Heterocyclic compounds
09840509 · 2017-12-12
Assignee
Inventors
- Ranjit C. Desai (Gujarat, IN)
- Rajesh Bahekar (Gujarat, IN)
- Dipam Patel (Gujarat, IN)
- Kiran Shah (Gujarat, IN)
Cpc classification
A61K31/522
HUMAN NECESSITIES
A61K31/519
HUMAN NECESSITIES
A61P29/00
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
A61K31/5377
HUMAN NECESSITIES
A61K31/4985
HUMAN NECESSITIES
A61P37/06
HUMAN NECESSITIES
A61K31/55
HUMAN NECESSITIES
International classification
A61K31/522
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
A61K31/5377
HUMAN NECESSITIES
A61K31/55
HUMAN NECESSITIES
A61K31/519
HUMAN NECESSITIES
Abstract
The present invention relates to heterocyclic compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs. The invention also relates to processes for the preparation of the compounds of invention, pharmaceutical compositions containing the compounds and their use as selective Bruton's Tyrosine Kinase (BTK) inhibitors. ##STR00001##
Claims
1. Compound having the structure of general formula (I) ##STR00299## and their pharmaceutically acceptable salts, enantiomers and their diastereomers, Bicyclic ring A-B is selected from the group consisting of: ##STR00300## Wherein R.sub.2 is selected from the following ring system: ##STR00301## ##STR00302## R.sub.3 at each occurrence is independently selected from C(O)NH(C.sub.1-7)alkyl, C(O)—CH═CH.sub.2, C(O)—CH≡C—R.sub.11, C(O)—CH═CH—R.sub.4, C(O)—C(CN)═CH.sub.2, C(O)—C(CN)═CH—R.sub.4, SO.sub.2—NH(C.sub.1-7)alkyl, SO.sub.2—CH═CH.sub.2, SO.sub.2—CH═CH—R.sub.4 groups; wherein, R.sub.11 is independently selected from hydrogen and alkyl group; R.sub.4 at each occurrence is selected from —(CH.sub.2)n-NR.sub.5R.sub.6; wherein, n=0-7 and each of R.sub.5 and R.sub.6 are independently selected from hydrogen, haloalkyl, C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.2-7 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(C.sub.1-7)alkyl, heterocycloalkyl(C.sub.1-7)alkyl; ‘U’ is selected from unsubstituted or substituted groups selected from heteroaryl, heterocycle, heterocycloalkyl, aryloxyaryl, aryloxyalkyl, aryloxyheteroaryl, heteroaryloxyaryl, heteroaryloxyalkyl, heteroaryloxyheteroaryl, Ph-CO—N(R.sub.7R.sub.8), Ph-N(R.sub.9)—CO—R.sub.10, wherein, R.sub.7, R.sub.8 and R.sub.10 are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, aryl, cycloalkyl, heteroaryl, heterocycloalkyl and wherein each of the alkyl, haloalkyl, alkoxy, aryl, cycloalkyl, heteroaryl, heterocycloalkyl groups are when substituted are further substituted with halogen, alkyl, alkoxy, haloalkoxy groups; R.sub.9 are independently selected from hydrogen, C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.2-7 alkynyl.
2. A compound as claimed in claim 1 selected from the group comprising of: 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(dibenzo[b,d]furan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; N-(6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide; 1-(5-(4-amino-3-(2-methoxybenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-yn-1-one; 1-(5-(4-amino-3-(3-methoxy-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide; 1-(5-(4-amino-3-(2-phenylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d] [1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 3-(4-phenoxyphenyl)-1-(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; (E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; 1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; (E)-2-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-3-cyclopropylacrylonitrile; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(4-methylpyridin-2-yl)benzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide; N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)picolinamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(benzo[d]thiazol-2-yl)benzamide; N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)pyrazine-2-carboxamide; 1-(5-(4-amino-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide; N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)benzamide; 1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; Z)-methyl 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzimidate; 6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)nicotinamide; 1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide; 1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; (E)-1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide; (Z)-methyl 4-(4-amino-1-(2-((E)-4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzimidate; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; 1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; (E)-1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide; (E)-1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; or (E)-1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one.
3. A compound as claimed in claim 1 selected from the group comprising of: 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(5-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(dibenzo[b,d]furan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; N-(6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide; 1-(5-(4-amino-3-(2-methoxybenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-yn-1-one; 1-(5-(4-amino-3-(3-methoxy-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide; 1-(5-(4-amino-3-(2-phenylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 3-(4-phenoxyphenyl)-1-(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; (E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; 1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; (E)-2-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-3-cyclopropylacrylonitrile; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(4-methylpyridin-2-yl)benzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide; N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)picolinamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(benzo[d]thiazol-2-yl)benzamide; N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)pyrazine-2-carboxamide; 1-(5-(4-amino-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide; N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)benzamide; 1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; Z)-methyl 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzimidate; 6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)nicotinamide; 1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide; 1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; (E)-1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide; (Z)-methyl 4-(4-amino-1-(2-((E)-4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzimidate; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; 1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; (E)-1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide; (E)-1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one; 2-acryloyl-5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-dihydrocyclopenta[c]pyrrole-4,6(1H,5H)-dione; 2-acryloyl-5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrole-1,3 (2H,4H)-dione; 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2-en-1-one; 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6-tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1l-yl)-4, 5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-6-azabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one; N-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen-2-yl)acrylamide; 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1l-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-isoindol-2(3H)-yl)prop-2-en-1-one; 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6-tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en-1-one; 1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1l-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one; 1-(7-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1l-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one; 1-(7-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1l-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one; 1-(7-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one; 2-acryloyl-5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3-dihydrocyclopenta[c]pyrrole-4,6(1H,5H)-dione; 2-acryloyl-5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrole-1,3 (2H,4H)-dione; 1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2-en-1-one; 1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6-tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4, 5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one; 1-(3-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-6-azabicyclo[3.2.0]heptan-6-yl)prop-2-en-1-one; N-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen-2-yl)acrylamide; 1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-isoindol-2(3H)-yl)prop-2-en-1-one; 1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,5,6-tetrahydrocyclopenta[b]pyrrol-1(4H)-yl)prop-2-en-1-one; 1-(4-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one; 1-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one; 1-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one; 1-(7-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[b]pyridin-1-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one; N-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen-2-yl)acrylamide; 1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)prop-2-en-1-one; 1-(6-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)prop-2-en-1-one 1-(6-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)prop-2-en-1-one; N-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen-2-yl)acrylamide; 1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)prop-2-en-1-one; N-(6-(1-(2-acryloyl-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide; N-(6-(1-(2-acryloyloctahydro-1H-cyclopenta[c]pyridin-6-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide; N-(5-(3-(2-acetamidobenzo[d]thiazol-6-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydropentalen-2-yl)acrylamide; (E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5,6-dihydrocyclopenta[c]pyrrol-2(1H,3H,4H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydro-1H-cyclopenta[c]pyridin-2(3H)-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(6-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azabicyclo[3.2.0]heptan-3-yl)-4-(dimethylamino)but-2-en-1-one; (E)-1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4,6,7-tetrahydro-1H-cyclopenta[c]pyridin-2(5H)-yl)-4-(dimethylamino)but-2-en-1-one; 1-(5-(4-amino-3-(4-benzoylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-phenylbenzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-N-phenylbenzamide 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-phenylbenzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N,2-dimethyl-N-phenylbenzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-methyl-N-phenylbenzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-N-(pyridin-2-yl)benzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(pyridin-2-yl)benzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-N-(4-methylpyridin-2-yl)benzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; 4-(1-(2-acryloyl-1,2,3,4, 5,6-hexahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide; 4-(1-(1-acryloyloctahydrocyclopenta[b]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide; 4-(4-amino-1-(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide; (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide; (E)-4-(4-amino-1-(2-(4-(cyclopropyl(methyl)amino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide; (Z)-4-(4-amino-1-(2-(2-cyano-3-cyclopropylacryloyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-phenylbenzamide; 1-(5-(4-amino-3-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(5-chloropyridin-2-yl)benzamide; 1-(5-(4-amino-3-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-(piperidin-1-ylmethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-((tetrahydrofuran-2-yl)oxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-(1-morpholinoethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-(pyrrolidin-1-ylmethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-((dimethylamino)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)acetamide; 1-(5-(4-amino-3-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 2-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)isoindoline-1,3-dione; 1-(5-(4-amino-3-(4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-(azepan-1-ylmethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-((hexahydro-1H-isoindol-2(3H)-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-(thiomorpholinomethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; 1-(5-(4-amino-3-(4-((1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one; or 2-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzyl)isoindolin-1-one.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as claimed in claim 1 and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.
5. A method of treating autoimmune and/or allergic disorders selected from rheumatoid arthritis, systemic lupus erythromatosis, scleroderma, asthma, allergic rhinitis, allergic eczema, B-cell lymphoma, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, graft versus host disease, psoriatic arthritis, ankylosing spondylitis and uveritis, B cell lymphoma, multiple sclerosis, diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia and B-cell prolymphocytic leukemia, the method comprising: administering to a patient in need the compound of Formula (I) of claim 1, and a suitable pharmaceutically acceptable agent selected from anti-cancer and anti-inflammatory agents or their pharmaceutically acceptable salts for the treatment of the autoimmune and/or allergic disorders.
6. A method of treating autoimmune and/or allergic disorders selected from rheumatoid arthritis, systemic lupus erythromatosis, scleroderma, asthma, allergic rhinitis, allergic eczema, B-cell lymphoma, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, graft versus host disease, psoriatic arthritis, ankylosing spondylitis and uveritis, B cell lymphoma, multiple sclerosis, diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia and B-cell prolymphocytic leukemia, the method comprising: administering to a patient in need the pharmaceutical composition of claim 4, and a suitable pharmaceutically acceptable agent selected from anti-cancer and anti-inflammatory agents or their pharmaceutically acceptable salts for the treatment of autoimmune and/or allergic disorders.
Description
DESCRIPTION OF THE INVENTION
(1) Accordingly, the present invention relates to the compounds of the general formula (I) represented below and their pharmaceutically acceptable salts, enantiomers and their diastereomers;
(2) ##STR00002##
(3) Wherein, V, W, X, Y & Z independently represents, ‘C’ or ‘N’; R.sub.1, represents groups selected from hydrogen, keto, halogen, unsubstituted or substituted groups selected from cyano, alkyl, haloalkyl, aryl, alkoxy, acyloxy, aryloxy, arylalkyl, heteroaryl, heterocyclyl, heterocycloalkyl, cycloalkyl, cycloalkylalkyl, aryloxyaryl, aryloxyalkyl, aryloxyheteroaryl groups;
(4) R.sub.2 represent the following ring system:
(5) ##STR00003## ##STR00004##
(6) Wherein R.sub.3 at each occurrence is independently selected from hydrogen, haloalkyl, C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.2-7 alkynyl, aryl, cycloalkyl, heterocycloalkyl, cycloalkyl(C.sub.1-7)alkyl, heterocycloalkyl(C.sub.1-7)alkyl, C(O)NH(C.sub.1-7)alkyl, C(O)—CH═CH.sub.2, C(O)—CH═CH—R.sub.4, C(O)—C(CN)═CH.sub.2, C(O)—C(CN)═CH—R.sub.4, SO.sub.2—NH(C.sub.1-7)alkyl, SO.sub.2—CH═CH.sub.2, SO.sub.2—CH═CH—R.sub.4 groups;
(7) R.sub.4 is selected from —(CH.sub.2)n-NR.sub.5R.sub.6; wherein, n=0-7 and each of R.sub.5 and R.sub.6 are independently selected from hydrogen, haloalkyl, C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.2-7 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(C.sub.1-7)alkyl, heterocycloalkyl(C.sub.1-7)alkyl; ‘U’ represent unsubstituted or substituted groups selected from alkyl, alkenyl, alkynyl, alkoxy, acyloxy, aryl, aryloxy, arylalkyl, cycloalkyl, cycloalkylalkyl, biaryl, heteroaryl, heterocycle, heterocycloalkyl, O-aryl, O-cycloalkyl, O-heteroaryl, O-heterocycle, O-heterocycloalkyl, aryloxyaryl, aryloxyalkyl, aryloxyheteroaryl, heteroaryloxyaryl, heteroaryloxyalkyl, heteroaryloxyheteroaryl, Ph-CO—N(R.sub.7R.sub.8), Ph-N(R.sub.9)—CO—R.sub.10, wherein, R.sub.7, R.sub.8 and R.sub.10 are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy; aryl, cycloalkyl, heteroaryl, heterocycloalkyl; further substituted with halogen, alkyl, alkoxy, haloalkoxy groups and R.sub.9 are independently selected from hydrogen, C.sub.1-7 alkyl, C.sub.2-7 alkenyl, C.sub.2-7 alkynyl.
(8) In a preferred embodiment, the groups, radicals described above may be selected from:
(9) “Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means a carbon chain which may further be substituted with an oxygen atom as is well understood by a skilled artisan, which may further be either linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl group include but not are limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.-butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C.sub.3-10, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, C.sub.1-6 is intended.
(10) “Alkenyl” means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkenyl include vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl etc. Where the specified number of carbon atoms permits, e. g., from C.sub.5-10, the term alkenyl also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, C.sub.(2-6) is intended.
(11) “Alkynyl” means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl etc. When no number of carbon atoms is specified, C.sub.(2-6) is intended.
(12) As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). In a broader perspective, the term carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues;
(13) “Cycloalkyl” is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclic unless otherwise stated. Cycloalkyl groups are saturated unless and otherwise stated.
(14) The “alkoxy” refers to the straight or branched chain alkoxides of the number of carbon atoms specified.
(15) “Aryl” means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
(16) The terms “Heterocycle” or “heterocyclyl” refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S, N further optionally including the oxidized forms of sulfur, namely SO & SO.sub.2. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, etc. The term “heterocycloalkyl” refers to a heterocyclic group as defined above connected to an alkyl group as defined above;
(17) “Heteroaryl” means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to the other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic. Examples of heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl etc. For heterocyclyl and heteroaryl groups, rings and ring systems containing from 3-15 carbon atoms are included, forming 1-3 rings.
(18) An “aryloxy” group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenyloxy, and the like;
(19) “Cycloalkylalkyl” means an alkyl radical substituted with cycloalkyl group as defined herein. cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
(20) An “arylalkyl” group as used herein is an aromatic substituent that is linked to an alkyl group having from one to about six carbon atoms. examples of arylalkyl groups include benzyl group, phenethyl and the like.
(21) The “acyloxy” group used either alone or in combination with other radicals, is selected from a suitable acyl group, directly attached to an oxygen atom; more preferably such groups are selected from acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy and the like;
(22) The term “Haloalkyl” means a alkyl structure in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another.
(23) In certain other embodiment in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.
(24) “Aryloxyalkyl” means an alkyl radical substituted with aryloxy group as defined herein.
(25) “Aryloxyaryl” means an aryl radical substituted with aryloxy group as defined herein.
(26) “Aryloxyheteroaryl” means a heteroaryl radical substituted with aryloxy group as defined herein.
(27) “Halo/Halogen” refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.
(28) Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
(29) The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
(30) “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include mineral or organic acid salts of the basic residues. Such conventional non-toxic salts include those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.
(31) The term ‘optional’ or ‘optionally’ means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not. For example, ‘optionally substituted alkyl’ means either ‘alkyl’ or ‘substituted alkyl’. Further an optionally substituted group includes an unsubstituted group.
(32) Unless otherwise stated in the specification, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
(33) Particularly useful compounds may be selected from the following:
(34) TABLE-US-00001 TABLE 1 Compd Structures IUPAC Names 1
or pharmaceutically acceptable salts of any of the compounds above.
Following is a list of abbreviations used in the description of the preparation of the compounds of the present invention:
ALL: Acute lymphoblastic leukemia
ATP: Adenosine triphosphate
BTK: Bruton's Tyrosine Kinase
bs: broad singlet
CLL: Chronic lymphocytic leukemia
CDCl.sub.3: Deuterated chloroform
CHCl.sub.3: Chloroform
d: doublet
dd: doublet of doublet
dt: doublet of triplet
DCM: Dichloromethane
DMAC: N,N-(Dimethylacetamide)
DMAP: 4-(Dimethylamino) pyridine
DMF: N,N-Dimethyl formamide
DMSO: Dimethyl sulfoxide
EDTA: Ethylenediaminetertraacetic acid
EtOAc: Ethyl acetate
EtOH: Ethanol
HCl(g): Hydrogen chloride (gas)
K.sub.2CO.sub.3: Potassium carbonate
MeOH: Methanol
m: multiplet
mmol: millimoles
□g: microgram
MS: Mass spectrum
NHL: Non-Hodgkin's lymphoma
Na.sub.2CO.sub.3: Sodium carbonate
ng: nanogram
NIS: N-iodosuccinimide
.sup.1H NMR: Proton nuclear magnetic resonance
Pet ether: Petroleum ether, boiling range (60-80° C.)
POCl.sub.3: Phosphorylchloride
s: singlet
t: Triplet
td: triplet of doublet
THF: Tetrahydrofuran
TLC: Thin layer chromatography
The novel compounds of the present invention can be prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.
(35) The reactions can be performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being affected. Preferred methods include those described below, where all symbols are as defined earlier unless and otherwise defined below.
(36) The compounds of the formula (I) can be prepared as described in schemes below along with suitable modifications/variations which are well within the scope of a person skilled in the art.
(37) ##STR00062##
(38) Wherein ‘U’, R.sub.2 and R.sub.3 are as defined earlier. Compound of formula (I) can be prepared by variety of methods familiar to those skilled in art. Compound of formula (i) was transformed into compound (ii) by reacted with hydrazine hydrate (Scheme-I). Compound of formula (ii) was cyclized using formamide to afford the compound of formula (iii). Compound (iii) was reacted with N-iodosuccinimide to get compound (iv). Compound (iv) reacted with compound (v) using different base to furnish the compound of formula (vi). Compound (vi) can subjected to Suzuki type of reaction, with compound (vii) using suitable catalysts, base and appropriate solvents to obtain compound of formula (viii). The deprotection of compound (viii) gives compound (ix). Compound (ix) is reacted with optionally substituted acid chlorides (x) to obtain compounds of formula (I).
(39) The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
(40) The compounds of formula (I) may also be synthesized as described in Scheme II. wherein ‘U’, R.sub.2 and R.sub.3 are as defined earlier. Compound (i) may be continently prepared by variety of methods familiar to those skilled in art. Compound (i) was transformed into compound (ii) by reacting with dibenzyl amine using different bases. Compound of formula (ii) was reacted with different protected cycloalkyl amines (iii) using suitable bases to furnish compound (iv). Compound (iv) was reduced to amine to afford the compound (v). Compound (v) was reacted with Triphosgene to get the compound (vi). Compound (vi) was deprotected to using Pd(OH).sub.2 to afford compound (vii). Compound (vii) was reacted with different Boronic acid to obtain compound (viii). Compound (viii) was deproted using suitable acid to get the compound (ix). Compound (ix) was reacted with optionally substituted acid chlorides using base to obtain compound of formula (I).
(41) ##STR00063##
(42) The compounds of formula (I) may also be synthesized as described in Scheme III. wherein ‘U’, R.sub.2 and R.sub.3 are as defined earlier. Compound (i) may be continently prepared by variety of methods familiar to those skilled in art. Compound (i) was transformed into compound (ii) using Ammonia. Compound (ii) reacted with compound (iii) using different base to furnish the compound of formula (iv). Compound (iv) can be subjected to Suzuki type of reaction, with compound (v) using suitable catalysts, base and appropriate solvents to obtain compound of formula (vi). Compound (vi) can be halogenated to afford compound (vii). The deprotection of compound (vii) gives compound (viii). Compound (viii) is reacted with optionally substituted acid chlorides to obtain compounds of formula (I).
(43) ##STR00064##
(44) Compounds of the present invention can be isolated either as free amine form or as a salt corresponding to the acid used such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, oxalic acid, maleic acid, fumeric acid, succinic acid, p-toluene sulfonic acid or benzene sulfonic acid. The compounds can be purified where ever required, by recrystallization, trituration, precipitation, preparative thin layer chromatography, flash chromatography or by preparative HPLC method. The compounds of the present invention can be used either alone or in combination with one or more therapeutic agents or pharmaceutically acceptable salts thereof. Such use will depend on the condition of the patient being treated and is well within the scope of a skilled practitioner.
(45) The invention is further illustrated by the following examples which describe the preferred way of carrying out the present invention. These are provided without limiting the scope of the present invention in any way.
(46) .sup.1H NMR spectral data given in the examples (vide infra) are recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and reported in 6 scale. Until and otherwise mentioned the solvent used for NMR is CDCl.sub.3 using TMS as the internal standard.
Example: 1
Synthesis of 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one (compound No: 1)
(47) Synthesis of titled compound was carried out, as described in Scheme-IV and step-wise procedure is described below.
(48) ##STR00065##
Step-1: Synthesis of tert-butyl 5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta [c]pyrrole-2(1H)-carboxylate (3)
(49) ##STR00066##
(50) Intermediate 1 (2.0 g, 7.66 mmol), prepared as per general process disclosed in US 2012/0088912 and triphenylphosphine (6.53 g) were mixed together, in THF (20 mL). Tert-butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 2 (3.47 g, 15.32 mmol) was added to the mixture followed by the addition of diisopropyl diazodicarboxylate (2.26 mL, 11.49 mmol). The reaction mixture was stirred at room temperature overnight, filtered and concentrated. The residue obtained was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH=98/2) to get intermediate 3 as a white solid (2.75 g, 76% Yield). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 1.40 (s, 9H), 1.94-2.00 (m, 2H), 2.17-2.24 (m, 2H), 2.82-3.00 (m, 2H), 3.10-3.14 (m, 2H), 3.45-3.50 (m, 2H), 5.27-5.30 (m, 1H), 8.29 (s, 1H). MS (ESI-MS): m/z 471.10 (M+H).sup.+.
Step-2: Synthesis of tert-butyl5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (5)
(51) ##STR00067##
(52) To a stirred solution Intermediate 3 (2.7 g, 5.74 mmol), dissolved in dry DMF (27 mL), PdCl.sub.2(PPh.sub.3).sub.2(0.4 g, 0.57 mmol), 4-phenoxyphenylboronicacid 4 (1.84 g, 8.61 mmol) and KHCO.sub.3 (3.44 g, 34.46 mmol) was added. The reaction mixture was heated at 90° C. for 2 hrs, under N.sub.2 atmosphere. Mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (2×25 mL) and brine solution (25 mL), dried over Na.sub.2SO.sub.4, and concentrated to dryness. The residue obtained was purified by column chromatography (using 0-5% methanol in DCM as a mobile phase) to obtain Intermediate 5 as an off white solid (2.2 g, 74% Yield). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 1.48 (s, 9H), 1.98-2.04 (m, 2H), 2.27-2.34 (m, 2H), 2.89 (s, 2H), 3.13-3.17 (m, 2H), 3.47 (q, 2H, J=8.0 Hz), 5.36 (q, 1H, J=8.0 Hz), 7.10-7.14 (m, 4H), 7.144-7.20 (m, 1H), 7.40-7.43 (m, 2H), 7.65-7.68 (m, 2H), 8.23 (s, 1H). ESI-MS (ESI-MS): m/z 535.23 (M+Na).sup.+.
Step-3: Synthesis of 1-(octahydrocyclopenta[c]pyrrol-5-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6)
(53) ##STR00068##
(54) To a solution of Intermediate 5 (2.1 g, 4.09 mmol) in CH.sub.2Cl.sub.2 (40 mL) was added TFA (1.25 mL, 16.37 mmol). After stirring 2 hrs at room temperature, the solvent was removed and the residues were dissolved in a mixture of ethyl acetate (50 mL) and dilute aq. K.sub.2CO.sub.3. The organic layer was separated, dried over MgSO.sub.4, filtered and concentrated to provide Intermediate 6 as a white solid (1.2 g, 71% Yield). .sup.1H NMR (400 MHz) δ ppm: 1.92-1.96 (m, 2H), 2.31-2.39 (m, 2H), 2.74-2.78 (m, 2H), 2.89-2.30 (m, 2H), 3.12-3.20 (m, 2H), 5.43-5.37 (m, 1H), 7.11-7.20 (m, 5H), 7.41-7.45 (m, 2H), 7.64-7.66 (m, 2H), 8.24 (s, 1H); MS (ESI-MS): m/z 413.20 (M+H).sup.+.
Step-4: Synthesis of 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one, compound No: 1
(55) ##STR00069##
(56) To a solution of Intermediate 6 (1.1 g, 2.66 mmol), dissolved in CH.sub.2Cl.sub.2 (30 mL), tri-ethyl amine (1.11 mL, 8.00 mmol) was added followed by addition of acryl chloride (0.2 mL, 2.53 mmol). The reaction was stopped after 2 hrs. The reaction mixture was washed with water and then with brine. The organic layer was separated, dried over MgSO.sub.4, filtered and concentrated. Residue obtained was purified by flash chromatography (using CH.sub.2Cl.sub.2/MeOH=25/1, as a mobile phase) to get compound 1 as a white solid (0.75 g, 60% Yield). .sup.1H NMR: (CDCL.sub.3, 400 MHz): δ 8.36 (S, 1H), 7.66-7.62 (m, 2H), 7.37-7.41 (m, 2H), 7.13-7.20 (s, 3H), 7.07-7.09 (m, 2H), 6.36-6.50 (m, 2H), 5.68-5.71 (m, 1H), 5.53-5.59 (m, 3H), 3.82-3.87 (m, 2H), 3.45-3.53 (m, 2H), 3.10-3.21 (m, 2H), 2.50-2.58 (m, 2H), 2.11-2.17 (m, 2H); ESI-MS: (+ve mode) 467.20 (M+H).sup.+ (100%); UPLC: 98.09%.
Example: 2
Synthesis of 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide (compound No: 13)
(57) Synthesis of titled compound was carried out, as described in Scheme-V and step-wise procedure is described below.
(58) ##STR00070##
Step-1: Synthesis of tert-butyl 5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocylcopenta[c]pyrrole-2(1H)-carboxylate (3)
(59) ##STR00071##
(60) Intermediate 1 (0.22 g, 0.851 mmol) and triphenylphosphine (0.71 g) were mixed together in THF (10 mL). Tert-butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 2 (0.38 g, 1.7 mmol) was added to the reaction mixture followed by the addition of diisopropyl diazodicarboxylate (0.24 mL, 1.22 mmol). The reaction mixture was stirred at room temperature overnight, filtered and concentrated. The residue obtained was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH=98/2) to get intermediate 3 as a white solid (0.3 g, 76% Yield). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 1.40 (s, 9H), 1.94-2.00 (m, 2H), 2.17-2.24 (m, 2H), 2.82-3.00 (m, 2H), 3.10-3.14 (m, 2H), 3.45-3.50 (m, 2H), 5.27-5.30 (m, 1H), 8.29 (s, 1H). MS (ESI-MS): m/z 471.10 (M+H).sup.+.
Step-2: Synthesis of tert-butyl 5-(4-amino-3-(4-(pyridin-2-ylcarbamoyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (5)
(61) ##STR00072##
(62) To a stirred solution of intermediate 3 (0.3 g, 0.638 mmol), dissolved in dry DMF (3 mL) were added PdCl.sub.2(PPh.sub.3).sub.2(0.089 g, 0.127 mmol), (4-(pyridin-2-ylcarbamoyl)phenyl)boronic acid 4 (0.31 g, 0.95 mmol) and KHCO.sub.3 (0.340 g, 3.56 mmol). The reaction mixture was heated at 90° C. for 2 hrs, under N.sub.2 atmosphere. Mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (2×25 mL) and brine solution (25 mL), dried over Na.sub.2SO.sub.4 and concentrated to dryness. The residue obtained was purified by column chromatography (silica gel, 0-5% methanol in DCM) to obtain intermediate 5 as an off white solid (0.25 g, 72.56% Yield). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 1.59 (s, 9H), 2.11-2.17 (m, 2H), 2.49-2.57 (m, 2H), 3.07-3.09 (m, 2H), 3.28 (bs, 2H), 3.64 (bs, 2H), 5.55 (q, 1H, J=8.0 Hz), 7.11 (q, 1H, J=8.0 Hz), 7.78-7.81 (m, 1H), 7.82 (m, 2H), 8.10 (d, 2H, J=8.0 Hz), 8.35 (m, 1H), 8.41-8.43 (m, 2H), 8.63 (s, 1H). ESI-MS (ESI-MS): m/z 541.41 (M+H).sup.+.
Step-3: Synthesis of 4-(4-amino-1-(octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide (6)
(63) ##STR00073##
(64) To a solution of Intermediate 5 (0.25 g, 0.462 mmol) in CH.sub.2Cl.sub.2 (10 mL), TFA (1.0 mL, 15.87 mmol) was added and the reaction mixture was stirred for 2 hrs at room temperature. The solvent was removed and the residue obtained was dissolved in a mixture of ethyl acetate (50 mL) and dilute aq. K.sub.2CO.sub.3. The organic layer was dried over MgSO.sub.4, filtered and concentrated to get Intermediate 6 as a white solid (0.13 g, 63.85% Yield). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 1.15-1.23 (m, 2H), 2.32-2.37 (m, 2H), 2.54-2.58 (m, 2H), 2.93-2.97 (m, 2H), 3.24-3.29 (m, 2H), 5.33-5.37 (m, 1H), 7.16-7.19 (m, 1H), 7.77 (q, 2H, J=12.0 Hz), 7.84-7.88 (m, 1H), 8.18-8.20 (m, 2H), 8.22-8.24 (m, 1H), 8.25-8.30 (m, 1H), 8.40-8.41 (m, 1H), 10.83 (s, 1H); MS (ESI-MS): m/z 441.15 (M+H).sup.+.
Step-4: Synthesis of 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide; compound No: 13
(65) ##STR00074##
(66) To a solution of Intermediate 6 (0.13 g, 0.295 mmol), dissolved in CH.sub.2Cl.sub.2 (30 mL) and tri-ethyl amine (0.090 g, 0.886 mmol), acryl chloride (0.026 g, 0.295 mmol) was added and the reaction mixture was stirred for 2 hrs. The reaction mixture was washed with water and brine solution. The organic layer was dried over MgSO.sub.4, filtered, concentrated and residue obtained was purified by flash chromatography, using CH.sub.2Cl.sub.2/MeOH (25/1) to get compound 13 as a white solid (0.03 g, 20.58% Yield). .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 8.72 (s, 1H), 8.43 (d, 1H, J=6.4 Hz), 8.39 (s, 1H), 8.35-8.34 (m, 1H), 8.13 (d, 2H, J=8.4 Hz), 7.88 (d, 2H, J=8.4 Hz), 7.83-7.79 (m, 1H), 7.14-7.11 (m, 1H), 6.49 (dd, 1H, J.sub.1=10.0 Hz, J.sub.2=16.8 Hz), 6.42 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=16.8 Hz), 5.72 (dd, 1H, J.sub.1=2.8 Hz, J.sub.2=10.0 Hz), 5.61-5.55 (m, 3H), 3.89-3.84 (m, 2H), 3.57-3.47 (m, 2H), 3.24-3.21 (m, 1H), 315-3.12 (m, 1H), 2.60-2.52 (m, 2H), 2.21-2.14 (m, 1H); ESI-MS: (+ve mode) 495.4 (M+H).sup.+ (100%); HPLC: 99.09.
Example: 3
Compound 2: (1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(67) ##STR00075##
(68) .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 9.11 (s, 1H), 8.41 (s, 1H), 8.34-8.30 (m, 2H), 7.87 (dd, 1H, J.sub.1=1.6 Hz, J.sub.2=8.4 Hz), 6.49 (dd, 1H, J.sub.1=9.6 Hz, J.sub.2=16.8 Hz), 6.42 (dd, 1H, J.sub.1=2.8 Hz, J.sub.2=16.8 Hz), 5.72 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=9.6 Hz), 5.64-5.57 (m, 1H), 5.50 (bs, 2H), 3.89-3.84 (m, 2H), 3.57-3.47 (m, 2H), 3.25-3.20 (m, 1H), 3.17-3.11 (m, 1H), 2.62-2.54 (m, 2H), 2.22-2.13 (m, 2H); ESI-MS: (+ve mode) 431.9 (M+H).sup.+ (100%); HPLC: 96.04%.
Example: 4
Compound 3: 1-(5-(5-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one
(69) ##STR00076##
(70) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.27 (S, 1H), 8.11-8.09 (m, 1H), 7.63-7.61 (m, 2H), 7.44-7.40 (m, 1H), 7.48-7.44 (m, 2H), 7.19-7.17 (m, 1H), 7.13-7.09 (m, 5H), 6.56-6.49 (m, 1H), 6.44-6.41 (m, 1H), 6.11-6.06 (m, 1H), 5.64-5.61 (m, 1H), 5.39 (s, 2H), 4.41-4.39 (m, 2H), 3.81-3.80 (m, 1H), 3.64-3.57 (m, 2H), 3.46-3.45 (m, 2H), 3.19-3.16 (m, 2H); ESI-MS: (+ve mode) 559.35 (M+H).sup.+ (100%); HPLC: 95.82%.
Example: 5
Compound 4: 1-(5-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)prop-2-en-1-one
(71) ##STR00077##
(72) .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 8.37 (s, 1H), 7.65 (dd, 2H, J.sub.1=2.0 Hz, J.sub.2=6.4 Hz), 7.40 (t, 2H, J=4.4 Hz), 7.18-7.13 (m, 3H), 7.09 (d, 2H, J=7.6 Hz), 6.37-6.27 (m, 2H), 5.61 (dd, 1H, J.sub.1=3.6 Hz, J.sub.2=9.2 Hz), 5.41 (bs, 2H), 3.79-3.68 (m, 2H), 3.35 (dd, 1H, J.sub.1=4.8 Hz, J.sub.2=12.8 Hz), 3.27 (dd, 1H, J.sub.1=4.8 Hz, J.sub.2=10.4 Hz), 3.08-3.05 (m, 1H), 2.96 (t, 1H, J=6.0 Hz), 2.89-2.86 (m, 1H), 2.77-2.75 (m, 1H), 2.70-2.57 (m, 4H); ESI-MS: (+ve mode) 496.15 (M+H).sup.+ (100%); HPLC: 96.62%.
Example: 6
Compound 5: 1-(5-(4-amino-3-(2-methylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(73) ##STR00078##
(74) .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 8.40 (s, 1H), 8.19 (d, 1H, J=2.0 Hz), 8.12 (d, 1H, J=8.4 Hz), 7.77 (dd, 1H, J.sub.1=2.0 Hz, J.sub.2=8.4 Hz), 6.49 (dd, 1H, J.sub.1=10.0 Hz, J.sub.2=16.8 Hz), 6.42 (dd, 1H, J.sub.1=2.8 Hz, J.sub.2=16.8 Hz), 5.72 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=9.6 Hz), 5.61-5.57 (m, 1H), 5.31 (bs, 2H), 3.89-3.83 (m, 2H), 3.56-3.47 (m, 2H), 3.24-3.22 (m, 1H), 3.14-3.12 (m, 1H), 2.91 (s, 3H), 2.59-2.55 (m, 2H), 2.19-2.14 (m, 2H); ESI-MS: (+ve mode) 446.0 (M+H).sup.+ (100%); HPLC: 95.09%.
Example: 7
Compound 6: 1-(5-(4-amino-3-(benzo[b]thiophen-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(75) ##STR00079##
(76) .sup.1H NMR: (DMSO, 400 MHz): δ 8.24 (s, 1H), 8.16 (dd, 2H, J.sub.1=6.0 Hz, J.sub.2=4.4 Hz), 7.85 (d, 1H, J=5.6 Hz), 7.65 (dd, 1H, J=8.4 Hz, J.sub.2=1.6 Hz), 7.56 (d, 1H, J=5.2 Hz), 7.62 (dd, 1H, J.sub.1=10.4 Hz, J.sub.2=16.8 Hz), 6.14 (dd, 1H, J.sub.1=16.8 Hz, J.sub.2=2.4 Hz), 5.67 (dd, 1H, J.sub.1=10.0 Hz, J.sub.2=2.4 Hz), 5.45-5.41 (m, 1H), 3.81-3.76 (m, 1H), 3.66-3.60 (m, 1H), 3.54-3.50 (m, 1H), 3.42-3.35 (m, 1H), 3.00-3.08 (m, 1H), 23.00-2.98 (m, 1H), 2.38-2.31 (m, 2H), 2.09-2.04 (m, 2H); ESI-MS: (+ve mode) 431.0 (M+H).sup.+ (100%), 453.2 (M+Na).sup.+ (25%); UPLC: 98.53%.
Example: 8
Compound 7: 1-(5-(4-amino-3-(2,3-dihydrobenzo[b]thiophen-5-yl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(77) ##STR00080##
(78) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 8.22 (s, 1H), 7.55-7.51 (m, 2H), 7.42-7.38 (m, 2H), 6.65-6.58 (m, 1H), 6.16-6.11 (dd, 1H, J.sub.1=2.8 Hz, J.sub.2=17.2 Hz), 5.68-5.66 (m, 1H), 5.64-5.39 (m, 1H), 3.42-3.40 (m, 1H), 3.39-3.37 (m, 1H), 3.35-3.35 (m, 1H), 3.32-3.30 (m, 3H), 3.10-2.83 (m, 2H), 2.82-2.80 (m, 2H), 2.33-2.29 (m, 3H), 2.04-2.03 (m, 2H); (ESI-MS): (+ve mode) 433.05 (M+H).sup.+. (100%), UPLC: 95.80%.
Example: 9
Compound 8: 1-(5-(4-amino-3-(dibenzo[b,d]furan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(79) ##STR00081##
(80) .sup.1H NMR: (DMSO, 400 MHz): δ 8.30-8.28 (m, 1H), 8.26 (s, 1H), 8.22-8.20 (m, 1H), 7.92 (d, 1H, J=0.8 Hz), 7.75-7.69 (m, 2H), 7.58-7.54 (m, 1H), 7.46-5.43 (m, 1H), 6.66-6.59 (m, 1H), 6.14 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=16.8 Hz), 5.67 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=10.4 Hz), 5.46-5.43 (m, 1H), 3.82-3.77 (m, 1H), 3.65-3.61 (m, 1H), 3.55-3.51 (m, 1H), 3.39-3.35 (m, 1H), 3.17-2.92 (m, 2H), 2.41-2.33 (m, 2H), 2.11-2.05 (m, 2H); ESI-MS: (+ve mode) 465.1 (M+H).sup.+ (100%), 487.3 (M+Na).sup.+ (10%); UPLC: 95.50.
Example: 10
Compound 9: N-(6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo [3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide
(81) ##STR00082##
(82) .sup.1H NMR: (DMSO, 400 MHz): δ 12.41 (s, 1H), 8.24 (s, 2H), 8.87-8.85 (m, 1H), 7.69-7.67 (m, 1H), 6.65-6.58 (m, 1H), 6.14 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=14.4 Hz), 5.66 (dd, 1H, J.sub.1=1.2 Hz, J.sub.2=10.4 Hz), 5.44-5.41 (m, 1H), 3.81-3.38 (m, 3H), 3.40-3.33 (m, 1H), 3.11-2.99 (m, 2H), 2.50-2.37 (m, 2H), 2.20 (s, 3H), 2.12-1.90 (m, 2H); ESI-MS: (+ve mode) 489.3 (M+H).sup.+ (100%), 511.0 (M+Na)+(10%); UPLC: 95.29%.
Example: 11
Compound 10: 1-(5-(4-amino-3-(2-methoxybenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d] pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(83) ##STR00083##
(84) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 8.23 (s, 1H), 8.17 (s, 1H), 7.79 (m, 1H, J=8.4 Hz), 7.67-7.65 (m, 1H), 6.64-6.58 (m, 1H), 6.30-6.11 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=16.8 Hz), 5.70-5.65 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=10.4 Hz), 5.45-5.42 (m, 1H), 4.19 (s, 3H), 3.80-3.76 (m, 1H), 3.62-3.53 (m, 1H), 3.40-3.38 (m, 1H), 3.10-2.83 (m, 1H), 2.82-2.80 (m, 2H), 2.36-2.32 (m, 2H), 2.06-2.05 (m, 2H); (ESI-MS): (+ve mode) 462.05 (M+H).sup.+. (100%), UPLC: 95.22%, Ret. time=3.09 min.
Example: 12
Compound 11: 1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-yn-1-one
(85) ##STR00084##
(86) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.23 (s, 1H), 7.67-7.64 (m, 2H), 7.44-7.40 (m, 2H), 7.19-7.10 (m, 5H), 5.4 (s, 1H), 4.21-4.18 (m, 1H), 3.83-3.74 (m, 1H), 3.65-3.61 (m, 2H), 3.05-3.03 (m, 2H), 2.34-2.31 (m, 2H), 2.05-2.03 (m, 2H); ESI-MS: (+ve mode) 465.50 (M+H).sup.+ (100%); HPLC: 99.12%.
Example: 13
Compound 12: 1-(5-(4-amino-3-(3-methoxy-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(87) ##STR00085##
(88) .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 8.38 (s, 1H), 7.37-7.33 (m, 3H), 7.22 (dd, 1H, J.sub.1=8.0 Hz, J.sub.2=2.0 Hz), 7.14-7.08 (m, 2H), 7.03 (d, 2H, J=8.0 Hz), 6.51-6.37 (m, 2H), 5.70 (dd, 1H, J.sub.1=10.0 Hz, J.sub.2=2.4 Hz), 5.65 (bs, 2H), 5.60-5.53 (m, 1H), 3.95 (s, 3H), 3.89-3.84 (m, 2H), 3.55-3.51 (m, 2H), 3.24-3.21 (m, 1H) 3.15-3.11 (m, 1H), 2.63-2.54 (m, 2H), 2.21-2.12 (m, 2H); ESI-MS: (+ve mode) 497.1 (M+H).sup.+ (100%), 519.25 (M+Na).sup.+ (50%); UPLC: 95.90%.
Example: 14
Compound 14: 1-(5-(4-amino-3-(2-phenylbenzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(89) ##STR00086##
(90) .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 8.41 (s, 1H), 8.27 (d, 1H, J=1.6 Hz), 8.23 (d, 1H, J=8.0 Hz), 8.15-8.13 (m, 2H), 7.82 (dd, 1H, J.sub.1=8.0 Hz, J.sub.2=2.0 Hz), 7.56-7.53 (m, 3H), 6.52-6.38 (m, 2H), 5.70 (dd, 1H, J.sub.1=10.0 Hz, J.sub.2=2.0 Hz), 5.63-5.59 (m, 1H), 5.49 (bs, 2H), 3.90-3.84 (m, 2H), 3.57-3.48 (m, 2H), 3.25-3.22 (m, 1H), 3.17-3.14 (m, 1H), 2.63-2.55 (m, 2H), 2.22-2.13 (m, 2H); ESI-MS: (+ve mode) 507.6 (M+H).sup.+ (100%), 530.1 (M+Na).sup.+ (30%); UPLC: 97.51%.
Example: 15
Compound 15: 1-(5-(4-amino-3-(benzo[d] [1,3]dioxol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(91) ##STR00087##
(92) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.21 (s, 1H), 7.15-7.13 (m, 1H), 7.12-7.10 (m, 1H), 7.09-7.07 (m, 1H), 6.65-6.58 (m, 1H), 6.16-6.12 (m, 1H), 6.11 (s, 2H), 5.68-5.64 (m, 1H), 5.42-5.35 (m, 1H), 3.83-3.81 (m, 1H), 3.80-3.75 (m, 1H), 3.65-3.60 (m, 1H), 3.50-3.49 (m, 1H), 3.08-3.06 (m, 1H), 2.99-2.96 (m, 1H), 2.36-2.82 (m, 2H), 2.07-2.04 (m, 2H); ESI-MS: (+ve mode) 419.58 (M+H).sup.+ (100%); HPLC: 96.33%.
Example: 16
Compound 16: 1-(5-(4-amino-3-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(93) ##STR00088##
(94) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.25 (s, 1H), 8.13-8.11 (d, 2H, J=8.0 Hz), 7.89-7.87 (d, 2H, J=8.0 Hz), 6.65-6.58 (m, 1H), 6.16-6.11 (dd, 1H, J.sub.1=2.8 Hz, J.sub.2=16.8 Hz), 5.68-6.65 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=20 Hz), 5.46-5.41 (m, 1H), 3.78-3.76 (m, 1H), 3.64-3.61 (m, 1H), 3.54-3.50 (m, 1H), 3.39-3.34 (m, 1H), 3.23-3.08 (m, 1H), 3.07-3.00 (m, 1H), 2.61 (s, 3H), 2.38-2.32 (m, 2H), 2.07-2.05 (m, 2H); ESI-MS: (+ve mode) 457.10 (M+H).sup.+ (100%); UPLC: 95.87%.
Example: 17
Compound 17: 1-(5-(4-amino-3-(benzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(95) ##STR00089##
(96) .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 8.40 (s, 1H), 8.22 (s, 1H), 7.99-7.97 (m, 2H), 7.74-7.72 (m, 1H), 6.47-6.42 (m, 1H), 5.73-5.70 (m, 1H), 5.78-5.60 (m, 2H), 3.86-3.84 (m, 2H), 3.57-3.55 (m, 2H), 3.22-3.19 (m, 2H), 2.56-2.54 (m, 2H), 2.18-2.16 (m, 2H); ESI-MS: (+ve mode) 416.78 (M+H).sup.+ (100%); HPLC: 96.12%.
Example: 18
Compound 18: 3-(4-phenoxyphenyl)-1-(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(97) ##STR00090##
(98) .sup.1H NMR: (DMSO, 400 MHz): δ 8.24 (s, 1H), 7.64 (dd, 2H, J.sub.1=6.8 Hz, J.sub.2=2.0 Hz), 7.44-7.40 (m, 2H), 7.19-7.10 (m, 5H), 6.94-6.87 (m, 1H), 6.21 (d, 1H, J=10.0 Hz), 6.15 (d, 1H, J=16.8 Hz), 5.41-65.30 (m, 1H), 3.29-3.24 (m, 2H), 3.04-3.01 (m, 4H), 2.34-2.32 (m, 2H), 2.10-1.90 (m, 2H); ESI-MS: (+ve mode) 503.15 (M+H).sup.+ (100%); UPLC: 95.16%.
Example: 19
Compound 19: 1-(5-(4-amino-3-(2-phenylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(99) ##STR00091##
(100) .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 8.41 (s, 1H), 8.32-8.30 (m, 2H), 7.96-7.93 (m, 2H), 7.73-7.70 (m, 1H), 7.59-7.57 (m, 3H), 6.52-6.43 (m, 1H), 5.72-5.69 (m, 1H), 5.62-5.59 (m, 1H), 5.50-5.49 (m, 1H), 3.90-3.84 (m, 2H), 3.58-3.48 (m, 2H), 3.23-3.19 (m, 2H), 2.60-2.58 (m, 2H), 2.20-2.17 (m, 2H); ESI-MS: (+ve mode) 492.35 (M+H).sup.+ (100%); HPLC: 95.63%.
Example: 20
Compound 20: 1-(5-(4-amino-3-(2-phenoxybenzo[d]thiazol-6-yl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(101) ##STR00092##
(102) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 8.22 (s, 1H), 7.82 (d, 1H, J=8.4 Hz), 7.70-7.68 (m, 1H), 7.56-7.53 (m, 2H), 7.49-7.47 (m, 2H), 7.42-7.40 (m, 1H), 6.65-6.61 (m, 1H), 6.16 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=14.4 Hz), 5.68 (dd, 1H, J1=2.4 Hz, J.sub.2=10.4 Hz), 5.64-5.40 (m, 1H), 3.58-3.50 (m, 1H), 3.38-3.36 (m, 1H), 3.35-3.33 (m, 1H), 3.25-2.84 (m, 2H), 2.82-2.80 (m, 2H), 2.36-2.32 (m, 2H), 2.08-2.00 (m, 2H); (ESI-MS): (+ve mode) 524.15 (M+H).sup.+. (100%), UPLC: 95.74%.
Example: 21
Compound 21: 1-(5-(4-amino-3-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(103) ##STR00093##
(104) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 8.38 (s, 1H), 7.86-7.83 (m, 1H), 7.71-7.70 (m, 3H), 7.69-7.63 (m, 2H), 6.51-6.37 (m, 2H), 5.72-5.69 (m, 1H), 5.59-5.44 (m, 2H), 3.99 (s, 1H), 3.50-3.46 (m, 2H), 3.23-3.14 (m, 2H), 2.57-2.55 (m, 2H), 2.18-2.14 (m, 2H), 1.68-1.59 (m, 2H); (ESI-MS): (+ve mode) 455.10 (M+H).sup.+. (100%), HPLC: 95.98%.
Example: 22
Compound 22: 1-(5-(4-amino-3-(benzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(105) ##STR00094##
(106) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.84 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.93-7.91 (d, 1H, J=8.0 Hz), 7.73-7.71 (d, 1H, J=8.0 Hz), 6.65-6.58 (m, 1H), 6.16-6.11 (dd, 1H, J.sub.1=2.8 Hz, J.sub.2=16.8 Hz), 5.68-5.65 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=11.2 Hz), 5.44-5.41 (m, 1H), 3.78-3.66 (m, 2H), 3.63-3.60 (m, 2H), 3.53-3.50 (m, 1H), 3.40-3.38 (m, 1H), 3.15-2.85 (m, 2H), 2.07-2.05 (m, 2H); ESI-MS: (+ve mode) 416.10 (M+H).sup.+ (100%); UPLC: 95.64%.
Example: 23
Compound 23: (5-(4-amino-3-(2-phenylbenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(107) ##STR00095##
(108) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.24-8.27 (m, 3H), 8.02-8.01 (d, 1H, J=4.0 Hz), 7.95-7.93 (d, 1H, J=8.0 Hz), 7.73-7.70 (m, 1H), 7.67-7.63 (m, 3H), 6.66-6.59 (m, 1H), 6.16-6.12 (m, 1H), 5.68-5.65 (m, 1H), 5.45-5.42 (m, 1H), 3.81-3.66 (m, 1H), 3.64-3.61 (m, 1H), 3.55-3.50 (m, 1H), 3.39-3.35 (m, 1H), 3.10-3.00 (m, 2H), 2.44-2.31 (m, 2H), 2.09-2.04 (m, 2H); ESI-MS: (+ve mode) 492.05 (M+H).sup.+ (100%); UPLC: 97.40%.
Example: 24
Compound 24: (E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one
(109) ##STR00096##
(110) .sup.1H NMR: (D.sub.2O, 400 MHz): δ 8.38 (s, 1H), 7.65 (d, 2H, J=6.8 Hz), 7.62-7.47 (m, 2H), 7.46-7.45 (m, 1H), 7.29-7.16 (m, 2H), 6.81-6.69 (m, 2H), 5.56-5.52 (m, 1H), 3.99-3.91 (m, 3H), 3.80 (dd, 1H, J.sub.1=8.4 Hz, J.sub.2=13.2 Hz), 3.63 (dd, 1H, J.sub.1=4.4 Hz, J.sub.2=11.2 Hz), 3.50 (dd, 1H, J.sub.1=4.8 Hz, J.sub.2=13.2 Hz), 3.20-3.11 (m, 2H), 2.93 (s, 6H), 2.47-2.41 (m, 2H), 2.23-2.16 (m, 2H); ESI-MS: (+ve mode) 525.7 (M+H).sup.+ (100%); HPLC: 97.25%.
Example: 25
Compound 25: 9-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-6-amino-7-(4-phenoxyphenyl)-5,7-dihydro-4H-purin-8(9H)-one
(111) ##STR00097##
(112) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 8.12 (s, 1H), 7.45-7.41 (m, 4H), 7.20-7.17 (m, 1H), 7.15-7.11 (m, 1H), 6.63-6.56 (m, 1H), 6.15 (dd, 1H, J.sub.1=4.0 Hz, J.sub.2=16.0 Hz), 5.74-5.72 (m, 2H), 5.97-5.64 (m, 1H), 5.01-4.93 (m, 1H), 3.62-3.46 (m, 3H), 3.40-3.35 (m, 2H), 3.20-2.90 (m, 3H), 1.90-1.97 (m, 2H); (ESI-MS): (+ve mode) 483.10 (M+H).sup.+. (100%); HPLC: 98.02%.
Example: 26
Compound 26: 1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(113) ##STR00098##
(114) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.84-8.83 (d, 1H, J=4.0 Hz), 8.31-8.26 (m, 4H), 8.12-8.08 (m, 1H), 7.95-7.93 (d, 2H, J=8.0 Hz), 7.69-7.66 (m, 1H), 6.65-6.59 (m, 1H), 6.16-6.12 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=16.8 Hz), 5.65-5.68 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=10.4 Hz), 5.47-5.44 (m, 1H), 3.81-3.77 (m, 1H), 3.65-3.61 (m, 1H), 3.55-3.50 (m, 1H), 3.39-3.33 (m, 1H), 3.12-2.90 (m, 2H), 2.42-2.31 (m, 2H), 2.09-2.07 (m, 2H); ESI-MS: (+ve mode) 520.20 (M+H).sup.+ (85%); UPLC: 95.96%.
Example: 27
Compound 27: 1-(5-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(115) ##STR00099##
(116) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 8.13 (s, 1H), 7.46-7.41 (m, 4H), 7.21-7.19 (m, 1H), 7.15-7.13 (m, 2H), 7.11-7.09 (m, 2H), 6.65-6.54 (m, 1H), 6.16 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=16.8 Hz), 5.68 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=10.4 Hz), 5.35-5.33 (m, 1H), 3.52-3.50 (m, 1H), 3.38-3.34 (m, 1H), 3.33-3.31 (m, 1H), 3.12-2.83 (m, 1H), 2.81-2.80 (m, 1H), 2.67-2.65 (m, 2H), 2.37-2.35 (m, 1H), 2.33-2.00 (m, 2H); (ESI-MS): (+ve mode) 546.15 (M+H).sup.+. (100%); UPLC: 95.60%.
Example: 28
Compound 28: 2-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydrocyclopenta[c]pyrrole-2-carbonyl)-3-cyclopropylacrylonitrile
(117) ##STR00100##
(118) .sup.1H NMR: (CDCl.sub.3-d.sub.1, 400 MHz): δ 8.38 (s, 1H), 7.67-7.65 (m, 2H), 7.42-7.32 (m, 2H), 7.19-7.15 (m, 3H), 7.11-7.09 (m, 2H), 6.87-6.84 (d, 1H, J=11.6 Hz), 5.59-5.53 (m, 1H), 5.41 (s, 2H), 4/05-3.88 (m, 2H), 3.68-3.54 (m, 2H), 3.23-3.12 (m, 2H), 2.62-2.52 (m, 2H), 2.17-2.08 (m, 2H), 1.44-1.26 (m, 2H), 0.98-0.93 (m, 2H), 0.89-0.87 (m, 1H); ESI-MS: (+ve mode) 532.25 (M+H).sup.+ (100%); UPLC: 95.05%.
Example: 29
Compound 29: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-N-(4-methylpyridin-2-yl)benzamide
(119) ##STR00101##
(120) .sup.1H NMR: (DMSO, 400 MHz): δ 10.42 (s, 1H), 8.26 (s, 1H), 8.23-8.21 (m, 1H), 8.16-8.10 (m, 1H), 8.07 (d, 1H, J=8.0 Hz), 7.45-7.42 (m, 2H), 7.03-7.02 (m, 1H), 6.66-6.59 (m, 1H), 6.15 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=16.4 Hz), 5.67 (dd, 1H, J.sub.1=2.8 Hz, J.sub.2=10.4 Hz), 5.46-5.42 (m, 1H), 4.08 (s, 3H), 3.85-3.75 (m, 1H), 3.70-3.57 (m, 1H), 3.56-3.45 (m, 2H), 3.15-2.90 (m, 2H), 2.45-2.38 (m, 5H), 2.18-2.06 (m, 2H); ESI-MS: (+ve mode) 539.2 (M+H).sup.+ (100%); UPLC: 96.93%.
Example: 30
Compound 30: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)benzamide
(121) ##STR00102##
(122) .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 8.59 (bs, 1H), 8.39 (s, 1H), 8.26 (s, 2H), 8.19 (d, 1H, J=5.2 Hz), 8.11 (d, 2H, J=8.0 Hz), 7.87 (d, 2H, J=8.0 Hz), 6.95 (d, 1H, J=5.2 Hz), 6.48 (dd, 1H, J.sub.1=10.0 Hz, J.sub.2=16.8 Hz), 6.40 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=16.8 Hz), 5.70 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=12.4 Hz), 5.60-5356 (m, 1H), 5.44 (bs, 2H), 3.88-3.83 (m, 2H), 3.56-3.46 (m, 2H), 3.23-3.21 (m, 1H), 3.14-3.12 (m, 1H), 2.59-2.54 (m, 2H), 2.43 (s, 3H), 2.20-2.09 (m, 2H); ESI-MS: (+ve mode) 509.1 (M+H).sup.+ (100%); HPLC: 96.67%.
Example: 31
Compound 31: 1-(5-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(123) ##STR00103##
(124) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 8.16 (s, 1H), 7.45-7.41 (m, 3H), 7.15-7.13 (m, 2H), 6.70-6.66 (m, 5H), 6.86-6.59 (m, 1H), 6.16 (dd, 1H, J.sub.1=2.8 Hz, J.sub.2=10.4 Hz), 5.68 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=10.4 Hz), 5.30-5.24 (m, 1H), 3.80-3.78 (m, 1H), 3.66-3.51 (m, 2H), 3.51-3.35 (m, 1H), 3.10-2.95 (m, 1H), 2.37-2.34 (m, 1H), 2.32-2.25 (m, 3H), 2.07-2.05 (m, 2H); (ESI-MS): (+ve mode) 466.05 (M+H).sup.+. (100%); UPLC: 97.65%.
Example: 32
Compound 32: N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)picolinamide
(125) ##STR00104##
(126) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ10.82 (s, 1H), 8.77-8.76 (m, 1H), 8.23 (s, 1H), 8.18-8.12 (m, 1H), 8.11-8.09 (m, 3H), 7.71-7.65 (m, 3H), 6.65-6.59 (m, 1H), 6.16-6.11 (m, 1H), 5.68-5.65 (m, 1H), 5.43-5.41 (m, 1H), 3.82-3.79 (m, 1H), 3.76-3.73 (m, 1H0, 3.50-3.48 (m, 1H), 3.37-3.35 (m, 1H), 3.23-3.19 (m, 2H), 2.35-2.32 (m, 2H), 2.08-2.04 (m, 2H); ESI-MS: (+ve mode) 495.15 (M+H).sup.+ (100%); HPLC: 98.31%.
Example: 33
Compound 33: 6-amino-7-(4-phenoxyphenyl)-9-(2-(vinylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)-7H-purin-8(9H)-one
(127) ##STR00105##
(128) .sup.1H NMR: (DMSO, 400 MHz): δ 8.12 (s, 1H), 7.45-7.40 (m, 4H), 7.21-7.19 (m, 1H), 7.17-7.13 (m, 4H), 6.94-6.87 (m, 1H), 6.21-6.12 (m, 2H), 5.71 (m, 1H), 4.97 (m, 1H), 3.34-3.33 (m, 1H), 3.00-2.96 (m, 4H), 2.61-2.59 (m, 2H), 1.86-1.81 (m, 2H); ESI-MS: (+ve mode) 519.15 (M+H).sup.+ (100%); 541.35 (M+Na).sup.+ (10%); UPLC: 95.21%.
Example: 34
Compound 34: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(benzo[d]thiazol-2-yl)benzamide
(129) ##STR00106##
(130) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 13.0 (s, 1H), 8.32-8.30 (m, 2H), 8.26 (s, 1H), 8.19-8.17 (m, 1H), 7.86-7.84 (m, 2H), 7.82-7.80 (m, 1H), 7.49-7.47 (m, 1H), 7.36-7.34 (m, 1H), 6.66-6.59 (m, 1H), 6.17-6.12 (m, 1H), 5.68-5.65 (m, 1H), 5.49-5.47 (m, 1H), 3.83-3.81 (m, 1H), 3.76-3.73 (m, 1H), 3.09-3.06 (m, 1H), 2.45-2.44 (m, 2H), 2.37-2.35 (m, 2H); ESI-MS: (+ve mode) 551.78 (M+H).sup.+ (100%); HPLC: 97.74%.
Example: 35
Compound 35: N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)pyrazine-2-carb oxamide
(131) ##STR00107##
(132) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 10.92 (s, 1H), 9.32 (s, 1H), 8.95 (s, 1H), 8.84-8.83 (m, 1H), 8.23 (s, 1H), 8.11-8.09 (d, 2H, J=8.0 Hz), 7.69-7.67 (d, 2H, J=8.0 Hz), 6.65-6.59 (m, 1H), 6.16-6.11 (dd, 1H, J.sub.1=2.8 Hz, J.sub.2 16.8 Hz), 5.68-5.43 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=10.4 Hz), 5.43-5.40 (m, 1H), 3.81-3.76 (m, 1H), 3.66-3.61 (m, 1H), 3.54-3.50 (m, 1H), 3.38-3.34 (m, 1H), 3.10-3.08 (m, 1H), 3.00-2.98 (m, 1H), 2.37-2.32 (m, 2H), 2.08-2.03 (m, 2H); ESI-MS: (+ve mode) 496.15 (M+H).sup.+ (100%); UPLC: 95.55%.
Example: 36
Compound 36: 1-(5-(4-amino-3-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(133) ##STR00108##
(134) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.19 (s, 1H), 7.21-7.19 (m, 1H), 7.17-7.14 (m, 1H), 7.07-7.05 (m, 1H), 6.59-6.55 (m, 1H), 6.15-6.12 (m, 1H), 5.67-5.64 (m, 1H), 5.40-5.32 (m, 1H), 3.81-3.79 (m, 1H), 3.78-3.75 (m, 1H), 3.59-3.57 (m, 1H), 3.51-3.48 (m, 1H), 3.03-3.00 (m, 1H), 2.97-2.93 (m, 1H), 2.36-2.82 (m, 2H), 2.02-2.00 (m, 2H); ESI-MS: (+ve mode) 455.78 (M+H).sup.+ (100%); HPLC: 96.22%.
Example: 37
Compound 37: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide
(135) ##STR00109##
(136) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 11.22 (s, 1H), 9.45 (s, 1H), 8.50-8.49 (m, 1H), 8.44-8.43 (m, 1H), 8.23-8.22 (m, 2H), 7.83-7.81 (m, 2H), 6.66-6.59 (m, 1H), 6.16-6.12 (m, 1H), 5.68-5.65 (m, 1H), 5.47-5.44 (m, 1H), 3.81-3.80 (m, 1H), 3.79-3.76 (m, 1H), 3.54-3.53 (m, 1H), 3.39-3.38 (m, 2H), 3.08-3.01 (m, 2H), 2.39-2.31 (m, 2H), 2.09-2.06 (m, 2H); ESI-MS: (+ve mode) 496.25 (M+H).sup.+ (100%); HPLC: 96.38%.
Example: 38
Compound 38: N-(4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)benzamide
(137) ##STR00110##
(138) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 10.44 (s, 1H), 8.24 (s, 1H), 7.98 (d, 4H, J=8.0 Hz), 7.65 (d, 2H, J=8.4 Hz), 7.60-7.53 (m, 3H), 6.62 (dd, 1H, J.sub.1=16.8 Hz, J.sub.2=10.2 Hz), 6.14 (dd, 1H, J.sub.1=16.8 Hz, J.sub.2=2.4 Hz), 5.67 (dd, 1H, J.sub.1=10.2 Hz, J.sub.2=2.4 Hz), 5.42-5.38 (m, 1H), 3.78-3.75 (m, 1H), 3.66-3.60 (m, 1H), 3.55-3.50 (m, 1H), 3.37-3.33 (m, 1H), 3.10-3.06 (m, 1H), 3.01-2.98 (m, 1H), 2.37-2.32 (m, 2H), 2.08-2.05 (m, 2H); ESI-MS: (+ve mode) 494.1 (M+H).sup.+ (100%); UPLC: 96.83%.
Example: 39
Compound 39: 1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo [3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(139) ##STR00111##
(140) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.74-8.76 (m, 1H), 8.33-8.35 (m, 1H), 8.22-8.26 (m, 3H), 8.08-8.15 (m, 1H), 7.87-7.89 (m, 2H), 7.62-7.64 (m, 1H), 6.59-6.66 (m, 1H), 6.12-6.17 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=16.8 Hz), 5.65-5.68 (m, 1H), 5.41-5.48 (m, 1H), 3.75-3.90 (m, 1H), 3.58-3.68 (m, 1H), 3.55-3.58 (m, 1H), 3.35-3.37 (m, 1H), 2.90-3.10 (m, 2H), 2.35-2.37 (m, 2H), 2.07-2.08 (m, 2H); ESI-MS: (+ve mode) 536.05 (M+H).sup.+ (100%); UPLC: 97.81%.
Example: 40
Compound 40: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide
(141) ##STR00112##
(142) .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 9.02 (bs, 1H), 8.73 (s, 1H), 8.51 (d, 1H, J=5.2 Hz), 8.39 (s, 1H), 8.14 (d, 2H, J=8.4 Hz), 7.89 (d, 2H, J=8.4 Hz), 7.33 (dd, 1H, J.sub.1=0.8 Hz, J.sub.2=5.2 Hz), 6.48 (dd, 1H, J.sub.1=10.0 Hz, J.sub.2=16.8 Hz), 6.40 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=16.8 Hz), 5.69 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=9.6 Hz), 5.60-5.56 (m, 3H), 3.87-3.83 (m, 2H), 3.56-3.47 (m, 2H), 3.25-3.20 (m, 1H), 3.18-3.09 (m, 1H), 2.57-2.53 (m, 2H), 2.18-2.15 (m, 2H); ESI-MS: (+ve mode) 563.3 (M+H).sup.+ (100%); HPLC: 99.55%.
Example: 41
Compound 41: (1-(5-(4-amino-3-(benzo[d]thiazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(143) ##STR00113##
(144) .sup.1H NMR: (CDCl.sub.3, 400 MHz): δ 8.47 (d, 2H, J=8.4 Hz), 8.32 (s, 2H), 7.75 (d, 2H, J=8.4 Hz), 7.53 (d, 1H, J=6.4 Hz), 6.52-6.45 (m, 2H), 6.42 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=16.8 Hz), 5.72 (dd, 1H, J.sub.1=2.8 Hz, J.sub.2=10.0 Hz), 5.59-5.55 (m, 1H), 3.91 (s, 3H), 3.87-3.83 (m, 2H), 3.56-3.47 (m, 2H), 3.26-3.21 (m, 1H), 3.16-3.11 (m, 1H), 2.58-2.53 (m, 2H), 2.36 (s, 3H), 2.19-2.15 (m, 2H); ESI-MS: (+ve mode) 523.2 (M+H).sup.+ (100%); HPLC: 98.58%.
Example: 42
Compound 42: 6-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl)nicotinamide
(145) ##STR00114##
(146) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 10.77 (s, 1H), 8.26-8.25 (m, 2H), 8.19-8.17 (m, 2H), 8.08 (m, 1H), 7.80-7.78 (m, 2H), 7.03-7.02 (m, 1H), 6.66-6.59 (m, 1H), 6.16-6.12 (m, 1H), 5.68-5.65 (m, 1H), 5.48-5.43 (m, 1H), 3.81-3.79 (m, 1H), 3.77-3.74 (m, 1H), 3.61-3.58 (m, 1H), 3.22-3.18 (m, 2H), 3.13-3.07 (m, 2H), 2.35 (s, 3H), 2.08-2.06 (m, 2H); ESI-MS: (+ve mode) 509.35 (M).sup.+ (100%); HPLC: 97.99%.
Example: 43
Compound 43: 1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(147) ##STR00115##
(148) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.24 (s, 1H), 8.20-8.18 (dd, 1H, J.sub.1=8.0 Hz, J.sub.2=8.0 Hz), 7.90-7.86 (m, 1H), 7.71-7.69 (d, 2H, J=8.0 Hz), 7.29-7.27 (d, 2H, J=16 Hz), 7.18-7.15 (m, 1H), 7.11-7.09 (d, 1H, J=8.0 Hz), 6.65-6.58 (m, 1H), 6.16-6.11 (dd, 1H, J.sub.1=4.0 Hz, J.sub.2=8.0 Hz), 5.68-5.65 (dd, 1H, J.sub.1=2.4 Hz, J.sub.2=10 Hz), 5.44-5.40 (m, 1H), 3.80-3.76 (m, 1H), 3.65-3.50 (m, 3H), 3.08-3.07 (m, 1H), 3.00-2.97 (m, 1H), 2.38-2.32 (m, 2H), 2.08-2.03 (m, 2H); ESI-MS: (+ve mode) 468.00 (M+H).sup.+ (100%); UPLC: 95.99%.
Example: 44
Compound 44: (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl) octahydrocyclopenta [c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl) benzamide
(149) ##STR00116##
(150) .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm: 10.89 (s, 1H), 9.83-9.81 (m, 1H), 8.35-8.29 (m, 1H), 8.28-8.23 (m, 1H), 8.22-8.20 (m, 3H), 7.89-7.81 (m, 1H), 7.80-7.78 (m, 1H), 6.72-6.70 (m, 1H), 6.66-6.64 (m, 1H), 5.53-5.50 (m, 1H), 3.91-3.89 (m, 2H), 2.79 (d, 6H, J=4.4 Hz); (ESI-MS): (+ve mode) 552.40 (M+H).sup.+. (100%); UPLC: 98.02%.
Example: 45
Compound 45: (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methylpyridin-2-yl) benzamide
(151) ##STR00117##
(152) .sup.1H NMR: (D.sub.2O, 400 MHz): δ 8.47 (s, 1H), 8.34 (d, 1H, J=6.4 Hz), 8.23 (d, 2H, J=8.4 Hz), 7.96 (d, 2H, J=8.4 Hz), 7.59-7.56 (m, 2H), 6.83-6.70 (m, 2H), 5.64-5.51 (m, 1H), 4.01-3.95 (m, 3H), 3.83 (dd, 1H, J.sub.1=8.4 Hz, J.sub.2=13.2 Hz), 3.67 (dd, 1H, J.sub.1=4.8 Hz, J.sub.2=11.2 Hz), 3.55 (dd, 1H, J.sub.1=4.8 Hz, J.sub.2=13.2 Hz), 3.27-3.23 (m, 1H), 3.21-3.18 (m, 1H), 2.91 (s, 6H), 2.65 (s, 3H), 2.54-2.47 (m, 2H), 2.30-2.24 (m, 2H); ESI-MS: (+ve mode) 566.3 (M+H).sup.+ (100%); HPLC: 96.24%.
Example: 46
Compound 46: 1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(153) ##STR00118##
(154) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 9.53 (s, 1H), 8.87-8.85 (m, 2H), 8.27-8.25 (m, 3H), 7.90-7.88 (d, 2H, J=8.0 Hz), 6.66-6.59 (m, 1H), 6.17-6.12 (m, 1H), 5.68-5.65 (m, 1H), 5.47-5.42 (m, 1H), 3.80-3.78 (m, 1H), 3.56-3.52 (m, 1H), 3.37-3.33 (m, 1H), 3.10-2.90 (m, 3H), 2.39-2.32 (m, 2H), 2.10-2.07 (m, 2H); ESI-MS: (+ve mode) 537.20 (M+H).sup.+ (100%); HPLC: 97.71%.
Example: 47
Compound 47: (E)-1-(5-(4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one
(155) ##STR00119##
(156) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.24 (s, 1H), 8.21-8.19 (m, 1H), 7.90-7.86 (m, 1H), 7.71-7.69 (m, 2H), 7.30-7.28 (m, 2H), 7.19-7.15 (m, 1H), 7.12-7.10 (d, 1H, J=8.0 Hz), 6.66-6.60 (m, 1H), 6.42-6.38 (d, 1H, J=16 Hz), 5.44-5.41 (m, 1H), 3.77-3.74 (m, 1H), 3.62-3.59 (m, 1H), 3.52-3.48 (m, 1H), 3.37-3.36 (m, 1H), 3.09-2.99 (m, 4H), 2.36-2.31 (m, 2H), 2.15 (s, 6H), 2.08-2.04 (m, 2H); ESI-MS: (+ve mode) 525.45 (M+H).sup.+ (100%); HPLC: 96.91%.
Example: 48
Compound 48: (E)-1-(5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one
(157) ##STR00120##
(158) .sup.1H NMR: (CD.sub.3OD, 400 MHz): δ 8.43 (s, 1H), 8.09 (d, 2H, J=6.4 Hz), 7.45-7.41 (m, 2H), 7.22-7.16 (m, 3H), 7.13-7.11 (m, 2H), 6.87 (d, 1H, J=15.2 Hz), 6.77 (dd, 1H, J.sub.1=6.8 Hz, J.sub.2=14.0 Hz), 5.69-5.64 (m, 1H), 3.98 (d, 2H, J=6.8 Hz), 3.97-3.92 (m, 1H), 3.83-3.78 (m, 1H), 3.67-3.64 (m, 4H), 3.54 (dd, 1H, J.sub.1=4.8 Hz, J.sub.2=13.2 Hz), 3.32-3.28 (m, 1H), 3.21-3.17 (m, 1H), 2.93 (s, 6H), 2.55-2.50 (m, 2H), 2.24-2.19 (m, 2H); ESI-MS: (+ve mode) 524.3 (M+H).sup.+ (100%); HPLC: 97.39%.
Example: 49
Compound 49: (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl) octahydrocyclopenta [c] pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyrazin-2-yl)benzamide
(159) ##STR00121##
(160) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 11.25 (s, 1H), 9.45 (s, 1H), 8.51-8.50 (m, 1H), 8.44 (m, 1H), 8.26 (s, 1H), 8.23-8.21 (m, 2H), 7.83-7.81 (m, 2H), 6.64-6.61 (m, 1H), 6.43-6.39 (m, 1H), 5.48-5.45 (m, 1H), 3.81-3.78 (m, 1H), 3.76-3.72 (m, 1H), 3.68-3.62 (m, 1H), 3.20-3.18 (m, 1H), 3.04-3.02 (m, 3H), 2.99-2.97 (m, 1H), 2.37-2.15 (m, 2H), 2.15 (m, 6H), 2.08 (m, 2H); ESI-MS: (+ve mode) 553.45 (M+H).sup.+ (100%); HPLC: 95.44%.
Example: 50
Compound 50: (Z)-methyl 4-(4-amino-1-(2-((E)-4-(dimethylamino)but-2-enoyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-methyl pyridin-2-yl) benzimidate
(161) ##STR00122##
(162) .sup.1H NMR: (CD.sub.3OD, 400 MHz): δ 8.73 (d, 1H, J=6.4 Hz), 8.47 (s, 1H), 8.31 (d, 2H, J=8.4 Hz), 8.13 (s, 1H), 7.98 (d, 2H, J=8.4 Hz), 7.77-7.76 (m, 1H), 6.87 (d, 1H, J=15.2 Hz), 6.78 (dd, 1H, J.sub.1=6.8 Hz, J.sub.2=13.6), 5.72-5.68 (m, 1H), 4.31 (s, 3H), 3.98 (d, 2H, J=7.2 Hz), 3.96-3.93 (m, 1H), 3.81 (dd, 1H, J.sub.1=8.0 Hz, J.sub.2=12.8 Hz), 3.68 (dd, 1H, J.sub.1=4.8 Hz, J.sub.2=11.2 Hz), 3.53 (dd, 1H, J.sub.1=4.8 Hz, J.sub.2=13.2 Hz), 3.31-3.26 (m, 2H), 2.70 (s, 3H), 2.57-2.52 (m, 2H), 2.26-2.24 (m, 2H); ESI-MS: (+ve mode) 580.5 (M+H).sup.+ (100%); HPLC: 96.62%.
Example: 51
Compound 51: (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl)octahydrocyclopenta [c] pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl) pyridine-2-yl)benzamide
(163) ##STR00123##
(164) .sup.1H NMR: (CD.sub.3OD, 400 MHz): δ 8.68 (d, 1H, J=5.6 Hz), 8.55 (s, 1H), 8.48 (s, 1H), 8.30 (d, 2H, J=8.4 Hz), 7.94 (d, 2H, J=8.4 Hz), 7.65 (dd, 1H, J.sub.1=1.2 Hz, J.sub.2=5.6 Hz), 6.9 (d, 1H, J=15.2 Hz), 6.80-6.75 (m, 1H), 5.69-5.66 (m, 1H), 4.09 (d, 2H, J=7.2 Hz), 4.00-3.94 (m, 1H), 3.81 (dd, 1H, J.sub.1=8.0 Hz, J.sub.2=12.8 Hz), 3.69 (dd, 1H, J.sub.1=4.4 Hz, J.sub.2=11.2 Hz), 3.53 (dd, 1H, J.sub.1=4.4 Hz, J.sub.2=13.2 Hz), 3.32-3.27 (m, 2H), 2.93 (s, 6H), 2.57-2.52 (m, 2H), 2.28-2.23 (m, 2H); ESI-MS: (+ve mode) 620.4 (M+H).sup.+ (100%); HPLC: 97.87%.
Example: 52
Compound 52: 1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)prop-2-en-1-one
(165) ##STR00124##
(166) .sup.1H NMR: (CDCl.sub.3-di, 400 MHz): δ 8.50-8.46 (m, 2H), 8.35 (s, 1H), 7.70-7.68 (d, 2H, J=8.0 Hz), 7.43-7. 7.34 (m, 2H), 7.21-7.19 (d, 2H, J=8.0 Hz), 6.47-6.39 (m, 2H), 5.73-5.70 (m, 1H), 5.59-5.55 (m, 1H), 3.88-3.83 (m, 2H), 3.61-3.47 (m, 4H), 3.23-3.13 (m, 2H), 2.57-2.52 (m, 2H), 2.18-2.16 (m, 2H); ESI-MS: (+ve mode) 468.15 (M+H).sup.+ (100%); HPLC: 95.64%.
Example: 53
Compound 53: (E)-1-(5-(4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one
(167) ##STR00125##
(168) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.47-8.48 (m, 1H), 8.41-8.39 (m, 1H), 8.23 (s, 1H), 7.70-7.67 (m, 2H), 7.58-7.55 (m, 1H), 7.48-7.45 (m, 1H), 7.23-7.21 (m, 2H), 6.64-6.59 (m, 1H), 6.42-6.38 (m, 1H), 5.43-5.40 (m, 1H), 3.77-3.74 (m, 1H), 3.64-3.61 (m, 1H), 3.52-3.49 (m, 1H), 3.09-2.96 (m, 5H), 2.35-2.30 (m, 2H), 2.15 (s, 6H), 2.06-2.04 (m, 2H); ESI-MS: (+ve mode) 525.45 (M+H).sup.+ (100%); HPLC: 95.44%.
Example: 54
Compound 54: 4-(1-(2-acryloyloctahydrocyclopenta[c]pyrrol-5-yl)-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methylpyridin-2-yl)benzamide
(169) ##STR00126##
(170) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.23 (s, 1H), 8.21-8.20 (m, 1H), 7.58 (d, 1H, J=8.4 Hz), 7.12-7.10 (m, 1H), 7.04-7.02 (m, 1H), 6.65-6.58 (m, 1H), 6.16-6.11 (m, 1H), 5.40-5.38 (m, 1H), 3.77-3.75 (m, 1H), 3.62-3.59 (m, 1H), 3.53-3.49 (m, 1H), 3.43 (s, 3H), 3.11-3.08 (m, 1H), 2.98-2.96 (m, 1H), 2.34-2.29 (m, 3H), 2.21 (s, 3H), 2.06-2.03 (m, 2H); ESI-MS: (+ve mode) 523.35 (M+H).sup.+ (100%); HPLC: 98.29%.
Example: 55
Compound 55: (E)-4-(4-amino-1-(2-(4-(dimethylamino)but-2-enoyl) octahydrocyclopenta [c] pyrrol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methyl-N-(4-methyl pyridin-2-yl)benzamide
(171) ##STR00127##
(172) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.22 (s, 1H), 8.20 (d, 1H, J=8.4 Hz), 7.57-7.55 (m, 2H), 7.43-7.41 (m, 2H), 7.11-7.09 (m, 1H), 7.03-7.02 (m, 1H), 6.63-6.59 (m, 1H), 6.41 (m, 1H), 5.39 (m, 1H), 3.79-3.72 (m, 1H), 3.59-3.57 (m, 2H), 3.43-3.42 (m, 2H), 3.08 (s, 3H), 3.05-3.03 (m, 2H), 2.32-2.30 (m, 2H), 2.16-2.09 (m, 3H), 2.09-2.06 (m, 3H), 2.04-2.02 (m, 6H); ESI-MS: (+ve mode) 580.55 (M+H).sup.+ (100%); HPLC: 96.27%.
Example: 56
Compound 56: (E)-1-(5-(4-amino-3-(4-(5-(pyrazin-2-yl)-1,3,4-thiadiazol-2-yl) phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one
(173) ##STR00128##
(174) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 9.54 (S, 1H), 8.88-8.86 (m, 2H), 8.27-8.25 (m, 3H), 7.90-7.88 (d, 2H, J=8.0 Hz), 6.66-6.59 (m, 1H), 6.43-6.39 (d, 2H, J=16 Hz), 5.47-5.43 (m, 1H), 3.80-3.75 (m, 1H), 3.65-3.60 (m, 1H), 3.53-3.51 (m, 1H), 3.83-3.33 (m, 1H), 3.09-3.00 (m, 4H), 2.40-2.32 (m, 2H), 2.15 (s, 6H), 2.09-2.07 (m, 2H); ESI-MS: (+ve mode) 594.40 (M+H).sup.+ (100%); HPLC: 97.57%.
Example: 57
Compound 57: (E)-1-(5-(4-amino-3-(4-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-(dimethylamino)but-2-en-1-one
(175) ##STR00129##
(176) .sup.1H NMR: (DMSO-d.sub.6, 400 MHz): δ 8.85-8.84 (m, 1H), 8.32-8.27 (m, 4H), 8.13-8.09 (m, 1H), 7.95-7.93 (m, 2H), 7.69-7.67 (m, 1H), 6.50-6.61 (m, 1H), 6.43-6.39 (m, 1H), 5.47-5.44 (m, 1H), 3.77-3.75 (m, 1H), 3.62-3.60 (m, 1H), 3.52-3.50 (m, 1H), 3.17-3.03 (m, 5H), 2.37-2.32 (m, 2H), 2.15 (s, 6H), 2.12-2.08 (m, 2H); ESI-MS: (+ve mode) 577.55 (M+H).sup.+ (100%); HPLC: 99.24%.
(177) Using the above procedures, following compounds (Table-2) can be prepared, using different boronic acids and finally reacting with optionally substituted acid chlorides.
(178) TABLE-US-00002 TABLE 2 Compd Structures IUPAC Names 58
Testing of Compounds of the Invention
Biological Studies:
In vitro BTK Inhibitory Activity Assay:
(179) In vitro BTK inhibitory activity of test compounds were screened using BTK kinase assay on ADP Glo platform (Li, H., Totoritis, R. D., Lor, L. A., Schwartz, B., Caprioli, P., Jurewicz, A. J and Zhang, G., Assay Drug Dev. Technol., 2009, 7(6), 598-605). Briefly, fixed amount of recombinant purified human BTK (3 ng/reaction from SignalChem, USA) were incubated with increasing concentration of test compounds, in 1× kinase reaction buffer (40 mM Tris-Cl, pH7.5, 20 mM MgCl.sub.2, 2 mM MnCl.sub.2, 0.1 mg/ml BSA and 50 μM DTT). Enzymatic reaction was initiated by adding a substrate cocktail containing 50 M of ATP (final concentration) and 5 g of polyGln4Tyr1 (Signal Chem) in total 25 μl of reaction, in round bottom white 96 well plate. The reaction mixture was incubated at room temperature for 2 hr. After 2 hr of incubation, 10 μl of the reaction mix was mixed with 10 t of ADP Glo reagent, in another round bottom white 96 well plate and incubated at room temperature for 40 min. This was followed by addition of kinase detection reagent (20 μl per reaction) and incubation at room temperature for 30 min. Finally, plate was read for luminescence at an integration time of 500 millisecond per well. Data were plotted taking Enzyme with no inhibitor set as the 100% kinase activity and for dose response curve, % Kinase activity was plotted against conc on Log scale and IC.sub.50 was determined by non linear curve fitting method using GraphPad Prism software 6. The in vitro BTK inhibitory activity (IC.sub.50) for representative compounds are listed in
(180) TABLE-US-00003 TABLE 3 Table 3: Invitro (IC.sub.50) BTK inhibitory & CYP inhibition data of representative compounds In-vitro BTK compd inhibitory CYP inhibition @ 10 M concn No. activity: IC.sub.50 (nM) 1A2 2C8 2C9 2C19 2D6 3A4 1 1.3 A A A A A A 2 1.1 A A A A A A 3 8 A A B A A A 4 2 A A A A A A 5 8 A A A A A B 6 1.7 A A A A A A 7 6 A A B A A B 8 4 A A A B A A 9 28 A B B A A B 10 25 A B A A B B 11 13 A A A A A A 12 37 A B B A A B 13 1.8 A A A B A A 14 1.4 A A A A A A 15 18 A A A A A B 16 1.7 A A A A A A 17 5 A A A A A B 18 218 A B B A A B 19 4 A A A A A A 20 223 A B B A A B 21 50 B A A A A A 22 40 A A A A B A 23 48 A B B A A B 24 2.5 A A A A A A 25 5 A A A A A A 26 1.1 A A A A A A 27 1.6 A A A A A A 28 16 A A B A A B 29 1.2 A A A A A A 30 6 A A A A A A 31 0.6 A A A A A A 32 4 A A A A A B 33 1.5 A A A A A A 34 359 B A A B A B 35 1.2 A A A A A A 36 1.1 A A A A A A 37 1 A A A A A A 38 17 A A A A B A 39 1.4 A A A A A A 40 6 B A B A A A 41 3.5 A A A A A B 42 0.1 A A A A A A 43 2 A A A A A A 44 1.4 A A A A A A 45 10 B A A A A A 46 1 A A A A A A 47 3 A A A A A A 48 50 B A A A A B 49 2.5 A A A A A A 50 19 A A A A B B 51 100 A B B A A B 52 162 B A A B A B 53 10 A A A A A B 54 0.1 A A A A A A 55 80 A B B B A B 56 50 B B B A A B 57 100 A B B A A B A: <50% CYP inhibition @ 10
M concentrations; B: >50% CYP inhibition @ 10
M concentrations
CYP Inhibition Studies:
CYP inhibition studies were performed with test compounds, at two concentrations (2 M and 10 μM), using human liver microsomes (Yao, M., Zhu, M., Sinz, M. W., Zhang, H., Humphreys, W. F., Rodrigues, A. D and Dai, R., Journal of Pharmaceutical and Biomedical Analysis, 2007, 44, 211-223; Walsky, R. L and Obach, R. S., Drug Metab. Dispos., 2004, 32, 647-660). Human liver microsomes were mixed with 100 mM phosphate buffer (pH 7.4) and probe substrate and warmed to 370 in microcentrifuge tubes. Aliquots of this mixture (499 μL) were transferred to each pre-labeled microcentrifuge tubes, followed by addition of the 1 μL of inhibitors (test compound/CYP-specific positive control inhibitor) or control solvent (DMSO). Aliquots of this mixture (90 μL) were transferred to each pre-labeled microcentrifuge tubes in duplicate. Final solvent concentrations were 0.2% (v/v) or less. Incubations were commenced with the addition of 10 μL NADPH stock (assay concentration, 1 mM) to a final incubation volume of 100 μL and incubated in shaking water bath (at 37° C. and 100 rpm), for the period defined in Tables 1. Incubations were terminated by addition of 400 μL of termination solvent (CH.sub.3CN) containing internal standard. The terminated samples were vortex-mixed, centrifuged at 10000 rpm for 5 min and supernatant transferred into HPLC vials for LC-MS/MS analysis to monitor metabolites produced by marker CYP reactions. CYP inhibitory activity (% inhibition) of test compounds is listed in Table 3.
In Vivo Efficacy Studies:
Demonstration of in vivo efficacy of test compounds in rats mice, oral routes of administration.
Animals
(181) All the animal experiments were carried out in female rats and mice, bred in-house. Animals were housed in groups of 6 animals per cage, for a week, in order to habituate them to vivarium conditions (25±4° C., 60-65% relative humidity, 12: 12 h light: dark cycle, with lights on at 7.30 am). All the animal experiments were carried out according to the internationally valid guidelines following approval by the ‘Zydus Research Center animal ethical committee’.
(182) SCW Arthritis
(183) Female Sprague dawley (SD) rats were primed with an intra-articular injection of 20 μl of peptidoglycan polysaccharide (PGPS), at 0.5 mg/ml of rhamnose in the right ankle. At 2 weeks the paw swelling were measured using a plethysmometer and rats assigned to groups based on initial paw swelling. On day 14 after model initiation, rats were dosed orally (po) with the test compounds. Following the dose administration, 1 h later, the rats received a booster dose of 0.5 ml of PGPS (0.5 mg/ml of rhamnose) via i.v. injection using their tail vein. Compounds were dosed for the following two more days and their paw volumes were measured for 3 more days. The efficacy of the compound was determined as percentage inhibition of paw swelling verses the control (untreated) group. Representative data of some of the test compounds are listed in Table-4.
(184) Diffused Large B Cell Lymphoma Xenografts Using TMD-8 Cell Line
(185) Female SCID mice were inoculated sc with 10×10.sup.6 TMD-8 cells in 0.1 mL of PBS to the right flank. Animals were observed twice weekly for occurrence of tumor. Once the tumors became palpable (around 100 mm.sup.3) around 14 days after injection, treatment was initiated via oral route. Tumor volume was determined every alternate day using digital calipers and the tumor volume was calculated using the formula: [length/2]×[width.sup.2]. Body weights of the animals were also recorded 3 times a week as a measure of treatment related side effect. Treatment was continued for two more weeks and inhibition of tumor volume compared to vehicle control was considered as efficacy endpoint. Representative data of some of the test compounds are listed in Table-4.
(186) Protocol for Collagen Induced Arthritis (CIA) Study in Mice
(187) CIA is a frequently used animal model of human RA (Courtenay, J. S., Dallman, M. J., Dayan, A. D., Martin, A. and Mosedale, B., Nature, 1980, 283, 666-668; Bevaart, L., Vervoordeldonk, M. J., Tak, P. P., Methods Mol. Biol., 2010, 602, 181-192). Following 7 days acclimation, mice were randomly assigned to groups according body weight. Mice were immunized subcutaneously in the tail using bovine type II collagen mix in complete Freund's adjuvant (CFA). Twenty-one days after the first immunization, mice were given booster dose of collagen in incomplete Freund's adjuvant (IFA). Mice were monitored every other day after the booster dose for the development of arthritis. Mice were recruited for the study once clinical signs were visible. Eight animals were assigned each of three groups [vehicle, positive control and test compounds] and treatment was continued for four weeks and percentage inhibition in clinical score is recorded as per graded score. Body weights of the animals were also recorded 3 times a week as a measure of treatment related side effect, paw thickness measured twice a week and blood serum are collected at termination for cytokines profile. Representative data of some of the test compounds are listed in Table-4.
(188) TABLE-US-00004 TABLE 4 Invivo efficacy data of representative compounds % inhibition of paw inflammation, % Inhibition in % inhibition of Compounds Day-16, in tumor volume, Day- clinical score, Day- (Dose: 10 SCW Arthritis 16, in TMD-8 28, in CIA Arthritis mpk, po) Model Xenografts Model Model 25 69.6 ± 12.7 50.2 ± 10.1 90.1 ± 6.3 32 75.3 ± 6.2 56.1 ± 8.2 100 ± 3.9 42 51.3 ± 9.7 62.2 ± 8.8 100 ± 4.2 46 81.8 ± 11.2 54.3 ± 9.1 88 ± 7.1 54 89.2 ± 10.3 92.1 ± 13.1 98 ± 4.5 Date represent Mean ± SD, n = 8 animals in each group
(189) The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
(190) The compounds of formula (I) or pharmaceutical compositions containing them are useful as a medicament for the inhibition of BTK activity and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
(191) Thus, a pharmaceutical composition comprising the compounds of the present invention may comprise a suitable binder, suitable bulking agent &/or diluent and any other suitable agents as may be necessary. Optionally, the pharmaceutical composition may be suitably coated with suitable coating agents.
(192) The compounds of the present invention (I) are BTK inhibitors and are useful in the treatment of disease states mediated by BTK enzyme, preferably cancer, arthritis and related disorders.
(193) In one of the embodiments the present invention of formula (I) in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combination. Immunosuppressants (e.g., Methotrexate, mercaptopurine, cyclophosphamide), glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2 specific inhibitors, TNF- binding proteins (eg., Infliximab, etanercept), interferon-13, interferon-
, interleukin-2, antihistamines, beta-agonist, anticolinergics, anti-cancer agents or their suitable pharmaceutically acceptable salts. Further examples of anticancer agents for use in combination with BTK inhibitors include chemotherapy or a targeted therapy, alkylating agents, platinum compounds, DNA altering agents, Topoisomerase inhibitors, microtubule modifiers, antimetabolites, anticancer antibiotics, hormones, Aromatase inhibitors, antibodies, cytokines, vaccines, drug conjugates, inhibitors of mitogen-activated protein kinase signaling (ex: BAY 43-9006), Syk inhibitors, mTOR inhibitors, antibodies (Rituxan), other anticancer agents that can be employed in combination include, Vinblastin, Bleomycin, Cisplatin, Acivicin, Azacitidine, Decitabine, Doxorubicin, Enloplatin, Flurouracil, Methotrexate, Vinblastin, Vincristine and BCR/ABL antagonist
(194) The quantity of active component, that is, the compounds of Formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.