Method for treating a disease or condition using a pyrazole compound or formulation thereof

Patent metadata

Field	Value
Publication number	US-12357623-B2
Application number	US-202217684579-A
Country	US
Kind code	B2
Filing date	Mar 2, 2022
Priority date	Mar 3, 2021
Publication date	Jul 15, 2025
Grant date	Jul 15, 2025

Abstract

Disclosed herein are embodiments of a method for treating a disease or condition in a subject, comprising administering to the subject, a pyrazole compound according to formula I.

The compound may be administered as a composition, such as a spray-dried formulation. The disease or condition may be hidradenitis suppurativa, or a lymphoid neoplasm, and may be chronic myeloid leukemia or chronic myelomonocytic leukemia.

First claim

We claim:

1. A method for treating a disease or condition in a subject, comprising administering to the subject a compound, having a formula I

or a pharmaceutically acceptable salt thereof,
wherein:
R is aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkyl phosphoramidate, or alkyl phosphate; or
R is H and the compound is in the form of a salt;
wherein the disease or condition is myeloproliferative neoplasms (MPN) excluding polycythemia vera.

2. The method of claim 1 , wherein the myeloproliferative neoplasm is selected from chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), primary myelofibrosis (PMF), essential thrombocythemia, chronic eosinophilic leukemia, or a combination thereof.

3. The method of claim 2 , wherein the myeloproliferative neoplasm is chronic myeloid leukemia.

4. The method of claim 1 , wherein R is alkyl, acyl, carboxyl ester, amide, nonaromatic heterocyclyl, alkyl phosphoramidate, or alkyl phosphate.

5. The method of claim 1 , wherein:
R is C 1-4 alkyl phosphate, C 1-4 alkyl phosphoramidate, C 1-6 alkyl, C 1-6 acyl, —C(O)O—C 1-6 aliphatic, —C(O)N(R b ) 2 , or 5- or 6-membered nonaromatic heterocyclyl; and
each R b independently is H, unsubstituted C 1-6 alkyl, C 1-6 alkyl substituted with —N(R g ) 2 , carboxyl ester, or 5- or 6-membered nonaromatic heterocyclyl, or two Rb together with the nitrogen to which they are attached form a C 3-6 nonaromatic heterocyclyl moiety optionally interrupted with one or two —O— or —N(R g ), where R g is H or C 1-4 alkyl.

6. The method of claim 1 , wherein:
R is C 1-6 alkyl optionally substituted with a 5- or 6-membered nonaromatic heterocyclyl, OH, —OC(O)—R a , —N(R b ) 2 , —OC(O)—R c , carboxyl, or a combination thereof;
R a is 5-membered nonaromatic heterocyclyl, aryl substituted with —CH 2 N(R b ) 2 , C 3-6 cycloalkyl substituted with carboxyl, C 1-6 alkoxy, unsubstituted C 1-6 alkyl, or C 1-6 alkyl substituted with one or more of N(R b ) 2 , carboxyl, carboxyl ester, —OC 1-6 acyl, —NHC(O)(NH 2 )C 1-6 alkyl, or —(OCH 2 CH 2 ) 1-8 N(R b ) 2 ; and

—OC(O)—R c is derived from an amino acid where the —OC(O)— moiety of —OC(O)—R c corresponds to an acid moiety on the amino acid and R c comprises —N(R b ) 2 or a nitrogen-containing nonaromatic heterocyclyl.

7. The method of claim 6 wherein the amino acid is a naturally occurring amino acid.

8. The method of claim 6 , wherein the amino acid is selected from glycine, valine, alanine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine, glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine, or proline.

9. The method of claim 5 , wherein:
R is C 1-6 acyl moiety optionally substituted with —C(O)O—C 1-4 alkyl, —C(O)O—C 1-4 alkyl-N(R b ) 2 , N(R b ) 2 , —NHC(O)C 1-4 alkyl, or a combination thereof;
R is 5- or 6-membered nonaromatic heterocyclyl moiety optionally substituted with hydroxyl, hydroxymethyl, or a combination thereof;
R is —C(O)O—C 1-6 alkyl optionally substituted with —OC(O)C 1-4 alkyl or N(R b ) 2 ; or
R is —C(O)O—C 3-6 cycloalkyl optionally substituted with C 1-4 alkyl.

10. The method of claim 1 , wherein R is H and the salt is a hydrochloride, citrate, hemicitrate, hemitartrate, tartrate, benzene sulfonate, mesylate, sodium, hemisuccinate, or succinate salt.

11. The method of claim 1 , wherein R is alkyl phosphate or a salt thereof.

12. The method of claim 11 , wherein the compound is an alkali metal salt, an alkaline earth metal salt, an ammonium salt, an amino acid salt, an amino sugar salt, or a tris salt.

13. The method of claim 11 , wherein the compound is a mono-salt, or a di-salt.

14. The method of claim 11 , wherein the alkyl phosphate is a mono- or di-sodium salt, mono- or di-potassium salt, calcium salt, magnesium salt, arginine salt, lysine salt, mono- or di-tris salt, ammonium salt, choline salt, or meglumine salt.

15. The method of claim 1 , wherein the compound is selected from:
I-2: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
I-3: di-tert-butyl ((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl) phosphate;
I-4: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate disodium salt;
I-5: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-6: 2-(1-(acetyl-L-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-7: 1-methylcyclopropyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;
I-8: 1-(isobutyryloxy)ethyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;
I-9: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-10: 2-morpholinoethyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;
I-11: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hemi-tartrate salt;
I-12: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(morpholine-4-carbonyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-13: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-morpholinopropyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-14: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-15: 3-morpholinopropyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate;
I-16: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate hydrochloride;
I-17: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-prolinate hydrochloride;
I-18: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate;
I-19: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl glycinate hydrochloride;
I-20: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate disodium salt;
I-21: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate hydrochloride;
I-22: 2-(1-acetyl-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-23: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-2-methylpropanoate hydroch

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Chou lu
• Duan Matt
• Darwish Ihab
• Shaw Simon
• Bhamidipati Somasekhar
• Taylor Vanessa
• Chen Yan
• Fan Dazhong
• Luo Zhushou

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title