EA045541B1 - N-SUBSTITUTED DIOXOCYCLOBUTENYLAMINO-3-HYDROXYPICOLINAMIDES ACCEPTABLE AS CCR6 INHIBITORS - Google Patents

Description

Field of invention

The invention relates to N-substituted dioxocyclobutenylamino-3-hydroxypicolinamide compounds that inhibit CC chemokine receptor 6 (CCR6), pharmaceutical compositions that contain these compounds, and the use of these compounds for the treatment or prevention of diseases, conditions or disorders that are improved by inhibition of CCR6.

Prerequisites for creating the invention

Chemokine receptors are a large subfamily of seven cell surface transmembrane proteins. They can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte migration, and atypical chemokine receptors, which can signal through non-G protein-coupled mechanisms and act as chemokine scavengers to reduce inflammation or form gradients. chemokines [Bachelerie, 2014; Murphy, 2002]. Chemokines, natural ligands for chemokine receptors, are low molecular weight proteins that stimulate the recruitment of leukocytes. Based on the presence and mutual arrangement of NH2-terminal Cys residues, chemokines are structurally grouped into CC, CXC, CX3C and C chemokines [White, 2013]. In humans, chemokines and chemokine receptors form a pharmacologically complex system. In many cases, the recognition of one chemokine by different receptors, as well as the binding of different chemokines to the same receptor, leads to different signaling and migration responses [Kufareva, 2016]. Physiologically, members of the chemokine family stimulate the recruitment of well-defined subsets of leukocytes and play important roles 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 all Th17 cells), neutrophils, and a subset of Tregs. CCR6 is the only known receptor for the chemokine CCL20 (alternatively called LARC or MIP-3a). CCL20 is produced by synoviocytes, colonic epithelial cells, various skin cells (eg, keratinocytes and dermal fibroblasts), and alveolar epithelial cells. The CCL20-CCR6 ligand-receptor pair is responsible for the migration of immature dendritic cells and effector/memory T cells to skin and mucosal surfaces under homeostatic and inflammatory conditions, such as in autoimmune diseases such as psoriasis and inflammatory bowel disease [Liao, 1999; Schutyser, 2003].

CCL20 is an inducible chemokine that is highly regulated in inflammatory lesions in various autoimmune diseases, including psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis, and rheumatoid arthritis. Increased numbers of CCR6 positive T cells and dendritic cells were found in lesions that colocalized with CCL20 expression. These T cell-dendritic cell clusters, which are maintained by CCR6-CCL20 interactions, are critical for disease initiation and maintenance. In mice, both CCR6 knockout and neutralizing anti-CCL20 antibody were protective in a model of IL-23-induced skin inflammation, suggesting that blocking CCR6-CCL20-mediated immune cell recruitment represents an attractive mechanism for novel small molecule therapies in autoimmune and inflammatory diseases. 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 specific ligands for CXCR2 with 90% sequence homology. In clinical studies, dual CXCR1/2 antagonists such as Navarixin have shown a reversible reduction in absolute neutrophil counts in patients [Hastrup, 2015]. Patients with low neutrophil counts may be at increased risk of infection. Therefore, CCR6 antagonists with reduced CXCR2 receptor antagonism activity may offer an improved safety profile compared with nondiscriminatory antagonists. Human genetic data and knockout studies in mice suggest that neutrophil egress from the bone marrow is dependent on CXCR2 function and is mediated by the CXCR2-specific ligands CXCL1 (GRO alpha) and CXCL2 (GRO beta) [Auer, 2014; Ash, 2010]. Thus, to understand the pharmacology of CXCR2 inhibitors in bone marrow neutrophil mobilization, it is important to use the appropriate CXCR2 ligand (CXCL1 or CXCL2) in the primary human neutrophil assay system.

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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.

The essence of the invention

The present invention provides compounds of formulas (IA) and (IB) that inhibit CCR ₆ and are useful for the treatment or prevention of diseases that are ameliorated by inhibition of CCR ₆ in humans

or a pharmaceutically acceptable salt or hydrate thereof, wherein

R ₁ represents methyl;

R ₂ is methyl, ethyl or isopropyl;

R1 and _R2 taken together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered heterocycle which contains 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 (C ₁ -C ₄ ) alkyl groups;

R ₃ represents H;

A represents

N'R4

Rs^' ⁵ R6 ;

R ₄ represents methyl;

R ₅ is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano or cyclopropyl;

R6 is H;

B represents

R ₇ represents methyl;

n is 0.

In another embodiment, the present invention provides the compound (R)-4-((2(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,N-dimethylpicolinamide or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a connection structure

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, having X-ray diffraction

- 2 045541 new pattern containing diffraction peaks of 18.8 ± 0.2, 19.2 ± 0.2 and 20.4 ± 0.2 degrees two theta.

In another embodiment, the present invention provides crystalline monohydrate of (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, having an X-ray diffraction pattern containing diffraction peaks 17.6±0.2, 18.5±0.2, 18.8± 0.2, 19.2±0.2, and 20.4±0.2 degrees are two theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, having an X-ray diffraction pattern containing 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 theta.

In another embodiment, the present invention provides the compound (R)-((4-((2(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en-1 yl)amino)-2-(dimethylcarbamoyl)pyridin-3-yl)oxy)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a connection structure

He

Brief description of drawings

Fig. 1 is the X-ray structure (ORTEP graphic) of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3. 4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

Fig. 2 is the X-ray structure (ORTEP graphic) of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)- 3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

Fig. 3 is the X-ray structure (ORTEP graphic) of crystalline salt of (8)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylic acid ((1R,4aS,10aR)-7isopropyl-1,4a-dimethyl-1,2 ,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl)methanamine (Example 36F).

Fig. 4 is a powder X-ray diffraction analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)( 1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1 -en1 -yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

Fig. 5 is a differential scanning calorimetric analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1 -en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

Fig. 6 is a thermogravimetric analysis of crystalline (R)-4-((2-(((1,4dimethyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene -1 -yl)amino)-3hydroxy-N,N-dimethylpicolinamide monohydrate.

Fig. 7 is a powder X-ray diffraction analysis of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1 en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

Fig. 8 is a differential scanning calorimetric analysis of crystalline (R)-4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide monohydrate.

Fig. 9 is a thermogravimetric analysis of crystalline (R)-4-((2-(((4-chloro-1methyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3 hydroxy-N,N-dimethylpicolinamide monohydrate.

Fig. 10 is the X-ray structure (ORTEP graphic) of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3. 4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate.

Fig. 11 is the X-ray structure (ORTEP graphic) for the unit cell 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-K,Kdimethylpicolinamide, 0.5 calcium salt, monohydrate.

Fig. 12 is a powder X-ray diffraction analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1 -en

- 3 045541

1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate.

Detailed Description of the Invention

In another embodiment, the present invention provides compounds of formulas (IA) and (IB)

or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 represents methyl; R ₂ is methyl, ethyl or isopropyl, or R 1 and R ₂ 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 (C1- _C4 ) alkyl groups; R ₃ represents H; And ^R 5 k represents ^G ; R4 is methyl; R ₅ is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano or cyclopropyl; R ₆ represent H; B represents S'R ₇ represents methyl; n is 0.

In another embodiment, the present invention provides compounds of formula (IIA) o

Formula (HA) or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 represents methyl; R ₂ is methyl, ethyl or isopropyl; or R1 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 (C _g C ₄ ) alkyl groups; R ₃ represents H; R ₄ represents methyl; R ₅ is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano or cyclopropyl; R ₆ represents H; B represents - R ₇ represents methyl; and n is 0.

In another embodiment, the present invention provides compounds of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, wherein R1 and _R2 , taken together with the nitrogen atom to which they are attached, form morpholine or 4-methylpiperazine; R3 is H; R4 is methyl; R ₅ is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano ____....... ____. .. ____. ..

or cyclopropyl; R ₆ represents H; B represents · R ₇ represents methyl; n is 0.

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

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

In another embodiment, the present invention provides a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, for use as a drug

- 4 045541 drugs.

In another embodiment, the present invention provides a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, for use in the treatment or prevention of diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in humans.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IIA), or a pharmaceutically acceptable salt thereof or hydrate.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate.

In another embodiment, the present invention provides a method of treating or preventing inflammatory diseases, conditions or disorders in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing autoimmune diseases, conditions or disorders in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IIA ), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of (R)-4-((2-(((1,4-dimethyl-1H- pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-Ni-dimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a prodrug (R)-4-((2-(((1,4-dimethyl-1H -pyrazol3 -yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3 -hydroxy-N,N dimethylpicolinamide.

In another embodiment, the present invention provides the use of a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for the treatment of diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in humans.

In another embodiment, the present invention provides the use of a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for the treatment of diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for the treatment of an inflammatory disease, condition or disorder in a human.

In another embodiment, the present invention provides the use of a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for the treatment of an autoimmune disease, condition or disorder in a human.

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

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

In another embodiment, the present invention provides the use of prodrugs (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, or its pharmaceutical form

- 5 045541 acceptable salt or hydrate, in the manufacture of a medicinal product for the treatment of rheumatoid arthritis in humans.

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

In another embodiment, the present invention provides a pharmaceutical composition that contains (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-ul)(1methylcyclopentyl)methyl)amino)-3, 4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a pharmaceutical composition that contains prodrugs (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-ul)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains a compound of formula ( IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing an inflammatory disease, condition or disorder in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or a hydrate; and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease, condition or disorder in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or a hydrate; and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains (R)-4-((2-(((1,4 -dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide, or a pharmaceutically acceptable compound thereof a salt or hydrate; and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains prodrugs (R)-4-((2-((((1, 4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide, or its pharmaceutical form an acceptable salt or hydrate; and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains a compound of formula (IIA), or a pharmaceutically acceptable form thereof

- 6 045541 my salt or hydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for the treatment of diseases, conditions or disorders that are improved by inhibition of CCR6 in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for the treatment of diseases , conditions or disorders that are improved by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for the treatment of inflammatory diseases, conditions or disorders in a person.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for treating an autoimmune disorder. diseases, conditions or disorders in a person.

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

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-ul)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,dimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicinal product drug for the treatment of rheumatoid arthritis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains prodrugs (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,dimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture drug for the treatment of rheumatoid arthritis in humans.

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

In another embodiment, the present invention provides a pharmaceutical combination that contains (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-ul)(1methylcyclopentyl)methyl)amino)-3, 4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,dimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a pharmaceutical combination that contains prodrugs (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-ul)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Hdimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by CCR6 inhibition in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains a compound of formula ( IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or

- 7 045541 for the prevention of an inflammatory disease, condition or disorder in a person, which includes administering to a person in need thereof a therapeutically effective amount of a pharmaceutical combination that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease, condition or disorder in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains (R)-4-((2-(((1,4 -dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino)-3-hydroxy-N,K-dimethylpicolinamide, or a pharmaceutically acceptable compound thereof a salt or hydrate; and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains prodrugs (R)-4-((2-(((1, 4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, or its pharmaceutical form an acceptable salt or hydrate; and at least one anti-inflammatory agent.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of diseases, conditions or disorders, which are improved by CCR6 inhibition in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of diseases, conditions or disorders, which are improved by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of an inflammatory disease, condition or disorder in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains a compound of formula (IIA), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of an autoimmune disease, condition or disorder in humans.

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

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

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

- 8 045541

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

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

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,K-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains diffraction peaks 18.7±0.2, 19.1±0.2 and 20, 2±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,K-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains 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 theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-K,N-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains 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 theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-K,N-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains 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 are two theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,K-dimethylpicolinamide monohydrate, which has an x-ray diffraction pattern that contains from 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 theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-K,N-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains from 3 to 10 diffraction peaks presented in table. 7.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-K,N-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains diffraction peaks, are presented in table. 7.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,K-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern as shown in FIG. 4.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,K-dimethylpicolinamide monohydrate, which has a differential scanning calorimetric analysis as depicted in FIG. 5.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-K,N-dimethylpicolinamide monohydrate, which has thermogravimetric analysis as depicted in FIG. 6.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1yl)amino)-3-hydroxy-K,N-dimethylpicolinamide monohydrate for use as a medicinal product.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate for use in the treatment or prevention of diseases, conditions or disorders that are ameliorated by inhibition of CCR ₆ in humans.

In another embodiment, the present invention provides a method of treating or

- 9 045541 prevention of diseases, conditions or disorders that are improved by inhibition of CCR6 in a person, which includes administering to a person in need thereof a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl - 1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount 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-N ,Dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides a method of treating or preventing inflammatory diseases, conditions or disorders in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-((2-(((1,4 -dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en1 -yl)amino)-3-hydroxy-^Ndimethylpicolinamide monohydrate.

In another embodiment, the present invention provides a method of treating or preventing autoimmune diseases, conditions or disorders in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-((2-(((1,4 -dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R) -4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1-yl)amino)-3 -hydroxy-N,N-dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl-1Hpyrazole -3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyN,N-dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders that are ameliorated by inhibition of CCR ₆ in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the manufacture of a medicinal product for the treatment of an inflammatory disease, condition or disorder in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the manufacture of a medicinal product for the treatment of an autoimmune disease, condition or disorder in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-ul)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the production of a medicinal product for the treatment of psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the production of a drug for the treatment of rheumatoid arthritis in humans.

- 10 045541

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

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4 -((2-(((1,4dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-NA -dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R )-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino)- 3-hydroxy-K,K-dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing an inflammatory disease, condition or disorder in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4-((2-( ((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease, condition or disorder in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4-((2-( ((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl )amino)-3-hydroxy-K,Kdimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1, 4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide monohydrate, and, at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders that are improved by CCR6 inhibition in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-11 045541 methylcyclopentyl)methyl )amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicinal product for treating an inflammatory disease, condition or disorder in a person.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline ^)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for the treatment of an autoimmune disease, condition or disorder in a person.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for the treatment of psoriasis, non-specific ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-Dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for the treatment of rheumatoid arthritis in person.

In another embodiment, the present invention provides a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4 -((2-(((1,4dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-NA -dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R )-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino)- 3-hydroxy-K,K-dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing an inflammatory disease, condition or disorder in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-( ((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease, condition or disorder in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-( ((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1

- 12 045541 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1, 4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide monohydrate, and, at least one anti-inflammatory agent.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of diseases, conditions or disorders that are improved by inhibiting CCR6 in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of diseases, conditions or disorders that are improved due to inhibition of T-cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of an inflammatory disease, condition or disorder in humans .

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of an autoimmune disease, condition or disorder in a human .

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the production of a medicinal product for the treatment of psoriasis, ulcerative colitis, Crohn's disease , inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of rheumatoid arthritis in humans.

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

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-K,K-dimethylpicolinamide, 0.5 calcium salt, monohydrate, which has an X-ray diffraction pattern that contains diffraction peaks 7.8±0.2, 10.3 ±0.2 and 10.7±0.2 degrees are two theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1yl)amino)-3-hydroxy-K,K-dimethylpicolinamide, 0.5 calcium salt, monohydrate, which has an x-ray diffraction pattern that contains diffraction peaks 7.8±0.2, 10.3± 0.2, 10.7±0.2, 15.5±0.2 and 18.4±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1yl)amino)-3-hydroxy-K,K-dimethylpicolinamide, 0.5 calcium salt, monohydrate, which has an x-ray diffraction pattern that contains diffraction peaks 7.7±0.2, 7.8± 0.2,

- 13 045541

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 theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, which has an x-ray diffraction pattern that contains 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 theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,H-dimethylpicolinamide, 0.5 calcium salt, monohydrate, which has an x-ray diffraction pattern that contains 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, degrees two theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut - 1-en-1yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, which has an X-ray diffraction pattern that contains from 3 to 10 diffraction peaks presented in table. 10.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, which has an X-ray diffraction pattern that contains diffraction peaks, are presented in table. 10.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, which has an X-ray diffraction pattern as shown in FIG. 12.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,H-dimethylpicolinamide, 0.5 calcium salt, monohydrate for use as a medicinal product.

In another embodiment, the present invention provides crystalline (R)4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,H-dimethylpicolinamide, 0.5 calcium salt, monohydrate for use in the treatment or prevention of diseases, conditions or disorders that are ameliorated by inhibition of CCR ₆ in humans.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR ₆ in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline ((R)-4-(( 2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy- N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-( (2-(((1,4-dimethyl-1H-pyrazol-3-ul)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -ul)αmuno)-3-hydroxy-N ,Ndimethylpicolinamide, 0.5 calcium salt, monohydrate.

In another embodiment, the present invention provides a method of treating or preventing inflammatory diseases, conditions or disorders in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-((2-(((1,4 -dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1-yl)amino)-3-hydroxy-H,H-dimethylpicolinamide, 0.5 calcium salt, monohydrate.

In another embodiment, the present invention provides a method of treating or preventing autoimmune diseases, conditions or disorders in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-((2-(((1,4 -dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate.

In another embodiment, the present invention provides a method for treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which includes

- 14 045541 administration to a person in need thereof of a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino) -3,4-dioxocyclobut-1-en1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-((2-(((1,4-dimethyl-1Hpyrazole -3 -yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxyΝ,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobate -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders that are improved by inhibition of CCR6 in humans .

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders that are improved by T-cell inhibition chemotaxis in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, in the manufacture of a medicinal product for the treatment of an inflammatory disease, condition or disorder in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobate -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, in the manufacture of a medicinal product for the treatment of an autoimmune disease, condition or disorder in humans.

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

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobate -1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, in the production of a medicinal product for the treatment of rheumatoid arthritis in humans.

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

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4 -((2-(((1,4dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-N ,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R )-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-ul)amino)- 3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing an inflammatory disease, condition or disorder in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4-((2-( ((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N

- 15 045541 dimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease, condition or disorder in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4-((2-( ((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide, 0 .5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene-1-ud )αmino)-3-hydroxy-N,Ndimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1, 4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-Dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in manufacture a medicinal product for the treatment of diseases, conditions or disorders that are improved by inhibition of CCR6 in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-ene-1-ud)αamino)-3-hydroxy-N,Ndimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in manufacture a medicinal product for the treatment of diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-ul)αmino)-3-hydroxy-N,Ndimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in manufacture a medicinal product for the treatment of an inflammatory disease, condition or disorder in a person.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-Dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in manufacture a drug to treat an autoimmune disease, condition, or disorder in a person.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-Dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in manufacture a medicinal product for the treatment of psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-Dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in manufacture drug for the treatment of rheumatoid arthritis in humans.

- 16 045541

In another embodiment, the present invention provides a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)αmino)-3-hydroxy-N,Ndimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4 -((2-(((1,4dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3hydroxy-K , K-dimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R )-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino)- 3-hydroxy-K,K-dimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing an inflammatory disease, condition or disorder in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-( ((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide, 0 .5 calcium salt, monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease, condition or disorder in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-( ((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide, 0 .5 calcium salt, monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl) amino)-3-hydroxy-K,Kdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1, 4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-Dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicinal product for the treatment of diseases , conditions or disorders that are improved by CCR6 inhibition in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Kdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory

- 17 045541 body agent, in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (I)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of inflammatory diseases, conditions or disorders in a person.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (I.)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino) -3,4-dioxocyclobut-1-en-1 -ul)αmino)-3-hydroxy-N,Ndimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicinal product for the treatment an autoimmune disease, condition or disorder in a person.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-Dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of psoriasis , ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (I)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-Dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide, 0.5 calcium salt, monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicinal product for the treatment of rheumatoid arthritis in humans.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1 -en1 -yl)amino)-3 -hydroxy-K,K-dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains diffraction peaks 18.5±0.2, 18.8±0.2 and 19 ,2±0.2 degrees two theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains 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 theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains 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 theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide monohydrate, which has an x-ray diffraction pattern that contains from 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 theta.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains from 3 to 10 diffraction peaks presented in table. 8.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern that contains diffraction peaks, are presented in table. 8.

- 18 045541

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, which has an X-ray diffraction pattern as shown in FIG. 7.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-Ni-dimethylpicolinamide monohydrate, which has a differential scanning calorimetric analysis as depicted in FIG. 8.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, which has thermogravimetric analysis as depicted in FIG. 9.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate for use as a medicinal product.

In another embodiment, the present invention provides crystalline (R)4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4 -dioxocyclobut-1-en1-ul)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate for use in the treatment or prevention of diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in humans.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in a human, which comprises administering to a human in need thereof 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-K, Dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-( (2-(((4-chloro-1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy -N,Ndimethylpicolinamide monohydrate.

In another embodiment, the present invention provides a method of treating or preventing inflammatory diseases, conditions or disorders in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-((2-(((4-chloro -1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 en-1-ul)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides a method of treating or preventing autoimmune diseases, conditions or disorders in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-((2-(((4-chloro -1 -methyl-1H-pyrazol-3 -yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 en-1-ul)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)- 4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 en-1-yl)amino) -3-hydroxy-N,N-dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of crystalline (R)-4-((2-(((4-chloro-1-methyl -1Hpyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyΝ,N-dimethylpicolinamide monohydrate.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3 ,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders that are improved by inhibition of CCR6 in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3 ,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in production

- 19 045541 medicinal product for the treatment of diseases, conditions or disorders that are improved by inhibition of T-cell chemotaxis in humans.

In another embodiment, the present invention provides for the use of crystalline A)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3, 4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the manufacture of a medicinal product for the treatment of an inflammatory disease, condition or disorder in humans.

In another embodiment, the present invention provides the use of crystalline (R)-4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3 ,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the manufacture of a medicinal product for the treatment of an autoimmune disease, condition or disorder in humans.

In another embodiment, the present invention provides for the use of crystalline A)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3, 4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the production of a medicinal product for the treatment of psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans .

In another embodiment, the present invention provides for the use of crystalline A)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3, 4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, in the production of a drug for the treatment of rheumatoid arthritis in humans.

In another embodiment, the present invention provides a pharmaceutical composition that contains 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-N,Ndimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4 -((2-(((4chloro-1 -methyl- 1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy -N,N-dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R )-4-((2-(((4-chloro-1 -methyl- 1H-pyrazol-3 -yl)(1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino )-3-hydroxy-N,N-dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing an inflammatory disease, condition or disorder in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains 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-N,Ndimethylpicolinamide monohydrate; and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease, condition or disorder in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains 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-N,Ndimethylpicolinamide monohydrate; and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene-1 -yl)amino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient

- 20 045541 ent, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains crystalline (R)-4-((2-(((4- chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino )-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicinal product for the treatment of diseases , conditions or disorders that are improved by CCR6 inhibition in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino )-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicinal product for the treatment of diseases , conditions or disorders that are improved by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino )-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for the treatment of inflammatory diseases, conditions or disorders in a person.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3ul)(1-methylcyclopentyl)methyl)amino )-3,4-dioxocyclobut-1-en-1-ul)amino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicinal product for the treatment of autoimmune diseases, conditions or disorders in a person.

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

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

In another embodiment, the present invention provides a pharmaceutical combination that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino) -3,4-dioxocyclobut-1-en-1-ul)amino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a pharmaceutical combination that contains 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-N,Ndimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4 -((2-(((4chloro-1 -methyl- 1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1ul)amino)-3-hydroxy -N,N-dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are improved by inhibiting

- 21 045541

T cell chemotaxis in humans, which involves administering to a person in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol- 3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing an inflammatory disease, condition or disorder in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-( ((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-ide)αamino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease, condition or disorder in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains 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-K,Kdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene-1 -yl)amino)-3-hydroxy-K,Kdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains 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-K,K-dimethylpicolinamide monohydrate , and at least one anti-inflammatory agent.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino )-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders, which are improved by inhibition of CCR ₆ in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino )-3,4-dioxocyclobut-1-en-1-yl)αmino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicinal product for the treatment of diseases, conditions or disorders, which are improved by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino )-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of an inflammatory disease, condition or disorder in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino )-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of an autoimmune disease, condition or disorder in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino )-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Cdimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the production of a medicinal product for the treatment of psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in humans.

In another embodiment, the present invention provides for the use of pharmaceuticals

- 22 045541 chemical combination that contains crystalline A)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut - 1-en-1 -yl)amino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate, and at least one anti-inflammatory agent, in the manufacture of a medicinal product for the treatment of rheumatoid arthritis in humans.

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

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

In another embodiment, the present invention provides a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, for use as a drug.

In another embodiment, the present invention provides a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, for use in the treatment or prevention of diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in humans.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by CCR6 inhibition in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IIB), or a pharmaceutically acceptable salt thereof or hydrate.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate.

In another embodiment, the present invention provides a method of treating or preventing inflammatory diseases, conditions or disorders in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing autoimmune diseases, conditions or disorders in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IIB ), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound (S)-4-((2-(((1,4-dimethyl-1H -pyrazol3 -yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1 -yl)amino)-3-hydroxy-N,N dimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a prodrug compound (S)-4-((2-(((1,4-dimethyl1H- pyrazol-3 -yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyΝ,N-dimethylpicolinamide.

In another embodiment, the present invention provides the use of a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for the treatment of diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in humans.

In another embodiment, the present invention provides the use of a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for the treatment of diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of a medicament for the treatment of an inflammatory disease, condition or disorder in a human.

In another embodiment, the present invention provides the use of a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, in the manufacture of drugs.

- 23 045541 new drug for the treatment of an autoimmune disease, condition or disorder in humans.

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

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

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

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

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

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

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of CCR6 in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains a compound of formula ( IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing an inflammatory disease, condition or disorder in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or a hydrate; and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease, condition or disorder in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or a hydrate; and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis, or rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains (S)-4-((2-(((1,4 -dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, or a pharmaceutically acceptable compound thereof salt or guide

- 24 045541 rat, and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical composition that contains prodrugs (5)-4-((2-(((1, 4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, or its pharmaceutical form an acceptable salt or hydrate; and at least one pharmaceutically acceptable excipient, diluent or carrier.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for the treatment of diseases , conditions or disorders that are improved by CCR6 inhibition in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for the treatment of diseases , conditions or disorders that are improved by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for the treatment of inflammatory diseases, conditions or disorders in a person.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicament for treating an autoimmune disorder. diseases, conditions or disorders in a person.

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

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains (5)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,Ndimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture of a medicinal product drug for the treatment of rheumatoid arthritis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical composition that contains prodrugs (5)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,Ndimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier, in the manufacture drug for the treatment of rheumatoid arthritis in humans.

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

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

In another embodiment, the present invention provides a pharmaceutical combination that contains prodrugs (5)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,Ndimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by CCR6 inhibition in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains a compound of formula (IIB), or

- 25 045541 a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing diseases, conditions or disorders that are ameliorated by inhibition of T cell chemotaxis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains a compound of formula ( IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing an inflammatory disease, condition or disorder in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease, condition or disorder in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing psoriasis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains (S)-4-((2-(((1,4 -dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 en-1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide, or its pharmaceutical form an acceptable salt or hydrate; and at least one anti-inflammatory agent.

In another embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis in a human, which includes administering to a human in need thereof a therapeutically effective amount of a pharmaceutical combination that contains prodrugs (S)-4-((2-((((1, 4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,K-dimethylpicolinamide, or its pharmaceutical form an acceptable salt or hydrate; and at least one anti-inflammatory agent.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of diseases, conditions or disorders, which are improved by CCR6 inhibition in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of diseases, conditions or disorders, which are improved by inhibition of T cell chemotaxis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of an inflammatory disease, condition or disorder in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains a compound of formula (IIB), or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of an autoimmune disease, condition or disorder in humans.

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

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-K,X

- 26 045541 dimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of rheumatoid arthritis in humans.

In another embodiment, the present invention provides the use of a pharmaceutical combination that contains the prodrugs ^)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3 ,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-Ni-dimethylpicolinamide, or a pharmaceutically acceptable salt or hydrate thereof, and at least one anti-inflammatory agent, in the manufacture of a medicament for the treatment of rheumatoid arthritis in humans.

In another embodiment, the present invention provides a method of treating or preventing an immune disease in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or a pharmaceutical thereof. acceptable salt or hydrate.

In another embodiment, the present invention provides a method of treating or preventing an autoimmune disease in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or a pharmaceutical thereof. acceptable salt or hydrate.

In another embodiment, the present invention provides a method of treating or preventing a neurodegenerative or neuroinflammatory disease in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis, juvenile arthritis, Steele's disease, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, oligoarticular rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, rheumatoid polyarthritis, enteropathic arthritis, juvenile Reiter's syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile ial rheumatoid arthritis, juvenile rheumatoid arthritis with systemic onset, giant cell arteritis or secondary osteoarthritis from an inflammatory disease in a person, which involves administering to a person in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or a pharmaceutically acceptable salt or hydrate thereof .

In another embodiment, the present invention provides a method for treating or preventing lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, lupus nephritis, Sjögren's syndrome, scleroderma (systemic sclerosis), Raynaud's phenomenon, juvenile scleroderma, polymyositis, dermatomyositis, polymyositis-dermatomyositis, mixed joint/connective tissue disease, sarcoidosis, fibromyalgia, vasculitic microscopic polyangiitis, vasculitis, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome), granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), polyarteritis nodosa, Henoch-Schönlein purpura, idiopathic thrombocytopenic purpura, juvenile vasculitis, polyarteritis nodosa (also known as panarteritis nodosa, periarteritis nodosa, Kussmaul's disease, Kussmaul-Meyer disease or PAN), serum sickness, myasthenia gravis, Takayasu's arteritis, Behçet's syndrome, Kawasaki disease (mucocutaneous lymph node syndrome), Buerger's disease (thromboangiitis obliterans), Vogt-Koyanagi-Haradi syndrome, Addison's disease, Hashimoto's thyroiditis, sclerosing cholangitis, membranous glomerulopathy, polymyositis, myositis, atherosclerosis, autoimmune hemolytic anemia, autoimmune orchitis, or Goodpasture's disease in humans, which includes administering to a person in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method for treating or preventing inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac enteropathy, celiac disease, proctitis, eosinophilic gastroenteritis, autoimmune atrophic gastritis, pernietic anemia, or mastocytosis in a human, which comprises administering to a human, to the person in need thereof, a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method for treating or preventing psoriasis, atopic dermatitis, eczema dermatitis, dermatitis, pruritus, alopecia, autoimmune alopecia, vitiligo, epidermal hyperplasia, juvenile dermatomyositis or dermatomyositis; in some other embodiments, the psoriasis is psoriasis, guttate psoriasis, psoriatic epidermal hyperplasia, inverse psoriasis, pustule

- 27 045541 psoriasis, erythrodermic psoriasis, in humans, which includes administering to a person in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, autoimmune hepatitis, chronic aggressive hepatitis, or primary biliary sclerosis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IA ), (IB), (IIA), (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method for treating or preventing multiple sclerosis, amyotropic lateral sclerosis, Guillain-Barré disease, autoimmune encephalomyelitis, Alzheimer's disease, major depressive disorder, traumatic brain injury, epilepsy, Parkinson's disease, or bipolar disorder in a person who involves administering to a person in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB) or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method for treating or preventing Graves' disease, non-infectious uveitis, dry eye syndrome, sympathetic ophthalmia, Cogan's syndrome, keratoconjunctivitis, vernal conjunctivitis, uveitis, including uveitis associated with Behçet's disease and crystalline uveitis, keratitis , herpetic keratitis, conical keratitis, epithelial corneal dystrophy, corneal opacities, ocular premphigus, Moray ulcer, scleritis, keratoconjunctivitis sicca (dry eyes), phlyctenula, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, ocular neovasa cularization or proliferative diabetic retinotherapy in a human, which includes administering to a human in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing asthma, allergies, chronic obstructive pulmonary disease, or acute respiratory disease in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method for treating or preventing digestive/gastrointestinal cancer, colon cancer, liver cancer, skin cancer, including mast cell tumor and squamous cell cancer, breast and mammary cancer, ovarian cancer, prostate cancer gland, leukemia, diffuse large B-cell lymphoma, cutaneous T-cell lymphoma, non-Hodgkin's lymphoma, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma, including oral and metastatic melanoma, Kaposi's sarcoma , multiple myeloma, myeloproliferative diseases, myeloproliferative disorders, glioblastoma, oligodendroglioma, pancreatic cancer, brain tumors or gliomas, including astrocytoma; in some other embodiments, the leukemia is acute myeloid leukemia, T-cell acute lymphoblastic leukemia, or adult T-cell leukemia in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), (IIA), (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the present invention provides a method of treating or preventing type I diabetes mellitus, type II diabetes mellitus or juvenile diabetes mellitus in a human, which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (IA), (IB), ( IIA), (IIB), or a pharmaceutically acceptable salt or hydrate thereof.

Definitions

As used throughout this specification and the claims that accompany it, the following terms have the following meanings.

The term (C ₂ -C ₄ )alkenyl, as used herein, refers to a straight or branched chain hydrocarbon that contains from 2 to 4 carbon atoms, and which contains one carbon-carbon double bond. Illustrative examples of (C ₂ -C ₄ )alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl and 3-butenyl.

The term (C^CDalkoxy, as used herein, refers to a (C1- _C4 )alkyl group, as defined herein, that is attached to the parent molecular moiety via an oxygen atom. Illustrative examples of (C1- _C4 )alkoxy include, but but not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and t-butoxy.

The term (C1- _C3 )alkyl, as used herein, refers to a straight or branched chain hydrocarbon that contains from 1 to 3 carbon atoms. Illustrative examples of (C1C ₃ )alkyl include methyl, ethyl, n-propyl and isopropyl.

- 28 045541

The term C ₁ -C ₃ αlkyl-d ₁ . ₇ , as used herein, denotes a straight or branched chain hydrocarbon that contains from 1 to 3 carbon atoms, with one to seven hydrogen atoms being replaced by deuterium ( ^2H or D). Illustrative examples of C1- _C3 alkyld _1-7 include methyl- _d3 , ethyl- _d5 , and ethyl-2,2,2- _d3 .

The term (C1- _C4 )alkyl, as used herein, refers to a straight or branched chain hydrocarbon that contains from 1 to 4 carbon atoms. Illustrative examples of (C1C ₄ )alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.

The term (C ₁ -C ₄ )alkyl-d ₁ . ₉ , as used herein, denotes a straight or branched chain hydrocarbon that contains from 1 to 4 carbon atoms, with one to nine hydrogen atoms being replaced by deuterium ( ^2H or D). Illustrative Examples of (C1C ₄ )alkyl-d ₁ . ₉ include methyl-d ₃ , ethyl-d ₅ and ethyl-2,2,2-d ₃ .

The term (C1- _C6 )alkyl, as used herein, refers to a straight or branched chain hydrocarbon that contains from 1 to 6 carbon atoms. Illustrative examples of (C1C ₆ )alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term (C1- _C4 )alkylcarbonyl, as used herein, refers to a ( _C1C4 )alkyl group, as defined herein, that is attached to a parent molecular moiety via a carbonyl group, as defined herein. Illustrative examples of (C ₁ -C ₄ )alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, and 2,2-dimethyl-1-oxopropyl.

The term carbonyl, as used herein, denotes a -C(=O) group.

The term cyano, as used herein, refers to a -CN group.

The term (C ₃ -C ₄ )cycloalkyl, as used herein, refers to a saturated cyclic hydrocarbon group that consists of 3-4 carbon atoms. Examples of (C ₃ C ₄ )cycloalkyl include cyclopropyl and cyclobutyl; The (C ₃ -C ₄ )cycloalkyl groups of the present invention are optionally substituted with 1, 2 or 3 substituents, which are independently (C 1 -C ₄ )alkyl, CN, halogen or OH.

The term (C ₃ -C ₄ )cycloalkyl(C 1 -C ₄ )alkyl, as used herein, means a (C ₃ -C ₄ )cycloalkyl, as defined herein, that is attached to the parent molecular moiety via a (C ₁ -C ₄ )alkyl group as defined herein. Illustrative examples of (C ₃ -C ₄ )cycloalkyl(C1-C ₄ )alkyl include cyclopropylmethyl, 2-cyclopropylethyl, 2cyclopropylpropyl, 3-cyclopropylpropyl, cyclobutylmethyl, 2-cyclobutylethyl, 2-cyclobutylpropyl and 3-cyclobutylpropyl.

The term (C ₃ -C ₅ )cycloalkyl, as used herein, refers to a saturated cyclic hydrocarbon group that consists of 3 to 5 carbon atoms. Examples of (C ₃ C ₅ )cycloalkyl include cyclopropyl, cyclobutyl and cyclopentyl. The (C ₃ -C ₅ )cycloalkyl groups of the present invention are optionally substituted with 1, 2 or 3 substituents, which are independently (C 1 -C ₄ )alkyl, CN, halogen or OH.

The term halogen or halogen atom as used herein means -Cl, -Br, -I or -F.

The term halogen(C1- _C4 )alkoxy, as used herein, means at least one halogen atom, as defined herein, which is attached to the parent molecular moiety through a (C1- _C4 )alkoxy group, as defined herein. in this document. Illustrative examples of halogen(C1- _C4 )alkoxy include, but are not limited to, chloromethoxy, difluoromethoxy, 2-fluoroethoxy, trifluoromethoxy and pentafluoroethoxy.

The term halogenC1- _C3 alkyl, as used herein, refers to at least one halogen atom, as defined herein, that is attached to the parent molecular moiety via a C1- _C3 alkyl group, as defined herein. Illustrative examples of halogen(C1- _C3 )alkyl include, but are not limited to, chloromethyl, difluoromethyl, 2-fluoroethyl, trifluoromethyl, and pentafluoroethyl.

The term halogen(C1- _C4 )alkyl, as used herein, means at least one halogen atom, as defined herein, which is attached to the parent molecular moiety through a (C1- _C4 )alkyl group, as defined in this document. Illustrative examples of halogen(C1- _C4 )alkyl include, but are not limited to, chloromethyl, 2fluoroethyl, trifluoromethyl, and pentafluoroethyl.

The term heterocycle or heterocyclyl, as used herein, refers to a 4-, 5-, or 6-membered ring that contains one N-heteroatom and optionally 1 or 2 additional heteroatoms selected from the group consisting of O, N, and S. Illustrative Examples heterocyclyl include, but are not limited to, azetidinyl, imidazolidinyl, morpholinyl, oxadiazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrolidinyl, thiadiazolidinyl, thiazolidinyl and thiomorpholinyl. The heterocyclic groups of the present invention are optionally substituted 1, 2 or 3 (C ₁ -C ₄ ) alkyl groups.

- 29 045541

The term hydroxy(C1- _C4 )alkyl, as used herein, means at least one hydroxy group, as defined herein, that is attached to the parent molecular moiety via a (C1- _C4 )alkyl group, as defined in this document. Illustrative examples of hydroxy(C1- _C4 )alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,4-dihydroxybutyl and 2,3-dihydroxypropyl.

In another embodiment, the present invention provides pharmaceutical combinations for topical use that contain a compound of formula (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof, in combination with another pharmaceutical agent for the treatment of diseases, conditions and/or diseases described herein. Acceptable pharmaceutical agents that may be used in combination with the compounds of the present invention for topical administration include, but are not limited to: another compound of formula (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB) , or a pharmaceutically acceptable salt or hydrate thereof; a PDE4 isoenzyme inhibitor which includes, but is not limited to, ampremilast, roflumilast, rolipram, piclamilast, crisaborole, PF-07038124, PF-07091905, PF07090414, PF-07062087, PF-07062077, and PF-07057566; a corticosteroid which includes, but is not limited to, fluocinonide, deoxymethasone, mometasone, triamcinolone, betamethasone, alklometasone, desonide, hydrocortisone, LEO-134310A and mapracorate; a calcineurin inhibitor, which includes, but is not limited to, tacrolimus, pimecrolimus and cyclosporine; a JAK inhibitor, which includes, but is not limited to, tofacitinib, JTE-052, baricitinib, upadacitinib, PF-04965842, PF06651600 and PF-06700841; TYK inhibitors, which include, but are not limited to, PF-06826647 and BMS-986165; an ITK inhibitor, which includes, but is not limited to, JTE-051; a SYK inhibitor, which includes, but is not limited to, fostamatinib, cerdulatinib, entospletinib, TAK-659, ASN-002 and GS-9876; a tyrosine kinase inhibitor, which includes, but is not limited to, cerdulatinib; an IRAK4 inhibitor which includes, but is not limited to, 1-(((2S,3S,4S)-3-ethyl-4-fluoro-5oxopyrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6 carboxamide; an anti-inflammatory agent which includes, but is not limited to, WBI-1001 and MRX-6; retinoic acid derivatives, which include, but are not limited to, alitretinoin; a selective liver X receptor (LXR) agonist, which includes, but is not limited to, VTP-38543; H4 receptor antagonists, which include, but are not limited to, ZPL-389; NKI receptor antagonists, which include, but are not limited to, aprepitant and tradipitant; CRTH2 receptor antagonists, which include, but are not limited to, fevipiprant and OC-459; chymase inhibitors, which include, but are not limited to, SUN 13834; GATA-3 inhibitors, which include, but are not limited to, SB011; and an inverse agonist of RORC2, which includes, but is 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 present invention provides pharmaceutical combinations for oral administration that contain a compound of formula (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof, in combination with another pharmaceutical agent for the treatment of diseases, conditions and/or disorders described herein. Acceptable pharmaceutical agents that may be used in combination with the compounds of the present invention for oral administration include, but are not limited to: another compound of formula (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB ), or a pharmaceutically acceptable salt or hydrate thereof; oral anti-inflammatory agents, which include, but are not limited to, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, CELEBREX®, and pharmaceutically acceptable salts or prodrugs thereof; oral retinoic acid derivatives, which include, but are not limited to, alitretinoin; oral selective liver X receptor (LXR) agonists, which include, but are not limited to, VTP-38543; oral H4 receptor antagonists, which include, but are not limited to, ZPL-389; oral NKI receptor antagonists, which include, but are not limited to, aprepitant and tradipitant; oral CRTH2 receptor antagonists, which include, but are not limited to, fevipiprant and OC-459; oral chymase inhibitors, which include, but are not limited to, SUN 13834; oral GATA-3 inhibitors, which include, but are not limited to, SB-011; oral RORC2 inverse agonists, which include, but are not limited to, ESR-114, VTP-43742, ARN6039, TAK-828, RTA-1701, BOS-172767, AUR-101 and JTE-451; oral JAK inhibitors, which include, but are not limited to, tofacitinib, JTE-052, baricitinib, upadacitinib, PF-04965842, PF-06651600, and PF-06700841; oral TYK inhibitors, which include, but are not limited to, PF-06826647 and BMS-986165; oral ITK inhibitors, which include, but are not limited to, JTE-051; oral SYK inhibitors, which include, but are not limited to, fostamatinib, cerdulatinib, entospletinib, TAK-659, ASN-002 and GS-9876; oral S1P receptor modulators, which include, but are not limited to, ozanimod and etrasimod; and oral IRAK4 inhibitors, which include, but are not limited to, 1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrolidin-2-yl)methoxy)-7methoxyisoquinoline-6 carboxamide and BAY 1830839.

- 30 045541

In another embodiment, the present invention provides pharmaceutical combinations for injection that contain a compound of formula (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB), or a pharmaceutically acceptable salt or hydrate thereof, in combination with another pharmaceutical agent for the treatment of diseases, conditions and/or disorders described herein. Acceptable pharmaceutical agents that can be used in combination with the compounds of the present invention for injection include, but are not limited to: TNFa inhibitors, which include, but are not limited to, infliximab, adalimumab, golimumab and certolizumab pegol; anti-MAdCAM, which include, but are not limited to, SHP647; anti-IL-12 P40, which include, but are not limited to, ustekinumab; anti-IL-23 P19, which include, but are not limited to, rizankizumab, mirikizumab, brazicumab, guselkumab and tidrakizumab; anti-IL-17, which include, but are not limited to, secukinumab, brodalumab and ixekizumab; integrin inhibitors, which include, but are not limited to, natalizumab, vedolizumab and etrolizumab.

Combination therapy involves administering two or more therapeutic agents simultaneously or sequentially. Agents can be entered in any order. Alternatively, multiple therapeutic agents may be combined in a single composition that may be administered to a patient. For example, one pharmaceutical composition may contain a compound, or a pharmaceutically acceptable salt, hydrate, ester or prodrug thereof according to formula (IA), (IB), (IIA), (IIB), (IIIA) or (IMB), another therapeutic agent or a pharmaceutically acceptable salt, hydrate, ester or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier.

The term pharmaceutically acceptable salt or salt as used herein refers to salts that are 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, non-toxic acid addition salts are amino salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or using other methods that are 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, stearate, laurate, lactate, fumarate, ascorbate, aspartate, nicotinate, p-toluenesulfonate, camphorsulfonate , methanesulfonate, 2hydroxyethanesulfonate, gluconate, glucoheptonate, lactobionate, glycerophosphate, pectinate, lauryl sulfate, and the like, metal salts such as sodium, potassium, magnesium or calcium salts or amino salts such as ammonium salts, triethylamine salts, and the like, all from which can be obtained in accordance with conventional methods.

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

The present invention also includes pharmaceutically acceptable salts of prodrugs of the compounds of the present invention. Illustrative examples include, but are not limited to, the compounds shown below, wherein R ⁺ represents a lithium, sodium, potassium, ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium, and the like cation, and wherein R2+ represents a cation of calcium, magnesium, aluminum and the like.

The compounds of the present invention can be isolated and used by themselves in

- 31 045541 the form of their pharmaceutically acceptable salts, including salts of prodrugs. In accordance with the present invention, compounds with more than one basic nitrogen atom can form salts with different amounts of equivalents (eq.) of acid. Compounds with multiple acidic groups can form basic addition salts with varying numbers of equivalents (eqs) of the main addition molecule or positive counterion. Practitioners will appreciate that all such salts are included within the scope of the present invention.

The present invention covers compounds of formula (IA), (IB), (IIA), (IIB), (IIIA) or (IMB) obtained by synthetic or metabolic processes. The production of the compounds of the present invention by metabolic processes includes processes that occur in humans or animals (in vivo) or processes that occur in vitro.

The present invention also relates to pharmaceutically active metabolites that are formed by in vivo biotransformation of compounds of formula (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB). The term pharmaceutically active metabolite, as used herein, refers to a compound that is formed by in vivo biotransformation of compounds of formula (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB). A thorough discussion of biotransformation is presented in (Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition, 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 present invention can be used in pure form or, when such forms exist, in the form of a pharmaceutically acceptable salt, ester, amide or prodrugs. Alternatively, the compound may be administered as a pharmaceutical composition that contains the compound of interest in combination with one or more pharmaceutically acceptable carriers. The phrase a therapeutically effective amount of a compound of the present invention means a sufficient amount of a compound to treat the diseases, conditions or disorders described herein at a reasonable benefit/risk ratio as would be expected in any medical treatment. The specific therapeutically defective dose level for any particular patient will depend on various factors, including the disease being treated and the severity of the disease; the activity of the particular compound that is used; the specific composition that is used; the age, weight, general health, gender and diet of the patient; timing of administration, route of administration, and rate of elimination of the particular compound being used; duration of treatment; drugs that are used in combination with or are compatible with the particular compound that is used; and similar factors well known in the medical field.

Pharmaceutical compositions or preparations.

In another embodiment, the present invention provides pharmaceutical compositions, or preparations, that contain a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical compositions or preparations of the present invention can be administered to humans and other mammals topically, orally, parenterally, intracisternally, intravaginally, intraperitoneally, buccally, as an oral spray, as a nasal spray, rectally in the form of a suppository, or in the form of a liposome.

A typical pharmaceutical composition or preparation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Acceptable carriers, diluents and excipients include materials such as carbohydrates, waxes, water-soluble and/or water-repellent polymers, hydrophilic or hydrophobic materials, gelatin, oils, diluents, water and the like. The particular carrier, diluent or excipient that is used will depend on the means and purposes for which the compound of the present invention is used. Suitable aqueous diluents include water, ethanol, propylene glycol, polyethylene glycols (eg, PEG400, PEG300), and others, and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, matting agents, lubricants, processing aids, coloring agents, sweeteners, deodorizing agents, flavoring agents, agents and other known additives to provide an acceptable appearance to a drug product (ie, a compound of the present invention or a pharmaceutical composition thereof) or to assist in the manufacture of a pharmaceutical product (ie, for use in the manufacture of a drug product).

The preparations can be prepared using conventional dissolution and mixing procedures. For example, a parent drug substance (ie, a compound of the present invention or a stabilized form of the compound (eg, a complex and a cyclodextrin derivative or other known complexing agent)) is dissolved in an appropriate solvent in the presence of one or more of the excipients described above. The dissolution rate of poorly water-soluble compounds can be increased by using a spray-dried dispersion, such as the dispersion described in Takeuchi, H., et al. in Enhancement of the dissolution rate of a poorly water-soluble

- 32 045541 drug (tolbutamide) by a spray-drying solvent deposition method and disintegrants J. Pharm. Pharmacol. 39, 769-773 (1987); and EP0901786 B1 (US2002/009494), which are incorporated herein by reference. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide easily controlled dosage of the drug and to provide the patient with an aesthetically pleasing and user-friendly product.

The pharmaceutical composition or drug for use may be packaged in a variety of ways depending on the method used to administer the drug, typically the dispensing article includes a container in which the pharmaceutical drug is stored in an appropriate form. Acceptable containers include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cans, and the like. The container may also include a tamper-proof kit to prevent inadvertent access to the contents of the package. In addition, there is a label on the container that describes the contents of the container. The label may also contain appropriate warnings.

The term pharmaceutically acceptable carrier refers to a carrier medium that provides adequate delivery of an effective amount of the active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and is reasonably nontoxic to the host or patient. Exemplary carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers and the like. Additional information regarding media can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), which is incorporated herein by reference. Additional examples of materials that may serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose 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 as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; non-pyrogenic water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweeteners, flavoring and deodorizing agents, preservatives and antioxidants may also be present in the composition, in accordance with the decision of the formulator.

The term pharmaceutically acceptable topical carrier refers to pharmaceutically acceptable carriers, as described herein above, acceptable for topical use. An inactive liquid or cream carrier capable of suspending or dissolving the active agent(s), and which has the properties of being non-toxic and non-inflammatory when applied to the skin, nails, hair, claws or hooves is an example of a pharmaceutically acceptable topical carrier. This term is specifically intended to cover carrier materials approved for use also in cosmetics for topical use.

The term topical administration refers to the application of a pharmaceutical agent to the outer surface of the skin, nails, hair, claws or hooves such that the agent crosses the outer surface of the skin, nails, hair, claws or hooves and enters the tissues below. Topical administration includes applying the composition to intact skin, nail, hair, claw or hoof, or to a broken, broken or open wound of skin, nail, hair, claw or hoof. Local administration of a pharmaceutical agent may result in limited distribution of the agent to the skin and surrounding tissues or, when the agent is removed from the treatment area by the bloodstream, may result in systemic distribution of the agent.

Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, if required. Compounds that are volatile may require mixing with special formulation agents or special packaging materials to ensure proper dose delivery. In addition, compounds of the present invention that have poor permeation into human skin may require one or more penetration enhancers, while compounds that are rapidly absorbed through the skin may require formulation with absorption retarding agents or barriers.

Ointments, pastes, creams, lotions, gels, powders and solutions for topical use may contain, in addition to the active compound of the present invention, pharmaceutically acceptable excipients

- 33 045541 ents, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, preservatives, antioxidants, flavorings, emulsifiers, dyes, inerts fillers, anti-irritants, adhesives, flavoring agents, opacifying agents, antioxidants, gelling agents, stabilizers, surfactants, emollients, coloring agents, preservatives, buffering agents, penetration enhancers, or mixtures thereof. Excipients for external use should not interfere with the effectiveness of the biological activity of the active agent and should not be harmful to epithelial cells or their function.

The term permeation enhancer or penetration enhancer refers to increasing the permeability of the skin, nail, hair, claw or hoof to a drug to increase the rate of penetration of the drug through the skin, nail, hair, claw or hoof. The enhanced penetration achieved through the use of such enhancers can be observed, for example, by measuring the rate of diffusion of the drug through the skin, nails, hair, claw or hoof of an animal or human using a cell diffusion apparatus. The diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984), p. 161-162. The term permeation enhancer or penetration enhancer refers to an agent or mixture of agents that, alone or in combination, act to increase the permeability of the skin, nails, hair or hooves to a drug.

The term transdermal delivery refers to the diffusion of an agent across the barrier of the skin, nails, hair, claws or hooves as a result of topical administration or other application of the composition. The horny ball acts as a barrier, and only a few pharmaceuticals are able to penetrate intact skin. In contrast, the epidermis and dermis are permeable to many solutes, and thus drug absorption occurs more easily through skin, nails, hair, claw or hoof that are abraded or otherwise stripped of the horny ball to expose the epidermis. Transdermal delivery involves injection or other delivery through any portion of the skin, nails, hair, claws or hoofs, or mucous membrane and absorption or penetration through the remainder of the portion. Absorption through intact skin, nail, hair, claw or hoof may be enhanced by disposing of the active agent in an appropriate pharmaceutically acceptable vehicle prior to application to the skin, nail, hair, claw or hoof. Passive local administration may consist of applying the active agent directly to the treatment site in combination with emollients or penetration enhancers. As used herein, transdermal delivery is intended to involve delivery by penetration into or through the integumentary surface, ie, skin, nails, hair, claw or hoof.

Powders and sprays may contain, in addition to the compounds of the present invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons.

Solid dosage forms for oral administration include capsules, tablets, dragees, 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) excipients or carriers such as starches, lactose, sucrose, glucose, mannitol and salicylic acid. acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrolidinone, sucrose, and gum arabic; c) humectants such as glycerin; d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; f) agents that retard dissolution, 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 stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and dragees, the dosage form may also contain buffering agents.

Solid compositions of this type can also be used as fillers in soft and hard gelatin capsules using lactose or milk sugar, as well as high molecular weight polyethylene glycols and others.

Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings, such as enteric and other coatings well known in the field of pharmaceutical formulation. They may optionally contain opacifying agents and may also be compositions that release the active ingredient(s) only, or predominantly, in a specific part of the intestinal tract in a delayed manner. Examples of administration compositions that can be used include polymeric substances and waxes.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents, which are commonly used

- 34 045541 are available in the art, such as, for example, water or other diluents, 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 (especially cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof.

In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring and deodorizing agents.

The term parenteral, as used herein, refers to routes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intra-articular, and infusion. The pharmaceutical compositions of the present invention for parenteral injection contain pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or fillers include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin and the like), suitable mixtures thereof, vegetable oils (eg olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

Injectable depot forms are prepared by forming microencapsulated drug matrices in biodegradable polymers such as polylactide polyglycolide. Depending on the drug to polymer ratio and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable drugs are also prepared by introducing the drug into liposomes or microemulsions that are compatible with body tissues.

Injectable preparations can be sterilized, for example, by filtration through a bacterial filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injection medium immediately prior to use.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. Additionally, sterile fixed oils are commonly used as a solvent or suspension medium. Any soft fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injections.

Pharmaceutical compositions, or preparations, for rectal or vaginal administration are advantageously suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating carriers such as cocoa butter, polyethylene glycol or suppository wax that is solid at ambient temperature , but liquid at body temperature, and therefore melt in the rectum or vaginal cavity and release the active compound.

The compounds of the present invention can also be administered in the form of liposomes. Liposomes are typically derived from phospholipids or other lipid substances and are formed from mono- or multilayer hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in the form of liposomes may contain, in addition to the compounds of the present invention, stabilizers, preservatives and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), which are used alone or together. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., (1976), p 33 et seq.

The pharmaceutical compositions, or preparations, of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be achieved by various antibacterial agents.

- 35 045541 rial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and others. It may also be desirable to include isotonic agents such as sugars, sodium chloride and others. Prolonged absorption of the injectable pharmaceutical form can be achieved through the use of agents that delay absorption, for example, aluminum monostearate and gelatin.

The pharmaceutical compositions or preparations of the present invention are suspensions. Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

The actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and route of administration. The dosage level selected will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and previous medical history of the patient being treated. However, it is within the skill of one skilled in the art to begin dosing a compound at levels lower than those necessary to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of the present invention that are administered to humans or lower level animals may range from about 0.0001 to about 15 mg/kg/day. For purposes of oral administration, more preferred doses may range from about 0.01 to about 5 mg/kg/day. For topical use, more preferred doses may range from 0.001 mg/kg/day to about 5 mg/kg/day. If desired, the effective daily dose may be divided into multiple doses for administration purposes, for example, two to four separate doses per day.

Pharmaceutical compositions also include solvates and hydrates of the compounds of the present invention. The term solvate refers to a molecular complex of a compound represented by formula (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB), including pharmaceutically acceptable salts or hydrates thereof, with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical industry that are known to be harmless to the recipient, for example, water, ethanol, ethylene glycol, (S)-propylene glycol, (R)propylene glycol, and the like, the term hydrate referring to the complex , in which the solvent molecule is water. Solvates and/or hydrates predominantly exist in crystalline form. Other solvents can be used as intermediate solvates to obtain more desirable solvates. Intermediate solvents include, but are not limited to, methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, 1,4-butyn-diol and the like.

The compounds of the present invention may exist in more than one crystalline form. Polymorphs of compounds of formulas (IA), (IB), (IIA), (IIB), (IIIA) or (IIIB), and their salts (including solvates and hydrates) are part of this invention and can be prepared by crystallization of a compound of the present invention under different conditions, for example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; different cooling modes, from very fast to very slow cooling during crystallization. Polymorphs can also be prepared by heating or melting a compound of the present invention followed by gradual or rapid cooling. The presence of polymorphs can be determined using solid probe nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, differential scanning calorimetry, powder X-ray diffraction, or similar other methods.

The present invention also includes isotopically labeled compounds identical to those described by formulas (IA), (IB), (IIA), (IIB), (IIIA), and (NIB) except that one or more atoms are replaced by an atom that has an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur and fluorine, such as ^2H , ^3H , 13C, ^14C , ^{15N , 18O , 17O} , ³⁵ S, ³⁶ Cl, ¹²⁵ I, ¹²⁹ I and ¹⁸ F, respectively. Certain isotopically labeled compounds of the present invention, for example those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are useful in tissue distribution assays of drug and/or substrates. The isotopes tritium (ie ^3H ) and carbon-14 (ie ^14C ) are particularly preferred due to their ease of preparation and detection. In addition, substitution with heavy isotopes such as deuterium (i.e., ^2H ) may provide certain therapeutic benefits that arise from greater metabolic stability, such as increased in vivo half-life or reduced dosing requirements, and may therefore be advantageous in some cases. circumstances. Isotope me

- 36 045541 The compounds of the present invention can generally be prepared by following the procedures disclosed in the schemes and/or examples below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

In particular, the present invention includes deuterated compounds of formula (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB). The hydrogens contained in the compounds of the present invention may be replaced by deuterium, including pyridine hydrogens, as shown below.

Oh Oh

Illustrative examples of deuterated compounds of the present invention include, but are not limited to, Examples 39 and 40.

All US patents and publications cited (including all technical bulletins referenced in the examples) are hereby incorporated by reference in their entirety.

The compounds of the present invention, or pharmaceutically acceptable salts or hydrates thereof, can be prepared by the methods described below, together with synthetic methods known in the field of organic chemistry, or modifications and derivatizations known to those skilled in the art. The starting materials used herein are commercially available or can be prepared by conventional methods known in the art (such as methods disclosed in standard references, including the Compendium of Organic Synthetic Methods, Vol. I-VI, published by Wiley -lnterscience). Advantageous methods include, but are not limited to, the methods described below.

During any of the following synthetic sequences, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the corresponding molecules. This can be achieved using 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 Wley & Sons, 1999, which are hereby incorporated by reference.

The compounds of the present invention can be prepared as a single enantiomer or as a mixture of individual enantiomers, which includes racemic mixtures. Methods for producing a predominantly single enantiomer from a mixture of individual enantiomers or a racemic mixture are well known to those skilled in the art of organic chemistry. Such methods include, but are not limited to, preferential crystallization of diastereomeric salts (e.g., tartrate or camphorsulfonate), covalent derivatization with a chiral, non-racemic reagent, followed by separation of the resulting diastereomers by conventional means (e.g., crystallization, chromatographic separation, or distillation), and chemical reversion to scalemic compound, or by high/medium pressure liquid chromatography or supercritical liquid chromatography using a chiral stationary phase. These methods can be carried out on the final compounds of the present invention or on any intermediate compounds of the present invention that contain a stereogenic center. Additionally, to facilitate separation by any of the methods described above, the compounds of the present invention or any intermediates of the present invention that contain a stereogenic center can be transiently reacted with an achiral reagent, separated, and then converted to a scalemic compound using standard synthetic methods.

Stereoisomers are designated (R) or (S), depending on the configuration of substituents around the chiral carbon atom. The terms (R) and (S) as used herein represent configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976), 45: 13-30. In particular, the stereochemistry at the point of addition of the variables A and B n in W A of formulas (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB) may independently be either (R) or ( S). The enantiomers of the present invention are designated (R), (S), or * and are substantially free of another enantiomer. Substantially free means that the enantiomeric excess is greater than about 90%, preferably greater than about 95%, and more preferably

- 37 045541 significantly greater than approximately 99%. In the context of enantiomeric excess, the term approximately means ±1.0%. The symbol * denotes a chiral carbon atom as either (R) or (S) in stereochemistry depending on the configuration of substituents around the chiral carbon atom.

The compounds of the present invention, not designated (R), (S), or *, may exist as racemates (i.e., 50% (R) and 50% (S)) or as a mixture of two enantiomers, one enantiomer being in excess. For example, enantiomeric mixtures may include the (R) enantiomer at 51% and the (S) enantiomer at 49% or vice versa, or any combination with (R) and (S) other than a racemic mixture of 50% (R) and 50% (S). The present invention includes racemates and enantiomeric mixtures of the compounds of the present invention.

The compounds of the present invention can exist in different stable conformational forms, which can be separated. Torsional asymmetry due to limited rotation around an asymmetric single bond, such as through steric hindrance or ring deformation, may allow separation of different conformers. The compounds herein further include each conformational isomer of the compounds of formula (IA), (IB), (IIA), (IIB), (IIIA), (IIIB) and mixtures thereof.

Tautomers may exist in the compounds of the present invention and are specifically within the scope of the present invention. The term tautomer, as used herein, refers to the displacement of a proton from one atom of a molecule to another atom of the same molecule, where two or more structurally different compounds are in equilibrium with each other. The compounds of the present invention may exist as tautomers. The present invention contemplates tautomers resulting from the shift of protons from one atom to another atom of the same molecule, which forms two or more different compounds that are in equilibrium with each other. In particular, the bis(amino)cyclobut-3-ene-1,2-dione moiety that is contained in the compounds of the present invention can tautomerize as shown below and is included within the scope of the present invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be prepared in accordance with the reaction schemes and examples disclosed herein below. Unless otherwise indicated, R1, _R2 , _R3 , R4, R5, _R6 , _R7 , _{R8 R9} , m, n, A, B, X, R _A , R _B and R _C in the diagrams are as follows , as defined in formulas (IA) and (IB) of the Summary of the Invention section above. One skilled in the art will appreciate that the various symbols, superscripts, and subscripts that are used in the diagrams, methods, and examples are for convenience of presentation and/or display of the order in which they are introduced in the diagrams, and are not intended to necessarily answer symbols, superscripts or subscripts in the claims that are attached. The schemes represent methods that are used to synthesize the compounds of the present invention. They do not limit the scope of the invention in any way. Isolation and purification of the products are carried out according to standard procedures known to one skilled in the art.

Scheme A

r ₂ R ₂

A-1 A-3 A-5

Compounds of formula (IA) and (IB) can be prepared as described in Scheme A. Nucleophilic aromatic substitution between aminopyridine A-1 (prepared as described in Scheme B) and commercially available 3,4-diethoxycyclobut-3-ene-1, 2-dione (A-2) gives compounds of formula A-3. Another nucleophilic aromatic substitution between A-3 and amine A-4 (prepared as described in Scheme C-G) gives compounds of formula A-5.

- 38 045541

Scheme B

The compounds of formula A-1, which are used in scheme A, can be prepared as described in scheme B. Amidation between commercially available 4-chloro-3-methoxypicolinyl chloride (B1) and commercially available amine B-2 under basic conditions gives compounds of formula AT 3. The Buchwald coupling between B-3 and tert-butylcarbamate produces compounds of formula B-4, which can be subjected to acidic conditions in order to remove the Boc group and produces compounds of formula B-5. Demethylation of B-5 results in the compound of formula A-1.

Scheme C

I - - _Η2Ν λ _α ¹ X = Br, I ¹

I--- С-1 R = CN С-4 С-6 А-4 ► С-2 R = СНО

The compounds of formula A-4, which are used in scheme A, where the amines are enantiomerically enriched, can be prepared as described in scheme C. Titanium(IV) ethoxide-mediated condensation of aldehyde C-2 (either commercially available or prepared by reduction the corresponding C-1 nitrile, available or prepared by methods known in the art) with (3)-2-methylpropane-2-sulfinamide (C-3) gives compounds of formula C-4. Metalation with C-5 heteroaryl halides in which X is iodine or bromine gives highly diastereoselective addition to C-4, yielding sulfonamides of formula C-6 as the major diastereomer. Successive removal of the chiral auxiliary under acidic conditions results in the compound of formula A-4. The absolute stereochemistry of the A-4 amines can be determined using methods known to those skilled in the art, including Mosher amide analysis and single crystal X-ray crystallography, or obtained by analogy to known compounds.

Scheme D

C-6 X_ O A o NH ₂

A —~ A —~ A

R В А^ В А^ В

I--- D-1 R = OH D-3 A-4

L—D-2 R = NMeOMe

The compounds of formula A-4, which are used in scheme A, in which the amines are racemic mixtures or diastereomeric mixtures, can be prepared as described in scheme D. Carboxylic acids of formula D-1 (either commercially available or prepared as described in below) can be converted to the corresponding Weinreb amide D-2 by HATU-mediated condensation with methoxymethylamine. Metalation with C-5 heteroaryl halides, in which X is iodine or bromine, followed by reaction with D-2 gives ketones of formula D-3. Reductive amination of D-3 with ammonium in methanol gives compounds of formula A-4 as a racemic or diastereomeric mixture.

Scheme E

Alternatively, compounds of formula A-4, wherein in formula (IA) or (IB) variable A is

- 39 045541 defined as a substituted pyrazole, can be prepared from 3-halo-1-alkylpyrazoles E-1 (R ₄ = alkyl and X = bromine or iodine), as described in scheme E. Metalation of E-1 and its addition to or sulfinamine C-4 or Weinreb amide D-2 gives addition products of formula E-2 or E-4, respectively. Introduction of the R ₅ substituent can be accomplished either by electrophilic aromatic substitution or by reaction with NIS, and then the metal-mediated cross-coupling reaction of the resulting iodide gives compounds E-3 or E-5. The chiral auxiliary E-3 can then be removed under acidic conditions to give compounds of formula A-4. Reductive amination of E-5 with ammonium in methanol gives compounds of formula A-4.

Scheme F

Compounds of formula A-4, which are used in scheme A, where in 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 acids (F-1) can be converted to the corresponding Weinreb amide F-2 by HATU-mediated condensation with methoxymethylamine. Metalation of C-5 heteroaryl halides in which X is iodine or bromine followed by reaction with F-2 produces ketones of formula F-3. Subsequent alkylation of F-3 using an alkyl halide (such as iodomethane or iodethane) and a suitable base, followed by reductive amination using ammonium in methanol, gives compounds of formula A-4 as a racemic mixture.

Scheme G

Compounds of formula A-4 that are used in scheme A, where in 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 by methods known in the art, can be fused with methoxymethylamine in the presence of HATU to produce the Weinreb amides of formula G-2. Compound G-2 can be reacted with a Grignard reagent (such as isopropyl magnesium bromide or cyclopentyl magnesium bromide) to produce ketones of formula G-3 in which R and R' are methyl, or R and R' are taken together with a carbon atom to which they are attached to form a C3-5 cycloalkane ring. The following alkylation of G-3 using an alkyl halide (such as iodomethane or iodoethane) and a suitable base, followed by reductive amination using ammonium in methanol, gives compounds of formula A-4 as a racemic mixture.

Scheme H

The specific carboxylic acid D-1 that is used in scheme D, where in 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) allyltrimethylsilane gives ethyl 2-hydroxy-2methylpent-4-enoate (H-2). Epoxidation of the terminal alkene H-2 using 3-chloroperbenzoic acid followed by magnesium bromide-mediated intermolecular cyclization gives ethyl 4-hydroxy-2-methyltetrahydrofuran-2-carboxylate (H-4). Next oxidation WTO

- 40 045541 ric alcohol using pyridinium chlorochromate followed by fluorination using diethylaminosulfotrifluoride gives ethyl 4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate (H6). The H-6 ester was transesterified to the H-7 benzyl ester, which was then separated using chiral TOP. The following saponification of the ester gives the individual enantiomers of H-8, which can be used in scheme D. The absolute stereochemistry of H-8 was determined by single crystal X-ray crystallography (see Fig. 3).

Scheme I

1,4-Disubstituted-3-iodopyrazoles that can be used in the synthetic methodologies described in Schemes C, D, and F can be prepared as described in Scheme I. Iodination of Commercially Available 4-Substituted Pyrazoles (I-1) NIS gives compounds of formula I-2. The following Na-alkylation of I-2 with alkyl halides (eg, iodomethane, iodoethane) followed by separation of the regioisomers using chromatography provides compounds of formula C-5, which can be used in the synthetic methodologies described in the scheme above.

Scheme J

Alternatively, 1,4-disubstituted-3-iodopyrazoles, which can be used in the synthetic methodologies described in Schemes C, D, and F, can be prepared as described in Scheme J. 1,4-Disubstituted-3-aminopyrazoles (J-1) can be converted to compounds of formula C-5 by the Sandmeyer reaction using sodium nitrite and potassium iodide. Compounds of formula C-5 can also be prepared through direct iodination of commercially available 1,4-disubstituted pyrazoles J-2 NIS.

Scheme K

In another variation, the 1,4-disubstituted 3-iodopyrazoles that are used in Scheme CD and Scheme F can be prepared as described in Scheme K, particularly in which R ₄ = R ₅ = methyl. 3-Iodo-1-methyl-1H-pyrazole, K-1 can be formulated regioselectively with Vilsmeier's reagent, yielding 3-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (K-2), which in turn can be reduced ( TFO, triethylsilane), yielding 3-iodo-1,4-dimethyl-1H-pyrazole, K-3.

Scheme L

The 2,5-disubstituted 4-bromothiazoles that are used in Schemes C-D and Scheme F can be prepared as described in Scheme L. Bromination of commercially available 2,5-disubstituted thiazoles L-1 with NBS gives compounds of formula C-5.

- 41 045541

Scheme M

Alternatively, compounds of formula (IA) and (IB) can be prepared as described in Scheme M. Esterification of commercially available 4-chloro-3-methoxypicolinyl chloride (B-1) under basic conditions gives tert-butyl 4-chloro-3-methoxypicolinate (M-1). A 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 the amines of A-4 results in compound M-4. Hydrolysis of the ester under acidic conditions, followed by HATU-mediated amidation with B-2 amines, and O-demethylation using magnesium bromide gives compounds of formula A-5.

Scheme N

Compounds of formula (IA) and (IB) in which R ₃ is -CH ₂ OP(O)(OH) ₂ can be prepared as described in Scheme N. Alkylation of compounds of formula A-5 with commercially available di-tert- butyl(chloromethyl)phosphate under basic conditions gives N-1. Further elimination of the tert-butyl ester protecting groups under acidic or neutral conditions leads to compound N-2.

Examples

The present invention will be better understood by reference to the following examples, which are included only for the purpose of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the invention. The synthesis of various compounds of the present invention is illustrated below. Additional compounds that are within the scope of this invention can be prepared using the methods illustrated in these Examples and Schemes, either alone or in combination with methods well known in the art.

Typically, experiments were performed under an inert atmosphere (nitrogen or argon), especially when oxygen- or moisture-sensitive reagents or intermediates were used. Commercial solvents and reagents were generally used without further purification, including anhydrous solvents where appropriate. Mass spectrometry data are reported using either liquid chromatography-mass spectrometry (LC-MS), atmospheric pressure chemical ionization (APCI) or gas chromatography-mass spectrometry (GC-MS) equipment. Chemical shifts for nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, δ) with reference to the residual peaks of the deuterated solvents that were used. Interaction constants (J value) are presented in Hertz. For the syntheses that are submitted for procedures in other examples, reaction conditions (reaction time and temperature) may vary. In general, reactions were followed by thin layer chromatography or mass spectrometry and were amenable to processing when appropriate. Purification may vary between experiments: in general, solvents and solvent ratios used for eluents/gradients were chosen to provide appropriate Rf or retention time (RetT).

The compounds of the present invention have been named using Chemdraw Professional version 16.0 software or have been given names that appear to be consistent with Chemdraw nomenclature.

- 42 045541

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

The following SFC methods were used. SFC Method A: Chiral Tech OD-H 250 mm x 4.6 mm x 5 µm, 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 µm, 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 µm, 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 µm, 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 µm, from 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 µm, 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 µm, 5 to 40% 0.05% DEA in IPA, 2.5 ml/min, 40°C. SFC method H: Chiralcel OD-3 150x4.6 mm i.d. 3 µm, 5 to 40% 0.05% DEA in EtOH, 2.5 ml/min, 40°C). SFC method I: REGIS (c,s) WHELK-O1 250 mm x 30 mm x 5 µm 40% 0.05% DEA in EtOH, 2.5 ml/min, 35°C. SFC method J: Chiralpak AS-3 150x4.6 mmx3 µm, 5 to 40% 0.05% DEA in EtOH, 2.5 ml/min, 35°C. SFC method K: Chiralpak AS-3 100x4.6 mmx 3 µm, 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 µm, from 5 to 60% 0.2% NH ₃ in EtOH, 3 ml/min. SFC method M. Lux Cellulose, 150 mm x 4.6 mm, 3 µm, from 5 to 40% MeOH, 2 ml/min. SFC method N: Chiralpak AD-3 150 mm x 4.6 mm x 3 µm, 5 to 40% 0.1% ethanolamine in EtOH, 2.5 ml/min.

The following TOP methods were used. TOP method A: Chiralcel OD-RH, 150 mm x 4.6 mm x 5 µm, 10 to 80% MeCN in 0.069% TFO in H ₂ O, 0.8 ml/min, 30°C. TOP method B: Chiralpak AS-RH, 150 mm x 4.6 mm x 5 µm, 10 to 80% MeCN in 0.069% TFO in H ₂ O, 0.8 ml/min, 30°C.

Example 1.

(R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino )-3-hydroxy-N,N-dimethylpicolinamide

Stage 1A. 1-methylcyclopentane-1-carbonitrile.

To a solution of LHMDS (280 ml, 280 mmol, 1 M solution in THF) at -70°C, a solution of cyclopentanecarbonitrile (26.67 g, 280.3 mmol) in THF (20 ml) was added dropwise over 15 min. After stirring for 30 minutes, iodomethane (59.7 g, 26.2 mL, 420 mmol) was added dropwise and the reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The resulting yellow solution was cooled to 0 °C and quenched with a saturated aqueous solution of NH ₄ Cl (200 ml) and water (100 ml). The mixture was extracted with MTBE (2.5 Lx2), and the combined organic extracts were washed with brine (1 L), dried over Na ₂ SO ₄ , and filtered. The filtrate was concentrated in vacuo. The Syrian product was purified twice using silica gel column chromatography (100% petroleum ether) to give 60 g (65%) of the title compound as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ 2.20-2.10 (m, 2H), 1.90-1.70 (m, 4H), 1.65-1.55 (m, 2H), 1 .41 (s, 3H).

Stage 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 1methylcyclopentane-1-carbonyl (30 g, 275 mmol) in DCM (30 ml). The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was quenched with a saturated aqueous NH ₄ Cl solution (1 L) at -40°C and stirred vigorously at 25°C for 10 minutes. The mixture was diluted with DCM (1 L) and then filtered and the solids washed with DCM (500 ml x 3). The combined filtrate was washed with brine (1 L), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as a DCM/toluene solution (3/2.2 L). The solution was used directly without further purification, allowing for quantitative yield.

1H NMR (400 MHz, CDCl ₃ ) δ 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).

Stage 1C. (c,E)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide.

Titanium(IV) ethoxide (163 g, 717 mmol) was added to a solution of 1-methylcyclopentane-1-carbaldehyde (30.8 g, 275 mmol) in DCM/toluene (3/2, 2.0 L) at 20°C. The reaction mixture was stirred for 20 minutes and then (S)-2-methylpropane-2-sulfinamide (33.3 g, 275 mmol) was added. The resulting

- 43 045541 the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with water (250 ml). The mixture was filtered and the solids were washed with THF (3 Lx3). The combined organic layers were concentrated in vacuo. The Syrian product was purified using silica gel column chromatography (100% petroleum ether) to give 44.89 g (38%) of the title compound as a light yellow oil. RX-MS m/z 216.3 [M+H] ⁺ .

1H NMR (400 MHz, CDCI3) δ 7.94 (s, 1H), 1.93-1.85 (m, 2H), 1.80-1.60 (m, 4H), 1.55-1, 45 (m, 2H), 1.21 (s, 3H), 1.20 (s, 9H).

Stage 1D. 3-iodo-1,4-dimethyl-1H-pyrazole.

Method A.

3-Iodo-1,4-dimethyl-1H-pyrazole. To a solution of 1,4-dimethyl-1H-pyrazol-3-amine (1.0 g, 8.6 mmol) in conc. HCl (7.15 ml) at 0°C, a solution of sodium nitrite (1.22 g, 17 mmol) in water (1.78 ml) was added 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 minutes, and then warmed to ambient temperature and stirred for 2 hours. The reaction mixture was diluted with THF (8 ml) and water (8 ml), and extracted with EtOAc (30 mlx4). The combined organic extracts were washed with saturated aqueous Na ₂ S ₂ O ₃ (30 mlx2) followed by washing with water (30 ml) and brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The Syrian product was purified using silica gel column chromatography (0 to 60% EtOAc in heptane) to provide 988 mg (52%) of the title compound as a white solid. RX-MS m/z 223.0 [M+H] ⁺ .

1H NMR (400 MHz, CDCI3) δ 7.05 (s, 1H), 3.87 (s, 3H), 1.98 (s, 3H).

Method B.

Step 1. 3-iodo-1-methyl-1H-pyrazole-4-carbaldehyde. POCl ₃ (45.0 ml, 481 mmol) was added to a solution of 3-iodo-1-methyl-1H-pyrazole (25 g, 120.2 mmol) in DMF (150 ml) at 0°C. After 10 minutes, the reaction mixture was heated to 65°C for 18 hours. NaH ₂ PO ₄ solution (50 g in 200 ml) was slowly added to the reaction mixture, ensuring that the temperature was maintained between 25 and 35°C and the pH no greater than 4. After addition, the reaction mixture was stirred at room temperature for 45 minutes. and then made alkaline by carefully adding saturated Na2CO3 solution. The aqueous mixture was extracted with EtOAc. The organic layer was washed with brine, dried and filtered. The filtrate was concentrated. The resulting yellow oil was recrystallized with EtOAc/heptane to give 28.4 g (88%) of the title compound as a sandy brown solid.

1H NMR (400 MHz, CDCI3) δ 9.67 (s, 1H), 7.84 (s, 1H), 4.00 (s, 4H).

Step 2. 3-iodo-1,4-dimethyl-1H-pyrazole. Triethylsilane (5.08 ml, 0.32 mmol) and TFO (1.36 ml, 0.18 mmol) were added to a mixture of 3-iodo-1-methyl-1H-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 temperature and a saturated aqueous solution of NaHCO ₃ 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 using silica gel column chromatography (EtOAc/heptane) to obtain 0.64 g (68%) of the title compound.

1H NMR (400 MHz, CDCI3) δ 7.08 (s, 1H), 3.90 (s, 3H), 2.01 (s, 3H).

Method C.

Step 1. 3-iodo-4-methyl-1H-pyrazole. NIS (2196.0 g, 9.76 mol) was added portionwise to a solution of 4methyl-1H-pyrazole (800.0 g, 9.76 mol) in DMF (5 L) while maintaining the temperature below 25°C. The mixture was stirred at 25°C for 20 hours. The two batches were combined. The combined mixtures were poured into water (20 L) and then extracted with MTBE (5 Lx5). The combined organic layers were washed with brine (5 Lx3), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue triturated with petroleum ether/EtOAc (5 L, 10:1). The suspension was stirred at 16°C for 2 hours and then filtered. The resulting solid was dried in vacuo to give 1280.0 g (32%) of the title compound as a light yellow solid.

1H NMR ( _CDCl3 , 400 MHz) δ 7.42 (s, 1H), 2.07 (s, 3H).

Step 2. 3-iodo-1,4-dimethyl-1H-pyrazole. To a suspension of 60% NaH in mineral oil (165.0 g, 4.12 mol) in anhydrous THF (4.5 L), a mixture of 3-iodo-4-methyl-1H-pyrazole (710.0 g) was added dropwise , 3.41 mol) in anhydrous THF (1.5 L) at 0°C. The mixture was stirred at 10°C for 1 hour. Iodomethane (496.0 g, 3.49 mol) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at 20°C for 16 hours. The reaction mixture was quenched with water (4.5 L) and extracted with EtOAc (2.5 Lx3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified using silica gel column chromatography (petroleum ether:EtOAc=10:1 to 1:1) to obtain two fractions. The first fraction (150 g) was diluted with petroleum ether (200 ml) and stirred at 10°C for 30 min. The suspension was filtered. The solid was washed with petroleum ether (100 ml) and dried in vacuo to give 100.0 g of the title compound in

- 44 045541 in the form of a white solid. The filtrate was concentrated in vacuo, combined with the other fraction (1300 g), and purified using silica gel column chromatography (petroleum ether: EtOAc=10:1 to 1:1) to obtain additional amount of the desired compound (500.0 g). This compound was diluted with petroleum ether (800 ml) and stirred at 10°C for 30 minutes. The suspension was filtered. The filter cake was washed with petroleum ether (500 ml) and dried in vacuo to obtain 440.0 g of the title compound as a white solid. The total yield was 540 g (35.6%). RX-MS m/z 222.8 [M+H] ⁺ .

1H NMR ( _CDCl3 , 400 MHz) δ 7.04 (s, 1H), 3.86 (s, 3H), 1.97 (s, 3H).

Stage 1E. ^)-N(H)-(1,4-dimethyl-N-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane2-sulfinamide.

3-iodo-1,4-dimethyl-1H-pyrazole (33 g, 148.6 mmol) in THF (50 ml) was added over 1 hour to a solution of 1.0 M iPrMrCl-LiCl in THF (189 ml, 189 mmol), maintaining the internal temperature at 0-5°C in a nitrogen atmosphere. After 1 hour, (S,E)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (20 g, 92.85 mmol) in THF (50 ml) was added and the mixture was stirred at 25 °C for 18 hours. The reaction mixture was cooled to 0°C, and 10% acetic acid was added. The organic layer was separated and partially concentrated. MTBE and water were added. The mixture was stirred for 10 minutes and the layers were separated. The organic layer was concentrated to give the title compound (66% purity), which was used in the next step without further purification.

Stage 1F. (R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine.

Syria (S)-N-((R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2-methylpropane-2sulfinamide (231 g) was suspended in MTBE (300 ml ), cooled to 10°C, and added conc. HCl (38.4 ml, 2 eq.). The mixture was stirred at 10-20°C for 1 hour and then diluted with water (300 ml). The layers were separated and the organic layer was discarded. The aqueous layer was basified with 20% NaOH to pH 11-13 and extracted with MTBE (2x300 ml). The combined organic layers were concentrated to give 120 g of the title compound as an oil. The absolute stereochemistry of the named compound was inferred based on open transition state analysis as described in the literature (Robak, M. T.; Herbage, M. A. Ellman, J. A. Chem. Rev. 2010, 110, 3600) and was residually confirmed by Mosher amide analysis.

Stage 1G. (R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine salt of Lpyroglutamic acid.

L-pyroglutamic acid (77.7 g, 0.6 mol) was added to a solution of (R)-(1,4-dimethyl-1H-pyrazol3-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 hours, then cooled to 25°C over 18 hours. The solid was filtered and washed with THF (890 ml). The solid was dried in vacuo at 45°C for 6 hours to obtain 259.6 g (88%) of the title compound.

1H NMR (400 MHz, DMSO) δ 7.58 (b.s., 1H), 7.40 (s, 1H), 3.93 (s, 1H), 3.87-3.84 (m, 1H ), 3.77 (s, 3H), 2.27-2.14 (m, 1H), 2.12-2.02 (m, 2H), 1.98 (s, 3H), 1.96- 1.84 (m, 1H), 1.70-1.48 (m, 6H), 1.42-1.31 (m, 1H), 1.08-1.02 (m, 1H), 0. 97 (s, 3H). Chiral SFC (SFC method M) RT=3.81 min, 99% s.n.

Stage 1H. 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N dimethylpicolinamide.

4-((2-ethoxy-3,4-dioxocyclobut-1 -en-1 -ul)amino)-3-hydroxy-N,N-dimethylpicolinamide was prepared as described in WO/2010/131145.

Step 11. (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-1 - yl)amino)-3-hydroxy-N,N-dimethylpicolinamide.

Mixture with 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (180 g, 590 mmol), (R)-(1 ,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine salt of Lpyroglutamic acid (209 g, 625 mmol), EtOH (1L) and DIPEA (205 ml, 1180 mmol) were stirred at 20-30°C over 2 h, 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 approximately half volume. The mixture was diluted with water (3.2 L) and stirred for 1.5 hours. The resulting solid was filtered, washed with water and then dried in vacuum at 40-50°C for 20 hours to obtain 256 g (93%) the named compound as a yellow solid. RX-MS m/z 467.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 11.59 (br.s., 1H), 9.92 (b.s., 1H), 9.16 (s, 1H), 8.03-8, 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), 1.201.15 (m, 1H), 1.14-1.09 (m, 1H), 1.08 (s, 3H). [a] ²⁰ _D =78.4 (c=1.0, MeOH). Chiral SFC (SFC method N) RT=4.77 min, 98.5% s.n. The absolute configuration was established by X-ray diffraction analysis of the single crystal (Fig. 1).

- 45 045541

Example 2.

(S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino )-3-hydroxy-^Ndimethylpicolinamide

The title compound was prepared by analogy with Example 1 using (R)-2-methylpropane-2sulfinamide. RX-MS m/z 467.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (b.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 (sh.s., 3H), 3.05 (sh.s., 3H), 1.98 (s , 3H), 1.74-1.52 (m, 6H), 1.41-1.27 (m, 1H), 1.231.15 (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% s.n.

Example 3.

(R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino )-3-hydroxy-N-isopropyl-N-methylpicolinamide

Stage 3A. 4-chloro-3-methoxypicolinyl chloride.

To a solution of 4-chloro-3-methoxypicolinic acid (5.0 g, 30 mmol) in DCM (59 ml) was added dropwise oxallyl chloride (8.46 g, 5.71 ml, 66.6 mmol) at 0°C. The resulting mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo to give 5.49 g (100%) of the title compound as a light yellow solid. The syria product was used directly in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J=5.1 Hz, 1H), 7.71-7.51 (m, 1H), 4.01 (s, 3H).

Stage 3B. 4-chloro-N-isopropyl-3-methokCi-N-methylpicolinamide.

To a solution of 4-chloro-3-methoxypicoline chloride (175 g, 0.85 mol) in DCM (500 ml) was added Et ₃ N (172 g, 1.7 mol) at 0°C. N-methylpropan-2-amine (62 g, 0.85 mol) was then added while maintaining the internal temperature below 10°C. The mixture was stirred at 15°C for 16 hours. Water (500 ml) was added and the organic layer was separated. The aqueous layer was extracted with DCM (200 mlx2). The combined organic extracts were washed with brine (500 ml), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give 153 g (74%) of the title compound as a brown oil. The crude product was used directly without further purification.

Stage 3C. tert-butyl (2-(isopropyl(methyl)carbamoyl)-3-methoxypyridin-4-yl)carbamate.

To a solution of 4-chloro-N-isopropyl-3-methoxy-N-methylpicolinamide (153 g, 0.63 mol) in dioxane (1 L) was added NH ₂ Boc (88.5 g, 0.76 mol) and K ₂ CO ₃ (130 g, 0.95 mol). The mixture was purged with N ₂ 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 hours. The reaction mixture was cooled to 20°C and filtered through celite. The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (500 ml) and water (500 ml). The organic layer was separated and washed with brine (500 ml), dried over Na ₂ SO ₄ , and filtered. The filtrate was concentrated in vacuo and the crude product was purified using silica gel column chromatography (50 to 66% EtOAc in petroleum ether) to give 160 g (78%) of the title compound as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.24-8.20 (m, 1H), 8.07-8.04 (m, 1H), 7.24 (s, 1H), 5.03-5 .00 (m, 0.4N), 3.90 (s, 3H), 3.66-3.63 (m, 0.6N), 2.98 (s, 1.7N), 2.69 (s , 1.31-1), 1.54 (s, 9H), 1.25-1.20 (m, 3H), 1.16-1.13 (m, 3H).

Stage 3D. 4-Amino-N-isopropyl-3-methoxy-N-methylpicolinamide.

HCl/EtOAc (4.0 M, 750 ml). The mixture was stirred at 20°C for 4 hours. The reaction mixture was concentrated in vacuo to obtain 150 g (>100%) of the title compound as a brown solid. The Syriac product was used directly without further purification.

Stage 3E. 4-Amino-3-hydroxy-N-isopropyl-N-methylpicolinamide.

To a solution of 4-amino-N-isopropyl-3-methoxy-N-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, maintaining the internal temperature below 10°C. Stir the reaction mixture

- 46 045541 was heated at 20°C for 16 hours. The reaction mixture was quenched with a saturated aqueous solution of NaHCO ₃ (2.5 l), and the pH was adjusted to 6-7. The organic layer was separated and washed with water (500 ml). The combined aqueous layers were again extracted with DCM (1 Lx2). The combined organic extracts were concentrated in vacuo and the residue was treated with DCM:MeOH=10:1 (2 L) for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was treated with DCM:MeOH=10:1 (600 ml) for 1 hour and the mixture was filtered. The filtrate was concentrated in vacuo to give 140 g (99%) of the title compound as a pink solid. The Syriac product was used directly without further purification.

Stage 3F. 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-ul)amino)-3-hydroxy-N-isopropyl-Nmethylpicolinamide.

To a solution of 4-amino-3-hydroxy-N-isopropyl-N-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 hours. The reaction mixture was filtered and the filtrate was saved for later use. The filter cake was dissolved in water (500 ml), and the pH was adjusted to 6 using 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 hours and then filtered to give 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 using silica gel column chromatography (25 to 50% EtOAc in petroleum ether) to provide an additional 30 g (13%) of the title compound as a yellow solid. RX-MS m/z 334.2 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) δ 13.30 (s, 1H), 8.09 (s, 1H), 8.01-7.90 (m, 2H), 5.85-5.80 (m , 0.5N), 4.954.88 (m, 2.5N), 3.50-3.31 (m, 1.51-1), 3.03-2.95 (m, 1.5N), 1 .55-1.50 (m, 6H), 1.42-1.32 (m, 3H).

Stage 3G. (S)-N-((R)-(1,4-dimethyl-1H-pyrazol-3-ul)(1-methylcyclopentyl)methyl)-2-methylpropane2-sulfinamide.

i-PrMrCl-LiCl (67 mL, 87.1 mmol, 1.3 M solution in THF) was charged into an oven-dried round bottom flask. The solution was cooled to 0°C and then a solution of 3-iodo1,4-dimethyl-1H-pyrazole (15.5 g, 69.7 mmol) in THF (90 ml) was added dropwise over 15 minutes. using a dropping funnel. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The mixture was cooled again to 0°C, and (S,E)-2-methyl-N-((1methylcyclopentyl)methylene)propane-2-sulfinamide was added dropwise. preparative stage 1C) (10.0 g, 46.4 mmol) over 5 min. The mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was poured slowly into a saturated aqueous NH4Cl solution (300 ml) at 0°C. The mixture was then extracted with EtOAc (350 mlx2). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was taken into MTBE (50 ml) and heptane (100 ml) to give a homogeneous 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., allowing more solid to form. The suspension was filtered to obtain 11.5 g (80%) of the title compound as a white solid. RX-MS 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).

Stage 3H. (R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine hydrochloride.

To a solution of (3)-N-((R)-(1,4-dimethyl-1H-pyrazol-3-ul)(1-methylcyclopentyl)methyl)-2-methylpropane2-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 hours at 20°C, the solution was concentrated in vacuo to give the title compound as the mono-HCl salt, allowing quantitative yield. The crude product was used directly without further purification. PX-MS m/z 191.2 [M-NH ₂ ] ⁺ .

1H NMR (400 MHz, CD3OD) δ 7.39 (s, 1H), 4.25 (s, 1H), 3.86 (s, 3H), 2.07 (s, 3H), 1.75-1 .54 (m, 7H), 1.21-1.20 (m, 1H), 1.14 (s, 3H).

Step 31. (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-1 - yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide.

To a solution of (R)-(1,4-dimethyl-1H-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 minutes, a yellow suspension of 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide (4.0 g, 12.0 mmol) in EtOH (100 ml), and the resulting brown solution was stirred at the same temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (80% to 100% EtOAc in petroleum ether). The syria product was azeotropically distilled from EtOH (50 mlx2) and the resulting yellow suspension was concentrated to ~30 ml. Before

- 47 045541 additional EtOH (10 ml) was added and the suspension was stirred at 15°C for 20 minutes. The mixture was filtered and the filter cake was washed with EtOH (10 ml). The filtered cake was collected and dried to obtain 2.62 g (44%) of the title compound as a light yellow solid. RX-MS m/z 495.5 [M+H] ⁺ .

1H 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, 1H), 1.25-1.10 (m, 7H), 1.08 (s, 3H).[a] ² %= -49.8 (c=0.26, MeOH). Chiral SFC conditions (SFC method D) RT=4.62 min, 100% s.n.

Example 4.

(R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino )-N-ethyl-3-hydroxy-N-methylpicolinamide

Stage 4A. 4-chloro-N-ethyl-3-methoxy-N-methylpicolinamide.

N-Methylethanamine (138 g, 233 mmol) and triethylamine (32.3 mL, 233 mmol) were added to a solution of 4chloro-3-methoxypicolinyl chloride (Preparative Step 3A) (32 g, 155 mmol) in DCM (150 mL). The mixture was stirred at ambient temperature for 48 hours and then concentrated. The residue was purified using silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to give 22 g (62%) of the title compound as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) 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, 1H), 3.23-3.12 (m, 1H), 3.12-2.72 (m, 3H) , 1.35-1.05 (m, 3H).

Stage 4B. tert-butyl (2-(ethyl(methyl)carbamoyl)-3-methoxypyridin-4-yl)carbamate.

To a solution of 4-chloro-N-ethyl-3-methoxy-N-methylpicolinamide (21.3 g, 93 mmol) in dioxane (120 ml) was added NH ₂ Boc (21.8 g, 186 mmol) and K ₂ CO ₃ (25.7 g, 186 mmol). The mixture was protected under N ₂ 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 hours. The reaction mixture was cooled to 20°C and filtered through celite. The filtrate was concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to give 24 g (83%) of the title compound as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.25 (ddd, J=5.5, 3.8, 0.6 Hz, 1H), 8.09 (dd, J=5.5, 1.6 Hz , 1H), 7.26 (d, J=5.6 Hz, 1H), 3.92 (d, J=1.0 Hz, 3H), 3.64 (sq., J=7.2 Hz, 1H), 3.18 (sq., 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).

Stage 4C. 4-Amino-N-ethyl-3-methoxy-N-methylpicolinamide.

HCl/EtOAc solution (4.0 M, 40 mL) was added to tert-butyl (2-(ethyl(methyl)carbamoyl)-3methoxypyridin-4-yl)carbamate (16 g, 51.7 mmol) and the mixture was stirred at 20°C for 18 hours. The mixture was concentrated in vacuo to give 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, 1H), 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).

Stage 4D. 4-Amino-N-ethyl-3-hydroxy-N-methylpicolinamide.

To a solution of 4-amino-N-ethyl-3-methoxy-N-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, maintaining the internal temperature below 10°C. The reaction mixture was stirred at 10°C for 15 hours. The reaction mixture was quenched with aqueous NaOH/MeOH solution (200 ml MeOH, 11.5 g NaOH, 50 ml water), while maintaining the internal temperature at 0°C. The mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (3 to 9% MeOH in DCM) to give 3.1 g (78%) of the title compound as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (d, J=6.3 Hz, 1H), 7.39 (b.s., 3H), 6.85 (d, J=6, 2 Hz, 1H), 3.523.18 (m, 2H), 2.91 (sh.s., 3H), 1.37-0.80 (m, 3H).

Stage 4E. 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-Nmethylpicolinamide.

To a solution of 4-amino-N-ethyl-3-hydroxy-N-methylpicolinamide (7.01 g, 35.9 mmol) in EtOH (150 ml) was added K ₂ CO ₃ (4.96 g, 35.9 mmol) and 3,4-diethoxycyclobut-3-ene-1,2-dione (9.17 g, 53.9 mmol). The mixture was heated to 50°C and stirred for 16 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified using silica gel column chromatography (10 to 100% DCM in petroleum ether, 0 to 20% MeOH in DCM) to give 4.77 g (42%) of the title compound as a brown oil.

- 48 045541

1H NMR (400 MHz, CDCl ₃ ) δ 13.62 (br.s., 0.5H), 13.50 (b.s., 0.5H), 8.07 (d, J=5.2 Hz , 1H), 7.94 (s, 1H), 7.88 (s, 1H), 4.90 (sq., J=7.1 Hz, 2H), 4.16 (b.s., 1H) , 3.62 (b.s., 3H), 3.14 (b.s., 1H), 1.55 (t, J=7.1 Hz, 3H), 1.45-1.20 (m , 3H).

Stage 4F. (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino )-N-ethyl-3-hydroxy-N-methylpicolunamide.

A solution of 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N methylpicolinamide (5.92 g, 18.54 mmol) in EtOH ( 140 ml) was added to (R)-(1,4-dimethyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methanamine salt of L-pyroglutamic acid (Preparative Step 1G) (7.48 g, 22.2 mmol) and DIPEA (4.79 g, 37.1 mmol) in EtOH (50 ml). The reaction mixture was stirred at room temperature for 16 hours, and then the reaction mixture was concentrated. The residue was purified using silica gel column chromatography (petroleum ether/EtOAc, 1:5 to 0:1) to obtain 4.4 g (49%) of the title compound as a yellow solid. RX-MS m/z 481.1 [M+H]+.

1H NMR (400 MHz, CD3OD) δ 8.22 (br.s., 1H), 7.94 (b.s., 1H), 7.28 (s, 1H), 5.44 (s, 1H) , 3.83 (s, 3H), 3.65 (sh.s., 2H), 3.28-3.06 (m, 3H), 2.09 (s, 3H), 1.92-1, 58 (m, 6H), 1.53-1.42 (m, 1H), 1.38-1.21 (m, 4H), 1.17 (s, 3H). [a] ²⁶ _D = -77.88 (c = 0.5, MeOH). Chiral SFC (SFC method F) RT=3.52 min, 99% s.n.

Example 5.

(S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino )-N-ethyl-3-hydroxy-N-methylpicolinamide 'EN -/ O

The title compound was prepared by analogy to example 4, using (S)-(1,4-dimethyl-1H-pyrazol3-yl)(1-methylcyclopentyl)methanamine (example 2). RX-MS m/z 481.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.70 (b.s., 1H), 9.90 (b.s., 1H), 9.15 (b.s., 1H), 8, 00 (w.s., 2H), 7.43 (s, 1H), 5.34 (d, J=10.0 Hz, 1H), 3.80 (s, 3H), 3.54 (w. s., 2H), 3.17 (b.s., 1H), 3.02 (b.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% s.n.

Example 6.

(R)-3 -(((1,4-dimethyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-4-((3 -hydroxy-2(morpholine-4-carbonyl)pyridine -4-yl)amino)cyclobut-3-ene-1,2-dione

Stage 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, solution 4 was added dropwise -chloro-3-methoxypicolinyl chloride (preparative step 3A) (5.49 g, 26.7 mmol) in DCM (26.7 ml). The reaction mixture was stirred at 0°C for 15 minutes, warmed to ambient temperature, and then refluxed for 4 hours. The solvent was removed in vacuo and the residue was taken up and dissolved in EtOAc. The solution was washed with 1 N. aqueous NaOH and brine, filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 20% EtOAc in DCM) to give 3.10 g (48%) of the title compound as a liquid. RX-MS m/z 188.1 [M-tBu] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J=5.1 Hz, 1H), 7.42 (d, J=5.1 Hz, 1H), 3.98 (s, 3H) , 1.65 (s, 9H).

Stage 6B. tert-butyl 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-methoxypicolinate.

To a mixture with 3-amino-4-ethoxycyclobut-3-ene-1,2-dione (169.2 g, 1.2 mol) and Na ₂ CO ₃ (67.84 g, 0.64 mol) in THF ( 1.8 L) tert-butyl 4-chloro-3-methoxypicolinate (97.2 g, 0.4 mol) was added at 25°C. The mixture was degassed and bubbled with N ₂ 3 times. tBuXPhos-Pd-G ₃ (15.9 g, 0.02 mol) and tBuXPhos (8.48 g, 0.02 mol) were added. The reaction mixture was degassed and bubbled with N ₂ 3 times. The reaction mixture was heated to 80°C and stirred for 16 hours. The mixture was cooled to 25°C and then filtered through celite. The filtrate was concentrated in vacuo. The residue was purified using 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 hours. The mixture was filtered to obtain 84.7 g, 60% of the title compound as a light yellow solid. RX-MS m/z 349.1 [M+H] ⁺ .

- 49 045541

1H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J= 5.4 Hz, 1H), 7.93 (b.s., 2H), 4.95 (q.v., J=7.1 Hz, 2H), 4.01 (s, 3H), 1.68 (s, 9H), 1.59 (t, J=7.2 Hz, 3H).

Stage 6C. tert-butyl (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene-1 - yl)amino)-3-methoxypicolinate.

DIEA (6.0 g, 46.4 mmol) was added to a solution of (R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methanamine hydrochloride (preparative step 3H) (4.70 g, 19.3 mmol) in EtOH (70 ml). The mixture was stirred for 10 minutes 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 hours and then concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 80% EtOAc in petroleum ether) to give 5.85 g (100%) of the title compound as a yellow solid. RX-MS m/z 510.1 [M+H]+.

1H NMR (400 MHz, DMSO- _d6 ) δ 9.97 (s, 1H), 9.06-9.02 (m, 1H), 8.20-8.18 (m, 1H), 8.09 -8.07 (m, 1H), 7.44 (s, 1H), 5.36-5.33 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 1.98 (s, 3H), 1.72-1.53 (m, 15H), 1.35-1.30 (m, 1H), 1.24-1.15 (m, 1H), 1. 09 (s, 3H).

Stage 6D. (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino )-3-methoxypicolinic acid.

TFO (25 g, 16.3 mL, 219.3 mmol) was added to the solution of tert-butyl (R)-4-((2-(((1,4-dimethyl-1Hpyrazol-3-yl)(1-methylcyclopentyl )methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3 methoxypicolinate (6.60 g, 13.0 mmol) in DCM (50 ml). The resulting solution was stirred at ambient temperature for 44 hours. The mixture was concentrated in vacuo and the pH was adjusted to ~8 using saturated aqueous NaHCO ₃ solution. The mixture was extracted with DCM (20 ml). The aqueous layer was acidified to pH ~3 using 1 N. aqueous HCl solution and then extracted with DCM (100 mlx5). The combined organic extracts were concentrated in vacuo to give 5.8 g (99%) of the title compound as a yellow solid. RX-MS m/z 454.4 [M+H] ⁺ .

Stage 6E. (R)-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 (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3, 4-dioxocyclobut-1-en-1-yl)amino)-3-methoxypicolinic 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 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (10 ml) and washed with saturated aqueous KHCO ₂ solution (10 ml). The aqueous layer was extracted with EtOAc (40 ml x 3). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as a yellow solid. The syria product was used directly without further purification, allowing for a quantitative yield. RX-MS 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).

Stage 6F. (R)-3 -(((1,4-dimethyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-4-((3 hydroxy-2-(morpholine-4-carbonyl)pyridine -4-yl)amino)cyclobut-3-ene-1,2-dione.

To a solution of (R)-3 -(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3 methoxy-2-(morpholine-4-carbonyl MgBR2 (634 mg, 3 .44 mmol). The mixture was heated at 120°C for 2 hours.

The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified using preparative TOP (Agela Durashell C18 150 mm x 25 mm x 5 µm, 30 to 50% MeCN in 0.225% formic acid in water, 25 ml/min, 11 min.), yielding 66 mg (11%) of the title compound as yellow solid. RX-MS m/z 509.4 [M+H] ⁺ .

1H NMR (400 MHz, CD3OD) δ 8.22 (d, J=5.5 Hz, 1H), 7.91 (b.s., 1H), 7.28 (s, 1H), 5.44 ( s, 1H), 3.903.70 (m, 11H), 2.09 (s, 3H), 1.90-1.65 (m, 6H), 1.50-1.43 (m, 1H), 1 .35-1.26 (m, 1H), 1.17 (s, 3H). [a] ²⁰ _D = -65.6 (c = 0.17, MeOH). Chiral SFC conditions (SFC method K) RT=3.47 min, 100% s.n.

Example 7.

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

-N OH / O

The title compound was prepared by following a procedure similar to that of (R)-3-(((1,4-dimethyl-1H

- 50 045541 pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2-(morpholine-4-carbonyl)pyridin-4yl)amino)cyclobut-3-ene-1, 2-dione (Example 6) using 1-methylpiperazine to give 19.7 mg (9%) of the title compound as a yellow solid. RX-MS m/z 522.5 [M+H] ⁺ .

1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.24 (d, J=5.6 Hz, 1H), 7.90 (d, J=5.6 Hz, 1H), 7.28 (s, 1H), 5.44 (s, 1H), 3.92 (b.s., 4H), 3.82 (s., 3H), 2.80 (b.s., 4H) , 2.53 (s, 3H), 2.09 (s, 3H), 1.90-1.65 (m, 6H), 1.511.42 (m, 1H), 1.35-1.25 (m , 1H), 1.17 (s, 3H). Chiral SFC (SFC method F) RT=3.66 min, 98.6% s.n.

Example 8.

(R)-4-((2-(((4-Xhop- 1 -methyl- 1H-pyrazol-3 -yl)(1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1 -yl )amino)-3-hydroxy-N,N-dimethylpicolinamide

Stage 8A. (R)-2-Methyl-N-((R)-(1 -methyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)propane-2sulfinamide.

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 hours. The reaction mixture was cooled to -30°C and a solution of (S,E)-2-methyl-N-((1-methylcyclopentyl)methylene was added dropwise )npropane-2-sulfinamide (preparative step 1C) (3.0 g, 13.93 mmol) in THF (5 ml). The reaction mixture was heated to 30°C and stirred for 16 hours. The reaction mixture was poured slowly into a saturated aqueous solution of NH ₄ Cl (100 ml) at 5°C and diluted with water (20 ml). The mixture was then extracted with EtOAc (50 mlx2). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 80% EtOAc in petroleum ether) to give 3.48 g (84%) of the title compound as a yellow oil. RX-MS m/z 297.9 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.26 (d, J=2.1 Hz, 1H), 6.08 (d, J=2.2 Hz, 1H), 4.34 (d, J= 3.4 Hz, 1H), 3.86 (s, 3H), 3.59-3.55 (m, 1H), 1.80-1.55 (m, 6H), 1.50-1.43 (s, 1H), 1.18 (s, 9H), 1.18-1.12 (m, 1H), 0.98 (s, 3H).

Stage 8B. (R)-(1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine.

HCl (80 mL, 4.0 M solution in MeOH) was added to the (R)-2-methyl-N-((R)-(1-methyl-1H-pyrazol3-yl)(1-methylcyclopentyl)methyl)propane solution -2-sulfinamide (6.59 g, 22.15 mmol) in MeOH (50 ml). The resulting solution was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The title compound was isolated as a mono-HCl salt, allowing quantitative yield, and used directly without further purification. RX-MS 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 (s, 3H), 1.85-1.65 (m, 6H), 1.60-1.55 (m, 1H), 1.31-1.25 (m, 1H), 1. 05 (s, 3H). The absolute stereochemistry of the title compound was intended to be similar to that of Preparative Example 1F.

Stage 8C. tert-Butyl (R)-((1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)carbamate.

TEA (9 .25 ml, 66.5 mmol) and (Boc)2O (7.25 g, 33.2 mmol). The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified using silica gel column chromatography (0 to 20% EtOAc in petroleum ether) to give 5.72 g (88%) of the title compound as light. yellow oil. PX-MS m/z 176.8 [M-BocNH] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.24 (d, J=2.2 Hz, 1H), 6.07 (d, J=2.2 Hz, 1H), 5.39-5.30 ( m, 1H), 4.67 (d, J=9.5 Hz, 1H), 3.87 (s, 3H), 1.79-1.61 (m, 6H), 1.44 (s, 9H ), 1.38-1.17 (m, 2H), 0.94 (s, 3H).

Stage 8D. tert-Butyl (R)-((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)carbamate.

NCS (3.12 g, 23.4 mmol) was added portionwise to a solution of tert-butyl (R)-((1-methyl-1H-pyrazol-3yl)(1-methylcyclopentyl)methyl)carbamate (5.72 g, 19 .5 mmol) in DMF (100 ml). The mixture was heated at 50°C for 16 hours. After cooling to ambient temperature, the reaction mixture was poured into 3% aqueous LiCl solution (150 ml) and then extracted with EtOAc (70 mlx2). 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 give 6.0 g (94%) of the title compound as a light yellow oil. PX-MS m/z 210.7 [M-BocNH] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.25 (s, 1H), 5.32-5.29 (m, 1H), 4.79 (d, J=9.7 Hz, 1H), 3, 82(s, 3H), 1.801.55 (m, 6H), 1.42 (s, 9H), 1.40-1.30 (m, 1H), 1.21-1.12 (m, 1H) , 1.00 (s, 3H).

Stage 8E. (R)-(4-chloro-1 -methyl-1H-nirazol-3-yl)(1-methylcyclopentyl)methanamine.

Before mixture with tert-butyl (R)-((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)

- 51 045541 HCl (150 ml, 600 mmol, 4.0 M in MeOH) was added to carbamate (6.0 g, 18.3 mmol) in MeOH (20 ml) at 15°C. The mixture was stirred for 5 hours and then concentrated in vacuo. The title compound was isolated as a mono-HCl salt, allowing quantitative yield, and used directly without further purification. RX-MS m/z 228.0 [M+H] ⁺ .

1H NMR (400 MHz, CD ₃ OD) δ 7.77 (s, 1H), 4.32 (s, 1H), 3.92 (s, 3H), 1.90-1.55 (m, 7H) , 1.30-1.22 (m, 1H), 1.15 (s, 3H).

Stage 8F. (R)-4-((2-(((4-chloro-1-methyl-1H-nirazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl )amino)-3-hydroxy-X,X-dimethylpicolinamide.

DIEA (5.0 g, 38.7 mmol) was added to the suspension with (R)-(4-chloro-1-methyl-1H-nirazol-3-yl)(1methylcyclopentyl)methanamine (5.90 g, 22.3 mmol) in EtOH (100 ml). The mixture was stirred for 30 minutes, and then 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,Ndimethylpicolinamide was added (preparative step 1H) (5, 0 g, 16.4 mmol). The resulting mixture was stirred at 20°C for 16 hours. The reaction mixture was filtered and the solids were washed with EtOH (10 mlx3). The solids were suspended in water (30 ml) and heated at 50°C for 3 hours. The suspension was filtered. The solids were washed with water (10 mlx3) and dried to obtain 5.24 g (66%) of the title compound as a yellow solid. RX-MS m/z 487.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.67 (b.s., 1H), 9.95 (b.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 (sh.s., 3H), 3.05 (b.s., 3H), 1.78-1.58 (m, 6H), 1.39-1.31 (m, 1H), 1.21-1.10 (m, 1H) , 1.07 (s, 3H). [a] ²⁴ _D = -145.151 (c = 0.50, MeOH). Chiral SFC (SFC method F) RT=3.85 min, 100% s.n. The absolute configuration was established by X-ray diffraction analysis of the single crystal (Fig. 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-X,X-dimethylpicolinamide

The title compound was prepared by analogy with Example 8 using (R)-2-methylpropane-2sulfinamide. RX-MS m/z 487.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-66) δ 11.68 (b.s., 1H), 9.92 (b.s., 1H), 9.16 (b.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 (w. s., 3H), 3.05 (sh. s., 3H), 1.74-1.55 (m, 6H), 1.371.30 (m, 1H), 1.21-1.14 (m, 1H), 1.07 (s, 3H). [a] ²⁰ _D =+107.3 [c=1, MeOH). Chiral SFC (SFC-method L) RT=6.28 min, 98% s.n.

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-X-isopropyl-X-methylpicolinamide

O</λ—'

N y—NH H \ )=\

HE

--°

The title compound was prepared with 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-Chisopropyl-X-methylpicolinamide (preparative step 3F) and (R)-(4 -chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methanamine (Preparative Step 8E), following the same procedure as for Example 8. Yellow solid, 64 mg (41%). RX-MS m/z 515.3 [M+H] ⁺ .

1H NMR (400 MHz, CD3OD) δ 8.21 (d, J=5.1 Hz, 1H), 7.93 (b.s., 1H), 7.64 (s, 1H), 5.55 ( s, 1H), 4.704.55 (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] ²⁰ _D = -75.5 (c = 0.23, MeOH). Chiral SFC (SFC method B) RT=1.59 min, 100% s.n.

Example 11 (R)-3-hydroxy-N-isopropyl-4-((2-(((4-methoxy-1 -methyl-1H-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3, 4-dioxocyclobut-1-en-1-yl)amino)-X-methylpicolinamide

- 52 045541

Stage 11A. 3-iodo-4-methoxy-1-methyl-1H-pyrazole.

NIS (4.41 g, 19.6 mmol) was added to a solution of 4-methoxy-1-methyl-1H-pyrazole (2.20 g, 19.6 mmol) in DMF (20 ml). The reaction mixture was stirred at ambient temperature for 18 hours. The mixture was diluted with water (100 ml) and brine (20 ml), and extracted with EtOAc (50 mlx5). The combined organic extracts were concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 16% EtOAc in petroleum ether) to give 310 mg (7%) of the title compound as a brown solid. RX-MS m/z 238.8 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 6.91 (s, 1H), 3.86 (s, 3H), 3.78 (s, 3H).

Stage 11B. (R)-N-((R)-(4-methoxy-1-methyl-1H-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 i-PrMrCl-LiCl (3 ml, 3. 90 mmol, 1.3 M solution in THF). The resulting mixture was stirred at ambient temperature for 2 hours, and then cooled to -40°C. A solution of (S,E)-2-methyl-N-((1-methylcyclopentyl)methylene)propαn-2-sulfinamide (Preparative Step 1C) (250 mg, 1.16 mmol) in freshly distilled THF (1 mL) was added. The reaction mixture was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (1 ml) at 0° C. and extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to give 150 mg, 33% of the title compound as a yellow oil. RX-MS m/z 327.9 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 6.95 (s, 1H), 4.31-4.29 (m, 1H), 4.15-4.13 (m, 1H), 3.77 (s , 3H), 3.69 (s, 3H), 1.80-1.70 (m, 2H), 1.70-1.55 (m, 4H), 1.50-1.42 (m, 2H ), 1.11 (s, 9H), 1.02 (s, 3H).

Step 11 C. (R)-(4-methoxy-1-methyl-1H-nirαzol-3-yl)(1-methylcyclopentyl)methanamine.

HCl (2.5 mL, 4.0 M in 1,4-dioxane) was added to a solution of (R)-N-((R)-(4-methoxy-1-methyl-1H-pyrazol3-yl)(1- methylcyclopentyl)methyl)-2-methylpropane-2-sulfinamide (150 mg, 0.458 mmol) in MeOH (15 ml). The resulting solution was stirred for 4 hours and then concentrated in vacuo. The title compound was isolated as a mono-HCl salt, allowing quantitative yield, and was used directly without further purification. PX-MS m/z 207.3 [M-NH ₂ ] ⁺ .

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 of the title compound was intended by analogy with Preparative Example 1F.

Stage 11D. (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 with (R)-(4-methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine (2.43 g, 9.35 mmol) in EtOH (60 ml) at 5° DIEA (11.8 g, 91.5 mmol) was added. After stirring for 10 min, 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-Nmethylpicolinamide (preparative step 3F) was added (3, 05 mg, 9.15 mmol). The resulting solution was stirred for 3 days. The mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (20 to 100% EtOAc in petroleum ether). The Syrian product was taken into EtOH (30 ml) and stirred at 20° C. for 16 hours. The fine suspension was filtered to obtain 3.26 g (70%) of the title compound as a yellow solid. RX-MS m/z 511.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO- _d6 ) δ 11.34 (s, 0.3H), 10.84 (s, 0.71-1), 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 (sh.s., 0.3H), 4.18 (sh.s., 0.7N), 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, 1H), 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% s.n.

Example 12.

(R)-3 -hydroxy-4-((2-(((4-methoxy-1 -methyl- 1H-pyrazol-3 -yl)(1 -methylcyclopentyl)methyl)amino)3,4-dioxocyclobut-1 - en-1-yl)amino)-N,N-dimethylpicolinamide

The named compound was prepared with 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxyN,N-dimethylpicolinamide (preparative step 1H) and (R)-(4-methoxy -1-methyl-1H-πyrazol-3-yl)(1methylcyclopentyl)methanamine (Preparative Step 11 C) following a similar procedure to Example 11. Yellow solid, 45 mg (56%). RX-MS m/z 483.4 [M+H] ⁺ .

- 53 045541

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, 1H), 5.43 (s, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.24 (br.s., 3H), 3.17 (b.s., 3H) , 1.91-1.74 (m, 2H), 1.70-1.60 (m, 4H), 1.45-1.35 (m, 1H), 1.30-1.20 (m, 1H), 1.11 (s, 3H). [a] ²⁴ _D = -87.5 (c = 0.50, MeOH). Chiral SFC (SFC method F) RT=4.86 min, 97.4% s.n.

Example 13.

(R)-3-hydroxy-4-((2-((1-(4-methoxy-1-methyl-1H-nurazol-3-ul)-2,2-dimethylpropyl)amino)-3,4dioxocyclobut-1 -en-1-yl)amino)-I^-dimethylpicolinamide

Stage 13A. (S,E)-N-(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 minutes and then (S)-2-methylpropane-2sulfinamide (14.1 g, 116 mmol) was added. The resulting mixture was stirred at ambient temperature for 16 hours and then quenched with water (250 ml). The mixture was filtered and the solids were washed with THF (500 mlx2). The combined organic layers were concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 5% EtOAc in petroleum ether) to give 24.4 g (75%) of the title compound as a colorless oil. RX-MS m/z 190.2 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 1.20 (s, 9H), 1.16 (s, 9H).

Stage 13B. (R)-N-((R)-1-(4-methoxy-1-methyl-1H-pyrazol-3-yl)-2,2-dimethylpropyl)-2methylpropane-2-sulfinamide.

i-PrMrCl was added to a solution of 3-iodo-4-methoxy-1-methyl-1H-pyrazole (preparative step 11 A) (250 mg, 1.05 mmol) in freshly distilled THF (0.7 ml) at -40°C -LiCl (1.7 ml, 2.22 mmol, 1.3 M solution in THF). The resulting mixture was stirred at 15°C for 1 hour, and then cooled to -40°C. A solution of (S,E)-N-(2,2-dimethylpropylidene)-2-methylpropane-2-sulfinamide (140 mg, 0.74 mmol) in freshly distilled THF (0.5 ml) was added. The mixture was heated to 15°C and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (1 ml) at 0°C and extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to give 80 mg (36%) of the title compound as a yellow oil. RX-MS m/z 301.9 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 6.97 (s, 1H), 5.32-5.31 (m, 1H), 4.20-4.15 (m, 1H), 3.83 (s , 3H), 3.71 (s, 3H), 1.11 (s, 9H), 1.01 (s, 9H).

Stage 13C. (R)-1-(4-methoxy-1-methyl-III-pyrazol-3-yl)-2,2-dimethylpropan-1-amine.

HCl (1.2 mL, 4.0 M in MeOH) was added to a solution of (R)-N-((R)-1-(4-methoxy-1-methyl-1H-pyrazol-3yl)-2,2- dimethylpropyl)-2-methylpropane-2-sulfinamide (80 mg, 0.27 mmol) in MeOH (7 ml). The mixture was stirred at 15°C for 4 hours and then concentrated in vacuo. The title compound was isolated as a mono-HCl salt, allowing quantitative yield, and was used directly without further purification. PX-MS m/z 180.8 [M-NH ₂ ] ⁺ .

1H NMR (400 MHz, CD3OD) δ 7.43 (s, 1H), 4.10 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 1.05 (s , 9Н). Chiral SFC (SFC-method J) RT=1.85 min, 93.7% s.n. The absolute stereochemistry of the title compound was intended by analogy with Preparative Example 1F.

Stage 13D. (R)-3-hydroxy-4-((2-((1 -(4-methoxy-1 -methyl-1H-pyrazol-3-yl)-2,2dimethylpropyl)amino)-3,4-dioxocyclobut-1 -en-1-yl)amino)-N,N-dimethylpicolinamide.

To a solution of (R)-1-(4-methoxy-1-methyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-amine (60 mg, 0.26 mmol) in EtOH (3 ml) DIEA (63.5 mg, 0.49 mmol) was added at 15°C. After stirring for 10 min, 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,Ndimethylpicolinamide (preparative step 1H) (50 mg, 0 .16 mmol). The resulting mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. The residue was purified using preparative TOP (Agela Durashell C18 150 mm x 25 mm x 5 µm 14 to 54% CH3CN in 0.225% formic acid in water, 25 ml/min, 11 min.), yielding 42.1 mg (56%) of the title compound in as a yellow solid. RX-MS m/z 457.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.64 (b.s., 1H), 9.99 (s, 1H), 9.12 (d, J=8.8 Hz, 1H), 8 .01 (s, 2H), 7.49 (s, 1H), 5.22 (d, J=10.3 Hz, 1H), 3.79 (s, 3H), 3.67 (s, 3H) , 3.19 (b.s., 3H), 3.06 (b.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% s.n.

Example 14.

(R)-3-hydroxy-N-isopropyl-4-((2-((1 -(4-methoxy-1 -methyl-III-pyrazol-3-yl)-2,2dimethylpropyl)amino)-3,4 -dioxocyclobut-1-en-1-ul)amino)-N-methylpicolinamide

- 54 045541

The title compound was prepared with 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N isopropyl-N-methylpicolinamide (preparative step 3F) and (R)-1 -(4-methoxy-1-methyl-1H-pyrazol-3yl)-2,2-dimethylpropan-1-amine (Preparative Step 13C) following the same procedure as Example 13. Yellow solid, 18 mg (25% ). RX-MS m/z 485.4 [M+H] ⁺ .

1H NMR (400 MHz, CD3OD) δ 8.18 (br.s., 1H), 7.94 (b.s., 1H), 7.33 (s, 1H), 5.35 (s, 1H) , 4.64 (sh.s., 0.3H), 4.30 (sh.s., 0.7N), 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% s.n.

Example 15.

(R)-4-((2-(((4-(difluoromethoxy)-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-1 -yl)amino)-3-hydroxy-N,N-dimethylpicolinamide

Stage 15A. 4-(difluoromethoxy)-1-methyl-1H-pyrazole

To a solution of 1-methyl-1H-pyrazol-4-ol (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 temperature for 12 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography (33% EtOAc in petroleum ether) to give 700 mg (46%) of the title compound as a yellow oil. RX-MS m/z 148.9 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.37 (s, 1H), 7.32 (s, 1H), 6.34 (t, J=73.03 Hz, 1H), 3.98-3, 78 (s, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -83.6.

Stage 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-1H-pyrazole (1.40 g, 9.45 mmol) in acetonitrile (25 ml). The resulting mixture was heated at 50°C for 84 hours. The reaction mixture was diluted with water (15 ml) and extracted with EtOAc (20 mlx3). The combined organic extracts were washed with saturated aqueous Na ₂ S ₂ O ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified using preparative silica gel TLC (50% EtOAc in petroleum ether) to give 260 mg (10%) of the title compound as a yellow solid. RX-MS m/z 275.1 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.27 (s, 1H), 6.41 (t, J=73.03 Hz, 1H), 3.92 (s, 3H). ¹⁹ F NMR (376 MHz, CDCl3) δ -83.6.

Stage 15C. (R)-N-((R)-(4-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)2-methylpropane-2-sulfinamide.

i-PrMrCl-LiCl (0 .43 ml, 0.0.557 mmol, 1.3 M solution in THF). The resulting mixture was stirred at -10°C for 1 hour, and then cooled to -40°C. A solution of (S,E)-2-methyl-N-((1-methylcyclopentyl)methylene)propane-2-sulfinamide (Preparative Step 1C) (40 mg, 0.19 mmol) in THF (3 mL) was added. The reaction mixture was heated to 50°C and stirred overnight. The mixture was quenched with saturated aqueous NH ₄ Cl at 10°C and extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The residue was purified using preparative silica gel TLC (80% EtOAc in petroleum ether) to give 70 mg (46%) of the title compound as a yellow oil. RX-MS m/z 363.9 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.25 (s, 1H), 6.37 (t, J=73.03 Hz, 1H), 4.33 (d, J=6.8 Hz, 1H) , 3.90-3.71 (m, 4H), 1.77-1.55 (m, 6H), 1.54-1.42 (m, 1H), 1.28-1.13 (m, 10H), 1.08-0.98 (m, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -83.2.

Stage 15D. (R)-(4-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine.

HCl (1 mL, 4.0 M in MeOH) was added to the solution of (R)-N-((R)-(4-(difluoromethoxy)-1-methyl-1Hpyrazol-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 hours and then concentrated in vacuo.

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The title compound was isolated as a mono-HCl salt, allowing quantitative yield, and used directly without further purification. The absolute stereochemistry of the title compound was intended by analogy with Preparative Example 1F. PX-MS m/z 242.8 [M-NH ₂ ] ⁺ .

Stage 15E. (R)-4-((2-(((4-(difluoromethoxy)-1 -methyl- 1H-pyrazol-3-yl)( 1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene- 1-yl)amino)-3-hydroxy-N,Ndimethylpicolinamide.

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 DIEA (140 mg, 1.08 mmol) was added. After stirring for 5 min, 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,Ndimethylpicolinamide (preparative step 1H) (30 mg, 0.108 mmol) was added ). The resulting mixture was stirred at 30°C for 6 hours and then concentrated in vacuo. The residue was purified using preparative TOP (Xbridge 150 mm x 30 mm x 10 µm, 15 to 55% CH3CN in 0.225% formic acid in water, 25 ml/min, 10 min.), yielding 52 mg (55%) of the title compound as yellow solid. RX-MS m/z 519.3 [M+H] ⁺ .

1H NMR (400 MHz, CD3OD) δ 8.22 (d, J=5.5 Hz, 1H), 7.92 (b.s., 1H), 7.57 (s, 1H), 6.65 ( dd, J=75.5, 72.9 Hz, 1H), 5.46 (s, 1H), 3.86 (s, 3H), 3.24 (b.s., 3H), 3.17 ( w.s., 3H), 1.87-1.62 (m, 6H), 1.51-1.43 (m, 1H), 1.33-1.25 (m, 1H), 1.15 (s, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -85.1. Chiral SFC (SFC method B) RT=1.34 min, 100% s.n.

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-N,N-dimethylpicolinamide

Stage 16A. 3-amino-1-methyl-1H-pyrazole-4-carbonitrile.

K 2 CO 3 (23.0 g, 167 mmol) was added to a solution of 3-amino-1H-pyrazole-4-carbonitrile (15.0 g, 139 mmol) in _DMF (700 ml) at 0° _C . The mixture was stirred for 45 min and then MeI (23.6 g, 167 mmol) was added. The resulting mixture was heated at 90°C for 16 hours. The reaction mixture was poured into ice water (200 ml) and extracted with EtOAc (400 mlx8). The combined organic extracts were concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 20% EtOAc in petroleum ether) to give 3.30 g (20%) of the title compound as a white solid. RX-MS m/z 122.8 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (s, 1H), 5.53 (s, 2H), 3.61 (s, 3H).

Stage 16B. 3-iodo-1-methyl-1H-pyrazole-4-carbonitrile.

To a stirred solution of 3-amino-1-methyl-1H-pyrazole-4-carbonitrile (1.0 g, 8.19 mmol) and aqueous n-TsOH- (3.55 g, 18.7 mmol) in MeCN (30 ml) at 0°C, a solution of NaNO ₂ (1.29 g, 18.7 mmol) and KI (3.1 g, 18.7 mmol) in water (4.0 ml) was added dropwise. The resulting mixture was stirred at 15°C for 3 days. The reaction mixture was concentrated in vacuo. The residue was diluted with water (10 ml) and saturated aqueous Na ₂ SO ₃ solution (20 ml), and then neutralized with NaOH (1.0 N aqueous solution) to pH=8. The mixture was extracted with EtOAc (100 mlx4) and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to give 398 mg (21%) of the title compound as a yellow solid. RX-MS m/z 234.1 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 3.94 (s, 3H).

Stage 16C. (R)-N-((R)-(4-cyano-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2methylpropane-2-sulfinamide.

To a solution of 3-iodo-1-methyl-1H-pyrazole-4-carbonitrile (398 mg, 1.71 mmol) in freshly distilled THF (12 ml) at -65°C, i-PrMrCl-LiCl (2.60 ml, 3.38 mmol, 1.3 M solution in THF). The resulting mixture was stirred at -40°C for 1 hour, and then cooled to -65°C. A solution of (S,E)-2-methyl-N-((1-methylcyclonentyl)methylene)propane-2-sulfinamide (preparative step 1C) (260 mg, 1.21 mmol) in freshly distilled THF (3 ml) was added dropwise . The mixture was heated to 15°C and stirred for 3 days. The whole was poured into 25% aqueous NH ₄ Cl solution (20 ml) at 15°C, and extracted with EtOAc (50 mlx3). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to give 84 mg (17%) of the title compound as a yellow solid. RX-MS m/z 322.9 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.76 (s, 1H), 4.48-4.46 (m, 1H), 3.93 (s, 3H), 3.82-3.75 (m , 1H), 1.85-1.50 (m, 8H), 1.29 (s, 9H), 1.08 (s, 3H).

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Stage 16D. (R)-3 -(amino(1-methylcyclopentyl)methyl)-1-methyl-1H-pyrazole-4-carbonitrile.

To a solution of (R)-N-((R)-(4-cyano-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)-2methylpropane-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 heated to 15°C and stirred for 2 hours. The reaction mixture was then concentrated in vacuo. The title compound was isolated as a mono-HCl salt, allowing quantitative yield, and used directly without further purification. RX-MS 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 of the title compound was intended by analogy with Preparative Example 1F.

Stage 16E. (R)-4-((2-(((4-Cyano-1 -methyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl )amino)-3-hydroxy-N,N-dimethylpicolinamide.

DIEA (59 .3 mg, 0.459 mmol) and 4-((2-ethoxy-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (preparative step 1H) (28 mg, 0.092 mmol). The resulting solution was stirred at 20°C for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified using preparative TOP (Agela Durashell C18 150 mm x 25 mm x 5 µm, 18 to 58% MeCN in 0.225% formic acid in water, 25 ml/min, 12 min.), yielding 13 mg (18%) of the title compound as yellow solid. RX-MS 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 (b.s., 3H), 3.17 (b.s., 3H), 1.95-1.65 (m, 6H ), 1.55-1.45 (m, 1H), 1.44-1.35 (m, 1H), 1.15 (s, 3H). Chiral TOP (TOP method A) RT=8.65 min, 98.0% s.n.

Example 17.

(R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(5-methylspiro[2.3]hexan-5-yl)methyl)amino)-3,4dioxocyclobut- 1 -en-1 -yl)amino)-3-hydroxy-N,N-dimethylpicolinamide

Example 17A. N-methoxy-N-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-HCl (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 NH ₄ Cl and extracted with EtOAc. The combined organic extracts were washed with water (100 mlx2) and brine (100 ml), and concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 100% EtOAc in heptane) to give 440 mg (85%) of the title compound as an oil. GC-MS m/z 169.1 [M].

1H NMR (400 MHz, CDCl ₃ ) 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-1H-pyrazol-3-yl)(spiro[2.3]hexan-5-yl)methanone.

To a solution of 3-iodo-1,4-dimethyl-1H-pyrazole (preparative step 1D) (304 mg, 1.37 mmol) in THF (2.36 ml) was added dropwise i-PrMrCl-LiCl (1.82 ml , 2.36 mmol, 1.3 M solution in THF). The resulting yellow solution was warmed to ambient temperature and stirred for 1 hour. A solution of N-methoxy-N-methylsniro[2.3]hexane-5-carboxamide (200 mg, 1.18 mmol) in THF (1) was then added dropwise ml), and the mixture was stirred for 16 hours. The reaction mixture was poured into a saturated aqueous solution of NH ₄ Cl. The mixture was extracted with DCM and the combined organic extracts were concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 100% EtOAc in heptane) to give 220 mg (91%) of the title compound as a solid. RX-MS m/z 205.2 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.15 (s, 1H), 4.31 (tt, J=9.2, 7.6 Hz, 1H), 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).

Example 17C. (1,4-dimethyl-1H-pyrazol-3-yl)(5-methylspiro[2.3]hexan-5-yl)methanone.

NaH (47.0 mg, 1.17 mmol, 60 wt% in mineral oil) and iodomethane (208 mg, 1.47 mmol) were added to the (1,4-dimethyl-1H-pyrazol-3-yl) solution ( spiro[2.3]hexan-5-yl)methanone (72 mg, 0.37 mmol) in THF (9.79 ml). The resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl, and extracted with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo.

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The residue was purified using silica gel column chromatography (0 to 100% EtOAc in heptane) to give 40 mg (19%) of the title compound as a solid. RX-MS m/z 219.2 [M+H] ⁺ .

Example 17D. (1,4-dimethyl-1H-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 (1,4-dimethyl-1H-pyrazol3-yl)(5-methylspiro[2.3]hexan-5-yl)methanone (50 mg, 0 .23 mmol) in methanolic NH ₃ (0.983 ml, 7.0 M in MeOH). The resulting mixture was stirred at 40°C overnight. The reaction mixture was cooled to ambient temperature, diluted with MeOH (2 ml), and NaBH ₄ (13 mg, 0.344 mmol) was added. The mixture was stirred for 4 hours. The reaction mixture was quenched with a saturated aqueous NH ₄ Cl 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 DCM (30 ml). The aqueous layer was then made alkaline 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 give the title compound and used directly in the next step without further purification, allowing quantitative yield.

Example 17E. (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(5-methylspiro[2.3]hexan-5yl)methyl)amino)-3,4-dioxocyclobut-1 -en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide.

To a mixture of (1,4-dimethyl-1H-pyrazol-3-yl)(5-methylspiro[2.3]hexan-5-yl)methanamine (52 mg, 0.236 mmol) in EtOH (1.97 ml) at 20° DIEA (381 mg, 0.529 mL, 2.95 mmol) was added. The resulting solution was stirred for 20 minutes, and then 4-((2-ethoxy-3,4-dioxocyclobut-1-en1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide was added (preparative step 1H) (60 mg, 0.20 mmol). The resulting suspension was stirred at 20°C for 4 days and then concentrated in vacuo. The residue was purified using chiral SFC conditions (Chiral Tech OD-H 21.2 x 21.2 mm i.d. 5 µm, 45% (0.2% 7N ammonium in MeOH) in EtOH, 80 ml/min). Isolation of the first eluting isomer gave 21.6 mg (23%) of the title compound, and the other eluting isomer gave the corresponding enantiomer (24 mg, 26%). RX-MS m/z 479.8 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 9.93 (b.s., 1H), 9.18 (b.s., 1H), 8.04-8.00 (m, 2H), 7, 44 (s, 1H), 5.53 (d, J=10.1, 1H), 3.79 (s, 3H), 3.20 (br.s., 3H), 3.07 (b.s. ., 3H), 2.28 (d, J=11.7, 1H), 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), 0.45-0.28 (m, 4H). Chiral SFC conditions (Chiral Tech OD-H 21.2x21.2 mm i.d. 5 µm, 45% (0.2% 7N ammonium in MeOH) in EtOH, 80 ml/min) RT=5.39 min, 98.8% e.n. (named compound) and RT=5.98 min, 96% e.n. (enantiomer).

Receipts 1-14.

The named compounds in the table. 1 was prepared in a manner similar to the preparation of (R)-(1,4-dimethyl-1Hpyrazol-3-yl)(1-methylcyclopentyl)methanamine (preparative step 1F) from the corresponding aldehyde and heteroaryl halide.

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Table 1

Receipt No. Structure Chemical name and analytical data 1 Η ₂ Ν·γ4 Ν'Ν \ (/?)-(4-ethyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methanamine. RX-MS m/z 205.4 [MNH ₂ ] ^{+ 1H} NMR (400 MHz, CD3OD) δ 7.41 (s, 1H), 4.21 (s, 1H), 3.85 (s, ZH) , 2.52-2.42 (m, 2H), 1.85-1.48 (m, 8H), 1.24 (t, J = 7.5 Hz, ZN), 1.13 (s, ZN ) 2 _H2N ^^ _s (/?)-(2,5-Dimethylthiazol-4-yl)(1methylcyclopropyl)methanamine. RX-MS m/z 180.0 [MNH ₂ ] ^{+ 1H} NMR (400 MHz, CD3OD) δ 4.03 (s, 1H), 2.63 (s, 3N), 2.39 (s, 3N) , 1.15 (s, ZN), 0.85-0.77 (m, 1N), 0.660.40 (m, ZN) 3 h ₂ n\5 nn\ (G?)-(1,4-Dimethyl-1/-/-pyrazol-3-yl)(1 methylcyclopropyl)methanamine. RX-MS m/z 163.2 [MNH ₂ ] ^{+ 1H} NMR (400 MHz, CD3OD) δ 7.37 (s, 1H), 3.95 (s, 1H), 3.83 (s, ZH) , 2.04 (s, ZN), 1.18 (s, ZN), 0.84-0.82 (m, 1N), 0.65-0.45 (m, ZN) 4 h ₂ n\5 Nn\ (/?)-(4-ethyl-1 -methyl-1 /-/-pyrazol-3-yl)(1 methylcyclopropyl)methanamine. RX-MS m/z 177.1 [MNH ₂ ] ^{+ 1H} NMR (400 MHz, CD3OD) δ 7.42 (s, 1H), 3.97 (s, 1H), 3.85 (s, ZH) , 2.51-2.42 (m, 2N), 1.25-1.15 (m, ZN), 1.10 (s, ZN), 0.90-0.80 (m, 1N), 0 .59-0.50 (m, ZN) 5 Λ Ν'Ν \ (R)-1-(1,4-Dimethyl-1/-/-pyrazol-3-yl)-2,2dimethylpropan-1-amine. PX-MS m/z 165.2 [M-NH ₂ ] ⁺ . ^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, 9H) 6 ⁿ =/^tL nn\ (G?)-(1,4-Dimethyl-1 /-/-pyrazol-3-yl)(1 methylcyclopentyl)methanamine. RX-MS m/z 177.2 [MNH ₂ ] ^{+ 1H} NMR (400 MHz, CD3OD) δ 7.38 (s, 1H), 4.35 (s, 1H), 3.85 (s, ZH) , 2.30-2.15 (m, 2H), 2.09 (s, ZN), 2.051.95 (m, 1H), 1.85-1.70 (m, 2H), 1.65-1 .55 (m, 1H), 1.17

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7 (P)-(2,5-Dimethylthiazol-4-yl)(1-methylcyclolentyl)methanamine. PX-MC m/z 193.9 [MNH ₂ ] ⁺ . <H NMR (400 MHz, CDCla) 6 9.15 (C, 2H), 8.39 (C, 1H), 5.19 (s, 1H), 3.00 (s, ZH), 2.58 ( s, ZN), 2.65-2.55 (m, 1H), 2.35-2.26 (m, 1H), 2.15-1.77 (m, ZN), 1.70-1, 61 (m, 8 (R)-1-(2,5-Dimethylthiazo l-4-i l)-2,2-dimethyl lprolan-1 amine. PX-MC m/z 181.9 [M-NH ₂ J* 9 (R) - (4 -ethyl-1 - methyl -1H-pyrazol-3 -yl) (1 - methyl cyclopentyl) meta per min PX-MC m/z 191.0 [MNHif. <H NMR (400 MHz, CDiOD) 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, 1H), 1.85-1.70 (m, 2H), 1.64-1.55 (m, 1H ), 1.33 (s, ZN), 1.26-1.20 (w, ZN) 10 M-N (R)-1-(4-ethyl-1-methyl-1H-pyrazol-3-i l)-2,2dimethylpropan-1-amine. PX-MC m/z 179.1 [M-NH ₂ ]*. ^1H 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, ZN), 1.08 (s, 9N) eleven %vs 4 HO (R)-(4-(ami no(1-methyl cyclo pentyl)methyl Ubmethylthiazol-g-yl^ethanol PX-MC m/z 224.3 [M-NH ₂ y ¹ H NMR ( 400 MHz, CD3OD) 5 4.79 (s, 2H), 4.35 (s, 1H), 2.49 (s, ZN), 1.85-1.65 (m, 6H), 1.56- 1.51 (m, 1H), 1.321.25 (m, 1H), 1.13 (s, ZN) 12 VS (R) - (4-C and clo about p and l-1 -methyl l-1 N-pi times about l-3-i l)(1 methyl lcy clope ntype) meta for min. PX-MC m/z 217.3 [MNH ₂ J ⁺ 13 I ω (I)-(2,5-Dimethylthiazol-4-yl)(1-methylcyclopentyl)methanamine. PX-MC m/z 225.3 [M+H] ⁺ . ^1H NMR (400 MHz, CD ₃ OD) δ 4.27 (s, 1H), 2.59 (s, 3H), 2.39 (s, 3H), 1.76-1.41 (m, 7H ), 1.25-1.15 (s, 1H), 1.05 (s, ZN) 14 \co ΞΕ (I)-(5-Methoxy-2-methylthiazol-4-yl)(1methylcyclopentyl)methanamine. PX-MC m/z 223.8 [MNH ₂ ] ^{+ 1H} NMR (400 MHz, CD3OD) δ 4.27 (s, 1H), 3.99 (s, 3N), 2.64 (s, 3N) , 1.85-1.61 (m, 6H), 1.54-1.45 (m, 1H), 1.30-1.21 (m, 1H), 1.12 (s, ZN)

Examples 18-33.

The named compounds in the table. 2 was prepared in a manner similar to the preparation of (R)-4-((2-(((l,4dimethyl-1 H-pyrazol-3 -yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 - en-1 -yl)amino)-3hydroxy-I,X-dimethylpicolinamide (preparative step 11) with the corresponding amine and 4-((2ethoxy-3,4-dioxocyclobut-1-en-1 -yl)amino)-3 - hydroxy-X,K-dialkylpicolinamide.

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table 2

Etc. Structure Chemical name and analytical data 18 oAV ΝΗ ^ ^{ΝΗ ς} Aon Α^Ο 1 (I)-4-((2-(((4-ethyl-1 -methyl-1 /7-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-1 - yl)amino)-3-hydroxy-L/,L/dimethylpicolinamide. Yellow solid, 42.8 mg (34%). RX-MS m/z 481.4 [M+H] ⁺ . ^1H NMR (400 MHz, CD3OD) δ 8.25-8.22 (m, 1H), 7.95-7.85 (m, 1H), 7.33 (s, 1H), 5.44 (s , 1N), 3.85 (s, ZN), 3.23 (sh.s., ZN), 3.16 (sh.s., ZN), 2.65-2.45 (m, 2N), 1.90-1.60 (m, 6H), 1.50-1.40 (m, 1H), 1.40-1.30 (m, 1H), 1.20 (t, J = 7.5 Hz, ZN), 1.17 (s, ZN). [a] ²⁴ D = -28.65 (with 1.00, MeOH). RT = 1.56 min., 99.2% e.n. (SFC method B) 19 ο=Λ“ ⁿ 'h^ ^s or ^N VAh 1 (I)-4-((2-(((2,5-Dimethylthiazol-4-yl)(1methylcyclopropyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy- L/,L/dimethylpicolinamide. Yellow solid, 75.7 mg (41%). RX-MS m/z 456.1 [M+H] ^{+ 1H} NMR (400 MHz, CD3OD) δ 8.21 (d, J = 5.6 Hz, 1H), 7.90 (br.s., 1N), 5.32 (s, 1N), 3.21 (sh.s., ZN), 3.15 (sh.s., ZN), 2.60 (s, ZN), 2.40 (s , ZN), 1.21 (s, ZN), 0.80-0.75 (m, 1N), 0.50-0.45 (m, 1N), 0.43-0.3 (m, 2N ). RT = 4.44 min., 100% e.n. (SFC method D) 20 ° x<r 0=<^>—NH N' ^N x ^ ^{NH n} Ooh 1 (R)-4-((2-(((1,4-Dimethyl-1/7-pyrazol-3-yl)(1methylcyclopropyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino )-3-hydroxy-L/,L/dimethylpicolinamide. Yellow solid, 193 mg (45%). RX-MS m/z 439.3 [M+H] ⁺ . ^1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.4 Hz, 1H), 7.92 (b.s., 1H), 7.29 (s, 1H), 5.24 (s, 1N), 3.80 (s, ZN), 3.23 (sh.s., ZN), 3.15 (sh.s., ZN), 2.06 (s, ZN), 1, 21 (s, ZN), 0.820.74 (m, 1N), 0.48-0.38 (m, ZN). RT = 3.45 min., 100% e.n. (SFC method E) 21 A O=<^—NH Ah Aoh 1 (G?)-4-((2-(((4-ethyl-1 -methyl-1 /7-pyrazol-3-yl)(1 methylcyclopropyl)methyl)amino)-3,4dioxocyclobut-1 -ene-1 -yl)amino)-3-hydroxy-L/,L/dimethylpicolinamide. Yellow solid, 59 mg, (50%). RX-MS m/z 453.3 [M+H] ⁺ . ^1H NMR (400 MHz, CD ₃ OD) δ 8.22 (d, J = 5.5 Hz, 1H), 7.91 (b.s., 1H), 7.31 (s, 1H), 5 .27 (s, 1N), 3.80 (s, ZN), 3.23 (sh.s., ZN), 3.15 (sh.s., ZN), 2.55-2.40 (m , 2H), 1.21 (s, ZN), 1.20 (t, J = 7.6 Hz, ZN), 0.82-0.77 (m, 1H), 0.45-0.37 ( m, ZN). RT = 4.49 min., 94.1% e.n. (SFC method D) 22 ° \ X О=<^“ ^NH N' ^N ^ rf ^{H n} Ooh 1 (R)-4-((2-((1 -(1,4-Dimethyl-1 /7-pyrazol-3-yl)-2,2dimethylpropyl)amino)-3,4-dioxocyclobut-1-ene-1 yl)amino)-3-hydroxy-L/,L/-dimethylpicolinamide. Yellow solid, 57 mg (44%). RX-MS m/z 441.3 [M+H] ^{+ 1H} NMR (400 MHz, CD ₃ OD) δ 8.20 (d, J = 5.5 Hz, 1H), 7.89 (d, J = 5.5 Hz, 1H), 7.26 (s, 1H), 5.31 (s, 1H), 3.81 (s, ZN), 3.21 (sh. s., ZN), 3, 14 (sh.s., ZN), 2.06 (s, ZN), 1.05 (s, 9N). RT = 4.13 min., 99.1% e.n. (SFC method F)

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23 xYa O=L—NH N' ^N \ ^Ν γ%Η 1 (R)-4-((2-(((1,4-Dimethyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl) amino)-3-hydroxy-L/,L/dimethylpicolinamide. Yellow solid, 35 mg (34%). RX-MS m/z 453.3 [M+H] ⁺ . ^1H NMR (400 MHz, CD ₃ OD) δ 8.22 (d, 5.5 Hz, 1H), 7.89 (d, J = 5.6 Hz, 1H), 7.29 (s, 1H) , 5.45 (s, 1H), 3.82 (s, ZN), 3.22 (sh.s., ZN), 3.14 (sh.s., ZN), 2.28-2.17 (m, 2H), 2.07 (s, ZN), 2.021.88 (m, 1H), 1.85-1.59 (m, ZN), 1.32 (s, ZN). RT = 4.52 min., 99.7% e.n. (SFC method D) 24 o=(Umn ^r ^NH X<en 1 (I)-4-((2-(((2,5-Dimethylthiazol-4-yl)(1methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy- L/,L/dimethylpicolinamide. Yellow solid, 140 mg (34%). RX-MS m/z 470.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-de) δ 11.69 (s, 1H), 9.98 (s, 1H), 9.21 (d, J = 9.9 Hz, 1H), 8.01 ( s, 2H), 5.46 (d, J = 9.9 Hz, 1H), 3.20 (sh.s., ZN), 3.06 (sh.s., ZN), 2.62 (s , ZN), 2.40 (s, ZN), 2.19 (sq., J = 9.8 Hz, 1H), 2.04 (sq., 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, ZN). RT = 3.53 min, 97.2% e.n. (SFCmode F) 25 0=<A—NH nA ^ ^{NH Ν} γ%Η 1 (G?)-4-((2-((1-(2,5-Dimethylthiazol-4-yl)-2,2dimethylpropyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)- 3-hydroxy-L/,L/-dimethylpicolinamide. Yellow solid, 71 mg (18%). RX-MS m/z 458.3 [M+H] ^{+ 1H} NMR (400 MHz, DMSO-de) δ 11.74 (br.s., 1H), 10.03 (br.s., 1H) , 9.23 (s, 1H), 8.10-7.88 (m, 2H), 5.30 (d, J = 10.1 Hz, 1H), 3.18 (s, ZN), 3, 05 (s, ZN), 2.63 (s, ZN), 2.37 (s, ZN), 0.97 (s, 9N). RT = 3.23 min., 96.9% e.n. (SFC method F)

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26 0 X N-,/ Ji N O=<Q>—NH ^ ^{NH ς ν} Χοη 1 (G?)-4-((2-(((4-ethyl-1-methyl-1/-/-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene -1 -yl)amino)-3-hydroxy-L/,L/dimethylpicolinamide. Yellow solid, 23.5 mg (44%). RX-MS m/z 467.4 [M+H] ⁺ . ^1H NMR (400 MHz, CD ₃ OD) δ 8.22 (d, J 5.6 Hz, 1H), 7.90 (b.s., 1H), 7.32 (s, 1H), 5, 45 (s, 1N), 3.83 (s, ZN), 3.22 (sh.s., ZN), 3.15 (sh.s., ZN), 2.58-2.42 (m, 2H), 2.30-2.15 (m, 2H), 2.01-1.92 (m, 1H), 1.81-1.60 (m, ZN), 1.32 (s, ZN) , 1.19 (t, J = 7.5 Hz, ZN). RT = 4.61 min., 100% e.n. (SFCmode F) 27 ° Ο=Λ— NH ^Ν γ%Η 1 (R)-4-((2-((1 -(4-ethyl-1 -methyl-1 /-/-pyrazol-3-yl)-2,2dimethylpropyl)amino)-3,4-dioxocyclobut-1 - en-1 yl)amino)-3-hydroxy-L/,L/-Dimethylpicolinamide. Yellow solid, 41.4 mg (35%). RX-MS m/z 455.4 [M+H] ^{+ 1H} NMR (400 MHz, CD ₃ OD) δ 8.21 (d, J = 5.6 Hz, 1H), 7.91 (br.s ., 1Н), 7.33 (s, 1Н), 5.33 (s, 1Н), 3.86 (s, ZN), 3.22 (sh. s., ZN), 3.14 (sh. s., ZN), 2.60-2.42 (m, 2H), 1.18 (t, J = 7.5 Hz, ZN), 1.07 (s, 9H). RT = 4.17 min., 95.7% e.n. (SFC method G) 28 όξΜ O^YnH i% ^{NH N} y ₀ ⁴ N^O 1 (I)-3-Hydroxy-4-((2-(((2-(hydroxymethyl)-5methylthiazol-4-yl)(1 methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl) amino)-L/,L/dimethylpicolinamide. Yellow solid, 45.1 mg (46%) PX-MS m/z 500.4 [M+H] ⁺ . ^1H NMR (400 MHz, CD3OD) δ 8.21 (d, J = 5.6 Hz, 1H), 7.95-7.85 (m, 1H), 5.51 (s, 1H), 4, 79 (s, 2N), 3.21 (sh.s., ZN), 3.14 (sh.s., ZN), 2.50 (s, ZN), 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, ZN) . RT = 5.15 min., 98.7% e.n. (SFC method G)

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29 ° Λ_Λν ^Ζ Ο=Λ—NH V ^ ^nh 4 ^OH I (I)-4-((2-(((4-Cyclopropyl-1 -methyl-1 /7-pyrazol-Zyl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1 -yl )amino)-3-hydroxy-L/,L/dimethylpicolinamide. Yellow solid, 15.9 mg (33%). RX-MS m/z 493.4 [M+H] ^{+ 1H} NMR (400 MHz, CD ₃ OD) δ 8.22 (d, J = 5.5 Hz, 1H), 7.95-7.85 (m, 1H), 7.14 (s, 1H), 5.63 (s, 1H), 3.81 (s, ZN), 3.32-3.11 (m, 6H), 1.98- 1.75 (m, 2H), 1.75-1.60 (m, 5H), 1.531.42 (m, 1H), 1.39-1.30 (m, 1H), 1.20 (s, ZN), 0.89-0.86 (m, 2H), 0.54-0.52 (m, 1H), 0.44-0.41 (m, 1H). RT = 4.86 min., 100% e.n. (SFC method F) thirty V/ _z ^z '-^\ J \ (I)-4-((2-(((4-Cyano-1 -methyl-1 /7-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene- 1 -yl)amino)-L/-ethyl-3-hydroxyL/-methylpicolinamide. Yellow solid, 14.3 mg (23%). RX-MS m/z 492.5 [M+H] ^{+ 1H} NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.5 Hz, 1H), 8.19 (s, 1H), 7.98-7.90 (m, 1H), 5.53 (s, 1H), 3.96 (s, ZN), 3.71-3.60 (m, 2H), 3.23-3, 12 (m, ZN), 1.95-1.64 (m, 6N), 1.571.49 (m, 1N), 1.42-1.22 (m, 4N), 1.16 (s, ZN) . RT = 5.03 min., 98.5% e.n. (SFC method H) 31 ΐ aL ⁿ у Ο=Λ>—NH У γ4γ ^ΝΗ N A (I)-4-((2-(((4-cyano-1 -methyl-1 /7-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-1 - yl)amino)-3-hydroxy-Misopropyl-L/-methylpicolinamide. Yellow solid, 14.8 mg (24%). RX-MS m/z 506.4 [M+H] ⁺ . ^1H NMR (400 MHz, CD3OD) δ 8.24-8.20 (m, 1H), 8.19 (s, 1H), 7.93 (b.s., 1H), 5.53 (s, 1H), 4.35-4.25 (m, 1H), 3.96 (s, ZN), 3.02 (s, ZN), 1.95-1.65 (m, 6H), 1.60 -1.45 (m, 1H), 1.40-1.15 (m, 7H), 1.16 (s, ZN). RT = 4.49 min., 97.6% e.n. (SFC method J) 32 0=<γ—NH ^Ν γ ₀ I (I)-4-((2-(((2,5-Dimethylthiazol-4-yl)(1methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy- L/,L/dimethylpicolinamide. Yellow solid, 63 mg (30%). RX-MS m/z 484.4 [M+H] ^{+ 1H} NMR (400 MHz, CD3OD) δ 8.22 (d, J = 5.6 Hz, 1H), 7.92 (br.s., 1N), 5.48 (s, 1N), 3.24 (sh.s., ZN), 3.16 (sh.s., ZN), 2.62 (s, ZN), 2.45 (s , ZN), 1.90-1.75 (m, 2N), 1.75-1.55 (m, 4N), 1.50-1.40 (m, 1N), 1.40-1.30 (m, 1H), 1.14 (s, ZN). RT = 3.44 min., 98.6% e.n. (SFC method F) 33 a: I (I)-3-Hydroxy-4-((2-(((5-methoxy-2-methylthiazol-4yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino )-L/,L/dimethylpicolinamide. Yellow solid, 34.4 mg (42%). RX-MS m/z 500.4 [M+H] ^{+ 1H} NMR (400 MHz, CD ₃ OD) δ 8.22 (d, J = 5.6 Hz, 1H), 7.92 (br.s ., 1N), 5.46 (s, 1N), 3.94 (s, ZN), 3.22 (sh.s., ZN), 3.14 (sh.s., ZN), 2.58 (s, ZN), 1.88-1.76 (m, 2H), 1.70-1.60 (m, 4H), 1.43-1.38 (m, 1H), 1.32-1 .25 (m, 1H), 1.12 (s, ZN). RT = 1.46 min., 100% e.n. (SFC method B)

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Example 34.

(R)-4-((2-(((2,5-dimethyloxazol-4-yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en1-yl)amino)-3- hydroxy-^Ndimethylpicolinamide.

Stage 34A. (2,5-dimethyloxazol-4-yl)(1-methylcyclopentyl)methanamine.

The title compound was prepared in a manner similar to the preparation of (1,4-dimethyl-1H-pyrazol-3yl)(5-methylspiro[2.3]hexan-5-yl)methanamine (Preparative Step 17D) using 2,5-dimethyloxazole-4-carboxylic acid and cyclopentylmagnesium bromide. PX-MS m/z 192.2 [M-NH ₂ ] ⁺ .

Stage 34B. (R)-4-((2-(((2,5-dimethyloxazol-4-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino)-3 - hydroxy-N,N-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)-3-hydroxy-N,Ndimethylpicolinamide (preparative 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 enantiomeric resolution using chiral SFC conditions (Chiralcel OD, 250 mmx21 mmx5 μm, 5 to 60% 0.2% NH ₄ ⁺ (7 N in MeOH) in MeOH, 80 ml/min). Isolation of the first eluting isomer yielded 16 mg (21%) of the title compound, and the other eluting isomer yielded 23 mg (30%) of the corresponding enantiomer. RX-MS m/z 468.6 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.23-9.10 (m, 1H), 7.98-7.97 (m, 1H), 7.91 (b.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% e.n. (SFC method C).

Example 35.

(R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)( 1 -ethylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1 en-1-yl) amino)-3-hydroxy-N,N-dimethylpicolinamide

Stage 35A. (1,4-dimethyl-1H-pyrazol-3-yl)(1-ethylcyclobutyl)methanamine.

The title compound was prepared in a manner similar to the preparation of (1,4-dimethyl-1H-pyrazol-3yl)(5-methylspiro[2.3]hexan-5-yl)methanamine (Preparative Step 17D) using 1-ethylcyclobutane 1-carboxylic acid and 3 -iodo-1,4-dimethyl-1H-pyrazole. PX-MS m/z 190.8 [M-NH ₂ ] ⁺ .

Stage 35B. (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-ethylcyclobutyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl)amino )-3-hydroxy-N,N-dimethylpicolinamide.

4-((2-ethoxy-3,4 -dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,Ndimethylpicolinamide (preparative 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 preparative TOP (Agela Durashell C18 150 mm x 25 mm x 5 µm 13 to 53% CH3CN in 0.05% NH4OH in water, 25 ml/min, 11 xi.), yielding 100 mg of racemic product. The racemic mixture was subjected to enantiomeric resolution using chiral SFC conditions (REGIS (s,s) WHELK-O1 250 mm x 30 mm x 5 µm 45% 0.1% NH4OH in EtOH, 60 ml/min). Isolation of the first eluting isomer yielded 33 mg (18%) of the title compound as a yellow solid and the other eluting isomer yielded 34 mg (19%) of the corresponding enantiomer as a yellow solid. RX-MS 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% s.n. (compound named) and RT=14.45 min, 91.9% e.n. (enantiomer).

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Example 36.

4-((2-((^)-(^)-4,4-difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-III-pyrazol-3yl)methyl)amino)-3,4 -dioxocyclobut-1-en-1-yl)amino)-3-hydroxy^^-dimethylpicolinamide

Stage 36A. Ethyl 2-hydroxy-2-methylpent-4-enoate.

Titanium(IV) chloride (124 g, 655 mmol) was added to a solution of ethyl 2-oxopropanoate (76 g, 654.5 mmol) in DCM (380 ml) at -78°C. The resulting mixture was stirred at the same temperature for 30 minutes, during which time the won turned into a yellow suspension. Allyltrimethylsilane (97.2 g, 851 mmol) was then added and the reaction mixture was stirred for 2 hours. The reaction mixture was heated to 0°C and quenched with saturated aqueous Na ₂ CO ₃ (1.5 L) and extracted with DCM (3, 0 lx2). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography (5 to 10% EtOAc in petroleum ether) to give 134 g (63%) of the title compound as a light yellow oil. PX-MS m/z 158.8 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) δ 5.80-5.70 (m, 1H), 5.12 (s, 1H), 5.10-5.07 (m, 1H), 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).

Stage 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 for 20 minutes. The reaction mixture was stirred at 10°C for 1 hour, and then heated to 35°C and stirred for 16 hours. The mixture was cooled to 0°C and quenched with a saturated aqueous solution of Na ₂ S ₂ O ₃ . The organic layer was separated and washed with saturated aqueous Na ₂ CO ₃ solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography to obtain 81 g (80%) of the title compound as a light yellow oil, which consisted of a diastereomeric mixture.

1H NMR (400 MHz, CDCl ₃ ) δ 4.35-4.20 (m, 2H), 3.50 (s, 0.5H), 3.35 (s, 0.5H), 3.15-3 .05 (m, 1H), 2.802.70 (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).

Stage 36C. Ethyl 2-methyl-4-oxotetrahydrofuran-2-carboxylate.

Magnesium bromide (12 g, 65.4 mmol) was added to a solution of ethyl 2-hydroxy-2-methyl-3-(oxiran-2yl)propanoate (76 g, 436 mmol) in THF (957 ml). The mixture was heated at 80°C for 16 hours. 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 hours. Additional PCC (18.8 g, 87.3 mmol) was added and the mixture stirred at 30°C for 4 hours. The reaction mixture was filtered and the solids were washed with DCM (500 mlx2). The organic filtrate was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified using 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, CDCl ₃ ) 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), 1.32-1.28 (m, 3H).

Stage 36D. Ethyl 4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate.

DAST (37.4 g, 232 mmol) was added dropwise to a pure 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 temperature for 15 hours. The mixture was then diluted with DCM (50 ml), and poured into saturated aqueous NaHCO ₃ solution (500 ml) at 0°C. The mixture was extracted with DCM (500 mlx2) 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 syria product was used directly without further purification, allowing for a quantitative yield.

1H NMR (400 MHz, CDCl ₃ ) 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). ¹⁹ F NMR (376 MHz, CD3OD) δ -101, -98.0.

Stage 36E. Benzyl (S)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate.

A 1.0 M aqueous solution of LiOH (214 ml, 214 mmol). The mixture was stirred at 15°C for 2 hours and then concentrated in vacuo. The residue was acidified with 1.0 M aqueous HCl solution until the pH of the solution reached 3, and then extracted with DCM (600 mlx3) and DCM/MeOH (10/1, 600 mlx2).

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The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in acetonitrile (500 ml) and K ₂ CO ₃ (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 hours. 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 using 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 of the racemic product (5.0 g) was amenable to choral resolution using chiral normal phase chromatography conditions (Phenomenex Lux 10 µM Cellulose-3 45% EtOH in hexanes, 20 ml/min, 12 min). Isolation of the other elution peak provided 2.56 g of the title compound as a colorless oil. RX-MS m/z 274.2 [M+water].

1H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.34 (m, 5H), 5.21 (s, 2H), 4.15-4.04 (m, 2H), 2.96-2 .84 (m, 1H), 2.402.24 (m, 1H), 1.59 (s, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -101, -98.0.

Stage 36F. (S)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylic acid ((1R,4aS,10aR)-7isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a -octahydrophenanthrene-1-yl)methanamine salt.

The absolute stereochemistry of the named compound was determined by single crystal X-ray crystallography (Fig. 3). Benzyl (S)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate was hydrolyzed in the appropriate acid and crystallized with ((1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl1,2,3,4, 4a,9,10,10a-octahydrophenanthrene-1-yl)methanamine from ethanol.

Stage 36G. (S)-(4,4-difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1H-pyrazol-3-yl)methanone.

i-PrMrCl-LiCl ( 1.37 ml, 1.77 mmol, 1.3 M solution in THF). The resulting yellow solution was stirred at the same temperature for 2 hours, and then warmed to ambient temperature and stirred for 30 minutes. The mixture was cooled to 0°C and benzyl (8)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylate (413 mg, 1.61 mmol) was added. The mixture was stirred at 0°C for 30 minutes, and then warmed to ambient temperature and stirred for >12 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl, and the mixture was extracted with DCM. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 100% EtOAc in DCM) to give 351 mg (89%) of the title compound as an oil. RX-MS m/z 245.3 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) 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).

Stage 36H. (c,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-1H-pyrazol-3-yl)methanone (352 mg, 1.44 mmol) in methanolic ammonium ( 1.23 g, 10.3 mL, 72.1 mmol, 7.0 M in MeOH) titanium(IV) ethoxide (1.97 g, 1.81 mL, 8.65 mmol) was added. The resulting suspension was sealed and stirred at 60°C overnight. The reaction mixture was cooled to 0°C and NaBH4 (224 mg, 5.91 mmol) was added. The mixture was stirred at 0°C for 30 minutes, and then at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo. HCl (1.0 N aqueous solution) was added to the residue until the mixture was acidified, and then extracted with Et ₂ O. The aqueous layer was neutralized with NaOH (1.0 N aqueous solution), and then extracted with DCM (x2). The combined organic extracts were dried over Na ₂ SO ₄ , 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 minutes. and then concentrated in vacuo to give the title compound as a white solid as the mono-HCl salt. The product was isolated as a mixture of two diastereomers and used directly without further purification.

Stage 36I. 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-N,N-dimethylpicolinamide.

DIEA (131 mg, 1.02 mmol) and (c,R)-((S)-4,4-difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1Hpyrazol-3-yl)methanamine (292 mg, 1.19 mmol) was added to 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (preparative step 1G) (330 mg, 1.08 mmol) in EtOH (1.9 ml). The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was purified using silica gel column chromatography (0 to 10% MeOH in DCM). The resulting diastereomeric mixture was separated using chiral SFC chromatography (Chiral Tech OD-H, 250 mm x 30 mm, 5 µm, 25% ethanol, which contains

- 67 045541

0.2% 7n. ammonium in methanol, 80 ml/min). Isolation of the first elution peak provided 299 mg (55%) of the title compound as a yellow solid. RX-MS m/z 505.4 [M+H] ⁺ .

1H NMR (600 MHz, DMSO-a ₆ ) δ 10.48 (br.s., 2H), 9.23 (b.s., 1H), 7.99 (d, J=5.3 Hz, 1H), 7.91 (b.s., 1H), 7.49 (s, 1H), 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 (b.s., 3H), 3.03 (b.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% s.n.

Examples 37-38.

The named compounds in the table. 3 was prepared in a manner similar to the preparation of 4-((2-(((S)-((S)-4,4difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1H-pyrazol-3-yl) methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Example 36) using the appropriate heteroaryl halide.

Table 3

Etc. Structure Chemical name and analytical data 37 FF~/l___ O and / D / ^N O=Q>—NH ^^NH ' γ he ^Χ Ν^Ο 1 4-((2-(((5)-((5)-4,4-Difluoro-2-methyltetrahydrofuran2-yl)(4-ethyl-1 -methyl-1 /-/-pyrazol-3-yl)methyl )amino)3,4-Dioxocyclobut-1-en-1-yl)amino)-3-hydroxyL/,L/-dimethylpicolinamide. Yellow solid, 21.5 mg(15%). RX-MS m/z 519.3 [M+H] ⁺ . Ή NMR (400 MHz, CD ₃ OD) 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, ZN), 3.23 (sh.s., ZN), 3.16 (sh.s. , ZN), 2.75-2.65 (m, 1N), 2.60-2.45 (m, 2N), 2.35-2.20 (m, 1N), 1.60 (s, ZN ), 1.20 (t, J = 7.5 Hz, ZN). ¹⁹ F NMR (376 MHz, CD3OD) δ -104, -98.0. RT = 3.86 min., 100% e.n. (SFC method D) 38 F rsh_ ⁰ A O^N^ ^S uon 1 4-((2-(((5)-((5)-4,4-Difluoro-2-methyltetrahydrofuran2-yl)(2,5-dimethylthiazol-4-yl)methyl)amino)-3,4dioxocyclobut-1 -en-1 -yl)amino)-3-hydroxy-L/,L/dimethylpicolinamide. Yellow solid, 22.9 mg (9%). RX-MS 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 (sq., J = 10.9 Hz, 1H), 3.86 (dt, J = 18.6, 10.3 Hz, 1H), 3.23 (sh.s., ZN), 3.16 (sh.s., ZN), 2.85-2.70 (m, 1N), 2.64 (s, ZN), 2.47 (s, ZN), 2.26 (ddd, J = 17.7, 14.4, 8.0 Hz, 1H), 1.54 (s, ZN). ¹⁹ F NMR (376 MHz, CD3OD) δ -104, -98. RT = 4.14 min, 100.0% e.n. (SFC method H)

Example 39.

(R)-3-hydroxy-N,N-dimethyl-4-((2-(((1-methyl-4-(methyl-d ₃ )-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino )-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide

Stage 39A. 4,4,5,5-tetramethyl-2-(methyl-d ₃ )-1,3,2-dioxaborolane.

Mg metal (1.26 g, 51.7 mmol) and a crystal of iodine were added to a dried and nitrogen-filled flask equipped with a condenser and dropping funnel. The bottom of the flask was heated with a heat gun until the violet gas spread to the surface of the Mg. Et ₂ O (5 ml) was added. The solution was stirred until the iodine color disappeared. Once the solution became clear, a solution of iodomethane-d ₃ (5.0 g, 34.49 mmol) in Et ₂ O (45 ml) was slowly added. After the additions were complete, the reaction mixture was heated to reflux for 20 minutes. The resulting Grignard reagent was added dropwise to a solution of 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

- 68 045541 (5.45 g, 5.65 ml, 34.5 mmol) in Et ₂ O (20 ml) at -60°C. The reaction mixture was then allowed to warm to 20°C and stirred for 1 hour. The reaction mixture was quenched with a saturated solution of NH ₄ Cl and the layers were separated. The organic layer was dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated to give the title compound, which was used without further purification.

Stage 39B. N-methoxy-N,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)-HCl (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 hours and then concentrated. The residue was added to saturated aqueous Na ₂ CO ₃ solution (1 L) and extracted with EtOAc (2x1 L). The combined organic extracts were dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated and the residue was purified by distillation to obtain 62.1 g (77%) of the title compound as a colorless oil.

PX-MS 193.2 [M+H]+.

1H NMR (400 MHz, CDCl3) 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).

Stage 39C. (1-Methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanone.

3-iodo-1-methyl-1H-pyrazole (2.19 g, 10.5 mmol) was added dropwise to iPrMrCl-LiCl (10.8 mL, 14.0 mmol, 1.3 M THF solution) and THF ( 14 ml), cooled to 0°C in a nitrogen atmosphere. The mixture was allowed to stir at room temperature for 1 hour. N-methoxy-N,1dimethylcyclopentane-1-carboxamide (1.2 g, 7.0 mmol) was then added dropwise. The mixture was stirred at room temperature for 18 hours and then quenched with a saturated aqueous solution of NH ₄ Cl. The reaction mixture was extracted with EtOAc. The organic extract was dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated and the residue was purified using silica gel column chromatography (10-50% EtOAc/heptane) to obtain 992 mg (74%) of the title compound. RX-MS 172.4 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) 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).

Stage 3 9D. (4-Iodo-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanone.

NIS (702 mg, 3.12 mmol) was added to a solution of (1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methanone (400 mg, 2.08 mmol), acetic acid (4.2 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue was purified using silica gel column chromatography (0-20% EtOAc/heptane) to obtain 595 mg (90%) of the title compound as a white solid.

1H NMR (400 MHz, CDCl3) 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).

Stage 39E. (1-Methyl-4-(methyl-d ₃ )-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanone

Container that contains (4-iodo-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanone (532 mg, 1.67 mmol), 4,4,5,5-tetramethyl-2-( methyl-d ₃ )-1,3,2-dioxaborolane (1.7 g, 11.7 mmol), dioxane (8 ml) and aqueous K ₃ PO ₄ (3.55 g, 16.7 mmol, 8.36 ml, 2.0 M) was bubbled 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 hours. The reaction mixture was partitioned between EtOAc. The organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated and the residue was purified using silica gel column chromatography (50% DCM/heptane) to give 185 mg (53%) of the title compound.

1H NMR (400 MHz, CDCl3) 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).

Stage 39F. (1-methyl-4-(methyl-d ₃ )-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanone oxime.

Container containing NaOAc (129 mg, 1.58 mmol), hydroxylamine hydrochloride (219 mg, 3.15 mmol), (1-methyl-4-(methyl-d ₃ )-1H-pyrazol-3-yl)( 1-Methylcyclopentyl)methanone (165 mg, 0.788 mmol), and EtOH (3.94 ml) were heated at 95°C for 2 hours and then cooled to room temperature. The solvent was removed and the residue was partitioned between DCM and saturated aqueous NaCl. The layers were separated and the aqueous layer was extracted with DCM (2x20 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated to give 212 mg of the title compound as a solid. RX-MS m/z 225.2 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) 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).

Stage 3 9G. (1-methyl-4-(methyl-d ₃ )-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanamine.

HOAc (3 ml) then Zn (311 mg, 4.76 mmol) was added to the flask which contained (1-methyl-4(methyl-d ₃ )-1H-pyrazol-3-yl)(1-methylcyclopentyl)methanone oxime (178 mg, 0.79 mmol). The mixture was heated at 60°C overnight. After cooling to room temperature, the reaction mixture was filtered through celite and washed with HOAc. The filtrate was concentrated and azeotropically distilled with toluene (3 times). The residue was diluted with DCM and Et ₂ O, and the pH was adjusted to pH~14 with 50% aqueous NaOH. The layers were separated and the aqueous layer was extracted twice with DCM/Et ₂ O (2:8). The combined organic extracts were dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated to give 145 mg (87%) of the title compound.

- 69 045541 nia. PX-MS m/z 194.2 [M-NH ₂ ] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) 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).

Stage 39H. (R)-3-hydroxy-N,N-dimethyl-4-((2-(((1-methyl-4-(methyl-d ₃ )-1H-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-N,Ndimethylpicolinamide (preparative step 1H) (842 mg, 0 .7 mmol) and DIEA (267 mg, 0.36 mL, 2.07 mmol) were added to the flask which contained (1-methyl-4-(methyl-d ₃ )-1H-pyrazol-3-yl)(1methylcyclopentyl )methanamine (145 mg, 0.69 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified using silica gel column chromatography (6% MeOH/DCM) to give the racemic product. The racemate was separated using chiral SFC chromatography (Chiralcel OD, 250 mm * 30 mm, 5 μm, 80 ml/min, 25% MeOH which contains 0.2% 7N ammonium/MeOH). Isolation of the first enantiomer of the elution gave 70 mg of the title compound. RX-MS m/z 470.5 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-46) δ 11.70 (s, 1H), 9.92 (s, 1H), 9.13 (d, J=10.1 Hz, 1H), 8.02 (s , 2H), 7.44 (s, 1H), 5.35 (d, J=10.1 Hz, 1H), 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 other elution enantiomer was isolated to give 70 mg of the corresponding (B)-enantiomer.

Example 40.

4-((2-(((1R)-(1,4-dimethyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl-3,4-b ₂ )methyl)amino)-3,4dioxocyclobut-1- en-1 -yl)amino)-3-hydroxy-N,N-dimethylpicolinamide

Stage 40A. Cyclopent-3-ene-1-carboxylic acid.

LiOH (19 g, 793 mmol) was added to a solution of methyl 1-methylcyclopent-3-ene-1-carboxylate (50 g, 396 mmol) in THF:H ₂ O (500 ml:125 ml) at 25°C. 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 (3x1 L). The combined organic extracts were combined, dried (Na2SO4) and filtered. The filtrate was concentrated to give 40 g (90%) of the title compound as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ 5.68 (s, 2H), 3.29-3.03 (m, 1H), 2.82-2.53 (m, 4H).

Stage 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 temperature of -30°C. The mixture was heated to 25°C and stirred for 15 hours. 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 (3x1L). The combined organic extracts were dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified using silica gel column chromatography (EtOAc) to obtain 45 g (100%) of the title compound as an oil.

1H NMR (400 MHz, CDCl ₃ ) 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).

Stage 40C. N-methoxy-N,1-dimethylcyclopent-3-ene-1-carboxamide.

HN(Me)(OMe)-HCl (38.3 g, 392 mmol) was added to a solution of 1-methylcyclopent-3-ene-1-carboxylic acid (45 g, 357 mmol) in DCM (1 L) at 0°C. , TEA (148 g, 1.46 mol) and HATU (203 g, 535 mmol). After stirring at room temperature for 24 hours, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (1 L) and washed with saturated aqueous Na ₂ CO ₃ solution. The aqueous layer was further extracted with EtOAc (1 L). The combined organic extracts were dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified using silica gel column chromatography (PE:EtOAc, 20:1 to 5:1) to give 23.4 g (39%) of the title compound as a light yellow oil. RX-MS m/z 170.3 [M+H] ⁺ ;

1H NMR (400 MHz, CDCl ₃ ) 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).

Stage 40D. (1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopent-3-en-1-yl)methanone.

A 125 mL round bottom flask with a magnetic stem and equipped with a baffle was purged with nitrogen three times, then THF (7.0 mL) was added followed by 3-iodo-1,4dimethyl-1H-pyrazole (preparative step 1D) (917 mg , 4.13 mmol). A 1.3 M solution of iPrMrCl-LiCl in THF (5.45 ml) was added dropwise to this solution, and the mixture was stirred for 1 hour at room temperature. N-methoxy-N,1-dimethylcyclopent-3-ene-1-carboxamide (600 mg,

- 70 045541

3.55 mmol) in THF (5 ml). After stirring for 2 hours, the reaction mixture was quenched with saturated aqueous NH ₄ Cl (20 ml) and extracted with DCM (3x25 ml). The combined extracts were dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (EtOAc in heptane, 0-100%) to give 500 mg (69%) of the title compound as a colorless oil.

1H NMR (400 MHz, CDCl ₃ ) 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).

Stage 40E. N-((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopent-3-en-1-yl)methyl)formamide.

Formamide (10.5 ml) and formic acid (6 ml) were added to the flask which contained (1,4dimethyl-1H-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 hours and then cooled to room temperature. Water (60 ml) was added and the mixture was extracted with MTBE (3x50 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated to give the title compound, which was used in the next step without purification. RX-MS m/z=234.0 [M+H]+.

Stage 40F. (1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopent-3-en-1-yl)methanamine.

Water 1n. HCl (24 ml) was added to the flask which contained N-((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopent-3-en-1-yl)methyl)formamide (1.26 g, 5 .4 mmol). The mixture was heated at 100°C for 2 hours and then cooled to room temperature. The pH of the solution was adjusted to pH ~11 by solidifying NaOH. The mixture was extracted with MTBE (3x30 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated to obtain 1.1 g (100%) of the title compound. PX-MS m/z 189.1 [M-NH2] ⁺ .

1H NMR (400 MHz, CD3OD) δ 7.27 (s, 1H), 5.66-5.58 (m, 2H), 3.86 (s, 1H), 3.82 (s, 3H), 2 .67-2.51 (m, 2H), 2.09-1.97 (m, 4H), 1.93-1.83 (m, 1H), 1.10 (s, 3H).

Stage 40G. 4-((2-(((R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopent-3-en-1-yl)methyl)amino)3,4-dioxocyclobut- 1 -en-1 -yl)amino)-3-hydroxy-N,N-dimethylpicolinamide.

Mixture with 4-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (preparative step 1H) (300 mg, 0.983 mmol), ( 1,4-dimethyl-1H-πyrazol-3-yl)(1-methylcyclopent-3en-1-yl)methanamine (242 mg, 1.18 mmol), ethanol (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 using silica gel column chromatography (0-20% MeOH in DCM) to give 450 mg of racemic product. Enantiomers were separated using chiral SFC (Chiral Tech OD-H, 250 mm x 21.2 mm, 5 µm, 22.5% methanol containing 0.2% 7N ammonium/MeOH, 80 ml/min). Isolation of the first enantiomer of the elution gave 80 mg of the title compound. RX-MS m/z 465.4 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 12.84 (b.s., 1H), 8.27 (b.s., 1H), 8.02 (d, J=5.1 Hz, 1H), 7.97 (b.s., 1H), 7.22 (b.s., 1H), 7.11 (b.s., 1H), 5.63 (b.s., 2H), 5, 50 (b.s., 1H), 3.81 (s., 3H), 3.61 (b.s., 3H), 3.19 (b.s., 3H), 2.78-2.64 (m, 2H), 2.15-2.02 (m, 5H), 1.21 (s, 3H). The other elution enantiomer was isolated to give 100 mg of the corresponding (S)-enantiomer.

Stage 40N. 4-((2-(((1 R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl-3,4-d ₂ )methyl)amino)3,4-dioxocyclobut- 1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide.

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-N,N 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 psig. inch. The reaction mixture was stirred for 16 hours and then filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified using silica gel column chromatography (0-20% MeOH/DCM) to obtain 16 mg (80%) of the title compound as a yellow solid. PX-MS m/z 469.4 [M+H]+.

¹ H NMR (400 MHz, DMSO d ₆ ) δ 11.75 (br.s., 1H), 9.96 (b.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 (w .s., 3H), 3.07 (sh.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).

Example 41.

(R)-((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

He

Stage 41A. (R)-di-tert-butyl(((4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)( 1 methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut- 1 -en-1 -yl)amino)-2-(dimethylcarbamoyl)pyridine

- 71 045541

3-yl)oxy)methyl)phosphate.

K ₂ CO ₃ (89 mg, 0.643 mmol), TBAI (119 mg, 0.322 mmol) and di-tert-butyl(chloromethyl)phosphate (0.65 ml, 0.75 mmol) were added to the room temperature solution (R)- 4-((2-(((1,4-dimethyl-1H-nirazol-3yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 -yl)amino)-3 - hydroxy-N,N dimethylpicolinamide (example 1) (250 mg, 0.536 mmol)) in DMF. The reaction mixture was stirred at room temperature for 2 days, and then toluene:H ₂ O (4 ml:2 ml) was added. The layers were separated and the organic layer was washed with brine, H ₃ PO ₄ (1 M solution) and 10% Na ₂ CO ₃ . The organic layer was concentrated. The residue was taken into toluene:MTBE (1 ml:20 ml) and refrigerated. The solid precipitate was collected and the filtrate was concentrated. Heptane was added to the filtrate to effectively precipitate a solid, which was filtered, collected and dried under high vacuum to give 140 mg (38%) of the title compound. RX-MS 689.3 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) 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), 1.411.18 (m, 2H), 1.09 (s, 3H) .

Stage 41B. (R)-((4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-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-yl)(1 methylcyclopentyl)methyl)amino)-3,4- dioxocyclobut-1-en-1-yl)amino)-2-(dimethylcarbamoyl)pyridin3-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 hours, the solvent was removed to obtain 73 mg (100%) of the title compound as the HCl salt. RX-MS 577.5 [M+H] ⁺ .

1H NMR (400 MHz, CD3OD) δ 8.86 (d, J=7.0 Hz, 1H), 8.49 (d, J=6.6 Hz, 1H), 7.78 (s, 1H), 5.75-5.63 (m, 1H), 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, 1H), 1.50-1.41 (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-N,N-dimethylnicolinamide, 0.5 calcium salt, monohydrate

Method A: Calcium hydroxide (7.94 mg, 0.107 mmol) was added to a 7 mL magnetic bar container containing (R)-4-((2-(((1,4-dimethyl-1H-pyrazole-3 - yl)(1-methylcyclopentyl)methyl)amino)3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (example 1) (100 mg, 0.214 mmol) and MeOH (0.75 ml). The mixture was heated at 55°C for 2 hours, and then cooled to room temperature, and stirred for 72 hours. The resulting suspension was filtered, obtaining the title compound as yellow crystals, which has a powder X-ray diffraction (PXRD) pattern that agrees with the one shown in Fig. 12. When the desired PXRD pattern was not obtained, the resulting salt was loaded into MeOH (1 g material/10 ml MeOH) and suspended until the PXRD pattern was consistent with that shown in FIG. 12.

Method B. (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-1- yl)amino)-3-hydroxy-N,N-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) was added to a 250 ml round bottom flask with a magnetic bar. The suspension was stirred at 45°C for 4 hours and then at room temperature for 4 days. The suspension was filtered. The solids were then added to a 125 mL round bottom flask with a magnetic bar and suspended in MeOH (50 mL). The mixture was sealed with ~1 mg of the title compound, which has a PXRD pattern that is consistent with that shown in FIG. 12. The mixture was stirred at room temperature for 20 hours and then filtered to obtain 4.21 g of the title compound as a light yellow solid, which was determined to have the PXRD pattern in FIG. 12. X-ray MS m/z 467.5 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (br. d., J=8.2 Hz, 1H), 7.66 (d, J=4.7 Hz, 1H), 7.40 (s, 1H), 7.35 (m, 1H), 5.37 (d, J=9.8 Hz, 1H), 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).

- 72 045541

X-ray analysis of a single crystal of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene-1 -yl)amino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate.

A crystal acceptable for X-ray analysis was obtained by recrystallization from ethanol.

Data collection was carried out on a Bruker D8 Venture diffractometer at room temperature. Data collection consisted of omega and phi scans. The structure was determined by direct methods using the SHELX software suite in the P4(3) space group of the tetragonal system. The structure was then optimized using the least squares method in the full matrix approximation. All non-hydrogen atoms were found and optimized using anisotropic substitution parameters. Hydrogen atoms located on nitrogen and oxygen were calculated from the Fourier difference map and refined using limited distances. The remaining hydrogen atoms were placed in calculated positions and the carrier atoms were allowed to jump onto them. The final refinement included isotropic substitution parameters for all hydrogen atoms.

Absolute structure analysis using possible methods (Hooft 2008) was carried out using PLATON (Spek 2010). Assuming the sample presented is enantiopure. The results show that the absolute structure was correctly established. The final R-index was 4.3%. The Fourier residual difference revealed neither absence nor shift in electron density.

Fig. 1 is the resulting X-ray structure (ORTEP graphical representation) of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)3. 4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate. Crystal structure data are given in table. 4.

Table 4

Crystal data and structure refinement.

C24 H32 N6 05

Volume

0.254 and -0.280 e.A ³

X-ray analysis of a single crystal of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene -1 -yl)amino)-3 -hydroxy-Ν,Ν Consistency criteria for F2

Final R indices П>2sigma(1)

R-indexes (all data

Extinction coefficient

Largest diff. peak and pit

Empirical formula

Mass according to formula

Temperature

Wavelength

Crystal system

Space group

1.235 Mg/ ^m3

0.727 mm ^-

1032

Density(calculated

Absorption coefficient

F 000

Crystal size

Theta band for data acquisition

Index Ranges

Collected Reflections

Independent reflections

Occupancy to theta = 67.679

Absorption adjustment

Method of clarification

4856 R int = 0.0500

99.3%

Empirical

Least squares in full matrix

1,200

R1 =0.0426, wR2 = 0.1240

R1 = 0.0445, wR2 = 0.1259

484.55

296 2 K

1.54178 A

Tetragonal

0.140 x 0.080 x 0.040 mm

FROM 5.871 TO 70.212°.

-12<=p<=12, -12<=k<=12, -28<=K=25

72157 approaching F ²

Data / restrictions / parameters 4856 / 6 / 336

Unit cell parameters a = 10.6580(2) A

b = 10.6580(2) A c = 22.9487(6) A

2606.81(12) A ³

- 73 045541 dimethylpicolinamide monohydrate.

A crystal suitable for X-ray analysis was grown from a mixture of heptane, ethyl acetate, acetone and DCM by slow evaporation over 48 hours.

Data collection was carried out on a Bruker D8 Venture diffractometer at room temperature. Data collection consisted of omega and phi scans. The structure was determined by direct methods using the SHELX suite of tetragonal system software in space group P43. The structure was then optimized using the least squares method in the full matrix approximation. All non-hydrogen atoms were found and optimized using anisotropic substitution parameters. Water was found from the difference map with a refinement modeled with 0.33 occupancy. Hydrogen atoms associated with water were not included in the refinement. Hydrogen atoms located on nitrogen and oxygen were calculated from the Fourier difference map and refined using limited distances. The remaining hydrogen atoms were placed in calculated positions and the carrier atoms were allowed to jump onto them. The final refinement included isotropic substitution parameters for all hydrogen atoms.

Absolute structure analysis using possible methods (Hooft 2008) was carried out using PLATON (Spek 2010). Assuming that the sample presented is enantiopure, the results indicate that the absolute structure has been correctly assigned. The final R-index was 6.4%. The final Fourier difference revealed neither absence nor shift in electron density.

Fig. 2 is the resulting X-ray structure (ORTEP graphical representation) of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino) -3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate. Crystal structure data is shown in Table 5.

Table 5

Crystal data and structure refinement.

Volume

Data / restrictions / parameters 4250 / 214 / 329

1.133 mg/ ^m3

1.503 mm'

4250 R int = 0.0845

99.2%

Empirical formula

Mass according to formula

Temperature

Wavelength

Crystal system

Space group

Unit cell parameters

Consistency criteria on F2

Final R indices П>2sigma(1)

R-indexes (all data

Extinction coefficient

Largest diff. peak and pit

Density(calculated

Absorption coefficient

F 000

Crystal size

Theta band for data acquisition

Index ranges

Collected Reflections

Independent reflections

Occupancy to theta = 65.219

Absorption adjustment

There is no way to clarify

Least squares in full matrix

1.045

R1 = 0.0637, WR2 = 0.1550

R1 = 0.0872, WR2 = 0.1686 from 4.600 to 65.219.

-12<=P<=12, -12<=K<=10, -24<=1<=27

20312

C23 H26.67 Cl N6 O

438.62

296 2 K

1.54178 A

Tetragonal a = 10.5851(2) A

b = 10.5851(2) A c = 22.9584(5) A

2572.36(11) A ³

0.140 x0.040 x0.020 mm ³ approximation F ²

0.238 and -0.261 e.A' ³

X-ray analysis of a single crystal of crystalline (S)-4,4-difluoro-2-methyltetrahydrofuran-2carboxylic acid ((1 R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,1 Oa-octahydrophenanthrene-1 yl)methanamine salt (Example 36F).

A crystal acceptable for X-ray analysis was obtained by recrystallization from ethanol.

- 74 045541

Data collection was carried out on a Bruker D8 Venture diffractometer at room temperature. Data collection consisted of omega and phi scans. The structure was determined by direct methods using the SHELX software suite in the P21 space group of the monoclinic system. The structure was then optimized using the full-matrix least squares method. All non-hydrogen atoms were found and optimized using anisotropic substitution parameters. Hydrogen atoms located on nitrogen were found from the Fourier difference map and refined with limited distances. The remaining hydrogen atoms were placed in calculated positions and the carrier atoms were allowed to jump onto them. The final refinement included isotropic substitution parameters for all hydrogen atoms.

Stereochemistry was determined based on known chiral configurations from the C4(-R), C7(R), and C8(-S) centers of the backbone. The final R-index was 7.6%. The final Fourier difference revealed neither absence nor shift in electron density.

Fig. 3 is the resulting X-ray structure (ORTEP graphic) of crystalline (S)-4,4-difluoro-2-methyltetrahydrofuran-2-carboxylic acid ((1R,4aS,10aR)-7isopropyl-1,4a-dimethyl-1,2 ,3,4,4a,9,10,10a-octahydrophenanthrene-1-yl)methanamine salt. Crystal structure data are given in table. 6.

Table 6

Crystal data and structure refinement.

Empirical formula S52 N78 F4 N2 Ob Mass according to formula 903.16 Temperature 296(2) K Wavelength 1.54178 A Crystal system Monoclinic In the space group P21 Unit cell parameters a = 10.8650(6) A a = 90°. b = 6.0384(4) A β = 91.899(5)°. c = 37.758(3) And y = 90°. Volume 2475.8(3) A ³ Z 2 Density(calculated) 1.211 mg/ ^m3 Absorption coefficient 0.718 mm' ¹ F(000) 976 Crystal size 0.280 x 0.060 x 0.020 mm ³ Theta band for data acquisition from 3.513 to 70.682°. Index ranges -11<=h<=13, -6<=k<=6, -46<=l<=39 Collected Reflections 22232 Independent reflections 7301 [R(int) = 0.0683] Occupancy to theta = 67.679° 88.6% Absorption adjustment Empirical Method of clarification Least squares in full matrix

approaching F ²

Data / restrictions / parameters 7301 / 7 / 607

Consistency criterion on F2 1.038

Final R indices [1>2sigma(1)] R1 = 0.0762, wR2 = 0.1915

R-indices (all data) R1 = 0.1089, wR2 = 0.2102

Absolute structural parameters 0.04(15)

Extinction coefficient 0.0032(8)

Largest diff. peak and pit 0.253 and -0.209 e.A ^-3

Powder X-ray diffraction analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1Hpyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene- 1 -yl)amino)-3-hydroxyN,N-dimethylpicolinamide monohydrate.

Powder X-ray diffraction analysis was carried out using a Bruker AXS D8 Advance diffractometer equipped with a Cu radiation source. The diffraction radiation was detected by a LYNXEYE_EX detector with motorized slits. Both the primary and secondary detectors were equipped with 2.5 Soller slits. The X-ray tube voltage and strum strength were set to 40 kV and 40 mA, respectively. Data was collected in a theta-theta goniometer in a locked scan bet at Cu K-alpha wavelengths from 3.0 to 40.0 degrees 2-theta, using a step size of 0.01 degrees, using a scan speed of 1.0 seconds per stage. Samples were obtained by placing them 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 using EVA Diffrac Plus software (v4.2.1.10). In general, a threshold value of 1 and a width value of 0.3 were used to pre-assign peaks. To ensure accuracy, adjustments were made manually; the result of the automatic assignment was checked visually, and the position of the peaks was adjusted according to the maximum of the peak. In general, peaks with relative intensities >3% were selected. Peaks that were not resolved or were consistent with noise were not selected. The typical error associated with the peak position of a crystalline material with PXRD as specified in the USP is in the range of +/- 0.2° 2-Theta (USP-941).

Fig. 4 is the resulting powder X-ray diffraction pattern of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut- 1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate and table. 7 lists the diffraction peaks in terms of 2-theta values.

Table 7

Angle 2-theta (degrees) Relative efficiency (%) 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 19.5 5.2 20.2 100.0 21.1 7.3 22.0 10.2 22.8 6.5

- 76 045541

Differential scanning calorimetric analysis of crystalline (R)-4-((2-(((1,4dimethyl-III-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene- 1 -yl)amino)-3 hydroxy-N,N-dimethylpicolinamide monohydrate.

Differential scanning calorimetry (DSC) measurements were performed using Discovery DSC equipment (TA Instruments) equipped with a cooling accessory for cooling. All experiments were carried out in standard/Tzero aluminum crucibles. The cell constant was determined using indium and temperature calibrations were performed using indium and tin as standards. All measurements were carried out under continuous blowing with dry nitrogen (50 ml/min). Approximately 1-5 mg of solid sample was weighed into a Tzero aluminum crucible, sealed and heated from 25°C to at least 250°C at a heating rate of 10°C/min. Experimental data were analyzed using commercially available software (TA Universal Analysis 2000/Trios software, TA Instruments).

Fig. 5 is the resulting differential scanning calorimetric analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut- 1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

Thermogravimetric analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene-1- yl)amino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate Thermogravimetric analysis was carried out using a Discovery TGA thermogravimetric analyzer (TA instruments). Samples of approximately 10 mg were weighed into an aluminum crucible and heated from ambient temperature to at least 250°C at a heating rate of 10°C/minute in a nitrogen-free purge atmosphere (10 ml/min, for both the sample chamber and for scales).

Fig. 6 is the resulting thermogravimetric analysis of crystalline (R)-4-((2(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 yl)αmino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

Powder X-ray diffraction analysis of crystalline (R)-4-((2-(((4-chloro-1-methyl1H-pyrazol-3 -yl)(1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 - en-1 -yl)amino)-3-hydroxyN,N-dimethylpicolinamideα monohydrate.

- 77 045541

Powder X-ray diffraction analysis was performed as described above. Fig. 7 is the resulting powder X-ray diffraction pattern of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3. 4-dioxocyclobut-1 en-1-yl)αmino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate, and table. 8 lists the diffraction peaks in terms of 2-theta values.

Table 8

Angle 2-theta (degrees) Relative efficiency (%) 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 30.6 3.2 30.8 12.4 31.0 h,o 32.8 7.7 35.1 3.1 36.0 3.1 36.4 3.3

Differential scanning calorimetric analysis of crystalline (R)-4-((2-(((4-chloro1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1 - en-1 -yl)amino)-3 hydroxy-N,N-dimethylpicolinamide monohydrate.

DSC measurements were performed as described above.

Fig. 8 is the resulting differential scanning calorimetric analysis of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)( 1-methylcyclopentyl)methyl)amino)3,4 -dioxocyclobut-1 -en-1 -yl)amino)-3 -hydroxy-N,N - dimethylpicolinamide monohydrate.

Thermogravimetric analysis of crystalline (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene- 1 -yl)amino)-3-hydroxy-N,Ndimethylpicolinamide monohydrate Thermogravimetric analysis was carried out as described above. Fig. 9 is the resulting thermogravimetric analysis of crystalline (R)-4-((2(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut -1-en-1 yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate.

X-ray analysis of a single crystal of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene-1 -yl)amino)-3-hydroxy-N,Ndimethylpicolinamide, 0.5 calcium salt, monohydrate

Solid calcium hydroxide (0.978 mg, 0.0132 mmol, 0.50 eq.) was added to the TOP container with a magnetic bar. Solution of (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene-1- yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (Example 1) (0.504 ml, 0.0265 mmol, 1.00 eq, 25.4 mg/ml) in methanol was pipetted into the container. The mixture was stirred at 60°C for 3 hours. During this time, a yellow solid formed. Stirring was stopped and the mixture was slowly cooled to 21 °C at a rate of -0.1 °C/min. A yellow solid (powder) was still present after cooling to 21°C. The solid was allowed to precipitate from the mother liquor for several weeks at room temperature until acceptable crystals formed.

Data collection was carried out on a Bruker APEX diffractometer at room temperature. Data collection consisted of omega and phi scans. The structure was determined by direct methods using the SHELX software suite in space group P21212. The structure was then optimized using full matrix least squares. All non-hydrogen atoms were found and optimized using anisotropic substitution parameters. Hydrogen atoms located on nitrogen and oxygen were calculated from the Fourier difference map and refined by limited distances.

- 78 045541

The remaining hydrogen atoms were placed in calculated positions and the carrier atoms were allowed to jump onto them. The final refinement included isotropic displacement parameters for all hydrogen atoms.

Absolute structure analysis using possible methods (Hooft 2008) was performed using PLATON (Spek 2010). Assuming that the sample provided is enantiopure, the results indicate that the absolute structure has been correctly assigned. The final R-index was 6.92%. The final Fourier difference revealed neither an absence nor a shift in electron density.

Fig. 10 is the resulting X-ray structure (ORTEP graphic) of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)3. 4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate. Fig. 11 is an X-ray structure (ORTEP graphic) of the corresponding unit cell. Crystal structure data are given in table. 9.

Table 9

Crystal data and structure refinement.

Empirical formula C48 H62 Ca N12 O10 Mass according to formula 1007.17 Temperature 296(2) K Wavelength 1.54178 A Crystal system Orthorhombic In the space group P21212 Unit cell parameters a = 13.2412(15) A a = 90°. b = 22.094(3) A β = 90°. c = 8.7809(9) And y = 90°. Volume 2568.8(5) A ³ Z 2 Density (calculated) 1.302 mg/ ^m3 Absorption coefficient 1.617 mm ^-1 F(000) 1068 Crystal size 0.205 x 0.127 x 0.046 mm ³ Theta band for data acquisition 3.892 to 51.384°. Index Ranges -9<=h<=13, -21<=k<=22, -8<=1<=8 Collected Reflections 10761 Independent reflections 2654 [R(int) = 0.0553] Occupancy to theta = 51.384° 95.3% Absorption adjustment multi-scan

Max. and min. transmittance 0.7533 and 0.5516

A method for refining Least Squares in the full matrix approximation F2

Data / restrictions / parameters 2654 / 299 / 338

Consistency criterion on F2 1.218

Final R indices [1>2sigma(1)] R1 = 0.0697, wR2 = 0.1588

R-indices (all data) R1 = 0.0828, wR2 = 0.1644

Absolute structural parameters 0.183(12)

Largest diff. peak and pit 0.330 and -0.254 e.A' ³

Powder X-ray diffraction analysis of crystalline (R)-4-((2-(((1,4-dimethyl-1Hpyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene- 1 -yl)amino)-3 -hydroxyN,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate.

Powder X-ray diffraction analysis was performed using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit was set to 0.6 mm, while the secondary optics used offset slits. Diffracted radiation was detected using a PSD-Lynx Eye detector. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. Data were collected in a theta-2 theta goniometer on Cu (k-alpha mean) from 3.0 to 40.0 degrees 2-theta using a step size of 0.01 degrees and a step time of 1.0 seconds. The anti-scatter screen was set at a fixed distance of 1.5 mm. Samples were obtained by placing them in a silicon low-background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus Commander software (version 2.6.1) and analysis was performed using EVA Diffraction Plus software (version 3.1). File given

- 79 045541 new PXRDs were not processed before searching for peaks. By applying the peak finding algorithm in EVA software, peaks selected with a threshold value of 1 were used for preliminary peak assignment. To ensure reliability, adjustments were made manually. The result of the automatic assignment was checked visually, and the position of the peaks was adjusted according to the maximum of the peak. In general, peaks with relative intensities >3% were selected. Peaks that were not resolved or were consistent with noise were not selected. The typical error associated with the peak position of a crystalline material from PXRD specified in the USP is within +/- 0.2° 2-Theta (USP-941).

Fig. 12 is the resulting powder X-ray diffraction pattern of crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut- 1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide, 0.5 calcium salt, monohydrate and table. 10 lists the diffraction peaks in terms of 2-theta values.

Table 10

Angle 2-theta (degrees) Relative efficiency (%) 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 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+CCR ₆ +CXCR ₃ -T cells were isolated from leukopak from healthy donors using the EasySep™ Human Th17 Cell Enrichment Kit. (StemCell Technologies, 18162). To obtain large numbers of cells, CCR6+ T cells were activated using human Dynabeads T-activator (catalog No. 11132D, Gibco) at a density of 1 x 10 ⁶ cells/ml in growth medium (RPMI1640 medium with 10% serum, 4 ng/ml IL -2) with a ratio of 1:1.5 cells to beads. On day 4 after activation, Dynabeads were removed from the culture. Activated T cells were maintained at a concentration of 12 x 10 ⁶ cells/ml for 15 days, with fresh growth media supplied when necessary.

The CCR6+ T cell chemotaxis assay was performed 12–15 days after T cell activation using the ChemoTx® 96-well disposable chemotaxis system (Neuroprobe 101-5) according to the manufacturer's protocol. After one wash with assay buffer (1X HBSS, which

- 80 045541 rai contains 20 mM HEPES and 0.25% BSA), the cells were incubated with the test compounds for 30 minutes. at room temperature before chemotaxis begins. To determine IC ₅₀ , the top and bottom of the chemotaxis chamber contained the same concentration of the compound. DMSO was kept constant at 0.1% (v/v) in all cells. The final concentration of CCL20 (Peprotech 300-29A) at the bottom of the chamber is 0.5 nM. The fully assembled chemotaxis plate was placed in a cell culture incubator at 37°C, 5% CO ₂ for 1 hour. After incubation, the upper filter was removed, followed by rapid freezing of the lower chamber at -80°C for 1 hour. Migrated cells into The bottom of the chamber was stained with CyQUANT dye (Life Technologies, C7026) to determine the number of cells.

The IC ₅₀ value for the compounds of the present invention (Table 11) was determined using nonlinear regression analysis of dose response curves.

_____________Table 11___________

Example 1C ₅ o (nM) Example 1C ₅₀ (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 thirty 96.1 eleven 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 z, z 38 12.6 19 70.6 39 6.5 20 271 40 ND*

*No data available.

Analysis of human neutrophil chemotaxis.

Human neutrophils were purified from freshly isolated human whole blood by immunomagnetic negative selection using the EasySep™ Direct Neutrophil Isolation Kit (StemCell Technologies, no. 19666) according to the manufacturer's instructions.

Human neutrophil chemotaxis assay was performed using a 96-well Corning FluoroBlok cell injection system (Corning no. 351164). Purified neutrophils were resuspended in chemotaxis buffer (1X HBSS, which contains 25 mM 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 with chemotaxis buffer, resuspended as before, and used immediately. For analysis, the test compounds were examined in a dose-response format to determine the IC ₅₀ . Labeled neutrophils (50 μl) were preincubated with diluted test compound (50 μl) for 30 min. in a 96-well plate (Greiner). Next, 100 μL of the diluted compound was mixed with 100 μL of GROa (Peprotech #300-11, 2 nM) at the bottom of the chemotaxis chamber. The top portion (insert) of the chemotaxis system, which contains the porous FluoroBlok membrane, was then assembled together. 50 μl of preincubated neutrophils was added to the FluoroBlok insert (top), and chemotaxis was measured by the ability of neutrophils to migrate across the membrane to a specific CXCR2 ligand, GROa. An Envision multilabel reader (Perkin Elmer) and/or a Typhoon fluorescence imager (GE) were used to evaluate changes in the fluorescent signal (calcein-AM fluorophore) at 485/535 nm that was generated by labeled neutrophils that passed through the porous membrane.

The IC50 values for the compounds of the present invention (Table 12) were determined using nonlinear regression analysis of dose response curves. Navarixin ((R)-2-hydroxy-N,N-dimethyl-3((2-((1 -(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-ene-1 -yl)amino)benzamide) was used as a control reference in the analysis (IC ₅₀ =16.8, n=52).

- 81 045541

Table 12

Example 1C ₅ o (nM) Example 1C ₅ o (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 7 2,160 27 52.6 8 103 28 2,190 9 2,750 29 4,410 10 175 thirty 4,030 eleven 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 available.

In vivo mouse model of IL-23-induced psoriasis-like skin inflammation. The effectiveness of the CCR ₆ antagonist of the present invention is evaluated in an in vivo mouse model of psoriasis-like skin inflammation. Recombinant murine IL-23 was administered by intradermal injection into the left ears of female C57BL/6 mice aged 8-10 weeks. This results in increased psoriasis-like symptoms of the disease, including thickening and erythema in the skin of the left ears. Mice given IL-23 are treated from day 0 to day 11 with either daily (QD) oral doses of a CCR ₆ antagonist or twice daily doses (BID) of a CCR ₆ antagonist. In addition, a group of mice are treated with anti-IL-17 Ab as a positive control for efficacy. Exemplary dosing groups for the study consist of the following:

group that received orally twice daily (BID) vehicle, positive control group, group that received twice weekly intraperitoneal injection of anti-IL-17 Ab (5 mg/kg), positive control group, group that received orally Compound A at 3-100 mg/kg or once daily (QD) or twice daily (BID), untreated, naïve control group.

Ten mice are included in each treatment group, except for the naïve control group, which contains five mice. Study day 0 is the designated first treatment day, and ear thickness measurements are taken daily using an engineering micrometer (Mitutoyo, Aurora, IL, USA). Ear swelling measurements for each mouse were compared to baseline and expressed in microns.

The compounds of the present invention selectively inhibit T cell chemotaxis compared to neutrophil chemotaxis (see Table 13). This selectivity makes the compounds of the present invention viable therapeutic agents for the treatment of inflammatory, immune, autoimmune, neurodegenerative and neuroinflammatory diseases, conditions or disorders in people with a 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

- 82 045541

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 thirty 42 eleven 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 available.

** Not selective for T-cell chemotaxis compared to neutrophil chemotaxis.

Applicant has surprisingly discovered that the inhibition of T cell chemotaxis, compared to the inhibition of neutrophil chemotaxis, is enhanced by the replacement of hydrogen with an alpha methyl group at the point of attachment of the heteroaryl ring A (see Table 14).

Table 14

R = H, 1C ₅ o (nM) R = СНз, 1С ₅ о (nM) Compound of the present invention CCR6 T cell, CCL20 CXCR2 Neutroph sludge, GROD T-cell Chemotaksis CCR6 T cell, CCL20 CXCR2 Neutrofil, GROD T cell Chemotax IP Heh mota to sis Heh mota to sis Selectivity Chemotak sis Chemotak sis Selectivity ° t P IZ h L nuclear submarine 19.2 42.1 2.2 5.8 524 90.3 N—OH ⁷ O 32.1 346 10.8 2.7 332 123 'EN ^{R /} o 64.5 12.2 NS* 24.0 2510 104

* Not selective for T cell chemotaxis compared to neutrophil chemotaxis.

Comparison Data Document WO 2010/131145 discloses examples 112 and 120.

About η

Example 112

Example 120

The applicant provides comparative chemotaxis data in table. 15 for connections WO 2010/131145. The data is presented in table. 15 demonstrate that Examples 112 and 120 are more effective at inhibiting neutrophil migration than the compounds of the present invention and less potent at inhibiting T cell migration than the compounds of the present invention. The compounds of WO 2010/131145 are functionally selective for CXCR2 over CCR ₆ , as opposed to the compounds of the present invention. These data indicate that the compounds

- 83 045541

WO 2010/131145 is less attractive as a treatment for diseases, conditions or disorders that are improved by reducing T cell chemotaxis through CCR ₆ inhibition, and that the compounds of WO 2010/131145 also have a greater risk of neutropenia for patients compared to the compounds according to the present invention.

Table 15

1C ₅ o (nM) Example CCR6 T cell, CCL20 Chemotaxis a CXCR2 Neutrophil, GROD Chemotaxis T cell Chemotaxy Selectivity 112 267 23.2 NS* 120 388 5.7 NS*

* Not selective for T-cell chemotaxis compared to neutrophil chemotaxis.

WO 2013/061005 discloses examples 22, 50 and 53 and provides functional data CXCR2 and CCR ₆ for each compound, which is reproduced from WO 2013/061005 in table. 16 below. CXCR2 antagonist activity was determined by inhibiting α-arrestin recruitment following CXCL8 activation in HEK293 Path-Hunter cells. CCR ₆ antagonist activity was determined by inhibiting Ca ²⁺ flux in cells following CCR ₆ activation on the FLIPR TETRA® platform. An agent that is activated by CCR ₆ has not been reported.

* Data disclosed in WO 2013/061005.

The Applicant provides the following comparative chemotaxis data in table. 17 for connections WO 2013/061005. Data in table. 17 demonstrate that Example 22 is effective in inhibiting both T cell and neutrophil chemotaxis with slightly greater potency (1.5X) relative to CCR ₆ inhibition. The high affinity for both receptors, coupled with poor selectivity for CCR ₆ , makes this compound less attractive as an anti-inflammatory agent with reduced potency against neutropenia than the compounds of the present invention. Example 50 has low affinity for CCR ₆ and inhibits neurophilic chemotaxis better than T cell chemotaxis. The chemotaxis profile of Example 50 is less attractive for development as an anti-inflammatory agent than the compounds of the present invention. Example 53 is not an effective inhibitor of either T-cell chemotaxis or neutrophil chemotaxis. The lack of functional efficacy relative to CCR ₆ makes Example 53 less attractive for the treatment of inflammatory diseases than the compounds of the present invention.

Table 17

1C ₅ o (nM) Example CCR6 T cell, CCL20 Chemotaxis a CXCR2 Neutrophil, GROa Chemotaxis T cell Chemotaxis Selectivity 22 22.6 35.2 1.5 50 330 121 NS* 53 390 1143 3

*Not selective for T cell chemotaxis compared to neutrophil chemotaxis

-

Claims (12)

CLAIM 1. Compound of formula (IA) or (IB) or a pharmaceutically acceptable salt or hydrate thereof, in which R ₁ represents methyl; R ₂ is methyl, ethyl or isopropyl; or R1 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 (C1- _C4 ) alkyl groups; R ₃ represents H; A represents R ₄ represents methyl; R ₅ is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano or cyclopropyl; R ₆ represents H; B represents R ₇ represents methyl; n is 0. 2. Compound according to claim 1 of formula (IIA) or a pharmaceutically acceptable salt or hydrate thereof, in which R ₁ represents methyl; R ₂ is methyl, ethyl or isopropyl; or R ₁ and R ₂ , 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 (C1- _C4 ) alkyl groups; R ₃ represents H; R ₄ represents methyl; R ₅ is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano or cyclopropyl; R ₆ represents H; B represents R ₇ represents methyl; n is 0. 3. A compound according to claim 2 or a pharmaceutically acceptable salt or hydrate thereof, in which R ₁ and R ₂ taken together with the nitrogen atom to which they are attached form morpholine or 4methylpiperazine; - 85 045541 R ₃ represents H; R ₄ represents methyl; R ₅ is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano or cyclopropyl; R ₆ represents H; B represents (R ₈ )n, RyC/p R ₇ represents methyl; and n is 0. 4. A compound selected from the group consisting of (R)-4-((2-(((4-chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3 ,4dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-yl)amino )-3-hydroxy-Nisopropyl-N-methylpicolinamide; (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(5-methylspiro[2.3]hexa-5-ul)methyl)amino)-3,4dioxocyclobut-1 -en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide; 4-((2-(((S)-((S)-4,4-difluoro-2-methyltetrahydrofuran-2-yl)(4-ethyl-1 -methyl-1H-pyrazol-3 yl)methyl)amino )-3,4-dioxocyclobut-1 -en-1 -ul)amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-(((2,5-dimethylthiazol-4-yl)(1 -methylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1 -en-1 ul)amino)-3 -hydroxy-N,N-dimethylpicolinamide; (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut- 1-en-1 -ul)amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut- 1 -en-1 -ul)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide; (S)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut1-en-1-ul)amino )-N-ethyl-3-hydroxy-N-methylpicolinamide; (R)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2(morpholine-4-carbonyl)pyridine -4-yl)amino)cyclobut-3-ene-1,2-dione; (R)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2-(4methylpiperazin-1-carbonyl) pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione; (S)-4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl )amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-(((4-chloro-1 -methyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl )amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide; (R)-3-hydroxy-N-isopropyl-4-((2-(((4-methoxy-1 -methyl-1H-pyrazol-3-yl)(1 methylcyclopentyl)methyl)amino)-3,4- dioxocyclobut-1-en-1-yl)amino)-N-methylpicolinamide; (R)-3-hydroxy-4-((2-(((4-methoxy-1 -methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-ul)amino)-N,N-dimethylpicolinamide; (R)-3-hydroxy-4-((2-((1 -(4-methoxy-1 -methyl-1H-pyrazol-3-yl)-2,2-dimethylpropyl)amino)-3,4dioxocyclobut-1 -en-1-yl)amino)-N,N-dimethylpicolinamide; (R)-3 -hydroxy-N-isopropyl-4-((2-((1 -(4-methoxy-1 -methyl-1H-pyrazol-3-yl)-2,2dimethylpropyl)amino)-3,4 -dioxocyclobut-1-en-1-yl)amino)-N-methylpicolinamide; (R)-4-((2-(((4-(difluoromethoxy)-1 -methyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-1 -yl)amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-(((4-cyano-1 -methyl-1H-pyrazol-3-yl)(1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl )amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-(((2,5-dimethylthiazol-4-yl)(1-methylcyclopropyl)methyl)amino)-3,4-dioxocyclobut-1-ene- 1 -yl)amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopropyl)methyl)amino)-3,4-dioxocyclobut1-en-1-ul)amino )-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-(((4-ethyl-1 -methyl-1H-pyrazol-3-yl)(1 -methylcyclopropyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl )amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-((1 -(1,4-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropyl)amino)-3,4-dioxocyclobut-1-ene-1 ul)amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1 en-1-yl) amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-((1-(2,5-dimethylthiazol-4-yl)-2,2-dimethylpropyl)amino)-3,4-dioxocyclobut-1-en-1yl)amino)- 3-hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-(((4-ethyl-1 -methyl-1H-pyrazol-3-yl)(1 -methylcyclobutyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl )amino)-3-hydroxy-N,N-dimethylpicolinamide; - 86 045541 (R)-4-((2-(( 1 -(4-ethyl-1 -methyl-1 H-pyrazol-3 -yl)-2,2-dimethylpropyl)amino)-3,4-dioxocyclobut -1 en-1 -yl)amino)-3-hydroxy-N,N-dimethyl picolinamide; (K)-3-hydroxy-4-((2-(((2-(hydroxymethyl)-5-methylthiazol-4-yl)(1-methylcyclopentyl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)am and ho)-N, N-dimethyl picolinamide; (C)-4-((2-(((4-cyclopropyl-1 -methyl-1 H-pyrazol-3 -yl)( 1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-1 - yl)amino)-3-hydroxy-N,N-dimethylpicolinamide; (C)-4-((2-(((4-cyano-1 -methyl-1 H-pyrazol-3 -yl)( 1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-1 - yl)amino)-M-ethyl-3-hydrose and-N-methyl picolinam and yes; (I)-4-((2-(((4-cyano-1 -methyl-1 H-pyrazol-3 -yl)( 1 -methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-ene-1 - yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide; (K)-4-((2-(((2,5-dimethylthiazol-4-yl)( 1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1-yl)amino)-3 - hydroxy-N,N-dimethylpicolinamide; (K)-3-hydroxy-4-((2-(((5-methoxy-2-methylthiazol-4-yl)(1-methylcyclopentyl)methyl)amino)-3,4dioxocyclobut-1-en-1-yl )amino)-N,Ndimethyl picol ynamide; (K)-4-((2-(((2,5-dimethyloxazol-4-yl)( 1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en1-yl)amino)-3- hydroxy-N,N-dimethylpicolinamide; (R)-4-((2-((( 1,4-dimethyl-1 H-pyrazol-3 -yl)( 1 -ethylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1 en-1 -yl )amino)-3-hydroxy-N,N-dimethylpicolinamide; 4-((2-(((8)-((8)-4,4-difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1 H-pyrazol-3yl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide; (R)-3 -hydroxy-N, N-d and revenge-4-((2-((( 1 -methyl-4-(methyl-b ₃ )-1 H-pyrazol-3 -yl)( 1 methylcyclopentyl )methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide; 4-((2-((( 1 R)-( 1,4-dimethyl-1 H-pyrazol-3 -yl)( 1 -methylcyclopentyl-3,4-b ₂ )methyl)amino)-3,4dioxocyclobut- 1 -en-1 -yl)amino)-3 -hydroxy-N,N-dimethylpicolinamide; And 4-((2-(((8)-((8)-4,4-difluoro-2-methyltetrahydrofuran-2-yl)(2,5-dimethylthiazol-4-yl)methyl)amino)- 3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N - dimethylpicolinamide; or a pharmaceutically acceptable salt or hydrate thereof. 5. (R)-4-((2-((( 1,4-dimethyl-1 H-pyrazol-3 -yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-ene- 1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide or a pharmaceutically acceptable salt or hydrate thereof. 6. Connection structure 7. Crystalline (R)-4-((2-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)3,4-dioxocyclobut-1-ene- 1 -yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate having an x-ray diffraction pattern containing diffraction peaks of 18.8±0.2, 19.2±0.2 and 20.4±0.2 degrees two theta. 8. Crystalline (R)-4-((2-((( 1,4-dimethyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)3,4-dioxocyclobut-1-ene- 1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate according to claim 7, having an X-ray diffraction pattern additionally containing diffraction peaks of 17.6±0.2 and 18.5±0.2 degrees two theta. 9. Crystalline (R)-4-((2-((( 1,4-dimethyl-1 H-pyrazol-3 -yl)( 1 -methylcyclopentyl)methyl)amino)3,4-dioxocyclobut-1-ene- 1 -yl)amino)-3 -hydroxy-N,N-dimethylpicolinamide monohydrate, having an X-ray diffraction pattern containing 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 theta. 10. Crystalline (R)-4-((2-((( 1,4-dimethyl-1H-pyrazol-3-yl)( 1 -methylcyclopentyl)methyl)amino)3,4-dioxocyclobut-1-ene- 1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide monohydrate according to any one of claims 7 to 9, having an X-ray diffraction pattern as shown in FIG. 4. 11. (R)-((4-((2-((( 1,4-dimethyl-1 H-pyrazol-3 -yl)( 1 -methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-! - en-1 -yl)amino)-2-(dim ethylcarbamoyl)pyridin-3-yl)oxy)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof. 12. Connection structure