methylcyclopentyl)methyI)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy/V,/V-dimethylpicolinamide.
In another embodiment, the présent invention provides a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, for use as a médicament.
In another embodiment, the présent invention provides a compound of Formula (IIB), or 10 a pharmaceutically acceptable sait or hydrate thereof, for use in treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective 15 amount of a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically 20 effective amount of a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing inflammatory diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of 25 Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing autoimmune diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of (S)-4-((2-(((1,4-dimethyl1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-35 hydroxy-/V,N-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of a prodrug of (S)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-110 yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide.
In another embodiment, the présent invention provides the use of a compound of Formula (IlB), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
in another embodiment, the présent invention provides the use of a compound of
Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a compound of 20 Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a compound of
Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of (S)-4-((2-(((1,430 dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a prodrug of (S)-4-((2(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-120305 yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical composition comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate 5 thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a pharmaceutical composition comprising (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, 10 diluent, or carrier.
In another embodiment, the présent invention provides a pharmaceutical composition comprising a prodrug of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyc!obut-1-en-1-yl)amino)-3-hydroxy-A/,/Vdimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one 15 pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IIB), or a 20 pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically 25 effective amount of a pharmaceutical composition comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease, condition, or disorder in a human comprising administering 30 to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IIB), or a pharrnaceutically acceptable sait or hydrate thereof, and at least one pharrnaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or 5 preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IIB), or a pharrnaceutically acceptable sait or hydrate thereof, and at least one pharrnaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising (S)-4-((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1-methyIcyclopentyl)methyl)amino)-3,4-dioxocyclobut1_en-1-yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, or a pharrnaceutically acceptable sait or 15 hydrate thereof, and at least one pharrnaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a prodrug of (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,420 dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, or a pharrnaceutically acceptable sait or hydrate thereof, and at least one pharrnaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIB), or a pharrnaceutically acceptable sait or 25 hydrate thereof, and at least one pharrnaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIB), or a pharrnaceutically acceptable sait or 30 hydrate thereof, and at least one pharrnaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIB), or a pharrnaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising (S)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a prodrug of (S)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical combination comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a pharmaceutical combination comprising (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a pharmaceutical combination comprising a prodrug of (S)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(120305 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/Vdimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IlB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or 10 preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IlB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or 15 preventing an inflammatory disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or 20 preventing an autoimmune disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising (S)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut20305
1-en-1-yl)amino)-3-hydroxy-W,A/-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis in a human comprising administering to the human, in need of 5 such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a prodrug of (S)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,M-dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides the use of a pharmaceutical 10 combination comprising a compound of Formula (IlB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or 15 hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or 20 hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament 25 for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic 30 arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising (S)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a prodrug of (S)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/\/dimethylpicolinamide, or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating rheumatoid arthritis in a human.
In another embodiment, the présent invention provides compounds of Formula (IIIA)
Formula (IIIA) or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 are independently (Ci-C6)alkyl or Ri and R2 taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally 1 or 2 additional heteroatoms selected from the group consisting of O, N, and S, optionally substituted with (Ci-C^alkyl; R3 is H, (Ci-C6)alkyl, (Ci-C4)alkylcarbonyl, -C(=O)CH=CHCO2H, -SO2NH2, -CH2OC(=O)(Ci-C4)alkyl, -CH2OP(=O)(OH)2, or -C(=O)NRaRb, wherein the (C1C4)alkylcarbonyl is optionally substituted with -CO2H or -NH2, wherein the -CH2OC(=O)(CiC4)alkyl is optionally substituted with -NH2, and wherein Ra and Rb are independently H or (C1Ce)alkyl; R5 and R6 are independently H, deuterium, (Ci-C4)alkoxy, (Ci-C4)alkyl, (Ci-C4)alkyl-di-9, (C3-C4)cycloalkyl, cyano, halogen, halo(Ci-C4)alkoxy, or halo(Ci-C4)alkyl; B is
(Ci-C3)alkyl-di-7; Rs is deuterium or two R8s attached to the same carbon atom form a (C3C5)cycloalkyl group; n is 0 or 2; R9 at each occurance is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; Rs and Rs are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is R7%A i ; R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is
R7'^T“ ; R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is r ; R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; Rs and Rs are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is r7-— ; R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is ; R? is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is ; R? is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri 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 /JRsln 7 A ; R? is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IUA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is hr^
R Xl 7 A ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is /Ύ)η
R 7 A ; R? is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is /JRsL 7 A ; R? is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Ré is methyl or methoxy; B is
JR8)r,
RyrtK r ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (I II A), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is uR8)n
R '—1 7 i ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (ΙΙΙΑ), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri 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; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (ΙΙΙΑ), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; Rs is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is
R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (ΙΙΙΑ), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; Rs is methyl or hydroxymethyl; R8 is methyl or methoxy; B is
R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 420305 methylpiperazine; R3 is H; Rs and Re are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is (R8)n^^ ; R? is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R8 is methyl or methoxy; B is (Rs)n^^ ; R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; Re is methyl or methoxy; B is (R 8)n-; R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, CI, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is (R8X
P + ; R? is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is (R8)n
R? AL r ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IlIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is (R8)nx r7AL i ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (I II A), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is (R8)nx
R7AL z ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is (R8)nK r7al । ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (l II A), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is (R8)nx
R?Ak । ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (111 A), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 and Rs are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is (Rslm 7 A ; R7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is (Rgim
A 7 A ; R7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (I II A), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is (Rglm 7 A ; r7 îs methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is (Bglm
A 7 A ; r7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIIA), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is (Rs)m f ; R7 is methyl; R9 is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IHA), or a pharrnaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is (R9)m 7 T ; R7 is methyl; R9 is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIIB)
Formula (HIB) or a pharrnaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 are independently (Ci-C6)alkyl or Ri and R2 taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally 1 or 2 additional heteroatoms selected from the group consisting of O, N, and S, optionally substituted with (Ci-C4)alkyl; R3 is H, (Ci-Ce)alkyl, (Ci-C4)alkylcarbonyl, -C(=O)CH=CHCO2H, -SO2NH2, -CH2OC(=O)(Ci-C4)alkyl, -CH2OP(=O)(OH)2, or -C(=O)NRaRb, wherein the (CiC4)alkylcarbonyl is optionally substituted with -CO2H or -NH2, wherein the -CH2OC(=O)(CiC4)alkyl is optionally substituted with -NH2, and wherein Ra and Rb are independently H or (Ci-C6)alkyl; R5 and R6 are independently H, deuterium, (Ci-C4)alkoxy, (Ci-C4)alkyl, (Ci-C4)alkyl-di-9, (C3-C4)cycloalkyl, cyano, halogen, halo(Ci-C4)alkoxy, or halo(Ci-C4)alkyl; B is
(Ci-C^alkyl-dv?; R8 is deuterium or two R8s attached to the same carbon atom form a (C3-C5)cycloalkyl group; n is 0 or 2; R9 at each occurance is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri 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.
In another embodiment, the présent invention provides compounds of Formula (I 11 B), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is । ; R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri 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.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is ; R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano,· cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is
R7-X~ + ; R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morphohne or 4methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is R7-TX ; R7 is methyl.
In another embodiment, the présent invention provides compounds of Formula (I 11 B), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri 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
JR 8)n
Ry+XT r ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (I II B), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Rg is methyl or methoxy; B is
XRs)n । ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (111B), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is
JRs)n
R 7 T ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is
JR 8)n r ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (l II B), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 420305 methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is
AR8)n
R7Ak r ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is
ARA
R7AL r ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri 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; two Rss attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is
R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is (R8)nR 7 'τ'' ; r7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is 0 or 2.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is
R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is
R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; Rs is methyl or hydroxymethyl; R8 is methyl or methoxy; B is
R7 is methyl; two R8s attached to the same carbon atom form cyclopropyl; and n is or 2.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri 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 (R8)n r7%l “ ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; FL is methyl or methoxy; B is (R8)n
R?A ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (111B), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is (RsR
R/A r ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (111B), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is (R8)nx
R?A “i ; R? is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (I II B), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; R6 is methyl or methoxy; B is (R8)nx R?A ; R7 is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (lll B), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; Re is methyl or methoxy; B is (R8)nx
R?A
Γ ; R? is methyl; and n is 0.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri 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 (Rg)m
V 7 θ' ; R7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is (Rgim
V 7 T ; r7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri is methyl; R2 is methyl, ethyl, or isopropyl; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is (Rg)m 7 T ; r7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 and R6 are independently methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; B is (R9)m 7 । ; R7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, cyclopropyl, or hydroxymethyl; Re is methyl or methoxy; B is (Rg)m %
A ; r7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides compounds of Formula (HIB), or a pharmaceutically acceptable sait or hydrate thereof, wherein Y is O or S; Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; R3 is H; R5 is methyl or hydroxymethyl; R6 is methyl or methoxy; B is (Rg)m
A 7 A ; R7 is methyl; Rg is F; m is 2; and X is O.
In another embodiment, the présent invention provides a compound of Formula (IIIA) or (IlIB), or a pharmaceutically acceptable sait or hydrate thereof, for use as a médicament.
In another embodiment, the présent invention provides a compound of Formula (IIIA) or (HIB), or a pharmaceutically acceptable sait or hydrate thereof, for use in treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IIIA) or (IlIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IIIA) or (HIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing inflammatory diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IIIA) or (HIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing autoimmune diseases, conditions or disorders in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IlIA) or (IlIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic 5 arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IlIA) or (IlIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides the use of a compound of Formula (111A) or (IlIB), or a pharmaceutically acceptable sait or hydrate thereof, in the 10 manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a compound of Formula (111A) or (111B), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by 15 inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a compound of Formula (IIIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a compound of
Formula (IIIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a compound of 25 Formula (IlIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical composition comprising a compound of Formula (IlIA) or (IIIB), or a pharmaceutically acceptable sait or 30 hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IIIA) or (IIIB), or a
pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a 5 human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IlIA) or (IlIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IlIA) or (IlIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IIIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical composition comprising 25 a compound of Formula (IIIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or 30 carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent, or
carrier, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIIA) or (IIIB), or a pharrnaceutically acceptable 5 sait or hydrate thereof, and at least one pharrnaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IlIA) or (IIIB), or a pharrnaceutically acceptable 10 sait or hydrate thereof, and at least one pharrnaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical composition comprising a compound of Formula (IIIA) or (IIIB), or a pharrnaceutically acceptable 15 sait or hydrate thereof, and at least one pharrnaceutically acceptable excipient, diluent, or carrier, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a pharmaceutical combination comprising a compound of Formula (IlIA) or (IIIB), or a pharrnaceutically acceptable sait or 20 hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (11 IA) or (IIIB), or a 25 pharrnaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IIIA) or 30 (IIIB), or a pharrnaceutically acceptable sait or hydrate thereof, and at least one antiinflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing an inflammatory disease, condition, or disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical
combination comprising a compound of Formula (IIIA) or (111B), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disease, condition, or disorder in a human comprising administering 5 to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IIIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic 10 arthritis, or rheumatoid arthritis in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (IIIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent.
In another embodiment, the présent invention provides the use of a pharmaceutical 15 combination comprising a compound of Formula (IIIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of CCR6 in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical 20 combination comprising a compound of Formula (IIIA) or (111B), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating diseases, conditions or disorders ameliorated by inhibition of T cell chemotaxis in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical 25 combination comprising a compound of Formula (IIIA) or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating an inflammatory disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIIA) or (111B), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating an autoimmune disease, condition, or disorder in a human.
In another embodiment, the présent invention provides the use of a pharmaceutical combination comprising a compound of Formula (IIIA) or (111B), or a pharmaceutically acceptable sait or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a médicament for treating psoriasis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human.
In another embodiment, the présent invention provides a method for treating or preventing an immune disorder in a human comprising administering to the 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 sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing an autoimmune disorder in a human comprising administering to the 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 sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing a neurodegenerative or neuroinflammatory disorder in a human comprising administering to the 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 sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing rheumatoid arthritis, juvénile arthritis, Still's disease, juvénile rheumatoid arthritis, systemic onset rheumatoid arthritis, pauciarticular rheumatoid arthritis, pauciarticular juvénile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvénile Reiter's Syndrome, ankylosing spondylitis, juvénile ankylosing spondylitis, SEA Syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvénile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvénile idiopathic arthritis (JIA), juvénile psoriatic arthritis, juvénile rheumatoid arthritis, systemic onset juvénile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis from inflammatory diseases in a human comprising administering to the 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 sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing lupus, systemic lupus erythematosus, juvénile systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, scleroderma (systemic sclerosis), Raynaud's phenomenonjuvenile scleroderma, polymyositis, dermatomyositis, polymyositisdermatomyositis, mixed connective tissue disease, sarcoidosis, fibromyalgia, vasculitis microscopie polyangiitis, vasculitis, éosinophilie granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome), granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), polyarteritis nodosa, Henoch-Schonlein purpura, idiopathic
thrombocytopénie thrombotic purpura, juvénile vasculitis, polyarteritis nodossa (also known as panarteritis nodosa, periarteritis nodosa, Kussmaul disease, Kussmaul-Maier disease or PAN), sérum sickness, Myasthenia gravis, Takayasu's arteritis, Behçet's syndrome, Kawasaki's disease (mucocutaneous lymph node syndrome), Buerger's disease (thromboangiitis obliterans), Vogt-Koyanagi-Harada syndrome, Addison's disease, Hashimoto's thyroiditis, sclerosing cholangitis, membranous glomerulopathy, polymyositis, myositis, atherosclerosis, autoimmune hemolytic anémia, autoimmune orchitis, or Goodpasture's disease in a human comprising administering to the 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 10 acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing is inflammatory bowel diseases, Crohn's disease, ulcerative colitis, celiac sprue, celiac diseases, proctitis, éosinophilie gastroenteritis, autoimmune atrophie gastritis of pernicious anémia, or mastocytosis in a human comprising administering to the human, in need 15 of such treatment, a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing psoriasis, atopie dermatitis, eczema dermatitis, dermatitis, pruritus, alopecia, autoimmune alopecia, vitiligo, epidermal hyperplasia, juvénile dermatomyositis, or 20 dermatomyositis. In certain other embodiments, the psoriasis is plaque psoriasis, Guttate psoriasis, psoriatic epidermal hyperplasia, inverse psoriasis, pustular psoriasis, érythrodermie psoriasis in a human comprising administering to the 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 sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, autoimmune hepatitis, chronic aggressive hepatitis, or primary biliary sclerosis in a human comprising administering to the 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 sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing multiple sclerosis, amyotropic latéral sclerosis, Guillain-Barre disease, autoimmune encephalomyelitis, Alzheimer's disease, major dépressive disorder, traumatic brain injury, epilepsy, Parkinson’s disease, or bipolar disorder in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IlB), (IIIA), or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing Graves' disease, noninfectious uveitis, dry eye syndrome, sympathetic ophthalmia, Cogan's syndrome, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal épithélial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergie conjunctivitis, ocular neovascularization, or proliférative diabetic retinopathy in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IA), (IB), (IIA), (IlB), (IIIA), or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing ashma, allergy, chronic obstructive pulmonary disease, or acute respiratory disease in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IA), (IB), (HA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, leukemia, diffuse large B cell lymphoma, cutaneous T-cell lymphoma, non-Hodgkin lymphoma, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, multiple myeloma, myeloproliferative disorders, glioblastoma, oligodendroglioma, pancreatic cancer, brain tumors, or gliomas including astrocytoma. In certain other embodiments, the leukemia is acute myeloid leukemia, T cell acute lymphoblastic leukemia, or adult T cell leukemia in a human comprising administering to the human, in need of such treatment, a therapeutically effective amount of a compound of Formula (IA), (IB), (I1A), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof.
In another embodiment, the présent invention provides a method for treating or preventing Type I diabètes mellitus, Type II diabètes mellitus, or Juvénile onset diabètes in a human comprising administering to the 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 sait or hydrate thereof.
Définitions
As used throughout this spécification and the appended daims, the following terms hâve the following meanings.
The term (C2-C4)alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 4 carbons and containing one carbon-carbon double bond. Représentative examples of (C2-C4)alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, and 3-butenyl.
The term (Ci-C4)alkoxy as used herein, means a (Ci-C4)alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Représentative examples of (Ci-C4)alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.
The term (Ci-Csjalkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms. Représentative examples of (Ci-Csjalkyl include methyl, 15 ethyl, n-propyl, and iso-propyl.
The term “(Ci-Csjalkyl-di./' as used herein, means a straight or branced chain hydrocarbon containing from 1 to 3 carbon atoms wherein one to seven of the hydrogens hâve been exchanged for deuterium (2H or D). Représentative examples of (Ci-C3)alkyl-di.7 include methyl-ds, ethyl-d5, and ethyl-2,2,2-^3.
The term (Ci-C4)alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Représentative examples of (Ci-C4)alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl.
The term “(Ci-C4)alkyl-di.9 as used herein, means a straight or branced chain hydrocarbon containing from 1 to 4 carbon atoms wherein one to nine of the hydrogens hâve been exchanged for deuterium (2H or D). Représentative examples of (CrC4)alkyl-di.9 include methyl-d3, ethyl-d5, and ethyl-2,2,2-d3.
The term (Ci-C6)alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Représentative examples of (Ci-C6)alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 30 isopentyl, neopentyl, and n-hexyl.
The term (Ci-C4)alkylcarbonyl as used herein, means a (Ci-C4)alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Représentative examples of (Ci-C4)alkylcarbonyl include, but are not limited to, acetyl, 1oxopropyl, and 2,2-dimethyl-1-oxopropyl.
The term carbonyl as used herein, means a -0(=0)- group.
The term cyano as used herein, means a -CN group.
The term (C3-C4)cycloalkyl as used herein, means a saturated cyclic hydrocarbon group containing from 3 to 4 carbons, examples of (C3-C4)cycloalkyl include cyclopropyl and cyclobutyl. The (C3-C4)cycoalkyl groups of the invention are optionally substituted with 1,2, or 3 substituents that are independently (Ci-C4)alkyl, CN, halogen, or OH.
The term (C3-C4)cycloalkyl(Ci-C4)alkyl as used herein, means a (C3-C4)cycloalkyl as defined herein, appended to the parent molecuiar moiety through a (Ci-C4)alkyl group, as defined herein. Représentative examples of (C3-C4)cycloalkyl(Ci-C4)alkyl include cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopropylpropyl, 3-cyclopropylpropyl, cyclobutylmethyl, 2-cyclobutylethyl, 2-cyclobutylpropyl, and 3-cyclobutylpropyl.
The term (C3-C5)cycloalkyl as used herein, means a saturated cyclic hydrocarbon group containing from 3 to 5 carbons, examples of (C3-C5)cycloalkyl include cyclopropyl, cyclobutyl, and cyclopentyl. The (C3-C5)cycoalkyl groups ofthe invention are optionally substituted with 1,2, or 3 substituents that are independently (Ci-C4)alkyl, CN, halogen, or OH.
The term halo or halogen as used herein, means -Cl, -Br, -I or -F.
The term halo(Ci-C4)alkoxy as used herein, means at least one halogen, as defined herein, appended to the parent molecuiar moiety through a (Ci-C4)alkoxy group, as defined herein. Représentative examples of halo(Ci-C4)alkoxy include, but are not limited to, chloromethoxy, difluoromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
The term halo(C1-C3)alkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecuiar moiety through a (Ci-C3)alkyl group, as defined herein. Représentative examples of halo(Ci-C3)alkyl include, but are not limited to, chloromethyl, difluoromethyl, 2-fluoroethyl, trifluoromethyl, and pentafluoroethyl.
The term halo(Ci-C4)alkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecuiar moiety through a (Ci-C4)alkyl group, as defined herein. Représentative examples of halo(Ci-C4)alkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, and pentafluoroethyl.
The term heterocycle or heterocyclic as used herein, means a 4, 5, or 6 membered ring containing one N heteroatom and optionally 1 or 2 additional heteroatoms selected from the group consisting of O, N, and S. Représentative examples of heterocycle include, but are not limited to, azetidinyl, imidazolidinyl, morpholinyl, oxadiazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, thiadiazolidinyl, thiazolidinyl, and thiomorpholinyl. The heterocycle groups of the invention are optionally substituted with 1,2, or 3 (Ci-C4)alkyl groups.
The term hydroxy(Ci-C4)alkyl as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through a (Ci-C4)alkyl group, as defined herein. Représentative examples of hydroxy(Ci-C4)alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,4-dihydroxybutyl, and 2,3-dihydroxypropyl.
In another embodiment, the présent invention provides pharmaceutical combinations for topical administration comprising a compound of Formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, in combination with another pharmaceutical agent for the treatment of the diseases, conditions and/or disorders described herein. Suitable pharmaceutical agents that may be used in combination with the compounds of 10 the présent invention for topical administration include, but are not limited to: a second compound of Formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof; a PDE4 isoenzyme inhibitor including, but not limited to, ampremilast, roflumilast, rolipram, piclamilast, crisaborole, PF-07038124, PF-07091905, PF-07090414, PF07062087, PF-07062077, and PF-07057566; a corticosteroid including, but not limted to, 15 fluocinonide, desoximetasone, mometasone, triamcinolone, betamethasone, alclometasone, desonide, hydrocortisone, LEO-134310A and mapracorat; a calcineurin inhibitor including, but not limited to, tacrolimus, pimecrolimus and cyclosporine; a JAK inhibitor including, but not limited to, tofacitinib, JTE-052, baricitinib, upadacitinib, PF-04965842, PF-06651600 and PF06700841; aTYK inhibitors including, but not limited to, PF-06826647 and BMS-986165; an ITK 20 inhibitor including, but not limited to, JTE-051 ; a SYK inhibitor including, but not limited to, fostamatinib, cerdulatinib, entospletinib, TAK-659, ASN-002 and GS-9876; a tyrosine kinase inhbitor including, but not limited to, cerdulatinib; an IRAK4 inhibitor including, but not limited to, 1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6 carboxamide; an anti-inflammatory agent including, but not limited to, WBI-1001 and MRX-6;
retinoic acid dérivatives including, but not limited to, alitretinoin; a liver X receptor (LXR) sélective agonist including, but not limited to, VTP-38543; a H4 receptor antagonists including, but not limited to, ZPL-389; a NKI receptor antagonists including, but not limited to, Aprepitant and Tradipitant; a CRTH2 receptor antagonists including, but not limited to, Fevipiprant and OC459; a Chymase inhibitors including, but not limited to, SUN 13834; a GATA-3 inhibitors including, but not limited to, SB-011 ; and a RORC2 inverse agonist including, but not limited to, PF-06763809, ESR-114, VTP-43742, ARN6039, TAK-828, RTA-1701, BOS-172767, AUR-101 and JTE-451.
In another embodiment, the présent invention provides pharmaceutical combinations for oral administration comprising a compound of Formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof, in combination with another pharmaceutical agent for the treatment of the diseases, conditions and/or disorders described herein. Suitable pharmaceutical agents that may be used in combination with the compounds of the présent invention for oral administration include, but are not limited to: a second compound of Formula 5 (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable sait or hydrate thereof;
oral anti-inflammatory agents including, but not limited to, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, CELEBREX®, and pharmaceutically acceptable salts or prodrugs thereof; oral retinoic acid dérivatives including, but not limited to, alitretinoin; oral liver X receptor (LXR) sélective 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 Tradipitant; oral CRTH2 receptor antagonists including, but not limited to, Fevipiprant and OC-459; oral Chymase inhibitors including, but not limited to, SUN 13834; oral GATA-3 inhibitors including, but not limited to, SB-011; oral R0RC2 inverse agonists including, but not limited to, ESR-114, VTP15 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, upadacitinib, PF04965842, 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, fostamatinib, cerdulatinib, entospletinib, TAK-659, 20 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-4fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6 carboxamide and BAY 1830839.
In another embodiment, the présent invention provides pharmaceutical combinations for injectable administration comprising a compound of Formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), 25 or a pharmaceutically acceptable sait or hydrate thereof, in combination with another pharmaceutical agent for the treatment of the diseases, conditions and/or disorders described herein. Suitable pharmaceutical agents that may be used in combination with the compounds of the présent invention for injectable administration include, but are not limited to: TNFa inhibitors including, but not limited to, infliximab, adalimumab, golimumab, and certolizumab pegol; anti30 MAdCAM including, but not limited to, SHP647; anti IL-12 P40 including, but not limited to, ustekinumab; anti-IL-23 P19 including, but not limited to, risankizumab, mirikizumab, brazikumab, guselkumab, and tidrakizumab; anti-IL-17 including, but not limited to, secukinumab, brodalumab and ixekizumab; integrin inhibitors including, but not limited to, natalizumab, vedolizumab and etrolizumab.
Combination therapy includes administration of the two or more therapeutic agents concurrently or sequentially. The agents may be administered in any order. Alternatively, the multiple therapeutic agents can be combined into a single composition that can be administered to the patient. For instance, a single pharmaceutical composition could comprise the compound 5 or pharmaceutically acceptable sait, hydrate, ester or prodrug thereof according to the Formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), another therapeutic agent or a pharmaceutically acceptable sait, hydrate, ester or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier.
The term pharmaceutically acceptable sait or sait, as used herein, refers to salts that 10 are well known in the art. For example, S. M 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, nontoxic acid addition salts are salts of an amino group 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, 15 oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include nitrate, bisulfate, borate, formate, butyrate, valerate, 3-phenylpropionate, camphorate, adipate, benzoate, besylate, oleate, palmitate, stéarate, laurate, lactate, fumarate, ascorbate, aspartate, nicotinate, p-toluenesulfonate, camphorsulfonate, methanesulfonate, 2-hydroxyethanesulfonate, 20 gluconate, glucoheptonate, lactobionate, glycérophosphate, pectinate, lauryl sulfate, and the like, métal salts such as sodium, potassium, magnésium or calcium salts or amino salts such as ammonium, triethylamine salts, and the like, ail of which may be prepared according to conventional methods.
Basic addition salts can be prepared in situ during the final isolation and purification of 25 compounds of this invention by reacting the hydroxy group at the 3-position of the N,Ndimethylpicolinamide moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable métal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, 30 potassium, calcium, magnésium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tétraméthylammonium, tetraethylammonium, méthylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium and the like. Other représentative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
The présent invention also includes pharrnaceutically acceptable salts of the prodrugs of the compounds of the présent invention. Représentative examples include, but are not limited to, the compounds shown below wherein R+ is lithium, sodium, potassium, ammonium, tétraméthylammonium, tetraethylammonium, méthylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium and the like, and wherein R2+ is calcium, magnésium, aluminum, and the like.
The compounds of the présent invention may be isolated and used per se in the form of their pharrnaceutically acceptable salts, including salts of a prodrug. In accordance with the présent invention, compounds with multiple basic nitrogen atoms can form salts with varying number of équivalents (eq.) of acid. Compounds with multiple acidic groups may form basic addition salts with varying numbers of équivalents (eq.) of the basic addition molécule or positive counterion. It will be understood by practitioners that ail such salts are within the scope of the présent invention.
The présent invention encompasses compounds of Formula (IA), (IB), (HA), (IIB), (IIIA), or (IIIB), when prepared by synthetic processes or by metabolic processes. Préparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
The présent invention also contemplâtes pharrnaceutically active métabolites formed by in vivo biotransformation of compounds of Formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB). The term pharrnaceutically active métabolite, as used herein, refers to a compound formed by the in vivo biotransformation of compounds of Formula (IA), (IB), (HA), (IIB), (IIIA), or (IIIB). A thorough discussion of biotransformation is provided in (Goodman and Gilman’s, The Pharmacological Basis of Therapeutics, seventh édition, MacMillan Publishing Company, New York, NY, (1985)).
When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the présent invention can be employed in pure form or, where such forms exist, in pharrnaceutically acceptable sait, ester, amide, or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable carriers. The phrase therapeutically effective amount ofthe compound ofthe présent invention means a sufficient amount of the compound to treat the diseases, conditions, or disorders indicated herein at a reasonable benefit/risk ratio applicable to any medical treatment. The spécifie therapeutically effective dose level for any particular patient will dépend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the spécifie compound employed; the spécifie composition employed; the âge, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excrétion of the spécifie compound employed; the duration ofthe treatment; drugs used in combination or coincidental with the spécifie compound employed; and like factors well known in the medical arts.
Pharmaceutical Compositions or Formulations
In another embodiment, the présent invention provides pharmaceutical compositions, or formulations, comprising a therapeutically effective amount of a compound ofthe présent invention and a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical compositions, or formulations, of this invention may be administered to humans and other mammals topically, orally, parenterally , intracisternally, intravaginally, intraperitoneally, bucally, as an oral spray, as a nasal spray, rectally as a suppository, or in the form of a liposome.
A typical pharmaceutical composition or formulation is prepared by mixing a compound ofthe présent invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobie materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will dépend upon the means and purpose for which the compound of the présent invention is being applied. Suitable aqueous solvents include water, éthanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an élégant présentation ofthe drug (i.e., a compound ofthe présent invention or pharmaceutical composition thereof) or aid in the manufacturing ofthe pharmaceutical product (i.e., for use in the preparing a médicament).
The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound ofthe présent invention or stabilized form of the compound (e.g., complex with a cyclodextrin dérivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The dissolution rate of poorly water-soluble compounds may be enhanced by the use of a spray-dried dispersion, such as those described by Takeuchi, H., et al. in “Enhancement ofthe dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent déposition method and disintegrants” J. Pharm. Pharmacol., 39, 769-773 (1987); and EP0901786 B1 (US2002/009494), incorporated herein by reference. The compound ofthe présent invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an élégant and easily handleable product.
The pharmaceutical composition, or formulation, for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, métal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
The term pharmaceutically acceptable carrier refers to carrier medium that provides the appropriate delivery of an effective amount of a active agent as defined herein, does not interfère with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient. Représentative carriers include water, oils, both vegetable and minerai, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, pénétration enhancers, and the like. Additional information concerning carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005) which is incorporated herein by reference. Further examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its dérivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; 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; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnésium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonie saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnésium stéarate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be présent in the composition, according to the judgment of the formulator.
The term “pharmaceutically acceptable topical carrier refers to pharmaceutically acceptable carriers, as described herein above, suitable for topical application. An inactive liquid or cream vehicle capable of suspending or dissolving the active agent(s), and having the properties of being nontoxic and non-inflammatory when applied to the skin, nail, hair, claw or hoof is an example of a pharmaceutically-acceptable topical carrier. This term is specifically intended to encompass carrier materials approved for use in topical cosmetics as well.
The term topical administration refers to the application of a pharmaceutical agent to the external surface of the skin, nail, hair, claw or hoof, such that the agent crosses the external surface of the skin, nail, hair, claw or hoof and enters the underlying tissues. Topical administration includes application of the composition to intact skin, nail, hair, claw or hoof, or to an broken, raw or open wound of skin, nail, hair, claw or hoof. Topical administration of a pharmaceutical agent can resuit in a limited distribution of the agent to the skin and surrounding tissues or, when the agent is removed from the treatment area by the bloodstream, can resuit in systemic distribution of the agent.
Dosage forms for topical or transdermal administration of a compound of the présent invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under stérile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Compounds that are volatile in may require admixture with spécial formulating agents or with spécial packaging materials to assure proper dosage delivery. In addition, compounds of the présent invention that hâve poor human skin permeability may require one or more permeability enhancers whereas compounds rapidly absorbed through the skin may require formulation with absorption-retarding agents or barriers.
The ointments, pastes, creams, lotions, gels, powders, and solutions, for topical administration may contain, in addition to an active compound of the présent invention, pharmaceutically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose dérivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, preservatives, antioxidants, fragrances, emulsifiers, dyes, inert fillers, anti-irritants, tackifiers, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, émollients, coloring agents, preservatives, buffering agents, perméation enhancers, or mixtures thereof. Topical excipients should not interfère with the effectiveness of the biological activity of the active agent and not be deleterious to the épithélial cells or their function.
The terms permeability enhancer, or “perméation enhancer,” relates to an increase in 5 the permeability of the skin, nail, hair, claw or hoof to a drug, so as to increase the rate at which the drug permeates through the skin, nail, hair, claw or hoof. The enhanced perméation effected through the use of such enhancers can be observed, for example, by measuring the rate of diffusion ofthe drug through animal or human skin, nail, hair, claw or hoof using a diffusion cell apparatus. A diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Pénétration, 10 J of Controlled Release, 1 (1984) pp. 161-162. The term perméation enhancer or pénétration enhancer intends an agent or a mixture of agents, which, alone or in combination, act to increase the permeability of the skin, nail, hair or hoof to a drug.
The term transdermal delivery refers to the diffusion of an agent across the barrier of the skin, nail, hair, claw or hoof resulting from topical administration or other application of a 15 composition. The stratum corneum acts as a barrier and few pharmaceutical agents are able to penetrate intact skin. In contrast, the epidermis and dermis are permeable to many solutés and absorption of drugs therefore occurs more readily through skin, nail, hair, claw or hoof that is abraded or otherwise stripped ofthe stratum corneum to expose the epidermis. Transdermal delivery includes injection or other delivery through any portion of the skin, nail, hair, claw or 20 hoof or mucous membrane and absorption or perméation through the remaining portion.
Absorption through intact skin, nail, hair, claw or hoof can be enhanced by placing the active agent in an appropriate pharmaceutically acceptable vehicle before application to the skin, nail, hair, claw or hoof. Passive topical administration may consist of applying the active agent directly to the treatment site in combination with émollients or pénétration enhancers. As used 25 herein, transdermal delivery is intended to include delivery by perméation through or past the integument, i.e. skin, nail, hair, claw or hoof.
Powders and sprays can contain, in addition to the compounds of this invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as 30 chlorofluorohydrocarbons.
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 inert pharmaceutically acceptable carrier such as sodium citrate or calcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stéarate, magnésium stéarate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard10 filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be 15 of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Liquid dosage forms for oral administration include pharrnaceutically acceptable émulsions, microemulsions, solutions, suspensions, syrups and élixirs. In addition to the active 20 compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, 25 polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
The term parenterally, as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection 30 and infusion. Pharmaceutical compositions of this invention for parentéral injection comprise pharrnaceutically acceptable stérile aqueous or nonaqueous solutions, dispersions, suspensions or émulsions and stérile powders for reconstitution into stérile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, éthanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
Injectable depot forms are made by forming microencapsulated matrices of the drug in biodégradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodégradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of stérile solid compositions which can be dissolved or dispersed in stérile water or other stérile injectable medium just prior to use.
Injectable préparations, for example, stérile injectable aqueous or oleaginous suspensions may be formulated using suitable dispersing or wetting agents and suspending agents. The stérile injectable préparation may also be a stérile injectable solution, suspension or émulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1,3butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonie sodium chloride solution. In addition, stérile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the préparation of injectables.
Pharmaceutical compositions, or formulations, for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient température but liquid at body température and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds ofthe présent invention may also be administered in the form of liposomes. Liposomes are generally derived from phospholipids or other lipid substances and are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The présent compositions in liposome form may contain, in addition to the compounds of the présent invention, stabilizers, preservatives, and the like. The preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academie Press, New York, N. Y., (1976), p 33 etseq.
Pharmaceutical compositions, or formulations, of the présent invention may also contain 5 adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prévention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phénol, sorbic acid, and the like. It may also be désirable to include isotonie agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by 10 the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
The pharmaceutical compositions, or formulations, of the invention may be suspensions. Suspensions, in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and 15 mixtures thereof.
Actual dosage levels of active ingrédients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will dépend upon the activity of the particular 20 compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The total daily dose of the compounds of this invention administered to a human or lower 25 animal may range from about 0.0001 to about 15 mg/kg/day. For purposes of oral administration, more préférable doses can be in the range of from about 0.01 to about 5 mg/kg/day. For topical administration, more préférable doses can be in the range of 0.001 mg/kg/day to about 5 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
The pharmaceutical compositions also include solvatés and hydrates of the compounds of the présent invention. The term “solvaté” refers to a molecular complex of a compound represented by Formula (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), including pharmaceutically acceptable salts or hydrates thereof, with one or more solvent molécules. Such solvent molécules are those commonly used in the pharmaceutical art, which are known to be innocuous to the récipient, e.g., water, éthanol, ethylene glycol, (S)-propylene glycol, (R)propylene glycol, and the like, The term “hydrate” refers to the complex where the solvent molécule is water. The solvatés and/or hydrates preferably exist in crystalline form. Other solvents may be used as intermediate solvatés in the préparation of more désirable solvatés. Intermediate solvents include, but are not limited to, méthanol, methyl t-butyl ether, ethyl acetate, methyl acetate, 1,4-butyne-diol, and the like.
Compounds ofthe présent invention may exist in more than one crystal form. Polymorphs of compounds of Formulae (IA), (IB), (ΙΙΑ), (IIB), (IIIA), or (111B), and salts thereof (including solvatés and hydrates) form part of this invention and may be prepared by crystallization of a compound ofthe présent invention under different conditions. For example, using different solvents or different solvent mixtures for recrystallization; crystallization at different températures; various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting a compound of the présent invention followed by graduai or fast cooling. The presence of polymorphs may be determined by solid probe nuclear magnetic résonance (NMR) spectroscopy, infrared (IR) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
This invention also includes isotopically-labeled compounds, which are identical to those described by Formula (IA), (IB), (ΙΙΑ), (IIB), (ΙΙΙΑ), and (IIIB) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur and fluorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 170,35S, 36CI, 125l, 129l, and 18F respectively. Certain isotopically-labeled compounds ofthe présent invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., 3H), and carbon-14 (i.e., 14C), isotopes are particularly preferred for their ease of préparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the présent invention can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
In particular, the présent invention includes deuterated compounds of Formula (IA), (IB), (IIA), (IIB), (IIIA), and (1IIB). Any ofthe hydrogens contained on the compounds ofthe présent invention may be exchanged for deuterium including the pyridine hydrogens as shown below.
Représentative examples of deuterated compounds ofthe présent invention include, but are not limited to, Examples 39 and 40.
AH ofthe recited U.S. patents and publications (including ail technical bulletins referenced in the Examples) are incorporated herein by reference in their entireties.
The compounds of the présent invention, or their pharmaceutically acceptable salts or hydrates thereof, may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books including Compendium of Organic Synthetic Methods, Vol. I-VI, published by Wiley-lnterscience). Preferred methods include, but are not limited to, those described below.
During any of the following synthetic sequences it may be necessary and/or désirable to protect sensitive or reactive groups on any ofthe molécules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991, and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.
Compounds of the présent invention may be prepared as a single enantiomer or as a mixture of individual enantiomers which includes racemic mixtures. Methods to obtain preferentially a single enantiomer from a mixture of individual enantiomers or a racemic mixture are well known to those ordinarily skilled in the art of organic chemistry. Such methods include but are not limited to preferential crystallization of diastereomeric salts (e.g. tartrate or camphor sulfonate), covalent derivatization by a chiral, non-racemic reagent followed by séparation of the resulting diastereomers by common methods (e.g. crystallization, chromatographie séparation, or distillation) and Chemical reversion to scalemic compound, or high/medium-pressure liquid chromatography or supercritical fluid chromatography employing a chiral stationary phase. These techniques may be performed on the final compounds ofthe invention or on any intermediates to compounds ofthe invention which bear a stereogenic center. Also, to facilitate séparation by any ofthe methods described above, the compounds ofthe invention or any intermediates to the compounds of the invention which bear a stereogenic center may be transiently reacted with an achiral reagent, separated, and then reverted to scalemic compound by standard synthetic techniques.
Stereoisomers are designated (R) or (S), depending on the configuration of substituents around the chiral carbon atom. The terms (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30. In particular, the stereochemistry atthe point of attachment ofthe variables “A” and “B”
H B
A of Formulae (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB) may independently be either (R) or (S). The enantiomers of the présent invention indicated by (R), (S), or * are substantially free of the other enantiomer. “Substantially free” means that the enantiomeric excess is greater than about 90%, preferably greater than about 95%, and more preferably greater than about 99%. Within the context of enantiomeric excess, the term “about” means ±1.0%. The symbol * désignâtes a chiral carbon atom as either (R) or (S) stereochemistry depending on the configuration of substituents around the chiral carbon atom.
Compounds of the présent invention not designated (R), (S), or * may exist as racemates (i.e. 50% (R) and 50% (S)) or as a mixture oftwo enantiomers wherein one enantiomer is in excess. For example, enantiomeric mixtures may include the (R) enantiomer in 51% and the (S) enantiomer in 49% or vice versa or any combination of (R) and (S) other than the racemic mixture of 50% (R) and 50% (S). The présent invention includes racemates and enantiomeric mixtures of the compounds of the présent invention.
Compounds ofthe présent invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit séparation of different conformers. The compounds ofthe présent invention further include each conformational isomer of compounds of Formula (IA), (IB), (ΙΙΑ),(ΙΙΒ), (IIIA), (IIIB), and mixtures thereof.
Tautomers may exist in the compounds of the présent invention and are specifically included within the scope ofthe présent invention. The term tautomer, as used herein, means a proton shift from one atom of a molécule to another atom of the same molécule wherein two or more structurally distinct compounds are in equilibrium with each other. Compounds of the présent invention may exist as tautomers. The présent invention contemplâtes tautomers due to proton shifts from one atom to another atom of the same molécule generating two or more distinct compounds that are in equilibrium with each other. In particular, the bis(amino)cyclobut3-ene-1,2-dione moiety contained within the compounds ofthe présent invention may tautomerize as shown below and are included within the scope ofthe présent invention.
HO\ /P O. z° θχ z0H
M s — v — w
-^-1Hn4 -j-NZ Hn4~
Compounds ofthe présent invention or their pharmaceutically acceptable salts, can be prepared according to the reaction Schemes and Examples disclosed herein below. Unless otherwise indicated, Ri, R2, Ra, R4, Rs, Re, R7, Rs, Rg, m, n, A, B, X, Ra, Rb and Rc in the Schemes are as defined in Formulae (IA) and (IB) ofthe Summary section above. It will be understood by one skilled in the art that the various symbols, superscripts and subscripts used in the schemes, methods and examples are used for convenience of représentation and/or to reflect the order in which they are introduced in the schemes, and are not intended to necessarily correspond to the symbols, superscripts or subscripts in the appended daims. The schemes are représentative of methods useful in synthesizing the compounds of the présent invention. They are not to constrain the scope of the invention in any way. Isolation and purification of the products are accomplished by standard procedures known to one of ordinary skill in the art.
Scheme A
A-1
A-5
Compounds of Formula (IA) and (IB) can be prepared as described in Scheme A.
Nucleophilic aromatic substitution between an amino pyridine A-1 (prepared as described in 5 Scheme B) and commercially available 3,4-diethoxycyclobut-3-ene-1,2-dione (A-2) affords compounds of Formula A-3. A second nucleophilic aromatic substitution between A-3 and an amine A-4 (prepared as described in Schemes C-G) affords compounds of Formula A-5.
Scheme B
B-1
r2
R2
B-3
I B-4 R = NHBoc
L— B-5 R = NH2
Compounds of formula A-1 employed in Scheme A can be prepared as described in
Scheme B. Amidation between commercially available 4-chloro-3-methoxypicolinoyl çhloride (B-1) and a commercially available amine B-2 under basic conditions provides compounds of Formula B-3. Buchwald coupling between B-3 and tert-butyl carbamate affords compounds of Formula B-4, which can be subjected to acidic conditions to remove the Boc group and provide compounds of Formula B-5. Déméthylation of B-5 leads to compounds of Formula A-1.
Scheme C
I--- C-1 R = CN
L-- C-2 R = CHO
X = Br, I
C-4
C-6
A-4
Compounds of Formula A-4 employed in Scheme A where the amines are enantiomerically enriched can be prepared as described in Scheme C. Titanium (IV) ethoxidemediated condensation of an aldéhyde C-2 (either commercially available or obtained via réduction of the corresponding nitrile C-1 commercially available or prepared from methods known in the art) with (S)-2-methylpropane-2-sulfinamide (C-3) provides compounds of Formula C-4. Metalation of heteroaryl halides C-5 where X is iodine or bromine provides a highly diastereoselective addition to C-4 to afford sulfonamides of Formula C-6 as the major diastereomer. Subséquent removal of the chiral auxiliary under acidic conditions leads to compounds of Formula A-4. The absolute stereochemistry of amines A-4 can be established by methods known to those skilled in the art including Mosher’s amide analysis and single crystal X-ray crystallography, or derived by analogy to known compounds.
Scheme D
C-5 X. O A o NH2
R^B aX A^ B
I--- D-1 R = OH D-3 A-4
V D-2 R = NMeOMe
Compounds of Formula A-4 employed in Scheme A where the amines are either racemic mixtures or diastereomeric mixtures can be prepared as described in Scheme D. Carboxylic acids of the formula D-1 (either commercially available or prepared as described herein below) can be converted to the corresponding Weinreb amide D-2 by HATU-mediated condensation with methoxy methylamine. Metalation of heteroaryl halides C-5 where X is iodine or bromine followed by reaction with D-2 affords ketones of Formula D-3. Reductive amination of D-3 with ammonia in methanol affords compounds of Formula A-4 as a racemic or diastereomeric mixture.
Scheme E o
R4
E-1
X
Alternative^, compounds of Formula A-4 where the Formula (IA) or (IB) variable A is defined as a substituted pyrazole can be prepared from 3-halo-1-alkylpyrazoles E-1 (R4 = alkyl and X = Bromo or lodo) as described in Scheme E. Metalation of E-1 and its addition to either sulfinamine C-4 or Weinreb amide D-2 affords addition products of Formula E-2 or E-4, respectively. Installation of the R5 substituent can be accomplished by either electrophilic aromatic substitution or by the reaction with NIS and then a metal-mediated cross-coupling reaction 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 compounds of Formula A-4. Reductive amination of E-5 with ammonia in methanol affords compounds of Formula A-4.
Scheme F
C-5
O^R
I--- F-1 R = OH
F-2 R = NMeOMe
F-3 F-4 A-4
Compounds of Formula A-4 employed in Scheme A where the Formula (IA) or (IB) variable B is defined as 5-methylspiro[2,3]hexan-5-yl can be prepared as described in Scheme F. 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 methoxy methylamine. Metalation of heteroaryl halides C-5 where X is iodine or bromine followed by reaction with F-2 affords ketones of the Formula F-3. Subséquent alkylation of F-3 employing an alkyl halide (such as iodomethane or iodoethane) and a suitable base followed by reductive amination using ammonia in methanol affords compounds of the Formula A-4 as a racemic mixture.
Scheme G
I G-1 X = OH G-3 G-4
L-- G-2 X = NMeOMe
Compounds of Formula A-4 employed in Scheme A where the Formula (IA) or (IB) variable A is defined as a 2,5-disubstituted oxazole can be prepared as described in Scheme G.
Carboxylic acids of Formula G-1, commercially available or prepared from methods known in the art, can be condensed with methoxy methylamine in the presence of HATU to provide Weinreb amides of Formula G-2. Compound G-2 can be reacted with a Grignard reagent (such as isopropyl magnésium bromide or cyclopentyl magnésium bromide) to provide ketones of Formula G-3 where R and R' are methyl or R and R' taken together with the carbon atom that they are attached to form a C3.5cycloalkane ring. Subséquent alkylation of G-3 employing an alkyl halide (such as iodomethane or iodoethane) and a suitable base followed by reductive amination using ammonia in methanol affords compounds of Formula A-4 as a racemic mixture.
Scheme H
The spécifie carboxylic acid D-1 employed in Scheme D where the Formula (IA) or (IB) variable B is defined as (S) or (R)-4,4-difluoro-2-methyltetrahydrofuran-2-yl can be prepared as described in Scheme H. Titanium (IV) chloride-mediated allylation of commercially available ethyl 2-oxopropanoate (H-1) with allyltrimethylsilane gives ethyl 2-hydroxy-2-methylpent-4enoate (H-2). Epoxidation of the terminal alkene of H-2 using 3-chloroperbenzoic acid followed by magnésium bromide-mediated intramolecular cyclization provides ethyl 4-hydroxy-2methyltetrahydrofuran-2-carboxylate (H-4). Subséquent oxidation ofthe secondary alcohol using pyridinium chlorochromate followed by fluorination using diethylaminosulfur trifluoride affords ethyl 4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate (H-6). Ester H-6 was transesterified to the benzyl ester H-7 which was then resolved using chiral HPLC. Subséquent saponification of the ester affords the individual enantiomers H-8 which can be employed in Scheme D. The absolute stereochemistry of H-8 was established by single crystal X-ray crystallography (see Figure 3).
Scheme I
1-1
I-2
C-5
1,4-Disubstituted-3-iodopyrazoles that can be employed in the synthetic méthodologies described in Schemes C, D, and F can be prepared as described in Scheme I. lodination of commercially available 4-substituted pyrazoles (1-1) using NIS provides compounds of Formula I-2. Subséquent N-alkylation of I-2 with alkyl halides (e.g. iodomethane, iodoethane) followed by séparation of the regioisomers by chromatography affords compounds of Formula C-5 that can be used in the synthetic méthodologies described in the above schemes.
Scheme J
Y
J-1 Y = nh2
J-2 Y = H
Alternative^, 1,4-disubstituted-3-iodopyrazoIes that can be employed in the synthetic méthodologies described in Schemes C, D, and F can be prepared as described in Scheme J. 1,4-Disubstituted-3-aminopyrazoles (J-1) may be converted to compounds of Formula C-5 through the Sandmeyer reaction employing sodium nitrite and potassium iodide. Compounds of Formula C-5 can also be prepared via direct iodination of commercially available 1,4disubstituted pyrazoles J-2 using NIS.
Scheme K
i
OHC
I
r4
K-1
K-2
K-3
100
In another variation, 1,4-disubstituted 3-iodopyrazoles employed in Scheme C-D and Scheme F can be prepared as described in Scheme K, specifically were FU = Rs = methyl. 3lodo-1 -methyl-1H pyrazole, K-1 can be formylated regioselectively with Vilsmeier reagent to give 3-iodo-1-methyl-1/7-pyrazole-4-carbaldehyde (K-2), which in turn can be reduced (TFA, 5 triethylsilane) to give 3-iodo-1,4-dimethyl-1/7-pyrazole, K-3.
Scheme L
L-1
C-5
2,5-Disubstituted 4-bromothiazoles employed in Scheme C-D and Scheme F can be prepared as described in Scheme L. Bromination of commercially available 2,5-disubstituted thiazoles L-1 using NBS affords compounds ofthe Formula C-5.
Scheme M
M-5 |-- M-6 R= CH3
I— A-5 R = H
Alternatively, compounds of Formula (IA) and (IB) may be prepared as described in Scheme M. Estérification of commercially available 4-chloro-3-methoxypicolinoyl chloride (B-1 ) 15 under basic conditions provides tert-butyl 4-chloro-3-methoxypicolinate (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 amines A-4 leads to compounds M-4. Ester hydrolysis under acidic conditions followed by HATU-mediated amidation with amines B-2 and O-demethylation using magnésium bromide affords compounds ofthe formula A-5.
101
Scheme N
I-- N-1 R = CH2OP(O)(OtBu)2
L— N-2 R = CH2OP(O)(OH)2
A-5
Compounds of Formula (IA) and (IB) where R3 is -CH2OP(O)(OH)2 may be prepared as described in Scheme N. Alkylation of compounds of the formula A-5 with commercially available di-tert-butyl (chloromethyl) phosphate under basic conditions provides N-1. Subséquent cleavage of tert-butyl ester protecting groups under acid or neutral conditions leads to compound N-2.
Examples
The présent invention will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the présent invention, and are not intended to limit the invention. The following illustrate the synthesis of various compounds ofthe présent invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these
Examples and schemes, either alone or in combination with techniques generally known in the art.
Experiments were generally carried out under inert atmosphère (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were employed. Commercial solvents and reagents were generally used without further purification, 20 including anhydrous solvents where appropriate. Mass spectrometry data is reported from either liquid chromatography-mass spectrometry (LCMS), atmospheric pressure Chemical ionization (APCI) or gas chromatography-mass spectrometry (GCMS) instrumentation. Chemical shifts for nuclear magnetic résonance (NMR) data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents employed. Coupling constants (J values) are reported in Hertz. For synthèses referencing procedures in other Examples, reaction conditions (length of reaction and température) may vary. In general, reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate.
Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluants/gradients were chosen to provide appropriate Rf's or rétention times (RetT).
102
Compounds of the présent invention were named by Chemdraw Professional version 16.0 or were given names which appeared to be consistent with Chemdraw nomenclature.
The following abbreviations are used herein: DCM: dichloromethane; DAST: (diethylamino)sulfur trifluoride; DEA, diethylamine; DIPEA: diisopropylethylamine; DMF:
dimethylformamide; EtOAc: ethyl acetate; EtOH: éthanol; HATU: 1[bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; IPA: isopropyl alcohol; HPLC: high pressure liquid chromatography; LHMDS: lithium hexamethyldisilazide; MeOH: methanol; MTBE: methyl tert-butyl ether; NMM: Nmethylmorpholine; NIS: N-iodosuccinimide; PCC: pyridinium chlorochromate; PE: petroleum ether; SFC: super-critical fluid chromatography; TBAI: tetrabutyl ammonium iodide; TEA: triethylamine; TFA: trifluoroacetic acid; and THF: tetrahydrofuran.
The following SFC methods hâve been employed. SFC method A: Chiral Tech OD-H 250 mm x 4.6 mm x 5 pm, 5 to 60% 0.2% NH4 + (7 N in MeOH) in EtOH, 3.0 mL/min. SFC method B: Chiralpak AD-3 50 mm x 3 mm x 3 pm, 5 to 40% 0.05% DEA in EtOH, 2.5 mL/min,
40 °C. SFC method C: Chiralcel OD 250 mm x 4.6 mm x 5 pm, 5 to 60% 0.2% NH4+ (7 M in
MeOH) in EtOH, 3.0 mL/min. SFC method D: Chiralpak AD-3 150 mm x 4.6 mm x 3 pm, 5 to 40% 0.05% DEA in EtOH, 2.5 mL/min, 40 °C. SFC method E: Chiralcel OJ-H 150 mm x 4.6 mm x 5 pm, 5 to 40% 0.05% DEA in EtOH, 2.5 mL/min, 40 °C. SFC method F: Chiralcel OD-3 100 mm x 4.6 mm x 3 pm, 5 to 40% 0.05% DEA in EtOH, 2.8 mL/min, 40 °C. SFC method G:
Chiralpak AD-3 150 mm x 4.6 mm x 3 pm, 5 to 40% 0.05% DEA in IPA, 2.5 mL/min, 40 °C.
SFC method H: Chiralcel OD-3 150 x 4.6 mm I.D. 3 pm, 5 to 40% 0.05% DEA in EtOH, 2.5 mL/min, 40 °C). SFC method I: REGIS (s,s) WHELK-01 250 mm x 30 mm x 5 pm 40% 0.05% DEA in EtOH, 2.5 mL/min, 35 °C. SFC method J: Chiralpak AS-3 150 x 4.6 mm x 3 pm, 5 to 40% 0.05% DEA in EtOH, 2.5 mL/min, 35 °C. SFC method K: Chiralpak AS-3 100 x 4.6 mm x 3 pm, 5 to 40% 0.05% DEA in EtOH, 2.8 mL/min, 40 °C. SFC method L. Lux Amylose W-1,250 mm x 4.6 mm, 5 pm, 5 to 60% 0.2% NH3 in EtOH, 3 mL/min. SFC method M. Lux Cellulose, 150 mm x 4.6 mm, 3 pm, 5 to 40% MeOH, 2 mL/min. SFC method N: Chiralpak AD-3 150 mm x 4.6 mm x 3 pm, 5 to 40% 0.1% ethanolamine in EtOH, 2.5 mL/min.
The following HPLC methods hâve been employed. HPLC method A: Chiralcel OD-RH, 30 150 mm x 4.6 mm x 5 pm, 10 to 80% MeCN in 0.069% TFA in H2O, 0.8 mL/min, 30 °C. HPLC method B: Chiralpak AS-RH, 150 mm x 4.6 mm x 5 pm, 10 to 80% MeCN in 0.069% TFA in H2O, 0.8 mL/min, 30 °C.
103
Example 1 (/7)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1 -en-1 -yl)amino)-3-hydroxy-/\/,/\/-dimethylpicormamide
Step 1A. 1-Methylcyclopentane-1-carbonitrile
To a solution of LHMDS (280 mL, 280 mmol, 1 M solution in THF) at -70 °C was added dropwise a solution of cyclopentanecarbonitrile (26.67 g, 280.3 mmol) in THF (20 mL) over 15 min. After stirring for 30 min, iodomethane (59.7 g, 26.2 mL, 420 mmol) was added dropwise, and the reaction was allowed to warm to ambient température and stirred for 16 h. The resulting yellow solution was cooled to 0 °C and quenched with saturated aqueous NH4CI solution (200 mL) and water (100 mL). The mixture was extracted with MTBE (2.5 L x 2), and the combined organic extracts were washed with brine (1 L), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The crude product was purified twice using silica gel column chromatography (100% petroleum ether) to afford 60 g (65%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCI3) δ 2.20-2.10 (m, 2H), 1.90-1.70 (m, 4H), 1.65-1.55 (m, 2H), 1.41 (s, 3H).
Step 1B. 1-Methylcyclopentane-1-carbaldehyde
To a solution of DIBAL-H (824 mL, 824 mmol, 1 M in toluene) at -65 °C was added dropwise a solution of 1-methylcyclopentane-1-carbonitrile (30 g, 275 mmol) in DCM (30 mL). The mixture was stirred at the same température for 30 min. The reaction was quenched with saturated aqueous NH4CI solution (1 L) at -40 °C and stirred vigorously at 25 °C for 10 min. The mixture was diluted with DCM (1 L), and then filtered and the solids were washed with DCM (500 mL x 3). The combined filtrate was washed with brine (1 L), dried over Na2SO4, filtered and concentrated in vacuo 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. 1H NMR (400 MHz, CDCI3)ô 9.59 (s, 1H), 2.15-2.01 (m, 2H), 1.80-1.75 (m, 4H), 1.55-1.45 (m, 2H), 1.25 (s, 3H).
104
Step 1 C. (S,E)-2-Methyl-A/-((1 -methylcyclopentyl)methylene)propane-2-sulfinamide To a solution of 1-methylcyclopentane-1-carbaldehyde (30.8 g, 275 mmol) in DCM/toluene (3/2, 2.0 L) at 20 °C was added titanium (IV) ethoxide (163 g, 717 mmol). The reaction was stirred for 20 min, and then (S)-2-methylpropane-2-sulfinamide (33.3 g, 275 mmol) 5 was added. The resulting mixture was stirred at ambient température for 16 h. The reaction was quenched with water (250 mL). The mixture was filtered and the solids were washed with THF (3 L x 3). The combined organic layers were concentrated in vacuo. The crude product was purified by silica gel column chromatography (100% petroleum ether) to afford 44.89 g (38%) of the title compound as a light yellow oil. LCMS m/z 216.3 [M+H]+. 1H NMR (400 MHz, 10 CDCI3) δ 7.94 (s, 1 H), 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).
Step 1D. 3-lodo-1,4-dimethyl-1/-/-pyrazole Route A
3-lodo-1,4-dimethyl-1H-pyrazole. To a solution of 1 A-dimethyl-IH-pyrazol-S-amine (1.0 g, 8.6 mmol) in conc. HCl (7.15 mL) at 0 °C was added a solution of sodium nitrite (1.22 g, 17 mmol) in water (1.78 mL) over 5 min. A solution of potassium iodide (3.57 g, 21.5 mmol) in water (3.6 mL) was then added dropwise over 5 min. The mixture was stirred at 0 °C for 30 min, and then warmed to ambient température and stirred for 2 h. The reaction mixture was 20 diluted with THF (8 mL) and water (8 mL), and extracted with EtOAc (30 mL x 4). The combined organic extracts were washed with saturated aqueous Na2S2O3 solution (30 mL x 2) followed by water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0 to 60% EtOAc in heptane) to afford 988 mg (52%) of the title compound as a white solid. LCMS m/z 223.0 25 [M+H]+. 4H NMR (400 MHz, CDCI3) δ 7.05 (s, 1 H), 3.87 (s, 3H), 1.98 (s, 3H).
Route B
Stepl. 3-lodo-1-methyl-1/-/-pyrazole-4-carbaldehyde. POCI3 (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 30 °C. After 10 min, the reaction was heated to 65 °C for 18 h. A solution of NaH2PO4 (50 g in 200 mL) was added to the reaction slowly, ensuring the température remained between 25-35 °C and pH no greater than 4. After the addition, the reaction was stirred at room température for 45 min and then made basic by careful addition of saturated Na2CO3. The aqueous mixture was extracted with EtOAc. The organic layer was washed with brine, dried and filtered. The
105 filtrate was concentrated. The resulting yellow oil was recrystallized from EtOAc/heptane to provided 28.4 g (88%) ofthe title compound as a tan solid. 1H NMR (400 MHz, CDCF) δ 9.67 (s, 1H), 7.84 (s, 1H), 4.00 (s, 4H).
Step 2. 3-lodo-1,4-dimethyl-1/-/-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-1/-/-pyrazole-4-carbaldehyde (1.0 g, 0.042 mmol) in chlorobenzene (10 mL). The mixture was heated to 50 °C overnight. The reaction mixture was cooled to room température and saturated aqueous 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 afford 0.64 g (68%) ofthe title compound. 1H NMR (400 MHz, CDCI3) δ 7.08 (s, 1H), 3.90 (s, 3H), 2.01 (s, 3H).
Route C
Step 1: 3-lodo-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 température below 25 °C. The mixture was stirred at 25 °C for 20 h. Two batches were combined. The combined mixtures were poured into water (20 L) and then extracted with MTBE (5 L x 5). The combined organic layers were washed with brine (5 L x 3), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was triturated 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 in vacuo to afford 1280.0 g (32%) ofthe title compound as a light yellow solid. 1H NMR (CDCI3, 400 MHz) δ 7.42 (s, 1 H), 2.07 (s, 3H).
Step 2. 3-iodo-1,4-dimethyl-1H-pyrazole. To a suspension of 60% NaH in minerai oil (165.0 g, 4.12 mol) in anhydrous THF (4.5 L) was added a mixture of 3-iodo-4-methyl-1/-/pyrazole (710.0 g, 3.41 mol) in anhydrous THF (1.5 L) dropwise at 0 °C. The mixture was stirred at 10 °C for 1 h. lodomethane (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 reaction was quenched with water (4.5 L) and extracted with EtOAc (2.5 L x 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give 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
106 dried in vacuo to give 100.0 g of the title compound as a white solid. The filtrate was concentrated in vacuo, combined with the second fraction (1300 g), and purified by silica gel column chromatography (petroleum ether: EtOAc = 10: 1 to 1:1) to afford additional desired compound (500.0 g). This compound was diluted with petroleum ether (800 mL) and stirred at 5 10 °C for 30 min. The suspension was filtered. The filter cake washed with petroleum ether (500 mL) and dried in vacuo 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]+. 1H NMR (CDCI3, 400 MHz) δ 7.04 (s, 1 H), 3.86 (s, 3H), 1.97 (s, 3 H).
Step 1E. (S)-N-((F?)-(1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2methylpropane-2-sulfinamide
3-lodo-1,4-dimethyl-1H-pyrazole (33 g, 148.6 mmol) in THF (50 mL) was added over 1 h to a solution of 1.0 M iPrMgCI-UCI in THF (189 mL, 189 mmol) maintaining an internai température at 0-5 °C under nitrogen. After 1 h, (S,q-2-methyl-N-((1-methylcyclopentyl)15 methylene)propane-2-sulfinamide (20 g, 92.85 mmol) in THF (50 mL) was added and the mixture stirred at 25 °C for 18 h. The reaction was cooled to 0 °C and 10% acetic acid was added. The organic layer was seperated and was partially concentrated. MTBE and water were added. The mixture was stirred for 10 min and the layers separated. The organic layer was concentrated to afford the title compound (66% purity) which was used in the subséquent 20 step without further purification.
Step 1 F. (/7)-(1,4-Dimethyl-1/7-pyrazol-3-yl)(1 -methylcyclopentyl)methanamine
The crude ,4-dimethyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)-2methylpropane-2-sulfinamide (231 g) was suspended in MTBE (300 mL), cooled to 10 °C, and 25 conc. HCl (38.4 mL, 2 eq) was added. The mixture was stirred at 10-20 °C for 1 h and then was diluted with water (300 mL). The layers were separated and the organic layer discarded. The aqueous layer was made basic with 20% NaOH to pH 11 -13 and extracted with MTBE (2 x 300 mL). The combined organic layers were concentrated to afford 120 g of the title compound as an oil. The absolute stereochemistry of the title compound was assigned based on the open 30 transition State analysis as described in the literature (Robak, Μ. T.; Herbage, M. A. Ellman, J.
A. Chem. Rev. 2010, 110, 3600) and confirmed definitively by Mosher’s amide analysis.
Step 1G. (F?)-(1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methanamine L-pyroglutamic acid sait
107
L-pyroglutamic acid (77.7 g, 0.6 mol) was added to a solution of (/7)-(1,4-dimethyl-1/7pyrazol-3-yl)(1-methylcyclopentyl)methanamine (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, then cooled to 25 °C over 18 h. The solid was filtered and rinsed with THF (890 mL). The solid was dried under vacuum at 45 °C for 6 h to afford 259.6 g (88%) of the title compound. 1H NMR (400 MHz, DMSO-de) δ 7.58 (br. s., 1 H), 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, 1 H), 1.70-1.48 (m, 6H), 1.42-1.31 (m, 1 H), 1.08-1.02 (m, 1 H), 0.97 (s, 3H). Chiral SFC (SFC method M) RT = 3.81 min, 99% ee.
Step 1 H. 4-((2-Ethoxy-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide 4-((2-Ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide was prepared as described in WO/2010/131145.
Step 11. (/7)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethy!picolinamide
A mixture of 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/Vdimethylpicolinamide (180 g, 590 mmol), (/7)-(1,4-dimethyl-1 /7-pyrazol-3-yl)(1 methylcyclopentyl)methanamine L-pyroglutamic acid sait (209 g, 625 mmol), EtOH (1L) and DIPEA (205 mL, 1180 mmol) was stirred at 20-30 °C for 2h. HOAc (23.8 mL, 416 mmol) was added to adjust the pH to 6-7. The reaction mixture was then concentrated under reduced pressure to about half the volume. The mixture was diluted with water (3.2 L) and stirred for 1.5 hr. 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]+. Ή NMR (400 MHz, DMSO-de) δ 11.59 (br. s., 1H), 9.92 (br. s., 1H), 9.16 (s, 1H), 8.038.00 (m, 2H), 7.43 (s, 1H), 5.33 (d, J = 10.0 Hz, 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]2% = -78.4 (c = 1.0, MeOH). Chiral SFC (SFC method N) RT = 4.77 min, 98.5% ee. The absolute configuration was established by single crystal X-ray analysis (Figure 1).
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Example 2 (S)-4-((2-(((1,4-Dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1 -en-1 -yl)amino)-3-hydroxy-N,/V-dimethylpicolinamide
The title compound was prepared analogous to Example 1 employing (R)-2methylpropane-2-sulfinamide. LCMS m/z 467.4 [M+H]+. 1H NMR (400 MHz, DMSO-ds) δ 9.18 (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, 1 H), 1.23-1.15 (m, 1H), 1.08 (s, 3H). [a]29 D = + 88.49 (c = 0.5, MeOH). Chiral SFC (SFC method F) RT = 5.45 min, 100% ee.
Example 3 (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1 -en-i -y|)amino)-3-hydroxy-/V-isopropyl-/\/-methylpicolinamide
Step 3A. 4-Chloro-3-methoxypicolinoyl chloride
To a solution of 4-chloro-3-methoxypicolinic acid (5.0 g, 30 mmol) in DCM (59 mL) at 0 °C was added dropwise oxalyl chloride (8.46 g, 5.71 mL, 66.6 mmol). The resulting mixture was warmed to ambient température and stirred for 2 h. The reaction was concentrated in vacuo to afford 5.49 g (100%) of the title compound as a light yellow solid. The crude was used directly in the next step without further purification. 1H NMR (400 MHz, CDCI3) δ 8.43 (d, J = 5.1 Hz, 1 H), 7.71-7.51 (m, 1 H), 4.01 (s, 3H).
Step 3B. 4-Chloro-/V-isopropyl-3-methoxy-/V-methylpicolinamide
To a solution of 4-chloro-3-methoxypicolinoyl chloride (175 g, 0.85 mol) in DCM (500 mL) was added Et3N (172 g, 1.7 mol) at 0 °C. A/-Methylpropan-2-amine (62 g, 0.85 mol) was
109 then added keeping the internai température 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 x 2). The combined organic extracts were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 153 g (74%) of the title compound as a brown oil. The crude product was used directly without further purification.
Step 3C. tert-Butyl (2-(isopropyl(methyl)carbamoyl)-3-methoxypyridin-4-yl)carbamate
To a solution of 4-chloro-A/-isopropyl-3-methoxy-A/-methylpicolinamide (153 g, 0.63 mol) in dioxane (1 L) was added NH2Boc (88.5 g, 0.76 mol) and K2CO3 (130 g, 0.95 mol). The mixture was sparged with N2 and Pd(OAc)2 (11.3 g, 0.05 mol) and xantphos (36.4 g, 0.063 mol) were added. The mixture was heated to 120 °C and stirred for 16 h. The reaction was cooled to 20 °C and filtered through Celite. The filtrate was concentrated in vacuo. The residue was partisioned between EtOAc (500 mL) and water (500 mL). The organic layer was separated and washed with brine (500 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (50 to 66% EtOAc in petroleum ether) to afford 160 g (78%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCI3) δ 8.24-8.20 (m, 1 H), 8.07-8.04 (m, 1 H), 7.24 (s, 1 H), 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).
Step 3D. 4-Amino-A/-isopropyl-3-methoxy-A/-methylpicolinamide To a solution of tert-butyl (2-(isopropyl(methyl)carbamoyl)-3-methoxypyridin-4yl)carbamate (160 g, 0.50 mol) in EtOAc (320 mL) was added HCl/EtOAc (4.0 M, 750 mL). The mixture was stirred at 20 °C for 4 h. The reaction was concentrated in vacuo to afford 150 g (>100%) of the title compound as a brown solid. The crude was used directly without further purification.
Step 3E. 4-Amino-3-hydroxy-A/-isopropyl-N-methylpicolinamide
To a solution of 4-amino-A/-isopropyl-3-methoxy-A/-methylpicolinamide (150 g, 0.67 mol) in DCM (1.5 L) was added TBAI (168 g, 0.47 mol). The mixture was cooled to 0 °C and a solution of BBr3 (420 g, 1.68 mol) in DCM (500 mL) was added dropwise keeping the internai température below 10 °C. The reaction was stirred at 20 °C for 16 h. The reaction was quenched with saturated aqueous NaHCO3 solution (2.5 L) and adjusted pH to 6-7. The organic layer was separated and washed with water (500 mL). The combined aqueous layers
110 were back-extracted with DCM (1 L x 2). The combined organic extracts were concentrated in vacuo, and the residue was treated with DCM : MeOH = 10:1 (2 L) for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was treated with DCM : MeOH = 10:1 (600 mL) for 1 h, and the mixture was filtered. The filtrate was concentrated in vacuo to afford 140 g (99%) of the title compound as a pink solid. The crude was used directly without further purification.
Step 3F. 4-((2-Ethoxy-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-/\/-isopropyl-A/methylpicolinamide
To a solution of 4-amino-3-hydroxy-/V-isopropyl-A/-methylpicolinamide (140 g, 0.67 mol) in EtOH (1.4 L) was added DIPEA (147 g, 1.14 mol) and 3,4-diethoxycyclobut-3-ene-1,2-dione (159 g, 0.94 mol). The mixture was heated to 35 °C and stirred for 16 h. The reaction mixture was filtered and the filtrate was saved for later use. The filter cake was dissolved in water (500 mL) and adjusted pH to 6 with HCl (1.0 M aqueous solution), and extracted with DCM (500 mL x
2). The combined DCM extracts were washed with brine (1 L), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with MTBE (500 mL) for 2 h, and then filtered to afford 73 g (33%) of the title compound as a yellow solid. The mother liquor was combined with the filtrate isolated earlier and concentrated in vacuo. The residue was purified by silica gel column chromatography (25 to 50% EtOAc in petroleum ether) to afford additional 30 g (13%) of the title compound as a yellow solid. LCMS m/z 334.2 [M+H]+. 1H NMR (400 MHz, CDCh) δ 13.30 (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), 3.503.31 (m, 1,5H), 3.03-2.95 (m, 1.5H), 1.55-1.50 (m, 6H), 1.42-1.32 (m, 3H).
Step 3G. (S)-A/-((R)-(1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-225 methylpropane-2-sulfinamide
An oven-dried round bottom flask was charged with /-PrMgCI LiCI (67 mL, 87.1 mmol,
1.3 M solution in THF). The solution was cooled to 0 °C, and then a solution of 3-lodo-1,4dimethyl-1/-/-pyrazole (15.5 g, 69.7 mmol) in THF (90 mL) was added dropwise over 15 min via addition funnel. The reaction was warmed to ambient température and stirred for 1 h. The mixture was cooled back to 0 °C, and (S,E)-2-methyl-A/-((1 -methylcyclopentyl)methylene)propane-2-sulfinamide (Préparative step 1C) (10.0 g, 46.4 mmol) was added dropwise over 5 min. The mixture was warmed to ambient température and stirred for 18 h. The reaction mixture was poured slowly into a saturated aqueous NH4CI solution (300 mL) at 0 °C. The mixture was then extracted with EtOAc (350 mL x 2). The combined organic extracts were dried
111 over NasSÜA, filtered and concentrated in vacuo. The crude oil was taken up in MTBE (50 mL) and heptane (100 mL) to give a homogenous solution, which was concentrated in vacuo to give a solid. The solid was suspended in heptane (50 mL) and then concentrated in vacuo. This process was repeated twice, and the final suspension in heptane (50 mL) was cooled to 0 °C to 5 allow more solid to form. The suspension was filtered to afford 11.5g (80%) of the title compound as a white solid. LCMS m/z 312.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 4.37 (d, J = 6.5 Hz, 1H), 4.10 (d, J = 6.4 Hz, 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 = 1.8 Hz, 12H).
Step 3H. (/7)-(1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methanamine hydrochloride To a solution of (S)-/V-((/7)-(1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2methylpropane-2-sulfinamide (28.7 g, 92.14 mmol) in MeOH (150 mL) at 5 °C was added HCl (50 mL, 200 mmol, 4.0 M in 1,4-dioxane). After stirring for 3 h at 20 °C, the solution was concentrated in vacuo to afford the title compound as a mono-HCI sait assuming quantitative yield. The crude product was used directly without further purification. LCMS m/z 191.2 [MNH2]+. 1H NMR (400 MHz, CD3OD) δ 7.39 (s, 1H), 4.25 (s, 1H), 3.86 (s, 3H), 2.07 (s, 3H), 1.751.54 (m, 7H), 1.21-1.20 (m, 1H), 1.14 (s, 3H).
Step 3I. (/7)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methyIcyclopentyl)methyl)amino)-3,420 dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/-isopropyl-A/-methylpicolinamide
To a solution of (/7)-(1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methanamine hydrochloride (3.50 g, 14.36 mmol) in EtOH (50 mL) at 10 °C was added DIEA (3.10 g, 4.31 mL, 24.0 mmol). After stirring for 20 min, a yellow suspension of 4-((2-ethoxy-3,4-dioxocyclobut-1en-1-yl)amino)-3-hydroxy-/\/-isopropyl-/\/-methylpicolinamide (4.0 g, 12.0 mmol) in EtOH (100 mL) was added, and the resulting brown solution was stirred at the same température for 16 h. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography (80% to 100% EtOAc in petroleum ether). The crude product was azeotroped with EtOH (50 mL x 2), and the resulting yellow suspension was concentrated to ~30 mL. Additional EtOH (10 mL) was added and the suspension was stirred at 15°C for 20 min. The mixture was filtered and the filter cake was washed with EtOH (10 mL). The filter cake was collected and dried to afford 2.62 g (44%) ofthe title compound as a light yellow solid. LCMS m/z 495.5 [M+H]+. Ή NMR (400 MHz, DMSO-d6) δ 11.35 (s, 0.3H), 10.85 (s, 0.7H), 9.88 (s, 1H), 9.11 (d, J = 9.8 Hz, 1H), 8.05-7.90 (m, 2H), 7.43 (s, 1H), 5.33 (d, J = 10.0 Hz, 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,
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1H), 1.25-1.10 (m, 7H), 1.08 (s, 3Η).[α]2% = -49.8 (c = 0.26, MeOH). Chiral SFC conditions (SFC method D) RT = 4.62 min, 100% ee.
Example 4 (7)-4-((2-(((1,4-Dimethyl-17-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut
-en-1 -yl)amino)-A/-ethyl-3-hydroxy-A/-methylpicolinamide
Step 4A. 4-Chloro-/V-ethyl-3-methoxy-/V-methylpicolinamide N-Methylethanamine (138 g, 233 mmol) and triethylamine (32.3 mL, 233 mmol) were added to a solution of 4-chloro-3-methoxypicolinoyl chloride (Préparative Step 3A) (32 g, 155 mmol) in DCM (150 mL). The mixture was stirred at ambient température for 48 h and was then concentrated. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to afford 22 g (62%) of the title compound as a yellow oil. 1H NMR (400MHz, CDCI3) δ 8.25 (dd, J = 5.3, 6.8 Hz, 1H), 7.35 (d, J = 5.3 Hz, 1H), 3.94 (d, J = 1.8 Hz,
3H), 3.66-3.55 (m, 1 H), 3.23-3.12 (m, 1 H), 3.12-2.72 (m, 3H), 1.35-1.05 (m, 3H).
Step 4B. tert-Butyl (2-(ethyl(methyl)carbamoyl)-3-methoxypyridin-4-yl)carbamate To a solution of 4-chloro-/V-ethyl-3-methoxy-/V-methylpicolinamide (21.3 g, 93 mmol) in dioxane (120 mL) was added NH2Boc (21.8 g, 186 mmol) and K2CO3 (25.7 g, 186 mmol). The mixture was protected under N2 and Pd(OAc)2 (1.05 g, 4.7 mmol) and xantphos (2.7 g, 4.7 mmol) were added. The mixture was heated to 120 °C and stirred for 16 h. The reaction was cooled to 20 °C and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to afford 24 g (83%) ofthe title compound as a yellow solid. 1H NMR (400 MHz, CDCh) δ 8.25 (ddd, J = 5.5, 3.8, 0.6 Hz, 1 H), 8.09 (dd, J = 5.5, 1.6 Hz, 1 H), 7.26 (d, J = 5.6 Hz, 1 H), 3.92 (d, J = 1.0 Hz, 3H), 3.64 (q, J = 7.2 Hz, 1H), 3.18 (q, J = 7.1 Hz, 1H), 3.13 (s, 1.5H), 2.86 (s, 1.5H), 1.56 (s, 9H), 1.28 (t, J = 7.2 Hz, 1.5H), 1.13 (t, J = 7.1 Hz, 1.5H).
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Step 4C. 4-Amino-/V-ethyl-3-methoxy-/V-methylpicolinamide
A solution of HCI/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 in vacuo to afford 12.71 g (100%) of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.00 (dd, J = 6.9, 1.5 Hz, 1 H), 7.02 (dd, J = 6.8, 0.7 Hz, 1H), 3.86 (d, J = 2.7 Hz, 3H), 3.35-3.28 (m, 2H), 3.16 (s, 1.5H), 3.00 (s, 1.5), 1.33-1.17 (m, 3H).
Step 4D. 4-Amino-A/-ethyl-3-hydroxy-/V-methylpicolinamide
To a solution of 4-amino-A/-ethyl-3-methoxy-/\/-methylpicolinamide (5 g, 24 mmol) in DCM (100 mL) was added TBAI (5.7 g, 15.5 mmol). The mixture was cooled to 0 °C and a solution of BBr3 (23.9 g, 95.6 mmol) in DCM (100 mL) was added dropwise keeping the internai température below 10 °C. The reaction was stirred at 10 °C for 15 h. The reaction was quenched with a solution of aqueous NaOH/MeOH (200 mL MeOH, 11.5 g NaOH, 50 mL water) while keeping the internai température at 0 °C. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (3 to 9% MeOH in DCM) to afford 3.1 g (78%) ofthe title compound as a yellow solid. 1H NMR (400 MHz, DMSO-de) δ 7.81 (d, J = 6.3 Hz, 1H), 7.39 (br. s., 3H), 6.85 (d, J = 6.2 Hz, 1H), 3.52-3.18 (m, 2H), 2.91 (br. s., 3H), 1.370.80 (m, 3H).
Step 4E. 4-((2-Ethoxy-3,4-dioxocyclobut-1 -en-1 -yl)amino)-/V-ethyl-3-hydroxy-/Vmethylpicolinamide
To a solution of 4-amino-N-ethyl-3-hydroxy-A/-methylpicolinamide (7.01 g, 35.9 mmol) in EtOH (150 mL) was added K2CO3 (4.96 g, 35.9 mmol) and 3,4-diethoxycyclobut-3-ene-1,2dione (9.17 g, 53.9 mmol). The mixture was heated to 50 °C and stirred for 16 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (10 to 100% DCM in petroleum ether, 0 to 20% MeOH in DCM) to afford 4.77 g (42%) of the title compound as a brown oil. 1H NMR (400 MHz, CDCb) δ 13.62 (brs, 0.5H), 13.50 (br s, 0.5H), 8.07 (d, J = 5.2 Hz, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 4.90 (q, J = 7.1 Hz, 2H), 4.16 (brs, 1H), 3.62 (brs, 3H), 3.14 (brs, 1H), 1.55 (t, J = 7.1 Hz, 3H), 1.45-1.20 (m, 3H).
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Step 4F. (/7)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-A/-ethyl-3-hydroxy-A/-methylpicolinamide
A solution of 4-((2-ethoxy-3,4-dioxocyclobut-1 -en-1 -yl)amino)-/V-ethyl-3-hydroxy-/Vmethylpicolinamide (5.92 g, 18.54 mmol) in EtOH (140 mL) was added to (/7)-(1,4-dimethyl-1 Hpyrazol-3-yl)(1-methylcyclopentyl)methanamine L-pyroglutamic acid sait (Préparative step 1G) (7.48 g, 22.2 mmol) and DIPEA (4.79 g, 37.1 mmol) in EtOH (50 mL). The reaction was stirred at room température for 16 h and then the reaction mixture was 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]+. 1H NMR (400 MHz, CD3OD) δ 8.22 (br. s., 1 H), 7.94 (br. s„ 1 H), 7.28 (s, 1 H), 5.44 (s, 1 H), 3.83 (s, 3H), 3.65 (br. s., 2H), 3.28-3.06 (m, 3H), 2.09 (s, 3H), 1.92-1.58 (m, 6H), 1.53-1.42 (m, 1 H), 1.38-1.21 (m, 4H), 1.17 (s, 3H). [a]26D = -77.88 (c = 0.5, MeOH). Chiral SFC (SFC method F) RT = 3.52 min, 99% ee.
Example 5 (S)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1 -en-1 -yl)amino)-A/-ethyl-3-hydroxy-A/-methylpicolinamide
The title compound was prepared analogous to Example 4 employing (S)-(1,4-dimethyl1/7-pyrazol-3-yl)(1-methylcyclopentyl)methanamine (Example 2). LCMS m/z 481.4 [M+H]+. 1H NMR (400 MHz, DMSO-de) δ 11.70 (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 = 10.0 Hz, 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). [a]29 D = +80.8 (c = 0.5, MeOH). Chiral SFC (SFC method K) RT = 3.11 min, 99% ee.
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Example 6 (/-/)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2(morpholine-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione
Step 6A. tert-Butyl 4-chloro-3-methoxypicolinate
To a solution of pyridine (7.91 g, 8.05 mL, 100 mmol) and t-BuOH (7.90 g, 10.1 mL, 107 mmol) in DCM (32 mL) at 0 °C was added dropwise a solution of 4-chloro-3-methoxypicolinoyl çhloride (Préparative Step 3A) (5.49 g, 26.7 mmol) in DCM (26.7 mL). The reaction was stirred at 0 °C for 15 min, warmed to ambient température and then heated at reflux for 4 h. The solvent was removed in vacuo and the residue was taken dissolved in EtOAc. The solution was washed with 1 N aqueous NaOH solution and brine, filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 20% EtOAc in DCM) to afford 3.10 g (48%) of the title compound as a liquid. LCMS m/z 188.1 [M-tBu]+. 1H NMR (400 MHz, CDCI3) δ 8.30 (d, J = 5.1 Hz, 1 H), 7.42 (d, J = 5.1 Hz, 1 H), 3.98 (s, 3H), 1.65 (s, 9H).
Step 6B. tert-Butyl 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-methoxypicolinate To the 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) was added tert-butyl 4-chloro-3-methoxypicolinate (97.2 g, 0.4 mol) at 25 °C. The mixture was degassed and purged with N2 for 3 times. 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 with N2 for 3 times. The reaction mixture was heated to 80 °C and stirred for 16 hr. The mixture was cooled to 25 °C and then filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 50% DCM in petroleum ether, then 0 to 2.5% THF in DCM). The resulting oil was triturated with heptane (250 mL) and stirred at 25 °C for 3 h. The mixture was filtered to afford 84.7 g, 60% of the title compound as a light yellow solid. LCMS m/z 349.1 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 8.38 (d, J = 5.4 Hz, 1 H), 7.93 (br s, 2H), 4.95 (q, J = 7.1 Hz, 2H), 4.01 (s, 3H), 1.68 (s, 9H), 1.59 (t, J = 7.2 Hz, 3H).
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Step 6C. tert-Butyl (/7)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-methoxypicolinate
DIEA (6.0 g, 46.4 mmol) was added to a solution of (7)-(1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methanamine hydrochloride (Préparative step 3H) (4.70 g, 19.3 mmol) in EtOH (70 mL). The mixture was stirred for 10 min, and then tert-butyl 4-((2-ethoxy-3,4dioxocyclobut-1 -en-1 -yl)amino)-3-methoxypicolinate (4.0 g, 11.5 mmol) was added. The resulting mixture was stirred at 20 °C for 70 h and then was concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 80% EtOAc in petroleum ether) to afford 5.85 g (100%) ofthe title compound as a yellow solid. LCMS m/z 510.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1 H), 9.06-9.02 (m, 1 H), 8.20-8.18 (m, 1 H), 8.09-8.07 (m, 1 H), 7.44 (s, 1 H), 5.36-5.33 (m, 1 H), 3.84 (s, 3H), 3.80 (s, 3H), 1.98 (s, 3H), 1.72-1.53 (m, 15H), 1.351.30 (m, 1H), 1.24-1.15 (m, 1 H), 1.09 (s, 3H).
Step 6D. (7)-4-((2-(((1,4-Dimethyl-17-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1 -en-1 -yl)amino)-3-methoxypicolinic acid
TFA (25 g, 16.3 mL, 219.3 mmol) was added to a solution of tert-butyl (7)-4-((2-(((1,4dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-methoxypicolinate (6.60 g, 13.0 mmol) in DCM (50 mL). The resulting solution was stirred at ambient température for 44 h. The mixture was concentrated in vacuo, and the pH was adjusted to ~8 using saturated aqueous NaHCO3 solution. The mixture was extracted with DCM (20 mL). The aqueous layer was acîdified to pH ~3 with 1 N aqueous HCl solution and then was extracted with DCM (100 mL x 5). The combined organic extracts were concentrated in vacuo to afford 5.8 g (99%) of the title compound as a yellow solid. LCMS m/z 454.4 [M+H]+.
Step 6E. (7)-3-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3methoxy-2-(morpholine-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione
HATU (377 mg, 0.99 mmol) was added to a solution of (7)-4-((2-(((1,4-dimethyl-17pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3methoxypicolinic acid (300 mg, 0.66 mmol), morpholine (57.6 mg, 0.66 mmol) and TEA (134 mg, 1.32 mmol) in DCM (5 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 16 h and then was concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and washed with saturated aqueous KHCO2 solution (10 mL). The aqueous layer was extracted with EtOAc (40 mL x 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a yellow solid. The crude was used directly without further
117 purification assuming quantitative yield. LCMS m/z 523.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.28-8.26 (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).
Step 6F. (/7)-3-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-4-((3hydroxy-2-(morpholine-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione To a solution of (/7)-3-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-methoxy-2-(morpholine-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione (600 mg, 1.15 mmol) in 1,4-dioxane (5 mL) at 15 °C was added MgBr2 (634 mg, 3.44 mmol).
The mixture was heated at 120 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified using préparative HPLC (Agela Durashell C18 150 mm x 25 mm x 5 pm, 30 to 50% MeCN in 0.225% formic acid in water, 25 mUmin, 11 min) to afford 66 mg (11%) of the title compound as a yellow solid. LCMS m/z 509.4 [M+H]+. 1H
NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.5 Hz, 1 H), 7.91 (br s, 1 H), 7.28 (s, 1 H), 5.44 (s, 1 H), 3.90-3.70 (m, 11 H), 2.09 (s, 3H), 1.90-1.65 (m, 6H), 1.50-1.43 (m, 1 H), 1.35-1.26 (m, 1 H), 1.17 (s, 3H). [α]2% = -65.6 (c = 0.17, MeOH). Chiral SFC conditions (SFC method K) RT = 3.47 min, 100% ee.
Example 7 (/7)-3-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2-(4methylpiperazine-1-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione
The title compound was prepared following a similar procedure to the préparation of (/7)25 3-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2(morpholine-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione (Example 6) employing 1methylpiperazine to yield 19.7 mg (9%) of the title compound as a yellow solid. LCMS m/z 522.5 [M+H]+. Ή NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.24 (d, J = 5.6 Hz, 1H), 7.90 (d, J = 5.6 Hz, 1 H), 7.28 (s, 1 H), 5.44 (s, 1 H), 3.92 (br s, 4H), 3.82 (s, 3H), 2.80 (br s, 4H), 2.53 (s, 3H),
118
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.
Example 8 (R)-4-((2-(((4-Chloro-1-methyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide
Step 8A. (R)-2-Methyl-/V-((R)-(1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)propane-2sulfinamide
To a solution of /-PrMgCI· LiCl (20.1 mL, 26.2 mmol, 1.3 M solution in THF) at -30 °C was added a solution of 3-iodo-1-methyl-1H-pyrazole (4.35 g, 20.9 mmol) in THF (20 mL). The resulting yellow solution was stirred at 30-40 °C for 2 h. The reaction was cooled to -30 °C and a solution of (S,H)-2-methyl-A/-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (Preparactive Step 1C) (3.0 g, 13.93 mmol) in THF (5 mL) was added dropwise. The reaction mixture was warmed to 30 °C and stirred for 16 h. The reaction mixture was poured slowly into a saturated aqueous NH4CI solution (100 mL) at 5 °C and diluted with water (20 mL). The mixture was then extracted with EtOAc (50 mL x 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 80% EtOAc in petroleum ether) to afford 3.48 g (84%) of the title compound as a yellow oil. LCMS m/z 297.9 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 7.26 (d, J = 2.1 Hz, 1 H), 6.08 (d, J = 2.2 Hz, 1 H), 4.34 (d, J = 3.4 Hz, 1 H), 3.86 (s, 3H), 3.59-3.55 (m, 1 H), 1.80-1.55 (m, 6H), 1.50-1.43 (s, 1 H), 1.18 (s, 9H), 1.18-1.12 (m, 1 H), 0.98 (s, 3H).
Step 8B. (R)-(1-Methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine
HCl (80 mL, 4.0 M solution in MeOH) was added to a solution of (R)-2-methyl-A/-((R)-(1methyl-1R-pyrazol-3-yl)(1-methylcyclopentyl)methyl)propane-2-sulfinamide (6.59 g, 22.15 mmol) in MeOH (50 mL). The resulting solution was stirred at ambient température for 3 h and then concentrated in vacuo. The title compound was isolated as the mono-HCI sait assuming quantitative yield and used directly without further purification. LCMS m/z 193.8 [M+H]+. 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
119 (s, 3H), 1.85-1.65 (m, 6H), 1.60-1.55 (m, 1 H), 1.31-1.25 (m, 1 H), 1.05 (s, 3H). The absolute stereochemistry of the title compound was assigned by analogy to Préparative Example 1 F.
Step 8C. tert-Butyl (7)-((1-methyl-17-pyrazol-3-yl)(1-methylcyclopentyl)methyl)carbamate To a solution of (7)-(1-methyl-17-pyrazol-3-yl)(1-methylcyclopentyl)methanamine (5.09 g, 22.2 mmol) in MeOH (150 mL) at 15 °C was added TEA (9.25 mL, 66.5 mmol) and (Boc)2O (7.25 g, 33.2 mmol). The resulting mixture was stirred for 16 h. The reaction was concentrated in vacuo and the residue was purified by silica gel column chromatography (0 to 20% EtOAc in petroleum ether) to afford 5.72 g (88%) of the title compound as a light yellow oil. LCMS m/z 176.8 [M-BocNH]+. 1H NMR (400 MHz, CDCI3) δ 7.24 (d, J = 2.2 Hz, 1H), 6.07 (d, J = 2.2 Hz, 1 H), 5.39-5.30 (m, 1 H), 4.67 (d, J = 9.5 Hz, 1 H), 3.87 (s, 3H), 1.79-1.61 (m, 6H), 1.44 (s, 9H), 1.38-1.17 (m, 2H), 0.94 (s, 3H).
Step 8D. tert-Butyl (7)-((4-chloro-1-methyl-17-pyrazol-3-yl)(1-methylcyclopentyl)methyl)carbamate
NCS (3.12 g, 23.4 mmol) was added portionwise to a solution of tert-butyl (7)-((1 methyl-17-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 température, the reaction was poured into a 3% aqueous LiCI solution (150 mL) and then extracted with EtOAc (70 mL x 2). The combined organic extracts were concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 15% EtOAc in petroleum ether) to afford 6.0 g (94%) ofthe title compound as a pale yellow oil. LCMS m/z 210.7 [M-BocNH]+. 1H NMR (400 MHz, CDCh) δ 7.25 (s, 1H), 5.32-5.29 (m, 1H), 4.79 (d, J = 9.7 Hz, 1H), 3.82 (s, 3H), 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).
Step 8E. (7)-(4-Chloro-1-methyl-17-pyrazol-3-yl)(1-methylcyclopentyl)methanamine To a mixture of tert-butyl (7)-((4-chloro-1-methyl-17-pyrazol-3-yl)(1methylcyclopentyl)methyl)carbamate (6.0 g, 18.3 mmol) in MeOH (20 mL) at 15 °C was added HCl (150 mL, 600 mmol, 4.0 M in MeOH). The mixture was stirred for 5 h and then concentrated in vacuo. The title compound was isolated as the mono-HCI sait assuming quantitative yield and used directly without further purification. LCMS m/z 228.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.77 (s, 1H), 4.32 (s, 1H), 3.92 (s, 3H), 1.90-1.55 (m, 7H), 1.301.22 (m, 1H), 1.15 (s, 3H).
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Step 8F. (R)-4-((2-(((4-Chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide
DIEA (5.0 g, 38.7 mmol) was added to a suspension of (R)-(4-chloro-1-methyl-1Hpyrazol-3-yl)(1-methylcycIopentyl)methanamine (5.90 g, 22.3 mmol) in EtOH (100 mL). The mixture was stirred for 30 min, and then 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-/V,/V-dimethylpicolinamide (Préparative Step 1 H) (5.0 g, 16.4 mmol) was added. The resulting mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered and the solids were washed with EtOH (10 mL x 3). The solids were suspended in water (30 mL) and heated at 50 °C for 3 h. The suspension was filtered. The solids were washed with water (10 mL x 3) and dried to afford 5.24 g (66%) of the title compound as a yellow solid. LCMS m/z 487.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (br s, 1H), 9.95 (br s, 1H), 9.18 (s, 1H), 8.01 (s, 2H), 7.95 (s, 1H), 5.44 (d, J = 10.0 Hz, 1H), 3.86 (s, 3H), 3.18 (br s, 3H), 3.05 (br s, 3H), 1.781.58 (m, 6H), 1.39-1.31 (m, 1H), 1.21-1.10 (m, 1H), 1.07 (s, 3H). [a]24D = -145.151 (c = 0.50, MeOH). Chiral SFC (SFC method F) RT = 3.85 min, 100% ee. The absolute configuration was established by single crystal X-ray analysis (Figure 2).
Example 9 (S)-4-((2-(((4-Chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide
The title compound was prepared analogous to Example 8 employing (R)-2methylpropane-2-sulfinamide. LCMS m/z 487.4 [M+H]+. 1H NMR (400 MHz, DMSO-de) δ 11.68 (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 = 10.2 Hz, 1H), 3.86 (s, 3H), 3.18 (br. s., 3H), 3.05 (br. s., 3H), 1.74-1.55 (m, 6H), 1.37-1.30 (m, 1H), 1.21-1.14 (m, 1 H), 1.07 (s, 3H). [a]20 D = +107.3 [c = 1, MeOH). Chiral SFC (SFC method L) RT = 6.28 min, 98% ee.
121
Example 10 (R)-4-((2-(((4-Chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/-isopropyl-A/-methylpicolinamide
The title compound was prepared from 4-((2-ethoxy-3,4-dioxocyclobut-1 -en-1 -yl)amino)-
3-hydroxy-/V-isopropyl-A/-methylpicolinamide (Préparative Step 3F) and (R)-(4-chloro-1-methyl1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine (Préparative Step 8E) following the same procedure as the préparation of Example 8. Yellow solid, 64 mg (41%). LCMS m/z 515.3 [M+H]+. Ή NMR (400 MHz, CD3OD) δ 8.21 (d, J = 5.1 Hz, 1H), 7.93 (br s, 1H), 7.64 (s, 1H), 10 5.55 (s, 1 H), 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). [a]2% = -75.5 (c = 0.23, MeOH). Chiral SFC (SFC method B) RT = 1.59 min, 100% ee.
Example 11 (/?)-3-Hydroxy-/V-isopropyi-4-((2-(((4-methoxy-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-A/-methylpicolinamide
Step 11 A. 3-lodo-4-methoxy-1-methyl-1H-pyrazole
NIS (4.41 g, 19.6 mmol) was added to a solution of 4-methoxy-1-methyl-1/7-pyrazole (2.20 g, 19.6 mmol) in DMF (20 mL). The reaction mixture was stirred at ambient température for 18 h. The mixture was diluted with water (100 mL) and brine (20 mL), and extracted with EtOAc (50 mL x 5). The combined organic extracts were concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 16% EtOAc in petroleum ether) to afford 310 mg, (7%) ofthe title compound as a brown solid. LCMS m/z 238.8 [M+H]+. 1H NMR (400
MHz, CDCI3) δ 6.91 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H).
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Step 11 B. (R)-N-((R)-(4-Methoxy-1 -methyl-1/7-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)-2methylpropane-2-sulfinamide
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 was added /-PrMgCI·LiCI (3 mL, 3.90 mmol, 1.3 M solution in THF). The resulting mixture was stirred at ambient température for 2 h, and then cooled to -40 °C. A solution of (S,E)-2-methyl-A/-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (Preparactive Step 1C) (250 mg, 1.16 mmol) in freshly distilled THF (1 mL) was added. The reaction mixture was warmed to ambient température and stirred for 16 h. The reaction was quenched with saturated aqueous NH4CI solution (1 mL) at 0 °C, and extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to afford 150 mg, 33% ofthe title compound as a yellow oil. LCMS m/z 327.9 [M+H]+. 1H NMR (400 MHz, CDCb) δ 6.95 (s, 1H), 4.31-4.29 (m, 1H), 4.15^.13 (m, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 1.80-1.70 (m, 2H), 1.701.55 (m, 4H), 1.50-1.42 (m, 2H), 1.11 (s, 9H), 1.02 (s, 3H).
Step 11C. (R)-(4-Methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine
HCl (2.5 mL, 4.0 M in 1,4-dioxane) was added to a solution of (R)-A/-((F?)-(4-methoxy-1methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-suifinamide (150 mg, 0.458 mmol) in MeOH (15 mL). The resulting solution was stirred for 4 h and then was concentrated in vacuo. The title compound was isolated as a mono-HCI sait assuming quantitative yield and used directly without further purification. LCMS m/z 207.3 [M-NH2]+. 1H 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 ofthe title compound was assigned by analogy to Préparative Example 1 F.
Step 11 D. (R)-3-Hydroxy-N-isopropyl-4-((2-(((4-methoxy-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-methylpicolinamide To a suspension of (R)-(4-methoxy-1-methyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methanamine (2.43 g, 9.35 mmol) in EtOH (60 mL) at 5 °C was added DIEA (11.8 g, 91.5 mmol). After stirring for 10 min, 4-((2-ethoxy-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-Nisopropyl-/V-methylpicolinamide (Préparative Step 3F) (3.05 mg, 9.15 mmol) was added. The resulting solution was stirred for 3 d. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (20 to 100% EtOAc in petroleum ether). The crude product was taken up in EtOH (30 mL) and stirred at 20 °C for 16 h. The slurry was
123 filtered to afford 3.26 g (70%) of the title compound as a yellow solid. LCMS m/z 511.4 [M+H]+. 1H NMR (400 MHz, DMSO-de) δ 11.34 (s, 0.3H), 10.84 (s, 0.7H), 9.94 (s, 1H), 9.13 (d, J = 9.8 Hz, 1H), 7.99-7.94 (m, 2H), 7.48 (s, 1H), 5.34 (d, J = 10.3 Hz, 1H), 4.82 (br s, 0.3H), 4.18 (br s, 0.7H), 3.78 (s, 3H), 3.67 (s, 3H), 2.95-2.84 (m, 3H), 1.72-1.50 (m, 6H), 1.35-1.24 (m, 1 H),
1.21-1.10 (m, 7H), 1.02 (s, 3H). [a]24 D = -114.4 (c = 0.50, MeOH). Chiral SFC (SFC method B)
RT = 1.52 min, 100% ee.
Example 12 (R)-3-Hydroxy-4-((2-(((4-methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)10
3,4-dioxocyclobut-1-en-1-yl)amino)-A/,A/-dimethylpicolinamide
The title compound was prepared from 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)3-hydroxy-A/,A/-dimethylpicolinamide (Préparative Step 1H) and (R)-(4-methoxy-1-methyl-1Hpyrazol-3-yl)(1-methylcyclopentyl)methanamine (Préparative Step 11 C) following similar procedure as for the préparation of Example 11. Yellow solid, 45 mg (56%). LCMS m/z 483.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.21 (d, J = 5.5 Hz, 1H), 7.90 (d, J = 5.5 Hz, 1H), 7.30 (s, 1 H), 5.43 (s, 1 H), 3.78 (s, 3H), 3.74 (s, 3H), 3.24 (br s, 3H), 3.17 (br s, 3H), 1.91-1.74 (m, 2H), 1.70-1.60 (m, 4H), 1.45-1.35 (m, 1 H), 1.30-1.20 (m, 1 H), 1.11 (s, 3H). [a]24D = -87.5 (c = 0.50, MeOH). Chiral SFC (SFC method F) RT = 4.86 min, 97.4% ee.
Example 13 (R)-3-Hydroxy-4-((2-((1 -(4-methoxy-1 -methyl-1 /-/-pyrazol-3-yl)-2,2-dimethylpropyl)amino)-3,4dioxocyclobut-1 -en-1 -yl)amino)-A/,/V-dimethylpicolinamide
Step 13A. (S,E)-A/-(2,2-Dimethylpropylidene)-2-methylpropane-2-sulfinamide
Titanium (IV) ethoxide (68.9 g, 302 mmol) was added to a solution of pivaldehyde (10.0 g, 116 mmol) in DCM (830 mL). The mixture was stirred for 20 min, and then (S)-220305
124 methylpropane-2-sulfinamide (14.1 g, 116 mmol) was added. The resulting mixture was stirred at ambient température for 16 h and then was quenched with water (250 mL). The mixture was filtered and the solids were washed with THF (500 mL x 2). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 5% 5 EtOAc in petroleum ether) to afford 24.4 g (75%) of the title compound as a colorless oil. LCMS m/z 190.2 [M+H]+· 1H NMR (400 MHz, CDCI3) δ 7.92 (s, 1H), 1.20 (s, 9H), 1.16 (s, 9H).
Step 13B. (0)-^-((/7)-1 -(4-Methoxy-1 -methyl-1 H-pyrazol-3-yl)-2,2-dimethylpropyl)-2methylpropane-2-sulfinamide
To a solution of 3-iodo-4-methoxy-1 -methyl-1 H-pyrazole (Préparative Step 11 A) (250 mg, 1.05 mmol) in freshly distilled THF (0.7 mL) at -40 °C was added /'-PrMgCI-LiCI (1.7 mL, 2.22 mmol, 1.3 M solution in THF). The resulting mixture was stirred at 15 °C for 1 h, and then cooled to -40 °C. A solution of (S,5)-/V-(2,2-dimethylpropylidene)-2-methylpropane-2sulfinamide (140 mg, 0.74 mmol) in freshly distilled THF (0.5 mL) was added. The mixture was 15 warmed to 15 °C and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4CI solution (1 mL) at 0 °C and extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to afford 80 mg (36%) of the title compound as a yellow oil. LCMS m/z 301.9 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 6.97 (s, 1 H), 20 5.32-5.31 (m, 1 H), 4.20—4.15 (m, 1 H), 3.83 (s, 3H), 3.71 (s, 3H), 1.11 (s, 9H), 1.01 (s, 9H).
Step 13C. (/7)-1 -(4-Methoxy-1 -methyl-1/7-pyrazol-3-yl)-2,2-dimethylpropan-1 -amine HCl (1.2 mL, 4.0 M in MeOH) was added to a solution of (R)-/V-((R)-1-(4-methoxy-1methyl-1/7-pyrazoi-3-yl)-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (80 mg, 0.27 mmol) 25 in MeOH (7 mL). The mixture was stirred at 15 °C for 4 h, and then concentrated in vacuo. The title compound was isolated as a mono-HCI sait assuming quantitative yield and used directly without further purification. LCMS m/z 180.8 [M-NH2]+. 1H NMR (400 MHz, CD3OD) δ 7.43 (s, 1 H), 4.10 (s, 1 H), 3.84 (s, 3H), 3.78 (s, 3H), 1.05 (s, 9H). Chiral SFC (SFC method J) RT = 1.85 min, 93.7% ee. The absolute stereochemistry of the title compound was assigned by analogy to 30 Préparative Example 1 F.
Step 13D. (R)-3-Hydroxy-4-((2-((1 -(4-methoxy-1 -methyl-1/7-pyrazol-3-yl)-2,2-dimethylpropyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N,/\/-dimethylpicolinamide
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To a solution of (/7)-1 -(4-methoxy-1-methyl-1/7-pyrazol-3-yl)-2,2-dimethylpropan-1 -amine (60 mg, 0.26 mmol) in EtOH (3 mL) at 15 °C was added DIEA (63.5 mg, 0.49 mmol). After stirring for 10 min, 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/Vdimethylpicolinamide (Préparative Step 1H) (50 mg, 0.16 mmol) was added. The resulting mixture was stirred at ambient température for 16 h and then was concentrated in vacuo. The residue was purified using préparative HPLC (Agela Durashell C18 150 mm x 25 mm x 5 pm 14 to 54% CH3CN in 0.225% formic acid in water, 25 mUmin, 11 min) to afford 42.1 mg (56%) of the title compound as a yellow solid. LCMS m/z 457.4 [M+H]+. 1H NMR (400 MHz, DMSO-de) δ 11.64 (br s, 1 H), 9.99 (s, 1 H), 9.12 (d, J = 8.8 Hz, 1 H), 8.01 (s, 2H), 7.49 (s, 1 H), 5.22 (d, J =
10.3 Hz, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 3.19 (br s, 3H), 3.06 (br s, 3H), 0.94 (s, 9H). [a]24 D = -
110.8 (c = 0.33, MeOH). Chiral SFC (SFC method J) RT = 3.95 min, 100% ee.
Example 14 (R)-3-Hydroxy-A/-isopropyl-4-((2-((1 -(4-methoxy-1 -methyl-1 H-pyrazol-3-yl)-2,215 dimethylpropyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-A/-methylpicolinamide
The title compound was prepared from 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)3-hydroxy-A/-isopropyl-A/-methylpicormamide (Préparative Step 3F) and (/7)-1 -(4-methoxy-1methyl-1/7-pyrazol-3-yl)-2,2-dimethylpropan-1-amine (Préparative Step 13C) following similar procedures as the préparation of Example 13. Yellow solid, 18 mg (25%). LCMS m/z 485.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.18 (brs, 1H), 7.94 (br s, 1H), 7.33 (s, 1H), 5.35 (s, 1H), 4.64 (br s, 0.3H), 4.30 (br s, 0.7H), 3.81 (s, 3H), 3.76 (s, 3H), 3.02 (s, 3H), 1.33-1.20 (m, 6H), 1.04 (s, 9H). Chiral SFC (SFC method K) RT = 2.78 min, 98.7% ee.
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Example 15 (/7)-4-((2-(((4-(Difluoromethoxy)-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/\/-dimethylpicoIinamide
Step 15A. 4-(Difluoromethoxy)-1-methyl-1/-/-pyrazole
To a solution of 1-methyl-1/-/-pyrazol-4-oI (1.0 g, 10.2 mmol) in IPA (10 mL) at 15 °C was added KOH (2.86 g, 51.0 mmol) followed by chlorodifluoromethane (8.81 g, 102 mmol). The reaction was exothermic. The mixture was stirred at ambient température for 12 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (33% EtOAc in petroleum ether) to afford 700 mg (46%) of the title compound as a yellow oil. LCMS m/z 148.9 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 7.37 (s, 1H), 7.32 (s, 1H), 6.34 (t, J = 73.03 Hz, 1H), 3.98-3.78 (s, 3H). 19F NMR (376 MHz, CDCh) δ -83.6.
Step 15B. 4-(Difluoromethoxy)-3-iodo-1-methyl-1H-pyrazole
NIS (6.38 g, 28.4 mmol) was added to a solution of 4-(difluoromethoxy)-1-methyl-1Hpyrazole (1.40 g, 9.45 mmol) in acetonitrile (25 mL). The resulting mixture was heated at 50 °C for 84 h. The reaction was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with saturated aqueous NaaSaOs solution and brine, dried over NazSO^ filtered and concentrated in vacuo. The residue was purified using préparative silica gel TLC (50% EtOAc in petroleum ether) to afford 260 mg (10%) of the title compound as a yellow solid. LCMS m/z 275.1 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 7.27 (s, 1 H), 6.41 (t, J = 73.03 Hz, 1 H), 3.92 (s, 3H). 19F NMR (376 MHz, CDCIs) δ -83.6.
Step 15C. (R)-/\/-((R)-(4-(Difluoromethoxy)-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methyIpropane-2-sulfinamide
To a solution of 4-(difluoromethoxy)-3-iodo-1-methyl-1H-pyrazole (66.2 mg, 1.3 mmol) in THF (5 mL) at -40 °C was added dropwise /-PrMgCILiCI (0.43 mL, 0. 0.557 mmol, 1.3 M solution in THF). The resulting mixture was stirred at -10 °C for 1 h, and then cooled to -40 °C.
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A solution of (S,£)-2-methyl-A/-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (Preparactive Step 1C) (40 mg, 0.19 mmol) in THF (3 mL) was added. The reaction was warmed to 50 °C and stirred overnight. The mixture was quenched with saturated aqueous NH4CI solution at 10 °C and extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The residue was purified using préparative silica gel TLC (80% EtOAc in petroleum ether) to afford 70 mg (46%) of the title compound as a yellow oil. LCMS m/z 363.9 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 7.25 (s, 1H), 6.37 (t, J = 73.03 Hz, 1H), 4.33 (d, J = 6.8 Hz, 1 H), 3.90-3.71 (m, 4H), 1.77-1.55 (m, 6H), 1.54-1.42 (m, 1 H), 1.28-1.13 (m, 10H), 1.08-0.98 (m, 3H). 19F NMR (376 MHz, CDCI3) δ -83.2.
Step 15D. (R)-(4-(Difluoromethoxy)-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine
HCl (1 mL, 4.0 M in MeOH) was added to a solution of (R)-/V-((R)-(4-(difluoromethoxy)1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide (35 mg, 0.096 mmol) in MeOH (1 mL) at 5 °C. The mixture was stirred at 20 °C for 3 h, and then concentrated in vacuo. The title compound was isolated as a mono-HCI sait assuming quantitative yield and used directly without further purification. The absolute stereochemistry of the title compound was assigned by analogy to Préparative Example 1 F. LCMS m/z 242.8 [MNH2]+.
Step 15E. (R)-4-((2-(((4-(Difluoromethoxy)-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/-dimethylpicolinamide
To a solution of (R)-(4-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine (28 mg, 0.11 mmol) in EtOH (2 mL) at 20 °C was added DIEA (140 mg, 1.08 mmol). After stirring for 5 min, 4-((2-ethoxy-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide (Préparative Step 1H) (30 mg, 0.108 mmol) was added. The resulting mixture was stirred at 30 °C for 6 h and then was concentrated in vacuo. The residue was purified using préparative HPLC (Xbridge 150 mm x 30 mm x 10 pm, 15 to 55% CH3CN in 0.225% formic acid in water, 25 mL/min, 10 min) to afford 52 mg (55%) of the title compound as a yellow solid. LCMS m/z 519.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.5 Hz, 1H), 7.92 (br s, 1 H), 7.57 (s, 1 H), 6.65 (dd, J = 75.5, 72.9 Hz, 1 H), 5.46 (s, 1 H), 3.86 (s, 3H), 3.24 (br s, 3H), 3.17 (brs, 3H), 1.87-1.62 (m, 6H), 1.51-1.43 (m, 1H), 1.33-1.25 (m, 1H), 1.15 (s, 3H). 19F NMR (376 MHz, CDCI3) δ -85.1. Chiral SFC (SFC method B) RT =1.34 min, 100% ee.
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Example 16 (R)-4-((2-(((4-Cyano-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide
Step 16A. 3-Amino-1-methyl-1H-pyrazole-4-carbonitiile
To a solution of 3-amino-1H-pyrazole-4-carbonitrile (15.0 g, 139 mmol) in DMF (700 mL) at 0 °C was added K2CO3 (23.0 g, 167 mmol). The mixture was stirred for 45 min, and then Mel (23.6 g, 167 mmol) was added. The resulting mixture was heated at 90 °C for 16 h. The reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (400 mL x 8). The combined organic extracts were concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 20% EtOAc in petroleum ether) to afford 3.30 g (20%) of the title compound as a white solid. LCMS m/z 122.8 [M+H]+. 1H NMR (400 MHz, DMSO-de) δ 8.02 (s, 1H), 5.53 (s, 2H), 3.61 (s, 3H).
Step 16B. 3-lodo-1-methyl-1/-/-pyrazole-4-carbonitrile
To a stirred solution of 3-amino-1-methyl-1/7-pyrazole-4-carbonitrile (1.0 g, 8.19 mmol) and p-TsOH water (3.55 g, 18.7 mmol) in MeCN (30 mL) at 0 °C was added dropwise a solution of NaNO2 (1.29 g, 18.7 mmol) and Kl (3.1 g, 18.7 mmol) in water (4.0 mL). The resulting mixture was stirred at 15 °C for 3 d. The reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL) and saturated aqueous Na2SO3 solution (20 mL), and then neutralized with NaOH (1.0 N aqueous solution) until pH = 8. The mixture was extracted with EtOAc (100 mL x 4), and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to afford 398 mg (21 %) of the title compound as a yellow solid. LCMS m/z 234.1 [M+H]+. Ή NMR (400 MHz, CDCI3) δ 8.48 (s, 1H), 3.94 (s, 3H).
Step 16C. (R)-A/-((R)-(4-Cyano-1-methyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2methylpropane-2-sulfinamide
To a solution of 3-iodo-1-methyl-1/-/-pyrazole-4-carbonitrile (398 mg, 1.71 mmol) in freshly distilled THF (12 mL) at -65 °C was added dropwise /-PrMgCl·LiCI (2.60 mL, 3.38 mmol,
129
1.3 M solution in THF). The resulting mixture was stirred at -40 °C for 1 h, and then cooled to 65 °C. A solution of (S,E)-2-methyl-A/-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (Preparactive Step 1C) (260 mg, 1.21 mmol) in freshly distilled THF (3 mL) was added dropwise. The mixture was warmed to 15 °C and stirred for 3 d. The reaction mixture was poured into 25% aqueous NH4CI solution (20 mL) at 15 °C, and extracted with EtOAc (50 mLx 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to afford 84 mg (17%) of the title compound as a yellow solid. LCMS m/z 322.9 [M+H]+. Ή NMR (400 MHz, CDCI3) δ 7.76 (s, 1 H), 4.48^1.46 (m, 1 H), 3.93 (s, 3H), 3.82-3.75 (m, 1 H), 1.85-1.50 (m, 8H), 1.29 (s, 9H), 1.08 (s, 3H).
Step 16D. (R)-3-(Amino(1 -methylcyclopentyl)methyl)-1 -methyl-1 H-pyrazole-4-carbonitrile
To a solution of (R)-/V-((R)-(4-cyano-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide (84 mg, 0.26 mmol) in DCM (6 mL) at 0 °C was added HCl (2 mL, 4.0 M in EtOAc). The mixture was warmed to 15 °C and stirred for 2 h. The reaction mixture was then concentrated in vacuo. The title compound was isolated as a mono-HCI sait assuming quantitative yield and used directly without further purification. LCMS m/z 219.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 4.40 (s, 1H), 4.00 (s, 3H), 1.90-1.50 (m, 8H), 1.11 (s, 3H). The absolute stereochemistry ofthe title compound was assigned by analogy to Préparative Example 1 F.
Step 16E. (R)-4-((2-(((4-Cyano-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide
To a solution of (R)-3-(amino(1-methylcyclopentyl)methyl)-1-methyl-1/7-pyrazole-4carbonitrile (24 mg, 0.094 mmol) in EtOH (3 mL) at 0 °C was added DIEA (59.3 mg, 0.459 mmol) and 4-((2-ethoxy-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide (Préparative Step 1H) (28 mg, 0.092 mmol). The resulting solution was stirred at 20 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified using préparative HPLC (Agela Durashell C18 150 mm x 25 mm x 5 pm, 18 to 58% MeCN in 0.225% formic acid in water, 25 mL/min, 12 min) to afford 13 mg (18%) ofthe title compound as a yellow solid. LCMS m/z 478.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.5 Hz, 1H), 8.19 (s, 1H), 7.95-7.85 (m, 1H), 5.52 (s, 1H), 3.95 (s, 3H), 3.24 (br s, 3H), 3.17 (br s, 3H), 1.951.65 (m, 6H), 1.55-1.45 (m, 1 H), 1.44-1.35 (m, 1 H), 1.15 (s, 3H). Chiral HPLC (HPLC method A) RT = 8.65 min, 98.0% ee.
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Example 17 (/7)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(5-methylspiro[2.3]hexan-5-yl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide
Example 17A. A/-Methoxy-A/-methylspiro[2.3]hexane-5-carboxamide
NMM (1.09 g, 1.18 mL, 10.8 mmol) was added to a solution of N,O-dimethylhydroxylamine-HCI (300 mg, 3.07 mmol) in DMF (30.7 mL). The solution was stirred for 5 min, and then spiro[2.3]hexane-5-carboxylic acid (465 mg, 3.69 mmol) and HATU (1.75 g, 4.61 mmol) were added. The resulting mixture was stirred overnight. The reaction mixture was quenched with saturated aqueous NH4CI solution, and extracted with EtOAc. The combined organic extracts were washed with water (100 mL x 2) and brine (100 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in heptane) to afford 440 mg (85%) ofthe title compound as an oil. GCMS m/z 169.1 [M]. 1H NMR (400 MHz, CDCI3) δ 3.67 (s, 3H), 3.20 (s, 3H), 2.65-2.42 (m, 2H), 2.26-2.00 (m, 2H), 0.61-0.23 (m, 4H).
Example 17B. (1,4-Dimethyl-1/7-pyrazol-3-yl)(spiro[2.3]hexan-5-yl)methanone
To a solution of 3-iodo-1,4-dimethyl-1H-pyrazole (Préparative Step 1 D) (304 mg, 1.37 mmol) in THF (2.36 mL) was added dropwise i-PrMgCl·UCI (1.82 mL, 2.36 mmol, 1.3 M solution in THF). The resulting yellow solution was warmed to ambient température and stirred for 1 h. A solution of A/-methoxy-A/-methylspiro[2.3]hexane-5-carboxamide (200 mg, 1.18 mmol) in THF (1 mL) was then added dropwise, and the mixture was stirred for 16 h. The reaction mixture was poured into a saturated aqueous NH4CI solution. The mixture was extracted with DCM, and the combined organic extracts were concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in heptane) to afford 220 mg (91%) ofthe title compound as a solid. LCMS m/z 205.2 [M+H]+. 1H NMR (400 MHz, CDCh) δ 7.15 (s, 1H), 4.31 (tt, J = 9.2, 7.6 Hz, 1 H), 3.89 (s, 3H), 2.67-2.48 (m, 2H), 2.32 (s, 3H), 2.26-2.21 (m, 2H), 0.59-0.28 (m, 4H).
131
Example 17C. (1,4-Dimethyl-1 H-pyrazoI-3-yl) (5-methylspiro[2.3]hexan-5-yl)methanone NaH (47.0 mg, 1.17 mmol, 60 wt% in minerai oil) and iodomethane (208 mg, 1.47 mmol) were added to a solution of (1,4-dimethyl-1H-pyrazol-3-yl)(spiro[2.3]hexan-5-yl)methanone (72 mg, 0.37 mmol) in THF (9.79 mL). The resulting mixture was stirred at ambient température for 5 24 h. The reaction mixture was quenched with saturated aqueous NH4CI solution, and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in heptane) to afford 40 mg (19%) of the title compound as a solid. LCMS m/z 219.2 [M+H]+.
Example 17D. (1,4-Dimethyl-1/-/-pyrazol-3-yl)(5-methylspiro[2.3]hexan-5-yl)methanamine Titanium (IV) ethoxide (157 mg, 0.144 mL, 0.688 mmol) was added to a solution of (1,4dimethyl-1/-/-pyrazol-3-yl)(5-methylspiro[2.3]hexan-5-yl)methanone (50 mg, 0.23 mmol) in methanolic NH3 (0.983 mL, 7.0 M in MeOH). The resulting mixture was stirred at 40 °C 15 overnight. The reaction was cooled to ambient température, diluted with MeOH (2 mL) and NaBH4 (13 mg, 0.344 mmol) was added. The mixture was stirred for 4 h. The reaction mixture was quenched with saturated aqueous NH4CI solution and filtered through Celite. The filter cake was washed with 20% MeOH in DCM. The organic layer of the filtrate was separated, and the aqueous layer was acidified to pH 2 using 1.0 M HCl. The aqueous layer was extracted with 20 DCM (30 mL). The aqueous layer was then basified to pH 12 using NaOH, and extracted with DCM (20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound and used directly in the next step without further purification assuming quantitative yield.
Example 17E. (R)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(5-methylspiro[2.3]hexan-5yl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide
To a mixture of (1,4-dimethyl-1/7-pyrazol-3-yl)(5-methylspiro[2.3]hexan-5yl)methanamine (52 mg, 0.236 mmol) in EtOH (1.97 mL) at 20 °C was added DIEA (381 mg, 0.529 mL, 2.95 mmol). The resulting solution was stirred for 20 min, and then 4-((2-ethoxy-3,430 dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide (Préparative Step 1 H) (60 mg, 0.20 mmol) was added. The resulting suspension was stirred at 20 °C for 4 d and then was concentrated in vacuo. The residue was purified employing chiral SFC conditions (Chiral Tech OD-H 21.2 x 21.2 mm LD. 5 pm, 45% (0.2% 7N ammonia in MeOH) in EtOH, 80 mL/min). Isolation of the first eluting isomer afforded 21.6 mg (23%) of the title compound and the second
132 eluting isomer afforded the corresponding enantiomer (24 mg, 26%). LCMS m/z 479.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (br s, 1H), 9.18 (brs, 1H), 8.04-8.00 (m, 2H), 7.44 (s, 1H), 5.53 (d, J = 10.1, 1 H), 3.79 (s, 3H), 3.20 (br s, 3H), 3.07 (br s, 3H), 2.28 (d, J = 11.7, 1 H), 2.08 (d, J = 11.3, 1H), 2.01 (s, 3H), 1.73 (d, J = 11.3 Hz, 1H), 1.66 (d, J = 10.5 Hz, 1H), 1.35 (s, 3H), 5 0.45-0.28 (m, 4H). Chiral SFC conditions (Chiral Tech OD-H 21.2 x 21.2 mm I.D. 5 pm, 45% (0.2% 7N ammonia in MeOH) in EtOH, 80 mL/min) RT = 5.39 min, 98.8% ee (title compound) and RT = 5.98 min, 96% ee (enantiomer).
Préparations 1 to 14
The title compounds in Table 1 were prepared in a similar manner to (7)-(1,4-dimethyl17-pyrazol-3-yl)(1-methylcyclopentyl)methanamine (Préparative Step 1F) from the appropriate aldéhyde and heteroaryl halide.
Table 1
Prep No Structure Chemical Name and Analytical Data
1 h2n'''JA N~N \ (7) - (4-Ethy I-17-pyrazol-3-yl) (1 methylcyclopentyl)methanamine. LCMS m/z 205.4 [M-NH2X 1H NMR (400 MHz, CD3OD) δ 7.41 (s, 1H), 4.21 (s, 1H), 3.85 (s, 3H), 2.52-2.42 (m, 2H), 1.85-1.48 (m, 8H), 1.24 (t, J = 7.5 Hz, 3H), 1.13 (s, 3H)
2 h2n'' (7)-(2,5-Dimethylthiazol-4-yl)(1-methylcyclopropyl)methanamine. LCMS m/z 180.0 [M-NH2P. 1H NMR (400 MHz, CD3OD) δ 4.03 (s, 1H), 2.63 (s, 3H), 2.39 (s, 3H), 1.15 (s, 3H), 0.85-0.77 (m, 1H), 0.66-0.40 (m, 3H)
3 h2n' JA V \ (7)-(1,4-Dimethyl-17-pyrazol-3-yl)(1-methylcyclopropyl)methanamine. LCMS m/z 163.2 [M-NH2E. 1H NMR (400 MHz, CD3OD) δ 7.37 (s, 1H), 3.95 (s, 1H), 3.83 (s, 3H), 2.04 (s, 3H), 1.18 (s, 3H), 0.84-0.82 (m, 1 H), 0.65-0.45 (m, 3H)
133
Prep No Structure Chemical Name and Analytical Data
4 h2n' »7 N~n (R)-(4-Ethyl-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopropyl)methanamine. LCMS m/z 177.1 [M-NH2]+. 1H NMR (400 MHz, CD3OD) δ 7.42 (s, 1 H), 3.97 (s, 1 H), 3.85 (s, 3H), 2.51-2.42 (m, 2H), 1.25-1.15 (m, 3H), 1.10 (s, 3H), 0.90-0.80 (m, 1H), 0.59-0.50 (m, 3H)
5 h2n'- A n~n \ (R)-1 -(1,4-Dimethyl-1 /7-pyrazol-3-yl)-2,2-dimethylpropan-1 amine. LCMS m/z 165.2 [M-NH2]+. 1H NMR (400 MHz, CD3OD) δ 7.38 (s, 1H), 4.13 (s, 1H), 3.86 (s, 3H), 2.07 (s, 3H), 1.08 (s, 9 H)
6 n-n \ (R)-(1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclobutyl)methanamine. LCMS m/z 177.2 [M-NH2]+. 1H NMR (400 MHz, CD3OD) δ 7.38 (s, 1H), 4.35 (s, 1H), 3.85 (s, 3H), 2.30-2.15 (m, 2H), 2.09 (s, 3H), 2.05-1.95 (m, 1 H), 1.85-1.70 (m, 2H), 1.65-1.55 (m, 1H), 1.17 (s, 3H)
7 h2n' Y Ύ /~s (R)-(2,5-Dimethylthiazol-4-yl)(1-methylcyclobutyl)methanamine. LCMS m/z 193.9 [M-NH2]+. 1H NMR (400 MHz, CDCh) δ 9.15 (s, 2H), 8.39 (s, 1H), 5.19 (s, 1H), 3.00 (s, 3H), 2.58 (s, 3H), 2.65-2.55 (m, 1H), 2.35-2.26 (m, 1H), 2.15-1.77 (m, 3H), 1.70-1.61 (m, 1H), 1.42 (s, 3H)
8 H2Nc \^n As (R)-1-(2,5-Dimethylthiazol-4-yl)-2,2-dimethylpropan-1-amine. LCMS m/z 181.9 [M-NH2]+
9 H2N''\\ N-n \ (R)-(4-Ethyl-1-methyl-1/-/-pyrazol-3-yl)(1-methylcyclobutyl)methanamine. LCMS m/z 191.0 [M-NH2]+. 1H NMR (400 MHz, CDsOD) δ 7.43 (s, 1H), 4.34 (s, 1H), 3.86 (s, 3H), 2.58-2.47 (m, 2H), 2.21-2.16 (m, 2H), 2.05-1.95 (m, 1 H), 1.85-1.70 (m, 2H), 1.64-1.55 (m, 1 H), 1.33 (s, 3H), 1.26-1.20 (m, 3H)
134
Prep No Structure Chemical Name and Analytical Data
10 h2n'' yS n-n \ (/7)-1 - (4-Ethyl-1 -methyl-1 /7-pyrazol-3-yl)-2,2-dimethylpropan-1 amine. LCMS m/z 179.1 [M-NH2]+. Ή NMR (400 MHz, CD3OD) 5 7.44 (s, 1H), 4.13 (s, 1H), 3.88 (s, 3H), 2.52-2.42 (m, 2H), 1.26-1.20 (m,3H), 1.08 (s, 9H)
11 H <3 (/7)-(4-(amino(1-methylcyclopentyl)methyl)-5-methylthiazol-2yl)methanol. LCMS m/z 224.3 [M-NH2]+. 1H NMR (400 MHz, CD3OD) 5 4.79 (s, 2H), 4.35 (s, 1 H), 2.49 (s, 3H), 1.85-1.65 (m, 6H), 1.56-1.51 (m, 1H), 1.32-1.25 (m, 1H), 1.13 (s, 3H)
12 N-n \ (/7)-(4-Cyclopropyl-1 -methyl-1 /7-pyrazol-3-yl)(1- methylcyclopentyl)methanamine. LCMS m/z 217.3 [M-NH2]+
13 (/7)-(2,5-Dimethylthiazol-4-yl)(1 -methylcyclopentyl) methanamine. LCMS m/z 225.3 [M+H]+. 1H NMR (400 MHz, CD3OD) 5 4.27 (s, 1 H), 2.59 (s, 3H), 2.39 (s, 3H), 1.76-1.41 (m, 7H), 1.25-1.15 (s, 1 H), 1.05 (s, 3H)
14 a— H2Nols n4 (/7)-(5-Methoxy-2-methylthiazol-4-yl)(1-methylcyclopentyl)methanamine. LCMS m/z 223.8 [M-NH2]+. 1H NMR (400 MHz, CD3OD) 5 4.27 (s, 1 H), 3.99 (s, 3H), 2.64 (s, 3H), 1.85-1.61 (m, 6H), 1.54-1.45 (m, 1 H), 1.30-1.21 (m, 1 H), 1.12 (s, 3H)
135
Examples 18 to 33
The title compounds in Table 2 were prepared in a similar manner to (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/\/,/\/-dimethylpicolinamide (Préparative Step 11) from the appropriate amine 5 and a 4-((2-ethoxy-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-/V,/V-dialkylylpicolinamide.
Table 2
Ex. Structure Chemical Name and Analytical Data
18 î X-Tn/ o=£anh ,nh il I N X I (/7)-4-((2-(((4-Ethyl-1 -methyl-1 /-/-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide. Yellow solid, 42.8 mg (34%). LCMS m/z 481.4 [M+H]+. 1H NMR (400 MHz, CDsOD) δ 8.25-8.22 (m, 1 H), 7.95-7.85 (m, 1 H), 7.33 (s, 1H), 5.44 (s, 1H), 3.85 (s, 3H), 3.23 (br s, 3H), 3.16 (br s, 3H), 2.65-2.45 (m, 2H), 1.90-1.60 (m, 6H), 1.50-1.40 (m, 1H), 1.40-1.30 (m, 1 H), 1.20 (t, J = 7.5 Hz, 3H), 1.17 (s, 3H). [a]24 D = -28.65 (c 1.00, MeOH). RT = 1.56 min, 99.2% ee (SFC method B)
19 z, Jxj i / N X (/7)-4-((2-(((2,5-Dimethylthiazol-4-yl)(1-methylcyclopropyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxyΛ/,/V-dimethylpicolinamide. Yellow solid, 75.7 mg (41%). LCMS m/z 456.1 [M+H]+. Ή NMR (400 MHz, CD3OD) δ 8.21 (d, J = 5.6 Hz, 1 H), 7.90 (br s, 1 H), 5.32 (s, 1 H), 3.21 (br s, 3H), 3.15 (brs, 3H), 2.60 (s, 3H), 2.40 (s, 3H), 1.21 (s, 3H), 0.80-0.75 (m, 1H), 0.50-0.45 (m, 1H), 0.43-0.3 (m, 2H). RT = 4.44 min, 100% ee (SFC method D)
136
Ex. Structure Chemical Name and Analytical Data
20 o F J] O=^-NH N'N\ ,/,ΝΗ II T N Voh I (/7)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1methylcyclopropyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide. Yellow solid, 193 mg (45%). LCMS m/z 439.3 [M+H]+. Ή NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.4 Hz, 1 H), 7.92 (br s, 1 H), 7.29 (s, 1H), 5.24 (s, 1H), 3.80 (s, 3H), 3.23 (br s, 3H), 3.15 (br s, 3H), 2.06 (s, 3H), 1.21 (s, 3H), 0.82-0.74 (m, 1H), 0.48-0.38 (m, 3H). RT = 3.45 min, 100% ee (SFC method E)
21 \ CX/ o e —J \=z z— / (/7)-4-((2-(((4-Ethyl-1-methyl-1/7-pyrazol-3-yl)(1methylcyclopropyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide. Yellow solid, 59 mg, (50%). LCMS m/z 453.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.5 Hz, 1 H), 7.91 (br s, 1 H), 7.31 (s, 1 H), 5.27 (s, 1 H), 3.80 (s, 3H), 3.23 (br s, 3H), 3.15 (br s, 3H), 2.55-2.40 (m, 2H), 1.21 (s, 3H), 1.20 (t, J = 7.6 Hz, 3H), 0.82-0.77 (m, 1 H), 0.45-0.37 (m, 3H). RT = 4.49 min, 94.1% ee (SFC method D)
22 o F 1η O=C^Anh νΆ //,NH ?0H ΧΝΆ> 1 (/7)-4-((2-((1 -(1,4-Dimethyl-1 H-pyrazol-3-yl)-2,2dimethylpropyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3hydroxy-/V,/V-dimethylpicolinamide. Yellow solid, 57 mg (44%). LCMS m/z 441.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.20 (d, J = 5.5 Hz, 1H), 7.89 (d, J = 5.5 Hz, 1H), 7.26 (s, 1 H), 5.31 (s, 1 H), 3.81 (s, 3H), 3.21 (br s, 3H), 3.14 (br s, 3H), 2.06 (s, 3H), 1.05 (s, 9H). RT = 4.13 min, 99.1% ee (SFC method F)
137
Ex. Structure Chemical Name and Analytical Data
23 0 (F NH Ν'Νχ Ço„ 1 (/7)-4-((2-(((1,4-Dimethyl-1 H-pyrazol-3-yl)(1 methylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide. Yellow solid, 35 mg (34%). LCMS m/z 453.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.22 (d, 5.5 Hz, 1H), 7.89 (d, J = 5.6 Hz, 1H), 7.29 (s, 1 H), 5.45 (s, 1 H), 3.82 (s, 3H), 3.22 (br s, 3H), 3.14 (br s, 3H), 2.28-2.17 (m, 2H), 2.07 (s, 3H), 2.02-1.88 (m, 1H), 1.85-1.59 (m, 3H), 1.32 (s, 3H). RT = 4.52 min, 99.7% ee (SEC method D)
24 O YY _F ' F s o=4 N-nh r° il T xn τ> 1 (/7)-4-((2-(((2,5-Dimethylthiazol-4-yl)(1-methylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide. Yellow solid, 140 mg (34%). LCMS m/z 470.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1 H), 9.98 (s, 1 H), 9.21 (d, J = 9.9 Hz, 1 H), 8.01 (s, 2H), 5.46 (d, J = 9.9 Hz, 1 H), 3.20 (br s, 3H), 3.06 (br s, 3H), 2.62 (s, 3H), 2.40 (s, 3H), 2.19 (q, J = 9.8 Hz, 1 H), 2.04 (q, J = 9.6 Hz, 1H), 1.96-1.83 (m, 1H), 1.80-1.69 (m, 1H), 1.65-1.51 (m, 2H), 1.19 (s, 3H). RT = 3.53 min, 97.2% ee (SEC method F)
25 O \ Ας A Y% J Ο=ΥΥ^ΝΗ νΆ n%oh F'O 1 (/7)-4-((2-((1 -(2,5-Dimethylthiazol-4-yl)-2,2-dimethylpropyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-N,/\/dimethylpicolinamide. Yellow solid, 71 mg (18%). LCMS m/z 458.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.74 (brs, 1H), 10.03 (brs, 1H), 9.23 (s, 1H), 8.10-7.88 (m, 2H), 5.30 (d, J = 10.1 Hz, 1H), 3.18 (s, 3H), 3.05 (s, 3H), 2.63 (s, 3H), 2.37 (s, 3H), 0.97 (s, 9H). RT = 3.23 min, 96.9 % ee (SFC method F)
138
Ex. Structure Chemical Name and Analytical Data
26 ο=Δ-ν'η A Α.·-ζνη X CA 'n^o 1 (R)-4-((2-(((4-Ethyl-1-methyl-1H-pyrazol-3-yl)(1methylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide. Yellow solid, 23.5 mg (44%). LCMS m/z 467.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.22 (d, J 5.6 Hz, 1 H), 7.90 (br s, 1 H), 7.32 (s, 1 H), 5.45 (s, 1H), 3.83 (s, 3H), 3.22 (brs, 3H), 3.15 (br s, 3H), 2.58-2.42 (m, 2H), 2.30-2.15 (m, 2H), 2.01-1.92 (m, 1H), 1.81-1.60 (m, 3H), 1.32 (s, 3H), 1.19 (t, J = 7.5 Hz, 3H). RT = 4.61 min, 100% ee (SFC method F)
27 8 oAxn / χΝΗ Ah χΙο 1 (R)-4-((2-((1 - (4- Ethyl-1 -methyl-1 H-pyrazol-3-yl)-2,2dimethylpropyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3hydroxy-/V,A/-dimethylpicolinamide. Yellow solid, 41.4 mg (35%). LCMS m/z 455.4 [M+H]+. Ή NMR (400 MHz, CD3OD) δ 8.21 (d, J = 5.6 Hz, 1H), 7.91 (br s, 1H), 7.33 (s, 1H), 5.33 (s, 1H), 3.86 (s, 3H), 3.22 (brs, 3H), 3.14 (br s, 3H), 2.602.42 (m, 2H), 1.18 (t, J = 7.5 Hz, 3H), 1.07 (s, 9H). RT = 4.17 min, 95.7% ee (SFC method G)
28 ° Kr z, Ί 1 1 ζ ωΑ I V-O (R)-3-Hydroxy-4-((2-(((2-(hydroxymethyl)-5-methylthiazol-4yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1en-1-yl)amino)-A/,A/-dimethylpicolinamide. Yellow solid, 45.1 mg (46%) LCMS m/z 500.4 [M+H]+. Ή NMR (400 MHz, CD3OD) δ 8.21 (d, J = 5.6 Hz, 1 H), 7.95-7.85 (m, 1 H), 5.51 (s, 1H), 4.79 (s, 2H), 3.21 (brs, 3H), 3.14 (brs, 3H), 2.50 (s, 3H), 1.90-1.76 (m, 2H), 1.75-1.60 (m, 4H), 1.47-1.40 (m, 1H), 1.33-1.25 (m, 1H), 1.14 (s, 3H). RT = 5.15 min, 98.7% ee (SFC method G)
139
Ex. Structure Chemical Name and Analytical Data
29 J XA oII-νη Y rYH nYoh Y A I (R)-4-((2-(((4-Cyclopropyl-1 -methyl-1 /7-pyrazol-3-yl) (1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide. Yellow solid, 15.9 mg (33%). LCMS m/z 493.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.5 Hz, 1 H), 7.95-7.85 (m, 1 H), 7.14 (s, 1 H), 5.63 (s, 1 H), 3.81 (s, 3H), 3.32-3.11 (m, 6H), 1.981.75 (m, 2H), 1.75-1.60 (m, 5H), 1.53-1.42 (m, 1 H), 1.391.30 (m, 1H), 1.20 (s, 3H), 0.89-0.86 (m, 2H), 0.54-0.52 (m, 1 H), 0.44-0.41 (m, 1 H). RT = 4.86 min, 100% ee (SFC method F)
30 O ÏÏ /O N oAAnh L h T N Αόπ Yi^o (R)-4-((2-(((4-Cyano-1 -methyl-1 /7-pyrazol-3-yl)(1 methylcyclopentyI)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-A/-ethyl-3-hydroxy-/V-methylpicolinamide. Yellow solid, 14.3 mg (23%). LCMS m/z 492.5 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.5 Hz, 1H), 8.19 (s, 1H), 7.987.90 (m, 1 H), 5.53 (s, 1 H), 3.96 (s, 3H), 3.71-3.60 (m, 2H), 3.23-3.12 (m, 3H), 1.95-1.64 (m, 6H), 1.57-1.49 (m, 1 H), 1.42-1.22 (m, 4H), 1.16 (s, 3H). RT = 5.03 min, 98.5% ee (SFC method H)
31 VX Z=x Ai g z, Jx | i γ \___J Jx v? \ (R)-4-((2-(((4-cyano-1 -methyl-1 H-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-A/-isopropyl-A/-methylpicolinamide. Yellow solid, 14.8 mg (24%). LCMS m/z 506.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.24-8.20 (m, 1H), 8.19 (s, 1H), 7.93 (br s, 1 H), 5.53 (s, 1 H), 4.35-4.25 (m, 1 H), 3.96 (s, 3H), 3.02 (s, 3H), 1.95-1.65 (m, 6H), 1.60-1.45 (m, 1 H), 1.401.15 (m, 7H), 1.16 (s, 3H). RT = 4.49 min, 97.6% ee (SFC method J)
140
Ex. Structure Chemical Name and Analytical Data
32 Â O=/>—NH N \ il I I ° I (R)-4-((2-(((2,5-Dimethylthiazol-4-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy/V,/V-dimethylpicoIinamide. Yellow solid, 63 mg (30%). LCMS m/z 484.4 [M+H]+. Ή NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.6 Hz, 1H), 7.92 (br s, 1H), 5.48 (s, 1H), 3.24 (br s, 3H), 3.16 (brs, 3H), 2.62 (s, 3H), 2.45 (s, 3H), 1.90-1.75 (m, 2H), 1.75-1.55 (m, 4H), 1.50-1.40 (m, 1 H), 1.40-1.30 (m, 1 H), 1.14 (s, 3H). RT = 3.44 min, 98.6% ee (SFC method F)
33 Xi o z—4 >=o 1 1 z, x I γ \X /°^Z H (R)-3-Hydroxy-4-((2-(((5-methoxy-2-methylthiazol-4-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-A/,A/-dimethylpicolinamide. Yellow solid, 34.4 mg (42%). LCMS m/z 500.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.6 Hz, 1 H), 7.92 (br s, 1 H), 5.46 (s, 1 H), 3.94 (s, 3H), 3.22 (br s, 3H), 3.14 (br s, 3H), 2.58 (s, 3H), 1.881.76 (m, 2H), 1.70-1.60 (m, 4H), 1.43-1.38 (m, 1 H), 1.321.25 (m, 1H), 1.12 (s, 3H). RT = 1.46 min, 100% ee (SFC method B)
Example 34 (R)-4-((2-(((2,5-Dimethyloxazol-4-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en5 1 -yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide.
Step 34A. (2,5-Dimethyloxazol-4-yl)(1-methylcyclopentyl)methanamine
The title compound was prepared in a similar manner to (1,4-dimethyl-1H-pyrazol-3yl)(5-methylspiro[2.3]hexan-5-yl)methanamine (Préparative Step 17D) employing 2,520305
141 dimethyloxazole-4-carboxyIic acid and cyclopentyîmagnesium bromide. LCMS m/z 192.2 [MNH2]+.
Step 34B. (7)-4-((2-(((2,5-Dimethyloxazol-4-yl)(1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide.
To a solution of (2,5-dimethyloxazol-4-yl)(1-methylcyclopentyl)methanamine (45 mg, 0.22 mmol) in EtOH (1.6 mL) was added 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-/V,/V-dimethylpicolinamide (Préparative Step 1H) (50 mg, 0.16 mmol) and DIEA (318 mg, 2.46 mmol). The resulting solution was stirred at 40 °C overnight. The reaction mixture was concentrated in vacuo. The residue was subjected to enantiomer séparation employing chiral SPC conditions (Chiralcel OD, 250 mm x 21 mm x 5 pm, 5 to 60% 0.2% NH4 + (7 N in MeOH) in MeOH, 80 mL/min). Isolation ofthe first eluting isomer afforded 16 mg (21%) ofthe title compound and the second eluting isomer afforded 23 mg (30%) ofthe corresponding enantiomer. LCMS m/z 468.6 [M+H]+. 1H NMR (400 MHz, DMSO-de) δ 9.23—9.10 (m, 1 H), 7.98-7.97 (m, 1H), 7.91 (br s, 1H), 5.17-5.15 (s, 1H), 3.17 (s, 3H), 3.04 (s, 3H), 2.37 (s, 3H), 2.25 (s, 3H), 1.78-1.47 (m, 7H), 1.37-1.10 (m, 3H), 1.05 (s, 3H). RT = 5.58 min, 100% ee (SFC method C)
Example 35 (7)-4-((2-(((1,4-Dimethyl-17-pyrazol-3-yl)(1 -ethylcyclobutyl) methyl)amino)-3,4-dioxocyclobut-1 en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide
Step 35A. (1,4-Dimethyl-17-pyrazol-3-yl)(1-ethylcyclobutyl)methanamine
The title compound was prepared in a similar mannerto (1,4-dimethyl-17-pyrazol-3yl)(5-methylspiro[2.3]hexan-5-yl)methanamine (Préparative Step 17D) employing 1ethylcyclobutane-1-carboxylic acid and 3-iodo-1,4-dimethyl-1H-pyrazole. LCMS m/z 190.8 [MNH2]+
Step 35B. (7)-4-((2-(((1,4-Dimethyl-17-pyrazol-3-yl)(1-ethylcyclobutyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide
142
To a solution of (1,4-dimethyl-1/-/-pyrazol-3-yl)(1-ethylcyclobutyl)methanamine (800 mg, 3.28 mmol) in EtOH (15 mL) was added 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-/V,/V-dimethylpicolinamide (Préparative Step 1H) (120 mg, 0.39 mmol) and DIEA (152 mg, 1.18 mmol). The resulting solution was stirred at 30 °C overnight. The reaction mixture was concentrated in vacuo. The residue was purified using préparative HPLC (Agela Durashell C18 150 mm x 25 mm x 5 pm 13 to 53% CH3CN in 0.05% NH4OH in water, 25 mL/min, 11 min) to afford 100 mg of the racemic product. The racemic mixture was subjected to enantiomer séparation employing chiral SFC conditions (REGIS (s,s) WHELK-01 250 mm x 30 mm x 5 pm 45% 0.1 % NH4OH in EtOH, 60 mL/min). Isolation of the first eluting isomer afforded 33 mg (18%) of the title compound as a yellow solid and the second eluting isomer afforded 34 mg (19%) of the corresponding enantiomer as a yellow solid. LCMS m/z 467.4 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.27 (d, J = 5.6 Hz, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.31 (s, 1H), 5.51 (s, 1H), 3.84 (s, 3H), 3.30-3.10 (m, 6H), 2.46-2.38 (m, 1H), 2.15-2.05 (m, 4H), 1.95-1.60 (m, 6H), 1.00(t, J = 7.4, 3H). Chiral SFC (SFC method I) RT = 10.44 min, 97.2% ee (title compound) and RT = 14.45 min, 91.9% ee (enantiomer).
Example 36.
4-((2-(((S)-((S)-4,4-Difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1/-/-pyrazol-3yl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide
Step 36A. Ethyl 2-hydroxy-2-methylpent-4-enoate
To a solution of ethyl 2-oxopropanoate (76 g, 654.5 mmol) in DCM (380 mL) at -78 °C was added titanium (IV) çhloride (124 g, 655 mmol). The resulting mixture was stirred at the same température for 30 min as it turned into a yellow suspension. Allyltrimethylsilane (97.2 g, 851 mmol) was then added and the reaction was stirred for 2 h. The reaction was warmed to 0 °C and quenched with saturated aqueous Na2CO3 solution (1.5 L) and extracted with DCM (3.0 L x 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (5 to 10% EtOAc in Petroleum ether) to afford 134 g (63%) of the title compound as a light yellow oil. LCMS m/z 158.8 [M+H]+. Ή NMR (400 MHz, CDCl3) δ 5.80-5.70 (m, 1H), 5.12 (s, 1H), 5.10-5.07 (m, 1H),
143
4.25- 4.15 (m, 2H), 3.19 (s, 1H), 2.53-2.45 (m, 1H), 2.41-2.38 (m, 1H), 1.41 (s, 3H), 1.32-1.25 (m, 3H).
Step 36B. Ethyl 2-hydroxy-2-methyl-3-(oxiran-2-yl)propanoate
To a solution of ethyl 2-hydroxy-2-methylpent-4-enoate (46 g, 290.8 mmol) in DCM (1.45 L) at 0 °C was added m-CPBA (81.5 g, 378 mmol, 80% purity) in portions over 20 min. The reaction mixture was stirred at 10 °C for 1 h, and then warmed to 35 °C and stirred for 16 h. The mixture was cooled down to 0 °C and quenched with saturated aqueous Na2S2O3 solution. The organic layer was separated and washed with saturated aqueous Na2CO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 81 g (80%) of the title compound as a light yellow oil consisting of a diastereomeric mixture. 1H NMR (400 MHz, CDCI3) δ 4.35-4.20 (m, 2H), 3.50 (s, 0.5H), 3.35 (s, 0.5H), 3.15-3.05 (m, 1H), 2.80-2.70 (m, 1H), 2.50-2.42 (m, 1H), 2.01-1.85 (m, 2H), 1.48 (s, 1,5H), 1.45 (s, 1,5H), 1.35-1.30 (m, 3H).
Step 36C. Ethyl 2-methyl-4-oxotetrahydrofuran-2-carboxylate
Magnésium bromide (12 g, 65.4 mmol) was added to a solution of ethyl 2-hydroxy-2methyl-3-(oxiran-2-yl)propanoate (76 g, 436 mmol) in THF (957 mL). The mixture was heated at 80 °C for 16 h. The reaction mixture was then concentrated in vacuo. The residue was taken up in water (100 mL) and extracted with DCM (500 mL x 2). The combined organic extracts were concentrated in vacuo. The residue was dissolved in DCM (2080 mL) and cooled to 0 °C. Silica gel (78.6 g, 1310 mmol) and PCC (122 g, 567 mmol) were added, and the mixture was stirred at 10 °C for 16 h. Additional PCC (18.8 g, 87.3 mmol) was added and the mixture was stirred at 30 °C for 4 h. The reaction mixture was filtered and the solids were washed with DCM (500 mL x 2). The organic filtrate was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (10 to 15% EtOAc in petroleum ether) to give 24.3 g (32%) of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCI3) δ 4.26-4.20 (m, 2H), 4.14 (s, 2H), 2.90-2.85 (m, 1H), 2.47-2.41 (m, 1H), 1.63 (s, 3H), 1.321.28 (m, 3H).
Step 36D. Ethyl 4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate
DAST (37.4 g, 232 mmol) was added dropwise to a neat sample of ethyl 2-methyl-4oxotetrahydrofuran-2-carboxylate (20.0 g, 116.2 mmol) at 10 °C. The resulting mixture was stirred at the same température for 15 h. The mixture was then diluted with DCM (50 mL), and
144 poured into a saturated aqueous NaHCO3 solution (500 mL) at 0 °C. The mixture was extracted with DCM (500 mL x 2), and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow oil. The crude was used directly without further purification assuming quantitative yield. 1H NMR (400 MHz, CDCI3) δ 4.30-4.20 (m, 2H), 4.20-4.05 (m, 2H), 2.95-2.85 (m, 1H), 2.40-2.25 (m, 1H), 1.57 (s, 3H), 1.35-1.25 (m, 3H). 19F NMR (376 MHz, CD3OD) δ -101, -98.0.
Step 36E. Benzyl (S)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate
To a solution of ethyl 4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate (36.5 g, 140 mmol) in THF (1.5 L) at 15 °C was added a 1.0 M aqueous solution of LiOH (214 mL, 214 mmol). The mixture was stirred at 15 °C for 2 h, and then concentrated in vacuo. The residue was acidified with 1.0 M aqueous HCl solution until the solution pH reached 3, and then was extracted with DCM (600 mL x 3) and DCM/MeOH (10/1,600 mL x 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in acetonitrile (500 mL) and K2CO3 (25 g, 181 mmol) was added in portions. Benzyl bromide (25 g, 146 mmol) was then added dropwise. The resulting suspension was stirred at 60 °C for 16 h. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic extracts were concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 25% EtOAc in petroleum ether) to give the racemic product as a yellow oil (24.7 g, 80%). A portion ofthe racemic product (5.0 g) was subjected to chiral resolution employing normal phase chiral chromatography conditions (Phenomenex Lux 10 pm Cellulose-3 45% EtOH in hexanes, 20 mL/min, 12 min). Isolation of the second eluting peak afforded 2.56 g of the title compound as a colorless oil. LCMS m/z 274.2 [M+water]. 1H NMR (400 MHz, CDCI3) δ 7.39-7.34 (m, 5H), 5.21 (s, 2H), 4.15-4.04 (m, 2H), 2.96-2.84 (m, 1 H), 2.40-2.24 (m, 1 H), 1.59 (s, 3H). 19F NMR (376 MHz, CDCI3) δ -101, 98.0.
Step 36F. (S)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylic acid ((1 R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,1 Oa-octahydrophenanthren-1 30 yl)methanamine sait
145
The absolute stereochemistry of the title compound was determined by single crystal Xray crystallography (Figure 3). Benzyl (S)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate was hydrolyzed to the corresponding acid and crystallized with ((1 R,4aS,10aR)-7-isopropyl1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methanamine from éthanol.
Step 36G. (S)-(4,4-Difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1/7-pyrazol-3yl)methanone
To a solution of 3-iodo-1,4-dimethyl-1H-pyrazole (Préparative Step 1 D) (394 mg, 1.77 mmol) in THF (3.23 mL) at 0 °C was added dropwise i-PrMgCI· LiCI (1.37 mL, 1.77 mmol, 1.3 M 10 solution in THF). The resulting yellow solution was stirred at the same température for 2 h, and then warmed to ambient température and stirred for 30 min. The mixture was cooled to 0 °C, and benzyl (S)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate (413 mg, 1.61 mmol) was added. The mixture was stirred at 0 °C for 30 min, and then warmed to ambient température and stirred for >12 h. The reaction mixture was quenched with a saturated aqueous NH4CI solution and the mixture was extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 100% EtOAc in DCM) to afford 351 mg (89%) of the title compound as an oil. LCMS m/z 245.3 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 7.16 (s, 1H), 4.20-4.05 (m, 2H), 3.90 (s, 3H), 3.34-3.23 (m, 1H), 2.62-2.51 (m, 1H), 2.29 (s, 3H), 1.78 (s, 3H).
Step 36H. (S,R)-((S)-4,4-Difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1H-pyrazol-3yl)methanamine
To a solution of (S)-(4,4-difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1/7-pyrazol3-yl)methanone (352 mg, 1.44 mmol) in methanolic ammonia (1.23 g, 10.3 mL, 72.1 mmol, 7.0 25 M in MeOH) was added titanium (IV) ethoxide (1.97 g, 1.81 mL, 8.65 mmol). The resulting suspension was sealed and stirred at 60 °C overnight. The reaction was cooled down to 0 °C, and NaBH4 (224 mg, 5.91 mmol) was added. The mixture was stirred at 0 °C for 30 min, and then at ambient température for 1 h. The reaction mixture was concentrated in vacuo. HCl (1.0 N aqueous solution) was added to the residue until the mixture was acidic, and then was 30 extracted with Et2O. The aqueous layer was neutralized with NaOH (1.0 N aqueous solution), and then extracted with DCM (x 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in DCM (2 mL) and HCl (4 mL, 4.0 M in MeOH) was added. The solution was stirred for 10 min and then concentrated in vacuo
146 to afford the title compound as a white solid as a mono-HCI sait. The product was isolated as a mixture of two diastereomers and used directly without further purification.
Step 361. 4-((2-(((S)-((S)-4,4-difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1H-pyrazol-3yl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide
DIEA (131 mg, 1.02 mmol) and (S,R)-((S)-4,4-difluoro-2-methyltetrahydrofuran-2-yl)(1,4dimethyl-1H-pyrazol-3-yl)methanamine (292 mg, 1.19 mmol) was added to 4-((2-ethoxy-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide (Préparative Step 1G) (330 mg, 1.08 mmol) in EtOH (1.9 mL). The mixture was stirred at room température for 18 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (0 to 10% MeOH in DCM). The resulting diastereomeric mixture was separated by chiral SFC chromatography (Chiral Tech OD-H, 250 mm x 30 mm, 5 pm, 25% éthanol containing 0.2% 7N ammonia in methanol, 80 mL/min). Isolation ofthe first eluting peak afforded 299 mg (55%) of the title compound as a yellow solid. LCMS m/z 505.4 [M+H]+ 1H NMR (600 MHz, DMSO-de) δ 10.48 (br s, 2 H), 9.23 (br s, 1 H), 7.99 (d, J=5.3 Hz, 1 H), 7.91 (br. s., 1 H), 7.49 (s, 1 H), 5.56 (d, J = 8.4 Hz, 1H), 4.10-3.96 (m, 1H), 3.93-3.82 (m, 1H), 3.80 (s, 3H), 3.14 (br s, 3H), 3.03 (br s, 3H), 2.55-2.45 (m, 1H), 2.34-2.22 (m, 1H), 1.99 (s, 3H), 1.49 (s, 3H). Chiral SFC (SFC method A) RT = 5.26 min, 100% ee.
Examples 37 to 38
The title compounds in Table 3 were prepared in a similar manner to 4-((2-(((S)-((S)-4,4difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1/7-pyrazol-3-yl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide (Example 36) employing the appropriate heteroaryl halide.
147
Table 3
Ex. Structure Chemical Name and Analytical Data
37 F fQi__ A AAn/ 0=<Y>—NH ,NH X N AC γ OH Ά I 4-((2-(((S)-((S)-4,4-Difluoro-2-methyltetrahydrofuran-2-yl)(4ethyl-1-methyl-1/7-pyrazol-3-yl)methyl)amino)-3,4dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide. Yellow solid, 21.5mg (15%). LCMS m/z 519.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.24 (d, J = 5.6 Hz, 1H), 7.95-7.90 (m, 1H), 7.38 (s, 1H), 5.68 (s, 1H), 4.10-3.88 (m, 2H), 3.86 (s, 3H), 3.23 (brs, 3H), 3.16 (br s, 3H), 2.75-2.65 (m, 1 H), 2.60-2.45 (m, 2H), 2.35-2.20 (m, 1 H), 1.60 (s, 3H), 1.20 (t, J = 7.5 Hz, 3H). 19F NMR (376 MHz, CD3OD) δ -104, -98.0. RT = 3.86 min, 100% ee (SFC method D)
38 A z I χχ z o=/V-z o ° tA / 4-((2-(((S)-((S)-4,4-Difluoro-2-methyltetrahydrofuran-2-yl)(2,5dimethylthiazol-4-yl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-/\/,/\/-dimethylpicolinamide. Yellow solid, 22.9 mg (9%). LCMS m/z 522.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.24 (d, J = 5.5 Hz, 1H), 7.92 (d, J = 5.5 Hz, 1H), 5.71 (s, 1H), 4.02 (q, J = 10.9 Hz, 1H), 3.86 (dt, J = 18.6, 10.3 Hz, 1 H), 3.23 (br s, 3H), 3.16 (br s, 3H), 2.85-2.70 (m, 1 H), 2.64 (s, 3H), 2.47 (s, 3H), 2.26 (ddd, J = 17.7, 14.4, 8.0 Hz, 1H), 1.54 (s, 3H). 19F NMR (376 MHz, CD3OD) δ -104, -98. RT = 4.14 min, 100.0% ee (SFC method H)
Example 39 (R)-3-hydroxy-/\/,/\/-dimethyl-4-((2-(((1-methyl-4-(methyl-d3)-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide
148
Step 39A. 4,4,5,5-Tetramethyl-2-(methyl-d3)-1,3,2-dioxaborolane
To a dried and nitrogen filled flask equipped with a condenser and addition tunnel was added Mg métal (1.26 g, 51.7 mmol) and a flake of iodine. The bottom of flask was heated with a heat gun untill purple gas spread onto the Mg surface. Et2O (5 mL) was added. The solution was stirred until the iodine color disappeared. Once the solution turned colorless, a solution of iodomethane-d3 (5.0 g, 34.49 mmol) in Et2O (45 mL) was added slowly. After the addition was complété, the reaction was heated to reflux for 20 min. The formed Grignard reagent was added dropwise to a solution of 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.45 g, 5.65 mL, 34.5 mmol) in Et2O (20 mL) at -60 °C. The reaction was then allowed to warm to 20 °C and stirred for 1 h. The reaction mixture was quenched with saturated NH4CI and the layers separated. The organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated to afford the title compound, which was used without further purification.
Step 39B. A/-Methoxy-A/,1-dimethylcyclopentane-1-carboxamide
To a solution of 1-methylcyclopentane-1-carboxylic acid (60 g, 470 mmol) in DCM (1.5 L) was added HN(Me)(OMe)-HCI (50.2 g, 515 mmol), TEA (194 g, 1.92 mol) and HATU (267 g, 702 mmol) at 0 °C. The mixture was stirred at 25 °C for 15 h and then concentrated. The residue was added to saturated aqueous Na2CO3 (1 L) and extracted with EtOAc (2x1 L). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated and the residue was purified by distillation to afford 62.1 g (77%) of the title compound as a colorless oil. LCMS 193.2 [M+H]+. Ή NMR (400 MHz, CDCI3) δ 3.69 (s, 3H), 3.20 (s, 3H), 2.15-2.01 (m, 2H), 1.73-1.54 (m, 6H), 1.26 (s, 3H).
Step 39C. (1-Methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methanone 3-lodo-1-methyl-1 H-pyrazole (2.19 g, 10.5 mmol) was added dropwise to iPrMgCl·LiCI (10.8 mL, 14.0 mmol, 1.3 M THF solution) and THF (14 mL) cooled to 0 °C under a nitrogen atmosphère. The mixture was allowed to stir at room température for 1 h. A/-Methoxy-A/,1 dimethylcyclopentane-1-carboxamide (1.2 g, 7.0 mmol) was then added dropwise. The mixture was stirred at room température for 18 h and then was quenched with saturated aqueous NH4CI. The reaction mixture was extracted with EtOAc. The organic extract was dried (Na2SO4) and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (10-50% EtOAc/heptane) to afford 992 mg (74%) of the title compound. LCMS 172.4 [M+H]+· 1H NMR (400 MHz, CDCI3) δ 7.34 (d, J = 2.3 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 3.98 (s, 3H), 2.46-2.33 (m, 2H), 1.79-1.63 (m, 6H), 1.49 (s, 3H).
149
Step 39D. (4-lodo-1 -methyl-1 H-pyrazol-3-yl)(1 -methylcyclopentyl)methanone
NIS (702 mg, 3.12 mmol) was added to a solution of (1 -methyl-1 /-/-pyrazol-3-yl)(1methylcyclopentyl)methanone (400 mg, 2.08 mmol) in acetic acid (4.2 mL) and the mixture was stirred at room température for 18 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (0-20% EtOAc/heptane) to afford 595 mg (90%) of the title compound as a white solid. 1H NMR (400 MHz, CDCL) δ 7.47 (s, 1H), 3.98 (s, 3H), 2.43-2.32 (m, 2H), 1.80-1.60 (m, 6H), 1.47 (s, 3H).
Step 39E. (1-Methyl-4-(methyl-d3)-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methanone
A vial containing (4-iodo-1-methyl-1 H-pyrazol-3-yl)(1-methylcyclopentyl)methanone (532 mg, 1.67 mmol), 4,4,5,5-tetramethyl-2-(methyl-d3)-1,3,2-dioxaborolane (1.7 g, 11.7 mmol), dioxane (8 mL) and aqueous K3PO4 (3.55 g, 16.7 mmol, 8.36 mL, 2.0M) was purged with argon gas for 5 min. P(tBu)3 Pd-G2 (177 mg, 0.33 mmol) was added and the mixture was heated to 100 °C for 4 h. The reaction mixture was partitioned with EtOAc. The organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (50% DCM/heptane) to afford 185 mg (53%) of the title compound. 1H NMR (400 MHz, CDCI3) δ 7.14 (s, 1H), 3.90 (s, 3H), 2.43-2.32 (m, 2H), 1.78-1.61, (m, 6H), 1.49 (s, 3H).
Step 39F. (1-Methyl-4-(methyl-d3)-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanone oxime A vial containing NaOAc (129 mg, 1.58 mmol), hydroxylamine hydrochloride (219 mg, 3.15 mmol), (1-methyl-4-(methyl-d3)-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanone (165 mg, 0.788 mmol), and EtOH (3.94 mL) was heated at 95 °C for 2 h and then cooled to room température. The solvent was removed and the residue was partitioned between DCM and saturated aqueous NaCI. The layers were separated and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated to afford 212 mg of the title compound as a solid. LCMS m/z 225.2 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 7.21 (s, 1H), 3.89 (s, 3H), 2.11-1.99 (m, 2H), 1.77-1.60 (m, 4H), 1.53-1.40 (m, 2H), 1.25 (s, 3H).
Step 39G. (1-Methyl-4-(methyl-d3)-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine HOAc (3 mL), followed by Zn (311 mg, 4.76 mmol) were added to a flask containing (1 methyl-4-(methyl-c(3)-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methanone oxime (178 mg, 0.79
150 mmol). The mixture was heated at 60 °C overnight. After cooling to room température, the reaction mixture was filtered through Celite and washed with HOAc. The filtrate was concentrated and azeotroped with toluene (3 times). The residue was diluted with DCM and Et2O and pH was adjusted to pH~14 with 50% aqueous NaOH. The layers were separated and the aqueous layer extracted twice with DCM/Et2O (2:8). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated to afford 145 mg (87%) of the title compound. LCMS m/z 194.2 [M-NH2]+. Ή NMR (400 MHz, CDCI3) δ 7.05 (s, 1H), 3.81 (s, 3H), 3.55-3.47 (m, 1H), 1.81-1.14 (m, 8H), 1.05 (s, 3H).
Step 39H. (R)-3-Hydroxy-A/,N-dimethyl-4-((2-(((1-methyl-4-(methyl-c/3)-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide EtOH (3.0 mL), 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/Vdimethylpicolinamide (Préparative Step 1H) (842 mg, 0.7 mmol) and DIEA (267 mg, 0.36 mL, 2.07 mmol) were added to a flask containing (1-methyl-4-(methyl-c/3)-1/7-pyrazol-3-yl)(115 methylcyclopentyl)methanamine (145 mg, 0.69 mmol). The mixture was stirred at room température overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (6% MeOH/DCM) to afford the racemic product. The racemate was resolved by chiral SFC chromatography (Chiralcel OD, 250 mm x 30 mm, 5 pm, 80 mL/min, 25% MeOH containing 0.2% 7N ammonia/MeOH). Isolation of the first eluting enantiomer afforded 70 mg of the title compound. LCMS m/z 470.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 9.92 (s, 1H), 9.13 (d, J = 10.1 Hz, 1H), 8.02 (s, 2H), 7.44 (s, 1 H), 5.35 (d, J = 10.1 Hz, 1 H), 3.81 (s, 3H), 3.22-3.07 (m, 6H), 1.72-1.60 (m, 6H), 1.39-1.12 (m, 2H), 1.10 (s, 3H). The second eluting enantiomer was isolated to afford 70 mg of the corresponding (S)-enantiomer.
Example 40
4-((2-(((1 R)-(1,4-dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl-3,4-cymethyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/-dimethylpicolinamide
D
151
Step 40A. Cyclopent-3-ene-1-carboxylic acid
To a solution of methyl 1-methylcyclopent-3-ene-1-carboxylate (50 g, 396 mmol) in THF:H2O (500 mL:125 mL) at 25 °C was added LiOH (19 g, 793 mmol). After 15 h, the reaction mixture was extracted with EtOAc. The aqueous layer was then acidified to pH = 3 with 1N HCl and extracted with EtOAc (3 x 1L). The combined organic extracts were combined, dried (Na2SO4) and filtered. The filtrate was concentrated to afford 40 g (90%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCI3) δ 5.68 (s, 2H), 3.29-3.03 (m, 1H), 2.82-2.53 (m, 4H).
Step 40B. 1-Methylcyclopent-3-ene-1-carboxylic acid
To a solution of LDA (2M in THF/heptane/ethyl benzene, 446 mL) in THF (800 mL) was added dropwise a solution of cyclopent-3-ene-1-carboxylic acid (40 g, 357 mmol) in THF (200 mL) maintaining a température of -30 °C. The mixture was warmed to 25 °C and stirred for 15 h. The mixture was then cooled to -30 °C and iodomethane (50.6 g, 22.2 mL, 357 mmol) was added. After 2 h at 25 °C, the mixture was quenched with 3M HCl and extracted with EtOAc (3 x 1 L). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc) to afford 45 g (100%) ofthe title compound as an oil. 1H NMR (400 MHz, CDCI3) δ 5.64 (s, 2H), 2.98 (d, J = 14. 7 Hz, 2H), 2.28 (d, J = 14.7 Hz, 2H), 1.36 (s, 3H).
Step 40C. A/-Methoxy-/V,1-dimethylcyclopent-3-ene-1-carboxamide
To a solution of 1-methylcydopent-3-ene-1-carboxylic acid (45 g, 357 mmol) in DCM (1 L) at 0 °C was added HN(Me)(OMe)-HCI (38.3 g, 392 mmol), TEA (148 g, 1.46 mol) and HATU (203 g, 535 mmol). After stirring at room température for 24 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (1 L) and washed with saturated aqueous Na2CO3. The aqueous layer was further extracted with EtOAc (1 L). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE:EtOAc, 20:1 to 5:1) to afford 23.4 g (39 %) ofthe title compound as a light yellow oil. LC/MS m/z 170.3 [M+H]+; 1H NMR (400 MHz, CDCI3) δ 5.59 (s, 2H), 3.69 (s, 3H), 3.20 (s, 3H), 2.88 (d, J = 15.1 Hz, 2H), 2.23 (d, J = 15.1 Hz, 2H), 1.27 (s, 3H).
152
Step 40D. (1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopent-3-en-1-yl)methanone
A 125 mL round bottomed flask with stir bar and fitted with a septum was backfilled with nitrogen three times, after which THF (7.0 mL) was added followed by 3-iodo-1,4-dimethyl-1/7pyrazole (Préparative Step 1 D) (917 mg, 4.13 mmol). To this solution was added dropwise a 1.3 M solution of iPrMgCI-LiCI in THF (5.45 mL) and the mixture was stirred for 1 h at room température. N-Methoxy-A/,1-dimethylcyclopent-3-ene-1-carboxamide (600 mg, 3.55 mmol) in THF (5 mL) was added dropwise. After stirring for 2 h, the reaction mixture was quenched with saturated aqueous NH4CI (20 mL) and extracted with DCM (3 x 25 mL). The combined extracts were dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc in heptane, 0-100%) to afford 500 mg (69%) ofthe title compound as a colorless oil. 1H NMR (400 MHz, CDCh) δ 7.14 (s, 1H), 5.70-5.64 (m, 2H), 3.90 (s, 3H), 3.20-3.12 (m, 2H), 2.44-2.36 (m, 2H), 2.30 (s, 3H), 1.52 (s, 3H).
Step 40E. Λ/-((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopent-3-en-1-yl)methyl)formamide Formamide (10.5 mL) and formic acid (6 mL) was added to a flask containing (1,4dimethyl-1 H-pyrazol-3-yl)(1-methylcyclopent-3-en-1-yl)methanone (1.1 g, 5.4 mmol). The mixture was heated at 135 °C for 20 h and then cooled to room température. Water (60 mL) was added and the mixture was extracted with MTBE (3 x 50 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated to afford the title compound, which was used in next step without purification. LC/MS m/z = 234.0 [M+H]+.
Step 40F. (1,4-Dimethyl-1 H-pyrazol-3-yl)(1 -methylcyclopent-3-en-1-yl)methanamine
Aqueous 1N HCl (24 mL) was added to a flask containing A/-((1,4-dimethyl-1H-pyrazol-3yl)(1-methylcyclopent-3-en-1-yl)methyl)formamide (1.26 g, 5.4 mmol). The mixture was heated at 100 °C for 2 h and then cooled to room température. The pH ofthe solution was adjusted to pH ~11 with solid NaOH. The mixture was extracted with MTBE (3 x 30 mL). The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was concentrated to afford 1.1g (100%) ofthe title compound. LCMS m/z 189.1 [M-NH2]+. 1H NMR (400 MHz, CD3OD) δ 7.27 (s, 1 H), 5.66-5.58 (m, 2H), 3.86 (s, 1 H), 3.82 (s, 3H), 2.67-2.51 (m, 2H), 2.09-1.97 (m, 4H), 1.931.83 (m, 1H), 1.10 (s, 3H).
Step 40G. 4-((2-(((/3)-(1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopent-3-en-1yl)methyl)amino)-3,4-dioxocyc!obut-1-en-1-yl)amino)-3-hydroxy-/\/,/V-dimethylpicolinamide
153
A mixture of 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/Vdimethylpicolinamide (Préparative Step 1H) (300 mg, 0.983 mmol), (1,4-dimethyl-1/7-pyrazol-3yl)(1-methylcyclopent-3-en-1-yl)methanamine (242 mg, 1.18 mmol), éthanol (9.83 mL) and diisopropylethylamine (2.65 mL, 14.7 mmol) was stirred at 40 °C overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% MeOH in DCM) to afford 450 mg of racemic product. The enantiomers were resolved by chiral SFC (Chiral Tech OD-H, 250 mm x 21.2 mm, 5 pm, 22.5% methanol containing 0.2% 7N ammonia/MeOH, 80 mL/min). Isolation of the first eluting enantiomer afforded 80 mg of the title compound. LCMS m/z 465.4 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 12.84 (br. s., 1H), 8.27 (br. s., 1H), 8.02 (d, J = 5.1 Hz, 1H), 7.97 (br. s., 1H), 7.22 (br. s., 1 H), 7.11 (br. s., 1 H), 5.63 (br. s., 2H), 5.50 (br. s., 1 H), 3.81 (s, 3H), 3.61 (br. s., 3H), 3.19 (br. s., 3H), 2.78-2.64 (m, 2H), 2.15-2.02 (m, 5H), 1.21 (s, 3H). The second eluting enantiomer was isolated to afford 100 mg of the corresponding (S)-enantiomer.
Step 40H. 4-((2-(((1 R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl-3,4-d2)methyl)amino)3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide
To a Parr reactor with stir bar was added 4-((2-(((R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopent-3-en-1-yl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide (20 mg, 0.043 mmol), 10% Pd/C (6.05 mg) and MeOH (10 mL). The reactor was degassed with nitrogen and then charged with D2 gas to 10 psi. The reaction mixture was stirred for 16 h and then filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (0-20% MeOH/DCM) to afford 16 mg (80%) of the title compound as a yellow solid. LCMS m/z 469.4 [M+H]+. 1H NMR (400 MHz, DMSO d6) δ 11.75 (br. s., 1H), 9.96 (br. s., 1H), 9.17 (br. s., 1H), 8.05-7.89 (m, 2H), 7.44 (s, 1H), 5.35 (d, J = 10.2 Hz, 1H), 3.81 (s, 3H), 3.20 (br. s., 3H), 3.07 (br. s., 3H), 2.00 (s, 3H), 1.72-1.55 (m, 4H), 1.37-1.31 (m, 1H), 1.25-1.19 (m, 1H), 1.10 (s, 3H).
154
Example 41 (/7)-((4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1 -en-1 -yl)amino)-2-(dimethylcarbamoyl)pyridin-3-yl)oxy)methyl dihydrogen phosphate
Step 41 A. (/7)-Di-tert-butyl(((4-((2-(((1,4-dimethyl-1 H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-2-(dimethylcarbamoyl)pyridin-3-yl)oxy)methyl) phosphate
K2CO3 (89mg, 0.643 mmol), TBAI (119 mg, 0.322 mmol) and di-tert-butyl (chloromethyl) phosphate (0.65 mL, 0.75 mmol) were added to a room température solution of (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yi)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide (Example 1) (250 mg, 0.536 mmol)) in DMF. The reaction mixture was stirred at room température for 2 d and then toluene:H2O (4 mL:2 mL) was added. The layers were separated and the organic layer washed with brine, H3PO4 (1 M solution) and 10% Na2CO3. The organic layer was concentrated. The residue was taken up in toluene:MTBE (1 mL:20 mL) and placed in a refrigerator. The solid precipitate was collected and the filtrate concentrated. Heptane was added to the filtrate to effect précipitation of a solid, which was filtered, collected and dried on high vacuum to afford 140 mg (38%) ofthe title compound. LCMS 689.3 [M+H]+. 1H NMR (400 MHz, CDCh) δ 10.08 (s, 1H), 8.43—8.08 (m, 3H), 6.95 (s, 1H), 5.57 (s, 2H), 5.39 (d, J = 10.2 Hz, 1H), 3.68 (s, 3H), 3.06 (s, 3H), 2.75 (s, 3H), 2.00 (s, 3H), 1.82-1.53 (m, 6H), 1.45 (s, 9H), 1.43 (s, 9H), 1.41-1.18 (m, 2H), 1.09 (s, 3H).
Step 41 B. (/7)-((4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1 -en-1 -yl)amino)-2-(dimethylcarbamoyl)pyridin-3-yl)oxy)methyl dihydrogen phosphate
To a solution of (R)-di-tert-butyl(((4-((2-(((1,4-dimethyl-1H-pyrazol-3-ylW methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-2-(dimethylcarbamoyl)pyridin-3-yl)oxy)methyl) phosphate (80 mg, 0.12 mmol) in dioxane (1 mL) was added 4N HCl in dioxane (3 mL). After stirring for 45 h, the solvent was removed to afford 73 mg (100%) of the title compound as the HCl sait. LCMS 577.5 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.86 (d, J =
155
7.0 Hz, 1 H), 8.49 (d, J = 6.6 Hz, 1 H), 7.78 (s, 1 H), 5.75-5.63 (m, 1 H), 5.52-5.40 (m, 2H), 4.01 (s, 3H), 3.22 (s, 3H), 3.04 (s, 3H), 2.23 (s, 3H), 1.84-1.74 (m, 6H), 1.66-1.60 (m, 1 H), 1.501.41 (m, 1H), 1.22 (s, 3H).
Example 42 (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate
Method A. Calcium hydroxide (7.94 mg, 0.107 mmol) was added to a 7 mL vial with stir bar containing (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide (Example 1) (100 mg, 0.214 mmol) and MeOH (0.75 mL). The mixture was heated at 55 °C for 2 h and then cooled to room température and stirred for 72 h. The resulting suspension was filtered to afford the title compound as yellow crystals having a PXRD pattern consistent with that described in Figure 12. When the desired PXRD pattern was not obtained, the resulting sait was taken up in MeOH (1 g material/10 mL MeOH) and slurried until a PXRD pattern consistent with that described in Figure 12 was observed.
Method B. (R)-4-((2-((( 1,4-Dimethyl-1 H-pyrazol-3-yl) (1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide (Example 1) (6.0 g, 12.86 mmol), MeOH (45 mL), and water (3.6 mL) followed by calcium hydroxide (476 mg, 6.43 mmol) were added to a 250 mL round bottomed flask with stir bar. The suspension was stirred at 45 °C for 4 h and then at room température for 4 d. The suspension was filtered. The solids were then added to a 125 mL round bottomed flask with stir bar and suspended in MeOH (50 mL). The mixture was seeded with ~1 mg of the
156 title compound having a PXRD pattern consistent with that described in Figure 12. The mixture was stirred at room température for 20 h and then was filtered to afford 4.21 g of the title compound as a slightly yellow solid that was determined to hâve the PXRD pattern in Figure 12. LCMS m/z 467.5 [M+H]+. Ή NMR (400 MHz, DMSO-d6) δ 9.19 (br. d., J = 8.2 Hz, 1H), 7.66 (d, J = 4.7 Hz, 1 H), 7.40 (s, 1 H), 7.35 (m, 1 H), 5.37 (d, J = 9.8 Hz, 1 H), 3.77 (s, 3H), 3.06 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.72-1.59 (m, 6H), 1.22-1.20 (m, 1H), 1.19-1.18 (m, 1H), 1.09 (s, 3H).
Single Crystal X-Ray Analysis of crystalline (7)-4-((2-(((1,4-dimethyI-17-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/\/dimethylpicolinamide monohydrate
A crystal suitable for X-ray analysis was prepared by recrystallization from éthanol.
Data collection was performed on a Bruker D8 Venture diffractometer at room température. Data collection consisted of oméga and phi scans. The structure was solved by intrinsic phasing using SHELX software suite in the Tetragonal class space group P4(3). The structure was subsequently refined by the full-matrix least squares method. Ail non-hydrogen atoms were found and refined using anisotropic displacement parameters. The hydrogen atoms located on nitrogen and oxygen were found from the Fourier différence map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropie displacement parameters for ail hydrogen atoms.
Analysis ofthe absolute structure using likelihood methods (Hooft 2008) was performed using PLATON (Spek 2010). Assuming the sample submitted is enantiopure, the results indicate that the absolute structure has been correctly assigned. The final R-index was 4.3%. A final différence Fourier revealed no missing or misplaced électron density.
Figure 1 is the obtained X-ray structure (ORTEP drawing) of crystalline (7)-4-((2-(((1,4dimethyl-17-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide monohydrate. The crystal structure data is summarized in Table 4.
Table 4. Crystal data and structure refinement.
Empirical formula C24 H32 N6 05
Formula weight 484.55
Température 296(2) K
Wavelength 1.54178 Â
157
Crystal System Space group Unit cell dimensions Tetragonal P43 a = 10.6580(2) Â a = 90°. b = 10.6580(2) Â β = 90°. c = 22.9487(6) Â y = 90°.
Volume 2606.81(12) Â3
Z 4
Density (calculated) Absorption coefficient F(000) Crystal size Thêta range for data collection Index ranges Reflections collected 1.235 Mg/m3 0.727 mm 1 1032 0.140 x 0.080 x 0.040 mm3 5.871 to 70.212°. -12<=h<=12, -12<=k<=12, -28<=l<=25 72157
Independent reflections Completeness to thêta = 67.679° Absorption correction Refinement method 4856 [R(int) = 0.0500] 99.3 % Empirical Full-matrix least-squares on F2
Data / restraints / parameters Goodness-of-fit on F2 4856 /6/336 1.200
Final R indices [l>2sigma(l)] R indices (ail data) Extinction coefficient R1 = 0.0426, wR2 = 0.1240 R1 = 0.0445, wR2 = 0.1259 n/a
Largest diff. peak and hole 0.254 and -0.280 e.Â3
Single Crystal X-Ray Analysis of crystalline (R)-4-((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/dimethylpicolinamide monohydrate
A crystal suitable for X-ray analysis was grown from a mixture of heptane, ethyl acetate, acetone and DCM via slow évaporation over 48 hours.
Data collection was performed on a Bruker D8 Venture diffractometer at room température. Data collection consisted of oméga and phi scans. The structure was solved by intrinsic phasing using SHELX software suite in the Tetragonal class space group P43. The structure was subsequently refined by the full-matrix least squares method. Ail non-hydrogen
158 atoms were found and refined using anisotropic displacement parameters. Water was found from the différence map during refinement, modeled with 0.33 occupancy. The hydrogen atoms bonded to water were not included in the refinement. The hydrogen atoms located on nitrogen and oxygen were found from the Fourier différence map and refined with distances restrained.
The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropie displacement parameters for ail hydrogen atoms.
Analysis ofthe absolute structure using likelihood methods (Hooft 2008) was performed using PLATON (Spek 2010). Assuming the sample submitted is enantiopure, the results indicate that the absolute structure has been correctly assigned. The final R-index was 6.4%. A final différence Fourier revealed no missing or misplaced électron density.
Figure 2 is the obtained X-ray structure (ORTEP drawing) of crystalline (/7)-4-((2-(((4chloro-1 -methyl-1 /7-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)amino)-3-hydroxy-/\/,A/-dimethylpicolinamide monohydrate. The crystal structure data is summarized in Table 5.
Table 5. Crystal data and structure refinement.
Empirical formula Formula weight Température 20 Wavelength Crystal System Space group Unit cell dimensions 25 Volume Z Density (calculated) Absorption coefficient 30 F(000) Crystal size Thêta range for data collection Index ranges Reflections collected C23 H26.67 Cl N6 O 438.62 296(2) K 1.54178Â T etragonal P43 a = 10.5851(2) Â a = 90°. b = 10.5851(2) Â β = 90°. c = 22.9584(5) Â y = 90°. 2572.36(11) Â3 4 1.133 Mg/m3 1.503 mm'1 927 0.140 x 0.040 x 0.020 mm3 4.600 to 65.219°. -12<=h<=12, -12<=k<=10, -24<=l<=27 20312
Independent reflections Completeness to thêta = 65.219 Absorption correction Refinement method
Data / restraints / parameters Goodness-of-fit on F2
Final R indices [l>2sigma(l)]
R indices (ail data) Extinction coefficient Largest diff. peak and hole
159
4250 [R(int) = 0.0845]
99.2 %
None
Full-matrix least-squares on F: 4250/214/329
1.045
R1 = 0.0637, wR2 = 0.1550
R1 = 0.0872, wR2 = 0.1686 n/a
0.238 and -0.261 e.Â3
Single Crystal X-Ray Analysis of crystalline (S)-4,4-difluoro-2-methyltetrahydrofuran-2carboxylic acid ((1 R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10aoctahydrophenanthren-1-yl)methanamine sait (Example 36F)
A crystal suitable for X-ray analysis was prepared by recrystallization from éthanol.
Data collection was performed on a Bruker D8 Venture diffractometer at room température. Data collection consisted of oméga and phi scans. The structure was solved by intrinsic phasing using SHELX software suite in the Monoclinic class space group P21. The structure was subsequently refined by the full-matrix least squares method. Ail non-hydrogen atoms were found and refined using anisotropic displacement parameters. The hydrogen atoms located on nitrogen were found from the Fourier différence map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropie displacement parameters for ail hydrogen atoms.
Stereochemistry was based on the known chiral configurations from centers C4(-R), C7(-R), and C8(-S) of the base. The final R-index was 7.6%. A final différence Fourier revealed no missing or misplaced électron density.
Figure 3 is the obtained X-ray structure (ORTEP drawing) of crystalline (S)-4,4-difluoro2-methyltetrahydrofuran-2-carboxylic acid ((1 R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-
1,2,3,4,4a,9,10,1 Oa-octahydrophenanthren-1 -yl)methanamine sait. The crystal structure data is summarized in Table 6.
Table 6. Crystal data and structure refinement.
Empirical formula C52 H78 F4 N2 06
Formula weight 903.16
• 160
5 Température Wavelength Crystal System Space group Unit cell dimensions 296(2) K 1.54178Â Monoclinic P21 a = 10.8650(6) Â a = 90°.
10 Volume Z Density (calculated) b = 6.0384(4) Â β = 91.899(5)° c = 37.758(3) Â y = 90°. 2475.8(3) Â3 2 1.211 Mg/m3
15 Absorption coefficient F (000) Crystal size Thêta range for data collection Index ranges 0.718 mm'1 976 0.280x0.060x0.020 mm3 3.513 to 70.682°. -11<=h<=13, -6<=k<=6, -46<=l<=39
20 Reflections collected Independent reflections Completeness to thêta = 67.679° Absorption correction Refinement method 22232 7301 [R(int) = 0.0683] 88.6 % Empirical Full-matrix least-squares on F2
25 Data / restraints / parameters Goodness-of-fit on F2 Final R indices [l>2sigma(l)] R indices (ail data) Absolute structure parameter 7301 /7/607 1.038 R1 = 0.0762, wR2 = 0.1915 R1 = 0.1089, wR2 = 0.2102 0.04(15)
Extinction coefficient Largest diff. peak and hole 0.0032(8) 0.253 and -0.209 e.Â3
Powder X-ray diffraction analysis of crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1 30 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-/V,A/dimethylpicolinamide monohydrate
Powder X-ray diffraction analysis was conducted using a Bruker AXS D8 Advance diffractometer equipped with a Cu radiation source. Diffracted radiation was detected by a LYNXEYE_EX detector with motorized slits. Both primary and secondary detectors were
161 equipped with 2.5 soller slits. The X-ray tube voltage and amperage were set at 40kV and 40 mA, respectively. Data was collected in the Theta-Theta goniometer in a locked couple scan at Cu K-alpha wavelength from 3.0 to 40.0 degrees 2-Theta with an incrément of 0.01 degrees, using a scan speed of 1.0 seconds per step. Samples were prepared by placement in a Silicon low background sample holder (Bruker part number: C79298A3244B261). Data were collected and analyzed using Bruker DIFFRAC Plus software and analysis was performed by EVA Diffrac Plus software (v4.2.1.10). Generally a threshold value of 1 and a Width value of 0.3 were used to make preliminary peak assignments. To ensure validity, adjustments were manually made; the output of automated assignments was visually checked and peak positions were adjusted to the peak maximum. Peaks with relative intensity of > 3% were generally chosen. The peaks which were not resolved or were consistent with noise were not selected. A typical error associated with the peak position of crystalline material, from PXRD, stated in USP, is up to +10.2° 2-Theta (USP-941).
Figure 4 is the obtained powder X-ray diffraction pattern for crystalline (R)-4-((2-(((1,415 dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,/\/-dimethylpicolinamide monohydrate and Table 7 lists the diffraction peaks in terms of 2-theta values.
Table 7
Angle 2-Theta (degrees) Relative Intensity (%)
8.3 7.8
8.4 9.4
9.3 6.8
11.4 19.9
12.4 31.2
15.5 23.3
16.7 12.9
17.1 6.5
17.6 25.4
18.4 46.7
18.7 82.4
19.1 78.3
162
Angle 2-Theta (degrees) Relative Intensity (%)
19.5 5.2
20.2 100.0
21.1 7.3
22.0 10.2
22.8 6.5
23.7 16.9
24.0 7.4
24.3 32.4
24.9 13.2
26.4 21.9
26.8 20.2
27.0 17.4
27.6 7.5
28.5 9.4
28.8 7.7
29.0 3.2
29.7 13.2
30.0 10.5
30.3 10.8
30.5 26.8
30.8 6.0
31.3 4.8
32.5 10.5
33.0 5.0
33.2 3.9
33.7 4.7
34.2 5.6
34.5 6.0
34.8 7.5
34.9 8.4
35.6 13.1
163
Angle 2-Theta (degrees) Relative Intensity (%)
36.2 8.7
36.6 7.0
37.2 3.5
38.0 11.9
38.3 7.0
38.6 9.9
Differential scanning calorimeter analysis of crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,/Vdimethylpicolinamide monohydrate
Differential scanning calorimeter (DSC) measurements were performed with a Discovery DSC (TA instruments) equipped with a refrigerated cooling accessory. Ail the experiments were performed in standard/Tzero aluminum pans. The cell constant was determined using indium and température calibration was performed using indium and tin as standards. Ail the measurements were done under continuous dry nitrogen purge (50 mL/min). Approximately 1 -5 mg of solid sample was weighed into a Tzero aluminum pan, sealed non-hermetically and heated from 25 °C to at least 250 °C at a 10 °C/min heating rate. The experimental data were analyzed using commercially available software (TA Universal Analysis 2000/Trios software, TA Instruments).
Figure 5 is the obtained differential scanning calorimeter analysis for crystalline (/7)-4((2-(((1,4-dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1 -yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide monohydrate.
Thermogravimetric analysis of crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yI)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate
Thermogravimetric analysis was conducted using a Discovery TGA (TA instruments) thermogravimetric analyzer. Samples of approximately 10 mg were weighed into aluminum pans and heated from ambient to at least 250 °C at a 10 °C/minute heating rate under nitrogen purge (10 mL/min for both sample chamber and balance).
164
Figure 6 is the obtained thermogravimetric analysis for crystalline (/7)-4-((2-(((1,4dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,/V-dimethyIpicolinamide monohydrate.
Powder X-ray diffraction analysis of crystalline (/7)-4-((2-(((4-chloro-1 -methyl-1 /7-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/dimethylpicolinamide monohydrate
Powder X-ray diffraction analysis was conducted as described above. Figure 7 is the obtained powder X-ray diffraction pattern for crystalline (R)-4-((2-(((4-chloro-1 -methyl-1 H10 pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy/V,A/-dimethylpicolinamide monohydrate and Table 8 üsts the diffraction peaks in terms of 2theta values.
Table 8
Angle 2-Theta (degrees) Relative Intensity (%)
8.4 71.2
9.3 24.1
11.5 52.0
12.5 36.7
15.5 7.9
16.8 11.1
17.6 13.6
18.5 39.8
18.8 100.0
19.2 65.3
20.4 68.8
21.1 5.3
22.2 7.4
23.9 9.7
24.2 6.8
24.5 16.8
25.1 16.0
26.6 13.5
26.7 17.8
27.0 14.0
27.9 4.9
29.8 3.3
165
Angle 2-Theta (degrees) Relative Intensity (%)
30.6 3.2
30.8 12.4
31.0 3.0
32.8 7.7
35.1 3.1
36.0 3.1
36.4 3.3
Differential scanning calorimeter analysis of crystalline (/7)-4-((2-(((4-chloro-1-methyl-1/7pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide monohydrate
DSC measurements were performed as described above.
Figure 8 is the obtained differential scanning calorimeter analysis for crystalline (/7)-4((2-(((4-chloro-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1 -en-1 -yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide monohydrate.
Thermogravimetric analysis of crystalline (/7)-4-((2-(((4-chloro-1 -methyl-1 /7-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide monohydrate
Thermogravimetric analysis was performed as described above.
Figure 9 is the obtained thermogravimetric analysis for crystalline (/7)-4-((2-(((4-chloro-1methyl-1 /7-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyciobut-1 -en-1 -yl)amino)3-hydroxy-M,/\/-dimethylpicolinamide monohydrate.
Single Crystal X-Ray Analysis of crystalline (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/\/dimethylpicolinamide, 0.5 calcium sait,monohydrate
Solid calcium hydroxide (0.978 mg, 0.0132 mmol, 0.50 eq) was added to an HPLC vial with a stirbar. A solution of (/7)-4-((2-(((1,4-dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide (Example 1) (0.504 mL, 0.0265 mmol, 1.00 eq, 25.4 mg/mL) in méthanol was pipetted into the vial. The mixture was stirred at 60 °C for 3 h. During this time, a yellow solid formed. The stirring was turned off and the mixture slowly cooled to 21 °C at a rate of 20305
166
0.1 °C/min. A yellow solid (powder) was still présent after cooling to 21 °C. The solid was allowed to sit in the mother liquor for several weeks at room température until suitable crystals formed.
Data collection was performed on a Bruker APEX diffractometer at room température. Data collection consisted of oméga and phi scans. The structure was solved by intrinsic phasing using SHELX software suite in the space group P21212. The structure was subsequently refined by the full-matrix least squares method. Ail non-hydrogen atoms were found and refined using anisotropic displacement parameters. The hydrogen atoms located on nitrogen and oxygen were found from the Fourier différence map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included riding isotropie displacement parameters for ail hydrogen atoms.
Analysis of the absolute structure using likelihood methods (Hooft 2008) was performed using PLATON (Spek 2010). Assuming the sample submitted is enantiopure, the results indicate that the absolute structure has been correctly assigned. The final R-index was 6.92%. A final différence Fourier revealed no missing or misplaced électron density.
Figure 10 is the obtained X-ray structure (ORTEP drawing) of crystalline (/7)-4-((2-(((1,4dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/\/,/\/-dimethylpicolinamide, 0.5 calcium sait,monohydrate. Figure 11 is the X-ray structure (ORTEP drawing) ofthe corresponding unit cell. The crystal structure data is summarized in Table 9.
Table 9. Crystal data and structure refinement.
Empirical formula C48 H62 CaN12O10
Formula weight 1007.17
Température 296(2) K
Wavelength 1.54178Â
Crystal System Orthorhombic
Space group P21212
Unit cell dimensions a = 13.2412(15) Â a = 90°
b = 22.094(3) Â β = 90°
c = 8.7809(9) Â y = 90°.
Volume 2568.8(5) Â3
Z 2
Density (calculated) 1.302 Mg/m3
Absorption coefficient
F (000)
Crystal size
Thêta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to thêta = 51.384°
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [l>2sigma(l)]
R indices (ail data)
Absolute structure parameter
Largest diff. peak and hole
167
1.617 mm'1
1068 0.205x0.127x0.046 mm3 3.892 to51.384°.
-9<=h<=13, -21<=k<=22, -8<=l<=8 10761
2654 [R(int) = 0.0553]
95.3 % multi-scan 0.7533 and 0.5516
Full-matrix least-squares on F2 2654 / 299 / 338 1.218
R1 = 0.0697, wR2 = 0.1588
R1 = 0.0828, wR2 = 0.1644
0.183(12)
0.330 and -0.254 e-Â 3
Powder X-ray diffraction analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/\/dimethylpicolinamide, 0.5 calcium sait,monohydrate
Powder X-ray diffraction analysis was conducted using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit was set at 0.6 mm while the secondary optics used variable slits. Diffracted radiation was detected by a PSD-Lynx Eye detector. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was collected in the Theta-2Theta goniometer at the Cu (k-alpha average) from 3.0 to 40.0 degrees 2-Theta using a step size of 0.01 degrees and a time per step of 1.0 seconds. Samples were prepared by placing them in a Silicon low background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus XRD Commander (version 2.6.1) and analysis was performed by EVA diffract plus software (version 3.1). The PXRD data file was not processed prior to peak searching. Using the peak search algorithm in the EVA software, peaks selected with a threshold value of 1 were used to make preliminary peak assignments. To ensure validity, adjustments were manually made. The output of automated assignments was visually checked and peak positions were adjusted to the peak maximum.
168
Peaks with relative intensity of à 3% were generally chosen. The peaks which were not resolved or were consistent with noise were not selected. A typical error associated with the peak position of crystalline material, from PXRD, stated in USP, is up to +/- 0.2° 2-Theta (USP941).
Figure 12 is the obtained powder X-ray diffraction pattern for crystalline (/7)-4-((2-(((1,4dimethyl-1/-/-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-/V,/V-dimethylpicolinamide, 0.5 calcium sait, monohydrate and Table 10 lists the diffraction peaks in terms of 2-theta values.
Table 10
Angle 2-Theta (degrees) Relative Intensity (%)
7.7 43.0
7.8 100.0
10.3 35.3
10.7 22.2
11.9 18.6
12.6 8.6
13.2 11.0
13.6 26.0
14.4 11.8
15.5 24.2
16.6 25.3
17.0 52.5
18.4 15.1
20.0 11.2
20.5 25.7
20.8 43.1
21.0 47.9
21.5 3.8
22.3 43.4
22.6 9.3
23.3 15.9
24.0 61.2
24.5 10.2
24.9 21.7
25.6 34.4
26.1 24.6
27.0 10.4
169
Angle 2-Theta (degrees) Relative Intensity (%)
27.6 13.3
28.4 15.5
28.9 13.5
29.3 14.6
29.6 6.5
30.2 8.1
31.3 22.6
31.4 22.2
32.2 5.5
32.9 12.0
34.3 14.3
35.0 13.8
35.5 5.6
35.9 3.6
36.3 7.2
37.6 5.1
38.9 2.7
39.6 5.7
Biological Data CCR6+ T Cell Chemotaxis Assay.
Human CD4+CCR6+CXCR3-T cells were isolated from leukopak from healthy donors using EasySep™ Human Th17 Cell Enrichment Kit. (StemCell Technologies, 18162). To obtain large quantifies of cells, CCR6+ T cells were activated with Dynabeads Human T-activator (catalog no. 11132D, Gibco) at a density of 1x106 cell/mL in growth media (RPMI1640 media with 10% sérum, 4 ng/mL IL-2) with a 1:1.5 cell to bead ratio. Day 4 post activation, Dynabeads 10 were removed from the culture. The activated T cells were maintained at 1-2x106 cells/mL for days by feeding fresh growth media when needed.
The CCR6+ T cell chemotaxis assay was carried out on day 12 to 15 post T cell activation using 96 well ChemoTx® Disposable Chemotaxis System (Neuroprobe 101-5) according to the manufacturées protocol. After one wash with assay buffer (1X HBSS containing
20mM HEPES and 0.25%BSA), cells were incubated with test compounds for 30 min at room température priorto initiation of chemotaxis. For ICso détermination, the top and bottom of the chemotaxis chamber contained the same concentration of compound. DMSO was kept constant
170 at 0.1% (v/v) in ali wells. The final concentration of CCL20 (Peprotech 300-29A) in the bottom chamber is 0.5 nM. The fully assembled chemotaxis plate was placed in a cell culture incubator at 37 °C, 5% CO2 for 1 h. After incubation, the top filter was removed, followed by a quick freeze of the bottom chamber at -80 °C for 1 h. The migrated cells in the bottom chamber were stained with CyQUANT dye (Life Technologies, C7026) for cell number détermination.
IC50 values for compounds of the présent invention (Table 11) were determined by the non-linear régression analysis of dose response curves.
Table 11
Example IC50 (nM) Example IC50 (nM)
1 5.8 21 102
2 186 22 7.4
3 2.3 23 16.5
4 6.3 24 3.1
5 922 25 1.2
6 11.6 26 3.3
7 29.8 27 13.2
8 3.0 28 36.7
9 59.7 29 12.0
10 8.7 30 96.1
11 1.9 31 45.4
12 1.7 32 2.7
13 5.4 33 4.4
14 12.5 34 24.0
15 10.6 35 30.0
16 41.7 36 32.3
17 5.9 37 5.2
18 3.3 38 12.6
19 70.6 39 6.5
20 271 40 ND*
*No Data
171
Human Neutrophil Chemotaxis Assay.
Human neutrophile were purified from freshly drawn human whole blood by immunemagnetic négative sélection using the EasySepTM Direct Human Neutrophil Isolation Kit (StemCell Technologies, #19666) according to manufacturer’s instructions.
Human neutrophil chemotaxis assay was carried out with Corning FluoroBlok 96 well cell insert System (Corning #351164). Purified neutrophils were resuspended in chemotaxis buffer (1X HBSS containing 25mM HEPES, pH 7.4 and 0.25% BSA) to a working concentration of 2x106 cells/mL and incubated for 30 min at 37 °C with calcein-AM for cell staining. After 30 min, the labeled neutrophils were washed twice in chemotaxis buffer, resuspended as before and used immediately. For the assay, test compounds were tested in a dose-response format to détermine IC50. Labeled neutrophils (50 pL) were pre-incubated with diluted test compound (50 pL) for 30 min in a 96-well plate (Greiner). Next, 100 pL of diluted compound was mixed with 100 pL of GROa (Peprotech #300-11, 2 nM) in the bottom portion of the chemotaxis chamber. The top portion (insert) ofthe chemotaxis System containing the FluoroBlok porous membrane was then assembled together. 50 pL of the pre-incubated neutrophils were added to the FluoroBlok insert (top portion) and chemotaxis measured by the neutrophils ability to migrate through the membrane towards the spécifie CXCR2 ligand, GROa. The Envision multilabel reader (Perkin Elmer) and/or the Typhoon Fluorescent Imager (GE) was used to evaluate changes in fluorescent signal (calcein-AM fluorophore) at 485/535 nm generated by the labeled neutrophils that passed through the porous membrane.
IC50 values for compounds ofthe présent invention (Table 12) were determined by the non-linear régression analysis of dose response curves. Navarixin ((R)-2-hydroxy-A/,A/-dimethyl3-((2-((1 -(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)benzamide) was used as a reference control in the assay (IC50 = 16.8, n = 52).
Table 12
Example IC50 (nM) Example IC50 (nM)
1 524 21 293
2 7,310 22 141
3 1,530 23 248
4 886 24 1,010
5 ND* 25 355
6 586 26 142
172
Example IC50 (nM) Example IC50 (nM)
7 2,160 27 52.6
8 103 28 2,190
9 2,750 29 4,410
10 175 30 4,030
11 210 31 2,750
12 107 32 332
13 328 33 69.9
14 272 34 2,510
15 735 35 255
16 4,350 36 7,130
17 3,160 37 3,630
18 1,010 38 3,460
19 197 39 502
20 167 40 ND*
*No Data
Mouse in Vivo Model of IL-23-induced Psoriasis-like Skin Inflammation.
Efficacy of a CCR6 antagonist of the présent invention is evaluated in a mouse in vivo model of psoriasis-like skin inflammation. Recombinant mouse IL-23 is administered via intradermal injections into the left ears of female 8-10 weeks old C57BL/6 mice. This leads to increased psoriasis-like disease symptoms including thickening and erythema in the skin ofthe left ears. Mice given IL-23 are treated from Day 0 to Day 11 with either daily (QD) oral doses of a CCR6 antagonist ortwice daily (BID) doses of a CCR6 antagonist. Additionally, a group of mice are treated with an anti-IL-17 Ab as a positive efficacy control. Représentative dosing groups for the study consist of the following:
a group dosed orally twice daily (BID) with vehicle, négative control group, a group dosed by intraperitoneal injection twice weekly with an anti-IL-17 Ab (5 mg/kg), positive control group, a group dosed orally with Compound A at 3-100 mg/kg either once a day (QD) or twice a day (BID), an untreated, naive control group.
Ten mice are enrolled per treatment group with the exception of the naïve control group, which contains five mice. Study day 0 is designated as the first treatment day, and ear thickness
173 measurements are taken daily by an engineer’s micrometer (Mitutoyo, Aurora, IL, USA). Ear swelling measurements for each mouse was compared to baseline and expressed in microns.
The compounds of the présent invention selectively inhibit T cell chemotaxis compared to neutrophil chemotaxis (see Table 13). This selectivity renders the compounds of the présent 5 invention as viable therapeutic agents for treating inflammatory, immune, autoimmune, neurodegenerative and neuroinflammatory diseases, conditions, or disorders in humans with reduced risk of neutropenia.
Table 13
Example T Cell Chemotaxis Selectivity Example T Cell Chemotaxis Selectivity
1 90 21 3
2 39 22 19
3 665 23 15
4 140 24 325
5 ND* 25 296
6 51 26 43
7 72 27 4
8 34 28 60
9 46 29 367
10 20 30 42
11 110 31 60
12 63 32 123
13 60 33 16
14 22 34 104
15 69 35 8
16 104 36 220
17 535 37 698
18 306 38 274
19 3 39 77
20 NS** 40 ND*
*No Data ** Not sélective for T cell chemotaxis compared to neutrophil chemotaxis
174
Applicant discovered unexpectedly that T cell chemotaxis inhibition versus neutrophil chemotaxis inhibition was enhanced by replacing hydrogen with a methyl group alpha to the point of attachment of the heteroaryl “A” ring (see Table 14).
Table 14
R = H, IC5o (nM) R = CH3, IC50 (nM)
Compound of the Présent Invention CCR6 T cell, CCL20 Chemotaxis CXCR2 Neutrophil, GROa Chemotaxis T Cell Chemotaxis Selectivity CCR6 T cell, CCL20 Chemotaxis CXCR2 Neutrophil, GROa Chemotaxis T Cell Chemotaxis Selectivity
A N )-NH H Yp \ R N-< OH 7 O 19.2 42.1 2.2 5.8 524 90.3
A Ά, /A γΑ N AnH H A / \ ) \ R NY OH 7 O 32.1 346 10.8 2.7 332 123
A / Y' Ay- N 7—NH H M / \ ) \ R ° N-X OH 7 O 64.5 12.2 NS* 24.0 2510 104
* Not sélective for T cell chemotaxis compared to neutrophil chemotaxis
Comparator Data
WO 2010/131145 discloses Examples 112 and 120.
Example 112 Example 120
Applicant provides comparative chemotaxis data in Table 15 for the WO 2010/131145 compounds. The data in Table 15 demonstrates that Examples 112 and 120 are more potent at inhibiting neutrophil migration than the compounds of the présent invention and less potent at inhibiting T cell migration than the compounds of the présent invention. The WO 2010/131145 compounds are functionally sélective for CXCR2 compared to CCR6 in opposite to the compounds of the présent invention. This data suggests that the WO 2010/131145 compounds
175 are less attractive as agents for treating diseases, conditions, or disorders ameliorated by reducing T cell chemotaxis via CCR6 inhibition and that the WO 2010/131145 compounds also hâve a greater neutropenia risk to patients compared to the compounds of the présent invention.
176
Table 15
IC50 (nM)
Example CCR6 T cell, CCL20 Chemotaxis CXCR2 Neutrophil, GROa Chemotaxis T Cell Chemotaxis Selectivity
112 267 23.2 NS*
120 388 5.7 NS*
*Not sélective for T cell chemotaxis compared to neutrophil chemotaxis
WO 2013/061005 discloses Examples 22, 50 and 53 and provides CXCR2 and CCR6 5 functional data for each compound which is reproduced from WO 2013/061005 in Table 16 below. CXCR2 antagonist activity was determined via inhibition of β-arrestin recruitment following activation with CXCL8 in Path-Hunter HEK293 cells. CCR6 antagonist activity was determined via inhibition of Ca2+ flux in cells following activation of CCR6 in the FLIPR TETRA® platform. The CCR6 activating agent was not reported.
Example 22 Example 50 Example 53
Table 16*
Compound CXCR2 IC50 (nM) CCR6 IC50 (nM)
22 31 3.4
50 72 1.4
53 30 1.9
*Data disclosed in WO 2013/061005
Applicant provides the following comparative chemotaxis data in Table 17 for the WO
2013/061005 compounds. The data in Table 17 demonstrates that Example 22 is potent at both the inhibition of T cell and neutrophil chemotaxis with a slightly greater potency (1.5X) for inhibition of CCR6. The high affinity for both receptors combined with the poor selectivity for CCR6 renders this compound less attractive as an anti-inflammatory agent with reduced potential for neutropenia than the compounds of the présent invention. Example 50 has low affinity for CCR6 and inhibits neutrophil chemotaxis better than T cell chemotaxis. Example 50’s chemotaxis profile is less attractive for development as an anti-inflammatory agent than the
177 compounds of the présent invention. Example 53 is not a potent inhibitor of T cell chemotaxis nor neutrophil chemotaxis. The lack offunctional potency at CCR6 renders Example 53 less attractive for treating inflammatory diseases than the compounds of the présent invention.
Table 17
IC50 (nM)
Example CCR6 T cell, CCL20 Chemotaxis CXCR2 Neutrophil, GROct Chemotaxis T Cell Chemotaxis Selectivity
22 22.6 35.2 1.5
50 330 121 NS*
53 390 1143 3
* Not sélective for T cell chemotaxis compared to neutrophil chemotaxis

Claims (15)

  1. Claims
    1. A compound of Formula (IA) or (IB)
    Formula (IA)
    Formula (IB) or a pharmaceutically acceptable sait or hydrate thereof, wherein
    Ri is methyl;
    R2 is methyl, ethyl, or isopropyl ;
    or Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine;
    R3 is H or -CH2OP(=O)(OH)2;
    R4 is methyl;
    R5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl;
    Re is H;
    (R8)i
    R?
    B is
    R7 is methyl; and n is 0.
  2. 2.
    The compound according to claim 1 of Formula (IIA)
    Formula (IIA) or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri is methyl;
    R2 is methyl, ethyl, or isopropyl;
    or Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine;
    R3 is H or -CH2OP(=O)(OH)2;
    R4 is methyl ;
    Rs is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl; R6 is H;
    (R8)r
    R?
    B is
    R7 is methyl; and n is 0.
  3. 3. The compound according to claim 2, or a pharmaceutically acceptable sait or hydrate thereof, wherein Ri and R2 taken together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine
  4. 4. The compound according to claim 1 selected from the group consisting of (R)-4-((2-(((4-Chloro-1 -methyl-1 /-/-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide;
    (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/-isopropyl-A/-methylpicolinamide;
    (S)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/V-dimethylpicolinamide;
    180 (/7)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1 -en-1-yl)amino)-/V-ethyl-3-hydroxy-/V-methylpicolinamide;
    (S)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-A/-ethyl-3-hydroxy-A/-methylpicolinamide;
    (/7)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy2-(morpholine-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione;
    (/7)-3-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy2-(4-methylpiperazine-1-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione;
    (S)-4-((2-(((4-Chloro-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide;
    (/7)-4-((2-(((4-Chloro-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/-isopropyl-A/-methylpicolinamide;
    (/7)-3-Hydroxy-A/-isopropyl-4-((2-(((4-methoxy-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-A/-methylpicolinamide;
    (/7)-3-Hydroxy-4-((2-(((4-methoxy-1-methyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-/V,/V-dimethylpicolinamide;
    (/7)-4-((2-(((4-(Difluoromethoxy)-1-methyl-1/7-pyrazol-3-yl)(1-methylcycIopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/\/,/\/-dimethylpicolinamide;
    (/7)-4-((2-(((4-Cyano-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide;
    (/7)-4-((2-(((4-Ethyl-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopropyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,A/-dimethylpicolinamide;
    (/7)-4-((2-(((4-Cyclopropyl-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-/V,A/-dimethylpicolinamide;
    (R)-4-((2-(((4-Cyano-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1 -en-1 -yl)amino)-N-ethyl-3-hydiOxy-/V-methylpicolinamide; and (R)-4-((2-(((4-cyano-1-methyl-1/7-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydrOxy-A/-isopropyl-A/-methylpicolinamide;
    or a pharmaceutically acceptable sait or hydrate thereof.
  5. 5. The compound according to claim 1 that is (/7)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-A/,/\/dimethylpicolinamide or a pharmaceutically acceptable sait or hydrate thereof.
    181
  6. 7. The compound according to claim 1 that is Crystalline (/7)-4-((2-(((1,4-dimethyl-1H- pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide.
  7. 8. The compound according to claim 1 that is Crystalline (/7)-4-((2-(((1,4-dimethyl-1/7pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide monohydrate.
  8. 9. The compound according to claim 1 that is Crystalline (/7)-4-((2-(((1,4-dimethyl-1/7pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/./V-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 18.8 ± 0.2, 19.2 ± 0.2, and 20.4 ± 0.2 degrees two thêta.
  9. 10. The compound according to claim 1 that is Crystalline (/7)-4-((2-(((1,4-dimethyl-1/7pyrazol-3-yl)(Tmethylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/,A/-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 17.6 ± 0.2, 18.5 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, and 20.4 ± 0.2 degrees two thêta.
  10. 11. The compound according to claim 1 that is Crystalline (/7)-4-((2-(((1,4-dimethyl-1/7pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyA/./V-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 11.5 ± 0.2, 15.5 ± 0.2, 17.6 ± 0.2, 18.5 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 20.4 ± 0.2, and 24.5 ± 0.2 degrees two thêta.
  11. 12. The compound according to claim 1 that is Crystalline (/7)-4-((2-(((1,4-dimethyl-1/7pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-
    182
    Λ/,/V-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern as depicted in Figure 4.
  12. 13. The compound according to claim 1 that is (/7)-((4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-2- (dimethylcarbamoyl)pyridin-3-yl)oxy)methyl dihydrogen phosphate or a pharmaceutically acceptable sait thereof.
  13. 14. The compound according to claim 1 of structure
  14. 15. Use of a compound according to any one of daims 1 -14, or a pharmaceutically acceptable sait, hydrate, or a pharmaceutically acceptable sait monohydrate thereof, to préparé a médicament for treating rheumatoid arthritis, juvénile arthritis, juvénile rheumatoid arthritis, systemic onset rheumatoid arthritis, pauciarticular rheumatoid arthritis, pauciarticular juvénile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvénile Reiter's Syndrome, ankylosing spondylitis, juvénile ankylosing spondylitis, SEA Syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvénile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvénile idiopathic arthritis (JIA), juvénile psoriatic arthritis, juvénile rheumatoid arthritis, systemic onset juvénile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis from inflammatory diseases in a human.
  15. 16. A compound according to any one of daims 1 -14, or a pharmaceutically acceptable sait, monohydrate, or a pharmaceutically acceptable sait hydrate thereof, for use in a method of treating inflammatory bowel disease, Crohn's disease, or ulcerative colitis in a human.
OA1202100114 2018-09-21 2019-09-18 N-substituted-dioxocyclobutenylamino-3hydroxy-picolinamides useful as CCR6 Inhibitors. OA20305A (en)

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