Tricyclic urea compounds as JAK2 V617F inhibitors

Abstract

The present application provides tricyclic urea compounds that modulate the activity of the V617F variant of JAK2, which compounds 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 Art

[0002] Janus kinase (JAK) 2 plays a key role in signal transduction through several cytokine receptors. Mutant JAK2 V617F is the most common molecular event associated with myeloproliferative neoplasms. Selective targeting of the JAK2 V617F mutant can be used to treat a variety of lesions while retaining essential JAK2 functions. This application relates to this need and other needs. Summary of the invention

[0003] The present invention particularly relates to compounds of formula I:

[0004]

[0005] or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined herein.

[0006] The present invention further provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0007] The present invention further provides a method of inhibiting the activity of the V617F variant of JAK2 kinase, the method comprising contacting the kinase with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0008] The present invention further provides a method of treating a disease or condition associated with the 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 pharmaceutically acceptable salt thereof.

[0009] The present invention further provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0010] The invention further provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. DETAILED DESCRIPTION

[0011] The present application provides a compound of formula I:

[0012]

[0013] or a pharmaceutically acceptable salt thereof, wherein:

[0014] R 1is selected from phenyl, indazolyl and dihydroisobenzofuranyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl;

[0015] R 2 C 1-6 Alkyl or C 1-6 Haloalkyl;

[0016] R 3 Selected from halogen, C 1-6 Alkyl and C 1-6 alkoxy; and

[0017] R 4 C 1-6 alkyl.

[0018] In some embodiments:

[0019] R 1 is selected from phenyl and indazolyl, each of which is optionally substituted by 1, 2 or 3 independently selected from halo, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0020] R 2 C 1-6 alkyl;

[0021] R 3 Selected from halogen, C 1-6 Alkyl and C 1-6 alkoxy; and

[0022] R 4 C 1-6 alkyl.

[0023] 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.

[0024] 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.

[0025] In some embodiments, R 1is dihydroisobenzofuranyl, which is optionally substituted by 1, 2 or 3 independently selected from halogen, C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0026] In some embodiments, R 1 is dihydroisobenzofuranyl, which is optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl substituents are substituted.

[0027] In some embodiments, R 1 is dihydroisobenzofuranyl, which is optionally substituted by 1, 2 or 3 independently selected C 1-3 Alkyl substituents are substituted.

[0028] In some embodiments, R 1 is dihydroisobenzofuranyl, which is optionally substituted by 1 or 2 independently selected C 1-3 Alkyl substituents are substituted.

[0029] In some embodiments, R 1 is dihydroisobenzofuranyl optionally substituted with 1, 2 or 3 methyl substituents.

[0030] In some embodiments, R 1 is dihydroisobenzofuranyl which is optionally substituted by 1 or 2 methyl substituents.

[0031] In some embodiments, R 1 is dihydroisobenzofuranyl, which is replaced by 1 or 2 independently selected C 1-6 Alkyl substituents are substituted.

[0032] In some embodiments, R 1 is dihydroisobenzofuranyl, which is replaced by 1 or 2 independently selected C 1-3 Alkyl substituents are substituted.

[0033] In some embodiments, R 1 is dihydroisobenzofuranyl substituted by 1 or 2 methyl substituents.

[0034] 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, trideuteratedmethyl and methoxy.

[0035] In some embodiments, R 1 Selected from phenyl, fluorophenyl, trideuteromethoxyphenyl, (hydroxyisopropyl)phenyl, fluoromethoxyphenyl, dimethyldihydroisobenzofuranyl, isopropylindazolyl, (fluoro)(trideuteromethyl)indazolyl and difluoroethylindazolyl.

[0036] In some embodiments, R 1 Selected from trideuteromethoxyphenyl, (hydroxyisopropyl)phenyl, dimethyldihydroisobenzofuranyl, isopropylindazolyl, (fluoro)(trideuteromethyl)indazolyl and difluoroethylindazolyl.

[0037] In some embodiments, R 1 Selected from phenyl, fluorophenyl, fluoromethoxyphenyl and trideuterated methylindazolyl.

[0038] In some embodiments, R 1 Selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl and 1-(trideuteratedmethyl)-1H-indazol-5-yl.

[0039] In some embodiments, R 1 Selected from:

[0040]

[0041] In some embodiments, R 1 Selected from:

[0042]

[0043]

[0044] In some embodiments, R 1 It is phenyl.

[0045] In some embodiments, R 1 It is fluorophenyl.

[0046] In some embodiments, R 1 It is 3-fluorophenyl.

[0047] In some embodiments, R 1 It is 4-fluorophenyl.

[0048] In some embodiments, R 1 It is fluoromethoxyphenyl.

[0049] In some embodiments, R 1 It is 3-fluoro-4-methoxyphenyl.

[0050] In some embodiments, R 1 It is trideuterated methylindazolyl.

[0051] In some embodiments, R 1 It is 1-(trideuterated methyl)-1H-indazol-5-yl.

[0052] In some embodiments, R1 It is trideuterated methoxyphenyl.

[0053] In some embodiments, R 1 It is 4-trideuterated methoxyphenyl.

[0054] In some embodiments, R 1 It is (hydroxyprop-2-yl)phenyl.

[0055] In some embodiments, R 1 It is 4-(2-hydroxyprop-2-yl)phenyl.

[0056] In some embodiments, R 1 It is dimethyldihydroisobenzofuranyl.

[0057] In some embodiments, R 1 It is 1,1-dimethyl-1,3-dihydroisobenzofuranyl.

[0058] In some embodiments, R 1 It is 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl.

[0059] In some embodiments, R 1 It is isopropylindazolyl.

[0060] In some embodiments, R 1 It is 1-isopropyl-1H-indazol-5-yl.

[0061] In some embodiments, R 1 It is (fluoro)(trideuteratedmethyl)indazolyl.

[0062] In some embodiments, R 1 It is 7-fluoro-1-trideuterated methyl-1H-indazol-5-yl.

[0063] In some embodiments, R 1 It is difluoroethylindazolyl.

[0064] In some embodiments, R 1 It is 1-(2,2-difluoroethyl)-1H-indazol-5-yl.

[0065] In some embodiments, R 2 C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0066] In some embodiments, R 2 It is methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl and heptadeuteroisopropyl.

[0067] In some embodiments, R 2 C 1-6 Halogenated alkyl.

[0068] In some embodiments, R 2 C 1-3 Halogenated alkyl.

[0069] In some embodiments, R 2 It is difluoroethyl.

[0070] In some embodiments, R 2 It is 2,2-difluoroethyl.

[0071] In some embodiments, R 2 C 1-6 alkyl.

[0072] In some embodiments, R 2 C 1-3 alkyl.

[0073] In some embodiments, R 2 It is ethyl.

[0074] In some embodiments, R 2 It is a trideuterated methyl group.

[0075] In some embodiments, R 2 It is a pentadeuterated ethyl.

[0076] In some embodiments, R 2 It is heptadeuterated isopropyl.

[0077] In some embodiments, R 3 C 1-6 Alkoxy or halo.

[0078] In some embodiments, R 3 C 1-3 Alkoxy or halo.

[0079] In some embodiments, R 3 C 1-6 Alkoxy or fluorine.

[0080] In some embodiments, R 3 C 1-3 Alkoxy or fluorine.

[0081] In some embodiments, R 3 C 1-6 Alkoxy.

[0082] In some embodiments, R 3 C 1-3 Alkoxy.

[0083] In some embodiments, R 3 is methoxy or fluorine.

[0084] In some embodiments, R 3 It is a methoxy group.

[0085] In some embodiments, R 3 For fluorine.

[0086] In some embodiments, R 4 C 1-3 alkyl.

[0087] In some embodiments, R 4 It is methyl.

[0088] In some embodiments, R 4 It is a trideuterated methyl group.

[0089] In some embodiments:

[0090] R 1 is selected from phenyl, indazolyl and dihydroisobenzofuranyl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Hydroxyalkyl;

[0091] R 2 C 1-3 Alkyl or C 1-3 Haloalkyl;

[0092] R 3 Selected from halogen, C 1-3 Alkyl and C 1-3 alkoxy; and

[0093] R 4 C 1-3 alkyl.

[0094] In some embodiments:

[0095] 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;

[0096] R 2 is selected from the group consisting of methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl and heptadeuteroisopropyl;

[0097] R3 is methoxy or fluoro; and

[0098] R 4 It is methyl or trideuterated methyl.

[0099] In some embodiments:

[0100] R 1 Selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteriomethyl)-1H-indazol-5-yl, 4-trideuteriomethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteriomethyl-1H-indazol-5-yl and 1-(2,2-difluoroethyl)-1H-indazol-5-yl;

[0101] R 2 C 1-6 Alkyl or C 1-6 Haloalkyl;

[0102] R 3 Selected from halogen, C 1-6 Alkyl and C 1-6 alkoxy; and

[0103] R 4 C 1-6 alkyl.

[0104] In some embodiments:

[0105] R 1 Selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteriomethyl)-1H-indazol-5-yl, 4-trideuteriomethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteriomethyl-1H-indazol-5-yl and 1-(2,2-difluoroethyl)-1H-indazol-5-yl;

[0106] R 2 C 1-6 Alkyl or C 1-6 Haloalkyl;

[0107] R 3 Selected from halogen, C 1-6 Alkyl and C 1-6 alkoxy; and

[0108] R 4 C 1-6 alkyl.

[0109] In some embodiments:

[0110] R 1 Selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteriomethyl)-1H-indazol-5-yl, 4-trideuteriomethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteriomethyl-1H-indazol-5-yl and 1-(2,2-difluoroethyl)-1H-indazol-5-yl;

[0111] R 2 C 1-3 Alkyl or C 1-3 Haloalkyl;

[0112] R 3 Selected from halogen, C 1-3 Alkyl and C 1-3 alkoxy; and

[0113] R 4 C 1-3 alkyl.

[0114] In some embodiments:

[0115] R 1 Selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteriomethyl)-1H-indazol-5-yl, 4-trideuteriomethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteriomethyl-1H-indazol-5-yl and 1-(2,2-difluoroethyl)-1H-indazol-5-yl;

[0116] R 2 is selected from the group consisting of methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl and heptadeuteroisopropyl;

[0117] R 3 is methoxy or fluoro; and

[0118] R 4 C 1-3 alkyl.

[0119] In some embodiments:

[0120] R 1Selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteriomethyl)-1H-indazol-5-yl, 4-trideuteriomethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteriomethyl-1H-indazol-5-yl and 1-(2,2-difluoroethyl)-1H-indazol-5-yl;

[0121] R 2 is selected from the group consisting of methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl and heptadeuteroisopropyl;

[0122] R 3 is methoxy or fluoro; and

[0123] R 4 It is methyl or trideuterated methyl.

[0124] In some embodiments:

[0125] R 1 Selected from 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 1-(trideuteriomethyl)-1H-indazol-5-yl, 4-trideuteriomethoxyphenyl, 4-(2-hydroxypropan-2-yl)phenyl, 1,1-dimethyl-1,3-dihydroisobenzofuran-5-yl, 1-isopropyl-1H-indazol-5-yl, 7-fluoro-1-trideuteriomethyl-1H-indazol-5-yl and 1-(2,2-difluoroethyl)-1H-indazol-5-yl;

[0126] R 2 is selected from the group consisting of methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl and heptadeuteroisopropyl;

[0127] R 3 Selected from halogen, C 1-3 Alkyl and C 1-3 alkoxy; and

[0128] R 4 C 1-3 alkyl.

[0129] In some embodiments:

[0130] R 1 is selected from phenyl and indazolyl, each of which is optionally substituted by 1 or 2 independently selected from halo, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups;

[0131] R 2 C 1-3 alkyl;

[0132] R 3 Selected from halogen, C 1-3 Alkyl and C 1-3 alkoxy; and

[0133] R 4 C 1-3 alkyl.

[0134] In some embodiments:

[0135] R 1 is selected from phenyl and indazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from fluoro, trideuteratedmethyl and methoxy;

[0136] R 2 is methyl or trideuterated methyl;

[0137] R 3 is methoxy or fluoro; and

[0138] R 4 It is methyl or trideuterated methyl.

[0139] In some embodiments:

[0140] R 1 is selected from phenyl and indazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from fluoro, trideuteratedmethyl and methoxy;

[0141] R 2 is methyl;

[0142] R 3 is methoxy; and

[0143] R 4 It is methyl.

[0144] In some embodiments:

[0145] R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl and trideuterated methylindazolyl;

[0146] R 2 C 1-3 alkyl;

[0147] R 3 C 1-3 alkoxy or halo; and

[0148] R 4 C 1-3 alkyl.

[0149] In some embodiments:

[0150] R 1is selected from phenyl, fluorophenyl, fluoromethoxyphenyl and trideuterated methylindazolyl;

[0151] R 2 C 1-3 alkyl;

[0152] R 3 C 1-3 alkoxy; and

[0153] R 4 C 1-3 alkyl.

[0154] In some embodiments:

[0155] R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl and trideuterated methylindazolyl;

[0156] R 2 C 1-3 alkyl;

[0157] R 3 C 1-3 alkoxy or halo; and

[0158] R 4 It is methyl or trideuterated methyl.

[0159] In some embodiments:

[0160] R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl and trideuterated methylindazolyl;

[0161] R 2 C 1-3 alkyl;

[0162] R 3 C 1-3 alkoxy; and

[0163] R 4 It is methyl or trideuterated methyl.

[0164] In some embodiments:

[0165] R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl and trideuterated methylindazolyl;

[0166] R 2 C 1-3 alkyl;

[0167] R 3 C 1-3 alkoxy; and

[0168] R 4It is methyl.

[0169] In some embodiments:

[0170] R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl and trideuterated methylindazolyl;

[0171] R 2 is methyl or trideuterated methyl;

[0172] R 3 is methoxy or fluoro; and

[0173] R 4 It is methyl or trideuterated methyl.

[0174] In some embodiments:

[0175] R 1 is selected from phenyl, fluorophenyl, fluoromethoxyphenyl and trideuterated methylindazolyl;

[0176] R 2 is methyl;

[0177] R 3 is methoxy; and

[0178] R 4 It is methyl.

[0179] In some embodiments:

[0180] R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl and 1-(trideuteratedmethyl)-1H-indazol-5-yl;

[0181] R 2 C 1-3 alkyl;

[0182] R 3 C 1-3 alkoxy or halo; and

[0183] R 4 C 1-3 alkyl.

[0184] In some embodiments:

[0185] R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl and 1-(trideuteratedmethyl)-1H-indazol-5-yl;

[0186] R 2 C 1-3 alkyl;

[0187] R3 C 1-3 alkoxy; and

[0188] R 4 C 1-3 alkyl.

[0189] In some embodiments:

[0190] R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl and 1-(trideuteratedmethyl)-1H-indazol-5-yl;

[0191] R 2 C 1-3 alkyl;

[0192] R 3 C 1-3 alkoxy or halo; and

[0193] R 4 It is methyl or trideuterated methyl.

[0194] In some embodiments:

[0195] R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl and 1-(trideuteratedmethyl)-1H-indazol-5-yl;

[0196] R 2 is methyl or trideuterated methyl;

[0197] R 3 C 1-3 alkoxy or halo; and

[0198] R 4 It is methyl or trideuterated methyl.

[0199] In some embodiments:

[0200] R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl and 1-(trideuteratedmethyl)-1H-indazol-5-yl;

[0201] R 2 C 1-3 alkyl;

[0202] R 3 C 1-3 alkoxy; and

[0203] R 4 It is methyl or trideuterated methyl.

[0204] In some embodiments:

[0205] R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl and 1-(trideuteratedmethyl)-1H-indazol-5-yl;

[0206] R 2 is methyl or trideuterated methyl;

[0207] R 3 is methoxy or fluoro; and

[0208] R 4 It is methyl or trideuterated methyl.

[0209] In some embodiments:

[0210] R 1 is selected from phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl and 1-(trideuteratedmethyl)-1H-indazol-5-yl;

[0211] R 2 C 1-3 alkyl;

[0212] R 3 C 1-3 alkoxy; and

[0213] R 4 It is methyl.

[0214] In some embodiments, the compound of formula I is a compound of formula Ia:

[0215]

[0216] or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the compound of formula I is a compound of formula II:

[0218]

[0219] or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the compound of formula I is a compound of formula IIa:

[0221]

[0222] or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, the compound of formula I is a compound of formula III:

[0224]

[0225] or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the compound of formula I is a compound of formula IIIa:

[0227]

[0228] or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the compound of formula I is a compound of formula IV:

[0230]

[0231] or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the compound of formula I is a compound of formula IVa:

[0233]

[0234] or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the compound of formula I is a compound of formula V:

[0236]

[0237] or a pharmaceutically acceptable salt thereof, wherein each R 1A independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl.

[0238] In some embodiments, the compound of formula I is a compound of formula Va:

[0239]

[0240] or a pharmaceutically acceptable salt thereof, wherein each R 1A independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl.

[0241] In some embodiments of Formula V and Formula Va, each R 1A C for independent selection 1-6 alkyl.

[0242] In some embodiments of Formula V and Formula Va, each R1A C for independent selection 1-3 alkyl.

[0243] In some embodiments, the compound of Formula I is a compound of Formula Vb:

[0244]

[0245] or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the compound of formula I is a compound of formula Vc:

[0247]

[0248] or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, the compound of formula I is selected from:

[0250] 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;

[0251] 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;

[0252] 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;

[0253] 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;

[0254] ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-(methyl-d 3)-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester;

[0255] ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 )-8-(1-(methyl-d 3 )-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester;

[0256] ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-8-(4-fluorophenyl)-3-(methyl-d 3 )-methyl 2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate;

[0257] 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;

[0258] 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;

[0259] 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;

[0260] 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;

[0261] 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;

[0262] 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;

[0263] 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;

[0264] 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;

[0265] 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;

[0266] 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;

[0267] 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;

[0268] 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;

[0269] ((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)carbamic acid methyl ester; and

[0270] 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;

[0271] or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the compound of formula I is selected from:

[0273] 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;

[0274] 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;

[0275] 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;

[0276] 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

[0277] ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-(methyl-d 3 )-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester;

[0278] or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the compound of formula I is selected from:

[0280] ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 )-8-(1-(methyl-d 3 )-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester; and

[0281] ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-8-(4-fluorophenyl)-3-(methyl-d 3 )-methyl 2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate;

[0282] or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the compound of formula I is selected from:

[0284] 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;

[0285] 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;

[0286] 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;

[0287] 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;

[0288] 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;

[0289] 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;

[0290] 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;

[0291] 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;

[0292] 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;

[0293] 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;

[0294] 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;

[0295] 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;

[0296] ((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)carbamic acid methyl ester; and

[0297] 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;

[0298] or a pharmaceutically acceptable salt thereof.

[0299] 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 pharmaceutically acceptable salt thereof.

[0300] 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 pharmaceutically acceptable salt thereof.

[0301] 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 pharmaceutically acceptable salt thereof.

[0302] 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 pharmaceutically acceptable salt thereof.

[0303] In some embodiments, the compound of formula I is ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-(methyl-d 3 )-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the compound of formula I is ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 )-8-(1-(methyl-d 3 )-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the compound of formula I is ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-8-(4-fluorophenyl)-3-(methyl-d 3 )-methyl 2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0307] 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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, the compound of formula I is ((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)carbamic acid methyl ester or a pharmaceutically acceptable salt thereof.

[0320] It should be further understood that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination.

[0321] At various locations in this specification, divalent linking substituents are described. Each divalent linking substituent is expressly intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R") n -Including-NR(CR'R") n -and-(CR'R") n NR - both. Where a structure clearly requires a linking group, it is understood that the Markush variable listed for that group is the linking group.

[0322] The term "n-membered" (where n is an integer) generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl.

[0323] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. Substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent (e.g., oxo) may replace two hydrogen atoms. It is understood that substitution at a given atom is limited by valence.

[0324] As used herein, the phrase "each 'variable' is independently selected from" means substantially the same as "wherein the 'variable' at each occurrence is selected from".

[0325] Throughout this definition, the term “C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-3 , C 1-4 , C 1-5 , C 1-6 wait.

[0326] As used herein, the term “C n-m "Alkyl" refers to a saturated hydrocarbon group having n to m carbons which may be straight 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; higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the 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.

[0327] As used herein, the term “C n-m "Alkoxy" refers to a radical of the formula -O-alkyl, wherein the alkyl has n to m carbons. Example 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 has 1 to 6, 1 to 5, 1 to 4, or 1 to 3 carbon atoms.

[0328] As used herein, the term “C n-m "Hydroxyalkyl" refers to an alkyl group having one hydroxyl group (OH) to 2s+1 hydroxyl groups, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the hydroxyalkyl group comprises one hydroxyl group. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example hydroxyalkyl groups include, but are not limited to, hydroxymethyl (-CH 2 OH), hydroxyethyl (e.g. -CH 2 CH 2 OH and -CH(OH)CH 3 ), 1-hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 1-hydroxypropan-1-yl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, etc.

[0329] As used herein, "halo" refers to fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro.

[0330] In some places, definitions or embodiments refer to specific rings (e.g., phenyl ring, indazolyl ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member, provided that the valence of the atom is not exceeded. For example, the indazolyl ring can be attached at any position of the ring, while the indazol-5-yl ring is attached at the 5 position.

[0331] As used herein, the term "independently selected" means that each occurrence of a variable or substituent is independently selected from an applicable list at each occurrence.

[0332] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are contemplated. Compounds of the present disclosure containing asymmetrically substituted carbon atoms may be separated in optically active forms or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are considered in the present invention. The cis and trans geometric isomers of the compounds disclosed herein have been described and may be separated in the form of isomeric mixtures or in separate isomeric forms. In some embodiments, the compound has an (R)-configuration. In some embodiments, the compound has an (S)-configuration. The various formulas provided herein (e.g., Formula I, Formula Ia, etc.) include stereoisomers of the compound.

[0333] The resolution of the racemic mixture of compound can be implemented by any one of numerous methods known in the art. Example method includes the fractional recrystallization using chiral resolution acid, and the chiral resolution acid is an optically active salified organic acid. Suitable resolving agents for fractional recrystallization method are, for example, optically active acids, such as tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as β-camphorsulfonic acid in the form of D and L. Other resolving agents suitable for fractional crystallization method include stereoisomerically pure forms (such as S and R forms or diastereoisomerically pure forms) of α-methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.

[0334] The resolution of the racemic mixture can also be carried out by eluting on a column packed with an optically active resolving agent (eg dinitrobenzoylphenylglycine). The composition of the suitable elution solvent can be determined by those skilled in the art.

[0335] The compounds provided herein also include tautomeric forms. Tautomeric forms are derived from the exchange of single bonds with adjacent double bonds and the concomitant migration of protons. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Example prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms in which protons can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, 2-hydroxypyridines and 2-pyridones and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into a form by appropriate substitution.

[0336] All compounds and pharmaceutically acceptable salts thereof may exist together with other substances such as water and solvents (eg, hydrates and solvates), or may be isolated.

[0337] In some embodiments, preparation of the compounds may involve the addition of an acid or base to effect, for example, catalysis of a desired reaction or the formation of a salt form such as an acid addition salt.

[0338] In some embodiments, the compound or its salt provided herein is separated substantially. "Substantially separated" means that the compound is separated at least partially or substantially from the environment in which the compound is formed or detected. Partial separation may include, for example, a composition rich in the compound provided herein. Substantially separation may include a composition containing 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 compound or its salt provided herein.

[0339] The term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Unless otherwise specified, a compound identified herein by name or structure as one particular tautomeric form is intended to include the other tautomeric forms.

[0340] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0341] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); alkaline or organic salts of acidic residues (e.g., carboxylates); and the like. Pharmaceutically acceptable salts disclosed herein include conventional non-toxic salts of parent compounds formed, for example, by non-toxic inorganic or organic acids. Pharmaceutically acceptable salts disclosed herein can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (i.e., ACN or AcCN) are preferred. Lists of suitable salts are 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.

[0342] synthesis

[0343] As will be appreciated by those skilled in the art, the compounds provided herein, including salts and stereoisomers thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0344] Compounds of formula I can be prepared, for example, as shown in Scheme 1. Optionally protected (eg P = phenylsulfonyl) nitrobicyclic heterocycle 1-1 (wherein X 1 A halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) can react with an amine (e.g., 1-2) in a standard S N Ar conditions (e.g. in the presence of a base such as Et 3 N) to give 1-3. Nitroheterocycle 1-3 can be reduced under standard conditions (e.g., in the presence of Fe and acid) to give 1-4. Diamine 1-4 can be converted to cyclic urea 1-5 under standard conditions (e.g., in the presence of CDI). Cyclic urea 1-5 can be converted to cyclic urea 1-5 under standard S N 2 conditions (for example, under K 2 CO 3 and R 4 -X 2 In the presence of X 2Cyclic urea 1-6 can be converted to halide 1-7 under standard conditions (e.g., in the presence of LDA or alkyl lithium, 1,2-dibromotetrachloroethane in the case of bromination), wherein X 3 is a halogen (e.g., Cl, Br, or I). The halide 1-7 can be combined with 1-8 (where M 1 is boric acid, borate ester, potassium trifluoroborate or a suitably substituted metal (e.g. 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., in the presence of a palladium catalyst such as 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 (e.g., bromine) to give 1-10. The Boc group in compound 1-10 can be substituted under standard conditions (e.g., TFA in CH 2 Cl 2 Amine 1-11 can be converted to carbamate 1-12 under standard conditions (e.g., methyl chloroformate). Compound 1-12 can be reacted with R 1 -M 2 (where M 2 is boric acid, borate ester, potassium trifluoroborate or a suitably substituted metal (e.g. 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 Steele conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)) or under standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to give compound 1-13. Compound 1-13 can be deprotected under standard conditions (e.g., NaOH when P = phenylsulfonyl) to give a compound of formula I.

[0345] Solution 1.

[0346]

[0347] The reaction for preparing the compound described herein can be carried out in a suitable solvent, which can be easily selected by a technician in the field of organic synthesis. At the temperature of the reaction (for example, the temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent), the suitable solvent may not react substantially with the starting material (reactant), intermediate or product. A given reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the specific reaction step, a person skilled in the art can select a suitable solvent for a specific reaction step.

[0348] The expression "ambient temperature" or "room temperature" or "rt" as used herein is understood in the art and generally refers to a temperature about the temperature of the room where the reaction is carried out (e.g., reaction temperature), for example a temperature of about 20°C to about 30°C.

[0349] The preparation of the compounds described herein may involve the protection and deprotection of various chemical groups. One skilled in the art can easily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemistry of protecting groups can be found in, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley & Sons, Inc., New York (1999).

[0350] The reaction can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means (e.g., nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry) or by chromatographic methods (e.g., high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC)). Compounds can be purified by a variety of methods (including high performance liquid chromatography (HPLC) and normal phase silica chromatography) by those skilled in the art.

[0351] How to use

[0352] The compounds described herein can inhibit the activity of the V617F variant of the protein-tyrosine kinase JAK2 (i.e., "V617F" or "JAK2V617F"). Compounds that inhibit V617F can be used to provide a means of preventing tumor growth or inducing apoptosis of tumor cells, particularly by inhibiting angiogenesis. Therefore, it is expected that the compounds of the present disclosure can be used to treat or prevent proliferative disorders such as cancer. In particular, tumors with activating mutants of receptor tyrosine kinases or upregulated receptor tyrosine kinases may be particularly sensitive to inhibitors.

[0353] 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. WO 2022 / 006457, the disclosure of which is incorporated herein by reference in its entirety. The following compounds from WO 2022 / 006457 are provided herein as Comparative Examples AE:

[0354]

[0355]

[0356] In certain embodiments, the present disclosure provides a method for treating a V617F-related disorder in a patient in need thereof, comprising the step of administering to the patient a compound of the present disclosure or a pharmaceutically acceptable composition thereof.

[0357] Myeloproliferative disease (MPD) is a multipotent hematopoietic stem cell disorder characterized by 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 PV patients, 35% to 70% of ET patients, and 50% of IMF patients. In addition, JAK2 exon 12 mutations have been detected in some V617F-negative PV patients (Ma et al., J. Mol. Diagn., 11: 49-53, 2009). In some embodiments, the compounds of the present disclosure are useful for treating myeloproliferative disorders (e.g., myeloproliferative neoplasms), such as polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), etc., in patients in need thereof.

[0358] In some embodiments, the myeloproliferative disorder is a myeloproliferative neoplasm.

[0359] In some embodiments, the myeloproliferative disorder is myelofibrosis (eg, primary myelofibrosis (PMF) or post-polycythemia vera / post-essential thrombocythemia myelofibrosis (PV / post-ET MF)).

[0360] In some embodiments, the myeloproliferative disorder is primary myelofibrosis (PMF).

[0361] In some embodiments, the myeloproliferative disorder is post-essential thrombocythaemia myelofibrosis (post-ET MF).

[0362] In some embodiments, the myeloproliferative disorder is post-polycythemia vera myelofibrosis (post-PV MF).

[0363] In some embodiments, the myeloproliferative disorder is selected from primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET).

[0364] In some embodiments, the myeloproliferative neoplasm is primary myelofibrosis (PMF).

[0365] In some embodiments, the myeloproliferative neoplasm is polycythemia vera (PV).

[0366] In some embodiments, the myeloproliferative neoplasm is essential thrombocythaemia (ET).

[0367] Myeloproliferative disorders include disorders of bone marrow or lymph node derived cell types (e.g., white blood cells). Myeloproliferative disorders can manifest as abnormal cell division, resulting in abnormal levels of specific blood cell populations. The abnormal cell division behind proliferative blood disorders is usually intrinsic to the cells and is not a normal physiological response to infection or inflammation. Leukemia is a type of myeloproliferative disorder. Exemplary myeloproliferative diseases include, but are not limited to, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), chronic myeloid 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 disease (UMPD or MPD-NC). Lymphoma is a class of proliferative diseases that primarily involve lymphoid organs such as lymph nodes, liver, and spleen. Exemplary proliferative lymphoid disorders include lymphocytic lymphoma (also known as chronic lymphocytic leukemia), follicular lymphoma, large cell lymphoma, Burkitt's lymphoma, marginal zone lymphoma, lymphoblastic lymphoma (also known as acute lymphoblastic lymphoma).

[0368] For example, the compounds of the present disclosure can be used to treat cancer. Example 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 and oral cancer, squamous head and neck cancer), kidney cancer (e.g., renal cell carcinoma, urothelial carcinoma, sarcoma, Wilms tumor (Wilms tumor), liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma (e.g., intrahepatic, hilar or perihilar, distal extrahepatic), hepatic angiosarcoma, hepatoblastoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell and non-small cell carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer (e.g., pheochromocytoma, Merkel cell cancer, neuroendocrine cancer), skin cancer (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), and brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, pineal tumor).

[0369] Other example cancers 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 Macroglubul inemia, hairy cell lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

[0370] In certain embodiments, provided herein is a method 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.

[0371] Other cancers that may be treated with the compounds of the present disclosure include ocular tumors, glioblastoma, melanoma, leiomyosarcoma, and urothelial cancer (eg, ureter, urethra, bladder, urachal).

[0372] The compounds of the present disclosure may also be used to inhibit tumor metastasis.

[0373] In some embodiments, the compounds of the present disclosure as described herein can be used to treat Alzheimer's disease, HIV, or tuberculosis.

[0374] In some embodiments, the compounds of the present disclosure can be used to treat myelodysplastic syndrome (MDS) in a patient in need thereof. In some embodiments, the patient suffering from myelodysplastic syndrome (MDS) is dependent on red blood cell transfusions.

[0375] As used herein, myelodysplastic syndrome is intended to encompass heterogeneous and clonal hematopoietic disorders characterized by ineffective hematopoiesis of one or more major myeloid cell lineages. Myelodysplastic syndrome is associated with bone marrow failure, peripheral blood cell reduction, and a tendency to progress to acute myeloid leukemia (AML). In addition, clonal cytogenetic abnormalities can be detected in about 50% of MDS cases. In 1997, the World Health Organization (WHO) jointly proposed a new classification of hematopoietic neoplasms with the Society for Hematopathology (SH) and the European Association of Hematopathology (EAHP) (Harris et al., J Clin Oncol 1999; 17: 3835-3849; Vardiman et al., Blood 2002; 100: 2292-2302). For MDS, WHO not only utilizes the morphological criteria of the French-American-British (FAB) classification, but also incorporates available genetic, biological, and clinical characteristics to define subgroups 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 precise and prognostically relevant subclassification of monolineage dysplasia (Vardiman et al., Blood 2009;114:937-951; Swerdlow et al., WHOClassificationofTumoursofHaematopoieticand Lymphoid Tissues. 4th edition, Lyon France: IARC Press; 2008:88-103; Bunning and Germing, “Myelodysplastic syndromes / neoplasms,” Chapter 5, Swerdlow et al., eds. WHOClassificationof Tu moursof Haematopoietic andLymphoidTissues .(Version 4): Lyon, France: IARC Press; 2008:88-103).

[0376] Table 1. 2008 WHO new classification of myelodysplastic syndromes

[0377]

[0378]

[0379] In some embodiments, the myelodysplastic syndrome is refractory cytopenias with unilineage dysplasia (RCUD).

[0380] In some embodiments, the myelodysplastic syndrome is refractory anemia with ring sideroblasts (RARS).

[0381] In some embodiments, the myelodysplastic syndrome is refractory anemia with ring sideroblasts and thrombocytosis (RARS-T).

[0382] In some embodiments, the myelodysplastic syndrome is refractory cytopenias with multilineage dysplasia.

[0383] In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-1 (RAEB-1).

[0384] In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-2 (RAEB-2).

[0385] In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome unclassified (MDS-U).

[0386] In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome with isolated del(5q).

[0387] In some embodiments, the myelodysplastic syndrome is refractory to an erythropoiesis-stimulating agent.

[0388] In some embodiments, the compounds of the present disclosure may be used to treat myeloproliferative disorder / myelodysplastic overlap syndrome (MPD / MDS overlap syndrome).

[0389] In some embodiments, the compounds of the present disclosure may be used to treat leukemia.

[0390] In some embodiments, compounds of the present disclosure may be used to treat acute myeloid leukemia (AML).

[0391] In addition to oncogenic neoplasms, the compounds of the present disclosure may also be used to treat skeletal and chondrocyte disorders including, but not limited to, achondroplasia, hypochondrogenesis, dwarfism, thanatophoric dysplasia (TD) (clinical forms TD I and TDII), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis syndrome.

[0392] The compounds provided herein can further be used to treat fibrotic diseases, such as situations where the disease symptoms or conditions are characterized by fibrosis. Example fibrotic diseases include cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.

[0393] In some embodiments, the compounds provided herein are useful for treating hypophosphatemic disorders, such as X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets, or tumor-induced rickets.

[0394] In some embodiments, there is provided herein a method for extending the survival or progression-free survival of a patient, comprising administering a compound provided herein to the patient. In some embodiments, the patient suffers from cancer. In some embodiments, the patient suffers from a disease or condition as described herein. As used herein, progression-free survival refers to the length of time during and after solid tumor treatment, during which the patient coexists with the disease but the disease does not deteriorate. Progression-free survival may refer to the length of time from the first administration of a compound until death or disease progression in the earlier of the two. Disease progression may be defined by RECIST 1.1 (response evaluation criteria in solid tumors), as assessed by an independent centralized radiology review committee. In some embodiments, administration of a compound produces a progression-free survival 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 of 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 prolongs progression-free survival by 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.

[0395] The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any method described herein.

[0396] The present disclosure further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

[0397] As used herein, the term "cell" is intended to refer to a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell may be a portion of a tissue sample removed from an organism such as a mammal. In some embodiments, an in vitro cell may be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0398] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system 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 (e.g., a human) having a V617F variant, and, for example, introducing a compound described herein into a sample containing a cell or purified preparation containing the V617F variant.

[0399] As used herein, the terms "subject" or "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0400] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent, such as any solid form or salt thereof disclosed herein, that elicits the biological or medical response of a tissue, system, animal, individual or human being that is being sought by a researcher, veterinarian, physician or other clinician. The appropriate "effective" amount in any individual case can be determined using techniques known to those skilled in the art.

[0401] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0402] As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically 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 neither biologically nor otherwise undesirable, and include excipients or carriers that are acceptable for veterinary use as well as human medical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. See, e.g., 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; Ph armaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0403] As used herein, the terms "treating" or "treatment" refer to inhibiting a disease; e.g., inhibiting a disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms), or ameliorating a disease; e.g., ameliorating a disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease.

[0404] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein; for example, preventing or reducing the risk of developing a disease, disorder, or condition in an individual who may be susceptible to the disease, disorder, or condition, but who does not yet experience or display the signs or symptoms of the disease.

[0405] It will be appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (and the embodiments are intended to be combined as if written in multiple dependent form). Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0406] Combination therapy

[0407] One or more other pharmaceutical agents or treatment methods (e.g., antiviral agents, chemotherapeutic agents or other anticancer agents, immunopotentiators, immunosuppressants, radiation, anti-tumor and antiviral 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 V617F-related diseases, disorders or conditions or diseases or conditions as described herein. The agents may be combined with the compounds of the invention in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0408] The compounds described herein can be used in combination with one or more other kinase inhibitors for the treatment of diseases affected by various signaling pathways, such as cancer. For example, a 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. In addition, the solid form of the inhibitor as described herein can be combined with an inhibitor of the kinases associated with the PIK3 / Akt / mTOR signaling pathway (e.g., PI3K, Akt (including Akt1, Akt2 and Akt3) and mTOR kinases).

[0409] In some embodiments, the compounds described herein can be used in combination with one or more inhibitors of enzymes or protein receptors (e.g., 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, infection, inflammation, and neurodegenerative disorders.

[0410] In some embodiments, the compounds described herein can be used in combination with therapeutic agents targeting epigenetic regulators. Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. Histone deacetylase inhibitors include, for example, vorinostat.

[0411] For the treatment of cancer and other proliferative diseases, the compounds described herein can be used in combination with targeted therapies, including JAK kinase inhibitors (ruxolitinib, other JAK1 / 2 and JAK1 selective kinase inhibitors, baricitinib or itacitinib), Pim kinase inhibitors (e.g., LGH447, INCB053914, and SGI-1776), PI3 kinase inhibitors (including PI3K-δ selective inhibitors and broad-spectrum PI3K inhibitors (e.g., INCB50465 and INCB50797)), PI3K-γ inhibitors (e.g., PI3K-γ 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, mT OR inhibitors, 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 BTK inhibitors (e.g., ibrutinib).

[0412] For the treatment of cancer and other proliferative diseases, the compounds described herein can be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists or other antiproliferative agents. The compounds described herein can also be used in combination with medical therapy (e.g., surgery or radiotherapy, such as gamma-irradiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioisotopes).

[0413] Examples of suitable chemotherapeutic agents include any of the following: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretinoin, amidox, amsacrine, anastrozole, aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezovirax, tadalafil, tadalafil, selenomethoxazole ... mbi, bortezomib, brivanib, buparlisib, busulfan intravenous, busulfan oral, calusterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytara bine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium), dasatinib, actinomycin D, daunorubicin, decitabine, degarelix, denileukin, denileukin 2ox), deoxycoformycin, dexrazoxane, didox, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epipodophyllotoxin, epirubicin, epothilone, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiux etan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon α2a, irinotecan, lapatinib ditosylate ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lonafarnib, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate,phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumu mab, panobinostat, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur fur), temozolomide, teniposide, testolactone, tezacitabine, thalidomide, thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab, trastuzumab, tretinoi n, triapine, trimidox, triptorelin, uracil nitrogen mustard, valrubicin, vandetanib, vinblastine,lastine, vincristine, vindesine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

[0414] In some embodiments, the compounds described herein can be used in combination with immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors for, for example, the following immune checkpoint molecules: 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 (eg, INCAGN2385), TIM3 (eg, INCB2390), VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from the following: CD27, CD28, CD40, ICOS, OX40 (eg, INCAGN1949), GITR (eg, INCAGN1876), and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from the following: A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3 and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from the following: KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRβ inhibitors.

[0415] In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule PD-L1 inhibitor. In some embodiments, in the PD-L1 assays described in U.S. Patent Publication Nos. US20170107216, US20170145025, US20170174671, US20170174679, US20170320875, US20170342060, US20170362253, and US20180016260, the IC50 of the small molecule PD-L1 inhibitor is less than 1 μM, less than 100 nM, less than 10 nM, or less than 1 nM, and for all purposes, the patent disclosures are each incorporated by reference as a whole.

[0416] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-1 inhibitor, such as 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, ipilimumab 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 anticancer agents include antibody therapeutics, such as 4-1BB (eg, urelumab, utomilumab).

[0417] In some embodiments, the compounds of the present disclosure may be used in combination with INCB086550.

[0418] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-L1 inhibitor, 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.

[0419] In some embodiments, the inhibitor of the immune checkpoint molecule is a CTLA-4 inhibitor, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884 or CP-675,206.

[0420] In some embodiments, the inhibitor of the immune checkpoint molecule is a LAG3 inhibitor, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0421] In some embodiments, the inhibitor of the immune checkpoint molecule is a TIM3 inhibitor, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453 or TSR-022.

[0422] In some embodiments, the inhibitor of the immune checkpoint molecule is a GITR inhibitor, 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.

[0423] In some embodiments, the inhibitor of the immune checkpoint molecule is an OX40 agonist, such as 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.

[0424] In some embodiments, the inhibitor of the immune checkpoint molecule is a CD20 inhibitor, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0425] The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one domain of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGFβ receptor.

[0426] In some embodiments, the compounds of the present disclosure may 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 epasistat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

[0427] In some embodiments, the compounds described herein can be used in combination with one or more agents for treating diseases (e.g., cancer). In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. 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 immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0428] Suitable antiviral agents contemplated for use in combination with the compounds of the present disclosure may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.

[0429] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil (1592U89); dipivoxil) [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emitricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and designated β-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); de laviradine (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-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); 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.

[0430] Suitable agents 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 can be effectively combined with anti-hormonal agents for the treatment of breast cancer and other tumors. Suitable examples are anti-estrogens (including but not limited to tamoxifen and toremifene), aromatase inhibitors (including but not limited to letrozole, anastrozole, and exemestane), adrenocortical steroids (e.g., prednisone), progestins (e.g., megestrol acetate), and estrogen receptor antagonists (e.g., fulvestrant). Suitable anti-hormonal agents for the treatment of prostate cancer and other cancers can also be combined with the compounds described herein. These antihormonal agents include antiandrogens (including but not limited to flutamide, bicalutamide, and nilutamide), luteinizing hormone-releasing hormone (LHRH) analogs (including leuprorelin, goserelin, triptorelin, and histrelin), LHRH antagonists (e.g., degarelix), androgen receptor blockers (e.g., enzalutamide), and agents that inhibit androgen production (e.g., abiraterone).

[0431] The compounds described herein can be combined or sequentially combined with other agents for membrane receptor kinases, especially for patients who have developed primary or acquired resistance to targeted therapy. These therapeutic agents include inhibitors or antibodies for EGFR, Her2, VEGFR, c-Met, Ret, IGFR1 or Flt-3 and inhibitors or antibodies for cancer-related fusion protein kinases (such as Bcr-Abl and EML4-Alk). Inhibitors for EGFR include gefitinib and erlotinib, and inhibitors for EGFR / Her2 include (but are not limited to) dacomitinib, afatinib, lapatinib and neratinib. Antibodies for EGFR include (but are not limited to) cetuximab, panitumumab and nesimumab. C-Met inhibitors can be used in combination with FGFR inhibitors. These inhibitors include onartumzumab, tivantnib 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.

[0432] Angiogenesis inhibitors may be effective in some tumors in combination with the inhibitors described herein. These angiogenesis inhibitors include antibodies to VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies or other therapeutic proteins to VEGF include bevacizumab and aflibercept. Inhibitors of VEGFR kinases and other anti-angiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib and vandetanib.

[0433] Activation of intracellular signaling pathways is frequent in cancer, and agents targeting components of these pathways have been combined with receptor-targeted agents to enhance efficacy and reduce resistance. Examples of agents 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.

[0434] Agents against PI3 kinase include, but are not limited to, topilaralisib, idelalisib, buparisib. Inhibitors of mTOR, such as rapamycin, sirolimus, temsirolimus, and everolimus, can 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). Inhibitors of one or more JAKs (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin-dependent kinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARPs (e.g., olaparib), and proteasomes (e.g., bortezomib, carfilzomib) may also be combined with the compounds described herein. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2 and JAK3.

[0435] Other suitable agents for use in combination with the compounds described herein include chemotherapy combinations such as platinum-based doublets (cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed) or gemcitabine plus paclitaxel in conjunction with particles for use in lung cancer and other solid tumors.

[0436] Suitable chemotherapeutic or other anticancer agents include, for example, alkylating agents (including but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, methenchlor, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphamide, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, and temozolomide.

[0437] Other suitable agents for use in combination with the compounds described herein include steroids, including 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymethylenetestosterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorfenapyr, hydroxyprogesterone, aminoglutethimide, and medroxyprogesterone acetate.

[0438] Other suitable agents for use in combination with the compounds described herein include: dacarbazine (DTIC), optionally together with other chemotherapy drugs, such as carmustine (BCNU) and cisplatin; "Dartmouth regimen", which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine and DTIC; or temozolomide. The compounds described herein may also be combined with immunotherapy drugs (including cytokines such as interferon alpha, interleukin 2 and tumor necrosis factor (TNF)).

[0439] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including but not limited to, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.

[0440] Suitable chemotherapeutic or other anticancer agents also include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, actinomycin D, daunomycin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (particularly IFN-a), etoposide and teniposide.

[0441] Other cytotoxic agents include navelbine, CPT-11, anastrazole, letrazole, capecitabine, raloxafem, cyclophosphamide, ifosfamide, and zoloxifene.

[0442] Also suitable are cytotoxic agents, such as epipodophyllotoxins; antineoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes, such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutics; leucovorin; tegafur; and hematopoietic growth factors.

[0443] Other anticancer agents include antibody therapeutics such as trastuzumab (Herceptin), antibodies against co-stimulatory molecules (such as CTLA-4, 4-1BB, PD-L1 and PD-1 antibodies), or antibodies against cytokines (IL-10, TGF-β, etc.).

[0444] Other anticancer agents also include those that block the migration of immune cells, such as antagonists to chemokine receptors, including CCR2 and CCR4.

[0445] Other anti-cancer agents also include those that boost the immune system, such as adjuvant therapy or adoptive T-cell transfer.

[0446] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. In some embodiments, tumor vaccines include proteins from viruses associated with human cancers, 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 gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase peptides, or tumor cells transfected to express the cytokine GM-CSF.

[0447] The compounds of the present disclosure can be used in combination with bone marrow transplantation for the treatment of a variety of tumors of hematopoietic origin (eg, see U.S. Pat. Nos. 9,233,985; 10,065,974; 10,287,303; 8,524,867, the disclosures of which are incorporated herein by reference in their entireties).

[0448] Methods for safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in "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.

[0449] As provided throughout, other compounds, inhibitors, agents, etc. can be combined with the compounds of the present invention in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0450] Drug preparations and dosage forms

[0451] When used as medicine, 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 medical field and can be administered by a variety of 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 to mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including by a nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular 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 implemented, for example, by a continuous infusion pump. Pharmaceutical compositions and preparations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional drug carriers, aqueous, powdered or oily bases, thickeners, etc. may be necessary or desired.

[0452] The present disclosure also includes pharmaceutical compositions containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical application. When preparing the composition of the present disclosure, the active ingredient is usually mixed with an excipient, diluted with an excipient or encapsulated in such a carrier in the form of, for example, a capsule, a sachet, paper or other container. When an excipient is used as a diluent, it may be a solid, semisolid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Therefore, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of active compounds, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0453] In preparing the formulation, the active compound may be milled to provide an appropriate particle size prior to combining with other ingredients. If the active compound is substantially insoluble, it may be milled to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size may be adjusted by milling to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0454] The compounds of the present disclosure may be milled using known milling procedures (e.g., wet milling) to obtain particle sizes suitable for tablet formation and other formulation types. Fine powder (nanoparticulate) formulations of the compounds of the present disclosure may be prepared by processes known in the art, e.g., see International Application No. WO 2002 / 000196.

[0455] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents. The compositions of the present disclosure may be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by employing procedures known in the art.

[0456] The compositions can be formulated in unit dosage form, each dosage containing from about 5 mg to about 1000 mg (1 g), more usually from about 100 mg to about 500 mg of 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 quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0457] In some embodiments, the compositions of the present disclosure contain about 5 to about 50 mg of active ingredient. One of ordinary skill in the art will appreciate that this embodies a composition containing about 5 to about 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 25 to about 30 mg, about 30 to about 35 mg, about 35 to about 40 mg, about 40 to about 45 mg, or about 45 to about 50 mg of active ingredient.

[0458] In some embodiments, the compositions of the present disclosure contain about 50 to about 500 mg of active ingredient. One of ordinary skill in the art will appreciate that this embodies a composition containing about 50 to about 100 mg, about 100 to about 150 mg, about 150 to about 200 mg, about 200 to about 250 mg, about 250 to about 300 mg, about 350 to about 400 mg, or about 450 to about 500 mg of active ingredient.

[0459] In some embodiments, the compositions of the present disclosure contain about 500 to about 1000 mg of active ingredient. One of ordinary skill in the art will appreciate that this embodies a composition containing about 500 to about 550 mg, about 550 to about 600 mg, about 600 to about 650 mg, about 650 to about 700 mg, about 700 to about 750 mg, about 750 to about 800 mg, about 800 to about 850 mg, about 850 to about 900 mg, about 900 to about 950 mg, or about 950 to about 1000 mg of active ingredient.

[0460] Similar dosages of the compounds described herein may be used in the methods and uses of the present disclosure.

[0461] The active compound can be effective within a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the amount of compound actually administered will generally be determined by a physician based on relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0462] In order to prepare a solid composition (e.g., tablet), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulated composition containing a homogeneous mixture of the compounds of the present disclosure. When these preformulated compositions are referred to as homogeneous, the active ingredient is generally evenly dispersed throughout the composition so that the composition can be easily 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, containing, for example, about 0.1 to about 1000 mg of the active ingredient of the present disclosure.

[0463] Tablets or pills of the present disclosure may be coated or otherwise compounded to provide a dosage form with a lasting effect advantage. For example, a tablet or pill may include an inner dosage component and an outer dosage component, the latter being in the form of a coating on the former. The two components may be separated by an enteric layer that is used to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to delay release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0464] Liquid forms in which the compounds and compositions of the present disclosure may be incorporated for oral or injection administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0465] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory route to obtain local or systemic effects. The composition can be atomized by using an inert gas. The atomized solution can be breathed directly from the atomizing device or the atomizing device can be attached to a mask, curtain, or intermittent positive pressure breathing machine. The solution, suspension, or powder composition can be administered orally or nasally from a device that delivers the preparation in an appropriate manner.

[0466] The topical preparation may contain one or more conventional carriers. In some embodiments, the ointment may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline, etc. The carrier composition of the cream may be based on a combination of water with glycerol and one or more other components (e.g., glycerol monostearate, PEG-glycerol monostearate, and cetyl stearyl alcohol). The gel may be prepared using isopropyl alcohol and water, suitably in combination with other components (e.g., glycerol, hydroxyethyl cellulose, etc.). In some embodiments, the topical preparation contains at least about 0.1wt%, at least about 0.25wt%, at least about 0.5wt%, at least about 1wt%, at least about 2wt%, or at least about 5wt% of the compound of the present disclosure. The topical preparation may be suitably packaged in, for example, a 100g tube, which optionally has instructions for treating selected indications (e.g., psoriasis or other skin disorders).

[0467] The amount of the compound or composition administered to the patient will vary depending on the drug being administered, the purpose of administration (e.g., prevention or treatment), the patient's state, the mode of administration, etc. In therapeutic applications, the composition can be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially prevent 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 clinician based on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0468] The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques, or may be aseptically filtered. The aqueous solution may be packaged and used as is, or lyophilized, and the lyophilized preparation may be combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation will generally be between 3 and 11, more preferably 5 to 9 and most preferably 7 to 8. It should be understood that pharmaceutically acceptable salts will be formed using some of the above-mentioned excipients, carriers or stabilizers.

[0469] The therapeutic dose of the disclosed compounds may vary according to, for example, the specific use of the treatment being performed, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the disclosed compounds in the pharmaceutical composition may vary according to a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the disclosed compounds may be provided in a physiologically buffered aqueous solution containing about 0.1% to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg body weight / day to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day. The dosage may depend on, for example, the following variables: the type and degree of progression of the disease or condition, the overall health status of a particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose may be extrapolated from a dose-response curve derived from an in vitro or animal model test system.

[0470] The compositions of the present disclosure may also include one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are listed herein.

[0471] Labeled compounds and assays

[0472] Another aspect of the disclosure relates to labeled compounds of the disclosure (radioactive labels, fluorescent labels, etc.), which will be useful not only in imaging techniques, but also in in vitro and in vivo assays for localizing and quantifying V617F in tissue samples (including humans), and identifying V617F inhibitors by binding to labeled compounds. Substituting one or more atoms of the disclosed compounds can also be used to produce differential ADME (adsorption, distribution, metabolism and excretion). Therefore, the disclosure includes V617F assays containing such labeled or substituted compounds.

[0473] The present disclosure also includes isotopically labeled compounds of the present disclosure. An "isotopically" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., naturally occurring). Suitable radionuclides that may 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. 18F. 35 S. 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I. 124 I. 125 I and 131 I. For example, one or more hydrogen atoms in the disclosed compounds may be replaced by deuterium atoms (e.g., C 1-6 One or more hydrogen atoms of the alkyl group may be optionally replaced by a deuterium atom, e.g., -CD 3 (i.e. trideuterated methyl) substituted -CH 3 In some embodiments, the alkyl groups of the disclosed formulae (e.g., Formula I, Formula Ia, etc.) may be perdeuterated (e.g., trideuterated methyl (-CD 3 ), pentadeuterated ethyl (-CD 2 CD 3 ), heptadeuterated isopropyl (-CD(CD 3 ) 2 )wait).

[0474] In some embodiments, the alkoxy group of the disclosed formulae (e.g., Formula I, Formula Ia, etc.) can be perdeuterated (e.g., trideuterated methoxy (-OCD 3 ), pentadeuterated ethoxy (-OCD 2 CD 3 ), heptadeuterated isopropoxy (-OCD (CD 3 ) 2 )wait).

[0475] One or more constituent atoms of the compounds presented herein may be replaced or substituted by isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compounds include at least one deuterium atom. For example, one or more hydrogen atoms in the compounds presented herein may be replaced or substituted by deuterium (e.g., C 1-6 One or more hydrogen atoms of an alkyl group may be replaced by a deuterium atom, e.g., -CD 3 Substitute -CH 3 ). In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 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 can be replaced or substituted by deuterium atoms.

[0476] In some embodiments, each hydrogen atom of the compounds provided herein (e.g., hydrogen atoms attached to carbon atoms of alkyl, alkoxy, phenyl, dihydroisobenzofuranyl, and indazolyl substituents) is optionally replaced with a deuterium atom, as described herein.

[0477] In some embodiments, each hydrogen atom of the compounds provided herein (eg, hydrogen atoms attached to carbon atoms of alkyl, alkoxy, phenyl, and indazolyl substituents) is optionally replaced with a deuterium atom, as described herein.

[0478] In some embodiments, as described herein, each hydrogen atom of the compounds provided herein (e.g., hydrogen atoms attached to carbon atoms of alkyl, alkoxy, phenyl, and indazolyl substituents) is replaced with a deuterium atom (i.e., the alkyl, alkoxy, phenyl, dihydroisobenzofuranyl, and indazolyl substituents are perdeuterated).

[0479] In some embodiments, as described herein, each hydrogen atom of the compounds provided herein (e.g., hydrogen atoms attached to carbon atoms of alkyl, alkoxy, phenyl, and indazolyl substituents) is replaced with a deuterium atom (i.e., the alkyl, alkoxy, phenyl, and indazolyl substituents are perdeuterated).

[0480] In some embodiments, as described herein, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hydrogen atoms attached to carbon atoms of alkyl, alkoxy, phenyl, dihydroisobenzofuranyl and indazolyl substituents are optionally replaced with deuterium atoms.

[0481] In some embodiments, as described herein, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms attached to carbon atoms of alkyl, alkoxy, phenyl, dihydroisobenzofuranyl, and indazolyl substituents are optionally replaced with deuterium atoms.

[0482] In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hydrogen atoms attached to carbon atoms of alkyl, alkoxy, phenyl, and indazolyl substituents are optionally replaced with deuterium atoms, as described herein.

[0483] In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms attached to carbon atoms of alkyl, alkoxy, phenyl, and indazolyl substituents are optionally replaced with deuterium atoms, as described herein.

[0484] In some embodiments, the compounds provided herein (eg, compounds of any one of Formula I-Vc) or pharmaceutically acceptable salts thereof contain at least one deuterium atom.

[0485] In some embodiments, the compounds provided herein (eg, compounds of any one of Formula I-Vc) or pharmaceutically acceptable salts thereof contain two or more deuterium atoms.

[0486] In some embodiments, the compounds provided herein (eg, compounds of any one of Formula I-Vc) or pharmaceutically acceptable salts thereof contain three or more deuterium atoms.

[0487] In some embodiments, for a compound provided herein (eg, a compound of any one of Formula I to Formula Vc) or a pharmaceutically acceptable salt thereof, all hydrogen atoms are replaced with deuterium atoms (ie, the compound is "perdeuterated").

[0488] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange, Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling, James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds are useful in a variety of studies, such as NMR spectroscopy, metabolic experiments and / or assays.

[0489] Substitution with heavier isotopes (e.g., deuterium) may provide certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements, and therefore may be preferred in some cases. (See, for example, 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.

[0490] The radionuclide incorporated into the radiolabeled compounds of the invention will depend on the specific application of the radiolabeled compound. For example, for in vitro V617F labeling and competition assays, 3 H. 14 C. 82 Br,125 I. 131 I or 35 Compounds of S may be useful. For radioactive imaging applications, 11 C. 18 F. 125 I. 123 I. 124 I. 131 I. 75 Br, 76 Br or 77 Br may be useful.

[0491] It is understood that "radiolabeled" or "labeled compound" is a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of: 3 H. 14 C. 125 I. 35 S and 82 Br.

[0492] The present disclosure may also include synthetic methods for incorporating radioisotopes into the disclosed compounds.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 applicable to the disclosed compounds.

[0493] The labeled compounds disclosed herein can be used in screening assays to identify / evaluate compounds. For example, via tracking labels, the ability of a newly synthesized or identified compound (i.e., a test compound) to bind to V617F can be evaluated by monitoring the concentration change of the labeled newly synthesized or identified compound (i.e., a test compound) when in contact with V617F. For example, the ability of a test compound (labeled) to reduce the binding of another compound (i.e., a standard compound) known to bind to V617F can be evaluated. Therefore, the ability of a test compound to compete with a standard compound for binding to V617F is directly related to its binding affinity. In contrast, in some other screening assays, the standard compound is labeled, and the test compound is unlabeled. Therefore, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thereby determined.

[0494] Pill Box

[0495] The present disclosure also includes a medical kit useful, for example, for treating or preventing a V617F-related disease or condition as described herein, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. As will be apparent to those skilled in the art, such kits may also include one or more of the various conventional medical kit components, such as a container containing one or more pharmaceutically acceptable carriers, additional containers, etc., as desired. Instructions (as an insert or as a label) indicating the amounts of the components to be administered, instructions for administration, and / or instructions for mixing the components may also be included in the kit.

[0496] The present invention will be described in more detail by means of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will easily recognize multiple non-critical parameters that can be changed or modified to produce substantially the same result.

[0497] Example

[0498] Preparative LC-MS purification of some of the compounds prepared was performed on a Waters mass directed fractionation system. The basic equipment setup, protocols, and control software for operating these systems have been described in detail in the literature (e.g., see “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)).

[0499] The isolated compounds were usually subjected to analytical liquid chromatography-mass spectrometry (LCMS) under the following conditions for purity analysis: Instrument = Agilent 1100 series, LC / MSD; Column: Waters Sunfire TM C18 5 μm, 2.1×50 mm, buffer: mobile phase A: water containing 0.025% TFA and mobile phase B: acetonitrile; gradient 2% to 80% B in 3 minutes, flow rate 2.0 mL / min.

[0500] As also indicated in the Examples, some of the prepared compounds were separated on a preparative scale by reverse phase high performance liquid chromatography (RP-HPLC) with MS detection or flash chromatography (silica gel). Typical preparative reverse phase high performance liquid chromatography (RP-HPLC) column conditions were as follows:

[0501] pH = 2 Purification: Waters Sunfire TM C 18 5μm, 30×100mm or Waters XBridge TM C 18 5 μm, 30×100 mm column, eluted with mobile phase A: water containing 0.1% TFA (trifluoroacetic acid) and mobile phase B: acetonitrile; the flow rate was 60 ml / min, and the separation gradient of each compound was optimized using the compound-specific method optimization scheme described in the literature (for example, see “Preparative LCMS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

[0502] pH = 10 purification: Waters XBridge TM C 18 5 μm, 30 × 100 mm column, mobile phase A: containing 0.1% NH 4 OH water and mobile phase B: acetonitrile; the flow rate was 60 mL / min, and the separation gradient of each compound was optimized using a compound-specific method optimization protocol as described in the literature (e.g., see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

[0503] 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

[0504]

[0505] Step 1. tert-Butyl ((1R,3R)-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate

[0506]

[0507] 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 Et 3 A mixture of N (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 N 5 O 6 LC-MS of S (M+H) + Calculated value: m / z = 502.2; Found value 502.2.

[0508] Step 2. tert-Butyl ((1R,3R)-3-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate

[0509]

[0510] 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 and then washed with saturated NaHCO 3 The organic solution was concentrated to obtain the desired product.23 H 30 N 5 O 4 LC-MS of S (M+H) + Calculated value: m / z = 472.2; found value 472.3.

[0511] 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

[0512]

[0513] 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 and the residue was dissolved in ethyl acetate and washed sequentially 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) and K 2 CO 3 (5.60g, 40.5mmol) and MeI (2.53ml, 40.5mmol), and the reaction mixture was stirred at room temperature for 2h. The mixture was diluted with ethyl acetate and washed with water, and then the organic phase was dried and concentrated. The residue was purified on silica gel (120g, 0-80% EtOAc / hexane) to obtain the desired product. 25 H 30 N 5 O 5 LC-MS of S (M+H) + Calculated value: m / z = 512.2; Found value 512.2.

[0514] 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

[0515]

[0516] 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 point, 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 another 40 min, the mixture was heated to 40 °C by adding saturated NH 4 The reaction was quenched with Cl solution. The mixture was diluted with ethyl acetate and washed with water, and the organic phase was dried and concentrated. The resulting residue was purified on silica gel (120 g, 0-80% EtOAc / hexane) to give the desired product. 25 H 29 Bn 5 O 5 LC-MS of S (M+H) + Calculated value: m / z = 590.1, 592.1; Found value 590.2, 592.1.

[0517] 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

[0518]

[0519] 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-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.71 g, 19.80 mmol), K 3 PO 4 (7.00 g, 33.0 mmol) and Pd(Ph 3 P) 4A mixture of (1.907 g, 1.650 mmol) in dioxane (50.0 mL) / water (8.0 mL) was evacuated and backfilled with nitrogen (this process was repeated three times in total), 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 / hexane) to give the desired product. C 30 H 36 N 7 O 6 LC-MS of S (M+H) + Calculated value: m / z = 622.2; Found value 622.3.

[0520] 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

[0521]

[0522] At 0℃, CH 2 Cl 2 Bromine (1.542 g, 9.65 mmol) in 1% bromine (2.0 mL) was added to 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 CH 2 Cl 2 (40.0 mL) and then stirred for 30 min. By adding saturated NaHCO 3 The reaction was quenched 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. 30 H 35 Bn 7 O 6 LC-MS of S (M+H) + Calculated value: m / z = 700.2, 702.2; Found value 700.3, 702.3.

[0523] 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

[0524]

[0525] TFA (10 mL) was added to 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 CH 2 Cl 2 (10.0 mL), and the reaction was then stirred for 30 min. The mixture was concentrated, and the residue was then dissolved in CH 2 Cl 2 (40 mL) and water (20.0 mL), followed by the addition of Na 2 CO 3 (4.24 g, 40.0 mmol) and methyl chloroformate (0.929 mL, 12.00 mmol), and then stirred at room temperature for 10 min. The mixture was washed with CH 2 Cl 2 Dilute and wash with water, then dry the organic phase and concentrate. 2 Cl 2 The residue was purified on PBS to obtain the desired product. 27 H 29 Bn 7 O 6 LC-MS of S (M+H) + Calculated value: m / z = 658.1, 660.1; Found value 658.2, 660.3.

[0526] 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

[0527] 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), K 3 PO 4 (9.67 mg, 0.046 mmol), Pd(Ph 3 P) 4 (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 three times in total). The reaction mixture was stirred at 105 ° C for 2 h. 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 another 15 min to remove the protecting group. The mixture was diluted with acetonitrile / water and adjusted to pH about 1 by adding 6N HCl solution, and then purified using preparative LCMS (XBridge C18 column, eluted with acetonitrile / water gradient containing 0.1% TFA, flow rate of 60 mL / min) to give the product as a TFA salt. C 27 H 29 FN 7 O 4 LC-MS (M+H) + Calculated value: m / z = 534.2; found value 534.3. 1 H NMR(600MHz,DMSO)δ11.88(s,1H),8.30(s,1H),7.44(dt,J=16.2,7.2Hz,2H),7.38-7.32 (m,2H),6.96(d,J=6.9Hz,1H),6.86(s,1H),4.05(h,J=8.0Hz,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=13.2,8.4,4.8Hz,1H),1.9 0(m,1H),1.88(d,J=8.5Hz,1H),1.52-1.46(m,1H),1.29(q,J=11.3Hz,1H),0.81(m,1H).

[0528] 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

[0529]

[0530] 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 N 7 O 4 LCMS (M+H) + Calculated value m / z = 516.2; Found value 516.3. 1 H NMR (600MHz, DMSO) δ11.84(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=6.9Hz,1H),6.79(s,1H),4.02(h,J=7.0Hz,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=13.4,7.9,4.9Hz,1H),1.93-1. 80(m,2H),1.43(dt,J=10.7,8.2Hz,1H),1.22(td,J=11.8,8.2Hz,1H),0.80-0.71(m,1H).

[0531] 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

[0532]

[0533] This compound was prepared according to the procedure described in Step 8 of Example 1, substituting (3-fluorophenyl)boronic acid for (4-fluorophenyl)boronic acid. 27 H 29 FN 7 O 4 LC-MS (M+H) + Calculated value: m / z = 534.2; found value 534.3. 1H NMR (600MHz, DMSO) δ11.81(s,1H),8.25(d,J=2.5Hz,1H),7.56(q,J=7.4Hz,1H ),7.31(m,1H),7.25(d,J=7.9Hz,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=11.2Hz,1H),0.83(br,1H).

[0534] 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

[0535]

[0536] This compound was prepared according to the procedure described in Step 8 of Example 1, substituting (3-fluoro-4-methoxyphenyl)boronic acid for (4-fluorophenyl)boronic acid. 28 H 31 FN 7 O 5 LC-MS (M+H) + Calculated value: m / z = 564.2; found value 564.3. 1 HNMR(500MHz,DMSO)δ11.16(s,1H),8.12(s,1H),7.28(t,J=8.7Hz,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=13.5,8.5,5.1Hz,1 H), 2.05-1.90 (m, 2H), 1.57-1.50 (m, 1H), 1.33 (q, J = 11.3Hz, 1H), 0.91-0.81 (m, 1H).

[0537] Example 5. ((1R,3R)-3-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-(methyl-d 3 )-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester

[0538]

[0539] This compound was prepared according to the procedure described in Step 8 of Example 1 using (1-(methyl-d 3 )-1H-indazol-5-yl)boronic acid instead of (4-fluorophenyl)boronic acid. 29 H 29 D 3 N 9 O 4 LC-MS (M+H) + Calculated value: m / z = 573.3; Found value 573.3. 1 H NMR (600MHz, DMSO) δ11.68(s,1H),8.27(s,1H),7.33(dd,J=8.4,2.2Hz,1H),7.27(dd,J=8.3,2.3Hz,1H),7.1 2(dd,J=8.4,2.6Hz,1H),7.08(dd,J=8.4,2.8Hz,1H),6.84(d,J=6.8Hz,1H),6.81(s,1H),4.16-4.05(m,1H),3 .89(s,3H),3.79(t,J=5.1Hz,1H),3.60(s,3H),3.50(s,3H),3.39(s,3H),2.08(ddt,J=13.0,9.0,4.8Hz,1H), 1.92(s,1H),1.86(dt,J=12.7,6.5Hz,1H),1.46(dt,J=11.7,7.6Hz,1H),1.27(p,J=11.2Hz,1H),0.75(m,1H).

[0540] Example 6. ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 )-8-(1-(methyl-d 3 )-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester

[0541]

[0542] Step 1. tert-Butyl ((1R,3R)-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate

[0543]

[0544] 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 Et 3 A mixture of N (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 N 5 O 6 LC-MS of S (M+H) + Calculated value: m / z = 502.2; Found value 502.2.

[0545] Step 2. tert-Butyl ((1R,3R)-3-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentyl)carbamate

[0546]

[0547] 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 and then washed with saturated NaHCO 3 The organic solution was concentrated to give the desired product (12.02 g, 25.5 mmol, 86.4%) as a dark yellow amorphous solid. 23 H 30 N 5 O 4 LC-MS of S (M+H)+ Calculated value: m / z = 472.2; found value 472.3.

[0548] Step 3. ((1R,3R)-3-(3-(methyl-d 3 tert-Butyl)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate

[0549]

[0550] 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 and the residue was dissolved in ethyl acetate and washed sequentially 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) and K was added. 2 CO 3 (11.05 g, 80.0 mmol) and CD 3 I (11.59 g, 80.0 mmol), and then the reaction mixture was stirred at 50 ° C for 2 h. The mixture was diluted with ethyl acetate and washed with water, and then the organic phase was dried and concentrated. The residue was purified on silica gel (300 g, 0-100% EtOAc / hexane containing 5% dichloromethane) to give the desired product (9.36 g, 18.2 mmol, 71.4%) as a yellow amorphous solid. 25 H 27 D 3 N 5 O 5 LC-MS of S (M+H) + Calculated value: m / z = 515.2; Found value 515.2.

[0551] Step 4. ((1R,3R)-3-(7-bromo-3-(methyl-d 3 tert-Butyl)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate

[0552]

[0553] Lithium diisopropylamide (LDA, 2.0 M in THF / heptane / ethylbenzene, Sigma-Aldrich) (22.7 mL, 45.5 mmol) was added to ((1R,3R)-3-(3-(methyl-d 3 )-tert-butyl 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) 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 another 40 min, the mixture was heated to 40°C by adding saturated NH 4 The reaction was quenched with Cl solution. The mixture was diluted with ethyl acetate and washed with water, and the organic phase was dried and concentrated. The resulting residue was purified on silica gel (120 g, 0-100% EtOAc / hexane containing 5% dichloromethane) to give the desired product (8.90 g, 15.0 mmol. 82.4%) as a yellow amorphous solid. 25 H 26 D 3 Bn 5 O 5 LC-MS of S (M+H) + Calculated value: m / z = 593.1, 595.1; Found value 593.1, 595.1.

[0554] Step 5. ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 tert-Butyl)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate

[0555]

[0556] Step 6. 3-Fluoro-1-(methyl-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0557]

[0558] 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), and K 2 CO 3 (11.05 g, 80.0 mmol) and CD 3 I (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, and then the organic phase was dried and concentrated. The residue was purified on silica gel (300 g, 0-100% EtOAc / hexane containing 5% dichloromethane) to give the desired product (9.36 g, 18.2 mmol, 71.4%) as a brown amorphous solid. 10 H 14 D 3 BFN 2 O 2 LC-MS (M+H) + Calculated value: m / z = 230.2; Found value 230.2.

[0559] 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

[0560]

[0561] ((1R,3R)-3-(7-bromo-3-(methyl-d 3 )-tert-butyl 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-d 3 )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.36 g, 18.2 mmol), Cs 2 CO 3 (14.7 g, 45.0 mmol) and Pd(Ph 3 P) 4A mixture of (3.50 g, 3.0 mmol) in dioxane (100.0 mL) / water (20.0 mL) was evacuated and backfilled with nitrogen (this process was repeated three times in total), and the reactants were 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 / hexane containing 5% dichloromethane) to give the desired product (5.66 g, 9.2 mmol, 61.3%) as a yellow amorphous solid. 29 H 27 D 6 FN 7 O 5 LC-MS of S (M+H) + Calculated value: m / z = 616.3; found value 616.2.

[0562] Step 8. ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 tert-Butyl)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate

[0563]

[0564] At 0℃, CH 2 Cl 2 Bromine (1.61 g, 10.1 mmol) in 1% bromine (5.0 mL) was added dropwise to ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 tert-Butyl)-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 CH 2 Cl 2 (80.0 mL) and then stirred at the same temperature for 10 min. By adding saturated NaHCO 3 The reaction was quenched and the resulting mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to give the desired product (6.25 g, 9.0 mmol, 97.8%) as a yellow amorphous solid. 29 H 26 D 6 BrFN 7 O 5 LC-MS of S (M+H)+ Calculated value: m / z = 694.2, 696.2; Found value 694.2, 696.2.

[0565] Step 9. ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 )-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester

[0566]

[0567] TFA (10 mL) was added to ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 tert-Butyl)-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 CH 2 Cl 2 (10.0 mL), and the reaction was then stirred at room temperature for 10 min. The mixture was concentrated, and the residue was then dissolved in ethyl acetate (40 mL) and water (20.0 mL), followed by the addition of Na 2 CO 3 (4.24 g, 40.0 mmol) and methyl chloroformate (0.929 mL, 12.00 mmol), and then stirred at room temperature for 10 min. The mixture was washed with CH 2 Cl 2 The mixture was diluted and washed with water, and the organic phase was then dried and concentrated. 2 Cl 2 ) to give the desired product (5.65 g, 8.7 mmol, 96.2%). 26 H 20 D 6 BrFN 7 O 5 LC-MS of S (M+H) + Calculated value: m / z = 652.1, 654.1; Found value 652.1, 654.1.

[0568] Step 10. ((1R,3R)-3-(7-(3-fluoro-1-(methyl-d 3)-1H-pyrazol-4-yl)-3-(methyl-d 3 )-8-(1-(methyl-d 3 )-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester

[0569] A screw cap vial equipped with a magnetic stir bar was charged with ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 )-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester (15.0 mg, 0.023 mmol), (1-(methyl-d 3 )-1H-indazol-5-yl)boronic acid (10.0 mg, 0.056 mmol, Abovchem), Cs 2 CO 3 (15.0 mg, 0.046 mmol), Pd(Ph 3 P) 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. 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 another 15 min to remove the protecting groups. The mixture was diluted with acetonitrile, filtered and then analyzed using preparative LCMS (XBridge C18 column, acetonitrile / NH 4 Purification was performed by gradient elution with 0.5% OH in water at a flow rate of 60 mL / min to obtain the product (7.0 mg, 0.012 mmol, 53.7%) as an amorphous solid. 28 H 20 D 9 FN 9 O 3 LC-MS (M+H) + Calculated value: m / z = 567.3; Found value 567.3. 1 H NMRδ 1H 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).

[0570] Example 7. ((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)carbamic acid methyl ester

[0571]

[0572] A screw cap vial equipped with a magnetic stir bar was charged with ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 )-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester (15.0 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), Cs 2 CO 3 (15.0 mg, 0.046 mmol), Pd(Ph 3 P) 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. 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 another 15 min to remove the protecting groups. The mixture was diluted with acetonitrile, filtered and then analyzed using preparative LCMS (XBridge C18 column, acetonitrile / NH 4Purification was performed by gradient elution with 0.5% OH in water at a flow rate of 60 mL / min to obtain the product (6.5 mg, 0.012 mmol, 53.6%) as an amorphous solid. 26 H 20 D 6 F 2 N 7 O 3 LC-MS (M+H) + Calculated value: m / z = 528.2; Found value 528.2. 1 H NMR(600MHz,DMSO)δ1HNMR(600MHz,DMSO)δ11.93(s,1H),8.13(d,J=1.0Hz,1H),7 .44(d,J=1.9Hz,1H),7.40(s,2H),7.26(t,J=8.6Hz,2H),6.91(d,J=6.7Hz,1H),4. 05(Sixtet, J=7.8Hz,1H),3.88(s,1H),3.50(s,3H),2.06(ddd,J=13.3,8.4,5.1Hz,1H ),1.96-1.80(m,2H),1.46(q,J=9.0Hz,1H),1.33-1.20(m,1H),0.85-0.73(m,1H).

[0573] 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

[0574]

[0575] A screw cap vial equipped with a magnetic stir bar was charged with ((1R,3R)-3-(8-bromo-7-(3-fluoro-1-(methyl-d 3 )-1H-pyrazol-4-yl)-3-(methyl-d 3 )-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamic acid methyl ester (15.0 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), Cs 2 CO 3(15.0 mg, 0.046 mmol), Pd(Ph 3 P) 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. 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 another 15 min to remove the protecting groups. The mixture was diluted with acetonitrile, filtered and then analyzed using preparative LCMS (XBridge C18 column, acetonitrile / NH 4 Purification was performed by gradient elution with 0.5% OH in water at a flow rate of 60 mL / min to obtain the product (5.5 mg, 0.009 mmol, 41.2%) as an amorphous solid. 30 H 27 D 6 FN 7 O 4 LC-MS (M+H) + Calculated value: m / z = 580.3; Found value 580.3. 1 H NMR (600MHz, DMSO) δ11.91(s,1H),8.12(s,1H),7.45(d,J=24.5Hz,1H),7.33-7.20(m,3H),6.97(s,0.5H),6.82(s,0.5H),5.13(d,J=11.8Hz,0.5 H),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=5.5Hz,6H),1.38(m,1H),1.21(m,1H),0.66(m,1H).

[0576] Examples 9-21.

[0577] Examples 9-21 in Table 2 were prepared according to the procedure described in Example 8 using appropriately substituted starting materials.

[0578] Table 2.

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586] Example A. JAK2 LanthaScreen JH1 Binding Assay

[0587] The JAK2 JH1 binding assay utilizes the catalytic domain of human JAK2 (JH1, amino acids 826-1132) expressed as a biotinylated protein with an N-terminal FLAG tag in a baculovirus expression system (Carna Biosciences, catalog number 08-445-20N). The assay was performed in a 20 μL final reaction volume in a black 384-well polystyrene plate. The assay buffer (50 mM Tris, pH = 7.5, 10 mM MgCl 2 JAK2 JH1 (1.5 nM) was incubated with compounds (100 nL serially diluted in DMSO) in 50 nM fluorescent JAK2-JH1 tracer and 0.5 nM streptavidin-Tb cryptate (Cisbio, part number 610SATLB) in 4% paraffin-embedded PBS (0.01% Brij-35, 0.1% BSA, 1 mM EGTA, 5% glycerol, and 5 mM DTT). Nonspecific binding was performed in the presence of 2 mM ATP. LanthaScreen signals were read on a PHERAstar FS plate reader (BMG LABTECH) after incubation for 2 hours at 25°C. Data were analyzed using a four-parameter dose-response curve using IDBS XLfit and GraphPad Prism 5.0 software to determine the IC50 for each compound.

[0588] Example B. JAK2 LanthaScreen JH2-V617F Binding Assay

[0589] The JAK2 JH2-V617F binding assay utilizes the pseudokinase domain of the human V617F mutant JAK2 (JH2, amino acids 536-812 with three surface mutations W659A, W777A, F794H), which is expressed as a biotinylated protein with a C-terminal His-Avi tag in a baculovirus expression system (BPS Bioscience, catalog number 79498). The assay was performed in a black 384-well polystyrene plate with a final reaction volume of 20 μL. The 50 mM Tris, pH = 7.5, 10 mM MgCl 2JAK2 JH2-V617F (0.26 nM) was incubated with compounds (100 nL serially diluted in DMSO) in 50 nM fluorescent JAK2-JH2 tracer (MedChem Express, catalog number HY-102055) and 0.25 nM streptavidin-Tb cryptate (Cisbio, part number 610SATLB) in 4% paraffin-embedded culture medium (0.01% Brij-35, 0.1% BSA, 1 mM EGTA, 5% glycerol, and 5 mM DTT). Nonspecific binding was performed in the presence of 2 mM ATP. After incubation for 1 hour at 25°C, LanthaScreen signals were read on a PHERAstar FS plate reader (BMG LABTECH). Data were analyzed using a four-parameter dose-response curve using IDBS XLfit and GraphPad Prism 5.0 software to determine the IC50 for each compound.

[0590] Example C. FLT3 Enzymatic Assay

[0591] In the assay buffer (HEPES 50 mM, pH 7.0, NaN 3 0.02%、BSA0.01%、orthovanadate0.1mM、DTT1mM、MgCl 2 10mM) in a final volume of 10 μL and the kinase assay was performed at room temperature. Test compounds were prepared by serial dilution in DMSO and transferred to the wells containing 0.5% DMSO in the final assay by an ECHO liquid handler (Labcyte). The FLT3 / TK substrate-biotin mixture was prepared in an assay buffer containing 1000nM TK substrate-biotin and 125nM 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 ATP in the assay buffer. The final 10 μL kinase reaction consisted of 0.011nM FLT3, 1mM ATP, 500nM TK substrate-biotin and 62.5nM SEB reagent in the assay buffer. The reaction was incubated for 90 min and terminated by adding 10 μL of detection reagent, which contained 125nM streptavidin-XL665, TK antibody-cryptate in detection buffer (HEPES 50mM, pH 7.0, BSA0.1%, KF 0.8M, EDTA 20mM). The plate was then sealed and centrifuged at 1800rpm for 2 minutes. After incubation at room temperature for 60 minutes, product activity was determined by measuring fluorescence at 620nm and 665nm on a Pherastar microplate reader (BMG Labtech). The ratio (665 / 620nm) of each well was calculated. Wells containing only DMSO were used as positive controls, and wells without ATP were used as negative controls. IC was implemented by fitting a curve of control activity percentage to the logarithm of compound concentration using GraphPad Prism7.0 software 50 Determination.

[0592] Example D. KIT Enzymatic Assay

[0593] In the assay buffer (HEPES 50 mM, pH 7.0, NaN 3 0.02%, BSA 0.01%, orthovanadate 0.1mM, DTT 1mM, MgCl 2 10mM) in a final volume of 10 μL at room temperature for kinase assays. Test compounds were prepared by serial dilution in DMSO and transferred to plate wells containing 0.5% DMSO in the final assay via an ECHO liquid handler (Labcyte). A KIT / TK substrate-biotin mixture was prepared in assay buffer containing 1000nM TK substrate-biotin and 125nM 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 ATP in the assay buffer. The final 10 μL kinase reaction consisted of 0.12nM KIT, 1mM ATP, 500nM TK substrate-biotin and 62.5nM SEB reagent in the assay buffer. The reaction was incubated for 90 min and terminated by adding 10 μL of detection reagent, which contained 125nM streptavidin-XL665, TK antibody-cryptate in detection buffer (HEPES 50mM, pH7.0, BSA 0.1%, KF 0.8M, EDTA 20mM). The plate was then sealed and centrifuged at 1800rpm for 2 minutes. After incubation at room temperature for 60 minutes, product activity was determined by measuring fluorescence at 620nm and 665nm on a Pherastar microplate reader (BMG Labtech). The ratio (665 / 620nm) of each well was calculated. Wells containing only DMSO were used as positive controls, and wells without ATP were used as negative controls. IC was implemented by fitting a curve of control activity percentage to the logarithm of compound concentration using GraphPad Prism7.0 software 50 Determination.

[0594] The compounds of the present disclosure and the comparative examples were tested in one or more of the assays described in Examples A to D, and the resulting data are shown in Table A. Selectivity for tyrosine kinases (e.g., FLT3 and KIT) is desirable. Clinical studies have shown that inhibitors of KIT and FLT3 have myelosuppression, most likely due to the role these kinases play in the hematopoietic system. Both KIT and FLT3 are primarily expressed in hematopoietic stem cells and progenitor cells. Murine genetic models have shown that KIT is essential for hematopoiesis because the survival of hematopoietic stem cells depends on KIT. Similarly, mouse genetic studies have shown that FLT3 knockout mice have insufficient ability to rebuild B cells and T cells. The combined knockout of KIT and FLT3 leads to mouse death. Compared to the comparative examples, the compounds of the present disclosure exhibit greater selectivity for receptor tyrosine kinases (e.g., FLT3 and KIT). Without being bound by theory, it is believed that Comparative Example D will exhibit FLT3 and KIT IC50 similar to Comparative Examples A, B, C, and E.

[0595] Table A

[0596]

[0597] NT means "not tested"

[0598] + refers to IC 50 ≤10nM

[0599] ++ refers to IC 50 >10nM to ≤100nM

[0600] +++ refers to IC 50 >100nM to ≤500nM

[0601] ++++ refers to IC 50 >500nM to ≤1000nM

[0602] +++++ refers to IC 50 >1000nM

[0603] IC 50 ≤25nM

[0604] IC 50 >25nM to ≤250nM

[0605] IC 50 >250nM to ≤1250nM

[0606] IC 50 >1250nM to ≤2500nM

[0607] IC 50 >2500nM

[0608] Refers to selectivity ≤ 500 times

[0609] Refers to a selectivity of >500-fold to ≤1500-fold

[0610] Refers to a selectivity of >1500-fold to ≤1750-fold

[0611] Refers to selectivity >1750-fold to ≤5000-fold

[0612] Refers to selectivity >5000-fold to ≤12500-fold

[0613] Refers to selectivity > 12500 times

[0614] Example E. STAT5 (Tyr694) phosphorylation cell-based assay

[0615] SET-2 cells were purchased from DSMZ (Germany). RPMI1640 medium, fetal bovine serum and 384 white commercial flat-bottom small-volume plates were purchased from Thermo Fisher Scientific (Waltham, MA). Phospho-STAT5 (Tyr694) HTRF kit was purchased from Perkin Elmer (Waltham, MA).

[0616] SET-2 cells were cultured in RPMI medium containing 20% ​​FBS in an atmosphere supplied with 5% CO.2 The cells were cultured at 37°C in a humidified incubator. On the day of the assay, the cells were centrifuged to remove the culture medium and resuspended in pre-warmed RPMI containing 10% FBS. Test compounds were prepared by serial dilution in DMSO, and 50 nL / well of the test compound was transferred to a 384 white low-volume cell culture plate (Greiner Bio-one) by an ECHO liquid handler (Labcyte). The cells were then plated with a Multidrop (Thermo Fisher, Waltham, MA) at 10 μL / well (7×10 6 Cells were distributed in 5% DMSO (100 cells / mL) and 0.5% DMSO was added to the final assay. The treated cells were incubated at 37°C / 5% CO 2 After incubation in an incubator for 2 hours, 4 μL / well of supplemented lysis buffer (100X blocking buffer diluted 25-fold in 4X lysis buffer, Perkin Elmer) was added and incubated at room temperature for 90 min on an orbital shaker at 600 rpm. Phospho-STAT5 cryptate antibody and phospho-STAT5 d2 antibody (1:1 volume / volume) were premixed and diluted 20-fold in detection buffer (Perkin Elmer). 4 μL of premixed antibody solution was added to each well, followed by incubation at room temperature for 24 hours at 600 rpm on an orbital shaker. Product activity was determined by measuring fluorescence at 620 nm and 665 nm on a Pherastar microplate reader (BMG Labtech). The ratio (665 / 620) of each well was calculated. Wells containing only DMSO were used as positive controls, and wells containing high concentrations of control compounds were used as negative controls. IC was implemented by fitting a curve of control activity percentage to the logarithm of compound concentration using GraphPad Prism 7.0 software 50 Determination.

[0617] Example F. pSTAT5 SET-2 Whole Blood MSD Assay

[0618] SET-2 cells were shipped from ABS, RPMI1640 medium, fetal bovine serum were from Gibco, phospho-STAT5a,b whole cell lysate kit was from Mesoscale, Retronectin (recombinant human fibronectin fragment) was from TaKaRa, 96-well flat-bottom cell culture plates were from Corning, lysis buffer was from Cell Signaling Technology, and sterile PBS was from Gibco. Whole blood was from BioIVT.

[0619] SET-2 cells were cultured in RPMI medium containing 20% ​​FBS in an atmosphere supplied with 5% CO. 2On the day of the assay, 40 uL / well of the diluted retronectin working solution was added to a sterile 96-well clear flat-bottom tissue culture plate (retronectin diluted 1:200 in sterile PBS) and incubated at 37C for 1 hour. After 1 hour, the retronectin working solution was aspirated and SET-2 cells were seeded at 100,000 / well in RPMI + 20% FBS. The cells were incubated at 37°C and 5% CO 2 The next day, the culture medium was removed and 40 μL of diluted compound in serum-free RPMI and whole blood was added to the cells and incubated at 37°C and 5% CO. 2 40 μ L 3X complete lysis buffer and vibrate at room temperature for 45-60 minutes to dissolve the cells (complete lysis buffer is composed of the Cell Signaling Technology lysis buffer diluted to 3X and supplemented with Mesoscale's protease inhibitors, phosphatase I inhibitors and phosphatase II inhibitors). The pSTAT5MSD plates are sealed by adding 150 μ L blocking agent A solutions to each well in the MSD plates, and incubated at room temperature for 1 hour or longer with 400 rpm vibrations. After sealing, the plates are washed 3 times with the 1X Tris washing buffer of 300 μ L / holes. After dissolution, 25 μ L / holes are added to the MSD plates to dissolve the samples, and the samples are wrapped in foil and incubated overnight at 4 ° C. The next day, the plates were washed again and 25 μL / well of the diluted 1X detection antibody solution, wrapped in foil, and incubated at room temperature for 1 hour with shaking at 400 rpm. The plates were then washed again and finally 150 μL / well of 1X Read Buffer T was added to all wells. The plates were analyzed on the MSD Discovery within 5 minutes. The inhibitory concentration (IC) for 50% inhibition of the control was 50 ) Inhibition of pSTAT5 signaling was calculated. Data analysis was performed in GraphPad Prism using a 4-parameter fit and data are reported as mean ± SD.

[0620] Example G. In vitro intrinsic clearance protocol

[0621] For in vitro metabolic stability experiments, the test compounds were incubated with human liver microsomes at 37°C. The incubation mixture contained the 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 was pre-incubated for 2 min at 37°C, and then NADPH was added. The reaction was started after the addition of NADPH, and quenched with ice-cold methanol at 0 min, 10 min, 20 min and 30 min. The terminated 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 Quad6500+ mass spectrometer (from Applied Biosystems, Foster City, CA). Hypersil Gold C18 columns (50 × 2.1 mm, 5 μM, Chromatographic separation of test compounds and internal standards was achieved with 5% HPLC-MS / MS (ThermoFisher Scientific, Waltham, MA). Mobile phase A consisted of water containing 0.1% formic acid, and mobile phase B consisted of acetonitrile containing 0.1% formic acid. The total LC-MS / MS run time was 2.75 minutes with 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.

[0622] Intrinsic clearance CL 固有，体外 The t disappeared by the test compound 1 / 2 Calculated as CL 固有，体外 =(0.693 / t 1 / 2 )×(1 / C 蛋白质 ), where C 蛋白质 is the protein concentration during the incubation period, and t 1 / 2 Determined by the slope (k) of the log-linear regression analysis of the concentration versus time profile; therefore, t 1 / 2 = ln2 / k. By using the physiologically based conversion factor, liver microsomal protein concentration (45 mg protein / g liver) and liver weight (21 g / kg body weight), CL 固有，体外 The values ​​were converted to human in vivo values. Using the equation CL 固有 =CL 固有，体外 × (mg protein / g liver weight) × (g liver weight / kg body weight). Then, in a well-stirred liver model, by using CL 固有and liver blood flow Q (20 mL min in humans -1 kg -1 ) does not consider all combinations according to CL H =(Q × CL 固有 ) / (Q+CL 固有 ) to calculate the in vivo hepatic clearance (CL H ). The liver extraction rate was calculated as CL H Divide by Q.

[0623] Example H. In vivo pharmacokinetics

[0624] 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 via IV bolus in rats or via 10 min IV infusion in monkeys using a formulation of 10% dimethylacetamide (DMAC), 10% propylene glycol (PG) in acidified saline. For oral (PO) administration, test compounds were administered at 3.0 mg / kg using 5% DMAC in 0.5% methylcellulose in citrate buffer (pH approximately 2.5). Blood samples were collected at various time points before and after dosing up to 24 hours. 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 methods. The concentrations of the test compounds were determined using WinNonlin software program (version 8.0, Pharsight Corporation) or similar software, using the measured plasma concentrations to calculate PK parameters by standard non-compartmental methods. In rats and monkeys, cassette dosing of the test compound is performed to obtain preliminary PK parameters. In vivo pharmacokinetic experiments in male beagle dogs can be implemented under the conditions described above.

[0625] The compounds of the present disclosure and comparative examples were tested in one or more of the assays described in Examples E to H, and the resulting data are shown in Table B. The compounds of the present disclosure exhibited improved intrinsic clearance and oral exposure in cynomolgus monkeys. Without being bound by theory, it is believed that Comparative Examples C to D will exhibit IC values ​​comparable to those measured for Comparative Examples A, B, and E. 50 Similar SET2 whole blood (WB) IC 50 Values ​​and rat AUC values, and Comparative Examples C to E will exhibit similar cynomolgus monkey AUC values ​​as Comparative Examples A to B (eg, see intrinsic clearance values).

[0626] Table B

[0627]

[0628]

[0629] NT means "not tested"

[0630] IC 50 ≤300nM

[0631] IC 50 >300nM to ≤800nM

[0632] IC 50 >800nM

[0633] IC 50 ≤2500nM

[0634] IC 50 >2500nM to ≤5000nM

[0635] IC 50 >5000nM to ≤7500nM

[0636] IC 50 >7500nM

[0637] Refers to h-IntCL < 0.7 L / h / kg

[0638] Refers to h-IntCL ≥ 0.7 L / h / kg to ≤ 1 L / h / kg

[0639] It means h-IntCL>1L / h / kg

[0640] AUC≤500nM*h

[0641] Refers to AUC>500nM*h to ≤1500nM*h

[0642] AUC>1500nM*h

[0643] Example I. TRKA Enzymatic Assay

[0644] In assay buffer (HEPES 50 mM, pH 7.0, NaN 30.02%, BSA 0.01%, orthovanadate 0.1mM, DTT 1mM, MgCl 2 10mM) in a final volume of 10 μL at 24°C. The test compounds were prepared by serial dilution in DMSO and transferred to the wells containing 0.5% DMSO in the final assay by an ECHO liquid handler (Labcyte). The TRKA / TK substrate-biotin mixture was prepared in an assay buffer containing 1000nM TK substrate-biotin and 125nM SEB reagent. 5μL of the mixture was added to a polystyrene 384-well small volume black plate (Greiner Bio-One). The reaction was started by adding 5μL ATP in the assay buffer. The final 10μL kinase reaction consisted of 0.58nM TRKA, 1mM ATP, 500nM TK substrate-biotin and 62.5nM SEB reagent in the assay buffer. The reaction was incubated for 90min and terminated by adding 10μL detection reagent, which contained 125 nM streptavidin-XL665, TK antibody-cryptate in detection buffer (HEPES 50 mM, pH 7.0, BSA 0.1%, KF 0.8 M, EDTA 20 mM). After incubation for 60 min 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) was calculated for each well. Wells containing only DMSO were used as positive controls, and wells without ATP were used as negative controls. IC was performed by fitting a curve of percent control activity versus logarithm of compound concentration using Gene data. 50 Determination.

[0645] Table C

[0646]

[0647]

[0648] NT means "not tested"

[0649] + refers to IC 50 ≤10nM

[0650] ++ refers to IC 50 >10nM to ≤100nM

[0651] +++ refers to IC 50 >100nM to ≤500nM

[0652] ++++ refers to IC 50>500nM to ≤1000nM

[0653] +++++ refers to IC 50 >1000nM

[0654] IC 50 ≤25nM

[0655] IC 50 >25nM to ≤250nM

[0656] IC 50 >250nM to ≤1250nM

[0657] IC 50 >1250nM to ≤2500nM

[0658] IC 50 >2500nM

[0659] Refers to selectivity ≤ 500 times

[0660] Refers to a selectivity of >500-fold to ≤1500-fold Refers to a selectivity of >1500-fold to ≤1750-fold

[0661] Refers to selectivity >1750-fold to ≤5000-fold

[0662] Refers to selectivity >5000-fold to ≤12500-fold

[0663] Refers to selectivity > 12500 times

[0664] According to the foregoing description, various modifications of the present invention other than those modifications set forth herein will also be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications and disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from phenyl, indazolyl and dihydroisobenzofuranyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl; R 2 C 1-6 Alkyl or C 1-6 Haloalkyl; R 3 Selected from halogen, C 1-6 Alkyl and C 1-6 alkoxy; and R 4 C 1-6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from phenyl, indazolyl and dihydroisobenzofuranyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl; R 2 C 1-6 Alkyl or C 1-6 Haloalkyl; R 3 Selected from halogen, C 1-6 Alkyl and C 1-6 alkoxy; and R 4 C 1-6 alkyl.

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

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is dihydroisobenzofuranyl substituted by 1, 2 or 3 methyl substituents.

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

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

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from phenyl, fluorophenyl, trideuteromethoxyphenyl, (hydroxyisopropyl)phenyl, fluoromethoxyphenyl, dimethyldihydroisobenzofuranyl, isopropylindazolyl, (fluoro)(trideuteromethyl)indazolyl and difluoroethylindazolyl.

8. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from phenyl and indazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from fluoro, trideuteratedmethyl and methoxy.

9. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from phenyl, fluorophenyl, fluoromethoxyphenyl and trideuterated methylindazolyl.

10. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 and 3 to 9, wherein R 2 C 1-3 Alkyl or C 1-3 Halogenated alkyl.

11. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 and 3 to 9, wherein R 2 C 1-3 Halogenated alkyl.

12. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 and 3 to 9, wherein R 2 It is difluoroethyl.

13. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 and 3 to 9, wherein R 2 Selected from methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl and heptadeuteroisopropyl.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 2 C 1-3 alkyl.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 2 Selected from methyl, ethyl, trideuteromethyl, pentadeuteroethyl and heptadeuteroisopropyl.

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 2 It is methyl.

17. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9, wherein R 2 It is a trideuterated methyl group.

18. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 3 C 1-6 Alkoxy or halo.

19. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 3 C 1-6 Alkoxy.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein R 3 It is a methoxy group.

21. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 3 It is a halogen group.

22. A compound as claimed in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 3 For fluorine.

23. A compound as described in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 4 C 1-3 alkyl.

24. A compound as described in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 4 It is methyl.

25. A compound as described in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a trideuterated methyl group.

26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from phenyl, indazolyl and dihydroisobenzofuranyl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Hydroxyalkyl; R 2 C 1-3 Alkyl or C 1-3 Haloalkyl; R 3 Selected from halogen, C 1-3 Alkyl and C 1-3 alkoxy; and R 4 C 1-3 alkyl.

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: 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; R 2 is selected from the group consisting of methyl, ethyl, trideuteromethyl, difluoroethyl, pentadeuteroethyl and heptadeuteroisopropyl; R 3 is methoxy or fluoro; and R 4 It is methyl or trideuterated methyl.

28. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from phenyl and indazolyl, each of which is optionally substituted by 1 or 2 independently selected from halo, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups; R 2 C 1-3 alkyl; R 3 Selected from halogen, C 1-3 Alkyl and C 1-3 alkoxy; and R 4 C 1-3 alkyl.

29. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from phenyl and indazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from fluoro, trideuteratedmethyl and methoxy; R 2 is methyl or trideuterated methyl; R 3 is methoxy or fluoro; and R 4 It is methyl or trideuterated methyl.

30. The compound of any one of claims 1 to 29, wherein the compound of formula I is a compound of formula Ia: or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1 or 2, wherein the compound of formula I is a compound of formula II: or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 1, 2 and 30, wherein the compound of formula I is a compound of formula IIa: or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1 or 2, wherein the compound of formula I is a compound of formula III: or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1, 2 and 30, wherein the compound of formula I is a compound of formula IIIa: or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1 or 2, wherein the compound of formula I is a compound of formula IV: or a pharmaceutically acceptable salt thereof.

36. The compound of any one of claims 1, 2 and 30, wherein the compound of formula I is a compound of formula IVa: or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1, wherein the compound of formula I is a compound of formula V: or a pharmaceutically acceptable salt thereof, wherein each R 1A independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl.

38. The compound of claim 1 or 30, wherein the compound of formula I is a compound of formula Va: or a pharmaceutically acceptable salt thereof, wherein each R 1A independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Hydroxyalkyl.

39. The compound of claim 1, wherein the compound of formula I is a compound of formula Vb: or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1 or 30, wherein the compound of formula I is a compound of formula Vc: or a pharmaceutically acceptable salt thereof.

41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein the compound comprises at least one deuterium atom.

42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein the compound comprises two or more deuterium atoms.

43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein the compound comprises three or more deuterium atoms.

44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein the compound comprises three to nine deuterium atoms.

45. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 40, wherein all hydrogen atoms in the compound are replaced by deuterium atoms.

46. ​​The compound of claim 1 or 2, wherein the compound is selected from: 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 pharmaceutically acceptable salt thereof.

47. The compound of claim 1 or 2, selected from: 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 pharmaceutically acceptable salt thereof.

48. The compound of claim 1, selected from the group consisting of: 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; ((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)carbamic acid methyl ester; 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 pharmaceutically acceptable salt thereof.

49. A compound, which 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 pharmaceutically acceptable salt thereof.

50. A compound, which 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 pharmaceutically acceptable salt thereof.

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

52. A method of inhibiting the activity of the V617F variant of JAK2 kinase, the method comprising contacting the kinase with a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof.

53. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof.

54. The method of claim 53, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, stomach 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.

55. The method of claim 53, wherein the cancer is a blood cancer.

56. The method of claim 53, wherein the cancer is selected from the group consisting of 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's lymphoma or non-Hodgkin's lymphoma, myeloproliferative neoplasm, myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

57. A method of treating a myeloproliferative disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof.

58. The method of claim 57, wherein the myeloproliferative disorder is selected from the group consisting of polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, primary myelofibrosis, post-essential thrombocythemia myelofibrosis, post-polycythemia vera myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, and systemic mast cell disease.

59. A method of treating myelodysplastic syndrome in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof.

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