Thienothiadiazines, their preparation and their therapeutic application

Abstract

Disclosed are compounds of formula (I), or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, A, and n are defined herein. Also disclosed are methods of preparing such compounds, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders.

Description

THIENOTHIADIAZINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to European Application No. EP23306384.1, filed August 17, 2023, the disclosure of which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] Disclosed herein are substituted thienothiadiazine compounds, processes for their preparation, pharmaceutical compositions containing the compounds, as well as therapeutic uses thereof. BACKGROUND

[0003] MRGPRX2 is a G-protein coupled receptor (GPCR) expressed on mast cells involved in inflammation pathways, including the non-histaminergic activation of mast cells. See Meixong, J., et al., Immunity, 50, 1163-1171 (2019). MRGPRX2 is a member of the X subfamily of the Mas family of GPCRs. MRGPRX2 is activated by numerous secretagogues, including neuropeptides, eosinophil granule proteins, and antimicrobial peptides. In response to MRGPRX2 activation, mast cells may undergo degranulation and release tryptase, which preferentially triggers non- histaminergic itch, as well as chymase, carboxipeptidases, histamine, serotonin, chemokines, and cytokines. See Corbiere, A., et al., Experimental Dermatology 30, 193-200 (2020). This activation can lead to type 2 inflammation, pruritis, and pain. Preclinical data demonstrates that blocking the activation of MRGPRX2 has the potential to effectively treat a range of mast-cell-mediated diseases. See, e.g., Meixong, J., et al.; Ogasawara, H. & Noguchi, M., Cells, 10, 2906 (2021); Quan, P.L., et al., Intl. J. Molecular Sciences, 22, 4421 (2021); Al Hamwi, G., et al., Pharmacology & Therapeutics, 2:38, 108529 (2022).

[0004] Currently used treatments for inflammatory diseases typically have one or more of the following drawbacks: limited efficacy, need for injection, or significant side effects. MRGPRX2 antagonists of the present disclosure may provide safe, oral, and efficacious treatments for diseases, disorders and conditions involving inflammation, itch, and / or pain. BRIEF SUMMARY

[0005] The present disclosure describes substituted thienothiadiazine compounds, processes for their preparation, pharmaceutical compositions containing the compounds, as well as therapeutic uses thereof.

[0006] One aspect of the present disclosure is a compound of formula I, I, wherein: R1is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, heteroaryl, - C(=O)R10, -C(=O)OR11, and -C(=O)NR11R12, wherein when R1 is alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, or heteroaryl, R1 is unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or - S(=O)2NR11R12; R2is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, heteroaryl, - C(=O)R10, -C(=O)OR11, and -C(=O)NR11R12, wherein when R2is alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, or heteroaryl, R2is unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or - S(=O)2NR11R12; R3 is selected from hydrogen, halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6haloalkyl; each instance of R4is independently selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl; R5is selected from halogen, cyano, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, -OR7, -NR7R8, -N+(O-)R7R8, -SR7, - C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -OC(=O)R6, -OC(=O)OR7, -OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, -NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8, wherein when R5 is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, aryl, or heteroaryl, R5is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, - OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from alkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, - S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or -S(=O)(=NR9)NR11R12; R7and R8are independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, - N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12; each instance of R9is independently selected from hydrogen and C1-C4alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, 3- to 6-membered heterocyclyl, C1-C33- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl; each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, C1-C4heteroalkyl, 3- to 6-membered heterocyclyl, C1-C33- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3monocyclic heteroarylalkyl, C1-C3acyl, and C1- C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; A is a monocyclic ring selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; and n is 0, 1, or 2, provided that when A is a phenyl ring, n is 1 or 2; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0007] One embodiment is a compound of formula I, wherein: R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6 phenylalkyl, phenyl, monocyclic heteroaryl, -C(=O)R10, -C(=O)OR11, and - C(=O)NR11R12, wherein when R1is C1-C6alkyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6phenylalkyl, phenyl, or monocyclic heteroaryl, R1is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6 phenylalkyl, phenyl, monocyclic heteroaryl, -C(=O)R10, -C(=O)OR11, and - C(=O)NR11R12, wherein when R2 is C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6phenylalkyl, phenyl, or monocyclic heteroaryl, R2is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R5 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6-membered heterocyclylalkyl, C1-C6 phenylalkyl, C1-C6 monocyclic heteroarylalkyl, phenyl, monocyclic heteroaryl, -OR7, -NR7R8, -N+(O-)R7R8, -SR7, - C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -OC(=O)R6, -OC(=O)OR7, - OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, -NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8, wherein when R5is C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6-membered heterocyclylalkyl, C1-C6 phenylalkyl, C1-C6 monocyclic heteroarylalkyl, phenyl, or monocyclic heteroaryl, R5 is unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - S(=O)2R10, or -S(=O)2NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6-membered heterocyclylalkyl, phenyl, C1-C6phenylalkyl, monocyclic heteroaryl, and C1-C6 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or -S(=O)(=NR9)NR11R12; andR7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3- C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6- membered heterocyclylalkyl, phenyl, C1-C6 phenylalkyl, monocyclic heteroaryl, and C1-C6 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12; A is a monocyclic ring selected from C5-C6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and monocyclic heteroaryl; and or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0008] One embodiment is a compound of formula I, wherein: R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R2is selected from hydrogen, C1-C6alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R2is C1-C6alkyl, benzyl, or phenyl, R2is unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, or -NR11R12; R3is selected from hydrogen, halogen, and C1-C4alkyl; R4 is selected from halogen and C1-C4 alkyl; R5 is selected from halogen, C1-C6 alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12;R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; A is selected from phenyl, piperidinyl, and tetrahydropyridinyl; and n is 1; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0009] One embodiment is a compound of formula I, wherein: R1 is selected from methyl and benzyl; R2 is selected from hydrogen and acetyl; R3is selected from hydrogen, chloro, fluoro, bromo, methyl, and ethyl; R4is selected from chloro, fluoro, and methyl; R5is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7and R8are independently selected from hydrogen and C1-C4alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom;A is selected from phenyl, piperid-4-yl, and 1,2,3,6-tetrahydropyridin-4-yl; and n is 1; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0010] One embodiment is a compound of formula I, wherein the compound is of formula I- A1,I-A1, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0011] One embodiment is a compound of formula I, wherein the compound is of formula I- A2 ,or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0012] One embodiment is a compound of formula I, wherein the compound is of formula I- B1, I-B1, wherein is a single or a double bond; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0013] One embodiment is a compound of formula I, wherein R1is selected from hydrogen, C1-C6alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R2is C1-C6alkyl, benzyl, or phenyl, R2is unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, or -NR11R12; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0014] One embodiment is a compound of formula I, wherein R2 is hydrogen; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0015] One embodiment is a compound of formula I, wherein R3 is selected from hydrogen, halogen, and C1-C4 alkyl; and R4 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0016] One embodiment is a compound of formula I, whereinR5 is selected from halogen, C1-C6 alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NH)R6; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0017] One embodiment is a compound selected from: 3-(Benzylamino)-6-chloro-5-(2,3-difluorophenyl)-4H-thieno[3,2-e][1,2,4]thiadiazine 1,1- dioxide (Compound 1); N-Benzyl-5-(2,3-difluorophenyl)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (Compound 2); 6-Chloro-5-(2,3-difluorophenyl)-3-(methylamino)-2H-thieno[3,2-e][1,2,4]thiadiazine 1,1- dioxide (Compound 3); 5-(2,3-Difluorophenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (Compound 4); 6-Chloro-5-(2-chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 5); 5-(2-Chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- amine (Compound 6); 5-(2-Chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 7); 5-(2-Chloro-4-methylsulfinyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 8); 5-(2-Chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 9); 5-[2-Chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 10); N-[6-Chloro-5-(2-chloro-3-fluoro-phenyl)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- yl]-N-methyl-acetamide (Compound 11); Methyl 3-chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]benzoate (Compound 12); 3-Chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzoic acid (Compound 13);3-Chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzamide (Compound 14); 5-(2-Chloro-3-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine (Compound 15); 5-(3-Chloro-2-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine (Compound 16); N-[5-(2-Chloro-3-fluoro-phenyl)-6-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-yl]-N-methyl-acetamide (Compound 17); 6-Chloro-5-(2-chloro-4-(methylsulfinyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide (Compound 18); 6-Chloro-5-[2-chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (Compound 19); 6-Chloro-5-(2-chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 20); 5-(2-Chloro-3-fluoro-phenyl)-6-ethyl-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 21); 5-(2-Chloro-4-(methylsulfonyl)phenyl)-6-ethyl-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide (Compound 22); 6-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 23); 6-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (atropisomer 1) (Compound 24); 6-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (atropisomer 2) (Compound 25); 6-Chloro-5-(2-chloro-4-(ethylthio)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide (Compound 26); 6-Chloro-5-(2-chloro-4-(ethylsulfinyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide (Compound 27); 6-Chloro-5-(2-chloro-4-(ethylsulfonyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide (Compound 28);6-Ethyl-N-methyl-5-[(3S*,4S*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (Compound 29); and 6-Ethyl-N-methyl-5-[(3R*,4R*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (Compound 30); or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0018] Another aspect of the present disclosure is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0019] Another aspect of the present disclosure is a method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from an inflammatory disorder, an allergic disorder, a skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.

[0020] Another aspect of the present disclosure is a method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, heriditary alpha tryptasemia, chronic itch, and chronic pain.

[0021] In one embodiment, the disease, disorder, or condition is selected from atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma.

[0022] Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0023] Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.

[0024] Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, heriditary alpha tryptasemia, chronic itch, and chronic pain.

[0025] In one embodiment, the disease, disorder, or condition is selected from atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma.

[0026] Another aspect of the present disclosure is a medicament, characterized in that it comprises the compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0027] Another aspect of the present disclosure is the use of a compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, for preparing a medicament intended for the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder. DETAILED DESCRIPTION

[0028] It is to be understood that the disclosed embodiments are merely examples of the disclosure, which may be embodied in various forms. Well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail. Therefore,specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed structure.

[0029] As used herein, the term “alkyl” refers to a linear or branched saturated hydrocarbon group. A CX-CYalkyl group refers to an alkyl group having between X and Y carbon atoms, for example a C1-C6alkyl group refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, pentyl, isopentyl, neopentyl, and the like.

[0030] As used herein, the term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms have been substituted by a halogen atom. A CX-CY haloalkyl group refers to a haloalkyl group having between X and Y carbon atoms, for example a C1-C6haloalkyl group refers to a haloalkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms (in addition to one or more halogen atoms). Exemplary haloalkyl groups include chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1,2-difluoroethyl, 1,1,2,2-tetrafluoroethyl, and the like.

[0031] As used herein, the term “halogen” refers to fluoro, chloro, bromo, and iodo.

[0032] As used herein, the term “heteroalkyl” refers to a linear or branched, non-cyclic saturated group containing 1, 2, or 3 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different. Heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylthio, and alkylthioalkyl groups. A CX-CYheteroalkyl group refers to a heteroalkyl group having between X and Y carbon atoms, for example a C1-C6 heteroalkyl group refers to a heteroalkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms (in addition to 1, 2, or 3 heteroatoms). Exemplary heteroalkyl groups include methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxymethyl, 2-methoxyethyl, 2-methoxyethoxy, (2-hydroxyethoxy)ethyl, (2-methoxyethoxy)ethyl, 3-hydroxy-2- (hydroxymethyl)propyl, 3-methoxy-2-(methoxymethyl)propyl, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, methanethiolato, ethanethiolato, or the like.

[0033] As used herein, the term “aryl” refers to an aromatic monocyclic or bicyclic ring system containing between 5 and 10 carbon atoms. Exemplary aryl groups include phenyl and naphthyl.

[0034] As used herein, the term “arylalkyl” refers to an alkyl group substituted with an aryl group. A CX-CY arylalkyl group refers to an arylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3 arylalkyl group refers to an arylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with an aryl group. Exemplary arylalkyl groups include benzyl and phenethyl.

[0035] As used herein, the term “cycloalkyl” refers to a non-aromatic monocyclic ring system. A CX-CY cycloalkyl group refers to a cycloalkyl group having between X and Y carbon atoms, for example a C3-C6 cycloalkyl group refers to a cycloalkyl group having 3, 4, 5, or 6 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0036] As used herein, the term “heteroaryl” refers to a cyclic aromatic group containing between 1 and 10 carbon atoms and containing between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different, wherein the group contains between 5 and 10 carbon atoms or heteroatoms. Heteroaryl groups include those where a nitrogen atom of the heteroaryl ring is substituted with an oxide (-O-), for example, pyridinyl N-oxide and the like, where the context so permits. Heteroaryl groups may be monocyclic or bicyclic. As used herein, the term “monocyclic heteroaryl” means a cyclic aromatic group containing 1 to 5 carbon atoms and containing between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more hetero atoms may be the same or different, wherein the monocyclic ring contains between 5 and 6 carbon atoms or heteroatoms. Exemplary heteroaryl groups include benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzotriazolyl, benzoxazolyl, furanyl, furazanyl, indolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridinyl N-oxide, pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrrolyl, 1,2,4-thiadiazolyl, 1,2,4-triazinyl, 1,3,4-thiadiazolyl, thiazolyl, triazolyl, tetrazolyl, thiophenyl, and the like.

[0037] As used herein, the term “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group. A CX-CY heteroarylalkyl group refers to a heteroarylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3 heteroarylalkyl group refers to a heteroarylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a heteroaryl group. A “monocyclic heteroarylalkyl” group refers to an alkyl group substituted with amonocyclic heteroaryl group. Exemplary heteroarylalkyl groups include pyridylmethyl, pyrrolylmethyl, furanylmethyl, and the like.

[0038] As used herein, the term “heterocyclyl” refers to a non-aromatic (saturated or unsaturated) monocyclic group containing between 1 and 5 carbon atoms and between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different, wherein the monocyclic ring contains between 3 and 6 carbon atoms or heteroatoms. Heterocyclyl groups include those where one or more carbon atoms of the heterocyclyl ring is substituted with an oxo (=O), for example, lactones, lactams, oxopyrrolidinyl, oxopiperidinyl, oxoimidazolidinyl, oxo-4,5-dihydrotetrazolyl, and the like; or a nitrogen atom of the heterocyclyl ring is substituted with an oxide (-O-), for example, pyrrolidinyl N-oxide, piperidinyl N-oxide, and the like, where the context so permits. An X- to Y-membered heterocyclyl group refers to a heterocyclyl group having between X and Y ring atoms (which may be carbon or heteroatoms). Exemplary heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyridinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, lactones, lactams, oxopyrrolidinyl, oxopiperidinyl, oxoimidazolidinyl, oxo-4,5-dihydrotetrazolyl, pyrrolidinyl N- oxide, piperidinyl N-oxide, and the like.

[0039] As used herein, the term “heterocyclylalkyl” refers to an alkyl group substituted with a heteroaryl group. A CX-CY heterocyclylalkyl group refers to a heterocyclylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3 heterocyclylalkyl group refers to a heterocyclylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a heterocyclyl group. Exemplary heteroarylalkyl groups include piperidinylmethyl, pyrrolidinylmethyl, azetidinylmethyl, 2-(oxo-4,5-dihydrotetrazolyl)ethyl, and the like.

[0040] As used herein, the term “acyl” refers to a group attached through a carbonyl (-C(=O)-) linker, wherein the linker is bonded to an alkyl, hydroxy, alkoxy, amino, alkylamino, or dialkylamino group. A CX-CY acyl group refers to an acyl group that may have alkyl groups having between X and Y carbon atoms, for example, a C1-C3 acyl group refers to an acyl group selected from -C(=O)(C1-C3-alkyl), -C(=O)OH, -C(=O)O(C1-C3-alkyl), -C(=O)NH2, -C(=O)NH(C1-C3- alkyl), and -C(=O)N(C1-C3-alkyl)2.

[0041] As used herein, the term “sulfonyl” refers to a group attached through a sulfonyl (-S(=O)2-) linker, wherein the linker is bonded to an alkyl, amino, alkylamino, or dialkylamino group. A CX-CY sulfonyl group refers to a sulfonyl group that may have alkyl groups having between X and Y carbon atoms, for example, a C1-C3sulfonyl group refers to a sulfonyl group selected from -S(=O)2(C1-C3-alkyl), -S(=O)2NH2, -S(=O)2NH(C1-C3-alkyl), and -S(=O)2N(C1-C3- alkyl)2.

[0042] As used herein, the term “substituted” refers to a hydrogen radical of the designated moiety being replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise noted, a substituent can be in any position, provided that the respective compound is sufficiently stable and is suitable as a pharmaceutical active compound. The prerequisite that a specific group and a compound of the formula I are sufficiently stable and suitable as a pharmaceutical active compound applies in general with respect to the definitions of all groups in the compounds of the formula I, and compounds of a subformula of formula I.

[0043] As used herein, the terms “independently” or “independently selected” means that the same or different values may be selected for multiple instances of a given variable in a single compound.

[0044] As used herein, the term “unsubstituted” indicates that the respective group does not carry any of the specified non-hydrogen substituents.

[0045] As used herein, the term “pharmaceutically acceptable salt” refers to the relatively non- toxic, inorganic and organic acid and base addition salts, of a compound of formula I, or a compound of a subformula of formula I. These salts can be prepared in situ during the final isolation and purification of the compounds.

[0046] As used herein, “ ” indicates the bond between two atoms may be either a single or a double bond. When is a single bond between two carbon atoms, the carbon atoms each are bonded to one more hydrogen atom (or substituent in place of a hydrogen atom) than if had been a double bond. Correspondingly, when is a double bond, the carbon atoms each are bonded to one fewer hydrogen atom (or substituent in place of a hydrogen atom) than if had been a single bond. If two bonds are adjacent, both bonds may be a single bond, either may be single and the other a double bond, but both bonds may not be a double bond.

[0047] If the compounds of the formula I, or compounds of a subformula of formula I, comprise one or more acidic or basic groups, for example basic heterocyclic groups, the corresponding physiologically or toxicologically acceptable salts are also included in the disclosure, especially the pharmaceutically acceptable salts. The compounds of the formula I, or compounds of a subformula of formula I, may thus be deprotonated on an acidic group and be used for example as alkali metal salts or as ammonium salts. Compounds of the formula I, or compounds of a subformula of formula I, comprising at least one basic group may also be prepared and used in the form of their acid addition salts, for example in the form of pharmaceutically acceptable salts with inorganic acids and organic acids. Salts can in general be prepared from acidic and basic compounds of the formula I, or compounds of a subformula of formula I, by reaction with an acid or base in a solvent or diluent according to customary procedures. If the compounds of the formula I, or compounds of a subformula of formula I, simultaneously contain an acidic and a basic group in the molecule, the disclosure also includes internal salts (betaines, zwitterions) in addition to the salt forms mentioned. The present disclosure also comprises all salts of the compounds of the formula I, or compounds of a subformula of formula I, which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange.

[0048] As used herein, the term “pharmaceutically acceptable excipient” refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present disclosure to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the subject. The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

[0049] As used herein, the term “therapeutically effective amount” refers to an amount of a compound / composition according to the present disclosure effective in producing the desired therapeutic effect.

[0050] As used herein, the term “subject” refers to a human or animal subject. In some embodiments, the subject is human (i.e., a “patient”). In some embodiments, the subject is an animal.

[0051] As used herein, the term “compounds of formula I”, or “compounds of a subformula of formula I,” and equivalent expressions, include racemic compounds of formula I, or compounds of a subformula of formula I, and their enantiomers, diastereoisomers, tautomers, atropisomers, and mixtures thereof, where the context so permits. Tautomeric compounds of formula I are exemplified by formulas I (tautomer 1) and I (tautomer 2)..

[0052] As used herein, the term “subformula” refers to subsets of compound of formula I, such as compounds of formula I which are a compound of formula I-A, I-A1, I-A1-a, I-A1-b, I-A1-c, I-A1-d, I-A1-e, I-A1-f, I-A1-g, I-A2, I-A2-a, I-A2-b, I-A2-c, I-A2-d, I-A2-e, I-A2-f, I-A2-g, I-B, I-B1, I-B1-a, I-B1-b, I-B1-c, I-B1-d, I-B1-e, or I-B1-f, where the context so permits.

[0053] As used herein, the term "isomers" refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. The labels “isomer 1” and “isomer 2,” or the like, can be assigned to isomers of known absolute configuration or can be used to describe stereoisomers of unknown absolute configuration. Likewise, the labels “R*” or “S*” may be assigned to stereocenters of some enantiomeric compounds of unknown absolute configuration. Thus, the use of the labels “isomer 1,” “isomer 2,” R*, and S* is not to be interpreted as indicating that the absolute configuration of both isomers is known. The term “isomeric mixture” refers to a mixture of isomers.

[0054] As used herein, the term "stereoisomers" is a general term used for all isomers of the individual molecules that differ only in the orientation of their atoms in space. The term “diastereomers” refers to stereoisomers that are not mirror images of one another and the term “enantiomers” refers to stereoisomers that are non-superimposable mirror images of each other. An enantiomer can be characterized by the absolute configurations of its asymmetric centers,chiral axes and planes, and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer, individual diastereomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.” A mixture containing any proportions of the diastereomers is called a “diastereomeric mixture”. For a compound with two chiral centers in a cyclic system, "trans" refers to the substituents (other than hydrogen) of the chiral centers are on opposite sides of the ring; "cis" refers to the substituents of the chiral centers are on the same sides of the ring. “Racemic trans” refers to equal proportions of two trans enantiomers and “racemic cis” refers to equal proportions of two cis enantiomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can also be directly separated using chiral chromatographic techniques or indirectly using enzymatic methods. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present disclosure.

[0055] One aspect of the present disclosure provides a compound of formula I, I, wherein: R1is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, heteroaryl, - C(=O)R10, -C(=O)OR11, and -C(=O)NR11R12, wherein when R1is alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, or heteroaryl, R1 is unsubstituted or substituted with one or more of halogen, cyano,C1-C4 alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or - S(=O)2NR11R12; R2 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, heteroaryl, - C(=O)R10, -C(=O)OR11, and -C(=O)NR11R12, wherein when R2is alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, or heteroaryl, R2is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or - S(=O)2NR11R12; R3 is selected from hydrogen, halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; each instance of R4 is independently selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl; R5is selected from halogen, cyano, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, -OR7, -NR7R8, -N+(O-)R7R8, -SR7, - C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -OC(=O)R6, -OC(=O)OR7, - OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, -NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8, wherein when R5is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, aryl, or heteroaryl, R5is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, - OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from alkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, - S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or -S(=O)(=NR9)NR11R12; R7 and R8 are independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, - N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10is independently selected from C1-C4alkyl, C1-C4heteroalkyl, 3- to 6-membered heterocyclyl, C1-C33- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C4 heteroalkyl, 3- to 6-membered heterocyclyl, C1-C3 3- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C3 acyl, and C1- C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; A is a monocyclic ring selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; and n is 0, 1, or 2, provided that when A is a phenyl ring, n is 1 or 2; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0056] One embodiment is a compound of formula I, wherein: R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6phenylalkyl, phenyl, monocyclic heteroaryl, -C(=O)R10, -C(=O)OR11, and - C(=O)NR11R12, wherein when R1is C1-C6alkyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6phenylalkyl, phenyl, or monocyclic heteroaryl, R1is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6 phenylalkyl, phenyl, monocyclic heteroaryl, -C(=O)R10, -C(=O)OR11, and - C(=O)NR11R12, wherein when R2is C1-C6alkyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6phenylalkyl, phenyl, or monocyclic heteroaryl, R2is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R5 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6-membered heterocyclylalkyl, C1-C6 phenylalkyl, C1-C6 monocyclic heteroarylalkyl, phenyl, monocyclic heteroaryl, -OR7, -NR7R8, -N+(O-)R7R8, -SR7, - C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -OC(=O)R6, -OC(=O)OR7, -OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, -NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8, wherein when R5 is C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6-membered heterocyclylalkyl, C1-C6phenylalkyl, C1-C6monocyclic heteroarylalkyl, phenyl, or monocyclic heteroaryl, R5is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -SR11, -N+(O-)R11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6-membered heterocyclylalkyl, phenyl, C1-C6 phenylalkyl, monocyclic heteroaryl, and C1-C6 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or -S(=O)(=NR9)NR11R12; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3- C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6- membered heterocyclylalkyl, phenyl, C1-C6phenylalkyl, monocyclic heteroaryl, and C1-C6monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12; and A is a monocyclic ring selected from C5-C6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and monocyclic heteroaryl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0057] One embodiment is a compound of formula I, wherein: R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or - S(=O)2NR11R12;R2 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R2 is C1-C6 alkyl, benzyl, or phenyl, R2 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or - S(=O)2NR11R12; R3is selected from hydrogen, halogen, and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl; R5 is selected from halogen, C1-C6 alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; A is selected from phenyl, piperidinyl, and tetrahydropyridinyl; and n is 1; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0058] One embodiment is a compound of formula I, wherein: R1 is selected from methyl and benzyl; R2is selected from hydrogen and acetyl;R3 is selected from hydrogen, chloro, fluoro, bromo, methyl, and ethyl; R4 is selected from chloro, fluoro, and methyl; R5 is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6is selected from C1-C4alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; A is selected from phenyl, piperid-4-yl, and 1,2,3,6-tetrahydropyridin-4-yl; and n is 1; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0059] One embodiment is a compound of formula I which is a compound of formula I-A ,wherein R1, R2, R3, R4, R5, and n are as defined for a compound of formula I;or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0060] One embodiment is a compound of formula I which is a compound of formula I-A wherein: R1is selected from hydrogen, C1-C6alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1is C1-C6alkyl, benzyl, or phenyl, R1is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R2 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R2 is C1-C6 alkyl, benzyl, or phenyl, R2 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R3is selected from hydrogen, halogen, and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl; R5is selected from halogen, C1-C6alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; and n is 1;or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0061] One embodiment is a compound of formula I which is a compound of formula I-A wherein: R1is selected from methyl and benzyl; R2is selected from hydrogen and acetyl; R3 is selected from hydrogen, chloro, fluoro, bromo, methyl, and ethyl; R4 is selected from chloro, fluoro, and methyl; R5 is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6is selected from C1-C4alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; and n is 1; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0062] One embodiment is a compound of formula I which is a compound of formula I-A1,I-A1 wherein R1, R2, R3, R4, and R5are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0063] One embodiment is a compound of formula I which is a compound of formula I-A1 wherein: R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1is C1-C6alkyl, benzyl, or phenyl, R1is unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, or -NR11R12; R2is selected from hydrogen, C1-C6alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R2is C1-C6alkyl, benzyl, or phenyl, R2is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R3 is selected from hydrogen, halogen, and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R5is selected from halogen, C1-C6alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0064] One embodiment is a compound of formula I which is a compound of formula I-A1 wherein: R1 is selected from methyl and benzyl; R2is selected from hydrogen and acetyl; R3is selected from hydrogen, halogen, methyl, and ethyl; R4is selected from halogen and methyl; R5is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7and R8are independently selected from hydrogen and C1-C4alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl; and each instance of R11 and R12 is independently selected from hydrogen and C1-C4 alkyl;or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0065] One embodiment is a compound of formula I which is a compound of formula I-A1-a, I-A1-a wherein R1 and R5 are as defined for a compound of formula I; and each instance of X is independently selected from chloro and fluoro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0066] One embodiment is a compound of formula I which is a compound of formula I-A1-a wherein: R1is selected from hydrogen, C1-C6alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more halogen, C1-C4 alkyl, -OR11, or -NR11R12; R5 is selected from halogen, C1-C6 alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12;R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0067] One embodiment is a compound of formula I which is a compound of formula I-A1-a wherein: R1 is selected from methyl and benzyl; R5 is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6is selected from C1-C4alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0068] One embodiment is a compound of formula I which is a compound of formula I-A1-b,I-A1-b wherein R1is as defined for a compound of formula I; L is selected from -R6and -NR7R8; and each instance of X is independently selected from chloro and fluoro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0069] One embodiment is a compound of formula I which is a compound of formula I-A1-b wherein: R1is selected from hydrogen, C1-C6alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1is C1-C6alkyl, benzyl, or phenyl, R1is unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, or -NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or moreof halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0070] One embodiment is a compound of formula I which is a compound of formula I-A1-b wherein: R1is selected from methyl and benzyl; R6is selected from C1-C4alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0071] One embodiment is a compound of formula I which is a compound of formula I-A1-c, I-A1-c wherein R1is as defined for a compound of formula I; L is selected from -R6, -OR7, and -NR7R8; and each instance of X is independently selected from chloro and fluoro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0072] One embodiment is a compound of formula I which is a compound of formula I-A1-c wherein: R1is selected from hydrogen, C1-C6alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1is C1-C6alkyl, benzyl, or phenyl, R1is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12;each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0073] One embodiment is a compound of formula I which is a compound of formula I-A1-c wherein: R1 is selected from methyl and benzyl; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0074] One embodiment is a compound of formula I which is a compound of formula I-A1-d, I-A1-dwherein each instance of X is independently selected from chloro and fluoro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0075] One embodiment is a compound of formula I which is a compound of formula I-A1-e, I-A1-e wherein R4 and R5 are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0076] One embodiment is a compound of formula I which is a compound of formula I-A1-e wherein: R4is selected from halogen and C1-C4alkyl; R5 is selected from halogen, C1-C6 alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, andC1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0077] One embodiment is a compound of formula I which is a compound of formula I-A1-e wherein: R4is selected from halogen and methyl; R5is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7and R8are independently selected from hydrogen and C1-C4alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl; and each instance of R11 and R12 is independently selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0078] One embodiment is a compound of formula I which is a compound of formula I-A1-f, I-A1-f wherein R4and R5are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0079] One embodiment is a compound of formula I which is a compound of formula I-A1-f wherein: R4 is selected from halogen and C1-C4 alkyl; R5 is selected from halogen, C1-C6 alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; andeach instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0080] One embodiment is a compound of formula I which is a compound of formula I-A1-f wherein: R4 is selected from halogen and methyl; R5 is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6is selected from C1-C4alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0081] One embodiment is a compound of formula I which is a compound of formula I-A1-g,I-A1-g wherein R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0082] One embodiment is a compound of formula I which is a compound of formula I-A1-g wherein: R5 is selected from halogen, C1-C6 alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0083] One embodiment is a compound of formula I which is a compound of formula I-A1-g wherein: R5 is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8;R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7and R8are independently selected from hydrogen and C1-C4alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl; and each instance of R11 and R12 is independently selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0084] One embodiment is a compound of formula I which is a compound of formula I-A2, I-A2 wherein R1, R2, R3, R4, and R5are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0085] One embodiment is a compound of formula I which is a compound of formula I-A2 wherein: R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1is C1-C6alkyl, benzyl, or phenyl, R1is unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, or -NR11R12;R2 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R2 is C1-C6 alkyl, benzyl, or phenyl, R2 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R3is selected from hydrogen, halogen, and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl; R5is selected from halogen, C1-C6alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0086] One embodiment is a compound of formula I which is a compound of formula I-A2 wherein: R1 is selected from methyl and benzyl; R2 is selected from hydrogen and acetyl; R3 is selected from hydrogen, halogen, methyl, and ethyl; R4is selected from halogen and methyl;R5 is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0087] One embodiment is a compound of formula I which is a compound of formula I-A2-a, I-A2-a wherein R1 and R5 are as defined for a compound of formula I; and each instance of X is independently selected from chloro and fluoro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0088] One embodiment is a compound of formula I which is a compound of formula I-A2-a wherein:R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R5is selected from halogen, C1-C6alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0089] One embodiment is a compound of formula I which is a compound of formula I-A2-a wherein: R1is selected from methyl and benzyl; R5 is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11 and R12 is independently selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0090] One embodiment is a compound of formula I which is a compound of formula I-A2-b, I-A2-b wherein R1 is as defined for a compound of formula I; L is selected from -R6 and -NR7R8; and each instance of X is independently selected from chloro and fluoro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0091] One embodiment is a compound of formula I which is a compound of formula I-A2-b wherein: R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12;R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0092] One embodiment is a compound of formula I which is a compound of formula I-A2-b wherein: R1is selected from methyl and benzyl; R6is selected from C1-C4alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7and R8are independently selected from hydrogen and C1-C4alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl; and each instance of R11 and R12 is independently selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0093] One embodiment is a compound of formula I which is a compound of formula I-A2-c, I-A2-c wherein R1is as defined for a compound of formula I; L is selected from -R6, -OR7, and -NR7R8; and each instance of X is independently selected from chloro and fluoro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0094] One embodiment is a compound of formula I which is a compound of formula I-A2-c wherein: R1is selected from hydrogen, C1-C6alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1is C1-C6alkyl, benzyl, or phenyl, R1is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12;each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0095] One embodiment is a compound of formula I which is a compound of formula I-A2-c wherein: R1 is selected from methyl and benzyl; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more ofC1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0096] One embodiment is a compound of formula I which is a compound of formula I-A2-d, I-A2-d each instance of X is independently selected from chloro and fluoro;or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0097] One embodiment is a compound of formula I which is a compound of formula I-A2-e, I-A2-e wherein R4 and R5 are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0098] One embodiment is a compound of formula I which is a compound of formula I-A2-e wherein: R4 is selected from halogen and C1-C4 alkyl; R5 is selected from halogen, C1-C6 alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or moreof halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0099] One embodiment is a compound of formula I which is a compound of formula I-A2-e wherein: R4is selected from halogen and methyl; R5is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7and R8are independently selected from hydrogen and C1-C4alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl; and each instance of R11 and R12 is independently selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0100] One embodiment is a compound of formula I which is a compound of formula I-A2-f,I-A2-f wherein R4 and R5 are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0101] One embodiment is a compound of formula I which is a compound of formula I-A2-f wherein: R4is selected from halogen and C1-C4alkyl; R5is selected from halogen, C1-C6alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0102] One embodiment is a compound of formula I which is a compound of formula I-A2-f wherein: R4 is selected from halogen and methyl; R5 is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6is selected from C1-C4alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0103] One embodiment is a compound of formula I which is a compound of formula I-A2-g, I-A2-gwherein R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0104] One embodiment is a compound of formula I which is a compound of formula I-A2-g wherein: R5is selected from halogen, C1-C6alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0105] One embodiment is a compound of formula I which is a compound of formula I-A2-g wherein: R5 is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11 and R12 is independently selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0106] One embodiment is a compound of formula I which is a compound of formula I-B, I-B wherein R1, R2, R3, R4, R5 and n are as defined for a compound of formula I; and is a single or double bond, provided two adjacent are not both double bonds; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0107] One embodiment is a compound of formula I which is a compound of formula I-B wherein: R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12;R2 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R2 is C1-C6 alkyl, benzyl, or phenyl, R2 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R3is selected from hydrogen, halogen, and C1-C4alkyl; R4is selected from halogen and C1-C4alkyl; R5is selected from C1-C6alkyl, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; and n is 1; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0108] One embodiment is a compound of formula I which is a compound of formula I-B wherein: R1 is selected from methyl and benzyl; R2 is selected from hydrogen and acetyl; R3is selected from hydrogen, halogen, methyl, and ethyl;each R4 is independently selected from halogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)(NH)R6, - S(=O)2R6, and -S(=O)2NR7R8; R6is selected from C1-C4alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; and n is 1; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0109] One embodiment is a compound of formula I which is a compound of formula I-B1, I-B1 wherein R1, R2, R3, R4, and R5 are as defined for a compound of formula I; and is a single or double bond; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0110] One embodiment is a compound of formula I which is a compound of formula I-B1 wherein: R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1is C1-C6alkyl, benzyl, or phenyl, R1is unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, or -NR11R12; R2is selected from hydrogen, C1-C6alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R2 is C1-C6 alkyl, benzyl, or phenyl, R2 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R3 is selected from hydrogen, halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R5is selected from C1-C6alkyl, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0111] One embodiment is a compound of formula I which is a compound of formula I-B1 wherein: R1 is selected from methyl and benzyl; R2is selected from hydrogen and acetyl; R3is selected from hydrogen, halogen, methyl, and ethyl; R4is selected from halogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)(NH)R6, - S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen and C1-C4alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl; and each instance of R11 and R12 is independently selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0112] One embodiment is a compound of formula I which is a compound of formula I-B1-a, I-B1-a wherein R1and R5are as defined for a compound of formula I;M is selected from C1-C4 alkyl; X is selected from chloro and fluoro; and is a single or double bond; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0113] One embodiment is a compound of formula I which is a compound of formula I-B1-a wherein: R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R5is selected from C1-C6alkyl, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0114] One embodiment is a compound of formula I which is a compound of formula I-B1-a wherein: R1 is selected from methyl and benzyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)(NH)R6, - S(=O)2R6, and -S(=O)2NR7R8; R6is selected from C1-C4alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0115] One embodiment is a compound of formula I which is a compound of formula I-B1-b,I-B1-b wherein R1is defined for a compound of formula I; L is selected from -R6and -NR7R8; M is selected from C1-C4 alkyl;X is selected from chloro and fluoro; and is a single or double bond; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0116] One embodiment is a compound of formula I which is a compound of formula I-B1-b wherein: R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0117] One embodiment is a compound of formula I which is a compound of formula I-B1-b wherein: R1 is selected from methyl and benzyl; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11 and R12 is independently selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0118] One embodiment is a compound of formula I which is a compound of formula I-B1-c, I-B1-c wherein R1 is as defined for a compound of formula I; L is selected from -R6, -OR7, and -NR7R8; M is selected from C1-C4 alkyl; X is selected from chloro and fluoro; and is a single or double bond; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0119] One embodiment is a compound of formula I which is a compound of formula I-B1-c wherein:R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0120] One embodiment is a compound of formula I which is a compound of formula I-B1-c wherein: R1 is selected from methyl and benzyl; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl;or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0121] One embodiment is a compound of formula I which is a compound of formula I-B1-d, I-B1-d wherein R4 and R5 are as defined for a compound of formula I; and is a single or double bond; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0122] One embodiment is a compound of formula I which is a compound of formula I-B1-d wherein: R4 is selected from halogen and C1-C4 alkyl; R5 is selected from C1-C6 alkyl, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, andC1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; and each instance of R11and R12is independently selected from hydrogen, C1-C4alkyl, C1-C4heteroalkyl, C1-C3acyl, and C1-C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0123] One embodiment is a compound of formula I which is a compound of formula I-B1-d wherein: R4is selected from halogen and methyl; R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)(NH)R6, - S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7and R8are independently selected from hydrogen and C1-C4alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl; and each instance of R11 and R12 is independently selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0124] One embodiment is a compound of formula I which is a compound of formula I-B1-e, I-B1-e wherein R4and R5are as defined for a compound of formula I; and is a single or double bond; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0125] One embodiment is a compound of formula I which is a compound of formula I-B1-e wherein: R4is selected from halogen and C1-C4alkyl; R5is selected from C1-C6alkyl, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12;each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0126] One embodiment is a compound of formula I which is a compound of formula I-B1-e wherein: R4 is selected from halogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)(NH)R6, - S(=O)2R6, and -S(=O)2NR7R8; R6is selected from C1-C4alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0127] One embodiment is a compound of formula I which is a compound of formula I-B1-f, I-B1-f wherein R5is as defined for a compound of formula I; and is a single or double bond; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0128] One embodiment is a compound of formula I which is a compound of formula I-B1-f wherein: R5is selected from C1-C6alkyl, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; R7and R8are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; andeach instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0129] One embodiment is a compound of formula I which is a compound of formula I-B1-f wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)(NH)R6, - S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen and C1-C4 alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl; and each instance of R11and R12is independently selected from hydrogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0130] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I- A1-a, I-A1-b, I-A1-c, I-A2, I-A2-a, I-A2-b, I-A2-c, I-B, I-B1, I-B1a, I-B1-b, or I-B1-c, wherein R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1- C6alkyl, benzyl, or phenyl, R1is unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, or -NR11R12, wherein R10, R11, and R12are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0131] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I- A1-a, I-A1-b, I-A1-c, I-A2, I-A2-a, I-A2-b, I-A2-c, I-B, 1-B1, 1-B1a, 1-B1-b, or 1-B1-c, wherein R1 is methyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0132] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I- A1-a, I-A1-b, I-A1-c, I-A2, I-A2-a, I-A2-b, I-A2-c, I-B, I-B1, I-B1a, I-B1-b, or I-B1-c, wherein R1 is benzyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0133] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A2, I- B, or I-B1, wherein R2is selected from hydrogen, C1-C4alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R2 is C1-C6 alkyl, benzyl, or phenyl, R2 is unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, or -NR11R12, wherein R10, R11, and R12 are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0134] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A2, I- B, or I-B1, wherein R2is hydrogen; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0135] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A2, I- B, or I-B1, wherein R2 is acetyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0136] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A2, I- B, or I-B1, wherein R3is selected from hydrogen, halogen, or C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0137] One embodiment is a compound of formula I, wherein R3 is hydrogen, halogen, methyl, or ethyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0138] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A2, I- B, or I-B1, wherein R3is hydrogen; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0139] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A2, I- B, or I-B1, wherein R3 is chloro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0140] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A2, I- B, or I-B1, wherein R3 is methyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0141] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A2, I- B, or I-B1, wherein R3is ethyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0142] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A1-e, I-A1-f, I-A2, I-A2-e, I-A2-f, I-B, I-B1, I-B1-d, or I-B1-e, wherein n is 1; and R4 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0143] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A1-e, I-A1-f, I-A2, I-A2-e, I-A2-f, I-B, I-B1, I-B1-d, or I-B1-e, wherein n is 1; and R4is selected from halogen and methyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0144] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A1-e, I-A1-f, I-A2, I-A2-e, I-A2-f, I-B, I-B1, I-B1-d, or I-B1-e, wherein n is 1; and R4 is selected from chloro and fluoro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0145] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A1-e, I-A1-f, I-A2, I-A2-e, I-A2-f, I-B, I-B1, I-B1-d, or I-B1-e, wherein R4is methyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0146] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A1-a, I-A1-e, I-A1-f, I-A1-g, I-A2, I-A2-a, I-A2-e, I-A2-f, I-A2-g, I-B, I-B1, I-B1-a, I-B1-d, or I-B1-e, wherein R5is selected from halogen, C1-C6alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12, wherein R6, R7, R8, R9, R10, R11, and R12 are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0147] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A1-a, I-A1-e, I-A1-f, I-A1-g, I-A2, I-A2-a, I-A2-e, I-A2-f, I-A2-g, I-B, I-B1, I-B1-a, I-B1-d, or I-B1-e, wherein R5 is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein R6, R7, and R8are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0148] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A1-a, I-A1-e, I-A1-f, I-A1-g, I-A2, I-A2-a, I-A2-e, I-A2-f, I-A2-g, I-B, I-B1, I-B1-a, I-B1-d, or I-B1-e, wherein R5 is selected from chloro, fluoro, -SCH3, -SCH2CH3, -C(=O)OH, -C(=O)OCH3, - C(=O)NH2, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)(NH)CH3, and - S(=O)(NH)CH2CH3; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0149] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A1-a, I-A1-e, I-A1-f, I-A1-g, I-A2, I-A2-a, I-A2-e, I-A2-f, I-A2-g, I-B, I-B1, I-B1-a, I-B1-d, or I-B1-e,.

[0150] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A1-a, I-A1-e, I-A1-f, I-A1-g, I-A2, I-A2-a, I-A2-e, I-A2-f, I-A2-g, I-B, I-B1, I-B1-a, I-B1-d, or I-B1-e, wherein R5is selected from fluoro, chloro,,5

[0151] One embodiment is a compound of formula I, wherein A is phenyl or piperidinyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0152] One embodiment is a compound of formula I, wherein, wherein is a single or a double bond; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0153] One embodiment is a compound of formula I, wherein A is,diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0154] One embodiment is a compound of formula I, whereinenantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0155] One embodiment is a compound of formula I, whereinenantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0156] One embodiment is a compound of formula I, wherein A isenantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0157] One embodiment is a compound of formula I, wherein enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0158] One embodiment is a compound of formula I, wherein A isselected from hydrogen, halogen, and C1-C4alkyl; and R4is selected from halogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0159] One embodiment is a compound of formula I, wherein A is ,selected from hydrogen, halogen, and C1-C4alkyl; and R4is selected from halogen and C1-C4alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0160] One embodiment is a compound of formula I, whereinchloro or bromo; and R4 is chloro or fluoro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0161] One embodiment is a compound of formula I, whereinchloro or bromo; and R4is chloro or fluoro; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0162] One embodiment is a compound of formula I, wherein A is phenyl; and R5 is selected from halogen, C1-C6 alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12, wherein R6, R7, R8, R9, R10, R11, and R12are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0163] One embodiment is a compound of formula I, wherein A is phenyl; and R5 is selected from halogen, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0164] One embodiment is a compound of formula I, wherein A is phenyl; and R5is selected from halogen, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)2R6, and -S(=O)2NR7R8, wherein R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0165] One embodiment is a compound of formula I, wherein A is phenyl; and R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)2R6, and -S(=O)2NR7R8, wherein R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0166] One embodiment is a compound of formula I, wherein A is piperid-4-yl; and R5is selected from C1-C6alkyl, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6, wherein when R5 is C1-C6 alkyl, R5 is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12, wherein R6, R7, R8, R9, R10, R11, and R12 are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0167] One embodiment is a compound of formula I, wherein A is piperid-4-yl; and R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and - S(=O)(=NR9)R6, wherein R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0168] One embodiment is a compound of formula I, wherein A is piperid-4-yl; and R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)2R6, and -S(=O)2NR7R8, wherein R6, R7, and R8are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0169] One embodiment is a compound of formula I, wherein A is phenyl or piperid-4-yl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NH)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of C1- C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12, and hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12, wherein R10, R11, and R12 are as defined for a compound of formula I; or an enantiomer,diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0170] One embodiment is a compound of formula I, or a compound of formula I-A1, I-A1-a, I-A1-e, I-A1-f, I-A1-g, I-A2, I-A2-a, I-A2-e, I-A2-f, I-A2-g, I-B, I-B1, I-B1-a, I-B1-d, or I-B1-e, wherein R5is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NH)R6; R6is selected from C1-C4alkyl, C1-C4heteroalkyl, 4- to 6- membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12, and hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of C1-C4alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12, wherein R10, R11, and R12are as defined for a compound of formula I; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0171] All these subgroups taken alone or in combination are part of the description.

[0172] One embodiment is a compound of formula I, selected from: 3-(Benzylamino)-6-chloro-5-(2,3-difluorophenyl)-4H-thieno[3,2-e][1,2,4]thiadiazine 1,1- dioxide; N-Benzyl-5-(2,3-difluorophenyl)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine; 6-Chloro-5-(2,3-difluorophenyl)-3-(methylamino)-2H-thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide; 5-(2,3-Difluorophenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine; 6-Chloro-5-(2-chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 5-(2-Chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- amine; 5-(2-Chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 5-(2-Chloro-4-methylsulfinyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine;5-(2-Chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 5-[2-Chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; N-[6-Chloro-5-(2-chloro-3-fluoro-phenyl)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- yl]-N-methyl-acetamide; Methyl 3-chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]benzoate; 3-Chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzoic acid; 3-Chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzamide; 5-(2-Chloro-3-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine; 5-(3-Chloro-2-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine; N-[5-(2-Chloro-3-fluoro-phenyl)-6-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-yl]-N-methyl-acetamide; 6-Chloro-5-(2-chloro-4-(methylsulfinyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Chloro-5-[2-chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine; 6-Chloro-5-(2-chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 5-(2-Chloro-3-fluoro-phenyl)-6-ethyl-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 5-(2-Chloro-4-(methylsulfonyl)phenyl)-6-ethyl-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine;6-Chloro-5-(2-chloro-4-(ethylthio)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Chloro-5-(2-chloro-4-(ethylsulfinyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Chloro-5-(2-chloro-4-(ethylsulfonyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Ethyl-N-methyl-5-[(3S*,4S*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine; and 6-Ethyl-N-methyl-5-[(3R*,4R*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0173] One embodiment is a compound of formula I, selected from: 5-[2-Chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 6-Chloro-5-(2-chloro-4-(ethylthio)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Chloro-5-(2-chloro-4-(ethylsulfinyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; and 6-Chloro-5-(2-chloro-4-(ethylsulfonyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0174] One embodiment is a compound of formula I, or a compound of a subformula of formula I, that has sufficient solubility to avoid, for example, advanced formulations or advanced delivery systems, which include but are not limited to liposomal suspensions, inclusion complexes, solid dispersions in polymers, mechano-chemically activated systems, microparticles or nanoparticles, micro- or nano-emulsions, and vesicular systems. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 20 µM or greater at pH 7.4. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 100 µM or greater at pH 7.4. In some embodiments a compoundof formula I, or a compound of a subformula of formula I, has a solubility of 500 µM or greater at pH 7.4. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 1000 µM or greater at pH 7.4.

[0175] The compounds of formula I, and subformulas thereof, may comprise one or more asymmetric atoms and / or chiral axes. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures are provided herein.

[0176] Some of the compounds of formula I, and subformulas thereof, may exist in the form of acids or base-addition salts. Such addition salts form part of the disclosure. These salts are advantageously prepared with pharmaceutically acceptable bases or cations, but the salts of other bases or cations that are useful, for example, for purification or isolation of the compounds of formula I, and subformulas thereof, also form part of the disclosure.

[0177] Some of the compounds of formula I, and subformulas thereof, may exist in the form of bases or of acid-addition salts. Such addition salts form part of the disclosure. These salts are advantageously prepared with pharmaceutically acceptable acids or anions, but the salts of other acids or anions that are useful, for example, for purification or isolation of the compounds of formula I, and subformulas thereof, also form part of the disclosure.

[0178] Another aspect of the present disclosure is a process for preparing a compound of formula I, or a compound of a subformula of formula I, comprising reacting an intermediate of formula E2 with a catalyst and a base to give an intermediate of formula E3, according to the scheme:wherein R1 and R3 are as defined for a compound of formula I. In one embodiment, the catalyst is copper iodide or bronze. In one embodiment, the base is potassium carbonate or cesium carbonate. In one embodiment, the reaction is performed in the presence of N,N’-dimethylethane- 1,2-diamine.

[0179] Yet another aspect of the present disclosure is a pharmaceutical composition that includes a compound described herein as an active ingredient. These pharmaceutical compositions comprise a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0180] The said excipients may be selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

[0181] In these pharmaceutical compositions for oral, inhalative, topical, or transdermal administration, the active ingredient of formula I, or a compound of a subformula of formula I, or its pharmaceutically acceptable salt, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals or to human beings for the treatment of a disease, disorder, or condition.

[0182] Appropriate unit administration forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, forms for inhalative administration, and forms for topical or transdermal administration. For topical and transdermal administration, it is possible to use the herein described compounds in creams, gels, ointments, or lotions.

[0183] By the oral route, the dose of active principle per day may reach 2000 mg / day, taken all at once or in portions. By the inhalative route, the dose of active principle per day may reach 50 mg / day. By parenteral routes, the dose of active principle per day may reach 400 mg / day.

[0184] There may be particular cases in which higher or lower dosages are appropriate; such dosages do not depart from the scope of the disclosure. According to usual practice, the dosage that is appropriate for each subject is determined by the doctor according to the mode of administration and the weight and response of the said subject.

[0185] Compounds described herein have an antagonistic activity for MRGPRX2. The compounds according to the present disclosure can, therefore, be used for preparing medicaments, especially medicaments which are antagonists of MRGPRX2.

[0186] Accordingly, yet another aspect of the present disclosure is a medicament, characterized in that it comprises a compound of formula I, or a compound of a subformula offormula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0187] The medicaments of the present disclosure can be employed therapeutically, especially in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders. In yet another aspect, also provided is the use of a compound of formula I, or a compound of a subformula of formula I, for preparing a medicament for the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders.

[0188] In one embodiment, the disease, disorder, or condition is selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain.

[0189] In one embodiment, the disease, disorder, or condition is selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma. In one embodiment, the disease, disorder, or condition is atopic dermatitis. In one embodiment, the disease, disorder, or condition is chronic spontaneous urticaria. In one embodiment, the disease, disorder, or condition is prurigo nodularis. In one embodiment, the disease, disorder, or condition is asthma.

[0190] Yet another aspect of the present disclosure is a method of treating a disease, disorder, or condition associated with MRGPRX2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0191] One embodiment is a method for treating a disease, disorder, or condition associated with undesired mast cell activity or mast cell degranulation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound ofa subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0192] One embodiment is a method for treating a disease, disorder, or condition for which modulation of MRGPRX2 is indicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Modes of modulating MRGPRX2 include antagonism, inhibition, blocking, agonism, partial agonism, inverse agonism, and combinations thereof.

[0193] One embodiment is a method for treating a disease, disorder, or condition for which antagonism of MRGPRX2 is indicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0194] One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, mast cell disorders, pain disorders, and itch disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0195] One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0196] One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0197] One embodiment is a method for treating atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0198] One embodiment is a method for treating chronic spontaneous urticaria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0199] One embodiment is a method for treating prurigo nodularis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0200] One embodiment is a method for treating asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0201] According to another aspect, also provided is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease disorder or condition associated with MRGPRX2.

[0202] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition associated with undesired mast cell activity or mast cell degranulation.

[0203] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition for which modulation of MRGPRX2 is indicated. Modes of modulating MRGPRX2 include antagonism, inhibition, blocking, agonism, partial agonism, inverse agonism, and combinations thereof.

[0204] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition for which antagonism of MRGPRX2 is indicated.

[0205] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders.

[0206] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain.

[0207] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma.

[0208] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of atopic dermatitis.

[0209] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic spontaneous urticaria.

[0210] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of prurigo nodularis.

[0211] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of asthma.

[0212] One embodiment is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the compound of formula I is selected from the list: 3-(Benzylamino)-6-Chloro-5-(2,3-difluorophenyl)-4H-thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide; N-Benzyl-5-(2,3-difluorophenyl)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine; 6-Chloro-5-(2,3-difluorophenyl)-3-(methylamino)-2H-thieno[3,2-e][1,2,4]thiadiazine 1,1- dioxide; 5-(2,3-Difluorophenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine; 6-Chloro-5-(2-chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 5-(2-Chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- amine; 5-(2-Chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine;5-(2-Chloro-4-methylsulfinyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 5-(2-Chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 5-[2-Chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; N-[6-Chloro-5-(2-chloro-3-fluoro-phenyl)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- yl]-N-methyl-acetamide; Methyl 3-chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]benzoate; 3-Chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzoic acid; 3-Chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzamide; 5-(2-Chloro-3-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine; 5-(3-Chloro-2-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine; N-[5-(2-Chloro-3-fluoro-phenyl)-6-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-yl]-N-methyl-acetamide; 6-Chloro-5-(2-chloro-4-(methylsulfinyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Chloro-5-[2-chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine; 6-Chloro-5-(2-chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 5-(2-Chloro-3-fluoro-phenyl)-6-ethyl-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 5-(2-Chloro-4-(methylsulfonyl)phenyl)-6-ethyl-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide;6-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 6-Chloro-5-(2-chloro-4-(ethylthio)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Chloro-5-(2-chloro-4-(ethylsulfinyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Chloro-5-(2-chloro-4-(ethylsulfonyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Ethyl-N-methyl-5-[(3S*,4S*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine; and 6-Ethyl-N-methyl-5-[(3R*,4R*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine.

[0213] One embodiment is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the compound of formula I is selected from the list: 5-[2-Chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine; 6-Chloro-5-(2-chloro-4-(ethylthio)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; 6-Chloro-5-(2-chloro-4-(ethylsulfinyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide; and 6-Chloro-5-(2-chloro-4-(ethylsulfonyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide.

[0214] One embodiment is a compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament, wherein the compound of formula I is selected from the above list.

[0215] One embodiment is the use of a compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, in the preparation of a medicament for the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, wherein the compound of formula I is selected from the above list.

[0216] One embodiment is a compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, wherein the compound of formula I is selected from the above list.

[0217] One embodiment is a method of treating a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound of formula I, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from the above list.

[0218] GENERAL SYNTHETIC METHODS

[0219] The compounds of formula I herein can be prepared by the methods outlined in the following reaction schemes and examples.

[0220] In certain embodiments, intermediates for the preparation of the compounds of formula I can be prepared according to Scheme P-1.A1 A2A3

[0222] Thiophene intermediates of formula A1 may be commercially available or can be prepared by methods known to one skilled in the art. A thiophene intermediate of formula A1 can be converted to a tribromothiophene intermediate of formula A2 by reacting with a bromination agent, such as bromine, in an acidic solvent, such as acetic acid. The tribromothiophene intermediate of formula A2 can be converted to a 3,4-dibromothiophene intermediate of formula A3 by reacting with a lithiation agent, such as n-butyllithium or lithium diisopropyl amide (LDA), in an aprotic solvent such as THF, and quenching with water. In some embodiments of Scheme P-1, R3 is chloro.

[0223] In certain embodiments, intermediates for the preparation of the compounds of formula I can be prepared according to Scheme P-2.

[0224] Scheme P-2

[0225] Tetrabromothiophene may be commercially available or can be prepared by methods known to one skilled in the art. Tetrabromothiophene may be converted to a tribromothiophene intermediate of formula A4 by reacting with a lithiation agent, such as n-butyllithium, and an electrophilic reagent, such as methyl benzenesulfonate, in an aprotic solvent, such as THF. The tribromothiophene intermediate of formula A4 can be converted to a 3,4-dibromothiophene intermediate of formula A3 by reacting with a lithiation agent, such as n-butyllithium, in an aprotic solvent such as THF, and quenching with water. In some embodiments of Scheme P-2, R3 is methyl. In some embodiments of Scheme P-2, R3 is ethyl.

[0226] In certain embodiments, intermediates for the preparation of the compounds of formula I can be prepared according to Scheme P-3.

[0227] Scheme P-3

[0228] 3,4-Dibromothiophene may be commercially available or can be prepared by methods known to one skilled in the art. 3,4-Dibromothiophene may be converted to a 3,4- dibromothiophene intermediate of formula A3 by reacting with a base, such as n-butyllithium or LDA, and an alkyl halide, such as iodomethane or iodoethane, in an aprotic solvent, such as THF. In some embodiments of Scheme P-3, R3 is methyl. In some embodiments of Scheme P-3, R3 is ethyl.

[0229] In certain embodiments, intermediates for the preparation of the compounds of formula I can be prepared according to Scheme P-4.

[0230] Scheme P-4

[0231] Bromo-fluoro-phenyl intermediates of formula B1 may be commercially available or can be prepared by methods known to one skilled in the art. A bromo-fluoro-phenyl intermediate of formula B1 can be converted to a bromo-thioether-phenyl intermediate of formula B2 by reacting with a thiolate, such as sodium methanethiolate or sodium ethanethiolate, in an aprotic solvent such as DMSO. The bromo-thioether-phenyl intermediate of formula B2 can be converted to a boronic ester intermediate of formula B3 by reacting with bis(pinacolato)diboron in the presence of a catalyst, such as bis(diphenylphosphino)ferrocene palladium dichloride, and a base, such as potassium acetate, in a solvent, such as 1,4-dioxane. The boronic ester intermediate offormula B3 can be converted to a boronic acid intermediate of formula B4 by deprotection of the pinacol boronate ester, such as by reacting with ammonium acetate and sodium periodate in acetone and water.

[0232] In certain embodiments, the preparation of the compounds of formula I can be carried out according to Scheme 1.

[0234] 3-Bromo-thiophene intermediates of formula A5 may be commercially available, such as when R3 is Cl, or can be prepared by methods known to those skilled in the art. Boronic acid intermediates of formula B5 may be commercially available, can be prepared according to Scheme P-4 (as a boronic ester intermediate of formula B4), or can be prepared by methods known to those skilled in the art. A 3-bromo-thiophene intermediate of formula A5 can be coupled with a boronic acid intermediate B5 in the presence of a catalyst, such as bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2) or bis(di-tert-butylphosphino)ferrocene palladium dichloride (Pd(dtbpf)Cl2, and a base, such as potassium carbonate, potassium acetate, or DIEA, in a solvent, such as NMP, DMF, 1,4-dioxane, or DMSO, or mixture with water thereof, to give a 3-cyclyl- thiophene intermediate of formula C1.

[0235] The 3-cyclyl-thiophene intermediate of formula C1 can be converted to a sulfonylchloride intermediate C2 by reacting with phosphorous pentachloride in chlorosulfuric acid.

[0236] The sulfonylchloride intermediate of formula C2 can be converted to a sulfonamide intermediate of formula C3 by reacting with tert-butylamine in an aprotic solvent, such as THF.

[0237] The protected sulfonamide intermediate of formula C3 can be converted to an azide intermediate of formula C4 by reacting with a base, such as n-BuLi, and an azide reagent, such as N-diazo-4-methyl-benzenesufonamide, in an aprotic solvent, such as THF.

[0238] The azide intermediate of formula C4 can be converted to an amine intermediate of formula C5 by reacting with a reducing agent, such as sodium borohydride in the presence of tributyl(hexadecyl)phosphonium bromide (TBHDPB) and water, in an aprotic solvent such as toluene.

[0239] The amine intermediate of formula C5 can be deprotected to give a sulfonamide intermediate of formula C6 by reacting with an acid, such as TFA.

[0240] The sulfonamide intermediate of formula C6 can be converted to a thiourea intermediate of formula C7 by reacting with a base, such as potassium tert-butoxide, and an isothiocyanate intermediate of formula D1, which may be commercially available, such as benzyl isothiocyanate or methyl isothiocyanate, or prepared by methods known to those skilled in the art, in an aprotic solvent such as THF.

[0241] The thiourea intermediate of formula C7 can be cyclized to a compound of formula I by reacting with a base, such as triethylamine, and triphosgene in an aprotic solvent such as THF or toluene, or a mixture thereof.

[0242] In certain embodiments, the preparation of the compounds of formula I can be carried out according to Scheme 2.

[0243] Scheme 2

[0244] 3,4-Dibromo-thiophene intermediates of formula A3 may be commercially available, can be prepared according to Scheme P-1, P-2, or P-3, or can be prepared by methods known to those skilled in the art. A 3,4-dibromo-thiophene intermediate of formula A3 can be converted to a sulfonylchloride intermediate of formula E1 by reacting with thionyl chloride in chlorosulfuric acid.

[0245] Guanidinium salts of formula D2 may be commercially available or can be prepared by methods known to those skilled in the art. The sulfonylchloride intermediate of formula E1 can be converted to a guanidine intermediate of formula E2 by reacting with a guanidinium salt of formula D2, such as methylguanidine hydrochloride or benzylguanidine hydrochloride in an aprotic solvent such as toluene, in the presence of a base, such as aqueous sodium hydroxide.

[0246] The guanidine intermediate of formula E2 can be cyclized to a 5-bromo- thienothiazdiazine intermediate of formula E3 by reaction with a base, such as potassium carbonate or cesium carbonate, in the presence of a catalyst, such as bronze or copper iodide, and optionally a ligand, such as N,N’-dimethylethane-1,2-diamine, in a solvent such as NMP, 1,4-dioxane, or a mixture with water thereof.

[0247] The 5-bromo-thienothiadiazine compound of formula E3 can be converted to a compound of formula I by coupling with a boronic acid intermediate of formula B5, which may be commercially available, can be prepared according to Scheme P-4 (as a boronic ester intermediate of formula B4), or can be prepared by methods known to those skilled in the art. The coupling can be accomplished in the presence of a catalyst, such as bis(di-tert- butylphosphino)palladium dichloride (Pd(dtbpf)Cl2) or bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2), and a base, such as potassium carbonate, potassium acetate, or DIEA, in a solvent, such as NMP, DMF, 1,4-dioxane, or DMSO, or mixture with water thereof.

[0248] In certain embodiments, the preparation of the compounds of formula I can be carried out according to Scheme 3.

[0249] Scheme 3

[0250] 5-Bromo-thienothiadiazine intermediates of formula E3 can be prepared according to Scheme 2. The 5-bromo-thienothiadiazine intermediate of formula E3 can be converted to a compound of formula I, whereincoupling with a boronic acid intermediate of formula B6, which may be commercially available or can be prepared by methods known to those skilled in the art, in the presence of a catalyst, such as bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl2), or bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2), and abase, such as potassium carbonate, potassium acetate, or DIEA, in a solvent, such as NMP, DMF, 1,4-dioxane, or DMSO, or mixture with water thereof.

[0251] The compound of formula I, whereincan be converted into a compound of formula I, whereinreacting with a hydrogen source such as molecular hydrogen (H2), in the presence of a catalyst, such as palladium on carbon (Pd / C) or palladium dihydroxide, or a mixture thereof, in a solvent, such as methanol or ethanol.

[0252] In certain embodiments, the preparation of the compounds of formula I can be carried out according to Scheme 4.

[0253] Scheme 4preferably tert-butyl, can be converted to a piperidinium intermediate of formula F1 by reacting with an acid, such as hydrochloric acid in 1,4-dioxane, in a solvent such as DCM.

[0255] Sulfonyl chloride intermediates of formula G1 may be commercially available or can be prepared by methods known to those skilled in the art. The piperidinium intermediate of formula F1 can be converted to a compound of formula I, whereinreacting with a sulfonyl halide intermediate of formula G1, such as methanesulfonyl chloride, in the presence of a base, such as DIEA, in a solvent, such as dichloromethane.

[0256] In certain embodiments, a compound of formula I, for example a compound of formula I prepared according to Scheme 1, Scheme 2, Scheme 3, or Scheme 4, can also be an intermediate to one or more additional compounds of formula I.

[0257] For example, a compound of formula I, wherein R2 is hydrogen, can be converted to another compound of formula I, wherein R2is -C(=O)R10(e.g., acetyl), according to Scheme 5, by reacting with an acyl chloride, such as acetyl chloride, in an aprotic solvent, such as THF.

[0258] Scheme 5

[0259] As another example, a compound of formula I, wherein R3 is X and X is a halogen (e.g., chloro), can be converted to another compound of formula I, wherein R3is hydrogen, according to Scheme 6, by reacting with a hydrogen source such as molecular hydrogen (H2), inthe presence of a catalyst, such as palladium on carbon (Pd / C), and optionally in the presence of an acid, such as hydrochloric acid, in a solvent, such as methanol or ethanol.

[0260] Scheme 6

[0261] As another example, a compound of formula I, wherein R5 is -SR7 (e.g., -SCH3, -SCH2CH3), can be converted to another compound of formula I, wherein R5 is - S(=O)R6(e.g., -S(=O)CH3, -S(=O)CH2CH3), according to Scheme 7, by reacting with an oxidant, such as potassium monopersulfate triple salt (Oxone), in a solvent, such as a mixture of acetone and water.

[0262] Scheme 7

[0263] As another example, a compound of formula I, wherein R5 is -S(=O)R6 (e.g., -S(=O)CH3, -S(=O)CH2CH3), can be converted to another compound of formula I, wherein R is -S(=O)2R6 (e.g., -S(=O)2CH3, -S(=O)2CH2CH3), according to Scheme 8, by reacting with an oxidant, such as potassium monopersulfate triple salt (Oxone), in a solvent, such as acetone or a mixture of acetone and water.

[0264] Scheme 8

[0265] As another example, a compound of formula I, wherein R5 is -S(=O)R6 (e.g., -S(=O)CH3, -S(=O)CH2CH3), can be converted to another compound of formula I, wherein R5 is -S(=O)(NH)R6 (e.g., -S(=O)(NH)CH3, -S(=O)(NH)CH2CH3), according to Scheme 9, by reacting with an azide reagent, such as sodium azide, in Eaton’s reagent.

[0266] Scheme 9

[0267] As another example, a compound of formula I, wherein R5 is -C(=O)OR7 (e.g., -C(=O)OCH3, -C(=O)OCH2CH3), can be converted to another compound of formula I, wherein R5 is -C(=O)OH, according to Scheme 10, by reacting with a base, such as lithium hydroxide, in a solvent such as a mixture of THF and water.

[0268] Scheme 10

[0269] As another example, a compound of formula I, wherein R5 is -C(=O)OH, can be converted to another compound of formula I, wherein R5 is -C(=O)NH2, according to Scheme 11, by reacting with an ammonium source, such as ammonium chloride, a base, such as triethylamine, and an amidation agent, such as HATU, in a polar aprotic solvent, such as DMF.

[0270] Scheme 11

[0271] In another aspect, also provided are compounds of formula A1, A2, A3, A4, A5, B1, B2, B3, B4, B5, C1, C2, C3, C4, C5, C6, C7, E1, E2, E3, or F1. These compounds are useful as synthetic intermediates for the compounds of formula I, or compounds of a subformula of formula I. EXAMPLES

[0272] The embodiments provided herein will be explained more specifically with reference to the following examples, however, the scope of the embodiments provided herein is not limited to these examples. The isomeric configuration for stereocenters of some enantiomeric compoundsdescribed in the Examples has been assigned as R* or S*, but the absolute configuration has not been determined.

[0273] ABBREVIATIONS

[0274] Unless otherwise stated, the following abbreviations have the stated meanings: DCM dichloromethane DIEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dppf 1,1’-bis(diphenylphosphino)ferrocene dtbpf 1,1’-bis(di-tert-butyl-phosphino)ferrocene eq. equivalent Et ethyl EtOH ethanol EtOAc ethyl acetate FA formic acid HATU hexafluorophosphate azabenzotriazole tetramethyl uronium HPLC high performance liquid chromatography LCMS liquid chromatography-mass spectrometry LDA lithium diisopropylamide NMP N-Methyl-2-pyrrolidone Me methyl MeCN acetonitrile MeOH methanol MS mass spectrometry n-BuLi n-butyllithium NMR nuclear magnetic spectroscopy Pd / C palladium on carbon PE petroleum ether RT room temperature t-Bu tert-butyl TEA triethylamineTFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromotography

[0275] Generally, crude products were purified by column chromatography or flash chromatography. LCMS analysis or separation was performed using the following methods or methods described for specific examples.

[0276] LCMS METHODS

[0277] Method A

[0278] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95% B in 1.5min, 95% B for 1.5min; Flow Rate: 2.0ml / min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0279] Method B

[0280] A: H2O (0.1% FA), B: MeCN (0.1% FA); Gradient: 10% B for 0.2min, 10%-90% B in 1.3min, 90% B for 1.5min; Flow Rate: 2.0ml / min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0281] Method C

[0282] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95% B in 1.3min, 95% B for 1.7min, Flow Rate: 1.8ml / min, Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0283] Method D

[0284] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95% B in 1.0min, 95% B for 1.0min; Flow Rate: 1.8ml / min; Column: Agilent Poroshell 2.7μm, 3.0x30mm; Column Temperature: 50°C

[0285] Method E

[0286] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95% B in 1.3min, 95% B for 1.7min; Flow Rate: 2.0ml / min; Column: SunFire 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0287] Method F

[0288] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95% B in 8.0min, 95% B for 7.0min; Flow Rate: 1.8mL / min; Column: XBridge C18, 3.5μm, 4.6x150mm; Column Temperature: 45°C

[0289] Method G

[0290] A: H2O (0.01%TFA), B: MeCN (0.01%TFA); Gradient: 5%-95% B in 1.0min, 95% B for 1.0min; Flow Rate: 1.6mL / min; Column: Agilent Poroshell C18, 2.7μm, 3.0x30mm; Column Temperature: 50°C

[0291] Method H

[0292] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95% B in 1.4min; Flow Rate: 1.8ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C

[0293] Method I

[0294] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 10%-95% B in 1.5min, 95% B for 1.5min; Flow Rate: 1.8ml / min; Column: Agilent Poroshell 120 EC-C18, 4.0μm, 4.6x50mm; Column Temperature: 50°C

[0295] Method J

[0296] A: H2O (0.1% FA), B: MeCN (0.1% FA); Gradient: 10% B for 0.2min, 10%-90% B in 1.3min, 90% B for 1.5min; Flow Rate: 2.0ml / min; Column: Agilent Poroshell 120 C18, 4.0μm 4.6x50mm; Column Temperature: 50°C

[0297] Method K

[0298] A: H2O (10 mmol NH4HCO3), B: MeCN; Gradient: 5%-95% B in 1.5min; Flow Rate: 1.5ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0299] Method L

[0300] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95% B in 1.3min; Flow Rate: 2.0ml / min; Column: SunFire C18, 3.5μm, 4.6x50 mm; Column Temperature: 50°C

[0301] Method M

[0302] A: H2O (10 mM NH4HCO3), B: MeCN; Gradient: 5%-95% B in 1.3min, 95% B for 1.7min; Flow Rate: 1.8ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C

[0303] Method N

[0304] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95% B in 1.0min, 95% B for 0.8min; Flow Rate: 2.0ml / min; Column: Agilent Poroshell 120 EC-C18, 2.7μm, 3.0x30mm; Column Temperature: 50°C

[0305] Method O

[0306] A: H2O (0.01%TFA), B: MeCN (0.01%TFA); Gradient: 5%-95% B in 1.5min; Flow Rate: 1.8ml / min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0307] Method P

[0308] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 10%-95% B in 8.0min, 95% B for 7.0min; Flow Rate: 1.0ml / min; Column: XBridge C18, 3.5μm, 4.6x150mm; Column Temperature: 40°C

[0309] Method Q

[0310] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 10%-95% B in 8.0min; Flow Rate: 1.2ml / min. Column: XBridge C18, 3.5μm, 4.6x150mm; Column Temperature: 40°C

[0311] Method R

[0312] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 10%-90% B in 1.5min, 95% B for 3.0min, 95%-10%B in 0.1min; Flow Rate: 2.0ml / min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0313] Method S

[0314] A: H2O (10mmol NH4HCO3), B: MeCN; Gradient: 10%-95% B in 1.5min; Flow Rate: 1.8ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0315] Method T

[0316] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95% B in 1.5min; Flow Rate: 1.6ml / min; Column: Agilent Poroshell 120 EC C18, 2.7μm, 3.0x30mm; Column Temperature: 50°C

[0317] Method U

[0318] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-90% B in 1.5 min, 95% B for 3min; Flow Rate: 2.0ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C

[0319] Method V

[0320] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95% B in 1.0min, 95% B for 1.0min; Flow Rate: 1.6ml / min; Column: XBridge C18, 2.7μm, 3.0x30mm; Column Temperature: 50°C

[0321] Method W

[0322] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95% B in 1.4min, 95% B for 1.6min; Flow Rate: 1.8ml / min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C

[0323] Method X

[0324] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 10%-95% B in 1.0min, 95% B for 1.0min; Flow Rate: 1.8mL / min; Column: Agilent Poroshell 120EC-C18, 4.0μm, 4.6x50mm; Column Temperature: 50°C

[0325] Example 1: 3-(Benzylamino)-6-chloro-5-(2,3-difluorophenyl)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide

[0327] A mixture of 3-bromo-2-chloro-thiophene (9.7 g, 49 mmol), (2,3- difluorophenyl)boronic acid (11.6 g, 74 mmol), Pd(dppf)Cl2(1.2 g, 1.47 mmol) and DIEA (19.0 g, 147 mmol) in 1,4-dioxane / H2O (200 / 40 mL) was stirred at 80°C for 16 h. The resulting mixture was cooled to RT and poured into water (200 mL). The water layer^was extracted with DCM (200 mL x 3). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (100% PE) to give 2-chloro-3-(2,3-difluorophenyl)thiophene) (10.9 g, yield: 95%). MS (method A) m / z NA, t=2.02 min.

[0328] Step 2: Preparation of 5-chloro-4-(2,3-difluorophenyl)thiophene-2-sulfonyl chloride

[0329] PCl5(14.4 g,^69 mmol) was added to sulfurochloridic acid (20.2^g, 173 mmol) while stirring at RT. The mixture was stirred at RT for 1 h. The mixture was cooled to 0°C.2-chloro-3- (2,3-difluorophenyl)thiophene (8 g,^34 mmol) was added dropwise. After addition, the mixture was stirred at RT for 16 h. The resulting mixture was poured into ice water (300 mL). The water layer was extracted with DCM (300 mL x 3). The organic layers were combined, dried over Na2SO4, and concentrated to give 5-chloro-4-(2,3-difluorophenyl)thiophene-2-sulfonyl chloride (11 g, crude). MS (method B) m / z NA, t=2.37 min.

[0330] Step 3: Preparation of N-tert-butyl-5-chloro-4-(2,3-difluorophenyl)thiophene-2- sulfonamide

[0331] A solution of 5-chloro-4-(2,3-difluorophenyl)thiophene-2-sulfonyl chloride (11 g, 33.4 mmol) in THF (300 mL) was stirred at 0°C for 5 min.2-methylpropan-2-amine (14.7 g,^200 mmol) was added. The mixture was warmed to RT and stirred for 16 h. The resulting mixture was concentrated. The residue was purified on a silica gel column (50% DCM in PE) to give N-tert- butyl-5-chloro-4-(2,3-difluorophenyl)thiophene-2-sulfonamide (5.5 g, yield: 45%). MS (method B) m / z 388 [M+Na]+, t=2.24 min.

[0332] Step 4: Preparation of 3-azido-N-tert-butyl-5-chloro-4-(2,3-difluorophenyl)thiophene- 2-sulfonamide

[0333] A mixture of^ N-tert-butyl-5-chloro-4-(2,3-difluorophenyl)thiophene-2-sulfonamide (3.66 g, 10 mmol) in THF (dry, 80 mL) was stirred at -78°C for 5 min. n-BuLi (2.5 M in hexanes, 12 mL, 30 mmol) was added dropwise at -78°C. The mixture was warmed to 0°C and stirred for 1 h.^N-diazo-4-methyl-benzenesulfonamide (2.56 g, 13 mmol) in THF (dry, 20 mL) was added dropwise. After addition, the mixture was warmed to RT and stirred for 16 h. The resulting mixture was quenched with water. The water layer was extracted with EtOAc (30 mL x 3). The organic layers were combined, dried over Na2SO4, and concentrated to give 3-azido-N-tert-butyl- 5-chloro-4-(2,3-difluorophenyl)thiophene-2-sulfonamide (4.7 g, crude) without further purification. MS (method B) m / z 429 [M+Na]+, t=2.24 min.

[0334] Step 5: Preparation of 3-amino-N-tert-butyl-5-chloro-4-(2,3- difluorophenyl)thiophene-2-sulfonamide

[0335] A mixture of 3-azido-N-tert-butyl-5-chloro-4-(2,3-difluorophenyl)thiophene-2- sulfonamide (4.7 g,^crude, 10 mmol) and tributyl(hexadecyl)phosphonium bromide (1.50 g, 3 mmol) ^in toluene (50 mL) was stirred at 0°C for 5 min. NaBH4(1.12 g, 30 mmol) in water (10mL) was added dropwise. After addition, the mixture was warmed to RT and stirred for 16 h. Water (20 mL) was added. The water layer was extracted with EtOAc (50 mL x 3). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by reversed- phase column chromatography (NH4HCO3in water / MeOH) to give 3-amino-N-tert-butyl-5- chloro-4-(2,3-difluorophenyl)thiophene-2-sulfonamide (650 mg, yield: 17%, two steps). MS (method B) m / z 403 [M+Na]+, t=2.15 min.

[0336] Step 6: Preparation of 3-amino-5-chloro-4-(2,3-difluorophenyl)thiophene-2- sulfonamide

[0337] A mixture of 3-amino-N-tert-butyl-5-chloro-4-(2,3-difluorophenyl)thiophene-2- sulfonamide (700 mg, 1.84 mmol) in TFA (20 mL) was stirred at RT for 16 h. The resulting solution was concentrated. The residue was purified by reversed-phase column chromatography (NH4HCO3 in water / MeOH) to give 3-amino-5-chloro-4-(2,3-difluorophenyl)thiophene-2- sulfonamide (350 mg yield: 58%). MS (method B) m / z 325 [M+H]+, t=1.86 min.

[0338] Step 7: Preparation of 3-amino-N-(benzylcarbamothioyl)-5-chloro-4-(2,3- difluorophenyl)thiophene-2-sulfonamide

[0339] A mixture of^3-amino-5-chloro-4-(2,3-difluorophenyl)thiophene-2-sulfonamide (100 mg, 0.3 mmol) and KOt-Bu (104 mg, 0.9 mmol) in THF (dry, 3 mL) was stirred at 0°C for 5 min. Isothiocyanatomethylbenzene (92 mg, 0.6 mmol) was added. The mixture was warmed to RT andstirred for 16 h. The resulting mixture was filtered. The filtrate was concentrated and used for the next step without further purification. MS (method C) m / z 474 [M+H]+, t=1.55 min.

[0340] Step 8: Preparation of N-Benzyl-6-chloro-5-(2,3-difluorophenyl)-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0341] A mixture of 1-benzyl-3-[5-chloro-4-(2,3-difluorophenyl)-2-sulfamoyl-3- thienyl]thiourea (146 mg, crude, 0.3 mmol) and TEA (76 mg, 0.75 mmol) in THF (3 mL) was stirred at 0°C for 5 min. Triphosgene (107 mg, 0.36 mmol) in toluene (1 mL) was added. The mixture was warmed to RT and stirred for 6 h. The resulting mixture was filtered. The filtrate was concentrated and purified by prep-HPLC to afford the title compound (55 mg, yield: 41%). MS (method C) m / z 440 [M+H]+, t=1.68 min. 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.68 (dd, J = 17.0, 8.4 Hz, 1H), 7.48 – 7.23 (m, 8H), 4.42 (d, J = 5.6 Hz, 2H) ppm.

[0342] Example 2: N-Benzyl-5-(2,3-difluorophenyl)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine

[0343] A mixture of N-benzyl-6-chloro-5-(2,3-difluorophenyl)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (115 mg, 0.26 mmol) and Pd / C (10%, 80 mg) in MeOH (10 mL) was stirred under H2 at RT for 16 h. The resulting mixture was filtered. The filtrate was purified by prep-HPLC (FA condition) to afford the title compound (64 mg, 60% yield). MS (method B) m / z406 [M+H]+, t=1.90 min. 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.08 (s, 1H), 7.62- 7.56 (m, 1H), 7.41 – 7.24 (m, 8H), 4.44 (d, J = 5.6 Hz, 2H) ppm.

[0344] Example 3: 6-Chloro-5-(2,3-difluorophenyl)-3-(methylamino)-2H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide

[0345] Step 1: Preparation of 1-[[3-amino-5-chloro-4-(2,3-difluorophenyl)-2- thienyl]sulfonyl]-3-methyl-thiourea

[0346] A mixture of^3-amino-5-chloro-4-(2,3-difluorophenyl)thiophene-2-sulfonamide (200 mg, 0.6 mmol) and KOt-Bu (208 mg, 1.8 mmol) in THF (dry, 6 mL) was stirred at 0°C for 5 min. Isothiocyanatomethane (220 mg, 3 mmol) was added. The mixture was warmed to RT and stirred for 16 h. The resulting mixture was filtrated. The filtrate was used for the next step without further purification. MS (method D) m / z 398 [M +H]+, t= 1.98 min.

[0347] Step 2: Preparation of 6-chloro-5-(2,3-difluorophenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0348] A mixture of 1-[[3-amino-5-chloro-4-(2,3-difluorophenyl)-2-thienyl]sulfonyl]-3- methyl-thiourea (400 mg, crude, 0.6 mmol) and TEA (242 mg, 2.4 mmol) in THF (6 mL) was stirred at 0°C for 5 min. Triphosgene (215 mg, 0.72 mmol) in toluene (2 mL) was added. The mixture was warmed to RT and stirred for 16 h. The resulting mixture was filtered. The filtrate was purified with prep-HPLC to afford the title compound (80 mg, yield: 36%). MS (method B) m / z 364 [M +H]+, t=1.80 min. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.64 (dd, J = 17.2, 8.4 Hz, 1H), 7.40 (dd, J = 12.3, 7.8 Hz, 1H), 7.32 (t, J = 6.6 Hz, 1H), 6.73 (s, 1H), 2.71 (d, J = 4.0 Hz, 3H) ppm.

[0349] Example 4: 5-(2,3-Difluorophenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine

[0350] A mixture of 6-chloro-5-(2,3-difluorophenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (40 mg, 0.11 mmol), Pd / C (10%, 40 mg) and HCl (3M in water; 3 mL) in EtOH (20 mL) was stirred under H2 at 60°C for 6 days. The resulting mixture was cooled to RT and filtered. The filtrate was purified by reversed-phase column chromatography (water / MeCN) to afford the title compound (13 mg, 35% yield). MS (method E) m / z 330 [M +H]+, t=1.63 min. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.05 (s, 1H), 7.62-7.67 (m, 1H), 7.44 – 7.27 (m, 2H), 6.81 (s, 1H), 2.77 (d, J = 4.5 Hz, 3H) ppm.

[0351] Example 5: 6-Chloro-5-(2-chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0352] Step 1: Preparation of 2,3,4-tribromo-5-chloro-thiophene

[0353] To a mixture of 2-chlorothiophene (100 g, 845 mmol) in acetic acid (500 mL) was added bromine (675 g, 4.2 mol) slowly at room temperature. The reaction was stirred at 60°C for 48 h. The resulting mixture was cooled to RT and poured into ice water (2 L). The aqueous layer was extracted with DCM (900 mL x 3). The organic layers were combined, washed with water (900 mL x 2) and brine (900 mL x 2), dried over anhydrous Na2SO4 and concentrated. The residuewas purified by column chromatography (silica gel, 100% PE) to give 2,3,4-tribromo-5-chloro- thiophene (270 g, 90% yield). MS (method F) m / z NA, t=10.98 min.

[0354] Step 2: Preparation of 3,4-dibromo-2-chloro-thiophene

[0355] A mixture of 2,3,4-tribromo-5-chloro-thiophene (270 g, 760 mmol) in THF (dry, 3 L) was stirred at -78°C for 30 min. Then n-BuLi (2.5 M in hexanes, 304 mL, 760 mmol) was added dropwise. After addition, the mixture was stirred at -78°C for another 2 h. The mixture was quenched with water (300 mL) at -78°C and warmed to RT. Then the mixture was extracted with EtOAc (1 L x 4). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (100% PE) to give 3,4-dibromo-2-chloro-thiophene (200 g, 95% yield). MS (method F) m / z NA, t=9.91 min.

[0356] Step 3: Preparation of 3,4-dibromothiophene-2-sulfonyl chloride

[0357] 3,4-Dibromo-2-chloro-thiophene (200 g, 724 mmol) was added during 30 min to chlorosulfonic acid (337 g, 2.9 mol) with stirring at 0°C. After stirring at 0°C for 1 h, the resulting suspension was allowed to warm to RT and stirred for an additional 1 h. Then thionyl chloride (21.5 mL, 724 mmol) was added. The reaction mixture was stirred at RT for 16 h. Then the resulting mixture was poured slowly into a cooled mixture of water (600 mL) and toluene (1 L). The organic layer was washed with water (300 mL x 3), dried over anhydrous Na2SO4, and concentrated to give 3,4-dibromothiophene-2-sulfonyl chloride (201 g, crude), which was used for the next step without further purification. MS (method F) m / z NA, t=10.06 min

[0358] Step 4: Preparation of 1-[(3,4-dibromo-5-chloro -2-thienyl)sulfonyl]-3-methyl- guanidine

[0359] A mixture of 3,4-dibromo-5-chloro-thiophene-2-sulfonyl chloride (190 g, crude) and 1-methylguanidine hydrochloride (58.3 g, 532 mmol) in toluene (1900 mL) was stirred at RT. Then a solution of NaOH (81.1 g, 2.03 mol) in water (1900 mL) was added. The mixture was stirred at RT for 80 h. Then the mixture was poured into water (2000 mL) and filtered. The solid was washed with water (1000 mL) and dissolved in ethyl acetate (3000 mL) and THF (2000 mL). The organic layer was washed with 5% aqueous NaHCO3(3000 mL x 2) and brine (3000 mL), dried over anhydrous Na2SO4and concentrated to give the crude product 1-[(3,4-dibromo-5-chloro -2-thienyl)sulfonyl]-3-methyl-guanidine (74 g, 35% yield, 2 steps). MS (method G) m / z 412 [M+H]+, t=1.256 min.

[0360] Step 5: Preparation of 5-bromo-6-chloro-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine

[0361] To a solution of 1-[(3,4-dibromo-5-chloro-2-thienyl)sulfonyl]-3-methyl-guanidine (72 g, 175 mmol), Cs2CO3(114 g, 350 mmol) and N,N’-dimethylethane-1,2-diamine (150.2 g, 1.75 mol) in 1,4-dioxane (720 mL) was added CuI (16.7 g, 87.5 mmol) under nitrogen. The reaction was stirred at 50°C for 4 h. The resulting mixture was poured into water (3000 mL) and washed with EtOAc (1000 mL x 2). The aqueous phase was acidified with HCl (1M) to pH = 4. Theresulting suspension was stirred for 30 min. The precipitate was collected by filtration and washed with water (1000 mL). The solid was redissolved in DCM (3000 mL) and MeOH (600 mL). The organic phase was washed with water (1000 mL) and brine (1000 mL), dried over anhydrous Na2SO4, and concentrated to give 5-bromo-6-chloro-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (25 g, 42% yield). MS (method H) m / z 330.0 [M+H]+, t=1.47 min.

[0362] Step 6: Preparation of 6-chloro-5-(2-chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0363] A mixture of 5-bromo-6-chloro-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (2.0 g, 6.0 mmol), (2-chloro-3-fluoro-phenyl)boronic acid (2.11 g, 12.1 mmol), K2CO3(2.51 g, 18.1 mmol) and Pd(dtbpf)Cl2(789 mg, 1.21 mmol) in NMP (dry, 24 mL) was stirred at 60°C for 16 h under nitrogen. The resulting mixture was cooled to RT, filtered, and concentrated. The residue was purified by prep-HPLC (NH4HCO3 condition) to afford the title compound (260 mg, 11% yield). MS (method I) m / z 380 [M+H]+, t=1.87min.1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.72 – 7.50 (m, 2H), 7.40 (d, J = 7.4 Hz, 1H), 6.73 (s, 1H), 2.73 (d, J = 4.5 Hz, 3H) ppm.

[0364] Example 6: 5-(2-Chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine

[0365] A mixture of 6-chloro-5-(2-chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (21 mg, 0.05 mmol) and Pd / C (10%, 20 mg) in MeOH (3 mL) was stirred under H2at RT for 6 h. The resulting mixture was filtered. The filtrate was purified by^prep-TLC (3% MeOH in DCM) to afford the title compound (14 mg, 73% yield). MS (method C) m / z 346 [M+H]+, t=1.49 min.1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.99 (s, 1H), 7.59-7.53 (m, 2H), 7.34 (d, J = 7.4 Hz, 1H), 6.73 (s, 1H), 2.75 (d, J = 4.6 Hz, 3H) ppm.

[0366] Example 7: 5-(2-Chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0367] Step 1: Preparation of 3,4-dibromothiophene-2-sulfonyl chloride

[0368] 3,4-Dibromothiophene (5.0 g, 20.7 mmol) was added during 20 min to chlorosulfonic acid (5.2 mL, 77 mmol) with stirring at 10-15 °C. After 1 h, the resulting suspension was allowed to warm to room temperature and stirred for additional 1 h. Thionyl chloride (1.5 mL, 20.7 mmol) was added, and the reaction mixture was stirred overnight at RT. Then the mixture was poured slowly into a cooled mixture of water (50 mL) and toluene (75 mL). The organic layer was washed with water (25 mL x 2), dried over Na2SO4, and evaporated to dryness to give crude 3,4- dibromothiophene-2-sulfonyl chloride (6.1 g, 86% yield), which was used for the next step without further purification. MS (method G) m / z N / A, t=1.31 min.

[0369] Step 2: Preparation of 1-[(3,4-dibromo-2-thienyl)sulfonyl]-3-methyl-guanidine

[0370] A mixture of 3,4-dibromothiophene-2-sulfonyl chloride (5.8 g, 17 mmol) and 1- methylguanidine hydrochloride (1.96 g, 18 mmol) in toluene (25 mL) was stirred at RT. NaOH (2.73 g, 68 mmol) in water (25 mL) was added. The mixture was stirred at RT for 40 h. The mixture was filtrated. The solid was washed with water and toluene. The solid was dried in vacuo to give 1-[(3,4-dibromo-2-thienyl)sulfonyl]-3-methyl-guanidine (3.7 g, 57% yield). MS (method J) m / z 377 [M +H]+, t=1.58 min.

[0371] Step 3: Preparation of 5-bromo-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine

[0372] A mixture of 1-[(3,4-dibromo-2-thienyl)sulfonyl]-3-methyl-guanidine (1.8 g, 4.77 mmol), K2CO3 (2.31 g, 13.5 mmol) and bronze (0.87 g, 4.77 mmol) in NMP / H2O (15 / 3 mL) was stirred under N2 at 100°C for 16 h. The resulting mixture was cooled to RT and filtered. The solution was poured into water (100 mL). The water layer was extracted with EtOAc (100 mL x 4). The organic layers were combined, dried over Na2SO4and concentrated. The residue was purified by prep-HPLC to give 5-bromo-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- amine (400 mg, 28% yield). MS (method K) m / z 296 [M+H]+, t=1.42 min.1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.15 (s, 1H), 7.11 (s, 1H), 2.80 (d, J = 3.7 Hz, 3H) ppm.

[0373] Step 4: Preparation of 5-(2-chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0374] A mixture of 5-bromo-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (50 mg, 0.17 mmol), 2-(2-chloro-4-methylsulfanyl-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (58 mg, 0.2 mmol), K2CO3(47 mg, 0.34 mmol) and Pd(dppf)Cl2(13 mg, 0.017 mmol) in 1,4-dioxane / H2O (3 / 0.5 mL) was stirred under N2 at 80°C for 16 h. The resulting mixturewas cooled to RT and poured into water (2 mL). The water layer was extracted with DCM (3 mL x 3). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (3% MeOH in DCM) to afford the title compound (15 mg, 23% yield). MS (method L) m / z 374 [M +H]+, t=1.80 min. 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.89 (s, 1H), 7.51 (d, J = 1.4 Hz, 1H), 7.44 – 7.24 (m, 2H), 6.75 (d, J = 4.3 Hz, 1H), 2.75 (d, J = 4.6 Hz, 3H), 2.56 (s, 3H) ppm.

[0375] Example 8: 5-(2-Chloro-4-methylsulfinyl-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0376] A mixture of 5-bromo-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (300 mg, 1.0 mmol), 2-(2-chloro-4-methylsulfinyl-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (365 mg, 1.2 mmol), K2CO3 (280 mg, 2.0 mmol) and Pd(dppf)Cl2 (73 mg, 0.1 mmol) in 1,4-dioxane / H2O (10 / 2 mL) was stirred under N2at 80°C for 16 h. The resulting mixture was cooled to RT and purified by prep-HPLC to afford the title compound (60 mg, 15% yield. MS (method L) m / z 390 [M +H]+, t=1.50 min. 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 7.98 (s, 1H), 7.95 (d, J = 1.5 Hz, 1H), 7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 2.87 (s, 3H), 2.76 (d, J = 3.7 Hz, 3H) ppm.

[0377] Example 9: 5-(2-Chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0378] A mixture of 5-(2-chloro-4-methylsulfinyl-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (20 mg, 0.05 mmol) in acetone / H2O (3 / 1 mL) was stirred at RT. Potassium monopersulfate triple salt (Oxone) (31 mg, 0.05 mmol) was added. The mixture was stirred at RT for 16 h. The mixture was purified by reversed-phase column chromatography (NH4HCO3condition) to afford the title compound (9 mg, 43% yield). MS (method L) m / z 406 [M +H]+, t=1.61 min.1H NMR (400 MHz, CD3OD) δ 8.12 (d, J = 1.7 Hz, 1H), 7.96 (dd, J = 8.1, 1.8 Hz, 1H), 7.81 – 7.66 (m, 2H), 3.20 (s, 3H), 2.84 (s, 3H) ppm.

[0379] Example 10: 5-[2-Chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0380] A mixture of 5-(2-chloro-4-methylsulfinyl-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (30 mg, 0.076 mmol) and NaN3 (20 mg, 0.3 mmol) in Eaton's reagent (0.8 mL) was stirred at 50°C for 4 h. The resulting mixture was cooled to RT and purified by reversed-phase column chromatography (NH4HCO3 condition) to afford the title compound (25 mg, 80% yield). MS (method L) m / z 405 [M +H]+,t=1.48 min. 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.14 (d, J = 1.7 Hz, 1H), 8.11 – 7.90 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 6.74 (s, 1H), 4.52 (s, 1H), 4.24 (s, 1H), 3.19 (d, J = 7.2 Hz, 3H), 2.76 (d, J = 3.7 Hz, 3H) ppm.

[0381] Example 11: N-[6-Chloro-5-(2-chloro-3-fluoro-phenyl)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-yl]-N-methyl-acetamide

[0382] To a mixture of 6-chloro-5-(2-chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (72 mg, 0.18 mmol) and N,N-diisopropylethylamine (196 mg, 1.5 mmol) in THF (dry, 3 mL) was added acetyl chloride (90 mg, 1.14 mmol). The reaction was stirred at RT for 16 h. The resulting mixture was filtered and purified by prep-HPLC (NH4HCO3condition) to afford the title compound (28 mg, 35% yield). MS (method M) m / z 422 [M+H]+, t=1.52 min.1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 7.82 – 7.53 (m, 2H), 7.43 (s, 1H), 3.25 (s, 3H), 2.24 (s, 3H) ppm.

[0383] Example 12: Methyl 3-chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]benzoate

[0384] A mixture of 5-bromo-6-chloro-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (200 mg, ^0.6 mmol), (2-chloro-4-methoxycarbonyl-phenyl)boronic acid (260 mg, 1.2 mmol), K2CO3 (251 mg, 1.8 mmol) and Pd(dtbpf)Cl2 (79 mg, 0.12 mmol) in NMP (dry, 4 mL) was stirred at 60°C (microwave irradiation) for 8 h under N2. The resulting mixture was cooled to RT, filtered, and purified by prep-HPLC (TFA condition) to afford the title compound (49 mg, 19% yield). MS (method L) m / z 420 [M +H]+, t=1.88 min. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.16 (d, J = 1.5 Hz, 1H), 8.06 (dd, J = 8.0, 1.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 3.93 (s, 3H), 2.74 (d, J = 4.6 Hz, 3H) ppm.

[0385] Example 13: 3-Chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]benzoic acid

[0386] To a mixture of methyl 3-chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-5-yl]benzoate (36 mg, 0.086 mmol) in THF / H2O (3 / 1 mL) was added lithium hydroxide monohydrate (29 mg, 0.68 mmol). The reaction was stirred at RT for 4 h. The resulting mixture was purified by reversed-phase column chromatography (TFA condition) to afford the title compound (31 mg, 89% yield). MS (method L) m / z 406 [M+H]+, t=1.73 min. 1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 10.27 (s, 1H), 8.12 (d, J = 0.8 Hz, 1H), 8.03 (dd, J = 7.4, 1.5 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 6.77 (s, 1H), 2.73 (d, J = 4.6 Hz, 3H) ppm.

[0387] Example 14: 3-Chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]benzamide

[0388] To a mixture of 3-chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]benzoic acid (21 mg, 0.05 mmol), ammonium chloride (22 mg, 0.41 mmol), triethylamine (78 mg, 0.77 mmol) in DMF (dry, 2 mL) was added HATU (40 mg, 0.1 mmol). The reaction was stirred at RT for 16 h. The resulting mixture was purified by reversed- phase column chromatography (NH4HCO3condition) to afford the title compound (12.1 mg, 51% yield). MS (method C) m / z 405 [M+H]+, t=1.39 min. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.01 (s, 1H), 7.87 (d, J = 7.0 Hz, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 2.88 (d, J = 6.0 Hz, 3H) ppm.

[0389] Example 15: 5-(2-Chloro-3-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine

[0390] Step 1: Preparation of 2,3,4-tribromo-5-methyl-thiophene

[0391] A mixture of 2,3,4,5-tetrabromothiophene (40 g, 100 mmol) in THF (dry, 400 mL) was stirred at -78°C for 15 min. Then n-BuLi (2.5 M in n-hexane, 40 mL, 100 mmol) was added dropwise. After the addition, the mixture was stirred at -78°C for another 30 min. Then methyl benzenesulfonate (18.9 g, 110 mmol) was added. The mixture was stirred at -78°C for 1 h, warmed to RT slowly and stirred for another 16 h. The resulting mixture was poured into water (500 mL) and extracted with DCM (400 mL x 3). The organic layers were combined, washed with brine (400 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (100% PE) to give 2,3,4-tribromo-5-methyl- thiophene (31 g, 92% yield). MS (method L) m / z NA, t=2.38 min.

[0392] Step 2: Preparation of 3,4-dibromo-2-methyl-thiophene

[0393] A mixture of 2,3,4-tribromo-5-methyl-thiophene (31.1 g, 92.9 mmol) in THF (dry, 300 mL) was stirred at -78°C for 15 min. Then n-BuLi (2.5 M in n-hexane, 37.2 mL, 93 mmol) was added dropwise. After the addition, the mixture was stirred at -78°C for 1 h. The mixture was quenched with water (500 mL) and extracted with EtOAc (400 mL x 3). The organic layers were combined, washed with brine (400 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (100% PE) to give 3,4-dibromo-2-methyl-thiophene (22.3 g, 93% yield). MS (method L) m / z NA, t=2.21 min.

[0394] Step 3: Preparation of 3,4-dibromo-5-methyl-thiophene-2-sulfonyl chloride

[0395] 3,4-Dibromo-2-chloro-thiophene (22.3 g, 87 mmol) was added during 20 min to chlorosulfonic acid (23.2 mL, 348 mmol) at 0°C. The mixture was stirred at 0°C for 1 h. Then thionyl chloride (6.4 mL, 87 mmol) was added dropwise. The reaction was stirred at 0°C for another 3 h. The resulting mixture was poured slowly into a cooled mixture of water (300 mL) and toluene (600 mL). The organic layer was washed with water (300 mL x 2) and brine (300 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to give 3,4-dibromo-5- methyl-thiophene-2-sulfonyl chloride (27.4 g, crude), which was used for the next step without further purification. MS (method N) m / z NA, t=1.37 min.

[0396] Step 4: Preparation of 1-[(3,4-dibromo-5-methyl-2-thienyl)sulfonyl]-3-methyl- guanidine

[0397] A mixture of 3,4-dibromo-5-methyl-thiophene-2-sulfonyl chloride (27.4 g, crude) and 1-methylguanidine hydrochloride (8.86 g, 80.9 mmol) in toluene (100 mL) was stirred at RT. Then a solution of NaOH (12.3 g, 308 mmol) in water (100 mL) was added. The mixture was stirred at RT for 40 h. Then the mixture was filtered. The solid was washed with water (100 mL), toluene (100 mL) and dried in vacuo to give 1-[(3,4-dibromo-5-methyl-2-thienyl)sulfonyl]-3-methyl- guanidine (18 g, 53% yield, 2 steps). MS (method L) m / z 392 [M+H]+, t=1.13 min.

[0398] Step 5: Preparation of 5-bromo-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine

[0399] A mixture of 1-[(3,4-dibromo-5-methyl-2-thienyl)sulfonyl]-3-methyl-guanidine (1.7 g, 4.3 mmol), K2CO3(2.1 g, 15.2 mmol) and bronze (792 mg, 4.3 mmol) in NMP (10 mL) and water (2 mL) was stirred at 100°C for 16 h under N2. The resulting mixture was cooled to RT, filtered, and concentrated. The residue was purified by reversed-phase column chromatography to give 5- bromo-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (820 mg, 60% yield). MS (method L) m / z 310 [M+H]+, t=1.58 min. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.06 (s, 1H), 2.79 (d, J = 4.6 Hz, 3H), 2.44 (s, 3H) ppm.

[0400] Step 6: Preparation of 5-(2-chloro-3-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0401] A mixture of 5-bromo-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- amine (231 mg, 0.75 mmol), (2-chloro-3-fluoro-phenyl)boronic acid (260 mg, 1.5 mmol), K2CO3 (309 mg, 2.25 mmol) and Pd(dtbpf)Cl2 (97 mg, 0.15 mmol) in NMP (dry, 4 mL) was stirred at 60°C (microwave irradiation) for 6 h under N2. The resulting mixture was cooled to RT, filtered, and purified by prep-HPLC (NH4HCO3condition) to afford the title compound (51 mg, 19% yield). MS (method L) m / z 360 [M +H]+, t=1.78 min.1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.68 – 7.44 (m, 2H), 7.30 (d, J = 7.0 Hz, 1H), 6.63 (s, 1H), 2.73 (d, J = 4.6 Hz, 3H), 2.24 (s, 3H) ppm.

[0402] Example 16: 5-(3-Chloro-2-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine

[0403] A mixture of 5-bromo-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- amine (51 mg, 0.16 mmol), (3-chloro-2-fluoro-phenyl)boronic acid (57 mg, 0.33 mmol), K2CO3 (68 mg, 0.5 mmol) and Pd(dppf)Cl2 (12 mg, 0.016 mmol) in DMSO / H2O (1 / 0.2 mL) was stirred at 100°C for 16 h under N2. The resulting mixture was cooled to RT, filtered, and purified by prep-HPLC (NH4HCO3condition) to afford the title compound (9 mg, 15% yield). MS (method N) m / z 360 [M +H]+, t=1.15 min. 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.81 – 7.73 (m, 1H), 7.48 – 7.33 (m, 2H), 6.70 (s, 1H), 2.74 (d, J = 4.5 Hz, 3H), 2.30 (s, 3H) ppm.

[0404] Example 17: N-[5-(2-Chloro-3-fluoro-phenyl)-6-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-yl]-N-methyl-acetamide

[0405] To a mixture of 5-(2-chloro-3-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (31 mg, 0.08 mmol) and N,N-diisopropylethylamine (167 mg, 1.2 mmol) in THF (dry, 3 mL) was added acetyl chloride (68 mg, 0.8 mmol). The reaction was stirred at RT for 16 h. The resulting mixture was purified by reversed-phase column chromatography (NH4HCO3 condition) to afford the title compound (12 mg, 34% yield). MS (method L) m / z 402 [M +H]+, t=1.92 min. 1H NMR (400 MHz, CDCl3) δ 12.78 (s, 1H), 7.45 – 7.40 (m, 1H), 7.36 – 7.31 (m, 1H), 7.07 – 7.03 (m, 1H), 3.50 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H) ppm.

[0406] Example 18: 6-Chloro-5-(2-chloro-4-(methylsulfinyl)phenyl)-3-(methylamino)-4H- thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide

[0407] A mixture of 5-bromo-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- amine (231 g, ^0.70 mmol), (2-chloro-4-(methylsulfinyl)phenyl)boronic acid (229 mg, 1.05 mmol), K2CO3(290 mg, 2.1 mmol) and Pd(dtbpf)Cl2(91 mg, 0.14 mmol) in NMP (dry, 4 mL) was stirred at 60°C (microwave irradiation) for 3 h under N2. The resulting mixture was cooled to RT, filtered, and purified by prep-HPLC (NH4HCO3 condition) to afford the title compound (51 mg, 19% yield). MS (method L) m / z 424 [M+H]+, t=1.67 min.1H NMR (400 MHz, CDCl3) δ 9.44 (d, J = 34.4 Hz, 1H), 7.57 – 7.45 (m, 2H), 7.32 (s, 1H), 5.91 (d, J = 11.6 Hz, 1H), 2.91 (d, J = 3.0 Hz, 3H), 2.80 (d, J = 11.8 Hz, 3H) ppm.

[0408] Example 19: 6-Chloro-5-[2-chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1- dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0409] To a mixture of 6-chloro-5-(2-chloro-4-methylsulfinyl-phenyl)-N-methyl-1,1-dioxo- 4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (30 mg, 0.07 mmol) in Eaton's reagent (0.8 mL) was added NaN3 (18.2 mg, 0.28 mmol). The reaction was stirred at 50°C for 4 h. The resulting mixture was cooled to RT and purified by reversed-phase column chromatography (NH4HCO3 condition) to afford the title compound (19 mg, 61% yield). MS (method N) m / z 439 [M +H]+, t=1.05 min. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.20 (dd, J = 3.9, 1.7 Hz, 1H), 8.10 – 8.01 (m, 1H), 7.79 (dd, J = 8.0, 1.7 Hz, 1H), 6.76 (s, 1H), 4.58 (s, 1H), 3.22 (s, 3H), 2.74 (d, J = 4.6 Hz, 3H) ppm.

[0410] Example 20: 6-Chloro-5-(2-chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo- 4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0411] Step 1: Preparation of 1-bromo-2-chloro-4-methylsulfanyl-benzene

[0412] A solution of 1-bromo-2-chloro-4-fluoro-benzene (30 g, 0.143 mol and 20% sodium thiomethoxide aq. solution (55 g, 0.158 mol) in DMSO (50 mL) was heated to 100°C and stirred for 12 h. LCMS indicated the reaction was completed. The reaction mixture was cooled to RT, diluted with water (400 mL), and extracted with ethyl acetate (300 mL x 3). The combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (Biotage Flash, 5% ethyl acetate in PE) to afford 1-bromo-2-chloro-4-methylsulfanyl-benzene (20 g, 75.7 mmol, purity: 90%, yield: 58%). MS (method M) m / z NA, t= 2.04 min.

[0413] Step 2: Preparation of 2-(2-chloro-4-methylsulfanyl-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane

[0414] A mixture of 1-bromo-2-chloro-4-methylsulfanyl-benzene (10 g, 42.1 mmol), bis(pinacolato)diboron (12.8 g, 50.5 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (924 mg, 1.26 mmol) and potassium acetate (12.4 g, 126 mmol) in dry 1,4-dioxane (100 mL) was stirred at 100°C for 10 h under nitrogen. LCMS indicated the reaction was completed. The reaction mixture was cooled to RT, diluted with water (300 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (Biotage Flash, 5% ethyl acetate in PE) to afford 2-(2-chloro-4-methylsulfanyl-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (12.0 g, 37.9 mmol, purity: 90%, yield: 90%). MS (method O) m / z NA, t= 2.39 min.

[0415] Step 3: Preparation of (2-chloro-4-methylsulfanyl-phenyl)boronic acid

[0416] To a solution of 2-(2-chloro-4-methylsulfanyl-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (12 g, 42.2 mmol) in acetone (100 mL) and water (100 mL) was added ammonium acetate (9.1 g, 118 mmol) slowly. Then sodium periodate (29.8 g, 139 mmol) was added in portions. The reaction mixture was stirred at RT for 16 h. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (Biotage Flash, 20% ethyl acetate in PE) to afford (2-chloro-4-methylsulfanyl- phenyl)boronic acid (2.6 g, 12.2 mmol, purity: 95%, yield: 29%). MS (method I) m / z NA, t=1.72 min.

[0417] Step 4: Preparation of 6-chloro-5-(2-chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1- dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0418] A mixture of 5-bromo-6-chloro-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (1.0 g, 3.02 mmol), (2-chloro-4-methylsulfanyl-phenyl)boronic acid (919 mg, 4.54 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladiumdichloride (394 mg, 0.605 mmol) and potassium carbonate (1.25 g, 9.07 mmol) in dry NMP (10 mL) was purged with nitrogen for 10 min. The mixture was stirred at 70°C (microwave irradiation) for 8 h. LCMS indicated the reaction was completed. The reaction mixture was cooled to RT, diluted with water (100 mL) and ethyl acetate (100 mL), filtered through filter cloth to remove the precipitate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with brine (100 mL x 3), dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Biotage Flash, 80% ethyl acetate in PE) to give the crude product, which was purified by prep-HPLC to afford the title compound (402 mg, 0.975 mmol, purity: 99%, yield: 32.2%). MS (method P) m / z 408 (M+H)+, t=7.52 min. 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.47 – 7.37 (m, 2H), 6.75 (s, 1H), 2.74 (d, J = 4.6 Hz, 3H), 2.57 (s, 3H) ppm.

[0419] Example 21: 5-(2-Chloro-3-fluoro-phenyl)-6-ethyl-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0420] Step 1: Preparation of 3,4-dibromo-2-ethyl-thiophene

[0421] A mixture of 3,4-dibromothiophene (50 g, 207 mmol) in THF (dry, 400 mL) was stirred at -78°C for 5 min. LDA (2 M in THF, 103 mL, 207 mmol) was added dropwise. After the addition, the mixture was stirred at -78°C for 30 min. Then iodoethane (38.7 g, 248 mmol) was added. The mixture was stirred at -78°C for 1 h, warmed to RT slowly and stirred for 16 h. The resulting mixture was poured into water (600 mL) and extracted with DCM (400 mL x 3). The organic layers were combined, washed with brine (600 mL x 2) dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (100% PE) to give 3,4-dibromo-2-ethyl-thiophene (48 g, crude). MS (method O) m / z NA, t=2.32 min.

[0422] Step 2: Preparation of 3,4-dibromo-5-ethyl-thiophene-2-sulfonyl chloride

[0423] 3,4-Dibromo-2-ethyl-thiophene (48 g, 178 mmol) was added during 20 min to chlorosulfonic acid (47 mL, 711 mmol) with stirring at 0°C. After stirring at 0°C for 1 h, thionyl chloride (13 mL, 178 mmol) was added. The reaction mixture was stirred at 0°C for 3 h. The resulting mixture was poured slowly into ice water (500 mL) and extracted with DCM (500 mL x 3). The organic layers were combined, washed with brine (600 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give 3,4-dibromo-5-ethyl-thiophene-2-sulfonyl chloride (41 g, crude), which was used for the next step without further purification. MS (method R) m / z NA, t=1.95 min.

[0424] Step 3: Preparation of 1-[(3,4-dibromo-5-ethyl-2-thienyl)sulfonyl]-3-methyl-guanidine

[0425] A mixture of 3,4-dibromo-5-ethyl-thiophene-2-sulfonyl chloride (41 g, crude) and 1- methylguanidine hydrochloride (128 g, 117 mmol) in toluene (200 mL) was stirred at RT. Then a solution of NaOH (17.8 g, 444 mmol) in water (150 mL) was added. The mixture was stirred at RT for 60 h. Then the mixture was filtered. The solid was washed with water (150 mL), toluene (150 mL) and dried in vacuo to give 1-[(3,4-dibromo-5-ethyl-2-thienyl)sulfonyl]-3-methyl- guanidine (20 g, 3 steps’ yield: 23.9%). MS (method S) m / z 406 [M+H]+, t=1.73 min.

[0426] Step 4: Preparation of 5-bromo-6-ethyl-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine

[0427] A mixture of 1-[(3,4-dibromo-5-ethyl-2-thienyl)sulfonyl]-3-methyl-guanidine (9 g, 22 mmol), K2CO3 (9.21 g, 66 mmol) and bronze (4.05 mg, 22 mmol) in DMF (50 mL) and water (10 mL) was stirred at 100°C for 16 h under nitrogen. The resulting mixture was cooled to RT, filtered, and concentrated. The residue was purified with silica gel column chromatography (7% MeOH in DCM) to give 5-bromo-6-ethyl-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (4.8 g, 66% yield). MS (method R) m / z 324 [M+H]+, t=1.52 min.

[0428] Step 5: Preparation of 5-(2-chloro-3-fluoro-phenyl)-6-ethyl-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0429] A mixture of 5-bromo-6-ethyl-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine (130 mg, ^0.4 mmol), (2-chloro-3-fluoro-phenyl)boronic acid (140 mg, 0.8 mmol), K2CO3(166 mg, 1.2 mmol) and Pd(dtbpf)Cl2(40 mg, 0.06 mmol) in NMP (dry, 3 mL) was stirred at 60°C for 16 h under N2. The resulting mixture was cooled to RT, filtered, and purified by prep-HPLC (NH4HCO3condition) to afford the title compound (31 mg, 20% yield). MS (method I) m / z 374 [M+H]+, t=1.86 min. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.72 – 7.47 (m, 2H), 7.31 (d, J = 7.6 Hz, 1H), 6.61 (s, 1H), 2.72 (d, J = 4.5 Hz, 3H), 2.59 (q, J = 7.6 Hz, 2H), 1.10 (t, J = 7.5 Hz, 3H) ppm.

[0430] Example 22: 5-(2-Chloro-4-(methylsulfonyl)phenyl)-6-ethyl-3-(methylamino)-4H- thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide

[0431] Step 1: Preparation of 5-(2-chloro-4-(methylthio)phenyl)-6-ethyl-3-(methylamino)- 4H-thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide

[0432] A mixture of 5-bromo-6-ethyl-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine (1.2 g, ^3.7 mmol), (2-chloro-4-(methylthio)phenyl)boronic acid (1.5 g, 7.4 mmol), K2CO3(1.5 g, 11.1 mmol) and Pd(dtbpf)Cl2 (492 mg, 0.74 mmol) in NMP (dry, 10 mL) was purged with nitrogen for 10 min. The mixture was stirred at 70°C (microwave irradiation) for 8 h. The resulting mixture was cooled to RT, diluted with water (100 mL), and extracted with ethyl acetate (100 mLx 2). The combined organic layers were washed with brine (100 mL x 2), dried with anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (Biotage Flash, 70% ethyl acetate in PE) to give 5-(2-chloro-4-(methylthio)phenyl)-6-ethyl-3- (methylamino)-4H-thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide (900 mg, 60% yield). MS (method G) m / z 402 [M+H]+, t=1.47 min.

[0433] Step 6: Preparation of 5-(2-chloro-4-(methylsulfonyl)phenyl)-6-ethyl-3- (methylamino)-4H-thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide

[0434] To a solution of 5-(2-chloro-4-(methylthio)phenyl)-6-ethyl-3-(methylamino)-4H- thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide (500 mg, ^1.24 mmol) in acetone (20 mL) and water (10 mL) was added potassium monopersulfate triple salt (Oxone) (1.5 g, 2.5 mmol) slowly. The reaction was stirred at RT for 16 h. Then the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were dried with anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (Biotage Flash, 80% ethyl acetate in PE) to afford the title compound (412 mg, yield: 76.6%). MS (method T) m / z 434 [M+H]+, t=1.54 min.1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.22 (s, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 6.4, H), 6.52 (s, 1H), 3.39 (s, 3H), 2.73 (d, J = 3.6 Hz, 3H), 2.59 (q, J = 6.0 Hz, 2H), 2.73 (t, J = 6.0 Hz, 3H) ppm.

[0435] Example 23: 6-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo- 4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0436] To a solution of 6-chloro-5-(2-chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo- 4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (350 mg, 0.857 mmol) in acetone (20 mL) and water (10 mL) was added potassium monopersulfate triple salt (Oxone) (1.05 g, 1.71 mmol) slowly. The reaction was stirred at RT for 16 h. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (Biotage Flash, 90% ethyl acetate in PE) to afford the title compound (320 mg, 0.719 mmol, purity: 99%, yield: 83.9%). MS (method Q) m / z 440 [M+H]+, t= 5.53 min.1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.25 (s, 1H), 8.07 (dd, J = 8.0, 1.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 3.41 (s, 3H), 2.74 (d, J = 4.4 Hz, 3H) ppm.

[0437] Example 24 and Example 25: 6-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N- methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (atropisomer 1) and 6-chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (atropisomer 2)

[0438] The atropisomers of 6-chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1- dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (70 mg, 0.159 mmol) were separated by chiral HPLC to afford 6-chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine atropisomer 1 (16.7 mg, 0.038 mmol, purity: 99%, yield: 23.9%) and 6-chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine atropisomer 2 (24.6 mg, 0.056 mmol, purity: 99%, yield: 35.1%).

[0439] Preparative chiral HPLC conditions: Instrument: SFC-150 (Waters); Column: AS 20x250mm, 10μm (REGIS); Column temperature: 35°C; Mobile phase: CO2 / MeOH (0.2% NH3 (7M in MeOH))=50 / 50; Flow rate: 100 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 6.9 min; Sample solution: 70 mg dissolved in 22 ml methanol and DCM; Injection volume: 4.8 ml.

[0440] Analytical chiral HPLC conditions: Column: AS-H 4.6*100mm 5µm; Column temperature: 40°C; Mobile phase: CO2 / MeOH (0.2% NH3 (7M in MeOH)); Flow rate: 3 ml / min; Back pressure: 2000 psi; Detection wavelength: 214 nm

[0441] Atropisomer 1: 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.25 (s, 1H), 8.07 (d, J = 8.0, 1H), 7.85 (d, J = 8.0 Hz, 1H), 6.72 (s, 1H), 3.41 (s, 3H), 2.74 (d, J = 3.6 Hz, 3H) ppm. Chiral HPLC: t=1.28 min (85.7%), t=3.07 min (14.3%).

[0442] Atropisomer 2: 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.25 (s, 1H), 8.07 (dd, J = 8.0, 1H), 7.85 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 3.40 (s, 3H), 2.73 (d, J = 3.2 Hz, 3H) ppm. Chiral HPLC: t=1.28 min (16.2%), t=3.03 min (83.8%).

[0443] Example 26: 6-Chloro-5-(2-chloro-4-(ethylthio)phenyl)-3-(methylamino)-4H- thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide

[0444] Step 1: Preparation of (4-bromo-3-chlorophenyl)(ethyl)sulfane

[0445] A solution of 1-bromo-2-chloro-4-fluoro-benzene (26 g, 124 mmol) and sodium ethanethiolate (15.6 g, 186 mmol) in DMSO (200 mL) was heated to 100°C and stirred for 16 h. LCMS indicated the reaction was completed. The reaction mixture was cooled to RT, diluted with water (400 mL), and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (Biotage Flash, 5% ethyl acetate in PE) to afford (4-bromo-3-chlorophenyl)(ethyl)sulfane (22 g, 87.4 mmol, purity: 95%, yield: 67 %). MS (method U) m / z NA, t=2.07 min.

[0446] Step 2: Preparation of 2-(2-chloro-4-(ethylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane

[0447] A mixture of (4-bromo-3-chlorophenyl)(ethyl)sulfane (22 g, 87.4 mmol), bis(pinacolato)diboron (26.7 g, 104.8 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 g, 8.7 mmol) and potassium acetate (24.6 g, 261 mmol) in dry dioxane (200 mL) was stirred at 100°C for 16 h under nitrogen. LCMS indicated the reaction was complete. The reaction mixture was cooled to RT, diluted with water (300 mL), and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (Biotage Flash, 5% ethyl acetate in PE) to afford 2-(2-chloro-4- (ethylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25 g, 83 mmol, purity: 90%, yield: 90%). MS (method V) m / z 299 [M+H]+, t=1.71 min.

[0448] Step 3: Preparation of (2-chloro-4-(ethylthio)phenyl)boronic acid

[0449] To a solution of 2-(2-chloro-4-(ethylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (25 g, 83 mmol) in acetone (200 mL) and water (200 mL) was added ammonium acetate (17.9 g, 232 mmol) slowly. Then sodium periodate (59.1 g, 274 mmol) was added into the reaction system in portions. The reaction mixture was stirred at RT for 16 h. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic layers were washed with brine (300 mL x 2), dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (Biotage Flash, 30% ethyl acetate in PE) to afford (2-chloro-4-(ethylthio)phenyl)boronic acid (4.5 g, 20 mmol, purity: 95%, yield: 25.4%). MS (method V) m / z 217 [M+H]+, t=1.32 min.

[0450] Step 4: Preparation of 6-chloro-5-(2-chloro-4-(ethylthio)phenyl)-3-(methylamino)-4H- thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide

[0451] A mixture of 5-bromo-6-chloro-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (2.2 g, 6.66 mmol), (2-chloro-4-(ethylthio)phenyl)boronic acid (1.6 g, 7.4 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladiumdichloride (960 mg, 1.48 mmol) and potassium carbonate (2.04 g, 14.8 mmol) in dry NMP (20 mL) was purged with nitrogen for 10 min. The mixture was stirred at 80°C for 16 h. LCMS indicated the reaction was complete. The reaction mixture was cooled to RT, diluted with water (100 mL) and ethyl acetate (100 mL), filtered through filter cloth to remove the precipitate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with brine (100 mL x 3), dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Biotage Flash, 80% ethyl acetate in PE) to give the crude product (870 mg, purity: 70%, yield: 22%). 70 mg of the crude was further purified by prep-HPLC to afford the title compound (19 mg, 0.045 mmol, purity: 99%). MS (method W) m / z 422 [M+H]+, t=1.87 min.1H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 7.57 (s, 1H), 7.41 (d, J = 3.0 Hz, 2H), 6.77 (s, 1H), 3.12 (q, J = 7.5 Hz, 2H), 2.73 (d, J = 4.5 Hz, 3H), 1.31 (t, J = 7.5 Hz, 3H) ppm.

[0452] Example 27: 6-Chloro-5-(2-chloro-4-(ethylsulfinyl)phenyl)-3-(methylamino)-4H- thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide

[0453] To a solution of 6-chloro-5-(2-chloro-4-(ethylthio)phenyl)-3-(methylamino)-4H- thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide (200 mg, 0.474 mmol, purity: 70% ) in acetone (5 mL)and water (5 mL) was added potassium monopersulfate triple salt (Oxone) (41 mg, 0.119 mmol) slowly. The reaction was stirred at RT for 16 h. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (Biotage Flash, 90% ethyl acetate in PE) to afford the title compound (23 mg, 0.045 mmol, purity: 99%, yield: 15.8 %). MS (method W) m / z 438 [M+H]+, t=1.62 min. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.78-7.76 (m, J = 8.0 Hz, 2H), 6.89 (s, 1H), 3.22-3.19 (m, 1H), 2.94-2.87 (m, 1H), 2.72 (s, 3H), 1.13-1.09 (m, 3H) ppm.

[0454] Example 28: 6-Chloro-5-(2-chloro-4-(ethylsulfonyl)phenyl)-3-(methylamino)-4H- thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide

[0455] To a solution of 6-chloro-5-(2-chloro-4-(ethylthio)phenyl)-3-(methylamino)-4H- thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide (200 mg, 0.474 mmol, purity: 70% ) in acetone (5 mL) and water (5 mL) was added potassium monopersulfate triple salt (Oxone) (82 mg, 0.237 mmol) slowly. The reaction was stirred at RT for 16 h. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried with anhydrous sodiumsulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (Biotage Flash, 90% ethyl acetate in PE) to afford the title compound (23 mg, 0.05 mmol, purity: 99%, yield: 15.3 %). MS (method W) m / z 454 [M+H]+, t=1.64 min. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.19 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 8.5 Hz , 1H), 6.75 (s, 1H), 3.50 (q, J = 7.5 Hz, 2H), 2.73 (d, J = 4.0 Hz, 3H), 1.19 (t, J = 7.5 Hz, 3H) ppm.

[0456] Example 29 and Example 30: 6-Ethyl-N-methyl-5-[(3S*,4S*)-3-methyl-1- methylsulfonyl-4-piperidyl]-1,1-dioxo-2H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (cis-isomer 1)and 6-ethyl-N-methyl-5-[(3R*,4R*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (cis-isomer 2)

[0457] Step 1: Preparation of tert-butyl 4-[6-ethyl-3-(methylamino)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate

[0458] A mixture of 5-bromo-6-ethyl-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine (150 mg, 0.46 mmol), (1-tert-butoxycarbonyl-3-methyl-3,6-dihydro-2H-pyridin-4- yl)boronic acid (223 mg, 0.92 mmol), K2CO3(192 mg, 1.4 mmol) and Pd(dtbpf)Cl2(60 mg, 0.092 mmol) in DMF (dry, 5 mL) was stirred at 80°C for 16 h under N2. The resulting mixture was cooled to RT and purified by prep-HPLC (NH4HCO3 condition) to give tert-butyl 4-[6-ethyl-3- (methylamino)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-5-yl]-3-methyl-3,6-dihydro-2H- pyridine-1-carboxylate (120 mg, 58% yield). MS (method O) m / z 441 [M+H]+, t=2.05 min.

[0459] Step 2: Preparation of tert-butyl 4-[6-ethyl-3-(methylamino)-1,1-dioxo-2H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]-3-methyl-piperidine-1-carboxylate

[0460] A mixture of tert-butyl 4-[6-ethyl-3-(methylamino)-1,1-dioxo-2H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (50 mg, 0.11 mmol), palladium on carbon (50 mg) and Pd(OH)2 (50 mg) in EtOH (3 mL) was stirred at 60°C for 16 h under H2. The resulting mixture was cooled to RT and filtered. The filtrate was concentrated to give tert-butyl 4-[6-ethyl-3-(methylamino)-1,1-dioxo-2H-thieno[3,2-e][1,2,4]thiadiazin-5-yl]-3- methyl-piperidine-1-carboxylate (41 mg, yield: 81%) without further purification. MS (method O) m / z 443 [M+H]+, t=2.24 min.

[0461] Step 3: Preparation of 6-ethyl-N-methyl-5-(3-methyl-4-piperidyl)-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine hydrochloride

[0462] To a mixture of tert-butyl 4-[6-ethyl-3-(methylamino)-1,1-dioxo-2H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]-3-methyl-piperidine-1-carboxylate (41 mg, 0.093 mmol) in DCM (2 mL) was added HCl in 1,4-dioxane (4 M, 1 mL). The reaction was stirred at RT for 4 hours. The resulting mixture was concentrated to give 6-ethyl-N-methyl-5-(3-methyl-4-piperidyl)-1,1-dioxo- 2H-thieno[3,2-e][1,2,4]thiadiazin-3-amine hydrochloride (40 mg, crude) without further purification. MS (method O) m / z 343 [M+H]+, t=1.78 min.

[0463] Step 4: Preparation of 6-ethyl-N-methyl-5-(3-methyl-1-methylsulfonyl-4-piperidyl)- 1,1-dioxo-2H-thieno[3,2-e][1,2,4]thiadiazin-3-amine

[0464] A mixture of 6-ethyl-N-methyl-5-(3-methyl-4-piperidyl)-1,1-dioxo-2H-thieno[3,2- e][1,2,4]thiadiazin-3-amine hydrochloride (40 mg, crude) and N,N-diisopropylethylamine (36 mg, 0.28 mmol) in DCM (3 mL) was stirred at 0°C for 5 min. Then methanesulfonyl chloride (16 mg, 0.14 mmol) was added. The mixture was warmed to RT and stirred for 3 h. The resulting mixture was concentrated and the residue was purified by prep-TLC (5% MeOH in DCM) to give 6-ethyl- N-methyl-5-(3-methyl-1-methylsulfonyl-4-piperidyl)-1,1-dioxo-2H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (20 mg, two steps’ yield: 51%). MS (method X) m / z 421 [M+H]+, t=1.70 min.

[0465] Step 5: Preparation of 6-ethyl-N-methyl-5-[(3S*,4S*)-3-methyl-1-methylsulfonyl-4- piperidyl]-1,1-dioxo-2H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (cis-isomer 1) and 6-ethyl-N- methyl-5-[(3R*,4R*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (cis-isomer 2)

[0466] Racemic 6-ethyl-N-methyl-5-(3-methyl-1-methylsulfonyl-4-piperidyl)-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (20 mg, 0.048 mmol) was separated by chiral SFC to give 6-ethyl-N-methyl-5-[(3S*,4S*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (cis-isomer 1) (6.1 mg, yield: 31%) and 6-ethyl-N-methyl- 5-[(3R*,4R*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (cis-isomer 2) (4.5 mg, yield: 23%).

[0467] Preparative chiral SFC conditions: Instrument: SFC-150 (Waters); Column: AS 20x250mm, 10μm (REGIS); Column temperature: 35°C; Mobile phase: CO2 / MeOH (0.2% NH3 (7M in MeOH)) =50 / 50; Flow rate: 100 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 10 min; Sample solution 20 mg dissolved in 4 ml Methanol; Injection volume: 4.8 ml.

[0468] Analytical chiral HPLC conditions: Column: AS-H 4.6*100mm 5µm, Column temperature: 40°C; Mobile phase: CO2 / MeOH (0.2% NH3 (7M in MeOH)); Flow rate: 3.0 ml / min; Back pressure: 2000 psi; Detection wavelength: 214 nm

[0469] 6-Ethyl-N-methyl-5-[(3S*,4S*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo- 2H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (cis-isomer 1): MS (method I) m / z 421 [M+H]+, t=1.70 min. 1H NMR (400 MHz, CDCl3) δ 9.27-8.70 (m, 1H), 5.96-5.38 (m, 1H), 4.05-3.75 (m, 2H), 3.12-2.48 (m, 10H), 2.27-2.04 (m, 2H), 1.92-1.76 (m, 1H), 1.38-1.21 (m, 4H), 0.79 (d, J = 6.4 Hz, 3H) ppm. Chiral HPLC t=0.67 min.

[0470] 6-Ethyl-N-methyl-5-[(3R*,4R*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo- 2H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (cis-isomer 2): MS (method I) m / z 421 [M+H]+, t=1.70 min. 1H NMR (400 MHz, CDCl3) δ 9.25-8.62 (m, 1H), 5.91-5.27 (m, 1H), 4.05-3.75 (m, 2H), 3.12-2.48 (m, 10H), 2.27-2.04 (m, 2H), 1.92-1.76 (m, 1H), 1.38-1.20 (m, 4H), 0.79 (d, J = 6.4 Hz, 3H) ppm. Chiral HPLC t=1.67 min.

[0471] PHARMACOLOGY AND PHYISCOCHEMICAL PROPERTIES

[0472] The in vitro potency of compounds described herein in antagonizing MRGPRX2, and solubility and logD of compounds described herein may be determined by the procedures detailed below.

[0473] Human MRGPRX2 calcium mobilization assay

[0474] The assay employs MRGPRX2 expressing cells pre-labelled with a calcium-sensitive dye. In particular, HEK293T cell line (MultiscreenTMHEK293T, catalog no. C1257a, Multispan, Inc.) stably expressing the human MRGPRX2 receptor (MAS-related G-protein coupled receptor X2; NM_054030 with FLAG tag sequence at N-terminus) and the Calcium 6-QF assay kit (Molecular Devices) were used. Stimulation of the receptor results in an intracellular rise of calcium (Ca2+) levels. In the assay, the Ca2+-influx into cells results in fluorescence changes of acalcium sensitive dye which is included in the Calcium 6-QF assay kit (Molecular Devices). When the dye complexes calcium, a large increase of the fluorescence quantum yield occurs and can be measured with the Fluorometric Imaging Plate Reader (FLIPR Tetra, Molecular Devices). The fluorescent dye enters the cell. Hence, influx of calcium to the cytoplasm can be detected and serve as a proxy for receptor activation.

[0475] In brief, frozen assay-ready HEK293T cells stably expressing hMRGPRX2 were plated at 12,500 cells / well (25 µl / well) in 384-well poly-D-Lysin coated plates (Corning # 356697) and incubated overnight at 37°C and 5% CO2. On the second day, culture media was removed and cells were washed two times with a Biotek EL406 plate washer (residual volume 15 µl) (HBSS, 20 mM Hepes, 0,01% Pluronic F68). Subsequently, 10 µl Calcium 6-QF dye solution was added using a Multidrop Combi and cells were incubated for 90 min at 37°C, 5% CO2without lid. This was followed by incubation for 30 min at RT without lid. Next, 12.5 µl compound solution was added (4x concentrated) within the FLIPR Tetra device while recording fluorescence changes live (Ex 470-495; Em 515-575). Fluorescence changes during the first 15 min indicate agonistic compound activities. After 15 min, 12.5 µl pruritogenic neuropeptide Substance P (Sigma S6883) solution was added (4x concentrated; final concentration EC90 of hMRGPRX2 agonist) in the FLIPR Tetra. Fluorescence was recorded for an additional 240 sec. The maximum signal for each well (time-frame: 30 sec before, 240 sec after Substance P addition) was extracted.

[0476] To determine the activity of antagonist compounds, the maximum signal was used and the percent (%) inhibition at each concentration of a test compound was calculated relative to the responses in control wells contained within each assay plate. 0% inhibition was the activity determined from control wells lacking compound and 100% inhibition was derived from the measured activity in control wells containing a reference antagonist (1-(10H-phenazin-5- yl)ethanone) at 100 µM. The concentrations and percent inhibition values for a test compound were plotted and dose-response parameters including relative IC50 values were determined using a four parameter logistic dose-response equation.

[0477] Determination of thermodynamic solubility using DMSO stock solution (high throughput method)

[0478] In a first run, the actual compound concentration in a DMSO stock solution (nominal concentration 10 mM) is determined after dilution (1:40 with DMSO) using UPLC-UV / ELSD(Evaporative Light Scattering Detector) and quantifying against a standard solution of indometacin. This data point is used for the two-point calibration curve to quantify the solubility sample in a second run. Therefore, the DMSO stock solution on a U-shaped 96-well multi-titer plate is first evaporated to obtain a dry film (~100 µg). The dissolution medium to be tested (160 µL, e.g., phosphate buffer pH 7.4) is added to the dry film together with a stirring bead and the sample is shaken for 16 h at 25 °C on a thermomixer with 600 rpm after sealing the plate. This is followed by a centrifugation (5min, 4000 rcf) and filtration (filter 0.45 µm) step to obtain a supernatant that is quantified using UPLC-UV against the calibration curve determined above.

[0479] Determination of thermodynamic solubility using solid material

[0480] For the calibration samples (in duplicate) and for each buffer medium (selected from pH 1.1, pH 4.5, pH 6.5, pH 7.4, pH 9.0, FaSSIF, and FeSSIF buffer solution) approx. 1 mg of the test item is accurately (with 3 decimal digits) weighed into a 1 ml HPLC glass vial. An adjusted volume of DMSO is added to the two calibration samples to obtain a starting concentration of 1 mg / ml for the calibration curves. From each calibration sample a DMSO dilution series is created in a U-shaped 96-well multititer plate with the concentration steps 500 µg / ml, 250 µg / ml, 100 µg / ml, 50 µg / ml, 20 µg / ml, 10 µg / ml, 5 µg / ml, 2 µg / ml, and 1 µg / ml. The two dilution series are measured using UPLC-UV (A: H2O (0.05% TFA), B: MeCN (0.045% TFA); Gradient: 2%-98% B in 11.5 min, 98% B for 1 min; Flow Rate: 0.7 ml / min; Column: Waters Acquity CSH C181.7 µm 2.1 x 75 mm; Column Temperature: 50°C) and a mean calibration curve (polynomial 2 order) is calculated using these data points.

[0481] An adjusted volume of the selected buffers is added to each buffer sample to reach a maximum concentration of 1 mg / ml. The cap sealed samples are then shaken for 16 h at 25 °C on a thermomixer with 600 rpm. This is followed by a centrifugation (10 min, 2500 rcf) and filtration (filter 0.45 µm) step to obtain a supernatant that is quantified using UPLC-UV against the calibration curve determined above.

[0482] Determination of logD 7.4 by RP-UHPLC

[0483] The octanol / water distribution coefficient at pH 7.4 (logD7.4) is determined by a standardized reversed phase UHPLC-UV method (A: H2O, B: MeCN, C: MOPS 100 mmol pH 7.4; Gradient: 95% / 0% / 5% – 0% / 95% / 5% in 6.0 min, 0% / 95% / 5% for 1 min; Flow Rate: 0.7ml / min; Column: Waters BEH C18 1.7 µm 2.1x50 mm; Column Temperature: 30°C), which allows the fast relative differentiation of test items which are similar to standard compounds. Comparison of the retention times of the test items with those of standard compounds of known distribution coefficient between octanol and water at pH 7.4 (logD7.4) allows the calculation of the logD7.4 value for the test items. The retention times of the reference compounds in the calibration mixture (four basic and four acidic / neutral compounds – see Table 1 & 2) are plotted against their known logD7.4 values. The slope and the intercept of this calibration function are used to calculate the logD7.4 value of the test item from its retention time. The test sample solutions are prepared by diluting 5 µL of a 10 mM stock solution in DMSO with 195 µL of DMSO.

[0484] Table 1: HPLC logD7.4 standards for basic compounds Standard logD7.4 tR / min Metoprolol -0.30 2.3 Desipramine 1.40 3.1 Ticlopidine 4.46 4.3 Amiodarone 6.44 5.0

[0485] Table 2: HPLC logD7.4 standards for acidic / neutral compounds Standard logD7.4 tR / min Caffeine -0.20 1.9 Antipyrine 0.43 2.1 Ketoconazole 3.19 3.6 Triphenylene 5.50 4.6

[0486] Biological and Physical Property Data

[0487] Table 3 below lists the IC50 values obtained as described for the hMRGPRX2 calcium mobilization assay, logD values at pH 7.4 obtained by RP-HPLC as described herein, thermodynamic solubility values obtained using a DMSO stock solution method, except where otherwise indicated, as described herein, and the molecular weights for exemplified compounds.

[0488] Table 3 MRGPRX2 Solubility Compound / FLIPR LogD pH 7.4 MW Example Name IC50 / nM pH 7.4 µM g / mol 1 3-(Benzylamino)-6-chloro-5- (2,3-difluorophenyl)-4H- 8 3.5 <2 440 thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide 2 N-Benzyl-5-(2,3- 8 2.9 <3 405 difluorophenyl)-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amine 3 6-Chloro-5-(2,3- 74 2.5 <3 364 difluorophenyl)-3- (methylamino)-2H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide 4 5-(2,3-Difluorophenyl)-N- 664 1.7 57 329 methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amine 5 6-Chloro-5-(2-chloro-3-fluoro- 11.4 2.7 203a380 phenyl)-N-methyl-1,1-dioxo- 4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine 6 5-(2-Chloro-3-fluoro-phenyl)- 53 1.9 42 346 N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amine 7 5-(2-Chloro-4-methylsulfanyl- 48 2.5 <3 374 phenyl)-N-methyl-1,1-dioxo- 4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine 8 5-(2-Chloro-4-methylsulfinyl- phenyl)-N-methyl-1,1-dioxo- 4H-thieno[3,2- 376 0.9 206 390 e][1,2,4]thiadiazin-3-amine 9 5-(2-Chloro-4-methylsulfonyl- 324 1.3 >1232 406 phenyl)-N-methyl-1,1-dioxo- 4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine 10 5-[2-Chloro-4- 148 N / A >1235 405 (methylsulfonimidoyl)phenyl]- N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amineN-[6-Chloro-5-(2-chloro-3- 1173 2.1 >1184 422 fluoro-phenyl)-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- yl]-N-methyl-acetamide Methyl 3-chloro-4-[6-chloro-3- 19 2.8 4 420 (methylamino)-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzoate 3-Chloro-4-[6-chloro-3- 790 0.7 >1230 406 (methylamino)-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzoic acid 3-Chloro-4-[6-chloro-3- 100 1.5 24 405 (methylamino)-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzamide 5-(2-Chloro-3-fluoro-phenyl)- 138 2.3 22 360 N,6-dimethyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amine 5-(3-Chloro-2-fluoro-phenyl)- 403 2.4 3 360 N,6-dimethyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amine N-[5-(2-Chloro-3-fluoro- 2083 1.9 >1244 402 phenyl)-6-methyl-1,1-dioxo- 4H-thieno[3,2- e][1,2,4]thiadiazin-3-yl]-N- methyl-acetamide 6-Chloro-5-(2-chloro-4- 32 1.6 >1178 424 (methylsulfinyl)phenyl)-3- (methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide 6-Chloro-5-[2-chloro-4- (methylsulfonimidoyl)phenyl]- N-methyl-1,1-dioxo-4H- 20 1.4 22 439 thieno[3,2-e][1,2,4]thiadiazin-3- amine 6-Chloro-5-(2-chloro-4- 15 3.2 <2 408 methylsulfanyl-phenyl)-N- methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amine5-(2-Chloro-3-fluoro-phenyl)-6- 24.9 2.7 31 374 ethyl-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amine 5-(2-Chloro-4- 22 2.1 9 434 (methylsulfonyl)phenyl)-6- ethyl-3-(methylamino)-4H- thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide 6-Chloro-5-(2-chloro-4- 13.6 2.0 7a440 methylsulfonyl-phenyl)-N- methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amine 6-Chloro-5-(2-chloro-4- 9 2.1 68 440 methylsulfonyl-phenyl)-N- methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amine (atropisomer 1) 6-Chloro-5-(2-chloro-4- 290 2.1 80 440 methylsulfonyl-phenyl)-N- methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3- amine (atropisomer 2) 6-Chloro-5-(2-chloro-4- 29 3.6 <2 422 (ethylthio)phenyl)-3- (methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide 6-Chloro-5-(2-chloro-4- 17 1.9 11 438 (ethylsulfinyl)phenyl)-3- (methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide 6-Chloro-5-(2-chloro-4- 10 2.3 <2 454 (ethylsulfonyl)phenyl)-3- (methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide 6-Ethyl-N-methyl-5- 2273 1.8 >1189 421 [(3S*,4S*)-3-methyl-1- methylsulfonyl-4-piperidyl]- 1,1-dioxo-2H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (cis-isomer 1) 6-Ethyl-N-methyl-5- 166 1.8 >1189 421 [(3R*,4R*)-3-methyl-1- methylsulfonyl-4-piperidyl]- 1,1-dioxo-2H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (cis-isomer 2) a Thermodynamic solubility determined from solid as described herein

[0489] From the foregoing, those skilled in the art will appreciate that certain modifications can also be made to the present disclosure without departing from the scope of the same. The above description should not be construed as limiting, but merely as exemplifications of particular embodiments. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Claims

CLAIMS 1. A compound of formula I, I, wherein: R1is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, heteroaryl, - C(=O)R10, -C(=O)OR11, and -C(=O)NR11R12, wherein when R1is alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, or heteroaryl, R1is unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or - S(=O)2NR11R12; R2 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, heteroaryl, - C(=O)R10, -C(=O)OR11, and -C(=O)NR11R12, wherein when R2 is alkyl, cycloalkyl, heterocyclyl, arylalkyl, aryl, or heteroaryl, R2is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or - S(=O)2NR11R12; R3 is selected from hydrogen, halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; each instance of R4 is independently selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6alkyl, C1-C6heteroalkyl, and C1-C6haloalkyl; R5is selected from halogen, cyano, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, -OR7, -NR7R8, -N+(O-)R7R8, -SR7, - C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -OC(=O)R6, -OC(=O)OR7, - OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, -NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8, wherein whenR5 is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, aryl, or heteroaryl, R5 is unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, - OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6is selected from alkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, - S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or -S(=O)(=NR9)NR11R12; R7and R8are independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, - N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12; each instance of R9is independently selected from hydrogen and C1-C4alkyl; each instance of R10is independently selected from C1-C4alkyl, C1-C4heteroalkyl, 3- to 6-membered heterocyclyl, C1-C33- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C4 heteroalkyl, 3- to 6-membered heterocyclyl, C1-C3 3- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3monocyclic heteroarylalkyl, C1-C3acyl, and C1- C3sulfonyl, provided R11is not C1-C3sulfonyl when R11is bonded to an oxygen or sulfur atom; A is a monocyclic ring selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; and n is 0, 1, or 2, provided that when A is a phenyl ring, n is 1 or 2; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

2. The compound of formula I according to claim 1, wherein: R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6 phenylalkyl, phenyl, monocyclic heteroaryl, -C(=O)R10, -C(=O)OR11, and - C(=O)NR11R12, wherein when R1is C1-C6alkyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6phenylalkyl, phenyl, or monocyclic heteroaryl, R1is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6 phenylalkyl, phenyl, monocyclic heteroaryl, -C(=O)R10, -C(=O)OR11, and - C(=O)NR11R12, wherein when R2 is C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C6phenylalkyl, phenyl, or monocyclic heteroaryl, R2is unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -SR11, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R5 is selected from halogen, cyano, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6-membered heterocyclylalkyl, C1-C6 phenylalkyl, C1-C6 monocyclic heteroarylalkyl, phenyl, monocyclic heteroaryl, -OR7, -NR7R8, -N+(O-)R7R8, -SR7, - C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -OC(=O)R6, -OC(=O)OR7, - OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, -NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8, wherein when R5is C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6-membered heterocyclylalkyl, C1-C6 phenylalkyl, C1-C6 monocyclic heteroarylalkyl, phenyl, or monocyclic heteroaryl, R5 is unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - S(=O)2R10, or -S(=O)2NR11R12; R6is selected from C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6-membered heterocyclylalkyl, phenyl, C1-C6phenylalkyl, monocyclic heteroaryl, and C1-C6 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or -S(=O)(=NR9)NR11R12; andR7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3- C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C63- to 6- membered heterocyclylalkyl, phenyl, C1-C6 phenylalkyl, monocyclic heteroaryl, and C1-C6 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12; A is a monocyclic ring selected from C5-C6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and monocyclic heteroaryl; and or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

3. The compound of formula I according to claim 1 or 2, wherein: R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, or -NR11R12; R2is selected from hydrogen, C1-C6alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R2is C1-C6alkyl, benzyl, or phenyl, R2is unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, or -NR11R12; R3 is selected from hydrogen, halogen, and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R5 is selected from halogen, C1-C6 alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)(=NR9)R6, -S(=O)2R6, and -S(=O)2NR7R8, wherein when R5is C1-C6alkyl, R5is unsubstituted or substituted with one or more of halogen, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -S(=O)2R10, or -S(=O)2NR11R12; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12;R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10is independently selected from C1-C4alkyl and C1-C4heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; A is selected from phenyl, piperidinyl, and tetrahydropyridinyl; and n is 1; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

4. The compound of formula I according to any one of claims 1 to 3, wherein: R1 is selected from methyl and benzyl; R2is selected from hydrogen and acetyl; R3is selected from hydrogen, chloro, fluoro, bromo, methyl, and ethyl; R4is selected from chloro, fluoro, and methyl; R5is selected from halogen, -SR7, -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, - S(=O)R6, -S(=O)(NH)R6, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C4 alkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or - S(=O)2NR11R12; R7and R8are independently selected from hydrogen and C1-C4alkyl, which groups are unsubstituted or substituted with one or more of -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, - C(=O)NR11R12, -OC(=O)R10, -NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl;each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; A is selected from phenyl, piperid-4-yl, and 1,2,3,6-tetrahydropyridin-4-yl; and n is 1; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

5. The compound of formula I according to any one of claims 1 to 4, wherein the compound is of formula I-A1,I-A1, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

6. The compound of formula I according to any one of claims 1 to 4, wherein the compound is of formula I-A2, I-A2, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

7. The compound of formula I according to any one of claims 1 to 4, wherein the compound is of formula I-B1I-B1, wherein is a single or a double bond; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

8. The compound of formula I according any one of claims 1 to 7, wherein R1 is selected from hydrogen, C1-C6 alkyl, benzyl, phenyl, and -C(=O)R10, wherein when R1 is C1-C6 alkyl, benzyl, or phenyl, R1 is unsubstituted or substituted with one or more of halogen, C1-C4alkyl, -OR11, or -NR11R12; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

9. The compound of formula I according to any one of claims 1-8, wherein R2 is hydrogen; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

10. The compound of formula I according to any one of claims 1-9, wherein R3 is selected from hydrogen, halogen, and C1-C4 alkyl; and R4 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

11. The compound of formula I according to any one of claims 1-10, wherein R5is selected from halogen, C1-C6alkyl, -OR7, -NR7R8, -SR7, -C(=O)R6, -C(=O)OR7, - C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NH)R6; or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

12. A compound selected from: 3-(Benzylamino)-6-chloro-5-(2,3-difluorophenyl)-4H-thieno[3,2-e][1,2,4]thiadiazine 1,1- dioxide (Compound 1); N-Benzyl-5-(2,3-difluorophenyl)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (Compound 2); 6-Chloro-5-(2,3-difluorophenyl)-3-(methylamino)-2H-thieno[3,2-e][1,2,4]thiadiazine 1,1- dioxide (Compound 3);5-(2,3-Difluorophenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3-amine (Compound 4); 6-Chloro-5-(2-chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 5); 5-(2-Chloro-3-fluoro-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- amine (Compound 6); 5-(2-Chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 7); 5-(2-Chloro-4-methylsulfinyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 8); 5-(2-Chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 9); 5-[2-Chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 10); N-[6-Chloro-5-(2-chloro-3-fluoro-phenyl)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-3- yl]-N-methyl-acetamide (Compound 11); Methyl 3-chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-5-yl]benzoate (Compound 12); 3-Chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzoic acid (Compound 13); 3-Chloro-4-[6-chloro-3-(methylamino)-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin-5- yl]benzamide (Compound 14); 5-(2-Chloro-3-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine (Compound 15); 5-(3-Chloro-2-fluoro-phenyl)-N,6-dimethyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-amine (Compound 16); N-[5-(2-Chloro-3-fluoro-phenyl)-6-methyl-1,1-dioxo-4H-thieno[3,2-e][1,2,4]thiadiazin- 3-yl]-N-methyl-acetamide (Compound 17); 6-Chloro-5-(2-chloro-4-(methylsulfinyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide (Compound 18);6-Chloro-5-[2-chloro-4-(methylsulfonimidoyl)phenyl]-N-methyl-1,1-dioxo-4H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (Compound 19); 6-Chloro-5-(2-chloro-4-methylsulfanyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 20); 5-(2-Chloro-3-fluoro-phenyl)-6-ethyl-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 21); 5-(2-Chloro-4-(methylsulfonyl)phenyl)-6-ethyl-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide (Compound 22); 6-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (Compound 23); 6-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (atropisomer 1) (Compound 24); 6-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-N-methyl-1,1-dioxo-4H-thieno[3,2- e][1,2,4]thiadiazin-3-amine (atropisomer 2) (Compound 25); 6-Chloro-5-(2-chloro-4-(ethylthio)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide (Compound 26); 6-Chloro-5-(2-chloro-4-(ethylsulfinyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide (Compound 27); 6-Chloro-5-(2-chloro-4-(ethylsulfonyl)phenyl)-3-(methylamino)-4H-thieno[3,2- e][1,2,4]thiadiazine 1,1-dioxide (Compound 28); 6-Ethyl-N-methyl-5-[(3S*,4S*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (Compound 29); and 6-Ethyl-N-methyl-5-[(3R*,4R*)-3-methyl-1-methylsulfonyl-4-piperidyl]-1,1-dioxo-2H- thieno[3,2-e][1,2,4]thiadiazin-3-amine (Compound 30); or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 12, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

14. A compound of formula I according to any one of claims 1 to 12, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament.

15. A compound of formula I according to any one of claims 1 to 12, or an enantiomer, diastereomer, tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.

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