US 10,246,457 B2Granted

Indazole and azaindazole Btk inhibitors

AssigneeMerck Sharp & Dohme Corp.

InventorsTony Siu, Michael D. Altman, Brian M. Andresen, Jian Liu, Joseph Kozlowski, Sobhana Babu Boga, Younong Yu, Rajan Anand, Jiaqiang Cai, Dahai Wang, Shilan Liu

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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.

Claims8

Dependent claims

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.

23 more elements

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.

26 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/564,352Filed 4 Apr 2016
Priority: WO PCT/CN2015/0760418 Apr 2015
Published: US 2018/0127411 A110 May 2018
Granted: 2 Apr 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
C07D 231/56
Condensed with carbocyclic rings or ring systems: benzopyrazoles; Hydrogenated benzopyrazoles

Family

US 2018/0127411 A1Pre-grant publication · published 10 May 2018
US 10,246,457 B2This patent

From the US filing history. Foreign family members aren’t listed.

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