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EA-053295-B1 - JAK1/JAK2/TYK2 INHIBITORS FOR TOPICAL TREATMENT OF DERMATOLOGICAL DISEASES

EA053295B1EA 053295 B1EA053295 B1EA 053295B1EA-053295-B1

Abstract

4-pyrazolyl-X-heteroarylpyrimidin-2-amine compounds of formula (I), (II) or (III): are provided as potent TYK2/JAK1/JAK2 inhibitors with low systemic exposure when administered topically, and pharmaceutical compositions thereof. These compounds and compositions are thus suitable for the topical treatment of JAK1/JAK2/TYK2-associated dermatological disorders such as atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis or lichen planus.

Inventors

  • Лян Кунсинь
  • Ли Шуанцзян
  • Тан Сяоцзин
  • Хуан Цзюньминь

Assignees

  • ХАНЧЖОУ ХАЙЛАЙТЛЛ ФАРМАСЬЮТИКАЛ КО., ЛТД

Dates

Publication Date
20260504
Application Date
20230810
Priority Date
20220822

Claims (20)

  1. For example, any claim that depends on another claim may be amended to include one or more limitations present in any other claim that depends on the same main claim. Where elements are presented in list form, such as in the Markush group format, each subgroup of elements is also disclosed, and any element(s) may be deleted from the group. It should be understood that, in general, when the present invention or aspects of the present invention are referred to as comprising specific elements and/or features, certain embodiments of the present invention or aspects of the present invention consist of or consist essentially of such elements and/or features. For simplicity, said embodiments are not specifically recited in the same terms in the present invention. It should also be noted that the terms including and comprising are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise stated or obvious from the context and understanding of one skilled in the art, values expressed as ranges may take any specific value or subrange within the stated ranges in various embodiments of the present invention down to the tenth unit of the lower limit of the range, unless the context clearly dictates otherwise. The present invention relates to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the present specification, the specification shall prevail. Furthermore, any specific embodiment of the present invention that relates to the prior art may be expressly excluded from any one or more claims. Because such embodiments are believed to be known to those skilled in the art, they may be excluded even if the exclusion is not expressly set forth in the present invention. Any specific embodiment of the present invention may be excluded from any claim for any reason, regardless of whether it is related to the existence of prior art. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described in the present invention. It is intended that the scope of the embodiments described in the present invention is not limited by the above description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications can be made to the present description without departing from the spirit or scope of the present invention, as defined in the following claims. CLAUSES OF THE INVENTION 1. Compound of formula I: or a pharmaceutically acceptable salt thereof, where: R 1 is C 1-3 alkyl, C 3-4 cycloalkyl or halogen; R 3 is R 2 R 4 is C 1-3 alkyl or 4-7 membered heterocyclyl containing 1 O heteroatom, where C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from R 5 , oxo or OH, - 34 053295 where R 5 is a 4-7-membered heterocyclyl containing 1 or 2 heteroatoms selected from N and O.
  2. 2. Compound of formula (II): or a pharmaceutically acceptable salt thereof, where: R 1 is C 1-3 alkyl, C 3-4 cycloalkyl or halogen; R 2 is R 4 is C 1-3 alkyl or 4-7 membered heterocyclyl containing 1 O heteroatom, wherein C 1-3 alkyl is optionally substituted with 1 or 2 independently selected from R 5 , oxo or OH, wherein R 5 is 4-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N and O.
  3. 3. Compound of formula (III): or a pharmaceutically acceptable salt thereof, where: R 1 is C 1-3 alkyl, C 3-4 cycloalkyl or halogen; R 2 is R 4 is C 1-3 alkyl or 4-7 membered heterocyclyl containing 1 O heteroatom, wherein C 1-3 alkyl is optionally substituted with 1 or 2 independently selected from R 5 , oxo or OH, wherein R 5 is 4-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N and O.
  4. 4. A compound according to any one of claims 1, 2, 3 or a pharmaceutically acceptable salt thereof, where R 2 represents R 4 is C 1-3 alkyl, or 4-7-membered heterocyclyl containing 1 O heteroatom, wherein C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from R 5 , oxo or OH, wherein R 5 is 4-7-membered heterocyclyl containing 1 or 2 heteroatoms selected from N and O.
  5. 5. A compound according to any one of claims 1, 2, 3 or a pharmaceutically acceptable salt thereof, where R 2 represents
  6. 6. A compound according to any one of claims 1, 2, 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is - 35 053295
  7. 7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-3 alkyl, C 3-4 cycloalkyl or halogen.
  8. 8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-3 alkyl.
  9. 9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 .
  10. 10. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3-4 cycloalkyl.
  11. 11. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen.
  12. 12. A compound according to any one of claims 1 to 7 or 11, or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl.
  13. 13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein: R 4 is C1.3 alkyl optionally substituted with 1 or 2 substituents independently selected from R 5 , oxo or OH, wherein R 5 is 4-7 membered heterocyclyl containing 1 or 2 heteroatoms selected from N and O.
  14. 14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein: g? V R 4 is CH 2 R 5 , R 5 is 111111 ·
  15. 15. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein: R 4 is a 4-7 membered heterocyclyl containing 1 O heteroatom.
  16. 16. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein: R represents '
  17. 17. A compound according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein said compound is: 2-(3-(4-(5-cyclopropyl-2-(isoxazol-4-ylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (1); 2-(3 -(4-(5-cyclopropyl-2 -((1 -methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1 -yl)-1 (ethylsulfonyl)azetidin-3-yl)acetonitrile (2); 2-(1 -(ethylsulfonyl)-3 -(4-(2-(isoxazol-4-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1 -yl)azetidin-3-yl)acetonitrile (3); 2-(1 -(ethylsulfonyl)-3 -(4-(2-((1 -(2-hydroxyethyl)- 1H-pyrazol-4-yl)amino)-5 - methylpyrimidin-4yl)- 1H-pyrazol-1 -yl)azetidin-3 -yl)acetonitrile (12); 2-(3 -(4-(5-chloro-2-((1 -(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1 -yl)1 -(ethylsulfonyl)azetidin-3-yl)acetonitrile (13); 2-(1-(ethylsulfonyl)-3-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1Hpyrazol-1 -yl)azetidin-3-yl)acetonitrile (17); 2-(1-(ethylsulfonyl)-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1 -yl)azetidin-3-yl)acetonitrile (18); 2-(1-(ethylsulfonyl)-3-(4-(5-methyl-2-((1-methyl-1H-benzo[d]umidazol-6-yl)amino)pyrimidin-4yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (26); 2-(3 -(4-(5-chloro-2-((1 -methyl-1H-benzo[d]imudazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1 -yl)-1 (ethylsulfonyl)azetidin-3-yl)acetonitrile (27).
  18. 18. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein said compound is: (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (4); (R)-3-cyclopentyl-3-(4-(2-(isoxazol-4-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (5); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (6); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (7); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1 -(oxetan-3 -yl)- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- 1Hpyrazol-1-yl)propanenitrile (8); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(oxetan-3-ylmethyl)-1H-nirazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (9); - 36 053295 (R)-3-(4-(5-chloro-2-((1 -(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1 yl)-3-cyclopentylpropanenitrile (10); ((R)-3-(4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1Hpyrazol-1-yl)-3-cyclopentylpropanenitrile (11); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (15); (R)-3-cyclopentyl-3-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1Hpyrazol-1-yl)propanenitrile (16); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)1H-pyrazol-1 -yl)propanenitrile (23); (R)-3-cyclopentyl-3-(4-(2-((1 -(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5 - methylpyrimidin-4-yl)1H-pyrazol-1-yl)propanenitrile (24); (R)-3-(4-(5-chloro-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)3-cyclopentylpropanenitrile (25).
  19. 19. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein said compound is: (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4yl)-1H-pyrazol-1-yl)propanenitrile (4):
  20. 20. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein said compound is: (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (23):

Description

State of the art The Janus kinase family includes four known family members: JAKs 1, 2, 3, and tyrosine kinase 2 (TYK2). These cytoplasmic tyrosine kinases associate with membrane cytokine receptors such as the common gamma chain receptors and the transmembrane proteins glycoprotein 130 (gp 130) (Murray, J. Immunol. 178(5):2623–2629, 2007). Nearly 40 cytokine receptors signal through combinations of these four JAK family members and their seven downstream substrates: members of the signal transducer and activator of transcription (STAT) family (Ghoreschi et al., Immunol Rev. 228(1):273–287, 2009). Cytokine binding to its receptor initiates JAK activation through trans- and autophosphorylation. JAK family kinases, in turn, phosphorylate cytokine receptor moieties, creating binding sites for sarcoma homology 2 (SH2) domain-containing proteins, such as STATs and other regulators, which are subsequently activated by JAK phosphorylation. Activated STATs enter the nucleus, initiating the expression of survival factors, cytokines, chemokines, and molecules that facilitate leukocyte migration (Schindler et al., J. Biol. Chem. 282(28):20059–20063, 2007). JAK activation also leads to cell proliferation via pathways mediated by phosphoinositide 3-kinase (PI3K) and protein kinase B. Tofacitinib, a JAK1/JAK3/JAK2 inhibitor, was the first JAK inhibitor approved by the FDA for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. JAK1-selective compounds, upadacitinib and abrocitinib, were recently approved for the treatment of atopic dermatitis (Nakashima et al. Allergol Int. 2022 Jan; 71(1):40-46). The selective TYK2 inhibitor deucravacitinib showed positive phase 2 and phase 3 results in patients with psoriasis (Papp et al. N Engl J Med. 2018, 379; 14) and is FDA-approved for the treatment of psoriasis. A topical formulation of ruxolitinib (Opzelura™), a selective JAK1/JAK2 inhibitor, is also approved for the treatment of mild to moderate atopic dermatitis and is in clinical development for the treatment of psoriasis, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis, and lichen planus. Thus, JAK inhibitors are suitable for the treatment of various dermatological diseases such as atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis, or lichen planus (Zhang et al. J Injlamm Res. 2022 Mar 18;15: 1935-1941). However, the approved oral medications, upadacitinib and abrocitinib, carry black box warnings about risks such as serious infections, nonmelanoma skin cancer, thrombosis, and thrombocytopenia. Interestingly, the topical formulation of ruxolitinib also carries similar risks, likely because its systemic exposure is also high, with a Cmax of 449±883 nM when applied topically, 1.2-37.6 g per application, twice daily (FDA-approved Patient Information for the Product, 09/2021), which is significantly higher than its IC50 for inhibition of JAK1 and JAK2 in a biochemical assay (3.3 nM and 2.8 nM, respectively) or inhibition in JAK1, JAK2-related cellular assays (maximum effect at -300 nM, FDA 2011 ruxolitinib pharmacology review). Many of the described JAK inhibitors, such as tofacitinib, abrocitinib, ruxolitinib, baricitinib, oclacitinib, share a common pyrrolopyrimidine core structure as shown below: Tofacitinib Abrocitinib Ruxolitinib Baricitinib Oclacitinib - 1 053295 WO 2009/064835 discloses compounds represented by D1 and D2 as JAK2 inhibitors. WO 2012/062704 and WO 2020/119819 disclose compounds represented by D3 as JAK1/JAK2/TYK2 inhibitors. WO 2014/111037 discloses compounds represented by D4 as JAK1/JAK2/JAK3 inhibitors. WO 2021/078022 discloses compounds represented by D5 as JAK1/JAK2/TYK2 inhibitors. N N N N DI D2 D3 D4 D5 The present invention discloses novel 4-pyrazolyl-N-heteroarylpyrimidin-2-amine compounds as potent TYK2/JAK1/JAK2 inhibitors with low systemic exposure when administered topically. Thus, said compounds and compositions containing a compound of the present invention are suitable as a topical treatment for JAK1/JAK2/TYK2-associated dermatological disorders such as atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis, or lichen planus. Brief description of the invention The present invention provides novel 4-pyrazolyl-N-heteroarylpyrimidin-2-amine compounds or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof as TYK2/JAK1/JAK2 kinase inhibitors that can be rapidly degraded by liver microsomes and, due to such advantageous properties, are suitable as a to