# US 10,246,457 B2 · Indazole and azaindazole Btk inhibitors

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- Number: US 10,246,457 B2
- Document ID: US10246457B2
- Status: Granted
- Kind: B2
- Application number: 15/564,352
- Filed: 2016-04-04
- Published: 2018-05-10
- Granted: 2019-04-02
- Earliest claimed: 2015-04-08
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Tony Siu; Michael D. Altman; Brian M. Andresen; Jian Liu; Joseph Kozlowski; Sobhana Babu Boga; Younong Yu; Rajan Anand; Jiaqiang Cai; Dahai Wang; Shilan Liu
- Web page: https://patentgrep.com/patent/US10246457B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula (I), or pharmaceutically acceptable salts thereof, wherein X1, X2, R1, R7, R8 and R9 are as herein described. The present invention also provides pharmaceutical compositions comprising these compounds and methods for their use in therapy. In particular, the present invention relates to the use of Btk inhibitor compounds of Formula (I) in the treatment of Btk mediated disorders.

## Claims

### Claim 1

A compound of Formula (I)
wherein:
X1 is N or C(H);
X2 is N or C(R6);
R1 is H, C1-3akyl, or —CH2—R1a, wherein R1a is phenyl or pyridyl;
R6 is H or C1-3alkyl;
R7 is:
(a.) a group of the formula —C(O)N(R7a)(R7b), wherein R7a and R7b are independently H or C1-3alkyl; or alternatively, R7a and R7b together with the N to which they are attached form a 5- to 6-membered heterocyclyl optionally containing 1 additional heteroatom selected from N or O;
(b.) Cy, wherein Cy is phenyl or a 5- or 6-membered heteroaryl containing 1 to 3 N ring atoms; wherein Cy is unsubstituted or substituted by 1 to 2 Rc substituents selected from:
(i.) C1-4alkyl,
(ii.) a group of the formula —C(R7d)2CO2H,
wherein R7d is H or C1-3alkyl;
(iii.) —CH2CH2OCH3; or
(iv.) tetrahydropyranyl;
or alternatively, two Rc substituents, together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl containing 1 N ring atom;
(c.) —C(O)OH;
(d.) H;
(e.) C1-3alkyl; or
(f.) C1-3fluoroalkyl;
R8 is H, C1-3alkyl or C1-3hydroxyalkyl;
R9 is:
or
a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X2 is C(R6).

### Claim 3 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are both C(H).

### Claim 4 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is H.

### Claim 5 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R7 is
(a.) a group of the formula —C(O)N(R7a)(R7b), wherein R7a and R7b are independently H or methyl; or alternatively, R7a and R7b together with the N to which they are attached form a morpholinyl ring;
(b.) Cy,wherein Cy is phenyl, pyrazolyl, or pyridinyl; wherein Cy is unsubstituted or substituted by 1 to 2 Rc substituents selected from:
(i.) C1-4alkyl,
(ii.) a group of the formula —C(R7d )2CO2H,
wherein R7d is H or methyl;
(iii.) —CH2CH2OCH3; or
(iv.) tetrahydropyranyl;
(c.) —C(O)OH;
(d.) H;
(e.) methyl; or
(f.) trifluoromethyl.

### Claim 6 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R8 is hydroxymethyl or methyl.

### Claim 7

A compound which is:
3-amino-5-[3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl]-1H-indazole-7-carboxylic acid,
2-[3-(3-amino-6-methyl-1H-indazol-5-yl)-2-(hydroxymethyl)phenyl]-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
3-amino-5-[3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl]-1H-indazole-7-carboxamide,
2-{3-[3-amino-7-(trifluoromethyl)-1H-indazol-5-yl]-2-(hydroxymethyl)phenyl}-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
3-amino-5-[3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl]-1-methyl-1H-indazole-7-carboxamide,
2-[3-{3-amino-7-[1-(1-methylethyl)-1H-pyrazol-4-yl]-1H-indazol-5-yl}-2-(hydroxymethyl)phenyl]-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
3-amino-5-(3-{[(4-tert-butyl-2-fluorophenyl)carbonyl]amino}-2-methylphenyl)-1H-indazole-7-carboxamide,
3-amino-5-[3-({[2-fluoro-4-(2,2,2-trifluoro-1,1-dimethylethyl)phenyl]carbonyl}amino)-2-methylphenyl]-1H-indazole-7-carboxamide,
2-{3-[3-amino-7-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl]-2-(hydroxymethyl)phenyl}-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
2[3-(3-3-(3-amino-7-pyridin-3-yl-1H-indazol-5-yl)-2-(hydroxymethyl)phenyl]-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
3-amino-5[3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl]-N-methyl-1H-indazole-7-carboxamide,
2-{3[3-amino-1-(pyridin-4-ylmethyl)-1H-indazol-5-yl]-2-(hydroxymethyl)phenyl}-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
N-{3[3-amino-7-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl]-2-methylphenyl}-4-tert-butylbenzamide,
2-{3-[3-amino-7-(morpholin-4-ylcarbonyl)-1H-indazol-5-yl]-2-(hydroxymethyl)phenyl}-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
N-{3-[3-amino-7-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl]-2-methylphenyl1}-4-tert-butyl-2-fluorobenzamide,
3-amino-5-[3-(6-tert-butyl-8-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-2-(hydroxymethyl)phenyl]-1H-indazole-7-carboxamide,
2-[3-{3-amino-7-[-1-(1-methylethyl)-1H-pyrazol-3-yl]-1H-indazol-5-yl}-2-(hydroxymethyl)phenyl]-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
N-{3-[3-amino-7-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl]-2-(hydroxymethyl)phenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide,
2-[3-(3-amino-7-phenyl-1H-indazol-5-yl)-2-(hydroxymethyl)phenyl]-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
2-[3-(3-amino-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-(hydroxymethyl)phenyl]-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
2-[3-(3-amino-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-(hydroxymethyl)phenyl]-6-tert-butyl-8-fluorophthalazin-1(2H)-one,
2-(3-(3-amino-7-(pyridin-2-yl)-1H-indazol-5-yl)-2-(hydroxymethyl)phenyl)-6-(tert-butyl)-8-fluorophthalazin-1(2H)-one,
2-(4-(3-amino-5-(3-(6-(tert-butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-indazol-7-yl)-1H-pyrazol-1-yl)acetic acid,
2-(4-(3-amino-5-(3-(6-(tert-butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-indazol-7-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid,
2-(3-(3-amino-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-(hydroxymethyl)phenyl)-6-(tert-butyl)-8-fluorophthalazin-1(2H)-one,
2-(3-(3-amino-7-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-(hydroxymethyl)phenyl)-6-(tert-butyl)-8-fluorophthalazin-1(2H)-one,
2-(3-(3-amino-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-2-(hydroxymethyl)phenyl)-6-(tert-butyl)-8-fluorophthalazin-1(2H)-one,
2-(3-(3-amino-7-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-1H-indazol-5-yl)-2-(hydroxymethyl)phenyl)-6-(tert-butyl)-8-fluorophthalazin-1(2H)-one,
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.