Compounds and uses thereof

Abstract

The present disclosure features compounds useful for the treatment of CBP-related disorders.

Description

[0001] PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 401 N-[(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-methyl-1,3-thiazol-5- yl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{1-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazainden-3-yl]-1,2,3,4-tetrahydro-1,7-diaza-6- naphthyl}-1,2,4-benzotriazine-3-carboxamide 402N-[(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]- 6-{4-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- triazainden-3-yl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-1,2,4- benzotriazine-3-carboxamide 403 N-[(S)-1-{[(2S,4R)-4- -thiazol-5- yl)phenyl]methyl}carbamoyl) - -pyrro dny]carbony}- , -dimethylpropyl]- 6-{5-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- triazainden-3-yl]-5,6,7,8-tetrahydro-1,5-diaza-2-naphthyl}-1,2,4- benzotriazine-3-carboxamide 251 PATENT Attorney Docket No.: 51121-100WO2 405N-[(S)-1-{[(2 ({[p-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}ca inyl]carbonyl}-2,2-dimethylpropyl]- 6-(5-{[5-acetyl-1-(te -4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- triazainden-3-yl]-N-methylamino}-3-fluoro-2-pyridyl)-1,2,4-benzotriazine- 3-carboxamide 406 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]- 6-{1-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- triazainden-3-yl]-4-methyl-1,2,3,4-tetrahydro-6-quinoxalinyl}-1,2,4- benzotriazine-3-carboxamide 252 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 407 methyl 3-[(4-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol- 5-yl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-3- (difluoromethyl)phenyl)-N-methylamino]-1-(tetrahydro-2H-pyran-4-yl)- 4,5,6,7-tetrahydro-1H-1,2,5-triazaindene-5-carboxylate 408 methyl 3-[(6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol- 5-yl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-3-pyridyl)-N- methylamino]-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- triazaindene-5-carboxylate 409 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]- 6-(5-{[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- triazainden-3-yl]-N-methylamino}-2-pyrimidinyl)-1,2,4-benzotriazine-3- carboxamide 253 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 410 N-[(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-methyl-1,3-thiazol-5- yl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{5-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazainden-3-yl]-5,6,7,8-tetrahydro-1,5-diaza-2- naphthyl}-1,2,4-benzotriazine-3-carboxamide 411 methyl 3-(6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol- 5-yl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1,2,3,4-tetrahydro-1,5- diaza-1-naphthyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- 1,2,5-triazaindene-5-carboxylate 412 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]- 6-(p-{[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- triazainden-3-yl]-N-methylamino}phenyl)-1,2,4-benzotriazine-3- carboxamide 254 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 255 PATENT Attorney Docket No.: 51121-100WO2 Compound # 416 ydroxy-1- py tyl-1-(tetrahydro- 2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-125-triazainden-3-yl]-N- methylamino}-2-pyrid 417 N-[(S)-1-{[(2S,4R)-2 carbamoyl)-4-hydroxy-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]-6-(p-{[5-acetyl-1-(tetrahydro- 2H-pyran-4-yl)-4,5,6,7-t 1H-1,2,5-triazainden-3-yl]-N- methylamino}phenyl) zotriazine-3-carboxamide 418 N-[(S)-1-{[(2S,4R)-2-(N-methylcarbamoyl)-4-hydroxy-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]-6-{1-[5-acetyl-1-(tetrahydro-2H- pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5-triazainden-3-yl]-4-methyl- 1,2,3,4-tetrahydro-6-quinoxalinyl}-1,2,4-benzotriazine-3-carboxamide 256 PATENT Attorney Docket No.: 51121-100WO2 yl-1,3-thiazol-5- idinyl]carbonyl}-2,2- H-pyran-4-yl)-4,5,6,7- mino}-2-pyridyl)-1,2,4- e N-[(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol-5- henyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2-methylpropyl]-6- [5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- iazainden-3-yl]-N-methylamino}-2-pyridyl)-1,2,4-benzotriazine-3- carboxamide 257 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure - - 258 PATENT Attorney Docket No.: 51121-100WO2 -1- n-6- dro- te yl]- ,5- l}- 427 methyl 3-(6-{3-[N-(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-methyl-1,3-thiazol-5- yl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1,2,3,4-tetrahydro-1,5- diaza-1-naphthyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- 1,2,5-triazaindene-5-carboxylate 259 PATENT Attorney Docket No.: 51121-100WO2 430 (R)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1-[5-acetyl-1- (tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5-triazainden-3-yl]- 7-fluoro-1,2,3,4-tetrahydro-4-quinolinecarboxylic acid 260 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 433 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(1-methyl-5- pyrazolyl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{5-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazainden-3-yl]-3-(difluoromethyl)-5,6,7,8- tetrahydro-1,5-diaza-2-naphthyl}-1,2,4-benzotriazine-3-carboxamide 261 PATENT Attorney Docket No.: 51121-100WO2 iazol-5- methylpropyl]- dro-1H-1,2,5- 7-naphthyl}- 435 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]- 6-{1-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- triazainden-3-yl]-1,2,3,4-tetrahydro-1,7-diaza-6-naphthyl}-1,2,4- benzotriazine-3-carboxamide 436 methyl 3-(6-{3-[N-(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-methyl-1,3-thiazol-5- yl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-4-methyl-1,2,3,4- tetrahydro-1-quinoxalinyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazaindene-5-carboxylate 262 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 437 N-[(S)-1-{[(2S,4R)-2-(N-methylcarbamoyl)-4-hydroxy-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]-6-[5-(5-acetyl-1-cyclopropyl- 4,5,6,7-tetrahydro-1H-1,2,5-triazainden-3-yl)-5,6,7,8-tetrahydro-1,5- diaza-2-naphthyl]-1,2,4-benzotriazine-3-carboxamide 438 tetrahydro-1H-1,2,5-triazainden-3-yl]-3-(difluoromethyl)-5,6,7,8- tetrahydro-1,5-diaza-2-naphthyl}-1,2,4-benzotriazine-3-carboxamide 263 PATENT Attorney Docket No.: 51121-100WO2 264 PATENT Attorney Docket No.: 51121-100WO2 N-[(S)-1-{[(2S,4R)-2-(N-isopropylcarbam pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]-6-{4-[5 -2H- pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5-tr (difluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin- ine- 3-carboxamide 445 N-[(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-methyl-1,3-thiazol-5- yl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(5-{[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- 265 PATENT Attorney Docket No.: 51121-100WO2 Comp ridyl)- 4 o-2H- - 4 2- ,7- tetrahydro-1H-1,2,5-triazainden-3-yl]-3,4-dihydro-2H-1-oxa-4,6- diazanaphth-7-yl}-1,2,4-benzotriazine-3-carboxamide 266 PATENT Attorney Docket No.: 51121-100WO2 Com 4 -5- 1,7- H- 4 -1- -2H- zine- 4 N-[(S)-1-{[(2S,4R)-2-(N-cyclobutylcarbamoyl)-4-hydroxy-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]-6-{4-[5-acetyl-1-(tetrahydro-2H- pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5-triazainden-3-yl]-6- (difluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-1,2,4-benzotriazine- 3-carboxamide 267 PATENT Attorney Docket No.: 51121-100WO2 Comp 4 y-1- -2H- zine- 4 y-1- -2H- zine- 4 N-[(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-methyl-1,3-thiazol-5- yl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{5-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazainden-3-yl]-3-(difluoromethyl)-5,6,7,8- tetrahydro-1,5-diaza-2-naphthyl}-1,2,4-benzotriazine-3-carboxamide 268 PATENT Attorney Docket No.: 51121-100WO2 C roxy-1- ydro-2H- 3- 2,4- hydroxy- ahydro- ]-3- 2,4- 5- nyl}-2,2- ethyl)- n-4-yl)- 269 PATENT Attorney Docket No.: 51121-100WO2 Comp 4 l-5- }-2,2- hyl)- -yl)- 4 ol-5- 2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-5-luoro-3-pyridyl)-N- methylamino]-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- triazaindene-5-carboxylate 459 methyl 3-(7-{3-[N-(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-methyl-1,3-thiazol-5- yl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-3,4-dihydro-2H-1-oxa- 4,6-diazanaphth-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H- 1,2,5-triazaindene-5-carboxylate 270 PATENT Attorney Docket No.: 51121-100WO2 Comp 4 zol- )-N- 2,5- 4 H- N-[(S)-1-{[(2S,4R)-2-({[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]methyl}carbamoyl)-4-hydroxy-1-pyrrolidinyl]carbonyl}- 2,2-dimethylpropyl]-6-{5-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazainden-3-yl]-3-(difluoromethyl)-5,6,7,8- tetrahydro-1,5-diaza-2-naphthyl}-1,2,4-benzotriazine-3-carboxamide 271 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 1,3-thiazol-5- 2,2-dimethylpropyl]- trahydro-1H-1,2,5- aphth-7-yl}-1,2,4- yl]-4-hydroxy-1- yl-1-(tetrahydro-2H- nden-3-yl]-6- 1,2,4-benzotriazine- N-[(S)-1-{[(2S,4R)-2-{[(2,2-difluorocyclopropyl)methyl]carbamoyl}-4- hydroxy-1-pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]-6-{4-[5-acetyl-1- (tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5-triazainden-3-yl]- 6-(difluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-1,2,4- benzotriazine-3-carboxamide 272 PATENT Attorney Docket No.: 51121-100WO2 yl]carbamoyl}-4- ]-6-{4-[5-acetyl-1- ,5-triazainden-3-yl]- in-7-yl}-1,2,4- -4-hydroxy-1- yl-1-(tetrahydro-2H- nden-3-yl]-6- 1,2,4-benzotriazine- N-[(S)-1-{[(2S,4R)-2-({[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]methyl}carbamoyl)-4-hydroxy-1-pyrrolidinyl]carbonyl}- 2,2-dimethylpropyl]-6-{4-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazainden-3-yl]-6-(difluoromethyl)-3,4-dihydro-2H- 1,4-benzoxazin-7-yl}-1,2,4-benzotriazine-3-carboxamide 273 PATENT Attorney Docket No.: 51121-100WO2 ,3-thiazol-5- ,2-dimethylpropyl]- rahydro-1H-1,2,5- ro-1,5-diaza-2- mide ,3-thiazol-5- ,2-dimethylpropyl]- rahydro-1H-1,2,5- 2-naphthyl}-1,2,4- N-[(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]- 6-{5-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5- triazainden-3-yl]-3-methyl-5,6,7,8-tetrahydro-1,5-diaza-2-naphthyl}-1,2,4- benzotriazine-3-carboxamide 274 PATENT Attorney Docket No.: 51121-100WO2 nyl]-4-hydroxy-1- 4-benzotriazin-6- yl)-1-(tetrahydro- e-5-carboxylate hiazol-5- arbonyl}-2,2- -4-yl)-4,5,6,7- ro-1H-4-oxa-1,5- xamide methyl 3-(7-{3-[N-(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-6-(difluoromethyl)-3,4- dihydro-2H-1,4-benzoxazin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazaindene-5-carboxylate 275 PATENT Attorney Docket No.: 51121-100WO2 ,3-thiazol-5- ,2-dimethylpropyl]- rahydro-1H-1,2,5- iaza-2-naphthyl}- (1-methyl-5- inyl]carbonyl}-2,2- -6-yl}-3- o-2H-pyran-4-yl)- rboxylate ydroxy-1- 4-[5-acetyl-1- 5-triazainden-3-yl]- n-7-yl}-1,2,4- benzotriazine-3-carboxamide 276 PATENT Attorney Docket No.: 51121-100WO2 3-thiazol-5- 2-dimethylpropyl]- ahydro-1H-1,2,5- 2-naphthyl}-1,2,4- oyl)-4-hydroxy-1- ,4-benzotriazin-6- yl)-1-(tetrahydro- ne-5-carboxylate methyl 3-[(4-{3-[N-(S)-1-{[(2S,4R)-2-(N-methylcarbamoyl)-4-hydroxy-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-3-(difluoromethyl)phenyl)-N-methylamino]-1-(tetrahydro-2H-pyran-4- yl)-4,5,6,7-tetrahydro-1H-1,2,5-triazaindene-5-carboxylate 277 PATENT Attorney Docket No.: 51121-100WO2 Compound # Str tr 481 482 483 y 278 PATENT Attorney Docket No.: 51121-100WO2 )-1-(p- nyl}carbonyl)-2,2- -(difluoromethyl)- ro-2H-pyran-4-yl)- arboxylate -(1-methyl-5- dinyl]carbonyl}-2,2- 4-methyl-1,2,3,4- n-4-yl)-4,5,6,7- oxylate methyl 3-(6-{3-[N-(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-4-methyl-1,2,3,4- tetrahydro-1-quinoxalinyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazaindene-5-carboxylate 279 PATENT Attorney Docket No.: 51121-100WO2 moyl)-4-hydroxy-1- ,2,4-benzotriazin-6- trahydro-2H-pyran- 5-carboxylate moyl)-4-hydroxy-1- ,2,4-benzotriazin-6- etrahydro-2H-pyran- 5-carboxylate moyl)-4-hydroxy-1- ,2,4-benzotriazin-6- -4-yl)-1-(tetrahydro- ene-5-carboxylate 280 PATENT Attorney Docket No.: 51121-100WO2 moyl)-4-hydroxy-1- ,2,4-benzotriazin-6- trahydro-2H-pyran- 5-carboxylate moyl)-4-hydroxy-1- ,2,4-benzotriazin-6- l)-1-(tetrahydro-2H- ne-5-carboxylate [p-(1-methyl-5- l]carbonyl}-2,2- in-6-yl}-3- ro-2H-pyran-4-yl)- , , , -e a y o- - , , - a a e e- -carboxylate 281 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 493 494 282 PATENT Attorney Docket No.: 51121-100WO2 3-thiazol-5- yl]carbonyl}-2,2- ran-4-yl)-4,5,6,7- methyl)-5,6,7,8- e-3-carboxamide N-[(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{5-[5-acetyl-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazainden-3-yl]-3-(trifluoromethyl)-5,6,7,8- tetrahydro-1,5-diaza-2-naphthyl}-1,2,4-benzotriazine-3-carboxamide 283 PATENT Attorney Docket No.: 51121-100WO2 hiazol-5- arbonyl}-2,2- dro-2H-pyran-4- fluoromethyl)- zotriazine-3- 4 ,2- -4- - 4 methyl 3-(6-{3-[N-(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(4-methyl-1,3-thiazol-5- yl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-7-chloro-4-methyl- 284 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure yran-4-yl)-4,5,6,7- xylate oyl)-4-hydroxy-1- 2,4-benzotriazin-6- )-1-(tetrahydro-2H- e-5-carboxylate thyl-5- ]carbonyl}-2,2- an-4-yl)-4,5,6,7- lamino}-2- arboxamide 285 PATENT Attorney Docket No.: 51121-100WO2 hyl-5- dinyl]carbonyl}-2,2- ran-4-yl)-4,5,6,7- ylamino}-2- carboxamide hyl-5- dinyl]carbonyl}-2,2- an-4-yl)-4,5,6,7- ethyl)-5,6,7,8- e-3-carboxamide N-[(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{5-[5-(N-methylcarbamoyl)-1-(tetrahydro-2H-pyran-4- yl)-4,5,6,7-tetrahydro-1H-1,2,5-triazainden-3-yl]-3-(difluoromethyl)- 5,6,7,8-tetrahydro-1,5-diaza-2-naphthyl}-1,2,4-benzotriazine-3- carboxamide 286 PATENT Attorney Docket No.: 51121-100WO2 287 PATENT Attorney Docket No.: 51121-100WO2 methyl 3-(7-{3-[N-(R)-1-({(2S,4R)-2-[N-(S)-1-(p- fluorophenyl)ethylcarbamoyl]-4-hydroxy-1-pyrrolidinyl}carbonyl)-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-6-(difluoromethyl)-3,4- dihydro-2H-1,4-benzoxazin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazaindene-5-carboxylate 288 PATENT Attorney Docket No.: 51121-100WO2 methyl 3-[(4-{3-[N-(S)-1-{[(2S,4R)-2-(N-methylcarbamoyl)-4-hydroxy-1- pyrrolidinyl]carbonyl}-2-fluoro-2-methylpropylcarbamoyl]-1,2,4- benzotriazin-6-yl}-3-fluorophenyl)-N-methylamino]-1-(tetrahydro-2H- pyran-4-yl)-4,5,6,7-tetrahydro-1H-1,2,5-triazaindene-5-carboxylate 289 PATENT Attorney Docket No.: 51121-100WO2 methyl 3-(7-{3-[N-(S)-1-{[(2S,4R)-2-{N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl}-4-hydroxy-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1-methyl-1,2,3,4- tetrahydro-1,4,6-triaza-4-naphthyl)-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7- tetrahydro-1H-1,2,5-triazaindene-5-carboxylate 290 PATENT Attorney Docket No.: 51121-100WO2 1-methyl-5- idinyl]carbonyl}- n-6-yl}-3- 2H-pyran-4-yl)- boxylate yl-1,3-thiazol-5- arbonyl}-2,2- cyano-1,2,3,4- an-4-yl)-4,5,6,7- ylate yl)-4-hydroxy-1- moyl]-1,2,4- benzoxazin-4-yl)- -(tetra ydro- -pyran- -y)- ,5,6, -tetra ydro- - , ,5-triazaindene-5- carboxylate 291 PATENT Attorney Docket No.: 51121-100WO2 ol-5- onyl}-2,2- yl)-4,5,6,7- ahydro-1,5- ide ethyl-5- arbonyl}-2,2- romethyl)-2- 7-tetrahydro- ethyl-5- carbonyl}-2- 3- y p y y y -pyran-4-yl)- 4,5,6,7-tetrahydro-1H-1,2,5-triazaindene-5-carboxylate 292 PATENT Attorney Docket No.: 51121-100WO2 y , , y 293 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure -methyl-5- nyl]carbonyl}-2,2- ihydro-2H-1-oxa- ,7-tetrahydro-1H- oro-1-methyl-5- nyl]carbonyl}-2,2- methyl-1,2,3,4- ran-4-yl)-4,5,6,7- ylate yl)-4-hydroxy-1- enzotriazin-6-yl)- 1-(tetrahydro-2H- -5-carboxylate 294 PATENT Attorney Docket No.: 51121-100WO2 5- l]carbonyl}-2,2- 4-yl)-4,5,6,7- etrahydro-1,5- amide thyl-5- l]carbonyl}-2,2- 4-yl)-4,5,6,7- etrahydro-1,5- amide -[N-(S)-1-[p-(4- dinyl]carbonyl}- ,3,4-tetrahydro- aza-1,4,6,7- 295 PATENT Attorney Docket No.: 51121-100WO2 (1-methyl-5- l]carbonyl}-2,2- an-4-yl)-1,2,5-triaza- )-1,5-diaza-5,6,7,8- -carboxamide 4-hydroxy-2-[N-(S)-1- yrrolidinyl]carbonyl}- yl}-1,5-diaza-1,2,3,4- 2,5-triaza-1,4,6,7- te methyl 3-[7-(difluoromethyl)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1- [p-(1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}- 2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1,5-diaza-1,2,3,4- 296 PATENT Attorney Docket No.: 51121-100WO2 297 PATENT Attorney Docket No.: 51121-100WO2 -hydroxy-2-[N-(S)-1- thylcarbamoyl]-1- ,2,4-benzotriazin-6- ydro-4H-pyran-4-yl)- carboxylate y-2-[N-(S)-1-[p-(1- dinyl]carbonyl}-2,2- 1,5-diaza-1,2,3,4- 1,2,5-triaza-1,4,6,7- e y-2-[N-(S)-1-[p-(1- dinyl]carbonyl}-2,2- 1,5-diaza-1,2,3,4- 1,2,5-triaza-1,4,6,7- e 298 PATENT Attorney Docket No.: 51121-100WO2 roxy-2-[N-(S)-1-[p-(1- rolidinyl]carbonyl}-2,2- yl}-1,5-diaza-1,2,3,4- yl)-1,2,5-triaza-1,4,6,7- ylate )-4-hydroxy-2-[N-(S)-1- -pyrrolidinyl]carbonyl}- 6-yl}-1,5-diaza-1,2,3,4- an-3-yl]-1,2,5-triaza- boxylate 542 methyl 3-(7-cyano-4-methyl-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1- [p-(4-methyl-1,3-thiazol-5-yl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-1,2,3,4-tetrahydro-1-quinoxalinyl)-1-(tetrahydro-4H-pyran-4-yl)-1,2,5- triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 299 PATENT Attorney Docket No.: 51121-100WO2 xy-2-[N-(S)-1-[p-(4- rbamoyl]-1- 1,2,4-benzotriazin-6- n-4-yl)-1,2,5-triaza- xylate 4-hydroxy-2-[N-(S)-1- p y py y p y ylcarbamoyl]-1- yl]-1,2,4-benzotriazin-6- o-4H-pyran-4-yl)-1,2,5- -carboxylate -4-hydroxy-2-(N- ethylpropylcarbamoyl]- l)amino]-1-(tetrahydro- -indene-5-carboxylate 300 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 546 methyl 3-(7-fluoro-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4- fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-1,5-diaza-1,2,3,4-tetrahydro-1-naphthyl)-1-(tetrahydro-4H-pyran-4-yl)- 1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 547 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-({[p-(1-methyl-5- pyrazolyl)phenyl]methyl}carbamoyl)-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[3-(difluoromethyl)-5-[5-(N-methylcarbamoyl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]- 1,5-diaza-5,6,7,8-tetrahydro-2-naphthyl]-1,2,4-benzotriazine-3- carboxamide 548 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{5-[5-acetyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl]-3-cyano-1,5-diaza-5,6,7,8-tetrahydro-2- naphthyl}-1,2,4-benzotriazine-3-carboxamide 301 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 549 methyl 3-[7-(difluoromethyl)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1- [p-(1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}- 2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1,5-diaza-1,2,3,4- tetrahydro-1-naphthyl]-1-[(R)-tetrahydro-2H-pyran-3-yl]-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 550 methyl 3-[N-methyl(4-{3-[N-(R)-2-fluoro-1-{[(2 droxy-2-(N- methylcarbamoyl)-1-pyrrolidinyl]carbonyl}-2-m lcarbamoyl]- 1,2,4-benzotriazin-6-yl}-3-(trifluoromethyl)phen 1-(tetrahydro- 4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7-tetrahydro-5 5-carboxylate lcarbamoyl)-1- methyl)-4-[5-(N- 5-triaza-4,5,6,7- xazin-7-yl]-1,2,4- 302 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 552 methyl 3-{[3-(2,2-difluoroethyl)-4-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N- (S)-1-[p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}phenyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 4-hydroxy-2-[N-(S)- amoyl]-1- ,2,4-benzotriazin-6- dro-4H-pyran-4-yl)- arboxylate -1-[p-(1-methyl-5- carbonyl}-2,2- xa-1,3,5-triaza-6,7- 1,2,5-triaza-1,4,6,7- e 303 PATENT Attorney Docket No.: 51121-100WO2 (2S,4R)-4-hydroxy- onyl}-2- yl]-N-methylamino}- hydro-5H-indene-5- y-2-[N-(S)-1-[p-(4- amoyl]-1- ,2,4-benzotriazin-6- trahydro-4H-pyran- 5-carboxylate N-[(S)-1-{[(2S,3S,4R)-3-fluoro-4-hydroxy-2-(N-methylcarbamoyl)-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropyl]-6-{4-[5-acetyl-1-(tetrahydro-4H- pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]-6- (difluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-1,2,4-benzotriazine- 3-carboxamide 304 PATENT Attorney Docket No.: 51121-100WO2 -1-methyl-5- rbonyl}-2,2- carbamoyl)-1- ,5-diaza-5,6,7,8- boxamide ydroxy-2-[N-(S)-1- bamoyl]-1- 4-benzotriazin-6- xypropyl)-1,2,5- xylate ydroxy-2-[N-(S)-1- bamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-1,5-diaza-1,2,3,4-tetrahydro-1-naphthyl]-1-(2-hydroxyethyl)-1,2,5- triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 305

[0002] S)-1- in-6- 4-yl)- -[N- in-6- a- N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{1-[5-acetyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl]-1,7-diaza-1,2,3,4-tetrahydro-6- naphthyl}-1,2,4-benzotriazine-3-carboxamide 306 PATENT Attorney Docket No.: 51121-100WO2 Compound # 564 565566 307 PATENT Attorney Docket No.: 51121-100WO2 droxy-2-[N-(S)-1- bamoyl]-1- 4-benzotriazin-6- oxycyclobutyl)- boxylate droxy-2-[N-(R)-2- 5- rbonyl}-2,2- -diaza-1,2,3,4- ,5-triaza-1,4,6,7- -1-methyl-5- rbonyl}-2,2- 4-yl)-1,2,5-triaza- ifluoromethyl)-3- de 308 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 570 methyl 3-[7-(difluoromethyl)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(R)-1- [p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]-2-(2- methoxyethoxy)ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1,5-diaza-1,2,3,4- tetrahydro-1-naphthyl]-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate 571 methyl 3-(6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1- methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-7-(trifluoromethyl)-1,5- diaza-1,2,3,4-tetrahydro-1-naphthyl)-1-(tetrahydro-4H-pyran-4-yl)-1,2,5- triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 572 methyl 3-(6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-7-(trifluoromethyl)-1,5- diaza-1,2,3,4-tetrahydro-1-naphthyl)-1-(tetrahydro-4H-pyran-4-yl)-1,2,5- triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 309 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 573 N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-[3-(difl 4H-pyran-4- yl)-1, -5,6,7,8- t ide 574 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{7-fluoro-1-[5-(N-methylcarbamoyl)-1-(tetrahydro-4H- pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]-4-oxa-1,5- diaza-2,3-dihydro-1H-naphth-6-yl}-1,2,4-benzotriazine-3-carboxamide 575 N-[ -4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{1-[5-(N-methylcarbamoyl)-1-(tetrahydro-4H-pyran-4- yl)-1,25-tri z -4567-tetrahydro-1H-inden-3-yl]-1,7-diaza-1,2,3,4- t yl}-1,2,4-benzotriazine-3-carboxamide 310 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 576 - yl)-5- ]-1,5- amide 577N-[( 4-fluoro-1-methyl-5- pyr dinyl]carbonyl}-2,2- dimethyl trahydro-4H-pyran-4-yl)- 1,2,5-tr 3-(difluoromethyl)-1,5- diaza-5,6,7,8-tetrahydro-2-naphthyl}-1,2,4-benzotriazine-3-carboxamide 578 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-{3-difluoromethoxy-5-[5-(N-methylcarbamoyl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]- 1,5-diaza-5,6,7,8-tetrahydro-2-naphthyl}-1,2,4-benzotriazine-3- carboxamide 311 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure , dimethylpropyl]-6-[2-(difluoromethyl)-4-{N-methyl[5-(N-methylcarbamoyl)- 1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl]amino}phenyl]-1,2,4-benzotriazine-3-carboxamide oyl]- benzoxazin-4-yl)-1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate methyl 1-isopropyl-3-(7-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-(N- methylcarbamoyl)-1-pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]- 1,2,4-benzotriazin-6-yl}-6-(trifluoromethyl)-2,3-dihydro-4H-1,4- benzoxazin-4-yl)-1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 312 PATENT Attorney Docket No.: 51121-100WO2 -yl)-1,2,5-triaza- )-4-hydroxy-2-[N- arbamoyl]-1- 4-benzotriazin-6- acid -1-methyl-5- bonyl}-2,2- dro-4H-pyran-4- uoromethyl)-1,5- e-3-carboxamide -1-methyl-5- bonyl}-2,2- carbamoyl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl]amino}phenyl)-1,2,4-benzotriazine-3-carboxamide 313 PATENT Attorney Docket No.: 51121-100WO2 -1-methyl-5- bonyl}-2,2- o-4H-pyran-4-yl)- hylamino}-4- arboxamide ydroxy-2-[N-(S)- oyl]-1- 4-benzotriazin-6- -yl)-1,2,5-triaza- te ydroxy-2-[N-(S)- bamoyl]-1- 4-benzotriazin-6- yl}-3-pyridyl)amino]-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate 314 PATENT Attorney Docket No.: 51121-100WO2 ethyl-5- bonyl}-2,2- -(tetrahydro-4H- -yl]-4-oxa-1,5- 3-carboxamide -[N-(S)-1-[p-(1- l]carbonyl}-2,2- a-1,5-diaza-2,3- ,5-triaza-1,4,6,7- -[p-(1-methyl-5- bonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-7-(trifluoromethyl)-4- oxa-1,5-diaza-2,3-dihydro-1H-naphth-1-yl)-1-(tetrahydro-4H-pyran-4-yl)- 1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 315 PATENT Attorney Docket No.: 51121-100WO2 droxy-2-(N- ropylcarbamoyl]- dro-4H-1,4- ne-5-carboxylate 4-yl)-1,2,5-triaza- -{3-[N-(S)-1- ethyl-5- bonyl}-2,2- enzoic acid -[N-(S)-1-[p-(4- oyl]-1- 4-benzotriazin-6- hydro-4H-pyran- 4-yl)-1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 316 PATENT Attorney Docket No.: 51121-100WO2 ethyl-5- bonyl}-2,2- dro-4H-pyran-4- oromethyl)-1,5- -3-carboxamide -1-methyl-5- bonyl}-2,2- -4H-pyran-4-yl)- romethyl)-1,5- -3-carboxamide 4R)-4-hydroxy-2- amoyl]-1- 4-benzotriazin-6- -triaza-1,4,6,7- 317 PATENT Attorney Docket No.: 51121-100WO2 ethyl-5- bonyl}-2,2- ethylcarbamoyl)- dro-1H-inden-3- xamide roxy-2-[N-(S)- l]-1- enzotriazin-6- )-1,2,5-triaza- ethyl-5- l}-2,2- (N- -4,5,6,7- , , zine-3- carboxamide 318 PATENT Attorney Docket No.: 51121-100WO2 romethoxy-4-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-(N- -pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]- -yl}phenyl)-N-methylamino]-1-(tetrahydro-4H-pyran- za-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 601 N-[(R (1-methyl-5- pyrazol ]carbonyl}-2,2- dimethylprop ahydro-4H-pyran-4- yl)-1,2,5-triaz trifluoromethyl)-1,5- diaza-5,6,7,8-tetrahydro-2-naphthyl}-1,2,4-benzotriazine-3-carboxamide 602 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(2-difluoromethoxy-4-{N-methyl[5-(N- methylcarbamoyl)-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl]amino}phenyl)-1,2,4-benzotriazine-3- carboxamide 319 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 603 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-( pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[2-(difluoromethyl)-6-{N-methyl[5-(N-methylcarbamoyl)- 1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl]amino}-3-pyridyl]-1,2,4-benzotriazine-3-carboxamide methyl 3-{[3-(difluoromethyl)-4-{3-[N-(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy- yl]-1- triazin-6- 5-triaza- methyl 3-(6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1- methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-7-(trifluoromethyl)-4- oxa-1,5-diaza-2,3-dihydro-1H-naphth-1-yl)-1-(tetrahydro-4H-pyran-4-yl)- 1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 320 PATENT Attorney Docket No.: 51121-100WO2 610 methyl 3-{[4-(dimethylamino)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[p-(1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 321 PATENT Attorney Docket No.: 51121-100WO2 l-5- ,2- bamoyl)- nden-3- l-5- ,2- yl)-1- den-3- 613 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(3-methoxy-5-{N-methyl[5-(N-methylcarbamoyl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl]amino}-2-pyridyl)-1,2,4-benzotriazine-3-carboxamide 322 PATENT Attorney Docket No.: 51121-100WO2 -1-methyl-5- bonyl}-2,2- lcarbamoyl)-1- ro-1H-inden-3- xamide [N-(S)-1- - riazin-6- -3- xylate 616 methyl 3-[7-(difluoromethyl)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1- [p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-1,5-diaza-1,2,3,4-tetrahydro-1-naphthyl]-1-(1-methyl-4-piperidyl)- 1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 323 PATENT Attorney Docket No.: 51121-100WO2 (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]- 1,5-diaza-5,6,7,8-tetrahydro-2-naphthyl}-1,2,4-benzotriazine-3- carboxamide 619 (R)-7-fluoro-1-[5-methoxycarbonyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5- triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]-6-{3-[N-(S)-1-{[(2S,4R)-4- hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1,2,3,4-tetrahydro-4- quinolinecarboxylic acid 324 PATENT Attorney Docket No.: 51121-100WO2 pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-1,5-diaza-1,2,3,4-tetrahydro-1-naphthyl]-1-(tetrahydro-4H-pyran-4-yl)- 1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 325 PATENT Attorney Docket No.: 51121-100WO2 thyl-5- -2,2- hydro-4H- 5-diaza- xamide hydroxy-2- l]-1- otriazin-6- -1,4,6,7- thyl-5- -2,2- moyl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl]amino}-2-pyridyl)-1,2,4-benzotriazine-3-carboxamide 326 PATENT Attorney Docket No.: 51121-100WO2 628 methyl 3-[7-(difluoromethyl)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1- [p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-1,5-diaza-1,2,3,4-tetrahydro-1-naphthyl]-1-[(S)-3-pyrrolidinyl]-1,2,5- triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 327 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure xy-2-[N-(S)-1- oyl]-1- enzotriazin-6- 1,2,5-triaza- xy-2-[N-(S)-1- nyl]carbonyl}- iaza-1,2,3,4- ,7-tetrahydro- methyl-5- yl}-2,2- hyl)-5-(N- n-3-yl]-1,5- aza- , , , -era y ro- -nap y]- , , - enzorazne- -carboxamide 328 PATENT Attorney Docket No.: 51121-100WO2 ethyl-5- l}-2,2- ahydro-4H- ,5-diaza- oxamide xy-2-[N-(S)- 1-[p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}phenyl]-N-methylamino}-1-(2-hydroxyethyl)-1,2,5-triaza-1,4,6,7- tetrah dro-5H-indene-5-carbox late methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-(2-hydroxyethyl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate 329 PATENT Attorney Docket No.: 51121-100WO2 S,4R)-4-hydroxy-2-[N-(S)- yl]ethylcarbamoyl]-1- moyl]-1,2,4-benzotriazin-6- ropyl]-1,2,5-triaza-1,4,6,7- boxylate 638 methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 330 PATENT Attorney Docket No.: 51121-100WO2 -methyl-5- arbonyl}-2,2- -4-yl)-1,2,5-triaza- difluoromethyl)-3- pyridyl)-1,2,4-benzotriazine-3-carboxamide methyl 3-[7-(di R)-4-hydroxy-2-[N-(S)- 1-[p-( arbamoyl]-1- pyrrolidinyl]carb l]-1,2,4-benzotriazin-6- yl}-1,5-diaza-1, ahydro-4H-pyran-4-yl)- 1,2,5-tr -5-carboxylate 641 N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-{7-fluoro-1-[5-(N-methylcarbamoyl)-1-(tetrahydro-4H-pyran-4-yl)-1,2,5- triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]-4-oxa-1,5-diaza-2,3-dihydro-1H- naphth-6-yl}-1,2,4-benzotriazine-3-carboxamide 331 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 642 methyl 3-[(2-methoxy-6-{3-[N-(S)- fluoro-1-methyl-5-pyraz pyrrolidinyl]carbonyl}-2,2-dimethyl yl}-3-pyridyl)-N-methylamino]-1-( 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 643 -(1-methyl-5- yl]carbonyl}-2,2- oyl)-1-(tetrahydro-4H- den-3-yl]amino}-4- (trifluoromethyl)-3-pyridyl)-1,2,4-benzotriazine-3-carboxamide methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[p-(1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2-methylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}- 2-pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 332 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure meth l 3-{[4-(difluorometh l)-5-{3-[N-(S)-1-{[(2S,4S)-4-hydroxy-2-[N-(S)- zolyl)phenyl]ethylcarbamoyl]-1- ylpropylcarbamoyl]-1,2,4-benzotriazin-6- -(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- o-5H-indene-5-carboxylate 1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(6-methoxy-5-{N-methyl[5-(N-methylcarbamoyl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl]amino}-2-pyridyl)-1,2,4-benzotriazine-3-carboxamide 333 PATENT Attorney Docket No.: 51121-100WO2 C Structure 648 -methyl-5- nyl}-2,2- etrahydro-4H- l]amino}-4- oxamide -[( )- -{[( , )- - ydroxy- -[ -( )- -[p-( - uoro- -methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(6-{[5-acetyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl]-N-methylamino}-4-(difluoromethyl)-3- amide 650 -{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- pyrazolyl)phenyl]ethylcarbamoyl]-1- hylpropylcarbamoyl]-1,2,4-benzotriazin-6- 1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- o-5H-indene-5-carboxylate 334 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure {3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- pyrazolyl)phenyl]ethylcarbamoyl]-1- hylpropylcarbamoyl]-1,2,4-benzotriazin-6- -(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- o-5H-indene-5-carboxylate -[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1- yrazolyl)phenyl]ethylcarbamoyl]-1- py y y , hylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-1,5-diaza-1,2,3,4-tetrahydro-1-naphthyl]-1-(3-methoxycyclobutyl)- 1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 653 methyl 3-[N-methyl(6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4- fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-3-pyridyl)amino]-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate 335 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 654 methyl 3-(6-difluoromethoxy-7-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-(N- methylcarbamoyl)-1-pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]- 1,2,4-benzotriazin-6-yl}-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5- carboxylate 655 methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-[(1s)-3-hydroxycyclobutyl]-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 656 methyl 3-{[4-(difluoromethyl)-5-{3-[N-(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy- 2-[N-(S)-1-[p-(1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2-methylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}- 2-pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 336 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 659 methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[p-(3,4-difluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 337 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure l)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(R)- thyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- imethylpropylcarbamoyl]-1,2,4-benzotriazin-6- no}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- hydro-5H-indene-5-carboxylate yl}phenyl)-N-methylamino]-1-(1-methyl-4-piperidyl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(5-fluoro-4-methoxy-6-{N-methyl[5-(N- methylcarbamoyl)-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl]amino}-3-pyridyl)-1,2,4-benzotriazine-3- carboxamide 338 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure met yamno]- , ,5-traza- , ,6, -tetra ydro-5 -ndene-5-carboxyate N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(2-difluoromethoxy-4-{N-methyl[5-(N- methylcarbamoyl)-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl]amino}-6-tolyl)-1,2,4-benzotriazine-3- carboxamide 339 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 667 668 methyl 1-[3-( oromethyl)-6-{3-[N- (S)-1-{[ , o-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1,5-diaza-1,2,3,4- tetrahydro-1-naphthyl]-1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5- carboxylate 669 methyl 3-[(4-methoxy-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(1- methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-2-pyridyl)-N- methylamino]-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate 340 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 670 N-[(S)-1-{[(2S,4R)-4-hydroxy pyrazolyl)phenyl]ethylcarba dimethylpropyl]-6-[3-(dimethy (tetrahydro-4H-pyran-4-yl)-1,2,5- 1,5-diaza-5,6,7,8-tetrahydro car 671 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[3-(difluoromethyl)-5-{1-[3-(dimethylamino)cyclobutyl]- N h l l 12 i 4 7 h 1H i l 1 tetrahydro-1-naphthyl]-1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5- carboxylate 341 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure -[ - -[ , - - y o y- -[ - - -[p- - uoo- - e y- - pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(4-methoxy-6-{N-methyl[5-(N-methylcarbamoyl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl)-1,2,4-benzotriazine-3-carboxamide 675 droxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- carbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- romethyl)-5-[1-(4-hydroxycyclohexyl)-5-(N- iaza-4,5,6,7-tetrahydro-1H-inden-3-yl]-1,5- aphthyl]-1,2,4-benzotriazine-3-carboxamide 342 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 676 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[3-(difluoromethyl)-5-[1-(4-hydroxycyclohexyl)-5-(N- methylcarbamoyl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]-1,5- diaza-5,6,7,8-tetrahydro-2-naphthyl]-1,2,4-benzotriazine-3-carboxamide 677 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[3-(difluoromethyl)-5-{1-[(1R,3R)-3- hydroxycyclopentyl]-5-(N-methylcarbamoyl)-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl}-1,5-diaza-5,6,7,8-tetrahydro-2-naphthyl]-1,2,4- benzotriazine-3-carboxamide 678 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- 343 PATENT Attorney Docket No.: 51121-100WO2 Compound # St dimethylpropyl]-6-[3-(difluorometh entyl]- 5-(N-methylcarbamoyl)-1,2,5-triaz l}-1,5- diaza-5,6,7,8-tetrahydro-2-napht mide methyl 3-(7-fluoro-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4- fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-4-oxa-1,5-diaza-2,3-dihydro-1H-naphth-1-yl)-1-(2-hydroxyethyl)-1,2,5- triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 680 N-methyl-7-(difluoromethyl)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1- [p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-3'-(tetrahydro-4H-pyran-4-yl)-1,2',4',5,7'-pentaaza-1,2,3,4,5',6',7',8'- octahydro[1,1'-binaphthyl]-7'-carboxamide 344 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 681 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[3-(difluoromethyl)-5-[1-(2-hydroxyethyl)-5-(N- methylcarbamoyl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]-1,5- diaza-5,6,7,8-tetrahydro-2-naphthyl]-1,2,4-benzotriazine-3-carboxamide 683 methyl 3-{[3-(difluoromethyl)-4-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}phenyl]-N-methylamino}-1-[(S)-2-hydroxypropyl]-1,2,5-triaza-1,4,6,7- oxylate 684 methyl 3-(7-fluoro-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4- fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-4-oxa-1,5-diaza-2,3-dihydro-1H-naphth-1-yl)-1-(3-hydroxycyclobutyl)- 1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 345 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(3-fluoro-6-methyl-5-{N-methyl[5-(N-methylcarbamoyl)- 1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl]amino}-2-pyridyl)-1,2,4-benzotriazine-3-carboxamide 346 PATENT Attorney Docket No.: 51121-100WO2 Compound # Structure 688 N-[(S)-1-{[(2S, -(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]e yrrolidinyl]carbonyl}-2,2- dimethylpropyl yl)-6-(N-methyl{5-[(2- oxetanyl)carbonyl]-1-( y py an-4-yl)-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl}amino)-3-pyridyl]-1,2,4-benzotriazine-3- carboxamide 689 methyl 3-[7-(methylamino)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1- [p-(1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}- 2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1,5-diaza-1,2,3,4- tetrahydro-1-naphthyl]-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate 690 methyl 3-{[4-(difluoromethyl)-5-{3 oxy-2-[N-(S)- 1-[p-(4-fluoro-1-methyl-5-py moyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethy p opyca a oy]- , , - enzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-[(1r)-3-hydroxycyclobutyl]-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 347 PATENT Attorney Docket No.: 51121-100WO2 Compound # Struc 691 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[ pyrazolyl)phenyl]ethylcarbamo dimethylpropyl]-6-(3-fluoro-6-methoxy-5-{N-methyl[5-(N- methylcarbamoyl)-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl]amino}-2-pyridyl)-1,2,4-benzotriazine-3- carboxamide -(S)- in-6- za- S)-1- [p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-1,5-diaza-1,2,3,4-tetrahydro-1-naphthyl]-1-(3-methoxycyclobutyl)- 1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 348 PATENT Attorney Docket No.: 51121-100WO2 pyl]- dro- -3- - -yl]- 696 methyl 3-{[3-(difluoromethyl)-4-{3-[N-(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy- 2-[N-(S)-1-[p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2-methylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}phenyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 349 PATENT Attorney Docket No.: 51121-100WO2 (S)- -6- a- (4- in-6- ,6,7- 699 methyl 3-[N-methyl(5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4- fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyrazinyl)amino]-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate 350 PATENT Attorney Docket No.: 51121-100WO2 za- ,8- 1- -3- methyl 3-[7-(2,2-difluoroethyl)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[p-(1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-1,5-diaza-1,2,3,4-tetrahydro-1-naphthyl]-1-(tetrahydro-4H-pyran-4-yl)- 1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 351 PATENT Attorney Docket No.: 51121-100WO2 (S)- in-6- a- (S)- in-6- a- methyl 3-[7-(difluoromethyl)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1- [p-(2-methyl-1-imidazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}- 2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-1,5-diaza-1,2,3,4- tetrahydro-1-naphthyl]-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate 352 PATENT Attorney Docket No.: 51121-100WO2 (4- in-6- ,7- N- 5- ide N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[4-(difluoromethyl)-6-({1-[(1r)-3-hydroxycyclobutyl]-5- (N-methylcarbamoyl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl}-N- methylamino)-3-pyridyl]-1,2,4-benzotriazine-3-carboxamide 353 PATENT Attorney Docket No.: 51121-100WO2 (4- in-6- - oyl)- n-3- 711 methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[6-(4-fluoro-1-methyl-5-pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 354 PATENT Attorney Docket No.: 51121-100WO2 -(N- aza- dyl)- 714 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(4-{[5-acetyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl]-N-methylamino}-2-methoxyphenyl)- 1,2,4-benzotriazine-3-carboxamide 355 PATENT Attorney Docket No.: 51121-100WO2 7- 7- N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-[4-(difluoromethyl)-6-{N-methyl[5-(N-methylcarbamoyl)-1-(tetrahydro- 4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]amino}-3- pyridyl]-1,2,4-benzotriazine-3-carboxamide 356 PATENT Attorney Docket No.: 51121-100WO2 5- - -yl]- - 7- N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[6-(4-fluoro-1-methyl-5- pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[3-(difluoromethyl)-5-[5-(N-methylcarbamoyl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]- 357 PATENT Attorney Docket No.: 51121-100WO2 - -yl]- 3- N- methylcarbamoyl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]-1,5- diaza-5,6,7,8-tetrahydro-2-naphthyl]-1,2,4-benzotriazine-3-carboxamide 358 PATENT Attorney Docket No.: 51121-100WO2 (S)- -yl}- a- l)-1- -3- N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-(4-methoxy-6-{N-methyl[5-(N-methylcarbamoyl)-1-(tetrahydro-4H- pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]amino}-3- pyridyl)-1,2,4-benzotriazine-3-carboxamide 359 PATENT Attorney Docket No.: 51121-100WO2 p-(4- -yl}- a- - de N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-(6-{[5-acetyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl]-N-methylamino}-4-(difluoromethyl)-3-pyridyl)- 1,2,4-benzotriazine-3-carboxamide 360 PATENT Attorney Docket No.: 51121-100WO2 tyl]- -1,5- ide tyl]- -1,5- ide 733 N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-[4-(difluoromethyl)-6-{N-methyl[5-(N-methylcarbamoyl)-1-(tetrahydro- 4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]amino}-3- pyridyl]-1,2,4-benzotriazine-3-carboxamide 361 PATENT Attorney Docket No.: 51121-100WO2 oyl]- ,2,5- oyl)- n-3- N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-[3-(difluoromethyl)-5-[5-(N-methylcarbamoyl)-1-(tetrahydro-4H-pyran-4- yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]-1,5-diaza-5,6,7,8- tetrahydro-2-naphthyl]-1,2,4-benzotriazine-3-carboxamide 362 PATENT Attorney Docket No.: 51121-100WO2 -yl)- -(S)- in-6- za- 742 N-[(S)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-[3-(difluoromethyl)-5-[5-(N-methylcarbamoyl)-1-(tetrahydro-4H-pyran-4- yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl]-1,5-diaza-5,6,7,8- tetrahydro-2-naphthyl]-1,2,4-benzotriazine-3-carboxamide 363 PATENT Attorney Docket No.: 51121-100WO2 oyl)- oyl)- N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-[2-(difluoromethyl)-4-{N-methyl[5-(N-methylcarbamoyl)-1-(tetrahydro- 4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl]amino}phenyl]-1,2,4-benzotriazine-3-carboxamide 364 PATENT Attorney Docket No.: 51121-100WO2 yl-5- pyl]- dro- 7- - 748 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-[2-(difluoromethyl)-4-{N-methyl[5-(N-methylcarbamoyl)-1-(tetrahydro- 4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl]amino}phenyl]-1,2,4-benzotriazine-3-carboxamide 365 PATENT Attorney Docket No.: 51121-100WO2 -(S)- in-6- za- aza- dyl)- 753 methyl 1-[(1r)-3-hydroxycyclobutyl]-3-[(3-methoxy-4-{3-[N-(S)-1- {[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}phenyl)-N- methylamino]-1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 366 PATENT Attorney Docket No.: 51121-100WO2 [N- -yl}- a- - -1- in-6- za- 758 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[4-(difluoromethyl)-6-({1-[(1s)-4-hydroxycyclohexyl]-5- (N-methylcarbamoyl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl}-N- methylamino)-3-pyridyl]-1,2,4-benzotriazine-3-carboxamide 367 PATENT Attorney Docket No.: 51121-100WO2 ]-5- -N- aza- )-3- N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[6-({5-acetyl-1-[(1r)-4-hydroxycyclohexyl]-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl}-N-methylamino)-4-(difluoromethyl)-3- pyridyl]-1,2,4-benzotriazine-3-carboxamide 368 PATENT Attorney Docket No.: 51121-100WO2 5- - -yl]- - -1- in-6- -yl)- 369 PATENT Attorney Docket No.: 51121-100WO2 ntyl]- -1,5- ide ntyl]- -1,5- ide 766 N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-(4-methoxy-6-{N-methyl[5-(N-methylcarbamoyl)-1-(tetrahydro-4H- 370 PATENT Attorney Docket No.: 51121-100WO2 - - oyl)- n-3- pyl]- y y y y py y ,2,4- benzotriazine-3-carboxamide 371 PATENT Attorney Docket No.: 51121-100WO2 (S)- in-6- za- za- )-3- methyl 3-{[4-(difluoromethyl)-5-{3-[N-(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy- 2-[N-(S)-1-[6-(4-fluoro-1-methyl-5-pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2-methylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}- 2-pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 372 PATENT Attorney Docket No.: 51121-100WO2 za- )-3- (S)- in-6- za- methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[6-(4-fluoro-1-methyl-5-pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-[(1r)-3-hydroxycyclobutyl]-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 373 PATENT Attorney Docket No.: 51121-100WO2 yl-5- pyl]- yl)- aza- )-3- 777 N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[6-(4-fluoro-1-methyl-5- pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2- methylpropyl]-6-(6-{[5-acetyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl]-N-methylamino}-4-(difluoromethyl)-3- pyridyl)-1,2,4-benzotriazine-3-carboxamide 374 PATENT Attorney Docket No.: 51121-100WO2 aza- dyl)- S)-1- in-6- e-5- 780 methyl 3-[7-(difluoromethyl)-6-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1- [p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-1,5-diaza-1,2,3,4-tetrahydro-1-naphthyl]-1-[3- (hydroxymethyl)cyclobutyl]-1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5- carboxylate 375 PATENT Attorney Docket No.: 51121-100WO2 yl-5- - oyl)- n-3- aza- )-2- 783 N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[6-(4-fluoro-1-methyl-5- pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2- methylpropyl]-6-[4-(difluoromethyl)-6-{N-methyl[5-(N-methylcarbamoyl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- yl]amino}-3-pyridyl]-1,2,4-benzotriazine-3-carboxamide 376 PATENT Attorney Docket No.: 51121-100WO2 yl-5- pyl]- - (S)- in-6- 2,5- 786 methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[p-(1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-[(1s)-3-(dimethylamino)cyclobutyl]-1,2,5- triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 377 PATENT Attorney Docket No.: 51121-100WO2 yl-5- pyl]- - - -3- methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[p-(4-fluoro-1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-[(1r)-3-(dimethylamino)cyclobutyl]-1,2,5- triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 378 PATENT Attorney Docket No.: 51121-100WO2 4- -1- -N- 4- -1- -N- 792 methyl 3-{[4-(difluoromethyl)-5-[3-(N-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p- (1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}cyclopentylcarbamoyl)-1,2,4-benzotriazin-6-yl]-2- pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate 379 PATENT Attorney Docket No.: 51121-100WO2 1-[p- -2- ,6,7- S)-1- o-1- 2- ,6,7- 795 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[6-(4-fluoro-1-methyl-5- pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[4-(difluoromethyl)-6-({1-[(1r)-3-hydroxycyclobutyl]-5- (N-methylcarbamoyl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3-yl}-N- methylamino)-3-pyridyl]-1,2,4-benzotriazine-3-carboxamide 380 PATENT Attorney Docket No.: 51121-100WO2 ]-5- -N- (S)- in-6- 2,5- 798 N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-(6-{[5-acetyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl]-N-methylamino}-4-(difluoromethyl)-3-pyridyl)- 1,2,4-benzotriazine-3-carboxamide 381 PATENT Attorney Docket No.: 51121-100WO2 - -1- -N- 4- -1- -N- 801 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[4-(difluoromethyl)-6-({1-[(1r)-3- (hydroxymethyl)cyclobutyl]-5-(N-methylcarbamoyl)-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl}-N-methylamino)-3-pyridyl]-1,2,4-benzotriazine- 3-carboxamide 382 PATENT Attorney Docket No.: 51121-100WO2 6,7- ine- o-1- ate 804 methyl 1-[(1r)-3-hydroxycyclobutyl]-3-[(4-methoxy-5-{3-[N-(S)-1- {[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2- methylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}-2-pyridyl)-N- methylamino]-1,2,5-triaza-1,4,6,7-tetrahydro-5H-indene-5-carboxylate 383 PATENT Attorney Docket No.: 51121-100WO2 1- -3- 2- oyl)- n-3- 807 methyl 3-[(4-methoxy-5-{3-[N-(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N- (S)-1-[6-(1-methyl-5-pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2-methylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}- 2-pyridyl)-N-methylamino]-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 384 PATENT Attorney Docket No.: 51121-100WO2 yl-5- za- y-3- 2-[N- in-6- za- methyl 3-[(4-methoxy-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[6-(4- fluoro-1-methyl-5-pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2-methylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}- 2-pyridyl)-N-methylamino]-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 385 PATENT Attorney Docket No.: 51121-100WO2 7- -3- aza- )-3- 813 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[6-(4-fluoro-1-methyl-5- pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[6-({5-acetyl-1-[(1r)-4-hydroxycyclohexyl]-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl}-N-methylamino)-4-(difluoromethyl)-3- pyridyl]-1,2,4-benzotriazine-3-carboxamide 386 PATENT Attorney Docket No.: 51121-100WO2 yl-5- pyl]- - yl-5- pyl]- - 816 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[5-({5-acetyl-1-[(1s)-4-hydroxycyclohexyl]-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl}-N-methylamino)-3-methoxy-2-pyridyl]- 1,2,4-benzotriazine-3-carboxamide 387 PATENT Attorney Docket No.: 51121-100WO2 za- dyl]- (S)- 1- in-6- za- methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[2-(4-fluoro-1-methyl-5-pyrazolyl)-5-pyrimidinyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 388 PATENT Attorney Docket No.: 51121-100WO2 aza- )-2- za- )-2- N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-[6-({5-acetyl-1-[(1s)-4-hydroxycyclohexyl]-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl}-N-methylamino)-4-(difluoromethyl)-3-pyridyl]- 1,2,4-benzotriazine-3-carboxamide 389 PATENT Attorney Docket No.: 51121-100WO2 yl-5- pyl]- yl]- za- y-3- 825 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[6-({5-acetyl-1-[(1s)-4-hydroxycyclohexyl]-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl}-N-methylamino)-4-methoxy-3-pyridyl]- 1,2,4-benzotriazine-3-carboxamide 390 PATENT Attorney Docket No.: 51121-100WO2 za- dyl]- (S)- - in-6- za- 828 N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[4-(difluoromethyl)-6-[5-(N-methylcarbamoyl)-1- (tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H-inden-3- ylamino]-3-pyridyl]-1,2,4-benzotriazine-3-carboxamide 391 PATENT Attorney Docket No.: 51121-100WO2 (R)- l]-1- in-6- za- (S)- in-6- za- 831 bis{N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[3-fluoro-4-(1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(6-{[5-acetyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl]-N-methylamino}-4-(difluoromethyl)-3- pyridyl)-1,2,4-benzotriazine-3-carboxamide} 392 PATENT Attorney Docket No.: 51121-100WO2 pyl]- yl]- pyl]- yl]- N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2-methylpropyl]- 6-[6-({5-acetyl-1-[(1r)-3-hydroxycyclobutyl]-1,2,5-triaza-4,5,6,7- tetrahydro-1H-inden-3-yl}-N-methylamino)-4-(difluoromethyl)-3-pyridyl]- 1,2,4-benzotriazine-3-carboxamide 393 PATENT Attorney Docket No.: 51121-100WO2 pyl]- yl]- 3- H- N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[4-(difluoromethyl)-6-(N-methyl{1-[(R)-1-methyl-3- oxobutyl]-5-(N-methylcarbamoyl)-1,2,5-triaza-4,5,6,7-tetrahydro-1H- inden-3-yl}amino)-3-pyridyl]-1,2,4-benzotriazine-3-carboxamide 394 PATENT Attorney Docket No.: 51121-100WO2 -(S)- in-6- za- [N- -yl}- aza- N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(6-{[5-acetyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl]-N-methylamino}-4-difluoromethoxy-3- pyridazinyl)-1,2,4-benzotriazine-3-carboxamide 395 PATENT Attorney Docket No.: 51121-100WO2 yl-5- za- )-3- yl-5- za- )-2- methyl 3-{[5-(dimethylamino)-6-{3-[N-(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy- 2-[N-(S)-1-[6-(4-fluoro-1-methyl-5-pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2-methylpropylcarbamoyl]-1,2,4-benzotriazin-6-yl}- 3-pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 396 PATENT Attorney Docket No.: 51121-100WO2 yl-5- -(N- - yl-5- -(N- - N-[(R)-2-fluoro-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[6-(4-fluoro-1-methyl-5- pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2- methylpropyl]-6-[6-({5-acetyl-1-[(1s)-4-hydroxycyclohexyl]-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl}-N-methylamino)-4-(difluoromethyl)-3- pyridyl]-1,2,4-benzotriazine-3-carboxamide 397 PATENT Attorney Docket No.: 51121-100WO2 yl-5- za- )-3- oyl)- n-3- methyl 3-{[4-(difluoromethyl)-5-{3-[N-(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)- 1-[5-fluoro-6-(4-fluoro-1-methyl-5-pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1- pyrrolidinyl]carbonyl}-2,2-dimethylpropylcarbamoyl]-1,2,4-benzotriazin-6- yl}-2-pyridyl]-N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 1,4,6,7-tetrahydro-5H-indene-5-carboxylate 398 PATENT Attorney Docket No.: 51121-100WO2 yl-5- pyl]- dyl)- S)-1- 1- 2- ,6,7- N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[5-fluoro-6-(4-fluoro-1-methyl-5- pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-(6-{[5-acetyl-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl]-N-methylamino}-4-(difluoromethyl)-3- pyridyl)-1,2,4-benzotriazine-3-carboxamide 399 PATENT Attorney Docket No.: 51121-100WO2 S)-1- o-1- dyl]- - S)-1- o-1- dyl]- - N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[p-(4-fluoro-1-methyl-5- pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[4-(difluoromethyl)-6-{[1-(3-hydroxy-3- methylcyclobutyl)-5-(N-methylcarbamoyl)-1,2,5-triaza-4,5,6,7-tetrahydro- 1H-inden-3-yl]-N-methylamino}-3-pyridyl]-1,2,4-benzotriazine-3- carboxamide 400 PATENT Attorney Docket No.: 51121-100WO2 yl-5- pyl]- yl]- yl-5- pyl]- yl]- N-[(S)-1-{[(2S,4R)-4-hydroxy-2-[N-(S)-1-[6-(4-fluoro-1-methyl-5- pyrazolyl)-3-pyridyl]ethylcarbamoyl]-1-pyrrolidinyl]carbonyl}-2,2- dimethylpropyl]-6-[5-({5-acetyl-1-[(1s)-4-hydroxycyclohexyl]-1,2,5-triaza- 4,5,6,7-tetrahydro-1H-inden-3-yl}-N-methylamino)-3-(difluoromethyl)-2- pyridyl]-1,2,4-benzotriazine-3-carboxamide 401 PATENT Attorney Docket No.: 51121-100WO2 za- )-2- S)-1- o-1- dyl]- - S)-1- [p-(1-methyl-5-pyrazolyl)phenyl]ethylcarbamoyl]-1-pyrrolidinyl]-2-oxo-1- [(R)-perhydro-3-furyl]ethylcarbamoyl]-1,2,4-benzotriazin-6-yl}-2-pyridyl]- N-methylamino}-1-(tetrahydro-4H-pyran-4-yl)-1,2,5-triaza-1,4,6,7- tetrahydro-5H-indene-5-carboxylate 402 PATENT Attorney Docket No.: 51121-100WO2 aza- )-2- za- )-2- yl-5- pyl]- y y y y y , , , , , tetrahydro-1H-inden-3-yl}-N-methylamino)-3-(difluoromethyl)-2-pyridyl]- 1,2,4-benzotriazine-3-carboxamide 403 PATENT Attorney Docket No.: 51121-100WO2 g any of the ly acceptable ivity of a CBP 5 i he foregoing vity of a MYC i he foregoing 10 tivity of a AR, i ount of any of r in a subject 15 i of any of the hod involving armaceutical 20 CBP in a cell, mpounds, or EP300 loss of 25 ct an effective ncer. In other example, is etermined to 30 i , the method i pounds or a need thereof, 35 g compounds In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, gastric cancer, renal cell carcinoma, 40 melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, 404 PATENT Attorney Docket No.: 51121-100WO2 rcoma, clear id sarcoma, senchymoma a), non-small 5 er. In some al carcinoma, cer, prostate odiments, the cancer (e.g., 10 the cancer is a is synovial lung cancer, astric cancer, 15 cells contain o not contain 20 cells contain cancer. cancer. 25 a subject in the foregoing n thereof. In ated disorder 30 l carcinoma, dder, bowel, and stomach; on-Hodgkin's ding Ewing's 35 oepithelioma, liobastomas, eningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, 40 esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; 405 PATENT Attorney Docket No.: 51121-100WO2 which may be ample, acute emia (AML), r, anaplastic 5 mphoma, bile r, brain stem uble negative of estrogen, cer, estrogen 10 east cancer, e or negative sitive breast drosarcoma, er, colorectal 15 toma, ductal geal cancer, a, gallbladder stinal stromal ead and neck 20 al carcinoma , intrahepatic coma, kidney liposarcoma, r, lymphoma, 25 Merkel cell east cancer, toma, mouth elodysplastic uroendocrine 30 ancer, ocular geal cancer, m cell tumor, reatic cancer, er, peripheral 35 toma, pineal ) lymphoma, p rostate cancer, recta cancer, rena ce carcnoma, rena pevs cancer, r abdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell 40 carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, Diffuse large B cell lymphoma (DLBCL), 406 PATENT Attorney Docket No.: 51121-100WO2 t r ca tonsil cancer, t nal ncer, urethral uter cancer, T-cell l acut peripheral T- 5 pho oma, Burkitts l a, ositive CML, j my AML), large lym ma, follicular l a; c lymphoma, 10 nal arginal zone l a ( ymphomatoid mato able, splenic ed p , for example, avy cell myeloma, 15 plas er lymphoma, toc ein-Barr virus DLB ry cutaneous leg ma arising in ssoc with features 20 i iate with features i iate In s ant cancer or d to PD1 inhibitor, i n th an, a CAR-T 25 t her atin, taxanes pa Adriamycin®, bine can, gemzar, R2 i bitor). In l carcinoma, 30 rcin dder, bowel, ervi and stomach; l as; on-Hodgkin's l a; ding Ewing's , he oepithelioma, 35 synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; 40 carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be 407 PATENT Attorney Docket No.: 51121-100WO2 ample, acute emia (AML), r, anaplastic mphoma, bile 5 r, brain stem uble negative of estrogen, cer, estrogen east cancer, 10 e or negative sitive breast drosarcoma, er, colorectal toma, ductal 15 geal cancer, a, gallbladder stinal stromal ead and neck al carcinoma 20 , intrahepatic coma, kidney liposarcoma, r, lymphoma, Merkel cell 25 east cancer, toma, mouth elodysplastic uroendocrine ancer, ocular 30 geal cancer, m cell tumor, reatic cancer, er, peripheral toma, pineal 35 ) lymphoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, 40 thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal 408 PATENT Attorney Docket No.: 51121-100WO2 nocarcinoma, stic leukemia cell leukemia, Philadelphia 5 ytic leukemia mia, Adult T- ed Lymphatic homa, nodal arginal zone 10 ymphomatoid able, splenic for example, ell myeloma, er lymphoma, 15 ein-Barr virus ry cutaneous ma arising in with features with features 20 ll lymphoma, atic cancer, arcoma (e.g., rcoma, adult 25 all round cell osi sarcoma, eath tumors, quamous or a malignant, 30 dder cancer, a, melanoma, a or Ewing’s er, or breast sarcoma). In 35 determined tations are homozygous. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an epidermal growth factor receptor (EGFR) mutation. In some 40 embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to 409 PATENT Attorney Docket No.: 51121-100WO2 r does not of the astic ds, the 5 of the to CBP (e.g., cell with an ereof, or any 10 nfection is an nodeficiency ukemia virus patitis C virus omegalovirus 15 V-2), human (e.g., Human mily (e.g., JC ubella virus). 1, NF-2, or 20 bject in need of the utoimmune 25 ffective arthritis, ermatitis, us 30 -anterior -severe adiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, refractory, moderate- 35 to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (post- polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109 / L, polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile idiopathic arthritis. 410 PATENT Attorney Docket No.: 51121-100WO2 s non- nsegmental oses, ndrome, or 5 arthritis, ermatitis, us -anterior 10 AK inhibitor. nib, filgotinib, r medical 15 g to the ). and 20 ated by c arthritis, , Crohn’s me, que 25 ated by itis (e.g., te-to-severe ermediate- 30 ) t-essential eroid- urse juvenile i 35 ated by catricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus. 411 PATENT Attorney Docket No.: 51121-100WO2 ated by c arthritis, , Crohn’s me, 5 d plaque a subject in present 10 autoimmune unt of a T cell ncluding 15 a o CBP such ents, the .g., two or 20 (b) reduced i val of r can result i le, after 25 20%, 30%, r can result i tion is r) relative to 30 i r can result i ay is altered ents, i F-γ, IL-6, IL- 35 ther IL-2, IL-4, IL- , , , . In another aspect, the disclosure provides a method for treating a viral infection in a subject in need thereof. This method includes administering to the subject an effective amount of any of the foregoing 40 compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical 412 PATENT Attorney Docket No.: 51121-100WO2 viridae family .g., human T family (e.g., (e.g., Human 5 virus, herpes rpesvirus K*, , HPV E1)), d BK virus), 10 ancer, breast f, the method i mpounds or ma, prostate 15 bject in need he foregoing ogression of gic cancer in 20 ompounds or lonization of gic cancer in ompounds or 25 tivity of CBP ll carcinoma, hod including armaceutical 30 reast cancer, hematologic ound reduces 35 , 30%, 35%, 4 , , , , , , , , , , , or ) as compare o a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of CBP by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of CBP by 40 at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%). 413 PATENT Attorney Docket No.: 51121-100WO2 ound reduces %, 45%, 50%, n of the level el of CBP by 5 to percent of that reduces as compared / or activity of 10 %, 55%, 60%, .g., 14 hours, or more). In ity of CBP by , 60%, 65%, 15 days, 6 days, ound reduces , 30%, 35%, reference. In 20 vity of EP300 a reference. vity of EP300 / or activity of 25 , 50%, 55%, ours (e.g., 14 urs, or more). vity of EP300 %, 60%, 65%, 30 days, 6 days, presses CBP or EP300. In identified as 35 r subject has (e.g., uveal er is prostate cancer. In some embodiments, the cancer is a hematologic cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A 40 lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute 414 PATENT Attorney Docket No.: 51121-100WO2 l tic leukemia), cer is breast st cancer, or g’s sarcoma). 5 ription Factor is metastatic ration and / or i iogenesis. In ents, the cell 10 ancer spread rnatively, the atogenously. f CBP and / or 15 ontacting the apy, surgery, therapy is a , asparagine- bitor, histone 20 ciated kinase i se inhibitor. ts, cytotoxic l, docetaxel, in L. Brunton, 25 Therapeutics, CDK4 / 6 i omprises 30 administered bject. otoxic agents ts such as by a cancer that 35 e cancer has s, the cancer is resistant or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) 415 PATENT Attorney Docket No.: 51121-100WO2 i nhibitor (e.g., 5 ents and is dicates that be n, may be 10 2 alkyl group ber of e carbonyl nitrogen, or c ring. 15 aturated bon atoms, to a straight 20 carbon 20 to a straight 0 carbon endently, H, 25 , arylalkyl, e recited alkylene, and escribed 30 al of 6 to 12 t limited to, yl group. Unsubstituted arylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, 35 such as C1-C6 alkyl C6-C10 aryl, C1-C10 alkyl C6-C10 aryl, or C1-C20 alkyl C6-C10 aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each are further substituted with 1, 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups. The term “carbocyclyl,” as used herein, refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl 40 groups and unsaturated carbocyclyl radicals. A carbocyclylene is a divalent carbocyclyl group. 416 PATENT Attorney Docket No.: 51121-100WO2 valent mono- fully erm is heptyl, 5 ups (e.g., (bromo), or i which one or 10 ome roups as sed herein, in, in which 15 ur. In some groups as ch, as used n, in which 20 ur. In some groups as ch, as used al of 5 to 12 25 n, oxygen, heteroaryl azoyl, a heteroaryl 30 r from 7 to 0 alkyl C2- d with 1, 2, to 12 atoms 35 o ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. A heterocyclylene is a divalent heteroocyclyl group. The term “hydroxyl,” as used herein, represents an –OH group. 40 The term “thiol,” as used herein, represents an –SH group. 417 PATENT Attorney Docket No.: 51121-100WO2 , cycloalkyl), 5 ed, there will example: herein, e.g., tuted and nsubstituted 10 amino), oups may d and an exist in 15 ates, or mixtures solution of th a chiral isomeric 20 e, most iral center. not st commonly 25 e pound can ell-known ds based nd 30 . uch mixtures er" means i ouble bond, rbon- 35 bon double " "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the40 conformers. The compounds described herein may be prepared as individual isomers by either isomer- 418 PATENT Attorney Docket No.: 51121-100WO2 nclude d (followed m of each n and 5 eric pair emoval of duct using pound is 0%, 90%, 10 med or %, or 99.9% depicted or nt optical e weight of 15 er or over med or 99%, or named or %, or 99.9% 20 picted or Percent ntiomer plus oles of the losed 25 compound either f the r. When a and has 30 iastereomer mixtures of tereomer is ore ese forms. 35 e meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and 419 PATENT Attorney Docket No.: 51121-100WO2 onflict, the 5 stood to “including” sented by 0% above or 10 m 4.5 to 5.5 n (e.g., a stem. xample, in 15 cal, enteral, ctal, l, vaginal, 20 affected by that leads to 2%, 5%, 25 ns include, ncer) that %, 5%, 10%, 30 lastic cells, t two (or ent regimen of 35 administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a 40 symptom, or other parameter related to the disorder is greater than what would be observed with one 420 PATENT Attorney Docket No.: 51121-100WO2 agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially dditiv wh ll dditiv r r t r th n dditiv ( n r i ti ) S nti l r b t nti lly simulta ding, but not 5 mucou rent routes. injectio by method ess 10 (e.g., p to obtain t ue from an value). immun 15 immun ent polariza desorpt s spectro cytome 20 activity t. ient amount d herein r benefic 25 thereto cer, it is an ent respon level and / or describ h 30 as the disorde ut can ne cally effective amount” of an agent that reduces the level and / or activity of CBP of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control. As defined 35 herein, a therapeutically effective amount of an agent that reduces the level and / or activity of CBP of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response. As used herein, the term “inhibitor” refers to any agent which reduces the level and / or activity of a protein (e.g., CBP). Non-limiting examples of inhibitors include small molecule inhibitors, degraders, 40 antibodies, enzymes, or polynucleotides (e.g., siRNA). 421 PATENT Attorney Docket No.: 51121-100WO2 referen “increa A level, a %, 5 about 2 t 60%, a %, about 1 of more th s compar out 10 0.1-fold fold, about 1 old, about 5 about 1 L, mg / mL 15 , or a relate n the art, a compo for 20 admini manufa regime or exampl for topical s a 25 sterile s ny other p the compo compo t. 30 Excipie , disinteg fragran dispers ited to: buty , 35 croscar gelatin, , mannit , polyvin n dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), 40 stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. 422 PATENT Attorney Docket No.: 51121-100WO2 accept le salts of medica 5 toxicity, Pharm le salts ar Salts: P lts can be r 10 separat n as pharma ic acids o inorgan 15 accept le pharma e well-kn ases includin adipate 20 camph ethane hydrob lauryl s te, oleate, 25 pivalate , and val m, calcium includin dimeth 30 referen . The ref le” can be, ” or a prior al 35 cell or om a subje mple from a or RNA (e meant ed 40 value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a 423 PATENT Attorney Docket No.: 51121-100WO2 normal X”), or a low lue for a pa referen ase 5 or disor ed embodi t least o e of levels o also be use 10 ce with the therape , non-hu , be receivin y a 15 trained measur disease t are not ase; 20 stabiliz conditio remissi t necess se. Treatm 25 Treatm nt. Compo exampl naturall 30 substa ce describ The de feature claims. 35 ation moiety, on of the p , e.g., in 424 PATENT Attorney Docket No.: 51121-100WO2 degrad se that me 5 Fig.1a ound 1a (10 g / kg, 10 mg / Fig.1b ound 10 1a (10 g / kg, 10 mg / Fig.1c nd 1 (0.1 mg Fig.1d nd 1 15 (0.1 mg Fig. 2a e to Compo s, 10 mg / kg days as desc 20 Fig.2b ound 1a (50 QID for 3 w ribed in Exa Fig.2c d 1a 25 (50mg / D for 3 week ed in Example 870. Fig.2d is a graph illustrating the effect on % MYC on the tumor model LU99, in response in response to Compound 1a (50mg / kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg / kg QID for 3 weeks, 10 30 mg / kg QID for 3 weeks, 10mg / kg BID for 3 weeks or 50 mg / kg for 3 weeks, subcutaneous) over 27 days as described in Example 870. Fig. 3a is a graph illustrating the effect on tumor volume on the tumor model A549, in response to Compound 1a (50mg / kg QD for 5 weeks, subcutaneous) and Compound 1 (1mg / kg QID for 5 weeks, 3 mg / kg QID for 5 weeks, 10mg / kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 35 871. Fig.3b is a graph illustrating the effect on body weight on the tumor model A549, in response to Compound 1a (50mg / kg QD for 5 weeks, subcutaneous) and Compound 1 (1mg / kg QID for 5 weeks, 3 mg / kg QID for 5 weeks, 10mg / kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 871. Fig.3c is a graph illustrating the effect on % CBP on the tumor model A549, in response in response to 40 Compound 1a (50mg / kg QD for 5 weeks, subcutaneous) and Compound 1 (1mg / kg QID for 5 weeks, 3 425 PATENT Attorney Docket No.: 51121-100WO2 mg / kg mple 871. Fig.3d se to Compo ks, 3 5 mg / kg mple 871. Fig.4A d DMSO Fig.4B nM, 10 25nM, describ Fig.5A d DMSO Fig.5B nM, 15 2.5nM, describ 20 related ds useful f cer (e.g., s Compo 25 downst herein wherei A is a C B is a d L has t wherein A1is a bond between the linker and A; A2is a bond between B and the linker, 426 PATENT Attorney Docket No.: 51121-100WO2 or a ph eutic CBP a us in ki 5 differen , org among . Pr er. Cytokin w-m he host inf tory ion, and ca ulate 10 approp to p (JAKs) ein here are fou n m leukocy KL; AT family rs t 15 STAT5 d ST bee couple ph T- cell rec pons catalyz sph as 20 H3 and ses a mecha at c ther, it was o ed th us, treatme JA BP. AK- 25 inflamm and ib, delgoci edra ib. Other J ibito nib, gusacit aciti e as 30 autoim disor compo des me e itor. In som odim oclaciti ficiti 35 inhibito -49 itacitini elo b, baricitin goci 490, brepoci erd , nezulci r ritl 427 PATENT Attorney Docket No.: 51121-100WO2 inib is approv use or use in ate-t phic axial sp oart 5 modera eve ulcerati tis a ic dermat pr inhibito AK upadac n s ts, 10 the infl ory arthritis losi ulcerati tis, tini interme or h 15 thromb mia sk primary con a platelet bel ed to over esis n glioblas mult s a 20 JAK2 in . In nts, the dis int ial thromb mia vera or sse itini ved 25 for use acto use in mod o-se e or high-ris lofib st- essenti mbo st disease nic t of 30 COVID com pus erythe s an cortico s. B syndro he c cer activity st lu 35 JAK1 / 2 or. I some embodiments, the inflammatory and / or autoimmune disorder is refractory, moderate-to-severe atopic dermatitis, moderate-to-severe rheumatoid arthritis, intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, or 40 chronic graft-versus-host disease. In some embodiments, the inflammatory and / or autoimmune disorder 428 PATENT Attorney Docket No.: 51121-100WO2 is a res autoim rdi- Goutièr iatic 5 arthritis ar course tofacitin nib for trea inhibito 10 inflamm arthritis active a a result o e disorde 15 an. Delgoc embodi autoim e disorde 20 embodi autoim and cicatric 25 lymphc a, T- cell lym ris, 30 inflamm o severe among myelofi 35 st- essenti 40 lympho 429 PATENT Attorney Docket No.: 51121-100WO2 deucra autoim 5 compo therap ated with JA 10 rheum hic axial s rate- to-seve r post-es polycyt 15 109 / L, t diseas psoriat pic dermat 20 anterio ntal vitiligo, palmop or system 25 psoriat , alopeci erythe r uveitis, 30 atic arthritis dermat compri pharm 35 p , p p g y autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia 40 areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, 430 PATENT Attorney Docket No.: 51121-100WO2 Aicardi dermat adminis baricitin 5 r medica tive amoun embodi ritis, psoriati , 10 alopeci erythe uveitis, r medica g to 15 the sub salt thereof e embodi tion (STAT) membe s, 20 axial sp s disease Sjogren psorias a 25 subject compo autoim an effectiv 30 T cell res method , or a phar se, 35 a canc transpl effectiv some e s, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, 40 myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder. In some 431 PATENT Attorney Docket No.: 51121-100WO2 embodi e disease sensitiz embodi 5 cancer, disease myelom thromb myelom , or 10 system myelofi n some e MF). In myelofi 15 CDK4 / d CDK6), rs disrupt used in y 20 and me nd abema aromat shown 25 inhibito re genera ore precise 30 Palboci break. ed continu toleran d to 150 mg 35 maximi most ef including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4 / 6 inhibitor, or a 432 PATENT Attorney Docket No.: 51121-100WO2 pharma e embodi cancer, myelofi 5 cancer subject thod includin pharma 10 pharma e embodi s of functio Pharm 15 und by theo , and / or h as can 20 amoun ore of): (a) ed tumor p tumor r subject 25 treatme , 90%, o reprodu ter of the t 30 treatme 0%, 90%, o reprodu rs visible 35 organs nodule ter) relative reprodu ed 433 PATENT Attorney Docket No.: 51121-100WO2 by coun or 50x). h as infla 5 compo or more, t ced inflamm subject ell 10 (e.g., C activity er) relative measur 15 inflamm , 30%, 4 may be ine signalin ion, 20 or a do a JAK pa lso phosph me phosph - CSF, IL ct 25 the imm 10, IL-22, t , and / or subject s. For exa ys, 30 or 120 ible means. calcula compo red, for exa st 35 round o decrea populat or 25%). A 40 reprodu ed 434 PATENT Attorney Docket No.: 51121-100WO2 deaths compo or exampl followin nd 5 describ Combi agent, 10 sympto inflamm or more o e. For exa be deduce ges 15 of the c cytotox ng agents, vinca a s, 20 platinu adreno antiand leucovo s of chemot 25 sulfona meture triethyl ine; acetog e topotec ic 30 analog (includi yin; spongi ine, ifosfam phenes ocin, 35 fotemu , caliche Intl. Ed Eng ; an espera c chromo phores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, 40 carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 435 PATENT Attorney Docket No.: 51121-100WO2 5-oxo-L - doxoru marcell peplom 5 ubenim acid an fludara azacitid androg 10 anti-ad id; aceglat bisantr epothil maytan 15 phena polysac spiroge y T- 2 toxin, mitobro 20 taxoids cremop Partner chloran coordin 25 (VP-16 edatrex inhibito pharma chemot 30 therape wn in the a Douilla c such a 35 embodi b (AVAS onal antibod fragme en important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); 40 SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® 436 PATENT Attorney Docket No.: 51121-100WO2 (trastuz (ibritum I- 131); R (nataliz 5 SOLIRI (canaki NUMA (ipilimu trastuz s. 10 e second tumor t int is an in 15 may be protein ent, such a checkp some e 20 molecu ipilimu bitor (e.g., a pembro t is an inhi 46; 25 MEDI4 inhibito fusion ., an inhi 3, GAL9, 30 combin some e antigen art. For exa the 35 CAR to ed from a monon infectio inventio ell is 40 an auto e 437 PATENT Attorney Docket No.: 51121-100WO2 protein d, for exa 6,905,6 6,867,0 5 inhibito ruxolitin gusacit ents 10 are ad admini to 6 hours, to 13 hou 21 hours, ter 15 the sec Pharm tical compo 20 admini ts, solvate method admini ill 25 be und exampl al admini include ary, intrathe us 30 infusion r with an y be compre ic admini orm 35 of inge compo ed herein Dispers f with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may 40 contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients 438 PATENT Attorney Docket No.: 51121-100WO2 for the Pharm Formul include ion 5 of steril he extent t conven de a soluti aqueou 10 contain y, the sea aerosol age form in as compre can 15 also ta include as sugar, ntly in the f compo tion. 20 Intratu r discret . A compo le injectio interve r 25 subject by implant in combin determ d 30 standar Dosag describ he 35 compo tent of the s clearan approp ed initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In 40 general, satisfactory results may be obtained when the compounds described herein are administered to 439 PATENT Attorney Docket No.: 51121-100WO2 a huma m). Dose r exampl may 5 range f Kits t that red sert 10 with ins es (a) a ph cell or subj packag 15 20 25 30 35 40 45 50 440 PATENT Attorney Docket No.: 51121-100WO2 5 10 Unless t further nitroge 15 Prepar Interm (tetrah 20 Step 1. tert-Butyl 3-amino-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate A solution of tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (20 g, 89 mmol) in EtOH (200 mL) was treated with hydrazine hydrate (80%) (6.7 g, 130 mmol) at 0°C. The reaction mixture was stirred for 2 h at 80°C. The reaction mixture was concentrated under reduced pressure, diluted with water (1.5 L) and 25 extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: CH2Cl2 / MeOH (20:1)) affording the title compound (16 g, 67 mmol) as white solid. LCMS (ESI) m / z [M+H]+= 239.1. 441 PATENT Attorney Docket No.: 51121-100WO2 Step 2. CuBr2 pyrazol , 63 5 mmol) . The mi mL), w Na2SO purified 10 triturati m / z [M Step 3. c]pyrid 15 Cs2CO 5H- pyrazol te (8.95 g g mixture ers were c te 20 was co (THF:M concen le phase, le compo 25 Step 4. l)- 1,4,6,7 t-BuON n of tert-But 30 carbox ,4- dioxan ated under r the title co 35 Step 5. pyran- NBS (1 (difluor pyrazol o[4,3-c]pyridine-5-carboxylate (3.1 g, 6.3 mmol) in ACN (30.0 mL). Ater stirring at room 40 temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The crude residue 442 PATENT Attorney Docket No.: 51121-100WO2 was pu w solid. L Step 6. 5 pyrazo A mixtu pyran-4 mL) and TF er (700 m 10 brine (6 reduce H]+ = 467.1 Step 7. -yl)- 15 1,4,6,7 Ac2O ( hyl)- 1-(1-(te tetrahy oom temper (600 20 mL x 3) s Na2SO d by FCC (E 1H NM , 4.01 – – 25 2.70 (m [M+H]+ 443 PATENT Attorney Docket No.: 51121-100WO2 Interm ran- 4-yl)-1, Step 1. o- 5 5H-pyr RuPho on of tert-b carbox reactio L), 10 washed red and ev H (10:1)) 439.2. 15 Step 2. tetrahy NBS (7 dihydro - carbox 20 temper d brine (3 (Colum le Phase 220 nm; RT / z 25 [M+H]+ 444 PATENT Attorney Docket No.: 51121-100WO2 Step 3. yl)- 1,2,3,4 A soluti tetrahy 0.3 5 mL) wa pressu next step dir Step 4. dro- 10 5H-pyr Acetic (1- (tetrahy ne (138 m for 1h at ro by 15 reverse gradien ite solid. L Interm - 20 methyl Step 1. A soluti 1.66 25 mmol) i minute oom temperature. The reaction was quenched by the addition of saturated NH4Cl (aq.) (30 mL) at 0°C, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by 445 PATENT Attorney Docket No.: 51121-100WO2 FCC (E phase 0% gradien solid. L 5 Step 2. - 5H-pyr RuPho n of tert-but 6 10 mmol) e reactio extract ed over an by reverse 15 gradien solid. L Step 3. tetrahy 20 NBS (2 4- dihydro mg, 0.17 m mixture organic 25 FCC (E produc 2. Step 4. l)- 1,2,3,4 30 A soluti tetrahy mL) was sti ure to affor ep directly 35 Step 5. ro- 5H-pyr Acetic (difluoro methyl)-1-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-1,2,3,4-tetrahydroquinoline 40 (160 mg, 0.40 mmol) and TEA (122 mg, 1.21 mmol) in DCM (4 mL). The resulting mixture was stirred for 446 PATENT Attorney Docket No.: 51121-100WO2 1 h at r (30 mL x 2) cuo. The res , 0.16 m 5 Interm benzo[ din- 5-yl)et 10 Step 1. LDA (2 .4 mmol) i 15 min. A added nd 15 extract dried o C (Eluent . LCMS 20 Step 2. Iron po (difluor reactio ere combin 25 reduce e compo Step 3. KI (10. 30 chloroe s heated 150 mL). Th d and wa e The res g, 35 28.8 mmol) as an off-white solid. LCMS (ESI) m / z [M+H]+= 186.1. 447 PATENT Attorney Docket No.: 51121-100WO2 Interm -2- yl)-2,3- e Step 1. 5 Hydraz -4- oxopip h at 80°C pressu combin on, 10 the filtr s a white s Step 2. CuBr2 ( on of 15 tert-but anhydr ture was th 3), and bri remove ht to 20 obtain t d to make a afford t 304.0. 25 Step 3. Cs2CO3 (63.3 g, 203 mmol) was added to a stirred solution of tert-butyl 3-bromo-1H,4H,6H,7H- pyrazolo[4,3-c]pyridine-5-carboxylate (20.5 g, 67.8 mmol) and oxan-4-yl methanesulfonate (18.3 g, 101.7 448 PATENT Attorney Docket No.: 51121-100WO2 mmol) i as diluted d and wa ved under r two 5 isomer fraction compo Step 4. 10 TFA (1 c]pyridi . The rea e (20 mL ext step wi 15 Step 5. yl)etha TEA (1 tetrahy s 20 stirred as added i extract remove to afford t 25 Step 6. -4- yl)-1,4, Cs2CO - (difluor 30 pyran-4 en degass s then co A (300 m Na2SO OH 35 in DCM+= 433.1. 449 PATENT Attorney Docket No.: 51121-100WO2 Step 7. pyrazo NBS (3 benzo[ 5 yl)etha resultin ers were c ced pressur nd (10.6 g 10 Step 8. benzox Pd(dpp ,3- dihydro 15 mmol), The resultin uted with wa ed with bri der reduce 20 without Interm yl)phe 450 PATENT Attorney Docket No.: 51121-100WO2 Step 1. yl)phe Ethyl 2 (1S)-1- 5 butoxy n mixture with wa s sodium reverse 10 10 min; de SI) m / z [M Step 2. ide TFA (2 ol-5- 15 yl)phen ure was sti re to give , ACN in compo 20 Step 3. yl)phe HATU ( methylt 25 butoxy MF (7 mL). d with Et combin t. The cru 30 Water ( (578 mg, 1.1 Step 4. - carbox 35 To a sti yl)phen DCM (1 The reactio as a white 40 451 PATENT Attorney Docket No.: 51121-100WO2 Interm Step 1. 12 N hy 5 mmol) i ite (17.5 g ld suspen l) was im ed at room d 10 washed d (57 g, c Step 2. NH3(g) 15 nitroph ture was sti mixture under v .1 20 Step 3. A stirre cid (70 mL nitroph concen 25 The pre was co chroma solid. L 30 Step 4. K2CO3 (4.41 g, 31.9 mmol) was added to a stirred solution of ethyl 6-bromobenzo[e][1,2,4]triazine-3- carboxylate (3 g, 10.6 mmol) in MeCN (20 mL) and H2O (20 mL). The resulting mixture was stirred for 1 h 452 PATENT Attorney Docket No.: 51121-100WO2 at 60oC OAc (300 m x 2). The org fied by Prep m; 5 Mobile 1% B to 12 (1.2 g, 4.72 (m, 1H). LC 10 Interm Step 1. NaNO2 chlorob 15 resultin d extract ried over an de produc compo 20 Step 2. (Trifluo on of 6-bro was stirred ted 25 with Et anhydr produc (1.32 g 30 Step 3. (2-Etho of 6- bromo- , 4.34 m resultin ed 35 organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography, 453 PATENT Attorney Docket No.: 51121-100WO2 (elution mg, 1.44 m Interm 5 Step 1. 1,3,5-tr red solution trifluoro for 10 1 h at r Ac (50 mL Na2SO d by flash C affordin 15 Interm e Step 1. DAST ( 20 carbald mixture was stirred for an additional 2 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 (aq.) at 0 °C. The mixture was extracted with DCM (500 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was 454 PATENT Attorney Docket No.: 51121-100WO2 concen eluted DMSO- 5 Step 2. t-BuON to a stirre diphen ng mixture 10 water ( with bri der reduce ed in the n 15 Step 3. 1M HC (difluor temper to pH 8 w ted 20 with Et er anhydr was purified d (9.4 g) , 1H), 7. 25 Step 4. NBS (9 -5- (difluor for 1 h at r ed 30 with sa combin filtratio column a yello , 35 7.08 (t, Step 5. K2CO3 mo- 6-chloro-5-(difluoromethyl)pyridin-3-amine (11.8 g, 45.8 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl- 40 1,3,2-dioxaborolan-2-yl)prop-2-enoate (8.8 mg, 0.039 mmol) in dioxane (100 mL) and H2O (20 mL) under 455 PATENT Attorney Docket No.: 51121-100WO2 nitroge he resultin ined organic filtrate 5 chroma LCMS Step 6. Rh(PP 10 (difluor stirred uced pressur as concen as used in 15 Step 7. AcOH ( (difluor resultin 20 mixture with Et er anhydr was purified d (5.5 g) H), 25 7.47 (s Step 8. BH3-TH hyl)- 3,4-dih 30 atmosp . The res concen eluted [M+H]+ H), 35 2.77 (t, 456 PATENT Attorney Docket No.: 51121-100WO2 Interm n-4- yl)-4H, Step 1. 5 DAST ( chlorob om temper cted with CH over anhydr 10 gradien MS (ESI) m Step 2. XPhos 15 (difluor 2.29 mmol) 80 °C und ith EtOAc anhydr h 20 chroma e compo Step 3. mine NaH (9 25 (difluor mL). The res I (101 m additio CH2Cl2 (200 mL x 3). The combined organic layers were washed with brine (200 mL), then dried over 457 PATENT Attorney Docket No.: 51121-100WO2 anhydr h chroma e compo 5 Step 4. - c]pyrid (Cp*Rh (difluor HCOO 10 reactio 0 mL x 3) sodium in the nex 15 Step 5. pyrazo Acetic (difluor , 0.736 m t 20 room te purified % FA)) aff Interm 25 4H,6H, Step 1. yl}etha GPhos 30 4H,6H, 70.08 stirred ced pressur Ac (1000 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous 35 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by 458 PATENT Attorney Docket No.: 51121-100WO2 reverse ase, MeCN compo 5 Step 2. c]pyrid NaH (1 - yl)amin 200 mL). Af 10 solution e was qu he combin O4. After fil by reverse ase, 15 MeCN compo Interm n-3- yl]-6-b 20 Step 1. Pd(dpp 5 mmol) t at 100° er 25 (300 m e (400 m pressur CN in water (containing 0.05% FA)) affording the title compound (2.1 g, crude) as a brown solid. LCMS (ESI) m / z [M+H]+= 206.1. 459 PATENT Attorney Docket No.: 51121-100WO2 Step 2. PtO2 (1 .24 mmol) i of 5 hydrog uced pressur MeCN I) m / z [M 10 Step 3. carbox XPhos tetrahy .02 g, 7.17 for 15 2 h at 8 extract ried over an residue (contai H]+= 20 411.2. Step 4. - quinoli PtO2 (3 25 c]pyridi ed The res The resultin the title co purifica 30 Step 5. ro- 2H-qui Ac2O ( 4H,5H, ) 35 and TE temper h C18-fla g the title 460 PATENT Attorney Docket No.: 51121-100WO2 Step 6. 3,4- dihydr NBS (1 (oxan-4 0 5 mg, 1.1 resultin x 3). The co Na2SO h chroma 10 compo (t, J = 12.4 , 3.61 – 1.72 (m, 2H) 15 Interm pyrazo trifluor 20 Step 1. Benzyl .4 g, 7.86 mmol), TBAHS (267 mg, 0.786 mmol) and NaOH (314 mg, 7.86 mmol) in DCM (15 mL). The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (400 mL) and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine 461 PATENT Attorney Docket No.: 51121-100WO2 (300 m d pressur directly 5 Step 2. Methyl difluoro lting mixture mL) and ext L) 10 and dri e. The cru ing the title Step 3. 15 Fe (1.2 nitropyr resultin concen (elution ow 20 solid. L Step 4. BH3-TH ro- 1H,3H- 25 stirred th H2O (3 h brine (3 reduce petrole 30 261.1. Step 5. 3- dihydr XPhos dro- 35 1H-pyri g, 3.57 m ed for 3 h hed with Et s purified by FCC (elution gradient 0 to 10% MeOH in DCM) affording the title compound (989 mg) as a 40 yellow solid. LCMS (ESI) m / z [M+H]+= 462.2. 462 PATENT Attorney Docket No.: 51121-100WO2 Step 6. 3- c]pyrid [Rh(Cp -1- 5 (1-(tetr (969 m t room te d with Et nd dried o 10 afford t purifica Step 7. 2H- pyran-15 Ac2O ( H- pyran-4 (800 m d for 1 h at r produc 666 20 mg) as Step 8. pyran- To a sti 25 (tetrahy 7 mmol) i overnig filtered ed under r t 0 30 to 100 w solid. L Step 9. l)-7- fluoro- 35 1,1,1-T added (tetrahy 08 mmol) temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 40 3). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. 463 PATENT Attorney Docket No.: 51121-100WO2 After fil y FCC (e a brown 5 Interm 4H,6H, 10 Step 1. ate XPhos quinox 27 mmol) °C under n 0 15 mL x 3) . After fil y flash C NH4HC 436.2. 20 Step 2. ne- 1-carb PtO2 (1 c]pyridi lting 25 mixture g mixture was then filtered to remove insoluble solids and the filtrate was concentrated to afford the title compound (840 mg, crude) as a white solid that was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+ = 440.33. 464 PATENT Attorney Docket No.: 51121-100WO2 Step 3. dihydr TEA (5 - 5 pyrazol anhydri temper combin n, the filtr sh 10 chroma compo Step 4: dihydr 15 NBS (3 n-4- yl)-4H, mmol) i mixture ed organic te 20 was co chroma compo Step 5. 25 c]yridi TFA (3 (oxan-4 mg, 1.22 m g mixture 30 chroma e compo Step 6. c]pyrid 35 NaBH3 3,4- dihydro 3 mmol) 2 h at r mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After40 filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash C18- 465 PATENT Attorney Docket No.: 51121-100WO2 flash ch e title co Interm 5 (methy Step 1. Cesium nyl)- 10 4-hydro was sti t 0 °C drop on mixture h EtOAc 15 magne mn chroma ol) as a co Step 2. 20 2-benz ed in 4M H as diluted carbox 25 Step 3. hydrox Triethyl f (S)-2-(( 0 °C und 30 benzyl nd the reac tion mixture was allowed to stir at rt. After 1 h the reaction was quenched with DI water (20 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with saturated citric acid 466 PATENT Attorney Docket No.: 51121-100WO2 solution anhydr sh column 2.03 m 5 Step 4. -2- carbox Pd / C (2 - butoxyc in 10 EtOH ( balloon celite p compo 15 Step 5. - oxoeth DIPEA (2S,4R acid (652 m 20 allowed mmol) water ( brine (1 e produc 25 MeOH) BOC)+ ), 5.07 (s (m, 1H), 2. 9H), 1.06 (d 30 467 PATENT Attorney Docket No.: 51121-100WO2 Interm 1- (oxan- Step 1: 5 Pd(dpp g, 21 mm O4 (8.98 g at 80°C u d with Et 10 anhydr ord interme s used in Step 2: 15 4M HC (4.4 g, 19.3 as basified organic resultin 20 nitroph t further Step 3: DAST ( nitrophenyl)acetaldehyde (4.2 g, 20.9 mmol) in DCM (50 mL) at 0°C under nitrogen atmosphere. The 468 PATENT Attorney Docket No.: 51121-100WO2 resultin s quench nic layers concen o 5 0:1)) af [M+H]+Step 4: Ammon 10 nitrobe ing mixture d pressur ,2- difluoro 15 Step 5: XPhos 750 mg, 3.9 g, 7.8 mm atmosp x 20 3). The er filtratio C (Eluent yl)pyra 25 Step 6: in-3- amine PtO2 (4 - yl)pyra rred for 4 h and 30 the filte sure to affor amine ( . LCMS 35 Step 7: pyrazo MeOH mmol) oom temperature. To the above mixture was added N-[4-chloro-3-(2,2-difluoroethyl)phenyl]-1-(oxan-4- 40 yl)pyrazolo[4,3-c]pyridin-3-amine (200 mg, 0.5 mmol). The resulting mixture was stirred for 1 h at room 469 PATENT Attorney Docket No.: 51121-100WO2 temper 3). The co filtratio lash C18-fla ord 5 methyl -5- carbox Step 8: pyrazo 10 CH3I (1 difluoro .26 mmol) oom temper 3). The r 15 filtratio h C18-fla ord the title Interm N- 20 methyl Step 1 A soluti nd Na2CO 25 added d for an a NH4Cl brine (1 ced 470 PATENT Attorney Docket No.: 51121-100WO2 pressur compo Step 2: 5 DAST ( hydrox d for 1 h with Et er anhydr 10 produc (contai [M+H]+Step 3: 15 Pd / C (5 fluoro-3 h at 70°C was washed afford t 20 without Step 4: 1- oxobut TCFH ( 25 fluoro-3 y- N-meth ng mixture and extract mL) and dri e. 30 The cru in water ( m / z [M+H]+Step 5: 35 carbox TFA (1 (methyl (4 mL). Th concentrated under reduced pressure to afford the title compound (221.5 mg, crude) as a light yellow oil 40 that was used in the next step without further purification. LCMS (ESI) m / z [M+H]+= 262.1. 471 PATENT Attorney Docket No.: 51121-100WO2 Interm (methy 5 Step 1: (2S)-1- (120.0 t 23 °C. The s 10 cooled organic pressur compo 15 Step 2: 2-benz tetrahy HF at -78 ° time T 20 remove n mixture resultin with brine (1 reduce 0.0 25 mL), co rtion and stir extract Step 3: 30 benzyl NaBH4 (148 mg, 3.91 mmol) was added to a solution of 2-benzyl 1-(tert-butyl) (2R)-3-fluoro-4- oxopyrrolidine-1,2-dicarboxylate (1.32 g, 3.91 mmol) in THF (9.24 mL) and EtOH (9.24 mL) at rt. The 472 PATENT Attorney Docket No.: 51121-100WO2 resultin was ac 75 mL X 3 ved under r the 5 two pro 52 mg) an g). Step 4: HCl 4 10 solution g, 447.9 μ en atmosp freeze 15 Step 5: hydrox Benzyl in DMF (4 - dimeth 20 mixture as quench d over an s purified ne providi 25 Step 6: hydrox Pd / C (4 butoxyc 254.1 μ 30 atmosp s concen without Step 7: hyl- 35 1-oxob (2R,3R carbox 159 μL, 910 607.1 μ 40 atmosphere at rt. The crude solution was directly purified by flash C18-flash chromatography (elution 473 PATENT Attorney Docket No.: 51121-100WO2 gradien ro- 4-hydro Interm 1- 5 yl]-N-m Step 1: NBS (1 (1 10 g, 5.6 g mixture ed by the d with Et anhydr was 15 purified to 50% gr LCMS Step 2: 20 Cs2CO b]pyridi mol) in DMF resultin 0 mL x 3) 4. 25 After fil reverse gradien S (ESI) m / z [M+H] =340.1 474 PATENT Attorney Docket No.: 51121-100WO2 Step 3: yl)pyra XantPh of meth 5 chloro- ) in dioxan was stirred nd extract d over an 10 resultin n water ( / z [M+H]+ Step 4: 15 yl)pyra NMI (4 of meth 3- b]pyridi s added 20 atmosp phy (elution mg) as Interm 25 naphth Step 1: (E)-2-(6-bromo-3-chloropyridin-2-yl)-N,N-dimethylethen-1-amine DMF-DMA (5.77 g, 48.435 mmol) was added to a solution of 6-bromo-3-chloro-2-methylpyridine (2 g, 9.687 mmol) in DMF (20 mL). The resulting mixture was stirred overnight at 100°C. The resulting mixture 475 PATENT Attorney Docket No.: 51121-100WO2 was dil were w ted to give d the title 5 Step 2: NaIO4 ( en- 1-amin ture. The res 10 combin and concen M in PE) to =219.9 15 Step 3: DAST ( chlorop d overnig aqueou rs 20 were w . The cru 5 mg) as Step 4: din- 25 3-amin XPhos (difluor yl)pyra as stirred f L) 30 and ext then dri uct was pu 2- yl)-1-(te (ESI) m 35 Step 5: pyrazol Pentam ed solution of N-(5-chloro-6-(difluoromethyl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3- 40 c]pyridin-3-amine (290 mg, 0.764 mmol) in TEA (2.8 mL) and formic acid (2 mL). The resulting mixture 476 PATENT Attorney Docket No.: 51121-100WO2 was sti .) and ext , then dr re. The res 5 NH4HC mg) as Step 6: tetrahy 10 Acetic (difluor 3- amine ( e was sti ure. The res ter 15 (contai+=426.1 Step 7: 4H,6H, 20 NaH (1 (difluor c]pyridi 0.211 stirred of 25 sat. NH washed concen chroma compo 30 477 PATENT Attorney Docket No.: 51121-100WO2 Interm naphth Step 1: 5 4-(pyrid nitropyr mmol) i g mixture nic layers 10 concen in PE) to Step 2: NBS (5 (6 15 g, 32.6 re. The res u ng mxure was quenc e w sa. a2 2 3 ( m ) an exrace w c ( m x 3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by 478 PATENT Attorney Docket No.: 51121-100WO2 FCC (E m / z [M+H]+Step 3: 5 Cs2CO chlorop lan- 2-yl)pro n of Pd(dpp 80 °C u d 10 with Et anhydr product a yello 15 Step 4: PtO2 (3 oxopro was stirred f filtered, 20 reduce Water ( interme Step 5: 25 AcOH ( oxopro s stirred f c (400 m Na2SO 30 purified d. LCMS Step 6: LiOH.H -5H- 35 1,5-nap e resultin Cl (aq.). T the desired ther purification. LCMS (ESI) m / z [M+H]+=227.01. 40 479 PATENT Attorney Docket No.: 51121-100WO2 Step 7: DPPA ( naphth L). The res as 5 diluted e washed d under r afford t 10 Step 8: Borane solution mmol) i ure under n ng 15 mixture layers concen in PE) to 20 Step 9: din- 3-yl}car XantPh solution mmol) 25 XantPh as stirred mL) and ext dried o he resultin n 30 water ( [M+H]+Step 1 e HCl in n-4- 35 yl)pyra n DCM (4 to pH 9 w s were w concentrated under reduced pressure to afford the desired intermediate (551 mg) as a brown solid that 40 was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+=385.15. 480 PATENT Attorney Docket No.: 51121-100WO2 Step 1 naphth NaH (1 5 yl)pyra (5 mL) in n atmosp g mixture as quench 10 layers concen chroma compo 15 Step 1 -6H- 1,5-nap Bis[(pe solution naphth as 20 stirred d extract d over an resultin n water ( I) 25 m / z [M Step 1 4H,6H, TEA (4 30 methan temper pyrazol ng mixture resultin n 35 water ( +H]+=475.2 481 PATENT Attorney Docket No.: 51121-100WO2 Interm Step 1: 5 K2CO3 59.375 mixture and extract anhydr 10 produc interme Step 2: Fe (13. ate 15 (11.5 g stirred concen to 60% E Step 3: 20 Borane 1H,3H- stirred om temper d with Na d 25 with bri reduce desired Step 4: 30 NCS (3 b][1,4]oxazine (3.5 g, 22.706 mmol) in DMF (50 mL). The resulting mixture was stirred for 1h at room temperature. The mixture was quenched with saturated Na2CO3 (aq.) (800 mL) and extracted with EtOAc 482 PATENT Attorney Docket No.: 51121-100WO2 (800 m us Na2SO purified solid. L 5 Interm amine Step 1: 10 AcOK ( bromop , 7.328 ng mixture (100 mL). Th 15 washed under r compo Step 2: 20 Pd / C (3 1- methyl- 1.5 equiv) i n atmosp he filtrate 25 (5:1)) t Step 3: Trifluor 1H- pyrazol 30 stirred o 483 PATENT Attorney Docket No.: 51121-100WO2 afford t without Step 4: 5 1-Chlor mol) was ad ,2,2- trifluoro 0 °C. The organic te 10 was co (colum in 10 min; [M+H]+ 15 Interm oro- 1-[4-(2- Step 1: Titaniu o- 20 benzal HF (60 mL thyl acetate mixture concen was 25 used in Step 2: t-BuOK methyl 30 mmol) i . The res combined organic layers were washed with brine (200 mL), then dried over anhydrous sodium sulfate, 484 PATENT Attorney Docket No.: 51121-100WO2 filtered fford the title Step 3: de 5 XPhos )- 2,2-difl yl- 1,3-dio dioxan atmosp x 10 3). The sulfate, E) to afford t Step 4: 15 HCl in methyl mL) an under v used in the n 20 Step 5: yl)phen TCFH ( butoxy 53 25 mmol), mmol) temper 0 mL x 3) . After fil y 30 flash C to afford t Step 6: yl)phen 35 HCl in - difluoro oxobut temper (205 mg, crude) as a white oil that was used in the next step directly without further purification. LCMS 40 (ESI) m / z [M+H]+=464.24. 485 PATENT Attorney Docket No.: 51121-100WO2 Interm methyl 5 Step 1: 4-(chlo 3.153 mmol) i resultin d 10 organic ate was co EA in P Step 2: 15 XantPh methox mg, 1.133 (6 mL). Th mixture ic 20 layers concen chroma a brow 25 Step 3: ine NaH (3 yl)pyrazolo[4,3-c]pyridin-3-yl]pyridin-2-amine (310 mg, 0.821 mmol) in DMF (4 mL) in portions at 0 °C. The resulting mixture was stirred for 0.5 h at room temperature. To the above mixture was added CH3I 486 PATENT Attorney Docket No.: 51121-100WO2 (69.88 The reactio 3). The r filtratio - 5 flash ch desired Step 4: - yl]pyrid 10 Pentam ed solution amine ( d FA (2 mL). ied to pH 8 yers 15 were w concen d that wa Step 5: 20 pyrazol N-meth -3- fluoro-4 (190 mg, 0.4 for 1 h at r M 25 (50 mL Na2SO d by flash C afford t 487 PATENT Attorney Docket No.: 51121-100WO2 Interm methyl Step 1: 5 K2CO3 mg, 2.399 stirred EtOAc over anhydr 10 produc (contai mg, 83 Step 2: 15 XantPh solution zolo[4, 0.180 atmosp x 20 3). The anhydr produc mg) as 25 Step 3: ine NaH (8 yl)pyra in portion ture. To the reaction mixture was added CH3I (176.61 mg, 1.244 mmol). The resulting mixture was stirred for 1 488 PATENT Attorney Docket No.: 51121-100WO2 h at roo extract mL), dr re. The cru in 5 water ( S (ESI) m Step 4: yloxy)p 10 Platinu yl)pyra L). The res H 8 with Na with bri 15 reduce interme purifica Step 5: 20 pyrazol TEA (1 4H,5H, d N-meth was stirred d 25 with Et d over an de produc (contai ]+=477.1 30 489 PATENT Attorney Docket No.: 51121-100WO2 Interm naphth 5- carbox 5 Step 1: Ms2O ( hydrox 0°C. The res g mixture 10 layers concen l that wa Step 2: 15 K2CO3 (metha c]pyridi 2 h und with Et 20 anhydr product (contai ]+=352.0 Step 3: tert-butyl (1s,3s)-3-{3-[6-chloro-7-(difluoromethyl)-3,4-dihydro-2H-1,5-naphthyridin-1- 25 yl]pyrazolo[4,3-c]pyridin-1-yl}cyclobutane-1-carboxylate 490 PATENT Attorney Docket No.: 51121-100WO2 XantPh bromop (difluor os (131.42 ure 5 was sti (50 mL) an mL), dried o he crude p ) as a light y 10 Step 4: 4H,5H, Pentam ed solution 15 yl]pyra 84 mmol) i The resultin mL x 3) . After fil 20 (356 m MS (ESI) m Step 5: butoxyc 25 TEA (9 (497.84 as stirred - dihydro (480 m 30 temper x 3). The co filtratio h C18-fla the title co 35 Step 6: (metho TFA (0 ht hyridin-1-yl]-1-[(1s,3s)-3-(tert-butoxycarbonyl)cyclobutyl]-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 40 (105 mg, 0.190 mmol) in DCM (2 mL). The resulting mixture was stirred for 1 h at room temperature. The 491 PATENT Attorney Docket No.: 51121-100WO2 resultin crude) [M+H]+5 Step 7: (methyl HATU ( (difluor c]pyridi 1 10 mg, 0.3 d for 1 h at r Ac (30 mL Na2SO purified % 15 FA)) to Interm (difluo 20 Step 1: Cs2CO mmol) i chlorod ted with DC 25 anhydr desired purifica Step 2: 30 Pd(OA 3 g, 22.046 mmol), tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (6.62 g, 22.046 mmol) and AcOK (6.49 g, 66.138 mmol) in 1,4-dioxane (30 mL). The resulting mixture was stirred at 90°C for 4 h under 492 PATENT Attorney Docket No.: 51121-100WO2 nitroge (200 m Na2SO purified . 5 LCMS Step 3: HCl in -4- fluorop ting 10 mixture d pressur step dir Step 4: 15 henyl}e HATU ( fluorop butoxy 7 mmol) 20 temper ash chroma uct (197 m Step 5: zol- 25 5-yl)ph HCl in 1S)- 1-{4-[2- dimeth stirred o 30 afford t directly 493 PATENT Attorney Docket No.: 51121-100WO2 Interm (dimet carbox 5 Step 1: 2-(tribu tert- butyl N , 9.488 m diluted d 10 and wa ude product ite solid. L Step 2: 15 Hydraz bromop resultin and ext L), dried over anhydrous Na2SO4, filtered and concentrated to afford crude product. The crude product was 20 purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.05% TFA). Pure fractions were evaporated to dryness to afford the title compound (778 mg) as a white solid. LCMS ( Step 3: 25 Sodium 2- amino- 58 mmol) i re was diluted and washed ng 30 mixture (containing 0.05% FA)). Pure fractions were evaporated to dryness to afford the title compound (285 mg) as a white solid. LCMS (ESI) m / z [M+H]+=343.09. 494 PATENT Attorney Docket No.: 51121-100WO2 Step 4: mate Pd(OA tert- butyl (R -1- methyl for 5 overnig h EtOAc er anhydr chroma e compo 10 Step 5: HCl in -(4- fluoro-1 e resultin nder 15 reduce ext step dir Step 6: yl)phen 20 HATU ( azol- 3-yl)ph butoxyc mmol) and DI ature for 1 h. nic 25 layers concen nt 0 to 100% e title compo 30 Step 7: methyl HCl in (dimeth n-1- yl)-3,3- xture 35 was sti ssure to affor without 495 PATENT Attorney Docket No.: 51121-100WO2 Interm - fluoro- carbox 5 Step 1: Tetrabu [(1R)- 1-(4-br 97 g, 15.815 temper mL) 10 and ext , dried over an rude product s a light ye 15 Step 2: ethyl]ca Pd(OA enyl)- 2-(2-m 2.084 mmol) 0°C 20 for 4 h cted with Et r anhydr product a light yellow 25 Step 3: de HCl (4. methyl mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated 496 PATENT Attorney Docket No.: 51121-100WO2 under r used in the n Step 4 5 methox HATU methox R)-1- [(2S)-2 76.11 mg, 0.5 red at 10 room te sh chroma e compo Step 5: 15 yl)phen HCl (4. -[4-(4- fluoro-2 3,3- dimeth s stirred to 20 afford t tly without Interm n-1- yl]-N-m 25 Step 1: K2CO3 (8.06 g, 58.302 mmol) was added to a stirred solution of 1-tert-butyl 3-methyl 4-oxopiperidine-1,3- 30 dicarboxylate (5 g, 19.434 mmol) and oxane-4-carboximidamide hydrochloride (3.20 g, 19.434 mmol) in 497 PATENT Attorney Docket No.: 51121-100WO2 DMF (50 mL). The resulting mixture was stirred at 80°C for 3 h under nitrogen atmosphere. The resulting mixture anic layers as concen graphy 5 (elution to drynes Step 2 PPh3 (1 H,8H- 10 pyrido[ der nitroge was stirred mL) and ext mL), dried o The 15 crude p mg) as a light Step 3: 5H,7H, 20 Pd2(db solutio , 0.707 mg, 0.707 rred at 80°C d 25 extract ied over an rude produc (contai SI) m / z [M 30 Step 4: hydro- 2H-1,5- HCl (4. (difluor ne-6- 35 carbox ature for 1h. oduct (153 m tion. LCMS 498 PATENT Attorney Docket No.: 51121-100WO2 Step 5: 5H,7H, TEA (9 n-4- yl)-5H, g, 5 0.321 resultin er (20 mL) an mL), dried o The crude p 2 mg) 10 as a wh Interm H- pyrazo 15 Step 1: DAST ( ehyde (5 g, 26 ature. The res c (200 mL x 3) 20 Na2SO gel column ow liquid. L Step 2: 25 A mixtu mol) and NH lting mixture e crude p ord 499 PATENT Attorney Docket No.: 51121-100WO2 the title 6.71 (dd, J = Step 3: 5 Cu(OA (1 g, 5.631 dioxan ted with wa ganic layers as 10 concen 18 silica g 4 nm) to affor Step 4: 15 yl)prop XantPh pyrazol niline (561.13 mol) in dioxan he 20 mixture ere combin rated to give gradien yellow 25 Interm methyl Step 1: 6-chloro-5-fluoro-2-methoxypyridin-3-amine 500

[0003]

[0004]

[0005]

[0006]

[0007]

[0008]

[0009]

[0010]

[0011]

[0012]

[0013]

[0014] Compound # Structure

[0015]

[0016]

[0017] Compound # Structure

[0018] Compound # Structure

[0019] Compound # Structure

[0020] Compound # Structure

[0021]

[0022]

[0023]

[0024] In another aspect, the disclosure features a pharmaceutical composition including any of the foregoing compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

[0025] In another aspect, the invention features a method of decreasing the levels and / or activity of a CBP in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0026] In another aspect, the invention features a method of decreasing the levels of or activity of a MYC in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0027] In another aspect, the invention features a method of decreasing the levels of or activity of a AR, i.e. androgen receptor, in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0028] In some embodiments, the cell is a cancer cell.

[0029] In another aspect, the invention features a method of treating a CBP-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0030] In some embodiments, the CBP-related disorder is cancer.

[0031] In a further aspect, the invention features a method of inhibiting CBP, the method involving contacting a cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.

[0032] In an aspect, the disclosure features a method of inhibiting the level and / or activity of CBP in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0033] In another aspect, the invention features a method of treating a disorder related to a EP300 loss of function mutation in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0034] In some embodiments, the disorder related to a EP300 loss of function mutation is cancer. In other embodiments, the subject is determined to have a EP300 loss of function disorder, for example, is determined to have a EP300 loss of function cancer (for example, the cancer has been determined to include cancer cells with loss of EP300 function).

[0035] In another aspect, the invention features a method of inducing apoptosis in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.

[0036] In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.

[0037] In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, gastric cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, neuroblastoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

[0038] In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, head and neck cancer, prostate cancer, acute leukemia, gastric cancer, or breast cancer.

[0039] In some embodiments, the cancer is gastric cancer.

[0040] In some embodiments, the breast cancer is found to be ER positive i.e. the cancer cells contain estrogen receptors.

[0041] In some embodiments, the breast cancer is found to be ER negative i.e. cancer cells do not contain estrogen receptors.

[0042] In some embodiments, the prostate cancer is found to be AR positive i.e. cancer cells contain androgen receptors.

[0043] In some embodiments, the prostate cancer is CRPC i.e. castration-resistant prostate cancer.

[0044] In some embodiments, the prostate cancer is CRPC i.e. castration-sensitive prostate cancer.

[0045] In an aspect, the disclosure features a method of treating a CBP-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof. In some embodiments, the CBP-related disorder is cancer. In some embodiments, the CBP-related disorder is infection.

[0046] In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt’s lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (1LC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, Diffuse large B cell lymphoma (DLBCL), testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T- cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis;; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0047] In some embodiments of any of the foregoing methods, the cancer is a drug resistant cancer or has failed to respond to a prior therapy (e.g., vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 inhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, perjeta, tamoxifen, xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inihibitors, alimta, abraxane, Adriamycin®, gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, ARN810, an mTOR inhibitor, topotecan, gemzar, a VEGFR2 inhibitor, a folate receptor antagonist, demcizumab, fosbretabulin, or a PDL1 inhibitor).

[0048] In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing’s sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T- cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); Diffuse large B cell lymphoma (DLBCL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis;; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0049] In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

[0050] In some embodiments of any of the foregoing methods, the cancer has or has been determined to have CBP mutations. In some embodiments of any of the foregoing methods, the GBP mutations are homozygous. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an EP300 mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, a EP300 mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the foregoing methods, the cancer has, or has been determined to have, a KRAS mutation. In some embodiments of any of the foregoing methods, the CBP mutation is chromosomal translocation.

[0051] In another aspect, the disclosure provides a method of treating a disorder related to CBP (e.g., cancer or viral infections) in a subject in need thereof. This method includes contacting a cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the disorder is a viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1 ), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, varicella-zoster virus), Papillomaviridae family (e.g., Human Papillomavirus (HPV, HPV E1 )), Parvoviridae family (e.g., Parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., Measles virus), Togaviridae family (e.g., Rubella virus). In some embodiments, the disorder is Coffin Siris, Neurofibromatosis (e.g., NF-1 , NF-2, or Schwannomatosis), or Multiple Meningioma.

[0052] In another aspect, the disclosure provides a method of treating gastric cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.

[0053] In another aspect, the disclosure provides a method of treating inflammatory and / or autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.

[0054] In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis.

[0055] In some embodiments, the inflammatory and / or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, refractory, moderate- to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (postpolycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109 / L, polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile idiopathic arthritis. In some embodiments, the inflammatory and / or autoimmune disorder is non-infectious non- anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus.

[0056] In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.

[0057] In some embodiments, the method further comprises administering to the subject a JAK inhibitor.

[0058] In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

[0059] In another aspect, the disclosure provides a method of treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway, the method including administering to the subject an effective amount of a compound of the present disclosure.

[0060] In some embodiments, the member of the JAK-STAT pathway is a janus kinase (JAK).

[0061] In some embodiments, the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT).

[0062] In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.

[0063] In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, refractory, moderate-to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109 / L, polycythemia vera, steroid- refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile idiopathic arthritis.

[0064] In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is non-infectious non-anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus. In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.

[0065] In another aspect, the disclosure provides a method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.

[0066] In another aspect, the disclosure provides a method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.

[0067] In another aspect, the disclosure provides a method of suppressing a memory CD8+T cell response in a subject in a subject having or at risk of developing an inflammatory response, including administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutical composition thereof.

[0068] An aspect of the present invention relates to a method of treating a disorder related to CBP such as inflammation and / or autoimmune disorders in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced T cell (e.g., CD8+memory T cells) activity, (b) reduced inflammation, (c) reduced thrombopoiesis, (d) reduced B cell proliferation, (e) increased survival of subject, and (f) increased progression free survival of a subject.

[0069] In some embodiments, treating an inflammatory disorder and / or autoimmune disorder can result in a reduction in T cell (e.g., CD8+memory T cells) activity. In some embodiments, for example, after treatment, T cell (e.g., CD8+memory T cells) activity is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.

[0070] In some embodiments, treating an inflammatory disorder and / or autoimmune disorder can result in a reduction in inflammation. In some embodiments, for example, after treatment, inflammation is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.

[0071] In some embodiments, treating an inflammatory disorder and / or autoimmune disorder can result in a change in cytokine signaling, typically when phosphorylation within the JAK-STAT pathway is altered (e.g., by JAK inhibition, or a downstream affect such as CBP degradation). In some embodiments, inhibiting JAK2 may affect phosphorylation of EPO, TPO, GM-CSF, IL-3, IL-5, IL-12, IL-23, INF-y, IL-6, IL- 1 1 , IL-13, IL-25, IL-27, and / or IL-31 , which in turn can affect the immune system response. Other cytokines that interact with JAK1 , JAK3, and / or TYK2 include IL-10, IL-22, type 1 IFNs (a / p) , IL-2, IL-4, IL- 7, IL-9, IL-15, and IL-21 .

[0072] In another aspect, the disclosure provides a method for treating a viral infection in a subject in need thereof. This method includes administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1 ), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, varicella-zoster virus), Papillomaviridae family (e.g., Human Papillomavirus (HPV, HPV E1 )), Parvoviridae family (e.g., Parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., Measles virus), or Togaviridae family (e.g., Rubella virus).

[0073] In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0074] In another aspect, the invention features a method of reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0075] In another aspect, the invention features a method of suppressing metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0076] In another aspect, the invention features a method of suppressing metastatic colonization of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0077] In another aspect, the invention features a method of reducing the level and / or activity of CBP and / or EP300 in a melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophageal, stomach, or hematologic cancer cell, the method including contacting the cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0078] In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophagael, stomach, or hematologic cell is in a subject.

[0079] In some embodiments of any of the above aspects, the effective amount of the compound reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of CBP by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of CBP by at least 90% (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%). In some embodiments of any of the above aspects, the effective amount of the compound reduces the level of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to the percent of reduction of the level of EP300. In some embodiments, the effective amount of the compound that reduces the level of CBP by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to percent of reduction of the level of EP300. In some embodiments, the effective amount of the compound that reduces the level of CBP by at least 90% (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) as compared to the percent of reduction of the level of EP300.

[0080] In some embodiments, the effective amount of the compound reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the effective amount of the compound that reduces the level and / or activity of CBP by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).

[0081] In some embodiments of any of the above aspects, the effective amount of the compound reduces the level and / or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of EP300 by at least 90% (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0082] In some embodiments, the effective amount of the compound reduces the level and / or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the effective amount of the compound that reduces the level and / or activity of EP300 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).

[0083] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses CBP and / or EP300 protein and / or the cell or subject has been identified as expressing CBP and / or EP300. In some embodiments, the cancer expresses CBP protein and / or the cell or subject has been identified as expressing CBP. In some embodiments, the cancer expresses EP300 protein and / or the cell or subject has been identified as expressing EP300. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematologic cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments, the cancer is breast cancer (e.g., an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer). In some embodiments, the cancer is a bone cancer (e.g., Ewing’s sarcoma). In some embodiments, the cancer is a renal cell carcinoma (e.g., a Microphthalmia Transcription Factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). The metastatic cancer can include cells exhibiting migration and / or invasion of migrating cells and / or include cells exhibiting endothelial recruitment and / or angiogenesis. In other embodiments, the migrating cancer is a cell migration cancer. In still other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. The metastatic cancer can be a cancer spread via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces. Alternatively, the metastatic cancer can be a cancer spread via the lymphatic system, or a cancer spread hematogenously. In some embodiments, the effective amount of an agent that reduces the level and / or activity of CBP and / or EP300 is an amount effective to inhibit metastatic colonization of the cancer to the liver.

[0084] In some embodiments, the method further includes administering to the subject or contacting the cell with an anticancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation. In some embodiments, the anticancer therapy is a chemotherapeutic or cytotoxic agent, e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparaginespecific enzyme, bisphosphonates, antineoplastic, alkylating agent, DNA-Repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory, janus-associated kinase inhibitor, phosphinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor. Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum). A list of additional compounds having anticancer activity can be found in L. Brunton, B. Chabner and B. Knollman (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition, 201 1 , McGraw Hill Companies, New York, NY.

[0085] In some embodiments, the anticancer agent is a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib. In some embodiments, the method further comprises administering hormone therapy.

[0086] In some embodiments, the anticancer therapy and the compound of the invention are administered within 28 days of each other and each in an amount that together are effective to treat the subject.

[0087] In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the cancer has been determined to be resistant to chemotherapeutic or cytotoxic agents such as by genetic markers, or is likely to be resistant, to chemotherapeutic or cytotoxic agents such as a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent). In some embodiments, the cancer has failed to respond to one or more chemotherapeutic or cytotoxic agents. In some embodiments, the cancer is resistant or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp O, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0088] Chemical terms

[0089] The terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0090] For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.

[0091] The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). An alkylene is a divalent alkyl group.

[0092] The term “alkenyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0093] The term “alkynyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0094] The term “amino,” as used herein, represents -N(RN1 )2, wherein each RN1 is, independently, H, OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited RN1 groups can be optionally substituted; or two RN1 combine to form an alkylene or heteroalkylene, and wherein each RN2 is, independently, H, alkyl, or aryl. The amino groups of the compounds described herein can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(RN1)2).

[0095] The term “aryl,” as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,2-dihydronaphthyl, indanyl, and 1 H-indenyl.

[0096] The term “arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Unsubstituted arylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -C6 alkyl C6-C10 aryl, C1 -C10 alkyl C6-C10 aryl, or C1 -C20 alkyl C6-C10 aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each are further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.

[0097] The term “carbocyclyl,” as used herein, refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals. A carbocyclylene is a divalent carbocyclyl group. The term “cycloalkyl,” as used herein, refers to a saturated, non-aromatic, and monovalent monodi-, or tricyclic radical of 3 to 10, preferably 3 to 6 carbon atoms. The cycloalkyl group may be fully saturated or contain 1 or more double or triple bonds, provided that no ring is aromatic. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. The term “cycloalkoxy” as used herein, refers to cycloalkyl-O- groups (e.g., cyclopropoxy and cyclobutoxy).

[0098] The term “halo,” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0099] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group.

[0100] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkenyl groups. Examples of heteroalkenyl groups are an “alkenoxy” which, as used herein, refers alkenyl-O- A heteroalkenylene is a divalent heteroalkenyl group.

[0101] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkynyl groups. Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers alkynyl-O-. A heteroalkynylene is a divalent heteroalkynyl group.

[0102] The term “heteroaryl,” as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1 , 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.

[0103] The term “heteroarylalkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group. Unsubstituted heteroarylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1 -C6 alkyl C2-C9 heteroaryl, C1 -C10 alkyl C2-C9 heteroaryl, or C1 -C20 alkyl C2- C9 heteroaryl). In some embodiments, the alkyl and the heteroaryl each are further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.

[0104] The term “heterocyclyl,” as used herein, refers a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing 1 , 2, 3, or 4 ring atoms selected from N, O or S, wherein no ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1 ,3-dioxanyl. A heterocyclylene is a divalent heteroocyclyl group.

[0105] The term “hydroxyl,” as used herein, represents an -OH group.

[0106] The term “thiol,” as used herein, represents an -SH group. The term “carbonyl,” as used herein, represents an -C(O)- group.

[0107] The term “thiocarbonyl,” as used herein, represents an -C(S)- group.

[0108] The term “sulfonyl,” as used herein, represents an -S(O)2- group.

[0109] The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified. Substituents include, for example: alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).

[0110] Compounds described herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement.

[0111] Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and / or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e. , they do not rotate the plane of polarized light. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carboncarbon double bond may be in an E (substituents are on 25 opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds described herein may be prepared as individual isomers by either isomer- specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide 35 of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer. Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s), or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

[0112] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0113] Definitions

[0114] In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; and (iii) the terms “including” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.

[0115] As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.

[0116] As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.

[0117] As used herein, the term “CBP” refers to the Creb-binding protein in a human cell.

[0118] As used herein, the term “CBP-related disorder” refers to a disorder that is caused or affected by the level of activity of CBP.

[0119] As used herein, the term “CBP loss of function mutation” refers to a mutation in CBP that leads to the protein having diminished activity (e.g., at least 1% reduction in CBP activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity). Exemplary CBP loss of function mutations include, but are not limited to, a homozygous CBP mutation and chromosomal translocations.

[0120] As used herein, the term “CBP loss of function disorder” refers to a disorder (e.g., cancer) that exhibits a reduction in CBP activity (e.g., at least 1% reduction in CBP activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity).

[0121] The term “cancer” refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0122] As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.

[0123] By “determining the level of a protein” or RNA is meant the detection of a protein or an RNA, by methods known in the art, either directly or indirectly. “Directly determining” means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value. “Indirectly determining” refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners. Methods to measure RNA levels are known in the art.

[0124] As used herein, the terms “effective amount,” “therapeutically effective amount,” and “a “sufficient amount” of an agent that reduces the level and / or activity of CBP (e.g., in a cell or a subject) described herein refer to a quantity sufficient to, when administered to the subject, including a human, effect beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends on the context in which it is being applied. For example, in the context of treating cancer, it is an amount of the agent that reduces the level and / or activity of CBP sufficient to achieve a treatment response as compared to the response obtained without administration of the agent that reduces the level and / or activity of CBP. The amount of a given agent that reduces the level and / or activity of CBP described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, and / or weight) or host being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. Also, as used herein, a “therapeutically effective amount” of an agent that reduces the level and / or activity of CBP of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of an agent that reduces the level and / or activity of CBP of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.

[0125] As used herein, the term “inhibitor” refers to any agent which reduces the level and / or activity of a protein (e.g., CBP). Non-limiting examples of inhibitors include small molecule inhibitors, degraders, antibodies, enzymes, or polynucleotides (e.g., siRNA). By “level” is meant a level of a protein, or mRNA encoding the protein, as compared to a reference. The reference can be any useful reference, as defined herein. By a “decreased level” or an “increased level” of a protein or RNA is meant a decrease or increase, respectively, in a protein or RNA level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01 -fold, about 0.02-fold, about 0.1 -fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1 .2-fold, about 1 .4-fold, about 1 .5-fold, about 1 .8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). A level of a protein may be expressed in mass / vol (e.g., g / dL, mg / mL, pg / mL, ng / mL) or percentage relative to total protein in a sample.

[0126] By “decreasing the activity of CBP” is meant decreasing the level of an activity related to CBP, or a related downstream effect. The activity level of a CBP may be measured using any method known in the art, e.g., HIBit assay.

[0127] The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human. Typically, a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

[0128] A “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound, for example, any compound of Formula I. Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid.

[0129] The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0130] By a “reference” is meant any useful reference used to compare protein or RNA levels. The reference can be any sample, standard, standard curve, or level that is used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. A “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound of the invention; a sample from a subject that has been treated by a compound of the invention; or a sample of a purified protein or RNA (e.g., any described herein) at a known normal concentration. By “reference standard or level” is meant a value or number derived from a reference sample. A “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound of the invention. In preferred embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein or RNA, e.g., any described herein, within the normal reference range can also be used as a reference.

[0131] As used herein, the term “subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.

[0132] As used herein, the terms "treat," "treated," or "treating" mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Compounds of the invention may also be used to “prophylactically treat” or “prevent” a disorder, for example, in a subject at increased risk of developing the disorder.

[0133] As used herein, the terms “variant” and “derivative” are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein. A variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material. The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[0134] As used herein, the term “degrader” refers to a small molecule compound including a degradation moiety, wherein the compound interacts with a protein (e.g., CBP) in a way which results in degradation of the protein, e.g., binding of the compound results in at least 5% reduction of the level of the protein, e.g., in a cell or subject. As used herein, the term “degradation moiety” refers to a moiety whose binding results in degradation of a protein, e.g., CBP. In one example, the moiety binds to a protease or a ubiquitin ligase that metabolizes the protein, e.g., CBP.

[0135] BRIEF DESCRIPTION OF THE DRAWINGS

[0136] Fig. 1a is a graph illustrating the effect on tumor volume on the tumor model AGS, in response to Compound 1 a (10 mg / kg, BID for 5weeks, subcutaneous) and Compound 1 (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg QD for 5 weeks, subcutaneous) over 55 days as described in Example 869.

[0137] Fig. 1b is a graph illustrating the effect on body weight on the tumor model AGS, in response to Compound 1 a (10 mg / kg, BID for 5weeks, subcutaneous) and Compound 1 (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg QD for 5 weeks, subcutaneous) over 55 days as described in Example 869.

[0138] Fig. 1c is a graph illustrating the effect on % CBP on the tumor model AGS, in response to Compound 1 (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg for 5 weeks, subcutaneous) as described in Example 869.

[0139] Fig. 1d is a graph illustrating the effect on % MYC on the tumor model AGS, in response to Compound 1 (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg for 5 weeks, subcutaneous) as described in Example 869.

[0140] Fig. 2a is a graph illustrating the effect on tumor volume on the tumor model LU99, in response to Compound 1 a (50mg / kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg / kg QID for 3 weeks, 10 mg / kg QID for 3 weeks, 10 mg / kg BID for 3 weeks or 50 mg / kg for 3 weeks, subcutaneous) over 27 days as described in Example 870.

[0141] Fig. 2b is a graph illustrating the effect on body weight on the tumor model LU99, in response to Compound 1 a (50mg / kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg / kg QID for 3 weeks, 10 mg / kg QID for 3 weeks, 10mg / kg BID for 3 weeks or 50 mg / kg for 3 weeks, subcutaneous) over 27 days as described in Example 870.

[0142] Fig. 2c is a graph illustrating the effect on % CBP on the tumor model LU99, in response to Compound 1 a (50mg / kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg / kg QID for 3 weeks, 10 mg / kg QID for 3 weeks, 10mg / kg BID for 3 weeks or 50 mg / kg for 3 weeks, subcutaneous) over 27 days as described in Example 870.

[0143] Fig. 2d is a graph illustrating the effect on % MYC on the tumor model LU99, in response in response to Compound 1 a (50mg / kg BID for 3 weeks, subcutaneous) and Compound 1 (3mg / kg QID for 3 weeks, 10 mg / kg QID for 3 weeks, 10mg / kg BID for 3 weeks or 50 mg / kg for 3 weeks, subcutaneous) over 27 days as described in Example 870.

[0144] Fig. 3a is a graph illustrating the effect on tumor volume on the tumor model A549, in response to Compound 1 a (50mg / kg QD for 5 weeks, subcutaneous) and Compound 1 (1 mg / kg QID for 5 weeks, 3 mg / kg QID for 5 weeks, 10mg / kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 871 .

[0145] Fig. 3b is a graph illustrating the effect on body weight on the tumor model A549, in response to Compound 1 a (50mg / kg QD for 5 weeks, subcutaneous) and Compound 1 (1 mg / kg QID for 5 weeks, 3 mg / kg QID for 5 weeks, 10mg / kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 871 .

[0146] Fig. 3c is a graph illustrating the effect on % CBP on the tumor model A549, in response in response to Compound 1 a (50mg / kg QD for 5 weeks, subcutaneous) and Compound 1 (1 mg / kg QID for 5 weeks, 3 mg / kg QID for 5 weeks, 10mg / kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 871 .

[0147] Fig. 3d is a graph illustrating the effect on % MYC on the tumor model A549, in response in response to Compound 1 a (50mg / kg QD for 5 weeks, subcutaneous) and Compound 1 (1 mg / kg QID for 5 weeks, 3 mg / kg QID for 5 weeks, 10mg / kg QD for 5 weeks, subcutaneous) over 27 days as described in Example 871 .

[0148] Fig. 4A are a series of images illustrating the effect of the combination of abemaciclib, fulvestrant, and DMSO over 14 days as described in Example 867 in MCF7 cells.

[0149] Fig. 4B are a series of images illustrating the effect of the combination of abemaciclib (e.g, 0 nM, 12.5nM, 25nM, or 50nM), fulvestrant (e.g. 0 nM, 0.05nM, 0.1 nM), and 1 nM Compound 140 over 14 days as described in Example 867 in MCF7 cells.

[0150] Fig. 5A are a series of images illustrating the effect of the combination of abemaciclib, fulvestrant, and DMSO over 14 days as described in Example 867 in T47D cells.

[0151] Fig. 5B are a series of images illustrating the effect of the combination of abemaciclib (e.g, 0 nM, 1 ,25nM, 2.5nM, or 5.0nM), fulvestrant (e.g. 0 nM, 0.05nM, 0.1 nM), and 1 nM Compound 140 over 14 days as described in Example 867 in T47D cells.

[0152] DETAILED DESCRIPTION OF THE INVENTION

[0153] The present disclosure features compositions and methods useful for the treatment of CBP- related disorders (e.g., cancer and infection). The disclosure further features compositions and methods useful for inhibition of the level and / or activity of CBP, e.g., for the treatment of disorders such as cancer (e.g., sarcoma) and infection (e.g., viral infection), e.g., in a subject in need thereof.

[0154] Compounds

[0155] Compounds described herein reduce the level of an activity related to CBP, or a related downstream effect, or reduce the level of CBP in a cell or subject. Exemplary compounds described herein have the structure according to Formula I.

[0156] A-L-B

[0157] Formula I, wherein

[0158] A is a CBP binding moiety;

[0159] B is a degradation moiety; and

[0160] L has the structure wherein

[0161] A1is a bond between the linker and A;

[0162] A2is a bond between B and the linker, or a pharmaceutically acceptable salt thereof.

[0163] CBP and Janus Kinase (JAK) Pathway

[0164] Protein kinases (PKs) regulate diverse biological processes including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer. Cytokines, low-molecular weight polypeptides or glycoproteins, regulate many pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and can modulate both pro-inflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. Signaling of a wide range of cytokines involves the Janus kinase family (JAKs) of protein tyrosine kinases and Signal Transducers and Activators of Transcription (STATs). There are four known mammalian JAKs: JAK1 (Janus kinase- 1 ), JAK2, JAK3 (also known as Janus kinase, leukocyte; JAKL; and L- JAK), and TYK2 (protein-tyrosine kinase 2). There are seven mammalian STAT family members that have been identified: STAT1 , STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6.

[0165] It has been observed that in memory CD8+ T cells, Janus kinase 2 (JAK2) hyperactivation is coupled to the phosphorylation of CBP, and that phosphorylated CBP is important for CD8+ memory T- cell recall response (J Biol Chem. 2019 Feb 15; 294(7): 2397-2406). It was suggested that JAK2- catalyzed phosphorylation allows CBP to bind with higher affinity to acetylated histone peptides such as H3 and increases the number of acetylated histone markers that CBP recognizes. This may indicate a mechanism that could contribute to initiation of transcriptional programs in memory CD8+ T cells. Further, it was observed that CBP is essential for conventional effector and memory CD8+ T-cell formation. Thus, treatment with JAK inhibitors (e.g., JAK2 inhibitors) may also inhibit CBP via non-phosphorylation of CBP.

[0166] The JAK-STAT pathway plays a role in transduction of cytokines and growth factor signals in inflammatory and autoimmune diseases. Globally approved JAK inhibitors include abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, and upadacitinib. Other JAK inhibitors include AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, and ritlecitinib.

[0167] In one aspect, the present disclosure provides a method of treating inflammatory and / or autoimmune disorders, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the method further comprises administering to the subject a JAK inhibitor. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib. In some embodiments, the JAK inhibitor is AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib. Filgotinib, oclacitinib, and upadacitinib are JAK1 inhibitors. Filgotinib (e.g., Jyseleca, Europe) is approved for use in moderate to severe rheumatoid arthritis. Upadacitinib (e.g., Rinvoq) is approved for use in moderate-to-severe rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, and refractory, moderate-to-severe atopic dermatitis. Filgotinib showed promising response to Crohn’s disease and ulcerative colitis and was also tested in psoriatic arthritis. Oclacitinib is approved for treatment of atopic dermatitis and pruritus associated with allergic dermatitis in dogs. In some embodiments, the JAK inhibitor is a JAK1 inhibitor. In some embodiments, the JAK inhibitor is filgotinib, oclacitinib, or upadacitinib. In some embodiments, the JAK inhibitor is filgotinib or upadacitinib. In some embodiments, the inflammatory and / or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, and refractory, moderate-to-severe atopic dermatitis.

[0169] Fedratinib and pacritinib are JAK2 inhibitors. Fedratinib (e.g., Inrebic) is approved for use in intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. Pacritinib (e.g., Vonjo) is approved for use in intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109 / L. Pacritinib acts as an inhibitor of both JAK2 and FLT3 that could be used to overcome resistance in existing acute myeloid leukaemia (AML) treatments. Pacritinib was tested in glioblastoma multiforme in combination with temozolomide. In some embodiments, the JAK inhibitor is a JAK2 inhibitor. In some embodiments, the JAK2 inhibitor is fedratinib or pacritinib. In some embodiments, the disorder is intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis or intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109 / L.

[0170] Abrocitinib, baricitinib, and ruxolitinib are JAK1 / 2 inhibitors. Abrocitinib (e.g., Cibinqo) is approved for use in refractory, moderate-to-severe atopic dermatitis. Baricitinib (e.g., Olumiant) is approved for use in moderate-to-severe rheumatoid arthritis. Ruxolitinib (e.g., Jakafi) is approved for use in intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and postessential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease. Baricitinib was authorized for emergency use for treatment of COVID-19 in combination with remdesivir. Baricitinib was shown to improve symptoms of systemic lupus erythematosus and decrease inflammation / pruritus in atopic dermatitis when used with topical corticosteroids. Baricitinib is being studied in Aicardi-Goutieres syndrome and primary Sjogren’s syndrome. The combination of ruxolitinib and ERBB1 / 2 / 4 inhibitors also displayed synergistic anticancer activity against lung, breast, and ovarian cancer cells. In some embodiments, the JAK inhibitor is a JAK1 / 2 inhibitor. In some embodiments, the JAK1 / 2 inhibitor is abrocitinib, baricitinib, or ruxolitinib. In some embodiments, the inflammatory and / or autoimmune disorder is refractory, moderate-to-severe atopic dermatitis, moderate-to-severe rheumatoid arthritis, intermediate or high-risk myelofibrosis (including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis), polycythemia vera, steroid-refractory acute graft-versus-host disease, or chronic graft-versus-host disease. In some embodiments, the inflammatory and / or autoimmune disorder is a result of a COVID-19 infection in the lung. In some embodiments, the inflammatory and / or autoimmune disorder is systemic lupus erythematosus, inflammation / pruritus in atopic dermatitis, Aicardi- Goutieres syndrome or primary Sjogren’s syndrome.

[0171] Tofacitinib is a JAK1 / 2 / 3 inhibitor. Tofacitinib (e.g., Xeljanz) is approved for use in active psoriatic arthritis, moderate-to severe-rheumatoid arthritis, moderate-to-severe active ulcerative colitis, particular course juvenile idiopathic arthritis, and active ankylosing spondylitis. Trials are underway to study tofacitinib in COVID-19 related lung problems. Tofacitinib is being studied in combination with abrocitinib for treatment of toxic epidermal necrolysis. In some embodiments, the JAK inhibitor is a JAK1 / 2 / 3 inhibitor. In some embodiments, the JAK1 / 2 / 3 inhibitor is tofacitinib. In some embodiments, the inflammatory and / or autoimmune disorder is active psoriatic arthritis, moderate-to severe-rheumatoid arthritis, moderate-to-severe active ulcerative colitis, particular course juvenile idiopathic arthritis, and active ankylosing spondylitis. In some embodiments, the inflammatory and / or autoimmune disorder is a result of a COVID-19 infection in the lung. In some embodiments, the inflammatory and / or autoimmune disorder is toxic epidermal necrolysis.

[0172] Delgocitinib is a non-selective JAK inhibitor that is approved for use in atopic dermatitis in Japan. Delgocitinib was tested and showed improvement in psoriasis and chronic hand eczema. In some embodiments the JAK inhibitor is delgocitinib. In some embodiments, the inflammatory and / or autoimmune disorder is atopic dermatitis. In some embodiments, the inflammatory and / or autoimmune disorder is psoriasis or chromic hand eczema.

[0173] Peficitinib is a pan-JAK inhibitor approved for use in rheumatoid arthritis in Japan. In some embodiments the pan-JAK inhibitor is peficitinib. In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis.

[0174] Brepocitinib is being evaluated in active non-infectious non-anterior uveitis, dermatomyositis, and cicatricial alopecia.

[0175] Cerdulatinib is being evaluated for relapsed / refractory peripheral T-cell lymphoma, chronic lymphcytic leukemia, small lymphocytic lymphoma, B-cell non-hodgkin lymphoma, follicular lymphoma, T- cell lymphoma and vitiligo.

[0176] Decernotinib is a JAK3 inhibitor being evaluated for rheumatoid arthritis.

[0177] Deucravacitinib is being evaluated in pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pstulosis, Crohn’s disease, ulcerative colitis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, and systemic lupus erythematosus, among others.

[0178] Gandotinib is a JAK2 inhibitor being evaluated for myeloproliferative disorders including myelofibrosis, graft-versus host disease, and rheumatoid arthritis.

[0179] Itacitinib is a JAK1 inhibitor being evaluated for acute graft-versus-host disease.

[0180] Momelotinib is being evaluated for primary myelofibrosis, polycythemia vera myelofibrosis, postessential thrombocytopenia myelofibrosis, and non-small cell lung cancer, among others.

[0181] Nezulcitinib is being evaluated in COVID-19 related lung problems.

[0182] Ritlecitinib is a JAK3 inhibitor being evaluated for nonsegmental vitiligo, cutaneous T-cell lymphoma, cicatricial alopecia, and alopecia areata. In some embodiments, the JAK inhibitor is brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, icacitinib, momelotinib, nezulcitinib.or ritlecitinib.

[0183] In one aspect, the present disclosure provides a method of treating inflammatory and / or autoimmune disorders, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, a compound as described herein is administered as a replacement therapy for treating a disease associated with JAK activity. In some embodiments, the disease associated with JAK activity is an inflammatory and / or autoimmune disorder.

[0185] In some embodiments, the inflammatory and / or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, refractory, moderate- to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (postpolycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109 / L, polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile idiopathic arthritis.

[0186] In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, ulcerative colitis, Crohn’s disease, atopic dermatitis, polycythemia vera, graft-versus-host disease, or juvenile idiopathic arthritis.

[0187] In some embodiments, the inflammatory and / or autoimmune disorder is non-infectious non- anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus.

[0188] In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.

[0189] In one aspect, the present disclosure provides a method of treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, ulcerative colitis, Crohn’s disease, atopic dermatitis, polycythemia vera, graft-versus-host disease, or juvenile idiopathic arthritis, the method comprising administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.

[0190] In another aspect, the present disclosure provides a method of treating inflammatory and / or autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis. In some embodiments, the method further comprises administering to the subject a JAK inhibitor. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

[0191] In another aspect, the present disclosure provides a method of treating a disease, disorder, or medical condition mediated by JAK activity, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder, or medical condition mediated by JAK activity is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.

[0192] In another aspect, the present disclosure provides a method of treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the member of the JAK-STAT pathway is a janus kinase (JAK). In some embodiments, the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT). In some embodiments, the treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.

[0193] In another aspect, the present disclosure provides a method of inducing immune tolerance in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.

[0194] In another aspect, the present disclosure provides a method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.

[0195] In another aspect, the present disclosure provides a method of suppressing a memory CD8+ T cell response in a subject in a subject having or at risk of developing an inflammatory response, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.

[0196] In another aspect, the present disclosure provides a method of treating an autoimmune disease, a cancer, a myeloproliferative disorder, an inflammatory disease, a bone resorption disease, or organ transplant rejection in a patient in need thereof, the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder. In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is a skin disorder. In some embodiments, the skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, Castleman's disease or pancreatic cancer. In some embodiments, the cancer is lymphoma, leukemia, or multiple myeloma. In some embodiments, the myeloproliferative disorder is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD). In some embodiments, the myeloproliferative disorder is myelofibrosis. In some embodiments, the myeloproliferative disorder is primary myelofibrosis (PMF). In some embodiments, the myeloproliferative disorder is post polycythemia vera myelofibrosis (Post-PV MF). In some embodiments, the myeloproliferative disorder is post- essential thrombocythemia myelofibrosis (Post-ET MF).

[0197] CDK4 / 6 Inhibitors

[0198] CDK4 / 6 inhibitors are a class of drugs that target cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), enzymes crucial for cell division and proliferation. By inhibiting these kinases, CDK4 / 6 inhibitors disrupt the cell cycle, preventing cancer cells from growing and dividing. These inhibitors are primarily used in the treatment of hormone receptor-positive (HR+), HER2-negative breast cancer, both in early and metastatic stages. Common CDK4 / 6 inhibitors include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).

[0199] CDK4 / 6 inhibitors are often administered in combination with hormone therapy, such as aromatase inhibitors or fulvestrant, to enhance their effectiveness. This combination therapy has been shown to improve progression-free survival and overall survival in patients. Side effects of CDK4 / 6 inhibitors can include fatigue, gastrointestinal disturbances, and bone marrow suppression, but they are generally less severe than those associated with traditional chemotherapy.

[0200] These inhibitors represent a significant advancement in targeted cancer therapy, offering a more precise approach to treating certain types of breast cancer and improving patient outcomes.

[0201] The dosing of CDK4 / 6 inhibitors varies depending on the specific drug and clinical setting. Palbociclib is typically administered at a dose of 125 mg once daily for 21 days, followed by a 7-day break. Ribociclib is given at 600 mg once daily for 21 days, with a 7-day off period. Abemaciclib is dosed continuously at 200 mg twice daily. Dose adjustments are often necessary based on the patient's tolerance and side effects, such as neutropenia or diarrhea. For instance, abemaciclib may be reduced to 150 mg or 100 mg twice daily if adverse reactions occur. These dosing schedules are designed to maximize therapeutic efficacy while managing potential side effects, ensuring that patients receive the most effective treatment with minimal discomfort.

[0202] In another aspect, the present disclosure provides a method of treating cancer the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof (see e.g., Figs. 4A / 4B and 5A / 5B and Example 867). In some embodiments, the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophogeal, stomach, or lung cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is metastatic. In some embodiments, the subject or cancer has a EP300 loss of function mutation.

[0203] In another aspect, the present disclosure provides a method of treating gastric cancer the method including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is metastatic. In some embodiments, the subject or cancer has a EP300 loss of function mutation.

[0204] Pharmaceutical Uses

[0205] The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to modulate the level, status, and / or activity of CBP, e.g., by inhibiting the activity or level of the CBP in a cell within a mammal.

[0206] An aspect of the present invention relates to methods of treating disorders related to CBP such as cancer in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, and (i) increased progression free survival of a subject.

[0207] Treating cancer can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. For example, the size of a tumor may be measured as a diameter of the tumor.

[0208] Treating cancer may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0209] Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).

[0210] An aspect of the present invention relates to methods of treating disorders related to CBP such as inflammation and / or autoimmune disorders in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced T cell (e.g., CD8+memory T cells) activity, (b) reduced inflammation, (c) reduced thrombopoiesis, (d) reduced B cell proliferation, (e) increased survival of subject, and (f) increased progression free survival of a subject.

[0211] Treating inflammatory disorders and / or autoimmune disorders can result in a reduction in T cell (e.g., CD8+memory T cells) activity. For example, after treatment, T cell (e.g., CD8+memory T cells) activity is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. T cell activity may be measured by any reproducible means of measurement.

[0212] Treating inflammatory disorders and / or autoimmune disorders can result in a reduction in inflammation. For example, after treatment, inflammation is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. T cell activity may be measured by any reproducible means of measurement.

[0213] Treating inflammatory disorders and / or autoimmune disorders can result in a change in cytokine signaling, typically when phosphorylation within the JAK-STAT pathway is altered (e.g., by JAK inhibition, or a downstream affect such as CBP degradation). Specifically, each cytokine receptor is paired with a JAK pair. When the JAK pair is cross-linked by its cytokine, the JAKs phosphorylate each other and also phosphorylate the cytokine receptor, which creates a STAT binding site for a STAT to then also become phosphorylated. In some embodiments, inhibiting JAK2 may affect phosphorylation of EPO, TPO, GM- CSF, IL-3, IL-5, IL-12, IL-23, INF-y, IL-6, IL-11 , IL-13, IL-25, IL-27, and / or IL-31 , which in turn can affect the immune system response. Other cytokines that interact with JAK1 , JAK3, and / or TYK2 include IL-10, IL-22, type 1 IFNs (a / p), IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 .Treating cancer, inflammatory disorders, and / or autoimmune disorders can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[0214] Treating cancer, inflammatory disorders, and / or autoimmune disorders can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[0215] Combination Therapies

[0216] A method of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer, inflammatory disorders, and / or autoimmune disorders or symptoms associated therewith, or in combination with other types of therapies to treat cancer, inflammatory disorders, and / or autoimmune disorders. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)). In this case, dosages of the compounds when combined should provide a therapeutic effect.

[0217] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1 -TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2"-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041 -1047 (2000).

[0218] In some embodiments, the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-l- 131 ); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOLIRIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab); NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (ado- trastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibody-drug conjugates.

[0219] The second agent may be a therapeutic agent which is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and / or surgical excision of tumor tissue.

[0220] The second agent may be a checkpoint inhibitor. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody or fusion a protein such as ipilimumab / YERVOY® or tremelimumab). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / OPDIVO®; pembrolizumab / KEYTRUDA®; pidilizumab / CT-011 ). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2 / lg fusion protein such as AMP 224). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, A2aR, B-7 family ligands, or a combination thereof.

[0221] In some embodiments, the anti-cancer therapy is a T cell adoptive transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. The T cell may be modified to express a chimeric antigen receptor (CAR). CAR modified T (CAR-T) cells can be generated by any method known in the art. For example, the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art, may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466;

[0222] 6,905,681 ; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041 ; and U.S. Patent Application Publication No. 20060121005.

[0223] The second agent may be a Janus Kinase (JAK) inhibitor. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, AG-490, brepocitinib, cerdulatinib, decernotinib, deucravacitinib, gandotinib, gusacitinib, itacitinib, momelotinib, nezulcitinib, or ritlecitinib.

[0224] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1 -7, 1 -14, 1 -21 or 1 -30 days before or after the second therapeutic agent.

[0225] Pharmaceutical Compositions

[0226] The pharmaceutical compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

[0227] The compounds described herein may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the methods described herein. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, intratumoral, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0228] A compound described herein may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound described herein may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. A compound described herein may also be administered parenterally. Solutions of a compound described herein can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2012, 22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF36), published in 2018. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or nonaqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter. A compound described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional, or systemic administration also may be appropriate. A compound described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm intervals. In the case of surgical intervention, the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection. Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature.

[0229] The compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

[0230] Dosages

[0231] The dosage of the compounds described herein, and / or compositions including a compound described herein, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds described herein are administered to a human at a daily dosage of, for example, between 0.01 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg).

[0232] Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1 -50 mg / kg (e.g., 0.25-25 mg / kg).

[0233] Kits

[0234] The invention also features kits including (a) a pharmaceutical composition including an agent that reduces the level and / or activity of CBP in a cell or subject described herein, and (b) a package insert with instructions to perform any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent that reduces the level and / or activity of CBP in a cell or subject described herein, (b) an additional therapeutic agent (e.g., an anti-cancer agent), and (c) a package insert with instructions to perform any of the methods described herein.

[0235] Examples

[0236] ACN acetonitrile Ac2O acetic anhydride tBuOK potassium tert-butoxide DCM dichloromethane DIEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide dppf bis(diphenylphosphino)ferrocene ESI electrospray ionization

[0237] Et3N or TEA triethylamine EtOAc ethyl acetate EtOH ethyl alcohol FA formic acid FCC flash column chromatography h hours HATU 2-(3H-[ 1 ,2,3 ]triazolo[ 4,5-b ]pyridin-3-yl)-l, 1 ,3,3- tetramethylisouronium

[0238] HPLC high performance liquid chromatography KOAc potassium acetate L liter LCMS liquid chromatography / mass spectrometry □HMDS lithium hexamethyldisilazide MeOH methyl alcohol mL milliliter mmol millimole mg milligrams MHz megahertz MS mass spectrometry MTBE methyl t-butylether m / z mass / charge ratio NBS N-bromosuccinimide nm nanometer NMR nuclear magnetic resonance PPm parts per million rt room temperature RT retention time Ruphos Pd 3G (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1 ,1 '- biphenyl)[2-(2'- amino-1 ,1 '-biphenyl)]palladi um(l I) methanesulfonate

[0239] SFC supercritical fluid chromatography

[0240] TFA trifluoroacetic acid

[0241] THF tetrahydrofuran

[0242] XPhos Pd 3G (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '- biphenyl)[2-(2'-amino-1 ,1 '-biphenyl)]palladium(l I) methanesulfonate

[0243] Materials

[0244] Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere.

[0245] Preparation of Intermediates

[0246] Intermediate 1 : Preparation of 1-(3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-

[0247] (tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

[0248] Step 1. tert-Butyl 3-amino-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0249] A solution of tert-butyl 3-cyano-4-oxopiperidine-1 -carboxylate (20 g, 89 mmol) in EtOH (200 mL) was treated with hydrazine hydrate (80%) (6.7 g, 130 mmol) at 0°C. The reaction mixture was stirred for 2 h at 80°C. The reaction mixture was concentrated under reduced pressure, diluted with water (1 .5 L) and extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: CH2CI2 I MeOH (20:1 )) affording the title compound (16 g, 67 mmol) as white solid. LCMS (ESI) m / z [M+H]+= 239.1 . Step 2. tert-Butyl 3-bromo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0250] CuBr2 (15.5 g, 69 mmol) was added to a stirred solution of tert-Butyl 3-amino-1 ,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (15 g, 63 mmol) in ACN (100 mL). 3-methylbutyl nitrite (11 .1 mL, 63 mmol) was then added dropwise at 0°C. The reaction mixture was stirred for an additional 3 h at 60°C. The mixture was allowed to cool down to room temperature. The mixture was diluted with EtOAc (500 mL), washed with saturated NH4CI (aq.) (500 mL x 7), brine (500 mL x 2), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: PE / THF (3:1)) affording the semi-pure product, which was then purified by trituration with PE I EtOAc (5:1 ) to afford title compound (10.2 g, 34 mmol) as white solid. LCMS (ESI) m / z [M+H]+ = 302.0

[0251] Step 3. tert-Butyl 3-bromo-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-5-carboxylate

[0252] Cs2CO3 (32.4 g, 99.3 mmol) was added to a stirred solution of tert-Butyl 3-bromo-1 ,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (10 g, 33.1 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (8.95 g, 49.6 mmol) in DMF (100 mL). The reaction mixture was stirred for 3.5 h at 80°C. The resulting mixture was then diluted with water (700 mL) and extracted with EtOAc (700 mL x 2). The organic layers were combined and washed with brine (1 L x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by FCC (Eluent: PE I (THF:MTBE=1 :1) (1 .5:1)) to afford two isomers. The second eluting isomer was collected and concentrated under reduced pressure. The residue was purified by reverse FCC (C18 silica gel; mobile phase, ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford the title compound (6.7 g, 17 mmol) as a white solid. LCMS (ESI) m / z [M+H]+ = 386.1 .

[0253] Step 4. tert-Butyl 3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)- 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate t-BuONa (2.31 g, 24.1 mmol) and RuPhos Pd 3G (671 mg, 0.80 mmol) were added to a stirred solution of tert-Butyl 3-bromo-1 -(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate (3.1 g, 8.0 mmol) and 7-(difluoromethyl)-1 ,2,3,4-tetrahydroquinoline (1 .5 g, 8.0 mmol) in 1 ,4- dioxane (30 mL). The reaction mixture was stirred for 8 h at 85°C. The resulting mixture was concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: PE I EtOAc (1 :1 )) affording the title compound (3.1 g, 6.3 mmol) as yellow solid. LCMS (ESI) m / z [M+H]+= 489.2.

[0254] Step 5. tert-Butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H- pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0255] NBS (1 .0 g, 5.6 mmol) was added in portions at 0 °C to a stirred solution of tert-Butyl 3-(7- (difluoromethyl)-3,4-dihydroquinolin-1 (2H)-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxylate (3.1 g, 6.3 mmol) in ACN (30.0 mL). After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: PE I EtOAc (1 :1 )) affording the title compound (3.5 g, 6.2 mmol) as yellow solid. LCMS (ESI) m / z [M+H]+= 567.2.

[0256] Step 6. 6-Bromo-7-(difluoromethyl)-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1 H- pyrazolo[4,3-c]pyridin-3-yl)-1 ,2,3,4-tetrahydroquinoline

[0257] A mixture of tert- Butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1 (2H)-yl)-1 -(tetrahydro-2H- pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3.5 g, 6.1 mmol) in DCM (28 mL) and TFA (7 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (700 mL) and extracted with EtOAc (700 mL x 3). The organic layers were combined and washed with brine (600 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, to afford the title compound (2.5 g, 5.3 mmol) as a yellow oil. LCMS (ESI) m / z [M+H]+ = 467.1 .

[0258] Step 7. 1-(3-(6-Bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)- 1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

[0259] AC2O (596 mg, 5.8 mmol) was added in portions at 0°C to a stirred mixture of 6-Bromo-7-(difluoromethyl)- 1 -(1 -(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl)-1 ,2,3,4- tetrahydroquinoline (2.5 g, 5.3 mmol) and TEA (1 .6 g, 15.9 mmol) in DCM (25.0 mL). After stirring at room temperature for 2 h, the reaction mixture was diluted with water (600 mL) and extracted with CH2CI2 (600 mL x 3). The organic layers were combined and washed with brine (500 mL x 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by FCC (Eluent: CH2CI2 1 MeOH (20:1 )) to afford the title compound (2.1 g, 4.1 mmol) as a yellow solid.1H NMR (300 MHz, DMSO-d6) 5 = 7.32 (s, 1 H), 7.12 - 6.59 (m, 2H), 4.37 - 4.24 (m, 1 H), 4.18 (s, 2H), 4.01 - 3.91 (m, 2H), 3.74 (t, J = 5.8 Hz, 2H), 3.62 - 3.55 (m, 2H), 3.49 (td, J = 11 .7, 2.3 Hz, 2H), 2.92 - 2.70 (m, 4H), 2.08 (s, 2H), 2.03 - 1 .89 (m, 5H), 1 .81 (dt, J = 9.4, 4.1 Hz, 2H) ppm. LCMS (ESI) m / z [M+H]+ = 509.1 .

[0260] Intermediate 2: Preparation of 1-(3-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran- 4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

[0261] Step 1. tert-Butyl 3-(3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0262] RuPhos Pd 3G (108 mg, 0.13 mmol) and t-BuONa (498 mg, 5.2 mmol) were added To a stirred solution of tert-butyl 3-bromo-1 -(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate (500 mg, 1.3 mmol) and tetrahydroquinoline (172 mg, 1.3 mmol) in dioxane (7 mL). The reaction mixture was stirred for 2 h at 80°C. The reaction mixture was then diluted with EtOAc (100 mL), washed with water (50 mL x 2) and brine (50 mL x 1 ). The organic layer was dried over Na2SO4, filtered and evaporated to afford the crude product. The residue was purified by FCC (Eluent: CH2CI21 MeOH (10:1 )) to afford the title compound (451 mg, 1.0 mmol) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 439.2.

[0263] Step 2. tert-Butyl 3-(6-bromo-3,4-dihydroquinolin-1 (2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0264] NBS (74.7 mg, 0.42 mmol) was added in portions at 0°C to a stirred solution of tert-butyl 3-(3,4- dihydroquinolin-1 (2H)-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- carboxylate (230 mg, 0.52 mmol) in ACN (3 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with EtOAc (30 mL), washed with water (30 mL x 2) and brine (30 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5pm, n; Mobile Phase A: Water (0.1 %FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 63% B to 80% B in 9 min, 80% B; Wave Length: 254 / 220 nm; RT1 (min): 7.68) to afford the title compound (112 mg, 0.21 mmol) as a white solid. LCMS (ESI) m / z [M+H]+ = 517.4. Step 3. 6-Bromo-1-(1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)- 1 ,2,3,4-tetrahydroquinoline

[0265] A solution of tert-Butyl 3-(6-bromo-3,4-dihydroquinolin-1 (2H)-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (112 mg, 0.22 mmol) in DCM (0.9 mL) and TFA (0.3 ml_) was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to afford Intermediate 4 (138 mg, crude) as a yellow oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+ = 417.35.

[0266] Step 4. 1-(3-(6-Bromo-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

[0267] Acetic anhydride (37.1 mg, 0.36 mmol) was added dropwise at 0°C to a stirred solution of 6-Bromo-1 -(1 - (tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl)-1 ,2,3,4-tetrahydroquinoline (138 mg, 0.33 mmol) and TEA (100 mg, 0.99 mmol) in DCM (2 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure and purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford the title compound (84 mg, 0.18 mmol) as an off-white solid. LCMS (ESI) m / z [M+H]+ = 453.3.

[0268] Intermediate 3: Preparation of 1-(3-(6-Bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1- methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

[0269] Step 1. tert-Butyl 3-bromo-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0270] A solution of tert-butyl 3-bromo-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (500 mg, 1.66 mmol) in DMF (10 mL) was treated with NaH (119 mg, 5.0 mmol) at 0°C. After stirring at 0°C for 30 minutes, Mel (352 mg, 2.48 mmol) was added. The reaction mixture was stirred for additional 2 h at room temperature. The reaction was quenched by the addition of saturated NH4CI (aq.) (30 mL) at 0°C, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (Eluent: PE / THF (8:1 )) to obtain semi-pure product. The product was then purified by reversed- phase FCC (column, C18 silica gel; mobile phase, MeOH in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (450 mg, 1 .4 mmol) as a white solid. LCMS (ESI) m / z [M+H]+ = 315.9.

[0271] Step 2. tert-Butyl 3-(7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1 -methyl-1 ,4, 6, 7-tetrahydro- 5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0272] RuPhos Pd G3 (106 mg, 0.13 mmol) and t-BuONa (365 mg, 3.8 mmol) were added to a stirred solution of tert-butyl 3-bromo-1 -methyl-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (400 mg, 1 .26 mmol) and 7-(difluoromethyl)-1 ,2,3,4-tetrahydroquinoline (232 mg, 1.26 mmol) in dioxane (12 mL). The reaction mixture was stirred for 1 h at 100°C. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1 % FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (80 mg, 0.19 mmol) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 419.2.

[0273] Step 3. tert-Butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-methyl-1 ,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0274] NBS (29.7 mg, 0.17 mmol) was added at 0 °C to a stirred solution of tert-butyl 3-(7-(difluoromethyl)-3,4- dihydroquinoli n-1 (2H)-yl)-1 -methyl-1 ,4,6,7-tetrahydro-5H-pyrazoio[4,3-c]pyridine-5-carboxyiate 3 (70 mg, 0.17 mmol) in ACN (1 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (30 mL x 2) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FCC (Eluent: PE / EA 1 :1 ) affording the title compound (107 mg, crude) as a white solid. The crude product was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+ = 497.2.

[0275] Step 4. 6-Bromo-7-(difluoromethyl)-1-(1-methyl-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl)- 1 ,2,3,4-tetrahydroquinoline

[0276] A solution of tert-Butyl 3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1 (2H)-yl)-1 -methyl-1 ,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.20 mmol) and TFA (1 mL) in DCM (3 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford the title compound (165 mg, crude) as a black oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+ =397.0.

[0277] Step 5. 1-(3-(6-Bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-1 -methyl-1 ,4, 6, 7-tetrahydro- 5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

[0278] Acetic anhydride (61 .6 mg, 0.60 mmol) was added at 0°C to a stirred solution of 6-Bromo-7- (difluoromethyl)-l -(1 -methyl-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl)-1 ,2,3,4-tetrahydroquinoline (160 mg, 0.40 mmol) and TEA (122 mg, 1 .21 mmol) in DCM (4 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with DCM (50 mL) and washed with water (30 mL x 2) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FCC (Eluent: CH2CI21 MeOH (20:1 )) affording the title compound (69 mg, 0.16 mmol) as a white solid. LCMS (ESI) m / z [M+H]+ = 439.1 .

[0279] Intermediate 4: Preparation of 1-(3-(7-bromo-6-(difluoromethyl)-2,3-dihydro-4H- benzo[b][1,4]oxazin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin- 5-yl)ethan-1-one

[0280] Step 1. 1-(2-chloroethoxy)-4-(difluoromethyl)-2-nitrobenzene

[0281] LDA (2M in THF, 39.5 ml, 79.1 mmol) was added dropwise to a solution of 2-chloroethanol (5.09 g, 63.4 mmol) in THF (110 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 15 min. A solution of 4-(difluoromethyl)-1 -fluoro-2-nitrobenzene (10.1 g, 52.8 mmol) in THF (1 OmL) was added to the reaction mixture at room temperature. After stirring for 2h, was added water (150 mL), and extracted with EA (300 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SC , and removed under reduced pressure. The residue was purified by FCC (Eluent: 0 to 30% EA in heptane) to afford the title compound (13.0 g, 51 .8 mmol) as an off-white solid. LCMS (ESI) m / z [M+H]+= 252.1 .

[0282] Step 2. 2-(2-chloroethoxy)-5-(difluoromethyl)aniline

[0283] Iron powder (17.3 g, 310.8 mmol, 6 eq) was added to a stirred solution of 1 -(2-chloroethoxy)-4- (difluoromethyl)-2-nitrobenzene (13.0 g, 51.8 mmol) in AcOH (60 mL). After stirring for 4 hours, the reaction was quenched with water (150 mL) and extracted with EA (300 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SC , and concentrated under reduced pressure. The residue was purified by FCC (Eluent: 0 to 25% EA in heptane) to afford the title compound (8.90 g, 40.4 mmol) as an off-white solid. LCMS (ESI) m / z [M+H]+= 222.1 .

[0284] Step 3. 6-(difluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0285] KI (10.3 g, 62.6 mmol) and K2CO3 (12.9 g, 93.9 mmol) were added to a stirred solution of 2-(2- chloroethoxy)-5-(difluoromethyl)aniline (6.95 g, 31 .3 mmol) in DMAc (35 mL). The reaction mixture was heated at 90°C for 7 h. The reaction was then cooled to room temperature and quenched with water (150 mL). The reaction mixture was then extracted with EA (300 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SCU, and removed under reduced pressure The residue was purified by FCC (Eluent: 0 to 25% EA in heptane) to afford the title compound (5.79 g, 28.8 mmol) as an off-white solid. LCMS (ESI) m / z [M+H]+= 186.1. Intermediate 5: Preparation of 1-{3-[6-(Difluoromethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-2,3-dihydro- 1,4-benzoxazin-4-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethenone

[0286] Step 1. tert-Butyl 3-amino-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0287] Hydrazine hydrate (50-60% in water) (105 mL, 1 .35 mol) was added to a solution of tert-butyl 3-cyano-4- oxopiperidine-1 -carboxylate (10 g, 0.45 mol) in EtOH (600 mL). The resulting mixture was stirred for 2 h at 80°C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was diluted with water (1 .5 L) and extracted with DCM (1 L x 3). The combined organic layers were washed with brine (1 L x 2), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (107 g, 445 mmol) as a white solid. LCMS (ESI) m / z [M+H]+= 239.1 .

[0288] Step 2. tert-Butyl 3-bromo-1H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0289] CuBr2 (108 g, 484 mmol) and 3-methylbutyl nitrite (64.4 mL, 484 mmol) were added to a stirred solution of tert-butyl 3-amino-1 H,4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate 2 (106.6 g, 445 mmol) in anhydrous MeCN (170 mL) at 0°C. The resulting mixture was stirred for 2 h at 60°C. The reaction mixture was then diluted with EtOAc (1 L) and washed with sat. NH4CI (aq.) (600 mL x 4), 1 M HCI (600 mL x 3), and brine (600 mL x 2). The organic phases were combined and dried over anhydrous Na2SC>4 and removed the solvents under reduced pressure. The crude was dried under a high vacuum for overnight to obtain the reddish solid. Methyl tert-butyl ether (MTBE) was added portion-wise to the crude and stirred to make a slurry. The solid was filtered off and washed with minimum amount of MTBE and heptane to afford the title compound (68 g, 224 mmol) as an off-white crystalline solid. LCMS (ESI) m / z [M+H]+= 304.0.

[0290] Step 3. tert-Butyl 3-bromo-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0291] CS2CO3 (63.3 g, 203 mmol) was added to a stirred solution of tert-butyl 3-bromo-1 H,4H,6H,7H- pyrazolo[4,3-c]pyridine-5-carboxylate (20.5 g, 67.8 mmol) and oxan-4-yl methanesulfonate (18.3 g, 101 .7 mmol) in DMAc (130 mL). The resulting mixture was stirred for 3.5 h at 80°C. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (400 mL x 2). The organic layers were combined and washed with brine (100 mL). The organic layer was then dried over anhydrous Na2SC>4 and removed under reduced pressure. The residue was purified by FCC (Eluent: 0 to 45% EA in heptane) to obtain two isomers. The retention time of the desired isomer was higher than that of the undesired isomer. The fractions containing the desired isomer were combined and solvents were removed to afford the title compound (13.1 g, 34.0 mmol) as a white solid. LCMS (ESI) m / z [M+H]+= 386.2.

[0292] Step 4. 3-Bromo-1-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine

[0293] TFA (15 mL) was added to a solution of tert-butyl 3-bromo-1 -(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3- c]pyridine-5-carboxylate (21 .6 g, 55.6 mmol) in DCM (60 mL). The reaction mixture was stirred for 4 h. The reaction was then concentrated under reduced pressure and TFA was co-evaporated with toluene (20 mL x 2) to afford the title compound (~24 g, crude) as a yellow gum. The crude was used for the next step without further purification. LCMS (ESI) m / z [M+H]+= 288.1 .

[0294] Step 5. 1-(3-Bromo-1-(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-1-one

[0295] TEA (19.3 mL, 138 mmol) was added to a solution of 3-bromo-1 -(tetrahydro-2H-pyran-4-yl)-4, 5,6,7- tetrahydro-1 H-pyrazolo[4,3-c]pyridine (15.8 g, 55.4 mmol) in DCM (150 mL). The reaction mixture was stirred for 15 min. The mixture was cooled to 0°C and added acetic anhydride (5.75 mL, 60.9 mmol) was added in two portions. After 2 h, water (150 ml) was added to quench the reaction. The crude was extracted with DCM (300 mL x 3), washed with brine (100 mL), dried over anhydrous Na2SC and removed under reduced pressure. The residue was purified by FCC (Eluent: 0 to 5% MeOH in DCM) to afford the title compound (15.8 g, 47.6 mmol) as an off-white solid. LCMS (ESI) m / z [M+H]+= 328.1 .

[0296] Step 6. 1-(3-(6-(Difluoromethyl)-2,3-dihydro-4H-benzo[b][1 ,4]oxazin-4-yl)-1-(tetrahydro-2H-pyran-4- yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

[0297] CS2CO3 (20.7 g, 63.6 mmol) and XPhos Pd 3G (2.15 g, 2.5 mmol) was added to a stirred solution of 7- (difluoromethyl)-l ,2,3,4-tetrahydroquinoline 7 (3.94 g, 21 .2 mmol) and 1 -(3-bromo-1 -(tetrahydro-2H- pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1 -one (8.99 g, 27.4 mmol) in nitrogen degassed 1 ,4-dioxane (100 mL). The resulting mixture was stirred for 18 h at 120°C. The reaction was then cooled to room temperature and quenched with water (300 mL). The crude was extracted with EA (300 mL x 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SC , and removed under reduced pressure. The residue was purified by FCC (Eluent: 0 to 5% MeOH in DCM) to afford the title compound (9.07 g, 21 .0 mmol) as an off-white solid. LCMS (ESI) m / z [M+H]+= 433.1 . Step 7. 1-{3-[6-Bromo-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-1-yl]-1-(oxan-4-yl)-4H,6H,7H- pyrazolo[4,3-c]pyridin-5-yl}ethanone

[0298] NBS (3.73 g, 21 .0 mmol) was added to a stirred solution of 1 -(3-(6-(difluoromethyl)-2,3-dihydro-4H- benzo[b][1 ,4]oxazin-4-yl)-1 -(tetrahydro-2H-pyran-4-yl)-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)ethan-1 -one (9.07 g, 21 .0 mmol) in MeCN (100 ml_) in 3 portions at 0 °C. After stirring for 2 h, the resulting mixture was diluted with water (100 mL) and extracted with EA (400 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SC>4, removed under reduced pressure. The residue was purified by FCC (Eluent: 0 to 5% MeOH in DCM) to afford the title compound (10.6 g, 20.7 mmol) as an off-white solid. LCMS (ESI) m / z [M+H]+= 511 .1 .

[0299] Step 8. 1-{3-[6-(Difluoromethyl)-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro- 1 ,4- benzoxazin-4-yl]-1-(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone

[0300] Pd(dppf)Cl2 (0.14 g, 0.196 mmol) was added to a stirred solution of 1 -{3-[7-bromo-6-(difluoromethyl)-2,3- dihydro-1 ,4-benzoxazin-4- yl]-1 -(oxan-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}ethanone (1 g, 1 .96 mmol), bis(pinacolato)diboron (0.74 g, 2.93 mmol) and KOAc (0.38 g, 3.91 mmol) in dioxane (10 mL). The resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (150 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (1 .75 g, crude) as a brown solid that was used directly without further purification. LCMS (ESI) m / z [M+H]+= 559.28.

[0301] Intermediate 6: Preparation of (2S,4R)-1-(L-Valyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0302] Intermediate 6 Step 1. tert-Butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1 -carboxylate

[0303] Ethyl 2-ethoxy-1 ,2-dihydroquinoline-1 -carboxylate (2.7 g, 11 mmol) was added to a stirred solution of (1 S)-1 -[4-(4-methyl-1 ,3-thiazol-5-yl)phenyl]ethanamine (2 g, 9.2 mmol) and (2S,4R)-1 -(tert- butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.1 g, 9.2 mmol) in DCM (20 ml_). The reaction mixture was stirred for 2 h at room temperature. The mixture was diluted with DCM (100 mL), washed with water (50 mL x 2) and brine (50 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by reverse FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (1 .06 g, 2.5 mmol) as a white solid. LCMS (ESI) m / z [M+H]+ = 432.2.

[0304] Step 2. (2S,4R)-4-Hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TFA (2 mL) was added to a stirred solution of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1 -carboxylate (1 g, 2.3 mmol) in DCM (8 mL). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude product that was purified by reverse phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (682 mg, 2.1 mmol) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 332.1 .

[0305] Step 3. tert-Butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

[0306] HATU (936 mg, 2.5 mmol) was added to a stirred solution of (2S,4R)-4-hydroxy-N-((S)-1 -(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (680 mg, 2.0 mmol), (2S)-2-[(tert- butoxycarbonyl)amino]-3-methylbutanoic acid (446 mg, 2.0 mmol) and DIEA (796 mg, 6.2 mmol) in DMF (7 mL). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with water (70 mL x 2) and brine (70 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by reverse phase FCC (column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) affording the title compound (578 mg, 1 .1 mmol) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 531 .3.

[0307] Step 4. (2S,4R)-1 -(L-Valyl)-4-hydroxy-N-((S)-1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide

[0308] To a stirred solution of tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1 -yl)-3-methyl-1 -oxobutan-2-yl)carbamate (80 mg, 0.15 mmol) in DCM (1 mL) was added TFA (0.3 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to afford the title compund (71 mg, crude) as a white solid. LCMS (ESI) m / z [M+H]+ = 431 .2. Intermediate 7: Preparation of tert-butyl 6-bromobenzo[e][1,2,4]triazine-3-carboxylic acid.

[0309] Step 1. Ethyl (Z)-2-(2-(4-bromo-2-nitrophenyl)hydrazineylidene)-2-chloroacetate

[0310] 12 N hydrochloric acid (13.5 mL) was added to a stirred solution of 4-bromo-2-nitroaniline (50 g, 230 mmol) in methanol (50 mL). The mixture was cooled in an ice-water bath and a solution of sodium nitrite (17.5 g, 253 mmol) in water (10 mL) was added dropwise with stirring over a 15 minute period. The cold suspension was filtered, the solid was filtered out, and ethyl-2-chloroacetoacetate (1 .4 mL, 10.1 mmol) was immediately added to the filtrate with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The suspension was filtered, and the filtered solid was collected, and washed with water (200 mL x 4). The yellow solid was dried under vacuum to afford the title compound (57 g, crude) as a yellow solid. LCMS (ESI) m / z [M+H]+= 349.9

[0311] Step 2. Ethyl (Z)-2-amino-2-(2-(4-bromo-2-nitrophenyl)hydrazineylidene)acetate

[0312] NHs(g) 7N in MeOH (25 mL) was added to a stirred solution of ethyl (Z)-2-(2-(4-bromo-2- nitrophenyl)hydrazineylidene)-2-chloroacetate (57 g, 0.014 mmol) in EtOH (50 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was poured into water (200 mL) and the mixture was filtered. The filtered red solid was collected and washed with water (200 mL x4) and dried under vacuum to afford the title compound (42 g, crude) as a red solid. LCMS (ESI) m / z [M+H]+= 331 .1

[0313] Step 3. Ethyl 6-bromobenzo[e][1,2,4]triazine-3-carboxylate

[0314] A stirred mixture of iron powder (16.9 g, 302 mmol), water (120 mL), and concentrated hydrochloric acid (70 mL) was added dropwise a solution of ethyl (Z)-2-amino-2-(2-(4-bromo-2- nitrophenyl)hydrazineylidene)acetate (25 g, 75.5 mmol) in a mixture of acetic acid (280 mL) and concentrated hydrochloric acid (40 mL). The reaction mixture was stirred at room temperature for 2 h. The precipitated solids were collected by filtration and then dissolved with EA (1 L), filtered, the filtrate was concentrated and the crude product was purified by flash chromatography over silica gel column chromatography, eluting with PE I EA (3:1 ) to afford the title compound (7.2 g, 25.5 mmol) as a yellow solid. LCMS (ESI) m / z [M+H]+= 282.1

[0315] Step 4. 6-Bromobenzo[e][1 ,2,4]triazine-3-carboxylic acid

[0316] K2CO3 (4.41 g, 31 .9 mmol) was added to a stirred solution of ethyl 6-bromobenzo[e][1 ,2,4]triazine-3- carboxylate (3 g, 10.6 mmol) in MeCN (20 mL) and H2O (20 mL). The resulting mixture was stirred for 1 h at 60°C. The mixture was acidified to pH 5 with 1 N HCI (aq.). The reaction mixture was diluted with EtOAc (300 mL x 2), the resulting mixture was washed with water (300 mL x 2) and saturated brine (300 mL x 2). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product (1 .9 g) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm, 5pm; Mobile Phase A: Water(0.05% HCI), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 11% B to 127% B in 8 min; Wave Length: 254nm / 220nm nm; RT1 (min): 9.68) to afford the title compound (1 .2 g, 4.72 mmols) as a yellow solid.1H NMR (300 MHz, DMSO-d6) 5 = 8.67 - 8.59 (m, 2H), 8.35 - 8.27 (m, 1 H). LCMS (ESI) m / z [M+H]+= 254.0.

[0317] Intermediate 8: Preparation of Ethyl 6-bromo-8-chlorobenzo[e][1,2,4]triazine-3-carboxylate

[0318] Step 1 Step 2 Step 3 Intermediate 8

[0319] Step 1. 6-Bromo-4-chloro-3H-1,2,3-benzotriazole

[0320] NaNO2 (0.68 g, 9.84 mmol) was added in portions at 0°C to a stirred solution of 5-bromo-3- chlorobenzene-1 ,2-diamine (2 g, 9.03 mmol) and AcOH (1 .08 g, 18.06 mmol) in H2O (21 mL). The resulting mixture was stirred for 1 h at 80°C. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (elution gradient 0 to 60% EtOAc in petroleum ether) affording the title compound (1 .9 g) as a yellow solid. LCMS (ESI) m / z [M+H]+= 231 .9

[0321] Step 2. 6-Bromo-4-chloro-1-trifluoromethanesulfonyl-1 ,2,3-benzotriazole

[0322] (Trifluoromethane)sulfonyl trifluoromethanesulfonate (3.88 g, 13.8 mmol) was added to a stirred solution of 6-bromo-4-chloro-3H-1 ,2,3-benzotriazole (1 .6 g, 6.88 mmol) in DCE (40 mL). The resulting mixture was stirred for 1 h at 80°C. The mixture was neutralized to pH = 7 with saturated NaHCOs (aq.) and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by FCC (elution gradient 0 to 10% MeOH in CH2CI2) affording the title compound (1 .32 g) as a yellow solid. LCMS (ESI) m / z [M+H]+= 363.9

[0323] Step 3. Ethyl 6-bromo-8-chloro-1,2,4-benzotriazine-3-carboxylate (2-Ethoxy-2-oxoethyl)dimethylsulfanium bromide (1 .00 g, 4.34 mmol) was added to a stirred solution of 6- bromo-4-chloro-1 -trifluoromethanesulfonyl-1 ,2,3-benzotriazole (1 .32 g, 3.62 mmol) and K2CO3 (0.60 g, 4.34 mmol) in i-PrOH (20 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography, (elution gradient 0 to 100% MeCN in water (containing 0.1 % TFA)) affording the title compound (457 mg, 1 .44 mmol) as a yellow solid. LCMS (ESI) m / z [M+H]+=315.9

[0324] Intermediate 9: Preparation of Ethyl 6-bromo-5-chlorobenzo[e][1,2,4]triazine-3-carboxylate

[0325] Step 1

[0326] Intermediate 9

[0327] Step 1. Ethyl 6-bromo-5-chloro-1,2,4-benzotriazine-3-carboxylate

[0328] 1 ,3,5-trichloro-1 , 3, 5-triazinane-2, 4, 6-trione (33 mg, 0.142 mmol) was added in portions at 0°C to a stirred solution of ethyl 6-bromo-1 ,2,4-benzotriazine-3-carboxylate (100 mg, 0.354 mmol) and trifluoromethanesulfonic acid (2.66 mg, 0.018 mmol) in HFIP (1 mL). The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SC . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash C18-flash chromatography (elution gradient 0 to 100% MeCN in water (containing 0.1 % FA)) affording the title compound (69 mg, 0.22 mmol) as a yellow solid. LCMS (ESI) m / z [M+H]+= 315.9

[0329] Intermediate 10: Preparation of 6-Chloro-7-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

[0330] Step 1. 5-Bromo-2-chloro-3-(difluoromethyl)pyridine

[0331] DAST (43.9 g, 272.2 mmol) was added dropwise to a stirred mixture of 5-bromo-2-chloropyridine-3- carbaldehyde (20.0 g, 90.7 mmol) in DCM (100 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for an additional 2 h at room temperature. The reaction mixture was quenched with sat. NaHCOs (aq.) at 0 °C. The mixture was extracted with DCM (500 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous Na2SC . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (20:1 ) to afford the title compound (18.8 g) as a yellow oil.1H NMR (300 MHz, DMSO-cfe) 6 8.78 (s, 1 H), 8.41 (s, 1 H), 7.51 - 6.92 (m, 1 H).

[0332] Step 2. N-(6-chloro-5-(difluoromethyl)pyridin-3-yl)-1 ,1-diphenylmethanimine t-BuONa (9.3 g, 96.5 mmol), XantPhos (8.6 g, 14.8 mmol) and Pd2(dba)s (6.8 g, 7.4 mmol) was added to a stirred mixture of 5-bromo-2-chloro-3-(difluoromethyl)pyridine (18.0 g, 74.2 mmol) and diphenylmethanimine (13.5 g, 74.2 mmol) in toluene (200 mL) under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was diluted with water (300 mL), then extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (34.2 g, crude) as brown oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+= 342.95.

[0333] Step 3. 6-Chloro-5-(difluoromethyl)pyridin-3-amine

[0334] 1 M HCI (200 mL, 200 mmol) was added dropwise to a stirred solution of N-(6-chloro-5- (difluoromethyl)pyridin-3-yl)-1 ,1 -diphenylmethanimine (34.2 g, 99.8 mmol) in THF (200 mL) at room temperature. The resulting mixture was stirred for 6 h at room temperature. The mixture was basified to pH 8 with saturated NaHCOs (aq.). The resulting mixture was diluted with water (200 mL), then extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EtOAc (5:1 ) to afford the title compound (9.4 g) as a light yellow oil. LCMS (ESI) m / z [M+H]+= 179.10.1H NMR (300 MHz, DMSO-afe) 6 7.85 (s, 1 H), 7.26 (d, J = 2.9 Hz, 1 H), 7.05 (t, J = 54.3 Hz, 1 H), 5.85 (s, 2H).

[0335] Step 4. 2-Bromo-6-chloro-5-(difluorornethyl)pyridin-3-amine

[0336] NBS (9.37 g, 52.6 mmol) in ACN (50 mL) was added dropwise at 0 °C to a stirred solution of 6-chloro-5- (difluoromethyl)pyridin-3-amine (9.4 g, 52.6 mmol) in ACN (100 mL). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed under reduced pressure. The residue was quenched with saturated Na2S20s (aq.). The resulting mixture was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EtOAc (10:1 ) to afford the title compound (1 1 .8 g) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 256.8 & 258.8.1H NMR (300 MHz, DMSO-d6) 6 7.40 (s, 1 H), 7.08 (t, J = 54.0 Hz, 1 H), 6.06 (s, 2H).

[0337] Step 5. Ethyl (E)-3-(3-amino-6-chloro-5-(difluoromethyl)pyridin-2-yl)acrylate

[0338] K2CO3 (19.0 g, 137.5 mmol) and Pd(dppf)Cl2 (3.4 g, 4.6 mmol) was added to a stirred mixture of 2-bromo- 6-chloro-5-(difluoromethyl)pyridin-3-amine (1 1 .8 g, 45.8 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)prop-2-enoate (8.8 mg, 0.039 mmol) in dioxane (100 mL) and H2O (20 mL) under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 60 °C under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL), then extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EtOAc (10:1 ) to afford the title compound (9.1 g) as a yellow solid. LCMS (ESI) m / z [M+H]+ = 276.80.

[0339] Step 6. Ethyl 3-(3-amino-6-chloro-5-(difluoromethyl)pyridin-2-yl)propanoate

[0340] Rh(PPh3)3CI (1 .5 g, 1 .6 mmol) was added to a stirred solution of ethyl (E)-3-(3-amino-6-chloro-5- (difluoromethyl)pyridin-2-yl)acrylate (9.1 g, 32.9 mmol) in MeOH (150 mL). The resulting mixture was stirred for 1 h at room temperature under hydrogen atmosphere. The solvent was removed under reduced pressure. The mixture was filtered, the filter cake was washed with EtOAc (200 mL x 2). The filtrate was concentrated under reduced pressure to afford the title compound (9.2 g, crude). The crude product was used in the next step directly without further purification. LCMS (ESI) m / z [M+H]+ = 279.00

[0341] Step 7. 6-Chloro-7-(difluoromethyl)-3,4-dihydro-1 ,5-naphthyridin-2(1 H)-one

[0342] AcOH (5.7 mL, 99.0 mmol) was added dropwise to a stirred solution of ethyl 3-(3-amino-6-chloro-5- (difluoromethyl)pyridin-2-yl)propanoate (9.2 g, 33.0 mmol) in EtOH (90 mL) at room temperature. The resulting mixture was stirred for 3 h at 80 °C. The solvent was removed under reduced pressure. The mixture was neutralized to pH 8 with saturated NaHCOs (aq.). The mixture was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EtOAc (1 :1 ) to afford the title compound (5.5 g) as a white solid. LCMS (ESI) m / z [M+H]+ = 233.2.1H NMR (300 MHz, DMSO-cfc) 5 10.39 (s, 1 H), 7.47 (s, 1 H), 7.16 (t, J = 54.1 Hz, 1 H), 3.14 - 2.98 (m, 2H), 2.73 - 2.57 (m, 2H).

[0343] Step 8. 6-Chloro-7-(difluoromethyl)-1 ,2,3,4-tetrahydro-1 ,5-naphthyridine

[0344] BH3-THF (70.93 mL, 70.94 mmol) was added dropwise to a stirred solution of 6-chloro-7-(difluoromethyl)- 3,4-dihydro-1 ,5-naphthyridin-2(1 H)-one (5.5 g, 23.6 mmol) in THF (50 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched by the addition of MeOH (100 mL) at 0 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10:1 ) to afford the title compound (4.53 g) as a white solid. LCMS (ESI) m / z [M+H]+ = 219.00.1H NMR (400 MHz, DMSO-d6) 6 7.19 - 6.83 (m, 2H), 6.36 (s, 1 H), 3.26 - 3.1 1 (m, 2H), 2.77 (t, J = 6.5 Hz, 2H), 1 .95 - 1 .77 (m, 2H) ppm. Intermediate 11 : Preparation of 1-(3-{[4-chloro-3-(difluoromethyl)phenyl](methyl)amino}-1-(oxan-4- yl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl)ethenone

[0345] Step 1. 4-Bromo-1-chloro-2-(difluoromethyl)benzene

[0346] DAST (18.36 g, 1 13.9 mmol) was added dropwise at 0°C to a stirred solution of 5-bromo-2- chlorobenzaldehyde (5 g, 22.78 mmol) in DCM (60 mL). The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by saturated aqueous NH4HCO3 (500 mL) at 0 °C and extracted with CH2CI2 (600 mL x 3). The combined organic layers were washed with brine (600 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by FCC (elution gradient 0 to 100% EtOAc in petroleum ether) affording the title compound (4 g) as a white liquid. LCMS (ESI) m / z [M+H]+= 240.93.

[0347] Step 2. N-[4-Chloro-3-(difluoromethyl)phenyl]-1-(oxan-4-yl)pyrazolo[4,3-c]pyridin-3-amine

[0348] XPhos Pd G3 (194 mg, 0.229 mmol) was added to a stirred solution of 4-bromo-1 -chloro-2- (difluoromethyl)benzene (553 mg, 2.29 mmol), 1 -(oxan-4-yl) pyrazolo[4,3-c]pyridin-3-amine (500 mg, 2.29 mmol) and CS2CO3 (2.24 g, 6.87 mmol) in dioxane (8 mL). The resulting...

Claims

1. PATENT Attorney Docket No.: 51121-100WO2 What is claimed is: CLAIMS 1. A compound having the structure of Formula I: A-L-B Formula I, wherein A is a CBP binding moiety; B is a degradation moiety; and L has the structurewherein, A1is a bond between the linker and A; and A2is a bond between B and the linker; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the CBP binding moiety has the structure of Formula III:Formula III wherein R1is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, or C2-C12 heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 carbocycle, and C2-C12 heterocycle of R1is optionally substituted with A1and / or one or more groups Rb; R2is C6-C20aryl, C1-C20heteroaryl, (C6-C20aryl)(C1-20heteroaryl), (C1-C20heteroaryl)(C6-C20aryl), and (C1-C20 heteroaryl)(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, (C6-C20 aryl)(C1- C20 heteroaryl) and (C1-C20 heteroaryl)(C1-C20 heteroaryl) is independently optionally substituted with A1and / or one or more substituent groups independently selected from Rc, oxo, F, Cl, Br, I, NO2, N(Ra)2, CN, C(O)N(Ra)2, S(O)N(Ra)2, S(O)2N(Ra)2, ORa, SRa, OC(O)Ra, OC(O)ORa, C(O)Ra, C(O)ORa, S(O)Ra, S(O)2Ra, OC(O)N(Ra)2, N(Ra)C(O)ORa, N(Ra)C(O)N(Ra)2, N(Ra)C(O)Ra, N(Ra)S(O)Ra, N(Ra)S(O)2Ra, N(Ra)S(O)N(Ra)2, and N(Ra)S(O)2N(Ra)2; R3is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12alkyl, C2-C12alkenyl, C2-C12alkynyl, 3-12 membered carbocycle, and 3- 12 membered heterocycle of R3is optionally substituted with A1and / or one or more groups Re; or R2and R3of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A1and / or one or more groups Re; 1022PATENT Attorney Docket No.: 51121-100WO2 R4is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, C1-C5 heterocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, C(O)Rh, C(O)ORh, S(O)Rh, or S(O)2Rh, wherein any C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 carbocycle, and C2-C5 heterocycle is optionally substituted with A1and / or one or more substituent groups independently selected from F, Cl, Br, I, C3-C5 carbocycle, C(O)N(Rh)2, S(O)N(Rh)2, S(O)2N(Rh)2, ORh, SRh, OC(O)Rh, OC(O)ORh, C(O)Rh, C(O)ORh, S(O)Rh, S(O)2Rh, OC(O)N(Rh)2, N(Rh)C(O)ORh, N(Rh)C(O)N(Rh)2, N(Rh)C(O)Ra, N(Rh)S(O)Rh, N(Rh)S(O)2Rh, N(Rh)S(O)N(Rh)2, and N(Rh)S(O)2N(Rh)2; each Rais, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1-C6 alkyl that is optionally substituted with A1and / or one or more groups independently selected from oxo and halo; or two Raare taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rbis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)ORc, OC(O)ORc, C(O)Rc, C(O)ORc, S(O)Rc, S(O)2Rc, OC(O)N(Rc)2, N(Rc)C(O)ORc, N(Rc)C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rc, N(Rc)S(O)N(Rc)2, or N(Rc)S(O)2N(Rc)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C6-C10 aryl, and C2-C12 heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rc)2, CN, C(O)N(Rc)2, S(O)N(Rc)2, S(O)2N(Rc)2, ORc, SRc, OC(O)Rc, C(O)Rc, S(O)Rc, S(O)2Rc, C(O)N(Rc)2, N(Rc)C(O)Rc, N(Rc)S(O)Rc, N(Rc)S(O)2Rc, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rcis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(Rd)2, CN, C(O)N(Rd)2, S(O)N(Rd)2, S(O)2N(Rd)2, ORd, SRd, OC(O)Rd, C(O)Rd, C(O)ORd, S(O)Rd, S(O)2Rd, C(O)N(Rd)2, N(Rd)C(O)Rd, N(Rd)S(O)Rd, N(Rd)S(O)2Rd, and C1-C6 alkyl, which C3-C12 carbocyclyl and C1-C6 alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rd)2, ORd, C3-C12 heterocyclyl, and C3-C12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; each Rdis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rdare taken together with the nitrogen to which they are attached to form a C2-C12 heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, 1023PATENT Attorney Docket No.: 51121-100WO2 halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Reis, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, OC(O)ORf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, OC(O)N(Rf)2, N(Rf)C(O)ORf, N(Rf)C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, N(Rf)S(O)N(Rf)2, or N(Rf)S(O)2N(Rf)2, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, NO2, N(Rf)2, CN, C(O)N(Rf)2, S(O)N(Rf)2, S(O)2N(Rf)2, ORf, SRf, OC(O)Rf, C(O)Rf, C(O)ORf, S(O)Rf, S(O)2Rf, C(O)N(Rf)2, N(Rf)C(O)Rf, N(Rf)S(O)Rf, N(Rf)S(O)2Rf, C3-C12 carbocycle, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rfis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from oxo, C3-C12 carbocyclyl, C3-C12 heterocyclyl, halo, NO2, N(Rg)2, CN, C(O)N(Rg)2, S(O)N(Rg)2, S(O)2N(Rg)2, ORg, SRg, OC(O)Rg, C(O)Rg, C(O)ORg, S(O)Rg, S(O)2Rg, C(O)N(Rg)2, N(Rg)C(O)Rg, N(Rg)S(O)Rg, N(Rg)S(O)2Rg, and C1-C6 alkyl, which C3-C12 carbocyclyl and C1-C6 alkyl are optionally substituted with A1and / or one or more groups independently selected from oxo, halo, C1-C6 alkyl, cyano, N(Rg)2, ORg, C2-C12 heterocyclyl, and C3-C12 carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-C6 alkyl; each Rgis, independently, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, or C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with A1and / or one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rgare taken together with the nitrogen to which they are attached to form a C2-C12 heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and each Rhis, independently, hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C12 heterocyclyl, or C2-C5 cycloalkyl, wherein each C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C12 heterocyclyl, and C2-C5 cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-C3 alkoxy, and C1-C3 alkyl that is optionally substituted with A1and / or one or more groups independently selected from halo; wherein one and only one of R1, R2, R3, or R4comprises A1.

3. The compound of claim 2, wherein R1is methyl, ethyl, propyl, butyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, cyclopropanyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidyl, or 1024PATENT Attorney Docket No.: 51121-100WO2 pyrrolidinyl, wherein each methyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxothiolanyl, piperidyl, or pyrrolidinyl of R1is optionally substituted with one or more groups Rb. The compound of claim 2 or 3, wherein R1is methyl,.

5. The compound of any one of claims 2 to 4, wherein R1is.7 The compound of claim 2 or 3, wherein R1.

8. The compound of any one of claims 2 to 5, wherein R4is acetyl, ethylcarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, oxetanylcarbonyl, propanoyl, cyclopropylcarbonyl, methyl sulfonyl, butanoyl, difluoroacetyl, trifluoroacetyl, thiadiazolyl or isoxazolyl.

9. The compound of any one of claims 2 to 7, wherein R4has the structure:1025PATENT Attorney Docket No.: 51121-100WO2 10. The compound of any one of claims 2 to 5, wherein R4has the structure:

11. The compound of any one of claims 2 to 7, wherein R4has the structure:. 1 The compound of any one of claims 2 to 7, wherein R4has the structure:.

13. The compound of any one of claims 2 to 7, wherein R4has the structure:.

14. The compound of any one of claims 2 to 7, wherein R4has the structure: .

15. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure: ,1026PATENT Attorney Docket No.: 51121-100WO21027PATENT Attorney Docket No.: 51121-100WO21028PATENT Attorney Docket No.: 51121-100WO21029PATENT Attorney Docket No.: 51121-100WO21030PATENT Attorney Docket No.: 51121-100WO2 16. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:

17. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:

18. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:.

19. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure: 1031PATENT Attorney Docket No.: 51121-100WO2.

20. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:.

21. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:.

22. The compound of any one of claims 2 to 21, wherein R2and R3taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1and / or one or more groups Re.

23. The compound of any one of claims 2 to 22, wherein R2and R3taken together with the nitrogen to which they are attached form a 9- or 10-membered bicyclic heterocycle that is optionally substituted with A1and / or one or more groups Re; and wherein the 9- or 10-membered bicyclic heterocycle comprises at least one aromatic ring.

24. The compound of any one of claims 2 to 23, wherein NR2R3taken together has the structure: 1032PATENT Attorney Docket No.: 51121-100WO2wherein X3is NRN2, CH2, CH(COOH), or O; X4is N, CH; X9is N, or CR14; R14is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, C1-C3 alkoxy, or CN; and RN2is C1-C3 alkyl or H.

25. The compound of claim 24, wherein X3is CH2, X4is CH, and X9is CR14.

26. The compound of claim 24, wherein X3is O, X4is CH, and X9is CR14.

27. The compound of claim 24, wherein X3is O, X4is N, and X9is CR14.

28. The compound of claim 24, wherein X3is O, X4is CH, and X9is N.

29. The compound of claim 24, wherein X3is CH2, X4is N, and X9is N.

30. The compound of claim 24, wherein X3is CH2, X4is N, and X9is CR14.

31. The compound of claim 24, wherein X3is NRN2, X4is CH, and X9is CR14.

32. The compound of claim 24, wherein X3is NRN2, X4is CH, and X9is N.

33. The compound of claim 24, wherein X3is CH(COOH), X4is CH, and X9is CR14.

34. The compound of claim 24, wherein R14is optionally substituted C1-C3 alkyl.

35. The compound of claim 24, wherein R14is CHF2, CF3, CHCl2, CH3.

36. The compound of claim 24, wherein R14is optionally substituted C1-C3 alkoxy.

37. The compound of claim 24, wherein R14is OCH3.

38. The compound of claim 24, wherein R14is halo. 1033PATENT Attorney Docket No.: 51121-100WO2 39. The compound of claim 24, wherein R14is F or Cl.

40. The compound of claim 24, wherein R14is CN.

41. The compound of claim 24, wherein RN2is H.

42. The compound of claim 24, wherein RN2is C1-C3 alkyl.

43. The compound of claim 24, wherein C1-C3 alkyl is methyl.

44. The compound of any one of claims 2 to 24, wherein NR2R3taken together has the structure:1034PATENT Attorney Docket No.: 51121-100WO2 45. The compound of any one of claims 2 to 24, wherein NR2R3taken together has the structure:1035PATENT Attorney Docket No.: 51121-100WO2 46. The compound of claim 24, wherein NR2R3taken together has the structure:.

47. The compound of claim 24, wherein NR2R3taken together has the structure:.

48. The compound of claim 24, wherein NR2R3taken together has the structure:.

49. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:1036PATENT Attorney Docket No.: 51121-100WO21037PATENT Attorney Docket No.: 51121-100WO21038PATEN Attorne , ,1039PATENT Attorney Docket No.: 51121-100WO21040PATENT Attorney Docket No.: 51121-100WO250. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:1041PATENT Attorney Docket No.: 51121-100WO21042PATENT Attorney Docket No.: 51121-100WO21043PATENT Attorney Docket No.: 51121-100WO21044PATENT Attorney Docket No.: 51121-100WO21045PATENT Attorney Docket No.: 51121-100WO21046PATENT Attorney Docket No.: 51121-100WO21047PATENT Attorney Docket No.: 51121-100WO21048PATENT Attorney Docket No.: 51121-100WO21049PATENT Attorney Docket No.: 51121-100WO21050PATENT Attorney Docket No.: 51121-100WO21051PATENT Attorney Docket No.: 51121-100WO2.

51. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:1052PATENT Attorney Docket No.: 51121-100WO2 52. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:.

53. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:

54. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:1053PATENT Attorney Docket No.: 51121-100WO2 55. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:

56. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:.

57. The compound of any one of claims 2 to 20, wherein R2is C6-C20 aryl or C1-C20 heteroaryl optionally substituted with A1and / or one or more groups Rc.

58. The compound of any one of claims 2 to 20, and 47, wherein R3is C1-C12 alkyl.

59. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure: 1054PATENT Attorney Docket No.: 51121-100WO21055PATENT Attorney Docket No.: 51121-100WO21056PATENT Attorney Docket No.: 51121-100WO2 60. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:1057PATENT Attorney Docket No.: 51121-100WO21058PATENT Attorney Docket No.: 51121-100WO21059PATENT Attorney Docket No.: 51121-100WO21060PATENT Attorney Docket No.: 51121-100WO21061PATENT Attorney Docket No.: 51121-100WO21062PATENT Attorney Docket No.: 51121-100WO21063PATENT Attorney Docket No.: 51121-100WO21064PATENT Attorney Docket No.: 51121-100WO2The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:1065PATENT Attorney Docket No.: 51121-100WO21066PATENT Attorney Docket No.: 51121-100WO21067PATENT Attorney Docket No.: 51121-100WO21068PATENT Attorney Docket No.: 51121-100WO21069PATENT Attorney Docket No.: 51121-100WO263. The compound of claim 1 or 2, wherein the CBP binding moiety has the structure:.

64. The compound of any one of claims 1 to 63, wherein the degradation moiety is a ubiquitin ligase binding moiety. 1070PATENT Attorney Docket No.: 51121-100WO2 65. The compound of claim 64, wherein the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel- Lindau (VHL) ligands, or derivatives or analogs thereof.

66. The compound of any one of claims 1 to 65, wherein the degradation moiety comprises the structure of Formula IVab:Formula IVab, wherein Xa is CH, CRB6, or N; RB1is H, A2, C(O)-A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl; RB3is A2, C(O)-A2, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl; RB4is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl; RB4’is H, halo, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RB5is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; each RB6is, independently, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, hydroxy, thiol; and RB9is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or A2; wherein one and only one of RB1, RB3, or RB9comprises A2or C(O)-A2, or a pharmaceutically acceptable salt thereof.

67. The compound of claim 66, wherein RB6is optionally substituted C2-C9 heteroaryl. 1071PATENT Attorney Docket No.: 51121-100WO2 68. The compound of claim 66 or 67, wherein RB6is:

69. The compound of any one of claims 66 to 68, wherein the structure of Formula IVab is:derivative or analog thereof.

70. The compound of any one of claims 66 to 68, wherein the structure of Formula IVab is:1072PATENT Attorney Docket No.: 51121-100WO2 71. The compound of any one of claims 66 to 68, wherein the structure of Formula IVab is:thereof.

72. The compound of any one of claims 66 to 68, wherein the structure of Formula IVab is:derivative or analog thereof.

73. The compound of any one of claims 1 to 65, wherein the degradation moiety comprises the structure of Formula IVa:Formula IVa, wherein RB1is H, A2, C(O)A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl; RB3is A2, C(O)A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl; RB4is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl; RB5is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2 is 0, 1, 2, 3, or 4; 1073PATENT Attorney Docket No.: 51121-100WO2 each RB6is, independently, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, hydroxy, thiol; and RB9is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or A2; wherein one and only one of RB1, RB3, or RB9comprises A2or C(O)A2, or a pharmaceutically acceptable salt thereof.

74. The compound of claim 73, wherein RB6is optionally substituted C2-C9 heteroaryl.

75. The compound of claim 73 or 74, wherein RB6is:

76. The compound of claim 73 or 74, wherein RB6is:1074PATENT Attorney Docket No.: 51121-100WO2 77. The compound of claim 1 or 73, wherein the degradation moiety is: t78. The compound of claim 1 or 73, wherein the degradation moiety is: t79. The compound of claim 1 or 73, wherein the degradation moiety is:1075PATENT Attorney Docket No.: 51121-100WO2thereof.

80. The compound of claim 1 or 73, wherein the degradation moiety is:1076PATENT Attorney Docket No.: 51121-100WO21077PATENT Attorney Docket No.: 51121-100WO21078PATENT Attorney Docket No.: 51121-100WO281. The compound of claim 1 or 73, wherein the degradation moiety is:derivative or analog thereof. 1079PATENT Attorney Docket No.: 51121-100WO2 82. The compound of claim 1 or 73, wherein the degradation moiety is:1080PATENT Attorney Docket No.: 51121-100WO283. The compound of claim 73, wherein RB6is halogen or optionally substituted C2-C6 alkynyl.

84. The compound of claim 73, wherein RB6is optionally substituted C1-C6 heteroalkyl.

85. The compound of claim 84, wherein optionally substituted C1-C6 heteroalkyl is methoxy. 1081PATENT Attorney Docket No.: 51121-100WO2 86. The compound of claim 73 or 83, wherein the structure of Formula IVa is:

87. The compound of claim 73 or 83, wherein the structure of Formula IVa is:derivative or analog thereof.

88. The compound of any one of claims 1 to 65, wherein the degradation moiety comprises the structure of Formula IVbb:Formula IVbb, wherein RB1is H, A2, C(O)-A2, C(O)-J2,optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RB3is A2, C(O)-A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl wherein alkyl, heteroalkyl, carbocyclyl or aryl is optionally substituted with A2and / or one or more groups RJ2; RB4is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-10 aryl; 1082PATENT Attorney Docket No.: 51121-100WO2 RB4’is H, halo, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RB5is A2, H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl; RB5'is H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of RB5’is optionally substituted with A2and / or one or more groups Re’; or RB5and RB5’of Formula (IVbb) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A2and / or one or more groups Re’; each Re’is, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, NH2, or CN,, wherein any C1-6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A2and / or one or more groups independently selected from oxo, halo, NO2, NH2, CN, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RJ2is, independently, hydrogen, C1-C6 alkyl, carbocyclyl, and heterocyclyl, wherein each C1- C6 alkyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from halo, amino, hydroxyl, C1-C6 alkoxy, carbocyclyl, heterocyclyl, or C1-C6 alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; and wherein one and only one of RB1, RB3, RB5, RB5’, or RJcomprises A2, or a pharmaceutically acceptable salt thereof.

89. The compound of claim 88, wherein the structure of Formula IVbb is:1083PATENT Attorney Docket No.: 51121-100WO2 90. The compound of any one of claims 1 to 65, wherein the degradation moiety comprises the structure of Formula IVb:Formula IVb, wherein RB1is H, A2, C(O)-A2, C(O)-J2,optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RB3is A2, C(O)-A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl wherein alkyl, heteroalkyl, carbocyclyl or aryl is optionally substituted with A2and / or one or more groups RJ2; RB4is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl; RB5is A2, H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl; RB5'is H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein each C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of RB5’is optionally substituted with A2and / or one or more groups Re’; or RB5and RB5’of Formula (IVb) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with A2and / or one or more groups Re’; each Re’is, independently, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, C2-C12 heteroaryl, F, Cl, Br, I, NO2, NH2, or CN,, wherein any C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclyl, C3-C12 heterocyclyl, C2-C9 aryl, and C2-C10 heteroaryl is optionally substituted with A2and / or one or more groups independently selected from oxo, halo, NO2, NH2, CN, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each RJ2is, independently, hydrogen, C1-C6 alkyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl, wherein each C1-C6 alkyl, C3-C12 carbocyclyl, and C3-C12 heterocyclyl is optionally substituted with one or more groups independently selected from halo, amino, hydroxyl, C1-C6 alkoxy, C3-C12 carbocyclyl, C3-C12 heterocyclyl, or C1-C6 alkyl that is optionally substituted with A2and / or one or more groups independently selected from oxo and halo; and wherein one and only one of RB1, RB3, RB5, RB5’, or RJcomprises A2, or a pharmaceutically acceptable salt thereof. 1084PATENT Attorney Docket No.: 51121-100WO2 91. The compound of claim 90, wherein the structure of Formula IVb is:

92. The compound of claim 90, wherein RB5and RB5’taken together with the nitrogen to which they are attached form a 3- or 4-membered heterocycle that is optionally substituted with A2and / or one or more groups Re’.

93. The compound of claim 90, wherein the structure of Formula IVb is: 1085PATENT Attorney Docket No.: 51121-100WO2derivative or analog thereof.

94. The compound of any one of claims 1 to 65, wherein the degradation moiety comprises the structure of Formula IVac:Formula IVac, wherein Xb is CH, CR11a, or N; Xc is CH, CR11a, or N; Xd is CH, CR11a, or N; Xe is CH, CR11a, or N; RB1ais H, A2, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RB2ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RB3ais H, A2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted C6-C10 aryl wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl; RB3’ais H; or RB3aand RB3’aof Formula IVac taken together with the carbon to which they are attached form an optionally substituted 3-12 membered carbocycle or 3-12 membered heterocycle; RB4ais H, optionally substituted C1-C6 alkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C6-C10 aryl; RB4’ais H, halo, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; RB5ais H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; v2a is 0, 1, 2, 3, or 4; each RB6ais, independently, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkenyl, hydroxy, thiol, or optionally substituted amino; and 1086PATENT Attorney Docket No.: 51121-100WO2 RB9aand RB10aare, independently, H, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 heteroalkyl, or A2, or RB9aand RB10aof Formula IVac taken together with the carbon to which they are attached form an optionally substituted 3-12 membered carbocycle; Each R11ais independently, H, or halo; wherein one and only one of RB1RB3, RB9or RB10comprises A2, or a pharmaceutically acceptable salt thereof.

95. The compound of claim 94, wherein Xb is CH, Xc is CH, and Xd is CH, and Xe is CH.

96. The compound of claim 94, wherein Xb is CH, Xc is N, and Xd is CH, and Xe is CH.

97. The compound of claim 94, wherein Xb is N, and Xc is N, Xd is CH, and Xe is CH.

98. The compound of claim 94, wherein Xb is CH, and Xc is CH, Xd is CH, and Xe is CH.

99. The compound of claim 94, wherein Xb is N, and Xc is CH, Xd is CH, and Xe is CH.

100. The compound of claim 94, wherein Xb is CH, Xc is N, Xd is CH, and Xe is N.

101. The compound of claim 94, wherein Xb is CH, Xc is N, Xd is N, and Xe is CH.

102. The compound of claim 94, wherein Xb is CH, Xc is CH, and Xd is CH, and Xe is CR11a.

103. The compound of claim 94, wherein Xb is CH, Xc is CH, and Xd is CH, and Xe is CF.

104. The compound of claim 94, wherein RB1ais A2.

105. The compound of claim 94, wherein RB3ais optionally substituted C1-C6 alkyl. 106.

107. The compound of claim 94, wherein RB3ais optionally substituted C3-C10 carbocyclyl. 1087PATENT Attorney Docket No.: 51121-100WO2108. The compound of claim 94, wherein RB3a isor, 109. The compound of claim 94, wherein RB3ais optionally substituted C2-C10 heterocyclyl.

110. The compound of claim 94, wherein.

111. The compound of claim 94, wherein RB3aand RB3’aof Formula IVac taken together with the carbon to which they are attached form an optionally substituted 3-12 membered carbocycle or optionally substituted 3-12 membered heterocycle.

112. The compound of claim 94, wherein RB3aand RB3’aof Formula IVac taken together with the carbon to which they are attached form113. The compound of claim 94, wherein RB4ais H.

114. The compound of claim 94, wherein RB4’ais H.

115. The compound of claim 94, wherein RB4’ais F.

116. The compound of claim 94, wherein RB9ais optionally substituted C1-C6 alkyl.

117. The compound of claim 94, wherein RB9ais.

118. The compound of claim 94, wherein RB9ais optionally substituted C1-C6 heteroalkyl.

119. The compound of claim 94, wherein RB9ais. 1088PATENT Attorney Docket No.: 51121-100WO2 120. The compound of claim 94, wherein RB9aand RB10aof Formula IVac taken together with the carbon to which they are attached form an optionally substituted 3-12 membered carbocycle.

121. The compound of claim 94, wherein RB9aand RB10aof Formula IVac taken together with the122. The compound of claim 94, wherein RB6ais optionally substituted C2-C9 heteroaryl.

124. The compound of claim 1 or 94, wherein the degradation moiety has the structure: ,1089PATENT Attorney Docket No.: 51121-100WO21090PATENT Attorney Docket No.: 51121-100WO21091PATENT Attorney Docket No.: 51121-100WO21092PATENT Attorney Docket No.: 51121-100WO21093PATENT Attorney Docket No.: 51121-100WO21094PATENT Attorney Docket No.: 51121-100WO2125. The compound of claim 1 or 2, wherein the compound is any one of compounds 1-95, 97-131, 134-137, 139-149, 150-223, 226-251, 253-282, 284-300, 302-349, 352, 356-369, 372, 375-380, 382-604, 607-632, 634-663, 665-681, 683-730, 733, 737-750, 753, 756-861, 865-866, or a pharmaceutically acceptable salt thereof.

126. The compound of claim 1 or 2, wherein the compound is any one of compounds 1-95, 97-131, 134-137, and 139-149, or a pharmaceutically acceptable salt thereof. 1095PATENT Attorney Docket No.: 51121-100WO2 127. The compound of claim 1 or 2, wherein the compound is any one of compounds 150-223, 226- 251, 253-282, 284-300, 302-349, 352, 356-369, 372, and 375-380, or a pharmaceutically acceptable salt thereof.

128. The compound of claim 1 or 2, wherein the compound is any one of compounds 382-604, 607- 632, 634-663, 665-681, 683-730, 733, 737-750, 753, 756-861, 865-866, or a pharmaceutically acceptable salt thereof.

129. A pharmaceutical composition comprising a compound of any one of claims 1 to 128 and a pharmaceutically acceptable excipient.

130. A method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 128, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 129.

131. The method of claim 130, wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophageal, stomach, or lung cancer.

132. The method of claim 131, wherein the cancer is gastric cancer.

133. A method of treating gastric cancer in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 128, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 129.

134. The method of any one of claims 130 to 133, wherein the cancer is metastatic.

135. The method of any one of claims 130 to 134, wherein the subject or cancer has a EP300 loss of function mutation.

136. The method of any one of claims 130 to 135, wherein the method further comprises administering to the subject an anticancer therapy.

137. The method of claim 136, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof.

138. A method of treating inflammatory and / or autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 128, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 129. 1096PATENT Attorney Docket No.: 51121-100WO2 139. The method of claim 138, wherein the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutières syndrome, Sjogren’s syndrome, chronic hand eczema, non- anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis.

140. The method of claim 138 or 139, wherein the method further comprises administering to the subject a JAK inhibitor.

141. The method of claim 140, wherein the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

142. A method of treating a disease, disorder, or medical condition mediated by member of the JAK- STAT pathway, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 128, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 129.

143. The method of claim 142, wherein the member of the JAK-STAT pathway is a janus kinase (JAK).

144. The method of claim 142, wherein the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT).

145. The method of claim 142, wherein the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi-Goutières syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.

146. A method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of a compound of any one of claims 1 to 128, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 129.

147. A method for inhibiting an inflammatory or autoimmune response in a subject in need thereof, including administering to the subject an effective amount of a compound of any one of claims 1 to 128, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 129. 1097PATENT Attorney Docket No.: 51121-100WO2 148. A method of suppressing a memory CD8+T cell response in a subject in a subject having or at risk of developing an inflammatory response, including administering to the subject an effective amount of a compound of any one of claims 1 to 128, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 129.

149. A method of treating an infection in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 128, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 129.

150. The method of claim 149, wherein the infection is Herpesvirus K*.

151. A method of treating Rubinstein Taybi syndrome in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 128, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 129.

152. The claim of 136, wherein the anticancer agent is a CDK4 / 6 inhibitor.

153. The claim of claim 152, wherein the CDK4 / 6 inhibitor is abemaciclib, ribociclib, or palbociclib.

154. The method of claims 152 or 153, wherein the method further comprises administering hormone therapy. 1098

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