Inhibitors of MYST family lysine acetyltransferase

Abstract

Provided herein are compounds of Formula (I). Processes for the preparation of the compounds of formula (I) and intermediates useful in the preparation of the compounds of formula (I) are described herein. The compounds of formula (I) are useful as inhibitors of MYST family lysine acetyltransferase (KAT) for the treatment and / or prevention of hyperproliferative diseases, disorders or conditions such as cancer. In particular, the compounds of formula (I) can be used to inhibit KAT6A and KAT6B, which are enzymes that are frequently mutated, overexpressed, amplified and / or translocated in cancer, thereby altering their normal expression, activity and function. Further set forth is the use of the compounds of formula (I) in the manufacture of pharmaceutical compositions or for the treatment of cancer, including in combination with other anti-cancer agents for the treatment of cancer. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 324,619 filed on March 28, 2022, U.S. Provisional Patent Application No. 63 / 324,624 filed on March 28, 2022, and U.S. Provisional Patent Application No. 63 / 476,826 filed on December 22, 2022. The disclosure of each of the above-mentioned applications is incorporated herein by reference in its entirety. Technical Field

[0003] Provided herein are compounds of formula (I). Methods for preparing the compounds of formula (I) and intermediates that can be used to prepare the compounds of formula (I) are described herein. The compounds of formula (I) can be used as inhibitors of MYST family lysine acetyltransferases (KAT) for treating and / or preventing hyperproliferative diseases, disorders or conditions such as cancer. In particular, the compounds of formula (I) can be used to inhibit KAT6A and KAT6B, which are enzymes that frequently mutate, overexpress, amplify and / or translocate in cancer, thereby changing their normal expression, activity and function. Further described are the uses of the compounds of formula (I) in the manufacture of pharmaceutical compositions or for the treatment of cancer, including in combination with other anticancer agents for the treatment of cancer. Background Art

[0004] Epigenetic regulation is a complex dynamic process, which is essential to the control of cell physiology and gene expression, cell cycle progression, cell proliferation rate and stem cell maintenance and differentiation (Allis and Jenuwein, Nature Reviews Genetics 2016, Vol. 17, pp. 487-500). Lysine acetyltransferase (KAT) and histone deacetylase (HDAC) play a key role in epigenetic regulation. KAT is a multi-family enzyme of acetylated histones and non-histone proteins. Histone is the key component of chromatin-DNA complex and its acetylation state is essential to its function (Vernarecci et al., Epigentics 2009, Vol. 5, pp. 105-111). KAT catalyzes the post-translational modification of histones via the epsilon amino group of lysine on acetylated histones. This acetylation gives the conformation of chromatin opening and usually promotes gene transcription.

[0005] A key family of KAT enzymes is called the MYST family. This family consists of five members, including KAT6A (also known as MOZ or MYST3), KAT6B (also known as MORF or MYST4), KAT5 (also known as Tip60), KAT7 (also known as HBO1 or MYST2) and Kat8 (also known as MOF or MYST1) (Wiesel-Motiuk and Assaraf, Drug Resistance Updates 2020, Vol. 53, 100729; Wapenaar and Dekker, Clinical Epigenetics 2016, 8: 59, 1 (DOI10.1186 / s13148-016-0225-2), "Wapenaar et al., 2016"). MYST family KAT is particularly important in the regulation of the cell cycle (Carrozza et al., Trends in Genetics 2003, Vol. 19, pp. 321-329).

[0006] Dysregulation of KAT6 protein expression supports tumor progression (Trisciuoglio et al., Emerging role of histone acetyltransferase in stem cells and Cancer. Stem Cells Int. Vol. 2018, Article ID 8908751 (https: / / doi.org / 10.1155 / 2018 / 8908751). Dysregulation through gene amplification, overexpression or mutation of KAT6A has been described in a variety of cancer types, including breast cancer, lung adenocarcinoma, ovarian cancer, colon and rectal adenocarcinoma, and cervical cancer (Huang et al., Molecular and Cellular Biology 2016, Vol. 63, pp. 1900-1907; Zack et al., Nature Genetics 2016, Vol. 63, pp. 1900-1907). 2013, Vol. 45, pp. 1134-1140). The locus containing the KAT6A gene (8p11-p12 amplicon) is reported to be the 12th most frequently amplified region of the genome in all cancer types (Zack et al., 2013). In acute myeloid leukemia (AML), recurrent oncogenic fusions of KAT6A have been documented to drive transformation to a malignant state (Sheikh et al., Blood 2015, Vol. 125, pp. 1910-1921). Translocations of KAT6A and fusions with partners such as CBP, p300, TIF2, and NCOA3 are known to lead to aggressive forms of AML (Sheikh et al., 2015).

[0007] The key aspect of the catalytic mechanism of KAT family enzymes is to use cofactor Ac-CoA as an acetyl donor to acetylate lysine residues. A possible catalytic mechanism is to gradually transfer acetyl from acetyl coenzyme A (Ac-CoA) to form an acetyl-enzyme intermediate instantaneously. This acetyl-enzyme intermediate is then transferred to the source of the acetyl group of the substrate (usually lysine on histones) (Wapenaar et al., 2016). In MYST family KAT, there is a conserved cysteine, which is instantaneously acylated as a part of the catalytic cycle, as indicated by the arrow below.

[0008] Amino acid sequence alignment near the Ac-CoA binding site of MYST family KATs

[0009]

[0010] In one embodiment, the present disclosure provides compounds that can covalently bind to this conserved cysteine.

[0011] Enzyme inhibitors that covalently interact with conserved cysteines at or near the active site of the enzyme are an important therapeutic modality. Therapeutic agents that covalently and specifically react with active site cysteines to form covalent adducts offer potential advantages in terms of efficacy, possible lower doses, and increased duration of target engagement, thereby reducing dosing frequency.

[0012] In addition to the role of KAT in epigenetic regulation, KAT also acetylates non-histone proteins (Glozak et al., 2005; Das and Kundu, 2008). By modifying the acetylation state of non-histone proteins, KAT is involved in regulating protein function and stability, protein-protein interaction and protein-DNA interaction, and regulating enzyme activity (Glozak et al., Gene 2005, Vol. 363, pp. 15-23; Das and Kundu, IUBMB Life 2005, Vol. 57, pp. 137-148).

[0013] Provided herein are compounds of formula (I) that can inhibit MYST family lysine acetyltransferases. The compounds described in this disclosure inhibit MYST family members, including KAT6A. In some embodiments, inhibition is carried out via covalent modification of the cysteine ​​residues at the Ac-CoA binding site. The compounds described herein can be used to treat cancer, including breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, uterine / cervical cancer and leukemia. The compounds of formula I can be used as a single agent or in combination with standard care treatments for specific cancers. Summary of the invention

[0014] Provided herein are compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions to treat conditions, diseases, or disorders, including hyperproliferative disorders and cancer, by inhibiting MYST family lysine acetyltransferases, including KAT6A and KAT6B.

[0015] In one aspect, a compound of formula (I) is provided:

[0016]

[0017] Where R 1 is optionally replaced by 1, 2 or 3 R 1a Substituted C 3 -C 8 Cycloalkyl; C 3 -C 8 Cycloalkyl-C 1 -C 6 Alkyl, wherein the C 3 -C 8 The cycloalkyl group is optionally substituted by 1, 2 or 3 R 1a substituted; optionally substituted by 1, 2 or 3 R 1b substituted phenyl; optionally substituted by 1, 2 or 3 R 1b Substituted phenyl-C 1 -C 6 Alkyl; optionally substituted by 1, 2 or 3 R 1b or optionally substituted with 1, 2 or 3 R 1b substituted 5-membered or 6-membered monocyclic heteroaryl; optionally substituted by 1, 2 or 3 R 1b substituted 8- to 10-membered bicyclic heteroaryl;

[0018] Each R 1a are independently selected from hydrogen, halogen, C 1 -C 6 Alkoxy and C 3 -C 8 Cycloalkyloxy;

[0019] Each R 1b are independently selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, hydroxyalkyloxy, -O-alkylene-NR 1b1 R 1b4 、-O-alkylene-C(O)OR 1b1 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , Cyano, -(CH2 ) 0-2 C(O)-OR 1b1 、-(CH 2 ) 0-2 C(O)NR 1b1 R 1b2 、-(CH 2 ) 0-2 NR 1b1 C(O)R 1b3 、-(CH 2 ) 0-2 OH and C 3 -C 8 Cycloalkyloxy;

[0020] R 1b1 is hydrogen or C 1 -C 6 Alkyl; R 1b2 is hydrogen or C 1 -C 6 Alkyl; R 1b3 is hydrogen or C 1 -C 6 alkyl; and R 1b4 It is hydrogen,

[0021] R 2 Selected from the group consisting of:

[0022]

[0023] R 2a is hydrogen or C 1 -C 6 alkyl;

[0024] Each R 2b are independently hydrogen, halogen, -(CH 2 ) 0-2 OH, C 1 -C 3 Alkyl, cyclopropyl, cyano, -CHF 2 , -CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 、-OCF 3 or C 3 -C 8 Cycloalkyloxy;

[0025] Each R 2e are independently hydrogen, -OH, halogen, C 1 -C 6 Alkyl, halo-C 1 -C6 Alkyl, C 3 -C 8 Cycloalkyl, C 1 -C 6 Alkoxy, halo-C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyloxy;

[0026] yes

[0027] Among them, for rings (a), (b) and (c)

[0028] One X 1 Yes CR 3 And other X 1 Independently selected from N and CR 2b ;

[0029] R 2d is hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyloxy;

[0030] R 3 Yes-(CH 2 ) 0-2 Y or -(CH 2 ) 0-2 -LY;

[0031] L is -L 1 -L 2 -L 3 -, where L 1 , L 2 and L 3 are each independently a bond, -CRR-, O, S(O) 0-2 , C(O) or NR, wherein each R is independently H or alkyl;

[0032] Y is R Y substituted and optionally by R 2e substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 6-membered monocyclic aromatic or heteroaromatic group; Y is replaced by R Y and optionally substituted with 1 or 2 R 2esubstituted 8-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1, 2 or 3 R 2e substituted 9-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1, 2 or 3 R 2e substituted 10-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 8-membered or 9-membered bicyclic heterocyclic ring; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl; Y is Y is -(CH 2 ) 0-3 NR 3b R Y ; or Y is -(CH 2 ) 0-3 NR 3b C(O)R Y ;

[0033] R Y Yes-(CH 2 ) 0-3 NR 3b C(O)R 3a 、-(CH 2 ) 0-2 NR 3b S(O) 2 R 3a 、-C(O)R 3a 、-S(O) 2 R 3a 、-C(O)NR 3b R 3a , by -C(O)R 3a Substituted C 3 -C 8 Heterocycloalkyl; -(CH 2 ) 0-3 NR 3b (C 1 -C 6 Alkylene)NR 3b1 C(O)R 3a 、-(CH 2 ) 0-3 NR 3b (C 1 -C 6 Alkylene)NR 3b1 S(O) 2 R 3a 、-(CH 2 ) 0-3 NR3b C(O)(C 1 -C 6 Alkylene)NR 3b1 C(O)R 3a or -(CH 2 ) 0-3 NR 3b C(O)(C 1 -C 6 Alkylene)NR 3b1 S(O) 2 R 3a ,

[0034] R 3a , R 3b and R 3b1 Selected from (i), (ii) or (iii):

[0035] (i)R 3a , R 3b and R 3b1 One of them is selected from group a): C substituted by 1 or 2 independently selected halogen groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C substituted by fluoroalkoxy 1 -C 6 Alkyl; C substituted by aryloxy or heteroaryloxy 1 -C 6 alkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 3c R 3d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6Alkynyl; -CH≡CH-CH 2 -NR 3c R 3d ; CH≡CH-CH 2 -OH; -CH≡CH-CH 2 -OC 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; chloropyridinyl; fluoropyridinyl; chloropyrazinyl; fluoropyrazinyl; chloropyrimidinyl; fluoropyrimidinyl; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl, difluorophenyl; and monofluorophenyl; and R 3a , R 3b and R 3b1 The others are selected from the group b): hydrogen and C 1 -C 6 Alkyl; or

[0036] (ii) R 3a , R 3b and R 3b1 One of them is selected from the group a): hydrogen; C 1 -C 6 Alkyl; C substituted by aryloxy or heteroaryloxy 1 -C 6 Alkyl, each of which is optionally substituted by 1-3 substituents each independently selected from the following: 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl; C 2 -C 6 Alkenyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 alkynyl; spirocycloalkyl; pyridinyl; pyrimidinyl; and phenyl; and R 3a , R 3b and R 3b1 The others are selected from the group b): hydrogen and C 1 -C 6 Alkyl; or

[0037] (iii) R 3a , R 3b and R 3b1 are independently hydrogen or C 1 -C 6 alkyl;

[0038] R 3c is hydrogen or C 1-C 6 Alkyl, and R 3d is hydrogen or C 1 -C 6 Alkyl; or R 3c and R 3d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring wherein the other 2-7 ring members are carbon; and

[0039] Het1 is C 3 -C 8 Heterocycloalkyl;

[0040] Among them, for ring (d),

[0041] X 2a is O or S;

[0042] One X 2 Yes CR 4 And other X 2 Independently selected from N and CR 2b ;

[0043] R 4 Yes-(CH 2 ) 0-3 NR 4b C(O)R 4a 、-(CH 2 ) 0-2 NR 4b S(O) 2 R 4a 、-C(O)R 4a 、-C(O)NR 4b R 4a 、-NR 4b (C 1 -C 6 Alkylene)NR 4b1 C(O)R 4a 、-(CH 2 ) 0-3 NR 4b C(O)(C 1 -C 6 Alkylene)NR 4b1 C(O)R 4a 、-C(O)NR 4b (C 1 -C 6 Alkylene)NR 4b1 C(O)R 4a 、-C(O)-HET1-C(O)R 4a 、-C(O)-HET1-NR 4b C(O)R 4a 、-(CH 2 )0-3 NR 4b C(O)-HET1-C(O)R 4a , by -C(O)R 4a Substituted C 3 -C 8 Heterocycloalkyl (preferably, wherein the C 3 -C 8 Heterocycloalkyl via C 3 -C 8 A carbon in the heterocycloalkyl ring is attached to ring (d)); or -(CH 2 ) 0-2 HET2-C(O)R 4a ;

[0044] R 4a , R 4b and R 4b1 Selected from (i), (ii) and (iii):

[0045] (i)R 4a , R 4b and R 4b1 One of them is selected from the group a): alkyl substituted by 1 or 2 independently selected halo groups; C substituted by cyano groups 1 -C 6 Alkyl; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 4c R 4d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 4c R 4d ; CH≡CH-CH 2 -OH; CH≡CH-CH 2 -OC 1 -C 6alkyl; spirocycloalkyl substituted with cyano; chloropyridinyl, fluoropyridinyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and R 4a , R 4b and R 4b1 The others are selected from the group b): hydrogen and C 1 -C 6 alkyl;

[0046] (ii) R 4a , R 4b and R 4b1 One of them is selected from the group a): hydrogen; alkyl; C 2 -C 6 Alkenyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 alkynyl; spirocycloalkyl; pyridinyl; pyrazinyl; pyrimidinyl; and phenyl; and R 4a , R 4b and R 4b1 The others are selected from the group b): hydrogen and C 1 -C 6 Alkyl; or

[0047] (iii) R 4a , R 4b and R 4b1 are independently hydrogen or C 1 -C 6 alkyl;

[0048] R 4c is hydrogen or C 1 -C 6 Alkyl, and R 4d is hydrogen or C 1 -C 6 Alkyl; or R 4c and R 4d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon;

[0049] Het1 is C 3 -C 8 heterocycloalkyl; and

[0050] HET2 is optionally replaced by 1 or 2 R 2e substituted 8-, 9- or 10-membered bicyclic heterocycle;

[0051] Among them, for rings (e) and (f),

[0052] R 5 is substituted by Z and optionally by R 2e Substituted 5-membered monocyclic heteroaryl; R 5 is substituted by Z and optionally by R 2e Substituted 6-membered monocyclic heteroaryl; R 5 Yes-C(O)N(R 5b )Z; R 5 is substituted by Z and optionally by R 2e Substituted heterocycloalkyl; R 5 Yes-(CH 2 ) 0-2 O-HET1-Z;

[0053] R 5 Yes-(CH 2 ) 0-2 OZ;

[0054] Z is -(CH 2 ) 0-3 NR 5b C(O)R 5a 、-(CH 2 ) 0-2 NR 5b S(O) 2 R 5a 、-C(O)R 5a 、-S(O) 2 R 5a 、-(CH 2 ) 0-3 -C(O)NR 5b R 5a 、-(CH 2 ) 0-3 NR 5b (C 1 -C 6 Alkylene)NR 5b1 C(O)R 5a 、Be-NR 5b C(O)R 5a Substituted C 3 -C 8 Heterocycloalkyl, -S(O) 2 R 5a Substituted C 3 -C 8 Heterocycloalkyl, or -C(O)R 5a Substituted C 3 -C 8 Heterocycloalkyl;

[0055] R 5a , R 5b and R 5b1Selected from (i), (ii) or (iii):

[0056] (i)R 5a , R 5b and R 5b1 One of them is selected from group a): C substituted by 1 or 2 independently selected halogen groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 5c R 5d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 5c R 5d ; CH≡CH-CH 2 -OH; CH≡CH-CH 2 -OC 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; chloropyridinyl, fluoropyridinyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl, and R 5a , R 5b and R 5b1 The others are selected from the group b): hydrogen and C 1 -C 6 alkyl;

[0057] (ii) R 5a , R 5b and R 5b1 One of them is selected from the group a): hydrogen; C 1 -C 6 Alkyl; C 2 -C 6 Alkenyl; C 3 -C 8 Cycloalkenyl; -C(O)-C3 -C 8 Cycloalkyl; C 2 -C 6 alkynyl; spirocycloalkyl; pyridinyl; pyrazinyl; pyrimidinyl; and phenyl; and R 5a , R 5b and R 5b1 The others are selected from the group b): hydrogen and C 1 -C 6 Alkyl; or

[0058] (iii) R 5a , R 5b and R 5b1 are independently hydrogen or C 1 -C 6 alkyl;

[0059] Each R 5c are independently hydrogen or C 1 -C 6 Alkyl and R 5d is hydrogen or C 1 -C 6 Alkyl; or R 5c and R 5d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon;

[0060] Het1 is C 3 -C 8 Heterocycloalkyl;

[0061] Among them, for ring (g),

[0062] Q 1 Yes CR Q1 , Q 2 is N, and Q 3 is O; or Q 1 Yes CR Q1 , Q 2 is O, and Q 3 is N; or Q 1 Yes S, Q 2 is N, and Q 3 is N; or Q 1 Yes N, Q 2 is N, and Q 3 is O; or Q 1 It's O, Q 2 is N, and Q 3 is N; where R Q1 is hydrogen, C(O)C 1 -C 6 Alkyl or Cl;

[0063] R6 is substituted by Q and optionally by R 2e substituted 5-membered or 6-membered monocyclic heteroaryl; or R 6 It is Q;

[0064] Q is -(CH 2 ) 0-3 NR 6b C(O)R 6a 、-(CH 2 ) 0-2 NR 6b S(O) 2 R 6a 、-C(O)R 6a 、-C(O)NR 6b R 6a , or -C(O)R 6a Substituted C 3 -C 8 Heterocycloalkyl;

[0065] R 6a and R 6b Selected from (i), (ii) or (iii):

[0066] (i)R 6a and R 6b One of them is selected from group a): C substituted by 1 or 2 independently selected halogen groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 6c R 6d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)cycloalkyl; Alkynyl; -CH≡CH-CH 2 -NR 6c R 6d ; CH≡CH-CH 2 -OH; CH≡CH-CH 2 -OC 1 -C 6alkyl; spirocycloalkyl substituted with cyano; chloropyridinyl, fluoropyridinyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and R 6a and R 6b The other one of the following is selected from the group b): hydrogen and C 1 -C 6 alkyl;

[0067] (ii) R 6a and R 6b One of which is selected from the group a): C 1 -C 6 Alkyl; C 2 -C 6 Alkenyl; C 3 -C 8 cycloalkenyl; -C(O)cycloalkyl; alkynyl; spirocycloalkyl; pyridinyl; pyrazinyl; pyrimidinyl; and phenyl; and R 6a and R 6b The other one of the following is selected from the group b): hydrogen and C 1 -C 6 Alkyl; or

[0068] (iii) R 6a and R 6b are independently hydrogen and C 1 -C 6 alkyl;

[0069] R 6c is hydrogen or C 1 -C 6 Alkyl and R 6d is hydrogen or C 1 -C 6 Alkyl; or R 6c and R 6d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring wherein the other 2-7 ring members are carbon; and

[0070] Each R 7 are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyl;

[0071] or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

[0072] In one aspect, a compound of formula (I) is provided:

[0073]

[0074] Where R 1 is optionally replaced by 1, 2 or 3 R 1a Substituted C 3 -C 8 Cycloalkyl; C 3 -C 8 Cycloalkyl-C 1 -C 6 Alkyl, wherein the C 3 -C 8 The cycloalkyl group is optionally substituted by 1, 2 or 3 R 1a substituted; optionally substituted by 1, 2 or 3 R 1b substituted phenyl; optionally substituted by 1, 2 or 3 R 1b Substituted phenyl-C 1 -C 6 Alkyl; optionally substituted by 1, 2 or 3 R 1b or optionally substituted with 1, 2 or 3 R 1b substituted 5-membered or 6-membered monocyclic heteroaryl; optionally substituted by 1, 2 or 3 R 1b substituted 8- to 10-membered bicyclic heteroaryl;

[0075] Each R 1a are independently selected from hydrogen, halogen, C 1 -C 6 Alkoxy and C 3 -C 8 Cycloalkyloxy;

[0076] Each R 1b are independently selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, hydroxyalkyloxy, -O-alkylene-NR 1b1 R 1b4 、-O-alkylene-C(O)OR 1b1 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , Cyano, -(CH 2 ) 0-2 C(O)-OR 1b1 、-(CH 2 ) 0-2 C(O)NR 1b1 R 1b2 、-(CH 2 ) 0-2 NR 1b1 C(O)R 1b3、-(CH 2 ) 0-2 OH and C 3 -C 8 Cycloalkyloxy;

[0077] R 1b1 is hydrogen or C 1 -C 6 Alkyl; R 1b2 is hydrogen or C 1 -C 6 Alkyl; R 1b3 is hydrogen or C 1 -C 6 alkyl; and R 1b4 It is hydrogen,

[0078] R 2 Selected from the group consisting of:

[0079]

[0080] R 2a is hydrogen or C 1 -C 6 alkyl;

[0081] Each R 2b are independently hydrogen, halogen, -(CH 2 ) 0-2 OH, C 1 -C 3 Alkyl, cyclopropyl, cyano, -CHF 2 , -CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 、-OCF 3 or C 3 -C 8 Cycloalkyloxy;

[0082] Each R 2e are independently hydrogen, -OH, halogen, C 1 -C 6 Alkyl, halo-C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, C 1 -C 6 Alkoxy, halo-C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyloxy;

[0083] yes

[0084] Among them, for rings (a), (b) and (c)

[0085] One X 1 Yes CR 3 And other X 1 Independently selected from N and CR 2b ;

[0086] R 2d is hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyloxy;

[0087] R 3 Yes-(CH 2 ) 0-2 Y;

[0088] Y is R Y substituted and optionally by R 2e substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 6-membered monocyclic aromatic or heteroaromatic group; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 8-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1, 2 or 3 R 2e substituted 9-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1, 2 or 3 R 2e substituted 10-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 8-membered or 9-membered bicyclic heterocyclic ring; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl; Y is Y is -(CH 2 ) 0-3 NR 3b R Y ; or Y is -(CH 2 ) 0-3 NR 3b C(O)R Y ;

[0089] R Y Yes-(CH 2 ) 0-3 NR 3b C(O)R 3a 、-(CH 2 ) 0-2 NR 3b S(O) 2 R 3a 、-C(O)R 3a 、-S(O) 2 R 3a 、-C(O)NR 3b R 3a , by -C(O)R 3a Substituted C 3 -C 8 Heterocycloalkyl; -(CH 2 ) 0-3 NR 3b (C 1 -C 6 Alkylene)NR 3b1 C(O)R 3a 、-(CH 2 ) 0-3 NR 3b (C 1 -C 6 Alkylene)NR 3b1 S(O) 2 R 3a 、-(CH 2 ) 0-3 NR 3b C(O)(C 1 -C 6 Alkylene)NR 3b1 C(O)R 3a or -(CH 2 ) 0-3 NR 3b C(O)(C 1 -C 6 Alkylene)NR 3b1 S(O) 2 R 3a ,

[0090] R 3a , R 3b and R 3b1 One of them is selected from group a): C substituted by 1 or 2 independently selected halogen groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C substituted by fluoroalkoxy 1 -C6 Alkyl; C substituted by aryloxy or heteroaryloxy 1 -C 6 alkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 3c R 3d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 3c R 3d ; CH≡CH-CH 2 -OH; -CH≡CH-CH 2 -OC 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; chloropyridinyl; fluoropyridinyl; chloropyrazinyl; fluoropyrazinyl; chloropyrimidinyl; fluoropyrimidinyl; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl, difluorophenyl; and monofluorophenyl; and R 3a , R 3b and R 3b1 The others are selected from the group b): hydrogen and C 1 -C 6 alkyl;

[0091] R 3c is hydrogen or C 1 -C 6 Alkyl, and R 3d is hydrogen or C 1 -C 6 Alkyl; or R 3c and R 3d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring wherein the other 2-7 ring members are carbon; and

[0092] Het1 is C 3 -C 8 Heterocycloalkyl;

[0093] Among them, for ring (d),

[0094] X 2a is O or S;

[0095] One X 2 Yes CR 4 And other X 2 Independently selected from N and CR 2b ;

[0096] R 4 Yes-(CH 2 ) 0-3 NR 4b C(O)R 4a 、-(CH 2 ) 0-2 NR 4b S(O) 2 R 4a 、-C(O)R 4a 、-C(O)NR 4b R 4a 、-NR 4b (C 1 -C 6 Alkylene)NR 4b1 C(O)R 4a 、-(CH 2 ) 0-3 NR 4b C(O)(C 1 -C 6 Alkylene)NR 4b1 C(O)R 4a 、-C(O)NR 4b (C 1 -C 6 Alkylene)NR 4b1 C(O)R 4a 、-C(O)-HET1-C(O)R 4a 、-C(O)-HET1-NR 4b C(O)R 4a 、-(CH 2 ) 0-3 NR 4b C(O)-HET1-C(O)R 4a , by -C(O)R 4a Substituted C 3 -C 8 Heterocycloalkyl (preferably, wherein the C 3-C 8 Heterocycloalkyl via C 3 -C 8 A carbon in the heterocycloalkyl ring is attached to ring (d)); or -(CH 2 ) 0-2 HET2-C(O)R 4a ;

[0097] R 4a , R 4b and R 4b1 One of them is selected from the group a): alkyl substituted by 1 or 2 independently selected halo groups; C substituted by cyano groups 1 -C 6 Alkyl; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 4c R 4d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 4c R 4d ; CH≡CH-CH 2 -OH; CH≡CH-CH 2 -OC 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; chloropyridinyl, fluoropyridinyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and

[0098] R 4a , R 4b and R 4b1 The others are selected from the group b): hydrogen and C 1 -C 6 alkyl;

[0099] R 4c is hydrogen or C 1 -C 6 Alkyl, and R 4d is hydrogen or C1 -C 6 Alkyl; or R 4c and R 4d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon;

[0100] Het1 is C 3 -C 8 heterocycloalkyl; and

[0101] HET2 is optionally replaced by 1 or 2 R 2e substituted 8-, 9- or 10-membered bicyclic heterocycle;

[0102] Among them, for rings (e) and (f),

[0103] R 5 is substituted by Z and optionally by R 2e Substituted 5-membered monocyclic heteroaryl; R 5 is substituted by Z and optionally by R 2e Substituted 6-membered monocyclic heteroaryl; R 5 Yes-C(O)N(R 5b )Z; R 5 is substituted by Z and optionally by R 2e Substituted heterocycloalkyl; R 5 Yes-(CH 2 ) 0-2 O-HET1-Z;R 5 Yes-(CH 2 ) 0-2 OZ;

[0104] Z is -(CH 2 ) 0-3 NR 5b C(O)R 5a 、-(CH 2 ) 0-2 NR 5b S(O) 2 R 5a 、-C(O)R 5a 、-S(O) 2 R 5a 、-(CH 2 ) 0-3 -C(O)NR 5b R 5a 、-(CH 2 ) 0-3 NR 5b (C 1 -C 6 Alkylene)NR 5b1 C(O)R 5a 、Be-NR5b C(O)R 5a Substituted C 3 -C 8 Heterocycloalkyl, -S(O) 2 R 5a Substituted C 3 -C 8 Heterocycloalkyl, or -C(O)R 5a Substituted C 3 -C 8 Heterocycloalkyl;

[0105] R 5a , R 5b and R 5b1 One of them is selected from group a): C substituted by 1 or 2 independently selected halogen groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C substituted by cyano 2 -C 6 Alkenyl; C 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 5c R 5d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 5c R 5d ; CH≡CH-CH 2 -OH; CH≡CH-CH 2 -OC 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; chloropyridinyl, fluoropyridinyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl, and

[0106] R 5a , R 5b and R 5b1 The others are selected from the group b): hydrogen and C 1 -C 6 alkyl;

[0107] Each R 5c are independently hydrogen or C 1 -C 6 Alkyl and R 5d is hydrogen or C 1 -C 6 Alkyl; or R 5c and R 5d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon;

[0108] Het1 is C 3 -C 8 Heterocycloalkyl;

[0109] Among them, for ring (g),

[0110] Q 1 Yes CR Q1 , Q 2 is N, and Q 3 is O; or Q 1 Yes CR Q1 , Q 2 is O, and Q 3 is N; or Q 1 Yes S, Q 2 is N, and Q 3 is N; or Q 1 Yes N, Q 2 is N, and Q 3 is O; or Q 1 It's O, Q 2 is N, and Q 3 is N; where R Q1 is hydrogen, C(O)C 1 -C 6 Alkyl or Cl;

[0111] R 6 is substituted by Q and optionally by R 2e substituted 5-membered or 6-membered monocyclic heteroaryl; or R 6 It is Q;

[0112] Q is -(CH 2 ) 0-3 NR 6b C(O)R 6a 、-(CH 2 ) 0-2 NR 6b S(O) 2 R 6a 、-C(O)R 6a 、-C(O)NR 6b R 6a, or -C(O)R 6a Substituted C 3 -C 8 Heterocycloalkyl;

[0113] R 6a and R 6b One of them is selected from group a): C substituted by 1 or 2 independently selected halogen groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 6c R 6d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)cycloalkyl; Alkynyl; -CH≡CH-CH 2 -NR 6c R 6d ; CH≡CH-CH 2 -OH; CH≡CH-CH 2 -OC 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; chloropyridinyl, fluoropyridinyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and

[0114] R 6a and R 6b The other one of the following is selected from the group b): hydrogen and C 1 -C 6 alkyl;

[0115] R 6c is hydrogen or C 1 -C 6 Alkyl and R 6d is hydrogen or C 1 -C 6 Alkyl; or R 6c and R 6d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring wherein the other 2-7 ring members are carbon; and

[0116] Each R7 are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyl;

[0117] or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

[0118] In another aspect, a compound is provided that comprises an alkenyl- or alkynyl-containing electrophilic group that is capable of irreversibly and / or covalently binding to KAT6A or KAT6B. Other electrophilic groups, such as nitriles and halomethyl ketones, are also included.

[0119] In one aspect, a compound of formula (I) is provided:

[0120]

[0121] Where R 1 is optionally replaced by 1, 2 or 3 R 1a Substituted C 3 -C 8 Cycloalkyl; C 3 -C 8 Cycloalkylalkyl, wherein the C 3 -C 8 The cycloalkyl group is optionally substituted by 1, 2 or 3 R 1a substituted; optionally substituted by 1, 2 or 3 R 1b substituted phenyl; optionally substituted by 1, 2 or 3 R 1b substituted naphthyl; optionally substituted by 1, 2 or 3 R 1b substituted 5-membered or 6-membered monocyclic heteroaryl; or optionally substituted by 1, 2 or 3 R 1b substituted 8-10 membered bicyclic heteroaryl;

[0122] Each R 1a are independently selected from H, halo, C 1 -C 6 Alkoxy and C 3 -C 8 Cycloalkyloxy;

[0123] Each R 1b are independently selected from H, halo, C 1 -C 6 Alkoxy, cyano and C 3 -C 8 Cycloalkyloxy;

[0124] R 2Selected from the group consisting of:

[0125]

[0126] Among them, for ring (a),

[0127] R 2b is hydrogen or C 1 -C 6 alkyl;

[0128] One X 1 It is C(CH 2 R 2c ), and the other two X 1 Independently selected from N and CR 2e ;

[0129] R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 6-membered monocyclic heteroaryl; R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 9-membered bicyclic heteroaryl; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 10-membered bicyclic heteroaryl; and

[0130] Each R 2c1 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl, -CN, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyloxy, -(CH 2 ) 0-1 NH 2 、-NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f, a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0131] Among them, for ring (b),

[0132] One X 1 It is C(CH 2 R 2c ), and the other two X 1 Independently selected from N and CR 2e ;

[0133] R 2c Is R 2c2 substituted and optionally by R 2c3 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c Is R 2c2 substituted and optionally by R 2c3 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c Is R 2c2 and optionally substituted with 1 or 2 R 2c3 Substituted 6-membered monocyclic heteroaryl; R 2c Is R 2c2 and optionally substituted with 1 or 2 R 2c3 substituted 9-membered bicyclic heteroaryl; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 10-membered bicyclic heteroaryl;

[0134] R 2c2 It is hydrogen, C 1 -C 6 Alkylcarbonyl, -CN, -CH 2 NH 2 , C 1 -C 6 Alkoxy, -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-CH 2 NHC(O)R 2f 、-(CH2 ) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0135] R 2c3 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 cycloalkyloxy; and

[0136] Each R 2c1 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyloxy, -CN, -CH 2 NH 2 、-NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-CH 2 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0137] Among them, for ring (c),

[0138] One X1 It is C(CH 2 R 2c ), and the other two X 1 Independently selected from N and CR 2e ;

[0139] yes

[0140] R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 6-membered monocyclic heteroaryl; R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 9-membered bicyclic heteroaryl; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 10-membered bicyclic heteroaryl; and

[0141] Each R 2c1 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl, -CN, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyloxy, -CH 2 NH 2 、-NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-CH 2 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0142] R 2d Is a halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 cycloalkyloxy; and

[0143] Each R 2e are independently hydrogen, halogen, C 1 -C 3 Alkyl, cyclopropyl, -CHF 2 , -CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 or -OCF 3 ;

[0144] or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

[0145] In another aspect, the present invention provides R 2 NH 2 (Formula A) compound, wherein

[0146] R 2 Selected from the group consisting of:

[0147]

[0148] Among them, for ring (a),

[0149] R 2b is hydrogen or C 1 -C 6 alkyl;

[0150] One X 1 It is C(CH 2 R 2c ), and the other two X 1 Independently selected from N and CR 2e ;

[0151] R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 6-membered monocyclic heteroaryl; R 2c is optionally replaced by 1, 2 or 3 R2c1 substituted 9-membered bicyclic heteroaryl; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 10-membered bicyclic heteroaryl; and

[0152] Each R 2c1 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl, -CN, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyloxy, -(CH 2 ) 0-1 NH 2 、-NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0153] Among them, for ring (b),

[0154] One X 1 It is C(CH 2 R 2c ), and the other two X 1 Independently selected from N and CR 2e ;

[0155] R 2c Is R 2c2 substituted and optionally by R 2c3 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c Is R 2c2and optionally substituted with 1 or 2 R 2c3 Substituted 6-membered monocyclic heteroaryl; R 2c Is R 2c2 and optionally substituted with 1 or 2 R 2c3 substituted 9-membered bicyclic heteroaryl; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 10-membered bicyclic heteroaryl;

[0156] R 2c2 It is C 1 -C 6 Alkylcarbonyl, -CN, -(CH 2 ) 0-1 NH 2 , C 1 -C 6 Alkoxy, -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0157] R 2c3 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 cycloalkyloxy; and

[0158] Each R 2c1 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl, C 1 -C 6 Alkoxy, C 3 -C8 Cycloalkyloxy, -CN, -(CH 2 ) 0-1 NH 2 、-NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0159] Among them, for ring (c),

[0160] One X 1 It is C(CH 2 R 2c ), and the other two X 1 Independently selected from N and CR 2e ;

[0161] yes

[0162] R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 6-membered monocyclic heteroaryl; R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 9-membered bicyclic heteroaryl; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 10-membered bicyclic heteroaryl; and

[0163] Each R 2c1 are independently H, halo, C 1 -C 6Alkyl, C 1 -C 6 Alkylcarbonyl, -CN, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyloxy, -(CH 2 ) 0-1 NH 2 、-NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0164] R 2d Is a halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 cycloalkyloxy; and

[0165] Each R 2e are independently hydrogen, halogen, C 1 -C 3 Alkyl, Cyclopropyl, CHF 2 CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 or -OCF 3 ;

[0166] or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

[0167] In another aspect, provided herein are pharmaceutical compositions, single unit dosage forms, and kits suitable for treating disorders by inhibiting MYST family lysine acetyltransferases, including KAT6A and KAT6B, comprising a therapeutically effective amount of a compound provided herein (e.g., a compound of some or any embodiments of Formula (A)-7, (Ia-7, (Ib-7, (Ic-8, (Id-1), (Ie-1), (If-1), (Ig-1), (Ih-7, (Ii-1), (Ij-2), (Ia-3), (Ib-3), (Ic-4), (Id-2), (Ie-3), (If-1), or (Ig-3)) and a specific compound and a pharmaceutically acceptable carrier thereof.

[0168] In another aspect, provided herein is a method for treating a condition, disease or disorder by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B, the method comprising a) administering a therapeutically effective amount of a compound provided herein (e.g., a compound of some or any embodiments of Formula (A)-7, (Ia)-8, (Ib)-9, (Ic)-10, (Id)-11, (Ie)-12, (If)-13, (Ig)-14, (Ih)-15, (Ii)-16, (Ij)-17, (Ia-2)-18, (Ic-3)-19, (Id-4)-20, (Ie-5)-21, (Ig-6)-22, (Id-5)-23, (Ie-5)-24, (Ig-6)-25, (Ig-7)-26, (Ig-8)-27, (Ig-9)-28, (Id-1)-29, (Ie-1)-30, (Ig-1)-31, (Ig-1)-32, (Ig-1)-33, (Ig-1)-34, (Ig-1)-35 , a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof, or b) administering a therapeutically effective amount of a composition comprising a compound provided herein (e.g., a compound of some or any embodiments of Formula (A)-7, Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ia-1), Formula (Ib-1), Formula (Ic-2), Formula (Id-1), Formula (Ie-1), Formula (If-1), or Formula (Ig-1)) and a specific compound or a stereoisomer thereof, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

[0169] In another aspect, the present invention provides a method for preparing a compound of formula (I) and a specific compound or a stereoisomer, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof, the method comprising treating

[0170]

[0171] or a salt thereof, wherein

[0172] R 1is optionally replaced by 1, 2 or 3 R 1a Substituted C 3 -C 8 Cycloalkyl; C 3 -C 8 Cycloalkyl-C 1 -C 6 Alkyl, wherein the C 3 -C 8 The cycloalkyl group is optionally substituted by 1, 2 or 3 R 1a substituted; optionally substituted by 1, 2 or 3 R 1b substituted phenyl; optionally substituted by 1, 2 or 3 R 1b or optionally substituted with 1, 2 or 3 R 1b substituted 5-membered or 6-membered monocyclic heteroaryl; optionally substituted by 1, 2 or 3 R 1b substituted 8- to 10-membered bicyclic heteroaryl;

[0173] Each R 1a are independently selected from hydrogen, halogen, C 1 -C 6 Alkoxy and C 3 -C 8 Cycloalkyloxy;

[0174] Each R 1b are independently selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, hydroxyalkyloxy, -O-alkylene-NR 1b1 R 1b4 、-O-alkylene-C(O)OR 1b1 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , Cyano, -(CH 2 ) 0-2 C(O)OR 1b1 、-(CH 2 ) 0-2 C(O)NR 1b2 R 1b3 、-(CH 2 ) 0-2 NRC(O)R,-(CH 2 ) 0-2 OH and C 3 -C 8 Cycloalkyloxy;

[0175] R 1b1 is hydrogen or C 1 -C 6Alkyl; R 1b2 is hydrogen or C 1 -C 6 Alkyl; R 1b3 is hydrogen or C 1 -C 6 alkyl; and R 1b4 It is hydrogen,

[0176] a) Where R 2x yes and

[0177] R 2a is hydrogen or C 1 -C 6 alkyl;

[0178] Each R 2b are independently hydrogen, halogen, C 1 -C 3 Alkyl, -(CH 2 ) 0-2 OH, cyclopropyl, cyano, -CHF 2 , -CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 、-OCF 3 or C 3 -C 8 Cycloalkyloxy;

[0179] Each R 2e are independently hydrogen, -OH, halogen, C 1 -C 6 Alkyl, halo-C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, C 1 -C 6 Alkoxy, halo-C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyloxy;

[0180] yes

[0181] One X 1 Yes CR 3 And other X 1 Independently selected from N and CR 2b ;

[0182] R2d is hydrogen, halogen, C 1 -C 6 Alkyl, C 1-6 Cycloalkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyloxy;

[0183] R 3 Yes-(CH 2 ) 0-2 Y x or -(CH 2 ) 0-2 -LY x ;

[0184] L is -L 1 -L 2 -L 3 -, where L 1 , L 2 and L 3 are each independently a bond, -CRR-, O, S(O) 0-2 , C(O) or NR, wherein each R is independently H or alkyl; and

[0185] Y x is optionally replaced by R 2e Substituted 5-membered monocyclic heteroaryl; Y x is optionally replaced by 1 or 2 R 2e Substituted 8-membered bicyclic heteroaryl; Y x is optionally replaced by 1, 2 or 3 R 2e Substituted 9-membered bicyclic heteroaryl; Y x is optionally replaced by 1, 2 or 3 R 2e Substituted 10-membered bicyclic heteroaryl; Y x is optionally replaced by 1 or 2 R 2e Substituted 8-membered or 9-membered bicyclic heterocycle; Y x is optionally replaced by 1 or 2 R 2e substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl; or Y x yes

[0186] a1) wherein Y has a substitutable nitrogen as a ring atom contained in a 5-membered monocyclic heteroaryl, an 8-membered bicyclic heteroaryl, a 9-membered bicyclic heteroaryl, a 10-membered bicyclic heteroaryl, and an 8-membered or 9-membered bicyclic heterocycle; or

[0187] a2) where Y is -(CH 2 ) 0-2 -NH 2 or -(CH 2 )0-2 -NH-(C 1 -C 6 Alkylene)NH 2 replace;

[0188] The formula LG-C(O)R 3a or

[0189] wherein the group in a2) is treated with an intermediate of the formula: LG-C(O)R 3a , Type LG-S(O) 2 R 3a Formula LG-C(O)(C 1 -C 6 Alkylene)NR 3b C(O)R 3a , formula LG-C(O)(C 1 -C 6 Alkylene)NR 3b S(O) 2 R 3a ,in

[0190] LG is a leaving group such as a halide or OH activated with a reagent such as HATU, HBTU, T3P, EDCI / HOBt or other reagents known to those skilled in the art;

[0191] R 3a and R 3b One of them is selected from group a): C substituted by 1 or 2 independently selected halogen groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C substituted by fluoroalkoxy 1 -C 6 Alkyl; C substituted by aryloxy or heteroaryloxy 1 -C 6 Alkyl, each of which may be further substituted by 1-3 substituents independently selected from the following: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 3c R3d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 3c R 3d ; -CH≡CH-CH 2 -OC 1 -C 6 Alkyl; -CH≡CH-CH 2 -OC 1 -C 6 alkyl; chloropyridinyl, fluoropyridinyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and

[0192] R 3a and R 3b The other one of the following is selected from the group b): hydrogen and C 1 -C 6 alkyl;

[0193] R 3c is hydrogen or C 1 -C 6 Alkyl, and R 3d is hydrogen or C 1 -C 6 Alkyl; or R 3c and R 3d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring wherein the other 2-7 ring members are carbon; or

[0194] b) Where R 2x yes and

[0195] Each R 2b are independently hydrogen, halogen, C 1 -C 3 Alkyl, -(CH 2 ) 0-2 OH, cyclopropyl, cyano, -CHF 2 , -CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 、-OCF 3 or C 3 -C8 Cycloalkyloxy;

[0196] Each R 2e are independently hydrogen, halogen, -OH, C 1 -C 6 Alkyl, halo-C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, C 1 -C 6 Alkoxy, halo-C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyloxy;

[0197] X 2a is O or S;

[0198] One X 2 Yes CR 4x And other X 2 Independently selected from N and CR 2b ;and

[0199] b1)R 4x Yes-(CH 2 ) 0-2 Het2;R 4x Y-C(O)-HET1; R 4x Yes-(CH 2 ) 0-3 NR 4b C(O)-HET1; or R 4x It is C 3 -C 8 Heterocycloalkyl; and wherein HET2 is optionally substituted by 1 or 2 R 2e substituted 8-, 9- or 10-membered bicyclic heterocycle and having a substitutable nitrogen as a ring atom, and HET1 is C 3 -C 8 heterocycloalkyl and containing as a ring atom a substitutable nitrogen in HET1;

[0200] b2)R 4x Yes-(CH 2 ) 0-2 NH 2 ; R 4x Yes - NR 4b (C 1 -C 6 Alkylene)NH 2 ; R 4x Yes-(CH 2 ) 0-3 NR4b C(O)(C 1 -C 6 Alkylene)NH 2 ; R 4x Yes-C(O)NR 4b (C 1 -C 6 Alkylene)NH 2 ; or R 4x Y-C(O)-HET1-NH 2 ;

[0201] The formula LG-C(O)R 4a or

[0202] The formula LG-C(O)R 4a Or type LG-S(O) 2 R 4a The intermediate of b2) is treated with a group; and

[0203] in

[0204] LG is a leaving group such as a halide or OH activated with a reagent such as HATU, HBTU, T3P, EDCI / HOBt or other reagents known to those skilled in the art;

[0205] R 4a is alkyl substituted by 1 or 2 independently selected halo groups; C substituted by cyano 1 -C 6 Alkyl; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 4c R 4d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 4c R 4d ; CH≡CH-CH 2 -OH; CH≡CH-CH 2 -OC1 -C 6 Alkyl; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl;

[0206] R 4b is hydrogen or C 1 -C 6 alkyl;

[0207] R 4c is hydrogen or C 1 -C 6 Alkyl, and R 4d is hydrogen or C 1 -C 6 Alkyl; or R 4c and R 4d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon;

[0208] c) Where R 2x yes and

[0209] Each R 2b are independently hydrogen, halogen, C 1 -C 3 Alkyl, -(CH 2 ) 0-2 OH, cyclopropyl, cyano, -CHF 2 , -CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 、-OCF 3 or C 3 -C 8 Cycloalkyloxy;

[0210] R 5x It was Z x substituted and optionally by R 2e Substituted 5-membered monocyclic heteroaryl; R 5x It was Z x substituted and optionally by R 2e Substituted 6-membered monocyclic heteroaryl; R 5x Yes-C(O)LG 1 ; R 5x Yes-(CH 2 ) 0-2 O-HET1; or R 5x Yes-(CH 2 ) 0-2 O-(CH 2 ) 0-3 NH2 LG 1 is a leaving group such as a halide or OH activated with a reagent such as HATU, HBTU, T3P, EDCI / HOBt or other reagents known to those skilled in the art;

[0211] c1)Z x Yes-(CH 2 ) 0-3 NH 2 ; or Z x Yes-(CH 2 ) 0-3 NR 5b (C 1 -C 6 Alkylene)NH 2 ;

[0212] c2)Z x It is C 3 -C 8 heterocycloalkyl and contains substitutable nitrogen as a ring atom;

[0213] Among them, LG 2 -C(O)R 5a Or LG 2 -S(O) 2 R 5a intermediates to treat the groups in c1);

[0214] Among them, LG 2 -C(O)R 5a The intermediate of c2) is treated with a group; and

[0215] in

[0216] LG 2 is a leaving group such as a halide or OH activated with a reagent such as HATU, HBTU, T3P, EDCI / HOBt or other reagents known to those skilled in the art;

[0217] R 5a is C substituted with 1 or 2 independently selected halo groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C substituted by cyano 2 -C 6 Alkenyl; C 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 5c R 5d; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 5c R 5d ; CH≡CH-CH 2 -OH; CH≡CH-CH 2 -OC 1 -C 6 alkyl; chloropyridinyl; fluoropyridinyl; chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl; and

[0218] R 5b is hydrogen or C 1 -C 6 alkyl;

[0219] Each R 5c are independently hydrogen or C 1 -C 6 Alkyl and R 5d is hydrogen or C 1 -C 6 Alkyl; or R 5c and R 5d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon;

[0220] The compound of formula (I) and a specific compound; or a stereoisomer, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof are obtained.

[0221] In another aspect, provided herein is a method for preparing compounds of formula (I), formula (Ih), formula (Ii) and formula (Ij) and specific compounds or stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts thereof, the method comprising reacting R with R using coupling conditions described herein or known to those of ordinary skill in the art. 1 S(O) 2 X (wherein X is a halide, preferably chlorine) is treated with R 2 NH 2 (Formula A). In some or any embodiments, the halo is bromo. BRIEF DESCRIPTION OF THE DRAWINGS

[0222] Figure 1Results of the reversibility / irreversibility assays showing the compounds provided herein (see Biological Example 2). DETAILED DESCRIPTION

[0223] definition

[0224] When referring to the compounds provided herein, unless otherwise indicated, the following terms have the following meanings. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art are generally understood. In the case where there are multiple definitions of the term herein, unless otherwise indicated, those definitions in this section shall prevail. Unless otherwise specified, when the term is defined as unsubstituted or substituted, the groups in the substituent list are themselves unsubstituted. For example, a substituted alkyl group may be substituted by, for example, a cycloalkyl group, and unless otherwise specified, a cycloalkyl group is not further substituted.

[0225] Reference herein to "about" a value or parameter includes (and describes) variations about the value or parameter itself. For example, description referring to "about X" includes description of "X".

[0226] As used herein and unless otherwise specified, the terms "about" and "approximately" when used in conjunction with the temperature, dose, amount or weight % of an ingredient of a composition or dosage form means a dose, amount or weight percentage recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from a specified dose, amount or weight percentage. Specifically, the terms "about" and "approximately" when used in this context contemplate a dose, amount or weight percentage within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1% or within 0.5% of a specified dose, amount or weight percentage.

[0227] As used herein, the terms "a" or "an" mean one or more than one, unless the context clearly indicates otherwise.

[0228] "Alkyl" means a straight or branched chain hydrocarbon group having 1 to 8 carbon atoms. "Lower alkyl" or "C 1 -C 6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. In some embodiments, the lower alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, and the like. "C 0 "Alkyl (as in "C 0 -C 6 Alkyl) is a covalent bond. 6 "Alkyl" refers to, for example, n-hexyl, isohexyl, etc.

[0229] "Alkoxy" means a -OR group, wherein R is an alkyl group as defined herein. In some embodiments, R is C 1 -C 6 alkyl.

[0230] "Alkyloxyalkyl" means an alkyl group, as defined herein, substituted with an alkoxy group, as defined herein. In some embodiments, alkyloxyalkyl is -CH 2 OCH 3 .

[0231] "Alkenyl" means a straight or branched hydrocarbon group having 2 to 8 carbon atoms and at least one double bond and includes ethenyl, propen-1-yl, propen-2-yl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl, etc. "Lower alkenyl" means an alkenyl group having 2 to 6 carbon atoms.

[0232] "Alkynyl" means a straight or branched hydrocarbon group having 2 to 8 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl, etc. "Lower alkynyl" means an alkynyl group having 2 to 6 carbon atoms.

[0233] "Cycloalkyl" means a monocyclic or polycyclic hydrocarbon group having 3 to 13 carbon atoms. The cycloalkyl group may be saturated or partially unsaturated, but cannot contain an aromatic ring. In some embodiments, the cycloalkyl group is C 3 -C 8 In some embodiments, the cycloalkyl group is C 3 -C 6 Cycloalkyl. In some embodiments, cycloalkyl includes fused, bridged, and spiro ring systems. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0234] "Cycloalkylalkyl" means an alkyl group substituted with one or two cycloalkyl groups as defined herein. In some embodiments, cycloalkylalkyl includes cyclopropylmethyl, 2-cyclobutyl-ethyl, and the like.

[0235] "Spirocycloalkyl substituted by cyano" means In some embodiments, the spirocycloalkyl substituted with cyano is In some embodiments, the spirocycloalkyl substituted with cyano is In some embodiments, the spirocycloalkyl substituted with cyano is

[0236] "Cycloalkyloxy" means a -OR group where R is cycloalkyl as defined herein.

[0237] "Cycloalkenyl" means a cycloalkyl group as defined herein containing at least one double bond, but wherein the ring is not aromatic.

[0238] "Haloalkyl" means an alkyl group, as defined herein, substituted with one or more halogens (eg, one, two, three, four, or five halogen atoms). Representative examples include 2,2-difluoroethyl, trifluoromethyl, and 2-chloro-1-fluoroethyl, and the like.

[0239] "Haloalkoxy" means a -OR' group wherein R' is haloalkyl as defined herein, in some embodiments, haloalkoxy is trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

[0240] "Heteroaryl" means a monocyclic or bicyclic monovalent aromatic group of 5-10 ring atoms, which contains one or more heteroatoms independently selected from oxygen, nitrogen and sulfur (e.g., one, two or three ring heteroatoms), and the remaining ring atoms are carbon. Unless otherwise specified, the point of attachment may be located on any atom of any ring of the heteroaryl group when valence rules permit. In some embodiments, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, tetrazolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, tetrazolyl, etc. and N-oxides thereof. When the heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5-membered or 6-membered heteroaryl. "Heteroaryl" as used herein also includes "8-10 membered bicyclic heteroaryl".

[0241] As used herein, "heterocycloalkyl" means a saturated or partially unsaturated (but non-aromatic) monovalent monocyclic radical of 3 to 9 ring atoms, or a saturated or partially unsaturated (but non-aromatic) monovalent fused bicyclic radical of 5 to 12 ring atoms, wherein one or more heteroatoms (e.g., one, two, three or four ring heteroatoms) are independently selected from -O-, -S(O-), ... n -(n is 0, 1 or 2), -N=, -N(R y )-(where R y is a substituent as provided in any embodiment of heterocycloalkyl, including, for example, -C(O)R 4a and similar groups), the remaining ring atoms are carbon. One or two ring carbon atoms may be replaced by -C(O)-, -C(S)-, or -C(=NH)- groups. Fused bicyclic groups include bridged ring systems and spirocyclic systems. Unless otherwise specified, the point of attachment of a group may be located on any atom of any ring within the group when valence rules permit. Specifically, when the point of attachment is on a nitrogen atom, R yMore specifically, the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiomorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidine, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolinyl, tetrahydrofuranyl, octahydropyrrolo[3,4-c]pyrrolyl, (3aR,6aS)-hexahydro-1H-5λ 2 -pyrrolo[3,4-c]pyrrolyl and tetrahydropyranyl and N-oxides thereof.

[0242] As used herein and unless otherwise specified, "bicyclic heterocycle" refers to a bicyclic ring system containing one non-aromatic ring and one aromatic ring; wherein one or more (in some or any embodiments, 1, 2, 3 or 4) of any ring atoms in the bicyclic ring system are independently selected from O, S(O), 0-2 In some or any embodiments, the bicyclic heterocyclic ring comprises one, two or three heteroatoms independently selected from nitrogen and oxygen. In some or any embodiments, the bicyclic heterocyclic ring comprises one or two oxygen heteroatoms. In some or any embodiments, the bicyclic heterocyclic ring comprises one, two or three nitrogen heteroatoms (wherein nitrogen can be substituted as described in any aspect or embodiment as described herein). In some or any embodiments, the bicyclic heterocyclic ring contains one heteroatom in the non-aromatic ring, or contains one or two heteroatoms in the aromatic ring, or contains two heteroatoms in the aromatic ring, or contains two heteroatoms, one of which is in the aromatic ring and the other is in the non-aromatic ring, or contains two heteroatoms in the aromatic ring and one heteroatom in the non-aromatic ring. In some or any embodiments, the bicyclic heterocyclic group can be a bridged or non-bridged and / or fused or non-fused bicyclic group. One or more nitrogen and sulfur atoms can be optionally oxidized, one or more nitrogen atoms can be optionally quaternized, and one or more carbon atoms can be optionally quaternized. Replacement. The bicyclic heterocycle can be connected to the main structure at any heteroatom or carbon atom, which will produce a stable compound. The bicyclic heterocycle can be connected to the main structure via any of its rings (including any aromatic or non-aromatic rings), regardless of whether the ring contains heteroatoms. In some or any embodiments, the bicyclic heterocycle includes a 5-membered heteroaryl, preferably a pyrazolyl, fused to a non-aromatic ring (preferably containing nitrogen ring atoms), such as 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridinyl, or 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinyl; in some or any embodiments, the remainder of the compound of formula (I) is connected to a 5-membered heteroaryl fused to a non-aromatic ring (preferably containing nitrogen ring atoms) via a 5-membered heteroaryl moiety. Aryl (preferably pyrazolyl), for example 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-1-yl, 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-1-yl, 4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl, 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-1-yl, or 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl. When the bicyclic heterocycle is substituted, it may be substituted on any ring, i.e. on any aromatic or non-aromatic ring contained in the bicyclic heterocycle. In some or any embodiments, bicyclic heterocycles include, but are not limited to, 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, benzofuranonyl, dihydrobenzofuranyl, benzotetrahydrothienyl, 2,2-dioxo-1,3-dihydrobenzo[c]thienyl, dihydrofuranyl, dihydroisoindolyl, indolyl, 2-oxo-indolyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isoindolyl, 1-oxo-isoindolyl, 1,3-dioxo-isoindolyl; each of which is optionally substituted with 1, 2, 3, or 4 groups as defined throughout this specification.

[0243] As used herein and unless otherwise specified, "hydroxyalkyl" refers to an alkyl group as defined herein substituted with 1, 2, or 3 hydroxy groups (provided that more than one hydroxy group is not on the same carbon). In some embodiments, hydroxyalkyl is hydroxyC 1-6 In some embodiments, the hydroxyalkyl group is hydroxyethyl.

[0244] As used herein and unless otherwise specified, "hydroxyalkyloxy" refers to an -OR group, wherein R is hydroxyalkyl as defined herein. In some embodiments, hydroxyalkyloxy is hydroxyethyloxy.

[0245] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference; or SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977; 66: 1-19, both of which are incorporated herein by reference. It is also understood that a compound may have one or more pharmaceutically acceptable salts associated therewith.

[0246] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and those formed with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, gluconic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid and salicylic acid, etc.

[0247] Examples of pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred salts are ammonium, potassium, sodium, calcium, and magnesium. Salts derived from pharmaceutically acceptable non-toxic organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucosamine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0248] The term "substantially free" or "substantially absent" of a stereoisomer with respect to a composition refers to a composition comprising at least 85% or 90%, in certain embodiments 95%, 98%, 99%, or 100% by weight of a specified stereoisomer of the compound in the composition. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of stereoisomers.

[0249] Similarly, the term "isolated" with respect to a composition refers to a composition that includes at least 85%, 90%, 95%, 98%, 99% to 100% by weight of the specified compound, with the remainder comprising other chemical species or stereoisomers.

[0250] As used herein and unless otherwise specified, the term "solvate" refers to a compound or salt thereof provided herein that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0251] As used herein and unless otherwise specified, the term "isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance of a given atom. Atoms containing their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, the atoms of the compounds listed herein are intended to represent any stable isotope of the atom. For example, unless otherwise specified, when a position is explicitly designated as "H" or "hydrogen", the position is understood to be a hydrogen with its natural isotopic composition.

[0252] As used herein and unless otherwise specified, the term "isotopic enrichment" refers to the percentage of the natural isotopic abundance of the atom in a given atom in a molecule, incorporating a certain amount of a specific isotope to replace the atom. In certain embodiments, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at a specified position. Since the natural distribution of deuterium is about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0253] As used herein and unless otherwise specified, the term "isotopically enriched" refers to the isotopic composition of atoms that is different from the natural isotopic composition of the atoms. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition that is different from the natural isotopic composition of the atoms.

[0254] As used herein, "alkyl," "cycloalkyl," and "heterocycloalkyl" optionally contain deuterium at one or more positions where there are hydrogen atoms, and wherein the deuterium composition of one or more atoms is different from the natural isotopic composition.

[0255] Also as used herein, "alkyl," "cycloalkyl," and "heterocycloalkyl" optionally contain carbon-13 in an amount that differs from the natural isotopic composition.

[0256] As used herein and unless otherwise specified, the term “IC 50 ” refers to the amount, concentration or dose of a particular test compound that achieves a 50% inhibition of the response in an assay measuring a maximal response.

[0257] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "subjects" refer to animals, such as mammals, including non-primates (e.g., cattle, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys, such as cynomolgus monkeys, chimpanzees, and humans), and in certain embodiments, humans. In certain embodiments, the subject is a farm animal (e.g., horse, cattle, pig, etc.) or a pet (e.g., dog or cat). In certain embodiments, the subject is a human.

[0258] Reference to "administration" and variations thereof of a compound of the invention (in some embodiments, "administering" a compound) means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or a prodrug thereof is provided in combination with one or more other active agents (in some embodiments, surgery, radiation, chemotherapy, etc.), "administration" and variations thereof are each understood to include both simultaneous and sequential introduction of the compound or its prodrug and the other agent.

[0259] A "therapeutically effective amount" is an amount of a compound or composition that, when administered to a patient, is sufficient to effect the described treatment of a disorder, disease or condition (e.g., to improve disease symptoms). The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, etc. A therapeutically effective amount can be determined by one of ordinary skill in the art in a routine manner, given the knowledge of one of ordinary skill in the art and the present disclosure.

[0260] As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any agent that can be used to treat or prevent a disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes compounds provided herein. In certain embodiments, a therapeutic agent is an agent that is known to be useful, or has been used, or is currently being used to treat or prevent a disorder or one or more symptoms thereof.

[0261] As used herein, "treating" or "treatment" of a disease, disorder or syndrome includes (i) preventing the disease, disorder or syndrome from occurring in humans, even though clinical symptoms of the disease, disorder or syndrome will not develop in an animal that may be exposed to or susceptible to the disease, disorder or syndrome, but has not yet experienced or displayed symptoms of the disease, disorder or syndrome; (ii) inhibiting the disease, disorder or syndrome, i.e., preventing its development (stabilizing the disease); and (iii) alleviating the disease, disorder or syndrome, e.g., alleviating or reducing its symptoms and / or causing the disease, disorder or syndrome to regress. As is known in the art, adjustments for local delivery, age, weight, general health, sex, diet, time of administration, drug interactions, and severity of the disorder, disease or syndrome may be necessary for systemic effects and will be determined by one of ordinary skill in the art using routine experimentation. In certain embodiments, "treating" or "treatment" of any disorder, disease or condition refers to improving the disorder, disease or condition present in a subject. In another embodiment, "treating" or "treatment" includes improving at least one physical parameter that may not be discernible by the subject. In another embodiment, "treating" or "treatment" includes modulating the disorder, disease or condition physically (e.g., stabilizing discernible symptoms) or physiologically (e.g., stabilizing a physical parameter), or both. In another embodiment, "treating" or "treatment" includes delaying the onset of a disorder, disease or condition.

[0262] The terms "inhibit" and "reduce" or any variation of these terms include any measurable reduction or complete inhibition to achieve a desired result. For example, compared to normal, the reduction in activity can be about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more or any range derived therefrom.

[0263] As used herein, the terms "prophylactic agent" and "prophylactic agents" refer to any agent that can be used to prevent an illness, disease, or condition, or one or more symptoms thereof. In certain embodiments, the term "prophylactic agent" includes a compound as provided herein. In certain other embodiments, the term "prophylactic agent" does not refer to a compound as provided herein. In certain embodiments, a prophylactic agent may be an agent that is known to be useful, has been used, or is currently being used to prevent or hinder the onset, development, progression, and / or severity of an illness, disease, or condition.

[0264] As used herein, the phrase "prophylactically effective amount" refers to the amount of a therapy (e.g., a prophylactic agent) sufficient to prevent or reduce the development, recurrence or onset of one or more symptoms associated with a disorder, disease or condition, or to enhance or improve the prophylactic effect of another therapy (e.g., another prophylactic agent).

[0265] Compound

[0266]

[00136] Embodiments described herein include the listed compounds and one or more pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, or mixtures thereof.

[0267] In some or any embodiments, the compound is according to Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1). In some or any embodiments, the pharmaceutical composition comprises a compound according to Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1). In some or any embodiments, the treatment methods include administering a compound according to Formula (I), Ia-1, Ib-1, Ic-2, Id-1, Ie-1, If-1, or Ig-1.

[0268] Embodiment A: In some or any embodiments, the compound is a compound wherein:

[0269] R 1 It is C 3 -C 8 Cycloalkyl-C 1 -C 6 or optionally 1, 2 or 3 R 1b Substituted phenyl;

[0270] Each R 1b independently selected from hydrogen, alkyl, -C(O)OH, -C(O)O(C 1-3 Alkyl), halogen and C 1 -C 6 Alkoxy;

[0271] R 2 Selected from the group consisting of:

[0272]

[0273] R 2a It is hydrogen;

[0274] Each R 2b are independently hydrogen, C 1 -C 3 Alkyl or -(CH 2 ) 0-2 OH;

[0275] Each R 2e It is hydrogen;

[0276] Among them, for ring (a) and ring (b)

[0277] One X 1 Yes CR 3 And other X 1 Each is CH;

[0278] R 2d It is C 1 -C 3 Alkoxy;

[0279] R 3 Yes-(CH 2 ) 0-2 Y or -(CH 2 ) 0-2 -LY;

[0280] L is -L 1 -L 2 -L 3 -, where L 1 , L 2 and L 3 are each independently a bond, -CRR-, O, S(O) 0-2, C(O) or NR, wherein each R is independently H or alkyl;

[0281] Y is R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocyclic ring; or Y is replaced by R Y and optionally substituted with 1 or 2 R 2e Substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl;

[0282] R Y Yes-(CH 2 ) 0-3 NR 3b C(O)R 3a 、-(CH 2 ) 0-2 NR 3b S(O) 2 R 3a 、-C(O)R 3a 、-S(O) 2 R 3a 、-C(O)NR 3b R 3a or -C(O)R 3a Substituted C 3 -C 8 Heterocycloalkyl;

[0283] R 3a is C substituted by 1 or 2 halogen groups 1 -C 6 Alkyl; C substituted by fluoroalkoxy 1 -C 6 Alkyl; C substituted by aryloxy or heteroaryloxy 1 -C 6 Alkyl, each of which may be further substituted by 1-3 substituents independently selected from the following: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 6 Alkenyl; C substituted by halogen 2 -C 6 Alkenyl; -CH=CH-CH 2 -NR 3c R 3d ; -CH=CH-CH 2 -OC 1 -C6 Alkyl; Tetrafluorophenyl; Trifluorophenyl; C 2 -C 6 Alkynyl; or -CH≡CH-CH 2 -NR 3c R 3d ;

[0284] R 3b and R 3b1 are independently hydrogen or C 1 -C 6 Alkyl; and

[0285] R 3c is hydrogen or C 1 -C 6 Alkyl, and R 3d is hydrogen or C 1 -C 6 alkyl;

[0286] Among them, for ring (d),

[0287] X 2a It is O;

[0288] One X 2 Yes CR 4 And other X 2 Each is CH;

[0289] R 4 Yes-(CH 2 ) 0-3 NR 4b C(O)R 4a 、-NR 4b (C 1 -C 6 Alkylene)NR 4b1 C(O)R 4a 、-(CH 2 ) 0-3 NR 4b C(O)(C 1 -C 6 Alkylene)NR 4b C(O)R 4a 、-C(O)NR 4b (C 1 -C 6 Alkylene)NR 4b C(O)R 4a 、-C(O)-HET1-C(O)R 4a 、-C(O)-HET1-NR 4b C(O)R 4a 、-(CH 2 ) 0-3 NR4b C(O)-HET1-C(O)R 4a , by -C(O)R 4a Substituted C 3 -C 8 Heterocycloalkyl (preferably, wherein the C 3 -C 8 Heterocycloalkyl via C 3 -C 8 A carbon in the heterocycloalkyl ring is attached to ring (d)); or -(CH 2 ) 0-2 HET2-C(O)R 4a ;

[0290] R 4a It is C 2 -C 6 Alkenyl or C 2 -C 6 Alkynyl;

[0291] R 4b and R 4b1 Each is hydrogen;

[0292] HET1 is a C containing at least one nitrogen 3 -C 8 heterocycloalkyl; and

[0293] HET2 is an 8-, 9- or 10-membered bicyclic heterocycle containing at least one nitrogen ring atom, and -C(O)R 4a is linked to HET2 via at least one nitrogen ring atom in the HET2 ring;

[0294] Among them, for rings (e) and (f),

[0295] R 5 is a 5-membered monocyclic heteroaryl substituted by Z; or R 5 is a 6-membered monocyclic heteroaryl substituted by Z;

[0296] Z is -(CH 2 ) 0-3 NR 5b C(O)R 5a 、-(CH 2 ) 0-3 NR 5b (C 1 -C 6 Alkylene)NR 5b1 C(O)R 5a , by -S(O) 2 R 5a Substituted C 3 -C 8 Heterocycloalkyl, or C(O)R5a Substituted C 3 -C 8 Heterocycloalkyl;

[0297] R 5a It is C 2 -C 6 Alkenyl or C 2 -C 6 Alkynyl;

[0298] R 5b and R 5b1 Each is hydrogen;

[0299] Among them, for ring (g),

[0300] Q 1 It is CH, Q 2 is N, and Q 3 It is O;

[0301] R 6 is a 5-membered monocyclic heteroaryl substituted by Q; or R 6 It is Q;

[0302] Q is -(CH 2 ) 0-3 NR 6b C(O)R 6a ;

[0303] R 6a It is C 2 -C 6 alkenyl;

[0304] R 6b is hydrogen; and

[0305] Each R 7 are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyl;

[0306] or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

[0307] Embodiment 1: Provided are compounds according to formula (I), wherein R 1 It is C 3 -C 8 Cycloalkylalkyl, wherein the C 3 -C 8 Cycloalkylalkyl is optionally substituted by 1, 2 or 3 R 1a or optionally substituted by 1, 2 or 3 R1b substituted phenyl; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein.

[0308] Embodiment 2: Provided are compounds according to formula (I), wherein R 1 It is C 3 -C 8 Cycloalkylalkyl, wherein the C 3 -C 8 Cycloalkylalkyl is optionally substituted by 1, 2 or 3 R 1a substituted; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein.

[0309] Embodiment 3: Provided is a compound according to formula (I), wherein R 1 is optionally replaced by 1, 2 or 3 R 1a Substituted C 3 -C 8 cycloalkyl; and all other groups are as defined in the Summary or in some or any embodiments provided herein.

[0310] Embodiment 4: Provided is a compound according to formula (I), wherein each R 1a is independently hydrogen; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-3.

[0311] Embodiment 5: Provided are compounds according to formula (I), wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted phenyl; and all other groups are as defined in the Summary of the Invention or in some or any of the Embodiments provided herein (including Embodiment 1).

[0312] Embodiment 6: Provided are compounds according to formula (I), wherein R 1 is optionally replaced by 1, 2 or 3 R 1b Substituted phenyl-C 1 -C 6 alkyl; and all other groups are as defined in the Summary of the Invention or in some or any embodiments provided herein.

[0313] Embodiment 7: Provided are compounds according to formula (I), wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted naphthyl; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein.

[0314] Embodiment 8: Provided are compounds according to formula (I), wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted 5-membered or 6-membered monocyclic heteroaryl; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein.

[0315] Embodiment 9: Provided is a compound according to formula (I), (wherein R 1 is an 8-10 membered bicyclic heteroaryl; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein.

[0316] Embodiment 10: Provided is a compound according to formula (I), wherein each R 1b are independently selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, hydroxyl C 1-6 Alkyloxy, -O-alkylene-NR 1b1 R 1b4 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , -(CH 2 ) 0-2 C(O)OR 1b1 、-(CH 2 ) 0-2 C(O)NR 1b2 R 1b3 and -(CH 2 ) 0- 2 NR 1b1 C(O)R 1b3 ; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1 and 5-9). In a sub-embodiment of Embodiment 10, a compound of formula (I) is provided, wherein each R 1b are independently selected from hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, hydroxyl C 1-4 -alkyloxy, -C(O)OR 1b1 、-C(O)NHR 1b3 and -NHC(O)R 1b3 In a sub-embodiment of embodiment 10, there is provided a compound of formula (I) wherein each R 1bindependently selected from hydrogen, fluorine, ethyl, methoxy, hydroxyethyloxy, -C(O)OH, -C(O)OCH 3 and -C(O)NHCH 3 In one sub-embodiment of Embodiment 10 and its sub-embodiments, there is provided a compound of Formula (I) wherein one or two R 1b In one sub-embodiment of embodiment 10 and its sub-embodiments, there is provided a compound according to formula (I) wherein there is one R 1b In one sub-embodiment of Embodiment 10 and its sub-embodiments, there is provided a compound of Formula (I) wherein there are two R 1b .

[0317] Embodiment 11. provides a compound of formula (I) according to formula (Ia):

[0318]

[0319] Where R 1 , R 2a , R 2d and X 1 and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or stereoisomers or mixtures of stereoisomers thereof. In some or any embodiments of Embodiment 1, R 2a In some or any embodiments, there is provided a compound of formula (I) according to formula (Ia-1):

[0320]

[0321] Where R 1 , R 2a , R 2d , R 3 and X 1 and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments of Embodiment 11, a compound of Formula (Ia) or Formula (Ia-1) is provided, wherein R 2a is hydrogen or C 1 -C 3 In some or any embodiments of Embodiment 11, provided are compounds of Formula (Ia) or Formula (Ia-1), wherein R 2aIn some or any embodiments of Embodiment 11, compounds of Formula (Ia) or Formula (Ia-1) are provided, wherein R 2a In some or any embodiments of Embodiment 11, provided are compounds of Formula (Ia) or Formula (Ia-1), wherein R 2a It is C 1 -C 6 In some or any embodiments of Embodiment 11, provided are compounds of Formula (Ia) or Formula (Ia-1), wherein R 2a It is C 1 -C 3 In some or any embodiments of Embodiment 11, provided are compounds of Formula (Ia) or Formula (Ia-1), wherein R 2a It's methyl.

[0322] Embodiment 12. provides a compound of formula (I) according to formula (Ib):

[0323]

[0324] Where R 1 , R 2d and X 1 and all other groups as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, a compound of formula (I) according to formula (Ib-1) is provided:

[0325]

[0326] Where R 1 , R 2d , R 3 and X 1 and other groups as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0327] Embodiment 13. provides a compound of formula (I) according to formula (Ic):

[0328]

[0329] Where R 1 , R 2d , X 1 , and all other groups as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, a compound of formula (I) according to formula (Ic-1) is provided:

[0330]

[0331] Where R 1 , R 2d , R 3 , X 1 , and all other groups as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, a compound of formula (I) according to formula (Ic-2) is provided:

[0332]

[0333] Where R 1 , R 2d , R 3 , X 1 and all other groups as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0334] Embodiment 14. Provided is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein R 2d is hydrogen, halogen, C 1 -C 6 Alkyl, C 1-6 Cycloalkyl, C 1 -C 3 Alkoxy or C 3 -C 6 cycloalkyloxy, and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-13). In some or any embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2) is wherein R 2dis a compound wherein R is a halogen, methyl, methoxy, isopropoxy or cyclopropyloxy. In some or any embodiments, the compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2) is a compound wherein R 2d It is C 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy or methoxy compounds.

[0335] Embodiment 15. provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein each R 2b is hydrogen, and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 1-14. Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein one R 2b Is a halogen, C 1 -C 3 Alkyl, -(CH 2 ) 0-2 OH, cyclopropyl, cyano, -CHF 2 , -CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 、-OCF 3 or C 3 -C 8 Cycloalkyloxy and other R 2b Each is hydrogen, and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-14.

[0336] Embodiment 16: Provided are compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Ia-1), formula (Ib-1), formula (Ic-1) or formula (Ic-2), wherein one X 1 Yes CR 3 (optionally in R 2d The inter-position), an X 1 is N, and other X 1 Yes CR 2b ; or one of the X 1 Yes CR 3 (optionally in R 2d The inter-position) and other X1 Yes CR 2b (optionally CH); and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-15.

[0337] Embodiment 16a. Provided is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein one X 1 Yes CR 3 (optionally in R 2d The inter-position), an X 1 is N, and other X 1 Yes CR 2b ; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-15). In some or any embodiments, one X 1 Yes CR 3 (optionally in R 2d The inter-position), an X 1 is N, and other X 1 It is CH.

[0338] Embodiment 16b. Provided is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein one X 1 Yes CR 3 (optionally in R 2d The inter-position) and other X 1 Yes CR 2b ; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-15). In some or any embodiments, one X 1 Yes CR 3 (optionally in R 2d The inter-position) and other X 1 It is CH.

[0339] Embodiment 17. Provided are compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein R 3 Yes-(CH 2 )-Y; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of Embodiments 1-16b.

[0340] Embodiment 17a. Provided is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein R 3 Yes-(CH 2 )-LY; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of Embodiments 1-16b.

[0341] Embodiment 17b. Provides a compound of formula (Ib) or formula (Ib-1), wherein R 3 Yes-(CH 2 )-LY; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of Embodiments 1-16b.

[0342] Embodiment 17c. provides a compound of formula (Ib) or formula (Ib-1), wherein R 3 Yes-(CH 2 )-LY; L is -L 1 -L 2 -; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-16b).

[0343] Embodiment 17d. provides a compound of formula (Ib) or formula (Ib-1), wherein R 3 Yes-(CH 2 )-LY; L is -CH 2 -O- or -O-CH 2 -; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-16b).

[0344] Embodiment 18. provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein Y is replaced by R Y substituted and optionally by R 2e substituted 5-membered monocyclic heteroaryl (in some embodiments, pyrazolyl); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y and optionally substituted with 1 or 2 R 2esubstituted 6-membered monocyclic aromatic group; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 6-membered monocyclic heteroaryl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 8-membered bicyclic heteroaryl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y and optionally substituted with 1, 2 or 3 R 2e substituted 9-membered bicyclic heteroaryl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y and optionally substituted with 1, 2 or 3 R 2e substituted 10-membered bicyclic heteroaryl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y and optionally substituted with 1 or 2 R 2e Substituted 8- or 9-membered bicyclic heterocycle (in some embodiments (where R Y Yes-C(O)R 3a , where R 3aselected from group a); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y and optionally substituted with 1 or 2 R 2e Substituted 8- or 9-membered bicyclic heterocycle (in some embodiments (where R Y Yes-C(O)R 3a , where R 3a selected from group a); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y and optionally substituted with 1 or 2 R 2e Substituted 8- or 9-membered bicyclic heterocycle (in some embodiments (where R Y Yes-C(O)R 3a , where R 3a selected from group a); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is And all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 1-17.

[0345] Embodiment 18a. Provided are compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein Y is replaced by R Ysubstituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; Y is And R Y Yes-S(O) 2 R 3a or -C(O)R 3a , where R 3a is selected from group a); or Y is R Y substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; Y is And R Y Yes-C(O)R 3a , where R 3a is selected from group a); or Y is R Y substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein, including any of Embodiments 1-17.

[0346] Embodiment 18b. Provided is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; or Y is And R Y Yes-S(O) 2 R 3a or -C(O)R 3a , where R 3a selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by RY substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; or Y is And R Y Yes-C(O)R 3a , where R 3a is selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-17).

[0347] Embodiment 18c. provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; Y is And R Y Yes-S(O) 2 R 3a or -C(O)R 3a , where R 3a is selected from group a); or Y is R Y substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; Y is And R Y Yes-C(O)R 3a , where R 3a is selected from group a); or Y is R Y substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein, including any of Embodiments 1-17.

[0348] Embodiment 18d. provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Ysubstituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; or Y is And R Y Yes-S(O) 2 R 3a or -C(O)R 3a , where R 3a selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; or Y is And R Y Yes-C(O)R 3a , where R 3a is selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-17).

[0349] Embodiment 18e. Provided are compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; or Y is And R Y Yes-S(O) 2 R 3a or -C(O)R 3a , where R 3a selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-17). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; or Y is And R Y Yes-C(O)R3a , where R 3a is selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-17).

[0350] Embodiment 18f. provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein Y is And R Y Yes-S(O) 2 R 3a or -C(O)R 3a , where R 3a is selected from Group a); HET1 is a 5- to 7-membered heterocycloalkyl group; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 1-17. Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is And R Y Yes-S(O) 2 R 3a or -C(O)R 3a , where R 3a is selected from group a); HET1 is a 5- to 7-membered heterocycloalkyl group containing 1 or 2 nitrogen atoms in the ring; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any one of Embodiments 1-17).

[0351] Embodiment 19. Provided is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein R 3b and R 3b1 each is hydrogen; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-18a.

[0352] Embodiment 20. provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein R Y Yes-(CH 2 ) 0-3 NHC(O)R 3a 、-(CH 2 ) 0-2 NHS(O) 2R 3a 、-C(O)R 3a 、-S(O) 2 R 3a 、-(CH 2 ) 0-3 NR 3b (C 1 -C 6 Alkylene)NR 3b1 C(O)R 3a 、-(CH 2 ) 0-3 NR 3b (C 1 -C 6 Alkylene)NR 3b1 S(O) 2 R 3a 、-(CH 2 ) 0-3 NR 3b C(O)(C 1 -C 6 Alkylene)NR 3b1 C(O)R 3a 、-(CH 2 ) 0-3 NR 3b C(O)(C 1 -C 6 Alkylene)NR 3b1 S(O) 2 R 3a , or -C(O)R 3a Substituted C 3 -C 8 Heterocycloalkyl; wherein R 3a is selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-19).

[0353] Embodiment 21. provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein R 3a Yes-CH 2 (halo); -(CH 2 ) 1-2 CN; -CH 2 OCH(CF 3 ) 2 ; -CH 2 O(trifluorophenyl); -CH 2 O(tetrafluorophenyl); -CH 2O(isoxazolyl, optionally substituted by 1-3 substituents each independently selected from the following: halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl); -CH 2 O(pyrimidinyl, optionally substituted by 1-3 substituents each independently selected from the following: halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl); -CH 2 O(pyridyl, optionally substituted by 1-3 substituents each independently selected from the following: halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl); C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 4 Alkenyl (in some embodiments -C(CN)(=CH 2 )); C substituted by halogen 2 -C 4 Alkenyl (in some embodiments, C 2 -C 4 alkenyl); -CH=CH-CH 2 -NR 3c R 3d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; trifluorophenyl; tetrafluorophenyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 3c R 3d ; or -CH≡CH-CH 2 -OC 1 -C 6 alkyl; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-20.

[0354] Embodiment 21a. provides a compound of formula (Ib) or formula (Ib-1), wherein R 3ais C substituted with 1 or 2 independently selected halo groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C substituted by cyano 2 -C 6 Alkenyl (in some embodiments -C(CN)(=CH 2 )); C substituted by halogen 2 -C 6 Alkenyl (in some embodiments, C 2 -C 4 alkenyl); -CH=CH-CH 2 -NR 3c R 3d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 3c R 3d ; CH≡CH-CH 2 -OH; -CH≡CH-CH 2 -OC 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 1-20.

[0355] Embodiment 22. Provides a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein R Y yes

[0356] And all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 1-19.

[0357] Embodiment 22a. Provided is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein RY yes

[0358] And all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 1-19.

[0359] Embodiment 23. Provided is a compound of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Ia-1), Formula (Ib-1), Formula (Ic-1) or Formula (Ic-2), wherein one R 2b Fluorine, C 1 -C 3 Alkyl, -(CH 2 ) 0-2 OH, cyclopropyl, -CHF 2 , -CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 or -OCF 3 , and the other is hydrogen; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-22). Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein each R 2e is hydrogen or -OH; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-22.

[0360] Embodiment 24. provides a compound of formula (I) according to formula (Id):

[0361]

[0362] Where R 1 , X 2a , X 2 and all other groups as defined in the Summary of the Invention or some or any embodiments provided herein (including any one of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof. In some or any embodiments, a compound of formula (I) according to formula (Id-1) is provided:

[0363]

[0364] Where R 1 , X 2a , R 4 and X2 and other groups as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0365] Embodiment 25. provides a compound of formula (I), formula (Id) or formula (Id-1), wherein each R 2b is hydrogen; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10 and 24). Provided are compounds of Formula (I), (Id) or (Id-1), wherein one R 2b Is a halogen, C 1 -C 3 Alkyl, -(CH 2 ) 0-2 OH, cyclopropyl, cyano, -CHF 2 , -CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 、-OCF 3 or C 3 -C 8 Cycloalkyloxy and other R 2b Each is hydrogen, and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-9 and 24.

[0366] Embodiment 26: In some or any embodiments, an X 1 Yes CR 3 (optionally in R 2d The inter-position), an X 1 is N, and other X 1 Yes CR 2b ; or one of the X 1 Yes CR 3 (optionally in R 2d The inter-position) and other X 1 Yes CR 2b (optionally CH), and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10, 24, and 25). In some or any embodiments, one X 1 Yes CR 3 (optionally in R 2d The inter-position), an X 1 is N, and other X 1 Yes CR 2b, and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10, 24, and 25). In some or any embodiments, one X 1 Yes CR 3 (optionally in R 2d The inter-position), an X 1 Yes CR 3 (optionally in R 2d The inter-position) and other X 1 Yes CR 2b (optionally CH), and all other groups are as defined in the Summary or some or any embodiments provided herein (including any of Embodiments 1-10, 24, and 25).

[0367] Embodiment 26. Provides a compound of formula (I), formula (Id) or formula (Id-1), wherein one X 2 Yes CR 4 And other X 2 Yes CR 2b ; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10, 24, and 25). In some or any embodiments, one X 2 Yes CR 4 And other X 2 It is CH.

[0368] Embodiment 27. provides a compound of formula (I), formula (Id) or formula (Id-1), wherein X 2a is O; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10 and 24-26). Provided are compounds of Formula (I), (Id) or (Id-1), wherein X 2a is S; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of Embodiments 1-10 and 24-26.

[0369] Embodiment 28. provides a compound of formula (I), formula (Id) or formula (Id-1), wherein R 4b and R 4b1 each is hydrogen; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-10 and 24-27.

[0370] Embodiment 29. provides a compound of formula (I), formula (Id) or formula (Id-1), wherein R 4Yes-(CH 2 ) 0-3 NR 4b C(O)R 4a 、-(CH 2 ) 0-2 NR 4b S(O) 2 R 4a 、-C(O)R 4a 、-C(O)NR 4b R 4a 、-NR 4b (C 1 -C 6 Alkylene)NR 4b1 C(O)R 4a 、-(CH 2 ) 0-3 NR 4b C(O)(C 1 -C 6 Alkylene)NR 4b1 C(O)R 4a 、-C(O)NR 4b (C 1 -C 6 Alkylene)NR 4b1 C(O)R 4a 、-C(O)-HET1-C(O)R 4a 、-C(O)-HET1-NR 4b C(O)R 4a 、-(CH 2 ) 0-3 NR 4b C(O)-HET1-C(O)R 4a , by -C(O)R 4a Substituted C 3 -C 8 Heterocycloalkyl (preferably, wherein the C 3 -C 8 Heterocycloalkyl via C 3 -C 8 A carbon in the heterocycloalkyl ring is attached to ring (d)); or -(CH 2 ) 0-2 HET 2-C(O)R 4a ; where R 4a is selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10 and 24-28).

[0371] Embodiment 29a. provides a compound of formula (I), formula (Id) or formula (Id-1), wherein R 4 yes

[0372] -(CH 2 ) 0-2 NHC(O)R 4a ;

[0373] -NH(C 2 -C 4 -alkylene)NHC(O)R 4a ;

[0374] C 3 -C 8 Heterocycloalkyl, wherein said C 3 -C 8 The nitrogen ring atom in the heterocycloalkyl group is replaced by -C(O)R 4a Substituted (preferably, wherein the C 3 -C 8 Heterocycloalkyl via C 3 -C 8 A carbon in the heterocycloalkyl ring is attached to ring (d));

[0375] -C(O)-HET1-C(O)R 4a , where -C(O)R 4a connected to the nitrogen ring atom in HET1;

[0376] -C(O)-HET1-NHC(O)R 4a , wherein -C(O)- is attached to a nitrogen ring atom in HET1;

[0377] -C(O)NH(C 1 -C 6 Alkylene)NHC(O)R 4a ;

[0378] -(CH 2 ) 0-2 HET2-C(O)R 4a , wherein HET2 is a 5-membered monocyclic heteroaryl or an 8-membered or 9-membered bicyclic heterocycle, and wherein -C(O)R 4a connected to HET2 via a nitrogen ring atom in HET2;

[0379] -(CH 2 ) 0-3 NHC(O)(C 1 -C 6 Alkylene)NHC(O)R 4a ;or

[0380] -(CH 2 ) 0-3 NHC(O)-HET1-C(O)R 4a ;

[0381] Where R 4a is selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10 and 24-28).

[0382] Embodiment 30. provides a compound of formula (I), formula (Id) or formula (Id-1), wherein R 4a Yes-CH 2 (halo); -(CH 2 ) 1-2 CN; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 4 Alkenyl; C substituted by halogen 2 -C 4 Alkenyl; -CH=CH-CH 2 -NR 4c R 4d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 4c R 4d ; or -CH≡CH-CH 2 -OC 1 -C 6 alkyl; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-10 and 24-29a.

[0383] Embodiment 30a. provides a compound of formula (I), formula (Id) or formula (Id-1), wherein R 4a is C substituted with 1 or 2 independently selected halo groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C substituted by cyano 2 -C 6 Alkenyl (in some embodiments -C(CN)(=CH 2 )); C substituted by halogen 2 -C 6 Alkenyl (in some embodiments, C 2 -C 4 alkenyl); -CH=CH-CH 2 -NR4c R 4d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C 3 -C 8 Cycloalkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 4c R 4d ; CH≡CH-CH 2 -OH; -CH≡CH-CH 2 -OC 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10 and 24-29a).

[0384] Embodiment 31. provides a compound of formula (I), formula (Id) or formula (Id-1), wherein HET1-C(O)R 4a yes HET1-NHC(O)R 4a yes And HET2-C(O)R 4a yes Where R 4a is selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10 and 24-30).

[0385] Embodiment 32. provides a compound of formula (I), formula (Id) or formula (Id-1), wherein R 4 yes

[0386] And all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 1-10 and 24-28.

[0387] Embodiment 32a. provides a compound of formula (I), formula (Id) or formula (Id-1), wherein R 4 yes

[0388] And all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 1-10 and 24-28.

[0389] Embodiment 33. provides a compound of formula (I) according to formula (Ie):

[0390]

[0391] Where R 1 , R 2b , R 5 and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, a compound of formula (I) according to formula (Ie-1) is provided:

[0392]

[0393] Where R 1 , R 2b , R 5 and other groups as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0394] Embodiment 34. provides a compound of formula (I) according to formula (If):

[0395]

[0396] Where R 1 , R 2b , R 5 and all other groups as defined in the Summary of the Invention or some or any embodiments provided herein (including any one of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof. In some or any embodiments, a compound of formula (I) according to formula (If-1) is provided:

[0397]

[0398] Where R 1 , R 2b , R 5and all other groups as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0399] Embodiment 35. provides a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein each R 2b are independently hydrogen or C 1 -C 3 and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10 and 34). In some or any embodiments, each R 2b is independently hydrogen or methyl.

[0400] Embodiment 36. provides a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein R 5 is pyridyl, pyrazolyl or imidazolyl; each of which is substituted by Z and optionally by R 2e substituted; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10, 34, and 35).

[0401] Embodiment 36a. provides a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein R 5 Yes-C(O)N(R 5b )Z, where R 5b selected from group b); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10, 34, and 35). In a sub-embodiment of Embodiment 36a, a compound of Formula (I), Formula (Ie), Formula (If), Formula (Ie-1), or Formula (If-1) is provided, wherein R 5 is -C(O)NHZ; and all other groups are as defined in the Summary or some or any Embodiments provided herein, including any of Embodiments 1-10, 34, and 35.

[0402] Embodiment 36b. Provided is a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein R 5 is substituted by Z and optionally by R 2esubstituted heterocycloalkyl (in some embodiments, pyrrolidinyl); and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10, 34, and 35).

[0403] Embodiment 36c. provides a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein R 5 Yes-(CH 2 ) 0-2 O-HET1-Z; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10, 34, and 35).

[0404] Embodiment 36d. provides a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein R 5 Yes-(CH 2 ) 0-2 OZ; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10, 34, and 35).

[0405] Embodiment 37. provides a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein R 5a Yes-CH 2 (halo); -(CH 2 ) 1-2 CN; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 4 Alkenyl; C substituted by halogen 2 -C 4 Alkenyl; -CH=CH-CH 2 -NR 5c R 5d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 5c R 5d ; CH≡CH-CH 2 -OH; -CH≡CH-CH 2 -OC 1 -C 6alkyl; spirocycloalkyl substituted with cyano; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10 and 34-36).

[0406] Embodiment 38. provides a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein each R 5b and R 5b1 each is hydrogen; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-10 and 34-37.

[0407] Embodiment 39. provides a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein Z is -(CH 2 ) 0-3 NHC(O)R 5a 、-(CH 2 ) 0-2 NHS(O) 2 R 5a 、-C(O)R 5a 、-S(O) 2 R 5a 、-(CH 2 ) 0-3 -C(O)NHR 5a 、-(CH 2 ) 0-3 NH(C 1 -C 6 Alkylene)NH C(O)R 5a 、NHC(O)R 5a Substituted C 3 -C 8 Heterocycloalkyl, -S(O) 2 R 5a Substituted C 3 -C 8 Heterocycloalkyl, or -C(O)R 5a Substituted C 3 -C 8 Heterocycloalkyl; wherein R 5a is selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10 and 34-38).

[0408] Embodiment 40. provides a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein Z is

[0409] And all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 1-10 and 34-36.

[0410] Embodiment 40. provides a compound of formula (I), formula (Ie), formula (If), formula (Ie-1) or formula (If-1), wherein Z is

[0411] And all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 1-10 and 34-36.

[0412] Embodiment 41. provides a compound of formula (I) according to formula (Ig):

[0413]

[0414] Where R 1 , Q 1 , Q 2 , Q 3 , R 6 , R 7 and all other groups as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof. In some or any embodiments, a compound of formula (I) according to formula (Ig-1) is provided:

[0415]

[0416] Where R 1 , Q 1 , Q 2 , Q 3 , R 6 , R 7 and all other groups as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

[0417] Embodiment 42. provides a compound of formula (I), formula (Ig) or formula (Ig-1), wherein Q 1 Yes CR Q1 , Q 2 is O, and Q 3is N; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10 and 41). Provided are compounds of Formula (I), Formula (Ig), or Formula (Ig-1), wherein Q 1 Yes S, Q 2 is N, and Q 3 is N; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10 and 41). Provided are compounds of Formula (I), Formula (Ig), or Formula (Ig-1), wherein Q 1 Yes N, Q 2 is N, and Q 3 is O; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10 and 41). Provided are compounds of Formula (I), Formula (Ig), or Formula (Ig-1), wherein Q 1 It's O, Q 2 is N, and Q 3 is N; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 1-10 and 41). Provided are compounds of Formula (I), Formula (Ig), or Formula (Ig-1), wherein Q 1 Yes CR Q1 (optionally wherein R Q1 is hydrogen), Q 2 is N, and Q 3 is O; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10 and 41). In some or any embodiments, R Q1 is hydrogen, C(O)CH 3 In some or any embodiments, R Q1 It's hydrogen.

[0418] Embodiment 43. provides a compound of formula (I), formula (Ig) or formula (Ig-1), wherein R 6 is substituted by Q and optionally by R 2e Substituted pyrazolyl; or R 6 Yes-(CH 2 ) 0-3 NHC(O)R 6a ; where R 6a is selected from Group a); and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein (including any of Embodiments 1-10 and 42).

[0419] Embodiment 44. provides a compound of formula (I), formula (Ig) or formula (Ig-1), wherein R 6a Yes-CH 2 (halo); -(CH 2 ) 1-2 CN; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 4 Alkenyl; C substituted by halogen 2 -C 4 Alkenyl; -CH=CH-CH 2 -NR 3c R 3d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; Tetrafluorophenyl; Trifluorophenyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 3c R 3d ; or -CH≡CH-CH 2 -OC 1 -C 6 alkyl; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of Embodiments 1-10 and 43.

[0420] Embodiment 44a. provides a compound of formula (I), formula (Ig) or formula (Ig-1), wherein R 6a is C substituted with 1 or 2 independently selected halo groups 1 -C 6 Alkyl; C substituted by cyano 1 -C 6 Alkyl; C substituted by cyano 2 -C 6 Alkenyl (in some embodiments -C(CN)(=CH 2 )); C substituted by halogen 2 -C 6 Alkenyl (in some embodiments, C 2 -C 4 alkenyl); -CH=CH-CH 2 -NR 6c R 6d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; C 3 -C 8 Cycloalkenyl; -C(O)-C3 -C 8 Cycloalkyl; tetrafluorophenyl; trifluorophenyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 6c R 6d ; CH≡CH-CH 2 -OH; -CH≡CH-CH 2 -OC 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; and all other groups are as defined in the Summary of the Invention or some or any Embodiments provided herein, including any of Embodiments 1-10 and 43.

[0421] Embodiment 45. provides a compound of formula (I), formula (Ig) or formula (Ig-1), wherein R 6b is hydrogen; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-10 and 42.

[0422] Embodiment 46. provides a compound of formula (I), formula (Ig) or formula (Ig-1), wherein one R 7 It is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 cycloalkyl; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 1-10 and 45.

[0423] Embodiment 47. Provided are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1) or (Ig-1), wherein R 3c , R 3d , R 4c , R 4d , R 5c , R 5d , R 6c and R 6d are independently hydrogen or C 1 -C 3 Alkyl; or each pair of R 3c and R 3d , R 4c and R4d , R 5c and R 5d and R 6c and R 6d together with the nitrogen to which it is attached form a pyrrolidinyl or piperidinyl; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of the preceding embodiments.

[0424] Embodiment 47a. Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1) or (Ig-1), wherein R 3a , R 4a , R 5a and R 6a Yes-CH 2 (halo); -(CH 2 ) 1-2 CN; C 2 -C 6 Alkenyl; C substituted by cyano 2 -C 4 Alkenyl; C substituted by halogen 2 -C 4 Alkenyl; -CH=CH-CH 2 -NR 3c R 3d ; -CH=CH-CH 2 -OC 1 -C 6 Alkyl; Tetrafluorophenyl; Trifluorophenyl; C 2 -C 6 Alkynyl; -CH≡CH-CH 2 -NR 3c R 3d ; or -CH≡CH-CH 2 -OC 1 -C 6 alkyl; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of the preceding embodiments.

[0425] Embodiment 47b. Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1) or (Ig-1), wherein

[0426] R Y yes

[0427]

[0428] R 4 yes and

[0429] Z is And all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of the preceding embodiments.

[0430] Embodiment 47c. Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1) or (Ig-1), wherein

[0431] R Y yes

[0432]

[0433] R 4 yes and

[0434] Z is

[0435] And all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of the preceding embodiments.

[0436] Embodiment 48: A compound is provided, wherein the 8- or 9-membered bicyclic heterocyclic ring (optionally substituted as provided herein) is a 5-membered heteroaryl, preferably pyrazolyl, optionally substituted as provided herein, which is fused to a non-aromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic ring. In one embodiment of embodiment 48, a compound is provided, wherein the 8- or 9-membered bicyclic heterocyclic ring (optionally substituted as provided herein) is a 5-membered heteroaryl, preferably pyrazolyl, optionally substituted as provided herein, which is fused to a non-aromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group; and wherein the remainder of the molecule is connected to the 5-membered heteroaryl fused to the non-aromatic cyclic group via the 5-membered heteroaryl portion. In one embodiment of embodiment 48, a compound is provided, wherein the non-aromatic portion of the 8- or 9-membered bicyclic heterocyclic ring (optionally substituted as provided herein) contains a heteroatom, preferably nitrogen, in the ring.

[0437] Embodiment 49: Provided is a pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 48 or a stereoisomer, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0438] Embodiment 50: Provided is a method for treating a condition, disease or disorder by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-48 or its stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts or a therapeutically effective amount of the composition of Embodiment 4.

[0439] Embodiment 51: A method according to embodiment 50 is provided, wherein the disorder, disease or condition is a hyperproliferative disease, such as cancer. In some or any embodiments, the cancer is a specific type selected from the following: lymphoma, melanoma, carcinoma (e.g., adenocarcinoma, hepatocellular carcinoma, medullary carcinoma, papillary carcinoma, squamous cell carcinoma), astrocytoma, glioma, medulloblastoma, myeloma, meningioma, neuroblastoma and sarcoma (e.g., angiosarcoma, chondrosarcoma, osteosarcoma). In some or any embodiments, the cancer may be a MYST overexpressing cancer; the cancer may overexpress MYST protein relative to non-cancerous tissue; the cancer may overproduce MYST mRNA relative to non-cancerous tissue; the cancer may be a MYST overexpressing cancer, wherein the overexpressed MYST protein or MYST mRNA may be any one of the KATs of the MYST family, such as KAT6A. In some or any embodiments, the cancer is selected from one or more of the following: leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, breast ductal carcinoma, colorectal cancer, colon cancer, squamous cell carcinoma, gastric cancer, adrenocortical carcinoma, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, female reproductive system cancer, male reproductive system cancer (including testicular cancer and penile cancer), central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, Kaposi's sarcoma (Kaposi's sarcoma), kidney cancer, laryngeal cancer, liver cancer, malignant fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nervous system cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm, primary CNS lymphoma, rectal cancer, respiratory system cancer, retinoblastoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thyroid cancer, urinary system cancer, uterine cancer, uterine sarcoma, vaginal cancer, endocrine cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitary adenoma, vascular system cancer, Waldenstrom's macroglobulinemia (Waldenstrom's macroglobulinemia and / or Wilms' tumor.In some or any embodiments, the cancer is breast cancer, including ER-positive breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, or a blood cancer (including leukemia or lymphoma).

[0440] Embodiment B: In one embodiment is a compound of formula (I), wherein

[0441] R 1 is the unsubstituted C 3-8 Cycloalkylalkyl (preferably cyclohexylmethyl), or phenyl, wherein the phenyl is optionally substituted by one or two independently selected from halo (preferably fluoro) and C 1-3 Alkoxy (preferably methoxy) group substitution;

[0442] R 2 is a ring (a) or a ring (b); one of the X 1 It is C(CH 2 R 2c ), and the other two X 1 Each is CH; preferably, C(CH 2 R 2c ) is in R 2d The interposition;

[0443] R 2b is hydrogen or C 1 -C 6 Alkyl, preferably hydrogen or methyl;

[0444] R 2c is optionally substituted by cyano or -CH 2 NHC(O)CH 3 substituted 5-membered heteroaryl, preferably pyrazol-1-yl; or R 2c is optionally C 1-6 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl substituted with alkylcarbonyl; or R 2c is a 6-membered heteroaryl group, preferably pyridin-2-yl;

[0445] R 2d It is C 1-3 Alkoxy; or

[0446] one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

[0447] Embodiment 52. provides a compound of formula (I) according to formula (Ih):

[0448]

[0449] Where R 1 , R 2b , R2d and X 1 and all other groups are as defined in the Summary of the Invention or in some or any embodiments provided herein; or one or more pharmaceutically acceptable salts thereof; and / or stereoisomers or mixtures of stereoisomers thereof. In some or any embodiments of Embodiment 52, R 2b is hydrogen or methyl.

[0450] Embodiment 53. provides a compound of formula (I) according to formula (Ii):

[0451]

[0452] Where R 1 , R 2d and X 1 and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein; or one or more pharmaceutically acceptable salts thereof; and / or stereoisomers or mixtures of stereoisomers thereof.

[0453] Embodiment 54. provides a compound of formula (I) according to formula (Ij):

[0454]

[0455]

[0456] Where R 1 , R 2d , X 1 and X 2 and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein; or one or more pharmaceutically acceptable salts thereof; and / or stereoisomers or mixtures of stereoisomers thereof.

[0457] Embodiment 55: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein R 1 It is C 3 -C 8 Cycloalkylalkyl, wherein the C 3 -C 8 Cycloalkylalkyl is optionally substituted by 1, 2 or 3 R 1a or optionally substituted by 1, 2 or 3 R 1b substituted phenyl; and all other groups are as defined in the Summary of the Invention or some or any Embodiments provided herein, including any of Embodiments 52-54.

[0458] Embodiment 56: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein R 1It is C 3 -C 8 Cycloalkylalkyl, wherein the C 3 -C 8 Cycloalkylalkyl is optionally substituted by 1, 2 or 3 R 1a substituted; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 52-54.

[0459] Embodiment 57: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein each R 1a is independently H; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 52-56.

[0460] Embodiment 58: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (IIc), wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted phenyl; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of Embodiments 52-55.

[0461] Embodiment 59: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted naphthyl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 52-54.

[0462] Embodiment 60: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted 5- or 6-membered monocyclic heteroaryl; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein, including any of Embodiments 52-54.

[0463] Embodiment 60a: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein R 1 is an 8-10 membered bicyclic heteroaryl; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of Embodiments 52-54.

[0464] Embodiment 61: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein each R 1b are independently selected from H, halo and C 1 -C 6 and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 52-55 and 58-60). In a sub-embodiment of Embodiment 61, compounds of Formula (I), (Ih), (Ii) or (Ij) are provided, wherein each R 1b are independently selected from H, halo and C 1 -C 3 In a sub-embodiment of embodiment 61, a compound of formula (I), formula (Ih), formula (Ii) or formula (Ij) is provided, wherein each R 1b In one sub-embodiment of Embodiment 61 and its sub-embodiments, compounds of Formula (I), Formula (Ih), Formula (Ii) or Formula (Ij) are provided, wherein there are one or two R 1b In one sub-embodiment of Embodiment 61 and its sub-embodiments, a compound of Formula (I), Formula (Ih), Formula (Ii) or Formula (Ij) is provided, wherein there is one R 1b In one sub-embodiment of Embodiment 61 and its sub-embodiments, compounds of Formula (I), Formula (Ih), Formula (Ii) or Formula (Ij) are provided, wherein there are two R 1b .

[0465] Embodiment 62: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein R 2d Is a halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or C 3 and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any one of Embodiments 52-61). In a sub-embodiment of Embodiment 62, compounds of Formula (I), (Ih), (Ii) or (Ij) are provided, wherein R 2d It is C 1 -C 6 Alkoxy, preferably C 1 -C 3 In a sub-embodiment of embodiment 62, a compound of formula (I), formula (Ih), formula (Ii) or formula (Ij) is provided, wherein R 2dIt is methoxy, isopropoxy or cyclopropyloxy.

[0466] Embodiment 63: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein each R 2e are independently hydrogen, fluorine, C 1 -C 3 Alkyl, cyclopropyl, -CHF 2 , -CF 3 , C 1 -C 4 Alkoxy, -OCHF 2 or -OCF 3 ; And all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any one of Embodiments 52-61). In a sub-embodiment of Embodiment 63, a compound of Formula (I), Formula (Ih), Formula (Ii) or Formula (Ij) is provided, wherein each R 2e It's hydrogen.

[0467] Embodiment 64: Provided are compounds according to formula (I) or formula (Ih), wherein

[0468] R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 6-membered monocyclic heteroaryl; and

[0469] Each R 2c1 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl, -CN, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyloxy, -(CH 2 ) 0-1 NH 2 、-(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f 、-NH(C 1 -C 6 Alkyl), -N(C 1 -C6 alkyl) 2 , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0470] and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In a sub-embodiment of Embodiment 64, a compound is provided wherein R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 substituted 8-membered bicyclic heterocycle; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 6-membered monocyclic heteroaryl.

[0471] Embodiment 64a: In one embodiment of embodiment 64, a compound is provided, wherein each R 2c1 is hydrogen (i.e. R 2c is not substituted); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In a sub-embodiment of Embodiment 64, a compound is provided wherein one R 2c1 is hydrogen and the other R 2c1 Selected from C 1 -C 6 Alkylcarbonyl, -CN, -(CH 2 ) 0-1 NH 2 and -(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f ; where R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C3 and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In a sub-embodiment of Embodiment 64, a compound is provided wherein one R 2c1 is hydrogen and the other R 2c1 is -CN; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 55-63.

[0472] Embodiment 64b: In a sub-embodiment of embodiment 64 or 64a, a compound is provided, wherein R 2c is pyrazolyl, pyridinyl or 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is optionally substituted by 1 or 2 R 2c1 In a sub-embodiment of embodiment 64 or 64a, a compound is provided wherein R 2c is optionally replaced by 1 or 2 R 2c1 In a sub-embodiment of embodiment 64 or 64a, a compound is provided, wherein R 2c is optionally replaced by 1 or 2 R 2c1 In a sub-embodiment of embodiment 64 or 64a, a compound is provided wherein R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 6-membered monocyclic heteroaryl.

[0473] Embodiment 64c: In one embodiment of embodiment 64, a compound is provided, wherein R 2c is pyrazolyl, preferably pyrazol-2-yl, and is unsubstituted (ie, both R 2c1 is hydrogen) or by an R 2c1 (which is preferably cyano) substituted (ie another R 2c1 is hydrogen); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In one embodiment of Embodiment 64, a compound is provided wherein R 2c is pyridinyl, preferably pyridin-2-yl, and is unsubstituted (ie, both R 2c1 is hydrogen) or by an R 2c1 (which is cyano) substituted (i.e. another R 2c1is hydrogen); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In one embodiment of Embodiment 64, a compound is provided wherein R 2c is 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, preferably 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, and is unsubstituted (ie, both R 2c1 is hydrogen) or by an R 2c1 Replace (ie another R 2c1 is hydrogen), one of the R 2c1 is alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of Embodiments 55-63.

[0474] Embodiment 64d: In one embodiment of embodiment 64 or 64a, a compound is provided, wherein R 2c is optionally replaced by 1 or 2 R 2c1 substituted 8- or 9-membered bicyclic heterocycle; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein, including any of Embodiments 55-63.

[0475] Embodiment 64d-1: In a sub-embodiment of embodiment 64d, a compound is provided, wherein the 8-membered or 9-membered bicyclic heterocyclic ring (optionally surrounded by 1 or 2 R 2c1 substituted) is optionally substituted with 1 or 2 R 2c1 A substituted 5-membered heteroaryl, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably forms an 8-membered bicyclic heterocycle.

[0476] Embodiment 64d-2: In a sub-embodiment of embodiment 64d, a compound is provided, wherein the 8-membered or 9-membered bicyclic heterocyclic ring (optionally surrounded by 1 or 2 R 2c1 substituted) is optionally substituted with 1 or 2 R 2c1 A substituted 5-membered heteroaryl, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group; and wherein the remainder of the molecule is attached to the 5-membered heteroaryl fused to the non-aromatic cyclic group via the 5-membered heteroaryl moiety.

[0477] Embodiment 64d-3: In a sub-embodiment of any one of embodiments 64d, 64d-1 and 64d-2, a compound is provided wherein the 8-membered or 9-membered bicyclic heterocyclic ring (optionally surrounded by 1 or 2 R 2c1 The non-aromatic moiety of the (substituted) group contains a heteroatom in the ring, preferably nitrogen.

[0478] Embodiment 64d-4: In a sub-embodiment of any one of embodiments 64d, 64d-1, 64d-2 and 64d-3, a compound is provided wherein the 8-membered or 9-membered bicyclic heterocyclic ring is replaced by one R 2c1 (which is hydrogen) and the second R 2c1 (which is selected from hydrogen and C 1 -C 6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl).

[0479] Embodiment 65: Provided are compounds according to formula (I) or formula (Ii), wherein

[0480] R 2c Is R 2c2 substituted and optionally by R 2c3 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c Is R 2c2 substituted and optionally by R 2c3 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c Is R 2c2 and optionally substituted with 1 or 2 R 2c3 substituted 6-membered monocyclic heteroaryl; and

[0481] R 2c2 It is C 1 -C 6 Alkylcarbonyl, -CN, -(CH 2 ) 0-1 NH 2 , C 1 -C 6 Alkoxy, -NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C1 -C 3 Alkyl; and

[0482] R 2c3 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy or C 3 -C 8 Cycloalkyloxy;

[0483] Each R 2c1 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyloxy, -CN, -(CH 2 ) 0-1 NH 2 、-NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0484] and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In a sub-embodiment of Embodiment 65, a compound is provided wherein R 2c Is R 2c2 substituted and optionally by R 2c3 substituted 5-membered monocyclic heteroaryl; optionally substituted by 1 or 2 R 2c1 Substituted 8-membered bicyclic heterocycle; R 2c Is R2c2 substituted and optionally by R 2c3 substituted 8-membered bicyclic heterocycle; or R 2c Is R 2c2 and optionally substituted with 1 or 2 R 2c3 Substituted 6-membered monocyclic heteroaryl.

[0485] Embodiment 65a: In one embodiment of embodiment 65, a compound is provided, wherein each R 2c1 is hydrogen (i.e. R 2c is not substituted); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In a sub-embodiment of Embodiment 65, a compound is provided wherein one R 2c1 is hydrogen and the other R 2c1 Selected from C 1 -C 6 Alkylcarbonyl, -CN, -(CH 2 ) 0-1 NH 2 and -(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f ; where R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In a sub-embodiment of Embodiment 65, a compound is provided wherein one R 2c1 is hydrogen and the other R 2c1 is -CN; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 55-63.

[0486] Embodiment 65b: In one embodiment of embodiment 65, a compound is provided, wherein R 2c2 It is C 1 -C 6 Alkylcarbonyl, -CN, -(CH 2 ) 0-1 NH 2or -(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f ; where R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein, including any of Embodiments 55-63.

[0487] Embodiment 65c: In one embodiment of embodiment 65 or 65b, a compound is provided, wherein each R 2c3 is hydrogen; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 55-63.

[0488] Embodiment 65d: In a sub-embodiment of embodiment 65, 65b or 65c, a compound is provided, wherein R 2c is pyrazolyl, pyridinyl or 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is replaced by R 2c2 substituted and optionally by R 2c3 and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In a sub-embodiment of Embodiments 65, 65b or 65c, a compound is provided wherein R 2c Is R 2c2 substituted and optionally by R 2c3 In a sub-embodiment of embodiment 65, 65b or 65c, a compound is provided wherein R 2c Is R 2c2 substituted and optionally by R 2c3 In a sub-embodiment of embodiment 65, 65b or 65c, a compound is provided wherein R 2c Is R 2c2 substituted and optionally by R 2c3 Substituted 6-membered monocyclic heteroaryl.

[0489] Embodiment 65e: In one embodiment of embodiment 65, a compound is provided, wherein R 2c Is R 2c2 (which is cyano) substituted pyrazolyl, preferably pyrazol-2-yl, and R 2c3 is hydrogen; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In one embodiment of Embodiment 65, a compound is provided wherein R 2c Is R 2c2 (which is cyano) substituted pyridinyl, preferably pyridin-2-yl, and R 2c3 is hydrogen; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In one embodiment of Embodiment 65, a compound is provided wherein R 2c Is R 2c2 Substituted 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, preferably 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, wherein R 2c2 is alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl, and wherein R 2c3 is hydrogen; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 55-63.

[0490] Embodiment 65f: In one embodiment of embodiment 65, a compound is provided, wherein R 2c is optionally replaced by 1 or 2 R 2c1 substituted 8- or 9-membered bicyclic heterocycle; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein, including any of Embodiments 55-63.

[0491] Embodiment 65f-1: In a sub-embodiment of embodiment 65f, a compound is provided, wherein the 8-membered or 9-membered bicyclic heterocyclic ring (optionally surrounded by 1 or 2 R 2c1 substituted) is optionally substituted with 1 or 2 R 2c1 A substituted 5-membered heteroaryl, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably forms an 8-membered bicyclic heterocycle.

[0492] Embodiment 65f-2: In a sub-embodiment of embodiment 65f, a compound is provided, wherein the 8-membered or 9-membered bicyclic heterocyclic ring (optionally surrounded by 1 or 2 R 2c1 substituted) is optionally substituted with 1 or 2 R 2c1A substituted 5-membered heteroaryl, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group; and wherein the remainder of the molecule is attached to the 5-membered heteroaryl fused to the non-aromatic cyclic group via the 5-membered heteroaryl moiety.

[0493] Embodiment 65f-3: In a sub-embodiment of any one of embodiments 65f, 65f-1 and 65f-2, a compound is provided wherein the 8-membered or 9-membered bicyclic heterocyclic ring (optionally surrounded by 1 or 2 R 2c1 The non-aromatic moiety of the (substituted) group contains a heteroatom in the ring, preferably nitrogen.

[0494] Embodiment 65f-4: In a sub-embodiment of any one of embodiments 65f, 65f-1, 65f-2 and 65f-3, a compound is provided wherein the 8-membered or 9-membered bicyclic heterocyclic ring is replaced by one R 2c1 (which is hydrogen) and the second R 2c1 (which is selected from hydrogen and C 1 -C 6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl).

[0495] Embodiment 65g: In one embodiment of embodiment 65, a compound is provided, wherein R 2c Is R 2c2 substituted and optionally by R 2c3 substituted 8- or 9-membered bicyclic heterocycle; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein, including any of Embodiments 55-63.

[0496] Embodiment 65g-1: In a sub-embodiment of embodiment 65g, a compound is provided, wherein the 8-membered or 9-membered bicyclic heterocyclic ring (replaced by R 2c2 substituted and optionally by R 2c3 Replaced by R 2c2 substituted and optionally by R 2c3 A substituted 5-membered heteroaryl, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably forms an 8-membered bicyclic heterocycle.

[0497] Embodiment 65g-2: In a sub-embodiment of embodiment 65g, a compound is provided, wherein the 8-membered or 9-membered bicyclic heterocyclic ring (replaced by R 2c2 substituted and optionally by R 2c3 Replaced by R 2c2 substituted and optionally by R 2c3A substituted 5-membered heteroaryl, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group; and wherein the remainder of the molecule is attached to the 5-membered heteroaryl fused to the non-aromatic cyclic group via the 5-membered heteroaryl moiety.

[0498] Embodiment 65g-3: In a sub-embodiment of any one of embodiments 65g, 65g-1 and 65g-2, a compound is provided wherein the 8-membered or 9-membered bicyclic heterocyclic ring (replaced by R 2c2 substituted and optionally by R 2c3 The non-aromatic moiety of the (substituted) group contains a heteroatom in the ring, preferably nitrogen.

[0499] Embodiment 65g-4: In a sub-embodiment of any one of embodiments 65g, 65g-1, 65g-2 and 65g-3, a compound is provided wherein the 8-membered or 9-membered bicyclic heterocyclic ring is replaced by C 1 -C 6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl, and R 2c3 It's hydrogen.

[0500] Embodiment 66: Provided are compounds according to formula (I) or formula (Ij), wherein

[0501] R 2c is optionally replaced by 1 or 2 R 2c1 substituted 5-membered monocyclic heteroaryl; optionally substituted by 1 or 2 R 2c1 substituted 8-membered or 9-membered bicyclic heterocycle; or optionally substituted by 1, 2 or 3 R 2c1 substituted 6-membered monocyclic heteroaryl; and

[0502] Each R 2c1 are independently H, halo, C 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl, -CN, C 1 -C 6 Alkoxy, C 3 -C 8 Cycloalkyloxy, -(CH 2 ) 0-1 NH 2 、-NH(C 1 -C 6 Alkyl), -N(C 1 -C 6 alkyl) 2 、-(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 )0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C 3 alkyl;

[0503] and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In a sub-embodiment of Embodiment 66, a compound is provided wherein R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 substituted 8-membered bicyclic heterocycle; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 6-membered monocyclic heteroaryl.

[0504] Embodiment 66a: In one embodiment of embodiment 66, a compound is provided, wherein each R 2c1 is hydrogen (i.e. R 2c is not substituted); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In a sub-embodiment of Embodiment 66, a compound is provided wherein one R 2c1 is hydrogen and the other R 2c1 Selected from C 1 -C 6 Alkylcarbonyl, -CN, -(CH 2 ) 0-1 NH 2 and -(CH 2 ) 0-1 NHC(O)R 2f 、-(CH 2 ) 0-1 NHC(O)OR 2f ; where R 2f It is C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkyl C 1 -C3 and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In a sub-embodiment of Embodiment 66, a compound is provided wherein one R 2c1 is hydrogen and the other R 2c1 is -CN; and all other groups are as defined in the Summary or some or any embodiments provided herein, including any of Embodiments 55-63.

[0505] Embodiment 66b: In a sub-embodiment of embodiment 66 or 66a, a compound is provided, wherein R 2c is pyrazolyl, pyridinyl or 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is optionally substituted by 1 or 2 R 2c1 In a sub-embodiment of embodiment 66 or 66a, a compound is provided wherein R 2c is optionally replaced by 1 or 2 R 2c1 In a sub-embodiment of embodiment 66 or 66a, a compound is provided, wherein R 2c is optionally replaced by 1 or 2 R 2c1 In a sub-embodiment of embodiment 66 or 66a, a compound is provided wherein R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 6-membered monocyclic heteroaryl.

[0506] Embodiment 66c: In one embodiment of embodiment 66, a compound is provided, wherein R 2c is pyrazolyl, preferably pyrazol-2-yl, and is unsubstituted (ie, both R 2c1 is hydrogen) or by an R 2c1 (which is preferably cyano) substituted (ie another R 2c1 is hydrogen); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In one embodiment of Embodiment 66, a compound is provided wherein R 2c is pyridinyl, preferably pyridin-2-yl, and is unsubstituted (ie, both R 2c1 is hydrogen) or by an R 2c1 (which is cyano) substituted (i.e. another R 2c1is hydrogen); and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 55-63). In one embodiment of Embodiment 66, a compound is provided wherein R 2c is 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, preferably 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, and is unsubstituted (ie, both R 2c1 is hydrogen) or by an R 2c1 Replace (i.e. another R 2c1 is hydrogen), one of the R 2c1 is alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl; and all other groups are as defined in the Summary of the Invention or some or any embodiments provided herein, including any of Embodiments 55-63.

[0507] Embodiment 66d: In one embodiment of embodiment 66 or 66a, a compound is provided, wherein R 2c is optionally replaced by 1 or 2 R 2c1 substituted 8- or 9-membered bicyclic heterocycle; and all other groups are as defined in the Summary of the Invention or in some or any of the embodiments provided herein, including any of Embodiments 55-63.

[0508] Embodiment 66d-1: In a sub-embodiment of embodiment 66d, a compound is provided, wherein the 8-membered or 9-membered bicyclic heterocyclic ring (optionally surrounded by 1 or 2 R 2c1 substituted) is optionally substituted with 1 or 2 R 2c1 A substituted 5-membered heteroaryl, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably forms an 8-membered bicyclic heterocycle.

[0509] Embodiment 66d-2: In a sub-embodiment of embodiment 66d, a compound is provided, wherein the 8-membered or 9-membered bicyclic heterocyclic ring (optionally surrounded by 1 or 2 R 2c1 substituted) is optionally substituted with 1 or 2 R 2c1 A substituted 5-membered heteroaryl, preferably pyrazolyl, fused to a non-aromatic cyclic group, preferably forming an 8-membered bicyclic heterocyclic group; and wherein the remainder of the molecule is attached to the 5-membered heteroaryl fused to the non-aromatic cyclic group via the 5-membered heteroaryl moiety.

[0510] Embodiment 66d-3: In a sub-embodiment of any one of embodiments 66d, 66d-1 and 66d-2, a compound is provided wherein the 8-membered or 9-membered bicyclic heterocyclic ring (optionally surrounded by 1 or 2 R 2c1 The non-aromatic moiety of the (substituted) group contains a heteroatom in the ring, preferably nitrogen.

[0511] Embodiment 66d-4: In a sub-embodiment of any one of embodiments 66d, 66d-1, 66d-2 and 66d-3, a compound is provided wherein the 8-membered or 9-membered bicyclic heterocyclic ring is replaced by one R 2c1 (which is hydrogen) and the second R 2c1 (which is selected from hydrogen and C 1 -C 6 alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl).

[0512] Embodiment 67: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein one X 1 It is C(CH 2 R 2c ), and the other two X 1 Each is CR 2e ; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 52 to 66d-4). In a subembodiment, each CR 2e In one subembodiment, C(CH 2 R 2c ) is in R 2d The interposition.

[0513] Embodiment 68: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein one X 1 It is C(CH 2 R 2c ), the second X 1 is N, and the third X 1 Yes CR 2e ; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 52 to 66d-4). In one subembodiment, CR 2e In one subembodiment, C(CH 2 R 2c ) is in R 2d The interposition.

[0514] Embodiment 69: Provided are compounds according to formula (I), formula (Ih), formula (Ii) or formula (Ij), wherein one X 1 It is C(CH 2 R 2c ), and the other two X 1Each is N; and all other groups are as defined in the Summary of the Invention or some or any of the embodiments provided herein (including any of Embodiments 52 to 66d-4). In one subembodiment, C(CH 2 R 2c ) is in R 2d The interposition.

[0515] Embodiment 70: Provided is a pharmaceutical composition comprising a compound according to any one of Embodiments 52-69 or a stereoisomer, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0516] Embodiment 71: Provided is a method for treating a condition, disease or disorder by inhibiting MYST family lysine acetyltransferases including Kat6a and Kat6b, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Embodiments 52-69 or its stereoisomers, mixtures of stereoisomers and / or pharmaceutically acceptable salts or a therapeutically effective amount of a composition of Embodiment 70.

[0517] Embodiment 72: A method of embodiment 71 is provided, wherein the disorder, disease or condition is a hyperproliferative disease, such as cancer. In some or any embodiments, the cancer is a specific type selected from the following: lymphoma, melanoma, carcinoma (e.g., adenocarcinoma, hepatocellular carcinoma, medullary carcinoma, papillary carcinoma, squamous cell carcinoma), astrocytoma, glioma, medulloblastoma, myeloma, meningioma, neuroblastoma and sarcoma (e.g., angiosarcoma, chondrosarcoma, osteosarcoma). In some or any embodiments, the cancer may be a MYST overexpressing cancer; the cancer may overexpress MYST protein relative to non-cancerous tissue; the cancer may overproduce MYST mRNA relative to non-cancerous tissue; the cancer may be a MYST overexpressing cancer, wherein the overexpressed MYST protein or MYST mRNA may be any one of the KATs of the MYST family, such as KAT6A. In some or any embodiments, the cancer is selected from one or more of the following: leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, breast ductal carcinoma, colorectal cancer, colon cancer, squamous cell carcinoma, gastric cancer, adrenocortical carcinoma, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, female reproductive system cancer, male reproductive system cancer (including testicular cancer and penile cancer), central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, malignant fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nervous system cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm, primary CNS lymphoma, rectal cancer, respiratory system cancer, retinoblastoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thyroid cancer, urinary system cancer, uterine cancer, uterine sarcoma, vaginal cancer, endocrine cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitary adenoma, vascular system cancer, Waldenstrom's macroglobulinemia and / or Wilm's tumor. In some or any embodiments, the cancer is breast cancer, including ER-positive breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, or a blood cancer (including leukemia or lymphoma).

[0518] In some embodiments, provided herein is:

[0519] (a) compounds as described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B, and 1-72), and pharmaceutically acceptable salts and compositions thereof;

[0520] (b) compounds as described herein (e.g., compounds of Formula (A), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-2), (Id-1), (Ie-1), (If-1) or (Ig-1), Embodiments A, B and 1-72) and pharmaceutically acceptable salts and compositions thereof for use in treating a condition, disease or disorder by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B;

[0521] (c) methods for preparing compounds as described herein (e.g., compounds of Formula (A), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-2), Embodiments A, B, and 1-72), as described in more detail elsewhere herein;

[0522] (d) a pharmaceutical formulation comprising a compound as described herein (e.g., a compound of Formula (A)-7, (Ia)-8, (Ib)-9, (Ic)-10, (Id)-11, (Ie)-12, (If)-13, (Ig)-14, (Ih)-15, (Ii)-16, (Ij)-17, (Ia-2), (Ib-3), (Ic-4), (Ic-5), (Id-6), (Ie-7), (If-1), or (Ig-1), Embodiments A, B, and 1-72), or a stereoisomer, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;

[0523] (e) a method of treating a condition, disease or disorder in a subject by inhibiting a MYST family lysine acetyltransferase, including KAT6A and KAT6B, the method comprising administering a therapeutically effective amount of a compound as described herein (e.g., a compound of Formula (A)-7, (la-1), (la-2), (la-3), (la-4), (la-5), (la-6), (la-7), (la-8), (la-9), (la-10), (la-11), (la-12), (la-13), (la-14), (la-15), (la-16), (la-17), (la-18), (la-19), (la-20), (la-21), (la-22), (la-33), (la-34), (la-35), (la-36), (la-37), (la-38), (la-39), (la-40), (la-41), (la-42), (la-43), (la-44), (la-55), (la-56), (la-57), (la-58), (la-59),

[0524] (f) a pharmaceutical formulation comprising a compound as described herein (e.g., a compound of Formula (A)-7, (Ia)-8, (Ib)-9, (Ic)-10, (Id)-11, (Ie)-12, (If)-13, (Ig)-14, (Ih)-15, (Ii)-16, (Ij)-17, (Ia-2), (Ib-3), (Ic-4), (Ic-5), (Id-6), (Ie-7), (If-7), (Ig-8), (Ig-9), (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B, and 1-72), or a stereoisomer, mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof, and one or more other effective agents for treating a condition, disease, or disorder by inhibiting MYST family lysine acetyltransferases, including KAT6A and KAT6B, optionally in a pharmaceutically acceptable carrier; or

[0525] (g) a method of treating a condition, disease or disorder in a subject by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B, the method comprising administering a therapeutically effective amount of a compound as described herein (e.g., a compound of Formula (A)-7, (Ia)-8, (Ib)-9, (Ic)-1, (Id)-1, (Ie)-1, (If)-2, (Id-2), (Ie-2), (If-2), (If-3), (Ig-4), (Ig-5), (Ig-6), (Ig-7), (Ig-8), (Ig-9), (Ig-1), (Ig-1), (Ig-1), or (Ig-1), Embodiments A, B, and 1-72), a pharmaceutically acceptable salt or composition thereof, in combination and / or alternating with one or more agents that treat a condition, disease or disorder by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B.

[0526] Optically active compounds

[0527] It should be understood that the compounds provided herein have several chiral centers and can exist and separate in optically active and racemic forms. It should be understood that any racemic, optically active, diastereoisomerism, tautomeric or stereoisomeric forms of the compounds provided herein with useful properties as described herein or mixtures thereof are within the scope of the present invention. The manner of preparing optically active forms is well known in the art (in certain embodiments, the racemic form is split by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

[0528] In some or any embodiments, the term "stereoisomer" includes diastereomers, enantiomers, rotamers, atropisomers, regioisomers, and geometric isomers; and mixtures thereof.

[0529] In certain embodiments, methods of obtaining optically active materials are known in the art and include at least the following methods.

[0530] i) Physical separation of crystals - a technique to manually separate macroscopic crystals of individual stereoisomers. This technique can be used if crystals of individual stereoisomers are present, i.e. the material is a conglomerate, and the crystals are visually distinct;

[0531] ii) simultaneous crystallization - a technique in which the individual stereoisomers are crystallized separately from a solution of the racemate, which is possible only if the latter is a solid mass;

[0532] iii) Enzymatic resolution - a technique that partially or completely separates racemates by taking advantage of the different reaction rates of stereoisomers with enzymes;

[0533] iv) Enzymatic asymmetric synthesis - a synthetic technique in which at least one synthetic step uses an enzymatic reaction to obtain a stereomerically pure or enriched synthetic precursor of the desired stereoisomer;

[0534] v) Chemical asymmetric synthesis - a synthetic technique for synthesizing the desired stereoisomer from achiral precursors under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries;

[0535] vi) Diastereoisomer separation - In said technique, the racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences, and the chiral auxiliary is later removed to obtain the desired enantiomer;

[0536] vii) First and second order asymmetric transformations - in these techniques, diastereomers from the racemate are equilibrated to produce a predominance in solution of the diastereomer of the desired enantiomer, or preferential crystallization of the diastereomer of the desired enantiomer disturbs the equilibrium so that eventually in principle all of the material is converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then liberated from the diastereomers;

[0537] viii) Kinetic resolution - This technique refers to the partial or complete resolution of racemates (or further resolution of partially resolved compounds) achieved under kinetic conditions by means of the different reaction rates of stereoisomers with chiral, non-racemic reagents or catalysts;

[0538] ix) Stereospecific synthesis from non-racemic precursors - synthetic techniques that obtain the desired stereoisomer from achiral starting materials and in which the stereochemical integrity is not or only minimally compromised during the synthesis;

[0539] x) Chiral liquid chromatography - a technique for separating stereoisomers of a racemate in a liquid mobile phase by means of their different interactions with the stationary phase. The stationary phase can be made of a chiral material, or the mobile phase can contain another chiral material to stimulate different interactions;

[0540] xi) Chiral gas chromatography - a technique in which the racemate is volatilized and the stereoisomers are separated by means of their different interactions in the gaseous mobile phase with a column containing a stationary non-racemic chiral adsorbent phase;

[0541] xii) Chiral solvent extraction - a technique for separating stereoisomers by virtue of the preferential solubility of one stereoisomer in a specific chiral solvent;

[0542] xiii) Transport across chiral membranes - In this technique, the racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. The separation occurs due to the non-racemic chiral nature of the membrane, which allows only one stereoisomer of the racemate to pass.

[0543] Isotopically enriched compounds

[0544] Also provided herein are isotopically enriched compounds, including but not limited to isotopically enriched disubstituted pyrazoles.

[0545] Isotopic enrichment (in certain embodiments, deuteration) of pharmaceutical products has been demonstrated previously with some classes of drugs to improve pharmacokinetic ("PK"), pharmacodynamic ("PD"), and toxicity profiles. See, e.g., Lijinsky et al., Food Cosmet. Toxicol., 20:393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et al., Mutation Res. 308:33 (1994); Gordon et al., Drug Metab. Dispos., 15:589 (1987); Zello et al., Metabolism, 43:487 (1994); Gately et al., J. Nucl. Med., 27:388 (1986); Wade D, Chem. Biol. Interact. 117:191 (1999).

[0546] In certain embodiments, isotopic enrichment of a drug can be used to (1) reduce or eliminate undesirable metabolites, (2) extend the half-life of the parent drug, (3) reduce the number of doses required to achieve a desired effect, (4) reduce the amount of dose required to achieve a desired effect, (5) increase the formation of active metabolites (if formed), and / or (6) reduce the production of deleterious metabolites in specific tissues and / or produce more effective drugs and / or safer drugs for combination therapy, whether or not the combination therapy is intended.

[0547] Replacing an atom with one isotope of the atom will generally result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the kinetic isotope effect ("KIE"). For example, if a C-H bond breaks during the rate-determining step (i.e., the step with the highest transition state energy) in a chemical reaction, replacing the hydrogen with deuterium will result in a decrease in the reaction rate and the process will slow down. This phenomenon is known as the deuterium kinetic isotope effect ("DKIE"). See, e.g., Foster et al., Adv. Drug Res., Vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., Vol. 77, pp. 79-88 (1999).

[0548] The magnitude of the DKIE can be expressed as the ratio between the rate of a given reaction of C-H bond rupture and the rate of the same reaction of replacing hydrogen with deuterium. The DKIE can range from about 1 (no isotope effect) to extremely large values ​​(e.g., 50 or more), meaning that the reaction can be 50 times slower or more when deuterium is substituted for hydrogen. High DKIE values ​​can be attributed in part to a phenomenon called tunneling, which is a result of the uncertainty principle. Tunneling is attributed to the small mass of the hydrogen atom, and occurs because transition states involving protons can sometimes form in the absence of the required activation energy. Since deuterium has a greater mass than hydrogen, its probability of statistically experiencing this phenomenon is much lower.

[0549] Tritium ("T") is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with 2 neutrons in the nucleus and an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T. 2 O. Tritium decays slowly (half-life = 12.3 years) and emits low energy beta particles that cannot pass through the outer layer of human skin. Internal exposure is the primary hazard associated with this isotope, but large quantities must be ingested to pose a significant health risk. Compared to deuterium, smaller amounts of tritium must be consumed before dangerous levels of tritium are reached. Substituting tritium ("T") for hydrogen produces a stronger bond than deuterium and gives a numerically larger isotope effect. Similarly, substituting isotopes for other elements (including but not limited to 13 C or 14 C replaces carbon, with 33 S. 34 S or 36 S replaces sulfur, 15 N replaces nitrogen, and with 17 O or 18 O replacing oxygen) can produce a similar kinetic isotope effect.

[0550] For example, DKIE is used to reduce the hepatotoxicity of ethyl halides by potentially limiting the production of reactive species such as trifluoroacetyl chloride. However, this approach may not be applicable to all drug classes. For example, the incorporation of deuterium may lead to metabolic switching. The concept of metabolic switching asserts that when clamped by a phase I enzyme, a xenobiotic can transiently bind and rebind in multiple conformations prior to a chemical reaction (e.g., oxidation). The relatively large binding pockets in many phase I enzymes and the promiscuous nature of many metabolic reactions support this hypothesis. Metabolic switching can potentially produce known metabolites in different proportions as well as completely new metabolites. This new metabolic profile may confer more or less toxicity.

[0551] The animal body expresses a variety of enzymes for eliminating foreign substances, such as therapeutic agents, from its circulatory system. In certain embodiments, such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases to react with these foreign substances and convert the foreign substances into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) or carbon-carbon (CC) pi bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacokinetics, pharmacodynamics, and acute and long-term toxicity profiles relative to the parent compound. For many drugs, such oxidation is rapid. Therefore, these drugs generally require administration of multiple or high daily doses.

[0552] Thus, isotopic enrichment at certain positions of the compounds provided herein will produce a detectable KIE, which will affect the pharmacokinetic, pharmacological and / or toxicological profiles of the compounds provided herein, compared to similar compounds having natural isotopic compositions.

[0553] Pharmaceutical compositions and methods of administration

[0554] The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein.Any compound disclosed herein can be provided in an appropriate pharmaceutical composition and administered via a suitable route of administration.

[0555] The methods provided herein encompass the administration of pharmaceutical compositions containing at least one compound as described herein, including compounds of Formula (A)-7, (Ia)-8, (Ib)-9, (Ic)-10, (Id)-11, (Ie)-12, (If)-13, (Ig)-14, (Ih)-15, (Ii)-16, (Ij)-17, (Ia-2), (Ib-3), (Ic-4), (Ic-5), (Id-6), (Ie-7), (If-7), (Ig-8), (Ig-9), (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B, and 1-72, in salt form where appropriate, alone or in combination with one or more compatible and pharmaceutically acceptable carriers (e.g., diluents or adjuvants), or with another agent for treating a condition, disease, or disorder by inhibiting MYST family lysine acetyltransferases, including KAT6A and KAT6B.

[0556] In certain embodiments, the second dose can be prepared or packaged with the compound provided herein. The second dose will only be prepared with the compound provided herein when the co-formulation does not interfere with the activity of any dose or method of administration according to the judgment of those skilled in the art. In certain embodiments, the compound provided herein and the second dose are prepared separately. They can be packaged together, or packaged separately, for the convenience of professionals in the art.

[0557] In clinical practice, the active agents provided herein can be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (eg, in the form of an aerosol). In certain embodiments, the compounds provided herein are administered orally.

[0558] Tablets, pills, hard gelatin capsules, powders or granules can be used as solid compositions for oral administration. In these compositions, the active product is mixed with one or more inert diluents or adjuvants (such as sucrose, lactose or starch).

[0559] These compositions may contain substances other than diluents, for example lubricants such as magnesium stearate, or coatings intended for controlled release.

[0560] Pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents (e.g., water or liquid paraffin) can be used as liquid compositions for oral administration. These compositions may also contain substances other than diluents, and in certain embodiments contain wetting, sweetening or flavoring products.

[0561] Compositions for parenteral administration may be emulsions or sterile solutions. Propylene glycol, polyethylene glycol, vegetable oils (particularly olive oil) or injectable organic esters (ethyl oleate in certain embodiments) may be used as solvents or vehicles. These compositions may also contain adjuvants, particularly wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization may be performed in several ways, using a bacterial filter, by radiation or by heating in certain embodiments. It may also be prepared in the form of a sterile solid composition, which may be dissolved in sterile water or any other injectable sterile medium when used.

[0562] Compositions for rectal administration are suppositories or rectal capsules containing, in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

[0563] The composition may also be an aerosol. For use in the form of a liquid aerosol, the composition may be a stable sterile solution or solid composition dissolved in pyrogen-free sterile water, saline or any other pharmaceutically acceptable vehicle at the time of use. For use in the form of anhydrous aerosols intended for direct inhalation, the active ingredient is finely powdered and combined with a water-soluble solid diluent or vehicle (in certain embodiments, polydextrose, mannitol or lactose).

[0564] In certain embodiments, the composition provided herein is a pharmaceutical composition or a single unit dosage form. The pharmaceutical composition and single unit dosage form provided herein include one or more preventive or therapeutic agents (e.g., compounds or other preventive or therapeutic agents provided herein) and one or more pharmaceutically acceptable carriers in a preventive or therapeutically effective amount. In a specific embodiment and in this context, the term "pharmaceutically acceptable" means approved by a federal or state government regulatory agency or listed in the U.S. Pharmacopoeia or other recognized pharmacopeia for use in animals, and more specifically in humans. The term "carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant, complete and incomplete), excipient, or vehicle administered together with the therapeutic agent. Any embodiment is described for "excipient". Such drug carriers can be sterile liquids, such as water and oil, including those oils of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water can be used as a carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmac eutical Press; 22nd edition (September 15, 2012).

[0565] Typical pharmaceutical compositions and dosage forms include one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and in certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. Whether a particular excipient is suitable for inclusion in a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form will be applied to the subject and the specific active ingredient in the dosage form. Where necessary, the composition or single unit dosage form may also contain a small amount of a wetting agent or emulsifier or a pH buffer.

[0566] The lactose-free compositions provided herein may include excipients well known in the art and listed in the U.S. Pharmacopoeia (USP 36-NF 31S2) in certain embodiments. Generally speaking, lactose-free compositions include active ingredients, binders / fillers, and lubricants that are pharmaceutically compatible and pharmaceutically acceptable. Exemplary lactose-free dosage forms include active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0567] Anhydrous pharmaceutical compositions and dosage forms comprising active ingredients are further contemplated herein, because water can promote the degradation of some compounds. For example, the addition of water (e.g., 5%) is recognized in the pharmaceutical field as a means of simulating long-term storage to determine, for example, the shelf life or the characteristics of the stability of the formulation over time. See, for example, Jens T.Carstensen, Drug Stability:Principles & Practice, 2nd edition, Marcel Dekker, New York, 1995, pages 379-80. In fact, water and heat can accelerate the decomposition of some compounds. Therefore, the effect of water on the formulation may be crucial, because moisture and / or humidity are usually encountered during the manufacture, handling, packaging, storage, transportation, and use of the formulation.

[0568] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low-moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity is expected during manufacture, packaging, and / or storage.

[0569] Anhydrous pharmaceutical compositions should be prepared and stored so that their anhydrous nature is maintained. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable formulary kits. In certain embodiments, suitable packaging includes, but is not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0570] Further provided are pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate at which the active ingredient will decompose. Such compounds (referred to herein as "stabilizers") include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0571] Pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, etc. Oral formulations can include standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions and dosage forms will contain a preventive or therapeutically effective amount of a preventive or therapeutic agent, in a purified form in certain embodiments, and an appropriate amount of a carrier to provide a form suitable for administration to a subject. The preparation should be suitable for the mode of administration. In a certain embodiment, the pharmaceutical composition or single unit dosage form is sterile and in a form suitable for administration to a subject (in certain embodiments, an animal subject, such as a mammalian subject, in certain embodiments, a human subject).

[0572] The pharmaceutical composition is formulated to be compatible with its intended route of administration. In certain embodiments, the route of administration includes, but is not limited to, parenteral administration, such as intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intratumoral, intrasynovial, and rectal administration. In a specific embodiment, the composition is formulated according to conventional procedures to be suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans. In one embodiment, the pharmaceutical composition is formulated according to conventional procedures for subcutaneous administration to humans. Typically, the composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. If necessary, the composition may also include a solubilizing agent and a local anesthetic (such as lidocaine (lignocamne)) to relieve pain at the injection site.

[0573] In certain embodiments, dosage forms include, but are not limited to, tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; lozenges; troches; dispersions; suppositories; ointments; poultices; pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.

[0574] The composition, shape, and type of dosage forms provided herein will generally vary depending on their use. In certain embodiments, a dosage form for the initial treatment of a viral infection may contain a larger amount of one or more active ingredients than a dosage form for the maintenance treatment of the same infection. Similarly, a parenteral dosage form may contain a smaller amount of one or more active ingredients than an oral dosage form for the treatment of the same disease or condition. These and other ways in which the specific dosage forms contemplated herein will differ from one another will be readily apparent to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0575] Typically, the components of the composition are supplied separately or mixed together in unit dosage form, in certain embodiments as an anhydrous lyophilized powder or anhydrous concentrate in a hermetically sealed container (e.g., an ampoule or sachet indicating the amount of active agent). When the composition is to be administered by infusion, it can be dispensed using an infusion bottle containing sterile pharmaceutical grade water or saline. When the composition is to be administered by injection, an ampoule of sterile water for injection or saline can be provided so that the components can be mixed before administration.

[0576] Typical dosage forms include a compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, ranging from about 0.1 mg to about 1000 mg / day, administered in a single dose once daily in the morning, or in divided doses throughout the day with food. Specific dosage forms may have about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1.0 mg, 2.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 50.0 mg, 100 mg, 200 mg, 250 mg, 500 mg, or 1000 mg of active compound.

[0577] Oral dosage form

[0578] Pharmaceutical compositions suitable for oral administration may be presented in discrete dosage forms such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined amount of active ingredient and may be prepared by pharmaceutical methods well known to those skilled in the art. See generally Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd Edition (September 15, 2012).

[0579] In certain embodiments, the oral dosage form is solid and is prepared under anhydrous conditions using anhydrous ingredients, as described in detail herein. However, the scope of the compositions provided herein extends beyond anhydrous solid oral dosage forms. Therefore, other forms are described herein.

[0580] Typical oral dosage forms are prepared by combining the active ingredient in an intimate mixture with at least one excipient according to conventional pharmaceutical formulation techniques. Excipients can take a variety of forms, depending on the form of the preparation required for administration. In certain embodiments, excipients suitable for oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. In certain embodiments, excipients suitable for solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0581] Tablets and capsules represent the most advantageous oral dosage unit forms due to ease of administration, in which case solid excipients are employed. Tablets may be coated by standard aqueous or nonaqueous techniques, if desired. Such dosage forms may be prepared by any pharmaceutical method. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier, a finely powdered solid carrier, or both, and then shaping the product into the desired presentation (if necessary).

[0582] In certain embodiments, tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing the active ingredient (such as powder or granules) in a free-flowing form, optionally mixed with an excipient, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0583] In certain embodiments, excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums (e.g., gum arabic), sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethylcellulose), polyvinyl pyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., No. 2208, No. 2906, No. 2910), microcrystalline cellulose, and mixtures thereof.

[0584] In certain embodiments, fillers suitable for use in pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. Binders or fillers in pharmaceutical compositions are typically present in about 50% to about 99% by weight of the pharmaceutical composition or dosage form.

[0585] In certain embodiments, suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL PH 101, AVICEL PH 103, AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A particular binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC 581. Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103™ and Starch 1500LM.

[0586] Disintegrants are used in compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate in storage, while tablets containing too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Therefore, a sufficient amount of disintegrant that is neither too much nor too little to deleteriously alter the release of the active ingredient should be used to form a solid oral dosage form. The amount of disintegrant used varies based on the type of formulation and can be easily discerned by those skilled in the art. Typical pharmaceutical compositions contain about 0.5% to about 15% by weight of disintegrant, particularly about 1% to about 5% by weight of disintegrant.

[0587] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0588] Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. In certain embodiments, other lubricants include syloid silica gel (AEROSIL 200, manufactured by WR Grace Co. of Baltimore, MD), condensation aerosols of synthetic silica (sold by Degussa Co. of Plano, TX), CAB O SIL (a fumed silica product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used, lubricants are typically used in an amount of less than about 1% by weight of the pharmaceutical composition or dosage form into which they are incorporated.

[0589] Delayed release dosage form

[0590] The active ingredients, such as compounds provided herein, can be administered by controlled release means or delivery devices well known to those of ordinary skill in the art. In certain embodiments, but not limited to, those controlled release members or delivery devices are described in the following U.S. Patents: U.S. Patent No. 3,845,770; U.S. Patent No. 3,916,899; U.S. Patent No. 3,536,809; U.S. Patent No. 3,598,123; U.S. Patent No. 4,008,719; U.S. Patent No. 5,674,533; U.S. Patent No. 5,059,595; U.S. Patent No. 5,591,767; U.S. Patent No. 5,120,548; U.S. Patent No. 5,073,543; U.S. Patent No. 5,639,476; U.S. Patent No. 5,354,556; U.S. Patent No. 5,639,480; U.S. Patent No. 5,733,566; U.S. Patent No. 5,739,108; U.S. Patent No. 5,89 No. 1,474; U.S. Pat. No. 5,922,356; U.S. Pat. No. 5,972,891; U.S. Pat. No. 5,980,945; U.S. Pat. No. 5,993,855; U.S. Pat. No. 6,045,830; U.S. Pat. No. 6,087,324; U.S. Pat. No. 6,113,943; U.S. Pat. No. 6,197,350; U.S. Pat. No. 6,248,363; U.S. Pat. No. 6,264,970; U.S. Pat. No. 6,267,981; U.S. Pat. No. 6,376,461; U.S. Pat. No. 6,419,961; U.S. Pat. No. 6,589,548; U.S. Pat. No. 6,613,358; and U.S. Pat. No. 6,699,500; each of which is incorporated herein by reference in its entirety. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients, using hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres or combinations thereof in certain embodiments to provide desired release profiles in different proportions. Suitable controlled release formulations known to those of ordinary skill in the art (including those described herein) can be easily selected for use with the active ingredients provided herein. Therefore, single unit dosage forms suitable for oral administration are contemplated herein, such as, but not limited to, tablets, capsules, gel caps and caplets suitable for controlled release.

[0591] The common goal of all controlled release pharmaceutical products is to improve drug therapy compared to what is achieved with their non-controlled counterparts. Ideally, the use of optimally designed controlled release formulations in medical treatments is characterized by using a minimum of drug substance to cure or control an illness, disease or condition in a minimum amount of time. The advantages of controlled release formulations include extended drug activity, reduced dosage frequency and increased subject compliance. In addition, controlled release formulations can be used to affect the time or other characteristics (e.g., blood levels of the drug) of the onset of action, and therefore can affect the occurrence of side effects (e.g., adverse effects).

[0592] Most controlled-release formulations are designed to initially release a certain amount of drug (active ingredient) to rapidly produce the desired therapeutic effect, and gradually and continuously release other amounts of drug to maintain this level of therapeutic or preventive effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. A variety of conditions can stimulate the controlled release of an active ingredient, including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0593] In certain embodiments, the drug can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In certain embodiments, a pump can be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al., N. Engl. J. Med. 321: 574 (1989)). In another embodiment, a polymer material can be used. In another embodiment, a controlled release system can be placed in a subject at an appropriate site determined by one skilled in the art, i.e., so that only a portion of the systemic dose is required (see, e.g., Goodson, Medical Applications of Controlled Release, Vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in Langer's review (Science 249: 1527-1533 (1990)). The active ingredient can be dispersed in a solid internal matrix such as polymethyl methacrylate, polybutyl methacrylate, plasticized or non-plasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of acrylates and methacrylates, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, which is insoluble in water. The external polymer film in the body fluid is surrounded by, for example, polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride and vinyl acetate, vinylidene chloride, copolymer of ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer and ethylene / vinyloxyethanol copolymer. Then, the active ingredient diffuses via the external polymer film in the release rate controlling step. The percentage of active ingredient in such parenteral compositions is highly dependent on its specific properties and the needs of the experimenter.

[0594] Parenteral Dosage Forms

[0595] In certain embodiments, parenteral dosage forms are provided. Parenteral dosage forms can be administered to a subject by a variety of routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because its administration usually bypasses the subject's natural defenses against contaminants, parenteral dosage forms are generally sterile or can be sterilized before being administered to a subject. In certain embodiments, parenteral dosage forms include, but are not limited to, solutions ready for injection, anhydrous products ready for dissolution or suspension in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[0596] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. In certain embodiments, suitable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0597] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into parenteral dosage forms.

[0598] Transdermal, topical and mucosal dosage forms

[0599] Transdermal, topical and mucosal dosage forms are also provided. Transdermal, topical and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th edition, Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues in the oral cavity can be formulated as mouthwashes or oral gels. In addition, transdermal dosage forms include "reservoir-type" or "matrix-type" patches that can be applied to the skin and retained for a specific period of time to allow the desired amount of active ingredient to penetrate.

[0600] Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms as contemplated herein are well known to those skilled in the art of medicine and depend on the specific tissue to which a given pharmaceutical composition or dosage form will be administered. In view of the above facts, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form non-toxic and pharmaceutically acceptable lotions, tinctures, creams, emulsions, gels, or ointments. Where desired, moisturizers or humectants may also be added to pharmaceutical compositions and dosage forms. Examples of such additional ingredients are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0601] Depending on the specific tissue to be treated, additional components may be used prior to, concurrently with, or after treatment with the provided active ingredient. In certain embodiments, a penetration enhancer may be used to aid in the delivery of the active ingredient to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols, such as ethanol, oleyl alcohol, and tetrahydrofurfuryl alcohol; alkyl sulfoxides, such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones, such as polyvinyl pyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters, such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

[0602] The pH of the tissue of pharmaceutical composition or dosage form or administration of pharmaceutical composition or dosage form can also be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity of the solvent carrier, its ionic strength or tension can be adjusted to improve delivery. For example, the compound of stearate can also be added to the pharmaceutical composition or dosage form to advantageously change the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In this regard, stearate can serve as the lipid vehicle, emulsifier or surfactant and delivery enhancer or penetration enhancer of preparation. Different salts, hydrates or solvates of active ingredient can be used to further adjust the property of the resulting composition.

[0603] Dosage and unit dosage form

[0604] In human therapeutics, the doctor will determine that it thinks the most appropriate posology according to preventive or curative treatment and according to age, body weight, infection stage and other factors specific to the subject to be treated. In certain embodiments, dosage is about 1 mg to about 1000 mg / day (for adults) or about 5 mg to about 250 mg / day or about 10 mg to 50 mg / day (for adults). In certain embodiments, dosage is about 5 mg to about 400 mg / day or 25 mg to 200 mg / day / adult. In certain embodiments, it is also expected that the dosage rate of about 50 mg to about 500 mg / day.

[0605] In other aspects, a method for treating a subject's illness, disease or condition by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B is provided, the method being implemented by administering an effective amount of a compound provided herein or its stereoisomer, a mixture of stereoisomers and / or a pharmaceutically acceptable salt to a subject in need. The amount of the compound or composition that will effectively treat the condition or one or more symptoms thereof will vary with the nature and severity of the condition, disease or condition and the route of administering the active ingredient. The frequency and dosage will also vary according to the specific factors of each subject, depending on the specific therapy (e.g., therapeutic agent or preventive agent) administered, the severity of the condition, disease or condition, the route of administration, and the age, body, weight, reaction and previous medical history of the subject. The effective dose can be extrapolated from a dose-response curve derived from an in vitro or animal model test system.

[0606] In certain embodiments, the exemplary dosage of the composition includes milligrams or micrograms of the active compound per kilogram of subject or sample weight (e.g., about 10 micrograms / kg to about 50 milligrams / kg, about 100 micrograms / kg to about 25 milligrams / kg, or about 100 micrograms / kg to about 10 milligrams / kg). For the compositions provided herein, in certain embodiments, based on the weight of the active compound, the dosage applied to the subject is 0.140 mg / kg to 3 mg / kg subject body weight. In certain embodiments, the dosage applied to the subject is between 0.20 mg / kg and 2.00 mg / kg or between 0.30 mg / kg and 1.50 mg / kg subject body weight.

[0607] In certain embodiments, the recommended daily dose range of the compositions provided herein for the illness, disease or condition described herein is within the range of about 0.1 mg to about 1000 mg / day, given in a single dose once a day or in divided doses throughout the day. In certain embodiments, the daily dose is administered twice a day in equal divided doses. In certain embodiments, the daily dose range should be about 10 mg to about 200 mg / day, between about 10 mg and about 150 mg / day in other embodiments, between about 25 mg and about 100 mg / day in other embodiments, between about 100 mg and about 300 mg / day in other embodiments. In some cases, it is necessary to use the dosage of the active ingredient outside the disclosed range herein, as is apparent to those of ordinary skill in the art. In addition, it should be noted that the clinician or treating physician will know the mode and time of interrupting, adjusting or terminating the therapy in conjunction with the subject's response.

[0608] Different therapeutically effective amounts may be applicable to different illnesses, diseases or conditions, as readily known to those of ordinary skill in the art. Similarly, the dosage amounts and dosage frequency schedules described herein also encompass amounts sufficient to prevent, manage, treat or improve such conditions, but not sufficient to cause adverse effects associated with the compositions provided herein or sufficient to mitigate the adverse effects. In addition, when multiple doses of the compositions provided herein are administered to a subject, all doses need not be the same. In certain embodiments, the dose administered to a subject may be increased to improve the preventive or therapeutic effect of the composition, or it may be reduced to mitigate one or more side effects that a particular subject is experiencing.

[0609] In certain embodiments, the daily dose of the compositions provided herein administered to prevent, treat, manage, or improve a condition, disorder, disease, or one or more symptoms thereof in a subject is about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, based on the weight of the active compound. In some embodiments, the present invention relates to an oral dosage form of at least about 1 mg / kg to about 200 mg / kg of an oral dosage form. In some embodiments, the present invention relates to an oral dosage form of at least about 1 mg / kg to about 200 mg / kg of an oral dosage form. In some embodiments, the present invention relates to an oral dosage form of at least about 1 mg / kg to about 200 mg / kg of an oral dosage form. In certain embodiments, the daily dose of the compositions provided herein administered to prevent, treat, manage, or ameliorate a condition, disorder, disease, or one or more symptoms thereof in a subject is between (including end values) about 1-10 mg / kg, about 10 mg / kg, about 25-50 mg / kg, about 50-100 mg / kg, about 50-150 mg / kg, about 100-150 mg / kg, about 100-200 mg / kg, about 150-200 mg / kg, about 150-250 mg / kg, about 250-300 mg / kg, about 300-350 mg.kg, about 300-400 mg / kg, about 200-400 mg / kg, about 100-300 mg / kg, or about 400-500 mg / kg based on the weight of the active compound.

[0610] In certain embodiments, the twice daily dose of a composition provided herein administered to prevent, treat, manage, or ameliorate a condition, disorder, disease, or one or more symptoms thereof in a subject is about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 225 mg / kg, about 250 mg / kg, about 275 mg / kg, or about 300 mg / kg based on the weight of the active compound. In certain embodiments, the twice daily dose of the compositions provided herein administered to prevent, treat, manage, or improve a condition, disorder, disease, or one or more symptoms thereof in a subject is between (including end values) about 1-10 mg / kg, about 10 mg / kg, about 25-50 mg / kg, about 50-100 mg / kg, about 50-150 mg / kg, about 100-150 mg / kg, about 100-200 mg / kg, about 150-200 mg / kg, or about 150-250 mg / kg based on the weight of the active compound.

[0611] In certain embodiments, the same composition can be administered repeatedly and the administrations can be separated by at least 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, the same preventive or therapeutic agent can be administered repeatedly and the administrations can be separated by at least 4 hours, 6 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0612] In some aspects, provided herein is a unit dose in a form suitable for administration, the unit dose comprising a compound or its stereoisomer, a mixture of stereoisomers and / or a pharmaceutically acceptable salt. Such forms are described in detail herein. In certain embodiments, the unit dose comprises 1 mg to 1000 mg, 5 mg to 250 mg or 10 mg to 50 mg active ingredient. In a specific embodiment, the unit dose comprises about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 125 mg, 250 mg, 500 mg or 1000 mg active ingredient. Such unit doses can be prepared according to techniques familiar to those skilled in the art.

[0613] In certain embodiments, the dosage of the second agent to be used in the combination therapy is provided herein. In certain embodiments, the dosage used in the combination therapy provided herein is lower than the dosage used or currently used to treat illness, disease or condition by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B. The recommended dosage of the second agent can be obtained according to the knowledge of those skilled in the art. For those second agents approved for clinical use, the recommended dosage is described in, for example, Hardman et al., ed., 1996, Goodman and Gilman's The Pharmacological Basis Of Therapeutics 9th Edition, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th Edition, 2003, Medical Economics Co., Inc., Montvale, NJ; The full text of the document is incorporated herein by reference.

[0614] In various embodiments, therapy (e.g., a compound provided herein and a second agent) is administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, about 1 hour apart, about 1 hour apart, about 2 hours apart, about 3 hours apart, about 4 hours apart, about 4 hours apart, about 5 hours apart, about 6 hours apart, about 7 hours apart, about 8 hours apart, about 9 hours apart, about 10 hours apart, about 10 hours apart, about 11 hours apart, about 12 hours apart, about 12 hours apart, 18 hours apart, 24 hours apart, 36 hours apart, 36 hours apart, 48 hours apart, 52 hours apart, 60 hours apart, 72 hours apart, 84 hours apart, 84 hours apart, or 96 hours apart. In various embodiments, therapy is administered no more than 24 hours apart or no more than 48 hours apart. In certain embodiments, two or more therapies are administered within the same patient visit.In other embodiments, the compound provided herein and the second agent are administered simultaneously.

[0615] In other embodiments, the compound provided herein and the second dose are administered about 2 to 4 days apart, about 4 to 6 days apart, about 1 week apart, about 1 to 2 weeks apart, or more than 2 weeks apart.

[0616] In certain embodiments, the same dose can be administered repeatedly and the administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, the same dose can be administered repeatedly and the administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0617] In certain embodiments, the compound provided herein and the second agent are applied to the patient in a certain order and within a certain time interval, and in certain embodiments are applied to mammals, such as humans, so that the compound provided herein can work together with another agent to provide an increased benefit than when the agent is applied in other ways. In certain embodiments, the second activating agent can be applied sequentially in any order at the same time or at different time points; however, if not applied at the same time, its application time should be close enough to provide the desired treatment or preventive effect. In certain embodiments, the compound provided herein and the second activating agent play their role at the overlapping time. Each second activating agent can be applied separately in any appropriate form and by any suitable route. In other embodiments, the compound provided herein is applied before, at the same time as, or after the application of the second activating agent.

[0618] In certain embodiments, the compound provided herein and the second agent are periodically administered to the patient. Cyclic therapy involves administering a first agent (e.g., a first preventive or therapeutic agent) over a period of time, followed by administering a second agent and / or a third agent (e.g., a second and / or third preventive or therapeutic agent) over a period of time, and repeating this sequential administration. Cyclic therapy can reduce the development of resistance to one or more therapies, avoid or mitigate the side effects of a therapy, and / or improve the efficacy of treatment.

[0619] In certain embodiments, the compound and the second activating agent provided herein are used in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days, or about once a week. A cycle can include administering the compound and the second agent provided herein by infusion in about 90 minutes per cycle, about 1 hour per cycle, about 45 minutes per cycle. Each cycle can include at least 1 week of drug withdrawal, at least 2 weeks of drug withdrawal, at least 3 weeks of drug withdrawal. The number of cycles used is about 1 to about 12 cycles, more generally about 2 to about 10 cycles, and more generally about 2 to about 8 cycles.

[0620] In other embodiments, multiple courses of treatment are administered to the patient simultaneously, i.e., individual doses of the second agent are administered separately within a certain time interval, so that the compound provided herein can work together with the second active agent. In certain embodiments, a component administered once a week can be combined with other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimen can be implemented simultaneously, even if each therapeutic agent is not administered simultaneously or on the same day.

[0621] The second agent can be added or synergistic with the compound provided herein. In certain embodiments, the compound provided herein is administered simultaneously with one or more second agents in the same pharmaceutical composition. In another embodiment, the compound provided herein is administered simultaneously with one or more second agents in a separate pharmaceutical composition. In another embodiment, the compound provided herein is administered before or after the second agent is administered. It is also contemplated that the compound provided herein and the second agent are administered by the same or different routes of administration (e.g., oral and parenteral). In certain embodiments, when the compound provided herein is administered simultaneously with a second agent that potentially produces adverse side effects (including but not limited to toxicity), the second active agent can be advantageously administered at a dose lower than the critical value that causes adverse side effects.

[0622] Pill Box

[0623] Also provided is a medicine box for treating a disease, a disease or a condition by inhibiting a MYST family lysine acetyltransferase including KAT6A and KAT6B. The medicine box may include a compound or composition provided herein, a second dose or composition, and instructions for providing information about the usage of treating a disease, a disease or a condition by inhibiting a MYST family lysine acetyltransferase including KAT6A and KAT6B to a health care provider. The instructions may be provided in a printed form or in an electronic media form (such as a floppy disk, CD or DVD) or in the form of a website where such instructions may be obtained. The unit dose of the compound or composition or the second dose or composition provided herein may include a dose such that when applied to a subject, the effective plasma level of the treatment or prevention of the compound or composition may be maintained in the subject for at least 1 day. In some embodiments, the compound or composition may be included in a sterile aqueous pharmaceutical composition or a dry powder (e.g., lyophilized) composition.

[0624] In some embodiments, suitable packaging is provided. As used herein, "packaging" includes a solid matrix or material that is generally used in systems and can accommodate a compound provided herein and / or a second dose that is suitable for application to a subject within a fixed limit. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic foil laminated envelopes, etc. If electron beam sterilization technology is adopted, packaging should have a sufficiently low density to allow the contents to be sterilized.

[0625] How to use

[0626] It is believed that inhibitors of post-translational lysine acetylation mediated by KATs of the MYST family are promising anti-tumor agents and thus may be useful therapeutic agents, for example, for the treatment of cancer. Such agents may also be used as therapeutic agents for the treatment of cancers that exhibit overexpression of MYST proteins.

[0627] Provided herein is a method for treating a condition, disease or disorder in a subject by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ia-1), Formula (Ib-2), Formula (Ic-1) ), compounds of Formula (Ic-2), Formula (Id-1), Formula (Ie-1), Formula (If-1) or Formula (Ig-1), Embodiments A, B and 1-72, including single enantiomers, mixtures of enantiomeric pairs, individual diastereomers, mixtures of diastereomers, individual stereoisomers, mixtures of stereoisomers, individual geometric isomers, mixtures of geometric isomers or tautomeric forms thereof); or a pharmaceutically acceptable salt, solvate, prodrug, phosphate ester or active metabolite thereof.

[0628] In certain embodiments, provided herein is a method for treating a subject's illness, disease or condition by inhibiting a MYST family lysine acetyltransferase including KAT6A and KAT6B. In certain embodiments, the method encompasses the following steps: administering to a subject in need a combination of a compound and a second agent that effectively treats an illness, disease or condition by inhibiting a MYST family lysine acetyltransferase including KAT6A and KAT6B. The compound may be any compound as described herein, and the second agent may be any second agent described in the art or herein. In certain embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.

[0629] Diseases that can be treated with compounds according to any of the formulae described herein, including compounds in Embodiments A, B, and 1-72, include leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, breast ductal carcinoma, colorectal cancer, colon cancer, squamous cell carcinoma, gastric cancer, adrenocortical carcinoma, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumors, female reproductive system cancer, male reproductive system cancer (including testicular cancer and penile cancer), central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer , hepatocellular carcinoma, hypopharyngeal cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, liver cancer, malignant fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nervous system cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm, primary CNS lymphoma, rectal cancer, respiratory system cancer, retinoblastoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thyroid cancer, urinary system cancer, uterine cancer, uterine sarcoma, vaginal cancer, endocrine cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitary adenoma, vascular system cancer, Waldenstrom's macroglobulinemia and / or Wilm's tumor.

[0630] Determination method

[0631] The efficacy of a compound in treating a condition, disease or disorder by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B can be determined according to any assay known to those of skill in the art. Exemplary assay methods are provided elsewhere herein.

[0632] Second therapeutic agent

[0633] In certain embodiments, the compounds and compositions provided herein can be used in methods for treating an illness, disease or condition by inhibiting a MYST family lysine acetyltransferase including KAT6A and KAT6B, the method comprising further administering a second agent. The second agent can be any agent known to those skilled in the art that effectively treats an illness, disease or condition by inhibiting a MYST family lysine acetyltransferase including KAT6A and KAT6B, including those currently approved by the United States Food and Drug Administration or other similar agencies in countries outside the United States.

[0634] In some embodiments, the disease is cancer and the second agent is a cancer treatment. In some embodiments, the disease is cancer and the second agent is a standard of care treatment for the specific cancer to be treated. In some embodiments, the disease is cancer and the second agent is a chemotherapeutic agent. In some embodiments, the second agent is selected from an alkylating agent (e.g., cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine (DTIC), nitrosoureas, temozolomide (oral dacarbazine)); an anthracycline (e.g., daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin); a cytoskeletal disruptor (taxanes, such as paclitaxel, albumin-bound paclitaxel, and docetaxel); an epothilone; a histone deacetylase inhibitor (e.g., voriconazole; voriconazole; valrubicin); orinostat and romidepsin); topoisomerase I inhibitors (e.g., irinotecan and topotecan); topoisomerase II inhibitors (e.g., etoposide, teniposide, and tafluposide); kinase inhibitors (e.g., sorafenib, cobimetinib, cabozantanib, lapatinib, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib); murafenib and vismodegib); nucleotide analogs and precursor analogs (e.g., azacitidine, azathiopurine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, and thioguanine);peptide antibiotics (e.g., bleomycin and actinomycin); platinum agents (e.g., carboplatin, cisplatin, and oxaliplatin); retinoids (e.g., tretinoin, alitretinoin, and bexarotene); vinca alkaloids or derivatives (e.g., capecitabine, vinblastine, vincristine, vindesine, and vinorelbine); eribulin; ixabepilone; radiation; bevacizumab. izumab); olaparib; aromatase inhibitors (e.g., letrozole, anastrozole, and exemestane); rituximab; ibritumomab; prednisone; kinase inhibitors, such as sorafenib, cobiminib, cabozantinib, lapatinib, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, and vismodegib; CDK1, CDK4, and / or CDK6 inhibitors, such as palbociclib, Kisqali, or Verzenio; immunotherapies, such as checkpoint inhibitors (e.g., pembrolizumab, nivolumab, and atezolizumab); and enzalutamide. ;

[0635] In some embodiments, the disease is cancer and the second agent is a CDK1, CDK4 and / or CDK6 inhibitor. In some embodiments, the disease is cancer and the second agent is palbociclib, ribociclib or abemaciclib.

[0636] In some embodiments, the disease is cancer and the second agent is an immunotherapy, such as a checkpoint inhibitor (eg, pembrolizumab, nivolumab, and atezolizumab).

[0637] In some embodiments, the disease is breast cancer and the second agent is fulvestrant.

[0638] In some embodiments, the disease is breast cancer (e.g., postmenopausal breast cancer) and the second agent is radiation, docetaxel, paclitaxel, a platinum agent (cisplatin, carboplatin), vinorelbine, capecitabine, liposomal doxorubicin, gemcitabine, mitoxantrone, ixabepilone, albumin-bound paclitaxel, eribulin, trastuzumab, pertuzimab, ado-trastuzumab, lapatinib, bevacizumab, olaparib, radiation, an aromatase inhibitor (e.g., letrozole, anastrozole, and exemestane), or tamoxifen.

[0639] In some embodiments, the disease is liver cancer (eg, hepatocellular carcinoma, hepatocellular carcinoma unsuitable for surgery or local therapy) and the second agent is sorafenib.

[0640] In some embodiments, the disease is prostate cancer and the second agent is radiation, abiraterone, or enzalutamide.

[0641] In some embodiments, the disease is pancreatic adenocarcinoma and the second agent is radiation.

[0642] In some embodiments, the disease is ovarian cancer and the second agent is bevacizumab, olaparib, radiation, an aromatase inhibitor (eg, letrozole, anastrozole, and exemestane), or tamoxifen.

[0643] In some embodiments, the disease is B-cell lymphoma and the second agent is rituximab, radiation, ibritumomab tiuxetan, cyclophosphamide, doxorubicin, vincristine, or prednisone.

[0644] In certain embodiments, the compounds provided herein are administered in combination with one second agent. In other embodiments, the compounds provided herein are administered in combination with two second agents. In other embodiments, the compounds provided herein are administered in combination with two or more second agents.

[0645] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more preventive and / or therapeutic agents). The use of the term "combination" does not limit the order in which therapy (e.g., preventive and / or therapeutic agents) are administered to a subject with a disorder. The first therapy (e.g., preventive or therapeutic agent, such as a compound provided herein) can be administered to a subject with a disorder before the second therapy (e.g., preventive or therapeutic agent) is administered (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), simultaneously with it, or thereafter (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks).

[0646] As used herein, the term "synergistic" includes a combination of a compound provided herein and another therapy (e.g., a preventive or therapeutic agent) that has been used or is currently being used to prevent, manage, or treat a condition, which is more effective than the additive effect of the therapy. The synergistic effect of a combination of therapies (e.g., a combination of preventive or therapeutic agents) allows the use of one or more therapies at lower doses and / or the less frequent administration of the therapy to a subject with the condition. The ability to use a lower dose of a therapy (e.g., a preventive or therapeutic agent) and / or the less frequent administration of the therapy reduces the toxicity associated with administering the therapy to the subject without reducing the efficacy of the therapy in terms of preventing or treating the condition). In addition, the synergistic effect can improve the efficacy of the agent in terms of preventing or treating the condition. Finally, the synergistic effect of a combination of therapies (e.g., a combination of preventive or therapeutic agents) can avoid or mitigate the adverse or undesirable side effects associated with the use of any therapy alone.

[0647] The active compounds provided herein can be combined or administered alternately with another therapeutic agent, particularly an agent that effectively treats an illness, disease or condition by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B. In combination therapy, effective doses of two or more agents are administered together, wherein each dose of the effective dose is administered continuously or sequentially, as in alternating or sequential step therapy. The dose administered will depend on the absorption, inactivation and excretion rate of the drug and other factors known to those skilled in the art. It should be noted that the dose value will also vary with the severity of the illness, disease or condition to be treated. It should be further understood that for any particular subject, the specific dosage regimen and schedule should be adjusted over time according to individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition.

[0648] Preparation of compounds

[0649] The compounds provided herein can be prepared, separated or obtained by any method that is obvious to those skilled in the art. The compounds provided herein can be prepared according to the exemplary preparation schemes provided below. The reaction conditions, steps and reactants not provided in the exemplary preparation schemes should be obvious and known to those skilled in the art.

[0650] Other steps and reagents not provided in the exemplary preparation schemes should be known to those skilled in the art. Exemplary preparation methods are described in detail in the examples herein.

[0651] General Scheme 1

[0652] General Scheme 1A illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (b); an X 1 Yes CR 3 , and the other two are CH; and all other groups are as defined in the Summary of the Invention or any embodiment described herein. General Scheme 1B illustrates the preparation of compounds of formula (I), wherein R 2 is a ring (b); an X 1 Yes CR 3 , and the other two are CH; R 3 Yes-(CH 2 )Y; Y is And all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein.

[0653] General Scheme 1 illustrates the preparation of compounds of formula (I)

[0654]

[0655] Scheme (A) illustrates a method for preparing appropriately substituted benzo[d]isoxazole compounds, wherein in step 1, 2-fluorobenzonitrile can be converted to the benzo[d]isoxazole-3-amine scaffold by reaction with N-hydroxyacetamide in the presence of a base such as potassium tert-butoxide. In step 2, the free amine is reacted with R 1 S(O) 2 Cl reacts in the presence of a base (such as triethylamine, pyridine or sodium hydride).

[0656] Scheme (B) illustrates a compound (wherein R 3 Yes-(CH 2 )Y and Y is a suitably substituted 5-membered heteroaryl such as pyrazole). Those skilled in the art can extend this synthesis to other heteroaryls, including C-linked heteroaryls.

[0657] The synthesis of benzo[d]isoxazole compounds can be initiated from appropriately substituted 2-fluoro-4-(hydroxymethyl)benzonitrile. The hydroxyl group can be reacted with a compound of formula Ms-X (wherein Ms-X is ) in alkali (such as CsCO 3 ) to the substituted pyrazole moiety, as shown in step 1 above. Fluorobenzonitrile can be converted to the benzo[d]isoxazole-3-amine scaffold by reacting it with N-hydroxyacetamide in the presence of a base such as potassium tert-butoxide (step 2 above). In the next step (step 3), the free amine is reacted with R 1 S(O) 2 Cl is reacted in the presence of a base such as triethylamine, pyridine or sodium hydride. The final step involves deprotection of the amine (step 4) followed by amide formation in step 5 (via reaction with R in the presence of a base such as triethylamine). 3a C(O)Cl reaction, where R 3a Selected from group a), or by activating R using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art 3a C(O)OH, where R 3a selected from group a), or with sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a Selected from group a)) to form a sulfonamide.

[0658] General Scheme 2

[0659] General Scheme 2 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (c); yes R 3 Yes-(CH 2 )Y and Y is pyrazolyl or pyridinyl, each of which is replaced by R Y substituted; and all other groups are as defined in the Summary of the Invention or in any embodiments described herein.

[0660]

[0661] [1,2,4]triazolo[4,3-a]pyridine compounds can be prepared starting with appropriately substituted 2-chloroisonicotinate methyl ester. In Scheme (A) above, the ester can be reduced to the alcohol (step 1 above) using a reducing agent such as LiBH4. The hydroxyl group can be catalyzed by reacting with 1-(methylsulfonyl)-1H-pyrazole of formula X in the presence of a base such as CsCO 3) in the presence of a substituted pyrazole moiety, as shown in step 2 above. The resulting 2-chloropyridine can be converted to the corresponding 2-hydrazinylpyridine by heating in the presence of hydrazine hydrate (step 3). In step 4, reaction with cyanogen bromide can lead to the assembly of the [1,2,4]triazolo[4,3-a]pyridin-3-amine scaffold. In the presence of a base (such as triethylamine, pyridine or sodium hydride) with R 1 S(O) 2 Cl reaction can produce N-linked pyrazole substituted compounds. The final step involves deprotection of the amine (step 4) followed by amide formation in step 6 in the presence of a base such as triethylamine (via reaction with R 3a C(O)Cl reaction, where R 3a Selected from group a), or by activating R using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art 3a C(O)OH, where R 3a selected from the group a), or with sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a Selected from group a)) to form a sulfonamide.

[0662] For C-linked heteroaryl substituted final compounds, a slightly modified version of Scheme (B) can be used. In this case, the main difference is that the hydroxymethylpyridine can be converted to the bromomethyl group using phosphorus tribromide (step 2). Finally, this bromomethyl group can be subjected to Negishi coupling conditions with a 2-bromoheteroaryl compound (2-bromopyridine in Scheme (B)) via zinc powder followed by a palladium catalyst such as tetrakis(triphenylphosphine)palladium. This method can also be applied to other heteroaryl analogs.

[0663] General solution 3

[0664] General Scheme 3 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (c); yes R 3 Yes-(CH 2 )Y and Y is R Y substituted and optionally by R 2e substituted pyrazolyl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein.

[0665]

[0666] [1,2,3]triazolo[1,5-a]pyridine compounds can be synthesized using substituted 2-cyanopyridine compounds. The N-linked pyrazole moiety can be introduced using the procedures described above for [1,2,4]triazolo[4,3-a]pyridine compounds (steps 1 and 2). Assembly of the core scaffold is described above in steps 3 and 4. 2-Cyanopyridine can be converted to 1-amino 2-cyanopyridine by reaction with sulfonylated hydroxylamine (step 3) followed by cyclization in the presence of hydroxylamine and acetic anhydride. In the final step (step 5), the free amine can be reacted with R 1 S(O) 2 Cl reacts in the presence of a base such as triethylamine, pyridine or sodium hydride. Y can be a group having an amine with a suitable protecting group. After the scaffold assembly in step 5, the final step may involve deprotection of the amine followed by amide formation (via reaction with R 3a C(O)Cl reaction, where R 3a Selected from group a), or by activating R using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art 3a C(O)OH, where R 3a selected from the group a), or with sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a Selected from group a)) to form a sulfonamide.

[0667] General Scheme 4

[0668] General Scheme 4 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (a) and R 3 Yes-(CH 2 )Y; and all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein.

[0669]

[0670] Benzopyrazole compounds can be synthesized by using appropriately substituted 2-fluorobenzonitrile as starting material. Step 1, Step 2 and Step 3 can be performed as previously described in General Schemes 2 and 3 above. The fluorobenzonitrile intermediate can be converted to N-methylbenzopyrazole (Step 4, using methylhydrazine) or unsubstituted benzopyrazole (Step 5, using hydrazine) as shown above. In Step 6, the free amine can be reacted with R 1 S(O) 2 Cl reacts in the presence of a base (such as triethylamine, pyridine or sodium hydride). In this scheme, Y can be a substituent R YAfter the scaffold assembly in step 6, the final step may involve deprotection of the amine followed by amide formation (via reaction with R 3a C(O)Cl reaction, where R 3a Selected from group a), or by activating R using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art 3a C(O)OH, where R 3a selected from the group a), or with sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a Selected from group a)) to form a sulfonamide.

[0671] General Solution 5

[0672] General Scheme 5 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (c); yes R 3 Yes-(CH 2 )Y; and all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein.

[0673]

[0674] Starting from an appropriately substituted 2-cyano-4-formylpyridine. Step 1 consists of reacting 2-cyano-4-formylpyridine with NaBH 4 Reduction of the aldehyde to the alcohol followed by substitution with a leaving group such as methylsulfonyl or halide can be performed as described previously in steps 2 and 3 of general scheme 4. Reduction in step 2 can be achieved by treatment of pyridinecarbonitrile with LAH in THF. Treatment of the 2-aminomethylpyridine intermediate with cyanogen bromide in toluene (step 3) can provide the imidazo[1,5-a]pyridin-3-amine intermediate, which can be catalyzed using R 1 S(O) 2 Cl and a base (such as pyridine, triethylamine or sodium hydride) to the desired compound of formula I, as shown in step 2 and described in general scheme 1 (A). In this scheme, Y can be a substituent R Y After the scaffold assembly in step 4, the final step may involve deprotection of the amine followed by amide formation (via reaction with R 3a C(O)Cl reaction, where R 3a Selected from group a), or by activating R using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art 3aC(O)OH, where R 3a selected from the group a), or with sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a Selected from group a)) to form a sulfonamide.

[0675] General Solution 6

[0676] General Scheme 6 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (c); yes R 3 Yes-(CH 2 )Y; and all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein.

[0677]

[0678] The appropriately substituted 2-cyano-5-formylpyridine can be subjected to steps 1 and 2 following the procedure described in Scheme 5 above. Steps 3 and 4 involve N-formylation followed by reflux in phosphorus oxychloride to construct the imidazo[1,5-a]pyridine ring. Nitration and reduction using the reagents in step 5 can generate the substituted imidazo[1,5-a]pyridin-1-amine. The final sulfonamide product can be obtained by reacting this amine with R 1 S(O) 2 Cl and a base such as pyridine, triethylamine or sodium hydride to generate, as shown in Step 6 and described in General Scheme 1. In this scheme, Y can be a substituent R Y After the scaffold assembly in step 6, the final step may involve deprotection of the amine followed by amide formation (via reaction with R 3a C(O)Cl reaction, where R 3a Selected from group a), or by activating R using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art 3a C(O)OH, where R 3a selected from the group a), or with sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a Selected from group a)) to form a sulfonamide.

[0679] General Scheme 7

[0680] General Scheme 7 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (d); X 2a It's an O; an X 2 Yes CR4 And other X 2 each is CH; and all other groups are as defined in the Summary of the Invention or in any embodiments described herein.

[0681]

[0682] The synthesis of benzofuran compounds can start with an appropriately substituted 2-hydroxybenzaldehyde compound. Cyclization to a benzofuran compound is performed by heating with ethyl bromoacetate in the presence of a base such as K2CO3 (step 1). The resulting acid can be converted to the corresponding primary amide using ammonium chloride and an amide coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art in the presence of a base (step 2). The acylsulfonamide in step 3 can be synthesized by deprotonating the primary amide with a base such as NaH and then reacting with an appropriately substituted sulfonyl chloride. Step 4 constitutes the deprotection of the amine protecting group, followed by step 5, in which the amine is coupled with an appropriately substituted acid using a coupling agent such as HBTU, or with an appropriately substituted acyl chloride or sulfonyl chloride in the presence of a base such as triethylamine. In this scheme, R 4 It may be a linker with an amine having an appropriate protecting group. After the scaffold assembly in step 3, the final step may involve deprotection of the amine followed by amide formation (via reaction with R 3a C(O)Cl reaction, where R 3a Selected from group a), or by activating R using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art 3a C(O)OH, where R 3a selected from the group a), or with sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a Selected from group a)) to form a sulfonamide.

[0683] General Scheme 8

[0684] General Scheme 8 illustrates the preparation of compounds of formula (I) wherein R 2 is ring (e) or ring (f); and all other groups are as defined in the Summary of the Invention or in any embodiment described herein.

[0685] The synthesis of N'-benzoylsulfonyl hydrazide compounds of formula (I) can be initiated by Suzuki coupling of an appropriately substituted 2-bromoheteroaryl with methyl or ethyl 3-carboxyphenylboronic acid / ester or Chan-Lam coupling of an appropriately substituted pyrazole (e.g.) with methyl or ethyl 3-carboxyphenylboronic acid / ester (step 1). In step 2, the ester can be reacted with hydrazine hydrate under heating to convert to the corresponding hydrazide. The hydrazide can be converted to the sulfonyl hydrazide by reaction with an appropriately substituted sulfonyl chloride in the presence of a base such as pyridine. In this general scheme, R 5 may be substituted by Z and optionally by R 2e Substituted 5-membered or 6-membered monocyclic heteroaryl.

[0686]

[0687] Z has an amine with a suitable protecting group. After the scaffold assembly in step 3, the final step may involve deprotection of the amine followed by amide formation (via reaction with R) in the presence of a base such as triethylamine. 3a C(O)Cl reaction, where R 3a Selected from group a), or by activating R using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art 3a C(O)OH, where R 3a selected from the group a), or with sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a Selected from group a)) to form a sulfonamide.

[0688] General Scheme 9

[0689] General Scheme 9 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (g), where Q 1 and Q 2 Each is N and Q 3 is O; or Q 2 and Q 3 Each is N and Q 1 is S or O; or Q 1 It is CH, Q 2 is N, and Q 3 It's O.

[0690] Ring (g) can be obtained by reacting an appropriately substituted phenyl-heteroarylamine with R 1 S(O) 2 Cl is assembled by reaction in the presence of a base (such as triethylamine, pyridine or sodium hydride). In ring (g), R 6 is substituted by Q and optionally by R 2eSubstituted monocyclic heteroaryl; or R 6 is Q. Q initially has an amine with a suitable protecting group. After the scaffold assembly in step 1, the final step may involve deprotection of the amine followed by amide formation (via reaction with R) in the presence of a base such as triethylamine. 3a C(O)Cl reaction, where R 3a Selected from group a), or by activating R using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art 3a C(O)OH, where R 3a selected from the group a), or with sulfonyl chloride (R 3a S(O) 2 Cl, where R 3a Selected from group a)) to form a sulfonamide.

[0691]

[0692] The assembly of the key intermediate (phenyl-heteroarylamine) shown in Step 1(A) can be carried out in a variety of ways as known to those skilled in the art. Some examples are depicted in Scheme 9(B). In row (1), the appropriately substituted benzoic acid can be activated using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art and then reacted with guanidine. Cyclization to the aminoheteroaryl intermediate can be mediated by iodophenyldiacetic acid. In row (2), the appropriately substituted benzaldehyde can be condensed with semicarbazide / thiosemicarbazide in the presence of (but not limited to) NaOAc. The reaction can be carried out in the presence of iodine and a base such as K 2 CO 3 or Cs 2 CO 3 ) in the presence of an oxidative cyclization to a key aminoheteroaryl intermediate. In another example (row 3), an appropriately substituted methyl benzoate can be converted to the corresponding 3-oxo-3-phenylpropionitrile using a base (such as LDA) and reacting with acetonitrile. Cyclization to an aminoisoxazole compound in the presence of hydroxylamine. Row 4 illustrates another general method for assembling this key intermediate. The protected 2-amino 5-bromo substituted heteroaryl compound can be subjected to a Suzuki coupling (or other coupling conditions known to those skilled in the art) with an appropriately substituted phenylboronic acid (or boronate). Subsequent deprotection of the amine can provide the desired key intermediate.

[0693] General plan 10

[0694] General Scheme 10 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (b); an X 1 It is C(CH 2 R 2c ), and the other two X 1Yes CR 2e ; and R 2c It is two R 2c1 substituted pyrazol-1-yl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein.

[0695]

[0696] The synthesis of benzo[d]isoxazole compounds can be started from appropriately substituted 2-fluoro-4-(hydroxymethyl)benzonitrile. The hydroxyl group can be substituted by reacting with 1-(methylsulfonyl)-1H-pyrazole of formula X in the presence of a base such as CsCO 3 ) to the substituted pyrazole moiety, as shown in step 1 above. Fluorobenzonitrile can be converted to the benzo[d]isoxazole-3-amine scaffold by reacting it with N-hydroxyacetamide in the presence of a base such as potassium tert-butoxide (step 2 above). In the final step (step 3), the free amine can be reacted with R 1 S(O) 2 Cl reacts in the presence of a base (such as triethylamine, pyridine or sodium hydride).

[0697] General Scheme 11

[0698] General Scheme 11 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (c); yes One X 1 It is C(CH 2 R 2c ), and the other two X 1 Yes CR 2e ; and R 2c It is two R 2c1 substituted pyrazol-1-yl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein.

[0699]

[0700] [1,2,4]triazolo[4,3-a]pyridine compounds can be prepared starting with appropriately substituted 2-chloroisonicotinate methyl ester. In Scheme (A) above, a reducing agent such as LiBH 4 ), the ester can be reduced to the alcohol (step 1 above). The hydroxyl group can be reacted with 1-(methylsulfonyl)-1H-pyrazole of formula X in the presence of a base (e.g., CsCO 3) in the presence of a substituted pyrazole moiety, as shown in step 2 above. The resulting 2-chloropyridine can be converted to the corresponding 2-hydrazinylpyridine by heating in the presence of hydrazine hydrate (step 3). In step 4, reaction with cyanogen bromide can lead to the assembly of the [1,2,4]triazolo[4,3-a]pyridin-3-amine scaffold. In the presence of a base (such as triethylamine, pyridine or sodium hydride) with R 1 S(O) 2 Cl reaction can produce N-linked pyrazole-substituted final compounds.

[0701] For C-linked heteroaryl substituted final compounds, a slightly modified version of protocol (B) can be used. In this case, the main difference is that the hydroxymethylpyridine can be converted to the bromomethyl group using phosphorus tribromide (step 2). Finally, this bromomethyl group can be subjected to Negishi coupling conditions mediated by zinc powder followed by a palladium catalyst such as tetrakis(triphenylphosphine)palladium. This approach can also be applied to other heteroaryl analogs.

[0702] General Scheme 12

[0703] General Scheme 12 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (c); yes One X 1 It is C(CH 2 R 2c ), and the other two X 1 Yes CR 2e ; and R 2c It is two R 2c1 substituted pyrazol-1-yl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein.

[0704]

[0705] [1,2,3]triazolo[1,5-a]pyridine compounds can be synthesized using substituted 2-cyanopyridine compounds. The N-linked pyrazole moiety can be introduced using the procedures described above for [1,2,4]triazolo[4,3-a]pyridine compounds (steps 1 and 2). Assembly of the core scaffold is described above in steps 3 and 4. 2-Cyanopyridine can be converted to 1-amino 2-cyanopyridine by reaction with sulfonylated hydroxylamine (step 3) followed by cyclization in the presence of hydroxylamine and acetic anhydride. In the final step (step 5), the free amine can be reacted with R 1 S(O) 2 Cl reacts in the presence of a base (such as triethylamine, pyridine or sodium hydride).

[0706] General Scheme 13

[0707] General Scheme 13 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (a); an X 1 It is C(CH 2 R 2c ), and the other two X 1 Yes CR 2e ; and R 2c It is two R 2c1 substituted pyrazol-1-yl; and all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein.

[0708]

[0709] Benzopyrazole compounds can be synthesized by using appropriately substituted 2-fluorobenzonitrile as starting material. Step 1, Step 2, and Step 3 can be performed as described in the previous synthesis of [1,2,4]triazolo[4,3-a]pyridine compounds (General Schemes 2 and 3 above). The fluorobenzonitrile intermediate can be converted to N-methylbenzopyrazole (Step 4, using methylhydrazine) or unsubstituted benzopyrazole (Step 5, using hydrazine) as shown above. In the final step (Step 6), the free amine can be reacted with R 1 S(O) 2 Cl reacts in the presence of a base (such as triethylamine, pyridine or sodium hydride).

[0710] General Scheme 14

[0711] General Scheme 14 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (c); yes and all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein, and can be prepared as shown below:

[0712]

[0713] Starting from an appropriately substituted 2-cyano-4-formylpyridine. Step 1 consists of reacting 2-cyano-4-formylpyridine with NaBH 4 Reduction of the aldehyde to the alcohol followed by R 2c -LG substitution, where R 2c is as defined in any aspect or embodiment provided herein, and LG is a leaving group such as methylsulfonyl or a halide, and can be performed as previously described in steps 2 and 3 of General Scheme 13. The reduction in step 2 can be achieved by treating pyridinecarbonitrile with LAH in THF. Treatment of the 2-aminomethylpyridine intermediate with cyanogen bromide in toluene (step 3) can provide an imidazo[1,5-a]pyridine-3-amine intermediate, which can be used to obtain the pyridinecarbonitrile. 1 S(O) 2Cl and a base such as pyridine, triethylamine or sodium hydride to the desired compound of formula II as shown in step 4 and described in general scheme 10.

[0714] General Scheme 15

[0715] General Scheme 15 illustrates the preparation of compounds of formula (I) wherein R 2 is a ring (c); yes and all other groups are as defined in the Summary of the Invention or in any of the embodiments described herein, and can be prepared as shown below:

[0716]

[0717] The appropriately substituted 2-cyano-5-formylpyridine can be subjected to steps 1 and 2 following the procedure described above in Scheme A. Steps 3 and 4 involve N-formylation followed by reflux in phosphorus oxychloride to construct the imidazo[1,5-a]pyridine ring. Nitration and reduction using reagents in step 5 can yield the substituted imidazo[1,5-a]pyridin-1-amine. This amine can be reacted with R 1 S(O) 2 Cl and a base such as pyridine, triethylamine or sodium hydride are reacted to produce the final sulfonamide product as shown in Step 6 and described in General Scheme 10.

[0718] Example

[0719] As used herein, the symbols and conventions used in these methods, schemes, and examples, whether or not specific abbreviations are explicitly defined, are consistent with those used in the contemporary scientific literature (e.g., Journal of the American Chemical Society or Journal of Biological Chemistry). Specifically, but not limiting, the following abbreviations may be used in the examples and throughout this specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimolar); μM (micromolar); Hz (hertz); MHz (megahertz); mmol (millimolar); h, hr or hrs (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization); rt (room temperature); Rf (retention factor); TLC (thin layer chromatography); LCMS (liquid chromatography-mass spectrometry); HPLC (high performance liquid chromatography); AcOH (acetic acid); n-BuLi (n-butyllithium); t BuOK (potassium tert-butoxide); CDCl 3 (Chloroform-d); CH 3 CN (acetonitrile); Cs 2 CO3 (cesium carbonate); DMF (N,N-dimethylformamide); DCM (dichloromethane); DEA (diethylamine); DIPEA (diisopropylethylamine); DMSO (dimethyl sulfoxide); DMSO-d 6 (dimethyl sulfoxide-d6); EtOAc or EA (ethyl acetate); Et 3 N (triethylamine); EtOH (ethanol); HCl (hydrochloric acid); H 2 SO 4 (sulfuric acid); K 2 CO 3 (potassium carbonate); LiOH (lithium hydroxide); MsCl (methanesulfonyl chloride); MeI (methyl iodide); MeOH (methanol); MeOH-d 4 (Methanol-d 4 ); NaBH 4 (sodium borohydride); NaH(sodium hydride); NaHCO 3 (sodium bicarbonate); NaNO 2 (sodium nitrite); NaOH (sodium hydroxide); NaOMe (sodium methoxide); Na 2 SO 4 (sodium sulfate); Pd(PPh 3 ) 4 (Tetrakis(triphenylphosphine)palladium(0)); SO 2 (sulfur dioxide); SO 2 Cl 2 (sulfuryl chloride); T3P (propanephosphonic anhydride); THF (tetrahydrofuran); TMEDA (1,2-bis(dimethylamino)ethane); Zn (zinc); ZnCN 2 (zinc cyanide).

[0720] For all the following examples, standard processing and purification methods known to those skilled in the art can be used. Unless otherwise indicated, all temperatures are expressed in ° C (degrees Celsius). Unless otherwise noted, all reactions are carried out at room temperature. The synthetic methods illustrated herein are intended to illustrate applicable chemistry through the use of specific examples and do not indicate the scope of the present disclosure.

[0721] Synthetic intermediate examples

[0722] Scheme 1: Synthesis of cyclohexylmethanesulfonyl chloride (3)

[0723]

[0724] Step 1: Synthesis of S-(cyclohexylmethyl)thioacetate (2)

[0725] Potassium thioacetate (1.93 g, 17 mmol) was added to a stirred solution of compound 1 (2 g, 11.3 mmol) in DMF (20 mL) in portions at room temperature. The reaction mixture was stirred at 50 ° C for 1 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave the title compound 2 (1.8 g, 92.61%) as a dark brown liquid. TLC: Heptane (R f :0.7). 1 H NMR (400 MHz, CDCl 3 ): δ2.79(d,J=6.8Hz,2H),2.33(s,3H),1.79-1.61(m,5H),1.49-1.38(m,1H),1.27-1.12(m,3H),1.05-0.89(m,2H).

[0726] Step 2: Synthesis of cyclohexylmethanesulfonyl chloride (3):

[0727] To a stirred solution of N-chlorosuccinimide (2.7 g, 20.3 mmol) in 2N HCl (1.7 mL) at 0 °C was added a solution of compound 2 (1 g, 0.58 mmol) pre-dissolved in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo and the residue was extracted with diethyl ether. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 The crude compound was purified by column chromatography on silica gel (100-200 mesh) using a gradient of 0-5% EtOAc / heptane to afford the title compound 3 (0.81 g, 71%) as a yellow liquid. TLC: 10% EtOAc / heptane (R f :0.25). 1 H NMR (400 MHz, CDCl 3 ): δ3.63(d,J=6.4Hz,2H),2.24-2.18(m,1H),2.01-1.96(m,2H),1.80-1.66(m,3H),1.40-1.29(m,2H),1.25-1.11(m,3H).

[0728] Scheme 2: Synthesis of 2,6-dimethoxybenzenesulfonyl chloride (5)

[0729]

[0730] To a stirred solution of 1,3-dimethoxybenzene 4 (2 g, 14.4 mmol) and TMEDA (2.4 mL, 15.9 mmol) in THF (20 mL) was added dropwise at 0 °C under nitrogen atmosphere. n BuLi [2.5 M solution in hexane] (6.3 mL, 15.9 mmol) was added while maintaining the internal reaction temperature below 5 °C. The contents were stirred at the same temperature for 30 min, then cooled to -78 °C and heated with SO 2 The gas was bubbled for 30 min. The reaction mixture was then slowly warmed to 10 °C and the resulting precipitate was collected by filtration and washed with anhydrous diethyl ether. The solid was suspended in hexane (20 ml), cooled to 0 °C and SO was added dropwise 2 Cl 2 (2.2 mL, 28.8 mmol) in hexanes (20 mL) while maintaining the internal temperature below 3 °C. The reaction mixture was then stirred at 0 °C for 1 h and the solid was collected by filtration and washed with cold hexanes. The solid was partitioned between diethyl ether and water and the layers were separated; the aqueous layer was further extracted with diethyl ether. The combined organic extracts were purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound 5 (1 g, 29.23%) as a white solid. TLC: 10% EtOAc / heptane (R f :0.3). 1 H NMR (400 MHz, DMSO-d 6 ): δ7.27(t,J=8.0Hz,1H), 6.64(d,J=8.8Hz,2H), 3.72(s,6H).

[0731] Scheme 3: Synthesis of tert-butyl ((1-(methylsulfonyl)-1H-pyrazol-4-yl)methyl)-carbamate (7)

[0732]

[0733] To a stirred solution of compound 6 (0.1 g, 0.5 mmol) in DMF (2 mL) was added NaHMDS (0.5 mL, 0.5 mmol) followed by methanesulfonyl chloride (0.04 mL, 0.55 mmol) at -40 °C and the resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was washed with saturated NH 4 The solution was quenched with Cl and extracted with ethyl acetate. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure to give the title compound 7 (0.06 g, 42.98%) as a white gummy solid. TLC: 50% EtOAc / heptane (R f :0.4). 1 H NMR (400 MHz, DMSO-d 6 ):δ8.08(s,1H),7.84(s,1H),7.29(broad single peak,1H),4.02(broad single peak,2H),3.50(s,3H),1.39(s,9H). 10 H 17 N 3 O 4 LCMS calculated for S: 275.32; found: 299.90 (M+23).

[0734] Scheme 4: Synthesis of tert-butyl ((1-(methylsulfonyl)-1H-pyrazol-3-yl)methyl)-carbamate (10)

[0735]

[0736] Step 1: Synthesis of tert-butyl ((1H-pyrazol-3-yl)methyl)carbamate (9)

[0737] To a stirred solution of compound 8 (1 g, 10.30 mmol) in DCM (50 mL) was added (Boc) at 0 °C. 2 O (2.12mL, 9.27mmol), and the reaction mixture was stirred at room temperature for 3h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water and extracted with DCM. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave the title compound 9 (1.7 g, 83.7%) as a white solid. TLC: 70% EtOAc / heptane (R f :0.3). C 9 H 15 N 3 O 2 LCMS calculated value: 197.24; found value: 198.2 (M+1).

[0738] Step 2: Synthesis of tert-butyl ((1-(methylsulfonyl)-1H-pyrazol-3-yl)methyl)carbamate (10) and tert-butyl ((1-(methylsulfonyl)-1H-pyrazol-5-yl)methyl)carbamate (10A)

[0739] To a stirred solution of compound 9 (1.7 g, 8.62 mmol) in DMF (25 mL) was added NaHMDS (8.6 mL, 8.62 mmol) followed by methanesulfonyl chloride (0.72 mL, 9.40 mmol) at -40 °C and the resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was washed with saturated NH 4 The solution was quenched with Cl and extracted with ethyl acetate. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 Drying and concentration under reduced pressure afforded the title compound 10 (0.9 g, 38.1%) as a white gummy solid. TLC: 50% EtOAc / heptane (R f :0.4). 1 H NMR (400 MHz, DMSO-d 6 ): δ8.18(d,J=2.4Hz,1H),7.41(t,J=6.0Hz,1H),6.43(d,J=2.4Hz,1H),4.15(d,J=6.4Hz,2H),3.50(s,3H),1.40(s,9H). 1 H NMR indicated that 10 was the major isomer. 10 H 17 N 3 O 4 LCMS calcd for S: 275.32; found: 273.95 (M-1), and 10A was the minor isomer and was found less pure and discarded.

[0740] Scheme 5: Synthesis of tert-butyl 2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (7)

[0741]

[0742] To a stirred solution of compound 11 (2.0 g, 9.56 mmol) in DMF (20 mL) was added NaHMDS (9.5 mL, 9.56 mmol) at 0°C, followed by methanesulfonyl chloride (0.85 mL, 10.51 mmol), and the resulting reaction mixture was stirred at -40°C for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, water was added to the residue and extracted with ethyl acetate. The organic layer was collected and washed with saturated NaHCO 3 solution, then washed with brine, and then with anhydrous Na 2 SO 4 The mixture was dried and concentrated under reduced pressure to give the title compound 12 (1.2 g, 43.69%) as a pale yellow liquid. TLC: 50% EtOAc / heptane (Rf :0.4). 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.00-8.10 (m, 1H), 4.50-4.52 (m, 2H), 4.33-4.31 (m, 2H), 3.53 (s, 3H), 1.45 (s, 9H). VT NMR at 80° C. indicated a 1:1 mixture of rotamers.

[0743] Synthesis of the compound of formula (I)

[0744] Synthesis Examples 1-3

[0745] Scheme 6: Scheme for the synthesis of N-(6-((5-acryloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide, 1-cyclohexyl-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)methanesulfonamide and 1-cyclohexyl-N-(6-((5-(4-(dimethylamino)but-2-ynyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide

[0746]

[0747] (Note that only one regioisomer of compounds 16, 17, 18, and 18a is depicted in the above schemes and throughout Examples 1-3; however, both were present in the reaction mixture.)

[0748]

[0749] Synthesis of 2,6-difluoro-4-(hydroxymethyl)benzonitrile (14)

[0750] To a stirred solution of compound 13 (5 g, 29.00 mmol) in THF (50 mL) was added NaBH at 0 °C. 4 (1.6 g, 44.00 mmol), and the resulting reaction mixture was stirred at the same temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave the title compound 14 (4.5 g, 88.93%) as a yellow solid. TLC: 30% EtOAc / heptane (R f:0.35). 1 H NMR (400 MHz, DMSO-d 6 ): δ7.35-7.32(m,2H),5.69(t,J=6.0Hz,1H),4.60(d,J=6.0Hz,2H).

[0751] Synthesis of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (15)

[0752] To a stirred solution of compound 14 (4 g, 23.12 mmol) in MeOH (60 mL) was added NaOMe (5.1 g, 94.00 mmol) at -40 °C, and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the solvent was concentrated under high vacuum. Water was added to the residue and extracted with ethyl acetate. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave the title compound 15 (3.5 g, 81.69%) as a yellow solid. TLC: 50% EtOAc / heptane (R f :0.25). 1 H NMR (400 MHz, CDCl 3 ):δ6.81-6.78 (m, 2H), 4.75 (s, 2H), 3.96 (s, 3H). No OH protons were observed.

[0753] Synthesis of tert-butyl 2-(4-cyano-3-fluoro-5-methoxybenzyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (16)

[0754]

[0755] To a stirred solution of compound 15 (1.0 g, 5.5 mmol) in acetonitrile (5 mL) was added Cs 2 CO 3 (3.22 g, 9.90 mmol), followed by compound 12 (1.74 g, 6.07 mmol), and the resulting reaction mixture was heated at 70 ° C for 6 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4The crude compound was purified by column chromatography on silica gel (100-200 mesh) using a gradient method of 0-50% EtOAc / heptane to afford the title compound 16 as a yellow solid (1.0 g, 48.65%, separated as an inseparable regioisomeric mixture). TLC: 80% EtOAc / heptane (R f :0.45). C 19 H 21 FN 4 O 3 LCMS calculated value: 372.40; found value: 373.85 (M+1). 1 H NMR was complex and indicated an isomeric mixture. This compound was used as a mixture for the synthesis of the final compound where a single regioisomer was drawn.

[0756] Synthesis of tert-butyl 2-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (17)

[0757]

[0758] To a stirred solution of compound 16 (0.50 g, 1.34 mmol) in DMF (7 mL) was added acetohydroxamic acid (0.31 g, 4.02 mmol), followed by t BuOK (0.45 g, 4.02 mmol) was added, and the reaction mixture was stirred at 65 ° C for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with ice water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 The crude compound was purified by column chromatography on silica gel (100-200 mesh) using a gradient method of 0-50% EtOAc / heptane to afford the title compound 17 as an off-white solid (0.20 g, 38.64%, separated as an inseparable regioisomeric mixture). TLC: 70% EtOAc / heptane (R f :0.40). C 19 H 23 N 5 O 4 LCMS calculated value: 385.42; found value: 386.00 (M+1). 1 H NMR was complex and indicated a regioisomeric mixture.

[0759] Synthesis of tert-butyl 2-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (18)

[0760]

[0761] To a stirred solution of compound 17 (0.160 g, 0.42 mmol) in DCM (3 mL) was added Et 3 N (0.15mL, 1.14mmol), followed by cyclohexylmethanesulfonyl chloride (3, 0.11g, 0.58mmol), and the resulting reaction mixture was stirred at room temperature for 2h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature again, diluted with DCM and extracted. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 The crude compound was purified by column chromatography on silica gel (100-200 mesh) using a gradient method of 0-60% EtOAc / heptane to afford the title compound 18 as an off-white solid (0.18 g, 79.60%, separated as an inseparable regioisomeric mixture). TLC: 80% EtOAc / heptane (R f :0.35). C 26 H 35 N 5 O 6 LCMS calculated value for S: 545.66; found value: 544.40 (M-1). 1 H NMR was complex and indicated a regioisomeric mixture.

[0762] Synthesis of 1-cyclohexyl-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide

[0763]

[0764] To a stirred solution of compound 18 (180 mg, 0.33 mmol) in DCM (3 mL) was added TFA (0.13 mL, 1.73 mmol) at 0°C, and the reaction was stirred at room temperature for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature again and quenched with saturated NaHCO 3 The solution was basified and extracted with DCM. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4Drying and concentration under reduced pressure afforded a crude residue which was triturated with diethyl ether / pentane to afford the title compound as a white solid (100 mg, 67.10%, isolated as an inseparable regioisomeric mixture) which was used in the next reaction without further purification. 21 H 27 N 5 O 4 LCMS calculated for S: 445.54; found: 446.50 (M+1). 1 H NMR was complex and indicated a regioisomeric mixture.

[0765] Synthesis Example 1

[0766] Synthesis of N-(6-((5-acryloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide and its regioisomer mixture

[0767]

[0768] To a stirred solution of 18a (0.050 g, 0.11 mmol) in DCM (3 mL) was added Et 3 N (0.045 mL, 0.63 mmol), followed by acryloyl chloride (0.01 g, 0.11 mmol). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and diluted with water and extracted with 5% MeOH / DCM. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. The crude compound was purified by reverse phase HPLC to afford the title compound as an off-white solid (7 mg, 9.9%, isolated as an inseparable regioisomeric mixture). TLC: 5% MeOH / DCM (R f :0.5). (See analytical data in Table 1).

[0769] Synthesis Example 2

[0770] Synthesis of 1-cyclohexyl-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)methanesulfonamide and its regioisomer mixture

[0771]

[0772] To a stirred solution of 18a (0.050 g, 0.11 mmol) in DMF (2 mL) at 0 °C was added DIPEA (0.06 mL, 0.39 mmol) followed by T 3 P (0.06mL, 0.22mmol). The reaction was stirred at room temperature for 20min. A solution of propiolic acid (8mg, 0.12mmol) pre-dissolved in DMF (0.5mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2h. After completion (monitored by TLC), the solvent was concentrated under high vacuum. The residue was quenched with water and extracted with DCM. The organic layer was collected, washed with brine, and washed with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. The crude compound was purified by reverse phase HPLC to give the title compound as an off-white solid (6.1 mg, 11%, isolated as an inseparable regioisomeric mixture). TLC: 5% MeOH / DCM (R f :0.5). (See analytical data in Table 1).

[0773] Synthesis of 4-(dimethylamino)but-2-ynoic acid (20)

[0774] To a stirred solution of compound 19 (2.0 g, 0.24 mmol) in THF (20 mL) was added n-BuLi (15 mL, 0.24 mmol, 1.6 M in hexanes) at -78 °C under inert atmosphere. The mixture was stirred at -78 °C for 1 h and then added to a flask containing crushed CO 2 (11.5g, 0.241mmol) in another flask, and the resulting reaction mixture was stirred at the same temperature for 30min. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into ice water and washed with ethyl acetate. The water layer was collected and concentrated under reduced pressure to provide a residue, which was diluted with MeOH and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 20 (1.4g, 45.74%) as a light brown solid. TLC: 10% MeOH / DCM (R f :0.3). 1 HNMR (400 MHz, DMSO-d 6 ):δ3.15(s,2H),2.14(s,6H). 6 H 9 NO 2 LCMS calculated value: 127.14; found value: 128.2 (M+1).

[0775] Synthesis Example 3

[0776] Synthesis of 1-cyclohexyl-N-(6-((5-(4-(dimethylamino)but-2-ynyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide

[0777]

[0778] To a stirred solution of compound 18a (70 mg, 0.16 mmol) in DMF (1 mL) was added DIPEA (0.09 mL, 0.51 mmol) followed by compound 20 (18 mg, 0.14 mmol) at 0°C. The resulting mixture was stirred at 0°C for 5 min. Afterwards, T 3 P (0.06 mL, 0.19 mmol) and the reaction was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction was quenched with water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. The crude compound was purified by preparative HPLC to give the title compound as a mixture of regioisomers as an off-white solid (7 mg, 8%). TLC: 10% MeOH / DCM (R f :0.5). (See analytical data in Table 1).

[0779] Synthesis Examples 4-6

[0780] Scheme 7: Scheme for the synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide, N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)acrylamide, N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propynamide and N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)ethylenesulfonamide

[0781]

[0782] Synthesis of tert-butyl ((1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazol-4-yl)methyl)carbamate (21)

[0783] To a stirred solution of compound 15 (0.5 g, 2.76 mmol) in acetonitrile (10 mL) was added Cs 2 CO 3 (2.7 g, 8.28 mmol), followed by the addition of compound 7 (1.13 g, 4.14 mmol), and the resulting reaction mixture was heated at 70 ° C for 4 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. The crude compound was purified by Combi flash chromatography using a gradient method of 40%-70% EtOAc / heptane to give the title compound 21 as a brown semi-solid (0.400 g, 40.22%). TLC: 80% EtOAc / heptane (R f :0.45). 1 H NMR (400 MHz, DMSO-d 6 ): δ7.72(s,1H),7.39(s,1H),7.18-7.12(m,1H),7.00(s,1H),6.69(d,J= 9.6Hz, 1H), 5.37 (s, 2H), 3.96 (d, J = 5.6Hz, 2H), 3.91 (s, 3H), 1.37 (s, 9H). C 18 H 21 FN 4 O 3 LCMS calculated value: 360.39; found value: 361.00 (M+1).

[0784] Synthesis of tert-butyl ((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (22)

[0785] Compound 21 (0.2 g, 0.55 mmol) was dissolved in DMF:H 2 To a stirred solution of a 6:1 mixture of 1,2-dihydroxamic acid (0.112 g, 1.50 mmol) and K 2 CO 3 (0.414 g, 3.0 mmol). The reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, ice water was added and extracted with ethyl acetate. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4Dry and concentrate under reduced pressure. The crude compound was purified by Combi flash chromatography using a gradient method of 40%-60% EtOAc / heptane to afford the title compound 22 (0.1 g, 48.25%) as a brown semisolid. TLC: 80% EtOAc / heptane (R f :0.40). 1 H NMR (400 MHz, DMSO-d 6 ): δ7.67(s,1H),7.35(s,1H),7.18-7.12(m,1H),6.69(s,1H),6.63(s,1H), 5.93(s,2H),5.34(s,2H),3.95(d,J=6.0Hz,2H),3.86(s,3H),1.36(s,9H). C 18 H 23 N 5 O 4 LCMS calculated value: 373.41; found value: 374.05 (M+1).

[0786] Synthesis of tert-butyl ((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (23)

[0787] To a stirred solution of compound 22 (0.1 g, 0.26 mmol) in DCM (3 mL) was added Et 3 N (0.11 mL, 0.80 mmol), followed by cyclohexyl methanesulfonyl chloride (3, 0.057 g, 0.29 mmol), and the reaction was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, water was added and extracted. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. The crude compound was purified by Combi flash column chromatography using a gradient method of 40%-60% EtOAc / heptane to afford the title compound 23 as an off-white solid (0.070 g, 48.98%). TLC: 80% EtOAc / heptane (R f :0.35). C 25 H 35 N 5 O 6 LCMS calculated value for S: 533.64; found value: 532.43 (M-1).

[0788] Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide

[0789] To a stirred solution of compound 23 (70 mg, 0.13 mmol) in DCM (2 mL) was added TFA (0.1 mL, 1.31 mmol) at 0°C and the reaction was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), it was concentrated under reduced pressure and the crude compound was purified by reverse phase HPLC to give the title compound as an off-white solid (4 mg, 7%). TLC: 5% MeOH / DCM (R f :0.5). 1 H NMR (400 MHz, DMSO-d 6 ):δ10.41 (broad single peak, 1H), 7.95 (broad single peak, 2H), 7.91 (s, 1H), 7.58 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 5.48 (s, 2H), 3.91 (combined s, 5H), 3.37 (combined d, J = 5.6 Hz, 2H), 2.04-1.91 (m, 1H), 1.86 (d, J = 12.4 Hz, 2H), 1.61 (d, J = 12.4 Hz, 2H), 1.59-1.51 (m, 1H), 1.29-1.04 (m, 5H); C 20 H 27 N 5 O 4 LCMS calculated for S: 433.53; found: 434.15 (M+1).

[0790] Synthesis Example 4

[0791] Synthesis of N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)acrylamide

[0792] To a stirred solution of compound 23a (60 mg, 0.13 mmol) in DCM (5 mL) was added Et 3 N (0.09 mL, 0.65 mmol), followed by acryloyl chloride (0.008 mL, 0.11 mmol), and the reactants were stirred at the same temperature for 20 min. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, water was added and extracted with 5% MeOH / DCM. The organic layer was collected, washed with brine, and purified by anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. The crude compound was purified by preparative HPLC to afford the title compound as an off-white solid (2.5 mg, 7.9%). TLC: 5% MeOH / DCM (R f:0.5). (See Table 1 for analytical data).

[0793] Synthesis Example 5

[0794] Synthesis of N-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl...

Claims

1. A compound of formula (I): R 1 is optionally replaced by 1, 2 or 3 R 1a Substituted C3-C8 cycloalkyl; C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is optionally substituted by 1, 2 or 3 R 1a substituted; optionally with 1, 2 or 3 R 1b substituted phenyl; optionally substituted by 1, 2 or 3 R 1b substituted phenyl-C1-C6 alkyl; optionally substituted by 1, 2 or 3 R 1b or optionally substituted with 1, 2 or 3 R 1b substituted 5-membered or 6-membered monocyclic heteroaryl; optionally substituted by 1, 2 or 3 R 1b substituted 8- to 10-membered bicyclic heteroaryl; Each R 1a independently selected from hydrogen, halo, C1-C6 alkoxy and C3-C8 cycloalkyloxy; Each R 1b independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyalkyloxy, -O-alkylene-NR 1b1 R 1b4 、-O-alkylene-C(O)OR 1b1 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , Cyano, -(CH2) 0-2 C(O)-OR 1b1 、-(CH2) 0-2 C(O)NR 1b1 R 1b2 、-(CH2) 0-2 NR 1b1 C(O)R 1b3 、-(CH2) 0-2 OH and C3-C8 cycloalkyloxy; R 1b1 is hydrogen or C1-C6 alkyl; R 1b2 is hydrogen or C1-C6 alkyl; R 1b3 is hydrogen or C1-C6 alkyl; and R 1b4 It is hydrogen, R 2 Selected from the group consisting of: R 2a is hydrogen or C1-C6 alkyl; Each R 2b are independently hydrogen, halo, -(CH2) 0-2 OH, C1-C3 alkyl, cyclopropyl, cyano, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, -OCF3 or C3-C8 cycloalkyloxy; Each R 2e are independently hydrogen, -OH, halo, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy or C3-C8 cycloalkyloxy; yes in, For rings (a), (b) and (c) One X 1 Yes CR 3 And other X 1 Independently selected from N and CR 2b ; R 2d is hydrogen, halogen, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy or C3-C8 cycloalkyloxy; R 3 Yes - (CH2) 0-2 Y or -(CH2) 0-2 -LY; L is -L 1 -L 2 -L 3 -, where L 1 , L 2 and L 3 are each independently a bond, -CRR-, O, S(O) 0-2 , C(O) or NR, wherein each R is independently H or alkyl; Y is R Y substituted and optionally by R 2e substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 6-membered monocyclic aromatic or heteroaromatic group; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 8-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1, 2 or 3 R 2e substituted 9-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1, 2 or 3 R 2e substituted 10-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 8-membered or 9-membered bicyclic heterocyclic ring; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl; Y is Y is -(CH2) 0-3 NR 3b R Y ; or Y is -(CH2) 0-3 NR 3b C(O)R Y ; R Y Yes - (CH2) 0-3 NR 3b C(O)R 3a 、-(CH2) 0-2 NR 3b S(O)2R 3a 、-C(O)R 3a 、-S(O)2R 3a 、-C(O)NR 3b R 3a , by -C(O)R 3a Substituted C3-C8 heterocycloalkyl; -(CH2) 0-3 NR 3b (C1-C6 alkylene)NR 3b1 C(O)R 3a 、-(CH2) 0-3 NR 3b (C1-C6 alkylene)NR 3b1 S(O)2R 3a 、-(CH2) 0-3 NR 3b C(O)(C1-C6 alkylene)NR 3b1 C(O)R 3a or -(CH2) 0-3 NR 3b C(O)(C1-C6 alkylene)NR 3b1 S(O)2R 3a , R 3a , R 3b and R 3b1 Selected from (i), (ii) or (iii): (i)R 3a , R 3b and R 3b1 One of them is selected from the group a): C1-C6 alkyl substituted by 1 or 2 independently selected halogen groups; C1-C6 alkyl substituted by cyano; C1-C6 alkyl substituted by fluoroalkoxy; C1-C6 alkyl substituted by aryloxy or heteroaryloxy, each of which is optionally substituted by 1-3 substituents independently selected from the following: halogen, C1-C6 alkyl; 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl; C2-C6 alkenyl; C2-C6 alkenyl substituted by cyano; C2-C6 alkenyl substituted by halide; -CH=CH-CH2-NR 3c R 3d ; -CH=CH-CH2-O-C1-C6 alkyl; C3-C8 cycloalkenyl; -C(O)-C3-C8 cycloalkyl; C2-C6 alkynyl; -CH≡CH-CH2-NR 3c R 3d ; CH≡CH-CH2-OH; -CH≡CH-CH2-O-C1-C6 alkyl; spirocycloalkyl substituted with cyano; chloropyridyl; fluoropyridyl; chloropyrazinyl; fluoropyrazinyl; chloropyrimidinyl; fluoropyrimidinyl; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl, difluorophenyl; and monofluorophenyl; and R 3a , R 3b and R 3b1 The others are selected from group b): hydrogen and C1-C6 alkyl; or (ii) R 3a , R 3b and R 3b1 one of which is selected from the group a): hydrogen; C1-C6 alkyl; C1-C6 alkyl substituted by aryloxy or heteroaryloxy, each of which is optionally substituted by 1-3 substituents independently selected from the following: C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 heterocycloalkyl; C2-C6 alkenyl; C3-C8 cycloalkenyl; -C(O)-C3-C8 cycloalkyl; C2-C6 alkynyl; spirocycloalkyl; pyridyl; pyrimidinyl; and phenyl; and R 3a , R 3b and R 3b1 The others are selected from group b): hydrogen and C1-C6 alkyl; or (iii) R 3a , R 3b and R 3b1 Each is independently hydrogen or C1-C6 alkyl; R 3c is hydrogen or C1-C6 alkyl, and R 3d is hydrogen or C1-C6 alkyl; or R 3c and R 3d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring wherein the other 2-7 ring members are carbon; and HET1 is a C3-C8 heterocycloalkyl group; Among them, for ring (d), X 2a is O or S; One X 2 Yes CR 4 And other X 2 Independently selected from N and CR 2b ; R 4 Yes - (CH2) 0-3 NR 4b C(O)R 4a 、-(CH2) 0-2 NR 4b S(O)2R 4a 、-C(O)R 4a 、-C(O)NR 4b R 4a 、-NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a 、-(CH2) 0-3 NR 4b C(O)(C1-C6 alkylene)NR 4b1 C(O)R 4a 、-C(O)NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a 、-C(O)-HET1-C(O)R 4a 、-C(O)-HET1-NR 4b C(O)R 4a 、-(CH2) 0-3 NR 4b C(O)-HET1-C(O)R 4a , by -C(O)R 4a Substituted C3-C8 heterocycloalkyl (preferably, wherein the C3-C8 heterocycloalkyl is connected to ring (d) via a carbon in the C3-C8 heterocycloalkyl ring); or -(CH2) 0-2 HET2-C(O)R 4a ; R 4a , R 4b and R 4b1 Selected from (i), (ii) and (iii): (i)R 4a , R 4b and R 4b1 One of them is selected from the group a): alkyl substituted by 1 or 2 independently selected halogen groups; C1-C6 alkyl substituted by cyano group; C2-C6 alkenyl; C2-C6 alkenyl substituted by cyano group; C2-C6 alkenyl substituted by halogen group; -CH=CH-CH2-NR 4c R 4d ; -CH=CH-CH2-O-C1-C6 alkyl; C3-C8 cycloalkenyl; -C(O)-C3-C8 cycloalkyl; C2-C6 alkynyl; -CH≡CH-CH2-NR 4c R 4d ; CH≡CH-CH2-OH; CH≡CH-CH2-O-C1-C6 alkyl; spirocycloalkyl substituted with cyano; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and R 4a , R 4b and R 4b1 The others are selected from group b): hydrogen and C1-C6 alkyl; (ii) R 4a , R 4b and R 4b1 one of which is selected from the group a): hydrogen; alkyl; C2-C6 alkenyl; C3-C8 cycloalkenyl; -C(O)-C3-C8 cycloalkyl; C2-C6 alkynyl; spirocycloalkyl; pyridyl; pyrazinyl; pyrimidinyl; and phenyl; and R 4a , R 4b and R 4b1 The others are selected from group b): hydrogen and C1-C6 alkyl; or (iii) R 4a , R 4b and R 4b1 Each is independently hydrogen or C1-C6 alkyl; R 4c is hydrogen or C1-C6 alkyl, and R 4d is hydrogen or C1-C6 alkyl; or R 4c and R 4d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon; HET1 is a C3-C8 heterocycloalkyl group; and HET2 is optionally replaced by 1 or 2 R 2e substituted 8-, 9- or 10-membered bicyclic heterocycle; Among them, for rings (e) and (f), R 5 is substituted by Z and optionally by R 2e Substituted 5-membered monocyclic heteroaryl; R 5 is substituted by Z and optionally by R 2e Substituted 6-membered monocyclic heteroaryl; R 5 Yes-C(O)N(R 5b )Z; R 5 is substituted by Z and optionally by R 2e Substituted heterocycloalkyl; R 5 Yes - (CH2) 0-2 O-HET1-Z; R 5 Yes - (CH2) 0-2 OZ; Z is -(CH2) 0-3 NR 5b C(O)R 5a 、-(CH2) 0-2 NR 5b S(O)2R 5a 、-C(O)R 5a 、-S(O)2R 5a 、-(CH2) 0-3 -C(O)NR 5b R 5a 、-(CH2) 0-3 NR 5b (C1-C6 alkylene)NR 5b1 C(O)R 5a 、Be-NR 5b C(O)R 5a Substituted C3-C8 heterocycloalkyl, -S(O)2R 5a Substituted C3-C8 heterocycloalkyl, or -C(O)R 5a Substituted C3-C8 heterocycloalkyl; R 5a , R 5b and R 5b1 Selected from (i), (ii) or (iii): (i)R 5a , R 5b and R 5b1 One of them is selected from the group a): C1-C6 alkyl substituted by 1 or 2 independently selected halogen groups; C1-C6 alkyl substituted by cyano group; C2-C6 alkenyl; C2-C6 alkenyl substituted by cyano group; C2-C6 alkenyl substituted by halogen group; -CH=CH-CH2-NR 5c R 5d ; -CH=CH-CH2-O-C1-C6 alkyl; C3-C8 cycloalkenyl; -C(O)-C3-C8 cycloalkyl; C2-C6 alkynyl; -CH≡CH-CH2-NR 5c R 5d ; CH≡CH-CH2-OH; CH≡CH-CH2-O-C1-C6 alkyl; spirocycloalkyl substituted with cyano; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl, and R 5a , R 5b and R 5b1 The others are selected from group b): hydrogen and C1-C6 alkyl; (ii) R 5a , R 5b and R 5b1 one of which is selected from the group a): hydrogen; C1-C6 alkyl; C2-C6 alkenyl; C3-C8 cycloalkenyl; -C(O)-C3-C8 cycloalkyl; C2-C6 alkynyl; spirocycloalkyl; pyridyl; pyrazinyl; pyrimidinyl; and phenyl; and R 5a , R 5b and R 5b1 The others are selected from group b): hydrogen and C1-C6 alkyl; or (iii) R 5a , R 5b and R 5b1 Each is independently hydrogen or C1-C6 alkyl; Each R 5c are independently hydrogen or C1-C6 alkyl and R 5d is hydrogen or C1-C6 alkyl; or R 5c and R 5d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon; HET1 is a C3-C8 heterocycloalkyl group; Among them, for ring (g), Q 1 Yes CR Q1 , Q 2 is N, and Q 3 is O; or Q 1 Yes CR Q1 , Q 2 is O, and Q 3 is N; or Q 1 Yes S, Q 2 is N, and Q 3 is N; or Q 1 Yes N, Q 2 is N, and Q 3 is O; or Q 1 It's O, Q 2 is N, and Q 3 is N; where R Q1 is hydrogen, C(O)C1-C6 alkyl or Cl; R 6 is substituted by Q and optionally by R 2e substituted 5-membered or 6-membered monocyclic heteroaryl; or R 6 It is Q; Q is -(CH2) 0-3 NR 6b C(O)R 6a 、-(CH2) 0-2 NR 6b S(O)2R 6a 、-C(O)R 6a 、-C(O)NR 6b R 6a , or -C(O)R 6a Substituted C3-C8 heterocycloalkyl; R 6a and R 6b Selected from (i), (ii) or (iii): (i)R 6a and R 6b One of them is selected from the group a): C1-C6 alkyl substituted by 1 or 2 independently selected halogen groups; C1-C6 alkyl substituted by cyano group; C2-C6 alkenyl; C2-C6 alkenyl substituted by cyano group; C2-C6 alkenyl substituted by halogen group; -CH=CH-CH2-NR 6c R 6d ; -CH=CH-CH2-O-C1-C6 alkyl; C3-C8 cycloalkenyl; -C(O)cycloalkyl; alkynyl; -CH≡CH-CH2-NR 6c R 6d ; CH≡CH-CH2-OH; CH≡CH-CH2-O-C1-C6 alkyl; spirocycloalkyl substituted with cyano; chloropyridyl, fluoropyridyl, chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and R 6a and R 6b The other of is selected from the group b): hydrogen and C1-C6 alkyl; (ii) R 6a and R 6b one of which is selected from the group a): C1-C6 alkyl; C2-C6 alkenyl; C3-C8 cycloalkenyl; -C(O)cycloalkyl; alkynyl; spirocycloalkyl; pyridyl; pyrazinyl; pyrimidinyl; and phenyl; and R 6a and R 6b The other of is selected from the group b): hydrogen and C1-C6 alkyl; or (iii) R 6a and R 6b are each independently hydrogen and C1-C6 alkyl; R 6c is hydrogen or C1-C6 alkyl and R 6d is hydrogen or C1-C6 alkyl; or R 6c and R 6d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring wherein the other 2-7 ring members are carbon; and Each R 7 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

2. The compound of claim 1, wherein: R 1 is optionally replaced by 1, 2 or 3 R 1a Substituted C3-C8 cycloalkyl; C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl is optionally substituted by 1, 2 or 3 R 1a substituted; optionally substituted by 1, 2 or 3 R 1b substituted phenyl; optionally substituted by 1, 2 or 3 R 1b substituted phenyl-C1-C6 alkyl; optionally substituted by 1, 2 or 3 R 1b or optionally substituted with 1, 2 or 3 R 1b substituted 5-membered or 6-membered monocyclic heteroaryl; optionally substituted by 1, 2 or 3 R 1b substituted 8- to 10-membered bicyclic heteroaryl; Each R 1a independently selected from hydrogen, halo, C1-C6 alkoxy and C3-C8 cycloalkyloxy; Each R 1b independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyalkyloxy, -O-alkylene-NR 1b1 R 1b4 、-O-alkylene-C(O)OR 1b1 , -O-alkylene-O-alkylene-NR 1b1 R 1b4 , Cyano, -(CH2) 0-2 C(O)OR 1b1 、-(CH2) 0-2 C(O)NR 1b2 R 1b3 、-(CH2) 0-2 NRC(O)R, -(CH2) 0-2 OH and C3-C8 cycloalkyloxy; R 1b1 is hydrogen or C1-C6 alkyl; R 1b2 is hydrogen or C1-C6 alkyl; and R 1b3 is hydrogen or C1-C6 alkyl; and R 1b4 It is hydrogen, R 2 Selected from the group consisting of: R 2a is hydrogen or C1-C6 alkyl; Each R 2b are independently hydrogen, halo, -(CH2) 0-2 OH, C1-C3 alkyl, cyclopropyl, cyano, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2, -OCF3 or C3-C8 cycloalkyloxy; Each R 2e are independently hydrogen, halo, -OH, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy or C3-C8 cycloalkyloxy; yes Among them, for rings (a), (b) and (c) One X 1 Yes CR 3 And other X 1 Independently selected from N and CR 2b ; R 2d is hydrogen, halogen, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy or C3-C8 cycloalkyloxy; R 3 Yes - (CH2) 0-2 Y; Y is R Y substituted and optionally by R 2e substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 6-membered monocyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 8-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1, 2 or 3 R 2e substituted 9-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1, 2 or 3 R 2e substituted 10-membered bicyclic heteroaryl; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 8-membered or 9-membered bicyclic heterocyclic ring; Y is replaced by R Y and optionally substituted with 1 or 2 R 2e substituted 4-9 membered monocyclic or bicyclic heterocycloalkyl; Y is Y is -(CH2) 0-3 NR 3b R Y ; or Y is -(CH2) 0-3 NR 3b C(O)R Y ; R Y Yes - (CH2) 0-3 NR 3b C(O)R 3a 、-(CH2) 0-2 NR 3b S(O)2R 3a 、-C(O)R 3a 、-S(O)2R 3a 、-C(O)NR 3b R 3a 、-(CH2) 0-3 NR 3b (C1-C6 alkylene)NR 3b1 C(O)R 3a 、-(CH2) 0-3 NR 3b (C1-C6 alkylene)NR 3b1 S(O)2R 3a 、-(CH2) 0- 3NR 3b C(O)(C1-C6 alkylene)NR 3b1 C(O)R 3a , or -(CH2) 0-3 NR 3b C(O)(C1-C6 alkylene)NR 3b1 S(O)2R 3a , or -C(O)R 3a Substituted C3-C8 heterocycloalkyl; R 3a , R 3b and R 3b1 One of them is selected from the group a): C1-C6 alkyl substituted by 1 or 2 independently selected halogen groups; C1-C6 alkyl substituted by cyano; C1-C6 alkyl substituted by fluoroalkoxy; C1-C6 alkyl substituted by aryloxy or heteroaryloxy, each of which is optionally substituted by 1-3 substituents independently selected from the following: halogen, C1-C6 alkyl; 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl; C2-C6 alkenyl; C2-C6 alkenyl substituted by cyano; C2-C6 alkenyl substituted by halide; -CH=CH-CH2-NR 3c R 3d ; -CH=CH-CH2-O-C1-C6 alkyl; C3-C8 cycloalkenyl; -C(O)-C3-C8 cycloalkyl; C2-C6 alkynyl; -CH≡CH-CH2-NR 3c R 3d ; CH≡CH-CH2-OH; -CH≡CH-CH2-O-C1-C6 alkyl; spirocycloalkyl substituted with cyano; chloropyridinyl; fluoropyridinyl; chloropyrazinyl; fluoropyrazinyl; chloropyrimidinyl; fluoropyrimidinyl; pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and R 3a , R 3b and R 3b1 The others are selected from group b): hydrogen and C1-C6 alkyl; R 3c is hydrogen or C1-C6 alkyl, and R 3d is hydrogen or C1-C6 alkyl; or R 3c and R 3d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon; HET1 is a C3-C8 heterocycloalkyl group; Among them, for ring (d), X 2a is O or S; One X 2 Yes CR 4 And other X 2 Independently selected from N and CR 2b ; R 4 Yes - (CH2) 0-3 NR 4b C(O)R 4a 、-(CH2) 0-2 NR 4b S(O)2R 4a 、-C(O)R 4a 、-C(O)NR 4b R 4a 、-NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a 、-(CH2) 0-3 NR 4b C(O)(C1-C6 alkylene)NR 4b1 C(O)R 4a 、-C(O)NR 4b (C1-C6 alkylene)NR 4b1 C(O)R 4a 、-C(O)-HET1-C(O)R 4a 、-C(O)-HET1-NR 4b C(O)R 4a 、-(CH2) 0-3 NR 4b C(O)-HET1-C(O)R 4a , by -C(O)R 4a Substituted C3-C8 heterocycloalkyl (preferably, wherein the C3-C8 heterocycloalkyl is connected to ring (d) via a carbon in the C3-C8 heterocycloalkyl ring); or -(CH2) 0-2 HET2-C(O)R 4a ; R 4a , R 4b and R 4b1 One of them is selected from the group a): alkyl substituted by 1 or 2 independently selected halogen groups; C1-C6 alkyl substituted by cyano group; C2-C6 alkenyl; C2-C6 alkenyl substituted by cyano group; C2-C6 alkenyl substituted by halogen group; -CH=CH-CH2-NR 4c R 4d ; -CH=CH-CH2-O-C1-C6 alkyl; C3-C8 cycloalkenyl; -C(O)-C3-C8 cycloalkyl; C2-C6 alkynyl; -CH≡CH-CH2-NR 4c R 4d ; CH≡CH-CH2-OH; CH≡CH-CH2-O-C1-C6 alkyl; spirocycloalkyl substituted with cyano; chloropyridyl; fluoropyridyl; chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and R 4a , R 4b and R 4b1 The others are selected from group b): hydrogen and C1-C6 alkyl; R 4c is hydrogen or C1-C6 alkyl, and R 4d is hydrogen or C1-C6 alkyl; or R 4c and R 4d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon; HET1 is a C3-C8 heterocycloalkyl group; and HET2 is optionally replaced by 1 or 2 R 2e substituted 8-, 9- or 10-membered bicyclic heterocycle; Among them, for rings (e) and (f), R 5 is substituted by Z and optionally by R 2e Substituted 5-membered monocyclic heteroaryl; R 5 is substituted by Z and optionally by R 2e Substituted 6-membered monocyclic heteroaryl; R 5 Yes-C(O)N(R 5b )Z; R 5 is substituted by Z and optionally by R 2e Substituted heterocycloalkyl; R 5 Yes - (CH2) 0-2 O-HET1-Z; R 5 Yes - (CH2) 0-2 OZ; Z is -(CH2) 0-3 NR 5b C(O)R 5a 、-(CH2) 0-2 NR 5b S(O)2R 5a 、-C(O)R 5a 、-S(O)2R 5a 、-(CH2) 0-3 -C(O)NR 5b R 5a 、-(CH2) 0-3 NR 5b (C1-C6 alkylene)NR 5b1 C(O)R 5a 、Be-NR 5b C(O)R 5a Substituted C3-C8 heterocycloalkyl, -S(O)2R 5a Substituted C3-C8 heterocycloalkyl, or -C(O)R 5a Substituted C3-C8 heterocycloalkyl; R 5a , R 5b and R 5b1 One of them is selected from the group a): C1-C6 alkyl substituted by 1 or 2 independently selected halogen groups; C1-C6 alkyl substituted by cyano group; C2-C6 alkenyl; C2-C6 alkenyl substituted by cyano group; C2-C6 alkenyl substituted by halogen group; -CH=CH-CH2-NR 5c R 5d ; -CH=CH-CH2-O-C1-C6 alkyl; C3-C8 cycloalkenyl; -C(O)-C3-C8 cycloalkyl; C2-C6 alkynyl; -CH≡CH-CH2-NR 5c R 5d ; CH≡CH-CH2-OH; CH≡CH-CH2-O-C1-C6 alkyl; spirocycloalkyl substituted with cyano; chloropyridyl; fluoropyridyl; chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and R 5a , R 5b and R 5b1 The others are selected from group b): hydrogen and C1-C6 alkyl; Each R 5c are independently hydrogen or C1-C6 alkyl and R 5d is hydrogen or C1-C6 alkyl; or R 5c and R 5d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring in which the other 2-7 ring members are carbon; HET1 is a C3-C8 heterocycloalkyl group; Among them, for ring (g), Q 1 Yes CR Q1 , Q 2 is N, and Q 3 is O; or Q 1 Yes CR Q1 , Q 2 is O, and Q 3 is N; or Q 1 Yes S, Q 2 is N, and Q 3 is N; or Q 1 Yes N, Q 2 is N, and Q 3 is O; or Q 1 It's O, Q 2 is N, and Q 3 is N; where R Q1 is hydrogen, C(O)C1-C6 alkyl or Cl; R 6 is substituted by Q and optionally by R 2e substituted 5-membered or 6-membered monocyclic heteroaryl; or R 6 It is Q; Q is -(CH2) 0-3 NR 6b C(O)R 6a 、-(CH2) 0-2 NR 6b S(O)2R 6a 、-C(O)R 6a 、-C(O)NR 6b R 6a , or -C(O)R 6a Substituted C3-C8 heterocycloalkyl; R 6a and R 6b One of them is selected from the group a): C1-C6 alkyl substituted by 1 or 2 independently selected halogen groups; C1-C6 alkyl substituted by cyano group; C2-C6 alkenyl; C2-C6 alkenyl substituted by cyano group; C2-C6 alkenyl substituted by halogen group; -CH=CH-CH2-NR 6c R 6d ; -CH=CH-CH2-O-C1-C6 alkyl; C3-C8 cycloalkenyl; -C(O)cycloalkyl; alkynyl; -CH≡CH-CH2-NR 6c R 6d ; CH≡CH-CH2-OH; CH≡CH-CH2-O-C1-C6 alkyl; spirocycloalkyl substituted with cyano; chloropyridyl; fluoropyridyl; chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl, pentafluorophenyl; tetrafluorophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; R 6a and R 6b The other of is selected from the group b): hydrogen and C1-C6 alkyl; R 6c is hydrogen or C1-C6 alkyl and R 6d is hydrogen or C1-C6 alkyl; or R 6c and R 6d Together with the nitrogen to which it is attached, it forms a 3-8 membered saturated ring wherein the other 2-7 ring members are carbon; and Each R 7 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

3. The compound as claimed in claim 2, wherein R 1 is C3-C8 cycloalkylalkyl, wherein the C3-C8 cycloalkylalkyl is optionally substituted by 1, 2 or 3 R 1a or optionally substituted by 1, 2 or 3 R 1b substituted phenyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

4. The compound as claimed in claim 2, wherein R 1 is optionally replaced by 1, 2 or 3 R 1a substituted C3-C8 cycloalkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

5. The compound as claimed in claim 2, wherein R 1 is C3-C8 cycloalkylalkyl, wherein the C3-C8 cycloalkylalkyl is optionally substituted by 1, 2 or 3 R 1a or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

6. The compound as claimed in claim 2, wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted phenyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

7. The compound of claim 2, wherein R 1 is optionally replaced by 1, 2 or 3 R 1b Substituted phenyl-C1-C6 alkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

8. The compound of claim 2, wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted naphthyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

9. The compound of claim 2, wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted 5-membered or 6-membered monocyclic heteroaryl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

10. The compound of any one of claims 1 to 4, wherein each R 1a is independently hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

11. A compound as described in any one of claims 2, 3 and 6-9, wherein each R 1b Independently selected from hydrogen, halo (in some embodiments, fluorine), -C(O)OH, -C(O)(OCH3), C1-C6 alkyl (in some embodiments, methyl, ethyl, n-propyl or isopropyl) and C1-C6 alkoxy; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

12. A compound as described in any one of claims 2 to 11, wherein R 2 Selected from the group consisting of: or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

13. A compound as described in any one of claims 2 to 12, wherein R 2 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

14. A compound as described in any one of claims 2 to 12, wherein R 2 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

15. A compound as described in any one of claims 2 to 11, wherein R 2 yes (In some embodiments, ); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

16. A compound as described in any one of claims 2 to 13, wherein R 2a is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

17. A compound as described in any one of claims 2 to 16, wherein R 2d is C1-C3 alkoxy (optionally methoxy); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

18. A compound as described in any one of claims 2 to 17, wherein each R 2b is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

19. The compound of any one of claims 2 to 18, wherein one X 1 Yes CR 3 (optionally in R 2d The inter-position), an X 1 is N, and other X 1 Yes CR 2b (in some embodiments, CH); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

20. The compound of any one of claims 2-18, wherein one X 1 Yes CR 3 (optionally in R 2d ), and other X 1 is CH; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

21. A compound as described in any one of claims 2 to 20, wherein R 3 is -(CH2)-Y; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

22. A compound as described in any one of claims 2 to 20, wherein R 3 is -(CH2)-LY; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

23. A compound as described in any one of claims 2 to 22, wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; or Y is or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

24. A compound as described in any one of claims 2-22, wherein Y is replaced by R Y substituted 5-membered monocyclic heteroaryl; Y is replaced by R Y substituted pyrazolyl; Y is replaced by R Y substituted 8-membered or 9-membered bicyclic heterocycle; or Y is or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

25. A compound as described in any one of claims 2-24, wherein each R 3b and R 3b1 is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

26. A compound as described in any one of claims 2 to 24, wherein R Y Yes - (CH2) 0-3 NHC(O)R 3a 、-(CH2) 0-2 NHS(O)2R 3a 、-C(O)R 3a 、-S(O)2R 3a 、-(CH2) 0-3 NH(C1-C6 alkylene)NHC(O)R 3a 、-(CH2) 0-3 NH(C1-C6 alkylene)NHS(O)2R 3a 、-(CH2) 0-3 NHC(O)(C1-C6 alkylene)NHC(O)R 3a 、-(CH2) 0-3 NHC(O)(C1-C6 alkylene)NHS(O)2R 3a , or -C(O)R 3a Substituted C3-C8 heterocycloalkyl; wherein R 3a Selected from group a); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

27. A compound as described in any one of claims 2 to 26, wherein R 3a is -CH2(halo); -(CH2) 1-2 CN; -CH2OCH(CF3)2; -CH2O(trifluorophenyl); -CH2O(tetrafluorophenyl); -CH2O(isoxazolyl, which is optionally substituted by 1-3 substituents independently selected from the following: halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 -CH2O(pyrimidinyl, which is optionally substituted by 1-3 substituents each independently selected from the following: halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 -CH2O(pyridyl, which is optionally substituted by 1-3 substituents each independently selected from the following: halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl or C 3-8 C2-C4 alkenyl substituted with cyano (in some embodiments, -C(CN)(=CH2)); C2-C4 alkenyl substituted with halo (in some embodiments, C2-C4 alkenyl substituted with fluorine); -CH=CH-CH2-NR 3c R 3d ; -CH=CH-CH2-O-C1-C6 alkyl; tetrafluorophenyl; trifluorophenyl; C2-C6 alkynyl; -CH≡CH-CH2-NR 3c R 3d ; or -CH≡CH-CH2-O-C1-C6 alkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

28. A compound as described in any one of claims 2 to 27, wherein R Y yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

29. A compound as described in any one of claims 2-28, wherein each R 2e is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

30. A compound as described in any one of claims 2 to 12, wherein R 2 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

31. A compound as described in any one of claims 2-12 and 30, wherein each R 2b is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

32. The compound of any one of claims 2-12, 30 and 31, wherein one X 2 Yes CR 4 , an X 2 is N, and other X 2 Yes CR 2b ; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

33. A compound as described in any one of claims 2-12 and 30-32, wherein one X 2 Yes CR 4 And other X 2 is CH; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

34. A compound as described in any one of claims 2-12 and 30-33, wherein R 2 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

35. A compound as described in any one of claims 2-12 and 30-34, wherein X 2a is O; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

36. A compound as described in any one of claims 2-12 and 30-34, wherein R 4b and R 3b each is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

37. A compound as described in any one of claims 2-12 and 30-36, wherein R 4 yes -(CH2) 0-2 NHC(O)R 4a ; -NH(C2-C4-alkylene)NHC(O)R 4a ; C3-C8 heterocycloalkyl, which is substituted with -C(O)R on the nitrogen ring atom in the C3-C8 heterocycloalkyl 4a substituted (preferably, wherein the C3-C8 heterocycloalkyl is attached to ring (d) via a carbon in the C3-C8 heterocycloalkyl ring); -C(O)-HET1-C(O)R 4a , where -C(O)R 4a connected to the nitrogen ring atom in HET1; -C(O)-HET1-NHC(O)R 4a , wherein -C(O)- is attached to a nitrogen ring atom in HET1; -C(O)NH(C1-C6 alkylene)NHC(O)R 4a ; -(CH2) 0-2 HET2-C(O)R 4a , wherein HET2 is a 5-membered monocyclic heteroaryl or an 8-membered or 9-membered bicyclic heterocycle, and wherein the -C(O)R 4a connected to HET2 via a nitrogen ring atom in HET2; -(CH2) 0-3 NHC(O)(C1-C6 alkylene)NHC(O)R 4a ;or -(CH2) 0-3 NHC(O)-HET1-C(O)R 4a ;and R 4a Selected from group a); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

38. A compound as described in any one of claims 2-12 and 30-37, wherein R 4a is CH2(halo); -(CH2) 1-2 CN; C2-C6 alkenyl; C2-C4 alkenyl substituted by cyano; C2-C4 alkenyl substituted by halide; -CH=CH-CH2-NR 4c R 4d ; -CH=CH-CH2-O-C1-C6 alkyl; tetrafluorophenyl; trifluorophenyl; C2-C6 alkynyl; -CH≡CH-CH2-NR 4c R 4d ; or -CH≡CH-CH2-O-C1-C6 alkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

39. A compound as described in any one of claims 2-12 and 30-38, wherein HET1-C(O)R 4a yes HET1-NHC(O)R 4a yes and HET2-C(O)R 4a yes And R 4a Selected from group a); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

40. A compound as described in any one of claims 2-12 and 30-36, wherein R 4 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

41. A compound as described in any one of claims 2-12, wherein R 2 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

42. A compound as described in any one of claims 2-12 and 41, wherein R 2 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

43. A compound as described in any one of claims 2-12, wherein R 2 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

44. A compound as described in any one of claims 2-12 and 43, wherein R 2 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

45. A compound as described in any one of claims 2-12 and 41-44, wherein each R 2b is independently hydrogen or C1-C3 alkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

46. ​​A compound as described in any one of claims 2-12 and 41-45, wherein R 5 is pyridyl, pyrazolyl or imidazolyl; each of which is substituted by Z and optionally by R 2e Replacement; or R 5 Yes-C(O)N(R 5b )Z, where R 5b Selected from group b); R 5 is substituted by Z and optionally by R 2e Substituted heterocycloalkyl (in some embodiments, pyrrolidinyl); R 5 Yes - (CH2) 0-2 O-HET1-Z; or R 5 Yes - (CH2) 0-2 OZ; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

47. A compound as described in any one of claims 2-12 and 41-46, wherein R 5a is -CH2(halo); -(CH2) 1- 2CN; C2-C6 alkenyl; C2-C4 alkenyl substituted by cyano; C2-C4 alkenyl substituted by halide; -CH=CH-CH2-NR 5c R 5d ; -CH=CH-CH2-O-C1-C6 alkyl; tetrafluorophenyl; trifluorophenyl; C2-C6 alkynyl; -CH≡CH-CH2-NR 5c R 5d ; or -CH≡CH-CH2-O-C1-C6 alkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

48. A compound as described in any one of claims 2-12 and 41-47, wherein each R 5b is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

49. A compound as described in any one of claims 2-12 and 41-48, wherein Z is -(CH2) 0-3 NHC(O)R 5a 、-(CH2) 0-2 NHS(O)2R 5a 、-C(O)R 5a 、-C(O)NHR 5a 、-(CH2) 0-3 NH(C1-C6 alkylene)NHC(O)R 5a 、NHC(O)R 5a Substituted C3-C8 heterocycloalkyl, -S(O)2R 5a Substituted C3-C8 heterocycloalkyl, or C(O)R 5a substituted C3-C8 heterocycloalkyl; and R 5a Selected from group a); or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

50. A compound as described in any one of claims 2-12 and 41-46, wherein Z is or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

51. The compound of claims 2-12, wherein R 2 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

52. The compound of claims 2-12 and 51, wherein R 2 yes or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

53. The compound of claims 2-12 and 51-52, wherein Q 1 Yes CR Q1 , Q 2 is N, and Q 3 is O; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

54. The compound of claims 2-12 and 51-53, wherein R Q1 is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

55. The compound of claims 2-12 and 51-54, wherein R 6 is substituted by Q and optionally by R 2e Substituted pyrazolyl; or R 6 Yes - (CH2) 0-3 NHC(O)R 6a ; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

56. The compound of claims 2-12 and 51-55, wherein R 6a is -CH2(halo); -(CH2) 1-2 CN; C2-C6 alkenyl; C2-C4 alkenyl substituted by cyano; C2-C4 alkenyl substituted by halide; -CH=CH-CH2-NR 3c R 3d ; -CH=CH-CH2-O-C1-C6 alkyl; tetrafluorophenyl; trifluorophenyl; C2-C6 alkynyl; -CH≡CH-CH2-NR 3c R 3d ; or -CH≡CH-CH2-O-C1-C6 alkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

57. The compound of claims 2-12 and 51-54, wherein R 6b is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

58. The compound of claims 2-12 and 51-57, wherein one R 7 is C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

59. A compound as claimed in any one of the preceding claims, wherein R 3c , R 3d , R 4c , R 4d , R 5c , R 5d , R 6c and R 6d are each independently hydrogen or C1-C3 alkyl; or wherein R 3c and R 3d , R 4c and R 4d , R 5c and R 5d and R 6c and R 6d Each pair of is taken together with the nitrogen to which it is attached to form a pyrrolidinyl or piperidinyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

60. The compound of claim 1, selected from or a stereoisomer, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof.

61. The compound of claim 1, wherein: R 1 is optionally replaced by 1, 2 or 3 R 1a Substituted C3-C8 cycloalkyl; C3-C8 cycloalkylalkyl, wherein the C3-C8 cycloalkyl is optionally substituted by 1, 2 or 3 R 1a substituted; optionally substituted by 1, 2 or 3 R 1b substituted phenyl; optionally substituted by 1, 2 or 3 R 1b substituted naphthyl; optionally substituted by 1, 2 or 3 R 1b substituted 5-membered or 6-membered monocyclic heteroaryl; or optionally substituted by 1, 2 or 3 R 1b substituted 8-10 membered bicyclic heteroaryl; Each R 1a independently selected from H, halo, C1-C6 alkoxy and C3-C8 cycloalkyloxy; Each R 1b independently selected from H, halo, C1-C6 alkoxy, cyano and C3-C8 cycloalkyloxy; R 2 Selected from the group consisting of: Among them, for ring (a), R 2b is hydrogen or C1-C6 alkyl; One X 1 It is C(CH2R 2c ), and the other two X 1 Independently selected from N and CR 2e ; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 6-membered monocyclic heteroaryl; R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 9-membered bicyclic heteroaryl; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 10-membered bicyclic heteroaryl; and Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, -CN, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -(CH2) 0-1 NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(CH2) 0-1 NHC(O)R 2f 、-(CH2) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkylC1-C3 alkyl; Among them, for ring (b), One X 1 It is C(CH2R 2c ), and the other two X 1 Independently selected from N and CR 2e ; R 2c Is R 2c2 substituted and optionally by R 2c3 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c Is R 2c2 substituted and optionally by R 2c3 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c Is R 2c2 and optionally substituted with 1 or 2 R 2c3 Substituted 6-membered monocyclic heteroaryl; R 2c Is R 2c2 and optionally substituted with 1 or 2 R 2c3 substituted 9-membered bicyclic heteroaryl; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 10-membered bicyclic heteroaryl; R 2c2 C1-C6 alkylcarbonyl, -CN, -CH2NH2, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CH2NHC(O)R 2f 、-(CH2) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkylC1-C3 alkyl; R 2c3 are independently H, halo, C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyloxy; and Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -CN, -CH2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CH2NHC(O)R 2f 、-(CH2) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkylC1-C3 alkyl; Among them, for ring (c), One X 1 It is C(CH2R 2c ), and the other two X 1 Independently selected from N and CR 2e ; yes R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c is optionally replaced by 1, 2 or 3 R 2c1 Substituted 6-membered monocyclic heteroaryl; R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 9-membered bicyclic heteroaryl; or R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 10-membered bicyclic heteroaryl; and Each R 2c1 are independently H, halo, C1-C6 alkyl, C1-C6 alkylcarbonyl, -CN, C1-C6 alkoxy, C3-C8 cycloalkyloxy, -CH2NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CH2NHC(O)R 2f 、-(CH2) 0-1 NHC(O)OR 2f , a 5-membered or 6-membered monocyclic heteroaryl, or a 9-membered or 10-membered bicyclic heteroaryl; wherein R 2f is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkylC1-C3 alkyl; R 2d is halo, C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyloxy; and Each R 2e are independently hydrogen, halo, C1-C3 alkyl, cyclopropyl, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2 or -OCF3; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

62. The compound of claim 61, wherein R 1 is C3-C8 cycloalkylalkyl, wherein the C3-C8 cycloalkylalkyl is optionally substituted by 1, 2 or 3 R 1a or optionally substituted by 1, 2 or 3 R 1b substituted phenyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

63. The compound of claim 61, wherein R 1 is optionally replaced by 1, 2 or 3 R 1a substituted C3-C8 cycloalkyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

64. The compound of claim 61, wherein R 1 is C3-C8 cycloalkylalkyl, wherein the C3-C8 cycloalkylalkyl is optionally substituted by 1, 2 or 3 R 1a or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

65. The compound of claim 61, wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted phenyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

66. The compound of claim 61, wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted naphthyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

67. The compound of claim 61, wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted 5-membered or 6-membered monocyclic heteroaryl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

68. The compound of claim 61, wherein R 1 is optionally replaced by 1, 2 or 3 R 1b substituted 8-10 membered bicyclic heteroaryl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

69. A compound as described in any one of claims 61-64, wherein each R 1a is independently H; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

70. A compound as described in any one of claims 61, 62 and 65-67, wherein each R 1b Independently selected from H, halo and C1-C6 alkoxy; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

71. A compound as described in any one of claims 61-70, wherein R 2d is halogen, C1-C3 alkyl, C1-C3 alkoxy or C3 cycloalkyloxy; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

72. A compound as described in any one of claims 61-70, wherein R 2d is C1-C6 alkoxy, preferably C1-C3 alkoxy, preferably methoxy; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

73. A compound as described in any one of claims 61-72, wherein R 2e independently hydrogen, fluorine, C1-C3 alkyl, cyclopropyl, -CHF2, -CF3, C1-C4 alkoxy, -OCHF2 or -OCF3; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

74. The compound of any one of claims 61-73, wherein one X 1 It is C(CH2R 2c ), and the other two X 1 Each is CR 2e , preferably each is CH; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

75. The compound of any one of claims 61-74, wherein one X 1 It is C(CH2R 2c ), the second X 1 is N, and the third X 1 Yes CR 2e , preferably CH; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

76. The compound of any one of claims 61-73, wherein one X 1 It is C(CH2R 2c ), and the other two X 1 each is N; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

77. A compound as described in any one of claims 61-76, wherein C(CH2R 2c ) is in R 2d or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

78. The compound of any one of claims 61-77, wherein the compound of formula (I) is according to formula (Ii): or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

79. A compound as described in any one of claims 61-78, wherein R 2c Is R 2c2 substituted and optionally by R 2c3 substituted 5-membered monocyclic heteroaryl; optionally substituted by 1 or 2 R 2c1 substituted 8-membered or 9-membered bicyclic heterocyclic ring; 2c2 substituted and optionally by R 2c3 substituted 8-membered or 9-membered bicyclic heterocyclic ring; 2c2 and optionally substituted with 1 or 2 R 2c3 substituted 6-membered monocyclic heteroaryl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

80. The compound of claim 79, wherein R 2c is an 8- or 9-membered bicyclic heterocyclic ring, preferably a 5-membered heteroaryl group (preferably pyrazolyl) fused to a non-aromatic cyclic group, wherein R 2c Optionally 1 or 2 R 2c1 or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

81. The compound of claim 79, wherein R 2c Is R 2c2 substituted and optionally by R 2c3 Substituted 5-membered monocyclic heteroaryl, preferably pyrazolyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

82. The compound of claim 79, wherein R 2c is an 8- or 9-membered bicyclic heterocyclic ring, preferably a 5-membered heteroaryl group (preferably pyrazolyl) fused to a non-aromatic cyclic group, wherein R 2c By R 2c2 substituted and optionally by R 2c3 or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

83. The compound of claim 79, wherein R 2c Is R 2c2 and optionally substituted with 1 or 2 R 2c3 Substituted 6-membered monocyclic heteroaryl, preferably pyridyl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

84. A compound as described in any one of claims 79 and 81-83, wherein R 2c2 is C1-C6 alkylcarbonyl, -CN, -CH2NH2 or -CH2NHC(O)R 2f 、-(CH2) 0-1 NHC(O)OR 2f ; where R 2f It is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkylC1-C3 alkyl; or one or more pharmaceutically acceptable salts thereof; and / or its stereoisomers or mixtures of stereoisomers.

85. A compound as described in any one of claims 79 and 81-84, wherein each R 2c3 is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

86. The compound of any one of claims 1-16, wherein the compound of formula (I) is according to formula (Ih): or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

87. A compound as described in any one of claims 61-77, wherein the compound of formula (I) is according to formula (Ij): or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

88. The compound of claim 86 or 87, wherein R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 5-membered monocyclic heteroaryl; R 2c is optionally replaced by 1 or 2 R 2c1 Substituted 8-membered or 9-membered bicyclic heterocycle; R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 6-membered monocyclic heteroaryl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

89. The compound of claim 86 or 87, wherein R 2c is optionally replaced by 1 or 2 R 2c1 substituted 5-membered monocyclic heteroaryl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

90. The compound of claim 86 or 87, wherein optionally 1 or 2 R 2c1 A substituted 8-membered or 9-membered bicyclic heterocycle; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

91. The compound of claim 86 or 87, wherein R 2c is optionally replaced by 1, 2 or 3 R 2c1 substituted 6-membered monocyclic heteroaryl; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or a mixture of stereoisomers thereof.

92. The compound of any one of claims 61-80 and 86-91, wherein each R 2c1 is hydrogen; or one R 2c1 Selected from C1-C6 alkylcarbonyl, -CN, -CH2NH2 and -CH2NHC(O)R 2f 、-(CH2) 0-1 NHC(O)OR 2f , where R 2f is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkylC1-C3 alkyl; and the other or both R 2c1 each is hydrogen; or one R 2c1 is -CN and one or two R 2c1 each is hydrogen; or one or more pharmaceutically acceptable salts thereof; and / or a stereoisomer or mixture of stereoisomers thereof.

93. The compound of claim 61, selected from or a regioisomer, a stereoisomer, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof.

94. A pharmaceutical composition comprising a compound according to any one of claims 1-93 or a stereoisomer, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

95. A method for treating a disorder, disease or condition by inhibiting MYST family lysine acetyltransferases including KAT6A and KAT6B, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a stereoisomer, a mixture of stereoisomers and / or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 93 or a therapeutically effective amount of a composition as described in claim 94 to a subject in need thereof.

96. The method of claim 95, wherein the disorder, disease or condition is a hyperproliferative disorder or cancer.

97. The method of claim 96, wherein the cancer is selected from one or more of the following: leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, breast ductal carcinoma, colorectal cancer, colon cancer, squamous cell carcinoma, gastric cancer, adrenocortical carcinoma, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, female reproductive system cancer, male reproductive system cancer (including testicular cancer and penile cancer), central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma , hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, malignant fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nervous system cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm, primary CNS lymphoma, rectal cancer, respiratory system cancer, retinoblastoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thyroid cancer, urinary system cancer, uterine cancer, uterine sarcoma, vaginal cancer, endocrine cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitary adenoma, vascular system cancer, Waldenstrom's macroglobulinemia and / or Wilm's tumor.

98. The method of claim 96, wherein the cancer is selected from one or more of the following: breast cancer including ER-positive breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, and blood cancer (including leukemia or lymphoma).

99. A method of inhibiting a MYST family lysine acetyltransferase, including KAT6A and KAT6B, the method comprising contacting a compound of any one of claims 1-93; or a stereoisomer, a mixture of stereoisomers, and / or a pharmaceutically acceptable salt thereof.

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