Compounds, compositions and methods

Abstract

The present disclosure relates generally to small molecule modulators of mucolipoprotein-1 (TRPML1) and their use as therapeutic agents.

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 515,017, filed July 21, 2023, pursuant to 35 USC §119(e), the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure generally relates to small molecule modulators of lipoprotein-1 (TRPML1) and their use as therapeutic agents. Background Technology

[0003] Transient receptor potential lipoprotein 1, also known as lipoprotein-1 (TRPML1 or ML-1), is a member of the transient receptor potential (TRP) ion channel superfamily. Electrophysiological experiments on isolated lysosomes have demonstrated that TRPML1 is a non-selective cation channel localized to late endosomes and lysosomes (LEL) (Dong X. et al., Nature 2008, 455, 7215 (992). Wild-type human TRPML1 has six transmembrane domains within each monomer unit, which aggregate to form a tetramer containing an ion pore located in the center of this complex. TRPML1 is permeable to a variety of monovalent and divalent cations, including Na. + K + Ca 2+ Fe 2+ and Zn 2+ Ca 2+ TRPML1 release from the LEL into the cytosol is associated with a variety of physiological processes, including activation of transcription factor EB (TFEB), lysosomal transport, exocytosis, phagosome formation, autophagy, and lysosomal biosynthesis (Venkatachalam, K. et al., 'TRPML1-Dependent Processes as Therapeutic Targets'). TRP Channels as Therapeutic Targets Arpad Szallasi (ed.), Academic Press, 2015, pp. 469-482. TRPML1 is effective against other ions (such as Fe). 2+ and Zn 2+ The electrical conductivity of lysosomes plays an important role in the regulation of trace metals within lysosomal reservoirs (Du et al., Cell Reports 2021, 37 Loss of function (LoF) in TRPML1 leads to Fe in lysosomes. 2+ and Zn 2+ Accumulation and signal transmission are impaired.

[0004] The TRPML1 protein is encoded by the MCOLN-1 gene (Di Paola, S. et al, Cell Calcium 2018, 69 , 112). LoF mutations in MCOLN-1 can cause autosomal recessive lysosomal storage disease (LSD) type IV mucolipidosis (MLIV). The two major mutations that cause MLIV are in the third intron, causing a splicing variant that lacks exons 4-5 and a ~6 kb deletion spanning exons 6-7. These two mutations are present in about 95% of patients diagnosed with MLIV, causing severe developmental deficits, including cognitive impairment, motor dysfunction, and retinal degeneration. Patients with these mutations typically do not live past adolescence. The root cause of these devastating symptoms is related to LoF TRPML1 -dependent lysosomal accumulation and dysfunction that leads to neuroinflammation and neurodegeneration.

[0005] Endogenous lipids have been found to modulate the activity of TRPML1. Phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2) is an endogenous lipid rich in LELs that agonize TRPML1 activity (Dong X. et al, Nature Communications 2010, 1, 38 ). Whereas phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is found primarily in the cytoplasmic membrane and inhibits TRPML1 activity on the plasma membrane during its trafficking to the LEL. TRPML1 is H + concentration, with the optimal pH coinciding with the pH of mature lysosomes (pH ~ 4.5) (Dong et al., 2008).

[0006] Mutations in the enzyme complex that mediates PI(3,5)P2 metabolism cause neurodegenerative diseases. The PIKfyve kinase is required for PI(3,5)P2 synthesis, and ablation of its activity causes defects in LEL trafficking and TRPML1 activity (Zolov et al., PNAS 2012, 109, 43 , 17472). LoF mutations in FIG4 (phosphoinositide phosphatase) are associated with Charcot-Marie-Tooth Disease (CMT4J). The FIG4 gene has been implicated as a genetic factor in 1-2% of patients with amyotrophic lateral sclerosis (ALS) (Chow et al., American Journal of Human Genetics 2009, 84, 85). LoF of FIG4 leads to reduced levels of PI(3,5)P2 and impaired TRPML1 function. Variants of VAC14, a scaffold protein in the PI(3,5)P2 metabolic complex, are also associated with Parkinson’s Disease (PD) and pediatric-onset neurological diseases. Dysfunction in TRPML1 is proposed as a potential mechanism for those PI(3,5)P2 deficient mutations. Preclinical studies demonstrate that TRPML1 activation can be beneficial in those disease models, suggesting therapeutic potential of TRPML1 agonism in CMT, ALS, PD and other neurodegenerative diseases (Dong X. et al, Nature 2008, 455, 7215 , 992).

[0007] TRPML1 has been associated with LSDs. Niemann-Pick (NP) disease is genetic and caused primarily by accumulation of lipids, including sphingomyelin and cholesterol, leading to severe neurological symptoms. Sphingomyelin accumulation in lysosomes inhibits TRPML1 activity. Activation of TRPML1 in NP disease cell models can reduce lipid accumulation, thereby restoring lysosomal trafficking of TRPML1 (Shen et al, Nature Communications 2012, 3 , 731). Increasing TPRML-1 activity via overexpression of TFEB increases lysosomal exocytosis and rescues the pathogenesis of mucopolysaccharidosis in cell culture and in vivo disease models. Many LSDs are described by lysosomal dysfunction, including trafficking, maturation, exocytosis, lipid and biomolecule accumulation, and Ca 2+ homeostasis. TRPML1 plays a major role in these processes and is therefore an attractive target for treating LSDs (Di Paola et al., 2018).

[0008] Lysosomal function in neurons is associated with neurodegenerative diseases (Cesan et al., Experimental Cell Research 2012, 318, 11 , 1245; Ghavami et al., Progress in Neurobiology 2014, 112,24). Specifically, TRPML1 activity is associated with hallmarks of Alzheimer’s Disease (AD). Patients infected with human immunodeficiency virus (HIV) can develop premature cognitive decline associated with accumulation of Aβ and sphingomyelin in cellular compartments. Agonism of TRPML1 in an HIV-pg120-induced sphingomyelin and Aβ accumulation model using primary neurons demonstrates clearance of these biomolecules (Bae et al., Journal of Neuroscience 2014, 34,34 , 11485). Furthermore, TFEB activation (a downstream effect of TRPML1 activation) reduces Tau pathology in preclinical models (Polito et al., 11485). EMBO Molecular Medicine June 2014 9 These studies demonstrate the therapeutic potential of TRPML1 in AD.

[0009] Duchenne muscular dystrophy (DMD) is caused by mutations in dystrophin, which weakens the plasma membrane of muscle cells. Patients with DMD suffer severe muscle damage during contraction (Yu et al., Science Advances 2020, 6 (eaaz2736). TRPML1 activation rescued these phenotypes in a mouse model of DMD, suggesting a broad therapeutic approach for this heterogeneous disease.

[0010] Targeting TRPML1 with small molecule modulators has been shown to rescue hallmark phenotypes in neurodegenerative diseases, LSD, prion and prion-like diseases, and muscular dystrophy-related diseases in cell-based and animal disease models. TRPML1 is intricately involved in many important cellular processes and can be a therapeutic target for a variety of human diseases. Several tool molecules exist to regulate TRPML1, but they are unsuitable as human drugs due to reduced potency, physicochemical properties, and in vivo pharmacokinetic characteristics. Many of the diseases associated with TRPML1 activity described above lack effective curative treatments. Therefore, there is a great need to develop clinically relevant small molecule modulators of TRPML1.

[0011] Therefore, there is a need to develop TRPML1 regulators to salvage impaired lysosomal function and autophagy, especially in neurodegenerative diseases. Detailed Implementation

[0012] This article provides compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, that may be used to treat and / or prevent diseases at least in part mediated by TRPML1.

[0013] In some implementations, a compound that activates TRPML1 is provided.

[0014] In another embodiment, a pharmaceutical composition is provided comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, and a pharmaceutically acceptable carrier.

[0015] In another embodiment, a method is provided for treating a disease or ailment at least partially mediated by TRPML1, the method comprising administering to a subject in need a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0016] This disclosure also provides compositions (including pharmaceutical compositions) comprising a compound or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers or a prodrug thereof, a cassette, a method of use (or administration) and preparation of said compound or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers or a prodrug thereof or intermediates thereof.

[0017] This disclosure further provides a method for treating a disease, condition, or disorder mediated at least in part by a compound or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug or a combination thereof.

[0018] Furthermore, this disclosure provides the use of a compound or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug or a combination thereof for the manufacture of an agent for treating at least partially TRPML1-mediated diseases, conditions, or disorders.

[0019] The description herein illustrates exemplary embodiments of the invention. However, it should be understood that this description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0020] 1. Definition A dash ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -C(O)NH2 is connected via a carbon atom. A dash at the beginning or end of a chemical group is for convenience; chemical groups may or may not be depicted with one or more dashes without losing their ordinary meaning. Wavy or dashed lines drawn along a straight line in a structure indicate the designated connection point of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply any directionality or stereochemistry.

[0021] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that an alkyl group has 1 to 6 carbon atoms.

[0022] In this document, the reference to "about" of a value or parameter includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes an indicated amount ± 10%. In other embodiments, the term "about" includes an indicated amount ± 5%. In some still embodiments, the term "about" includes an indicated amount ± 1%. Furthermore, the term "about X" includes a description of "X". Additionally, unless the context clearly specifies otherwise, the singular forms "a" and "the" include multiple indicators. Thus, for example, reference to "compound" includes multiple such compounds, and reference to "assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

[0023] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 12 carbon atoms (i.e., C464) 1-12 Alkyl groups, 1 to 8 carbon atoms (i.e., C464) 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C646) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4 Alkyl groups. Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by its chemical name or identified by its molecular formula, all positional isomers having that number of carbons can be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0024] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, and divalent heteroaryl groups may also be referred to as "alkylene" groups (e.g., methylene, ethylene, and propylene) and "arylene" groups (e.g., propylene, naphthylene (for arylene), or quinolinyl (for heteroarylene)). Furthermore, unless explicitly indicated otherwise, when a group combination is referred to herein as a part (e.g., cycloalkylalkyl, arylalkyl, heterocycloalkyl, heteroarylalkyl), the group is defined by its components, and the last group mentioned contains the atoms that connect the part to the remainder of the molecule.

[0025] "Alkenyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C20 ... 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkyl groups (alkenyl). Examples of alkenyl groups include, for example, vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0026] "Alkyne" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C360, C460, C560, C6 ... 2-20 alkynyl group), 2 to 12 carbon atoms (i.e., C12-C12). 2-12 acetylsyl), 2 to 8 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-8 acetylsyl), 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 Alkyl groups (alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0027] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0028] "Amino" refers to the -NR group. y R z , where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0029] "Formamidinyl" refers to -C(NR) y (NR) z 2), where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0030] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl groups have 6 to 20 cyclic carbon atoms (i.e., C64 ... 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12aryl group) or 6 to 10 carbon ring atoms (i.e., C46, ​​C56, C6 ... 6-10 Aryl groups. Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl groups do not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is heteroaryl, regardless of the bonding point. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is heterocyclic, regardless of the bonding point. If one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is cycloalkyl, regardless of the bonding point.

[0031] "Arylalkyl" or "arylalkyl" refers to the group "aryl-alkyl-".

[0032] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclic group having at least one double bond) and cycloalkenyl (a cyclic group having at least one sp). 3 A carbocyclic fused ring system with carbon atoms (i.e., at least one non-aromatic ring). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C1646667 ... 3-20 cycloalkyl groups), 3 to 14 cyclic carbon atoms (i.e., C1456 ... 3-12 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 Cycloalkyl. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclic [2.2.1]heptyl, bicyclic [2.2.2]octyl, adamantyl, norcamphenyl, decahydronaphthyl, 7,7-dimethyl-bicyclic [2.2.1]heptyl, etc. Furthermore, the term cycloalkyl is intended to cover any non-aromatic ring that can fuse to an aryl ring, regardless of the connection to the rest of the molecule. In addition, when two substitution positions are present on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0033] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.

[0034] "Halogen" refers to an atom that occupies Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0035] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, in the case where a residue is substituted with more than one halogen, the residue may be referred to by using a prefix corresponding to the number of halogen moieties to which it is attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may be (but are not necessarily) the same halogen. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0036] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens.

[0037] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom, are independently replaced by the same or different heteroatom groups, provided that the connection point to the rest of the molecule is via a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms can be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR. y -, -O-, -S-, -S(O)-, -S(O)2-, etc., among which R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.) and amines (e.g., -CH2NR). y CH3、-CH(CH3)NR y CH3、-CH2CH2NR y CH3、-CH2CH2NR y CH2CH2NR y CH3, etc., of which R yIt is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein. As used herein, heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom.

[0038] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 cyclic carbon atoms (i.e., C64 ... 1-20 (heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl) or 3 to 8 carbon ring atoms (i.e., C 3-8 The heteroaryl group comprises 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomium, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. In some cases, the heteroaryl group comprises a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each independently having 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomium, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzooxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indoleyl Azolyl, indolyl, indazole, isoindolyl, isoquinolinyl, isoxazolyl, naphridinyl, oxadiazolyl, oxazolyl, 1-oxo-pyridinyl, 1-oxo-pyrazinyl, 1-oxo-pyridazinyl, 1-oxo-pyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridyl, and imidazo[1,5-a]pyridyl, wherein the heteroaryl group can be linked via any ring of the fused system. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of the connection of the rest of the molecule (i.e., via any of the fused rings). Heteroaryl does not encompass or overlap with aryl groups as defined above.

[0039] "Heteroarylenealkyl" refers to the group "heteroarylene-alkyl-".

[0040] "Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. A heterocyclic group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spirocoupled, and can contain one or more (e.g., 1 to 3) oxo groups (=O) (such as -C(O), -S(O)-, -S(O)2-, etc.) or N-oxides (-O... - The heterocyclic group is defined as follows: Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered a heterocyclic group, independent of the connection to the rest of the molecule. For example, 6,7-dihydro-5 H The fused ring systems of -cyclopentadieno[b]pyridinyl, decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8-tetrahydroquinazolinyl are heterocyclic groups, independent of linkage (i.e., they can be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom, which can be fused to a cycloalkyl, aryl, or heteroaryl ring, independent of linkage to the rest of the molecule. As used herein, heterocyclic groups have 2 to 20 ring carbon atoms (i.e., C64 ... 2-20 Heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclic group) or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclic groups; having 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomium, wherein the cyclic heteroatoms are independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include, for example, azirrocyclobutyl, azirrocycloheptenyl, benzodioxanepentyl, benzo[b][1,4]dioxaneheptenyl, 1,4-benzodioxyl, benzopyranyl, benzodioxanehexenyl, benzopyranone, benzofuranone, dioxanepentyl, dihydropyranyl, hydrogenpyranyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazolinyl, indololinyl, inazinyl, isoindololinyl, isothiazolyl, isothiazolyl, iso... Oxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidylyl, oxazolidinyl, ethylene oxide, oxacyclobutyl, phenothiazinyl, phenothiazinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylyl, pyrazolyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, tetrahydropyranyl, trithiaalkyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When two substitution positions are present on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spiroheterocyclic rings include, for example, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindololinyl, wherein the heterocyclic group can be bonded via any ring of the fused system.

[0041] "Heterocyclic alkyl" refers to the group "heterocyclic-alkyl-".

[0042] "Oxime" refers to the group -CR y (=NOH), where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0043] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and this description includes both the scenario where the event or situation occurs and the scenario where the event or situation does not occur. Furthermore, the term “optionally substituted” means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a specified atom or group may or may not be substituted with any other than hydrogen.

[0044] As used herein, the term "substituted" means any of the aforementioned groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, and / or heteroalkyl) in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is substituted by a non-hydrogen atom, such as, but not limited to, halogen, hydroxyl, cyano, nitro, alkyl, alkenyl, alkoxy, heteroalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, oxo, thionyl, N-oxide, azide, oxime, thiocyanate, formamidinyl, guanidinyl, cycloalkylalkyl, arylalkyl, heterocyclicalkyl, heteroarylalkyl, -NR g R h -NR g C(O)R h -NR g C(O)NR g R h -NR g C(O)OR h -NR g S(O) 1-2 R h -C(O)R g -C(O)OR g -OC(O)OR g -OC(O)R g -C(O)NR g R h -C(NR) g )R h -OC(O)NR g R h -C(O)NR g C(O)R h or -N(C(O)R g )C(O)R h -SR g -S(O)R g -S(O)2R g -OS(O) 1-2 R g -S(O) 1-2 OR g -NR g S(O) 1-2 NR g R h =NSO2R g =NNR g R h -NR g NR g R h =NOR g -S(O)1-2 NR g R h -NR g S(O) 1-2 R h -CH2S(O) 1-2 R g -CH2S(O) 1- 2NR g R h -SF5, -SCF3 or -Si(R) y )3; wherein each alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, cycloalkylalkyl, arylalkyl, heterocyclic alkyl, and heteroarylalkyl is independently and optionally substituted with one to three oxo, halogen, cyano, hydroxyl, alkoxy, or alkyl groups, wherein the alkyl group is optionally substituted with an oxo, halogen, cyano, hydroxyl, or alkoxy group; each R y Independently, each R is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl; and each R g and R h Independently, it is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl; or R on the same atom g and R h or any two R atoms on different atoms g and R h Together with the atoms to which they are attached, they form heterocyclic groups optionally substituted with oxo, halogen, cyano, hydroxyl, alkoxy, or alkyl groups, wherein the alkyl group is optionally substituted with oxo, halogen, cyano, hydroxyl, or alkoxy groups.

[0045] This document is not intended to include polymers or similar indeterminate structures (e.g., substituted aryl groups having substituted alkyl groups, the substituted alkyl groups themselves being substituted by substituted aryl groups, the substituted aryl groups being further substituted by substituted heteroalkyl groups, etc.). Unless otherwise noted, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of a substituted aryl group by two other substituted aryl groups is limited to an aryl group substituted by ((substituted aryl)-substituted)-aryl. Similarly, the above definitions are not intended to include disallowed substitution patterns (e.g., methyl groups substituted with five fluorine atoms or heteroaryl groups having two adjacent oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein.

[0046] In some implementations, as used herein, the phrase "one or more" refers to one to five. In some implementations, as used herein, the phrase "one or more" refers to one to three.

[0047] Any compound or structure presented herein is also intended to represent both unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have the structures illustrated herein, but one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as… 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Various isotope-labeled compounds disclosed herein, such as radioisotopes (e.g., 3 H and 14 C) Those compounds incorporated therein. Such isotopically labeled compounds can be used for metabolic studies, reaction kinetic studies, detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or matrix tissue distribution assays) or radiotherapy of patients.

[0048] The term “isotope-enriched analogues” includes “deuterated analogues” of the compounds described herein, wherein one or more hydrogen atoms are replaced by deuterium, such as hydrogen atoms on carbon atoms. Such compounds exhibit increased resistance to metabolism and are therefore useful for prolonging the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol.Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0049] The deuterium-labeled or substituted therapeutic compounds of this disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages due to its greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18 F, 3 H or 11 C-labeled compounds can be used in PET, SPECT, or other imaging studies. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, following the procedures disclosed in the embodiments and preparations described below. It should be understood that deuterium is considered a substituent in the compounds described herein in this context.

[0050] The concentration of this heavier isotope (specifically deuterium) can be defined by the isotope enrichment factor. In the compounds disclosed herein, any atom not explicitly designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is explicitly designated as "H" or "hydrogen," that position should be understood as hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds disclosed herein, any atom explicitly designated as deuterium (D) is intended to represent deuterium.

[0051] In many cases, the compounds of this disclosure are able to form acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0052] Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” means compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0053] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Additionally, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, especially a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include (by example only) sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)) 2) Trienylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include (by example only) isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0054] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with their imine tautomers. Regardless of the type of tautomers exhibited or the nature of the equilibrium between them, those skilled in the art will understand that a compound comprises both its amide and imine tautomers. Therefore, amide-containing compounds should be understood to include their imine tautomers. Similarly, imine-containing compounds should be understood to include their amide tautomers.

[0055] The compounds disclosed herein, or their pharmaceutically acceptable salts, include an asymmetric center and thus can produce enantiomers, diastereomers, and other stereoisomers, which can be defined according to the absolute stereochemical definition ( R )-or( S (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), ( R )-and( S (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and / or fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from precursors suitable for optical purity or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0056] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but with different (non-interchangeable) three-dimensional structures. This disclosure covers various stereoisomers or mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0057] A "diastereomer" is a stereoisomer that has at least two asymmetric atoms that are not mirror images of each other.

[0058] Use the “thick bond” style (thick lines or parallel lines) to graphically indicate the relative centers of compounds as illustrated in this article, and use wedge bonds (thick lines or parallel lines) to illustrate absolute stereochemistry.

[0059] "Prodrug" means any compound that, when administered to a mammalian subject, releases an active parent drug according to the structure described herein in vivo. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein in a manner that allows the modification to cleave in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in compounds in a manner that allows the modification to cleave into the parent compound under normal operating conditions or in vivo. Prodrugs include compounds described herein, wherein the hydroxyl, amino, carboxyl, or thiol groups in the compounds described herein are respectively bonded to any group that can cleave in vivo to regenerate free hydroxyl, amino, or thiol groups. Examples of prodrugs include, but are not limited to, esters (e.g., acetates, formates, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc., of the hydroxyl functional group in the compounds described herein. The preparation, selection, and use of prodrugs are discussed in the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", ACS Symposium Series, Vol. 14; "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated in its entirety by reference.

[0060] 2. Compounds This document provides compounds as activators of TRPML1. In some embodiments, compounds of formula I are provided: I Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 1 R 2 R 3 R 4 R 5 R 6 L, X 1 t and t are independently as defined in this paper.

[0061] In some embodiments, a compound of formula I is provided: I Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 Is it N or CR? 7 ; L is a key, C 1-2 Alkylene, C2 alkenylene, C2 alkyneide, -CH2-C(O)NR 11 -*, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-*, -C(O)NR 11 -*、-S(O)NR 11 -* or -S(O)2NR 11 -*; where the * key is connected to R 4 ; R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 2 It is a halogen group, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; or R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; R 3 yes: or ; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; Each R 5 Independently, it is a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Halogenated, C 2-6 alkenyl or C 2-6 Alkyne group; or two R groups 5 Together they form C 3-6 cycloalkyl or 4-6 membered heterocyclic groups; wherein the C 3-6 The cycloalkyl group or the 4-6 membered heterocyclic group is independently and optionally surrounded by one to five Z groups. 1a replace; Or two Rs 5 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; or R 1 and R 5 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; or R 4 and R 5 Together with the atoms to which they are attached, they form heterocyclic groups or heteroaryl groups; wherein the heterocyclic group or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 6 and R 7 Each of these groups is independently hydrogen, hydroxyl, halogen, cyano, or C. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl thio or -NR a R b ; R a and R b Each is independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-2 -C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; Each R 8 Independently is -C(O)N(R) 11 2. C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; wherein the C 1-6 alkyl or the C 1-6 The haloalkyl group is independently and optionally surrounded by a cyano group, -N(R) 13 2. Halogenated group, hydroxyl group or C 1-6 Alkoxy substitution; or two Rs 8 The carbon atoms bonded to them can form oxo groups, fusion, or spiro groups together. 3-7 cycloalkyl, or fused, bridged, or spiro-4-7 membered heterocyclic groups; wherein the C 3-7 The cycloalkyl group or the 4-7 membered heterocyclic group is independently and optionally surrounded by a halogen group, a hydroxyl group, or a C-group. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy or C 1-6 Haloalkoxy substitution; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; t is 0, 1, or 2; m is 1 or 2; n is 1, 2, or 3; m1 is 0, 1, or 2; n1 is 0, 1, 2, or 3; m2 is 0, 1, or 2; n2 is 0, 1, 2 or 3; Where m + n is 2, 3, or 4; m1 + n1 is 0, 1, 2, 3 or 4; m2 + n2 is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13-NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0062] In some embodiments, a compound of formula I' is provided: I' Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 1 R 2 R 3 R 4 R 5 R 6 X1 t and t are independently as defined in this paper.

[0063] In some embodiments, a compound of formula I' is provided: I' Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 Is it N or CR? 7 ; R 1 It is a halogenated group, a cyano group, a nitro group, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 2 It is a halogen group, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; or R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; R 3 yes: or ; R 4 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; Each R 5 Independently, it is a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Halogenated, C 2-6 alkenyl or C 2-6 Alkyne group; or two R groups 5 Together they form C 3-6 cycloalkyl or 4-6 membered heterocyclic groups; wherein the C 3-6 The cycloalkyl group or the 4-6 membered heterocyclic group is independently and optionally surrounded by one to five Z groups. 1a replace; Or two Rs 5 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; or R 1 and R 5 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; or R 4and R 5 Together with the atoms to which they are attached, they form heterocyclic groups or heteroaryl groups; wherein the heterocyclic group or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 6 and R 7 Each of these groups is independently hydrogen, hydroxyl, halogen, cyano, or C. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl thio or -NR a R b ; R a and R b Each is independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-2 -C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; Each R 8 C is independent 1-6 Alkyl or C 1-6 Halogenated alkyl groups; wherein the C 1-6 alkyl or the C 1-6 The haloalkyl group is independently and optionally surrounded by a halogen group, a hydroxyl group, or a C group. 1-6 Alkoxy substitution; or two Rs 8 The carbon atoms bonded to them can form oxo groups together, either fused or spiro-C. 3-7 cycloalkyl, or fused or spiro-4-7 membered heterocyclic groups; wherein the C 3-7 The cycloalkyl group or the 4-7 membered heterocyclic group is independently and optionally surrounded by a halogen group, a hydroxyl group, or a C-group. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy or C 1-6 Haloalkoxy substitution; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or -OC 3-7 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-7 cycloalkyl or -OC 3-7 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; t is 0, 1, or 2; m is 1 or 2; n is 1, 2, or 3; m1 is 0, 1, or 2; n1 is 0, 1, 2, or 3; m2 is 0, 1, or 2; n2 is 0, 1, 2 or 3; Where m + n is 2, 3, or 4; m1 + n1 is 0, 1, 2, 3 or 4; m2 + n2 is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13)2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents, said substituents being selected from five halogen groups, cyano groups, -OH, -SH, -NH2, -NO2, -SF5, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0064] In some implementations, R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution.

[0065] In some implementations, R 1 It is C 1-6 alkyl.

[0066] In some implementations, R 1 It is a methyl group.

[0067] In some implementations, R 2 Is it -CD3 or C? 1-6 alkyl.

[0068] In some implementations, R 2 It is a methyl group.

[0069] In some implementations, R 1 It is C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution; and R 2 It is C 1-6 alkyl.

[0070] In some implementations, R 1 It is C 1-6 Alkyl and R 2 It is C 1-6 alkyl.

[0071] In some implementations, R 1 and R 2 It is a methyl group.

[0072] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace.

[0073] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl or 4-6 membered heterocyclic groups; wherein the C 3-6 The cycloalkyl group or the 4-6 membered heterocyclic group is independently and optionally surrounded by one to five Z groups. 1a replace.

[0074] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Replacement C 3-10 Cycloalkyl.

[0075] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Replacement C 3-6 Cycloalkyl.

[0076] In some implementations, R 1 and R 2 Together with the carbon atoms to which they are attached, they form groups optionally marked with one or two hydroxyl groups, halogen groups, cyano groups, or C groups. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 alkoxy or heteroaryl substituted C 3-6 Cycloalkyl.

[0077] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form C atoms that are optionally substituted with hydroxyl groups. 3-6 Cycloalkyl.

[0078] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Substituted heterocyclic groups.

[0079] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Substituted 4-6 membered heterocyclic groups.

[0080] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form heterocyclic groups.

[0081] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form 4-6 membered heterocyclic groups.

[0082] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form C atoms that are optionally substituted with hydroxyl groups. 3-4 Cycloalkyl.

[0083] In some implementations, R 1 and R 2 Together with the carbon atoms they are attached to, they form unsubstituted C atoms. 3-5 Cycloalkyl.

[0084] In some implementations, R 3 yes .

[0085] In some implementations, m is 1 or 2. In some implementations, m is 0. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3.

[0086] In some implementations, n is 1. In some implementations, n is 0. In some implementations, n is 2. In some implementations, n is 3.

[0087] In some implementations, m + n is 3. In some implementations, m + n is 2. In some implementations, both m and n are 1.

[0088] In some implementations, R 3 yes .

[0089] In some implementations, m1 is 0. In some implementations, m1 is 1. In some implementations, m1 is 2. In some implementations, m1 is either 1 or 2. In some implementations, m1 is either 0 or 1.

[0090] In some implementations, n1 is 0. In some implementations, n1 is 1. In some implementations, n1 is 2. In some implementations, n1 is 3. In some implementations, n1 is 1, 2, or 3. In some implementations, n1 is 1 or 2. In some implementations, n1 is 0 or 1.

[0091] In some implementations, m2 is 0. In some implementations, m2 is 1. In some implementations, m2 is 2. In some implementations, m2 is either 1 or 2. In some implementations, m2 is either 0 or 1.

[0092] In some implementations, n2 is 0. In some implementations, n2 is 1. In some implementations, n2 is 2. In some implementations, n2 is 3. In some implementations, n2 is 1, 2, or 3. In some implementations, n2 is 1 or 2. In some implementations, n2 is 0 or 1.

[0093] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 1 or 2. In some implementations, p is 0, 1, or 2. In some implementations, p is 0, 1, 2, or 3. In some implementations, p is 1, 2, or 3.

[0094] In some implementations, each R 8 Independently is -C(O)N(R) 11 2. C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; wherein the C 1-6 Alkyl groups are independently and optionally replaced by cyano groups, -N(R) 13 2. Halogenated group, hydroxyl group or C 1-6 Alkoxy substitution; or two Rs 8 The carbon atoms they are attached to can form oxo groups or bridged 4-7 membered heterocyclic groups.

[0095] In some implementations, each R 8 C is independent 1-6 alkyl.

[0096] In some implementations, or two R 8 Together with the carbon atoms they are attached to, they form bridging 4-7 membered heterocyclic groups. In the two R... 8 Together they form fused C 3-7 In the case of cycloalkyl or fused 4-7 membered heterocyclic groups, it should be understood that when two R... 8 When a bridging ring is formed, the bridging portion contains at least one (e.g., 1-3) atom (e.g., a carbon atom, such as -(CH2)). 1-3 Furthermore, in both R... 8 Together they form fused C 3-7 In the case of cycloalkyl or fused 4-7 membered heterocyclic groups, it should be understood that the two R groups forming the fused ring... 8 Connect to R 3 Adjacent atoms on a portion.

[0097] In some implementations, p is 1 or 2; and each R 8 It is a methyl group.

[0098] In some implementations, R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy or C 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 alkoxy or the C 3-10 The cycloalkyl group is independently and optionally surrounded by one to five halogen groups, cyano groups, hydroxyl groups, -S(O)2C groups. 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)NHC 1-6 Alkyl 2, -C(O)N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Halogenated, C 1-6 Haloalkoxy, C 3-7 Cycloalkyl, heterocyclic, or heteroaryl substitutions; wherein the heterocyclic group is optionally further substituted with a halogen or C- group. 1-6 Alkyl-substituted.

[0099] In some implementations, R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 alkoxy or the C 3-7 The cycloalkyl group is independently and optionally surrounded by one to five halogen groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated or C 3-7 Cycloalkyl substitution.

[0100] In some implementations, R 9 It is optionally divided by one to five halogen groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated or C 3-7 Cycloalkyl-substituted C 1-6 Alkyl group. In some embodiments, R 9 It is C 1-6 alkyl.

[0101] In some implementations, R 9 It is optionally divided by one to five halogen groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated or C 3-7 Cycloalkyl-substituted C 1-6 Alkyl group. In some embodiments, R 9 C is a C group that is optionally replaced by one to five halogen groups. 1-6 Alkyl group.

[0102] In some implementations, R 9 It is optionally divided by one to five halogen groups, C 1-6 Alkyl or C 1-6 Halogenated C 3-8 Cycloalkyl. In some embodiments, R 9 It is optionally divided by one to five halogen groups, C 1-6 Alkyl or C 1-6 Halogenated C 3-7 Cycloalkyl.

[0103] In some implementations, R 9 yes: , , , , , , , , , , , , , , , or .

[0104] In some implementations, partial -C(O)-R 9 yes: , , , , , , , , , , , , , , , or .

[0105] In some implementations, X 1 It is N.

[0106] In some implementations, X 1 It is CR 7 .

[0107] In some implementations, R 6 It is hydrogen.

[0108] In some implementations, R 7 It is hydrogen.

[0109] In some implementations, X 1 It is N; and R 6 It is hydrogen.

[0110] In some implementations, L is a key, C is a bond. 1-2 Alkylene, -CH2-C(O)NR 11 -*, -C(O)-, -S(O)2-, -C(O)O-* or -C(O)NR11 -*; where the * key is connected to R 4 .

[0111] In some implementations, L is a key.

[0112] In some implementations, L is C 1-2 Alkylene.

[0113] In some implementations, L is -CH2-C(O)NR 11 -*; where the * key is connected to R 4 .

[0114] In some implementations, L is -C(O)-.

[0115] In some implementations, L is -S(O)2-.

[0116] In some implementations, L is -C(O)O-*; wherein the * bond is connected to R. 4 .

[0117] In some implementations, L is -C(O)NR 11 -*; where the * key is connected to R 4 .

[0118] In some implementations, R 4 It is arbitrarily determined by one to five Z. 1a Replacement C 1-6 Alkyl group. In some embodiments, R 4 It is arbitrarily determined by one to five Z. 1a Replacement C 1-3 alkyl.

[0119] In some implementations, L is C 1-2 Alkylene, -CH2-C(O)NR 11 -*, -C(O)-, -S(O)2-, -C(O)O-* or -C(O)NR 11 -*; where the * key is connected to R 4 And R 4 It is arbitrarily determined by one to five Z. 1a Replacement C 1-6 Alkyl group. In some embodiments, R 4 It is arbitrarily determined by one to five Z. 1a Replacement C 1-3 alkyl.

[0120] In some implementations, R 4 It is arbitrarily determined by one to five Z. 1a Replacement C3-10 Cycloalkyl. In some embodiments, R 4 It is arbitrarily determined by one to five Z. 1a Replacement C 3-6 Cycloalkyl.

[0121] In some implementations, L is a bond or -C(O)-; and R 4 It is arbitrarily determined by one to five Z. 1a Replacement C 3-10 Cycloalkyl. In some embodiments, R 4 It is arbitrarily determined by one to five Z. 1a Replacement C 3-6 Cycloalkyl.

[0122] In some implementations, R 4 It is arbitrarily determined by one to five Z. 1a Substituted aryl group. In some embodiments, R 4 It is arbitrarily determined by one to five Z. 1a Substituted phenyl groups.

[0123] In some implementations, L is the key; and R 4 It is arbitrarily determined by one to five Z. 1a Substituted aryl group. In some embodiments, L is a bond; and R 4 It is arbitrarily determined by one to five Z. 1a Substituted phenyl groups.

[0124] In some implementations, R 4 It is arbitrarily determined by one to five Z. 1a Substituted heteroaryl groups.

[0125] In some implementations, L is the key; and R 4 It is arbitrarily determined by one to five Z. 1a Substituted heteroaryl groups.

[0126] In some implementations, R 4 It is arbitrarily determined by one to five Z. 1a Substituted 6-membered heteroaryl group.

[0127] In some implementations, R 4 It is a 6-membered heteroaryl group that is optionally substituted with a cyano group.

[0128] In some implementations, R 4 It is a pyridinyl group that is optionally substituted with a cyano group.

[0129] In some implementations, R 4 It is a pyridinyl group substituted with a cyano group.

[0130] In some implementations, R 4 It is 4-cyanopyridin-2-yl.

[0131] In some implementations, R 4 It is 4-cyanopyridin-2-yl, 4-cyano-5-fluoro-pyridin-2-yl, 2-cyanopyridin-4-yl, 6-cyanopyrimidine-4-yl, 6-cyanopyridazin-4-yl, 4-cyanopyrimidine-2-yl, 5-cyanopyridazin-3-yl, [1,2,4]triazolo[4,3-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-c]pyrimidine-7-yl, imidazo[1,2-c]pyrimidine-7-yl, imidazo[1,2-a]pyrazin-6-yl, 5-aminopyridinyl Azine-2-yl, 5-cyano-1-methyl-1H-pyrazole-3-yl, 3-cyano-5-fluorophenyl, 3,5-dicyanophenyl, 1-methyl-2-oxo-4-pyridyl, 6-aminopyrimidin-4-yl, 4-cyano-6-(hydroxymethyl)-2-pyridyl, 6-cyano-2-(trifluoromethyl)pyrimidin-4-yl, 7-(3-cyano-5-methylsulfonylphenyl), 5-cyano-2-methoxypyridin-3-yl, 5-cyano-2-oxo-1H-pyridin-3-yl, 7 -(6-cyano-2-methoxypyrimidin-4-yl), 6-chloro-4-cyanopyridin-2-yl, 7-(3-cyano-5-methylthiophenyl), 5-cyano-1-methyl-2-oxo-3-pyridyl, 2-cyano-5-fluoro-4-pyridyl, 6-cyano-2-oxo-1,2-dihydropyrimidin-4-yl, 6-cyano-3-methyl-2-oxo-1,2-dihydropyrimidin-4-yl, 1-acetylpyrrolidine-3-yl, 7-(3-cyanocyclopentyl), 1H-pyridine Azo[4,3-c]pyridin-6-yl, 3-cyanocyclobutyl, 2-chloro-6-cyanopyrimidin-4-yl, 3-cyanocyclohexyl, 3-cyano-3-methylcyclobutyl, 3-ethoxycarbonylcyclobutyl, 2-cyano-5-fluoropyridin-4-yl, cyclobutyl, 3-hydroxycyclobutyl, 3-(hydroxymethyl)-3-methyl-cyclobutyl, 2-chloro-5-fluoropyridin-4-yl, 6-chloropyridazin-4-yl, 2-cyano-5-fluoropyrimidin-4-yl or 6-cyano-3-methylpyridazin-4-yl.

[0132] In some implementations, L is the key; and R 4It is 4-cyanopyridin-2-yl, 4-cyano-5-fluoro-pyridin-2-yl, 2-cyanopyridin-4-yl, 6-cyanopyrimidine-4-yl, 6-cyanopyridazin-4-yl, 4-cyanopyrimidine-2-yl, 5-cyanopyridazin-3-yl, [1,2,4]triazolo[4,3-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-c]pyrimidine-7-yl, imidazo[1,2-c]pyrimidine-7-yl, imidazo[1,2-a]pyrazin-6-yl, 5-aminopyridinyl Azine-2-yl, 5-cyano-1-methyl-1H-pyrazole-3-yl, 3-cyano-5-fluorophenyl, 3,5-dicyanophenyl, 1-methyl-2-oxo-4-pyridyl, 6-aminopyrimidin-4-yl, 4-cyano-6-(hydroxymethyl)-2-pyridyl, 6-cyano-2-(trifluoromethyl)pyrimidin-4-yl, 7-(3-cyano-5-methylsulfonylphenyl), 5-cyano-2-methoxypyridin-3-yl, 5-cyano-2-oxo-1H-pyridin-3-yl, 7 -(6-cyano-2-methoxypyrimidin-4-yl), 6-chloro-4-cyanopyridin-2-yl, 7-(3-cyano-5-methylthiophenyl), 5-cyano-1-methyl-2-oxo-3-pyridyl, 2-cyano-5-fluoro-4-pyridyl, 6-cyano-2-oxo-1,2-dihydropyrimidin-4-yl, 6-cyano-3-methyl-2-oxo-1,2-dihydropyrimidin-4-yl, 1-acetylpyrrolidine-3-yl, 7-(3-cyanocyclopentyl), 1H-pyridine Azo[4,3-c]pyridin-6-yl, 3-cyanocyclobutyl, 2-chloro-6-cyanopyrimidin-4-yl, 3-cyanocyclohexyl, 3-cyano-3-methylcyclobutyl, 3-ethoxycarbonylcyclobutyl, 2-cyano-5-fluoropyridin-4-yl, cyclobutyl, 3-hydroxycyclobutyl, 3-(hydroxymethyl)-3-methyl-cyclobutyl, 2-chloro-5-fluoropyridin-4-yl, 6-chloropyridazin-4-yl, 2-cyano-5-fluoropyrimidin-4-yl or 6-cyano-3-methylpyridazin-4-yl.

[0133] In some implementations, R 4 It is methyl, ethyl, cyclobutyl, 2-cyanocyclopropyl-1-yl, 3-cyanocyclobutyl-1-yl, 1-methylcyclobutyl-1-yl, 3-cyanopropionyl, cyclopropylmethyl, 3-fluorocyclobutyl-1-yl, 2,2-difluorocyclobutyl-1-yl, 2,2-difluorocyclopropyl-1-yl, 1-fluorocyclobutyl-1-yl, 1-(cyanomethyl)cyclopropyl-1-yl, 1-methyl-1 H -pyrazol-4-yl, 2-cyano-1-methylcyclopropyl-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-cyanocyclobut-1-yl, 2-cyano-2-methylcyclopropyl-1-yl, 1-methyl-1 H -pyrazole-5-yl, 1 H -pyrazole-1-ylmethyl, 2-(1-methyl-1H -pyrazole-4-yl)ethyl, pyrrolidine-1-ylmethyl, pyrrolidine-2-yl or pyrrolidine-3-yl.

[0134] In some implementations, L is C 1-2 Alkylene, -CH2-C(O)NR 11 -*, -C(O)-, -S(O)2-, -C(O)O-* or -C(O)NR 11 -*; where the * key is connected to R 4 R 4 It is methyl, ethyl, cyclobutyl, 2-cyanocyclopropyl-1-yl, 3-cyanocyclobutyl-1-yl, 1-methylcyclobutyl-1-yl, 3-cyanopropionyl, cyclopropylmethyl, 3-fluorocyclobutyl-1-yl, 2,2-difluorocyclobutyl-1-yl, 2,2-difluorocyclopropyl-1-yl, 1-fluorocyclobutyl-1-yl, 1-(cyanomethyl)cyclopropyl-1-yl, 1-methyl-1 H -pyrazol-4-yl, 2-cyano-1-methylcyclopropyl-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-cyanocyclobut-1-yl, 2-cyano-2-methylcyclopropyl-1-yl, 1-methyl-1 H -pyrazole-5-yl, 1 H -pyrazole-1-ylmethyl, 2-(1-methyl-1 H -pyrazole-4-yl)ethyl, pyrrolidine-1-ylmethyl, pyrrolidine-2-yl or pyrrolidine-3-yl.

[0135] In some implementations, t is 0.

[0136] In some embodiments, a compound of formula IA is provided: IA Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 1 R 2 R 4 R 8 R 9 L, m, n, and p are independently as defined in this paper.

[0137] In some embodiments, compounds of formula IA' are provided: IA' Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 1 R 2 R 4 R 8 R9 m, n, and p are independently as defined in this paper.

[0138] In some embodiments, compounds of formula IA' are provided: IA' Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: R 1 It is a halogenated group, a cyano group, a nitro group, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 2 It is a halogen group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; or R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; R 4 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; Each R 8 C is independent 1-6 Alkyl or C 1-6 Halogenated alkyl groups; wherein the C 1-6 alkyl or the C 1-6 The haloalkyl group is independently and optionally surrounded by a halogen group, a hydroxyl group, or a C group. 1-6 Alkoxy substitution; or two Rs 8 The carbon atoms bonded to them can form oxo groups together, either fused or spiro-C. 3-7 cycloalkyl, or fused or spiro-4-7 membered heterocyclic groups; wherein the C 3-7 The cycloalkyl group or the 4-7 membered heterocyclic group is independently and optionally surrounded by a halogen group, a hydroxyl group, or a C-group. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy or C 1-6 Haloalkoxy substitution; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or -OC 3-7 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-7 cycloalkyl or -OC 3-7 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; m is 1 or 2; n is 1, 2, or 3; Where m + n is 2, 3, or 4; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0139] In some implementations, compounds of formula IB are provided: IB Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 1 R 2 R 4 and R 9 Independently as defined in this article.

[0140] In some implementations of formula IB, R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 2 It is a halogen group, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; or R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0141] In some implementations of formula IB, R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11)2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 2 It is a halogen group, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0142] In some implementations of formula IB, R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1bIndependently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0143] In some implementations of formula IB, R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution; R 2 Is it -CD3 or C? 1-6 Alkyl; or R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Replacement C 3-6 cycloalkyl; R 4 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0144] In some implementations of formula IB, R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution; R 2 Is it -CD3 or C? 1-6 alkyl; R 4 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0145] In some implementations of formula IB, R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Replacement C 3-6 cycloalkyl; R 4 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C.1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0146] In some implementations, a compound of formula IC is provided: IC Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 1 R 4 and R 9 Independently as defined in this article.

[0147] In some implementations of the IC, R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0148] In some implementations of the IC, R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0149] In some implementations of the IC, R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C1-6 Alkyl or heteroaryl substitution; R 4 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13)2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0150] In some implementations, a compound of formula ID is provided: ID Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 4 R 9 and Z 1a Independently as defined in this article.

[0151] In some implementations of the ID, R 4 It is C 1-6 Alkyl, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0152] In some implementations of the ID, R 4 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0153] In some implementations, the formula IE compound is provided: IE Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 1 R 2 R 4 and R 9 Independently as defined in this article.

[0154] In some implementations of the IE, R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 2 It is a halogen group, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; or R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0155] In some implementations of the IE, R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11)2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 2 It is a halogen group, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0156] In some implementations of the IE, R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1bIndependently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0157] In some implementations of the IE, R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution; R 2 Is it -CD3 or C? 1-6 Alkyl; or R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Replacement C 3-6 cycloalkyl; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0158] In some implementations of the IE, R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution; R 2 Is it -CD3 or C? 1-6 alkyl; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z.1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0159] In some implementations of the IE, R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Replacement C 3-6 cycloalkyl; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0160] In some implementations, a compound of formula IF is provided: IF Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 1 R 4 and R 9 Independently as defined in this article.

[0161] In some implementations of formula IF, R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0162] In some implementations of formula IF, R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0163] In some embodiments, an IG compound is provided: IG Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 4 R 9 and Z 1a Independently as defined in this article.

[0164] In some implementations of the IG, R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0165] In some implementations of the IG, R 4 It is C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13)2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0166] In some implementations of the IG, R 4 It is arbitrarily determined by one to five Z. 1a Replacement C 1-6 alkyl; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0167] In some embodiments, compounds of formula IH are provided: IH Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 1 R 2 and R 9 Independently as defined in this article.

[0168] In some implementations of formula IH, R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 2 It is a halogen group, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; or R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0169] In some implementations of formula IH, R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R2 It is a halogen group, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1- heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0170] In some implementations of formula IH, R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; R 9 It is C 1-6 Alkyl, C1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0171] In some implementations of formula IH, R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution; R 2 Is it -CD3 or C? 1-6 Alkyl; or R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Replacement C 3-6 cycloalkyl; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0172] In some implementations of formula IH, R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution; R 2 Is it -CD3 or C? 1-6 alkyl; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z.1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0173] In some implementations of formula IH, R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Replacement C 3-6 cycloalkyl; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1bIndependently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0174] In some embodiments, compounds of formula II are provided: II Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein R 1 and R 9 Independently as defined in this article.

[0175] In some embodiments of Formula II, R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 2 It is a halogen group, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13-C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0176] In some embodiments of Formula II, R 1It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0177] In some embodiments, compounds of formula IJ are provided: IJ Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R 9 and Z 1a Independently as defined in this article.

[0178] In some implementations of formula IJ, R 9 It is C1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0179] In certain implementations of any of the formulas IB-IF, R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy or C 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 alkoxy or the C 3-10 The cycloalkyl group is independently and optionally surrounded by one to five halogen groups, cyano groups, hydroxyl groups, -S(O)2C groups. 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)NHC 1-6 Alkyl 2, -C(O)N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated, C 1-6 Haloalkoxy, C 3-7 Cycloalkyl, heterocyclic, or heteroaryl substitutions; wherein the heterocyclic group is optionally further substituted with a halogen or C- group. 1-6 Alkyl-substituted.

[0180] In some embodiments, compounds selected from Table 1 or pharmaceutically acceptable salts, isotopically enriched analogs, prodrugs, stereoisomers, or mixtures of stereoisomers are provided: Table 1 In some embodiments, compounds selected from Table 2 or pharmaceutically acceptable salts thereof are provided.

[0181] Table 2 3. Methods "Treatment" is a method used to achieve a beneficial or desired outcome, including clinical outcomes. A beneficial or desired clinical outcome may include one or more of the following: a) suppressing a disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder, and / or reducing the severity of the disease or disorder); b) slowing or preventing the development of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder, and / or preventing or delaying the spread of the disease or disorder (e.g., metastasis)); and / or c) alleviating the disease, i.e., resolving clinical symptoms (e.g., improving the disease state, partially or completely resolving the disease or disorder, enhancing the effect of another agent, delaying disease progression, improving quality of life, and / or prolonging survival).

[0182] "Prevention" means any treatment of a disease or condition that prevents the development of clinical symptoms. In some implementations, the compound may be administered to subjects (including humans) who are at risk of developing a disease or condition or who have a family history of the disease or condition.

[0183] "Subject" refers to an animal, such as a mammal (including humans), that is or will be the subject of treatment, observation, or experimentation. The methods described herein can be used in human therapeutics and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0184] The term "therapeutic effective amount" or "effective amount" in relation to the compounds described herein or their pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs means an amount sufficient, when administered to a subject, to achieve therapeutic effect and provide a therapeutic benefit, such as improvement of symptoms or slowing of disease progression. For example, a therapeutic effective amount may be an amount sufficient to reduce symptoms of a disease or ailment as described herein. Therapeutic effective amounts can vary depending on the subject and the disease or ailment being treated, the subject's weight and age, the severity of the disease or ailment, and the method of administration, factors that can be readily determined by one of ordinary skill in the art.

[0185] The methods described herein can be applied to cell populations, either in vivo or in vitro. “In vivo” means within a living individual, such as an animal or human. In this context, the methods described herein can be used therapeutically in an individual. “In vitro” means outside a living individual. Examples of in vitro cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used in vitro to determine the optimal timing and / or dosage of administration of the disclosed compounds for a given indication, cell type, individual, and other parameters. Information gathered from such uses can be used for experimental purposes or in a clinic to establish in vivo treatment protocols. Other in vitro uses of the compounds and compositions described herein are described below or will become apparent to those skilled in the art. The compounds can be further characterized to examine safety or tolerable dosage in human or non-human subjects. Such characteristics can be checked using methods generally known to those skilled in the art.

[0186] In some implementations, regulation of TRPML1 includes the activation of TRPML1.

[0187] In some embodiments, this document provides a method for treating a disease or condition that can be treated by activating TRPML1, the method comprising administering to a subject in need a compound described herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically labeled derivative, or composition described herein.

[0188] In some embodiments, a compound that activates TRPML1 is provided, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. In some embodiments, the compound provided herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof activates TRPML1.

[0189] In some embodiments, a method for activating TRPML1 activity is provided, the method comprising contacting cells with an effective amount of a compound as disclosed herein (e.g., a compound of formula I or a derivative thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug. Activation may be performed in vitro or in vivo.

[0190] In some embodiments, a compound as disclosed herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug is provided for activating TRPML1 activity (e.g., in vitro or in vivo).

[0191] In some embodiments, this disclosure provides the use of compounds as disclosed herein (e.g., compounds of Formula I or its derivatives) or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs for the manufacture of agents for activating TRPML1 activity (e.g., in vitro or in vivo).

[0192] In some embodiments, this disclosure provides the use of compounds as disclosed herein (e.g., compounds of Formula I or its sub-formulas) or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs for the manufacture of medicaments for the treatment of diseases or conditions at least partially mediated by TRPML1.

[0193] In some embodiments, a method is provided for treating a disease or condition at least partially mediated by TRPML1, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0194] In some embodiments, a compound as disclosed herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is provided for the treatment of a disease or condition at least partially mediated by TRPML1 in a subject of need.

[0195] In some embodiments, a method is provided for treating a disease or condition that can be treated by modulating lysosomes, the method comprising administering to a subject in need a therapeutically effective amount of a compound such as that disclosed herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0196] In some embodiments, a method is provided for treating a disease or condition selected from the group consisting of: cilia, neurodegenerative or neurological diseases or conditions, lysosomal storage diseases or conditions, lysosomal transport diseases or conditions, glycogen storage diseases or conditions, cholesterol ester storage diseases or conditions, muscle diseases (e.g., muscular dystrophy), age-related diseases (e.g., photoaging of the skin), macular degeneration (e.g., Stargardt's or age-related), and cancers (e.g., cancers of the blood, brain, bone, lung, liver, kidney, bladder, stomach, breast, prostate, ovary, testis, colon, pancreas, or skin), said method comprising administering to a subject in need a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of formula I or a derivative thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0197] In some implementations, the condition or disease is aging, bone disease, cardiovascular disease, congenital developmental disorder, eye disease, hematologic and solid malignancies, infectious disease, inflammatory disease, liver disease, metabolic disease, neurodegenerative or neurological disease or condition, pancreatitis, kidney disease, skeletal muscle disease, obesity, lysosomal storage disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, inclusion body myositis, Paget's disease, or lung disease.

[0198] neurodegenerative or neurological disease or disorder In some implementations, treatment includes reducing one or more symptoms or characteristics of neurodegeneration.

[0199] In some embodiments, a method for treating neurodegenerative or neurological diseases or conditions is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0200] Transient receptor potential channel lipoprotein 1 (TRPML1) is a channel that can transport Ca2+. 2+ Fe 2+ and Zn 2+ The cation channel of TRPML1. The main function of TRPML1 is to induce Ca2+. 2+Release from endolysosomal compartments is a crucial process for endolysosomal function. Dysfunction of the TRPML1-associated endolysosomal pathway has been widely observed in preclinical and clinical samples from late-onset neurodegenerative diseases. Functions regulated by TRPML1 include TFEB family-dependent lysosomal biosynthesis, late endosome maturation into lysosomes; endolysosomal transport; nutrient sensing and adaptation; lysosomal localization, exocytosis, division, clearance, and reformation; and autophagy, phagocytosis, and clearance of aggregates and pathogens. Loss-of-function mutations in the human TRPML1 gene MCOLN1 cause mucoliposis type IV (MLIV), a rare recessive lysosomal storage disease (LSD). MLIV is characterized by neurodegeneration, psychomotor disorders, ophthalmic and intestinal defects. Cells from MLIV patients exhibit multiple endolysosomal abnormalities, including defects in endolysosomal transport, vacuolation, altered localization of endolysosomal compartments, impaired lysosomal maturation, pH dysregulation, and autophagy defects.

[0201] TRP channels are involved in intracellular calcium stores in both neurons and non-neuronal cells. 2+ Disruptions to homeostasis and their dysfunction lead to several neuronal diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). TRP is involved in neurite outgrowth, receptor signal transduction, and excitotoxic cell death in the central nervous system.

[0202] In some implementations, neurodegenerative or neurological diseases or conditions are selected from the group consisting of: Parkinson's disease, GBA-Parkinson's disease, LRRK2 Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, FTDP-17, corticobasal degeneration, Lewybody dementia, Pick's disease, and multiple system atrophy.

[0203] Alzheimer’s disease Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by severe memory loss and behavioral changes. The underlying pathology involves the accumulation of extracellular amyloid aggregates known as senile plaques and intracellular neurofibrillary tangles, leading to selective loss of synapses and neurons in the hippocampus and cerebral cortex. While the amyloid and tau hypotheses are the traditional explanations for AD, calcium homeostasis dysregulation has recently gained attention as a key factor in the pathogenesis of AD.

[0204] Calcium is an essential intracellular messenger, binding to a variety of proteins, receptors, and ion channels to regulate various physiological functions. During neurodegeneration, neurons become ineffective in regulating calcium levels. Enhanced pathological changes induce neurotoxicity and cytokines, leading to calcium homeostasis dysregulation and making neurons susceptible to excitotoxicity and apoptosis.

[0205] In some embodiments, a method for treating Alzheimer's disease is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0206] Parkinson’s disease Parkinson's disease (PD) is the second leading cause of age-related neurodegenerative disorders after Alzheimer's disease (AD). PD is characterized by motor impairments marked by the breakdown of dopaminergic neurons (DNs) in the substantia nigra (SN), which worsens over time. Lewy bodies, cytoplasmic inclusions formed by α-synuclein, are considered a major pathological marker of PD. Several factors in PD can lead to DN loss in the SN, such as oxidative stress, mitochondrial dysfunction, protein aggregation, and altered calcium homeostasis. Studies have reported that TRP channels can promote some mechanisms that drive disease progression.

[0207] In some embodiments, a method for treating Parkinson's disease is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0208] Huntington’s disease Huntington's disease (HD) is an autosomal neurodegenerative disorder triggered by the amplification of polyglutamine in the huntingtin protein, characterized by cognitive impairment, loss of moderately spinous neurons (MSNs) in the striatum, and seizure-like motor responses. Various channel alterations have been reported. + Homeostasis, such as in striatal stellate cells expressing the Kir4.1 channel in mutant HTT protein, disrupts extracellular K+. + Homeostasis, thus causing overexcitation in neurons, namely, HD motor symptoms in striatal neurons. However, normal Kir4.1 channels are ubiquitous in stellate cells. + Channels that balance the resting membrane potential of cells in the brain and buffer K+. + It plays an important role in ions. Furthermore, it indicates that HD mHTT protein modulates high-voltage stimulated Ca2+. 2+ Channel. Except Ca2+ In addition to dysfunction in other ion channels, reduced expression of other ion channels was also observed in several HD mouse models. Therefore, modifications to these ion channels disrupt ion homeostasis in cortical pyramidal neurons, thereby affecting synaptic integration, neurotransmitter release, and genetic expression, which plays a central role in cortical dysfunction in HD.

[0209] In some embodiments, a method for treating Huntington's disease is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0210] amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is a neurological disorder characterized by the progressive loss of motor neurons in the brainstem, motor cortex, and spinal cord, leading to muscle weakness, atrophy, and contraction. The disease is often attributed to sodium ions (Na+). + The continuous conduction of potassium ions (K) and the subsequent conduction of potassium ions (K) + This is related to axonal hyperexcitability caused by reduced conduction. Tongue muscles stimulated by motor neurons are also prone to ALS degeneration, which is associated with differential expression of voltage-gated calcium channels (VGCCs).

[0211] In some embodiments, a method for treating amyotrophic lateral sclerosis (ALS) is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0212] lysosomal storage disease In some embodiments, a method for treating lysosomal storage diseases or conditions is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound such as that disclosed herein (e.g., a compound of formula I or a subform thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug.

[0213] In some implementations, lysosomal storage diseases or conditions are selected from the group consisting of: Niemann-Pick disease, Gaucher's disease, neuropathic Gaucher's disease, neuronal ceroid lipofuscin deposition, sphingolipid deposition, Farber disease, Krabbe disease, galactosialidosis, ganglioside deposition, Gaucher's disease, lysosomal acid lipase deficiency, thiolipin deposition, mucopolysaccharide deposition, mucolipide deposition, lipid deposition, and oligosaccharide deposition.In some implementations, lysosomal storage diseases are selected from the group consisting of: sphingolipid storage diseases, Fabry disease, Clapey disease, galactosialidosis, Fabry disease, Schindler disease, β-galactosidase disorders, GM1 ganglioside storage diseases, GM2 ganglioside storage disease AB variant, GM2 ganglioside storage disease activator deficiency, Sandhoff disease, Tay-Sachs disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, sphingolipid activator B deficiency, multiple sulfatase deficiencies, Hurler syndrome, Scheie syndrome, Hurler-Scheiesyndrome, Hunter syndrome, Sanfilippo syndrome, and Morquio syndrome. This text appears to be a list of medical conditions and related medical conditions, including: Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialic acid deposition disease, I-cell disease, pseudo-Hurler polydystrophy, phosphotransferase deficiency, mucoprotein 1 deficiency, Santavuori-Haltia disease, Jansky-Bielchowsky disease, Batten-Spielmeyer-Vogt disease, Kufs disease, Finnish variant neuronal ceroid lipofuscinosis, late-infant variant neuronal ceroid lipofuscinosis, type 7 neuronal ceroid lipofuscinosis, Northern epilepsy neuronal ceroid lipofuscinosis, Turkish late-infant neuronal ceroid lipofuscinosis, German / Serbian late-infant neuronal ceroid lipofuscinosis, congenital cathepsin D deficiency, and Wolman disease. Lysosomal storage diseases include α-mannoside storage disease, β-mannoside storage disease, aspartic glucosamineuria, and fucoside storage disease. In some implementations, lysosomal storage diseases are selected from the group consisting of: Niemann-Pick disease, Gaucher disease, neuropathic Gaucher disease, and neuronal ceroid lipofuscin deposition disease.

[0214] In some embodiments, a method for treating lysosomal transport diseases or conditions is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound such as that disclosed herein (e.g., a compound of formula I or a derivative thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug. In some embodiments, the lysosomal transport disease or condition is selected from the group consisting of: cystinosis, osteogenesis imperfecta, Salla disease, sialic acid storage diseases, and infantile free sialic acid storage diseases.

[0215] In some embodiments, a method for treating glycogen storage diseases or conditions is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound such as that disclosed herein (e.g., a compound of formula I or a derivative thereof) or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug. In some embodiments, the glycogen storage disease or condition is selected from the group consisting of Pompe disease and Danon disease.

[0216] ciliopathy In some embodiments, a method for treating cilia is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound capable of modulating TRPML, or a therapeutically effective amount of a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient.

[0217] In some implementations, ciliary disorders are selected from the group consisting of: polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, tuberculosis, Joubert syndrome, Meckel-Gruber syndrome, mouth-face-finger syndrome, Senior Loken syndrome, Birt-Hogg-Dube syndrome, Leber's congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia. In some implementations, ciliopathy is autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or pancreatic cysts associated with autosomal dominant polycystic kidney disease. In some implementations, ciliopathy is polycystic kidney disease. In some implementations, ciliopathy is autosomal dominant polycystic kidney disease.

[0218] Other embodiments include the use of the compounds disclosed in this invention in therapeutic applications.

[0219] combination therapy In some embodiments of the methods and uses described herein, the methods or uses may further include the use of one or more additional therapeutic agents.

[0220] In some implementations, the additional therapeutic agent is selected from the group consisting of: mTOR inhibitors, V2 receptor antagonists, tyrosine kinase inhibitors, somatostatin analogs, glucose-ceramide synthase inhibitors, microRNA-17 inhibitors, siRNAs targeting p53, KEAP1-Nrf2 activators, xanthine oxidase inhibitors, PPARγ agonists, metformin, and β-hydroxybutyrate.

[0221] In some implementation schemes, the additional treatment agent is selected from the group consisting of: tolvaptan, lixivaptan, mozavaptan, satavaptan, sirolimus, tacrolimus, everolimus, bosutinib, tesavatinib, imatinib, gefitinib, erlotinib, dasatinib, octreotide, pasireotide, venglustat, eliglustat, miglustat, microRNA-17 inhibitors, and bardoxolone. Methyl), allopurinol, oxypurinol, pioglitazone, rosiglitazone, lobeglitazone, metformin, and β-hydroxybutyrate.

[0222] In some implementations, the additional therapeutic agent is selected from the group consisting of: immunomodulators, calcineurin inhibitors, renin-angiotensin-aldosterone system inhibitors, antiproliferators, alkylating agents, corticosteroids, angiotensin-converting enzyme inhibitors, adrenocorticotropic hormone stimulators, angiotensin receptor blockers, sodium-glucose transporter 2 inhibitors, double sodium-glucose transporter 1 / 2 inhibitors, nuclear factor-1 (erythrocyte-derived 2)-like 2 agonists, chemokine receptor 2 inhibitors, chemokine receptor 5 inhibitors, endothelin 1 receptor antagonists, beta-blockers, mineralocorticoid receptor antagonists, cyclic or thiazide diuretics, calcium channel blockers, statins, short-, intermediate-, or long-acting insulin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor agonists, sulfonylureas, apoptosis signaling kinase-1, rennet inhibitors, selective glycine cation inhibitors, renin inhibitors, interleukin-33 inhibitors, farnesol X receptor agonists, and so on. Soluble guanylate cyclase stimulants, thromboxane receptor antagonists, xanthine oxidase inhibitors, erythropoietin receptor agonists, cannabinoid receptor type 1 inverse agonists, NADPH oxidase inhibitors, anti-vascular endothelial growth factor B, anti-fibrotic agents, enkephalinase inhibitors, dual CD80 / CD86 inhibitors, CD40 antagonists, cellular cholesterol and lipid blockers, PDGFR antagonists, Slit guide ligand 2, APOLI inhibitors, Nr12 activators / NF-κB inhibitors, somatostatin receptor agonists, PPARs γ-agonists, AMP-activated protein kinase stimulators, tyrosine kinase inhibitors, glucosamine synthase inhibitors, arginine angiotensin receptor 2 antagonists, xanthine oxidase inhibitors, angiotensin receptor 2 antagonists, anti-amyloid beta antibodies, anti-Tau antibodies, anti-synuclein antibodies, dopamine precursors (e.g., L-DOPA), dopamine agonists (e.g., bromocriptine, cabergoline, pergolide, pramipexole, and apomorphine). Pharmacokinetics include acetylcholine inhibitors (such as rasagiline and selegiline), anticholinergics (such as orphenadrine, procyclidine, and trihexyphenidyl), β-glucocerebroside lipase activity enhancers (such as ambroxol and afegostat), amantadine, and agents that can treat Alzheimer's disease (such as acetylcholinesterase inhibitors).Examples include tacrine, rivastigmine, galantamine, donepezil, and NMDA receptor antagonists such as memantine.

[0223] In some implementations, the additional therapeutic agent is selected from the group consisting of: COX inhibitors, including arylcarboxylic acids (e.g., salicylic acid, acetylsalicylic acid, diflunisal, trisalicylic acid choline magnesium, salicylates, benorylate, flufenamic acid, mefenamic acid, meclofenamic acid, or triflumic acid), arylalkyl acids (e.g., diclofenac, fenclofenac, alclofenac, fentiazac, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen, suprafen, indoprofen, tiaprofenic acid). Drugs for treating pulmonary hypertension include benzoxaprofen, pirprofen, tolmetin, zomepirac, clopinac, indomethacin, or sulindac; enolic acids (e.g., phenylbutazone, oxyphenbutazone, azapropazone, feprazone, piroxicam, or isoxicam); and prostaglandins (e.g., epoprostenol, iloprost). ) or treprostinil; endothelin receptor antagonists (e.g., bosentan, ambrisentan, or macitentan); phosphodiesterase-5 inhibitors (e.g., sildenafil or tadalafil); sGC stimulators (e.g., riociguat); rho-kinase inhibitors (e.g., Y-27632, fasudil, or H-1152P); eprostol derivatives (e.g., prostacyclin, treprostinil, beraprost, or iloprost); serotonin blockers (e.g., sarpogrelate).Endothelin receptor antagonists (besentan, sitaxentan, ambrisentan, or TBC3711); PDE inhibitors (e.g., sildenafil, tadalafil, udenafil, or vardenafil); soluble guanylate cyclase inhibitors (e.g., riociguat or vericiguat); calcium channel blockers (e.g., amlodipine, benprodil). bepridil, cletiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, aranidipine, bamidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisodipine Nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, benzylcycline, etafenone, or perhexiline; tyrosine kinase inhibitors (e.g., imatinib); inhaled nitric oxide and nitric oxide donors (e.g., inhaled nitrites); IκB inhibitors (e.g., IMD 1041); prostacyclin receptor agonists (e.g., selexipag); hematopoietic stimulants (e.g., TXA 127 (angiotensin (1-7)), darbepoetin alfa, erythropoietin, or epietin alfa);Anticoagulants and platelet inhibitors, diuretics, dietary and nutritional supplements (e.g., acetyl-L-carnitine, octacosanol, evening primrose oil, vitamin B6, tyrosine, phenylalanine or vitamin C, L-dopa); immunosuppressants (for transplant and autoimmune-related RKD); antihypertensive drugs (for hypertension-related RKD, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers); insulin (for diabetic RKD); lipid / cholesterol lowering agents (e.g., HMG-CoA reductase inhibitors, such as atorvastatin or simvastatin); and treatments for hyperphosphatemia or hyperparathyroidism associated with CKD (e.g., sevelamer acetate, cinacalcet).

[0224] 4. Medicine box This document also provides a kit comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug, and suitable packaging. In some embodiments, the kit also includes instructions for use. In one aspect, the kit comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a prodrug, and a label and / or instructions for use regarding the indications for treatment with said compound (including the diseases or ailments described herein).

[0225] This document also provides articles comprising the compounds described herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, contained in a suitable container. The container may be a vial, can, ampoule, pre-loaded syringe, or intravenous bag.

[0226] 5. Drug composition and administration method The compounds described herein are typically administered as pharmaceutical compositions. Therefore, pharmaceutical compositions comprising one or more of the compounds described herein or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, and one or more pharmaceutically acceptable mediators selected from carriers, adjuvants, and excipients are also provided herein. Suitable pharmaceutically acceptable mediators may include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GS Banker and CT Rhodes).

[0227] The pharmaceutical composition may be administered in a single dose or in multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, transrectal, buccal, intranasal, and percutaneous routes. In some embodiments, the pharmaceutical composition may be administered via intra-arterial injection, intravenous injection, intraperitoneal injection, parenteral administration, intramuscular administration, subcutaneous administration, oral administration, topical administration, or inhalation.

[0228] One mode of administration is parenteral, such as by injection. Pharmaceutical compositions described herein that can be incorporated for administration by injection include, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextran, or sterile aqueous solutions and similar drug mediators.

[0229] Oral administration may be another route of administration for the compounds described herein. Administration may be via, for example, capsules or enteric-coated tablets. In preparing pharmaceutical compositions comprising at least one of the compounds described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, the active ingredient is typically diluted with an excipient and / or encapsulated in a carrier, such that it may be in the form of capsules, pouches, paper, or other containers. When the excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material, serving as a medium, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, rhomboid tablets, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0230] Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Formulations may also include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents.

[0231] Compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, can be formulated using procedures known in the art to provide a rapid, sustained, or delayed release of the active ingredient upon administration to a subject. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation used in the methods disclosed herein employs a percutaneous delivery device (“patch”). Such percutaneous patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of percutaneous patches for delivering pharmaceutical agents are well known in the art. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0232] To prepare solid compositions (such as tablets), a major active ingredient may be mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the compound described herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug. When these preformed compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition, making it easy to subdivide the composition into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0233] The tablets or pills of the compounds described herein may be coated or otherwise formulated to provide a dosage form with the advantage of prolonged action or protection against the acidic conditions of the stomach. For example, the tablets or pills may contain an internal dose component and an external dose component, the latter being coated on the former. These two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to pass intact into the duodenum or be released with a delayed effect. A variety of materials can be used for such enteric coatings or coatings, including various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0234] Compositions for inhalation or blowing may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered via oral or nasal inhalation to achieve local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered from a device that delivers the formulation in a suitable manner, in one embodiment, orally or nasally.

[0235] The amount of compounds in a pharmaceutical composition or formulation can vary throughout the range employed by those skilled in the art. Typically, based on the total formulation, the formulation will contain about 0.01-99.99 wt% of the compounds disclosed herein, with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compounds are present at a level of about 1-80 wt%. Representative pharmaceutical formulations are described below.

[0236] Formulation Example 1 - tablet formulation Mix the following ingredients thoroughly and compress them into single-score tablets.

[0237] Formulation Example 2 - capsule formulation Mix the following ingredients thoroughly and load them into hard-shell gelatin capsules.

[0238] Formulation Example 3 - suspension formulation Mix the following ingredients to form a suspension for oral administration.

[0239] Formulation Example 4 - injectable formulation Mix the following ingredients to form an injectable formulation.

[0240] Formulation Example 5 - suppository formulation A suppository with a total weight of 2.5 g was prepared by mixing the disclosed compound with Wiptsol® H-15 (a triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc., New York), and having the following composition:

[0241] 6. Administration The specific dosage level of the compounds of this application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination, and severity of the specific disease. For example, the dosage may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of the subject's body weight. Doses between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, doses between 0.5 mg / kg and 60 mg / kg may be appropriate. In some embodiments, doses of about 0.0001 to about 100 mg / kg body weight / day, about 0.001 to about 50 mg compound / kg body weight, or about 0.01 to about 10 mg compound / kg body weight may be appropriate. Normalization based on the subject's weight is particularly useful when adjusting the dosage between subjects of vastly different body sizes, such as when using a drug in children and adults or when converting an effective dose in non-human subjects (such as dogs) to a dose suitable for human subjects.

[0242] 7. Synthesis of Compounds Compounds can be prepared using the methods disclosed herein and their conventional modifications, which will be apparent from the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of typical compounds described herein can be carried out as illustrated in the following examples. Reagents and starting materials are commercially available, if applicable, from, for example, Sigma Aldrich or other chemical suppliers.

[0243] It should be understood that, given typical process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0244] Additionally, conventional protecting groups (“PG”) may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, and suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in the following literature: Wuts, PGM, Greene, TW, and Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and the references cited therein. For example, protecting groups for alcohols (such as hydroxyl groups) include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsiloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed by acids or fluoride ions such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt3. Other protecting groups of alcohols include acetyl, which is removed by acid or base; benzoyl, which is removed by acid or base; benzyl, which is removed by hydrogenation; methoxyethoxymethyl ether, which is removed by acid; dimethoxytriphenylmethyl, which is removed by acid; methoxymethyl ether, which is removed by acid; tetrahydropyranyl or tetrahydrofuranyl, which is removed by acid; and triphenylmethyl, which is removed by acid. Examples of protecting groups for amines include benzyloxycarbonyl, removed by hydrogenolysis; p-methoxybenzylcarbonyl, removed by hydrogenolysis; tert-butoxycarbonyl, removed by concentrated strong acids (such as HCl or CF3COOH) or by heating to above about 80°C; 9-fluorenylmethoxycarbonyl, removed by a base (such as piperidine); acetyl, removed by treatment with a base; benzoyl, removed by treatment with a base; benzyl, removed by hydrogenolysis; carbamate, removed by acid and mild heating; p-methoxybenzyl, removed by hydrogenolysis; 3,4-dimethoxybenzyl, removed by hydrogenolysis; p-methoxyphenyl, removed by cerium(IV)ammonium nitrate; toluenesulfonyl, removed by concentrated acids (such as HBr or H2SO4) and strong reducing agents (sodium-containing liquid ammonia or sodium naphthide); troc (trichloroethyl chloroformate), removed by insertion of Zn in the presence of acetic acid; and sulfonamides (Nosyl and Nps), removed by samarium iodide or tributyltin hydride.

[0245] Furthermore, the compounds disclosed herein may contain one or more chiral centers. Therefore, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched with stereoisomers, if desired. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of this disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0246] The starting materials for the following reactions are generally known compounds, or can be prepared by known procedures or their obvious modifications. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Other starting materials can be prepared by procedures or obvious modifications thereof as described in the following standard reference texts: Fieser and Fieser, Reagents for Organic Synthesis, Volumes 1–15 (John Wiley, and Sons, 1991); Rodd, Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); organic Reactions, Volumes 1–40 (John Wiley, and Sons, 1991); March, Advanced Organic Chemistry (John Wiley, and Sons, 5th edition, 2001); and Larock, Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0247] General synthesis Scheme I describes a general method that can be used to synthesize the compounds described herein (e.g., formulas I and I'), wherein X 1 R 1 R 2 R 3 R 4 R 5R 6 R 8 R 9 , L, t, p, m, n, m1, m2, n1 and n2 are each independently defined as in this paper, and LG is a leaving group (e.g., a halogen).

[0248] Option I In Scheme I, compounds of formula I or I' can be prepared by contacting compound I-1 or I'-1 with amine I-2 under suitable coupling reaction conditions, followed by optional functionalization or deprotection if desired. After the reaction is complete, compounds of formula I or I' can be recovered and purified using conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. Furthermore, further derivatization of the product formed by the process outlined in Scheme I can provide additional compounds of formula I or I'.

[0249] It should be understood that the starting compounds shown in Scheme I can be prepared using conventional methods or purchased from commercial sources. For example, compounds of formula I-1 and I'-1 used in Scheme I to provide a compound of formula I or formula I' where t is 0 (i.e., formula I-8 or formula II-8 hereinafter) can be provided in Scheme II. In Scheme II, L, X 1 R 1 R 2 R 3 R 4 and R 6 Each is independently defined as described herein, and each LG is independently a leaving group (e.g., a halogen).

[0250] Option II In scheme II, compound II-1 is deprotonated by using a strong base (e.g., NaH), and compounds II-2 and II-3 are added (where R... 2 With R 3 (same), or add compound II-2, followed by compound II-3 (where R 2 With R 3 Different methods were used to prepare compound II-4. For R... 1 and R 2Compounds that form rings together are bifunctionalized by adding a single reagent to include two leaving groups, such that the two leaving groups allow the formation of a spirocyclic ring. Reduction of compound II-4 yields compound II-5. Reacting compound II-5 with compound I-6 or II-6 under suitable coupling conditions (e.g., nucleophilic aromatic substitution reaction conditions) yields compound I-7 or II-7. Contacting compound I-7 or II-7 with compound I-2, as shown in Scheme I, yields compound I-8 or II-8. After the reaction is complete, compound I-8 or II-8 can be recovered and purified by conventional techniques (such as neutralization, extraction, precipitation, chromatography, filtration, etc.). Furthermore, further derivatization of the product formed by the process outlined in Scheme II can yield additional compound I.

[0251] Further derivatization of the compound or any intermediate provided by the steps outlined in Scheme I or Scheme II provides additional compounds of Formula I, Formula I-8, or Formula II-8. It should be understood that any compound or intermediate shown in Scheme I or Scheme II can be prepared using conventional methods or is available from commercial sources. Additionally, any intermediate or product obtained by the process outlined in Scheme I or Scheme II can be derivatized in any step to provide various compounds of Formula I, Formula I-8, or Formula II-8. In some embodiments, various substituents of the compounds or intermediates used as in Scheme I or Scheme II are as defined herein (e.g., for Formula I).

[0252] Scheme III shows the use for, for example, R 3 This is an exemplary method for further derivation. In Scheme III, each R... 8 R 9 p, m, n, m1, m2, n1 and n2 are independently as defined herein, and LG is a leaving group (e.g., halogen, alkoxy, etc.).

[0253] In Scheme III, the R protected by BOC 3 Partial deprotection is performed to release the free amine, which can then be functionalized with compound III-1 to provide the desired product.

[0254] In some embodiments, a process for providing a compound of formula I is provided, the process comprising: 1) Make compound I-1: I-1 With compound of formula I-2: I-2 Contact under conditions sufficient to provide compound of formula I, wherein L, X 1R 1 R 2 R 3 R 4 R 5 R 6 t and t are each defined independently as herein. In some embodiments, conditions include a base, such as an organic base, like DIEA.

[0255] In some embodiments, a process for providing a compound of formula I' is provided, the process comprising: 1) Make compound of formula I'-1: I'-1 With compound of formula I-2: I-2 Contact under conditions sufficient to provide compound I, wherein X 1 R 1 R 2 R 3 R 4 R 5 R 6 t and t are each defined independently as herein. In some embodiments, conditions include a base, such as an organic base, like DIEA.

[0256] Example The following embodiments are included to illustrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and can thus be considered as constituting specific patterns of practice of this disclosure. However, those skilled in the art, in view of this disclosure, will understand that various changes can be made to the disclosed specific embodiments without departing from the spirit and scope of this disclosure and still obtaining the same or similar results.

[0257] General experimental methods Unless otherwise noted, reagents and solvents obtained from commercial suppliers are used without purification or drying. Bruker NMR recordings tuned to 400 MHz are used. 1¹H NMR, with TMS used as an internal standard. LC-MS analysis was performed on a Waters UPLC with an SQD-2 mass detector (single quadrupole). HPLC analysis was performed on a WATERS Acquity UPLC ¹H CLASS or an AcquityArc system (with PDA and ELSD detectors). p-HPLC purification was performed using the following columns: Waters Xbridge Prep OBD 150 × 40 mm × 10 µm, Waters Xbridge BEH 100 × 30 mm × 10 µm, or Phenomenex Luna C18 100 × 40 mm × 3 µm.

[0258] General Method 1: Add LiAlH4 (2.5 M, in THF) to a solution of AlCl3 in THF. Stir the mixture at 20°C for 10 minutes, then cool to -40°C. Add the matrix dissolved in THF to the reactants and stir at -40°C under a N2 atmosphere for 2 hours. Quench the mixture with Na2SO4·10H2O, filter, and wash with THF. Concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography as specified.

[0259] General Method 2: Add K₂CO₃ and 2-fluoropyridine-4-carboxynitrile to a solution of amine in DMSO. Stir the mixture at 80°C for 16 hours. Pour the mixture into water and extract with EtOAc (3×). Wash the combined organic phases with brine, dry over anhydrous Na₂SO₄, filter, and concentrate under reduced pressure. Wet-mill the residue with MTBE and filter to obtain the desired product.

[0260] General Method 3: Degas the mixture of the aryl chloride starting material, the starting material amine, and the base in NMP and purge three times with N2. Stir the mixture at 140°C under N2 atmosphere for 16 hours (or until the reaction is complete). Cool the reactants to room temperature, then pour them into H2O and extract with EtOAc (3×). Wash the combined organic phases with brine, dry them over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the crude mixture as specified.

[0261] General Method 4: Dissolve the Boc-protected starting material in HCl / EtOAc (4N) and stir at 20°C for 1 hour. Concentrate the mixture under reduced pressure to obtain the desired compound, which is then used in the next step without further purification.

[0262] General Method 5: Dissolve the starting material amine in an aprotic solvent, then add a base. Cool the reaction mixture to 0°C under N2 and add the acid chloride or chloroformate dropwise. Stir the mixture at 20°C for 2 hours. Pour the reaction mixture into H2O and extract with DCM (3×). Wash the combined organic layers with brine, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude reaction product as specified.

[0263] General Method 6: Add the amine-containing solvent to the solution of the acid starting material, coupling reagent, and base. Stir the mixture at 20-60°C for 1-12 hours. Pour the mixture into H₂O and extract with EtOAc (3×). Wash the combined organic phases with brine, dry over anhydrous Na₂SO₄, filter, and concentrate under reduced pressure. Purify the crude material as specified.

[0264] Example 1 (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclopropane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester 4'-Chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7') H )-Ketone: 4-chloro-5,7-dihydro-6-ketone was added to a mixture of NaH (3.54 g, 88.46 mmol, 60% purity) in DMF (100 mL) at 0 °C under N2. H -pyrrolo[2,3-d]pyrimidin-6-one (3.0 g, 17.7 mmol). The mixture was stirred at 20 °C for 2 h and then cooled to 0 °C. 1,2-Dibromoethane (10.0 g, 53.1 mmol) was added. The reaction mixture was stirred at 20 °C for 12 h. The mixture was poured into an aqueous solution of NH4Cl (300 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) to give 4'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7') H )-ketone (1.8 g, 52% yield).

[0265] 4'-Chloro-6',7'-Dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]: General method 1-AlCl3 (1.84 g, 13.8 mmol), THF (20 mL), LiAlH4 (2.5 M, in THF, 5.5 mL), containing 4'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7' H )-one (900 mg, 4.6 mmol) in THF (20 mL). The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give 4'-chloro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine] (200 mg, 24% yield).

[0266] 2-(4'-Chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6') H 2-(4'-chloro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine](400 mg, 2.20 mmol), DMSO (2 mL), K₂CO₃ (913 mg, 6.61 mmol), and 2-fluoropyridine-4-carboxylonitrile (403 mg, 3.30 mmol). Product: 2-(4'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6') H )-Isoninonitrile (200 mg, 32% yield).

[0267] (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclopropane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1): General method 3-2-(4'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6') H (2)-Isoninonitrile (200 mg, 0.70 mmol), (2) R 5 S 2,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (453 mg, 2.11 mmol), DIEA (456 mg, 3.52 mmol), and NMP (4 mL) were used. The crude reactants were purified by p-HPLC under the following conditions: mobile phase: [H₂O (10 mM NH₄HCO₃)-ACN]; gradient: 8.0 min at 65%-95% B, yielding (2... R 5 S)-4-[7-(4-cyano-2-pyridyl)spiro[6 H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclopropane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (117 mg, 36% yield).

[0268] Example 2 2-[4-[(2 S 5 R )-4-(2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclopropane]-7-yl]pyridin-4-carboxynitrile 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6' H )-Isonicotinamide hydrochloride: General method 4-(2 R 5 S )-4-(7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3- d [Pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.07 mmol) and HCl / EtOAc (4N, 2 mL). Product: 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6') H )-Isoninonitrile hydrochloride (23 mg, 89% yield).

[0269] 2-[4-[(2 S 5 R )-4-(2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclopropane]-7-yl]pyridin-4-carboxylonitrile(2): General method 3-2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6' H)-(2,2-dimethylpropionyl chloride) isonicotinamide hydrochloride (22 mg, 0.06 mmol), DCM (1 mL), TEA (17 mg, 0.17 mmol), and 2,2-dimethylpropionyl chloride (8.00 mg, 0.07 mmol). The residues were purified by p-HPLC under the following conditions: mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 8.0 min 45%-75% B, to give 2-[4-[(2 S 5 R )-4-(2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclopropane]-7-yl]pyridine-4-carboxylonitrile (3.46 mg, 14% yield).

[0270] Example 3 (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester 4'-Chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7') H )-Ketone: Reacts at -78°C under N2 to 4-chloro-5,7-dihydro-6 H LiHMDS (1 M, in n-hexane, 27.1 mL) was added to a mixture of pyrrolo[2,3-d]pyrimidin-6-one (2 g, 11.8 mmol) in THF (30 mL). The mixture was stirred at -78 °C for 0.5 h, and then 1,3-diiodopropane (4.54 g, 15.3 mmol) was added. The mixture was stirred at 20 °C for 16 h. The mixture was poured into NH4Cl (60 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give 4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7') H )-ketone (0.9 g, 36%).

[0271] 4'-Chloro-6',7'-Dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]: General method 1-AlCl3 (1.53 g, 11.5 mmol), THF (20 mL), LiAlH4 (2.5 M, in THF, 4.6 mL), 4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7' H )-one (800 mg, 3.8 mmol). The residue was purified by silica gel column chromatography (SiO2, PE:EtOAc = 1:1 to 0:1) to give 4'-chloro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine] (200 mg, 27% yield).

[0272] 2-(4'-Chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6') H 2-(4'-chloro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine](170 mg, 0.87 mmol), DMSO (2 mL), K₂CO₃ (360 mg, 2.6 mmol), and 2-fluoropyridine-4-carboxylonitrile (159 mg, 1.3 mmol). Product: 2-(4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6') H )-Isoninonitrile (140 mg, 54%).

[0273] (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (3): General method 3-2-(4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6') H )-Isoninonitrile (70 mg, 0.26 mmol), (2 R 5 S 2,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (151 mg, 0.71 mmol), DIEA (152 mg, 1.18 mmol), and NMP (4 mL) were used. The crude product was purified by preparative HPLC under the following conditions: mobile phase: [H2O (10 mM FA)-ACN]; gradient: 8.0 min 60%-90% B, to obtain (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (22.1 mg, 20% yield).

[0274] Example 4 (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)-5,5-dimethyl-6 H -Pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester 4-Chloro-5,5-dimethyl-6,7-dihydro-5 H -Pyrrolo[2,3-d]pyrimidine: General method 1-AlCl3 (2.02 g, 15.2 mmol), THF (10 mL), LiAlH4 (2.5 M, in THF, 6.07 mL), containing 4-chloro-5,5-dimethyl-5,7-dihydro-6 H 10 mL of THF containing pyrrolo[2,3-d]pyrimidin-6-one (1 g, 5.1 mmol) was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give 4-chloro-5,5-dimethyl-6,7-dihydro-5-dimethyl-6,7-dihydro-6-dimethyl-6,3-dimethyl-6,7-dihydro-6,3 ...3-dimethyl-6,7-dihydro-6,3-dimethyl-6,3-dimethyl-6,3-dimethyl-6,3-dimethyl-6,3-dimethyl-6,3-dimethyl-6,3-dimethyl- H -Pyrrolo[2,3-d]pyrimidine (100 mg, 11%).

[0275] 2-(4-chloro-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidine-7(6) H 2-(4-chloro-5,5-dimethyl-6,7-dihydro-5-)isocyanate: General method H -pyrrolo[2,3-d]pyrimidine (100 mg, 0.54 mmol), DMSO (2 mL), K2CO3 (226 mg, 1.63 mmol) and 2-fluoropyridine-4-carboxynitrile (100 mg, 0.82 mmol). Product: 2-(4-chloro-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidine-7(6 H )-Isoninonitrile (100 mg, 64%).

[0276] (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)-5,5-dimethyl-6 H-Pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (4): General method 3-2-(4-chloro-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-7(6) H )-Isoninonitrile (100 mg, 0.35 mmol), (2) R 5 S 2,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (113 mg, 0.53 mmol), DIEA (226 mg, 1.75 mmol), and NMP (2 mL). The crude mixture was purified by preparative HPLC (neutral) under the following conditions: mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 8.0 min 55%-85% B, to obtain (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)-5,5-dimethyl-6 H -Pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (117 mg, 36%).

[0277] Example 5 (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclopentane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester 4'-Chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7') H )-Ketone: Reacts at -78°C under N2 to 4-chloro-5,7-dihydro-6 H A solution of pyrrolo[2,3-d]pyrimidin-6-one (2.0 g, 11.8 mmol) in THF (30 mL) was mixed with LiHMDS (1 M, in hexane, 29.5 mL). The mixture was stirred at -78 °C for 0.5 h, and then 1,4-diiodobutane (4.4 g, 14.2 mmol) was added. The mixture was stirred at 20 °C for 16 h. The mixture was poured into NH4Cl (60 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give 4'-chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7')H )-ketone (1.1 g, 42% yield).

[0278] 4'-Chloro-6',7'-Dihydrospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine]: General Procedure 1-THF (20 mL) containing AlCl3 (1.97 g, 14.8 mmol), LiAlH4 (2.5 M, in THF, 5.9 mL), containing 4'-chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7' H )-one (1.1 g, 4.9 mmol) in THF (20 mL). The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 1:2) to give 4'-chloro-6',7'-dihydrospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine] (180 mg, 17% yield).

[0279] 2-(4'-Chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6') H 2-(4'-chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6'-)isocyanonitrile: General method 2-4'-chloro-6',7'-dihydrospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine] (176 mg, 0.84 mmol), DMSO (2 mL), K2CO3 (348 mg, 2.52 mmol) and 2-fluoropyridine-4-carboxylonitrile (154 mg, 1.26 mmol). Product: 2-(4'-chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6'-)isocyanonitrile H )-Isoninonitrile (100 mg, 38%).

[0280] (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclopentane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (5): General method 3-(2 R 5 S 2,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (206 mg, 0.96 mmol), 2-(4'-chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6') H(2)-Isoninonitrile (100 mg, 0.33 mmol), DIEA (207 mg, 1.60 mmol), and NMP (4 mL). The crude mixture was concentrated under reduced pressure and purified by preparative HPLC (neutral) under the following conditions: mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 8.0 min 45%-75% B, to obtain (2) R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclopentane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (17.26 mg, 11%).

[0281] Example 6 (2 R )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tert-butyl ester (2 R )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tert-butyl ester (6): General method 3-2-(4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H ()-Isoninonitrile (130 mg, 0.44 mmol), () R 2-Methylpiperazine-1-carboxylic acid tert-butyl ester (262 mg, 1.31 mmol), NMP (1 mL), and DIEA (282 mg, 2.18 mmol). The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to obtain (2 R )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -Pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tert-butyl ester (90 mg, 45%).

[0282] Example 7 (3 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-3-methylpiperazine-1-carboxylic acid tert-butyl ester (3 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-3-methylpiperazine-1-carboxylic acid tert-butyl ester (7): General method 3-2-(4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H (200 mg, 0.67 mmol) isoniconitrile (200 mg, 0.67 mmol), ( S 3-Methylpiperazine-1-carboxylic acid tert-butyl ester (404 mg, 2.02 mmol), NMP (3 mL), and DIEA (434 mg, 3.36 mmol). The residues were purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the product (270 mg, 50% purity). The product was further purified by preparative HPLC under the following conditions: mobile phase: [A: water containing 10 mM FA, B: CH3CN; B% in A: 50%-80%], 8 min, to give pure (3) S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-3-methylpiperazine-1-carboxylic acid tert-butyl ester (11.9 mg, 38%).

[0283] Example 8 2-[4-[(2 S )-4-(2,2-dimethylpropionyl)-2-methylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile ( S )-2-(4'-(2-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isoninonitrile hydrochloride: General method 4-containing ( S )-4-(7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d1 mL of tert-butyl pyrimidine (150 mg, 0.32 mmol) in EtOAc and HCl / EtOAc (4 mL). Product: S )-2-(4'-(2-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isoninonitrile hydrochloride (140 mg).

[0284] ( S )-2-(4'-(2-methyl-4-neovalerylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Base)Isoninonitrile(8): General method 5-containing ( S )-2-(4'-(2-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H DCM (1 mL), TEA (76 mg, 0.75 mmol), and neopentanoyl chloride (120 mg, 0.10 mmol) of 90 mg (90 mg, 0.25 mmol) were added. The crude residue was purified by preparative HPLC under the following conditions: mobile phase: [A: water containing 10 mM FA, B: CH3CN; B% in A: 35%-75%], 8 min, to obtain ( S )-2-(4'-(2-methyl-4-neovalerylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isoninonitrile (16.7 mg, 15%).

[0285] Example 9 2-[4-[(2 S 5 R )-4-(2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H)-Isonicotinamide hydrochloride: General method 4-(2 R 5 S )-4-(7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d 2-(4'-((2-)-(4'-)-(2' ... S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isoniconitrile hydrochloride (240 mg, 89%).

[0286] 2-[4-[(2 S 5 R )-4-(2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (9): General method 5-containing 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H DCM (1 mL), TEA (22 mg, 0.22 mmol), and 2,2-dimethylpropionyl chloride (11 mg, 0.09 mmol) of 2-(2-)-isonicotinamide hydrochloride (30 mg, 0.07 mmol) were purified by p-HPLC under the following conditions: mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 8.0 min 60%-95% B, to obtain 2-[4-[(2-) ... S 5 R )-4-(2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (14 mg, 43%).

[0287] Example 10 2-[4-[(3 R )-4-(2,2-dimethylpropionyl)-3-methylpiperazin-1-yl]spiro[6 H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile ( R )-2-(4'-(3-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isoninonitrile hydrochloride: General method 4-containing ( R )-4-(7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d tert-butyl pyrimidine (70 mg, 0.15 mmol) in EtOAc (1 mL), HCl / EtOAc (4N, 5 mL). Product: ( R )-2-(4'-(3-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isoniconitrile hydrochloride (70 mg, >99%).

[0288] 2-[4-[(3 R )-4-(2,2-dimethylpropionyl)-3-methylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (10): General method 5-containing ( R )-2-(4'-(3-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H DCM (1 mL), TEA (27 mg, 0.26 mmol), and neopentanoyl chloride (21 mg, 0.18 mmol) were obtained from isonicotinamide hydrochloride (35 mg, 0.09 mmol). The residue was purified by preparative HPLC under the following conditions: mobile phase: [A: water containing 10 mM NH4HCO3, B: CH3CN; B% in A: 47%-75%], 8 min, to give 2-[4-[(3 R )-4-(2,2-dimethylpropionyl)-3-methylpiperazin-1-yl]spiro[6 H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (11 mg, 28%).

[0289] Example 11 (2R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H 2,2,2-trifluoroethyl pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid 2,2,2-trifluoroethyl ester (11): General method 5-containing ( R )-2-(4'-(3-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H DCM (1 mL), TEA (27 mg, 0.26 mmol), and 2,2,2-trifluoroethyl chloroformate (29 mg, 0.18 mmol) of isonicotinamide hydrochloride (35 mg, 0.09 mmol) were added. The residues were purified by preparative HPLC under the following conditions: mobile phase: [A: water containing 10 mM FA, B: CH3CN; B% in A: 40%-80%], 8 min, to obtain (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)spiro[6 H 2,2,2-trifluoroethyl pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid (6.5 mg, 15%).

[0290] Example 12 2-[4-[(2 S 5 R )-4-(bicyclo[2.1.1]hexane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(bicyclo[2.1.1]hexane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (12): General method 6-containing 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H DMF (1 mL) of 2-[4-[(2-]- ... S 5 R )-4-(bicyclo[2.1.1]hexane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (10.5 mg, 30%).

[0291] Example 13 2-[4-[(2 S 5 R )-4-(3-methoxy-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(3-methoxy-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (13): General method 6-DMF (1 mL) containing 3-methoxy-2,2-dimethyl-propionic acid (48 mg, 0.36 mmol), HATU (111 mg, 0.29 mmol), DIEA (94 mg, 0.73 mmol) and 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3-d [Pyrimidine]-7'(6' H )-(2-)isonicotinamide hydrochloride (100 mg, 0.24 mmol). The residue was purified by preparative HPLC under the following conditions: mobile phase: [H2O (0.2% FA)-ACN]; gradient: 8.0 min 40%-75% B, to obtain 2-[4-[(2-) ... S 5 R )-4-(3-methoxy-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (18 mg, 14%).

[0292] Example 14 2-[4-[(2 S 5 R )-4-(2-methoxy-2-methylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(2-methoxy-2-methylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (14): General method 6-containing 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H DMF (1 mL) of 2-[4-[(2-methylpropionic acid) hydrochloride (100 mg, 0.27 mmol), 2-methoxy-2-methylpropionic acid (47 mg, 0.40 mmol), HATU (121 mg, 0.32 mmol), and DIEA (103 mg, 0.80 mmol) were used to purify the mixture by preparative HPLC under the following conditions: mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 8.0 min 55%-85% B, to give 2-[4-[(2-methylpropionic acid) hydrochloride (100 mg, 0.27 mmol), 2-methoxy-2-methylpropionic acid (47 mg, 0.40 mmol), HATU (121 mg, 0.32 mmol), and DIEA (103 mg, 0.80 mmol). S 5 R )-4-(2-methoxy-2-methylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H-Pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (18 mg, 14%).

[0293] Example 15 2-[4-[(2 S 5 R )-4-(cyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(cyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (15): General method 5-2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-(2-)isonicotinamide hydrochloride (0.1 g, 0.24 mmol), DCM (1 mL) containing TEA (74 mg, 0.73 mmol), and cyclobutane carbonyl chloride (34 mg, 0.29 mmol). The residues were purified by preparative HPLC (FA conditions) under the following conditions: mobile phase: [H2O (0.2% FA)-ACN]; gradient: 8.0 min 30%-70% B, to give 2-[4-[(2 S 5 R )-4-(cyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (15 mg, 13%).

[0294] Example 16 2-[4-[(2 S 5 R )-2,5-dimethyl-4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R)-2,5-dimethyl-4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (16): General method 6-1-methylcyclobutanecarboxylic acid (33 mg, 0.29 mmol), PYAOP (151 mg, 0.29 mmol) and THF (2 mL) containing DIEA (156 mg, 1.21 mmol), 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-(2-)-(4-)-(2 ... S 5 R )-2,5-dimethyl-4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (20.2 mg, 18%).

[0295] Example 17 2-[4-[(2 S 5 R )-4-(3,3-difluoro-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(3,3-difluoro-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (17): General method 6-DMF (1 mL), HATU (111 mg, 0.29 mmol), DIEA (94 mg, 0.73 mmol) containing 3,3-difluoro-2,2-dimethylpropionic acid (50 mg, 0.36 mmol), and 2-(4'-((2 S 5R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isonicotinamide hydrochloride (100 mg, 0.24 mmol). The residue was purified by preparative HPLC under the following conditions: mobile phase: A: H2O containing 10 mM NH4HCO3, B: ACN; B% in A: 35%-70%; 8.0 min, to obtain 2-[4-[(2 S 5 R )-4-(3,3-difluoro-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (14.7 mg, 12%).

[0296] Example 18 2-[4-[(2 S 5 R )-4-(3-fluoro-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(3-fluoro-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (18): General method 6-DMF (0.5 mL) containing 3-fluoro-2,2-dimethylpropionic acid (13 mg, 0.11 mmol), HATU (33 mg, 0.09 mmol), DIEA (28 mg, 0.22 mmol) and 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isonicotinamide hydrochloride (30 mg, 0.07 mmol). The residue was purified by preparative HPLC under the following conditions: mobile phase: A: H2O containing 10 mM NH4HCO3, B: ACN; B% in A: 40%-70%; 8.0 min, to obtain 2-[4-[(2 S 5 R)-4-(3-fluoro-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (12.4 mg, 36%).

[0297] Example 19 2-[4-[(2 S 5 R )-4-(2-cyclopropyl-2-methylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(2-cyclopropyl-2-methylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (19): General method 6-2-cyclopropyl-2-methylpropionic acid (14 mg, 0.109 mmol), HATU (33 mg, 0.087 mmol), DMF (2 mL) containing DIEA (28 mg, 0.218 mmol), 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-(2-)isonicotinamide hydrochloride (0.03 g, 0.073 mmol). The residue was purified by preparative HPLC under the following conditions: mobile phase: A: [H2O (0.2% FA)-ACN], B: MeCN; B% in A: 25%-65%, 8 min, to obtain 2-[4-[(2-) ... S 5 R )-4-(2-cyclopropyl-2-methylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (8.4 mg, 24%).

[0298] Example 20 2-[4-[(2 S 5 R )-4-(bicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(bicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (20): General method 6-containing bicyclo[1.1.1]pentane-1-carboxylic acid (41 mg, 0.364 mmol), HATU (110 mg, 0.291 mmol), DMF (2 mL) containing DIEA (94 mg, 0.728 mmol) and 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-(2-)isonicotinamide hydrochloride (0.1 g, 0.243 mmol). The residue obtained was purified by preparative HPLC under the following conditions: mobile phase: A: [H2O (0.2% FA)-ACN], B: MeCN; B% in A: 25%-65%, 8 min, to obtain 2-[4-[(2-) ... S 5 R )-4-(bicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (17.1 mg, 15%).

[0299] Example 21 2-[4-[(2 S 5 R )-2,5-dimethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-2,5-dimethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]spiro[6 H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (21): General method 6-2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-(trifluoromethyl)isonicotinamide hydrochloride (100 mg, 0.24 mmol), DMF (2 mL) containing 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (61 mg, 0.36 mmol), DIEA (157 mg, 1.21 mmol) and HATU (111 mg, 0.29 mmol). The mixture was heated to 50 °C for 16 hours. The residue was purified by preparative HPLC under the following conditions: mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 8.0 min 56%-88% B, to give 2-[4-[(2 S 5 R )-2,5-dimethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (1.83 mg, 1.2%).

[0300] Example 22 2-[4-[(2 S 5 R )-4-(2,2-difluoro-1-methylcyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(2,2-difluoro-1-methylcyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (22): General method 6-containing DMF (1 mL), HATU (55 mg, 0.15 mmol), DIEA (47 mg, 0.36 mmol) and 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d[Pyrimidine]-7'(6' H )-Isonicotinamide hydrochloride (50 mg, 0.12 mmol). The mixture was purified by preparative HPLC under the following conditions: mobile phase: water containing 10 mM NH4HCO3, B: MeCN; B% in A: 60%-90%, 8.0 min, to obtain 2-[4-[(2 S 5 R )-4-(2,2-difluoro-1-methylcyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (19.9 mg, 33%).

[0301] Example 23 2-[4-[(2 S 5 R )-4-(3,3-difluoro-2,2-dimethylbutyryl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(3,3-difluoro-2,2-dimethylbutyryl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (23): General method 6-DMF (1 mL) containing 3,3-difluoro-2,2-dimethyl-butyric acid (55 mg, 0.36 mmol), 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isoniconitrile hydrochloride (100 mg, 0.24 mmol), HATU (110 mg, 0.29 mmol) and DIEA (94 mg, 0.73 mmol). The mixture was purified by preparative HPLC under the following conditions: mobile phase: water containing 10 mM NH4HCO3, B: MeCN; B% in A: 50%-90%, 8.0 min, to give 2-[4-[(2 S 5 R )-4-(3,3-difluoro-2,2-dimethylbutyryl)-2,5-dimethylpiperazin-1-yl]spiro[6 H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (3.13 mg, 3%).

[0302] Example 24 2-[4-[(2 S 5 R )-4-(4,4-difluoro-2,2-dimethylbutyryl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxynitrile 2-[4-[(2 S 5 R )-4-(4,4-difluoro-2,2-dimethylbutyryl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridin-4-carboxylonitrile (24): General method 6-containing 2-(4'-((2 S 5 R )-2,5-dimethylpiperazine-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H DMF (1 mL) of 2-[4-[(2-difluoro-2,2-dimethyl-butyric acid), 4,4-difluoro-2,2-dimethyl-butyric acid (27 mg, 0.18 mmol), HATU (55 mg, 0.15 mmol), and DIEA (47 mg, 0.36 mmol) was obtained. The mixture was purified by preparative HPLC under the following conditions: mobile phase A: water containing 10 mM NH4HCO3, B: MeCN; B% in A: 60%-90%, 8.0 min, to give 2-[4-[(2 ... S 5 R )-4-(4,4-difluoro-2,2-dimethylbutyryl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-7-yl]pyridine-4-carboxylonitrile (6.52 mg, 11%).

[0303] Example 25 (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)-3'-hydroxyspiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester tert-Butyl((1,3-dibromoprop-2-yl)oxy)dimethylsilane: Imidazole (2.23 g, 32.8 mmol), DMAP (364 mg, 3.0 mmol), and TBSCl (4.95 g, 32.8 mmol) were added to a solution of 1,3-dibromoprop-2-ol (6.5 g, 29.8 mmol) in DCM (70 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h. The mixture was quenched with H2O (30 mL) and extracted with DCM (3 × 40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (PE:EtOAc = 100:1 to 5:1) to give tert-Butyl((1,3-dibromoprop-2-yl)oxy)dimethylsilane (6.2 g, 63%).

[0304] 3-((tert-butyldimethylsilyl)oxy)-4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-6'(7' H )-Ketone: Reacts at 20°C under N2 to 4-chloro-5,7-dihydro-6-ketone. H -pyrrolo[2,3- d A mixture of pyrimidin-6-one (2 g, 11.8 mmol) in DMSO (60 mL) was mixed with NaH (1.09 g, 27.1 mmol, 60% dispersion in mineral oil). The mixture was stirred at 20 °C for 0.5 h, and then tert-butyl((1,3-dibromoprop-2-yl)oxy)dimethylsilane (4.70 g, 14.2 mmol) was added. The mixture was stirred at 20 °C for 16 h. The mixture was quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 4:1) to give 3-((tert-butyldimethylsilyl)oxy)-4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-6'(7' H )-ketone (1.9 g, 47%).

[0305] 3-((tert-butyldimethylsilyl)oxy)-4'-chloro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d[Pyrimidine]: General procedure 1-THF (42.5 mL) containing AlCl3 (2.00 g, 15.0 mmol), LiAlH4 (2.5 M, in THF, 6.00 mL), and 3-((tert-butyldimethylsilyl)oxy)-4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-6'(7' H )-one (1.7 g, 5.0 mmol). The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give 3-((tert-butyldimethylsilyl)oxy)-4'-chloro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine] (500 mg, 31%).

[0306] 2-(4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-(-)-Isononiconitrile: General method 2-2-fluoroisocyanonitrile (281 mg, 2.30 mmol), 3-((tert-butyldimethylsilyl)oxy)-4'-chloro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine] (500 mg, 1.53 mmol), DMSO (10 mL), K2CO3 (636 mg, 4.60 mmol). The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isoninonitrile (110 mg, 23%).

[0307] (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)-3'-hydroxyspiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (25): General method 3-2-(4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isoninonitrile (50 mg, 0.16 mmol), (2) R 5 S2,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (102 mg, 0.48 mmol), NMP (1 mL), DIEA (103 mg, 0.80 mmol). The residue was purified by preparative HPLC under the following conditions: mobile phase: A: water containing 10 mM NH4HCO3, B: MeCN; B% in A: 38%-67%, 8 min, to obtain (2 R 5 S )-4-[7-(4-cyano-2-pyridyl)-3'-hydroxyspiro[6 H -Pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (2.29 mg, 3%).

[0308] Example 38 (2R)-4-[7-(4-cyano-2-pyridyl)-3'-fluorospiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tert-butyl ester 2-(4'-chloro-3-fluorospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-yl)isonicotinonitrile: at 0°C, to 2-(4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H DAST (123 mg, 0.76 mmol) was added to a solution of 2-(4'-chloro-3-fluorospiro[cyclobutane-1,5'-pyrrolo[2,3-])-isonicotinamide (80 mg, 0.25 mmol) in DCM (1 mL). The mixture was stirred at 20 °C for 2 h. The mixture was quenched with H2O (2 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4'-chloro-3-fluorospiro[cyclobutane-1,5'-pyrrolo[2,3-]) d [Pyrimidine]-7'(6' H )-Isoninonitrile (35 mg, 43%).

[0309] (2R)-4-[7-(4-cyano-2-pyridyl)-3'-fluorospiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tert-butyl ester: General method 3- 2-(4'-chloro-3-fluorospiro[cyclobutane-1,5'-pyrrolo[2,3-d [Pyrimidine]-7'(6' H ()-Isoninonitrile (15 mg, 0.05 mmol), () R 2-methylpiperazine-1-carboxylic acid tert-butyl ester (19 mg, 0.1 mmol) and DIEA (6 mg, 0.05 mmol) were in NMP (0.3 mL) at 80 °C for 16 h. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 80 × 40 mm × 3 μm; mobile phase: A: water containing 10 mM NH4HCO3, B: MeCN; B% in A: 40%–70%, 8 min) to give (2R)-4-[7-(4-cyano-2-pyridyl)-3'-fluorospiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tert-butyl ester (4 mg, 16%).

[0310] Example 55 (2R,5S)-4-[7-(4-cyano-2-pyridyl)-1',1'-difluorospiro[6H-pyrrolo[2,3-d]pyrimidin-5,3'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester 2-(4'-chloro-3-oxospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-yl)isonicotinonitrile: to 2-(4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H 2-(4'-chloro-3-oxospiro[cyclobutane-1,5'-pyrrolo[2,3-))-isonicotinonitrile (180 mg, 0.57 mmol) was added to a solution in DCM (3 mL). The mixture was stirred at 40 °C for 5 hours. The mixture was poured into an aqueous solution of NaHCO3 (10 mL) and extracted with DCM (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give 2-(4'-chloro-3-oxospiro[cyclobutane-1,5'-pyrrolo[2,3-)) d [Pyrimidine]-7'(6' H )-Isoninonitrile (110 mg, 62%).

[0311] 2-(4'-chloro-3,3-difluorospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-yl)isonicotinonitrile: at 0°C, to 2-(4'-chloro-3-oxospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H 2-(4'-chloro-3,3-difluorospiro[cyclobutane-1,5'-pyrrolo[2,3-])isonicotinamide (110 mg, 0.35 mmol) was added to a solution of DCE (2 mL) with EtOH (33 mg, 0.71 mmol) and DAST (1.14 g, 7.06 mmol). The mixture was stirred at 50 °C for 4 hours. The mixture was poured into an aqueous solution of NaHCO3 (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4'-chloro-3,3-difluorospiro[cyclobutane-1,5'-pyrrolo[2,3-]) d [Pyrimidine]-7'(6' H )-Isoninonitrile (100 mg, 85%).

[0312] (2R,5S)-4-[7-(4-cyano-2-pyridyl)-1',1'-difluorospiro[6H-pyrrolo[2,3-d]pyrimidin-5,3'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester: General method 3- (2 R 5 S 2,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (51 mg, 0.24 mmol), DIEA (46 mg, 0.36 mmol), 2-(4'-chloro-3,3-difluorospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H (2R,5S)-4-[7-(4-cyano-2-pyridyl)-1',1'-difluorospiro[6H-pyrrolo[2,3-d]pyrimidin-5,3'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (7 mg, 11%) was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 µm; mobile phase: A: water containing 10 mM NH4HCO3, B: CH3CN; B% in A: 55%–90%, 8 min).

[0313] Example 56 (2R,5S)-4-((1r,3S)-7'-(4-cyanopyridin-2-yl)-3-hydroxy-3-methyl-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester 2-(4'-chloro-3-hydroxy-3-methylspiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-Isoninonitrile: at 0°C under N2, to 2-(4'-chloro-3-oxospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H CH3MgBr (3 M, 0.24 mmol, 0.08 mL, in THF) was added to a solution of 2-(4'-chloro-3-hydroxy-3-methylspiro[cyclobutane-1,5'-pyrrolo[2,3-])-isonicotinamide (50 mg, 0.16 mmol) in THF (1 mL). The mixture was stirred at 20 °C for 2 hours. The mixture was poured into an aqueous solution of NH4Cl (3 mL) and extracted with EtOAc (3 × 1 mL). The combined organic phases were washed with brine (1 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc = 1:1) to give 2-(4'-chloro-3-hydroxy-3-methylspiro[cyclobutane-1,5'-pyrrolo[2,3-]) d [Pyrimidine]-7'(6' H )-Isoninonitrile (29 mg, 55%).

[0314] (2 R 5 S )-4-((1 r ,3 S )-7'-(4-cyanopyridin-2-yl)-3-hydroxy-3-methyl-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]Pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester: General method 3-(2 R 5 S 2,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (28 mg, 0.13 mmol), DIEA (34 mg, 0.27 mmol), 2-(4'-chloro-3-hydroxy-3-methylspiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H2-Isoninonitrile (29 mg, 0.88 mmol) was in NMP (0.2 mL) at 140 °C for 12 h. The mixture was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 µm; mobile phase: A: water containing 10 mM NH4HCO3, B: CH3CN; B% in A: 35%-90%, 8 min) to obtain (2 R 5 S )-4-((1 r ,3 S )-7'-(4-cyanopyridin-2-yl)-3-hydroxy-3-methyl-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]Pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (8 mg, 19%).

[0315] Example 62 (2R,5S)-4-[7-(6-cyanopyridazin-4-yl)spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester 5-Chloropyridazine-3-carboxylonitrile: DPPF (74 mg, 0.13 mmol), Pd2(dba)3 (61 mg, 0.07 mmol), and Zn(CN)2 (158 mg, 1.34 mmol) were added to a solution of 3,5-dichloropyridazine (200 mg, 1.34 mmol) in DMF (2 mL) at 25 °C under N2. The mixture was stirred at 90 °C for 5 h. The reaction mixture was diluted with H2O (10 mL) at 0 °C. The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EtOAc = 3:1) to give 5-chloropyridazine-3-carboxylonitrile (80 mg, 42%).

[0316] 5-(4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-yl)pyridazine-3-carboxynitrile: General method 2-4'-chloro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d[Pyrimidine] (80 mg, 0.41 mmol), 5-chloropyridazine-3-carboxynitrile (74 mg, 0.53 mmol), and K2CO3 (170 mg, 1.23 mmol) were added to DMSO (2 mL). The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 0:1) to give 5-(4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]- 7'(6' H )-yl)pyridazine-3-carboxynitrile (50 mg, 49%).

[0317] (2R,5S)-4-[7-(6-cyanopyridazin-4-yl)spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester: General method 3- 5-(4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d [Pyrimidine]-7'(6' H )-pyridazine-3-carboxylonitrile (50 mg, 0.17 mmol), DIEA (108 mg, 0.84 mmol), and 2,5-dimethylpiperazine-1-carboxylate (72 mg, 0.33 mmol) were in NMP (1 mL). The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18 100 × 30 mm × 10 mm × 10 μm; mobile phase: [A: water containing 10 mM NH4HCO3, B: MeCN; B% in A: 50%-80%] 8.0 min) to give (2R,5S)-4-[7-(6-cyanopyridazin-4-yl)spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (35 mg, 28%).

[0318] Examples 68A and 68B (2R,5S)-4-[(5R)-7-(4-cyano-2-py...

Claims

1. A compound of formula I: I Or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 Is it N or CR? 7 ; L is a key, C 1-2 Alkylene, C2 alkenylene, C2 alkyneide, -CH2-C(O)NR 11 -*, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-*, -C(O)NR 11 -*、-S(O)NR 11 -* or -S(O)2NR 11 -*; where the * key is connected to R 4 ; R 1 It is a halogenated group, a cyano group, a nitro group, -CD3, or a C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -SR 11 -C(O)R 11 -C(O)OR 11 -S(O)R 11 -S(O)2R 11 -C(O)N(R) 11 )2、-NR 11 C(O)R 11 -NR 11 S(O)R 11 -NR 11 S(O)2R 11 -S(O)N(R) 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 2 It is a halogen group, -CD3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, aryl, heteroaryl; wherein the C 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; or R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; R 3 yes: or ; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, the C 3-10 The cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; Each R 5 Independently, it is a halogen group, a cyano group, or a C group. 1-6 Alkyl, C 1-6 Halogenated, C 2-6 alkenyl or C 2-6 Alkyne group; or two R groups 5 Together they form C 3-6 cycloalkyl or 4-6 membered heterocyclic groups; wherein the C 3-6 The cycloalkyl group or the 4-6 membered heterocyclic group is independently and optionally surrounded by one to five Z groups. 1a replace; Or two Rs 5 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; or R 1 and R 5 Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or heterocyclic groups; wherein the C 3-10 The cycloalkyl group or the heterocyclic group is independently and optionally surrounded by one to five Z. 1a replace; or R 4 and R 5 Together with the atoms to which they are attached, they form heterocyclic groups or heteroaryl groups; wherein the heterocyclic group or the heteroaryl group is independently and optionally surrounded by one to five Z groups. 1a replace; R 6 and R 7 Each of these groups is independently hydrogen, hydroxyl, halogen, cyano, or C. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl thio or -NR a R b ; R a and R b Each is independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(CH2) 0-2 -C 3-7 cycloalkyl and 3-7 membered heterocyclic groups; Each R 8 Independently is -C(O)N(R) 11 2. C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; wherein the C 1-6 alkyl or the C 1-6 The haloalkyl group is independently and optionally surrounded by a cyano group, -N(R) 13 2. Halogenated group, hydroxyl group or C 1-6 Alkoxy substitution; or two Rs 8 The carbon atoms bonded to them can form oxo groups, fused groups, or spiro groups together. 3-7 cycloalkyl, or fused, bridged, or spiro-4-7 membered heterocyclic groups; wherein the C 3-7 The cycloalkyl group or the 4-7 membered heterocyclic group is independently and optionally surrounded by a halogen group, a hydroxyl group, or a C-group. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy or C 1-6 Haloalkoxy substitution; R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-10 cycloalkyl or -OC 3-10 The cycloalkyl group is independently and optionally surrounded by one to five Z. 1a replace; Each R 11 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1a replace; t is 0, 1, or 2; m is 1 or 2; n is 1, 2, or 3; m1 is 0, 1, or 2; n1 is 0, 1, 2, or 3; m2 is 0, 1, or 2; n2 is 0, 1, 2 or 3; Where m + n is 2, 3, or 4; m1 + n1 is 0, 1, 2, 3 or 4; m2 + n2 is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each Z 1a Independently, it is a halogen group, a cyano group, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -SR 13 -C(O)R 13 -C(O)OR 13 -S(O)R 13 -S(O)2R 13 -C(O)N(R) 13 )2、-NR 13 C(O)R 13 -NR 13 S(O)R 13 -NR 13 S(O)2R 13 -S(O)N(R) 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each R 13 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 1b replace; Each Z 1b Independently, it can be a halogen group, a cyano group, -OH, -SH, -NH2, -NO2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -L 1 -C 1-6 Alkyl, -L 1 -C 2-6 alkenyl, -L 1 -C 2-6 alkynyl group, -L 1 -C 1-6 Halogenated groups, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -Aryl or -L 1 - heteroaryl; and Each L 1 Independently, they are -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (haloalkyl)-, -N(C) 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 yynyl)-, -C(O)N(C 1-6 (haloalkyl)-、-C(O)N(C 3-10 Cycloalkyl), -C(O)N(heterocyclic), -C(O)N(aryl), -C(O)N(heteroaryl), -NHC(O), -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and L 1 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 3-10 The cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further independently and optionally substituted by one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein R 1 It is -CD3, C 1-6 Alkyl, heteroaryl, -C(O)OR 11 or -C(O)N(R) 11 )2, wherein C 1-6 The alkyl group or the heteroaryl group is optionally surrounded by one to three halogen groups, cyano groups, hydroxyl groups, C6 groups, or C7 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -S(O)2C 1-6 Alkyl or heteroaryl substitution.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein R 2 Is it -CD3 or C? 1-6 alkyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein R 1 and R 2 Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl or 4-6 membered heterocyclic groups; wherein the C 3-6 The cycloalkyl group or the 4-6 membered heterocyclic group is independently and optionally surrounded by one to five Z groups. 1a replace.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein R 1 and R 2 Together with the carbon atoms they are attached to, they form a group optionally bounded by one to five Z atoms. 1a Replacement C 3-6 Cycloalkyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein R 1 and R 2 Together with the carbon atoms to which they are attached, they form groups optionally marked with one or two hydroxyl groups, halogen groups, cyano groups, or C groups. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 alkoxy or heteroaryl substituted C 3-6 Cycloalkyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein R 1 and R 2 Together with the carbon atoms they are attached to, they form unsubstituted C atoms. 3-5 Cycloalkyl.

8. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 3 yes .

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein m is 1 or 2.

10. The compound of claim 8 or 9 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein n is 1.

11. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein p is 0, 1, 2, or 3.

12. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein each R 8 Independently is -C(O)N(R) 11 2. C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; wherein the C 1-6 Alkyl groups are independently and optionally replaced by cyano groups, -N(R) 13 2. Halogenated group, hydroxyl group or C 1-6 Alkoxy substitution; or two Rs 8 The carbon atoms they are attached to can form oxo groups or bridged 4-7 membered heterocyclic groups.

13. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein p is 1 or 2; and each R 8 It is a methyl group.

14. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 9 It is C 1-6 Alkyl, C 1-6 Alkoxy or C 3-10 cycloalkyl; wherein the C 1-6 Alkyl, the C 1-6 alkoxy or the C 3-10 The cycloalkyl group is independently and optionally surrounded by one to five halogen groups, cyano groups, hydroxyl groups, -S(O)2C groups. 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)NHC 1-6 Alkyl 2, -C(O)N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated, C 1-6 Haloalkoxy, C 3-7 Cycloalkyl, heterocyclic, or heteroaryl substitutions; wherein the heterocyclic group is optionally further substituted with a halogen or C- group. 1-6 Alkyl-substituted.

15. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein X 1 It is N.

16. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 6 It is hydrogen.

17. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein L is a bond, C is a carbon ... 1-2 Alkylene, -CH2-C(O)NR 11 -*, -C(O)-, -S(O)2-, -C(O)O-* or -C(O)NR 11 -*; where the * key is connected to R 4 .

18. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 4 It is arbitrarily determined by one to five Z. 1a Replacement C 1-6 alkyl.

19. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 4 It is arbitrarily determined by one to five Z. 1a Replacement C 3-10 Cycloalkyl.

20. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 4 It is arbitrarily determined by one to five Z. 1a Substituted aryl groups.

21. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 4 It is arbitrarily determined by one to five Z. 1a Substituted heteroaryl groups.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein R 4 It is a pyridinyl group substituted with a cyano group.

23. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer, or a mixture of stereoisomers, wherein R 4 It is 4-cyanopyridin-2-yl, 4-cyano-5-fluoro-pyridin-2-yl, 2-cyanopyridin-4-yl, 6-cyanopyrimidine-4-yl, 6-cyanopyridazin-4-yl, 4-cyanopyrimidine-2-yl, 5-cyanopyridazin-3-yl, [1,2,4]triazolo[4,3-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-c]pyrimidine-7-yl, imidazo[1,2-c]pyrimidine-7-yl, imidazo[1,2-a]pyrazin-6-yl, 5-aminopyridinyl Azine-2-yl, 5-cyano-1-methyl-1H-pyrazole-3-yl, 3-cyano-5-fluorophenyl, 3,5-dicyanophenyl, 1-methyl-2-oxo-4-pyridyl, 6-aminopyrimidin-4-yl, 4-cyano-6-(hydroxymethyl)-2-pyridyl, 6-cyano-2-(trifluoromethyl)pyrimidin-4-yl, 7-(3-cyano-5-methylsulfonylphenyl), 5-cyano-2-methoxypyridin-3-yl, 5-cyano-2-oxo-1H-pyridin-3-yl, 7 -(6-cyano-2-methoxypyrimidin-4-yl), 6-chloro-4-cyanopyridin-2-yl, 7-(3-cyano-5-methylthiophenyl), 5-cyano-1-methyl-2-oxo-3-pyridyl, 2-cyano-5-fluoro-4-pyridyl, 6-cyano-2-oxo-1,2-dihydropyrimidin-4-yl, 6-cyano-3-methyl-2-oxo-1,2-dihydropyrimidin-4-yl, 1-acetylpyrrolidine-3-yl, 7-(3-cyanocyclopentyl), 1H-pyridine Azo[4,3-c]pyridin-6-yl, 3-cyanocyclobutyl, 2-chloro-6-cyanopyrimidin-4-yl, 3-cyanocyclohexyl, 3-cyano-3-methylcyclobutyl, 3-ethoxycarbonylcyclobutyl, 2-cyano-5-fluoropyridin-4-yl, cyclobutyl, 3-hydroxycyclobutyl, 3-(hydroxymethyl)-3-methyl-cyclobutyl, 2-chloro-5-fluoropyridin-4-yl, 6-chloropyridazin-4-yl, 2-cyano-5-fluoropyrimidin-4-yl or 6-cyano-3-methylpyridazin-4-yl.

24. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 4 It is methyl, ethyl, cyclobutyl, 2-cyanocyclopropyl-1-yl, 3-cyanocyclobutyl-1-yl, 1-methylcyclobutyl-1-yl, 3-cyanopropionyl, cyclopropylmethyl, 3-fluorocyclobutyl-1-yl, 2,2-difluorocyclobutyl-1-yl, 2,2-difluorocyclopropyl-1-yl, 1-fluorocyclobutyl-1-yl, 1-(cyanomethyl)cyclopropyl-1-yl, 1-methyl-1 H -pyrazol-4-yl, 2-cyano-1-methylcyclopropyl-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-cyanocyclobut-1-yl, 2-cyano-2-methylcyclopropyl-1-yl, 1-methyl-1 H -pyrazole-5-yl, 1 H -pyrazole-1-ylmethyl, 2-(1-methyl-1 H -pyrazole-4-yl)ethyl, pyrrolidine-1-ylmethyl, pyrrolidine-2-yl or pyrrolidine-3-yl.

25. The compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein t is 0.

26. The compound of claim 1, wherein the compound is represented by formula IA': IA' Or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof.

27. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a tautomer, a stereoisomer, or a mixture of stereoisomers thereof, or a compound selected from Table 2 or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound as described in any of the preceding claims or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer, or a mixture thereof, and a pharmaceutically acceptable carrier.

29. A method for activating TRPML1, the method comprising contacting cells with an effective amount of the compound of any one of claims 1-27 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a tautomer, or a mixture of stereoisomers, or the pharmaceutical composition of claim 28.

30. The method of claim 29, wherein the contact is in vivo.

31. A method for treating a disease or condition at least partially mediated by TRPML1, the method comprising administering to a subject in need an effective amount of a compound as described in any one of claims 1-27 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer or a mixture of stereoisomers, or a pharmaceutical composition as described in claim 28.

32. The method of claim 31, wherein the disease or condition is aging, bone disease, cardiovascular disease, congenital developmental disorder, eye disease, hematologic and solid malignancies, infectious disease, inflammatory disease, liver disease, metabolic disease, neurodegenerative or neurological disease or condition, pancreatitis, kidney disease, skeletal muscle disease, obesity, lysosomal storage disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, inclusion body myositis, Paget's disease, or lung disease.

33. The method of claim 32, wherein the disease or condition is ciliary disease, neurodegenerative disease or condition, lysosomal storage disease or condition, lysosomal transport disease or condition, glycogen storage disease or condition, cholesterol ester storage disease or condition, muscle disease, age-related disease, macular degeneration, or cancer.

34. The method of claim 33, wherein the neurodegenerative or neurological disease or condition is selected from the group consisting of: Parkinson's disease, GBA-Parkinson's disease, LRRK2 Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, FTDP-17, corticobasal degeneration, Lewy body dementia, Pick's disease, and multiple system atrophy.

35. The method of claim 33, wherein the lysosomal storage disease or condition is selected from the group consisting of: Niemann-Pick disease, Gaucher disease, neuropathic Gaucher disease, sphingolipidosis, Fabry disease, Clapey disease, galactosialidosis, ganglioside deposition, Gaucher disease, lysosomal acid lipase deficiency, thiolipin deposition, mucopolysaccharide deposition, mucolipide deposition, lipid deposition, and oligosaccharide deposition. In some implementations, lysosomal storage diseases are selected from the group consisting of: sphingolipid storage diseases, Fabry disease, Clapey disease, galactosialidosis, Fabry disease, Schindler disease, β-galactosidase disorders, GM1 ganglioside storage diseases, GM2 ganglioside storage disease AB variant, GM2 ganglioside storage disease activator deficiency, Sankhov disease, Tay-Sachs disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, sphingolipid activator B deficiency, multiple sulfatase deficiencies, Hurler syndrome, Schie syndrome, Hurler-Schie syndrome, Hunter syndrome, St. Philippian syndrome, Mochio syndrome, Marshall-Lagerl syndrome, and Slay syndrome. Hyaluronidase deficiency, sialic acid deposition disease, I-cell disease, pseudo-Huler's malnutrition, phosphotransferase deficiency, mucoprotein 1 deficiency, San-Ha disease, Jan-Bi disease, B.-S.W. disease, Kuffs disease, Finnish variant neuronal ceroid lipofuscin deposition disease, late-infant variant neuronal ceroid lipofuscin deposition disease, type 7 neuronal ceroid lipofuscin deposition disease, northern epileptic neuronal ceroid lipofuscin deposition disease, Turkish late-infant neuronal ceroid lipofuscin deposition disease, German / Serbian late-infant neuronal ceroid lipofuscin deposition disease, congenital cathepsin D deficiency, Wollman's disease, α-mannoside deposition disease, β-mannoside deposition disease, aspartate glucosamineuria, and fucoside deposition disease. In some implementations, lysosomal storage diseases are selected from the group consisting of: Niemann-Pick disease, Gaucher's disease, and neuropathic Gaucher's disease.

36. Use of a compound as described in any one of claims 1-27, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as described in claim 28, for the treatment of a disease or condition at least partially mediated by TRPML1.

37. The compound of any one of claims 1-27 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer or a mixture of stereoisomers thereof, or the pharmaceutical composition of claim 28, for use in a therapy.

38. The compound of any one of claims 1-27 or a pharmaceutically acceptable salt thereof, an isotopically enriched analog thereof, a stereoisomer, a tautomer or a mixture of stereoisomers thereof, or the pharmaceutical composition of claim 28, for the treatment of a disease or condition at least partially mediated by TRPML1.

39. Use of any compound as claimed in any one of claims 1-27, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as claimed in claim 28, for the manufacture of an agent for treating at least partially TRPML1-mediated diseases or conditions.

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