Pyrazole derivatives as MALT1 inhibitors

Patent metadata

Field	Value
Publication number	US-10888550-B2
Application number	US-201916440356-A
Country	US
Kind code	B2
Filing date	Jun 13, 2019
Priority date	Jun 18, 2018
Publication date	Jan 12, 2021
Grant date	Jan 12, 2021

Abstract

Disclosed are compounds, compositions and methods for treating of diseases, syndromes, conditions, and disorders that are affected by the modulation of MALT1. Such compounds are represented by Formula (I) as follows:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , G 1 and G 2 , are defined herein.

First claim

We claim:

1. A compound independently selected from the group consisting of:
5-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)imidazo[1,2-a]pyridine-8-carboxamide;
N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-cyanoimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-(5-chloro-6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-N-(6-(methylsulfonyl)-5-(trifluoromethyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-(5-chloro-6-(oxazol-2-yl)pyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-methylimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(methylsulfonyl)-1H-pyrazole-4-carboxamide;
N-(5-chloro-6-(5-methyloxazol-2-yl)pyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-(5-chloro-6-(4-methyloxazol-2-yl)pyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
1-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide;
4-(5-(trifluoromethyl)-4-((2-(trifluoromethyl)pyridin-4-yl)carbamoyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyridine-7-carboxamide;
N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
1-(7-chloropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide;
N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)-1-(7-chloropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide
4-(4-((5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyridine-7-carboxamide;
(*S)—N-(5-chloro-6-(1-methoxyethyl)pyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*R)—N-(5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-yl)-1-(8-chloroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*R)—N-(5-chloro-6-(1-methoxyethyl)pyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*S)—N-(5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-yl)-1-(8-chloroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*S)—N-(5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-yl)-1-(7-chloropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*R)—N-(5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-yl)-1-(7-chloropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*S)—N-(5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-yl)-1-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*R)—N-(5-chloro-6-(tetrahydrofuran-2-yl)pyridin-3-yl)-1-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*S)—N-(5-chloro-6-(1-methoxyethyl)pyridin-3-yl)-1-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*R)—N-(5-chloro-6-(1-methoxyethyl)pyridin-3-yl)-1-(7-cyanopyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*S)—N-(5-chloro-6-(1-methoxyethyl)pyridin-3-yl)-1-(7-chloropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
(*R)—N-(5-chloro-6-(1-methoxyethyl)pyridin-3-yl)-1-(7-chloropyrazolo[1,5-a]pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-(6-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)-5-methylpyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-(6-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)-5-(trifluoromethyl)pyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-N-(6-(S-methylsulfonimidoyl)-5-(trifluoromethyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
N-(6-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)-5-fluoropyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
and
N-(5-chloro-6-((dimethyl(oxo)-λ 6 -sulfanylidene)amino)pyridin-3-yl)-1-(8-fluoroimidazo[1,2-a]pyridin-5-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide
or an enantiomer, diastereomer, or a pharmaceutically acceptable salt form thereof.

2. A pharmaceutical composition comprising a compound of claim 1 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

3. The pharmaceutical composition of claim 2 , wherein the composition is a solid oral dosage form.

4. The pharmaceutical composition of claim 2 , wherein the composition is a syrup, an elixir or a suspension.

5. A method of treating a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 .

6. The method of claim 5 wherein said disease, syndrome, condition, or disorder is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn's disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

7. A method of treating a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1, comprising administering to a subject in need thereof a therapeutically effective amount of (a) a MALT1 inhibitor, and (b) a pharmaceutical agent selected from the group consisting of a BTK inhibitor, a SYK inhibitor, a PKC inhibitor, a PI3K pathway inhibitor, a BCL family inhibitor, a JAK inhibitor, a PIM kinase inhibitor, a B cell antigen-binding antibody, an immune cell redirection agent, an immunomodulatory agent, an anti-PD1 antibody, and an anti-PD-L1 antibody;
wherein said MALT1 inhibitor is a compound of claim 1
or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

8. The method of claim 7 wherein the BTK inhibitor is ibrutinib.

9. The method of claim 7 wherein the B cell antigen-binding antibody is rituximab.

10. The method of claim 7 wherein the immunomodulatory agent is daratumumab.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Lu Tianbao
• Connolly Peter J
• Cummings Maxwell David
• Diels Gaston Stanislas Marcella
• Thuring Jan Willem
• Philippar Ulrike
• Edwards James Patrick
• Berthelot Didier Jean-Claude
• Wu Tongfei

Classifications

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title