Heterocyclic inhibitors of IGF-1r for treatment of disease

Abstract

To provide heterocyclic inhibitors of IGF-1R for the treatment of disease.SOLUTION: The present invention relates to heterocyclic compounds and methods which may be useful as IGF-1R inhibitors for the treatment or prevention of thyroid eye disease (TED), also known as thyroid-associated ophthalmopathy (TAO), or Graves' ophthalmopathy or Graves' orbitopathy (GO).SELECTED DRAWING: None

Description

[Technical Field]

[0001] Disclosed herein are novel heterocyclic compounds and compositions and their use in treating diseases or disorders, including, but not limited to, thyroid eye disease (TED). Methods of inhibiting insulin-like growth factor 1 receptor (IGF-1R) activity in mammals are also provided for treating diseases and disorders such as thyroid eye disease (TED), also known as thyroid-associated ophthalmopathy (TAO), or Graves' ophthalmopathy or Graves' orbitopathy (GO). [Background technology]

[0002] TED is typically associated with Graves' hyperthyroidism, but it can also occur as part of other autoimmune conditions that affect the thyroid gland and cause involvement of the orbit and periorbital tissues, and rarely the pretibial skin (pretibial myxedema) or fingers (thyroid clubbing). TED is an autoimmune ophthalmopathy that primarily affects the orbit and periocular soft tissues, secondarily affecting the eyes and vision. In TED, as a result of inflammation and enlargement of the orbital soft tissues, primarily the eye muscles and fat, the eyes are pushed forward (bulged) from the orbit—a phenomenon called proptosis or exophthalmos.

[0003] TED is generally considered to be the autoimmune orbital manifestation of Graves' disease (GD). However, only approximately 30% of patients with Graves' hyperthyroidism exhibit clinically relevant ocular pathology, indicating mechanistic heterogeneity and differences between these conditions. Although the molecular mechanism underlying TED is unknown, it is recognized that the generation of autoantibodies that act as agonists against the thyroid-stimulating hormone receptor (TSHR) is the cause of Graves' hyperthyroidism. Pathogenic overstimulation of the TSHR leads to overproduction of thyroid hormones (T3 and T4) and increased metabolism in many tissues.

[0004] Antibodies that activate the insulin-like growth factor 1 receptor (IGF-1R) have also been detected and are involved in active TED. Without being bound by any theory, it is believed that TSHR and IGF-1R form a physical and functional complex in orbital fibroblasts, and that blocking IGF-1R attenuates both IGF-1- and TSH-dependent signaling. It has been suggested that blocking IGF-1R activity reduces both TSHR- and IGF-1-dependent signaling, thereby potentially inhibiting the pathological activity of autoantibodies that act as agonists on either receptor.

[0005] IGF-1R is a widely expressed heterotetrameric protein involved in regulating growth and metabolic function in many cell types. It is a tyrosine kinase receptor containing two subunits: IGF-1Rα contains the ligand-binding domain, while IGF-1Rβ is involved in signal transduction and contains the tyrosine phosphorylation site.

[0006] Management of hyperthyroidism due to Graves' disease is incomplete due to the lack of therapies targeting the specific pathogenic autoimmune mechanisms underlying the disease. Treatment of moderately to severely active TED is even more complex. Despite recent advances in our understanding of the pathogenesis of TED, therapeutic challenges and dilemmas remain. Intravenous glucocorticoids (ivGCs) and oral glucocorticoids have been used to treat patients with moderately to severely active TED, but results have been largely unsatisfactory. Partial responses are frequent, and relapse (rebound) after drug discontinuation is not uncommon. Adverse events occur, and many patients ultimately require functional-restorative surgery, which is performed when the disease progresses to inactive TED. Teprotumumab, a fully human IGF-1R inhibitory monoclonal antibody, is the only treatment specifically approved for patients with active moderate to severe TED.

[0007] There is a need for novel therapeutic agents, particularly small molecules, that inhibit IGF-1R activity. Disclosed herein are novel IGF-1R inhibitory compounds, methods of synthesizing the compounds, and methods of using the compounds, including administering the compounds to treat IGF-1R-mediated diseases or disorders in a patient. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] US Patent Application Publication No. 2019 / 0225696A1 [Non-patent literature]

[0009] [Non-Patent Document 1] Pharmaceutical Salts: Properties, Selection, and Use(Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002) [Non-patent document 2] Hydrolysis in Drug and Prodrug Metabolism:Chemistry,Biochemistry,and Enzymology(Testa,Bernard and Mayer,Joachim M.Wiley-VHCA,Zurich,Switzerland 2003) [Non-patent document 3] Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins [Non-patent document 4] Werner, SC American Journal of Ophthalmology, 1969, 68, no. 4, 646-648 [Non-patent document 5] Werner, SC American Journal of Ophthalmology, 1977, 83, no. 5, 725-727 [Non-patent document 6] Mourits et al.,British Journal of Ophthalmology,1989,73,no.8,639-644 [Non-Patent Document 7] Mourits et al.,Clinical Endocrinology,1997.47,no.1,9-14 [Non-patent document 8] Dolman, PJ, and Rootman, J., Ophthalmic Plastic and Reconstructive Surgery, 2006, 22, no. 5, 319-324 [Non-Patent Document 9] Dolman,PJ,Best Practice & Research Clinical Endocrinology & Metabolism,2012,26,no.3,229-248 [Non-Patent Document 10] Bartalena, L., et al., European Journal of Endocrinology, 2008, 158, no. 3, 273-285 Summary of the Invention [Means for solving the problem]

[0010] The compounds disclosed herein inhibit IGF-1R activity.

[0011] In one aspect, provided herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, R 1is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, or unsubstituted or substituted bicyclic heteroaryl; R 1 If is substituted, R A and 1 to 3 R 5 is replaced by; R A is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted 5- or 6-membered heteroaryl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C3-C6 cycloalkenyl, an unsubstituted or substituted 3- to 6-membered heterocycloalkyl, a halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; Or, R A teeth, [ka] and; R A2 is halogen, —OH, —CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxyl, or C1-C4 hydroxyalkyl; m is 0, 1, 2, or 3; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 Is it; Or, R 1 teeth, [ka] and; X 1 is CR 6 , or N, Each R 6 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; Y 1 -O-, -NR 11 - or -SO2-; R 11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 and; R 12 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 7 and R 8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; Or R7 and R 8 together with the carbon atoms to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; Or R 9 and R 10 together with the carbon atom to which they are attached to form -C(=O)-; Or R 9 and R 10 together with the carbon atoms to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)N(R 22 )2, -C(=O)R 21 , -C(=O)OR 22 , or -S(=O)2R 21 and; X 2 is CR 17 , or N, Each R 17are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 13 and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 fluoroalkyl, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, or -OC(=O)R 21 Is it; Or, R 13 and R 14 together with the carbon atom to which they are attached to form -C(=O)-; Or, R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 - and; Each R 15 and R 16are independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; Or R 14 and one R on the adjacent carbon atom 16 come together to form an alkene bond; n is 1 or 2; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0012] In another aspect, provided herein is a compound of formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof, R A is unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C3-C6 cycloalkenyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, —CN, —SF5, or —SiMe3; Or, R A teeth [ka] and; R A2 is halogen, —OH, —CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxyl, or C1-C4 hydroxyalkyl; m is 0, 1, 2, or 3; X 3 and X 4 are each independently 5 , or N; R 3is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; X 2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and; R 19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; R 20 is hydrogen or -CH3; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0013] In another aspect, provided herein is a compound of formula (III): [ka] or a pharmaceutically acceptable salt or solvate thereof, X 1 is CR 6 , or N, Each R 6are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; Y 1 -O-, -NR 11 - or -SO2-; R 11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 and; R 12 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 7 and R 8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; Or, R 7 and R 8 together with the carbon atoms to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; Or, R 9 and R 10together with the carbon atom to which they are attached to form -C(=O)-; Or, R 9 and R 10 together with the carbon atoms to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; X 2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted C1-C6 alkenyl, an unsubstituted or substituted C1-C6 alkynyl, an unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and; R 19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; R 20 is hydrogen or -CH3; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0014] In another aspect, provided herein is a compound of formula (IV): [ka] or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted or substituted bicyclic heteroaryl; R 1 If is substituted, R A and 1 to 3 R 5 is replaced by; R A is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted 3- to 6-membered heterocycloalkyl, a halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -ORA1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; X 2 is CR 17 , or N, Each R 17are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and; R 19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; R 20 is hydrogen or -CH3; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0015] In another aspect, provided herein is a compound of formula (V): [ka] or a pharmaceutically acceptable salt or solvate thereof, R A is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted 3- to 6-membered heterocycloalkyl, a halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 5 is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21, -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; X 2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and; R 19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; R 20 is hydrogen or -CH3; Each R 21are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0016] In another aspect, provided herein is a compound of formula (VI): [ka] or a pharmaceutically acceptable salt or solvate thereof, R A is unsubstituted or substituted C1-C6 alkyl; X 3 and X 4 are each independently 5 or N; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R21 and; X 2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted C1-C6 alkenyl, or an unsubstituted or substituted C1-C6 alkynyl; Or, R 18 is substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl; Or, R 18 is unsubstituted or substituted C5-C 10 Is a bicyclic cycloalkyl; Or, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; Or, R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle); R 20 is hydrogen or -CH3; Each R 21are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0017] In another aspect, the present invention provides a compound of formula (VII): [ka] or a pharmaceutically acceptable salt or solvate thereof, R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; X 3 and X 4 are each independently 5 or N; R 2 teeth, [ka] and; R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)N(R 22 )2, -C(=O)R 21 , -C(=O)OR 22 , or -S(=O)2R 21 and; X 2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 13 and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 fluoroalkyl, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, or -OC(=O)R 21 Is it; Or R 13 and R 14 together with the carbon atom to which they are attached to form -C(=O)-; Or R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 - and; Each R 15 and R 16 are independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; Or R 14 and one R on the adjacent carbon atom 16 come together to form an alkene bond; n is 1 or 2; Or, R 2 teeth, [ka] and; X 2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is a substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted C1-C6 alkenyl, or an unsubstituted or substituted C1-C6 alkynyl; Or R 18 is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or substituted cyclohexyl; Or R 18 is unsubstituted or substituted C5-C 10 Is a bicyclic cycloalkyl; Or R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; Or R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle); R 20 is hydrogen or -CH3; R 3is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0018] In another aspect, provided herein is a compound of formula (VIII): [ka] or a pharmaceutically acceptable salt or solvate thereof, R A is -SCF3, -S(=O)CF3, or -S(=O)2CF3; R 3is a C2-C6 alkyl that is unsubstituted or substituted with -OH, phenyl, benzyl, C3-C6 cycloalkyl, or -CH2OH; R 4 is hydrogen or methyl; Or, R 3 and R 4 together with the carbon atom to which they are attached form a cyclobutyl, cyclopentyl, or cyclohexyl group. is described.

[0019] In another aspect, provided herein is a compound of formula (IX): [ka] or a pharmaceutically acceptable salt or solvate thereof, R A -SR A1 , -S(=O)R A1 , or -S(=O)2R A1 and; R A1 is C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl; R 18 is a C1-C6 alkyl substituted with -CN, -OH, or -OMe; Or, R 18 is unsubstituted or substituted C1-C6 fluoroalkyl or unsubstituted or substituted C1-C6 heteroalkyl; Or, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; Or, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), or -CHR 20 -(unsubstituted or substituted 5-membered heteroaryl); R 20 is hydrogen or -CH3; Or, R 18 is -C(=O)R 19 and R 19 is an unsubstituted or substituted 3-10 membered heterocycloalkyl; Or, R 18 is -C(=O)NHR 19 and R 19 is unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0020] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, transdermal administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.

[0021] In any of the foregoing aspects, there are further embodiments in which an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered by injection to a mammal; and / or (e) administered topically to a mammal; and / or (f) administered by ocular administration; and / or (g) administered non-systemically or topically to a mammal.

[0022] In any of the above aspects, there are further embodiments comprising a single administration of an effective amount of the compound, for example, the compound is administered to the mammal once daily, or the compound is administered to the mammal multiple times throughout the day. In some embodiments, the compound is administered according to a continuous administration schedule. In some embodiments, the compound is administered according to a continuous daily administration schedule.

[0023] In any of the embodiments disclosed herein, the mammal is a human.

[0024] In some embodiments, the compounds provided herein are administered orally to a human.

[0025] Also described herein, in some embodiments, are compounds described herein, or pharmaceutically acceptable salts or solvates thereof, for use as pharmaceuticals.

[0026] Also described herein, in some embodiments, are compounds described herein, or pharmaceutically acceptable salts or solvates thereof, for use in treating a mammalian disease or condition that would benefit from modulation of the insulin-like growth factor 1 receptor (IGF-1R). In some embodiments, the disease or condition is dependent on IGF-1R activity. In some embodiments, the disease or condition is IGF-1R-mediated. In some embodiments, the disease or condition is selected from thyroid-associated ophthalmopathy (TAO) or thyroid eye disease (TED), also known as Graves' ophthalmopathy or Graves' orbitopathy (GO). In some embodiments, the disease or condition is thyroid eye disease (TED).

[0027] Also described herein, in some embodiments, is a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by inhibition of IGF-1R.

[0028] Also described herein, in some embodiments, are methods for inhibiting IGF-1R, comprising contacting IGF-1R with a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0029] Also described herein, in some embodiments, are methods for treating an IGF-1R-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease or condition is selected from thyroid-associated ophthalmopathy (TAO) or thyroid eye disease (TED), also known as Graves' ophthalmopathy or Graves' orbitopathy (GO). In some embodiments, the disease or condition is thyroid eye disease (TED).

[0030] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from the detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0031] The compounds disclosed herein have IGF-1R inhibitory activity. In some embodiments, the compounds disclosed herein are useful for treating diseases or disorders in which inhibition of IGF-1R activity is desired. Also provided is the use of certain compounds disclosed herein for the manufacture of a medicament for treating a disease or condition that is ameliorated by IGF-1R inhibition.

[0032] compound Disclosed herein are compounds that inhibit IGF-1R activity. In some embodiments, the IGF-1R inhibitors described herein are useful for treating diseases or disorders in which IGF-1R activity is significantly affected or that would benefit from inhibition of IGF-1R activity.

[0033] In one aspect, the present invention provides a compound of formula (A): [ka] or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, or unsubstituted or substituted bicyclic heteroaryl; R 1 If is substituted, R A and 1 to 3 R 5 is replaced by; R Ais an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted 5- or 6-membered heteroaryl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C3-C6 cycloalkenyl, an unsubstituted or substituted 3- to 6-membered heterocycloalkyl, a halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; Or, R A teeth, [ka] and; R A2 is halogen, —OH, —CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxyl, or C1-C4 hydroxyalkyl; m is 0, 1, 2, or 3; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 Is it; Or, R 1 teeth, [ka] and X 1 is CR 6 , or N, Each R 6 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; Y 1 -O-, -NR 11 - or -SO2-; R 11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 and; R 12 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 7 and R 8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; Or R 7 and R 8 together with the carbon atoms to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl; R 9 and R10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; Or R 9 and R 10 together with the carbon atom to which they are attached to form -C(=O)-; Or R 9 and R 10 together with the carbon atoms to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl; R 2 teeth, [ka] and; R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)N(R 22 )2, -C(=O)R 21 , -C(=O)OR 22 , or -S(=O)2R 21 and; X 2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 13 and R 14are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 fluoroalkyl, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, or -OC(=O)R 21 Is it; Or R 13 and R 14 together with the carbon atom to which they are attached to form -C(=O)-; Or R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 - and; Each R 15 and R 16 are independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; Or R 14 and one R on the adjacent carbon atom 16 come together to form an alkene bond; n is 1 or 2; Or, R 2 teeth, [ka] and; R 18is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and; R 19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl; R 20 is hydrogen or -CH3; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0034] In any and all embodiments, the substituents are selected from among a subset of the listed options. For example, in some embodiments, R 4 is hydrogen or C1-C6 alkyl. In some embodiments, R 4 is hydrogen or C1-C4 alkyl. In some embodiments, R 4 is hydrogen or methyl. In some embodiments, R 4 is methyl. In another embodiment, R 4 is hydrogen.

[0035] In some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; in some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, or unsubstituted or substituted C3-C6 cycloalkyl. 3 is unsubstituted or substituted C1-C6 alkyl, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is C1-C6 alkyl that is unsubstituted or substituted with —OH, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —CHOH. 3 is unsubstituted or C2-C6 alkyl substituted with -OH, phenyl, benzyl, or C3-C6 cycloalkyl, or -CH2OH.3 is ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —CH 2 OH.

[0036] In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0037] In some embodiments, R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0038] In some embodiments, R 1 is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, or unsubstituted or substituted bicyclic heteroaryl; R 1 If is substituted, R A and 1 to 3 R 5 In some embodiments, R 1 is unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic heteroaryl; R 1 If is substituted, R A and 1 to 3 R 5 In some embodiments, R 1 is unsubstituted or substituted bicyclic heteroaryl; R1 If is substituted, R A and 1 to 3 R 5 is replaced by .

[0039] In some embodiments, R 1 teeth, [ka] is.

[0040] In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 In some embodiments, each R 5 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R5 is hydrogen.

[0041] In some embodiments, R 1 teeth, [ka] (In the formula, X 3 and X 4 are each independently 5 or N; each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 In some embodiments, X 3 and X 4 are CR 5 and each R 5 is hydrogen.

[0042] In some embodiments, R A is C1-C6 alkyl, C1-C6 fluoroalkyl, halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 -SF5 or -SiMe3; R A1 is C1-C4 alkyl or C1-C4 fluoroalkyl; or R A teeth, [ka] and;R A2 is halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl; and m is 1. In some embodiments, R A is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -F, -Cl, -Br, -CN, -SCF3, -S(=O)CF3, -S(=O)2CF3, -S(=O)2CHF2, -S(=O)2C(CH3)3, -S(=O)2-(cyclopropyl), -SF5, or -SiMe3; or R Ateeth, [ka] is.

[0043] In some embodiments, R A is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted 5- or 6-membered heteroaryl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C3-C6 cycloalkenyl, an unsubstituted or substituted 3- to 6-membered heterocycloalkyl, a halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -SF5, or -SiMe3.

[0044] In some embodiments, R A teeth, [ka] and;R A2 is halogen, —OH, —CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxyl, or C1-C4 hydroxyalkyl; and m is 0, 1, 2, or 3.

[0045] In some embodiments, R A is unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C3-C6 cycloalkenyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, —CN, —SF5, or —SiMe3.

[0046] In some embodiments, R Ais an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted 3- to 6-membered heterocycloalkyl, a halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , —SF5, or —SiMe3.

[0047] In some embodiments, R A is unsubstituted or substituted C1-C6 alkyl.

[0048] In some embodiments, R A -SR A1 , -S(=O)R A1 , or -S(=O)2R A1 and;R A1 is C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl. A is —SCF, —S(═O)CF, —S(═O)CF, —S(═O)CHF, —S(═O)C(CH), or —S(═O)-(cyclopropyl). A is -SCF3, -S(=O)CF3, or -S(=O)2CF3.

[0049] In some embodiments, R 1 teeth, [ka] is.

[0050] In some embodiments, X 1 is CR 6 or N. In some embodiments, X 1 is CR 6 In some embodiments, X 1 is N.

[0051] In some embodiments, Y 1-O-, -NR 11 - or -SO2-. In some embodiments, Y 1 is -O- or -NR 11 In some embodiments, Y 1 is —O—. In some embodiments, Y 1 is -NR 11 In some embodiments, Y 1 is -SO2-.

[0052] In some embodiments, R 11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 In some embodiments, R 11 is hydrogen or C1-C6 alkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 is.

[0053] In some embodiments, R 12 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl. 12 is unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R 12 is C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 12 is C1-C6 alkyl. In some embodiments, R 12 is a C3-C6 cycloalkyl.

[0054] In some embodiments, each R 6are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 6 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 6 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 6 is independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments, each R 6 is hydrogen.

[0055] In some embodiments, R 7 and R 8are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy. 7 and R 8 are each independently hydrogen, —OH, or C1-C6 alkyl. 7 and R 8 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 7 and R 8 are each independently hydrogen or methyl.

[0056] In some embodiments, R 7 and R 8 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl. In some embodiments, R 7 and R 8 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R 7 and R 8 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl. In some embodiments, R 7 and R 8 taken together with the carbon atom to which they are attached form a 3- to 6-membered heterocycloalkyl. In some embodiments, R 7 and R 8 together with the carbon atom to which they are attached form a 3- or 4-membered heterocycloalkyl.

[0057] In some embodiments, R 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy. 9 and R 10are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 9 and R 10 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 9 and R 10 are each independently hydrogen or methyl.

[0058] In some embodiments, R 9 and R 10 together with the carbon atom to which they are attached to form -C(=O)-.

[0059] In some embodiments, R 9 and R 10 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl. In some embodiments, R 9 and R 10 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R 9 and R 10 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl. In some embodiments, R 9 and R 10 together with the carbon atoms to which they are attached form a 3- to 6-membered heterocycloalkyl. In some embodiments, R 9 and R 10 together with the carbon atom to which they are attached form a 3- or 4-membered heterocycloalkyl.

[0060] In some embodiments, R 1 teeth, [ka] and X 1 is CR 6or N; each R 6 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 is.

[0061] In some embodiments, Y 1 is -NR 11 - and;R 11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 and;R 12 is unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C3-C6 cycloalkyl.

[0062] In some embodiments, R 7 and R 8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; or R 7 and R 8 together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; or R 9 and R 10 together with the carbon atom to which they are attached form -C(=O)-; or R 9 and R 10together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl.

[0063] In some embodiments, R 2 teeth, [ka] is.

[0064] In some embodiments, R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)N(R 22 )2, -C(=O)R 21 , -C(=O)OR 22 , or -S(=O)2R 21 In some embodiments, R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)N(R 22 )2, -C(=O)R 21 , or C(=O)OR 22 In some embodiments, R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or -C(=O)OR 22 In some embodiments, R c is hydrogen, C1-C6 alkyl, or -C(=O)OR 22 In some embodiments, R c is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. c is hydrogen or C1-C6 alkyl. In some embodiments, R c is hydrogen.

[0065] In some embodiments, X 2 is CR 17 or N. In some embodiments, X 2 is CR 17 In some embodiments, X 2 is N.

[0066] In some embodiments, Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 In some embodiments, Y 2 is -(CR 15 R 16 ) n - and n is 1 or 2. In some embodiments, Y 2 is -(CR 15 R 16 )-, or -(CR 15 R 16 )-(CR 15 R 16 In some embodiments, Y 2 is —O—. In some embodiments, Y 2 -O-CR 15 R 16 -It is.

[0067] In some embodiments, R 13 and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 fluoroalkyl, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, or -OC(=O)R 21 In some embodiments, R 13 and R 14 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl. 13 and R 14 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 13 and R 14 are hydrogen atoms.

[0068] In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached to form -C(=O)-.

[0069] In some embodiments, R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a C-C cycloalkyl. In some embodiments, R 13 and R 14 taken together with the carbon atom to which they are attached form a 3- to 6-membered heterocycloalkyl. In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a 3- or 4-membered heterocycloalkyl.

[0070] In some embodiments, each R 15 and R 16 is independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl. 15 and R 16 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl. 15 and R 16 is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl.15 and R 16 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R 15 and R 16 is hydrogen.

[0071] In some embodiments, R 14 and one R on the adjacent carbon atom 16 together form an alkene bond.

[0072] In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 17 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 17 is hydrogen.

[0073] In some embodiments, R c is hydrogen, C1-C6 alkyl, or -C(=O)OR 22 and X 2 is CR 17 and each R 17 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 13 and R 14 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; or R 13 and R 14 together with the carbon atom to which they are attached form -C(=O)-; or R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C4 cycloalkyl; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 - and each R 15 and R 16 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; or R 14 and one R on the adjacent carbon atom 16 together form an alkene bond.

[0074] In some embodiments, R cis hydrogen; X 2 is CR 17 and each R 17 is hydrogen; R 13 and R 14 are each hydrogen; or R 13 and R 14 together with the carbon atom to which they are attached to form -C(=O)-; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 In some embodiments, each R 15 and R 16 are independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl.

[0075] In some embodiments, [ka] teeth, [ka] and;Y 2 -CR 15 R 16 - or -CR 15 R 16 -CR 15 R 16 In some embodiments, [ka] teeth, [ka] is.

[0076] In some embodiments, R 14 and one R on the adjacent carbon atom 16 together form an alkene bond.

[0077] In some embodiments, R 2 teeth, [ka] is.

[0078] In some embodiments, X 2 is CR 17 or N. In some embodiments, X 2 is CR 17 In some embodiments, X 2 is N.

[0079] In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R17 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 17 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 17 is hydrogen.

[0080] In some embodiments, X 2 is CR 17 and each R 17 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl.

[0081] In some embodiments, X 2 is CR 17 and each R 17 is hydrogen.

[0082] In some embodiments, R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 is.

[0083] In some embodiments, R 18is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl. 18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, or unsubstituted or substituted C1-C6 heteroalkyl. 18 is C1-C6 alkyl substituted with -CN, -OH, or -OMe. 18 is hydrogen.

[0084] In some embodiments, R 18 is an unsubstituted or substituted carbocycle, or an unsubstituted or substituted heterocycle. 18 is unsubstituted or substituted C3-C 10 In some embodiments, R is cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. 18 is an unsubstituted or substituted C3-C6 monocyclic cycloalkyl, an unsubstituted or substituted C5-C 10 In some embodiments, R is a bicyclic cycloalkyl, or an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl. 18 is an unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; or R 18 is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0085] In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle). In some embodiments, R 18 is -CHR 20-(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl; R 20 is hydrogen or -CH3.

[0086] In some embodiments, R 18 is -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and;R 19 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl.

[0087] In some embodiments, R 18 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted C1-C6 alkenyl, an unsubstituted or substituted C1-C6 alkynyl, an unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 is.

[0088] In some embodiments, R 18 is unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl. In some embodiments, R 18 is an unsubstituted or substituted C3-C6 monocyclic cycloalkyl, an unsubstituted or substituted C5-C 10In some embodiments, R is a bicyclic cycloalkyl, or an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl. 18 is an unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; or R 18 is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0089] In some embodiments, R 18 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl; or R 18 is substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl; or R 18 is unsubstituted or substituted C5-C 10 bicyclic cycloalkyl; or R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; or R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle); R 20 is hydrogen or -CH3.

[0090] In some embodiments, R 18 is substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl.

[0091] In some embodiments, R 18 is unsubstituted or substituted C5-C 10 In some embodiments, R 18is a C5-C bridged, fused, or spirocyclic cycloalkyl 10 It is cycloalkyl.

[0092] In some embodiments, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom. In some embodiments, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom, which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0093] In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle). In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl; R 20 is hydrogen or -CH3.

[0094] In some embodiments, R 18 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl; or R 18 is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or substituted cyclohexyl; or R 18 is unsubstituted or substituted C5-C 10 bicyclic cycloalkyl; or R 18is an unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl; or R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle); R 20 is hydrogen or -CH3.

[0095] In some embodiments, R 18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl; in some embodiments, R 18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, or unsubstituted or substituted C1-C6 heteroalkyl. 18 is a C1-C6 alkyl substituted with -CN, -OH, or -OMe.

[0096] In some embodiments, R 18 is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or substituted cyclohexyl.

[0097] In some embodiments, R 18 is an unsubstituted or substituted C5-C heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl 10 It is a bicyclic cycloalkyl.

[0098] In some embodiments, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl.

[0099] In some embodiments, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom.

[0100] In some embodiments, R 18 is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0101] In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl); R 20 is hydrogen or -CH3.

[0102] In some embodiments, each R 21 is independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In some embodiments, each R 21 is independently an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C3-C6 cycloalkyl, or an unsubstituted or substituted 3-6 membered heterocycloalkyl. 21 is independently C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl. 21 is independently C1-C6 alkyl or C3-C6 cycloalkyl. In some embodiments, each R 21 is independently C1 to C6 alkyl.

[0103] In some embodiments, each R 22are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 taken together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl. In some embodiments, each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocycloalkyl; or two R on the same N atom 22 taken together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl. In some embodiments, each R 22 are independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; or two R on the same N atom 22 are taken together with the N atom to which they are attached to form an N-containing heterocycloalkyl. In some embodiments, each R 22 are independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; or two R on the same N atom 22 are taken together with the N atom to which they are attached to form an N-containing heterocycloalkyl. In some embodiments, each R 22 are independently hydrogen or C1-C6 alkyl; or two R on the same N atom 22 taken together with the N atom to which they are attached form an N-containing heterocycloalkyl.

[0104] In some embodiments, each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23In some embodiments, the R groups, taken together with the N atom to which they are attached, form a 3- to 6-membered N-containing heterocycloalkyl. 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; or two R 23 In some embodiments, the R groups, taken together with the N atom to which they are attached, form a 3- to 6-membered N-containing heterocycloalkyl. 23 are independently selected from hydrogen and C1-C6 alkyl; or two R 23 The groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl.

[0105] In some embodiments, each R 24 is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. 24 is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl. 24 are independently selected from C1 to C6 alkyl.

[0106] In some embodiments, there are provided herein compounds of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, or unsubstituted or substituted bicyclic heteroaryl; R 1 If is substituted, R A and 1 to 3 R 5 is replaced by; R Ais an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted 5- or 6-membered heteroaryl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted C3-C6 cycloalkenyl, an unsubstituted or substituted 3- to 6-membered heterocycloalkyl, a halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; Or R A teeth, [ka] and; R A2 is halogen, —OH, —CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxyl, or C1-C4 hydroxyalkyl; m is 0, 1, 2, or 3; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 Is it; Or, R 1 teeth, [ka] and; X 1 is CR 6 , or N, Each R 6 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; Y 1 -O-, -NR 11 - or -SO2-; R 11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 and; R 12 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 7 and R 8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; Or R 7 and R 8 together with the carbon atoms to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl; R 9 and R 10are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; Or R 9 and R 10 together with the carbon atom to which they are attached to form -C(=O)-; Or R 9 and R 10 together with the carbon atoms to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)N(R 22 )2, -C(=O)R 21 , -C(=O)OR 22 , or -S(=O)2R 21 and; X 2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 13 and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 fluoroalkyl, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, or -OC(=O)R 21 Is it; Or, R 13 and R 14 together with the carbon atom to which they are attached to form -C(=O)-; Or, R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 - and; Each R 15 and R 16 are independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; Or R 14 and one R on the adjacent carbon atom 16 come together to form an alkene bond; n is 1 or 2; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0107] In some embodiments, R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)N(R 22 )2, -C(=O)R 21 , -C(=O)OR 22 , or -S(=O)2R 21 In some embodiments, R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)N(R 22 )2, -C(=O)R 21 , or -C(=O)OR 22 In some embodiments, R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or -C(=O)OR 22 In some embodiments, R c is hydrogen, C1-C6 alkyl, or -C(=O)OR 22 In some embodiments, R c is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. c is hydrogen or C1-C6 alkyl. In some embodiments, R c is hydrogen.

[0108] In some embodiments, X 2 is CR 17 or N. In some embodiments, X 2 is CR 17 In some embodiments, X 2 is N.

[0109] In some embodiments, Y 2 is -(CR 15 R 16 ) n-, -O-, or -O-CR 15 R 16 In some embodiments, Y 2 is -(CR 15 R 16 ) n - and n is 1 or 2. In some embodiments, Y 2 is -(CR 15 R 16 )-, or -(CR 15 R 16 )-(CR 15 R 16 In some embodiments, Y 2 is —O—. In some embodiments, Y 2 -O-CR 15 R 16 -It is.

[0110] In some embodiments, R 13 and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 fluoroalkyl, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, or -OC(=O)R 21 In some embodiments, R 13 and R 14 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl. 13 and R 14 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 13 and R 14 are hydrogen atoms.

[0111] In some embodiments, R 13 and R 14together with the carbon atom to which they are attached to form -C(=O)-.

[0112] In some embodiments, R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a C-C cycloalkyl. In some embodiments, R 13 and R 14 taken together with the carbon atom to which they are attached form a 3- to 6-membered heterocycloalkyl. In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a 3- or 4-membered heterocycloalkyl.

[0113] In some embodiments, each R 15 and R 16 is independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl. 15 and R 16 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl. 15 and R 16 is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl. 15 and R 16 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R15 and R 16 is hydrogen.

[0114] In some embodiments, R 14 and one R on the adjacent carbon atom 16 together form an alkene bond.

[0115] In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22)2. In some embodiments, each R 17 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 17 is hydrogen.

[0116] In some embodiments, R c is hydrogen, C1-C6 alkyl, or -C(=O)OR 22 and X 2 is CR 17 and each R 17 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 13 and R 14 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; or R 13 and R 14 together with the carbon atom to which they are attached form -C(=O)-; or R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C4 cycloalkyl; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 - and each R 15 and R 16 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; or R 14 and one R on the adjacent carbon atom 16 together form an alkene bond.

[0117] In some embodiments, R c is hydrogen; X 2 is CR 17 and each R 17 is hydrogen; R 13 and R 14are each hydrogen; or R 13 and R 14 together with the carbon atom to which they are attached to form -C(=O)-; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 In some embodiments, each R 15 and R 16 are independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl.

[0118] In some embodiments, [ka] teeth, [ka] and;Y 2 -CR 15 R 16 - or -CR 15 R 16 -CR 15 R 16 In some embodiments, [ka] teeth, [ka] is.

[0119] In some embodiments, R 14 and one R on the adjacent carbon atom 16 together form an alkene bond.

[0120] In some embodiments, R 3is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl. In some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, or unsubstituted or substituted C3-C6 cycloalkyl. 3 is unsubstituted or substituted C1-C6 alkyl, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is C1-C6 alkyl that is unsubstituted or substituted with —OH, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —CH 2 OH.

[0121] In some embodiments, R 4 is hydrogen or C1-C6 alkyl. In some embodiments, R 4 is hydrogen or C1-C4 alkyl. In some embodiments, R 4 is hydrogen or methyl.

[0122] In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 3and R 4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0123] In some embodiments, R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0124] In some embodiments, R 1 is unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic heteroaryl; R 1 If is substituted, R A and 1 to 3 R 5 is replaced by .

[0125] In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -N(R22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 In some embodiments, each R 5 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R 5 is hydrogen.

[0126] In some embodiments, R 1 teeth, [ka] (In the formula, X 3 and X 4 are each independently 5 or N; each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 In some embodiments, X 3 and X 4 are CR 5 and each R 5 is hydrogen.

[0127] In some embodiments, R A is C1-C6 alkyl, C1-C6 fluoroalkyl, halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -SF5, or -SiMe3; R A1 is C1-C4 alkyl or C1-C4 fluoroalkyl; or R A teeth, [ka] and;R A2is halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl; and m is 1. In some embodiments, R A is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -F, -Cl, -Br, -CN, -SCF3, -S(=O)CF3, -S(=O)2CF3, -S(=O)2CHF2, -S(=O)2C(CH3)3, -S(=O)2-(cyclopropyl), -SF5, or -SiMe3; or R A teeth, [ka] is.

[0128] In some embodiments, R 1 teeth, [ka] is.

[0129] In some embodiments, X 1 is CR 6 or N. In some embodiments, X 1 is CR 6 In some embodiments, X 1 is N.

[0130] In some embodiments, Y 1 -O-, -NR 11 - or -SO2-. In some embodiments, Y 1 is -O- or -NR 11 In some embodiments, Y 1 is —O—. In some embodiments, Y 1 is -NR 11 In some embodiments, Y 1 is -SO2-.

[0131] In some embodiments, R 11is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 In some embodiments, R 11 is hydrogen or C1-C6 alkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 is.

[0132] In some embodiments, R 12 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl. 12 is unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R 12 is C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 12 is C1-C6 alkyl. In some embodiments, R 12 is a C3-C6 cycloalkyl.

[0133] In some embodiments, each R 6 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21In some embodiments, each R 6 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 6 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 6 is independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments, each R 6 is hydrogen.

[0134] In some embodiments, R 7 and R 8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy. 7 and R 8 are each independently hydrogen, —OH, or C1-C6 alkyl. 7 and R 8 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 7 and R 8 are each independently hydrogen or methyl.

[0135] In some embodiments, R 7 and R 8are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl. In some embodiments, R 7 and R 8 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R 7 and R 8 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl. In some embodiments, R 7 and R 8 taken together with the carbon atom to which they are attached form a 3- to 6-membered heterocycloalkyl. In some embodiments, R 7 and R 8 together with the carbon atom to which they are attached form a 3- or 4-membered heterocycloalkyl.

[0136] In some embodiments, R 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy. 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 9 and R 10 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 9 and R 10 are each independently hydrogen or methyl.

[0137] In some embodiments, R 9 and R 10 together with the carbon atom to which they are attached to form -C(=O)-.

[0138] In some embodiments, R 9 and R10 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl. In some embodiments, R 9 and R 10 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R 9 and R 10 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl. In some embodiments, R 9 and R 10 together with the carbon atoms to which they are attached form a 3- to 6-membered heterocycloalkyl. In some embodiments, R 9 and R 10 together with the carbon atom to which they are attached form a 3- or 4-membered heterocycloalkyl.

[0139] In some embodiments, R 1 teeth, [ka] and X 1 is CR 6 or N; each R 6 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 is.

[0140] In some embodiments, Y 1 is -NR11 - and;R 11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 and;R 12 is unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C3-C6 cycloalkyl.

[0141] In some embodiments, R 7 and R 8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; or R 7 and R 8 together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; or R 9 and R 10 together with the carbon atom to which they are attached form -C(=O)-; or R 9 and R 10 together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl.

[0142] In some embodiments, the compounds of formula (II) are provided herein: [ka] or a pharmaceutically acceptable salt or solvate thereof, R A is unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C3-C6 cycloalkenyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, —CN, —SF5, or —SiMe3; Or, R A teeth, [ka] and; R A2 is halogen, —OH, —CN, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, or C1-C4 hydroxyalkyl; m is 0, 1, 2, or 3; X 3 and X 4 are each independently 5 , or N; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22S(=O)2R 21 and; X 2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and; R 19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl; R 20 is hydrogen or -CH3; Each R 21are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 or C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0143] In some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl. In some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, or unsubstituted or substituted C3-C6 cycloalkyl. 3 is unsubstituted or substituted C1-C6 alkyl, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is C1-C6 alkyl that is unsubstituted or substituted with —OH, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —CH 2 OH.

[0144] In some embodiments, R 4 is hydrogen or C1-C6 alkyl. In some embodiments, R 4 is hydrogen or C1-C4 alkyl. In some embodiments, R 4 is hydrogen or methyl.

[0145] In some embodiments, R 3 and R 4together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0146] In some embodiments, R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0147] In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -N(R22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 In some embodiments, each R 5 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R 5 is hydrogen.

[0148] In some embodiments, each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 is.

[0149] In some embodiments, X 3 and X 4 are CR 5 and each R 5 is hydrogen.

[0150] In some embodiments, R A is C1-C4 fluoroalkyl, halogen, —CN, —SF5, or —SiMe3; or R A teeth, [ka] and;R A2 is halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl; and m is 1.

[0151] In some embodiments, R A is —CF3, —F, —Cl, —Br, —CN, —SCF3, —SF5, or —SiMe3; or R A teeth, [ka] is.

[0152] In some embodiments, X 2 is CR 17 or N. In some embodiments, X 2 is CR 17 In some embodiments, X 2 is N.

[0153] In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22)2, or -C(=O)N(R 22 )2. In some embodiments, each R 17 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 17 is hydrogen.

[0154] In some embodiments, X 2 is CR 17 and each R 17 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. In some embodiments, X 2 is CR 17 and each R 17 is hydrogen.

[0155] In some embodiments, R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 is.

[0156] In some embodiments, R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl. 18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, or unsubstituted or substituted C1-C6 heteroalkyl. 18is a C1-C6 alkyl substituted with -CN, -OH, or -OMe. 18 is hydrogen.

[0157] In some embodiments, R 18 is an unsubstituted or substituted carbocycle, or an unsubstituted or substituted heterocycle. 18 is unsubstituted or substituted C3-C 10 In some embodiments, R is cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. 18 is an unsubstituted or substituted C3-C6 monocyclic cycloalkyl, an unsubstituted or substituted C5-C 10 In some embodiments, R is a bicyclic cycloalkyl, or an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl. 18 is an unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; or R 18 is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0158] In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle). In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl; R 20 is hydrogen or -CH3.

[0159] In some embodiments, R18 is -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and;R 19 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl.

[0160] In some embodiments, there are provided herein compounds of formula (III): [ka] or a pharmaceutically acceptable salt or solvate thereof, X 1 is CR 6 , or N, Each R 6 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 Is it; Y 1 -O-, -NR 11 - or -SO2-; R 11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 and; R 12is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 7 and R 8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; Or, R 7 and R 8 together with the carbon atoms to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; Or, R 9 and R 10 together with the carbon atom to which they are attached to form -C(=O)-; Or, R 9 and R 10 together with the carbon atoms to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; X 2 is CR 17, or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted C1-C6 alkenyl, an unsubstituted or substituted C1-C6 alkynyl, an unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and; R 19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; R 20 is hydrogen or -CH3; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0161] In some embodiments, R 3is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; in some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, or unsubstituted or substituted C3-C6 cycloalkyl. 3 is unsubstituted or substituted C1-C6 alkyl, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is C1-C6 alkyl that is unsubstituted or substituted with —OH, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —CH 2 OH.

[0162] In some embodiments, R 4 is hydrogen or C1-C6 alkyl. In some embodiments, R 4 is hydrogen or C1-C4 alkyl. In some embodiments, R 4 is hydrogen or methyl.

[0163] In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 3and R 4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0164] In some embodiments, R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0165] In some embodiments, X 1 is CR 6 or N. In some embodiments, X 1 is CR 6 In some embodiments, X 1 is N.

[0166] In some embodiments, Y 1 -O-, -NR 11 - or -SO2-. In some embodiments, Y 1 is -O- or -NR 11 In some embodiments, Y 1 is —O—. In some embodiments, Y 1 is -NR 11 In some embodiments, Y 1 is -SO2-.

[0167] In some embodiments, R 11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 In some embodiments, R 11 is hydrogen or C1-C6 alkyl. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is -C(=O)NH2, -C(=O)R 12, or -S(=O)2R 12 is.

[0168] In some embodiments, R 12 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl. 12 is unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R 12 is C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 12 is C1-C6 alkyl. In some embodiments, R 12 is a C3-C6 cycloalkyl.

[0169] In some embodiments, each R 6 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 6 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 6 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 6 is independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments, each R 6 is hydrogen.

[0170] In some embodiments, R 7 and R 8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy. 7 and R 8 are each independently hydrogen, —OH, or C1-C6 alkyl. 7 and R 8 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 7 and R 8 are each independently hydrogen or methyl.

[0171] In some embodiments, R 7 and R 8 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl. In some embodiments, R 7 and R 8 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R 7 and R 8taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl. In some embodiments, R 7 and R 8 taken together with the carbon atom to which they are attached form a 3- to 6-membered heterocycloalkyl. In some embodiments, R 7 and R 8 together with the carbon atom to which they are attached form a 3- or 4-membered heterocycloalkyl.

[0172] In some embodiments, R 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy. 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 9 and R 10 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 9 and R 10 are each independently hydrogen or methyl.

[0173] In some embodiments, R 9 and R 10 together with the carbon atom to which they are attached to form -C(=O)-.

[0174] In some embodiments, R 9 and R 10 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted C3-C6 cycloalkyl or an unsubstituted or substituted 3-6 membered heterocycloalkyl. In some embodiments, R 9 and R 10 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C6 cycloalkyl. In some embodiments, R 9 and R10 taken together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl. In some embodiments, R 9 and R 10 together with the carbon atoms to which they are attached form a 3- to 6-membered heterocycloalkyl. In some embodiments, R 9 and R 10 together with the carbon atom to which they are attached form a 3- or 4-membered heterocycloalkyl.

[0175] In some embodiments, R 1 teeth, [ka] and X 1 is CR 6 or N; each R 6 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 is.

[0176] In some embodiments, Y 1 is -NR 11 - and;R 11 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)NH2, -C(=O)R 12 , or -S(=O)2R 12 and;R 12 is unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted C3-C6 cycloalkyl.

[0177] In some embodiments, R 7 and R 8 are each independently hydrogen, —OH, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; or R 7 and R 8 together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy; or R 9 and R 10 together with the carbon atom to which they are attached form -C(=O)-; or R 9 and R 10 together with the carbon atom to which they are attached form an unsubstituted or substituted C3-C4 cycloalkyl.

[0178] In some embodiments, X 2 is CR 17 or N. In some embodiments, X 2 is CR 17 In some embodiments, X 2 is N.

[0179] In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 17 is independently hydrogen, halogen, C-C alkyl, or C-C fluoroalkyl. 17 is hydrogen.

[0180] In some embodiments, X 2 is CR 17 and each R 17 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl.

[0181] In some embodiments, X 2 is CR 17 and each R 17 is hydrogen.

[0182] In some embodiments, R 18is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted C1-C6 alkenyl, an unsubstituted or substituted C1-C6 alkynyl, an unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 is.

[0183] In some embodiments, R 18 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl; in some embodiments, R 18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, or unsubstituted or substituted C1-C6 heteroalkyl. 18 is a C1-C6 alkyl substituted with -CN, -OH, or -OMe.

[0184] In some embodiments, R 18 is unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl. In some embodiments, R 18 is an unsubstituted or substituted C3-C6 monocyclic cycloalkyl, an unsubstituted or substituted C5-C 10 In some embodiments, R is a bicyclic cycloalkyl, or an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl. 18 is an unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; or R 18is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0185] In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle). In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl; R 20 is hydrogen or -CH3.

[0186] In some embodiments, R 18 is -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and;R 19 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl.

[0187] In some embodiments, the compounds of formula (IV) are described herein: [ka] or a pharmaceutically acceptable salt or solvate thereof, R 1 is unsubstituted or substituted bicyclic heteroaryl; R 1 If is substituted, R A and 1 to 3 R 5 is replaced by; R Ais an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted 3- to 6-membered heterocycloalkyl, a halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 Is it; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; X2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and; R 19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; R 20 is hydrogen or -CH3; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0188] In some embodiments, R 3is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; in some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, or unsubstituted or substituted C3-C6 cycloalkyl. 3 is unsubstituted or substituted C1-C6 alkyl, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is C1-C6 alkyl that is unsubstituted or substituted with —OH, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —CH 2 OH.

[0189] In some embodiments, R 4 is hydrogen or C1-C6 alkyl. In some embodiments, R 4 is hydrogen or C1-C4 alkyl. In some embodiments, R 4 is hydrogen or methyl.

[0190] In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 3and R 4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0191] In some embodiments, R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0192] In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 In some embodiments, each R5 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R 5 is hydrogen.

[0193] In some embodiments, R A is C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl. A is C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl.

[0194] In some embodiments, R A is C1 to C4 alkyl, C1 to C4 fluoroalkyl, or C3 to C6 cycloalkyl. In some embodiments, R A is C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , -SF5, or -SiMe3; R A1is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 is.

[0195] In some embodiments, R A is C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl; each R 5 is independently halogen or C1 to C6 alkyl.

[0196] In some embodiments, X 2 is CR 17 or N. In some embodiments, X 2 is CR 17 In some embodiments, X 2 is N.

[0197] In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 17 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 17 is hydrogen.

[0198] In some embodiments, X 2 is CR 17 and each R 17 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl.

[0199] In some embodiments, X 2 is CR 17 and each R 17 is hydrogen.

[0200] In some embodiments, R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R19 , or -C(=O)NHR 19 is.

[0201] In some embodiments, R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl; in some embodiments, R 18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, or unsubstituted or substituted C1-C6 heteroalkyl. 18 is a C1-C6 alkyl substituted with -CN, -OH, or -OMe. 18 is hydrogen.

[0202] In some embodiments, R 18 is an unsubstituted or substituted carbocycle, or an unsubstituted or substituted heterocycle. 18 is unsubstituted or substituted C3-C 10 In some embodiments, R is cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. 18 is an unsubstituted or substituted C3-C6 monocyclic cycloalkyl, an unsubstituted or substituted C5-C 10 In some embodiments, R is a bicyclic cycloalkyl, or an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl. 18 is an unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; or R 18 is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0203] In some embodiments, R 18 is -CHR 20-(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle). In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl; R 20 is hydrogen or -CH3.

[0204] In some embodiments, R 18 is -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and;R 19 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl.

[0205] In some embodiments, X 2 is CR 17 and each R 17 is hydrogen.

[0206] In some embodiments, R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl; or R 18 is a substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl; or R 18 is C1-C6 alkyl substituted with -CN, -OH, or -OMe; or R 18 is unsubstituted or substituted C3-C 10cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or R 18 is an unsubstituted or substituted C3-C6 monocyclic cycloalkyl, an unsubstituted or substituted C5-C 10 bicyclic cycloalkyl, or unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl; or R 18 is an unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; or R 18 is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl that is a bridged, fused, or spirocyclic heterocycloalkyl; or R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl); R 20 is hydrogen or -CH3; or R 18 is -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and;R 19 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, unsubstituted or substituted cycloalkyl and 3-10 membered heterocycloalkyl.

[0207] In some embodiments, the compounds of formula (V) are described herein: [ka] or a pharmaceutically acceptable salt or solvate thereof, R Ais an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C3-C6 cycloalkyl, an unsubstituted or substituted 3- to 6-membered heterocycloalkyl, a halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 5 is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 Is it; X 2is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and; R 19 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; R 20 is hydrogen or -CH3; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0208] In some embodiments, R 3is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; in some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, or unsubstituted or substituted C3-C6 cycloalkyl. 3 is unsubstituted or substituted C1-C6 alkyl, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is C1-C6 alkyl that is unsubstituted or substituted with —OH, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —CH 2 OH.

[0209] In some embodiments, R 4 is hydrogen or C1-C6 alkyl. In some embodiments, R 4 is hydrogen or C1-C4 alkyl. In some embodiments, R 4 is hydrogen or methyl.

[0210] In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 3and R 4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0211] In some embodiments, R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0212] In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 In some embodiments, each R5 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R 5 is hydrogen.

[0213] In some embodiments, R A is C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl. A is C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl. A is C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl. A is C1-C4 alkyl. In some embodiments, R A is isopropyl or t-butyl. In some embodiments, R A is isopropyl. In some embodiments, R A is t-butyl.

[0214] In some embodiments, R Ais C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR A1 , -S(=O)R A1 , -S(=O)2R A1 , -OR A1 , -SF5, or -SiMe3; R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 In some embodiments, R A is C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl; each R 5 is independently halogen or C1 to C6 alkyl.

[0215] In some embodiments, X 2 is CR 17 or N. In some embodiments, X 2 is CR 17 In some embodiments, X 2 is N.

[0216] In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 17 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 17 is hydrogen.

[0217] In some embodiments, X 2 is CR 17 and each R 17 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl.

[0218] In some embodiments, X 2 is CR 17 and each R 17 is hydrogen.

[0219] In some embodiments, R 18is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR 20 -(unsubstituted or substituted carbocyclic ring), -CHR 20 -(unsubstituted or substituted heterocycle), -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 is.

[0220] In some embodiments, R 18 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl. 18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, or unsubstituted or substituted C1-C6 heteroalkyl. 18 is a C1-C6 alkyl substituted with -CN, -OH, or -OMe. 18 is hydrogen.

[0221] In some embodiments, R 18 is an unsubstituted or substituted carbocycle, or an unsubstituted or substituted heterocycle. 18 is unsubstituted or substituted C3-C 10 In some embodiments, R is cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. 18 is an unsubstituted or substituted C3-C6 monocyclic cycloalkyl, an unsubstituted or substituted C5-C 10 In some embodiments, R is a bicyclic cycloalkyl, or an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl.18 is an unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; or R 18 is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0222] In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle). In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl; R 20 is hydrogen or -CH3.

[0223] In some embodiments, R 18 is -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and;R 19 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl.

[0224] In some embodiments, X 2 is CR 17 and each R 17 is hydrogen.

[0225] In some embodiments, R 18is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl; or R 18 is a substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl; or R 18 is C1-C6 alkyl substituted with -CN, -OH, or -OMe; or R 18 is unsubstituted or substituted C3-C 10 cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or R 18 is an unsubstituted or substituted C3-C6 monocyclic cycloalkyl, an unsubstituted or substituted C5-C 10 bicyclic cycloalkyl, or unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl; or R 18 is an unsubstituted or substituted 3- to 10-membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; or R 18 is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl that is a bridged, fused, or spirocyclic heterocycloalkyl; or R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl); R 20 is hydrogen or -CH3; or R 18 is -C(=O)R 19 , -CO2R 19 , or -C(=O)NHR 19 and;R 19 is unsubstituted or substituted C1-C6 or unsubstituted or substituted, C3-C 10cycloalkyl, unsubstituted or substituted cycloalkyl and 3-10 membered heterocycloalkyl.

[0226] In some embodiments, the compounds of formula (VI) are described herein: [ka] or a pharmaceutically acceptable salt or solvate thereof, R A is unsubstituted or substituted C1-C6 alkyl; X 3 and X 4 are each independently 5 , or N; R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; X 2 is CR17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl; Or, R 18 is substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl; Or, R 18 is unsubstituted or substituted C5-C 10 Is a bicyclic cycloalkyl; Or, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; Or, R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle); R 20 is hydrogen or -CH3; Each R 21are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0227] In some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl. In some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, or unsubstituted or substituted C3-C6 cycloalkyl. 3 is unsubstituted or substituted C1-C6 alkyl, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is C1-C6 alkyl that is unsubstituted or substituted with —OH, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —CH 2 OH.

[0228] In some embodiments, R 4 is hydrogen or C1-C6 alkyl. In some embodiments, R 4 is hydrogen or C1-C4 alkyl. In some embodiments, R 4 is hydrogen or methyl.

[0229] In some embodiments, R 3 and R 4together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0230] In some embodiments, R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0231] In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 In some embodiments, each R 5 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R 5 is hydrogen.

[0232] In some embodiments, X 3 and X 4 are CR 5 and each R 5 is hydrogen.

[0233] In some embodiments, R A is C1-C4 alkyl. In some embodiments, R A is isopropyl or t-butyl. In some embodiments, R A is isopropyl. In some embodiments, R A is t-butyl.

[0234] In some embodiments, X 2 is CR 17 or N. In some embodiments, X 2 is CR 17 In some embodiments, X 2 is N.

[0235] In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 17 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 17 is hydrogen.

[0236] In some embodiments, X 2 is CR 17 and each R 17 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl.

[0237] In some embodiments, R 18 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl; in some embodiments, R 18 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, or unsubstituted or substituted C1-C6 alkynyl. 18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, or unsubstituted or substituted C1-C6 heteroalkyl.18 is a C1-C6 alkyl substituted with -CN, -OH, or -OMe.

[0238] In some embodiments, R 18 is substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl.

[0239] In some embodiments, R 18 is unsubstituted or substituted C5-C 10 In some embodiments, R 18 is a C5-C bridged, fused, or spirocyclic cycloalkyl 10 It is cycloalkyl.

[0240] In some embodiments, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom. In some embodiments, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom, which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0241] In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle). In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl; R 20 is hydrogen or -CH3.

[0242] In some embodiments, the compounds of formula (VII) are provided herein: [ka] or a pharmaceutically acceptable salt or solvate thereof, R A1 is C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; X 3 and X 4 are each independently 5 , or N; R 2 teeth, [ka] and; R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)N(R 22 )2, -C(=O)R 21 , -C(=O)OR 22 , or -S(=O)2R 21 and; X 2 is CR 17 , or N, Each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 13and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 fluoroalkyl, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, or -OC(=O)R 21 Is it; Or R 13 and R 14 together with the carbon atom to which they are attached to form -C(=O)-; Or R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 - and; Each R 15 and R 16 are independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; Or R 14 and one R on the adjacent carbon atom 16 come together to form an alkene bond; n is 1 or 2; Or, R 2 teeth, [ka] and; X 2 is CR 17 , or N, Each R 17are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; R 18 is a substituted C1-C6 alkyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted C1-C6 alkenyl, or an unsubstituted or substituted C1-C6 alkynyl; Or R 18 is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or substituted cyclohexyl; Or R 18 is unsubstituted or substituted C5-C 10 Is a bicyclic cycloalkyl; Or R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; Or, R 18 is -CHR 20 -(unsubstituted or substituted carbocycle), or -CHR 20 -(unsubstituted or substituted heterocycle); R 20 is hydrogen or -CH3; R 3is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R 4 is hydrogen or C1-C6 alkyl; Or, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; Each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 and; Each R 21 are independently unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R 22 are independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R on the same N atom 22 together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0243] In some embodiments, R 3 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; in some embodiments, R 3is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, or unsubstituted or substituted C3-C6 cycloalkyl. 3 is unsubstituted or substituted C1-C6 alkyl, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is C1-C6 alkyl that is unsubstituted or substituted with —OH, phenyl, benzyl, or C3-C6 cycloalkyl. In some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —CH 2 OH.

[0244] In some embodiments, R 4 is hydrogen or C1-C6 alkyl. In some embodiments, R 4 is hydrogen or C1-C4 alkyl. In some embodiments, R 4 is hydrogen or methyl.

[0245] In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0246] In some embodiments, R 3 is C1-C6 alkyl, and R 4 is C1-C6 alkyl; or R3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl.

[0247] In some embodiments, each R 5 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 5 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR 21 In some embodiments, each R 5 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R 5 is hydrogen.

[0248] In some embodiments, X 3 and X 4 are CR 5 and each R 5 is hydrogen.

[0249] In some embodiments, R A1 is -(C1-C4 alkyl, or C1-C4 fluoroalkyl). In some embodiments, R A1 is C1-C4 fluoroalkyl. In some embodiments, R A1 is -CF3.

[0250] In some embodiments, R 2 teeth, [ka] is.

[0251] In some embodiments, R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -C(=O)N(R 22 )2, -C(=O)R 21 , -C(=O)OR 22 , or -S(=O)2R 21 In some embodiments, R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl-C(=O)N(R 22 )2, -C(=O)R 21 , or -C(=O)OR 22 In some embodiments, R c is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or -C(=O)OR 22 In some embodiments, R c is hydrogen, C1-C6 alkyl, or -C(=O)OR 22 In some embodiments, R c is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. c is hydrogen or C1-C6 alkyl. In some embodiments, R c is hydrogen.

[0252] In some embodiments, X 2 is CR 17 or N. In some embodiments, X 2 is CR 17 In some embodiments, X 2 is N.

[0253] In some embodiments, Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 In some embodiments, Y 2is -(CR 15 R 16 ) n - and n is 1 or 2. In some embodiments, Y 2 is -(CR 15 R 16 )-, or -(CR 15 R 16 )-(CR 15 R 16 In some embodiments, Y 2 is —O—. In some embodiments, Y 2 -O-CR 15 R 16 -It is.

[0254] In some embodiments, R 13 and R 14 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 fluoroalkyl, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, or -OC(=O)R 21 In some embodiments, R 13 and R 14 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl. 13 and R 14 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 13 and R 14 are hydrogen atoms.

[0255] In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached to form -C(=O)-.

[0256] In some embodiments, R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl. In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a C-C cycloalkyl. In some embodiments, R 13 and R 14 taken together with the carbon atom to which they are attached form a 3- to 6-membered heterocycloalkyl. In some embodiments, R 13 and R 14 together with the carbon atom to which they are attached form a 3- or 4-membered heterocycloalkyl.

[0257] In some embodiments, each R 15 and R 16 is independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, phenyl, monocyclic heteroaryl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl. 15 and R 16 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl. 15 and R 16 is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl. 15 and R 16 is independently hydrogen or C1-C6 alkyl. In some embodiments, each R 15 and R 16 is hydrogen.

[0258] In some embodiments, R 14 and one R on the adjacent carbon atom 16 together form an alkene bond.

[0259] In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22 )2. In some embodiments, each R 17is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 17 is hydrogen.

[0260] In some embodiments, R c is hydrogen, C1-C6 alkyl, or -C(=O)OR 22 and X 2 is CR 17 and each R 17 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 13 and R 14 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl; or, alternatively, R 13 and R 14 together with the carbon atom to which they are attached form -C(=O)-; or R 13 and R 14 together with the carbon atoms to which they are attached form a C3-C4 cycloalkyl; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 - and each R 15 and R 16 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; or R 14 and one R on the adjacent carbon atom 16 together form an alkene bond.

[0261] In some embodiments, R c is hydrogen; X 2 is CR 17 and each R 17 is hydrogen; R 13 and R 14 are each hydrogen; or R 13 and R14 together with the carbon atom to which they are attached to form -C(=O)-; Y 2 is -(CR 15 R 16 ) n -, -O-, or -O-CR 15 R 16 In some embodiments, each R 15 and R 16 are independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl.

[0262] In some embodiments, [ka] teeth, [ka] and;Y 2 -CR 15 R 16 - or -CR 15 R 16 -CR 15 R 16 In some embodiments, [ka] teeth, [ka] is.

[0263] In some embodiments, R 14 and one R on the adjacent carbon atom 16 together form an alkene bond.

[0264] In some embodiments, R 2 teeth, [ka] is.

[0265] In some embodiments, X 2 is CR 17 or N. In some embodiments, X 2 is CR 17 In some embodiments, X 2 is N.

[0266] In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR 21 , -CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , ~CO2R 22 , -N(R 22 )2, -C(=O)N(R 22 )2, -OC(=O)R 21 , -NR 22 C(=O)R 21 , -S(=O)2N(R 22 )2, or -NR 22 S(=O)2R 21 In some embodiments, each R 17 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 21 , -N(R 22 )2, or -C(=O)N(R 22)2. In some embodiments, each R 17 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. 17 is hydrogen.

[0267] In some embodiments, X 2 is CR 17 and each R 17 are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 fluoroalkyl.

[0268] In some embodiments, R 18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C1-C6 alkenyl, unsubstituted or substituted C1-C6 alkynyl; in some embodiments, R 18 is substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, or unsubstituted or substituted C1-C6 heteroalkyl. 18 is a C1-C6 alkyl substituted with -CN, -OH, or -OMe.

[0269] In some embodiments, R 18 is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or substituted cyclohexyl.

[0270] In some embodiments, R 18 is an unsubstituted or substituted C5-C heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl 10 It is a bicyclic cycloalkyl.

[0271] In some embodiments, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl.

[0272] In some embodiments, R18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom.

[0273] In some embodiments, R 18 is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0274] In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR 20 -(unsubstituted or substituted phenyl), or -CHR 20 -(unsubstituted or substituted 5- or 6-membered heteroaryl; R 20 is hydrogen or -CH3.

[0275] In some embodiments, the compounds of formula (VIII) are provided herein: [ka] or a pharmaceutically acceptable salt or solvate thereof, R A is -SCF3, -S(=O)CF3, or -S(=O)2CF3; R 3 is a C2-C6 alkyl that is unsubstituted or substituted with -OH, phenyl, benzyl, C3-C6 cycloalkyl, or -CH2OH; R 4 is hydrogen or methyl; Or, R 3 and R 4 together with the carbon atom to which they are attached form a cyclobutyl, cyclopentyl, or cyclohexyl group. is described.

[0276] In some embodiments, R Ais —SCF or —S(═O)CF. In some embodiments, R A is -SCF3. In some embodiments, R A is —S(═O)CF. In some embodiments, R A is -S(=O)2CF3.

[0277] In some embodiments, R 3 is a C2-C6 alkyl group unsubstituted or substituted by -OH, phenyl, benzyl, C3-C6 cycloalkyl, or -CH2OH; R 4 is hydrogen or methyl. In some embodiments, R 3 is ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or —CHOH; R 4 is hydrogen or methyl.

[0278] In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form cyclobutyl, cyclopentyl, or cyclohexyl.

[0279] In some embodiments, the compounds of formula (IX) are described herein: [ka] or a pharmaceutically acceptable salt or solvate thereof, R A -SR A1 , -S(=O)R A1 , or -S(=O)2R A1 and; R A1 is C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl; R 18 is a C1-C6 alkyl substituted with -CN, -OH, or -OMe; Or, R 18 is unsubstituted or substituted C1-C6 fluoroalkyl or unsubstituted or substituted C1-C6 heteroalkyl; Or, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; Or, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), or -CHR 20 -(unsubstituted or substituted 5-membered heteroaryl); R 20 is hydrogen or -CH3; Or, R 18 is -C(=O)R 19 and R 19 is an unsubstituted or substituted 3-10 membered heterocycloalkyl; Or, R 18 is -C(=O)NHR 19 and R 19 is unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl is selected from halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR 23 , -CO2R 23 , -C(=O)N(R 23 )2, -N(R 23 )2, -NR 23 C(=O)R 24 , -SR 23 , -S(=O)R 24 , -SO2R 24 , or -SO2N(R 23 ) one or more R independently selected from the group consisting of s substituted with a group; Each R 23 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 23 groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R 24 are independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. is described.

[0280] In some embodiments, R A -SR A1 , or -S(=O)2R A1 In some embodiments, R A -SR A1 In some embodiments, R A is -S(=O)R A1 In some embodiments, R A is -S(=O)2R A1 is.

[0281] In some embodiments, R A1 is C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl. A1 is C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R A1 is C1-C4 fluoroalkyl. In some embodiments, R A1 is -CF3, -CHF2, -C(CH3)3, or -(cyclopropyl).

[0282] In some embodiments, R A is —SCF3, —S(═O)CF3, —S(═O)2CF3, —S(═O)2CHF2, —S(═O)2C(CH3)3, or —S(═O)2-(cyclopropyl).

[0283] In some embodiments, R 18 is a C1-C6 alkyl substituted with -CN, -OH, or -OMe.

[0284] In some embodiments, R 18 is unsubstituted or substituted C1-C6 fluoroalkyl, or unsubstituted or substituted C1-C6 heteroalkyl.

[0285] In some embodiments, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl.

[0286] In some embodiments, R 18 is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom.

[0287] In some embodiments, R 18 is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl.

[0288] In some embodiments, R 18 is -CHR 20 -(unsubstituted or substituted C3-C6 cycloalkyl), -CHR 20 -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), or -CHR 20 -(unsubstituted or substituted 5-membered heteroaryl); R 20 is hydrogen or -CH3.

[0289] In some embodiments, R 18 is -C(=O)R 19 and R 19 is an unsubstituted or substituted 3-10 membered heterocycloalkyl;

[0290] In some embodiments, R 18 is -C(=O)NHR 19and R 19 is unsubstituted or substituted C3-C 10 cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl.

[0291] Additionally, any of the above embodiments can be combined with any one or more of these embodiments, provided the combinations are not mutually exclusive.

[0292] As used herein, two embodiments are "mutually exclusive" if one is defined as being different from the other. For example, an embodiment in which two groups are bonded to form a cycloalkyl is mutually exclusive from an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is CH2 is mutually exclusive from an embodiment in which the same group is NH.

[0293] That is, any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0294] Exemplary compounds of the present invention include those set forth in the table below.

[0295] [Table 1]

[0296] [Table 2]

[0297] [Table 3]

[0298] [Table 4]

[0299]

Table 5

[0300]

Table 6

[0301]

Table 7

[0302]

Table 8

[0303]

Table 9

[0304]

Table 10

[0305]

Table 11

[0306]

Table 12

[0307]

Table 13

[0308]

Table 14

[0309] [Table 15]

[0310] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound listed in Table 1.

[0311] [Table 16]

[0312] [Table 17]

[0313] [Table 18]

[0314] [Table 19]

[0315] [Table 20]

[0316] [Table 21]

[0317] [Table 22]

[0318] [Table 23]

[0319] [Table 24]

[0320] Table 25

[0321] Table 26

[0322] Table 27

[0323] Table 28

[0324] Table 29

[0325] Table 30

[0326] Table 31

[0327] Table 32

[0328]

Table 33

[0329] Table 34

[0330] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound listed in Table 2.

[0331] [Table 35]

[0332] [Table 36]

[0333] [Table 37]

[0334] [Table 38]

[0335] [Table 39]

[0336] [Table 40]

[0337] [Table 41]

[0338] [Table 42]

[0339] [Table 43]

[0340] [Table 44]

[0341] [Table 45]

[0342] [Table 46]

[0343] [Table 47]

[0344] [Table 48]

[0345] [Table 49]

[0346] [Table 50]

[0347] [Table 51]

[0348] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound listed in Table 3.

[0349] [Table 52]

[0350] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound listed in Table 4.

[0351] [Table 53]

[0352] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound listed in Table 5.

[0353] [Table 54]

[0354] [Table 55]

[0355] [Table 56]

[0356] [Table 57]

[0357] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound listed in Table 6.

[0358] [Table 58]

[0359] [Table 59]

[0360] [Table 60]

[0361] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound listed in Table 7.

[0362] [Table 61]

[0363] [Table 62]

[0364] [Table 63]

[0365] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound listed in Table 8.

[0366] [Table 64]

[0367] [Table 65]

[0368] [Table 66]

[0369] [Table 67]

[0370] [Table 68]

[0371] [Table 69]

[0372] [Table 70]

[0373] [Table 71]

[0374] [Table 72]

[0375] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound listed in Table 9.

[0376] [Table 73]

[0377] [Table 74]

[0378] [Table 75]

[0379] [Table 76]

[0380] [Table 77]

[0381] [Table 78]

[0382] [Table 79]

[0383] [Table 80]

[0384] [Table 81]

[0385] [Table 82]

[0386] [Table 83]

[0387] [Table 84]

[0388] [Table 85]

[0389] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound listed in Table 10.

[0390] Also provided herein is a compound selected from the examples disclosed herein.

[0391] Further forms of the compound The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes the compounds listed above in the form of salts, including acid addition salts. Suitable salts include salts formed with both organic and inorganic acids. Such acid addition salts are usually pharmaceutically acceptable. However, salts that are not pharmaceutically acceptable may be useful in the preparation and purification of the compound in question. Basic addition salts may also be formed and may be pharmaceutically acceptable. For more detailed information on the preparation and selection of salts, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0392] The term "therapeutically acceptable salt," as defined herein, refers to a salt or zwitterionic form of a compound disclosed herein that is soluble or dispersible in water or oil and therapeutically acceptable, as defined herein. Salts can be prepared during the final isolation and purification of the compound, or separately, by reacting the free base form of the appropriate compound with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, gulurate, glycerophosphate, glycolate, hemisulfate, heptanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, and malonate. , DL-mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthylenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalate, pamoate, pectinic acid, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Additionally, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination of a compound with an alkali metal or alkaline earth ion. Thus, the present invention contemplates sodium, potassium, magnesium, calcium, and other salts of the compounds disclosed herein.

[0393] Base addition salts can be prepared during the final isolation and purification of the compound by reacting a carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0394] Salts of compounds can be made by reacting the free base form of the appropriate compound with a suitable acid.

[0395] The term "prodrug" refers to a compound that becomes more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the compounds. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment.

[0396] definition As used herein, the following terms have the meanings indicated below.

[0397] When a range of values ​​is disclosed and the notation "from n1 to n2" or "between n1 and n2" is used, where n1 and n2 are numbers, unless otherwise specified, this notation is intended to include the numbers themselves and the range therebetween. The range may be integer or continuous, between and including the end values. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. As an example, comparing the range "1 to 3 μM (micromolar)," this is intended to include 1 μM, 3 μM, and everything in between, to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0398] The term "about," as used herein, is intended to qualify the numerical value that it modifies and to indicate that such value may vary within a certain range. When a specific range is not recited, such as the error or standard deviation for the mean value shown in a chart or table of data, the term "about" should be understood to mean the greater of a range that includes the stated value, a range that is included when rounded up or down to that numerical value taking into account significant digits, and a range that includes the stated value plus or minus 20%.

[0399] The term "acyl," as used herein, refers to the group -C(=O)-R, where R is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom bonded to the carbonyl is carbon. An "acetyl" group refers to a -C(=O)CH group.

[0400] The term "alkenyl," as used herein, refers to a straight- or branched-chain hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, an alkenyl contains 2 to 6 carbon atoms. The term "alkenylene" refers to a divalent alkenyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0401] The term "alkoxy" refers to a (alkyl)-O group, where alkyl is as defined herein. In some embodiments, the alkoxy group is C1-C6, which refers to a (C1-C6 alkyl)-O group. Examples of alkyl groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0402] An "alkyl" group refers to an aliphatic hydrocarbon group. In some embodiments, an alkyl is a straight- or branched-chain aliphatic hydrocarbon group containing 1 to 20 carbon atoms. In certain embodiments, an alkyl comprises 1 to 10 carbon atoms. In further embodiments, an alkyl comprises 1 to 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, nonyl, and the like. In some embodiments, an alkyl is a C1-C6 alkyl. In one aspect, an alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. The term "alkylene" refers to a divalent alkyl, such as methylene (-CH2-). In some embodiments, an alkylene is a C1-C6 alkylene. In other embodiments, an alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0403] The term "amino" as used herein refers to -NRR ’ (where R and R ’ are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may together form a heterocycloalkyl, any of which may be optionally substituted. In one aspect, "amino," as used herein, refers to the group --NH.

[0404] The term "alkylthio," as used herein, refers to an alkylthioether (RS-) group, where the term alkyl is as defined above and sulfur may be singly or doubly oxidized. Examples of suitable alkylthioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like. In some embodiments, the term "alkylthio" refers to an -S-(alkyl) group. In some embodiments, the alkylthio group is a C1-C6 alkylthio, which refers to an -S-(C1-C6 alkyl) group.

[0405] The term "alkynyl," as used herein, refers to a straight- or branched-chain hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkynyl contains 2 to 6 carbon atoms. In further embodiments, the alkynyl contains 2 to 4 carbon atoms. In one embodiment, an alkynyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH, -C≡CCHCH, and -CHC≡CH. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene (-C≡C-). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, etc. Unless otherwise specified, the term "alkynyl" can include "alkynylene" groups.

[0406] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons (where n is an integer). The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0407] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, this term distinguishes carbocyclic from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0408] The term "aryl" as used herein refers to a carbocyclic aromatic system containing one, two, or three rings; such polycyclic ring systems are fused together. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C6-C8. 10 Aryl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0409] The term "aryloxy," as used herein, refers to an aryl group attached to the parent molecular moiety through an oxy. In some embodiments, aryloxy, as used herein, refers to an aryl-O- group. In some embodiments, aryloxy is a phenoxy or a phenyl-O- group.

[0410] The terms "benzo" and "benz," as used herein, refer to a fused bicyclic or polycyclic ring system formed with benzene as one of the rings. Examples include benzofuran, benzothiophene, and benzimidazole.

[0411] The term "cycloalkyl," as used herein, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, each ring moiety containing 3 to 12 carbon atom ring members, and may be a benzo-fused ring system, which may be optionally substituted as defined herein. In some embodiments, cycloalkyl groups include groups having 3 to 10 ring atoms. In certain embodiments, the cycloalkyl groups contain 5 to 7 carbon atoms. In certain embodiments, the cycloalkyl groups contain 3 to 6 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic" and "tricyclic" are intended to include fused ring systems, e.g., decahydronaphthalene, octahydronaphthalene, and polycyclic (multi-center) saturated or partially unsaturated types. Examples of the latter type of isomer include, in general, bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane. In some embodiments, cycloalkyl is C3-C6 cycloalkyl. In some embodiments, cycloalkyl is C3-C4 cycloalkyl.

[0412] The term "heterocycle" or "heterocyclic" refers to heteroaromatic (also known as heteroaryl) and heterocycloalkyl rings containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyl) include rings having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithia nyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolidinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, indolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups may be C-linked or N-linked where possible. For example, groups derived from pyrrole include both pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0413] The term "heteroaryl" or "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the term "heteroaryl," as used herein, refers to a 3- to 15-membered unsaturated heteromonocyclic ring or a fused monocyclic, bicyclic, or tricyclic ring system, in which at least one of the fused rings is aromatic and contains at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl contains 1 to 4 heteroatoms as ring members. In further embodiments, the heteroaryl contains 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl contains 5 to 7 carbon atoms. The term also encompasses fused polycyclic groups in which a heterocyclic ring is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzoindolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like. In some embodiments, heteroaryl contains 0 to 4 N atoms in the ring. In some embodiments, heteroaryl contains 1 to 4 N atoms in the ring.In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl is a C1-C9 heteroaryl. In some embodiments, a monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl.

[0414] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the term "heterocycloalkyl," as used herein, refers to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic), monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, respectively, where each heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl contains 1 to 4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl contains 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl contains 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl contains 3 to 7 ring members in each ring. In still further embodiments, the heterocycloalkyl contains 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of a tertiary nitrogen ring member, and carbocyclic and benzo-fused ring systems; in addition, both terms also include systems in which a heterocycle is fused to an aryl group, as defined herein, or to an additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Heterocyclic groups may be optionally substituted unless specifically prohibited. In one aspect, heterocycloalkyl is a C2-C 10 In another embodiment, heterocycloalkyl is a C4-C 10Heterocycloalkyl. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and has a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and has a 3-, 4-, 5-, or 6-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and has a 3- or 4-membered ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0415] The term "carbamate," as used herein, refers to an ester of carbamic acid (-NHCOO-), which may be attached to the parent molecular moiety through the nitrogen or acid terminus, and which may be optionally substituted as defined herein.

[0416] The terms "carboxyl" or "carboxy", as used herein, refer to -C(=O)OH or the corresponding "carboxylate" anion, for example, as in a carboxylic acid salt.

[0417] The term "cyano," as used herein, refers to --CN.

[0418] The term "halo" or "halogen," as used herein, refers to fluorine, chlorine, bromine, or iodine. In some embodiments, halo is fluoro, chloro, or bromo.

[0419] The term "haloalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with halogen. Specifically, monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups are included. Monohaloalkyl groups can have, for example, iodo, bromo, chloro, or fluoro atoms within the group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl group. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), and the like. In one aspect, haloalkyl is C1-C6 haloalkyl. In another aspect, haloalkyl is C1-C4 haloalkyl.

[0420] The term "haloalkoxy," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. In one aspect, a haloalkoxy is a C1-C6 haloalkoxy, which refers to a (C1-C6 haloalkyl)-O group. In another aspect, a haloalkoxy is a C1-C4 haloalkoxy, which refers to a (C1-C4 haloalkyl)-O group.

[0421] The term "heteroalkyl" refers to an alkyl in which one or more carbon atoms have been replaced with a heteroatom. In some embodiments, "heteroalkyl" refers to an alkyl in which one or more carbon atoms have been replaced with one or more heteroatoms independently selected from NH, -N(alkyl), O, S, S(=O), and S(=O). The bond of the heteroatom to the remainder of the compound is at a carbon atom of the heteroalkyl. In some embodiments, up to two heteroatoms can be consecutive, such as, for example, -CH-NH-OCH. In some embodiments, a "heteroalkyl" is an "alkoxyalkyl," "alkylthioalkyl," or "alkylaminoalkyl." An "alkoxyalkyl" refers to an alkyl in which one hydrogen atom has been replaced with an alkoxy group, as defined herein. In some embodiments, an alkoxyalkyl is a (C-C alkoxy)-C-C alkyl. Typical alkoxyalkyl groups include, but are not limited to, -CHOCH, -CHCHOCH, -CHCHCHOCH, -CHCHCHOCH, -CHCHCHCHOCH, -CHOCHCH, -CHCHOCHCH, -CHCHCHOCHCH, -CHCHCHCHOCHCH, and the like. "Alkylthioalkyl" refers to an alkyl in which one hydrogen atom is replaced by an alkylthio group, as defined herein. In some embodiments, the alkylthioalkyl is (C-C alkylthio)-C-C alkyl. Typical alkylthioalkyl groups include, but are not limited to, -CHSCH, -CHCHSCH, -CHCHCHSCH, -CHCHCHCHSCH, -CHSCHCH, -CHCHSCHCH, -CHCHSCHCH, -CHCHCHSCHCH, -CHCHCHCHSCHCH, and the like. "Alkylaminoalkyl" refers to an alkyl in which one hydrogen atom is replaced by an alkylamino group, as defined herein. In some embodiments, the alkylaminoalkyl is (C-C alkylamino)-C-C alkyl.Typical alkylaminoalkyl groups include, but are not limited to, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2CH2NHCH3, -CH2NHCH2CH3, -CH2CH2NHCH2CH3, -CH2CH2CH2NHCH2CH3, -CH2CH2CH2CH2NHCH2CH3, -CH2CH2CH2CH2NHCH2CH3, and the like.

[0422] The term "hydroxy" or "hydroxyl," as used herein, refers to --OH.

[0423] The term "hydroxyalkyl," as used herein, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group. In some embodiments, the hydroxyalkyl is a C1-C4 hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0424] The term "isocyanato" refers to an --NCO group.

[0425] The term "isothiocyanato" refers to the group --NCS.

[0426] The phrase "linear chain of atoms" refers to the longest linear chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0427] The term "nitro," as used herein, refers to --NO.sub.2.

[0428] The term "oxo" as used herein refers to =O.

[0429] The term "sulfanyl" as used herein refers to --S--.

[0430] The term "sulfinyl" as used herein refers to -S(=O)-.

[0431] The term "sulfonyl," as used herein, refers to a -S(=O)2-, -S(=O)2R, or -S(=O)2R- group, where R is as defined herein.

[0432] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, any last element of such a definition is the element that connects to the parent moiety. For example, the composite group alkylamido represents an alkyl group connected to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group connected to the parent molecule via an alkyl group.

[0433] When a group is defined to be "null," what is meant is that said group is absent.

[0434] In some embodiments, the term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more further groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=0)NH, -C(=0)NH(alkyl), -C(=0)N(alkyl), -S(=0)NH, -S(=0)NH(alkyl), -S(=0)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylthio. In some other embodiments, the optional substituents are independently selected from halogen, —CN, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, and —S(═O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CHF, -CF, -OCH, -OCHF, and -OCF. In some embodiments, substituents are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0435] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It is understood that the present invention encompasses all stereochemical isomers, e.g., diastereomeric, enantiomeric, and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be prepared by synthesis from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation, such as conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers by chiral chromatographic columns, or any other suitable method known in the art. Starting compounds of particular stereochemistry are commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusermen (Z) isomers, as well as the appropriate mixtures thereof. Furthermore, compounds may exist as tautomers, with all tautomers being provided by the present invention.

[0436] Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0437] The term "bond" refers to a covalent bond between two atoms or two moieties, when the atoms joined by the bond are considered to be part of a larger substructure. The bond may be a single, double, or triple bond, unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may or may not be present at that position.

[0438] As used herein, the term "disease" or "disorder" refers to a condition that impairs the normal functioning of the body, for example, a malfunction or dysfunction that impairs normal functioning.

[0439] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a condition or disorder described in this disclosure.

[0440] "IGF-1R inhibitor" as used herein refers to an inhibitor of an IGF-1R that exhibits an IC50 or IC60 inhibitor of an IGF-1R activity as measured by an IGF-1R assay as generally described herein. 50 "IC" is used to refer to compounds with an IC of about 100 μM or less, more typically about 50 μM or less. 50 " is the concentration of an inhibitor that reduces the activity of an enzyme (e.g., IGF-1R) to half of its maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibition against IGF-1R. In certain embodiments, the compounds have an IC of about 2 μM or less with respect to IGF-1R, as measured by the IGF-1R assay described herein. 50 and in still further embodiments, the compounds exhibit an IC 50 and in still further embodiments, the compound has an IC 50 Shows.

[0441] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used in the treatment of a disease or disorder or in the effect of a clinical endpoint.

[0442] The term "therapeutically acceptable" refers to compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio, and that are effective for their intended use.

[0443] As used herein, "treat," "treatment," and the like refer to improving a disease so as to reduce, ameliorate, or eliminate one or more of its causes, progression, severity, or symptoms, or to beneficially alter the disease in a subject. In certain embodiments, reference to "treating" or "treatment" of a subject at risk of developing a disease or at risk of worsening a disease is intended to include prevention. Prevention of a disease can include protecting against the disease altogether or preventing the progression of the disease. Prevention of a disease can also mean preventing the progression of a disease to a later stage of the disease.

[0444] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, non-human primates such as chimpanzees, and other ape and monkey species; livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0445] Pharmaceutical Compositions and Formulations The formulations may be prepared by any suitable method, typically by uniformly admixing the active compound with a liquid or finely divided solid carrier, or both, in the required proportions, and then, if necessary, shaping the resulting mixture into the desired presentation.

[0446] Conventional excipients such as binders, fillers, acceptable wetting agents, tableting lubricants, and disintegrants can be used in tablets and capsules for oral administration. Liquid formulations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, oral formulations can be in the form of dry powders that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives, such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring and coloring agents, can be added to liquid formulations. Parenteral dosage forms can be prepared by dissolving the compounds provided herein in a suitable liquid vehicle, sterilizing the solution by filtration, and then filling and sealing appropriate vials or ampoules. These are just a few examples of the many suitable methods well known in the art for preparing dosage forms.

[0447] The compound of the present invention can be formulated into pharmaceutical compositions by using techniques well known to those skilled in the art.Other suitable pharmaceutically acceptable carriers than those described herein are known in the art, for example, see Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins (editors: Gennaro et al.).

[0448] Thus, the compounds provided herein, together with conventional adjuvants, carriers, or diluents, can be placed into the form of pharmaceutical preparations and unit dosages thereof, and in such form can be used as solids, such as tablets or filled capsules, or as liquids, such as solutions, suspensions, emulsions, elixirs, gels, or compound-filled capsules, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof can contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the intended daily dose range used.

[0449] For oral administration, pharmaceutical compositions can be in the form of tablets, capsules, suspensions or liquids.Pharmaceutical compositions are preferably prepared in the form of dosage units that contain a certain amount of active ingredient.The example of such dosage units is capsules, tablets, powders, granules or suspensions, which contain conventional additives such as lactose, mannitol, corn starch or potato starch; binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatin; disintegrants such as corn starch, potato starch or sodium carboxymethylcellulose; and lubricants such as talc or magnesium stearate.Active ingredient can also be administered by injection as a composition, for example, physiological saline, dextrose or water can be used as suitable pharmaceutically acceptable carrier.

[0450] The compounds provided herein, or salts, solvates, or hydrates thereof, can be used as active ingredients in pharmaceutical compositions, specifically as IGF-1R inhibitors. The term "active ingredient," as defined in the context of a "pharmaceutical composition," refers to the component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to "inactive ingredients," which are generally recognized as not providing pharmaceutical benefit.

[0451] Dosages for the compounds provided herein can vary widely and are tailored to the specific conditions of each individual case, as is customary and known to physicians and other clinicians. This depends, for example, on the nature and severity of the disease being treated, the patient's condition, the compound being used, whether an acute or chronic disease state is being treated or prevented, or whether additional active compounds are being administered in addition to the compounds provided herein. Representative doses include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg. Multiple doses, e.g., 2, 3, or 4 doses, can be administered daily, particularly when relatively large amounts are deemed necessary. Depending on the individual and as deemed appropriate by the healthcare provider, it may be necessary to deviate upward or downward from the doses set forth herein.

[0452] The amount of active ingredient, or its active salt or derivative, required for therapeutic use will vary not only depending on the particular salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and is ultimately at the discretion of the attending physician or clinician. Generally, those skilled in the art understand how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some situations, these extrapolations may be based solely on the body weight of the animal model compared to another, such as a mammal, preferably a human, but more often, these extrapolations are not based solely on body weight but rather incorporate a variety of factors. Typical factors include the type, age, weight, sex, diet, and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics, and toxicity profile of the particular compound used, whether a drug delivery system is used, whether the disease condition being treated or prevented is acute or chronic, or whether prophylaxis is being performed, or whether additional active compounds are administered in addition to the compounds provided herein or as part of a drug combination. Dosage regimens for treating disease conditions using the compounds and / or compositions provided herein are selected according to a variety of factors, such as those cited above. Thus, the actual dosage regimen used may vary widely and may therefore deviate from the preferred dosage regimen; those skilled in the art will recognize that dosages and dosage regimens outside these typical ranges may be tested and, if appropriate, used in the methods provided herein.

[0453] Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solutions. Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.

[0454] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.

[0455] Also included are solid form preparations intended to be converted into liquid form preparations for oral administration immediately before use.Such liquid forms include solutions, suspensions and emulsions.These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0456] For topical administration to the epidermis, the compounds provided herein may be formulated as ointments, creams or lotions, or as a transdermal patch.

[0457] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents.Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

[0458] Pharmaceutical preparations are preferably in unit dosage form.In this form, the preparation is further divided into unit doses containing appropriate amounts of active ingredients.Unit dosage form can be a packaged preparation, and the package contains individual amounts of preparations, such as packaged tablets, capsules, and powders in vials or ampoules.Also, unit dosage form can be a tablet, capsule, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0459] Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

[0460] Indications and treatment methods Also provided herein are methods of treating an IGF-1R-mediated disorder in a mammal in need of such treatment, comprising administering to the mammal a compound disclosed herein in an amount effective to halt further progression, reduce the severity, reverse the effects, or prevent the recurrence of the disease or disorder in the subject. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of an IGF-1R-mediated disorder.

[0461] Particular diseases treated by the compounds, compositions, and methods disclosed herein include thyroid eye disease (TED), also known as thyroid-associated ophthalmopathy (TAO) or Graves' ophthalmopathy or Graves' orbitopathy (GO).

[0462] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals (e.g., horses, dogs, and cats), exotic animals, livestock, rodents, and the like.

[0463] Therefore, the present invention also relates to a method for inhibiting at least one IGF-1R function, comprising contacting IGF-1R with a compound described herein. Cell phenotype, cell proliferation, IGF-1R activity, changes in biochemical output produced by activated IGF-1R, IGF-1R expression, or binding of IGF-1R to a natural binding partner can be monitored. Such a method can be a method for treating a disease, a biological assay, a cellular assay, a biochemical assay, etc.

[0464] Also provided herein is a method for treating an IGF-1R mediated disease, comprising administering a therapeutically effective amount of a compound disclosed herein or a salt thereof to a patient in need thereof.

[0465] Thyroid eye disease (TED) As used herein, "thyroid eye disease" (TED), "thyroid-associated ophthalmopathy" (TAO), "thyroid inflammatory eye disease (TIED)," "Graves' ophthalmopathy" (GO), or "Graves' orbitopathy" (GO) refer to the same disease or disorder. These terms refer to inflammatory orbital lesions associated with several autoimmune thyroid disorders, most commonly "Graves' disease" (GD), but sometimes associated with other diseases, such as Hashimoto's thyroiditis.

[0466] The cause of TED is unknown. TED is typically associated with Graves' hyperthyroidism, but it can also occur as part of other autoimmune conditions that affect the thyroid gland and cause involvement of the orbit and periorbital tissues, and rarely the pretibial skin (pretibial myxedema) or fingers (thyroid clubbing). TED is an autoimmune ophthalmopathy that primarily affects the orbit and periocular soft tissues, secondarily affecting the eyes and vision. In TED, as a result of inflammation and enlargement of the orbital soft tissues, primarily the eye muscles and fat, the eyes are pushed forward (bulged) from the orbit—a phenomenon called proptosis or exophthalmos.

[0467] The annual incidence of TED has been estimated at 16 cases per 100,000 women and 2.9 cases per 100,000 men from a study based in one primarily rural area of ​​Minnesota. Women appear to be affected 2.5 to 6 times more frequently than men, but severe cases occur more frequently in men than women. Additionally, most patients are between 30 and 50 years of age, with severe cases more frequent in patients over 50 years of age. While most cases of TED do not result in vision loss, the condition can cause sight-threatening exposure keratopathy, troublesome diplopia (double vision), and compressive hypothyroidism optic neuropathy.

[0468] TED may precede, occur concurrently with, or follow the systemic complications of thyroid dysfunction. Ocular symptoms of TED include upper eyelid retraction, eyelid lag, swelling, redness (erythema), conjunctivitis, and protrusion of the eyeball (proptosis or exophthalmos), chemosis, periorbital edema, and altered eye movements with significant functional, social, and cosmetic consequences.

[0469] Many of the signs and symptoms of TED, including exophthalmos and ocular hyperemia, result from the expansion of orbital adipose tissue and periocular muscles. Adipose tissue volume increases in part due to the development of new adipocytes (adipogenesis) within the orbital fat. Accumulation of hydrophilic glycosaminoglycans, primarily hyaluronic acid, within the orbital adipose tissue and the perimysial connective tissue between extraocular muscle fibers further expands the adipose compartment and enlarges the extraocular muscle body. Hyaluronic acid is produced by fibroblasts present within the orbital fat and extraocular muscles, and its synthesis in vitro is stimulated by several cytokines and growth factors, such as IL-1β, interferon-γ, platelet-derived growth factor, thyroid-stimulating hormone (TSH), and insulin-like growth factor 1 (IGF-1).

[0470] TED is generally considered to be the autoimmune orbital manifestation of Graves' disease (GD). However, only approximately 30% of patients with Graves' hyperthyroidism exhibit clinically relevant ocular pathology, indicating mechanistic heterogeneity and differences between these conditions. The molecular mechanism underlying TED remains unclear. The production of autoantibodies that act as agonists against the thyroid-stimulating hormone receptor (TSHR) is recognized to be the cause of Graves' hyperthyroidism. Pathogenic overstimulation of TSHR leads to overproduction of thyroid hormones (T3 and T4) and increased metabolism in many tissues.

[0471] Antibodies that activate the insulin-like growth factor 1 receptor (IGF-1R) have also been detected and are involved in active TED. Without being bound by any theory, it is believed that TSHR and IGF-1R form a physical and functional complex in orbital fibroblasts, and that blocking IGF-1R attenuates both IGF-1- and TSH-dependent signaling. It has been suggested that blocking IGF-1R with antibody antagonists reduces both TSHR- and IGF-1-dependent signaling, thereby potentially inhibiting the pathological activity of autoantibodies that act as agonists on either receptor.

[0472] Immunoglobulins that activate IGF-1R signaling have been detected in patients with GD and TED. Furthermore, IGF-1 synergistically enhances the effects of thyrotropin. IGF-1R, a transmembrane tyrosine kinase receptor involved in development and metabolism, also stimulates immune function and may be a therapeutic target for autoimmune diseases. IGF-1R is overexpressed by orbital fibroblasts and by T and B cells in humans with GD and TED. It forms a signaling complex with TSHR and is transactivated by it. In vitro studies of orbital fibroblasts and fibrocytes have shown that IGF-1R-blocking antibodies can attenuate the effects of IGF-1, thyroid-stimulating hormone, thyroid-stimulating immunoglobulin, and immunoglobulins isolated from patients with GD and TED. These observations prompted the clinical trial of teprotumumab, a fully human IGF-1R-blocking monoclonal antibody, in patients with active, moderate-to-severe TED.

[0473] The terms "proptosis" and "exophthalmos" (also known as exophthalmus, exophthalmia, or exorbitism) refer to the forward protrusion, displacement, bulging, or protrusion of an organ. As used herein, these terms refer to the forward protrusion, displacement, bulging, or protrusion of the eye forward from the orbit. Some skilled in the art believe that proptosis and exophthalmos have the same meaning and are often used interchangeably, while others believe that there are subtle differences in their meaning. Exophthalmos is sometimes used to refer to severe proptosis or to refer to endocrine-related proptosis. Still others use the term exophthalmos when describing eye-related proptosis, for example, in subjects with TED (TAO or GO).

[0474] As used herein, the terms "proptosis" and "exophthalmos" are used interchangeably and refer to the forward protrusion, displacement, bulging, or protrusion of the eye from the orbit. Due to the rigid bony structure of the orbit, which has only an anterior opening for expansion, any increase in orbital soft tissue contents arising from the sides or posterior displaces the eyeball anteriorly. Proptosis or exophthalmos can be the result of several disease processes, including infection, inflammation, tumor, trauma, metastasis, endocrine lesions, vascular disease, and extraorbital pathologies. TED (TAO or GO) is now recognized as the most common cause of proptosis in adults. Exophthalmos can be bilateral, as is often seen with TED (TAO or GO), or unilateral (as is often seen with orbital tumors).

[0475] Measurement of the degree of exophthalmos can be performed using an exophthalmometer, an instrument used to measure the degree of anterior displacement of the eye. This device allows measurement of the anterior distance of the lateral orbital rim to the anterior part of the cornea.

[0476] Computed tomography (CT) scans and magnetic resonance imaging (MRI) can also be used to assess the degree of exophthalmos or proptosis. CT scans are the preferred imaging modality for diagnosing TED (TAO or GO). In addition to allowing visualization of enlarged extraocular muscles, CT scans provide the surgeon or clinician with a depiction of the bony anatomy of the orbit in cases where orbital decompression is necessary. MRI, with its multifaceted and inherent contrast capabilities, provides excellent imaging of the orbital contents without the radiation exposure associated with CT scans. While MRI provides better imaging of the optic nerve, orbital fat, and extraocular muscles, CT scans provide better images of the bony structures of the orbit.

[0477] Orbital ultrasound can also be used to diagnose and evaluate TED (TAO or GO) because it can be performed quickly and reliably. Hyperreflectivity and enlargement of the extraocular muscles are easily assessed, and serial ultrasound examinations can also be used to assess the progression or stability of the ophthalmopathy.

[0478] Based on technology currently available or that will become available in the future, one skilled in the art will be able to determine the best method for diagnosing and assessing the degree of exophthalmos or proptosis.

[0479] The normal range for proptosis is generally accepted to be 12 to 21 mm, but it should be noted that normal values ​​vary by age, sex, and race. For example, in normal adult Caucasian men, the mean distance of proptosis is 16.5 mm, with an upper limit of normal of 21.7 mm. In adult African Americans, the mean is 18.2 mm, with upper limits of normal of 24.1 mm for men and 22.7 mm for women. In Mexican adults, the mean is 15.2 mm for men and 14.8 mm for women. In Iranian subjects aged 20 to 70 years, the mean was 14.7 mm. In Taiwanese adults, when comparing normal subjects with Graves' ophthalmopathy, the mean reading in the normal group was 13.9 mm, compared with 18.3 mm in the TED group.

[0480] Even within a single group, there can be variation. Four ethnic groups in Southern Thailand had mean exophthalmos measurements ranging from 15.4 mm to 16.6 mm. In 2,477 Turkish patients, the median measurement was 13 mm, with an upper limit of 17 mm, and in a Dutch study, the upper limits were 20 mm in men and 16 mm in women.

[0481] The mean and upper limits of exophthalmos or proptosis vary widely, but it is accepted in the field that a difference of more than 2 mm between the eyes is significant and not normal.

[0482] A person skilled in the art, such as an ophthalmologist, surgeon, or other clinician skilled in the knowledge and treatment of eye disorders, will know what normal values ​​for proptosis are based on the subject's age, sex, and race, and will have the ability to diagnose or assess the presence or absence of proptosis and track its progression.

[0483] Measurement or evaluation of activities Several classification systems have been developed to evaluate the clinical manifestations of TED (TAO or GO). In 1969, Werner reported the NOSPECS classification (no physical signs or symptoms, signs only, soft tissue involvement, proptosis, extraocular muscle signs, corneal involvement, and visual loss) (Werner, SC American Journal of Ophthalmology, 1969, 68, no. 4, 646-648).

[0484] The revised NOSPECS was also published by Werner in 1977 and has since been widely used (Werner, SC American Journal of Ophthalmology, 1977, 83, no. 5, 725-727). This classification is a grade of clinical severity and does not provide a means to distinguish between active TED (inflammatory, progressive) and inactive TED (non-inflammatory, stationary). Therefore, indications for treatment were based solely on the severity of symptoms, regardless of whether the disease was active or inactive. In 1989, Mourits et al. described the Clinical Activity Score (CAS) (Mourits et al., British Journal of Ophthalmology, 1989, 73, no. 8, 639-644) as a method for assessing the degree of disease activity. This score was proposed as a clinical classification to easily distinguish active from inactive disease based on the classic signs of acute inflammation (pain, redness, swelling, and functional impairment), and was revised in 1997 (Mourits et al., Clinical Endocrinology, 1997, 47, no. 1, 9-14). This protocol is further described below.

[0485] As used herein, the term CAS refers to a protocol written and scored as disclosed below. According to this protocol, one point is awarded for the presence of each parameter assessed in the following list. The sum of all points defines clinical activity and provides the CAS. Patients assessed for the first time are scored on items 1-7 only. A CAS of ≥3 / 7 indicates active GO. Patients assessed at subsequent visits (typically 1-3 months later) are also scored on items 8-10, with a CAS of ≥4 / 10 indicating active disease. While 10-item CAS scales exist, clinical trials generally use a 7-item scale, which is more suitable for longitudinal studies involving multiple assessments.

[0486] CAS consists of seven components: 1. Spontaneous retrobulbar pain, 2. Pain when attempting eye movements (upward, sideward, downward), 3. Conjunctival hyperemia, 4. Redness of the eyelids, 5. Chemoedema (swelling / edema of the conjunctiva), 6. Swelling of the caruncle / folds, and 7. Swelling of the eyelids.

[0487] Each component is scored as present (1 point) or absent (0 point). The score for each efficacy assessment is the sum of all items present, giving a range of 0 to 7, with 0 or 1 constituting inactive disease and 7 constituting severe active ophthalmopathy. A change of more than 2 points is considered clinically significant.

[0488] Item 1, spontaneous orbital pain, can be pain or pressure in the eye or behind the eye. This pain can be caused by increased intraorbital pressure due to excessive extracellular matrix synthesis, fluid accumulation, and cellular infiltration and expansion, which increases orbital tissue volume. Item 2, gaze-induced orbital pain, is ocular pain when looking or attempting to look upward, downward, or to the side, i.e., pain associated with upward, downward, or lateral eye movement, or pain when attempting to look upward, downward, or to the side. This type of pain may result from the stretching of inflamed muscles, especially when attempting to raise one's gaze. This "stretching pain" is not caused by pressing the eyeball with a finger and is expected as a manifestation of increased intraorbital pressure. Both types of pain can be alleviated after anti-inflammatory treatment. Therefore, these types of pain are thought to be directly related to autoimmune inflammation in the orbit and are therefore useful for assessing TED activity.

[0489] Swelling in TED (TAO or GO) is seen as chemosis (edema of the conjunctiva) and swelling of the caruncle and / or semilunar fold, both of which are signs of active TED. Eyelid swelling can be caused by edema, fat herniation from the orbital septum, or fibrous degeneration. In addition to swelling, other symptoms indicative of active TED include redness and / or pain in the conjunctiva, eyelid, caruncle, and / or semilunar fold.

[0490] Other scoring systems have also been developed to assess TED (TAO or GO). The VISA classification (Vision, Inflammation, Strabismus, and Appearance) (Dolman, PJ, and Rootman, J., Ophthalmic Plastic and Reconstructive Surgery, 2006, 22, no. 5, 319-324 and Dolman, PJ, Best Practice & Research Clinical Endocrinology & Metabolism, 2012, 26, no. 3, 229-248) and the European Group of Graves' Orbitopathy (EUGOGO) classification (Bartalena, L., et al., European Journal of Endocrinology, 2008, 158, no. 3, 273-285) are two such examples. Both systems are based on the NOSPECS and CAS classifications and use indices to assess the signs and severity of activity. More importantly, they allow clinicians to guide the treatment of patients with GO. VISA is more commonly used in North America and Canada, while EUGOGO is used in Europe. The VISA and EUGOGO protocols are not compatible, so only one of them should be used as the reference for a particular patient.

[0491] Graves' Ophthalmopathy Quality of Life (GO-QoL) In addition to proptosis (or exophthalmos) and CAS, quality of life (QoL) was also assessed using the Graves' Ophthalmopathy Quality of Life (GO-QoL) questionnaire. This questionnaire is designed to determine improvement in quality of life after treatment. In some embodiments, the questionnaire may determine the reduction or absence of side effects after treatment with a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and the methods disclosed herein compared to treatment with a glucocorticoid.

[0492] The GO-QoL questionnaire has two self-assessment subscales. The first concerns the impact of visual function on daily activities, while the second concerns the self-perceived impact of appearance. Each subscale contains eight questions to which participants respond as follows: (i) yes—very much; (ii) yes—a little; or (iii) no—not at all. Each question is scored from 0 to 2, and the combined raw score is mathematically converted to a 0–100 scale, with 0 representing the most negative impact on quality of life and 100 representing no impact. A change of more than 8 points on the 0–100 scale is considered clinically significant. The combined score takes the raw scores from both subscales and again converts them to a single 0–100 scale.

[0493] Measuring severity The palpebral fissure was measured by measuring the distance (in millimeters) between the lid margins while the patient was sitting relaxed, looking straight ahead, and gazing into the distance. Eyelid swelling was measured / rated as "none / uncertain," "moderate," or "severe." Eyelid redness was present or absent. Conjunctival redness was present or absent. Chemoedema was present or absent. Caruncle or fold inflammation was present or absent. Exophthalmos was measured in millimeters for each patient using the same Hertel exophthalmometer and the same intercanthal distance. Subjective diplopia was scored from 0 to 3 (0 = no diplopia; 1 = intermittent, i.e., diplopia in straight-ahead gaze (during fatigue or first awakening); 2 = non-steady, i.e., diplopia at both ends of the line of sight; 3 = steady, i.e., continuous diplopia in straight-ahead gaze or reading position). Ocular muscle dysfunction was measured by measuring the ductus. Corneal involvement is either absent / punctate or keratopathy / ulcer. Optic neuropathy, i.e., best corrected visual acuity, color vision, optic nerve head, and relative afferent pupillary defect, may or may not be pathological. Additionally, if optic nerve compression is suspected, visual fields are checked.

[0494] Classification of severity Sight-threatening thyroid eye disease: Patients with hypothyroid optic neuropathy (DON) and / or corneal destruction. This category required immediate intervention.

[0495] Moderate to severe thyroid eye disease: Patients without sight-threatening disease, but whose eye disease sufficiently impacts daily life to justify the risk of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate to severe thyroid eye disease typically have one or more of the following: eyelid retraction of 2 mm or more, moderate or severe soft tissue involvement, exophthalmos of 3 mm or more from the normal range for their race and gender, or non-stationary or stationary diplopia.

[0496] Mild thyroid eye disease: Patients whose features of thyroid eye disease have minimal impact on daily life and are insufficient to justify immunosuppression or surgical treatment. They usually have one or more of the following: mild eyelid retraction (<2 mm), mild soft tissue involvement, exophthalmos less than 3 mm below the normal range for race and gender, transient or absent diplopia, and corneal exposure that responds to lubricants.

[0497] Gorman grading evaluation of diplopia The Gorman assessment of subjective diplopia has four categories: no diplopia (none), diplopia when the patient is tired or awake (intermittent), diplopia at both ends of the line of sight (unsteady), and continuous diplopia in straight-on or reading position (steady). Patients are scored according to the grade of diplopia they experience. An improvement of 1 grade or more is considered clinically significant.

[0498] Further studies, including clinical trial protocols and criteria, and lead-in studies, that can be conducted to determine the effectiveness of treatment for TED can be found in U.S. Patent Application Publication No. 2019 / 0225696A1, which is incorporated herein by reference in its entirety.

[0499] Additionally, the IGR-1R inhibitors described herein may be useful for treating TED in subjects who were proptosis non-responders in the induction study (less than 2 mm reduction in proptosis in the study eye) or who were proptosis responders in the induction study but meet criteria for retreatment due to relapse.

[0500] Treatment method Accordingly, provided herein are methods of treating an IGF-1R-mediated disorder in a mammal in need of such treatment, comprising administering to the subject a compound disclosed herein in an amount effective to alleviate or prevent the disorder in the subject. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of an IGF-1R-mediated disorder. Particular diseases treated by the compounds, compositions, and methods disclosed herein include thyroid-associated ophthalmopathy (TAO) or thyroid eye disease (TED), also known as Graves' ophthalmopathy or Graves' orbitopathy (GO).

[0501] In some embodiments, the disease is thyroid eye disease (TED).

[0502] Also provided herein are compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, for use as pharmaceuticals.

[0503] Also provided herein is a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament for the treatment of an IGF-1R mediated disease.

[0504] Also provided is a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for the treatment of an IGF-1R mediated disease.

[0505] Also provided is the use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, disclosed herein for the treatment of an IGF-1R mediated disease.

[0506] Also provided herein is a method for inhibiting IGF-1R, comprising contacting IGF-1R with a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0507] Combination therapy In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. [Example]

[0508] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. All IUPAC names were generated using CambridgeSoft's ChemDraw Professional 22.0.0.22.

[0509] I. Chemical synthesis As used above, and throughout the description of the present invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: List of commonly used abbreviations Ac(acetyl); ACN, CH3CN (acetonitrile); AcOH, HOAc (acetic acid); atm(atm); BH3-DMS complex, BMS (borane diethyl sulfide); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Boc(tert-butoxycarbonyl); Boc2O (di-tert-butyl dicarbonate); BuLi, n-BuLi (n-butyllithium); DCM (dichloromethane); DIPEA (diisopropylethylamine); DMAP (4-dimethylaminopyridine); DME (dimethyl ether); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); equiv. (equivalent); Et(ethyl); Et3N, TEA (triethylamine); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); mg (milligram); μg (microgram); h, hr, hrs(time); HCl (hydrochloric acid); HFIP (hexafluoro-2-propanol, hexafluoroisopropanol); HPLC (High Performance Liquid Chromatography); IGF-1R (insulin-like growth factor 1 receptor); i-Pr (isopropyl); i-PrOH, IPA (isopropanol); L (liter); mL (milliliter); μL (microliter); LAH (lithium aluminum hydride); LC-MS (liquid chromatography-mass spectrometry); LDA (lithium diisopropylamide); M (molar); mM (milmolar); μM (micromolar); Me(methyl); MeI (methyl iodide, iodomethane); MeLi (methyllithium); MeOH (methanol); min, mins(minutes); mol (mole); mmol (millimol); μmol (micromol); MS (mass spectrometry); MsCl (methanesulfonyl chloride, mesyl chloride); N2(g) (nitrogen gas); NaOtBu (sodium tert-butoxide); NBS (N-bromosuccinimide); NMP (N-methyl-2-pyrrolidone); NMR (nuclear magnetic resonance); Pd(OAc)2 (palladium(II) acetate); Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0); PE (petroleum ether); PhMe(toluene); Pr(propyl); psi (pounds per square inch); PTFE (polytetrafluoroethylene, Teflon®); PyBrop (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate); Rbf (round-bottom flask); Rt, RT (room temperature); SiO2 (silica); SOCl2 (thionyl chloride); TBABr (tetrabutylammonium bromide); "t-bu" (tert-butyl); tBu-Josiphos ((R)-(-)-1-[(S)-2-(dicyclohexyl-phosphino)ferrocenyl]ethyl-di-t-butylphosphine); tBuOH (tert-butyl alcohol, tert-butanol); TCFH (N'-tetramethylformamidinium hexafluorophosphate); THF (tetrahydrofuran); TLC (thin layer chromatography); μW (microwave); vol.(volume(volume equivalent)); XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene).

[0510] Synthesis method The following intermediates and examples can be synthesized using the general synthetic procedures described in the examples below.

[0511] General Procedure A [ka] A mixture of hydantoin 1 (1.0 equiv.), aryl halide 2 (1.0 equiv.), and CuO (1.0 equiv.) in DMF (0.4 M) was heated at 150 °C for 16 h under N. After cooling to room temperature, DMF was removed under reduced pressure. Water (15 vol.) was added, and the resulting slurry was stirred at room temperature for 30 min. NHOH (5 vol.) was then added, and stirring was continued for 30 min. The precipitate was collected by filtration, washed with water, and dried under vacuum. The hydantoin product 3 was typically >95% pure or, if necessary, further purified by flash chromatography (SiO, heptane / EtOAc).

[0512] The following compounds are prepared according to general procedure A:

[0513] [Table 86]

[0514] [Table 87]

[0515] General Procedure B [ka] Step 1: A mixture of appropriately substituted aryl or heteroaryl aniline 4 (1 equiv.) and toluene (0.05-0.1 M) was cooled in an ice bath with stirring. Diphosgene (1 equiv.) was added dropwise. The mixture was allowed to warm to room temperature and then heated to 70°C until LC-MS analysis indicated complete conversion to the corresponding isocyanate (approximately 3 h).

[0516] Step 2: The mixture from Step 1 was cooled to room temperature, and triethylamine (3 equiv.) and the substituted amino ester 5 (1.5 equiv.) were added with stirring. The reaction was heated (80-120 °C) in a sealed tube with stirring for 6 h. The reaction was cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and then brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. This crude material was typically used directly in the next step or, if necessary, purified by flash chromatography (SiO2, heptane / EtOAc) to give the corresponding hydantoin product 3.

[0517] The following compounds are prepared according to general procedure B:

[0518] [Table 88]

[0519] General procedure C [ka] Commercially available isocyanate 7 (1 equiv.) was stirred in toluene (0.05–0.1 M) at room temperature, and triethylamine (3 equiv.) and the substituted amino ester 5 (1.5 equiv.) were added with stirring. The reaction was heated (80–120 °C) in a sealed tube with stirring for 6 h. The reaction was cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. This crude material was typically used directly in the next step or, if necessary, purified by flash chromatography (SiO2, heptane / EtOAc) to give the corresponding hydantoin product 3.

[0520] The following compounds are prepared according to general procedure C:

[0521] [Table 89]

[0522] [Table 90]

[0523] General Procedure D [ka] Hydantoin 3 (1 equiv.) was dissolved in DMF (0.1 M). Sodium hydride (3.5 equiv.) was added under N2, and the resulting mixture was stirred at room temperature for 30 min. Then, a solution of benzyl halide 8 (1.1 equiv.) in DMF (0.5 M) was added dropwise. After stirring the reaction mixture at room temperature for 30 min, the reaction was carefully quenched with water. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with water, brine, and dried over Na2SO4. The crude mixture was purified by flash chromatography (SiO2, EtOAc / heptane) to give product 9.

[0524] General Procedure E [ka] Hydantoin 3 (1 equiv.) was dissolved in DMF (0.3 M). Cesium carbonate (2.0 equiv.) was added, followed by the addition of benzyl halide 10 (1.1 equiv.). The reaction mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with water, brine, and dried over Na2SO4. The crude mixture was purified by flash chromatography (SiO2, heptane / EtOAc) to give product 11.

[0525] Alternatively, hydantoin 3 (1 equiv.) was dissolved in DMF (0.1 M). Sodium hydride (3.5 equiv.) was added under N2, and the resulting mixture was stirred at room temperature for 10 min. Then, a solution of benzyl halide 10 (1.1 equiv.) in DMF (0.5 M) was added dropwise. After stirring the reaction mixture at room temperature for 75 min, the reaction was carefully quenched with water. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with water, brine, and dried over Na2SO4. The crude mixture was purified by flash chromatography (SiO2, EtOAc / heptane) to give product 11.

[0526] General Procedure F [ka] A mixture of appropriately substituted halopyridine 11 (1 equiv.), amine 12 (1.2 equiv.), a palladium source selected from Pd(OAc)2 or Pd2(dba)3 (0.05 equiv. Pd), a ligand selected from BINAP, Xantphos, or tBu-Josiphos (0.05 equiv.), and NaOtBu (1.4 equiv.) in a solvent selected from dioxane, toluene, or DME (0.1 M) was purged with N2. The reaction mixture was heated at temperatures ranging from 70 to 100 °C until LC-MS analysis indicated the reaction was complete. The reaction was diluted with EtOAc, washed with water and brine, and concentrated. The crude product was purified by flash chromatography (SiO2, eluting with heptane / EtOAc) or reverse-phase flash chromatography (C18, eluting with 10 mM ammonium bicarbonate or ammonium formate (aq.) / MeCN) to give the desired product 9.

[0527] General Procedure G [ka] A mixture of appropriately substituted halopyridine 11 (1 equiv.) and primary amine 12 (3 equiv.) or its hydrochloride salt was dissolved in DMSO (0.1 M) and water (10:1 ratio). The mixture was degassed with nitrogen for 5 min. Tribasic potassium phosphate (3 equiv. of free base amine or 6 equiv. of hydrochloride salt), ligand [(2,6-dimethylphenyl)amino](oxo)acetic acid (0.6 equiv.), and copper iodide (0.25 equiv.) were added, and the mixture was heated with stirring at 85 °C for 3–12 h. The reaction mixture was cooled to RT, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase flash chromatography (C18, eluting with MeCN / 10 mM ammonium bicarbonate (pH 10.3) or ammonium formate (pH 3.8) buffer) to give the desired product 9.

[0528] General Procedure H [ka] Ethyl (4-((5,5-dimethyl-2,4-dioxo-3-(4-((trifluoromethyl)thio)phenyl)imidazolidin-1-yl)methyl)pyridin-2-yl)carbamate (1 equiv.), an appropriately substituted amine (2–5 equiv.), and NMP (0.5–1 M) were heated in a microwave reactor at 140° C. for 1 h. The reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with aqueous NH4Cl, aqueous NaHCO3, and then brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase flash chromatography (C18, eluting with MeCN / 10 mM ammonium bicarbonate (pH 10.3) or ammonium formate (pH 3.8) buffer) to give the desired product.

[0529] General Procedure I [ka] A mixture of 1-((2-aminopyridin-4-yl)methyl)-5,5-dimethyl-3-(4-((trifluoromethyl)thio)phenyl)imidazolidine-2,4-dione, the corresponding aryl bromide (1–1.5 equiv.), cesium carbonate (3 equiv.), and dioxane (50–100 mM) was degassed. XantPhos Pd G2 (0.1–0.15 equiv.) was added, and the reaction was degassed. The reaction mixture was heated with stirring at 120 °C for 18 h. The reaction was cooled to room temperature and filtered through a plug of silica gel mixed with Celite. The cake was washed with EtOAc, and the product was then eluted with 20% MeOH / DCM. The filtrate was concentrated in vacuo and purified by reverse-phase flash chromatography (C18, eluting with MeCN / 10 mM ammonium bicarbonate (pH 10.3) or ammonium formate (pH 3.8) buffer) to give the desired product.

[0530] General procedure J [ka] In a reaction vessel, pyridine-N-oxide (1 equivalent), primary amine (1.2 equivalents), N,N-diisopropylethylamine (5 equivalents), and DCM (0.3 M) were mixed. The solution was treated with PyBrop (1.3 equivalents) at 0° C. The reaction was capped and stirred at room temperature overnight. Upon completion (LCMS analysis), the reaction was concentrated under reduced pressure. The crude product was purified by column chromatography to give the desired compound.

[0531] General Procedure K [ka] A reaction vessel containing Ar-I (1 equiv.), NHP ester (1.2–2 equiv.), NiCl2bpy (15 mol%), and Zn (8 equiv.) was evacuated and backfilled with N2 (×3), followed by the addition of DMA (0.2 M), followed by TMS-Cl (3 equiv.). The reaction vessel was immediately placed at 0 °C and vigorously stirred for 1–18 h. The reaction mixture was diluted with EtOAc and passed through a plug of silica gel or Celite (eluting with EtOAc). Volatiles were removed under reduced pressure, and the crude material was purified by column chromatography to give the desired product.

[0532] General procedure L [ka] To a stirred solution of carboxylic acid (1.00 equiv.), N-hydroxyphthalimide (1.05 equiv.), and DMAP (0.200 equiv.) at room temperature was added EDC (1.10 equiv.) and stirred overnight. The reaction mixture was diluted with DCM, and the organic layer was washed with 1 M HCl (×1), brine (×1), dried over MgSO4, filtered, and concentrated under reduced pressure to give the desired product, which was sufficiently pure for direct use in the next step.

[0533] The following compounds are prepared according to general procedure L:

[0534] [Table 91]

[0535] [Table 92]

[0536] General procedure M [ka] A 1-dram vial was charged with Pd2(dba)3 (10 mol%) and 4,6-bis(diphenylphosphino)phenoxazine (20 mol%), evacuated, and backfilled with N2 (x3), then freshly degassed (sparged with N2 for 15 min). THF (175 mM) was added under an inert atmosphere and stirred at room temperature for 15 min. Solid Ar-I (1.0 equiv.) was then added quickly, followed by the nitrile (2 equiv.), freshly degassed (sparged with N2 for 15 min). CPME (175 mM) and LiHMDS (1 M in THF, 3.6 equiv.) were then added, and the reaction was placed in a preheated 60 °C oil bath for 1-18 h. After the reaction mixture was cooled to ambient temperature, MeOH was added and stirred for 15 min. The volatiles were removed under reduced pressure, and the crude solid was purified by column chromatography to give the desired product.

[0537] General Procedure N [ka] To a solution of substituted indolone (1 equiv.) in THF (0.25 M) was added BH3·SMe2 (4 equiv.) dropwise at 0 °C. The reaction mixture was then refluxed at 60 °C for 16 h. The reaction mixture was quenched with MeOH and then concentrated to dryness. This procedure was repeated five times. The crude product was purified by normal phase chromatography (SiO2, eluting with hexane / EtOAc) to give the desired product.

[0538] General Procedure [ka] To a solution of substituted indolone (1 equiv.) in CHCl (0.25 M) at 0° C. was added pyridine (2 equiv.) and the appropriate acyl chloride or MsCl (1.1 equiv.). The reaction mixture was stirred at 0° C. for 1 h, followed by 1 h at room temperature. The reaction mixture was quenched with water and extracted with CHCl. ​​The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated to dryness. The crude product was purified by normal phase chromatography (SiO, eluting with hexane / EtOAc) to give the desired product.

[0539] General procedure P [ka] To a solution of substituted azaindole (1 equiv.) in THF (0.2 M) and HO (2 M) was added FeBr (0.1 equiv.). HO (4.4 equiv., 30% in water) was added and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with saturated NaSO and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated to dryness. The crude product was purified by reverse-phase chromatography to give the desired product.

[0540] General Procedure Q [ka] A flask containing azaindole (1 equiv.), pyridinium tribromide (6 equiv.), and tBuOH (55 mM) was stirred at 35° C. for 1 h. The reaction was diluted with EtOAc, and the organic layer was washed with saturated ammonium chloride (×1), brine (×1), dried over MgSO4, filtered, and concentrated under reduced pressure to give an orange solid. This solid was suspended in AcOH (45 mM), and zinc (6 equiv.) was added. The reaction was stirred at room temperature for 30 min, then diluted with EtOAc and filtered through a short pad of Celite (rinsing with EtOAc). The volatiles were removed under reduced pressure and dried overnight in vacuo. The crude material was purified by C18 reverse-phase column chromatography to give the product.

[0541] General Procedure R [ka] To a sealable reaction vessel was added substituted 6-bromoindolin-2-one (or 6-bromoindoline) (1.0 equiv.) and potassium carbonate (3.0 equiv.) dissolved in MeCN (0.25 M). The reaction vessel was sealed and purged with nitrogen. Iodomethane (2.5 equiv.) was added dropwise, and the reaction was heated to 70 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were dried over NaSO and concentrated onto silica. The reaction was purified by flash column chromatography on a silica gel column eluting with a solvent gradient of 0-30% EtOAc / hexanes.

[0542] General Procedures [ka] n-Butyllithium (3.0 equiv.) was added dropwise to a stirred solution of 6-bromoindolin-2-one (1.0 equiv.) and diisopropylamine (3.0 equiv.) in THF (0.2 M) at −78 °C. The mixture was stirred for 45 minutes while maintaining this temperature, after which 1,2-dibromoethane or 1,3-dibromopropane (3.0 equiv.) was added dropwise. Stirring was continued for 16 hours, during which time the temperature was allowed to slowly rise to room temperature. The reaction mixture was quenched with 4N HCl, and the aqueous layer was separated and further extracted with EtOAc (3×). The combined organic layers were washed with water and brine and then dried over NaSO. The material was concentrated onto silica gel for purification. The crude reaction was purified by flash column chromatography on a silica gel column eluting with a solvent gradient of 0–40% EtOAc / hexane to afford the spirocyclic product.

[0543] Example A-1: ​​Preparation of 5,5-dimethyl-3-(1'-methylspiro[cyclobutan-1,3'-indoline]-6'-yl)imidazolidine-2,4-dione [ka] Step 1: 6-Bromo-1-methylindolin-2-one: The title compound was prepared from 6-bromoindolin-2-one according to general procedure R. MS (m / z): [M+H] +:226.1.

[0544] [ka] Step 2: 6'-Bromo-1'-methylspiro[cyclobutane-1,3'-indolin]-2'-one: 6-Bromo-1-methylindolin-2-one (323 mg, 1.43 mmol) was dissolved in DMF (25.0 mL) under a nitrogen atmosphere. The reaction was cooled to 0 °C, sodium hydride (60% dispersion in mineral oil) (98 mg, 4.09 mmol) was added, and the reaction was stirred for 30 minutes while warming to room temperature. 1,3-Dibromopropane (417 mg, 2.04 mmol) was added dropwise, and the reaction was stirred for 16 hours. The crude material was purified by flash column chromatography (SiO2, 0-20% EtOAc / hexanes) to give 6'-bromo-1'-methylspiro[cyclobutane-1,3'-indolin]-2'-one (191 mg, 35%). MS (m / z): [M+H] + :266.1.

[0545] [ka] Step 3: 6'-Bromo-1'-methylspiro[cyclobutane-1,3'-indoline]: The title compound was prepared from 6'-bromo-1'-methylspiro[cyclobutane-1,3'-indoline]-2'-one according to general procedure N. MS (m / z): [M+H] + :252.1, 254.1.

[0546] [ka] Step 4: 5,5-Dimethyl-3-(1'-methylspiro[cyclobutane-1,3'-indoline]-6'-yl)imidazolidine-2,4-dione: The title compound was prepared from 6'-bromo-1'-methylspiro[cyclobutane-1,3'-indoline] according to general procedure A. MS (m / z): [M+H] + :300.2.

[0547] Example A-2: 3-(3,3-dimethyl-1-(methylsulfonyl)indolin-6-yl)-5,5-dimethylimidazolidine-2,4-dione [ka] Step 1: 6-Bromo-3,3-dimethyl-1-(methylsulfonyl)indolin-2-one: A flask was charged with 6-bromo-3,3-dimethylindolin-2-one (300 mg, 1.21 mmol) followed by DMF (5.8 mL, 0.2 M) and the suspension was cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil) (58 mg, 2.42 mmol) was added and the reaction was stirred for 5 minutes, followed by the addition of methanesulfonyl chloride (188 μL, 2.42 mmol). The reaction was allowed to warm to room temperature over 16 hours, at which point it was quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The crude reaction mixture was purified by reverse-phase chromatography (C18 column, 35-55% MeCN / 0.1% 10 mM ammonium formate buffer) to give 6-bromo-3,3-dimethyl-1-(methylsulfonyl)indolin-2-one (258 mg, 67%). MS (m / z): [M+H] + :319.9.

[0548] [ka] Step 2: 6-Bromo-3,3-dimethyl-1-(methylsulfonyl)indoline: The title compound was prepared from 6-bromo-3,3-dimethyl-1-(methylsulfonyl)indolin-2-one according to general procedure N. MS (m / z): [M+H] + :304.2.

[0549] [ka] Step 3: 3-(3,3-Dimethyl-1-(methylsulfonyl)indolin-6-yl)-5,5-dimethylimidazolidine-2,4-dione: The title compound was prepared from 6-bromo-3,3-dimethyl-1-(methylsulfonyl)indoline according to general procedure A. MS (m / z): [M+H] + :352.2.

[0550] Example A-3: 1-(4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)phenyl)cyclobutane-1-carbonitrile [ka] Step 1: Acetone (100 mL) was added to 4-nitrophenylacetonitrile (5.00 g, 30.2 mmol), potassium carbonate (10.9 g, 78.6 mmol), and tetrabutylammonium bromide (974 mg, 3.02 mmol). 1,3-Dibromopropane (3.73 mL, 36.3 mmol) was then added, and the reaction was heated to 55 °C and stirred for 20 h. The reaction was cooled to room temperature, and the precipitate was filtered through Celite, eluting with acetone, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO, 0–50% EtOAc / heptane) to give the product as a white solid (3.00 g, 49%). 1 H NMR(400MHz,CDCl3)δ(ppm):8.30-8.23(m,2H),7.64-7.56(m,2H),2.95-2.85(m,2H),2.71-2.59(m,2H),2.57-2.45(m,1H),2.20-2.07(m,1H).

[0551] Step 2: The material from the previous step (1.00 g, 4.95 mmol) was hydrogenated over 10% Pd / C (100 mg, 0.940 mmol) in MeOH (50.0 mL) under an atmosphere of H2 to give the product (0.763 g, 87%) as a pink solid.

[0552] Step 3: Using the material from the previous step (763 mg, 4.43 mmol), toluene (44.3 mL), trichloromethyl chloroformate (428 μL, 3.54 mmol), triethylamine (2.56 mL, 18.2 mmol), and methyl α-aminoisobutyrate hydrochloride (730 mg, 4.61 mmol), the title compound was synthesized according to general procedure B. The crude material was purified by column chromatography (SiO, 0-100% EtOAc / heptane) to afford the title compound (721 mg, 57%). LCMS: MS (m / z): [MH] - =282.2.

[0553] Example 1: 1-((2-aminopyridin-4-yl)methyl)-3-(4-(tert-butyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione: [ka] Step 1: The hydantoin core was prepared using 4-tert-butylphenyl isocyanate and methyl α-aminoisobutyrate hydrochloride according to general procedure C. The crude material was carried on directly to the next step.

[0554] Step 2: The title compound was prepared using the hydrobromide salt of 4-(bromomethyl)pyridin-2-amine following general procedure D. m / z: [M+H] + =367.6, 1 H NMR(400MHz,DMSO)δ(ppm):7.82(d,J=5.2Hz,1H),7.55-7.45(m,2H),7.37-7.28(m,2H),6. 46(dd,J=5.3,1.4Hz,1H),6.40(s,1H),5.87(s,2H),4.41(s,2H),1.36(s,6H),1.29(s,9H).

[0555] Example 2: Preparation of 1-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-5,5-dimethyl-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)imidazolidine-2,4-dione (Compound 7) [ka] The title compound was prepared using 4-(bromomethyl)-1H-pyrrolo[2,3-b]pyridine hydrobromide according to general procedure D. MS (m / z): [M+H] + =443.2, 1 H NMR(400MHz,DMSO)δ(ppm):11.69(s,1H),8.16(d,J=4.9Hz,1H),7.58(d,J=8.4Hz,2H),7.52-7.42(m, 3H),7.10(d,J=4.9Hz,1H),6.62(d,J=3.4Hz,1H),4.86(s,2H),1.39-1.30(m,8H),1.19-1.14(m,2H).

[0556] Example 3 Preparation of 1-((3-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-5,5-dimethyl-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)imidazolidine-2,4-dione (Compound 8) [ka] 1-((1H-Pyrrolo[2,3-b]pyridin-4-yl)methyl)-5,5-dimethyl-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)imidazolidine-2,4-dione (from Example 2) and NBS (20.1 mg, 113 μmol) were stirred in DMF (1.70 mL) for 2 h. The mixture was filtered and purified by reverse-phase chromatography (C18, 10 mM ammonium bicarbonate buffer pH 10.3 / MeCN, 30%-50%) to give the title compound as a gray solid (6.1 mg, 10%). MS (m / z): [M+H] + =521.1 / 523.0, 1 H NMR(400MHz,DMSO)δ(ppm):8.21(d,J=4.9Hz,1H),7.71(s,1H),7.58(d,J=8.4Hz,2H),7.49(d,J=8 .5Hz,2H),7.15(d,J=4.9Hz,1H),5.21(s,2H),1.42(s,6H),1.38-1.31(m,2H),1.20-1.13(m,2H).

[0557] Example 4 Preparation of 5,5-dimethyl-1-((2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)imidazolidine-2,4-dione (Compound 13) [ka] The compounds were prepared according to general procedure Q below.

[0558] Step 1: 1-((1H-Pyrrolo[2,3-b]pyridin-4-yl)methyl)-5,5-dimethyl-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)imidazolidine-2,4-dione (110 mg, 69.1 μmol), pyridinium tribromide (353 mg, 994 μmol) and tBuOH (5.4 mL) were stirred at 30° C. for 1 h. The reaction was diluted with EtOAc, washed with saturated ammonium chloride and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a brown semi-solid which was carried on directly to the next step.

[0559] Step 2: The residue from Step 1 was dissolved in AcOH (10 mL) and zinc powder (163 mg, 2.49 mmol) was added. The reaction was stirred at room temperature for 30 minutes. The mixture was filtered and the AcOH was removed in vacuo. The residue was dissolved in EtOAc and added to saturated sodium bicarbonate. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase chromatography (C18, 10 mM ammonium formate buffer pH 3.8 / MeCN, 25%-45%) to give the title compound (10.0 mg, 40%) as a white solid. MS (m / z): [M+H] + =459.2, 1H NMR(400MHz,DMSO)δ(ppm):10.99(s,1H),8.00(d,J=5.5Hz,1H),7.57(d,J=8.4Hz,2H),7.51-7.42 (m,2H),6.96(d,J=5.5Hz,1H),4.51(s,2H),3.62(s,2H),1.41-1.33(m,8H),1.15(d,J=5.5Hz,2H).

[0560] Example 5 Preparation of 1-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-5,5-dimethyl-3-(4-((trifluoromethyl)thio)phenyl)imidazolidine-2,4-dione (Compound 16) [ka] The title compound was prepared according to general procedure D using 5,5-dimethyl-3-(4-((trifluoromethyl)thio)phenyl)imidazolidine-2,4-dione and 4-(chloromethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine hydrochloride. MS (m / z): [M+H] + =437.2, 1 H NMR(400MHz,DMSO)δ(ppm):7.89-7.80(m,2H),7.69-7.60(m,3H),6.43(d,J=5.5Hz,1H ),6.33(s,1H),4.40(s,2H),3.46(t,J=8.6Hz,2H),3.01(t,J=8.4Hz,2H),1.38(s,6H).

[0561] Example 6 Preparation of 5,5-dimethyl-1-((2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)-3-(4-((trifluoromethyl)sulfonyl)phenyl)imidazolidine-2,4-dione (Compound 23) [ka] The title compound was prepared according to the procedure of Example 4 (General Procedure Q) to give a white solid (15.0 mg, 29%). MS (m / z): [M+H] + =483.1, 1H NMR(400MHz,DMSO)δ(ppm):11.00(s,1H),8.30(d,J=8.8Hz,2H),8.07-8.01(m,2H), 8.00(d,J=5.5Hz,1H),7.03(d,J=5.5Hz,1H),4.54(s,2H),3.65(s,2H),1.40(s,6H).

[0562] Example 7 Preparation of 2-(4-(4,4-dimethyl-2,5-dioxo-3-((2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)imidazolidin-1-yl)phenyl)-2-methylpropanenitrile (Compound 29) [ka] Step 1: 2-(4-(3-((1H-Pyrrolo[2,3-b]pyridin-4-yl)methyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)phenyl)-2-methylpropanenitrile: The title compound was prepared according to general procedure D using 2-(4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)phenyl)-2-methylpropanenitrile and tert-butyl 4-(chloromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate. The Boc group was removed using 4M HCl in dioxane (15 equivalents). MS (m / z): [M+H] + =402.

[0563] [ka] Step 2: The title compound was prepared according to the procedure in Example 4 (General Procedure Q) to give a white solid. MS (m / z): [M+H] + =418.4, 1 H NMR(400MHz,DMSO)δ(ppm):11.00(s,1H),8.01(d,J=5.5Hz,1H),7.67-7.61(m,2H),7.53 -7.47(m,2H),6.96(d,J=5.5Hz,1H),4.51(s,2H),3.63(s,2H),1.70(s,6H),1.38(s,6H).

[0564] Example 8 Preparation of 5,5-di...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R １ is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, or unsubstituted or substituted bicyclic heteroaryl; R １ When R is substituted, Ａ and 1 to 3 R ５ is substituted with; R Ａ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted C ３ ~C ６ Cycloalkenyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR Ａ１ , -S(=O)R Ａ１ , -S(=O) ２ R Ａ１ , -SF ５ or -SiMe ３ and R Ａ１ is C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; Or, R Ａ teeth, 【Chemistry 2】 and R Ａ２ is halogen, -OH, -CN, C １ ~C ４ Alkyl, C １ ~C ４ Fluoroalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Fluoroalkoxyl, or C １ ~C ４ is hydroxyalkyl; m is 0, 1, 2, or 3; Each R ５ are independently hydrogen, halogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ Is it; Or, R １ teeth, 【Chemistry 3】 and X １ is CR ６ or N, Each R ６ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and Y １ is -O-, -NR １１ - or -SO ２ - and R １１ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, -C(=O)NH ２ , -C(=O)R １２ Or -S(=O) ２ R １２ and R １２ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R ７ and R ８ are each independently hydrogen, —OH, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C １ ~C ６ Is alkoxy; Or R ７ and R ８ together with the carbon atom to which they are attached, represent an unsubstituted or substituted C ３ ~C ６ forming a cycloalkyl or an unsubstituted or substituted 3- to 6-membered heterocycloalkyl; R ９ and R １０ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C １ ~C ６ Is alkoxy; Or R ９ and R １０ together with the carbon atom to which they are attached form -C(=O)-; Or R ９ and R １０ together with the carbon atom to which they are attached, represent an unsubstituted or substituted C ３ ~C ６ forming a cycloalkyl or an unsubstituted or substituted 3- to 6-membered heterocycloalkyl; R ３ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R ４ is hydrogen or C １ ~C ６ Is it alkyl; Or, R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, or a 3- to 6-membered heterocycloalkyl; R ｃ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, -C(=O)N(R ２２ ) ２ , -C(=O)R ２１ , -C(=O)OR ２２ Or -S(=O) ２ R ２１ and X ２ is CR １７ or N, Each R １７ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -OC(=O)R ２１ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and R １３ and R １４ are each independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, phenyl, monocyclic heteroaryl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ or -OC(=O)R ２１ Is it; Or, R １３ and R １４ together with the carbon atom to which they are attached form -C(=O)-; Or, R １３ and R １４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, or a 3- to 6-membered heterocycloalkyl; Y ２ is -(CR １５ R １６ ) ｎ -, -O-, or -O-CR １５ R １６ - and Each R １５ and R １６ are independently hydrogen, halogen, cyano, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C １ ~C ６ Alkoxy, phenyl, monocyclic heteroaryl, C ３ ~C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; Or R １４ and one R on an adjacent carbon atom １６ together form an alkene bond; n is 1 or 2; Each R ２１ are independently unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R ２２ are independently hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R ２２ together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl may be selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR ２３ , -CO ２ R ２３ , -C(=O)N(R ２３ ) ２ , -N(R ２３ ) ２ , -NR ２３ C(=O)R ２４ , -SR ２３ , -S(=O)R ２４ , -SO ２ R ２４ , or -SO ２ N (R ２３ ) ２ One or more R independently selected from the group consisting of ｓ is substituted with a group; Each R ２３ are independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R ２３ the groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R ２４ is C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. or a pharma- ceutically acceptable salt or solvate thereof.

2. R ｃ is hydrogen, C １ ~C ６ Alkyl, or C(=O)OR ２２ and X ２ is CR １７ and Each R １７ are independently hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is fluoroalkyl; R １３ and R １４ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; Or R １３ and R １４ together with the carbon atom to which they are attached form -C(=O)-; Or R １３ and R １４ together with the carbon atom to which they are attached, ３ ~C ４ Forming a cycloalkyl; Y ２ is -(CR １５ R １６ ) ｎ -, -O-, or -O-CR １５ R １６ - and Each R １５ and R １６ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C ３ ~C ６ is cycloalkyl; Or R １４ and one R on an adjacent carbon atom １６ are taken together to form an alkene bond, 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

3. R ｃ is hydrogen; X ２ is CR １７ and Each R １７ is hydrogen; R １３ and R １４ are each hydrogen; Or R １３ and R １４ together with the carbon atom to which they are attached form -C(=O)-; Y ２ is -(CR １５ R １６ ) ｎ -, -O-, or -O-CR １５ R １６ - is, 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof.

4. Each R １５ and R １６ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C ３ ~C ６ is cycloalkyl, 4. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt or solvate thereof. 【Request 5】 【Chemical 4】 teeth, 【Chemistry 5】 and Y ２ is -CR １５ R １６ - or -CR １５ R １６ -CR １５ R １６ - is, 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt or solvate thereof. 【Request 6】 【Chemical 6】 teeth, 【Chemistry 7】 That is, 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt or solvate thereof.

7. R １４ and one R on an adjacent carbon atom １６ are taken together to form an alkene bond, 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt or solvate thereof.

8. R ３ is C １ ~C ６ is alkyl; R ４ is C １ ~C ６ Is it alkyl; Or R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, 8. The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt or solvate thereof.

9. R １ is unsubstituted or substituted phenyl, or unsubstituted or substituted monocyclic heteroaryl; R １ When R is substituted, Ａ and 1 to 3 R ５ has been replaced by 9. The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt or solvate thereof.

10. R １ teeth, 【Chemistry 8】 (In the formula, X ３ and X ４ are each independently ５ or N; Each R ５ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR ２１ (It is) 9. The compound according to any one of claims 1 to 8, which is: or a pharma- ceutically acceptable salt or solvate thereof.

11. X ３ and X ４ are CR ５ and Each R ５ is hydrogen, 11. The compound of claim 10, or a pharma- ceutically acceptable salt or solvate thereof.

12. R Ａ is C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, halogen, -CN, -SR Ａ１ , -S(=O)R Ａ１ , -S(=O) ２ R Ａ１ , -SF ５ or -SiMe ３ and R Ａ１ is C １ -C ４ Alkyl, or C １ -C ４ Is it fluoroalkyl; Or R Ａ teeth, 【Chemistry 9】 and R Ａ２ is halogen, -CN, C １ ~C ４ Alkyl, or C １ ~C ４ is fluoroalkyl; m is 1; 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt or solvate thereof.

13. R Ａ is -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -C(CH ３ ) ３ , -CF ３ , -F, -Cl, -Br, -CN, -SCF ３ , -S(=O)CF ３ , -S(=O) ２ CF ３ , -S(=O) ２ CHF ２ , -S(=O) ２ C (CH ３ ) ３ , -S(=O) ２ -(cyclopropyl), -SF ５ or -SiMe ３ Is it; Or R Ａ teeth, 【Chemistry 10】 That is, 13. The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt or solvate thereof.

14. R １ teeth, 【Chemistry 11】 and X １ is CR ６ or N; Each R ６ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ That is, 9. The compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt or solvate thereof.

15. Y １ is -NR １１ - and R １１ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, -C(=O)NH ２ , -C(=O)R １２ Or -S(=O) ２ R １２ and R １２ is unsubstituted or substituted C １ ~C ６ Alkyl, or unsubstituted or substituted C ３ ~C ６ is cycloalkyl, 15. The compound of claim 14, or a pharma- ceutically acceptable salt or solvate thereof.

16. R ７ and R ８ are each independently hydrogen, —OH, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C １ ~C ６ Is alkoxy; Or R ７ and R ８ together with the carbon atom to which they are attached, represent an unsubstituted or substituted C ３ ~C ４ Forming a cycloalkyl; R ９ and R １０ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C １ ~C ６ Is alkoxy; Or R ９ and R １０ together with the carbon atom to which they are attached form -C(=O)-; Or R ９ and R １０ together with the carbon atom to which they are attached, represent an unsubstituted or substituted C ３ ~C ４ forming a cycloalkyl, 16. A compound according to claim 14 or 15, or a pharma- ceutically acceptable salt or solvate thereof.

17. Formula (II): 【Chemistry 12】 [In the formula, R Ａ is unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted C ３ ~C ６ Cycloalkenyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, -CN, -SF ５ or -SiMe ３ Is it; Or R Ａ teeth, 【Chemistry 13】 and R Ａ２ is halogen, -OH, -CN, C １ ~C ４ Alkyl, C １ ~C ４ f fluoroalkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Fluoroalkoxyl, or C １ ~C ４ is hydroxyalkyl; m is 0, 1, 2, or 3; X ３ and X ４ are each independently ５ or N; R ３ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R ４ is hydrogen or C ４ Is it alkyl; Or R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, or a 3- to 6-membered heterocycloalkyl; Each R ５ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and X ２ is CR １７ or N, Each R １７ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and R １８ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, unsubstituted or substituted C １ ~C ６ Alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR ２０ -(unsubstituted or substituted carbocyclic ring), -CHR ２０ -(unsubstituted or substituted heterocycle), -C(=O)R １９ , -CO ２ R １９ or -C(=O)NHR １９ and R １９ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C １０ cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl; R ２０ is hydrogen or -CH ３ and Each R ２１ are independently unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R ２２ are independently hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R ２２ together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl may be selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR ２３ , -CO ２ R ２３ , -C(=O)N(R ２３ ) ２ , -N(R ２３ ) ２ , -NR ２３ C(=O)R ２４ , -SR ２３ , -S(=O)R ２４ , -SO ２ R ２４ , or -SO ２ N (R ２３ ) ２ One or more R independently selected from the group consisting of ｓ is substituted with a group; Each R ２３ are independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R ２３ the groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R ２４ is C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. or a pharma- ceutically acceptable salt or solvate thereof.

18. R ３ is C １ ~C ６ is alkyl; R ４ is C １ ~C ６ Is it alkyl; Or R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, 18. The compound of claim 17, or a pharma- ceutically acceptable salt or solvate thereof.

19. Each R ５ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR ２１ That is, 19. A compound according to claim 17 or 18, or a pharma- ceutically acceptable salt or solvate thereof.

20. X ３ and X ４ are CR ５ and Each R ５ is hydrogen, 20. The compound according to any one of claims 17 to 19, or a pharma- ceutically acceptable salt or solvate thereof.

21. R Ａ is C １ ~C ４ Fluoroalkyl, halogen, -CN, -SF ５ or -SiMe ３ Is it; Or R Ａ teeth, 【Chemistry 14】 and R Ａ２ is halogen, C １ ~C ４ Alkyl, or C １ ~C ４ is fluoroalkyl; m is 1; 21. The compound according to any one of claims 17 to 20, or a pharma- ceutically acceptable salt or solvate thereof.

22. R Ａ is -CF ３ , -F, -Cl, -Br, -CN, -SCF ３ , -SF ５ or -SiMe ３ Is it; Or R Ａ teeth, 【Chemistry 15】 That is, 22. The compound according to any one of claims 17 to 21, or a pharma- ceutically acceptable salt or solvate thereof.

23. X ２ is CR １７ and Each R １７ are independently hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is a fluoroalkyl; 23. The compound according to any one of claims 17 to 22, or a pharma- ceutically acceptable salt or solvate thereof.

24. X ２ is CR １７ and Each R １７ is hydrogen, 24. The compound according to any one of claims 17 to 23, or a pharma- ceutically acceptable salt or solvate thereof.

25. R １８ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, unsubstituted or substituted C １ ~C ６ is alkynyl, 25. The compound according to any one of claims 17 to 24, or a pharma- ceutically acceptable salt or solvate thereof.

26. R １８ is a substitution C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ is heteroalkyl, 26. The compound of claim 25, or a pharma- ceutically acceptable salt or solvate thereof.

27. R １８ is a C substituted with -CN, -OH, or -OMe １ ~C ６ is alkyl, 27. The compound of claim 26, or a pharma- ceutically acceptable salt or solvate thereof.

28. R １８ is unsubstituted or substituted C ３ ~C １０ cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; 25. The compound according to any one of claims 17 to 24, or a pharma- ceutically acceptable salt or solvate thereof.

29. R １８ is unsubstituted or substituted C ３ ~C ６ Monocyclic cycloalkyl, unsubstituted or substituted C ５ ~C １０ bicyclic cycloalkyl, or unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; 29. The compound of claim 28, or a pharma- ceutically acceptable salt or solvate thereof.

30. R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; Or R １８ is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused or spirocyclic heterocycloalkyl; 30. The compound of claim 29, or a pharma- ceutically acceptable salt or solvate thereof.

31. R １８ is -CHR ２０ - (unsubstituted or substituted C ３ -C ６ Cycloalkyl), -CHR ２０ -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR ２０ -(unsubstituted or substituted phenyl), or -CHR ２０ -(unsubstituted or substituted 5-6 membered heteroaryl); R ２０ is hydrogen or -CH ３ That is, 25. The compound according to any one of claims 17 to 24, or a pharma- ceutically acceptable salt or solvate thereof.

32. R １８ is -C(=O)R １９ , -CO ２ R １９ or -C(=O)NHR １９ and R １９ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C １０ cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl; 25. The compound according to any one of claims 17 to 24, or a pharma- ceutically acceptable salt or solvate thereof.

33. Formula (III): 【Chemistry 16】 [In the formula, X １ is CR ６ or N; Each R ６ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and Y １ is -O-, -NR １１ - or -SO ２ - and R １１ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, -C(=O)NH ２ , -C(=O)R １２ Or -S(=O) ２ R １２ and R １２ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R ７ and R ８ are each independently hydrogen, —OH, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C １ ~C ６ Is alkoxy; Or R ７ and R ８ together with the carbon atom to which they are attached, represent an unsubstituted or substituted C ３ ~C ６ forming a cycloalkyl or an unsubstituted or substituted 3- to 6-membered heterocycloalkyl; R ９ and R １０ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C １ ~C ６ Is alkoxy; Or R ９ and R １０ together with the carbon atom to which they are attached form -C(=O)-; Or R ９ and R １０ together with the carbon atom to which they are attached, represent an unsubstituted or substituted C ３ ~C ６ forming a cycloalkyl, or an unsubstituted or substituted 3- to 6-membered heterocycloalkyl; R ３ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R ４ is hydrogen or C １ ~C ６ Is it alkyl; Or, R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, or a 3- to 6-membered heterocycloalkyl; X ２ is CR １７ or N, Each R １７ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and R １８ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, unsubstituted or substituted C １ ~C ６ Alkynyl, unsubstituted or substituted C ３ ~C １０ Cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl, -CHR ２０ -(unsubstituted or substituted carbocyclic ring), -CHR ２０ -(unsubstituted or substituted heterocycle), -C(=O)R １９ , -CO ２ R １９ or -C(=O)NHR １９ and R １９ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C １０ cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; R ２０ is hydrogen or -CH ３ and Each R ２１ are independently unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R ２２ are independently hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R ２２ together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl may be selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR ２３ , -CO ２ R ２３ , -C(=O)N(R ２３ ) ２ , -N(R ２３ ) ２ , -NR ２３ C(=O)R ２４ , -SR ２３ , -S(=O)R ２４ , -SO ２ R ２４ , or -SO ２ N (R ２３ ) ２ One or more R independently selected from the group consisting of ｓ is substituted with a group; Each R ２３ are independently hydrogen, CC １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R ２３ the groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R ２４ is C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. or a pharma- ceutically acceptable salt or solvate thereof.

34. R ３ is C １ ~C ６ is alkyl; R ４ is C １ ~C ６ Is it alkyl; Or R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, 34. The compound of claim 33, or a pharma- ceutically acceptable salt or solvate thereof.

35. X １ is CR ６ or N, Each R ６ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ That is, 35. A compound according to claim 33 or 34, or a pharma- ceutically acceptable salt or solvate thereof.

36. Y １ is -NR １１ - and R １１ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, -C(=O)NH ２ , -C(=O)R １２ Or -S(=O) ２ R １２ and R １２ is unsubstituted or substituted C １ ~C ６ Alkyl, or unsubstituted or substituted C ３ ~C ６ is cycloalkyl, 36. The compound according to any one of claims 33 to 35, or a pharma- ceutically acceptable salt or solvate thereof.

37. R ７ and R ８ are each independently hydrogen, —OH, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C １ ~C ６ Is alkoxy; Or R ７ and R ８ together with the carbon atom to which they are attached, represent an unsubstituted or substituted C ３ ~C ４ Forming a cycloalkyl; R ９ and R １０ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C １ ~C ６ Is alkoxy; Or R ９ and R １０ together with the carbon atom to which they are attached form -C(=O)-; Or R ９ and R １０ together with the carbon atom to which they are attached, represent an unsubstituted or substituted C ３ ~C ４ forming a cycloalkyl, 37. The compound according to any one of claims 33 to 36, or a pharma- ceutically acceptable salt or solvate thereof.

38. X ２ is CR １７ and Each R １７ are independently hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is a fluoroalkyl; 38. The compound according to any one of claims 33 to 37, or a pharma- ceutically acceptable salt or solvate thereof.

39. X ２ is CR １７ and Each R １７ is hydrogen, 39. The compound according to any one of claims 33 to 38, or a pharma- ceutically acceptable salt or solvate thereof.

40. R １８ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, or unsubstituted or substituted C １ ~C ６ is alkynyl, 40. The compound according to any one of claims 33 to 39, or a pharma- ceutically acceptable salt or solvate thereof.

41. R １８ is a substitution C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ is heteroalkyl, 41. The compound of claim 40, or a pharma- ceutically acceptable salt or solvate thereof.

42. R １８ is a C substituted with -CN, -OH, or -OMe １ ~C ６ is alkyl, 42. The compound of claim 41, or a pharma- ceutically acceptable salt or solvate thereof.

43. R １８ is unsubstituted or substituted C ３ ~C １０ cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl; 40. The compound according to any one of claims 33 to 39, or a pharma- ceutically acceptable salt or solvate thereof.

44. R １８ is unsubstituted or substituted C ３ ~C ６ Monocyclic cycloalkyl, unsubstituted or substituted C ５ ~C １０ It is a bicyclic cycloalkyl, or an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl.

44. The compound of claim 43, or a pharma- ceutically acceptable salt or solvate thereof.

45. R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; Or R １８ is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused or spirocyclic heterocycloalkyl; 45. The compound of claim 44, or a pharma- ceutically acceptable salt or solvate thereof.

46. R １８ is -CHR ２０ - (unsubstituted or substituted C ３ ~C ６ Cycloalkyl), -CHR ２０ -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR ２０ -(unsubstituted or substituted phenyl), or -CHR ２０ -(unsubstituted or substituted 5-6 membered heteroaryl); R ２０ is hydrogen or -CH ３ That is, 40. The compound according to any one of claims 33 to 39, or a pharma- ceutically acceptable salt or solvate thereof.

47. R １８ is -C(=O)R １９ , -CO ２ R １９ or -C(=O)NHR １９ and R １９ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C １０ cycloalkyl, unsubstituted or substituted 3- to 10-membered heterocycloalkyl; 40. The compound according to any one of claims 33 to 39, or a pharma- ceutically acceptable salt or solvate thereof.

48. Formula (IV): 【Chemistry 17】 [In the formula, R １ is unsubstituted or substituted bicyclic heteroaryl; １ When R is substituted, Ａ and 1 to 3 R ５ is substituted with; R Ａ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR Ａ１ , -S(=O)R Ａ１ , -S(=O) ２ R Ａ１ , -OR Ａ１ , -SF ５ or -SiMe ３ and R Ａ１ is C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; Each R ５ are independently hydrogen, halogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and R ３ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R ４ is hydrogen or C １ ~C ６ Is it alkyl; Or, R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, or a 3- to 6-membered heterocycloalkyl; X ２ is CR １７ or N, Each R １７ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and R １８ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, unsubstituted or substituted C １ ~C ６ Alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR ２０ -(unsubstituted or substituted carbocyclic ring), -CHR ２０ -(unsubstituted or substituted heterocycle), -C(=O)R １９ , -CO ２ R １９ or -C(=O)NHR １９ and R １９ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C １０ cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; R ２０ is hydrogen or -CH ３ and Each R ２１ are independently unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R ２２ are independently hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R ２２ together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl may be selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR ２３ , -CO ２ R ２３ , -C(=O)N(R ２３ ) ２ , -N(R ２３ ) ２ , -NR ２３ C(=O)R ２４ , -SR ２３ , -S(=O)R ２４ , -SO ２ R ２４ , or -SO ２ N (R ２３ ) ２ One or more R independently selected from the group consisting of ｓ is substituted with a group; Each R ２３ are independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R ２３ the groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R ２４ is C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. or a pharma- ceutically acceptable salt or solvate thereof.

49. R ３ is C １ -C ６ is alkyl; R ４ is C １ -C ６ Is it alkyl; Or R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, 49. The compound of claim 48, or a pharma- ceutically acceptable salt or solvate thereof.

50. R Ａ is C １ ~C ４ Alkyl, C １ ~C ４ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR Ａ１ , -S(=O)R Ａ１ , -S(=O) ２ R Ａ１ , -OR Ａ１ , -SF ５ or -SiMe ３ and R Ａ１ is C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; Each R ５ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR ２１ That is, 50. A compound according to claim 48 or 49, or a pharma- ceutically acceptable salt or solvate thereof.

51. R Ａ is C １ ~C ４ Alkyl, C １ ~C ４ Fluoroalkyl, or C ３ ~C ６ is cycloalkyl; Each R ５ are independently hydrogen or C １ ~C ６ is alkyl, 51. The compound according to any one of claims 48 to 50, or a pharma- ceutically acceptable salt or solvate thereof.

52. X ２ is CR １７ and Each R １７ is hydrogen, 52. The compound according to any one of claims 48 to 51, or a pharma- ceutically acceptable salt or solvate thereof.

53. R １８ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, unsubstituted or substituted C １ ~C ６ is alkynyl; Or R １８ is a substitution C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ is heteroalkyl; Or R １８ is a C substituted with -CN, -OH, or -OMe １ ~C ６ Is it alkyl; Or R １８ is unsubstituted or substituted C ３ ~C １０ cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Or R １８ is unsubstituted or substituted C ３ ~C ６ Monocyclic cycloalkyl, unsubstituted or substituted C ５ ~C １０ a bicyclic cycloalkyl, or an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; Or R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; Or R １８ is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl; Or R １８ is -CHR ２０ - (unsubstituted or substituted C ３ ~C ６ Cycloalkyl), -CHR ２０ -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR ２０ -(unsubstituted or substituted phenyl), or -CHR ２０ - (unsubstituted or substituted 5- or 6-membered heteroaryl; R ２０ is hydrogen or -CH ３ Is it; Or R １８ is -C(=O)R １９ , -CO ２ R １９ or -C(=O)NHR １９ and R １９ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C １０ cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl; 53. A compound according to any one of claims 48 to 52, or a pharma- ceutically acceptable salt or solvate thereof.

54. Formula (V): 【Chemistry 18】 [In the formula, R Ａ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR Ａ１ , -S(=O)R Ａ１ , -S(=O) ２ R Ａ１ , -OR Ａ１ , -SF ５ or -SiMe ３ and R Ａ１ is C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; R ３ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R ４ is hydrogen or C １ ~C ６ Is it alkyl; Or, R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, or a 3- to 6-membered heterocycloalkyl; R ５ is hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and X ２ is CR １７ or N, Each R １７ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and R １８ is hydrogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, unsubstituted or substituted C １ -C ６ Heteroalkyl, unsubstituted or substituted C １ -C ６ Alkenyl, unsubstituted or substituted C １ -C ６ Alkynyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CHR ２０ -(unsubstituted or substituted carbocyclic ring), -CHR ２０ -(unsubstituted or substituted heterocycle), -C(=O)R １９ , -CO ２ R １９ or -C(=O)NHR １９ and R １９ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C １０ cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; R ２０ is hydrogen or -CH ３ and Each R ２１ are independently unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R ２２ are independently hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R ２２ together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl may be selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR ２３ , -CO ２ R ２３ , -C(=O)N(R ２３ ) ２ , -N(R ２３ ) ２ , -NR ２３ C(=O)R ２４ , -SR ２３ , -S(=O)R ２４ , -SO ２ R ２４ , or -SO ２ N (R ２３ ) ２ One or more R independently selected from the group consisting of ｓ is substituted with a group; Each R ２３ are independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R ２３ the groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R ２４ is C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. or a pharma- ceutically acceptable salt or solvate thereof.

55. R ３ is C １ ~C ６ is alkyl; R ４ is C １ ~C ６ Is it alkyl; Or R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, 55. The compound of claim 54, or a pharma- ceutically acceptable salt or solvate thereof.

56. R Ａ is C １ ~C ４ Alkyl, C １ ~C ４ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, halogen, -CN, -SR Ａ１ , -S(=O)R Ａ１ , -S(=O) ２ R Ａ１ , -OR Ａ１ , -SF ５ or -SiMe ３ and R Ａ１ is C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; Each R ５ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR ２１ It is.

56. A compound according to claim 54 or 55, or a pharma- ceutically acceptable salt or solvate thereof.

57. R Ａ is C １ ~C ４ Alkyl, C １ ~C ４ Fluoroalkyl, or C ３ ~C ６ is cycloalkyl; Each R ５ are independently hydrogen or C １ ~C ６ is alkyl, 57. A compound according to any one of claims 54 to 56, or a pharma- ceutically acceptable salt or solvate thereof.

58. X ２ is CR １７ and Each R １７ is hydrogen, 58. A compound according to any one of claims 54 to 57, or a pharma- ceutically acceptable salt or solvate thereof.

59. R １８ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, or unsubstituted or substituted C １ ~C ６ is alkynyl; Or R １８ is a substitution C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ is heteroalkyl; Or R １８ is a C substituted with -CN, -OH, or -OMe １ ~C ６ Is it alkyl; Or R １８ is unsubstituted or substituted C ３ ~C １０ cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Or R １８ is unsubstituted or substituted C ３ ~C ６ Monocyclic cycloalkyl, unsubstituted or substituted C ５ ~C １０ a bicyclic cycloalkyl, or an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; Or R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; Or R １８ is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused, or spirocyclic heterocycloalkyl; Or R １８ is -CHR ２０ - (unsubstituted or substituted C ３ ~C ６ Cycloalkyl), -CHR ２０ -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR ２０ -(unsubstituted or substituted phenyl), or -CHR ２０ - (unsubstituted or substituted 5- or 6-membered heteroaryl; R ２０ is hydrogen or -CH ３ Is it; Or R １８ is -C(=O)R １９ , -CO ２ R １９ or -C(=O)NHR １９ and R １９ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C １０ cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl; 59. A compound according to any one of claims 54 to 58, or a pharma- ceutically acceptable salt or solvate thereof.

60. Formula (VI): 【Chemistry 19】 [In the formula, R Ａ is unsubstituted or substituted C １ ~C ６ is alkyl; X ３ and X ４ are each independently ５ or N; R ３ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R ４ is hydrogen or C １ ~C ６ Is it alkyl; Or, R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, or a 3- to 6-membered heterocycloalkyl; Each R ５ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, -CN, -OH, -OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and X ２ is CR １７ or N, Each R １７ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and R １８ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, or unsubstituted or substituted C １ ~C ６ is alkynyl; Or R １８ is substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl; Or R １８ is unsubstituted or substituted C ５ ~C １０ is a bicyclic cycloalkyl; Or R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; Or R １８ is -CHR ２０ -(unsubstituted or substituted carbocycle), or -CHR ２０ -(unsubstituted or substituted heterocycle); R ２０ is hydrogen or -CH ３ and Each R ２１ are independently unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R ２２ are independently hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R ２２ together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl may be selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR ２３ , -CO ２ R ２３ , -C(=O)N(R ２３ ) ２ , -N(R ２３ ) ２ , -NR ２３ C(=O)R ２４ , -SR ２３ , -S(=O)R ２４ , -SO ２ R ２４ , or -SO ２ N (R ２３ ) ２ One or more R independently selected from the group consisting of ｓ is substituted with a group; Each R ２３ are independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R ２３ the groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R ２４ is C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. or a pharma- ceutically acceptable salt or solvate thereof.

61. R ３ is C １ ~C ６ is alkyl; R ４ is C １ ~C ６ Is it alkyl; Or R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, 61. The compound of claim 60, or a pharma- ceutically acceptable salt or solvate thereof.

62. Each R ５ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR ２１ That is, 62. A compound according to claim 60 or 61, or a pharma- ceutically acceptable salt or solvate thereof.

63. X ３ and X ４ are CR ５ and Each R ５ is hydrogen, 63. A compound according to any one of claims 60 to 62, or a pharma- ceutically acceptable salt or solvate thereof.

64. R Ａ is C １ ~C ４ is alkyl, 64. A compound according to any one of claims 60 to 63, or a pharma- ceutically acceptable salt or solvate thereof.

65. R Ａ is isopropyl or tert-butyl; 65. A compound according to any one of claims 60 to 64, or a pharma- ceutically acceptable salt or solvate thereof.

66. X ２ is CR １７ and Each R １７ are independently hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is a fluoroalkyl; 66. A compound according to any one of claims 60 to 65, or a pharma- ceutically acceptable salt or solvate thereof.

67. X ２ is CR １７ and Each R １７ is hydrogen, 67. A compound according to any one of claims 60 to 66, or a pharma- ceutically acceptable salt or solvate thereof.

68. R １８ is unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, or unsubstituted or substituted C １ ~C ６ is alkynyl, 68. A compound according to any one of claims 60 to 67, or a pharma- ceutically acceptable salt or solvate thereof.

69. R １８ is a substitution C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, or unsubstituted or substituted C １ ~C ６ is heteroalkyl; Or R １８ is a C substituted with -CN, -OH, or -OMe １ ~C ６ is alkyl, 69. The compound of claim 68, or a pharma- ceutically acceptable salt or solvate thereof.

70. R １８ is substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or unsubstituted or substituted cyclohexyl; 68. A compound according to any one of claims 60 to 67, or a pharma- ceutically acceptable salt or solvate thereof.

71. R １８ is an unsubstituted or substituted C which is a bridged, fused or spirocyclic cycloalkyl; ５ ~C １０ is a bicyclic cycloalkyl, 68. A compound according to any one of claims 60 to 67, or a pharma- ceutically acceptable salt or solvate thereof.

72. R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; Or R １８ is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl containing an oxygen atom which is a bridged, fused or spirocyclic heterocycloalkyl; 68. A compound according to any one of claims 60 to 67, or a pharma- ceutically acceptable salt or solvate thereof.

73. R １８ is -CHR ２０ - (unsubstituted or substituted C ３ ~C ６ Cycloalkyl), -CHR ２０ -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR ２０ -(unsubstituted or substituted phenyl), or -CHR ２０ -(unsubstituted or substituted 5-6 membered heteroaryl); R ２０ is hydrogen or -CH ３ That is, 68. A compound according to any one of claims 60 to 67, or a pharma- ceutically acceptable salt or solvate thereof.

74. Formula (VII): 【Chemistry 20】 [In the formula, R Ａ１ is C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; X ３ and X ４ are each independently ５ or N; R ２ teeth, 【Chemistry 21】 and R ｃ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, -C(=O)N(R ２２ ) ２ , -C(=O)R ２１ , -C(=O)OR ２２ Or -S(=O) ２ R ２１ and X ２ is CR １７ or N, Each R １７ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -OC(=O)R ２１ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and R １３ and R １４ are each independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, phenyl, monocyclic heteroaryl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, -OH, -OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ or -OC(=O)R ２１ Is it; Or R １３ and R １４ together with the carbon atom to which they are attached form -C(=O)-; Or R １３ and R １４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, or a 3- to 6-membered heterocycloalkyl; Y ２ is -(CR １５ R １６ ) ｎ -, -O-, or -O-CR １５ R １６ - and Each R １５ and R １６ are independently hydrogen, halogen, cyano, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C １ ~C ６ Alkoxy, phenyl, monocyclic heteroaryl, C ３ ~C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; Or R １４ and one R on an adjacent carbon atom １６ together form an alkene bond; n is 1 or 2; Or, R ２ teeth, 【Chemical 22】 and X ２ is CR １７ or N; Each R １７ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ fluoroalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ Cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, —CN, —OH, —OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and R １８ is a substitution C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, or unsubstituted or substituted C １ ~C ６ is alkynyl; Or R １８ is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or substituted cyclohexyl; Or R １８ is unsubstituted or substituted C ５ ~C １０ is a bicyclic cycloalkyl; Or R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; Or R １８ is -CHR ２０ -(unsubstituted or substituted carbocycle), or -CHR ２０ -(unsubstituted or substituted heterocycle); R ２０ is hydrogen or -CH ３ and R ３ is hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Alkoxy, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, or unsubstituted or substituted 3-6 membered heterocycloalkyl; R ４ is hydrogen or C １ ~C ６ Is it alkyl; Or, R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, or a 3- to 6-membered heterocycloalkyl; Each R ５ are independently hydrogen, halogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, -CN, -OH, -OR ２１ , -CO ２ R ２２ , -N(R ２２ ) ２ , -C(=O)N(R ２２ ) ２ , -NR ２２ C(=O)R ２１ , -S(=O) ２ N (R ２２ ) ２ , or -NR ２２ S (=O) ２ R ２１ and Each R ２１ are independently unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3-6 membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Each R ２２ are independently hydrogen, unsubstituted or substituted C １ ~C ６ Alkyl, unsubstituted or substituted C ３ ~C ６ cycloalkyl, unsubstituted or substituted 3- to 6-membered heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; or two R ２２ together with the N atom to which they are attached form an unsubstituted or substituted N-containing heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl may be selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR ２３ , -CO ２ R ２３ , -C(=O)N(R ２３ ) ２ , -N(R ２３ ) ２ , -NR ２３ C(=O)R ２４ , -SR ２３ , -S(=O)R ２４ , -SO ２ R ２４ , or -SO ２ N (R ２３ ) ２ One or more R independently selected from the group consisting of ｓ is substituted with a group; Each R ２３ are independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R ２３ the groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R ２４ is C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. or a pharma- ceutically acceptable salt or solvate thereof.

75. R ３ is C １ ~C ６ is alkyl; R ４ is C １ -C ６ Is it alkyl; Or R ３ and R ４ together with the carbon atom to which they are attached, ３ ~C ６ forming a cycloalkyl, 75. The compound of claim 74, or a pharma- ceutically acceptable salt or solvate thereof.

76. Each R ５ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, -CN, or -OR ２１ It is.

76. A compound according to claim 74 or 75, or a pharma- ceutically acceptable salt or solvate thereof.

77. X ３ and X ４ are CR ５ and R ５ is hydrogen, 77. A compound according to any one of claims 74 to 76, or a pharma- ceutically acceptable salt or solvate thereof.

78. R Ａ１ is C １ ~C ４ Alkyl, or C １ ~C ４ is a fluoroalkyl; 78. A compound according to any one of claims 74 to 77, or a pharma- ceutically acceptable salt or solvate thereof.

79. R ２ teeth, 【Chemistry 23】 That is, 79. A compound according to any one of claims 74 to 78, or a pharma- ceutically acceptable salt or solvate thereof.

80. R ｃ is hydrogen, C １ ~C ６ Alkyl, or -C(=O)OR ２２ and X ２ is CR １７ and Each R １７ are independently hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is fluoroalkyl; R １３ and R １４ are each independently hydrogen, halogen, or C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ cycloalkyl, or 3-6 membered heterocycloalkyl; Or R １３ and R １４ together with the carbon atom to which they are attached form -C(=O)-; Or R １３ and R １４ together with the carbon atom to which they are attached, ３ ~C ４ Forming a cycloalkyl; Y ２ is -(CR １５ R １６ ) ｎ -, -O-, or -O-CR １５ R １６ - and Each R １５ and R １６ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C ３ ~C ６ is cycloalkyl; Or R １４ and one R on an adjacent carbon atom １６ together form an alkene bond 80. The compound of claim 79, or a pharma- ceutically acceptable salt or solvate thereof.

81. R ｃ is hydrogen; X ２ is CR １７ and Each R １７ is hydrogen; R １３ and R １４ are each hydrogen; Or R １３ and R １４ together with the carbon atom to which they are attached form -C(=O)-; Y ２ is -(CR １５ R １６ ) ｎ -, -O-, or -O-CR １５ R １６ - is, 81. A compound according to claim 79 or 80, or a pharma- ceutically acceptable salt or solvate thereof.

82. Each R １５ and R １６ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, or C ３ ~C ６ is cycloalkyl, 82. A compound according to any one of claims 79 to 81, or a pharma- ceutically acceptable salt or solvate thereof. 【Request 83】 【Chemical 24】 teeth, 【Chemistry 25】 and Y ２ is -CR １５ R １６ - or -CR １５ R １６ -CR １５ R １６ - is, 83. A compound according to any one of claims 79 to 82, or a pharma- ceutically acceptable salt or solvate thereof.

84. 【Catalogue 26】 teeth, 【Chemical 27】 That is, 84. A compound according to any one of claims 79 to 83, or a pharma- ceutically acceptable salt or solvate thereof.

85. R １４ and one R on an adjacent carbon atom １６ are taken together to form an alkene bond, 84. A compound according to any one of claims 79 to 83, or a pharma- ceutically acceptable salt or solvate thereof.

86. R ２ teeth, 【Chemistry 28】 That is, 79. A compound according to any one of claims 74 to 78, or a pharma- ceutically acceptable salt or solvate thereof.

87. X ２ is CR １７ and Each R １７ are independently hydrogen, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is a fluoroalkyl; 87. The compound of claim 86, or a pharma- ceutically acceptable salt or solvate thereof.

88. X ２ is CR １７ and Each R １７ is hydrogen, 88. A compound according to claim 86 or 87, or a pharma- ceutically acceptable salt or solvate thereof.

89. R １８ is a substitution C １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ Heteroalkyl, unsubstituted or substituted C １ ~C ６ Alkenyl, unsubstituted or substituted C １ ~C ６ is alkynyl, 89. A compound according to any one of claims 86 to 88, or a pharma- ceutically acceptable salt or solvate thereof.

90. R １８ is replaced １ ~C ６ Alkyl, unsubstituted or substituted C １ ~C ６ Fluoroalkyl, unsubstituted or substituted C １ ~C ６ It is heteroalkyl. Or R １８ is a C substituted with -CN, -OH, or -OMe １ ~C ６ is alkyl, 90. The compound of claim 89, or a pharma- ceutically acceptable salt or solvate thereof.

91. R １８ is unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl, or substituted cyclohexyl; 89. A compound according to any one of claims 86 to 88, or a pharma- ceutically acceptable salt or solvate thereof.

92. R １８ is an unsubstituted or substituted C which is a bridged, fused or spirocyclic heterocycloalkyl; ５ ~C １０ is a bicyclic cycloalkyl, 89. A compound according to any one of claims 86 to 88, or a pharma- ceutically acceptable salt or solvate thereof.

93. R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; 89. A compound according to any one of claims 86 to 88, or a pharma- ceutically acceptable salt or solvate thereof.

94. R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; Or R １８ is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused or spirocyclic heterocycloalkyl; 94. The compound of claim 93, or a pharma- ceutically acceptable salt or solvate thereof.

95. R １８ is -CHR ２０ - (unsubstituted or substituted C ３ -C ６ Cycloalkyl), -CHR ２０ -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), -CHR ２０ -(unsubstituted or substituted phenyl), or -CHR ２０ -(unsubstituted or substituted 5-6 membered heteroaryl); R ２０ is hydrogen or -CH ３ That is, 89. A compound according to any one of claims 86 to 88, or a pharma- ceutically acceptable salt or solvate thereof.

96. Formula (VIII): 【Chemical 29】 [In the formula, R Ａ , -SCF ３ , -S(=O)CF ３ Or -S(=O) ２ CF ３ and R ３ is unsubstituted or is —OH, phenyl, benzyl, C ３ ~C ６ Cycloalkyl or -CH ２ C substituted with OH ２ ~C ６ is alkyl; R ４ is hydrogen or methyl; Or, R ３ and R ４ together with the carbon atom to which they are attached form a cyclobutyl, cyclopentyl, or cyclohexyl. or a pharma- ceutically acceptable salt or solvate thereof.

97. R Ａ , -SCF ３ Or -S(=O) ２ CF ３ That is, 97. The compound of claim 96, or a pharma- ceutically acceptable salt or solvate thereof.

98. R ３ is unsubstituted or is —OH, phenyl, benzyl, C ３ ~C ６ Cycloalkyl or -CH ２ C substituted with OH ２ ~C ６ is alkyl; R ４ is hydrogen or methyl; 98. A compound according to claim 96 or 97, or a pharma- ceutically acceptable salt or solvate thereof.

99. R ３ is ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or -CH ２ OH; R ４ is hydrogen or methyl; 99. The compound of claim 98, or a pharma- ceutically acceptable salt or solvate thereof.

100. R ３ and R ４ together with the carbon atom to which they are attached form cyclobutyl, cyclopentyl, or cyclohexyl; 98. A compound according to claim 96 or 97, or a pharma- ceutically acceptable salt or solvate thereof.

101. Formula (IX): 【Chemistry 30】 [In the formula, R Ａ is -SR Ａ１ , -S(=O)R Ａ１ Or -S(=O) ２ R Ａ１ and R Ａ１ is C １ ~C ４ Alkyl, C １ ~C ４ Fluoroalkyl, or C ３ ~C ６ is cycloalkyl; R １８ is a C substituted with -CN, -OH, or -OMe １ ~C ６ Is it alkyl; Or R １８ is unsubstituted or substituted C １ -C ６ Fluoroalkyl, or unsubstituted or substituted C １ -C ６ is heteroalkyl; Or R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; Or R １８ is -CHR ２０ - (unsubstituted or substituted C ３ ~C ６ Cycloalkyl), -CHR ２０ -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), or -CHR ２０ -(unsubstituted or substituted 5-membered heteroaryl); R ２０ is hydrogen or -CH ３ Is it; Or R １８ is -C(=O)R １９ and R １９ is an unsubstituted or substituted 3-10 membered heterocycloalkyl; Or, R １８ is -C(=O)NHR １９ and R １９ is unsubstituted or substituted C ３ ~C １０ cycloalkyl, or unsubstituted or substituted 3-10 membered heterocycloalkyl; Each substituted alkyl, substituted fluoroalkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocycloalkyl may be selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, 6-membered heteroaryl, -CN, -OR ２３ , -CO ２ R ２３ , -C(=O)N(R ２３ ) ２ , -N(R ２３ ) ２ , -NR ２３ C(=O)R ２４ , -SR ２３ , -S(=O)R ２４ , -SO ２ R ２４ , or -SO ２ N (R ２３ ) ２ One or more R independently selected from the group consisting of ｓ is substituted with a group; Each R ２３ are independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R ２３ the groups taken together with the N atom to which they are attached form a 3- to 6-membered N-containing heterocycloalkyl; Each R ２４ is C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. or a pharma- ceutically acceptable salt or solvate thereof.

102. R Ａ１ is C １ ~C ４ Alkyl, or C １ ~C ４ is a fluoroalkyl; 102. The compound of claim 101, or a pharma- ceutically acceptable salt or solvate thereof.

103. R Ａ , -SCF ３ , -S(=O)CF ３ , -S(=O) ２ CF ３ , -S(=O) ２ CHF ２ , -S(=O) ２ C (CH ３ ) ３ Or -S(=O) ２ -(cyclopropyl).

103. A compound according to claim 101 or 102, or a pharma- ceutically acceptable salt or solvate thereof.

104. R １８ is a C substituted with -CN, -OH, or -OMe １ ~C ６ is alkyl, 104. The compound according to any one of claims 101 to 103, or a pharma- ceutically acceptable salt or solvate thereof.

105. R １８ is unsubstituted or substituted C １ ~C ６ Fluoroalkyl, or unsubstituted or substituted C １ ~C ６ is heteroalkyl, 104. The compound according to any one of claims 101 to 103, or a pharma- ceutically acceptable salt or solvate thereof.

106. Or R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl; 104. The compound according to any one of claims 101 to 103, or a pharma- ceutically acceptable salt or solvate thereof.

107. R １８ is an unsubstituted or substituted 3-10 membered monocyclic or bicyclic heterocycloalkyl containing an oxygen atom; Or R １８ is an unsubstituted or substituted 5-10 membered bicyclic heterocycloalkyl which is a bridged, fused or spirocyclic heterocycloalkyl; 107. The compound of claim 106, or a pharma- ceutically acceptable salt or solvate thereof.

108. R １８ is -CHR ２０ - (unsubstituted or substituted C ３ ~C ６ Cycloalkyl), -CHR ２０ -(unsubstituted or substituted 3- to 6-membered heterocycloalkyl), or -CHR ２０ -(unsubstituted or substituted 5-membered heteroaryl); R ２０ is hydrogen or -CH ３ It is.

104. The compound according to any one of claims 101 to 103, or a pharma- ceutically acceptable salt or solvate thereof.

109. R １８ is -C(=O)R １９ and R １９ is unsubstituted or substituted 3-10 membered heterocycloalkyl; 104. The compound according to any one of claims 101 to 103, or a pharma- ceutically acceptable salt or solvate thereof.

110. R １８ is -C(=O)NHR １９ and R １９ is unsubstituted or substituted C ３ ~C １０ cycloalkyl, or unsubstituted or substituted 3- to 10-membered heterocycloalkyl; 104. The compound according to any one of claims 101 to 103, or a pharma- ceutically acceptable salt or solvate thereof.

111. A compound selected from any one of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, or Table 10, or a pharma- ceutically acceptable salt or solvate thereof.

112. A pharmaceutical composition comprising a compound according to any one of claims 1 to 111, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient.

113. 113. The pharmaceutical composition of claim 112, formulated for administration to a mammal by intravenous, subcutaneous, oral, inhalation, nasal, transdermal, or ocular administration.

114. 113. The pharmaceutical composition of claim 112, in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

115. 130. Use of a compound according to any one of claims 1 to 111, or a pharma- ceutically acceptable salt or solvate thereof, in the treatment of a disease or condition in a mammal that benefits from modulation of the insulin-like growth factor 1 receptor (IGF-1R).

116. 116. The use of claim 115, wherein the disease or condition is thyroid eye disease (TED).

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