Tricyclic ureas as JAK2 V617F inhibitors

Abstract

The present application provides tricyclic urea compounds that modulate the activity of the V617F variant of JAK2, which are useful in the treatment of various diseases, including cancer.

Description

[Technical field]

[0001] The present invention provides tricyclic urea compounds that modulate the activity of the V617F variant of JAK2 and are useful for treating diseases associated with the V617F variant of JAK2, including cancer. [Background technology]

[0002] Janus kinase (JAK) 2 plays an important role in signal transduction by several cytokine receptors. Mutant JAK2 V617F is the most common molecular event associated with myeloproliferative neoplasms. Selective targeting of the JAK2 V617F mutant may be useful to treat various disease states while omitting essential JAK2 function. The present application is directed to this and other needs. Summary of the Invention

[0003] The present invention relates in particular to compounds of formula I, [ka] or a pharma- ceutically acceptable salt thereof, members of which are defined herein.

[0004] The present invention further provides a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0005] The present invention further provides a method of inhibiting the activity of the V617F variant of JAK2 kinase, comprising contacting the kinase with a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0006] The present invention further provides a method of treating a disease or disorder associated with expression or activity of the V617F variant of JAK2 kinase in a patient by administering to the patient a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0007] The present invention further provides a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in any of the methods described herein.

[0008] The invention further provides the use of a compound of formula I, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present application relates to a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, R 1 is selected from phenyl, indazolyl, and dihydroisobenzofuranyl, each of which is selected from halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from hydroxyalkyl; R 2 is C 1-6 Alkyl or C 1-6 is haloalkyl; R 3 Halo, C 1-6 Alkyl, and C 1-6 alkoxy; and R 4 is C 1-6 The present invention provides a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0010] In some embodiments, R 1 is selected from phenyl and indazolyl, each of which is selected from halo, C 1-6 Alkyl, and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy; R2 is C 1-6 is alkyl; R 3 Halo, C 1-6 Alkyl, and C 1-6 alkoxy; and R 4 is C 1-6 It is an alkyl.

[0011] In some embodiments, R 1 is selected from phenyl, indazolyl, and dihydroisobenzofuranyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, methyl, isopropyl, trideuteromethyl, difluoroethyl, methoxy, trideuteromethoxy, and hydroxyisopropyl.

[0012] In some embodiments, R 1 is selected from phenyl, indazolyl, and dihydroisobenzofuranyl, each of which is optionally substituted with 1 or 2 substituents independently selected from fluoro, methyl, isopropyl, trideuteromethyl, difluoroethyl, methoxy, trideuteromethoxy, and hydroxyisopropyl.

[0013] In some embodiments, R 1 Halo, C 1-6 Alkyl, and C 1-6 and dihydroisobenzofuranyl optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy.

[0014] In some embodiments, R 1 is one, two, or three independently selected C 1-6 Dihydroisobenzofuranyl optionally substituted with alkyl substituents.

[0015] In some embodiments, R 1 is one, two, or three independently selected C 1-3Dihydroisobenzofuranyl optionally substituted with alkyl substituents.

[0016] In some embodiments, R 1 is one or two independently selected C 1-3 Dihydroisobenzofuranyl optionally substituted with alkyl substituents.

[0017] In some embodiments, R 1 is dihydroisobenzofuranyl optionally substituted with 1, 2, or 3 methyl substituents.

[0018] In some embodiments, R 1 is dihydroisobenzofuranyl optionally substituted with 1 or 2 methyl substituents.

[0019] In some embodiments, R 1 is one or two independently selected C 1-6 It is a dihydroisobenzofuranyl substituted with an alkyl substituent.

[0020] In some embodiments, R 1 is one or two independently selected C 1-3 It is a dihydroisobenzofuranyl substituted with an alkyl substituent.

[0021] In some embodiments, R 1 is dihydroisobenzofuranyl substituted by one or two methyl substituents.

[0022] In some embodiments, R 1 is selected from phenyl and indazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from fluoro, trideuteromethyl, and methoxy.

[0023] In some embodiments, R 1is selected from phenyl, fluorophenyl, trideuteromethoxyphenyl, (hydroxyisopropyl)phenyl, fluoromethoxyphenyl, dimethyldihydroisobenzofuranyl, isopropylindazolyl, (fluoro)(trideuteromethyl)indazolyl, and difluoroethylindazolyl.

[0024] In some embodiments, R 1 is selected from trideuteromethoxyphenyl, (hydroxyisopropyl)phenyl, dimethyldihydroisobenzofuranyl, isopropylindazolyl, (fluoro)(trideuteromethyl)indazolyl, and difluoroethylindazolyl.

[0025] In some embodiments, R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl, and trideuteromethylindazolyl.

[0026] In some embodiments, R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, and 1-(trideuteromethyl)-1H-indazol-5-yl.

[0027] In some embodiments, R 1 teeth, [ka] is selected from.

[0028] In some embodiments, R 1 teeth, [ka] is selected from.

[0029] In some embodiments, R 1 is phenyl.

[0030] In some embodiments, R 1 is fluorophenyl.

[0031] In some embodiments, R 1 is 3-fluorophenyl.

[0032] In some embodiments, R 1 is 4-fluorophenyl.

[0033] In some embodiments, R 1 is fluoromethoxyphenyl.

[0034] In some embodiments, R 1 is 3-fluoro-4-methoxyphenyl.

[0035] In some embodiments, R 1 is trideuteromethylindazolyl.

[0036] In some embodiments, R 1 is 1-(trideuteromethyl)-1H-indazol-5-yl.

[0037] In some embodiments, R 1 is trideuteromethoxyphenyl.

[0038] In some embodiments, R 1 is 4-trideuteromethoxyphenyl.

[0039] In some embodiments, R 1 is (hydroxypropan-2-yl)phenyl.

[0040] In some embodiments, R 1 is 4-(2-hydroxypropan-2-yl)phenyl.

[0041] In some embodiments, R 1is dimethyldihydroisobenzofuranyl.

[0042] In some embodiments, R 1 is 1,1-dimethyl-1,3-dihydroisobenzofuranyl.

[0043] In some embodiments, R 1 is 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl.

[0044] In some embodiments, R 1 is isopropylindazolyl.

[0045] In some embodiments, R 1 is 1-isopropyl-1H-indazol-5-yl.

[0046] In some embodiments, R 1 is (fluoro)(trideuteromethyl)indazolyl.

[0047] In some embodiments, R 1 is 7-fluoro-1-trideuteromethyl-1H-indazol-5-yl.

[0048] In some embodiments, R 1 is difluoroethylindazolyl.

[0049] In some embodiments, R 1 is 1-(2,2-difluoroethyl)-1H-indazol-5-yl.

[0050] In some embodiments, R 2 is C 1-3 Alkyl or C 1-3 It is haloalkyl.

[0051] In some embodiments, R 2are methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl, and heptadeuteroisopropyl.

[0052] In some embodiments, R 2 is C 1-6 It is haloalkyl.

[0053] In some embodiments, R 2 is C 1-3 It is haloalkyl.

[0054] In some embodiments, R 2 is difluoroethyl.

[0055] In some embodiments, R 2 is 2,2-difluoroethyl.

[0056] In some embodiments, R 2 is C 1-6 It is an alkyl.

[0057] In some embodiments, R 2 is C 1-3 It is an alkyl.

[0058] In some embodiments, R 2 is ethyl.

[0059] In some embodiments, R 2 is trideuteromethyl.

[0060] In some embodiments, R 2 is pentadeuteroethyl.

[0061] In some embodiments, R 2 is heptadeuteroisopropyl.

[0062] In some embodiments, R 3 is C 1-6 It is alkoxy or halo.

[0063] In some embodiments, R 3 is C 1-3 It is alkoxy or halo.

[0064] In some embodiments, R 3 is C 1-6 It is alkoxy or fluoro.

[0065] In some embodiments, R 3 is C 1-3 It is alkoxy or fluoro.

[0066] In some embodiments, R 3 is C 1-6 It is an alkoxy.

[0067] In some embodiments, R 3 is C 1-3 It is an alkoxy.

[0068] In some embodiments, R 3 is methoxy or fluoro.

[0069] In some embodiments, R 3 is methoxy.

[0070] In some embodiments, R 3 is fluoro.

[0071] In some embodiments, R 4 is C 1-3 It is an alkyl.

[0072] In some embodiments, R 4 is methyl.

[0073] In some embodiments, R 4 is trideuteromethyl.

[0074] In some embodiments, R 1 is selected from phenyl, indazolyl, and dihydroisobenzofuranyl, each of which is selected from halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 optionally substituted with 1 or 2 substituents independently selected from hydroxyalkyl; R 2 is C 1-3 Alkyl or C 1-3 is haloalkyl; R 3 Halo, C 1-3 Alkyl, and C 1-3 alkoxy; and R 4 is C 1-3 It is an alkyl.

[0075] In some embodiments, R 1 is selected from phenyl, indazolyl, and dihydroisobenzofuranyl, each of which is optionally substituted with 1 or 2 substituents independently selected from fluoro, methyl, isopropyl, trideuteromethyl, difluoroethyl, methoxy, trideuteromethoxy, and hydroxyisopropyl.

[0076] R 2 is selected from methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl, and heptadeuteroisopropyl; R 3 is methoxy or fluoro; and R 4 is methyl or trideuteromethyl.

[0077] In some embodiments, R 1is selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteromethyl)-1H-indazol-5-yl, 4-trideuteromethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteromethyl-1H-indazol-5-yl, and 1-(2,2-difluoroethyl)-1H-indazol-5-yl; R 2 is C 1-6 Alkyl or C 1-6 is haloalkyl; R 3 Halo, C 1-6 Alkyl, and C 1-6 alkoxy; and R 4 is C 1-6 It is an alkyl.

[0078] In some embodiments, R 1 is selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteromethyl)-1H-indazol-5-yl, 4-trideuteromethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteromethyl-1H-indazol-5-yl, and 1-(2,2-difluoroethyl)-1H-indazol-5-yl; R 2 is C 1-6 Alkyl or C 1-6 is haloalkyl; R 3 Halo, C 1-6 Alkyl, and C 1-6 alkoxy; and R 4 is C 1-6 It is an alkyl.

[0079] In some embodiments, R 1 is selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteromethyl)-1H-indazol-5-yl, 4-trideuteromethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteromethyl-1H-indazol-5-yl, and 1-(2,2-difluoroethyl)-1H-indazol-5-yl; R 2 is C 1-3 Alkyl or C 1-3 is haloalkyl; R 3 Halo, C 1-3 Alkyl, and C 1-3 alkoxy; and R 4 is C 1-3 It is an alkyl.

[0080] In some embodiments, R 1 is selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteromethyl)-1H-indazol-5-yl, 4-trideuteromethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteromethyl-1H-indazol-5-yl, and 1-(2,2-difluoroethyl)-1H-indazol-5-yl; R 2 is selected from methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl, and heptadeuteroisopropyl; R 3 is methoxy or fluoro; and R 4is C 1-3 It is an alkyl.

[0081] In some embodiments, R 1 is selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteromethyl)-1H-indazol-5-yl, 4-trideuteromethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteromethyl-1H-indazol-5-yl, and 1-(2,2-difluoroethyl)-1H-indazol-5-yl; R 2 is selected from methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl, and heptadeuteroisopropyl; R 3 is methoxy or fluoro; and R 4 is methyl or trideuteromethyl.

[0082] In some embodiments, R 1 is selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteromethyl)-1H-indazol-5-yl, 4-trideuteromethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteromethyl-1H-indazol-5-yl, and 1-(2,2-difluoroethyl)-1H-indazol-5-yl; R 2 is selected from methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl, and heptadeuteroisopropyl; R 3 Halo, C 1-3Alkyl, and C 1-3 alkoxy; and R 4 is C 1-3 It is an alkyl.

[0083] In some embodiments, R 1 is selected from phenyl and indazolyl, each of which is selected from halo, C 1-3 Alkyl, and C 1-3 optionally substituted by 1 or 2 substituents independently selected from alkoxy; R 2 is C 1-3 is alkyl; R 3 Halo, C 1-3 Alkyl, and C 1-3 alkoxy; and R 4 is C 1-3 It is an alkyl.

[0084] In some embodiments, R 1 is selected from phenyl and indazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from fluoro, trideuteromethyl, and methoxy; R 2 is methyl or trideuteromethyl; R 3 is methoxy or fluoro; and R 4 is methyl or trideuteromethyl.

[0085] In some embodiments, R 1 is selected from phenyl and indazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from fluoro, trideuteromethyl, and methoxy; R 2 is methyl; R 3 is methoxy; and R 4 is methyl.

[0086] In some embodiments, R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl, and trideuteromethylindazolyl; R 2 is C 1-3 is alkyl; R 3 is C 1-3 alkoxy or halo; and R 4 is C 1-3 It is an alkyl.

[0087] In some embodiments, R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl, and trideuteromethylindazolyl; R 2 is C 1-3 is alkyl; R 3 is C 1-3 is alkoxy; and R 4 is C 1-3 It is an alkyl.

[0088] In some embodiments, R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl, and trideuteromethylindazolyl; R 2 is C 1-3 is alkyl; R 3 is C 1-3 alkoxy or halo; and R 4 is methyl or trideuteromethyl.

[0089] In some embodiments, R 1is selected from phenyl, fluorophenyl, fluoromethoxyphenyl, and trideuteromethylindazolyl; R 2 is C 1-3 is alkyl; R 3 is C 1-3 is alkoxy; and R 4 is methyl or trideuteromethyl.

[0090] In some embodiments, R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl, and trideuteromethylindazolyl; R 2 is C 1-3 is alkyl; R 3 is C 1-3 is alkoxy; and R 4 is methyl.

[0091] In some embodiments, R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl, and trideuteromethylindazolyl; R 2 is methyl or trideuteromethyl; R 3 is methoxy or fluoro; and R 4 is methyl or trideuteromethyl.

[0092] In some embodiments, R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl, and trideuteromethylindazolyl; R 2 is methyl; R 3 is methoxy; and R 4 is methyl.

[0093] In some embodiments, R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, and 1-(trideuteromethyl)-1H-indazol-5-yl; R 2 is C 1-3 is alkyl; R 3 is C 1-3 alkoxy or halo; and R 4 is C 1-3 It is an alkyl.

[0094] In some embodiments, R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, and 1-(trideuteromethyl)-1H-indazol-5-yl; R 2 is C 1-3 is alkyl; R 3 is C 1-3 is alkoxy; and R 4 is C 1-3 It is an alkyl.

[0095] In some embodiments, R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, and 1-(trideuteromethyl)-1H-indazol-5-yl; R 2 is C 1-3 is alkyl; R 3 is C 1-3 alkoxy or halo; and R 4 is methyl or trideuteromethyl.

[0096] In some embodiments, R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, and 1-(trideuteromethyl)-1H-indazol-5-yl; R 2 is methyl or trideuteromethyl; R 3 is C 1-3 alkoxy or halo; and R 4 is methyl or trideuteromethyl.

[0097] In some embodiments, R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, and 1-(trideuteromethyl)-1H-indazol-5-yl; R 2 is C 1-3 is alkyl; R 3 is C 1-3 is alkoxy; and R 4 is methyl or trideuteromethyl.

[0098] In some embodiments, R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, and 1-(trideuteromethyl)-1H-indazol-5-yl; R 2 is methyl or trideuteromethyl; R 3 is methoxy or fluoro; and R 4 is methyl or trideuteromethyl.

[0099] In some embodiments, R 1is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, and 1-(trideuteromethyl)-1H-indazol-5-yl; R 2 is C 1-3 is alkyl; R 3 is C 1-3 is alkoxy; and R 4 is methyl.

[0100] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt thereof.

[0101] In some embodiments, the compound of formula I is a compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof.

[0102] In some embodiments, the compound of formula I is a compound of formula IIa: [ka] or a pharma- ceutically acceptable salt thereof.

[0103] In some embodiments, the compound of formula I is a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof.

[0104] In some embodiments, the compound of formula I is a compound of formula IIIa: [ka] or a pharma- ceutically acceptable salt thereof.

[0105] In some embodiments, the compound of formula I is a compound of formula IV: [ka] or a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, the compound of formula I is a compound of formula IVa: [ka] or a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments, the compound of formula I is a compound of formula V: [ka] or a pharma- ceutically acceptable salt thereof, 1A Halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 hydroxyalkyl.

[0108] In some embodiments, the compound of formula I is a compound of formula Va: [ka] or a pharma- ceutically acceptable salt thereof, 1A Halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 hydroxyalkyl.

[0109] In some embodiments of Formulas V and Va, each R 1A are independently selected C 1-6 It is an alkyl.

[0110] In some embodiments of Formulas V and Va, each R 1A are independently selected C 1-3 It is an alkyl.

[0111] In some embodiments, the compound of formula I is a compound of formula Vb: [ka] or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, the compound of formula I is a compound of formula Vc: [ka] or a pharma- ceutically acceptable salt thereof.

[0113] In some embodiments, the compound of formula I is Methyl ((1R,3R)-3-(8-(4-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(3-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(3-fluoro-4-methoxyphenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-fluorophenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-(methoxy-d3)phenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-(2-hydroxypropan-2-yl)phenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(1-(2,2-difluoroethyl)-3-fluoro-1H-pyrazol-4-yl)-8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(1-isopropyl-1H-indazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1-(2,2-difluoroethyl)-1H-indazol-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(1-(ethyl-d5)-3-fluoro-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(1-isopropyl-1H-indazol-5-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(7-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1-(2,2-difluoroethyl)-1H-indazol-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(1-(ethyl-d5)-3-fluoro-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(1-ethyl-3-fluoro-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; and Methyl ((1R,3R)-3-(7-(3-fluoro-1-(propan-2-yl-d7)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; or a pharma- ceutically acceptable salt thereof.

[0114] In some embodiments, the compound of formula I is Methyl ((1R,3R)-3-(8-(4-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(3-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(3-fluoro-4-methoxyphenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; and Methyl ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; or a pharma- ceutically acceptable salt thereof.

[0115] In some embodiments, the compound of formula I is Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; and Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-fluorophenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; or a pharma- ceutically acceptable salt thereof.

[0116] In some embodiments, the compound of formula I is Methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-(methoxy-d3)phenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-(2-hydroxypropan-2-yl)phenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(1-(2,2-difluoroethyl)-3-fluoro-1H-pyrazol-4-yl)-8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(1-isopropyl-1H-indazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1-(2,2-difluoroethyl)-1H-indazol-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(1-(ethyl-d5)-3-fluoro-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(1-isopropyl-1H-indazol-5-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(7-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1-(2,2-difluoroethyl)-1H-indazol-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(1-(ethyl-d5)-3-fluoro-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(1-ethyl-3-fluoro-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; and Methyl ((1R,3R)-3-(7-(3-fluoro-1-(propan-2-yl-d7)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; or a pharma- ceutically acceptable salt thereof.

[0117] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(8-(4-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0118] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0119] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(8-(3-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0120] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(8-(3-fluoro-4-methoxyphenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0121] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0122] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-fluorophenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0124] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0125] In some embodiments, the compound of formula I is ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-(methoxy-d3)phenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate methyl, or a pharma- ceutically acceptable salt thereof.

[0126] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-(2-hydroxypropan-2-yl)phenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0127] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0128] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(7-(1-(2,2-difluoroethyl)-3-fluoro-1H-pyrazol-4-yl)-8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0129] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(1-isopropyl-1H-indazol-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0130] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(8-(1-(2,2-difluoroethyl)-1H-indazol-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0131] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(7-(1-(ethyl-d5)-3-fluoro-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0132] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(1-isopropyl-1H-indazol-5-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0133] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(8-(7-fluoro-1-(methyl-d3)-1H-indazol-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0134] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(8-(1-(2,2-difluoroethyl)-1H-indazol-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0135] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(1-(ethyl-d5)-3-fluoro-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0136] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(1-ethyl-3-fluoro-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0137] In some embodiments, the compound of formula I is methyl ((1R,3R)-3-(7-(3-fluoro-1-(propan-2-yl-d7)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate, or a pharma- ceutically acceptable salt thereof.

[0138] It will be further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0139] At various places in the present specification, divalent linking substituents are described. Each divalent linking substituent is specifically intended to include both the forward and backward form of the linking substituent. For example, -NR(CR'R'') n-NR(CR'R'') n -and-(CR'R'') n Both NR-- and NR-- are included. When a structure explicitly calls for a linking group, the Markush variable recited for that group is understood to be the linking group.

[0140] The term "n-membered", where n is an integer, typically refers to the number of ring-forming atoms at the moiety where n is the number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0141] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. Substituents are independently selected, and substitution can be at any chemically available position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. It is understood that substitution at a given atom is limited by the valence of the atom.

[0142] As used herein, the phrase "each 'variable' is independently selected from" means substantially the same as "at each occurrence, 'variable' is selected from."

[0143] Through definition, "C n-m " denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include 1-3 , C 1-4 , C 1-5 , C 1-6 etc.

[0144] As used herein, the term "C" used alone or in combination with other terms means n-mThe term "alkyl" refers to a saturated hydrocarbon group having n to m carbons, which may be linear or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl, and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, an alkyl group contains 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0145] As used herein, the term "C" used alone or in combination with other terms means n-m The term "alkoxy" refers to a group of formula -O-alkyl, where the alkyl group has n to m carbons. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 5, 1 to 4, or 1 to 3 carbon atoms.

[0146] As used herein, the term "C" used alone or in combination with other terms means n-mThe term "hydroxyalkyl" refers to an alkyl group having one hydroxy (OH) group to 2s+1 hydroxy groups, where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbon atoms. In some embodiments, the hydroxyalkyl group contains one hydroxy group. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl (-CHOH), hydroxyethyl (e.g., -CHCHOH and -CH(OH)CH), 1-hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 1-hydroxypropan-1-yl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, and the like.

[0147] As used herein, "halo" refers to fluoro, chloro, bromo, and iodo. In some embodiments, halo is fluoro.

[0148] In certain places, definitions or embodiments refer to certain rings (e.g., phenyl ring, indazolyl ring, etc.).Unless otherwise specified, these rings can be bonded to any ring member, provided that the valence of the atom is not exceeded.For example, an indazolyl ring can be bonded at any position of the ring, whereas an indazol-5-yl ring is bonded at the 5-position.

[0149] As used herein, the term "independently selected from" means that each occurrence of a variable or substituent is independently selected at each occurrence from the applicable list.

[0150] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present disclosure containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compounds have the (R) configuration. In some embodiments, the compounds have the (S) configuration. The formulas provided herein (e.g., Formula I, Formula Ia, etc.) include stereoisomers of the compounds.

[0151] The resolution of a racemic mixture of a compound can be carried out by any of a number of methods well known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization are, for example, optically active acids such as D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0152] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0153] The compounds described herein also include tautomeric forms. Tautomeric forms are obtained by the exchange of adjacent double and single bonds with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position of a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole, and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms may be in equilibrium or can be sterically locked into one form by appropriate substitution.

[0154] All compounds and their pharma- ceutically acceptable salts may be found together with other substances such as water and solvents (eg, hydrates and solvates) or may be isolated.

[0155] In some embodiments, preparation of compounds may involve the addition of acids or bases, for example to affect catalysis of a desired reaction or the formation of salt forms, such as acid addition salts.

[0156] In some embodiments, the compounds described herein or salts thereof are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially separated from the environment in which they were formed or detected. Partial separation can include, for example, compositions enriched with the compounds described herein. Substantial separation can include compositions that contain at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds described herein or salts thereof.

[0157] The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein that are identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0158] The phrase "pharmacologically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals, within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0159] The present application also includes pharma- ceutically acceptable salts of the compounds described herein. As used herein, "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharma- ceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two, generally with non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (i.e., ACN or AcCN) being preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0160] synthesis As will be appreciated by those of skill in the art, the compounds provided herein, including their salts and stereoisomers, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes.

[0161] Compounds of formula (I) can be prepared, for example, as shown in Scheme 1. An optionally protected (e.g., P=phenylsulfonyl) nitro bicyclic heterocycle 1-1 (wherein X 1where x is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with an amine such as 1-2 under standard SNAr conditions (e.g., in the presence of a base such as Et3N) to give 1-3. The nitroheterocycle 1-3 can be reduced under standard conditions (e.g., in the presence of Fe and an acid) to give 1-4. The diamine 1-4 can be converted to the cyclic urea 1-5 under standard conditions (e.g., in the presence of CDI). The cyclic urea 1-5 can be converted to the cyclic urea 1-5 using standard S N Under two conditions (e.g., X 2 When R is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs), KCO and R 4 -X 2 In the presence of X, the cyclic urea 1-6 can be alkylated to give 1-6. 3When is a halogen (e.g., Cl, Br, or I), it can be converted to the halide 1-7 under standard conditions (e.g., in the presence of LDA or an alkyllithium, or 1,2-dibromotetrachloroethane in the case of bromination). The halide 1-7 can be coupled with 1-8 (wherein M1 is a boronic acid, a boronic ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu)3 or Zn) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., a carbonate base)) or under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)) or under standard Negishi conditions (e.g., tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to give compound 1-9. Compound 1-9 can be brominated with a suitable reagent, such as bromine, to give 1-10. The Boc group of compound 1-10 can be removed under standard conditions (e.g., TFA in CH2Cl2) to give amine 1-11. Amine 1-11 can be converted to carbamate 1-12 under standard conditions (e.g., methyl chloroformate). Compound 1-12 can be converted to carbamate 1-12 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., carbonate base)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) with R 1 -M 2 (In the formula, M 2 can be coupled with a boronic acid, boronic ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu)3 or Zn to give compounds 1-13. Compounds 1-13 can be deprotected under standard conditions (e.g., NaOH when P=phenylsulfonyl) to give compounds of Formula I.

[0162] Scheme 1. [ka] The reactions for preparing the compounds described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0163] As used herein, the expressions "ambient temperature" or "room temperature" or "rt" are understood in the art and generally refer to a temperature, e.g., a reaction temperature approaching the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20° C. to about 30° C.

[0164] Preparation of the compounds described herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in TW Greene and PG M Huts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999).

[0165] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry, or chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by one of skill in the art by a variety of methods, including high performance liquid chromatography (HPLC) and normal phase silica chromatography.

[0166] How to use The compounds described herein can inhibit the activity of the V617F variant of protein-tyrosine kinase JAK2 (i.e., "V617F" or "JAK2 V617F"). Compounds that inhibit V617F are particularly useful for preventing tumor growth or providing a means of inducing apoptosis by inhibiting angiogenesis. Thus, the compounds of the present disclosure are expected to be useful in treating or preventing proliferative disorders such as cancer. In particular, tumors with activating mutants of receptor tyrosine kinases or upregulation of receptor tyrosine kinases may be particularly sensitive to inhibitors.

[0167] As disclosed herein, the compounds of the present invention exhibit unexpectedly improved properties (e.g., improved efficacy and PK properties) compared to the compounds disclosed in International Publication No. WO2022 / 006457, the contents of which are incorporated herein by reference in their entirety. The following compounds from WO2022 / 006457 are provided herein as Comparative Examples A-E. [Table 1]

[0168] In certain embodiments, the present disclosure provides a method for treating a V617F-associated disorder in a patient in need thereof, the method comprising administering to the patient a compound of the present disclosure, or a pharma- ceutically acceptable composition thereof.

[0169] Myeloproliferative disorders (MPDs) are pluripotent hematopoietic stem cell disorders characterized by the overproduction of various blood cells. MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF). JAK2 V617F mutations have been reported in approximately 95% of patients with PV, 35%-70% of patients with ET, and 50% of patients with IMF. In addition, JAK2 exon 12 mutations have been detected in a proportion of V617F-negative PV patients (Ma et al., J. Mol. Diagn., 11:49-53, 2009). In some embodiments, compounds of the present disclosure may be useful for treating myeloproliferative disorders (e.g., myeloproliferative neoplasms) in patients in need of such treatment, such as polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), and systemic mast cell disease (SMCD).

[0170] In some embodiments, the myeloproliferative disorder is a myeloproliferative neoplasm.

[0171] In some embodiments, the myeloproliferative disorder is myelofibrosis (eg, primary myelofibrosis (PMF) or polycythemia vera / essential thrombocythemia myelofibrosis (Post-PV / ETMF)).

[0172] In some embodiments, the myeloproliferative disorder is primary myelofibrosis (PMF).

[0173] In some embodiments, the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis (Post-ET MF).

[0174] In some embodiments, the myeloproliferative disorder is post-polycythemia vera myelofibrosis (Post-PV MF).

[0175] In some embodiments, the myeloproliferative disorder is selected from primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET).

[0176] In some embodiments, the myeloproliferative neoplasm is primary myelofibrosis (PMF).

[0177] In some embodiments, the myeloproliferative neoplasm is polycythemia vera (PV).

[0178] In some embodiments, the myeloproliferative neoplasm is essential thrombocythemia (ET).

[0179] Myeloproliferative disorders include disorders of bone marrow or lymph node derived cell types, such as white blood cells. Myeloproliferative disorders may be manifested by abnormal cell division resulting in abnormal levels of certain blood cell populations. The abnormal cell division underlying proliferative blood disorders is typically intrinsic to the cells and is not a normal physiological response to infection or inflammation. Leukemia is a type of myeloproliferative disorder. Exemplary myeloproliferative disorders include, but are not limited to, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndromes (MDS), chronic myelogenous leukemia (CML), hairy cell leukemia, leukemic manifestations of lymphoma, multiple myeloma, polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), hypereosinophilic syndrome (HES), chronic neutrophilic leukemia (CNL), myelofibrosis with myeloid metaplasia (MMM), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis (SM), and unclassified myeloproliferative disorder (UMPD or MPD-NC). Lymphoma is a type of proliferative disease that primarily involves lymphoid organs such as lymph nodes, liver, and spleen. Exemplary proliferative lymphatic diseases include lymphocytic lymphoma (also called chronic lymphocytic leukemia), follicular lymphoma, large cell lymphoma, Burkitt's lymphoma, marginal zone lymphoma, and lymphoblastic lymphoma (also called acute lymphoblastic lymphoma).

[0180] For example, the compounds of the present disclosure are useful for treating cancer. Exemplary cancers include bladder cancer (e.g., urothelial carcinoma, squamous cell carcinoma, adenocarcinoma), breast cancer (e.g., hormone R positive, triple negative), cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer (e.g., gastrointestinal stromal tumor), head and neck cancer (e.g., laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, head and neck squamous cell carcinoma), kidney cancer (e.g., renal cell carcinoma, urothelial carcinoma, sarcoma, Wilms' tumor), liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma (e.g., intrahepatic, hilar or perihilar, distal extrahepatic), hepatic angiosarcoma, hepatoblastoma ... tumors), lung cancer (e.g., adenocarcinoma, small cell and non-small cell lung cancer, small cell and non-small cell carcinoma, bronchogenic carcinoma, bronchogenic adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine splenic carcinoma), stomach cancer, thyroid cancer, parathyroid cancer, neuroendocrine carcinoma (e.g., pheochromocytoma, Merkel cell carcinoma, neuroendocrine carcinoma), skin cancer (e.g., squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer), and brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuroexocrine tumor, pineal tumor).

[0181] Further examples of cancer include hematopoietic malignancies, such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, acute myeloid leukemia (AML), B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, myeloproliferative neoplasms (e.g., 8p11 myeloproliferative syndrome, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)), myelodysplastic syndromes, chronic eosinophilic leukemia, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myelogenous lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

[0182] In certain embodiments, provided herein are methods of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the cancer is selected from T lymphoblastic lymphoma, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

[0183] Other cancers treatable with the compounds of the present disclosure include eye tumors, glioblastoma, melanoma, leiomyosarcoma, and urothelial carcinoma (e.g., ureter, urethra, bladder, urachus).

[0184] Compounds of the present disclosure may also be useful in inhibiting tumor metastasis.

[0185] In some embodiments, the disclosed compounds described herein can be used to treat Alzheimer's disease, HIV, or tuberculosis.

[0186] In some embodiments, the compounds of the present disclosure may be useful for treating myelodysplastic syndrome (MDS) in patients in need of such treatment. In some embodiments, the patients with myelodysplastic syndrome (MDS) are red blood cell transfusion dependent.

[0187] As used herein, myelodysplastic syndrome is intended to encompass heterogeneous and clonal hematopoietic disorders characterized by ineffective hematopoiesis in one or more of the major myeloid cell lineages. Myelodysplastic syndrome is associated with bone marrow failure, peripheral cytopenia, and a tendency to progress to acute myeloid leukemia (AML). In addition, clonal cytogenetic abnormalities can be detected in about 50% of cases of MDS. In 1997, the World Health Organization (WHO), together with the Society of Hematology (SH) and the European Association of Hematology (EAHP), proposed a new classification of hematopoietic tumors (Harris, et al., J Clin Oncol 1999;17:3835-3849; Vardiman, et al., Blood 2002;100:2292-2302). For MDS, the WHO not only utilized morphologic criteria from the French-American-British (FAB) classification, but also incorporated available genetic, biological, and clinical features to define subsets of MDS (Bennett, et al., Br. J. Haematol. 1982;51:189-199). In 2008, the WHO classification of MDS (Table 1) was further refined by incorporating new clinical and scientific information to allow for accurate and prognostically relevant subclassification of single blood lineage dysplasias (Vardiman, et al., Blood 2009;114:937-951; Swerdlow, et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th Edition. Lyon France: IARC Press; 2008:88-103; Bunning and Germing, “Myelodysplastic syndromes / neoplasms” in Chapter 5, Swerdlow, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. (ed. 4th edition): Lyon, France: IARC Press; 2008:88-103). [Table 2]

[0188] In some embodiments, the myelodysplastic syndrome is refractory cytopenia with single lineage dysplasia (RCUD).

[0189] In some embodiments, the myelodysplastic syndrome is refractory anemia with ringed sideroblasts (RARS).

[0190] In some embodiments, the myelodysplastic syndrome is refractory anemia with ringed sideroblasts associated with thrombocytosis (RARS-T).

[0191] In some embodiments, the myelodysplastic syndrome is refractory cytopenia associated with multilineage dysplasia.

[0192] In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-1 (RAEB-1).

[0193] In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-2 (RAEB-2).

[0194] In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome, unclassified (MDS-U).

[0195] In some embodiments, the myelodysplastic syndrome is isolated del(5q)-associated myelodysplastic syndrome.

[0196] In some embodiments, the myelodysplastic syndrome is refractory to an erythropoiesis-stimulating agent.

[0197] In some embodiments, compounds of the present disclosure may be useful for the treatment of myeloproliferative disorder / myelodysplastic overlap syndrome (MPD / MDS overlap syndrome).

[0198] In some embodiments, compounds of the present disclosure may be useful in the treatment of leukemia.

[0199] In some embodiments, compounds of the present disclosure may be useful in the treatment of acute myeloid leukemia (AML).

[0200] In addition to carcinogenic tumors, the compounds of the present disclosure may be useful in the treatment of skeletal and chondrocyte disorders, including, but not limited to, achondroplasia, hypochondroplasia, dwarfism, tophatogenic dysplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Behle-Stevenson gyriform scalp syndrome, Pfeiffer syndrome, and craniosynostosis.

[0201] The compounds provided herein may further be useful in treating fibrotic diseases, such as when the disease condition or disorder is characterized by fibrosis. Examples of fibrotic diseases include liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.

[0202] In some embodiments, the compounds provided herein can be used to treat hypophosphatemic disorders, such as, for example, X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets, or tumor-induced osteomalacia.

[0203] In some embodiments, provided herein is a method of increasing a patient's survival or progression-free survival, comprising administering to the patient a compound provided herein. In some embodiments, the patient has cancer. In some embodiments, the patient has a disease or disorder described herein. As used herein, progression-free survival refers to the length of time that a patient lives with, but does not worsen, the disease during and after treatment of a solid tumor. Progression-free survival refers to the time from first administration of the compound to death or disease progression, whichever occurs first. Disease progression can be defined by RECIST v.1.1 (Response Evaluation Criteria in Solid Tumors) as assessed by an independent central radiological review committee. In some embodiments, administration of the compound results in a progression-free survival of greater than about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 12 months, about 16 months, or about 24 months. In some embodiments, administration of the compound results in a progression-free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. In some embodiments, administration of the compound results in an increase in progression-free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.

[0204] The disclosure further provides a compound described herein, or a pharma- ceutically acceptable salt thereof, for use in any of the methods described herein.

[0205] The disclosure further provides the use of a compound described herein, or a pharma- ceutically acceptable salt thereof, to prepare a medicament for use in any of the methods described herein.

[0206] As used herein, the term "cell" refers to a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that is living in an organism, such as a mammal.

[0207] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro or in vivo system. For example, "contacting" a V617F variant with a compound described herein includes administering a compound described herein to an individual or patient, such as a human, having a V617F variant, as well as introducing a compound described herein into a sample, including, for example, a cell preparation or purified preparation that contains the V617F variant.

[0208] As used herein, the terms "individual" or "patient", used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0209] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent, such as an amount of any of the solid forms or salts thereof disclosed herein, that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician. The appropriate "effective" amount in any individual case can be determined using techniques known to those of ordinary skill in the art.

[0210] As used herein, the phrase "pharmacologically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, within the bounds of safe medical judgment, and commensurate with a reasonable benefit / risk ratio.

[0211] As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams&Wilkins:Philadelphia,Pa.,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company:2007;Pharmaceutical Preformulation and Formulation, 2nd ed.;Gibson Ed.;CRC Press LLC:Boca Raton, Fla., 2009.

[0212] As used herein, the term "treating" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., halting further development of the pathology and / or symptomology), or ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology), e.g., reducing the severity of the disease.

[0213] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein, e.g., for preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder, but who has not yet experienced or exhibited any pathology or symptoms of the disease.

[0214] It is understood that certain features of the present disclosure that are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while those embodiments are intended to be combined as if described in multiple dependent forms). Conversely, various features of the present disclosure that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0215] Combination therapy For example, one or more additional pharmaceutical agents or therapeutic methods, such as antiviral agents, chemotherapeutic agents or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and / or tyrosine kinase inhibitors, may be used in combination with the compounds described herein for the treatment or prevention of a V617F-associated disease, disorder or condition, or a disease or condition as described herein. The agents may be combined with the compounds in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0216] The compounds described herein can be used in combination with one or more other kinase inhibitors for the treatment of diseases such as cancer that are affected by multiple signaling pathways.For example, the combination can include one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK -II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. Additionally, the solid forms of the inhibitors described herein may be combined with inhibitors of kinases associated with the PIK3 / Akt / mTOR signaling pathway, such as PI3K, Akt (including Akt1, Akt2, and Akt3), and mTOR kinases.

[0217] In some embodiments, the compounds described herein may be used in combination with one or more inhibitors of enzymes or protein receptors, such as HPK1, SBLB, TUT4, A2A / A2B, CD19, CD47, CDK2, STING, ALK2, LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1, for the treatment of diseases and disorders. Exemplary diseases and disorders include cancer, infectious diseases, inflammation, and neurodegenerative disorders.

[0218] In some embodiments, the compounds described herein can be used in combination with therapeutic agents that target epigenetic regulators.Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferase, histone arginine methyltransferase, histone demethylase, histone deacetylase, histone acetylase, and DNA methyltransferase.Histone deacetylase inhibitors include, for example, vorinostat.

[0219] For the treatment of cancer and other proliferative diseases, the compounds described herein are useful as therapeutic agents for treating cancer and other proliferative diseases, including but not limited to JAK kinase inhibitors (ruxolitinib, additional JAK1 / 2 and JAK1 selective, baricitinib or itacitinib), Pim kinase inhibitors (e.g., LGH447, INCB053914 and SGI-1776), PI3 kinase inhibitors including PI3K-delta selective and broad spectrum PI3K inhibitors (e.g., INCB50465 and INCB50797), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinase inhibitors (Tyro-3, Axl, and Mer, e.g., INCB81776), angiogenesis inhibitors, interleukin receptor inhibitors, cyclin dependent kinase inhibitors, BRAF inhibitors, mTOR inhibitors, It may be used in combination with targeted therapies, including proteasome inhibitors (bortezomib, carfilzomib), HDAC inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, such as OTX015, CPI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g., GSK2979552, INCB59872 and INCB60003), arginase inhibitors (e.g., INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat, NLG919 or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib), and inhibitors of BTK, such as ibrutinib.

[0220] To treat cancer and other proliferative diseases, the compounds described herein may be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other anti-proliferative agents. The compounds described herein may also be used in combination with medical therapies such as surgery or radiation therapy, e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes.

[0221] Examples of suitable chemotherapeutic agents include abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole, aphidicolone, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezomib, bortezomib, brivanib, bupallisib, busulfan intravenous, busulfan oral, calsterone, camptosar. le, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denoleukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, Eculizumab, enzalutamide, epidophyllotoxin, epirubicin, epothilone, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelarib, ifosfamide, imatinib mesylate, interferon alpha 2a, irinoside Tecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lonafarnib, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone fenopropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin, paclitaxel,Pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, piralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafin, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib malate, tamoxifen Xifene, tegafur, temozolomide, teniposide, testolactone, tezacitabine, thalidomide, thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

[0222] In some embodiments, the compounds described herein may be used in combination with immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors for immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (e.g., INCAGN2385), TIM3 (e.g., INCB2390), VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40 (e.g., INCAGN1949), GITR (e.g., INCAGN1876), and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFR beta inhibitor.

[0223] In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule PD-L1 inhibitor. In some embodiments, the small molecule PD-L1 inhibitor has an IC50 of less than 1 μM, less than 100 nM, less than 10 nM, or less than 1 nM in the PD-L1 assay described in U.S. Patent Publication Nos. US20170107216, US20170145025, US20170174671, US20170174679, US20170320875, US20170342060, US20170362253, and US20180016260, each of which is incorporated by reference in its entirety for all purposes.

[0224] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is retifanlimab (also known as MGA012), nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, ipilumimab, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1 antibody is nivolumab. In some embodiments, the anti-PD-1 monoclonal antibody is retifanlimab. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomirumab).

[0225] In some embodiments, compounds of the present disclosure can be used in combination with INCB086550.

[0226] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

[0227] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0228] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0229] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0230] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

[0231] In some embodiments, the inhibitor of immune checkpoint molecule is an agonist of OX40, for example, an OX40 agonist antibody or an OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998 or BMS-986178.In some embodiments, the OX40L fusion protein is MEDI6383.

[0232] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0233] The compounds of the present disclosure may be used in combination with bispecific antibodies, in some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or TGFβ receptor.

[0234] In some embodiments, the compounds of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors.In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase.Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0235] In some embodiments, the compounds described herein may be used in combination with one or more agents for the treatment of diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

[0236] Suitable antiviral agents contemplated for use in combination with the compounds of the present disclosure can include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, as well as other antiviral agents.

[0237] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emtricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C, beta-L-2',3'-dicreoxy-5-fluoro-cytidine); DAPD, ((-)-beta-D-2,6,-diamino-purine dioxolane); and rhodenosine (FddA). Exemplary suitable NNRTIs include nevirapine (BI-RG-587), delaviradine (BHAP, U-90152), efavirenz (DMP-266), PNU-142721, AG-1549, MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione), and (+)-calanolide A (NSC-6 75451) and B. Exemplary suitable protease inhibitors include saquinavir (Ro31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfnavir (AG-1343), amprenavir (141W94), lasinavir (BMS-234475), DMP-450, BMS-2322623, ABT-378, and AG-1 549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0238] Suitable drugs for use in combination with the compounds described herein for the treatment of cancer include chemotherapeutic agents, targeted cancer therapy, immunotherapy or radiation therapy.The compounds described herein may be effective in combination with antihormonal agents for the treatment of breast cancer and other tumors.Suitable examples include antiestrogens, including but not limited to tamoxifen and toremifene, aromatase inhibitors, including but not limited to letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g., prednisone), progestins (e.g., megastrol acetate), and estrogen receptor antagonists (e.g., fulvestrant).Suitable antihormonal agents used in the treatment of prostate cancer and other cancers may also be combined with the compounds described herein. These include antiandrogens, including but not limited to flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogues, including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g., degarelix), androgen receptor blockers (e.g., enzalutamide), and agents that inhibit androgen production (e.g., abiraterone).

[0239] The compounds described herein may be combined or sequenced with other agents against membrane receptor kinases, especially for patients who have developed primary or acquired resistance to targeted therapy. These therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or against Flt-3 and cancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk. Inhibitors against EGFR include gefitinib and erlotinib, and inhibitors against EGFR / Her2 include, but are not limited to, dacomitinib, afatinib, lapitinib, and neratinib. Antibodies against EGFR include, but are not limited to, cetuximab, panitumumab, and necitumumab. Inhibitors of c-Met can be used in combination with FGFR inhibitors. These include onartumuzumab, tivantinib, and INC-280. Agents directed against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib, and those directed against Alk (or EML4-ALK) include crizotinib.

[0240] Angiogenesis inhibitors may be effective in some tumors in combination with the inhibitors described herein.These include antibodies against VEGF or VEGFR, or kinase inhibitors of VEGFR.Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept.Inhibitors of VEGFR kinase and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0241] Activation of intracellular signaling pathways occurs frequently in cancer, and drugs that target components of these pathways are combined with receptor targeting agents to increase efficacy and reduce resistance. Examples of drugs that can be combined with the compounds described herein include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of the JAK-STAT pathway, and inhibitors of protein chaperones and cell cycle progression.

[0242] Drugs against PI3 kinase include, but are not limited to, topiralisib, idelalisib, buparlisib.Inhibitors of mTOR, such as rapamycin, sirolimus, temsirolimus, and everolimus, may be combined with the compounds described herein.Other suitable examples include, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors), and trametinib, selumetinib, and GDC-0973 (MEK inhibitors). One or more JAK inhibitors (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 inhibitors (e.g., tanespimycin), cyclin-dependent kinase inhibitors (e.g., palbociclib), HDAC inhibitors (e.g., panobinostat), PARP inhibitors (e.g., olaparib), and proteasome inhibitors (e.g., bortezomib, carfilzomib) can also be combined with the compounds described herein. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2 and JAK3.

[0243] Other suitable agents for use in combination with the compounds described herein include chemotherapy combinations such as platinum-based doublets (cisplatin or carboplatin + gemcitabine, cisplatin or carboplatin + docetaxel, cisplatin or carboplatin + paclitaxel, cisplatin or carboplatin + pemetrexed) or gemcitabine + paclitaxel-bound particles used in lung cancer and other solid tumors.

[0244] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethylenimine derivatives, alkylsulfonates, nitrosoureas, and triazenes) such as uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0245] Other suitable agents for use in combination with the compounds described herein include steroids, including 17alpha-ethynyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, and medroxyprogesterone acetate.

[0246] Other suitable agents for use in combination with the compounds described herein include dacarbazine (DTIC), optionally with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; a combination of cisplatin, vinblastine, and DTIC; or temozolomide. The compounds described herein may also be combined with immunotherapeutic agents, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF).

[0247] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including but not limited to antifolates, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0248] Suitable chemotherapeutic or other anti-cancer agents further include certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as, for example, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel, mithramycin, deoxyformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and tenoside.

[0249] Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[0250] Further preferred are cytotoxic agents such as epidophyllotoxins; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitory agents; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0251] Other anti-cancer agents include antibody therapeutics such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4, 4-1BB, PD-L1, and PD-1 antibodies, or antibodies against cytokines (IL-10, TGF-β, etc.).

[0252] Other anti-cancer agents include those that block immune cell migration, such as antagonists to chemokine receptors, including CCR2 and CCR4.

[0253] Other anti-cancer drugs also include those that enhance the immune system, such as adjuvants or adoptive T-cell transfer.

[0254] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. In some embodiments, tumor vaccines include proteins derived from viruses involved in human cancer, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0255] The compounds of the present disclosure may be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin (see, e.g., U.S. Pat. Nos. 9,233,985, 10,065,974, 10,287,303, and 8,524,867, the disclosures of which are incorporated by reference in their entireties herein).

[0256] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0257] As provided throughout, the additional compounds, inhibitors, agents, etc. can be combined with the present compounds in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0258] Pharmaceutical Preparations and Dosage Forms When used as a pharmaceutical, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0259] The present disclosure also includes pharmaceutical compositions that contain the compounds of the present disclosure or pharma- ceutically acceptable salts thereof as active ingredients in combination with one or more pharma- ceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. In making compositions of the present disclosure, typically the active ingredients are mixed with excipients, diluted by excipients, or enclosed in such carriers, for example, in the form of capsules, sachets, paper or other containers. When excipients function as diluents, they can be solid, semi-solid, or liquid materials that act as vehicles, carriers, or media for the active ingredients. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0260] When preparing formulation, active compound can be milled to provide suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.If active compound is substantially water-soluble, its particle size can be adjusted by milling to provide substantially uniform distribution in formulation, for example about 40 mesh.

[0261] The compounds of the present disclosure can be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tableting and other formulation types.Finely divided (nanoparticulate) preparations of the compounds of the present disclosure can be prepared by processes known in the art, see, for example, the disclosure of International Application No. WO2002 / 000196.

[0262] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methylbenzoate and propylhydroxybenzoate, sweeteners, and flavoring agents.The composition of the present disclosure can be formulated to provide quick, sustained, or delayed release of active ingredient after administration to a patient by using procedures known in the art.

[0263] The compositions can be formulated in unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually from about 100 to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0264] In some embodiments, the compositions of the present disclosure contain about 5 to about 50 mg of active ingredient. One of skill in the art will appreciate that this embodies compositions containing about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of active ingredient.

[0265] In some embodiments, the compositions of the present disclosure contain from about 50 to about 500 mg of active ingredient. One of skill in the art will appreciate that this embodies compositions containing from about 50 to about 100, from about 100 to about 150, from about 150 to about 200, from about 200 to about 250, from about 250 to about 300, from about 350 to about 400, or from about 450 to about 500 mg of active ingredient.

[0266] In some embodiments, the compositions of the present disclosure contain about 500 to about 1000 mg of active ingredient. One of skill in the art will appreciate that this embodies compositions containing about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of active ingredient.

[0267] Similar dosages of the compounds described herein may be used in the methods and uses of the present disclosure.

[0268] The active compound may be effective over a wide dosage range and is generally administered in a pharma- ceutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's condition, and the like.

[0269] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the compounds of the present disclosure. When these preformulation compositions are referred to as homogenates, the active ingredient is usually uniformly dispersed throughout the composition, so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, for example, containing about 0.1 to about 1000 mg of the active ingredient of the present disclosure.

[0270] The tablet or pill of the present disclosure can be coated or otherwise compounded to provide a dosage form that provides the advantage of long-term action.For example, the tablet or pill can include an inner dose and an outer dose component, the latter being in the form of an envelope on the former.The two components can be separated by an enteric layer that functions to prevent disintegration in the stomach and ensure that the inner component reaches the duodenum intact or is delayed in release.A variety of materials can be utilized as such enteric layers or coatings, including a number of polymeric acids, and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0271] Liquid forms into which the compounds and compositions of the present disclosure may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0272] Compositions for inhalation or insufflation include liquids and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0273] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. The carrier composition of creams may be based on water in combination with glycerol and one or more other components, for example, glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, preferably in combination with other components, such as, for example, glycerol, hydroxyethylcellulose, and the like. In some embodiments, topical formulations include at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of a compound of the present disclosure. Topical formulations may be suitably packaged in 100 g tubes, optionally accompanied by instructions for treating a selected indication, such as, for example, psoriasis or other skin conditions.

[0274] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, the compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease condition being treated and the judgment of the attending physician based on factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0275] The compositions administered to a patient may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for use as is or lyophilized, the lyophilized preparations being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations will typically be 3-11, more preferably 5-9, most preferably 7-8. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers will result in the formulation of pharmaceutical salts.

[0276] The therapeutic amount of a compound of the present disclosure may vary according to, for example, the particular application for which the treatment is to be performed, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition may vary depending on several factors, including the dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, a compound of the present disclosure may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage may depend on such variables as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative bioefficacy of the compound selected, the formulation of excipients, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0277] The compositions of the present disclosure can further comprise one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are listed herein.

[0278] Labeled Compounds and Assay Methods Another aspect of the present disclosure relates to the labeled compounds (radiolabeled, fluorescently labeled, etc.) of the present disclosure that may be useful in both in vitro and in vivo assays, as well as imaging techniques, to identify and quantify V617F in tissue samples, including humans, and to identify V617F inhibitors by binding the labeled compounds. Substitution of one or more atoms of the compounds of the present disclosure may also be useful in producing differential absorption, distribution, metabolism, and excretion (ADME). Thus, the present disclosure includes V617F assays that contain such labeled or substituted compounds.

[0279] The present disclosure further includes isotopically labeled compounds of the present disclosure. An "isotopically labeled" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms have been replaced or substituted with an atom having an atomic mass or mass number different from that normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present disclosure include, but are not limited to, 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced with deuterium atoms (e.g., -CD3 (i.e., trideuteromethyl) can be replaced with -CH3, etc., as desired, C of formula I. 1-6 One or more hydrogen atoms of the alkyl group can be replaced with a deuterium atom). In some embodiments, the alkyl groups of the disclosed formulas (e.g., Formula I, Formula Ia, etc.) can be perdeuterated (e.g., trideuteromethyl (-CD3), pentadeuteroethyl (-CD2CD3), heptadeuteroisopropyl (-CD(CD3)2, etc.

[0280] In some embodiments, the alkoxy groups of the disclosed formulas (e.g., Formula I, Formula Ia, etc.) can be perdeuterated (e.g., trideuteromethoxy (-OCD3), pentadeuteroethoxy (-OCD2CD3), heptadeuteroisopropoxy (-OCD(CD3)2, etc.).

[0281] One or more constituent atoms of the compounds presented herein may be replaced or substituted with an isotope of the atom at natural or non-natural abundance. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more hydrogen atoms in the compounds presented herein may be replaced or substituted with deuterium (C 1-6 One or more hydrogen atoms of the alkyl group may be replaced by a deuterium atom, such as -CD3 substituted for -CH3). In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1-2, 1-3, 1-4, 1-5, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, or 1-20 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted by deuterium atoms.

[0282] In some embodiments, each hydrogen atom of the compounds provided herein, such as a hydrogen atom bonded to a carbon atom of an alkyl, alkoxy, phenyl, dihydroisobenzofuranyl, and indazolyl substituent described herein, is optionally replaced by a deuterium atom.

[0283] In some embodiments, each hydrogen atom of the compounds provided herein, such as a hydrogen atom bonded to a carbon atom of an alkyl, alkoxy, phenyl, and indazolyl substituent described herein, is optionally replaced by a deuterium atom.

[0284] In some embodiments, each hydrogen atom of the compounds provided herein, such as the hydrogen atoms to the carbon atoms of the alkyl, alkoxy, phenyl, and indazolyl substituents described herein, is replaced by a deuterium atom (i.e., the alkyl, alkoxy, phenyl, dihydroisobenzofuranyl, and indazolyl substituents are perdeuterated).

[0285] In some embodiments, each hydrogen atom of the compounds provided herein, such as the hydrogen atoms to the carbon atoms of the alkyl, alkoxy, phenyl, and indazolyl substituents described herein, is replaced by a deuterium atom (i.e., the alkyl, alkoxy, phenyl, and indazolyl substituents are perdeuterated).

[0286] In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hydrogen atoms bonded to carbon atoms of the alkyl, alkoxy, phenyl, dihydroisobenzofuranyl, and indazolyl substituents described herein are optionally replaced by deuterium atoms.

[0287] In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms bonded to carbon atoms of the alkyl, alkoxy, phenyl, dihydroisobenzofuranyl, and indazolyl substituents described herein are optionally replaced by deuterium atoms.

[0288] In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hydrogen atoms bonded to carbon atoms of the alkyl, alkoxy, phenyl, and indazolyl substituents described herein are optionally replaced by deuterium atoms.

[0289] In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms bonded to carbon atoms of the alkyl, alkoxy, phenyl, and indazolyl substituents described herein are optionally replaced by deuterium atoms.

[0290] In some embodiments, a compound provided herein (e.g., a compound of any of Formulas I-Vc) or a pharma- ceutically acceptable salt thereof contains at least one deuterium atom.

[0291] In some embodiments, a compound provided herein (eg, a compound of any of Formulas I-Vc) or a pharma- ceutically acceptable salt thereof contains two or more deuterium atoms.

[0292] In some embodiments, a compound provided herein (eg, a compound of any of Formulas I-Vc) or a pharma- ceutically acceptable salt thereof contains three or more deuterium atoms.

[0293] In some embodiments, in the case of a compound provided herein (e.g., a compound of any of Formulas I-Vc) or a pharma- ceutically acceptable salt thereof, all of the hydrogen atoms are replaced by deuterium atoms (i.e., the compound is "perdeuterated").

[0294] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0295] Substitution with heavier isotopes, such as deuterium, can provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, due to greater metabolic stability, and therefore may be preferred in some cases (see, e.g., A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites may provide one or more therapeutic advantages.

[0296] The radionuclide incorporated into the present radiolabeled compounds will depend on the particular application of that radiolabeled compound. For example, for V617F labeling and competition assays in vitro, 3 H, 14 C. 82 Br, 125 I, 131 I, or 35 Compounds incorporating S may be useful. For radioimaging applications, 11 C. 18 F, 125 I, 123I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br may be useful.

[0297] It is understood that a "radiolabel" or "labeled compound" is a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S, and 82 Br.

[0298] The present disclosure can further include synthetic methods for incorporating radioisotopes into the compounds of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize methods that are applicable to the compounds of the present disclosure.

[0299] The labeled compounds of the present disclosure can be used in screening assays to identify / assess compounds. For example, a labeled newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to bind to V617F by monitoring its concentration fluctuations when contacting V617F through tracking of the label. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) that is known to bind to V617F. Thus, the ability of a test compound to compete with a standard compound for binding to V617F is directly correlated to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not labeled. Thus, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, and thus the relative binding affinity of the test compound is confirmed.

[0300] kit The present disclosure also includes pharmaceutical kits, useful, for example, in the treatment or prevention of a V617F-associated disease or disorder described herein, which include one or more containers housing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. As will be apparent to one of skill in the art, such kits can optionally further include one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container with one or more pharma- ceutically acceptable carriers, additional containers, etc. Instructions, either as an insert or label, indicating the amounts of components to be administered, administration guidelines, and / or guidelines for mixing the components, can also be included in the kit.

[0301] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to produce essentially the same results. EXAMPLES

[0302] Preparative LC-MS purification of some of the prepared compounds was carried out on a Waters mass fractionation system. The basic instrument setup, protocols, and control software for operating these systems are described in detail in the literature (see, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004)).

[0303] The separated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity analysis under the following conditions: Instrument = Agilent 1100 series, LC / MSD; Column: Waters Sunfire™ C 18 5 μm, 2.1 × 50 mm, buffer: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient 2% to 80% at B for 3 min, flow rate 2.0 mL / min.

[0304] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with MS detection as indicated in the examples. Typical preparative reversed-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0305] Purification at pH=2: Waters Sunfire™ C 18 , 5μm, 30×100mm or Waters XBridge™ C 18 , 5 μm, 30 × 100 mm column, elution with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; flow rate was 60 mL / min, and separation gradient was optimized for each compound using compound-specific method optimization protocols described in the literature (see, for example, "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

[0306] Purification at pH=10: Waters XBridge™ C 18 , 5 μm, 30 × 100 mm column, elution with mobile phase A: 0.1% NH4OH in water and mobile phase B: acetonitrile; flow rate was 60 mL / min, and separation gradient was optimized for each compound using compound-specific method optimization protocols described in the literature (see, e.g., "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

[0307] Example 1. Methyl ((1R,3R)-3-(8-(4-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] Step 1. tert-Butyl ((1R,3R)-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate [ka] A mixture of 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.07 g, 15.0 mmol), tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate (3.15 g, 15.75 mmol), and EtN (4.18 mL, 30.0 mmol) in acetonitrile (45 mL) was stirred at 70° C. for 1 h. The solvent was removed and the residue was washed with water, filtered, and dried to give the product. 23 H 28 N5O6S(M+H) + LC-MS calculated for: m / z=502.2; found: 502.2.

[0308] Step 2. tert-Butyl ((1R,3R)-3-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate [ka] To a solution of tert-butyl ((1R,3R)-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate (7.52 g, 15.0 mmol) in THF (18.0 mL) / ethanol (54.0 mL) was added iron (8.38 g, 150 mmol), followed by 1N HCl (5.0 mL), and the reaction mixture was then stirred at 70° C. for 4 h. The mixture was filtered through Celite and washed with ethyl acetate. The organic layer was concentrated and the resulting residue was dissolved in ethyl acetate, which was then washed with saturated NaHCO3 solution. The organic solution was concentrated to give the desired product. C 23 H 30 N5O4S(M+H) +LC-MS calculated for: m / z=472.2; found 472.3.

[0309] Step 3. tert-Butyl ((1R,3R)-3-(3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] A mixture of tert-butyl ((1R,3R)-3-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate (6.37 g, 13.5 mmol), DMAP (2.474 g, 20.25 mmol), and CDI (6.57 g, 40.5 mmol) in AcCN (30 mL) was stirred at 70° C. for 2 h. The solvent was removed, the residue was dissolved in ethyl acetate, and washed successively with water, cold 1N HCl, water, and brine. The organic phase was dried and concentrated. The resulting residue was dissolved in DMF (30.0 mL), K2CO3 (5.60 g, 40.5 mmol) and MeI (2.53 ml, 40.5 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate, washed with water, and then the organic phase was dried and concentrated. The residue was purified on silica gel (120 g, 0-80% EtOAc in hexanes) to give the desired product. 25 H 30 N5O5S(M+H) + LC-MS calculated for: m / z=512.2; found 512.2.

[0310] Step 4. tert-Butyl ((1R,3R)-3-(7-bromo-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] LDA (2.0 M in THF) (14.3 mL, 28.6 mmol) was added to a solution of tert-butyl ((1R,3R)-3-(3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (5.63 g, 11.00 mmol) in THF (110.0 mL) at −78° C. and stirred for 30 min. At this time, 1,2-dibromo-1,1,2,2-tetrachloroethane (5.01 g, 15.40 mmol) in THF (10 mL) was added to the reaction mixture. After stirring for an additional 40 min, the reaction was quenched by the addition of saturated NH4Cl solution. The mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried and concentrated. The resulting residue was purified on silica gel (120 g, 0-80% EtOAc in hexanes) to give the desired product. 25 H 29 BrNOS(M+H) + LC-MS calculated for: m / z = 590.1, 592.1; found 590.2, 592.1.

[0311] Step 5. tert-Butyl ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] tert-Butyl ((1R,3R)-3-(7-bromo-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (6.50 g, 11.0 mmol), 3-methoxy-1-methyl-4-(4,4,5,5 A mixture of -tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.71 g, 19.80 mmol), K3PO4 (7.00 g, 33.0 mmol), and Pd(Ph3P)4 (1.907 g, 1.650 mmol) was evacuated and backfilled with nitrogen (this process was repeated a total of three times), and the reaction was then stirred at 105 °C for 3 h. The mixture was diluted with ethyl acetate and washed with water, and the organic phase was then dried and concentrated. The residue was purified on silica gel (120 g, 0-100% EtOAc in hexanes) to give the desired product. 30 H 36 N7O6S(M+H) + LC-MS calculated for: m / z=622.2; found 622.3.

[0312] Step 6. tert-Butyl ((1R,3R)-3-(8-bromo-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] Bromine (1.542 g, 9.65 mmol) in CHCl (2.0 mL) was added to a solution of tert-butyl ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (5.00 g, 8.04 mmol) in CHCl (40.0 mL) at 0° C. and then stirred for 30 min. The reaction was quenched by addition of saturated NaHCO, and the resulting mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to give the desired product, which was used directly in the next step. C 30 H 35 BrN7O6S(M+H) + LC-MS calculated for: m / z=700.2, 702.2; found 700.3, 702.3.

[0313] Step 7. Methyl ((1R,3R)-3-(8-bromo-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] TFA (10 mL) was added to a solution of tert-butyl ((1R,3R)-3-(8-bromo-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (5.60 g, 8.0 mmol) in CHCl (10.0 mL) and the reaction was stirred for 30 min. The mixture was concentrated and the residue was then dissolved in CHCl (40 mL) and water (20.0 mL) followed by the addition of NaCO (4.24 g, 40.0 mmol) and methyl chloroformate (0.929 mL, 12.00 mmol) before stirring at room temperature for 10 min. The mixture was diluted with CH2Cl2 and washed with water, then the organic phase was dried and concentrated. The residue was purified on silica gel (120 g, 0-100% EtOAc in CH2Cl2) to give the desired product. 27 H 29 BrN7O6S(M+H) + LC-MS calculated for: m / z=658.1, 660.1; found 658.2, 660.3.

[0314] Step 8. Methyl ((1R,3R)-3-(8-(4-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate A screw-cap vial equipped with a magnetic stir bar was charged with methyl ((1R,3R)-3-(8-bromo-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (10.0 mg, 0.015 mmol), (4-fluorophenyl)boronic acid (4.25 mg, 0.030 mmol), KPO (9.67 mg, 0.046 mmol), Pd(PhP) (3.51 mg, 3.04 μmol), and dioxane (0.8 mL) / water (0.2 mL). The vial was sealed with a Teflon-lined septum, then evacuated and backfilled with nitrogen (this process was repeated a total of three times). The reaction mixture was stirred at 105° C. for 2 hours. Methanol (1.0 mL) and NaOH (4N, 0.20 mL) were then added to the mixture, and the mixture was stirred at 80° C. for an additional 15 minutes to remove the protecting groups. The mixture was diluted with acetonitrile / water, adjusted to pH ∼1 by adding 6N HCl solution, and then purified by preparative LCMS (XBridge C18 column, eluted with a gradient of acetonitrile / water containing 0.1% TFA at a flow rate of 60 mL / min) to give the product as a TFA salt. 27 H 29 FN7O4(M+H) + LC-MS calculated for: m / z=534.2; found 534.3. 1H NMR(600 MHz, DMSO)δ 11.88(s, 1H), 8.30(s, 1H), 7.44(dt, J= 16.2, 7.2 Hz, 2H), 7.38-7.32(m, 2H), 6.96(d, J= 6.9 Hz, 1H), 6.86(s, 1H), 4.05(h, J= 8.0 Hz, 1H), 3.97-3.90(m, 1H), 3.85(s, 3H), 3.61(s, 3H), 3.52(s, 3H), 3.39(s, 3H)2.09(ddd, J= 13.2, 8.4, 4.8 Hz, 1H), 1.90(m, 1H), 1.88(d, J= 8.5 Hz, 1H), 1.52-1.46(m, 1H), 1.29(q, J= 11.3 Hz, 1H), 0.81(m, 1H).

[0315] Example 2. Methyl ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] This compound was prepared according to the procedure described in Example 1, step 8, substituting phenylboronic acid for (4-fluorophenyl)boronic acid. 27 H 30 N7O4(M+H) + LCMS calculated m / z for = 516.2; found 516.3. 1H NMR(600 MHz, DMSO)δ 11.84(s, 1H), 8.30(s, 1H), 7.57-7.49(m, 3H), 7.41(dd, J= 16.0, 7.1 Hz, 2H), 6.81(d, J= 6.9 Hz, 1H), 6.79(s, 1H), 4.02(h, J= 7.0 Hz, 1H), 3.87(m, 1H), 3.84(s, 3H), 3.58(s, 3H), 3.52(s, 3H), 3.40(s, 3H), 2.07(ddd, J= 13.4, 7.9, 4.9 Hz, 1H), 1.93-1.80(m, 2H), 1.43(dt, J= 10.7, 8.2 Hz, 1H), 1.22(td, J= 11.8, 8.2 Hz, 1H), 0.80-0.71(m, 1H).

[0316] Example 3. Methyl ((1R,3R)-3-(8-(3-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] This compound was prepared according to the procedure described in Example 1, step 8, substituting (3-fluorophenyl)boronic acid for (4-fluorophenyl)boronic acid. 27 H 29 FN7O4(M+H) + LC-MS calculated for: m / z=534.2; found 534.3. 1H NMR(600 MHz, DMSO)δ 11.81(s, 1H), 8.25(d, J= 2.5 Hz, 1H), 7.56(q, J= 7.4 Hz, 1H), 7.31(m, 1H), 7.25(d, J= 7.9 Hz, 2H), 7.01(s, 1H), 6.88(s, 1H), 4.04(br, 1H), 3.84(m, 1H), 3.82(s, 3H), 3.62(s, 3H), 3.52(s, 3H), 3.40(s, 3H), 2.11(br, 1H), 1.92-1.87(m, 2H), 1.54-1.46(m, 1H), 1.24(q, J= 11.2 Hz, 1H), 0.83(br, 1H).

[0317] Example 4. Methyl ((1R,3R)-3-(8-(3-fluoro-4-methoxyphenyl)-7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] This compound was prepared according to the procedure described in Example 1, Step 8, substituting (3-fluoro-4-methoxyphenyl)boronic acid for (4-fluorophenyl)boronic acid. 28 H 31 FN7O5(M+H) + LC-MS calculated for: m / z=564.2; found 564.3. 1H NMR(500 MHz, DMSO)δ 11.16(s, 1H), 8.12(s, 1H), 7.28(t, J= 8.7 Hz, 1H), 7.23-7.14(m, 2H), 6.96(s, 1H), 6.51(br, 1H), 4.13-4.06(m, 1H), 4.02-3.97(m, 1H), 3.95(s, 3H), 3.86(s, 3H), 3.63(s, 3H), 3.54(s, 3H), 3.39(s, 3H), 2.17(ddd, J= 13.5, 8.5, 5.1 Hz, 1H), 2.05-1.90(m, 2H), 1.57-1.50(m, 1H), 1.33(q, J= 11.3 Hz, 1H), 0.91-0.81(m, 1H).

[0318] Example 5. Methyl ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] This compound was prepared according to the procedure described in Example 1, Step 8, substituting (1-(methyl-d3)-1H-indazol-5-yl)boronic acid for (4-fluorophenyl)boronic acid. 29 H 29 D3N9O4(M+H) + LC-MS calculated for: m / z=573.3; found 573.3. 1H NMR(600 MHz, DMSO)δ 11.68(s, 1H), 8.27(s, 1H), 7.33(dd, J= 8.4, 2.2 Hz, 1H), 7.27(dd, J= 8.3, 2.3 Hz, 1H), 7.12(dd, J= 8.4, 2.6 Hz, 1H), 7.08(dd, J= 8.4, 2.8 Hz, 1H), 6.84(d, J= 6.8 Hz, 1H), 6.81(s, 1H), 4.16-4.05(m, 1H), 3.89(s, 3H), 3.79(t, J= 5.1 Hz, 1H), 3.60(s, 3H), 3.50(s, 3H), 3.39(s, 3H), 2.08(ddt, J= 13.0, 9.0, 4.8 Hz, 1H), 1.92(s, 1H), 1.86(dt, J= 12.7, 6.5 Hz, 1H), 1.46(dt, J= 11.7, 7.6 Hz, 1H), 1.27(p, J= 11.2 Hz, 1H), 0.75(m, 1H).

[0319] Example 6. Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] Step 1. tert-Butyl ((1R,3R)-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate [ka] A mixture of 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (10.14 g, 30.0 mmol), tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate (6.30 g, 31.50 mmol), and EtN (4.18 mL, 64.6 mmol) in iPrOH (100 mL) was stirred at 80° C. for 1 h. The solvent was removed and the residue was washed with water, filtered, and dried to give the product as a yellow amorphous solid (14.81 g, 29.5 mmol, 98.3%). 23 H 28 N5O6S(M+H) + LC-MS calculated for: m / z=502.2; found: 502.2.

[0320] Step 2. tert-Butyl ((1R,3R)-3-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate [ka] To a solution of tert-butyl ((1R,3R)-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate (14.81 g, 29.5 mmol) in THF (200.0 mL) / ethanol (50.0 mL) was added iron (8.38 g, 150 mmol), followed by 1N HCl (20.0 mL), and the reaction mixture was then stirred at 70° C. for 2 h. The mixture was filtered through Celite and washed with ethyl acetate. The organic layer was concentrated and the resulting residue was dissolved in ethyl acetate, which was then washed with saturated NaHCO3 solution. The organic solution was concentrated to give the desired product as a dark yellow amorphous solid (12.02 g, 25.5 mmol, 86.4%). 23 H 30 N5O4S(M+H) + LC-MS calculated for: m / z=472.2; found 472.3.

[0321] Step 3. tert-Butyl ((1R,3R)-3-(3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] A mixture of tert-butyl ((1R,3R)-3-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate (12.02 g, 25.5 mmol) and carbonyldiimidazole (9.76 g, 80.0 mmol) in MeCN (100 mL) was stirred at 60° C. for 1 h. The solvent was removed, the residue was dissolved in ethyl acetate, and washed successively with water, cold 1N HCl, water, and brine. The organic phase was dried and concentrated. The resulting residue was then dissolved in DMF (60.0 mL), followed by the addition of K2CO3 (11.05 g, 80.0 mmol) and CD3I (11.59 g, 80.0 mmol), and the reaction mixture was then stirred at 50° C. for 2 h. The mixture was diluted with ethyl acetate, washed with water, and the organic phase was then dried and concentrated. The residue was purified on 300 g silica gel (0-100% EtOAc and 5% dichloromethane in hexanes) to give the desired product as a yellow amorphous solid (9.36 g, 18.2 mmol, 71.4%). 25 H 27 D3N5O5S(M+H) + LC-MS calculated for: m / z=515.2; found 515.2.

[0322] Step 4. tert-Butyl ((1R,3R)-3-(7-bromo-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] Lithium diisopropylamide (LDA, 2.0 M in THF / heptane / ethylbenzene, Sigma-Aldrich) (22.7 mL, 45.5 mmol) was added to a solution of tert-butyl ((1R,3R)-3-(3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (9.36 g, 18.2 mmol) in THF (200.0 mL) at -78 °C and stirred for 30 min. At this time, 1,2-dibromo-1,1,2,2-tetrachloroethane (7.09 g, 21.8 mmol) in THF (15 mL) was added to the reaction mixture. After stirring for an additional 40 min, the reaction was quenched by the addition of saturated NH4Cl solution. The mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried and concentrated. The resulting residue was purified on silica gel (120 g, 0-100% EtOAc and 5% dichloromethane in hexanes) to give the desired product as a yellow amorphous solid (8.90 g, 15.0 mmol, 82.4%). 25 H 26 D3BrNO5S(M+H) + LC-MS calculated for: m / z = 593.1, 595.1; found 593.1, 595.1.

[0323] Step 5. tert-Butyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] Step 6. 3-Fluoro-1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.0 g, 47.1 mmol, Pharmablock) was dissolved in THF (200.0 mL), followed by the addition of K2CO3 (11.05 g, 80.0 mmol) and CD3I (11.59 g, 80.0 mmol) and the reaction mixture was stirred at 40 °C for 2 h. The mixture was diluted with ethyl acetate and washed with water, then the organic phase was dried and concentrated. The residue was purified on silica gel 300 g, 0-100% EtOAc and 5% dichloromethane in hexanes) to give the desired product as a brown amorphous solid (9.36 g, 18.2 mmol, 71.4%). C 10 H 14 D3BFN2O2(M+H) + LC-MS calculated for: m / z=230.2; found 230.2.

[0324] Step 7. tert-Butyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] tert-Butyl ((1R,3R)-3-(7-bromo-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (8.90 g, 15.0 mmol), 3-fluoro-1-(methyl-d3)-4- A mixture of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.36 g, 18.2 mmol), Cs2CO3 (14.7 g, 45.0 mmol), and Pd(Ph3P)4 (3.50 g, 3.0 mmol) was evacuated and backfilled with nitrogen (this process was repeated a total of three times), and the reaction was then stirred at 105 °C for 3 h. The mixture was diluted with ethyl acetate and washed with water, and the organic phase was then dried and concentrated. The residue was purified on silica gel (120 g, 0-100% EtOAc and 5% dichloromethane in hexanes) to give the desired product as a yellow amorphous solid (5.66 g, 9.2 mmol, 61.3%). C 29 H 27 D6FN7O5S(M+H) + LC-MS calculated for: m / z=616.3; found 616.2.

[0325] Step 8. tert-Butyl ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] Bromine (1.61 g, 10.1 mmol) in CHCl (5.0 mL) was added dropwise to a solution of tert-butyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (5.65 g, 9.2 mmol) in CHCl (80.0 mL) at 0° C., then stirred at the same temperature for 10 min. The reaction was quenched by adding saturated NaHCO, and the resulting mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to give the desired product as a yellow amorphous solid (6.25 g, 9.0 mmol, 97.8%). C 29 H 26 D6BrFN7O5S(M+H) + LC-MS calculated for: m / z = 694.2, 696.2; found 694.2, 696.2.

[0326] Step 9. Methyl ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] TFA (10 mL) was added to a solution of tert-butyl ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (6.25 g, 9.0 mmol) in CHCl (10.0 mL) and the reaction was stirred at room temperature for 10 minutes. The mixture was concentrated and the residue was dissolved in ethyl acetate (40 mL) and water (20.0 mL) followed by the addition of NaCO (4.24 g, 40.0 mmol) and methyl chloroformate (0.929 mL, 12.00 mmol) before stirring at room temperature for 10 minutes. The mixture was diluted with CH2Cl2 and washed with water, then the organic phase was dried and concentrated. The residue was purified on silica gel (120 g, 0-100% EtOAc in CH2Cl2) to give the desired product (5.65 g, 8.7 mmol, 96.2%). 26 H 20 D6BrFN7O5S(M+H) + LC-MS calculated for: m / z = 652.1, 654.1; found 652.1, 654.1.

[0327] Step 10. Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate In a screw-cap vial equipped with a magnetic stir bar was placed methyl((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)caprate. The vial was charged with carbamate (15.0 mg, 0.023 mmol), (1-(methyl-d3)-1H-indazol-5-yl)boronic acid (10.0 mg, 0.056 mmol, Abovchem), Cs2CO3 (15.0 mg, 0.046 mmol), Pd(Ph3P)4 (7.02 mg, 6.08 μmol), and dioxane (0.8 mL) / water (0.2 mL). The vial was sealed with a Teflon-lined septum, then evacuated and backfilled with nitrogen (this process was repeated a total of three times). The reaction mixture was stirred at 105 °C for 30 min. To this mixture was then added methanol (1.0 mL) and NaOH (4N, 0.20 mL), and the mixture was stirred at 80 °C for an additional 15 min to remove the protecting groups. The mixture was diluted with acetonitrile, filtered, and then purified using preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing NH4OH at a flow rate of 60 mL / min) to give the product as an amorphous solid (7.0 mg, 0.012 mmol, 53.7%). 28 H 20 D9FN9O3(M+H) + LC-MS calculated for: m / z=567.3; found 567.3. 1 H NMR δ 1 H NMR(600 MHz, DMSO)δ 11.87(s, 1H), 8.12(s, 1H), 8.03(d, J= 11.5 Hz, 1H), 7.77-7.65(m, 2H), 7.46-7.32(m, 2H), 6.66-6.23(m, 1H), 3.89(sextet, J= 8.1 Hz, 1H), 3.82-3.52(m, 1H), 3.52-3.41(m, 3H), 2.14-1.46(m, 3H), 1.45-0.81(m, 2H), 0.38--0.22(m, 1H).

[0328] Example 7. Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-8-(4-fluorophenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] In a screw-cap vial equipped with a magnetic stir bar, add methyl ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (1 5.0 mg, 0.023 mmol, Example 6, step 9), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.0 mg, 0.042 mmol), Cs2CO3 (15.0 mg, 0.046 mmol), Pd(Ph3P)4 (7.02 mg, 6.08 μmol), and dioxane (0.8 mL) / water (0.2 mL) were charged into the vial. The vial was sealed with a Teflon-lined septum, then evacuated and backfilled with nitrogen (this process was repeated a total of three times). The reaction mixture was stirred at 105° C. for 30 min. To this mixture was then added methanol (1.0 mL) and NaOH (4N, 0.20 mL), and the mixture was stirred at 80° C. for an additional 15 min to remove the protecting groups. The mixture was diluted with acetonitrile, filtered, and then purified using preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing NH4OH at a flow rate of 60 mL / min) to give the product as an amorphous solid (6.5 mg, 0.012 mmol, 53.6%). 26 H 20 D6F2N7O3(M+H) + LC-MS calculated for: m / z=528.2; found 528.2. 1H NMR(600 MHz, DMSO)δ 1H NMR(600 MHz, DMSO)δ 11.93(s, 1H), 8.13(d, J= 1.0 Hz, 1H), 7.44(d, J= 1.9 Hz, 1H), 7.40(s, 2H), 7.26(t, J= 8.6 Hz, 2H), 6.91(d, J= 6.7 Hz, 1H), 4.05(sextet, J= 7.8 Hz, 1H), 3.88(s, 1H), 3.50(s, 3H), 2.06(ddd, J= 13.3, 8.4, 5.1 Hz, 1H), 1.96-1.80(m, 2H), 1.46(q, J= 9.0 Hz, 1H), 1.33-1.20(m, 1H), 0.85-0.73(m, 1H).

[0329] Example 8. Methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate [ka] In a screw-cap vial equipped with a magnetic stir bar, add methyl ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-3-(methyl-d3)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (1 5.0 mg, 0.023 mmol, Example 6, step 9), (1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)boronic acid (10.0 mg, 0.052 mmol, Enamine), Cs2CO3 (15.0 mg, 0.046 mmol), Pd(Ph3P)4 (7.02 mg, 6.08 μmol), and dioxane (0.8 mL) / water (0.2 mL). The vial was sealed with a Teflon-lined septum, then evacuated and backfilled with nitrogen (this process was repeated a total of three times). The reaction mixture was stirred at 105° C. for 30 min. To this mixture was then added methanol (1.0 mL) and NaOH (4N, 0.20 mL), and the mixture was stirred at 80° C. for an additional 15 min to remove the protecting groups. The mixture was diluted with acetonitrile, filtered, and then purified using preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile / water containing NH4OH at a flow rate of 60 mL / min) to give the product as an amorphous solid (5.5 mg, 0.009 mmol, 41.2%). 30 H 27 D6FN7O4(M+H) + LC-MS calculated for: m / z=580.3; found 580.3. 1H NMR(600 MHz, DMSO) δ 11.91(s, 1H), 8.12(s, 1H), 7.45(d, J= 24.5 Hz, 1H), 7.33-7.20(m, 3H), 6.97(s, 0.5H), 6.82(s, 0.5H), 5.13(d, J= 11.8 Hz, 0.5H), 5.00-4.89(m, 1.5H), 4.06(m, 1H), 3.91(m, 1H), 3.49(s, 3H), 2.05-1.81(m, 3H), 1.48(d, J= 5.5 Hz, 6H), 1.38(m, 1H), 1.21(m, 1H), 0.66(m, 1H).

[0330] Examples 9 to 21. Examples 9-21 in Table 2 were prepared following the procedure described in Example 8 using the appropriately substituted starting materials. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11]

[0331] Example A. JAK2 LanthaScreen JH1 Binding Assay The JAK2JH1 binding assay utilizes the catalytic domain of human JAK2 (JH1, amino acids 826-1132) expressed as an N-terminally FLAG-tagged, biotinylated protein in a baculovirus expression system (Carna Biosciences, product number 08-445-20N). The assay was performed in black 384-well polystyrene plates in a final reaction volume of 20 μL. JAK2JH1 (1.5 nM) was incubated with compounds (100 nL serially diluted in DMSO) in the presence of 50 nM fluorescent JAK2-JH1 tracer and 0.5 nM streptavidin-Tb cryptate (Cisbio Part, no. 610SATLB) in assay buffer (50 mM Tris, pH=7.5, 10 mM MgCl2, 0.01% Brij-35, 0.1% BSA, 1 mM EGTA, 5% glycerol, and 5 mM DTT). Nonspecific binding was accessed in the presence of 2 mM ATP. After 2 h of incubation at 25° C., the LanthaScreen signal was read on a PHERAstar FS plate reader (BMG LABTECH). Data was analyzed using four parameter dose-response curves with IDBS XLfit and GraphPad Prism 5.0 software to determine the IC50 for each compound.

[0332] Example B. JAK2 LanthaScreen JH2-V617F Binding Assay The JAK2 JH2-V617F binding assay utilizes the pseudokinase domain of human V617F mutant JAK2 (JH2, amino acids 536-812 with three surface mutations W659A, W777A, F794H) expressed as a C-terminally His-Avi tagged biotinylated protein in a baculovirus expression system (BPS Bioscience, catalog no. 79498). The assay was performed in black 384-well polystyrene plates in a final reaction volume of 20 μL. JAK2 JH2-V617F (0.26 nM) was incubated with compounds (100 nL serially diluted in DMSO) in the presence of 50 nM fluorescent JAK2-JH2 tracer (MedChem Express, Cat. No. HY-102055) and 0.25 nM streptavidin-Tb cryptate (Cisbio Part, No. 610SATLB) in assay buffer (50 mM Tris, pH=7.5, 10 mM MgCl2, 0.01% Brij-35, 0.1% BSA, 1 mM EGTA, 5% glycerol, and 5 mM DTT). Nonspecific binding was accessed in the presence of 2 mM ATP. After 1 h incubation at 25° C., the LanthaScreen signal was read on a PHERAstar FS plate reader (BMG LABTECH). Data was analyzed using four parameter dose-response curves with IDBS XLfit and GraphPad Prism 5.0 software to determine the IC50 for each compound.

[0333] Example C. FLT3 Enzyme Assay Kinase assays were performed at room temperature in assay buffer (50 mM HEPES, pH 7.0, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 1 mM DTT, 10 mM MgCl2) in a final volume of 10 μL. Test compounds were prepared by serial dilution in DMSO and transferred to plate wells by an ECHO liquid handler (LabCyte) with 0.5% DMSO in the final assay. FLT3 / TK substrate-biotin mixtures are prepared in assay buffer with 1000 nM TK substrate-biotin and 125 nM SEB reagent. 5 μL of the mixture was added to a polystyrene 384-well small volume black plate (Greiner Bio-One). The reaction was started by adding 5 μL of ATP in assay buffer. The final 10 μL kinase reaction contained 0.011 nM FLT3, 1 mM ATP, 500 nM TK substrate-biotin, and 62.5 nM SEB reagent in assay buffer. The incubation was carried out for 90 minutes and the reaction was terminated by adding 10 μL of detection reagent containing 125 nM streptavidin-XL665, TK antibody cryptate in HTRF® detection buffer (50 mM HEPES, pH 7.0, 0.1% BSA, 0.8 M KF, 20 mM EDTA). The plate was then sealed and centrifuged at 1800 rpm for 2 minutes. After 60 minutes of incubation at room temperature, product activity was determined by measuring fluorescence at 620 nm and 665 nm on a Pherastar microplate reader (BMG Labtech). The ratio (665 / 620 nm) for each well was calculated. Wells containing only DMSO were used as positive controls, and wells without ATP were used as negative controls. IC was calculated by fitting the percentage inhibition of activity curves against the logarithm of compound concentration using GraphPad Prism 7.0 software. 50 It was decided.

[0334] Example D. KIT Enzyme Assay Kinase assays were performed at room temperature in assay buffer (50 mM HEPES, pH 7.0, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 1 mM DTT, 10 mM MgCl2) in a final volume of 10 μL. Test compounds were prepared by serial dilution in DMSO and transferred to plate wells by an ECHO liquid handler (LabCyte) with 0.5% DMSO in the final assay. KIT / TK substrate-biotin mixtures are prepared in assay buffer with 1000 nM TK substrate-biotin and 125 nM SEB reagent. 5 μL of the mixture was added to a polystyrene 384-well small volume black plate (Greiner Bio-One). The reaction was started by adding 5 μL of ATP in assay buffer. The final 10 μL kinase reaction contained 0.12 nM KIT, 1 mM ATP, 500 nM TK substrate-biotin, and 62.5 nM SEB reagent in assay buffer. The reaction was terminated by adding 10 μL of detection reagent containing 125 nM streptavidin-XL665, TK antibody cryptate in HTRF® detection buffer (50 mM HEPES, pH 7.0, 0.1% BSA, 0.8 M KF, 20 mM EDTA). The plate was then sealed and centrifuged at 1800 rpm for 2 minutes. After 60 minutes of incubation at room temperature, product activity was determined by measuring fluorescence at 620 nm and 665 nm on a Pherastar microplate reader (BMG Labtech). The ratio (665 / 620 nm) for each well was calculated. Wells containing only DMSO were used as positive controls, and wells without ATP were used as negative controls. IC was calculated by fitting the percentage inhibition of activity curves against the logarithm of compound concentration using GraphPad Prism 7.0 software. 50 It was decided.

[0335] Compounds of the present disclosure and comparative examples were tested in one or more of the assays described in Examples A-D, and the data obtained are shown in Table A. It is desirable to have selectivity for tyrosine kinases such as FLT3 and KIT. Clinical studies have shown myelosuppressive effects with inhibitors of KIT and FLT3, likely due to the role these kinases play in the hematopoietic system. Both KIT and FLT3 are expressed primarily in hematopoietic stem and progenitor cells. Mouse genetic models have shown that KIT is essential for hematopoiesis, as hematopoietic stem cells depend on KIT for survival. Similarly, mouse genetic studies have shown that FLT3 knockout mice are deficient in their ability to repopulate B and T cells. Combined knockout of KIT and FLT3 results in lethality in mice. Compounds of the present disclosure showed higher selectivity for receptor tyrosine kinases such as FLT3 and KIT when compared to the comparative examples. Without being bound by theory, it is believed that Comparative Example D exhibits similar IC50s for FLT3 and KIT as Comparative Examples A, B, C, and E. [Table 4-1] [Table 4-2] [Table 4-3]

[0336] Example E. Cell-Based Assay of STAT5 (Tyr694) Phosphorylation SET-2 cells were purchased from DSMZ (Germany). RPMI1640 medium, fetal bovine serum, and 384 white flat-bottom small volume plates were purchased from Thermo Fisher Scientific (Waltham, MA). Phosphorylated STAT5 (Tyr694) HTRF kit was purchased from Perkin Elmer (Waltham, MA).

[0337] SET-2 cells were cultured in RPMI medium containing 20% ​​FBS at 37°C in a humidified incubator supplied with 5% CO2. On the day of the assay, cells were centrifuged to remove the medium and resuspended in pre-warmed RPMI containing 10% FBS. Test compounds were prepared in serial dilutions in DMSO and 50 nL / well of test compound was transferred to a 384 white low volume cell culture plate (Greiner Bio-one) by an ECHO liquid handler (Labcyte). For the final assay, cells were then transferred to 10 μL / well (7 × 10 6 Cells were dispensed into wells at 100x (cells / mL). Treated cells were incubated for 2 hours in a 37°C / 5% CO2 incubator, followed by addition of 4 μL / well of supplemented lysis buffer (100x blocking buffer diluted 25x in 4x lysis buffer, Perkin Elmer) and incubation for 90 minutes at room temperature on an orbital shaker at 600 rpm. Phospho-STAT5 cryptate antibody and phosphorylated STAT5d2 antibody (1:1 vol / vol) were premixed and diluted 20x in detection buffer (Perkin Elmer). 4 μL of premixed antibody solution was added to each well, followed by incubation for 24 hours at room temperature on an orbital shaker at 600 rpm. Product activity was determined by measuring fluorescence at 620 nm and 665 nm on a Pherastar microplate reader (BMG Labtech). The ratio (665 / 620) for each well was calculated. Wells containing only DMSO were used as positive controls, and wells containing high concentrations of control compound were used as negative controls. IC was calculated by fitting the percentage inhibition of activity versus the logarithm of compound concentration curves using GraphPad Prism 7.0 software. 50 It was decided.

[0338] Example F. pSTAT5 SET-2 Whole Blood MSD Assay SET-2 cells from Abs, RPMI1640 medium from Gibco, fetal bovine serum, phosphorylated STAT5a,b whole cell lysis kit from Mesoscal, RetroNectin (recombinant human fibronectin fragment) from TaKaRa, 96-well flat bottom cell culture plates from Corning, lysis buffer from Cell Signaling Technology, and sterile PBS from Gibco. Whole blood from BioIVT.

[0339] SET-2 cells were cultured in RPMI medium containing 20% ​​FBS at 37°C in a humidified incubator supplied with 5% CO2. On the day of the assay, RetroNectin working solution was added at 40uL per well to a sterile 96-well clear flat-bottom tissue culture plate (RetroNectin was diluted 1:200 in sterile PBS) and incubated for 1 hour at 37°C. After 1 hour, RetroNectin working solution was aspirated and SET-2 cells were seeded at 100,000 / well in RPMI+20% FBS. Cells were incubated overnight at 37°C and 5% CO2. The next day, medium was removed and 40μL of compound diluted in serum-free RPMI and whole blood was added to the cells and incubated for 2 hours at 37°C and 5% CO2. Starting compound concentration was 20μM with 2.5-fold serial dilutions down to 0.21nM. Whole blood and compound mixture was then aspirated using a BlueCat plate washer and washed once with PBS. Cells were lysed by adding 40 μL of 3x complete lysis buffer and shaking at room temperature for 45-60 min (complete lysis buffer consists of Cell Signaling Technology lysis buffer diluted 3x and supplemented with Mesoscale protease inhibitors, phosphatase I inhibitor, and phosphatase II inhibitor). pSTAT5 MSD plates were blocked by adding 150 μL of Blocker A solution per well to the MSD plate and incubated for >1 h at room temperature with shaking at 400 rpm. After blocking, plates were washed 3 times with 300 μL / well of 1x Tris wash buffer. After lysis, 25 μL of lysed sample per well was added to the MSD plate and incubated overnight wrapped in foil at 4°C with shaking. The next day, plates were washed again and 25 μL / well of 1x detection antibody dilution was added, wrapped in foil, and incubated for 1 h at room temperature with shaking at 400 rpm. Plates were then washed again and finally, 150 μL / well of 1x Read Buffer T was added to all wells. Plates were analyzed within 5 min on MSD Discovery. Inhibition of pSTAT5 signaling was measured using the inhibitory concentration for 50% inhibition (IC 50) relative to control. Data analysis was performed in GraphPad Prism using 4-parameter fitting and data are reported as mean ± SD.

[0340] Example G. In Vitro Intrinsic Clearance Protocol For in vitro metabolic stability experiments, test compounds were incubated with human liver microsomes at 37°C. The incubation mixture contained test compound (1 μM), NADPH (2 mM), and human liver microsomes (0.5 mg protein / mL) in 100 mM phosphate buffer (pH 7.4). The mixture is pre-incubated for 2 min at 37°C before the addition of NADPH. The reaction was initiated by the addition of NADPH and quenched with ice-cold methanol at 0, 10, 20, and 30 min. The completed incubation mixture was analyzed using an LC-MS / MS system. The analysis system consisted of a Shimadzu LC-30AD binary pump system and a SIL-30AC autosampler (Shimadzu Scientific Instruments, Columbia, MD) coupled to a Sciex Triple Quad 6500+ mass spectrometer from Applied Biosystems (Foster City, CA). Chromatographic separation of test compounds and internal standards was achieved using a Hypersil Gold C18 column (50×2.1 mm, 5 μM, 175 Å) from ThermoFisher Scientific (Waltham, MA). Mobile phase A consisted of 0.1% formic acid in water and mobile phase B consisted of 0.1% formic acid in acetonitrile. Total LC-MS / MS run time was 2.75 min at a flow rate of 0.75 mL / min. Peak area integration and peak area ratio calculations were performed using Analyst software (version 1.6.3) from Applied Biosystems.

[0341] In vitro intrinsic clearance, CL int,試験管内 is the t of disappearance of the test compound 1 / 2 From CL int,試験管内 =(0.693 / t 1 / 2 )×(1 / Cタンパク質 ) where C タンパク質 is the protein concentration in the incubation, and t 1 / 2 is determined by the slope (k) of the log-linear regression analysis of the concentration versus time profile, so t 1 / 2 = ln2 / k. CL int,試験管内 Values ​​were scaled to in vivo values ​​in humans by using physiological scaling factors, liver microsomal protein concentration (45 mg protein / g liver), and liver weight (21 g / kg body weight). The equation CL int =CL int,試験管内 × (mg protein / g liver weight) × (g liver weight / kg body weight) was used. H =(Q × CL int ) / (Q+CL int ) and ignore all bonds, CL int and hepatic blood flow Q in a well-stirred liver model (20 mL min in humans) -1 ·kg -1 ) to measure in vivo hepatic clearance (CL H The liver extraction ratio was calculated as CL H It was calculated as divided by Q.

[0342] Example H. In vivo pharmacokinetics Test compounds were administered intravenously or via oral gavage to male Sprague-Dawley rats or male and female cynomolgus monkeys. For intravenous (IV) administration, test compounds were administered at 1 mg / kg using a formulation of 10% dimethylacetamide (DMAC) and 10% propylene glycol (PG) in acidified saline via an IV bolus for rats or a 10-minute IV infusion for monkeys. For oral (PO) administration, test compounds were administered at 3.0 mg / kg using a solution containing 5% DMAC in 0.5% methylcellulose in citrate buffer (pH approx. 2.5). Blood samples were collected pre-dose and at various time points up to 24 hours post-dose. All blood samples were collected using EDTA as an anticoagulant and centrifuged to obtain plasma samples. Plasma concentrations of test compounds were determined by LC-MS / MS methodology. The measured plasma concentrations were used to calculate PK parameters by standard non-compartmental methods using the Phoenix® WinNonlin software program (version 8.0, Pharsight Corporation) or similar software. Cassette dosing of test compounds was performed in rats and monkeys to obtain preliminary PK parameters. In vivo pharmacokinetic studies in male beagle dogs may be performed under the conditions described above.

[0343] Compounds of the present disclosure and comparative examples were tested in one or more of the assays described in Examples E and H, and the resulting data are shown in Table B. Compounds of the present disclosure showed improved intrinsic clearance and oral exposure in cynomolgus monkeys. Without being bound by theory, Comparative Examples C-D showed improved IC20 values ​​compared to those measured in Comparative Examples A, B, and E. 50 Similar SET2 whole blood (WB) ICs 50 Values ​​and rat AUC values ​​are shown, and Comparative Examples C-E are believed to show similar AUC values ​​in cynomolgus monkeys (eg, see intrinsic clearance values) as Comparative Examples A-B. [Table 5-1] [Table 5-2]

[0344] Example I. TRKA Enzyme Assay Kinase assays were performed in assay buffer (50 mM HEPES, pH 7.0, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 1 mM DTT, 10 mM MgCl2) at 24°C in a final volume of 10 μL. Test compounds were prepared by serial dilution in DMSO and transferred to plate wells by an ECHO liquid handler (LabCyte) with 0.5% DMSO in the final assay. TRKA / TK substrate-biotin mixtures are prepared in assay buffer with 1000 nM TK substrate-biotin and 125 nM SEB reagent. 5 μL of the mixture was added to a polystyrene 384-well small volume black plate (Greiner Bio-One). The reaction was started by adding 5 μL of ATP in assay buffer. The final 10 μL kinase reaction contained 0.58 nM TRKA, 1 mM ATP, 500 nM TK substrate-biotin, and 62.5 nM SEB reagent in assay buffer. The reaction was terminated by adding 10 μL of detection reagent containing 125 nM streptavidin-XL665, TK antibody cryptate in HTRF® detection buffer (50 mM HEPES, pH 7.0, 0.1% BSA, 0.8 M KF, 20 mM EDTA). After 60 minutes of incubation at room temperature, product activity was determined by measuring fluorescence at 620 nm and 665 nm on a Pherastar microplate reader (BMG Labtech). The ratio (665 / 620 nm) for each well was calculated. Wells containing only DMSO were used as positive controls and wells without ATP were used as negative controls. Using gene data, IC was calculated by fitting a curve of percent inhibition of activity versus the logarithm of compound concentration. 50 It was decided. [Table 6-1] [Table 6-2] [Table 6-3]

[0345] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, R １ The compounds are selected from phenyl, indazolyl, and dihydroisobenzofuranyl, each of which is independently a halo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ Optionally substituted with one, two, or three substituents selected from hydroxyalkyl groups; R ２ C １－６ Alkyl or C １－６ It is a haloalkyl; R ３ is selected from halo, C １－６ alkyl, and C １－６ alkoxy; and R ４ C １－６ It is alkyl. A compound of or a pharmaceutically acceptable salt thereof.

2. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from phenyl, indazolyl, and dihydroisobenzofuranyl, each of which is optionally substituted independently with one or two substituents selected from fluoro, methyl, isopropyl, triduteromethyl, difluoroethyl, methoxy, triduteromethoxy, and hydroxyisopropyl.

3. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is dihydroisobenzofuranyl substituted with one, two, or three methyl substituents.

4. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is 1,1-dimethyl-1,3-dihydroisobenzofuranyl.

5. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl.

6. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is selected from phenyl, fluorophenyl, triduteromethoxyphenyl, (hydroxyisopropyl)phenyl, fluoromethoxyphenyl, dimethyldihydroisobenzofuranyl, isopropylindazolyl, (fluoro)(triduteromethyl)indazolyl, and difluoroethylindazolyl.

7. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from phenyl and indazolyl, each of which is optionally substituted independently with one or two substituents selected from fluoro, triduteromethyl, and methoxy.

8. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from phenyl, fluorophenyl, fluoromethoxyphenyl, and triduteromethylindazolyl.

9. R ２ C １－３ Alkyl or C １－３ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.

10. R ２ C １－３ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.

11. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is difluoroethyl.

12. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is selected from methyl, ethyl, triduteromethyl, difluoroethyl, pentaduteroethyl, and heptaduteroisopropyl.

13. R ２ C １－３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is alkyl.

14. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is selected from methyl, ethyl, triduteromethyl, pentaduteroethyl, and heptaduteroisopropyl.

15. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is methyl.

16. R ２ The compound according to claim 1, wherein the compound is triduteromethyl, or a pharmaceutically acceptable salt thereof.

17. R ３ C １－６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an alkoxy or a halo.

18. R ３ C １－６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an alkoxy.

19. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is methoxy.

20. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is a halo.

21. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is fluoro.

22. R ４ C １－３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is alkyl.

23. R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is methyl.

24. R ４ The compound according to claim 1, wherein the compound is triduteromethyl, or a pharmaceutically acceptable salt thereof.

25. R １ The compounds are selected from phenyl, indazolyl, and dihydroisobenzofuranyl, each of which is independently a halo, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkyl and C １－３ Optionally substituted with one or two substituents selected from hydroxyalkyl groups; R ２ C １－３ Alkyl or C １－３ It is a haloalkyl; R ３ Hello, C １－３ Alkyl and C １－３ Selected from alkoxy; and R ４ C １－３ It is alkyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

26. R １ is selected from phenyl, indazolyl, and dihydroisobenzofuranyl, each of which is optionally substituted independently with one or two substituents selected from fluoro, methyl, isopropyl, triduteromethyl, difluoroethyl, methoxy, triduteromethoxy, and hydroxyisopropyl; R ２ This is selected from methyl, ethyl, triduteromethyl, difluoroethyl, pentaduteroethyl, and heptaduteroisopropyl; R ３ is methoxy or fluoro; and R ４ is methyl or triduteromethyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

27. R １ The compounds are selected from phenyl and indazolyl, each of which is independently a halo, C １－３ Alkyl and C １－３ Optionally substituted with one or two substituents selected from alkoxy; R ２ C １－３ It is alkyl; R ３ Hello, C １－３ Alkyl and C １－３ Selected from alkoxy; and R ４ C １－３ It is alkyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

28. R １ These are selected from phenyl and indazolyl, each of which is optionally substituted with one or two substituents independently selected from fluoro, triduteromethyl, and methoxy; R ２ is methyl or triduteromethyl; R ３ is methoxy or fluoro; and R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is methyl or triduteromethyl.

29. The compound of formula I is the compound of formula Ia. 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

30. The compound of formula I is the compound of formula II. 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

31. The compound of formula I is the compound of formula IIa. 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

32. The compound of formula I is the compound of formula III. 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

33. The compound of formula I is the compound of formula IIIa. 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

34. The compound of formula I is the compound of formula IV. 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

35. The compound of formula I is the compound of formula IVa. 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

36. The compound of formula I is the compound of formula V. 【Chemistry 9】 And in the formula, each R １Ａ It is independently known as Haro, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ A compound according to claim 1, selected from hydroxyalkyl groups, or a pharmaceutically acceptable salt thereof.

37. The compound of formula I is the compound of formula Va. 【Chemistry 10】 And in the formula, each R １Ａ It is independently known as Haro, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl and C １－６ A compound according to claim 1, selected from hydroxyalkyl groups, or a pharmaceutically acceptable salt thereof.

38. The compound of formula I is the compound of formula Vb. 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

39. The compound of formula I is the compound of formula Vc. 【Chemistry 12】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

40. The compound is the compound according to claim 1, or a pharmaceutically acceptable salt thereof, comprising at least one deuterium atom.

41. The compound is the compound according to claim 1, or a pharmaceutically acceptable salt thereof, comprising two or more deuterium atoms.

42. The compound is the compound according to claim 1, or a pharmaceutically acceptable salt thereof, comprising three or more deuterium atoms.

43. The compound is the compound according to claim 1, or a pharmaceutically acceptable salt thereof, comprising 3 to 9 deuterium atoms.

44. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein all hydrogen atoms in the compound are replaced with deuterium atoms.

45. Methyl((1R,3R)-3-(8-(4-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazole-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazole-4-yl)-3-methyl-2-oxo-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(8-(3-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazole-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(8-(3-fluoro-4-methoxyphenyl)-7-(3-methoxy-1-methyl-1H-pyrazole-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; and Methyl((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazole-4-yl)-3-methyl-8-(1-(methyl-d ３ )-1H-indazole-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; and their pharmaceutically acceptable salts A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

46. Methyl((1R,3R)-3-(7-(3-fluoro-1-(methyl-d ３ )-1H-pyrazole-4-yl)-3-(methyl-d ３ )-8-(1-(methyl-d ３ )-1H-indazole-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; and Methyl ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d ３ )-1H-pyrazol-4-yl)-8-(4-fluorophenyl)-3-(methyl-d ３ )-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate; and their pharmaceutically acceptable salts A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

47. Methyl((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-8-(4-(methoxy-d3)phenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-8-(4-(2-hydroxypropane-2-yl)phenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(7-(1-(2,2-difluoroethyl)-3-fluoro-1H-pyrazole-4-yl)-8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-8-(1-isopropyl-1H-indazole-5-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(8-(1-(2,2-difluoroethyl)-1H-indazole-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(7-(1-(ethyl-d5)-3-fluoro-1H-pyrazole-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazole-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-8-(1-isopropyl-1H-indazole-5-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(8-(7-fluoro-1-(methyl-d3)-1H-indazole-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(8-(1-(2,2-difluoroethyl)-1H-indazole-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(1-(ethyl-d5)-3-fluoro-1H-pyrazole-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; Methyl ((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(1-ethyl-3-fluoro-1H-pyrazole-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; and Methyl((1R,3R)-3-(7-(3-fluoro-1-(propan-2-yl-d7)-1H-pyrazole-4-yl)-3-(methyl-d3)-8-(1-(methyl-d3)-1H-indazole-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate; and their pharmaceutically acceptable salts A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

48. A compound that is methyl((1R,3R)-3-(8-(4-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazole-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate, or a pharmaceutically acceptable salt thereof.

49. Methyl((1R,3R)-3-(7-(3-fluoro-1-(methyl-d ３ )-1H-pyrazole-4-yl)-8-(4-fluorophenyl)-3-(methyl-d ３ A compound that is a )-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate, or a pharmaceutically acceptable salt thereof.

50. Compounds that are methyl((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate, or pharmaceutically acceptable salts thereof.

51. A compound which is methyl((1R,3R)-3-(8-(4-fluorophenyl)-7-(3-methoxy-1-methyl-1H-pyrazole-4-yl)-3-methyl-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate.

52. A compound that is a methyl((1R,3R)-3-(7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-8-(4-fluorophenyl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate.

53. A compound which is a methyl((1R,3R)-3-(8-(1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl)-7-(3-fluoro-1-(methyl-d3)-1H-pyrazole-4-yl)-3-(methyl-d3)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)cyclopentyl)carbamate.

54. A pharmaceutical composition comprising a compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 51 to 53, and a pharmaceutically acceptable carrier.

55. A pharmaceutical agent for treating cancer in a patient requiring treatment for cancer, comprising a compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 51 to 53.

56. The pharmaceutical product according to claim 55, wherein the cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, stomach cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer, skin cancer, and brain cancer.

57. The pharmaceutical product according to claim 55, wherein the cancer is a blood cancer.

58. The pharmaceutical product according to claim 55, wherein the cancer is selected from leukemia, lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, acute myeloid leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma, myeloproliferative neoplasm, myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenström macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-associated lymphoma, and Burkitt lymphoma.

59. A pharmaceutical agent for treating a myeloproliferative disorder in a patient requiring treatment of a myeloproliferative disorder, comprising a compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 51 to 53.

60. The pharmaceutical product according to claim 59, wherein the myeloproliferative disorder is selected from polycythemia vera, essential thrombocythemia, myelofibrosis with myelogenesis, primary myelofibrosis, post-essential thrombocythemia myelofibrosis, post-polycythemia myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, eosinophilic syndrome, and systemic mast cell disease.

61. The pharmaceutical product according to claim 60, wherein the myeloproliferative disorder is polycythemia vera.

62. The pharmaceutical product according to claim 60, wherein the myeloproliferative disorder is essential thrombocythemia.

63. The pharmaceutical product according to claim 60, wherein the myeloproliferative disorder is myelofibrosis with myelometaplasia.

64. The pharmaceutical product according to claim 60, wherein the myeloproliferative disorder is primary myelofibrosis.

65. The pharmaceutical product according to claim 60, wherein the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis.

66. The pharmaceutical product according to claim 60, wherein the myeloproliferative disorder is post-polycythemia vera myelofibrosis.

67. A pharmaceutical agent for treating myelodysplastic syndrome in a patient requiring treatment for myelodysplastic syndrome, comprising a compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a compound according to any one of claims 51 to 53.

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