NADPH oxidase 4 inhibitors

• US 11,136,317 B2
• Filed: 01/30/2020
• Issued: 10/05/2021
• Est. Priority Date: 06/22/2015
• Status: Active Grant

• Current Assignee: Actelion Pharmaceuticals Limited (Johnson & Johnson)
• Original Assignee: Actelion Pharmaceuticals Limited (Johnson & Johnson)
• Inventors: Aissaoui, Hamed, Bolli, Martin, Boss, Christoph, Richard-Bildstein, Sylvia, Sieber, Patrick
• Primary Examiner(s): Moore, Susanna
• Application Number:
  US16/777,308
• Publication Number:
  US 20200165235A1
• Time in Patent Office: 614 Days
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 263/54 Benzoxazoles; Hydrogenated benzoxazoles
• CPC Class Codes: C07D 263/58 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 277/62 Benzothiazoles
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

The invention relates to 2,5-disubstituted benzoxazole and benzothiazole derivatives of Formula (I)

wherein L, X, Y, and ring (A) are as described in the description, their preparation and their use as pharmaceutically active compounds. Said compounds may be useful for the prevention or treatment of diseases or disorders associated with impaired reactive oxygen species (ROS) production, and/or for the prevention or treatment of various fibrotic diseases.

Claims

1. A compound of the Formula (I),

2. A compound according to claim 1, wherein the fragment

3. A compound according to claim 1, wherein the fragment

4. A compound according to claim 1;

wherein L represents —

CO—

NH—

*, wherein the asterisk (*) indicates the bond that is linked to the benzothiazole moiety;

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1;

wherein X represents S;

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1;

wherein

Y represents a group —

NR¹R², wherein

R¹ represents

C_1-4-alkyl;

C_2-4-alkyl which is mono-substituted with di-(C_1-3-alkyl)amino;

C_3-5-cycloalkyl-L¹-, wherein L¹ represents a direct bond or C_1-3-alkylene; and

wherein the C_3-5-cycloalkyl optionally contains one oxygen ring atom, and wherein said C_3-5-cycloalkyl is unsubstituted, or mono-substituted with methyl or fluoro;

or

1-(oxetan-3-yl)-piperidin-4-yl; and

R² represents hydrogen, C_1-3-alkyl, or C_3-5-cycloalkyl;

or Y represents a group

7. A compound according to claim 1;

wherein

Y represents

N—

(C_1-3-alkyl)amino, N,N-di-(C_1-3-alkyl)-amino, N-[2-(di-C_1-3-alkyl)amino)-ethyl]-N—

(C_1-3-alkyl)-amino, N—

(C_1-4-alkyl)-N-(oxetan-3-yl)-amino, N—

(C_3-5-cycloalkyl)-N-(oxetan-3-yl)-amino, N—

(C_1-4-alkyl)-N-(oxetan-3-yl-methyl)-amino, N-(3-methyl-oxetan-3-yl)-N-methylamino, N-(3-fluoro-oxetan-3-yl-methyl)-N-methylamino, or N-methyl-((N-(oxetan-3-yl)-piperidin)-4-yl)-amino;

or Y represents a saturated 4- to 7-membered monocyclic heterocyclyl selected from;

morpholin-4-yl;

2-oxo-pyrrolidin-1-yl;

1,1-dioxidothiomorpholin-4-yl;

or piperazin-1-yl optionally mono-substituted in position 4 with oxetan-3-yl or C_1-3-alkyl;

or azetidin-1-yl which is unsubstituted, or substituted with;

two fluoro substituents attached to the same ring carbon atom;

or

one phenyl or pyridinyl substituent, wherein said phenyl or pyridinyl is unsubstituted;

or

one substituent selected from hydroxy;

C_1-3-alkoxy;

—

CO—

C_1-4-alkoxy;

di-(C_1-3-alkyl)amino; and

C_1-3-alkyl which is mono-substituted with di-(C_1-3-alkyl)amino, hydroxy, or C_1-3-alkoxy;

or

two substituents, wherein one of said substituents is C_1-4-alkyl, and the other is independently selected from hydroxy, or di-(C_1-3-alkyl)amino;

or

one substituent selected from morpholin-4-yl;

1,1-dioxidothiomorpholin-4-yl;

one substituent selected from azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl;

wherein said groups independently are unsubstituted, or mono-substituted with hydroxy, or di-substituted with methyl and hydroxy;

or pyrrolidin-1-yl, or piperidin-1-yl;

wherein said pyrrolidin-1-yl, or piperidin-1-yl independently is unsubstituted, or substituted with;

two fluoro substituents attached to the same ring carbon atom;

or

one substituent selected from hydroxy;

C_1-3-alkoxy;

or di-(C_1-3-alkyl)amino;

or Y represents saturated 7- to 11-membered spiro-bicyclic heterocyclyl containing at least one nitrogen atom, wherein said nitrogen atom is bound to the benzothiazole moiety, and wherein said heterocyclyl optionally contains one further ring heteroatom independently selected from oxygen, nitrogen and sulfur;

wherein said heterocyclyl is unsubstituted, or substituted with;

two oxo substituents at a ring sulfur ring atom;

or

one C_1-3-alkyl substituent attached to a ring nitrogen atom having a free valency;

or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1;

wherein Y represents a group independently selected from the following groups A), B), C), or D);

9. A compound according to claim 1;

wherein Y represents a group independently selected from the following groups A) or B);

10. A compound according to claim 1, which is selected from the group consisting of:

2,3-Dihydro-benzofuran-5-carboxylic acid (2-piperidin-1-yl-benzothiazol-5-yl)-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid (2-morpholin-4-yl-benzothiazol-5-yl)-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid (2-pyrrolidin-1-yl-benzothiazol-5-yl)-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid (2-diethylamino-benzothiazol-5-yl)-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid (2-dimethylamino-benzothiazol-5-yl)-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1,1-dioxo-1l6-thiomorpholin-4-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-3-methyl-azetidin-1-yl)-benzothiazol-5-yl]-amide;

(S)—

N-(2-(3-hydroxypyrrolidin-1-yl)benzo[d]thiazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid {2-[methyl-(1-oxetan-3-yl-piperidin-4-yl)-amino]-benzothiazol-5-yl}-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(methyl-oxetan-3-yl-amino)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-piperidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-phenyl-azetidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-methoxymethyl-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-((S)-3-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-((R)-3-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide;

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-dimethylaminomethyl-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide;

2-Piperidin-1-yl-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide;

2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide;

2-(4-Methoxy-piperidin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide;

2-(4-Methyl-piperazin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide;

2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide;

2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide;

2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide; and

2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid benzo[1,3]dioxol-5-ylamide;

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising, as active principle, one or more compounds according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

12. A method of inhibition of myofibroblast differentiation in a patient in need thereof, comprising administering to said patient in need thereof an effective amount of the compound of claim 1, in free or pharmaceutically acceptable salt form.

13. The method according to claim 12, wherein the patient is suffering from a disease or disorder selected from a fibrotic disease;

pulmonary hypertension;

hypertension;

asthma;

acute respiratory distress syndrome;

myocardial infarction;

acute heart failure;

cardiac and skeletal myopathy;

stroke;

traumatic brain injury;

neuropathic pain;

ataxia telangiectasia;

ocular diseases; and

cancer.

14. The method according to claim 13, wherein said fibrotic disease is pulmonary fibrosis;

scleroderma;

pancreatic fibrosis;

liver fibrosis;

chronic kidney disease;

or cardiomyopathy.

15. The method according to claim 13, wherein the disease or disorder is Barth syndrome.