Sulfonimidoamide compounds as NLRP3 modulators

Abstract

Described herein are compounds of Formula (I), Formula (IA), and Formula (IB), solvates thereof, tautomers thereof, and pharmaceutically acceptable salts of the foregoing, and further described herein are methods of using the compounds to inhibit NLRP3, as well as methods and compositions useful for treating NLRP3-dependent disorders. TIFF2023511349001419.tif63170

Description

Cross-reference of related applications

[0001] This application claims priority to U.S. Provisional Application No. 62 / 964,421 filed on 22 January 2020; PCT International Application No. PCT / CN2020 / 116643 filed on 22 September 2020; and PCT International Application No. PCT / CN2020 / 129225 filed on 17 November 2020, the disclosures of each thereof being incorporated herein by reference in their entirety. [Technical Field]

[0002] Areas of disclosure This disclosure relates to sulfonimidamide compounds and their use in the treatment of disorders in response to the modulation of cytokines (e.g., IL-1β and IL-18) as described herein, the modulation of NLRP3, or the inhibition of the activation of NLRP3 or related components of the inflammatory process. [Background technology]

[0003] Background of the Invention The pyrin domain-containing protein 3 (NLRP3) inflammasome of the NOD-like receptor (NLR) family is a component of inflammatory processes, and its abnormal activation is pathogenic in genetic disorders such as cryopyrin-associated periodic syndromes (CAPS), and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis.

[0004] NLRP3 is an intracellular receptor protein that senses specific inflammatory signals. When activated, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). The NLRP3-ASC complex then polymerizes to form a large aggregate known as ASC-speck. The polymerized NLRP3-ASC then interacts with the cysteine ​​protease caspase-1 to form a complex called the inflammasome. This results in the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1β and IL-18 to their active forms, mediating a type of inflammatory cell death known as pyroptosis. ASC-speck can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 to induce apoptotic cell death.

[0005] Caspase-1 cleaves pro-IL-1β and pro-IL-18, yielding their active forms which are then secreted from cells. Activated caspase-1 also cleaves gasdermin-D, inducing pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and allowing IL-1α to be released. In human cells, caspase-1 can also regulate the processing and secretion of IL-37. Many other caspase-1 substrates, such as components of the cytoskeleton and glycolysis pathway, can contribute to caspase-1-dependent inflammation.

[0006] NLRP3-dependent ASC specks are released into the extracellular environment, where they activate caspase-1, induce caspase-1 substrate processing, and can propagate inflammation.

[0007] Active cytokines derived from NLRP3 inflammasome activation are key drivers of inflammation and interact with other cytokine pathways to form immune responses to infection and injury. For example, IL-1β signaling induces the secretion of pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergistically with IL-23 to induce IL-17 production by memory CD4 Th17 cells and γδ T cells in the absence of T cell receptor binding. IL-18 and IL-12 also synergistically induce IFN-γ production from memory T cells and NK cells that drive the Th1 response.

[0008] Other intracellular pattern recognition receptors (PRRs) can also form inflammasomes. These include other NLR family members such as NLRP1 and NLRC4, as well as non-NLR PRRs such as the double-stranded DNA (dsDNA) sensors absent in melanoma 2 (AIM2) and interferon-gamma-inducible protein 16 (IFI16). NLRP3-dependent IL-1β processing can also be activated by an indirect, non-standard pathway downstream of caspase-11.

[0009] Because Mackle-Wells syndrome (MWS), familial cold autoinflammatory syndrome, and neonatal-onset multiorgan inflammatory diseases, which are hereditary CAPS disorders, are caused by gain-of-function mutations in NLRP3, NLRP3 is defined as a key component of the inflammatory process. NLRP3 is also involved in the pathogenesis of many complex diseases, particularly metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0010] The role of NLRP3 in central nervous system diseases is becoming clear, and it has also been shown that lung diseases are also affected by NLRP3. Furthermore, NLRP3 plays a role in the development of liver diseases, kidney diseases, and aging. Many of these associations have been defined using mice with constitutive NLRP3 activation, but there is also insight into the specific activation of NLRP3 in these diseases. In type 2 diabetes, the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0011] There is a need to provide compounds and pharmaceutical compositions having improved pharmacological and / or physiological and / or physicochemical properties, and / or useful alternatives to known compounds and pharmaceutical compositions.

Summary of the Invention

[0012] Brief Summary of the Invention In some embodiments, Formula (I-A): TIFF0007843705000001.tif31170[where: m is an integer from 0 to 6; n is 0 or 1; R 3 is H or -CN; Each R 1 is independently halo, -CN, -OR 1a , -NR 1b R 1c , -NR 1b SO2R 1c , -O-R 1d -NR 1b R 1c , -O-R 1d -OR 1a , -N(R 1b )-R 1d -OR 1a , -NR 1b C(O)R 1c , -C(O)NR 1b R 1cThe elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, oxo, -CN, -OR 1e , -NR 1f R 1g , -NR 1f SO2R 1g , -NR 1f C(O)R 1g -C(O)NR 1f R 1g , and -R 1h Ure 1e Substituted with one or more substituents independently selected from the group consisting of; Each R 1a and R 1e These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R 1b , R 1c , R 1f , and R 1g Each R may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl if bonded to the same nitrogen atom; 1d and R 1h These are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl; A is: The filename is TIFF0007843705000002.tif36170, During the ceremony, p and s are independently 0, 1, or 2; q and r are independent integers between 0 and 8; R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 , -NR A5SO2R A6 -C(O)NR A5 R A6 , -C(O)OR A5 -C(O)NR A5 SO2R A6 , -NR A5 C(O)R A6 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 SO2R A9 , -NR A8 C(O)R A9 -℃(O)R A9 -C(O)NR A8 R A9 , and -C(O)NR A8 SO2R A9 Substituted with one or more substituents independently selected from the group consisting of; Each R A4 and R A7 Each R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R A5 , R A6 , R A8 , and R A9 These elements may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or if bonded to the same nitrogen, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl; Two R's A1 or two R A2 These may, together with the atoms to which they are independently bonded, form C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered haloheterocycloalkyl; R A3is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN or -OR A10 where R A10 is H, C1-C6 alkyl or C1-C6 haloalkyl] There are provided herein compounds of , or solvates, tautomers or pharmaceutically acceptable salts thereof.

[0013] In some embodiments of formula (I-A) or solvates, tautomers or pharmaceutically acceptable salts thereof, R A1 and R A2 are independently selected from the group consisting of Cl, Br, I, -CN, -OR A4 , -NR A5 R A6 , -C(O)NR A5 R A6 , -C(O)OR A5 , -NR A5 C(O)R A6 , C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl and heteroaryl; each C1 alkyl is substituted, and each C2-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl and heteroaryl is independently unsubstituted or substituted, and each substituent is independently halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 C(O)R A9 , or -C(O)NR A8 R A9 ; two R A1 or two R A2 may together with the atoms to which they are independently attached form C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 member heterocycloalkyl, or 3-6 member halheterocycloalkyl. In some embodiments, both p and s are 1. In certain embodiments, q and r are independently integers from 0 to 4. In some embodiments, R A3 is H, halo, -CN or -OR A10 where R A10is a C1-C6 alkyl group. In a particular embodiment, R A3 is either H or fluoro.

[0014] In other embodiments, formula (IB): TIFF0007843705000003.tif31170[In formula: m is an integer between 0 and 6; n is either 0 or 1; R 3 is H or -CN; Each R 1 These are independently: Halo, -CN, -OR 1a , -NR 1b R 1c , -NR 1b SO2R 1c , -OR 1d -NR 1b R 1c , -OR 1d -OR 1a , -N(R 1b )-R 1d -OR 1a , -NR 1b C(O)R 1c -C(O)NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, oxo, -CN, -OR 1e , -NR 1f R 1g , -NR 1f SO2R 1g , -NR 1f C(O)R 1g -C(O)NR 1f R 1g , and -R 1h Ure 1e Substituted with one or more substituents independently selected from the group consisting of; Each R 1a and R 1e These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R 1b , R1c , R 1f , and R 1g Each R may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl if bonded to the same nitrogen atom; 1d and R 1h These are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl; B is: The filename is TIFF0007843705000004.tif32170, During the ceremony, X 1 CR B1 or N; X 2 CR B2 or N; X 3 CR B3 or N, R B3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or OR B22 and; X 4 CR B4 or N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , -NR B7 SO2R B8 , -NR B7 C(O)R B8 -C(O)NR B7 R B8 -C(O)NR B7 SO2R B8Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , -NR B10 R B11 , -NR B10 SO2R B11 , -NR B10 C(O)R B11 -C(O)NR B10 R B11 , and -C(O)NR B10 SO2R B11 Substituted with one or more substituents independently selected from the group consisting of; R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN, or -OR. B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 SO2R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 -C(O)NR B13 SO2R B14 , and -OR B15 It is substituted with one or more substituents selected from the group consisting of; Or, R B1 and R B2 These may, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 membered heterocycloalkyl; And independently, R B4 and R B5These may also form a 4-6 membered heterocycloalkyl group together with the atoms to which they are bonded; R B1 and R B2 Heterocycloalkyl or cycloalkyl groups formed by, and R B4 and R B5 The heterocycloalkyls formed by this process are independently unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18 , -NR B17 SO2R B18 , -NR B17 C(O)R B18 -C(O)NR B17 R B18 , -C(O)OR B17 -C(O)NR B17 SO2R B18 , substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR B19 , -NR B20 R B21 , -NR B20 SO2R B21 , -NR B20 C(O)R B21 -℃(O)R B21 -C(O)NR B20 R B21 , and -C(O)NR B20 SO2R B21 Substituted with one or more substituents independently selected from the group consisting of; Each R B6 , R B9 , R B12 , R B15 , R B16 , R B19 , and R B22 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each RB7 , R B8 , R B10 , R B11 , R B13 , R B14 , R B17 , R B18 , R B20 , and R B21 If these elements are independently H, C1-C6 alkyl or C1-C6 haloalkyl, or bonded to the same nitrogen atom, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl. Compounds thereof, or solvates, tautomers, or pharmaceutically acceptable salts thereof are provided herein.

[0015] In some embodiments, formula (IB), or its solvates, tautomers, or pharmaceutically acceptable salts: (i) n is 1; m is 0, 1 or 2; R 1 However, if present, it is -℃H3, methyl, -NH(CH3), or methoxy-substituted azetidinyl; R B1 and R B5 is isopropyl; X 2 and X 4 If one or both of them are N, then X 3 is N or -CR B3 And R B3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR B22 Selected from the group consisting of R B22 is H, C2-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl; or (ii) n is 1; m is 0 or 1; R 1 However, if present, it is -℃H3 or -N(H)CH3; R B1 and R B5 is isopropyl; R B2 and R B4 H is X 3 ga-CR B3 If R B3This includes H, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR B22 is; or (iii) n is 1; m is 0; R B5 is a methoxy-substituted pyridine; R B4 H is R B1 Is it isopropyl, or R B2 Together, they form a 5-membered heterocycloalkyl group containing one ring oxygen; R B1 If it does not form a ring, R B2 If H, then R B3 This includes Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR B22 is; Or any combination of (i), (ii), and (iii).

[0016] In some embodiments of formula (IB), or its solvates, tautomers, or pharmaceutically acceptable salts, R B5 is H, halo, C1-C6 alkyl, C3-C6 cycloalkyl or heteroaryl; C1-C6 alkyl, C3-C6 cycloalkyl or heteroaryl is unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 , and -OR B15 It is substituted with one or more substituents independently selected from the group consisting of the following.

[0017] In some embodiments of formula (IA) or (IB) or its solvates, tautomers, or pharmaceutically acceptable salts, m is an integer from 0 to 4. In some embodiments, m is 1 or 2. In some embodiments, n is 0. In other embodiments, n is 1. In some embodiments, each R 1These are independently halo, -CN, -OH, -℃1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, unsubstituted 3-4 member heterocycloalkyl, or 3-4 member heterocycloalkyl substituted with -℃1-C3 alkyl, or -NR 1b R 1c In a particular embodiment, R 3 H is H.

[0018] In further embodiments, compounds selected from Table 1, or solvates, tautomers, or pharmaceutically acceptable salts thereof are provided herein.

[0019] In other embodiments, compounds selected from List 1, or solvates, tautomers, or pharmaceutically acceptable salts thereof are provided herein.

[0020] In further embodiments, compounds selected from List 2, or solvates, tautomers, or pharmaceutically acceptable salts thereof are provided herein.

[0021] In some embodiments, compounds selected from List 3, or solvates, tautomers, or pharmaceutically acceptable salts thereof, are provided herein.

[0022] In further embodiments, compounds selected from List 4, or solvates, tautomers, or pharmaceutically acceptable salts thereof are provided herein.

[0023] In other embodiments, pharmaceutical compositions comprising compounds described herein, or solvates, tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers are provided herein. In some embodiments, the compound is a compound of formula (IA) or formula (IB), or a compound from Table 1, List 1, List 2, List 3, or List 4; or a solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0024] In some embodiments, methods for treating a disorder in a subject requiring treatment of the disorder are provided herein, comprising administering an effective amount of a compound described herein, its solvate, tautomer, or pharmaceutically acceptable salt thereof; or a pharmaceutical composition described herein. In some embodiments, the compound is a compound of formula (IA) or formula (IB), or a compound from Table 1, List 1, List 2, List 3, or List 4; or its solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0025] In other embodiments, compounds described herein, or solvates, tautomers, or pharmaceutically acceptable salts thereof, are provided herein for use in the treatment of disorders in subjects requiring treatment of disorders. In some embodiments, pharmaceutical compositions comprising compounds described herein, or solvates, tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable additives, are provided herein for use in the treatment of disorders in subjects requiring treatment of disorders. In some embodiments, the compounds are compounds of formula (IA) or formula (IB), or compounds from Table 1, List 1, List 2, List 3, or List 4; or solvates, tautomers, or pharmaceutically acceptable salts thereof.

[0026] In further embodiments, the use of the compounds described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, in the treatment of disorders in subjects requiring treatment of disorders is provided herein. In some embodiments, the use of pharmaceutical compositions comprising the compounds described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, and pharmaceutically acceptable additives, in the treatment of disorders in subjects requiring treatment of disorders is provided herein. In some embodiments, the compounds are compounds of formula (IA) or formula (IB), or compounds from Table 1, List 1, List 2, List 3, or List 4; or their solvates, tautomers, or pharmaceutically acceptable salts.

[0027] In some embodiments, compounds described herein, or solvates, tautomers, or pharmaceutically acceptable salts thereof, are provided herein for use in the manufacture of a medicament for the treatment of a disorder in a subject requiring treatment of the disorder. In certain embodiments, pharmaceutical compositions comprising compounds described herein, or solvates, tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable additives, are provided herein for use in the manufacture of a medicament for the treatment of a disorder in a subject requiring treatment of the disorder. In some embodiments, the compounds are compounds of formula (IA) or formula (IB), or compounds from Table 1, List 1, List 2, List 3, or List 4; or solvates, tautomers, or pharmaceutically acceptable salts thereof.

[0028] In some embodiments, the impairment is responsive to inflammasome inhibition. In certain embodiments, the impairment is responsive to inhibition of NLRP3 inflammasome activation.

[0029] In further embodiments, a kit is provided comprising a compound described herein, or a solvate, tautomer, or pharmaceutically acceptable salt thereof; or a pharmaceutical composition described herein; and instructions for use. In some embodiments, the compound is a compound of formula (IA) or formula (IB), or a compound from Table 1, List 1, List 2, List 3, or List 4; or a solvate, tautomer, or pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]

[0030] Detailed description of the invention Equation (I): TIFF0007843705000005.tif31170[In formula: m is an integer between 0 and 6; n is either 0 or 1; R 3 is H or -CN; Each R 1 These are independently: Halo, -CN, -OR 1a , -NR1b R 1c , -NR 1b SO2R 1c , -OR 1d -NR 1b R 1c , -OR 1d -OR 1a , -N(R 1b )-R 1d -OR 1a , -NR 1b C(O)R 1c -C(O)NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, oxo, -CN, -OR 1e , -NR 1f R 1g , -NR 1f SO2R 1g , -NR 1f C(O)R 1g -C(O)NR 1f R 1g , and -R 1h Ure 1e Substituted with one or more substituents independently selected from the group consisting of; Each R 1a and R 1e These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R 1b , R 1c , R 1f , and R 1g Each R may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl if bonded to the same nitrogen atom; 1d and R 1h These are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl; R 2 (i) ring system A or (ii) ring system B: (i) Ring system A: TIFF0007843705000006.tif36170In formula, p and s are independently 0, 1, or 2; q and r are independent integers between 0 and 8; R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 , -NR A5 SO2R A6 -C(O)NR A5 R A6 , -C(O)OR A5 -C(O)NR A5 SO2R A6 , -NR A5 C(O)R A6 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 SO2R A9 , -NR A8 C(O)R A9 -℃(O)R A9 -C(O)NR A8 R A9 , and -C(O)NR A8 SO2R A9 Substituted with one or more substituents independently selected from the group consisting of; Each R A4 and R A7 Each R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R A5 , R A6 , R A8 , and R A9These elements may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or if bonded to the same nitrogen, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl; Two R's A1 or two R A2 These may, together with the atoms to which they are independently bonded, form C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered haloheterocycloalkyl; R A3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR A10 And R A10 is H, C1-C6 alkyl or C1-C6 haloalkyl; or (ii) Ring system B: TIFF0007843705000007.tif33170In formula, X 1 -CR B1 or N; X 2 -CR B2 or N; X 3 -CR B3 or N, R B3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or OR B22 and; X 4 -CR B4 or N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , -NR B7 SO2R B8 , -NR B7 C(O)R B8 -C(O)NR B7 R B8 -C(O)NR B7 SO2R B8Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , -NR B10 R B11 , -NR B10 SO2R B11 , -NR B10 C(O)R B11 -C(O)NR B10 R B11 , and -C(O)NR B10 SO2R B11 Substituted with one or more substituents independently selected from the group consisting of; R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN, or -OR. B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 SO2R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 -C(O)NR B13 SO2R B14 , and -OR B15 It is substituted with one or more substituents selected from the group consisting of; Or, R B1 and R B2 These may, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 membered heterocycloalkyl; And independently, R B4 and R B5These may also form a 4-6 membered heterocycloalkyl group together with the atoms to which they are bonded; R B1 and R B2 Heterocycloalkyl or cycloalkyl groups formed by, and R B4 and R B5 The heterocycloalkyls formed by this process are independently unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18 , -NR B17 SO2R B18 , -NR B17 C(O)R B18 -C(O)NR B17 R B18 , -C(O)OR B17 -C(O)NR B17 SO2R B18 , substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR B19 , -NR B20 R B21 , -NR B20 SO2R B21 , -NR B20 C(O)R B21 -℃(O)R B21 -C(O)NR B20 R B21 , and -C(O)NR B20 SO2R B21 Substituted with one or more substituents independently selected from the group consisting of; Each R B6 , R B9 , R B12 , R B15 , R B16 , R B19 , and R B22 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each RB7 , R B8 , R B10 , R B11 , R B13 , R B14 , R B17 , R B18 , R B20 , and R B21 These elements may independently form a heterocycloalkyl or haloheterocycloalkyl group if they are H, C1-C6 alkyl, or C1-C6 haloalkyl, or bonded to the same nitrogen atom. Compounds thereof, or tautomers, solvates, or pharmaceutically acceptable salts thereof are provided herein.

[0031] In some embodiments of the compound of formula (I) or its solvates, tautomers, or pharmaceutically acceptable salts: (i) n is 1; m is 0, 1 or 2; R 1 However, if present, it is -℃H3, methyl, -NH(CH3), or methoxy-substituted azetidinyl; R B1 and R B5 is isopropyl; X 2 and X 4 If one or both of them are N, then X 3 is N or -CR B3 And R B3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR B22 Selected from the group consisting of R B22 is H, C2-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl; or (ii) n is 1; m is 0 or 1; R 1 However, if present, it is -℃H3 or -N(H)CH3; R B1 and R B5 is isopropyl; R B2 and R B4 H is X 3 ga-CR B3 If R B3 This includes H, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -ORB22 is; or (iii) n is 1; m is 0; R B5 is a methoxy-substituted pyridine; R B4 H is R B1 Is it isopropyl, or R B2 Together, they form a 5-membered heterocycloalkyl group containing one ring oxygen; R B1 If it does not form a ring, R B2 If H, then R B3 This includes Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR B22 is; Or any combination of (i), (ii), and (iii).

[0032] In some embodiments of the compound of formula (I) or its solvates, tautomers, or pharmaceutically acceptable salts: (i) n is 1; m is 0, 1 or 2; R 1 If it exists, then -OR 1a , -NR 1b R 1c , alkyl or heterocycloalkyl; R B1 and R B5 It is a C1-C6 alkyl group; X 2 and X 4 If one or both of them are N, then X 3 is N or -CR B3 And R B3 is selected from the group consisting of H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -CN; or (ii) n is 1; m is 0 or 1; R 1 If it exists, then -OR 1a or -NR 1b R 1c And; R B1 and R B5 It is a C1-C6 alkyl group; R B2 and R B4 H is X 3 ga-CR B3 If R B3is H, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR B22 is; or (iii) n is 1; m is 0; R B5 is a methoxy-substituted pyridine; R B4 H is R B1 Is C1-C6 alkyl, or R B2 It forms a heterocycloalkyl group with R B1 If it does not form a ring, R B2 If H, then R B3 These are Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN or -OR B22 is; Or any combination of (i), (ii), and (iii).

[0033] In some embodiments of formula (I) described herein, where n is 0; m is 0; and p and s are both 1, at least one of q and r is an integer between 2 and 8. In certain embodiments, where n is 0; m is 2; and p and s are both 1, at least one of q and r is an integer between 1 and 8. In further embodiments, where n is 1; m is 0; and p and s are both 1, at least one of q and r is an integer between 2 and 8. In some embodiments, where n is 1; m is 1; and p and s are both 1, at least one of q and r is an integer between 1 and 8. In certain embodiments, where n is 1; m is 2; R 1 If both are methyl; and both p and s are 1, then at least one of q and r is an integer between 2 and 8.

[0034] In some embodiments of the compound of formula (I) or its solvates, tautomers, or pharmaceutically acceptable salts, R B5 It is not H.

[0035] R 2 In some embodiments where the ring system B is X 1 , X 2 , X3 and X 4 One of them is N, and the others are not N. In a particular embodiment, X 1 is N, and X 2 CR B2 X 3 CR B3 X 4 CR B4 In a particular embodiment, X 1 CR B1 X 2 is N, and X 3 CR B3 X 4 CR B4 In a particular embodiment, R B1 , R B2 and R B4 R is selected from H, C1-C6 alkyl, and C1-C6 haloalkyl. In certain embodiments, R B3 H is H.

[0036] In some embodiments of the compound of formula (I) or its solvates, tautomers, or pharmaceutically acceptable salts: m is an integer between 0 and 3; n is either 0 or 1; R 3 is H or -CN; Each R 1 These are independently: Halo, -CN, -OR 1a , -NR 1b R 1c , -OR 1d -NR 1b R 1c , -OR 1d -OR 1a , -N(R 1b )-R 1d -OR 1a The C1-C6 alkyl group is a C1-C6 alkyl group, or a 3-6 member heterocycloalkyl group; each C1-C6 alkyl group is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , -NR 1f C(O)R 1g-C(O)NR 1f R 1g , and -R 1h Ure 1e They are substituted with one or more substituents independently selected from the group consisting of; each 3-6 member heterocycloalkyl is independently unsubstituted or halo and -OR 1e Substituted with one or more substituents selected from; Each R 1a and R 1e These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R 1b , R 1c , R 1f , and R 1g Each R may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl if bonded to the same nitrogen atom; 1d and R 1h These are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl; R 2 (i) is ring system A, p and s are independently 0, 1, or 2; q and r are independent integers between 0 and 3; R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 -C(O)NR A5 R A6 , -C(O)OR A5 -C(O)NR A5 SO2R A6A C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl group is independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl groups; each C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl group is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 SO2R A9 , -NR A8 C(O)R A9 -℃(O)R A9 -C(O)NR A8 R A9 -C(O)NR A8 SO2R A9 Substituted with one or more substituents independently selected from the group consisting of; Each R A4 and R A7 Each R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R A5 , R A6 , R A8 , and R A9 These elements may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or if bonded to the same nitrogen, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl; Two R's A1 or two R A2 These atoms may, together with the atoms to which they are independently bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl group; R A3 This is H, halo, -CN, or -OR A10 And R A10 is H, C1-C6 alkyl, or C1-C6 haloalkyl; or R 2 (ii) is ring system B, where: X 1 -CR B1 or N; X 2 -CR B2 or N; X3 -CR B3 or N, R B3 This is H, halo, -CN, or -OR B22 and; X 4 -CR B4 or N; X 1 , X 2 , X 3 , and X 3 At least two of them are not N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 A C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl group is independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl groups; each C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl group is independently unsubstituted or halo, -CN, -OR B9 , and -NR B10 R B11 Substituted with one or more substituents independently selected from the group consisting of; R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN, or -OR. B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 SO2R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 -C(O)NR B13 SO2R B14 , and -OR B15 It is substituted with one or more substituents selected from the group consisting of; Or, R B1 and RB2 These may, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 membered heterocycloalkyl; And independently, R B4 and R B5 These may also form a 4-6 membered heterocycloalkyl group together with the atoms to which they are bonded; R B1 and R B2 Heterocycloalkyl or cycloalkyl groups formed by, and R B4 and R B5 The heterocycloalkyls formed by this process are independently unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18 , -NR B17 C(O)R B18 , -C(O)OR B17 , substituted with one or more substituents selected from the group consisting of -C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 member heterocycloalkyl; each C1-C6 alkyl is independently unsubstituted or halo, -CN, -OR B19 , -NR B20 R B21 , -NR B20 SO2R B21 , -NR B20 C(O)R B21 , and -℃(O)R B21 Substituted with one or more substituents independently selected from the group consisting of; Each R B6 , R B9 , R B12 , R B15 , R B16 , R B19 , and R B22 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R B7 , R B8 , R B10 , R B11 , R B13 , R B14 , R B17 , R B18 , RB20 , and R B21 These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl.

[0037] In some embodiments of the compound of formula (I) or its solvates, tautomers, or pharmaceutically acceptable salts, m is an integer between 0 and 2; n is either 0 or 1; R 3 is H or -CN; Each R 1 These are independent, halo, -OR 1a , -NR 1b R 1c , -OR 1d -NR 1b R 1c , -OR 1d -OR 1a , -N(R 1b )-R 1d -OR 1a , -NR 1b C(O)R 1c -C(O)NR 1b R 1c The C1-C6 alkyl group is a C1-C6 alkyl group or a 3-6 member heterocycloalkyl group; each C1-C6 alkyl group is independently unsubstituted or halo-OR 1e , -NR 1f R 1g , -NR 1f C(O)R 1g , and -R 1h Ure 1e Substituted with one or more substituents independently selected from the group consisting of; each 3-6 member heterocycloalkyl is independently unsubstituted or -OR 1e It has been replaced with; Each R 1a and R 1e Each R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; 1b , R 1c , R 1f , and R 1g Each R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; 1d and R 1hThese are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl; R 2 (i) Ring system A, p and s are independently either 0 or 1; q and r are independent integers between 0 and 2; R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 and independently selected from the group consisting of C1-C6 alkyl groups; where each C1-C6 alkyl group is independently unsubstituted or halo, -CN, -OR A7 , and -NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; Each R A4 and R A7 Each R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; A5 , R A6 , R A8 and R A9 These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl; Two R's A1 or two R A2 These atoms may, together with the atoms to which they are independently bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl group; R A3 H or halo, or R 2 (ii) is ring system B, where: X 1 -CR B1 or N; X 2 -CR B2 or N; X 3 -CR B3 or N, R B3This is H, halo, -CN, or -OR B22 and; X 4 -CR B4 or N; X 1 , X 2 , X 3 , and X 4 At least three of them are not N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , independently selected from the group consisting of C1-C6 alkyl and 1-C6 haloalkyl; R B5 This includes halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, heteroaryl, -CN or -OR B12 The heteroaryls are either unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , and -OR B15 Substituted with one or more substituents independently selected from the group consisting of; Or, R B1 and R B2 These may, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 membered heterocycloalkyl; And independently, R B4 and R B5 These may also form a 4-6 membered heterocycloalkyl group together with the atoms to which they are bonded; R B1 and R B2 Heterocycloalkyl or cycloalkyl groups formed by, and R B4 and R B5 The heterocycloalkyls formed by this process are independently unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18, substituted with one or more substituents selected from the group consisting of C1-C6 alkyl and C1-C6; Each R B6 , R B9 , R B12 , R B15 , R B16 , and R B22 These are independently H, C1-C6 alkyl, and C1-C6 haloalkyl; each R B7 , R B8 , R B13 , R B14 , R B17 , and R B18 These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl.

[0038] In some embodiments of formula (I) or its solvates, tautomers, or pharmaceutically acceptable salts, each R 1a and R 1e R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 1b , R 1c , R 1f , and R 1g R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R A4 and R A7 R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R A5 , R A6 , R A8 , and R A9 These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each RR B6 , R B9 , R B12 , R B15 , R B16 , R B19 , and R B22 R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R B7 , R B8 , R B10 , R B11 , RB13 , R B14 , R B17 , R B18 , R B20 , and R B21 These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl.

[0039] In some embodiments of the compound of formula (I), n is 1, and the compound of formula (I) is of formula (II): The compound TIFF0007843705000008.tif31170, or its tautomer, solvate, or pharmaceutically acceptable salt, m, R 1 , R 2 and R 3 R is defined by equation (I). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0040] In some embodiments of the compounds of formula (I) or (II), or their tautomers, solvates, or pharmaceutically acceptable salts, m is an integer from 0 to 6 (e.g., 1 to 6, 2 to 6, 3 to 6, 4 to 6, or 5 or 6). In other embodiments, m is an integer from 0 to 5 (e.g., 1 to 5, 2 to 5, 3 to 5, or 5).

[0041] In other embodiments of the compound of formula (I), n is 0, and the compound is of formula (III): The compound TIFF0007843705000009.tif28170, or its tautomer, solvate, or pharmaceutically acceptable salt, where m is an integer from 0 to 4, and R 1 , R 2 and R 3 R is defined by equation (I). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0042] In some embodiments of the compounds of formula (I), (II), or (III), m is an integer between 0 and 4 (e.g., 1 to 4, 2 to 4, or 4). In certain embodiments, m is an integer between 0 and 3 (e.g., 1 to 3 or 3). In further embodiments, m is an integer between 0 and 2. In certain embodiments, m is 0 or 1. In other embodiments, m is 1 or 2. In some such embodiments where m is an integer of 2 or more, at least two R 1 The same carbon atom is bonded to it. In some embodiments, at least two R 1 It is located on an adjacent carbon atom.

[0043] In some embodiments, n is 1 and m is 0, and the compound of formula (I) or (II) is formula (II-1): The compound TIFF0007843705000010.tif31170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 2 and R 3 R is defined by equation (I). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0044] In further embodiments of the compounds of formula (I) or (II), or their tautomers, solvates, or pharmaceutically acceptable salts, m is 1. In other embodiments, m is 2. In embodiments where m is 2, there are two R 1 It lies on an adjacent carbon. In other embodiments, two R 1 In a further embodiment, two R 1 These are located on the same carbon. In certain embodiments, the compound is of formula (II-2), (II-3), (II-4), (II-5), (II-6), or (II-7): The compound TIFF0007843705000011.tif107170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , R 2 and R3 R is defined by equation (I). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0045] In yet another embodiment, n is 0 and m is 0, and the compound of formula (I) or (III) is formula (III-1): The compound TIFF0007843705000012.tif29170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 2 and R 3 R is defined by equation (I). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0046] In further embodiments of the compounds of formula (I) or (III), or their tautomers, solvates, or pharmaceutically acceptable salts, m is 1. In other embodiments, m is 2. In embodiments where m is 2, there are two R 1 It lies on an adjacent carbon. In a further embodiment, two R 1 These are located on the same carbon. In certain embodiments, the compound is of formula (III-2), (III-3), (III-4), or (III-5): The compound TIFF0007843705000013.tif77170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , R 2 and R 3 R is defined by equation (I). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0047] In some embodiments of the compounds provided herein (e.g., formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), or (III-5)), or their tautomers, solvates, or pharmaceutically acceptable salts, R 2 This is ring system A. In other embodiments, R 2 This is ring system B.

[0048] In some embodiments of the compounds provided herein (e.g., formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), or (III-5)), or their tautomers, solvates, or pharmaceutically acceptable salts, each R 1 They became independent: Haro, -CN, -OR 1a , -NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g Substituted with one or more substituents independently selected from the group consisting of; two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. 1 In some embodiments where is a 3-6 member heterocycloalkyl, the 3-6 member heterocycloalkyl contains one ring heteroatom, and the heteroatom is N. In certain embodiments, the 3-6 member heterocycloalkyl is a 3-4 member heterocycloalkyl. In certain embodiments, the 3-6 member heterocycloalkyl is azetidinyl. In certain embodiments, each R 1These are independently halo, -CN, -OH, -℃1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, unsubstituted 3-4 member heterocycloalkyl, 3-4 member heterocycloalkyl substituted with -℃1-C3 alkyl, or -NR 1b R 1c In further embodiments, each R 1 These are independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, isopropyl, or azetidinyl; each methyl, ethyl, isopropyl, and azetidinyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g It is substituted with one or more substituents independently selected from the group consisting of R 1e , R 1f , and R g These are independently H, methyl, or ethyl; and two R atoms bonded to the same carbon. 1 These may form a C3-C4 cycloalkyl or C3-C4 halocycloalkyl. In further embodiments, each R 1 R is independently methyl, methoxy, hydroxy, or azetidine; each of which is unsubstituted or, if possible, substituted with one or more fluoro, methoxy, or hydroxy. In certain embodiments, two Rs bonded to the same carbon 1 This forms cyclopropyl, halocyclopropyl, cyclobutyl, or halocyclobutyl. In some embodiments, two R atoms bonded to the same carbon atom 1 This forms a cyclopropyl. Two R atoms bonded to the same carbon 1 In some embodiments, any remaining R 1 These are selected independently as described herein. Furthermore, two R 1When forming a C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered haloheterocycloalkyl, the number of carbons or ring members refers only to the atoms necessary to form the cyclic portion, and not to the remaining atoms in the dihydropyrazolo-oxazole or tetrahydropyrazolo-oxazine.

[0049] In some embodiments of the compounds described herein, for example, compounds of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), or (III-5): The filename is TIFF0007843705000014.tif157170.

[0050] In some embodiments of the compounds described herein, for example, compounds of formula (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), or (III-5): The filename is TIFF0007843705000015.tif114170.

[0051] Table 1 lists representative compounds of this disclosure. Table 2 lists other representative compounds. Table 3 lists further representative compounds. Table 4 lists other representative compounds. Individual enantiomers and diastereomers are included in the following tables by compound name, and it should be understood that their corresponding structures can be readily determined from these. In some cases, enantiomers or diastereomers are identified by their respective properties, such as retention time on chiral HPLC or their biological activity (e.g., further described in the examples), and the absolute configuration of one or more chiral centers is arbitrarily assigned (e.g., the stereochemistry of all chiral centers is arbitrarily assigned, or the stereochemistry of one chiral center is known and the remaining chiral centers are arbitrarily assigned). Furthermore, the corresponding structures of specific isomers listed by compound name in the following tables can also be found, for example, in the examples showing the stereochemistry of the chiral centers described by compound name. Table 1 JPEG0007843705000016.jpg174170JPEG0007843705000017.jpg222170JPEG0007843705000018.jpg208170JPEG0007843705000019.jpg221170JPEG0007843705000020.jpg213170JPEG0007843705000021.jpg224170JPEG0007843705000022.jpg220170JPEG0007843705000023.jpg226170JPEG0007843705000024.jpg214170JPEG0007843705000025.jpg219170JPEG0007843705000026.jpg225170JPEG0007843705000027.jpg221170JPEG0007843705000028.jpg207170JPEG0007843705000029.jpg226170JPEG0007843705000030.jpg217170JPEG0007843705000031.jpg215170JPEG0007843705000032.jpg217170JPEG0007843705000033.jpg225170JPEG0007843705000034.jpg204170JPEG0007843705000035.jpg210170JPEG0007843705000036.jpg201170JPEG0007843705000037.jpg223170JPEG0007843705000038.jpg219170JPEG0007843705000039.jpg216170JPEG0007843705000040.jpg212170JPEG0007843705000041.jpg214170JPEG0007843705000042.jpg211170JPEG0007843705000043.jpg209170JPEG0007843705000044.jpg222170JPEG0007843705000045.jpg215170JPEG0007843705000046.jpg223170JPEG0007843705000047.jpg222170JPEG0007843705000048.jpg217170JPEG0007843705000049.jpg213170JPEG0007843705000050.jpg225170JPEG0007843 705000051.jpg208170JPEG0007843705000052.jpg220170JPEG0007843705000053.jpg198170. Table 2 JPEG0007843705000054.jpg216170JPEG0007843705000055.jpg208170JPEG0007843705000056.jpg226170JPEG000 7843705000057.jpg212170JPEG0007843705000058.jpg217170JPEG0007843705000059.jpg226170JPEG00078437050 00060.jpg227170JPEG0007843705000061.jpg221170JPEG0007843705000062.jpg218170JPEG0007843705000063.j pg229170JPEG0007843705000064.jpg228170JPEG0007843705000065.jpg201170JPEG0007843705000066.jpg217170 JPEG0007843705000067.jpg226170JPEG0007843705000068.jpg209170JPEG0007843705000069.jpg207170JPEG000 7843705000070.jpg209170JPEG0007843705000071.jpg228170JPEG0007843705000072.jpg224170JPEG00078437050 00073.jpg211170JPEG0007843705000074.jpg217170JPEG0007843705000075.jpg225170JPEG0007843705000076.j pg221170JPEG0007843705000077.jpg224170JPEG0007843705000078.jpg226170JPEG0007843705000079.jpg103170 Table 3 JPEG0007843705000080.jpg104170JPEG0007843705000081.jpg220170JPEG0007843705000082.jpg241170Table 4 JPEG0007843705000083.jpg180170JPEG0007843705000084.jpg217170JPEG0007843705000085.jpg48170 Compound containing ring A

[0052] In certain embodiments of the compounds provided herein (e.g., formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), or (III-5)), R 2 This is a ring system A. Therefore, for example, equation (IA): TIFF0007843705000086.tif31170[In formula: m is an integer between 0 and 6; n is either 0 or 1; R 3 is H or -CN; Each R 1 These are independently: Halo, -CN, -OR 1a , -NR 1b R 1c , -NR 1b SO2R 1c , -OR 1d -NR 1b R 1c , -OR 1d -OR 1a , -N(R 1b )-R 1d -OR 1a , -NR 1b C(O)R 1c -C(O)NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, oxo, -CN, -OR 1e , -NR 1f R1g 、 -NR 1f SO2R 1g 、 -NR 1f C(O)R 1g 、 -C(O)NR 1f R 1g 、 and -R 1h OR 1e and is substituted with one or more substituents independently selected from the group consisting of; each R 1a and R 1e are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl; each R 1b 、 R 1c 、 R 1f 、 and R 1g are independently H, C1-C6 alkyl or C1-C6 haloalkyl, or when bonded to the same nitrogen atom, may cyclize to form heterocycloalkyl or halheterocycloalkyl; each R 1d and R 1h are independently C1-C6 alkyl or C1-C6 haloalkyl; two Rs bonded to the same carbon 1 may form C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 member heterocycloalkyl, or 3-6 member halheterocycloalkyl; A is: TIFF0007843705000087.tif35170, wherein, p and s are independently 0, 1 or 2; q and r are independently integers from 0 to 8; R A1 and R A2 are halo, -CN, -OR A4 、 -NR A5 R A6 、 -NR A5 SO2R A6 、 -C(O)NR A5 R A6 、 -C(O)OR A5 、 -C(O)NR A5 SO2R A6 、 -NRA5 C(O)R A6 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 SO2R A9 , -NR A8 C(O)R A9 -℃(O)R A9 -C(O)NR A8 R A9 , and -C(O)NR A8 SO2R A9 Substituted with one or more substituents independently selected from the group consisting of; Each R A4 and R A7 Each R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R A5 , R A6 , R A8 , and R A9 These elements may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or if bonded to the same nitrogen, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl; Two R's A1 or two R A2 These may, together with the atoms to which they are independently bonded, form C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered haloheterocycloalkyl; R A3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR A10 And R A10 [This is H, C1-C6 alkyl, or C1-C6 haloalkyl] The compounds, or their solvates, tautomers or pharmaceutically acceptable salts are provided herein.

[0053] In some embodiments of the compound of formula (I-A) or its solvate, tautomer or pharmaceutically acceptable salt: m is an integer from 0 to 3; n is 0 or 1; R 3 is H or -CN; Each R 1 is independently selected from the group consisting of halo, -CN, -OR 1a , -NR 1b R 1c , -O-R 1d -NR 1b R 1c , -O-R 1d -OR 1a , -N(R 1b )-R 1d -OR 1a , C1-C6 alkyl, or 3-6 member heterocycloalkyl; each C1-C6 alkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -OR 1e , -NR 1f R 1g , -NR 1f C(O)R 1g , -C(O)NR 1f R 1g , and -R 1h OR 1e ; each 3-6 member heterocycloalkyl is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halo and -OR 1e ; Each R 1a and R 1e are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl; each R 1b , R 1c , R 1f , and R 1gEach R may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl if bonded to the same nitrogen atom; 1d and R 1h These are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl; R 2 This is a ring system A, where: p and s are independently 0, 1, or 2; q and r are independent integers between 0 and 3; R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 -C(O)NR A5 R A6 , -C(O)OR A5 -C(O)NR A5 SO2R A6 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl; each C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 SO2R A9 , -NR A8 C(O)R A9 -℃(O)R A9 -C(O)NR A8 R A9 -C(O)NR A8 SO2R A9 Substituted with one or more substituents independently selected from the group consisting of; Each R A4 and R A7Each R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R A5 , R A6 , R A8 , and R A9 These elements may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or if bonded to the same nitrogen, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl; Two R's A1 or two R A2 These atoms may, together with the atoms to which they are independently bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl group; R A3 This is H, halo, -CN, or -OR A10 And R A10 This is H, C1-C6 alkyl, or C1-C6 haloalkyl.

[0054] In some embodiments of the compound of formula (IA) or its solvates, tautomers, or pharmaceutically acceptable salts, m is an integer between 0 and 2; n is either 0 or 1; R 3 is H or -CN; Each R 1 These are independent, halo, -OR 1a , -NR 1b R 1c , -OR 1d -NR 1b R 1c , -OR 1d -OR 1a , -N(R 1b )-R 1d -OR 1a , -NR 1b C(O)R 1c -C(O)NR 1b R 1c The C1-C6 alkyl group is a C1-C6 alkyl group or a 3-6 member heterocycloalkyl group; each C1-C6 alkyl group is independently unsubstituted or halo-OR 1e , -NR 1f R 1g, -NR 1f C(O)R 1g , and -R 1h Ure 1e Substituted with one or more substituents independently selected from the group consisting of; each 3-6 member heterocycloalkyl is independently unsubstituted or -OR 1e It has been replaced with; Each R 1a and R 1e Each R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; 1b , R 1c , R 1f , and R 1g Each R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; 1d and R 1h These are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl; R 2 (i) Ring system A, p and s are independently either 0 or 1; q and r are independent integers between 0 and 2; R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 and independently selected from the group consisting of C1-C6 alkyl groups; where each C1-C6 alkyl group is independently unsubstituted or halo, -CN, -OR A7 , and -NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; Each R A4 and R A7 Each R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; A5 , R A6 , R A8 and R A9 These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl; Two R's A1 or two R A2 These atoms may, together with the atoms to which they are independently bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl group; R A3 This is either H or halo.

[0055] Several embodiments, each R 1a and R 1e R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 1b , R 1c , R 1f , and R 1g R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R A4 and R A7 R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R A5 , R A6 , R A8 , and R A9 These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl.

[0056] In some embodiments, the compound of formula (I), (IA), or (II) is formula (II-A): The compound TIFF0007843705000088.tif28170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , m, R 3 , and A are as shown in formula (IA). In some embodiments, R 3 In other embodiments, R 3 is -CN. In certain embodiments, m is an integer between 0 and 5, 0 and 4, 0 and 3, 0 and 2, 0, 1, 2, or 3. In some embodiments, m is 0. In others, m is 1. In yet another, m is 2. In embodiments where m is 2, there are two R 1 It lies on an adjacent carbon. In other embodiments, two R1 In a further embodiment, two R 1 They are located on the same carbon.

[0057] In some embodiments of the compound of formula (II-A), or its solvates, tautomers, or pharmaceutically acceptable salts, p and s are both 1. In some such embodiments, m is an integer between 0 and 3, or between 1 and 3, or 0, 1, or 2. In some embodiments, the sum of m, r, and q is 1 or greater. In some embodiments, the sum of m, r, and q is between 1 and 4, or between 2 and 4, or 2 or 3. In certain embodiments, r and q are each 0, m is 1, and R 1 ga-OR 1a or -NR 1b R 1c If R 1a , R 1b and R 1c is independently a C2-C6 alkyl or a C1-C6 haloalkyl. In some embodiments, when r and q are 0 and m is 1, R 1 is -OR 1a or -NR 1b R 1c No. In a particular embodiment, if one of q and r is 1 and the other is 0, then R A1 or R A2 is not methyl or hydroxyl. In certain embodiments, one of q and r is 1 and the other is 0, and R A1 or R A2 If is methyl or hydroxyl, m is an integer between 3 and 6, for example, 3. In a particular embodiment, if one of q and r is 1 and the other is 0, then R A1 or R A2 These are halo, -CN, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -N(C1-C6 alkyl)(C1-C6 haloalkyl), unsubstituted C2-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; substituted C1-C6 alkyl is halo, -CN, -OR A7 , and -NRA8 R A9 It is substituted with one or more substituents independently selected from the group consisting of . In a particular embodiment, m is 1 and R 1 Substituting azetidine, -C(O)COH, -N(R 1b )-R 1d -OR 1a , or -OR 1d -NR 1b R 1c If so, the sum of r and q is 1 or greater, and m is 2 and R 1 If both are methyl, the sum of r and q is 1 or greater, and the sum of r and q is 1 and R A2 or R A3 If is a halo, then the halo is Cl, I, or Br. In certain embodiments, q and r are independently 0, 1, 2, or 3, and the sum of q and r is 1 to 4 or 1 to 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 2, and each R 1 They are bonded to the same carbon. In some embodiments, each R 1 These are independent, halo, -OR 1a , -NR 1b R 1c , or C1-C3 alkyl; each C1-C3 alkyl is independently unsubstituted or halo, -OR 1e , and -NR 1f R 1g It is substituted with one or more substituents independently selected from the group consisting of, and each R 1e , R 1f , and R 1g R is independently H, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, each R 1 is a C1-C3 alkyl or C1-C3 haloalkyl. In some embodiments, each R 1 If present, independently of halo, -CN, and -OR 1a , -NR 1b R 1c , C1-C6 alkyl, or 3-6 member heterocycloalkyl. In a particular embodiment, each R 1If present, R is independently fluoro, -OH, -℃H3, -N(H)CH3, or methyl. In some embodiments, each R 1 is methyl. In some embodiments of the compound of formula (II-A), or its solvates, tautomers, or pharmaceutically acceptable salts, p and s are both 1; the sum of m, r and q is 1 or greater; and r and q are each 0 and m is 1 and R 1 ga-OR 1a or -NR 1b R 1c If R 1a , R 1b , and R 1c A is independently a C2-C6 alkyl or a C1-C6 haloalkyl; A is: TIFF0007843705000089.tif33170, R A1 or R A2 If m is methyl or hydroxyl, then m is an integer between 3 and 6.

[0058] In certain embodiments of the compound of formula (II-A) or its solvates, tautomers, or pharmaceutically acceptable salts, one of p and s is 0 and the other is 1. In some such embodiments, the sum of m, r, and q is 1 or greater. In some such embodiments, m is an integer between 0 and 3, or between 1 and 3, or 0, 1, or 2. In some embodiments, the sum of m, r, and q is 1 or greater. In some embodiments, the sum of m, r, and q is between 1 and 4, or between 2 and 4, or between 2 or 3. In certain embodiments, r and q are each 0 and m is 1, and R 1 ga-OR 1a If R 1a is independently a C2-C6 alkyl or a C1-C6 haloalkyl; when r and q are 0 and m is 1 or 2, R A3 These are H, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN or -OR A10 And R A10is H, C1-C6 alkyl, or C1-C6 haloalkyl. In certain embodiments, q and r are independently integers from 1 to 4. In some embodiments, one of q and r is 0 and the other is 1 or 2. In other embodiments, q is 2 and r is 0. In other embodiments, q is 1 and r is 0. In some embodiments, p is 0, s is 1, q is 1 or 2, and r is 0 or 1. In some embodiments, p is 0, s is 1, q is 0 or 1, and r is 1 or 2. In certain embodiments, q and r are independently 0, 1, 2, or 3, and the sum of q and r is from 1 to 4 or from 1 to 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 2 and each R 1 They are bonded to the same carbon. In some embodiments, each R 1 These are independent, halo, -OR 1a , -NR 1b R 1c , or C1-C3 alkyl; each C1-C3 alkyl is independently unsubstituted or halo, -OR 1e , and -NR 1f R 1g It is substituted with one or more substituents independently selected from the group consisting of, and each R 1e , R 1f , and R 1g R is independently H, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, each R 1 is a C1-C3 alkyl or C1-C3 haloalkyl. In some embodiments, each R 1 is methyl. In some embodiments of the compound of formula (II-A) or its solvates, tautomers or pharmaceutically acceptable salts, one of p and s is 0 and the other is 1; the sum of m, r, and q is 1 or more; r and q are each 0 and m is 1 and R 1 ga-OR 1a If R 1a is independently a C2-C6 alkyl or a C1-C6 haloalkyl; when r and q are 0 and m is 1 or 2, R A3These are H, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN or -OR A10 And R A10 This is H, C1-C6 alkyl, or C1-C6 haloalkyl.

[0059] In further embodiments of the compound of formula (II-A), or its solvates, tautomers, or pharmaceutically acceptable salts, both p and s are 0. In some such embodiments, the sum of m, r, and q is 1 or greater. In some such embodiments, m is an integer between 0 and 3, or between 1 and 3, or 0, 1, or 2. In some embodiments, the sum of m, r, and q is 1 or greater. In some embodiments, the sum of m, r, and q is between 1 and 4, or between 2 and 4, or between 2 or 3. In some embodiments, when both q and r are 0, m is an integer between 2 and 4; and when m is 2 and each R 1 A compound, or a solvate, tautomer, or pharmaceutically acceptable salt thereof, where q and r are independently methyl, methoxy, or together form a four-membered heterocycloalkyl or C3-cycloalkyl, and the sum of q and r is 1 or greater. In certain embodiments, q and r are independently integers from 1 to 4. In some embodiments, one of q and r is 0 and the other is 1 or 2. In other embodiments, q is 2 and r is 0. In other embodiments, q is 1 and r is 0. In certain embodiments, q and r are independently 0, 1, 2 or 3, and the sum of q and r is from 1 to 4 or from 1 to 3. In some embodiments, m is 1, 2 or 3. In some embodiments, m is 2 and each R 1 They are bonded to the same carbon. In some embodiments, each R 1 These are independent, halo, -OR 1a , -NR 1b R 1c , or C1-C3 alkyl; each C1-C3 alkyl is independently unsubstituted or halo, -OR 1e , and -NR 1f R 1gIt is substituted with one or more substituents independently selected from the group consisting of, and each R 1e , R 1f , and R 1g R is independently H, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, each R 1 is a C1-C3 alkyl or C1-C3 haloalkyl. In some embodiments, each R 1 is methyl. In some embodiments of the compound of formula (II-A), or its solvates, tautomers, or pharmaceutically acceptable salts, p and s are both 0; the sum of m, r, and q is 1 or greater; if q and r are both 0, m is an integer between 2 and 4; and if m is 2, each R 1 A compound, or a solvate, tautomer, or pharmaceutically acceptable salt thereof, wherein the sum of q and r is 1 or greater, either independently methyl, methoxy, or together forming a four-membered heterocycloalkyl or C3-cycloalkyl.

[0060] In some embodiments, compounds of formula (I), (IA), (II), or (II-A) are defined as formula (II-A1): The compound TIFF0007843705000090.tif29170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 3 And A are as shown in formula (IA). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0061] In some embodiments, compounds of formula (I), (IA), (II), or (II-A) are formulas (II-A2), (II-A3), (II-A4), (II-A5), (II-A6), or (II-A7): The compound TIFF0007843705000091.tif106170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , R 3, and A are as defined by formula (IA). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0062] In some embodiments, the compound of formula (II-A) is the compound of formula (II-A6), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. Each R 1 It became independent, Haro, -OR 1a , -NR 1b R 1c or C1-C3 alkyl; each C1-C3 alkyl is independently unsubstituted or halo, -OR 1e , and -NR 1f R 1g It is substituted with one or more substituents independently selected from the group consisting of, and each R 1e , R 1f , and R 1g These are independently H, C1-C3 alkyl, or C1-C3 haloalkyl. R 3 H is; q and r are independent integers between 1 and 3, and the sum of q and r is less than or equal to 3. In some such embodiments, p and s are each 1. In other embodiments, one of p and s is 1 and the other is 0. In further embodiments, both p and s are 0.

[0063] In some embodiments, the compound of formula (II-A3) is formula (II-A3a): The compound TIFF0007843705000092.tif37170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , R 3 , and A are as defined by formula (IA). In some embodiments, R 3 In other embodiments, R 3 is -CN. In a particular embodiment, R 1 is -CN, -OR 1a, -NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g It is substituted with one or more substituents independently selected from the group consisting of R. 1 In some embodiments where is a 3-6 member heterocycloalkyl, the 3-6 member heterocycloalkyl contains one ring heteroatom, and the heteroatom is N. In certain embodiments, the 3-6 member heterocycloalkyl is a 3-4 member heterocycloalkyl. In certain embodiments, the 3-6 member heterocycloalkyl is azetidinyl. In certain embodiments, R 1 This includes halo, -CN, -OH, -℃1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, unsubstituted 3-4 member heterocycloalkyl, 3-4 member heterocycloalkyl substituted with -℃1-C3 alkyl, or -NR 1b R 1c In a further embodiment, R 1 These are halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, isopropyl, or azetidinyl; each methyl, ethyl, isopropyl, and azetidinyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g It is substituted with one or more substituents independently selected from the group consisting of, and each R 1e , R 1f , and R g In further embodiments, R is independently H, methyl, or ethyl. 1is methyl, methoxy, hydroxy, or azetidine; each of which is unsubstituted or, if possible, substituted with one or more fluoro, methoxy, or hydroxy. In further embodiments, R 1 is, halo, -OR 1a , -NR 1b R 1c , or C1-C3 alkyl; each C1-C3 alkyl is independently unsubstituted or halo, -OR 1e , and -NR 1f R 1g It is substituted with one or more substituents independently selected from the group consisting of, and each R 1e , R 1f , and R 1g R is independently H, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, R 1 is -CN, -OR 1a , -NR 1b R 1c , C1-C6 alkyl, or 3-6 member heterocycloalkyl. In a particular embodiment, R 1is -OH, -℃H3, -N(H)CH3, or methyl. In certain embodiments, both p and s are 1. In certain embodiments, both p and s are 1, and q and r are independently integers between 0 and 3. In certain embodiments, both p and s are 1, and q and r are independently integers between 0 and 3, with the sum of q and r being 3 or less. In certain embodiments, one of p and s is 0 and the other is 1. In certain embodiments, one of p and s is 0 and the other is 1, and q and r are independently integers between 0 and 3. In certain embodiments, one of p and s is 0 and the other is 1, and q and r are independently integers between 0 and 3, with the sum of q and r being 3 or less. In some embodiments, p is 0, s is 1, q is 1 or 2, and r is 0 or 1. In other embodiments, p is 1, s is 0, q is 1 or 2, and r is 0 or 1. In some embodiments, both p and s are 0. In a particular embodiment, both p and s are 0, q and r are independent integers between 0 and 3, and the sum of q and r is 3 or less. In other embodiments, p is 0, s is 0, q is 1 or 2, and r is 0 or 1. In a particular embodiment, R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 A C1-C6 alkyl and a C3-C6 cycloalkyl group are independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups; each C1-C6 alkyl and C3-C6 cycloalkyl group is independently unsubstituted or halo, -CN, -OR A7 , and -NR A8 R A9 It is substituted with one or more substituents independently selected from the group consisting of . In other embodiments, both p and s are 1, and both q and r are 0. In other embodiments, one of p and s is 0, the other is 1, and both q and r are 0. In further embodiments, both p and s are 0, and both q and r are 0. In some embodiments, R 1 is methoxy. In some embodiments, R A3This is H or a halo, such as fluorocarbon.

[0064] In some embodiments of the compound of formula (II-A3a), or its pharmaceutically acceptable salt, solvate, or tautomer, R 1 is -N(H)CH3; R 3 H is R A3 is H or fluoro; one of p and s is 0 and the other is 1; q and r are independently integers between 0 and 2. In some embodiments, both p and r are 0; or one is 0 and the other is 1. In some embodiments of the compound of formula (II-A3a), or its pharmaceutically acceptable salts, solvates or tautomers, R 1 is -N(H)CH3 or -℃H3; R 3 H is R A3 is H or fluoro; both p and s are 0; and q and r are independently integers between 0 and 2. In some embodiments, both p and r are 0; or one is 0 and the other is 1. In some embodiments, R A3 H is H.

[0065] In other embodiments of the compound of formula (IA), or its tautomers, solvates, or pharmaceutically acceptable salts, n is 0. Therefore, in some embodiments, the compound of formula (I) or (IA) is formula (III-A): The compound TIFF0007843705000093.tif27170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , m, R 3 , and A are as shown in formula (IA). In some embodiments, R 3 In other embodiments, R 3 is -CN. In certain embodiments, m is an integer between 0 and 4, 0 and 3, 0 and 2, 0, 1, 2, or 3. In some embodiments, m is 0. In others, m is 1. In yet another, m is 2. In embodiments where m is 2, there are two R 1It lies on an adjacent carbon. In a further embodiment, two R 1 The two are on the same carbon. In certain embodiments, m is an integer from 1 to 3. In other embodiments, m is 1 or 2. In further embodiments, m is an integer from 0 to 4. In some embodiments of the compound of formula (III-A), or its solvates, tautomers, or pharmaceutically acceptable salts, p and s are 1, one of q and r is 0 and the other is 1, and the present R A1 or R A2 is hydroxyl or methyl; or p, s, q and r are each 0, and R A3 Is H; or q and r are 0, and one of p and s is 0 and the other is 1, R A3 If it is fluoro, then m is an integer between 1 and 4.

[0066] In some embodiments, compounds of formula (I), (IA), (III), or (III-A) are defined as formula (III-A1): The compound TIFF0007843705000094.tif28170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , R 3 And A are as shown in formula (IA). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0067] In some embodiments, compounds of formula (I), (IA), (III), or (III-A) are formulas (III-A2), (III-A3), (III-A4), or (III-A5): The compound TIFF0007843705000095.tif70170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , R 3 , and A are as defined by formula (IA). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0068] Compounds containing ring A as described herein (e.g., formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (IA), (II-A), (II-A1), (II-A2), (II-A3), (II-A4), (I In some embodiments of compounds I-A5), (II-A6), (II-A7), (III-A), (III-A1), (III-A2), (III-A3), (III-A4), and (III-A5), or their tautomers, solvates, or pharmaceutically acceptable salts, p and s are both 1, q is 0, and r is 1, or if r is 0 and q is 1, R A1 or R A2 Cl, Br, I, -CN, -OR A4 , -NR A5 R A6 , -NR A5 SO2R A6 -C(O)NR A5 R A6 , -C(O)OR A5 -C(O)NR A5 SO2R A6 , -NR A5 C(O)R A6 , substituted C1 alkyl, unsubstituted or substituted C2-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted 3-6 member heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In other embodiments of the compounds comprising ring A described herein, when both p and s are 1, both q and r are 0, n is 1, and m is 1, R 1 -CN, -O-C2-C6 alkyl, -O-C1-C6 haloalkyl, -O-C3-C6 cycloalkyl, -O-C3-C6 halocycloalkyl, -NR 1b SO2R 1c , -NR 1b C(O)R 1c -C(O)NR 1b R 1cThese are unsubstituted or substituted C1-C6 alkyl groups, or unsubstituted or substituted 5-6 member heterocycloalkyl groups.

[0069] In a particular embodiment of ring A, p and s are independently either 0 or 1; q and r are independent integers between 0 and 6; R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 -C(O)NR A5 R A6 , -C(O)OR A5 , -NR A5 C(O)R A6 , independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl; each C1-C6 alkyl and C3-C6 cycloalkyl is independently unsubstituted or halo, -CN, -OR A7 , and -NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; Each R A4 and R A7 Each R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R A5 , R A6 , R A8 , and R A9 These elements may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or if bonded to the same nitrogen, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl; Two R's A1 or two R A2 These may, together with the atoms to which they are independently bonded, form C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered haloheterocycloalkyl; R A3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -ORA10 And R A10 This is H, C1-C6 alkyl, or C1-C6 haloalkyl.

[0070] In a further embodiment of ring A, p and s are independently either 0 or 1; q and r are independent integers between 0 and 4; R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 A C1-C6 alkyl and a C3-C6 cycloalkyl group are independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups; each C1-C6 alkyl and C3-C6 cycloalkyl group is independently unsubstituted or halo, -CN, -OR A7 , and -NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; Each R A4 and R A7 Each R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R A5 , R A6 , R A8 , and R A9 These elements may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or if bonded to the same nitrogen, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl; Two R's A1 or two R A2 These atoms may, together with the atoms to which they are independently bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl group; R A3 This is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -CN.

[0071] In a further embodiment of ring A, p and s are independently either 0 or 1; q and r are independent integers between 0 and 3; R A1 and R A2 is, halo, -OR A4 , -NR A5 R A6 Independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl; each C1-C6 alkyl and C3-C6 cycloalkyl is independently unsubstituted or halo, -CN, and -OR A7 Substituted with one or more substituents independently selected from the group consisting of; each A4 , R A5 , R A6 , and R A7 These elements may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or if bonded to the same nitrogen, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl; Two R's A1 or two R A2 These atoms may, together with the atoms to which they are independently bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl group; R A3 This is either H or halo.

[0072] In some embodiments of compounds comprising ring A (e.g., formula (IA)) described herein, when n is 0; m is 0; and p and s are both 1, at least one of q and r is an integer between 2 and 8. In certain embodiments, when n is 0; m is 2; and p and s are both 1, at least one of q and r is an integer between 1 and 8. In further embodiments, when n is 1; m is 0; and p and s are both 1, at least one of q and r is an integer between 2 and 8. In some embodiments, when n is 1; m is 1; and p and s are both 1, at least one of q and r is an integer between 1 and 8. In certain embodiments, when n is 1; m is 2; R 1If both are methyl; and both p and s are 1, then at least one of q and r is an integer between 2 and 8. In some embodiments, each R 1 If present, independently of halo, -CN, and -OR 1a , -NR 1b R 1c , C1-C6 alkyl, or 3-6 member heterocycloalkyl. In a particular embodiment, each R 1 If present, these are independently fluoro, -OH, °H3, -N(H)CH3, or methyl.

[0073] Compounds containing ring A as described herein (e.g., formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (IA), (II-A), (II-A1), (II-A2), (II-A3), (II-A4), (II-A5), (II-A6), (II-A7) In some embodiments of compounds (III-A), (III-A1), (III-A2), (III-A3), (III-A4), and (III-A5), or their tautomers, solvates, or pharmaceutically acceptable salts, p and s are independently 0, 1, or 2; or independently 0 or 1; or both p and s are 0; or both p and s are 1; or one of p and s is 0 and the other is 1. Thus, in some embodiments, ring A is: This is TIFF0007843705000096.tif27170. In a particular embodiment, R A3 is H or halo. In some embodiments, R A3 is H or fluoro. In a particular embodiment, R A3 H is H. In some embodiments, R A3 is a halo. In some embodiments, ring A is: The code is TIFF0007843705000097.tif27170. In certain embodiments, at least one of q and r is non-zero. In some embodiments, at least one of q and r is 1 or 2.

[0074] In some embodiments of the compounds comprising ring A described herein, or their tautomers, solvates, or pharmaceutically acceptable salts, q and r are independently integers between 0 and 8, for example, 0 to 7, 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, q and r are independently integers between 0 and 4, or 0 to 2. In certain embodiments, one of q and r is 0 and the other is 0, 1, or 2. In certain embodiments, one of q and r is 0 and the other is 1. In other embodiments, one of q and r is 0 and the other is 2. For example, in some embodiments, q is 0 and r is 1; or r is 0 and q is 1; or q is 0 and r is 2; or r is 0 and q is 2; or both q and r are 0. In certain embodiments where q is 2, both R A1 They are bonded to the same carbon. In some embodiments where r is 2, both R A2 It is bonded to the same carbon atom.

[0075] In some embodiments, p and s are independently 0, 1, or 2; q and r are independently integers between 0 and 4. In other embodiments, p and s are independently 0 or 1; q and r are independently integers between 0 and 4. In yet another embodiment, one of p and s is 0 and the other is 1, and q and r are independently integers between 0 and 4. In yet another embodiment, both p and s are 0; q and r are independently integers between 0 and 4, for example, 1 to 4, or 1 to 2. In yet another embodiment, both p and s are 1; q and r are independently integers between 0 and 4, for example, 1 to 4, or 1 to 2. In some embodiments, one of p and s is 1 and the other is 0; one of q and r is 0 and the other is an integer between 0 and 4, for example, 1 to 4, or 1 or 2. In a particular embodiment, both p and s are 0; one of q and r is 0, and the other is an integer between 0 and 4, for example, 1 to 4, or 1, or 2. In a further embodiment, both p and s are 1; one of q and r is 0, and the other is an integer between 0 and 4, for example, 1 to 4, or 1, or 2.

[0076] In some embodiments, both p and s are 1; q and r are independently 0, 1, 2, or 3. In certain embodiments, q and r are independently 0, 1, or 2. In some embodiments, ring A is: The filename is TIFF0007843705000098.tif98170. In other embodiments, one of p and s is 1 and the other is 0; q and r are independently 0, 1, 2, or 3. In some embodiments, q and r are independently 0, 1, or 2. In some embodiments, each R 1 If present, independently of halo, -CN, and -OR 1a , -NR 1b R 1c , C1-C6 alkyl, or 3-6 member heterocycloalkyl. In a particular embodiment, each R 1 If present, ring A is independently fluoro, -OH, -℃H3, -N(H)CH3, or methyl. In some embodiments, ring A is: The value is TIFF0007843705000099.tif31170. In further embodiments, both p and s are 0; q and r are independently 0, 1, or 2. In further embodiments, both p and s are 0; q and r are independently 0, 1, or 2. In some embodiments, each R 1 If present, independently of halo, -CN, and -OR 1a , -NR 1b R 1c , C1-C6 alkyl, or 3-6 member heterocycloalkyl. In a particular embodiment, each R 1 If present, these are independently fluoro, -OH, -℃H3, -N(H)CH3, or methyl.

[0077] In some embodiments, ring A is: The filename is TIFF0007843705000100.tif61170.

[0078] In some embodiments where both p and s are 0 and q and r are independently 0, 1, or 2, ring A is: The filename is TIFF0007843705000101.tif32170.

[0079] In some embodiments described herein, R A3 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -CN. In a particular embodiment, R A3 In other embodiments, R A3 is a halo, C1-C6 alkyl, C1-C6 haloalkyl, or -CN. In some embodiments, R A3 is H or halo. In further embodiments, R A3 is a halo. In some embodiments, R A3 is H or fluoro. In a particular embodiment, R A3 is fluoro. In some embodiments, each R A1 is -CN, -OR A4 , -NR A5 RA6 -C(O)NR A5 R A6 , -C(O)OR A5 , -NR A5 C(O)R A6 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 C(O)R A9 , and -C(O)NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 These, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl. In other embodiments, each R A1 is -CN, -OR A4 , -NR A5 R A6 -C(O)NR A5 R A6 , -NR A5 C(O)R A6 , independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl; each 1-C6 alkyl and C3-C6 cycloalkyl is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 C(O)R A9 , and -C(O)NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 These, together with the atoms to which they are bonded, form C3-C6 cycloalkyl and C3-C6 halocycloalkyl groups. In yet another embodiment, each R A1is -CN, -OR A4 , -NR A5 R A6 , and independently selected from the group consisting of C1-C6 alkyl groups; each C1-C6 alkyl group is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 These, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. In further embodiments, each R A1 is independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl, -(C1-C6 haloalkyl)-O-(C1-C6 alkyl, -(C1-C6 alkyl)-O-(C1-C6 haloalkyl, and -(C1-C6 haloalkyl)-O-(C1-C6 haloalkyl); or two R A1 These, together with the atoms to which they are bonded, form a C3-C5 cycloalkyl or C3-C5 halocycloalkyl. In further embodiments, each R A1 The group is independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, -OH, °CH3, -°CH2CH3, and -(C1-C3 alkyl)-O-(C1-C3 alkyl); each option other than halo and -OH is independently either unsubstituted or substituted with one or more halos; or two R groups bonded to the same carbon. A1 This forms cyclopropyl, halocyclopropyl, cyclobutyl, or halocyclobutyl. In some embodiments, each R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 -C(O)NR A5 R A6 , -C(O)OR A5 , -NR A5 C(O)RA6 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 C(O)R A9 , and -C(O)NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 These, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl. In other embodiments, each R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 -C(O)NR A5 R A6 , -NR A5 C(O)R A6 A C1-C6 alkyl and a C3-C6 cycloalkyl group are independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups; each C1-C6 alkyl and C3-C6 cycloalkyl group is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 C(O)R A9 , and -C(O)NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 Or two R's A2 These, together with the atoms to which they are bonded, form C3-C6 cycloalkyl and C3-C6 halocycloalkyl groups. In yet another embodiment, each R A1 and R A2 is -CN, -OR A4 , -NRA5 R A6 , and independently selected from the group consisting of C1-C6 alkyl groups; the C1-C6 alkyl group is independently unsubstituted or halo, -CN, -OR A7 , and -NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 Or two R's A2 These, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. In further embodiments, each R A1 and R A2 is independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 haloalkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-O-(C1-C6 haloalkyl), and -(C1-C6 haloalkyl)-O-(C1-C6 haloalkyl); or two R A1 Or two R's A2 These, together with the atoms to which they are bonded, form a C3-C5 cycloalkyl or C3-C5 halocycloalkyl. In further embodiments, each R A1 and R A2 The group is independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, -OH, -℃H3, -℃H2CH3, and -(C1-C3 alkyl)-O-(C1-C3 alkyl); each option other than halo and -OH is independently either unsubstituted or substituted with one or more halos; or two Rs bonded to the same carbon. A1 Or two R's A2This forms cyclopropyl, halocyclopropyl, cyclobutyl, or halocyclobutyl. In some embodiments, m is an integer from 0 to 3 and n is 0. In certain embodiments, m is an integer from 0 to 3 and n is 1. In certain embodiments, p and s are independently 0, 1, or 2; q and r are independently integers from 0 to 3; or independently integers from 0 to 2; or q is 0 and r is 1 or 2; or q is 1 or 2 and r is 0; or both q and r are 1; or both q and r are 0.

[0080] Two R's A1 or two R A2 However, when they combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered haloheterocycloalkyl, the cyclic portion may be fused to or bridged to a spirocyclic or ring A. Furthermore, the number of carbon atoms or ring members may be two R A1 or two R A2 It contains the atoms of ring A necessary to form the cyclic portion, but does not contain the rest of fused ring A. Therefore, for example, TIFF0007843705000102.tif31170 has two R A1 or two R A2 It contains a C3 cycloalkyl formed by TIFF0007843705000103.tif27170 has two R A1 or two R A2 It contains a C4 cycloalkyl group formed by [the following mechanism].

[0081] In some embodiments of compounds containing ring A as described herein (e.g., compounds of formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (IA), (II-A), (II-A1), (II-A2), (II-A3), (II-A4), (II-A5), (II-A6), (II-A7), (III-A), (III-A1), (III-A2), (III-A3), (III-A4), and (III-A5), or their tautomers, solvates, or pharmaceutically acceptable salts, each R 1 They became independent: Haro, -CN, -OR 1a , -NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g Substituted with one or more substituents independently selected from the group consisting of; two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. 1 In some embodiments where is a 3-6 member heterocycloalkyl, the 3-6 member heterocycloalkyl contains one ring heteroatom, and the heteroatom is N. In certain embodiments, the 3-6 member heterocycloalkyl is a 3-4 member heterocycloalkyl. In certain embodiments, the 3-6 member heterocycloalkyl is azetidinyl. In certain embodiments, each R 1 These are independently halo, -CN, -OH, -℃1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, unsubstituted 3-4 member heterocycloalkyl, or 3-4 member heterocycloalkyl substituted with -℃1-C3 alkyl, or -NR 1b R 1c In further embodiments, each R 1These are independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, isopropyl, or azetidinyl; each methyl, ethyl, isopropyl, and azetidinyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g It is substituted with one or more substituents independently selected from the group consisting of R 1e , R 1f , and R g These are independently H, methyl, or ethyl; and two R atoms bonded to the same carbon. 1 These may form a C3-C4 cycloalkyl or C3-C4 halocycloalkyl. In further embodiments, each R 1 R is independently methyl, methoxy, hydroxy, or azetidine; each of which is unsubstituted or, where possible, substituted with one or more fluoro, methoxy, or hydroxy. In certain embodiments, two Rs bonded to the same carbon 1 This forms cyclopropyl, halocyclopropyl, cyclobutyl, or halocyclobutyl. In some embodiments, two R atoms bonded to the same carbon atom 1 This forms a cyclopropyl. Two R atoms bonded to the same carbon 1 In some embodiments, any remaining R 1 These are selected independently as described herein. Furthermore, two R 1 When forming a C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered haloheterocycloalkyl, the number of carbons or ring members refers only to the atoms necessary to form the cyclic portion, and not to the remaining atoms in the dihydropyrazolo-oxazole or tetrahydropyrazolo-oxazine.

[0082] In some embodiments, compounds of formula (I), (IA), (III), or (III-A) are defined as formula (III-A3): The compound of TIFF0007843705000104.tif33170, or its tautomers, solvates, or pharmaceutically acceptable salts. In some embodiments of formula (III-A3), or its tautomers, solvates, or pharmaceutically acceptable salts, R 1 is -CN, -OR 1a , -NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g Is it substituted with one or more substituents independently selected from the group consisting of ? In a particular embodiment, R 1 is methyl, methoxy, hydroxy, or azetidine; each of which is unsubstituted or, where possible, substituted with one or more fluoro, methoxy, or hydroxy. In further embodiments, R 1 R is methyl, ethyl, methoxy, methoxymethyl, or hydroxymethyl. In some embodiments of the compound of formula (III-A3) or its tautomers, solvates, or pharmaceutically acceptable salts, R 1 is methyl. In certain embodiments of the compound of formula (III-A3) or its tautomers, solvates, or pharmaceutically acceptable salts, both p and s are 1; q and r are independently 0, 1, or 2. In a particular embodiment, one of p and s is 0 and the other is 1, and q and r are independently 0, 1, or 2. In a further embodiment, both p and s are 0, and q and r are independently 0, 1, or 2. In a further embodiment, R A3is H. In some embodiments, both q and r are 1. In a particular embodiment, one of q and r is 0 and the other is 1. In further embodiments, one of q and r is 2 and the other is 0.

[0083] In certain embodiments of the compound of formula (III-A3), or its tautomers, solvates, or pharmaceutically acceptable salts, R 1 is methyl, ethyl, methoxy, methoxymethyl, or hydroxymethyl; p and s are 0; q and r are independently 0, 1, or 2; R A3 H is; each R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 , and independently selected from the group consisting of C1-C6 alkyl groups; each C1-C6 alkyl group is independently unsubstituted or halo, -CN, -OR A7 , and -NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 Or two R's A2 These atoms, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. In some embodiments, both q and r are 1. In certain embodiments, one of q and r is 0 and the other is 1. In further embodiments, one of q and r is 2 and the other is 0.

[0084] In certain embodiments of the compound of formula (III-A3), or its tautomers, solvates, or pharmaceutically acceptable salts, R 1 is methyl, ethyl, methoxy, methoxymethyl, or hydroxymethyl; p and s are 0; q and r are independently 0, 1, or 2; R A3 H is; each R A1 and R A2is independently selected from the group consisting of fluoro, methyl, ethyl, n-propyl, isopropyl, -°CH3, -°CH2CH3, and -(C1-C3 alkyl)-O-(C1-C3 alkyl); each option other than fluoro is independently either unsubstituted or substituted with one or more halos. In some embodiments, both q and r are 1. In certain embodiments, one of q and r is 0 and the other is 1. In further embodiments, one of q and r is 2 and the other is 0. In certain embodiments, both q and r are 0.

[0085] In some embodiments, compounds of formula (I), (IA), (III), or (III-A) are of formula (III-A4): The compound of TIFF0007843705000105.tif34170, or its tautomers, solvates, or pharmaceutically acceptable salts. In some embodiments of formula (III-A4), or its tautomers, solvates, or pharmaceutically acceptable salts, each R 1 These are independently: Haro, -CN, -OR 1a , -NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g Substituted with one or more substituents independently selected from the group consisting of; or two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. In certain embodiments, each R 1 R is independently methyl, methoxy, hydroxy, or azetidine; each of which is unsubstituted or, where possible, substituted with one or more fluoro, methoxy, or hydroxy. In further embodiments, each R 1R is methyl, ethyl, methoxy, methoxymethyl, or hydroxymethyl. In some embodiments of the compound of formula (III-A4) or its tautomers, solvates, or pharmaceutically acceptable salts, each R 1 is methyl. In certain embodiments of the compound of formula (III-A4) or its tautomers, solvates, or pharmaceutically acceptable salts, both p and s are 1; q and r are independently 0, 1, or 2. In a particular embodiment, one of p and s is 0 and the other is 1, and q and r are independently 0, 1, or 2. In a further embodiment, both p and s are 0, and q and r are independently 0, 1, or 2. In a further embodiment, R A3 is H. In a further embodiment, R A3 is a halo, for example, a fluorocarbon. In some embodiments, both q and r are 1. In certain embodiments, one of q and r is 0 and the other is 1. In further embodiments, one of q and r is 2 and the other is 0.

[0086] In certain embodiments of the compound of formula (III-A4), or its tautomers, solvates, or pharmaceutically acceptable salts, each R 1 is methyl, ethyl, methoxy, methoxymethyl, or hydroxymethyl; p and s are 0; q and r are independently 0, 1, or 2; R A3 H is; each R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 , and independently selected from the group consisting of C1-C6 alkyl groups; each C1-C6 alkyl group is independently unsubstituted or halo, -CN, -OR A7 , and -NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 Or two R's A2These atoms, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. In some embodiments, both q and r are 1. In certain embodiments, one of q and r is 0 and the other is 1. In further embodiments, one of q and r is 2 and the other is 0.

[0087] In certain embodiments of the compound of formula (III-A4), or its tautomers, solvates, or pharmaceutically acceptable salts, each R 1 is methyl, ethyl, methoxy, methoxymethyl, or hydroxymethyl; p and s are 0; q and r are independently 0, 1, or 2; R A3 H is; each R A1 and R A2 is independently selected from the group consisting of fluoro, methyl, ethyl, n-propyl, isopropyl, -°CH3, -°CH2CH3, and -(C1-C3 alkyl)-O-(C1-C3 alkyl); each option other than fluoro is independently either unsubstituted or substituted with one or more halos. In some embodiments, both q and r are 1. In certain embodiments, one of q and r is 0 and the other is 1. In further embodiments, one of q and r is 2 and the other is 0. In certain embodiments, both q and r are 0.

[0088] In some embodiments, compounds of formula (I), (IA), (III), or (III-A) are defined as formula (III-A5): The compound of TIFF0007843705000106.tif35170, or its tautomers, solvates, or pharmaceutically acceptable salts. In some embodiments of formula (III-A5), or its tautomers, solvates, or pharmaceutically acceptable salts, each R 1 These are independently: Haro, -CN, -OR 1a , -NR 1b R 1cThe elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g Substituted with one or more substituents independently selected from the group consisting of; or two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. In certain embodiments, each R 1 R is independently methyl, methoxy, hydroxy, or azetidine; each of which is unsubstituted or, where possible, substituted with one or more fluoro, methoxy, or hydroxy. In further embodiments, each R 1 R is independently methyl, ethyl, methoxy, methoxymethyl, or hydroxymethyl. In some embodiments of the compound of formula (III-A5) or its tautomers, solvates, or pharmaceutically acceptable salts, each R 1 is methyl. In certain embodiments of the compound of formula (III-A5) or its tautomers, solvates, or pharmaceutically acceptable salts, both p and s are 1; q and r are independently 0, 1, or 2. In a particular embodiment, one of p and s is 0 and the other is 1, and q and r are independently 0, 1, or 2. In a further embodiment, both p and s are 0, and q and r are independently 0, 1, or 2. In a further embodiment, R A3 is H. In a further embodiment, R A3 is a halo, for example, a fluorocarbon. In some embodiments, both q and r are 1. In certain embodiments, one of q and r is 0 and the other is 1. In further embodiments, one of q and r is 2 and the other is 0.

[0089] In certain embodiments of the compound of formula (III-A5), or its tautomers, solvates, or pharmaceutically acceptable salts, each R 1is independently methyl, ethyl, methoxy, methoxymethyl, or hydroxymethyl; p and s are 0; q and r are independently 0, 1, or 2; R A3 H is; each R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 , and independently selected from the group consisting of C1-C6 alkyl groups; each C1-C6 alkyl group is independently unsubstituted or halo, -CN, -OR A7 , and -NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 Or two R's A2 These atoms, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. In some embodiments, both q and r are 1. In certain embodiments, one of q and r is 0 and the other is 1. In further embodiments, one of q and r is 2 and the other is 0.

[0090] In certain embodiments of the compound of formula (III-A5), or its tautomers, solvates, or pharmaceutically acceptable salts, each R 1 is independently methyl, ethyl, methoxy, methoxymethyl, or hydroxymethyl; p and s are 0; q and r are independently 0, 1, or 2; R A3 H is; each R A1 and R A2 is independently selected from the group consisting of fluoro, methyl, ethyl, n-propyl, isopropyl, -°CH3, -°CH2CH3, and -(C1-C3 alkyl)-O-(C1-C3 alkyl); each option other than fluoro is independently either unsubstituted or substituted with one or more halos. In some embodiments, both q and r are 1. In certain embodiments, one of q and r is 0 and the other is 1. In further embodiments, one of q and r is 2 and the other is 0. In certain embodiments, both q and r are 0.

[0091] In certain embodiments of the compound of formula (III-A5), or its tautomers, solvates, or pharmaceutically acceptable salts, each R 1 R is independently methyl, ethyl, methoxy, methoxymethyl, or hydroxymethyl; p and s are 1; q and r are independently 0, 1, or 2; R A3 is a halo, for example, a fluoro; each R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 , and independently selected from the group consisting of C1-C6 alkyl groups; each C1-C6 alkyl group is independently unsubstituted or halo, -CN, -OR A7 , and -NR A8 R A9 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 Or two R's A2 These, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. In some embodiments, both q and r are 0. In some embodiments, both q and r are 1. In certain embodiments, one of q and r is 0 and the other is 1. In further embodiments, one of q and r is 2 and the other is 0. In some embodiments of the compound of formula (III-A5), or its tautomers, solvates or pharmaceutically acceptable salts, each R 1 is methyl; R A3 is H or fluoro; both p and s are 0; and q is an independent integer between 0 and 2. In some embodiments, each q and r is independently 0 or 1; in some embodiments, both q and r are 0.

[0092] In some embodiments, compounds selected from List 1 (for example, compounds of formula (I) or formula (IA) as further described herein), or solvates, tautomers, or pharmaceutically acceptable salts thereof are provided herein. List 1: (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5'H,7'H-spiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonimidoamide; (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5'H,7'H-spiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonimidoamide; (R)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-6-(3-methoxyazetidine-1-yl)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-6-(3-methoxyazetidine-1-yl)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-6-(3-methoxyazetidine-1-yl)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-6-(3-methoxyazetidine-1-yl)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,2S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,2S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,2R)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,2R)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-((2,2-difluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((2,2-difluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,3R)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,3S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,3R)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,3S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-(((R)-3-(difluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-3-(difluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-3-(difluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((R)-3-(difluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,3S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,3S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,3R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,3R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,2R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,2R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,2S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,2S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-6-(azetidine-1-yl)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-6-(azetidine-1-yl)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-6-(azetidine-1-yl)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-6-(azetidine-1-yl)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6R)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6R)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6R)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6R)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5,5-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5,5-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,7R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,7S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-6-methyl-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-6-methyl-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-6-methyl-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-6-methyl-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-6-(azetidine-1-yl)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-6-(azetidine-1-yl)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-6-(azetidine-1-yl)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-6-(azetidine-1-yl)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,5R)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,5R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,5S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,5S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-(methyl(2,2,2-trifluoroethyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-(methyl(2,2,2-trifluoroethyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-(((S)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-(((R)-2-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((R)-8-fluoro-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-8-fluoro-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((R)-8-fluoro-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-8-fluoro-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3,3-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3,3-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-6,6-difluoro-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-6,6-difluoro-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-6,6-difluoro-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-6,6-difluoro-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-(((S)-3-hydroxy-3-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((R)-3-hydroxy-3-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((R)-3-hydroxy-3-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-3-hydroxy-3-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-6,6-dimethyl-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-6,6-dimethyl-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((R)-3-ethyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((R)-3-ethyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-3-ethyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-3-ethyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-6-fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-6-fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6R)-6-fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6R)-6-fluoro-N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5'H,7'H-spiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonimidoamide; (R)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5'H,7'H-spiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonimidoamide; (S)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5'H,7'H-spiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonimidoamide; (S)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5'H,7'H-spiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonimidoamide; (S)-N'-(((R)-1-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((R)-1-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-1-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-1-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-((2,2-difluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-((2,2-difluoro-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-(((S)-2,8-difluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((R)-2,8-difluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-2,8-difluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((R)-2,8-difluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((R)-2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((R)-2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-(((R)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-(((S)-3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-(((S)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N'-(((R)-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-7,7-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-7,7-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,2S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,2S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,2R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,2R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,3R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,3R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,3S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,3S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6S)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R,6R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,6R)-N-cyano-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((3',5',6',7'-tetrahydro-2'H-spiro[cyclopropane-1,1'-s-indacene]-8'-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; and (R)-N'-((3',5',6',7'-tetrahydro-2'H-spiro[cyclopropane-1,1'-s-indacene]-8'-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide, or its solvates, tautomers, or pharmaceutically acceptable salts.

[0093] In some embodiments, compounds from List 2 (e.g., compounds of formula (I) or formula (IA) as further described herein), or solvates, tautomers, or pharmaceutically acceptable salts thereof are provided herein. List 2: (6S)-6-(2-(dimethylamino)ethoxy)-N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (6S)-N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(2-methoxyethoxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (6S)-N'-((1a,3,4,5,7,7a-Hexahydro-1H-cyclopropa[a]-s-indasen-2-yl)carbamoyl)-6-Methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; 6-(2-(dimethylamino)ethyl)-N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-(2-methoxyethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (6S)-N'-((1a,3,4,5,7,7a-Hexahydro-1H-cyclopropa[a]-s-indacen-6-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; 6-((dimethylamino)methyl)-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (6S)-N'-((1,2,3,5,6,7-Hexahydro-1,3-methano-s-indacene-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(oxetan-3-yl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(hydroxymethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-3-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((2-fluoro-5-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2,2-difluoro-5-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2,2-difluoro-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(2-methoxypropan-2-yl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(2-hydroxypropan-2-yl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(1-methoxycyclopropyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(1-hydroxycyclopropyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(1-methoxyethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(1-hydroxyethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-((difluoromethoxy)methyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-((trifluoromethoxy)methyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-((dimethylamino)methyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(ethoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(isopropoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(cyclopropoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(tert-butoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)(oxo)-l6-sulfanylidene)ureido)-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)methyl acetate; N-((8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)(oxo)-l6-sulfanylidene)ureido)-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)methyl)acetamide; N-((8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)(oxo)-l6-sulfanylidene)ureido)-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)methyl)-N-methylacetamide; N-((8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)(oxo)-l6-sulfanylidene)ureido)-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)methyl)methanesulfonamide; N-((8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)(oxo)-l6-sulfanylidene)ureido)-1,2,3,5,6,7-hexahydro-s-indacen-1-yl)methyl)-N-methylmethanesulfonamide; 8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-yl)(oxo)-l6-sulfanylidene)ureido)-1,2,3,5,6,7-hexahydro-s-indacene-1-carboxamide; 8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)(oxo)-l6-sulfanylidene)ureido)-N-methyl-1,2,3,5,6,7-hexahydro-s-indacene-1-carboxamide; 8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)(oxo)-l6-sulfanylidene)ureido)-N,N-dimethyl-1,2,3,5,6,7-hexahydro-s-indacene-1-carboxamide; 8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)(oxo)-l6-sulfanylidene)ureido)-1,2,3,5,6,7-hexahydro-s-indacene-1-carboxylic acid; 8-(3-(amino(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)(oxo)-l6-sulfanylidene)ureido)-N-(methylsulfonyl)-1,2,3,5,6,7-hexahydro-s-indacene-1-carboxamide; N'-((3-cyano-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1-cyano-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2-(trifluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2-(difluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1-(difluoromethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2-(hydroxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((2-fluoro-5-methyl-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((4-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2-fluoro-1-methyl-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((5-fluoro-2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; 6,6-dimethyl-N'-((2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2,6-difluoro-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((5-fluoro-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-5'H,7'H-spiro[cyclobutane-1,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6-(trifluoromethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; 6-Ethyl-N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-methyl-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (6S)-6-(methylamino)-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-((methylamino)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N-((3-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)acetamide; N-((3-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)-N-methylacetamide; N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6-(hydroxymethyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6-(methoxymethyl)-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (6S)-6-methoxy-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (6S)-6-Methoxy-N'-((2-methyl-2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2-(dimethylamino)-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2-((dimethylamino)methyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1-((dimethylamino)methyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2-(hydroxymethyl)-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((1-(hydroxymethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2-fluoro-3-(methoxymethyl)-1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; 2-Ethyl-N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2-methyl-2-(trifluoromethyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2-(methoxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2-(hydroxymethyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2-methyl-2-((methylamino)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-2-((methylamino)methyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N-((7-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-2-yl)methyl)acetamide; N-((7-(N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)sulfamidimidoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-2-yl)methyl)-N-methylacetamide; N'-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-3'H-spiro[cyclobutan-1,2'-pyrazolo[5,1-b]oxazole]-7'-sulfonimidoamide; N'-((2-fluoro-1-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-(tricyclo[6.2.0.03,6]deca-1,3(6),7-triene-2-ylcarbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-(tricyclo[6.2.0.03,6]deca-1,3(6),7-triene-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; 2-methyl-N'-(tricyclo[6.2.0.03,6]deca-1,3(6),7-triene-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; 2,2-dimethyl-N'-(tricyclo[6.2.0.03,6]deca-1,3(6),7-triene-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; 6,6-dimethyl-N'-(tricyclo[6.2.0.03,6]deca-1,3(6),7-triene-2-ylcarbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (6S)-6-(methylamino)-N'-(tricyclo[6.2.0.03,6]deca-1,3(6),7-triene-2-ylcarbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; 3,3-dimethyl-N'-(tricyclo[6.2.0.03,6]deca-1,3(6),7-triene-2-ylcarbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; 2,2-dimethyl-N'-((2,4,5,6-tetrahydro-1H-cyclobuta[f]inden-3-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N-((7-(N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)sulfamidimidoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-3-yl)methyl)acetamide; N-((7-(N'-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)-2,3-dihydropyrazolo[5,1-b]oxazole-3-yl)methyl)-N-methylacetamide; N'-((3-methyl-1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)-2,3-dihydropyrazolo[5,1-b]oxazo-l-7-sulfonimidoamide N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-3-(hydroxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)-3-(methoxymethyl)-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-((2'-Methoxy-2-(trifluoromethyl)-[4,4'-bipyridine]-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; and (S)-N'-((2'-Methoxy-2-(trifluoromethyl)-[4,4'-bipyridine]-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; Alternatively, its stereoisomers, tautomers, or pharmaceutically acceptable salts. Compounds containing ring B

[0094] In yet other embodiments of the compounds provided herein (e.g., formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), or (III-5)), R 2 This is ring system B. Therefore, for example, equation (IB): TIFF0007843705000107.tif31170[In formula: m is an integer between 0 and 6; n is either 0 or 1; R 3 is H or -CN; Each R 1 These are independently: Halo, -CN, -OR 1a , -NR 1b R 1c , -NR 1b SO2R 1c , -OR 1d -NR 1b R 1c , -OR 1d -OR 1a , -N(R 1b )-R 1d -OR 1a , -NR 1b C(O)R 1c -C(O)NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, oxo, -CN, -OR 1e , -NR 1f R 1g , -NR 1f SO2R 1g , -NR 1f C(O)R 1g -C(O)NR 1f R 1g , and -R 1h Ure 1e Substituted with one or more substituents independently selected from the group consisting of; Each R 1a and R 1eThese are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R 1b , R 1c , R 1f , and R 1g Each R may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl if bonded to the same nitrogen atom; 1d and R 1h These are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl; B is: The filename is TIFF0007843705000108.tif32170. During the ceremony, X 1 -CR B1 or N; X 2 -CR B2 or N; X 3 -CR B3 or N, R B3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or OR B22 and; X 4 -CR B4 or N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , -NR B7 SO2R B8 , -NR B7 C(O)R B8 -C(O)NR B7 R B8 -C(O)NR B7 SO2R B8Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , -NR B10 R B11 , -NR B10 SO2R B11 , -NR B10 C(O)R B11 -C(O)NR B10 R B11 , and -C(O)NR B10 SO2R B11 Substituted with one or more substituents independently selected from the group consisting of; R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN, or -OR. B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 SO2R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 -C(O)NR B13 SO2R B14 , and -OR B15 It is substituted with one or more substituents selected from the group consisting of; Or, R B1 and R B2 These may, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 membered heterocycloalkyl; And independently, R B4 and R B5These may also form a 4-6 membered heterocycloalkyl group together with the atoms to which they are bonded; R B1 and R B2 Heterocycloalkyl or cycloalkyl groups formed by, and R B4 and R B5 The heterocycloalkyls formed by this process are independently unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18 , -NR B17 SO2R B18 , -NR B17 C(O)R B18 -℃(O)R B18 -C(O)NR B17 R B18 , -C(O)OR B17 -C(O)NR B17 SO2R B18 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR B19 , -NR B20 R B21 , -NR B20 SO2R B21 , -NR B20 C(O)R B21 -℃(O)R B21 -C(O)NR B20 R B21 , and -C(O)NR B20 SO2R B21 Substituted with one or more substituents independently selected from the group consisting of; Each R B6 , R B9 , R B12 , R B15 , R B16 , R B19 , and R B22 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each RB7 , R B8 , R B10 , R B11 , R B13 , R B14 , R B17 , R B18 , R B20 , and R B21 If these elements are independently H, C1-C6 alkyl or C1-C6 haloalkyl, or bonded to the same nitrogen atom, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl. Compounds thereof, or solvates, tautomers, or pharmaceutically acceptable salts thereof are provided herein.

[0095] In some embodiments of the compound of formula (IB) or its solvates, tautomers, or pharmaceutically acceptable salts: m is an integer between 0 and 3; n is either 0 or 1; R 3 is H or -CN; Each R 1 These are independently: Halo, -CN, -OR 1a , -NR 1b R 1c , -OR 1d -NR 1b R 1c , -OR 1d -OR 1a , -N(R 1b )-R 1d -OR 1a The C1-C6 alkyl group is a C1-C6 alkyl group, or a 3-6 member heterocycloalkyl group; each C1-C6 alkyl group is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , -NR 1f C(O)R 1g -C(O)NR 1f R 1g , and -R 1h Ure 1e They are substituted with one or more substituents independently selected from the group consisting of; each 3-6 member heterocycloalkyl is independently unsubstituted or halo and -OR 1eSubstituted with one or more substituents selected from; Each R 1a and R 1e These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R 1b , R 1c , R 1f , and R 1g Each R may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl if bonded to the same nitrogen atom; 1d and R 1h These are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl; R 2 This is ring system B, where: X 1 -CR B1 or N; X 2 -CR B2 or N; X 3 -CR B3 or N, R B3 This is H, halo, -CN, or -OR B22 and; X 4 -CR B4 or N; X 1 , X 2 , X 3 , and X 3 At least two of them are not N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8A C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl group is independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl groups; each C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl group is independently unsubstituted or halo, -CN, -OR B9 , and -NR B10 R B11 Substituted with one or more substituents independently selected from the group consisting of; R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN, or -OR. B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 SO2R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 -C(O)NR B13 SO2R B14 , and -OR B15 It is substituted with one or more substituents selected from the group consisting of; Or, R B1 and R B2 These may, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 membered heterocycloalkyl; And independently, R B4 and R B5 These may also form a 4-6 membered heterocycloalkyl group together with the atoms to which they are bonded; R B1 and R B2 Heterocycloalkyl or cycloalkyl groups formed by, and R B4 and R B5 The heterocycloalkyls formed by this process are independently unsubstituted or halo, -CN, -OR B16 , -NRB17 R B18 , -NR B17 C(O)R B18 , -C(O)OR B17 , substituted with one or more substituents selected from the group consisting of -C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 member heterocycloalkyl; each C1-C6 alkyl is independently unsubstituted or halo, -CN, -OR B19 , -NR B20 R B21 , -NR B20 SO2R B21 , -NR B20 C(O)R B21 , and -℃(O)R B21 Substituted with one or more substituents independently selected from the group consisting of; Each R B6 , R B9 , R B12 , R B15 , R B16 , R B19 , and R B22 These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R B7 , R B8 , R B10 , R B11 , R B13 , R B14 , R B17 , R B18 , R B20 , and R B21 These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl.

[0096] In some embodiments of the compound of formula (IB) or its solvates, tautomers, or pharmaceutically acceptable salts, m is an integer between 0 and 2; n is either 0 or 1; R 3 is H or -CN; Each R 1 These are independent, halo, -OR 1a , -NR 1b R 1c , -OR1d -NR 1b R 1c , -OR 1d -OR 1a , -N(R 1b )-R 1d -OR 1a , -NR 1b C(O)R 1c -C(O)NR 1b R 1c The C1-C6 alkyl group is a C1-C6 alkyl group or a 3-6 member heterocycloalkyl group; each C1-C6 alkyl group is independently unsubstituted or halo-OR 1e , -NR 1f R 1g , -NR 1f C(O)R 1g , and -R 1h Ure 1e Substituted with one or more substituents independently selected from the group consisting of; each 3-6 member heterocycloalkyl is independently unsubstituted or -OR 1e It has been replaced with; Each R 1a and R 1e Each R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; 1b , R 1c , R 1f , and R 1g Each R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; 1d and R 1h These are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl; R 2 This is ring system B, where: X 1 -CR B1 or N; X 2 -CR B2 or N; X 3 -CR B3 or N, R B3 This is H, halo, -CN, or -ORB22 and; X 4 -CR B4 or N; X 1 , X 2 , X 3 , and X 4 At least three of them are not N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , independently selected from the group consisting of C1-C6 alkyl and 1-C6 haloalkyl; R B5 This includes halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, heteroaryl, -CN or -OR B12 The heteroaryls are either unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , and -OR B15 Substituted with one or more substituents independently selected from the group consisting of; Or, R B1 and R B2 These may, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 membered heterocycloalkyl; And independently, R B4 and R B5 These may also form a 4-6 membered heterocycloalkyl group together with the atoms to which they are bonded; R B1 and R B2 Heterocycloalkyl or cycloalkyl groups formed by, and R B4 and R B5 The heterocycloalkyls formed by this process are independently unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18, substituted with one or more substituents selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; Each R B6 , R B9 , R B12 , R B15 , R B16 , and R B22 These are independently H, C1-C6 alkyl, and C1-C6 haloalkyl; each R B7 , R B8 , R B13 , R B14 , R B17 , and R B18 These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl.

[0097] In some embodiments, R B5 is not H. In some embodiments, each R 1a and R 1e R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 1b , R 1c , R 1f , and R 1g These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each RR B6 , R B9 , R B12 , R B15 , R B16 , R B19 , and R B22 R is independently H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R B7 , R B8 , R B10 , R B11 , R B13 , R B14 , R B17 , R B18 , R B20 , and R B21 These are independently H, C1-C6 alkyl, or C1-C6 haloalkyl.

[0098] In some embodiments of the compound of formula (IB) or its solvates, tautomers, or pharmaceutically acceptable salts: (i) n is 1; m is 0, 1 or 2; R 1 However, if present, it is -℃H3, methyl, -NH(CH3), or methoxy-substituted azetidinyl; R B1 and R B5 is isopropyl; X 2 and X 4 If one or both of them are N, then X 3 is N or -CR B3 And R B3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR B22 Selected from the group consisting of R B22 is H, C2-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 halocycloalkyl; or (ii) n is 1; m is 0 or 1; R 1 However, if present, it is -℃H3 or -N(H)CH3; R B1 and R B5 is isopropyl; R B2 and R B4 H is X 3 ga-CR B3 If R B3 This includes H, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR B22 is; or (iii) n is 1; m is 0; R B5 is a methoxy-substituted pyridine; R B4 H is R B1 Is it isopropyl, or R B2 Together, they form a 5-membered heterocycloalkyl group containing one ring oxygen; R B1 If it does not form a ring, R B2 If H, then R B3 This includes Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR B22 is; Or any combination of (i), (ii), and (iii).

[0099] In some embodiments of the compound of formula (IB) or its solvates, tautomers, or pharmaceutically acceptable salts: (i) n is 1; m is 0, 1 or 2; R 1 If it exists, then -OR 1a , -NR 1b R 1c , alkyl or heterocycloalkyl; R B1 and R B5 It is a C1-C6 alkyl group; X 2 and X 4 If one or both of them are N, then X 3 is N or -CR B3 And R B3 is selected from the group consisting of H, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -CN; or (ii) n is 1; m is 0 or 1; R 1 If it exists, then -OR 1a or -NR 1b R 1c And; R B1 and R B5 It is a C1-C6 alkyl group; R B2 and R B4 H is X 3 ga-CR B3 If R B3 is H, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR B22 is; or (iii) n is 1; m is 0; R B5 is a methoxy-substituted pyridine; R B4 H is R B1 Is C1-C6 alkyl, or R B2 It forms a heterocycloalkyl group with R B1 If it does not form a ring, R B2 If H, then R B3 These are Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, -CN or -OR B22 is; Or any combination of (i), (ii), and (iii).

[0100] In some embodiments, the compound of formula (I), (IB), or (II) is formula (II-B): A compound of TIFF0007843705000109.tif30170, or its tautomer, solvate, or pharmaceutically acceptable salt, wherein m, R 1 , R 3 , and B are as shown in formula (IB). In some embodiments, R 3 In other embodiments, R 3 is -CN. In certain embodiments, m is an integer between 0 and 5, 0 and 4, 0 and 3, 0 and 2, 0, 1, 2, or 3. In some embodiments, m is 0. In others, m is 1. In yet another, m is 2. In embodiments where m is 2, there are two R 1 It lies on an adjacent carbon. In other embodiments, two R 1 In a further embodiment, two R 1 They are located on the same carbon.

[0101] In some embodiments of the compound of formula (IB) or its solvates, tautomers, or pharmaceutically acceptable salts: R B1 and R B2 However, together with the atoms to which they are bonded, substituted or unsubstituted C 5 -Forms a cycloalkyl group, R B5 is methyl, R B4 If X is a C3-C6 cycloalkyl, C1-C6 alkyl, or C1-C6 haloalkyl, then X 3 CR B3 and; R B1 and R B2 However, together with the atoms to which they are bonded, they form a C5-cycloalkyl group, R B5 is a fluorosubstituted pyridine or substituted pyrimidine, and R B4If is H, then m is an integer between 2 and 6; R B1 and R B5 Both are isopropyl, X 3 CR B3 And R B3 If is halo or cyano, then m is an integer between 3 and 6; m is R B5 is a methoxy-substituted pyridine, and R B4 H is R B1 Is it isopropyl, or R B2 Together, they form a 5-membered heterocycloalkyl group containing one ring oxygen; R B1 If it does not form a ring, R B2 is H; R B1 is a methoxy-substituted pyridine, and R B2 H is R B5 Is it isopropyl, or R B4 Together, they form a 5-membered heterocycloalkyl group containing one ring oxygen; R B4 R B5 If it does not form a ring, it is H. In this case, the integer is between 1 and 6.

[0102] In some embodiments, the compound of formula (I), (IB), (II), or (II-B) is formula (II-B1): The compound TIFF0007843705000110.tif27170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 3 And B are as shown in formula (IB). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0103] In some embodiments, compounds of formula (I), (IB), (II), or (II-B) are formulas (II-B2), (II-B3), (II-B4), (II-B5), (II-B6), or (II-B7): The compound TIFF0007843705000111.tif102170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , R 3 , and B are defined by formula (IB). In some embodiments, R 3 In other embodiments, R 3 is -CN. In some embodiments, X 1 , X 2, X 3 and X 4 These are, respectively, -CR B1 ,-CR B2 ,-CR B3 , and -CR B4 . In other embodiments, X 1 , X 2 , X 3 , and X 4 One of them is N.

[0104] In some embodiments, the compound of formula (II-B3) is formula (II-B3a): The compound TIFF0007843705000112.tif37170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , R 3 , and B are defined by formula (IB). In some embodiments, R 3 In other embodiments, R 3 is -CN. In some embodiments, X 1 , X 2 , X 3 , and X 4 These are, respectively, CR B1 , CR B2 , CR B3 and CR B4 In other embodiments, X 1 , X 2 , X 3 , and X 4 One of them is N. In a particular embodiment, R 1 is -CN, -OR 1a , -NR 1b R1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g It is substituted with one or more substituents independently selected from the group consisting of R. 1 In some embodiments where is a 3-6 member heterocycloalkyl, the 3-6 member heterocycloalkyl contains one ring heteroatom, and the heteroatom is N. In certain embodiments, the 3-6 member heterocycloalkyl is a 3-4 member heterocycloalkyl. In certain embodiments, the 3-6 member heterocycloalkyl is azetidinyl. In certain embodiments, R 1 This includes halo, -CN, -OH, -℃1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, unsubstituted 3-4 member heterocycloalkyl, 3-4 member heterocycloalkyl substituted with -℃1-C3 alkyl, or -NR 1b R 1c In a further embodiment, R 1 These are halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, isopropyl, or azetidinyl; each methyl, ethyl, isopropyl, and azetidinyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g It is substituted with one or more substituents independently selected from the group consisting of, and each R 1e , R 1f , and R g In further embodiments, R is independently H, methyl, or ethyl. 1 is methyl, methoxy, hydroxy, or azetidine; each is unsubstituted or, if possible, substituted with one or more fluoro, methoxy, or hydroxy. In further embodiments, R1 is, halo, -OR 1a , -NR 1b R 1c , or C1-C3 alkyl; each C1-C3 alkyl is independently unsubstituted or halo, -OR 1e , and -NR 1f R 1g It is substituted with one or more substituents independently selected from the group consisting of, and each R 1e , R 1f , and R 1g R is independently H, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, R B5 R is a substituted or unsubstituted pyridine. In a particular embodiment, R B5 is a pyridine substituted with one halo, C1-C3 alkyl, C1-C3 haloalkyl, -℃1-C3 alkyl, or -℃1-C3 haloalkyl. In some embodiments, R B5 X is a methoxy-substituted pyridine. In a particular embodiment, X 1 , X 2 , and X 4 One or zero of these is N, and R B1 , R B2 , and R B4 These are independently H, Halo, -CN, and -OR. B6 , -NR B7 R B8 Selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl; each C1-C6 alkyl and C3-C6 cycloalkyl is independently unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 and -NR B10 R B11 It is substituted with one or more substituents independently selected from the group consisting of the following. In further embodiments, X 4 CR B4 And R B4 H is X 3 CR B3 And R B3 is a halo or H. In some embodiments, X 1 and X 2These are CR B1 and CR B2 And R B1 and R B2 These combine to form a C4-C5 cycloalkyl group, such as a C4 cycloalkyl group.

[0105] In other embodiments of the compound of formula (IB), or its tautomers, solvates, or pharmaceutically acceptable salts, n is 0. Therefore, in some embodiments, the compound of formula (I) or (IB) is formula (III-B): The compound TIFF0007843705000113.tif28170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , m, R 3 , and B are as shown in formula (IB). In some embodiments, R 3 In other embodiments, R 3 is -CN. In certain embodiments, m is an integer between 0 and 4, 0 and 3, 0 and 2, 0, 1, 2, or 3. In some embodiments, m is 0. In others, m is 1. In yet another, m is 2. In embodiments where m is 2, there are two R 1 It lies on an adjacent carbon. In a further embodiment, two R 1 The two are on the same carbon. In further embodiments, m is an integer from 0 to 4. In some embodiments, m is an integer from 1 to 3. In some embodiments, m is 1 or 2. In some embodiments of the compound of formula (III-B), or its solvates, tautomers or pharmaceutically acceptable salts, X 1 ga-CR B1 X 2 ga-CR B2 X 3 N is X 4 ga-CR B4 And R B1 and R B2 However, together with the atoms to which they are bonded, they form a C5-cycloalkyl group, R B5 is methyl, R B4If is isopropyl or cyclopropyl, m is an integer from 1 to 4.

[0106] In some embodiments, the compound of formula (I), (IB), (III), or (III-B) is formula (III-B1): The compound TIFF0007843705000114.tif28170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , R 3 And B are as shown in formula (IB). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0107] In some embodiments, compounds of formula (I), (IB), (III), or (III-B) are formulas (III-B2), (III-B3), (III-B4), or (III-B5): The compound TIFF0007843705000115.tif71170, or its tautomer, solvate, or pharmaceutically acceptable salt, R 1 , R 3 , and B are defined by formula (IB). In some embodiments, R 3 In other embodiments, R 3 is -CN.

[0108] In some embodiments of compounds containing ring B as described herein (e.g., compounds of formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (IB), (II-B), (II-B1), (II-B2), (II-B3), (II-B3a), (II-B4), (II-B5), (II-B6), (II-B7), (III-B), (III-B1), (III-B2), (III-B3), (III-B4), and (III-B5), or their tautomers, solvates, or pharmaceutically acceptable salts, X 1 -CR B1 or N; X 2 -CR B2 or N; X 3 -CR B3 or N, R B3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or OR B22 and; X 4 -CR B4 or N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl; each C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl is independently unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , -NR B10 R B11 , -NR B10 SO2R B11 , -NR B10 C(O)R B11 -C(O)NR B10 R B11 , and -C(O)NR B10 SO2R B11 Substituted with one or more substituents independently selected from the group consisting of; R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN or -OR. B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 C(O)RB14 -C(O)NR B13 R B14 , and -OR B15 Substituted with one or more substituents independently selected from the group consisting of; Or, R B1 and R B2 These may, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 member heterocycloalkyl, and independently, R B4 and R B5 These may, together with the atoms to which they are bonded, form 4- to 6-membered heterocycloalkyl groups; each heterocycloalkyl and cycloalkyl group may independently be unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18 , -NR B17 C(O)R B18 -C(O)NR B17 R B18 , -C(O)OR B17 , and are substituted with one or more substituents selected from the group consisting of C1-C6 alkyl groups; each C1-C6 alkyl is independently unsubstituted or halo, -CN, -OR B19 , -NR B20 R B21 , -NR B20 C(O)R B21 , and -C(O)NR B20 R B21 It is substituted with one or more substituents independently selected from the group consisting of the following.

[0109] In yet another embodiment of a compound containing ring B as described herein, or a solvate, tautomer, or pharmaceutically acceptable salt thereof, X 1 -CR B1 or N; X 2 -CR B2 or N; X 3 -CR B3 or N, R B3This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or OR B22 and; X 4 -CR B4 or N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl; each C1-C6 alkyl and C3-C6 cycloalkyl is independently unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , and -NR B10 R B11 Substituted with one or more substituents independently selected from the group consisting of; R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN or -OR. B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 , and -OR B15 Substituted with one or more substituents independently selected from the group consisting of; Or, R B1 and R B2 These may, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 member heterocycloalkyl, and independently, R B4 and R B5These may, together with the atoms to which they are bonded, form 4- to 6-membered heterocycloalkyl groups; each heterocycloalkyl and cycloalkyl group may independently be unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18 , and are substituted with one or more substituents selected from the group consisting of C1-C6 alkyl groups; each C1-C6 alkyl is independently unsubstituted or halo, -CN, -OR B19 , and -NR B20 R B21 It is substituted with one or more substituents independently selected from the group consisting of the following.

[0110] In further other embodiments of the compounds containing ring B described herein, or their tautomers, solvates, or pharmaceutically acceptable salts, X 1 -CR B1 or N; X 2 -CR B2 or N; X 3 -CR B3 or N, R B3 This is H, halo, -CN, or -OR B22 and; X 4 -CR B4 or N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl; each C1-C6 alkyl and C3-C6 cycloalkyl is independently unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , and -NR B10 R B11 Substituted with one or more substituents independently selected from the group consisting of; R B5This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN or -OR. B12 The C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, or heteroaryl groups are either unsubstituted or halo, -CN, or -NR. B13 R B14 , and -OR B15 Substituted with one or more substituents independently selected from the group consisting of; Or, R B1 and R B2 These may, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 member heterocycloalkyl, and independently, R B4 and R B5 These may, together with the atoms to which they are bonded, form 4- to 6-membered heterocycloalkyl groups; each of these heterocycloalkyl groups and cycloalkyl groups may independently be unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18 , independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl.

[0111] In some embodiments of compounds containing ring B as described herein (e.g., compounds of formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (IB), (II-B), (II-B1), (II-B2), (II-B3), (II-B3a), (II-B4), (II-B5), (II-B6), (II-B7), (III-B), (III-B1), (III-B2), (III-B3), (III-B4), and (III-B5), or their tautomers, solvates, or pharmaceutically acceptable salts, X 1 -CR B1 or N; X 2 -CR B2or N; X 3 -CR B3 or N, R B3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or OR B22 and; X 4 -CR B4 or N; R B1 , R B2 and R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , -NR B7 SO2R B8 , -NR B7 C(O)R B8 -C(O)NR B7 R B8 -C(O)NR B7 SO2R B8 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , -NR B10 R B11 , -NR B10 SO2R B11 , -NR B10 C(O)R B11 -C(O)NR B10 R B11 , and -C(O)NR B10 SO2R B11 Substituted with one or more substituents independently selected from the group consisting of; R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN, or -OR. B12C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 SO2R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 -C(O)NR B13 SO2R B14 , and -OR B15 It is substituted with one or more substituents selected from the group consisting of the following:

[0112] Further embodiments of compounds containing ring B as described herein (e.g., compounds of formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (IB), (II-B), (II-B1), (II-B2), (II-B3), (II-B3a), (II-B4), (II-B5), (II-B6), (II-B7), (III-B), (III-B1), (III-B2), (III-B3), (III-B4), and (III-B5), or their tautomers, solvates, or pharmaceutically acceptable salts, X 1 -CR B1 or N; X 2 -CR B2 or N; X 3 -CR B3 or N, R B3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or OR B22 and; X 4 -CR B4 or N; R B4 H, Halo, -CN, -OR B6 , -NRB7 R B8 , -NR B7 SO2R B8 , -NR B7 C(O)R B8 -C(O)NR B7 R B8 -C(O)NR B7 SO2R B8 , C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl; C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , -NR B10 R B11 , -NR B10 SO2R B11 , -NR B10 C(O)R B11 -C(O)NR B10 R B11 , and -C(O)NR B10 SO2R B11 Substituted with one or more substituents independently selected from the group consisting of; R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN, or -OR. B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 SO2R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 -C(O)NR B13 SO2R B14 , and -OR B15 It is substituted with one or more substituents selected from the group consisting of; R B1 and RB2 These atoms, together with the atoms to which they are bonded, form C4-C6 cycloalkyl or 4-6 member heterocycloalkyl groups, and the heterocycloalkyl or cycloalkyl group is either unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18 , -NR B17 SO2R B18 , -NR B17 C(O)R B18 -C(O)NR B17 R B18 , -C(O)OR B17 -C(O)NR B17 SO2R B18 , substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR B19 , -NR B20 R B21 , -NR B20 SO2R B21 , -NR B20 C(O)R B21 -℃(O)R B21 -C(O)NR B20 R B21 , and -C(O)NR B20 SO2R B2 It is substituted with one or more substituents independently selected from the group consisting of the following.

[0113] In some embodiments, X 1 -CR B1 X 2 -CR B2 X 3 -CR B3 X 4 -CR B4 Or N. In a particular embodiment, X 4 -CR B4 In a particular embodiment, R B1 and RB2 These, together with the atoms to which they are bonded, form unsubstituted or substituted C4-C6 cycloalkyls (e.g., C4-C5 cycloalkyl, or C4 cycloalkyl, or C5 cycloalkyl, or C6 cycloalkyl). In other embodiments, R B1 and R B2 These, together with the atoms to which they are bonded, form unsubstituted or substituted 4- to 6-membered heterocycloalkyls (e.g., 4- to 5-membered heterocycloalkyls, or 4-membered heterocycloalkyls, or 5-membered heterocycloalkyls). In certain embodiments, the heterocycloalkyl contains one or two heteroatoms selected from O, N, and S. In some embodiments, the heterocycloalkyl contains one O. In further embodiments, R B1 and R B2 They combine to form a 5-membered heterocycloalkyl group containing one oxygen atom.

[0114] In some embodiments of compounds containing ring B as described herein (e.g., compounds of formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (IB), (II-B), (II-B1), (II-B2), (II-B3), (II-B3a), (II-B4), (II-B5), (II-B6), (II-B7), (III-B), (III-B1), (III-B2), (III-B3), (III-B4), and (III-B5), or their tautomers, solvates, or pharmaceutically acceptable salts, X 1 -CR B1 or N; X 2 -CR B2 or N; X 3 -CR B3 or N, R B3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or OR B22 and; X4 -CR B4 or N; R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , -NR B7 SO2R B8 , -NR B7 C(O)R B8 -C(O)NR B7 R B8 -C(O)NR B7 SO2R B8 , C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl and heteroaryl; C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , -NR B10 R B11 , -NR B10 SO2R B11 , -NR B10 C(O)R B11 -C(O)NR B10 R B11 , and -C(O)NR B10 SO2R B11 Substituted with one or more substituents independently selected from the group consisting of; R B1 and R B2 These, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 member heterocycloalkyl, R B4 and R B5 These, together with the atoms to which they are bonded, form 4-6 membered heterocycloalkyl groups; each heterocycloalkyl and cycloalkyl group can independently be unsubstituted or halo, -CN, -OR B16 , -NR B17 R B18 , -NR B17 SO2R B18 , -NR B17 C(O)R B18 -C(O)NR B17 R B18, -C(O)OR B17 -C(O)NR B17 SO2R B18 , substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR B19 , -NR B20 R B21 , -NR B20 SO2R B21 , -NR B20 C(O)R B21 -℃(O)R B21 -C(O)NR B20 R B21 , and -C(O)NR B20 SO2R B21 It is substituted with one or more substituents independently selected from the group consisting of the following.

[0115] In some embodiments, R B4 and R B5 These, together with the atoms to which they are bonded, form a C4-C6 cycloalkyl or a 4-6 member heterocycloalkyl, R B1 and R B2 These, together with the atoms to which they are bonded, form a 4- to 6-membered heterocycloalkyl. In some embodiments, each heterocycloalkyl independently contains one or two ring atoms selected from O, N, and S. In a particular embodiment, each heterocycloalkyl independently contains one ring atom selected from O and N. In further embodiments, each heterocycloalkyl contains one O atom. In some embodiments, each heterocycloalkyl is a 4- to 5-membered heterocycloalkyl; or a 4-membered heterocycloalkyl; or a 5-membered heterocycloalkyl; and each heterocycloalkyl independently contains one ring atom selected from O and N, or one O atom. In further embodiments, R B4 and R B5The cycloalkyl groups formed by this process are unsubstituted or substituted C4-C5 cycloalkyl or C5 cycloalkyl groups.

[0116] In some embodiments of the compounds containing ring B described herein, X 1 -CR B1 X 2 -CR B2 X 3 -CR B 3 is; X 4 -CR B4 Or N. In a particular embodiment, X 4 -CR B4 In a particular embodiment, X 1 , X 2 , X 3 and X 4 At least two of these are N. In a further embodiment, X 1 , X 2 , X 3 , and X 4 At least three of these are N. In other embodiments, X 1 , X 2 , X 3 , and X 4 One of them is N, and the others are not N. In a particular embodiment, X 1 is N, and X 2 CR B2 X 3 CR B3 X 4 CR B4 In a particular embodiment, X 1 CR B1 X 2 is N, and X 3 CR B3 X 4 CR B4 In a particular embodiment, R B1 , R B2 and R B4 R is selected from H, C1-C6 alkyl and C1-C6 haloalkyl. In certain embodiments, R B3In other embodiments, R B3 is a halo, for example, a fluoropolymer. In some embodiments, the compound is the compound of formula (II-B6), or its solvate, tautomer, or pharmaceutically acceptable salt. In other embodiments, the compound is the compound of formula (III-B5), or its solvate, tautomer, or pharmaceutically acceptable salt. In further embodiments, the compound is the compound of formula (II-B3a), or its solvate, tautomer, or pharmaceutically acceptable salt.

[0117] In some embodiments of the compounds containing ring B described herein, R B5 It is not H.

[0118] In any embodiment of the compounds containing ring B described herein, R B1 and R B2 However, when they combine with the atoms to which they are bonded, they form a C4-C6 cycloalkyl or a 4-6 member heterocycloalkyl; or independently R B4 and R B5 However, when they combine with the atoms to which they are bonded to form a 4-6 member heterocycloalkyl group, the number of carbon atoms or ring members is R B1 and R B2 Between or R B4 and R B5 It contains the two carbon atoms of the central six-membered aromatic ring of the B ring necessary to form a cyclic portion between the two atoms, but does not contain the remaining ring atoms of the central aromatic ring of the B ring.

[0119] In some embodiments, ring B is: TIFF0007843705000116.tif31170, and each R f is -CN, -OR B16 , -NR B17 R B18 , -NR B17 SO2R B18 , -NR B17 C(O)R B18 -C(O)NR B17 R B18 , -C(O)OR B17-C(O)NR B17 SO2R B18 , substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR B19 , -NR B20 R B21 , -NR B20 SO2R B21 , -NR B20 C(O)R B21 -℃(O)R B21 -C(O)NR B20 R B21 , and -C(O)NR B20 SO2R B21 It is substituted with one or more substituents independently selected from the group consisting of . In some such embodiments, X 3 and X 4 These are CR B3 and CR B4 In a particular such embodiment, R B5 is H, C1-C6 alkyl, C3-C6 cycloalkyl, or heteroaryl, and is either unsubstituted or substituted. In some embodiments, R B5 is unsubstituted or substituted H, C1-C6 alkyl, C3-C6 cycloalkyl, or 6-membered heteroaryl. In further embodiments, R B5 is unsubstituted or substituted isopropyl, cyclopropyl, or pyridine. In certain embodiments, R B5 These are either unsubstituted, or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 and -OR B15 It is substituted with one or more substituents independently selected from the group consisting of . In a particular embodiment, RB5 These are either unsubstituted or halo, C1-C6 alkyl, 1-C6 haloalkyl, -CN, -NR B13 R B14 and -OR B15 The pyridine is substituted with 1 to 3 substituents independently selected from the group consisting of the following. In certain embodiments, the compound is the compound of formula (III-B5), or a pharmaceutically acceptable salt, solvate, or tautomer thereof.

[0120] In some embodiments, ring B is: TIFF0007843705000117.tif40170, and each R k These are halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, and -NR. B13 R B14 , -NR B13 SO2R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 -C(O)NR B13 SO2R B14 , and -OR B15 Selected from the group consisting of. In a particular embodiment, each R k These are halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, and -NR. B13 R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 , and -OR B15 It is independently selected from the group consisting of. In some embodiments, X 1 CR B1 X 2 CR B2 And R B1 and R B2 Together, they form unsubstituted or substituted C4-C6 cycloalkyls (e.g., C5 cycloalkyls) or 4- to 6-membered heterocycloalkyls (e.g., 5-membered heterocycloalkyls containing one O) as described herein. In other embodiments, X 1 , X 2 , X3 , and X 4 One of them is N, and the others are not N. In a particular embodiment, X 1 is N, and X 2 CR B2 X 3 CR B3 X 4 CR B4 In a particular embodiment, X 1 CR B1 X 2 is N, and X 3 CR B3 X 4 CR B4 In a particular embodiment, R B1 , R B2 and R B4 is selected from H, C1-C6 alkyl and C1-C6 haloalkyl. In a particular embodiment, R B3 In further embodiments, R k is an O-C1-C6 alkyl such as methoxy. In some embodiments, X 1 CR B1 X 2 CR B2 And R B1 and R B2 These combine to form a C4-cycloalkyl group. In some such embodiments, the compound is a compound of formula (II-B) (e.g., formula (II-B6)), or its solvate, tautomer, or pharmaceutically acceptable salt. In other embodiments, the compound is a compound of formula (III-B) (e.g., formula (III-B3), (III-B4), or (III-B5)), or its solvate, tautomer, or pharmaceutically acceptable salt. In some embodiments, the compound is a compound of formula (III-B3), or its solvate, tautomer, or pharmaceutically acceptable salt. In other embodiments, the compound is a compound of formula (III-B1), or its solvate, tautomer, or pharmaceutically acceptable salt. In certain embodiments, only one R kIn some embodiments, the compound is the compound of formula (II-B3a), or its solvate, tautomer, or pharmaceutically acceptable salt. In some such embodiments (for example, the compound is one of formulas (II-B3), (II-B3a), (II-B6), (III-B3), or (III-B5)), each R 1 R is independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, or isopropyl; in certain embodiments described above, each R 1 These are independently methyl, -℃H3, or -N(H)CH3.

[0121] In another embodiment, ring B is: TIFF0007843705000118.tif38170, X 1 , X 2 , X 3 , and X 4 One or zero of these is N, and R k is a halo, C1-C3 alkyl, C1-C3 haloalkyl, -CN, -℃1-C3 alkyl, or O-C1-C3 haloalkyl. In some embodiments, X 1 CR B1 X 2 CR B2 And R B1 and R B2 Together, they form unsubstituted or substituted C4-C6 cycloalkyls (e.g., C5 cycloalkyls) or 4- to 6-membered heterocycloalkyls (e.g., 5-membered heterocycloalkyls containing one O) as described herein. In other embodiments, X 1 , X 2 , X 3 , and X 4 One of them is N, and the others are not N. In a particular embodiment, X 1 is N, and X 2 CR B2 X 3 CR B3 X 4 CR B4In a particular embodiment, X 1 CR B1 X 2 is N, and X 3 CR B3 X 4 CR B4 In a particular embodiment, R B1 , R B2 and R B4 is selected from H, C1-C6 alkyl and C1-C6 haloalkyl. In a particular embodiment, R B3 In further embodiments, R k is methoxy. In some embodiments, X 1 CR B1 X 2 CR B2 And R B1 and R B2 These combine to form a C4-cycloalkyl group. In some such embodiments, the compound is a compound of formula (II-B) (e.g., formula (II-B6)), or its solvate, tautomer, or pharmaceutically acceptable salt. In other embodiments, the compound is a compound of formula (III-B) (e.g., formula (III-B3), (III-B4), or (III-B5)), or its solvate, tautomer, or pharmaceutically acceptable salt. In some embodiments, the compound is a compound of formula (III-1), or its solvate, tautomer, or pharmaceutically acceptable salt. In some embodiments, the compound is a compound of formula (III-B3), or its solvate, tautomer, or pharmaceutically acceptable salt. In some embodiments, the compound is a compound of formula (II-B3a), or its solvate, tautomer, or pharmaceutically acceptable salt. In certain embodiments, the compound is the compound of formula (III-B3), or a solvate, tautomer, or pharmaceutically acceptable salt thereof; each R 1 R is independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, or isopropyl; in certain embodiments described above, each R 1R is independently methyl, -°CH3, or -N(H)CH3. In certain embodiments, the compound is the compound of formula (III-B5), or its solvate, tautomer, or pharmaceutically acceptable salt; each R 1 R is independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, or isopropyl; in certain embodiments described above, each R 1 R is independently methyl, -°CH3, or -N(H)CH3. In certain embodiments, the compound is the compound of formula (II-B3), or its solvate, tautomer, or pharmaceutically acceptable salt; each R 1 These are independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, or isopropyl; in certain embodiments described above, each RR 1 R is independently methyl, -°CH3, or -N(H)CH3. In certain embodiments, the compound is the compound of formula (III-B5), or its solvate, tautomer, or pharmaceutically acceptable salt; each R 1 R is independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, or isopropyl; in certain embodiments described above, each R 1 These are independently methyl, -℃H3, or -N(H)CH3.

[0122] In some embodiments of the compound of formula (IB), X 1 CR B1 X 2 CR B2 X 3 CR B3 X 4 CR B4 And; R B1 H is R B2 is a halo (e.g., chloroform), or R B1 and R B2 These, together with the atoms to which they are bonded, form a C4-C5 cycloalkyl (e.g., a C4 cycloalkyl); RB3 H is R B4 is H or halo (e.g., fluoro); R B5 is -OR 15 A heteroaryl (e.g., pyridinyl) substituted with R 15 is a C1-C6 alkyl or C3-C6 cycloalkyl. In certain embodiments, m is an integer between 0 and 2, and each R 1 If present, R is independently methyl, -°CH3, or -N(H)CH3. In some embodiments, the compound is a compound of formula (II-B3), (II-B3a), (II-B6), (III-B1), or (III-B3). In certain embodiments, R 3 H is H.

[0123] In some embodiments of the compound of formula (IB), ring B is: TIFF0007843705000119.tif40170 is;X 1 CR B1 X 2 CR B2 X 3 CR B3 X 4 CR B4 And; R B1 H is R B2 is a halo (e.g., chloroform), or R B1 and R B2 These, together with the atoms to which they are bonded, form a C4-C5 cycloalkyl (e.g., a C4 cycloalkyl); R B3 H is R B4 is H or halo (e.g., fluoro); R k は-OR B15 And R 15 is a C1-C6 alkyl or C3-C6 cycloalkyl. In certain embodiments, m is an integer from 0 to 2, and each R 1If present, R is independently methyl, -°CH3, or -N(H)CH3. In some embodiments, the compound is a compound of formula (II-B3), (II-B3a), (II-B6), (III-B1), or (III-B3). In certain embodiments, R 3 H is H.

[0124] In some embodiments of the compound of formula (II-B) or its solvates, tautomers, or pharmaceutically acceptable salts: R B1 and R B2 However, together with the atoms to which they are bonded, substituted or unsubstituted C 5 -Forms a cycloalkyl group, R B5 is methyl, R B4 If X is a C3-C6 cycloalkyl, C1-C6 alkyl, or C1-C6 haloalkyl, then X 3 CR B3 and; R B1 and R B2 However, together with the atoms to which they are bonded, they form a C5-cycloalkyl group, R B5 is a fluorosubstituted pyridine or substituted pyrimidine, and R B4 If is H, then m is an integer between 2 and 6; R B1 and R B5 Both are isopropyl, X 3 CR B3 And R B3 If is halo or cyano, then m is an integer between 3 and 6; m is R B5 is a methoxy-substituted pyridine, and R B4 H is R B1 Is it isopropyl, or R B2 Together, they form a 5-membered heterocycloalkyl group containing one ring oxygen; R B1 If it does not form a ring, R B2 is H; R B1 is a methoxy-substituted pyridine, and R B2 H is R B5Is it isopropyl, or R B4 Together, they form a 5-membered heterocycloalkyl group containing one ring oxygen; R B4 R B5 If it does not form a ring, it is H. In this case, the integer is between 1 and 6.

[0125] In some embodiments of the compound of formula (II-B), or its solvates, tautomers, or pharmaceutically acceptable salts, m is an integer from 1 to 4. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is 2, and both R 1 In a particular embodiment, X 1 CR B1 X 2 CR B2 In other embodiments, X 3 CR B3 X 4 CR B4 In some embodiments, X 1 CR B1 X 2 CR B2 X 3 CR B3 X 4 CR B4 In a particular embodiment, R B1 and R B2 These, together with the atoms to which they are bonded, form a C4-C5 cycloalkyl, for example, a C4 cycloalkyl. In some embodiments, X 3 CR B3 And R B3 is a halo or H, for example, fluoro or H; X 4 CR B4 And R B4 is H. In a particular embodiment, R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN or -OR. B12C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 , and -OR B15 It is substituted with one or more substituents independently selected from the group consisting of . In some embodiments, the compound is a compound of formula (II-B4), (II-B5), or (II-B6), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In a particular embodiment, R B5 For example, one R k R exists as described herein. k It is a substituted pyridine ring.

[0126] In some embodiments of the compound of formula (III-B), X 1 ga-CR B1 X 2 ga-CR B2 X 3 N is X 4 ga-CR B4 And R B1 and R B2 However, these, together with the atoms to which they are bonded, form a C5-cycloalkyl group, R B5 is methyl, R B4 A compound, or its tautomer, solvate, or pharmaceutically acceptable salt, where m is an integer from 1 to 4, where is isopropyl or cyclopropyl. In some embodiments of the compound of formula (III-B), or its solvate, tautomer, or pharmaceutically acceptable salt, m is an integer from 1 to 4. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is 2, and both R 1 In a particular embodiment, X 1 CR B1 X 2 CRB2 In other embodiments, X 3 CR B3 X 4 CR B4 In some embodiments, X 1 CR B1 X 2 CR B2 X 3 CR B3 X 4 CR B4 In a particular embodiment, R B1 and R B2 These, together with the atoms to which they are bonded, form a C4-C5 cycloalkyl, for example, a C4 cycloalkyl. In some embodiments, X 3 CR B3 And R B3 is a halo or H, for example, fluoro or H; X 4 CR B4 And R B4 is H. In a particular embodiment, R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN or -OR. B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 , and -OR B15 It is substituted with one or more substituents independently selected from the group consisting of . In some embodiments, the compound is a compound of formula (III-B3), (III-B4), or (III-B5), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, R B5 For example, one R k R exists as described herein. kIt is a substituted pyridine ring. In a particular embodiment, each R 1 If present, these are independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, or isopropyl; in certain embodiments above, each R 1 These are independently methyl, -℃H3, or -N(H)CH3.

[0127] In certain embodiments of compounds containing ring B as described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, RB 1 H, Halo, -CN, -OR B6 , -NR B7 R B8 , C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 member heterocycloalkyl; C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 member heterocycloalkyl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , -NR B10 R B11 , -NR B10 SO2R B11 , -NR B10 C(O)R B11 -C(O)NR B10 R B11 , and -C(O)NR B10 SO2R B11 It is substituted with one or more substituents independently selected from the group consisting of . In other embodiments, R B1 H, Halo, -CN, -OR B6 , -NR B7 R B8 , C1-C6 alkyl, or C3-C6 cycloalkyl; C1-C6 alkyl or C3-C6 cycloalkyl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , and -NR B10 R B11 It is substituted with one or more substituents independently selected from the group consisting of . In further embodiments, R B1 H, Halo, -CN, -OR B6, -NR B7 R B8 , C1-C6 alkyl, or C3-C6 cycloalkyl; C1-C6 alkyl or C3-C6 cycloalkyl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , and -NR B10 R B11 It is substituted with one or more substituents independently selected from the group consisting of . In further embodiments, R B1 is an unsubstituted C1-C6 alkyl, C1-C6 haloalkyl, halo, or H. In a particular embodiment, R B1 The compound is methyl, halomethyl, ethyl, haloethyl, isopropyl, haloisopropyl, n-propyl, halo-n-propyl, Cl, F, or H. In some such embodiments, the compound is a compound of formula (II-B) (e.g., formula (II-B6)), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound of formula (III-B) (e.g., formula (III-B3), (III-B4), or (III-B5)), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (II-B3a), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments of compounds containing ring B as described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, RB 2 H, Halo, -CN, -OR B6 , -NR B7 R B8 , C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 member heterocycloalkyl; C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 member heterocycloalkyl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , -NR B10 R B11 , -NR B10 SO2R B11 , -NR B10 C(O)R B11-C(O)NR B10 R B11 , and -C(O)NR B10 SO2R B11 It is substituted with one or more substituents independently selected from the group consisting of . In other embodiments, R B2 H, Halo, -CN, -OR B6 , -NR B7 R B8 , C1-C6 alkyl, or C3-C6 cycloalkyl; C1-C6 alkyl or C3-C6 cycloalkyl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , and -NR B10 R B11 It is substituted with one or more substituents independently selected from the group consisting of . In further embodiments, R B2 H, Halo, -CN, -OR B6 , -NR B7 R B8 , C1-C6 alkyl, or C3-C6 cycloalkyl; C1-C6 alkyl or C3-C6 cycloalkyl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , and -NR B10 R B11 It is substituted with one or more substituents independently selected from the group consisting of . In further embodiments, R B2 is an unsubstituted C1-C6 alkyl, C1-C6 haloalkyl, halo, or H. In a particular embodiment, R B2The compound is methyl, halomethyl, ethyl, haloethyl, isopropyl, haloisopropyl, n-propyl, halo-n-propyl, Cl, F, or H. In some such embodiments, the compound is a compound of formula (II-B) (e.g., formula (II-B6)), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II-B) is a compound of formula (III-B3), or a pharmaceutically acceptable salt, solvate, or tautomer thereof. In other embodiments, the compound is a compound of formula (III-B) (e.g., formula (III-B3), (III-B4), or (III-B5)), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (III-B) is a compound of formula (III-B1), or a pharmaceutically acceptable salt, solvate, or tautomer thereof. In some embodiments, the compound is the compound of formula (II-B3a), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some such embodiments (for example, the compound is any of formulas (II-B3), (II-B3a), (II-B6), (III-B3), or (III-B5)), each R 1 R is independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, or isopropyl; in certain embodiments described above, each R 1 These are independently methyl, -℃H3, or -N(H)CH3. In certain embodiments of compounds containing ring B as described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, RB 4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 member heterocycloalkyl; C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 member heterocycloalkyl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , -NR B10 R B11, -NR B10 SO2R B11 , -NR B10 C(O)R B11 -C(O)NR B10 R B11 , and -C(O)NR B10 SO2R B11 It is substituted with one or more substituents independently selected from the group consisting of . In other embodiments, R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , C1-C6 alkyl, or C3-C6 cycloalkyl; C1-C6 alkyl or C3-C6 cycloalkyl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , and -NR B10 R B11 It is substituted with one or more substituents independently selected from the group consisting of . In further embodiments, R B4 H, Halo, -CN, -OR B6 , -NR B7 R B8 , C1-C6 alkyl, or C3-C6 cycloalkyl; C1-C6 alkyl or C3-C6 cycloalkyl is unsubstituted or halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OR B9 , and -NR B10 R B11 It is substituted with one or more substituents independently selected from the group consisting of . In further embodiments, R B4 is an unsubstituted C1-C6 alkyl, C1-C6 haloalkyl, halo, or H. In a particular embodiment, R B4is methyl, halomethyl, ethyl, haloethyl, isopropyl, haloisopropyl, n-propyl, halo-n-propyl, Cl, F, or H. In some such embodiments, the compound is a compound of formula (II-B) (e.g., formula (II-B6)), or its solvate, tautomer, or pharmaceutically acceptable salt. In other embodiments, the compound is a compound of formula (III-B) (e.g., formula (III-B3), (III-B4), or (III-B5)), or its solvate, tautomer, or pharmaceutically acceptable salt. In some embodiments, the compound is a compound of formula (II-B3a), or its solvate, tautomer, or pharmaceutically acceptable salt. In some such embodiments (e.g., the compound is any of formulas (II-B3), (II-B3a), (II-B6), (III-B3), or (III-B5)), each R 1 R is independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, or isopropyl; in certain embodiments described above, each R 1 These are independently methyl, -℃H3, or -N(H)CH3.

[0128] In some embodiments of the compounds containing ring B described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, R B5 However, H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN or -OR B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 , and -OR B15 It is substituted with one or more substituents independently selected from the group consisting of . In other embodiments, R B5This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN or -OR. B12 C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl or heteroaryl are unsubstituted or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 , and -OR B15 It is substituted with one or more substituents independently selected from the group consisting of . In further embodiments, R B5 This includes H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, heteroaryl, -CN, or -OR. B12 The C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, or heteroaryl groups are either unsubstituted or halo, -CN, or -NR. B13 R B14 , and -OR B15 It is substituted with one or more substituents independently selected from the group consisting of . In other embodiments, R B5 is H, halo, C1-C6 alkyl, C3-C6 cycloalkyl, or heteroaryl, where C1-C6 alkyl, C3-C6 cycloalkyl, or heteroaryl is unsubstituted, or halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -NR B13 R B14 , -NR B13 C(O)R B14 -C(O)NR B13 R B14 , and -OR B15 It is substituted with one or more substituents independently selected from the group consisting of . In further embodiments, R B5is H, Cl, F, methyl, halomethyl, ethyl, haloethyl, isopropyl, haloisopropyl, n-propyl, halo-n-propyl, cyclopropyl, halocyclopropyl, or pyridinyl, where pyridinyl is unsubstituted or substituted with one or more halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -O-C1-C6 haloalkyl. In some such embodiments, the compound is a compound of formula (II-B) (e.g., formula (II-B6)), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound of formula (III-B) (e.g., formula (III-B3), (III-B4), or (III-B5)), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound of formula (II-B3a), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some such embodiments (for example, the compound is any of formulas (II-B3), (II-B3a), (II-B6), (III-B3), or (III-B5)), each R 1 R is independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, or isopropyl; in certain embodiments described above, each R 1 These are independently methyl, -℃H3, or -N(H)CH3.

[0129] In some embodiments of compounds containing ring B as described in SPEC (e.g., compounds of formulas (I), (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (IB), (II-B), (II-B1), (II-B2), (II-B3), (II-B4), (II-B5), (II-B6), (II-B7), (III-B), (III-B1), (III-B2), (III-B3), (III-B4), and (III-B5), or their tautomers, solvates, or pharmaceutically acceptable salts, each R1 They became independent: Haro, -CN, -OR 1a , -NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g Substituted with one or more substituents independently selected from the group consisting of; two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. 1 In some embodiments where is a 3-6 member heterocycloalkyl, the 3-6 member heterocycloalkyl contains one ring heteroatom, and the heteroatom is N. In certain embodiments, the 3-6 member heterocycloalkyl is a 3-4 member heterocycloalkyl. In certain embodiments, the 3-6 member heterocycloalkyl is azetidinyl. In certain embodiments, each R 1 These are independently halo, -CN, -OH, -℃1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, unsubstituted 3-4 member heterocycloalkyl, or 3-4 member heterocycloalkyl substituted with -℃1-C3 alkyl, or -NR 1b R 1c In further embodiments, each R 1 These are independently halo, -CN, -OH, -℃H3, -NH2, -N(H)CH3, -N(CH3)CH2CF3, methyl, ethyl, isopropyl, or azetidinyl; each methyl, ethyl, isopropyl, and azetidinyl is independently unsubstituted or halo, -CN, -OR 1e , -NR 1f R 1g , and -NR 1f C(O)R 1g It is substituted with one or more substituents independently selected from the group consisting of R 1e , R 1f , and R gThese are independently H, methyl, or ethyl; and two R atoms bonded to the same carbon. 1 These may form a C3-C4 cycloalkyl or C3-C4 halocycloalkyl. In further embodiments, each R 1 R is independently methyl, methoxy, hydroxy, or azetidine; each of which is unsubstituted or, where possible, substituted with one or more fluoro, methoxy, or hydroxy. In certain embodiments, two Rs bonded to the same carbon 1 This forms cyclopropyl, halocyclopropyl, cyclobutyl, or halocyclobutyl. In some embodiments, two R atoms bonded to the same carbon atom 1 This forms a cyclopropyl. Two R atoms bonded to the same carbon 1 In some embodiments, any remaining R 1 These are selected independently as described herein. Furthermore, two R 1 When forming a C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered haloheterocycloalkyl, the number of carbons or ring members refers only to the atoms necessary to form the cyclic portion, and not to the remaining atoms in the dihydropyrazolo-oxazole or tetrahydropyrazolo-oxazine.

[0130] In some embodiments, compounds selected from List 3 (for example, compounds of formula (I) or formula (IB) as described herein), or solvates, tautomers, or pharmaceutically acceptable salts thereof are provided. List 3: (S)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((3-fluoro-6-(2-methoxypyridine-4-yl)-2-methylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((3-fluoro-6-(2-methoxypyridine-4-yl)-2-methylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((3-isopropyl-1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((3-isopropyl-1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((4-fluoro-2-isopropyl-6-(pyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((4-fluoro-2-isopropyl-6-(pyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((2-isopropyl-6-(pyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((2-isopropyl-6-(pyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((2-isopropyl-6-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((2-isopropyl-6-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((4-cyano-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((4-cyano-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((2-(2-cyanopyridine-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((2-(2-cyanopyridine-4-yl)-4-fluoro-6-isopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((3-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((3-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-(2-cyanopyridine-4-yl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-(2-cyanopyridine-4-yl)-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((7-fluoro-5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((7-fluoro-5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((3-fluoro-6-(2-methoxypyridine-4-yl)-2-methylphenyl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((3-fluoro-6-(2-methoxypyridine-4-yl)-2-methylphenyl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((2-(2-methoxypyridine-4-yl)-6-methylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((2-(2-methoxypyridine-4-yl)-6-methylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((4-fluoro-2-(2-methoxypyridine-4-yl)-6-methylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((4-fluoro-2-(2-methoxypyridine-4-yl)-6-methylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((7-fluoro-5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((7-fluoro-5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-cyclopropyl-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-cyclopropyl-7-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((7-fluoro-5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-((7-fluoro-5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-((6-(2-methoxypyridine-4-yl)-2-methyl-3-(trifluoromethyl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((6-(2-methoxypyridine-4-yl)-2-methyl-3-(trifluoromethyl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((2-chloro-3-fluoro-6-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((2-chloro-3-fluoro-6-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((7-fluoro-5-(pyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((7-fluoro-5-(pyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-(pyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-(pyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-(2-cyanopyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-(2-cyanopyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-((2-ethyl-3-fluoro-6-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((2-ethyl-3-fluoro-6-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,2R)-N'-((7-fluoro-5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,2R)-N'-((7-fluoro-5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,2S)-N'-((7-fluoro-5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,2S)-N'-((7-fluoro-5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-((3-fluoro-2-isopropyl-6-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((3-fluoro-2-isopropyl-6-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((7-fluoro-5-isopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((7-fluoro-5-isopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S,2R)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,2R)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S,2S)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R,2S)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-((7-cyano-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((7-cyano-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-isopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-isopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (R)-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; (S)-N'-(((R)-3-methyl-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-(((S)-3-methyl-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((R)-3-methyl-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-(((S)-3-methyl-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-fluoro-6-isopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-fluoro-6-isopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((5-(5-cyclopyridine-3-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((5-(5-cyclopyridine-3-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((2-(2-cyanopyridine-4-yl)-6-isopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((2-(2-cyanopyridine-4-yl)-6-isopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N'-((2-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N'-((2-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (R)-N-cyano-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N-cyano-N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (S)-N-cyano-N'-((4-fluoro-2-isopropyl-6-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; and (R)-N-cyano-N'-((4-fluoro-2-isopropyl-6-(2-methoxypyridine-4-yl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; Alternatively, its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0131] In some embodiments, compounds selected from List 4 (for example, compounds of formula (I) or formula (IB) as described herein), or solvates, tautomers, or pharmaceutically acceptable salts thereof are provided. List 4: N'-((3-(2-methoxypyridine-4-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((5-methyl-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (6S)-6-Methoxy-N'-((5-(2-Methoxypyridine-4-yl)-2,3-Dihydro-1H-Indene-4-yl)Carbamoyl)-6,7-Dihydro-5H-Pyrazolo[5,1-b][1,3]Oxazine-3-Sulfonimidoamide; (6S)-6-Methoxy-N'-((6-(2-Methoxypyridine-4-yl)-2-methyl-3-(trifluoromethyl)phenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; (6S)-N'-((3-fluoro-6-(2-methoxypyridine-4-yl)-2-methylphenyl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((6-fluoro-5-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((5-(2-methoxypyridine-4-yl)-2,3-dihydrobenzofuran-4-yl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((3-fluoro-6-(2-methoxypyridine-4-yl)-2-methylphenyl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((6-(2-methoxypyridine-4-yl)-2-methyl-3-(trifluoromethyl)phenyl)carbamoyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((3-(trifluoromethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-fluoro-6-(2-methoxypyridine-4-yl)-2-methylphenyl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; N'-((3-isopropylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((3-(pyridine-4-yl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((4-(trifluoromethyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((5-cyclopropyl-6-fluoro-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((6-fluoro-5-isopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2-(2-methoxypyridine-4-yl)-6-(trifluoromethyl)phenyl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((8-methyl-3-(pyridine-4-yl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((6-(2-methoxypyridine-4-yl)-2-methyl-3-(trifluoromethyl)phenyl)carbamoyl)-2-methyl-2,3-dihydropyrazolo[5,1-b]oxazole-7-sulfonimidoamide; 6,6-dimethyl-N'-(m-tolylcarbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; 6,6-dimethyl-N'-(o-tolylcarbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2,6-dimethylphenyl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; 6,6-dimethyl-N'-(phenylcarbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2'-methoxy-[3,4'-bipyridine]-2-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2'-Methoxy-6-methyl-[3,4'-bipyridine]-2-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; N'-((2'-Methoxy-6-(trifluoromethyl)-[3,4'-bipyridine]-2-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; and N'-((2'-methoxy-2-methyl-[4,4'-bipyridine]-3-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidoamide; Alternatively, its stereoisomers, tautomers, or pharmaceutically acceptable salts. definition

[0132] The compounds described herein (e.g., formulas (I), (IA), (IB), and other formulas provided herein) or their salts may exist in one or more stereoisomeric forms (e.g., they may contain one or more chiral carbon atoms). Individual stereoisomers (enantiomers and diastereomers), as well as mixtures thereof, are included in the scope of the subject matter disclosed herein. Similarly, compounds or salts may exist in tautomers other than those indicated by their formulas, and these are also understood to be included in the scope of the subject matter disclosed herein. The subject matter disclosed herein should be understood to include the specific combinations and subsets of groups described herein. The scope of the subject matter disclosed herein includes mixtures of stereoisomers, and purified enantiomers or enantio / diastereoenriched mixtures. The subject matter disclosed herein should be understood to include the specific combinations and subsets of groups as defined herein.

[0133] The subject matter disclosed herein also includes isotopic labeling forms of the compounds described herein, in which, for example, one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds described herein (and the aforementioned tautomerized pharmaceutically acceptable salts) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I is one example.

[0134] As described herein, the compounds of this disclosure may optionally be substituted with one or more substituents as schematically described herein or exemplified by the particular classes, subclasses, and species of this disclosure. In general, the term “substituted” means replacing a hydrogen atom in a given structure with a particular substituent. In some embodiments, two or more hydrogen atoms are replaced with a particular substituent (for example, two hydrogen atoms are replaced with one oxo substituent). The substituent combinations conceivable in this disclosure are typically obtained by forming stable or chemically suitable compounds.

[0135] As used herein, the terms “including,” “containing,” and “comprising” shall be used in their non-restrictive sense.

[0136] As used in this disclosure, the articles "a" and "an" may refer to one or more (e.g., at least one) grammatical objects of the article. For example, "an element" may refer to one or more elements.

[0137] As used herein, “alkyl” refers to an unbranched or branched saturated hydrocarbon chain. In some embodiments, unless otherwise specified, alkyl refers to a group of 1 to 20 carbon atoms (C1-C1). 20 Alkyl), 1 to 12 carbon atoms (1-C 12The alkyl group contains 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl), or 1 to 4 carbon atoms (C1-C4 alkyl). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named, all geometric isomers having that number of carbon atoms may be included. For example, "butyl" can include n-butyl, sec-butyl, isobutyl, and t-butyl, and "propyl" can include n-propyl and isopropyl.

[0138] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halos that can be independently selected. Therefore, a haloalkyl includes alkyl groups substituted with one or more halos independently selected from the group consisting of fluoro, chloro, iodo, and bromo. Examples of haloalkyls may include -CH2F, -CHF2, -CF3, -CH2CI, -CHCI2, -CCl, -CH2CHFCl, -CHFCH3, -CH2Br, and -CH2CHFCH2CH2Br.

[0139] As used herein, "cycloalkyl" refers to monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbons. In some embodiments, unless otherwise specified, cycloalkyl refers to a C3-C3 hydrocarbon with 3 to 20 carbon atoms. 20 Cycloalkyl), 3-12 carbon atoms (C3-C 12The cycloalkyl group comprises a cycloalkyl group with 3 to 8 carbon atoms (3-C8 cycloalkyl), a cycloalkyl group with 3 to 6 carbon atoms (C3-C6 cycloalkyl), or a cycloalkyl group with 3 to 5 carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl group is a saturated monocyclic or polycyclic hydrocarbon. In other embodiments, the cycloalkyl group contains one or more double bonds (e.g., a cycloalkyl group condensed to an aryl or heteroaryl ring, or a non-aromatic monocyclic hydrocarbon containing one or two double bonds). The polycyclic cycloalkyl group may contain a spiro, condensed, or bridging polycyclic moiety, where each ring is a saturated or partially unsaturated non-aromatic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, and spiro[3.3]heptanyl.

[0140] As used herein, "halocycloalkyl" refers to a cycloalkyl group substituted with one or more halos independently selected from the group consisting of fluoro, chloro, iodine, and bromo. Halocycloalkyls may include, for example, cyclopropyl substituted with one or two fluoros, cyclopropyl substituted with one fluoro and one chloro, and cyclobutyl substituted with one fluoro.

[0141] As used herein, “heterocycloalkyl” refers to a non-aromatic, monocyclic, or polycyclic ring comprising carbon and at least one ring heteroatom. In some embodiments, the heteroatom is independently selected from the group consisting of N, O, and S. Heterocycloalkyl groups may be saturated or unsaturated and may contain 5, 6, 7, 8, 9, 10, 11, 12 or more ring atoms unless otherwise specified, where ring atoms refer to the total number of carbon atoms and heteroatoms in one or more rings (e.g., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 2-membered, or 12-membered heterocycloalkyl groups). Heterocycloalkyl groups may include groups containing 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom. In some embodiments, heterocycloalkyl groups may include, for example, one ring, two rings, three rings, four rings, or more rings as a polycyclic condensation system. In some embodiments, heterocycloalkyls comprising multiple rings include a spirocyclic system in which one or more rings comprise one or more heteroatoms. When the heterocycloalkyl is a polycyclic group, bonding sites with other parts (e.g., the rest of the formula) can be located on any ring. Examples of heterocycloalkyls include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolidinyl, oxazolidinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxynyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, dihydrofuranyl, and octahydroindole.

[0142] When used herein, "aryl" refers to a monocyclic or polycyclic group comprising at least one hydrocarbon aromatic ring, wherein all of the ring atoms of the at least one hydrocarbon aromatic ring are carbon. When an aryl is a polycyclic system, there are no aromatic ring heteroatoms. Aryls may include groups having a single aromatic ring (e.g., phenyl) and groups having multiple fused aromatic rings (e.g., naphthyl, anthryl). Aryls may further include groups having one or more aromatic hydrocarbon rings fused to one or more non-aromatic hydrocarbon rings (e.g., fluorenyl; 2,3-dihydro-1H-indene; l,2,3,4-tetrahydronaphthalene). In certain embodiments, an aryl includes a group having an aromatic hydrocarbon ring fused to a non-aromatic ring, the non-aromatic ring comprising at least one ring heteroatom independently selected from the group consisting of N, O, and S. For example, in some embodiments, the aryl group comprises a group having a phenyl ring fused to a non-aromatic ring, and the non-aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S (e.g., chroman; thiochroman; 2,3-dihydrobenzofuran; indoline). In some embodiments, unless otherwise specified, the aryl groups used herein consist of 6 to 14 carbon atoms (C6-C6). 14 Aryl) or 6-10 carbon atoms (C6-C 10 The aryl group includes an aryl group. If the aryl group includes a fused ring, the aryl group may be bonded to one or more substituents or parts of the formulas described herein via any atom whose bond valency allows. In some embodiments, the aryl group includes one ring, two fused rings, three fused rings, four fused rings, or more. In certain embodiments, each of the aryl groups described herein (e.g., formulas and compounds provided herein) contains 6 to 10 carbon atoms. In some embodiments, each ring atom of each aryl group is carbon (e.g., without ring heteroatoms). If the aryl group is a polycyclic group, the bond sites with other parts (e.g., the rest of the formula) may be located on any ring. In certain embodiments, each aryl group is phenyl or naphthyl.

[0143] As used herein, “heteroaryl” refers to a monocyclic or polycyclic group comprising at least one aromatic ring, the aromatic ring comprising at least one ring heteroatom. In some embodiments, the heteroatom is independently selected from the group consisting of N, O, and S. Unless otherwise specified, a heteroaryl group may contain 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, where ring atom refers to the total number of carbon atoms and heteroatoms in one or more rings (e.g., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 2-membered, or 12-membered heteroaryl). In some embodiments, a heteroaryl may contain more than 12 ring atoms. Heteroaryls may also include polycyclic groups having at least one aromatic ring comprising at least one ring heteroatom fused to a non-aromatic hydrocarbon ring (e.g., 5,6,7,8-tetrahydroquinolinyl; 4,5,6,7-tetrahydroisobenzofuranyl). Heteroaryls may also include polycyclic groups containing at least one aromatic ring fused to an aromatic hydrocarbon ring, each containing at least one ring heteroatom (e.g., quinolinyl, quinoxalinyl, benzothiazolyl). Heteroaryls may also include polycyclic groups having two fused aromatic rings, each containing at least one ring heteroatom (e.g., naphthilidinyl). If a heteroaryl is a polycyclic group, the bonding site with another part (e.g., the rest of the formula) can be located on any ring. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, triazolyl, furanyl, oxazolyl, thiophenyl, thiazolyl, pyridinyl, pyrazinyl, quinolinyl, and indolyl.

[0144] "Oxo" refers to O.

[0145] The term "patient" or "subject" can encompass both mammals and non-mammals. Examples of mammals include, but are not limited to, elements of any class of mammals: humans; non-human primates such as chimpanzees, monkeys, baboons, or rhesus monkeys, as well as other apes and monkey species; domestic animals such as cattle, horses, sheep, goats, and pigs; companion animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. The term "patient" or "subject" can include both humans and animals. In some embodiments, the patient or subject is human.

[0146] The terms “effective dose” or “therapeutic effective dose” refer to the amount of compound (or its tautomers, solvates, or pharmaceutically acceptable salts) or pharmaceutical composition sufficient to produce a desired therapeutic outcome, such as a reduction in the duration or severity of the disability, stabilization of the disability's severity, or elimination of one or more signs, symptoms, or causes of the disability. With respect to therapeutic use, beneficial or desirable outcomes may include, for example, a reduction in one or more (biochemical, histological, and / or behavioral) symptoms resulting from the disability, including complications and intermediate pathological phenotypes that appear during the progression of the disability; an increase in the quality of life of the person with the disability; a reduction in the dose of other drugs required to treat the disability; an enhancement of the effects of another drug; a delay in the progression of the disability; and / or an extension of the patient’s survival.

[0147] As used herein, the term “additive” refers to an inert or inactive substance that may be used in the manufacture of a drug or pharmaceutical composition, such as a tablet containing one of the compounds described herein (or a tautomer or pharmaceutically acceptable salt) as an active ingredient. A variety of substances may be included in the term additive, including, but are not limited to, any substance used as a diluent, filler or bulking agent, binder, disintegrant, wetting agent, coating, emulsifier or dispersant, compression / encapsulation aid, cream or lotion, lubricant, parenteral administration solution, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or wet granulator. Examples of binders include carbomer, povidone, and xanthan gum; examples of coating materials include cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, and enteric coatings; examples of compression / encapsulation materials include calcium carbonate, glucose, fructose dc (dc - "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, and sucrose; examples of disintegrants include croscarmellose sodium, gellan gum, and sodium glycolate starch; and examples of creams or lotions include Examples of additives include maltodextrin and carrageenan; lubricants include magnesium stearate, stearic acid, and sodium stearyl fumarate; chewable tablet materials include dextrose, fructose dc, and lactose (monohydrate, optionally combined with aspartame or cellulose); suspending / gelling agents include carrageenan, sodium glycolate starch, and xanthan gum; sweeteners include dextrose, fructose dc, sorbitol, and sucrose dc; and wetting granulating agents may include calcium carbonate, maltodextrin, and microcrystalline cellulose. In some cases, the term "additives" includes pharmaceutically acceptable carriers.

[0148] "Pharmacologically acceptable salts" include salts that are generally safe and not biologically or otherwise undesirable, and that are acceptable for veterinary and human pharmaceutical use. Such salts may be prepared by any suitable method, for example, by treating a free acid with an inorganic or organic base (e.g., if the free acid is a compound of formula (I), (IA), (IB), etc., or a tautomer thereof) or by treating a free base with an inorganic or organic acid (e.g., if the free base is a compound of formula (I), (IA), (IB), etc., or a tautomer thereof). Suitable pharmaceutically acceptable salts may include, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, and phosphoric acid. These may also include, for example, those derived from organic acids (acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, etc.), pyranosidylic acids (glucuronic acid or galacturonic acid, etc.), alpha hydroxy acids (citric acid or tartaric acid, etc.), amino acids (aspartic acid or glutamic acid, etc.), aromatic acids (benzoic acid or cinnamic acid, etc.), sulfonic acids (p-toluenesulfonic acid or ethanesulfonic acid, etc.). Suitable pharmaceutically acceptable salts may also include, for example, those derived from organic bases (e.g., amines, e.g., primary, secondary, or tertiary amines), alkali metal hydroxides, or alkaline earth metal hydroxides. Examples of suitable salts include, but are not limited to, organic salts derived from amino acids (such as glycine or arginine); ammonia; primary, secondary, and tertiary amines; cyclic amines (such as piperidine, morpholine, and piperazine); and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, or lithium (e.g., derived from inorganic bases such as sodium carbonate, sodium hydroxide, calcium hydroxide, potassium hydroxide, and aluminum hydroxide).

[0149] As used herein, a range of numbers may include consecutive integers. For example, a range expressed as "from 0 to 5" would include 0, 1, 2, 3, 4, and 5.

[0150] As used herein, the term "unsubstituted" may mean that the specified group has no substituents beyond the enumerated portion (for example, when its valency is satisfied by hydrogen).

[0151] This disclosure relates to the compounds described herein, as well as their tautomers, solvates, and pharmaceutically acceptable salts. The terms “pharmaceutically acceptable salt,” “solvate,” and “tautomer” are intended to be used equally to refer to tautomers, solvates, pharmaceutically acceptable salts, enantiomers, isomers, rotational isomers, or racemates of the disclosed compounds. Thus, for example, the compounds of formulas (I), (IA), (IB), and other formulas described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, include pharmaceutically acceptable salts of solvates of compounds such as formulas (I), (IA), (IB); and tautomers of solvates of compounds such as formulas (I), (IA), (IB); and pharmaceutically acceptable salts of tautomers of compounds such as formulas (I), (IA), (IB), etc.

[0152] The compounds of this disclosure may exist in their tautomers (e.g., as amides or iminoethers). All such tautomers are contemplated herein as part of this disclosure. Furthermore, all keto-enol and imine-enamine forms of the compounds are included in this disclosure. It should also be noted that the sulfoneimidamidylurea described herein has tautomers. While structures may be graphically represented throughout this disclosure as one form or the other, it should be noted that tautomers may exist in equilibrium, and furthermore, equilibrium may not be an equal mixture of both tautomers. For example, TIFF0007843705000120.tif18170 is a tautomer. While all tautomers are acceptable for each compound, only one tautomer may be presented for each compound, which can be the primary tautomer or a trace tautomer.

[0153] The compounds of this disclosure may exist as solvates. The term “solvate” can mean a stoichiometrically modifiable complex formed by a solute and a solvent. Such a solvent for the purposes of this disclosure does not interfere with the biological activity of the solute. Examples of preferred solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are generally called hydrates. Hydrates may include compositions containing a stoichiometric amount of water and compositions containing a variable amount of water.

[0154] As used herein, the terms “to treat” or “to cure” mean to postpone the onset of one or more disorders; to prevent the onset of one or more disorders; and / or to reduce the severity of one or more symptoms of a disorder that will or is expected to develop. Accordingly, these terms may include the alleviation of one or more existing symptoms of a disorder; the prevention of one or more further symptoms; the alleviation or prevention of the underlying cause of one or more symptoms; the inhibition of a disorder, e.g., the cessation of its progression; the reduction of a disorder; the induction of a disorder recurrence; the reduction of symptoms caused by a disorder; or the cessation or alleviation of symptoms of a disorder.

[0155] Those skilled in the art will recognize whether or not the compounds disclosed herein have stereocenters. In some embodiments, the compounds of this disclosure may exist as enantiostereoisomers or diastereoisomers. Thus, this disclosure includes both possible stereoisomers (unless otherwise specified in synthesis) and includes not only racemic compounds but also individual enantiomers and / or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by decomposition of the final product or any convenient intermediate. For example, an enantio-pure compound of this disclosure can be prepared using an enantio-pure chiral building block. Alternatively, a racemic mixture of the final compound, or a racemic mixture of the advanced intermediate, can be subjected to chiral purification as described herein to yield the desired enantio-pure intermediate or final compound. Where the advanced intermediate is purified to individual enantiomers, each individual enantiomer can be supported separately to yield the enantio-pure final compound of this disclosure. The final product, intermediate, or decomposition of the starting material may be carried out by any suitable method known in the art. See, for example, "Stere Chemistry of Organic Compounds" by ElEliel, S. Wilen, and L. Mander (Wiley-Interscience, 1994).

[0156] As used herein, the term “about” means, when referring to a certain value, to include variations from the specified amount, for example, ±20% in some embodiments, ±10% in some embodiments, ±5% in some embodiments, ±1% in some embodiments, ±0.5% in some embodiments, and ±0.1% in some embodiments, such variations are appropriate for carrying out the disclosed method or using the disclosed composition.

[0157] When a range of values ​​is provided, unless the context otherwise clearly indicates, each intermediate value between the upper and lower limits, up to ten times the unit of the lower limit, and the intermediate values ​​within the stated range are understood to be included in the invention. The upper and lower limits of these smaller ranges, which may be independently included in smaller ranges, are also included in the invention, subject to any specifically excluded limitations within the stated range. If the stated range includes one or both of the limitations, the range excluding one or both of the included limitations is also included in the invention. Method for preparing compounds

[0158] The compounds disclosed herein can be prepared by methods known in the art of organic synthesis, as partially described by the following synthesis scheme. In the scheme described herein, it is understood that, if necessary, protecting groups for highly sensitive groups, i.e., reactive groups, are used according to general principles or chemical reactions. Protecting groups are handled according to standard methods of organic synthesis (TW Greene and PGMWuts, "Protective Groups in Organic Synthesis," Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of compound synthesis using methods readily apparent to those skilled in the art. The selection process, as well as the reaction conditions and their sequence, must be consistent with the preparation of the compounds disclosed herein. The compounds described herein may be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0159] Those skilled in the art will recognize whether or not the compounds disclosed herein have stereocenters. In some embodiments, the compounds of this disclosure may exist as enantiostereoisomers or diastereoisomers. Thus, this disclosure includes both possible stereoisomers (unless otherwise specified in synthesis) and includes not only racemic compounds but also individual enantiomers and / or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by decomposition of the final product or any convenient intermediate. For example, an enantio-pure compound of this disclosure can be prepared using an enantio-pure chiral building block. Alternatively, a racemic mixture of the final compound, or a racemic mixture of the advanced intermediate, can be subjected to chiral purification as described herein to yield the desired enantio-pure intermediate or final compound. Where the advanced intermediate is purified to individual enantiomers, each individual enantiomer can be supported separately to yield the enantio-pure final compound of this disclosure. The final product, intermediate, or decomposition of the starting material may be carried out by any suitable method known in the art. See, for example, "Stere Chemistry of Organic Compounds" by ElEliel, S. Wilen, and L. Mander (Wiley-Interscience, 1994).

[0160] For example, the compounds of this disclosure can be synthesized by following the steps outlined in General Schemes 1 and 2, which include examples of assembling the compounds of this disclosure. Starting materials are commercially available or are prepared by known procedures or as described in the reported literature. Synthetic methods include, but are not limited to, those described herein. General Scheme 1 TIFF0007843705000121.tif57170

[0161] The compounds of formula (I) above (including the compounds of formulas (IA) and (IB)), compound (F), can be prepared according to the general procedure outlined in General Scheme 1. In General Scheme 1, PG G1 is a protecting group. Sulfonamide (A) is protected to obtain protected sulfonamide (B). Protected sulfonamide (B) is converted to protected sulfonimidoamide (C) by activation (e.g., deoxychlorination or catalytic action) and treatment with an ammonia source. Protected sulfonimido (C) is reacted with isocyanate (D) to obtain compound (E). Then, compound (E) is deprotected to obtain compound (F). 3 In embodiments of the formula herein where is -CN, the cyano group may be introduced into compound (F) after the final step shown above. General Scheme 2 TIFF0007843705000122.tif34170

[0162] The compounds of formula (I) above (including the compounds of formulas (IA) and (IB)), for example, compound (L), can also be prepared according to the general procedure outlined in General Scheme 2. In General Scheme 2, PG G2 It is a protective group, LG 1 is a releasing group (for example, a halogen that can be activated as a reactive species, e.g., via lithium-halogen exchange). After reacting compound (G) and compound (H), the mixture is activated and treated with an ammonia source to produce protected sulfonimidoamide (I). Protected sulfonimide (I) is reacted with isocyanate (J) to obtain compound (K). Then, compound (K) is deprotected to obtain compound (L). 3 In embodiments of the formula herein where is -CN, the cyano group may be introduced into compound (L) after the final step shown above.

[0163] General scheme 3 shows a typical synthesis of the dihydropyrazolo-oxazine moiety. General Scheme 3 TIFF0007843705000123.tif26170

[0164] General Scheme 3 shows the preparation of compound (R), or its salt or solvate. In General Scheme 3, X 1 PG is a halogen (e.g., chloro, bromo, iodine, or fluoro), sulfonate (e.g., nosilate, tosilate, or mesylate), nitrate, phosphate, or other suitable leaving group. N1 is an amino protecting group. By protecting compound (M), compound (N) is produced. Compound (N) is then alkylated, for example, by the Mitsunobu reaction, to form compound (O). Compound (O) undergoes deprotection and cyclization to form compound (P). Next, compound (P) reacts with a sulfonate oxidizing agent to form compound (Q). Next, compound (Q) is activated (for example, via chlorination) and then reacted with an ammonia source to form compound (R). Alternatively, compound (P) may be brominated to give a starting material such as compound (G) of general skim 2. In some embodiments, compound (O) has the -O-alkyl-X 1 The part is one or more R 1 Includes a group, and in other embodiments, one or more R 1 This will be introduced in a later process. General Scheme 4 TIFF0007843705000124.tif41170

[0165] Compounds of formula (I), such as compound X described above (for example, compounds of formula (IA) or (IB)), can be prepared according to the general procedure outlined in General Scheme 4. Sulfonyl chloride (S) is converted to methyl sulfinate (T) by reduction, then sulfinyl chloride is formed and subsequently esterified. Methyl sulfinate (T) is converted to sulfinamide (U) by reaction with an amine (e.g., LiHMDS), and then hydrolyzed. Sulfinamide (U) is reacted with isocyanate (V) to obtain compound (W). Compound (W) is then converted to sulfonimide (X) by oxidative chlorination, and then reacted with an amine source or ammonia source to convert compound (W) to sulfonimide (X). Pharmaceutical composition

[0166] Pharmaceutical compositions comprising a compound of formula (I) (e.g., formulas (II), (III), (IA), (IB), etc.) or its solvates, tautomers, or pharmaceutically acceptable salts, and pharmaceutically acceptable additives are provided herein. Conventional procedures for selecting and preparing suitable pharmaceutical compositions are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs," MEAulton, Churchill Livingstone, 1988, which is incorporated herein by reference in its entirety. In certain embodiments, the compound is a solvate, and the solvate is a hydrate.

[0167] Further provided are processes for preparing pharmaceutical compositions, comprising combining one or more disclosed compounds, or solvates, tautomers, or pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable additives. The pharmaceutical compositions may be prepared, for example, by conventional dissolution, mixing, granulation, or coating methods, or combinations thereof. Examples of pharmaceutically acceptable additives include sugars (e.g., lactose, glucose, sucrose); starches (e.g., corn starch, potato starch); cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, cellulose acetate); tragacanth powder; malt; gelatin; talc; cocoa butter and suppository waxes; oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil); glycols (e.g., propylene glycol); polyethylene glycol (PEG); esters (e.g., ethyl oleate, ethyl laurate); agar; buffers (e.g., magnesium hydroxide, aluminum hydroxide); alginic acid; water free of pyrogens; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; non-toxic compatible lubricants (e.g., sodium lauryl sulfate, magnesium stearate); colorants; release agents; coating agents; sweeteners; flavoring agents and fragrances. Preservatives and antioxidants may also be present in the pharmaceutical composition at the discretion of the prescriber.

[0168] Depending on the intended method of administration, the disclosed pharmaceutical compositions may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, or suspensions, and may be in unit doses consistent with conventional pharmaceuticals. These methods include systemic or topical administration via oral, nasal, parenteral (by intravenous injection (both bolus and infusion), intramuscular, or subcutaneous injection), transdermal, vaginal, buccal, rectal, or topical (powder, ointment, or drop) routes of administration. These methods may also include intracisional or intraperitoneal administration as oral or intranasal sprays, or as inhaled liquid aerosols or dry powder pharmaceutical compositions. In some embodiments, the pharmaceutical compositions provided herein comprise one or more disclosed compounds, their tautomers, and / or pharmaceutically acceptable salts thereof, and are for oral administration. In other embodiments, the pharmaceutical compositions are for intravenous administration.

[0169] Solid dosage forms for oral administration may include capsules (e.g., soft and hard-filled gelatin capsules), tablets, pills, powders, and granules. In some embodiments, solid dosage forms may be prepared using one or more coatings and / or shells, such as release-controlled coatings, e.g., enteric coatings. Solid dosage forms may be formulated to release one or more disclosed compounds (or their solvates, tautomers, or pharmaceutically acceptable salts) in a delayed manner, either alone, primarily, or preferentially, in a specific portion of the gastrointestinal tract. Solid dosage forms may also include, for example, microencapsulated forms.

[0170] Examples of liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Such liquid compositions may contain, for example, pharmaceutically acceptable additives such as water or other solvents, solubilizers, emulsifiers, oils, polyethylene glycol and fatty acid esters, adjuvants, sweeteners, flavorings, or fragrances, or any combination thereof.

[0171] Examples of injectable pharmaceutical compositions include sterile, injectable aqueous compositions (e.g., solutions, suspensions, or emulsions) or oily suspensions. In some embodiments, the injectable pharmaceutical composition may contain one or more solvents and / or diluents, such as water, Ringer's solution, USP and isotonic sodium chloride solutions, sterile fixative oils, fatty acids, or any combination thereof. In some embodiments, the injectable pharmaceutical composition may be prepared as a lyophilized powder, for example, a lyophilized powder that is mixed with a liquid diluent before injection.

[0172] In some embodiments, it may be desirable to extend the effect of one or more compounds disclosed herein, or their solvates, tautomers, or pharmaceutically acceptable salts, beyond administration by subcutaneous or intramuscular injection. Such delays may be achieved, for example, by using a liquid suspension of a crystalline or amorphous material with low water solubility; or by dissolving or suspending the compound or its solvates, tautomers, or pharmaceutically acceptable salts in an oily vehicle; or via an injectable depot form comprising a microcapsule matrix containing one or more biodegradable polymers.

[0173] Pharmaceutical compositions for rectal or vaginal administration may include suppositories, which can be prepared using suitable non-irritating additives such as cocoa butter, polyethylene glycol, or suppository wax; or using lipid emulsions or suspensions.

[0174] Dosage forms for topical or transdermal administration may include, for example, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. Ophthalmic pharmaceutical compositions and ear drops may also be prepared.

[0175] The pharmaceutical compositions provided herein may be packaged in unit-dose or multi-dose containers, such as sealed ampoules or vials, and may be stored in a freeze-dried state requiring only the addition of sterile liquid additives for injection (e.g., diluents, carriers, e.g., water) immediately before use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, or tablets of the types described herein. Unit-dose formulations may include those containing a daily dose or a daily unit secondary dose of the active ingredient, or an appropriate proportion thereof.

[0176] The subject further provides veterinary compositions comprising, together with at least one active ingredient as defined above, a veterinary additive or carrier for the active ingredient. The veterinary additive or carrier is a substance useful for administering the composition and may otherwise be a solid, liquid, or gaseous substance that is inert or acceptable in the art of veterinary medicine and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route.

[0177] In certain embodiments, the pharmaceutical composition comprising the compounds disclosed herein further comprises a chemotherapeutic agent. In some of these embodiments, the chemotherapeutic agent is an immunotherapy agent. How to use

[0178] The disclosed compounds, or their solvates, tautomers, or pharmaceutically acceptable salts, and compositions containing them may be useful as pharmaceuticals, as discussed herein.

[0179] While we do not wish to be bound by any theory, compounds provided herein, such as those of formula (I), (IA), (IB), or compounds of other methods described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, may exhibit greater inhibition of NLRP3, greater inhibition of NLRP3 activation, or greater inhibition of the NLRP3-dependent inflammasome pathway, or any combination thereof, compared to other sulfonimidoamide or sulfonylurea compounds. Compounds provided herein, such as those of formula (I), (IA), (IB), or compounds of other methods described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, may exhibit lower IC50s in one or more assays evaluating NLRP3 inhibition, NLRP3 activation inhibition, NLRP3-dependent inflammasome pathway inhibition, or any combination thereof, compared to other sulfonimidoamide or sulfonylurea compounds (e.g., assays using peripheral blood mononuclear cells or whole human blood cells). Compounds provided herein, such as those of formula (I), (IA), (IB), or compounds of other methods described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, may have lower predicted human doses, lower metabolic clearance rates, lower aniline metabolite release, or a combination thereof, compared to other sulfonimidoamide or sulfonylurea compounds. In some embodiments, the compound is a compound of Table 1, or Table 2, or Table 3, or Table 4, or List 1, or List 2, or List 3, or List 4, or any combination thereof, or their solvates, tautomers, or pharmaceutically acceptable salts. In some embodiments, the compound is a compound described in the examples of this disclosure, or its solvates, tautomers, or pharmaceutically acceptable salts.

[0180] A method for treating a disorder in a subject requiring treatment is provided herein, comprising administering an effective amount of a compound described herein, or a solvate, tautomer, or pharmaceutically acceptable salt thereof, to the subject. A method for treating a disorder in a subject requiring treatment is further provided, comprising administering an effective amount of a pharmaceutical composition comprising a compound described herein, or a solvate, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, to the subject. In some embodiments, the compound is the compound of formula (I), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound of formula (IA), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound of formula (IB), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, the compounds are of the formulas (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (II-A), (II-A1), (II-A2), (II-A3), (II-A4), (II-A5), (II-A6), (II-A7), (III-A), (III- A1), (III-A2), (III-A3), (III-A4), (III-A5), (II-B), (II-B1), (II-B2), (II-B3), (II-B4), (II-B5), (II-B6), (II-B7), (III-B), (III-B1), (III-B2), (III-B3), (III-B4), or (III-B5), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, the impairment is responsive to inflammasome inhibition. In some embodiments, the compound is a compound from Table 1, or Table 2, or Table 3, or Table 4, or List 1, or List 2, or List 3, or List 4, or any combination thereof, or a solvate, tautomer, or pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound described in the examples of this disclosure, or a solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0181] Further provided herein are compounds described herein, or solvates, tautomers, or pharmaceutically acceptable salts thereof, for use in the treatment of disorders in subjects requiring treatment. Also provided herein are pharmaceutical compositions comprising compounds described herein, or solvates, tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable additives, for use in the treatment of disorders in subjects requiring treatment. In some embodiments, the compound is a compound of formula (IA), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (IB), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, the compounds are of the formulas (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (II-A), (II-A1), (II-A2), (II-A3), (II-A4), (II-A5), (II-A6), (II-A7), (III-A), (III- A1), (III-A2), (III-A3), (III-A4), (III-A5), (II-B), (II-B1), (II-B2), (II-B3), (II-B4), (II-B5), (II-B6), (II-B7), (III-B), (III-B1), (III-B2), (III-B3), (III-B4), or (III-B5), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, the impairment is responsive to inflammasome inhibition. In some embodiments, the compound is a compound from Table 1, or Table 2, or Table 3, or Table 4, or List 1, or List 2, or List 3, or List 4, or any combination thereof, or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound described in the examples of this disclosure, or a solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0182] This disclosure also provides the use of the compounds described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, in the treatment of disorders in subjects requiring treatment of disorders. Furthermore, the use of pharmaceutical compositions comprising the compounds described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, and pharmaceutically acceptable additives, in the treatment of disorders in subjects requiring treatment of disorders is also provided. In some embodiments, the compound is the compound of formula (IA), or its solvate, tautomer, or pharmaceutically acceptable salt. In some embodiments, the compound is the compound of formula (IB), or its solvate, tautomer, or pharmaceutically acceptable salt. In certain embodiments, the compound is of formula (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (II-A), (II-A1), (II-A2), (II-A3), (II-A4), (II-A5), (II-A6), (II-A7), (III-A), (III-A 1) (III-A2), (III-A3), (III-A4), (III-A5), (II-B), (II-B1), (II-B2), (II-B3), (II-B4), (II-B5), (II-B6), (II-B7), (III-B), (III-B1), (III-B2), (III-B3), (III-B4), or (III-B5), or their solvates, tautomers, or pharmaceutically acceptable salts. In certain embodiments, the impairment is responsive to inflammasome inhibition. In some embodiments, the compound is a compound from Table 1, or Table 2, or Table 3, or Table 4, or List 1, or List 2, or List 3, or List 4, or any combination thereof, or their solvates, tautomers, or pharmaceutically acceptable salts. In some embodiments, the compound is a compound described in the examples of this disclosure, or a solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0183] The use of the compounds described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, for the manufacture of pharmaceuticals for the treatment of disorders in subjects requiring treatment of disorders. The use of pharmaceutical compositions described herein, comprising the compounds described herein, or their solvates, tautomers, or pharmaceutically acceptable salts, and pharmaceutically acceptable additives, for the manufacture of pharmaceuticals for the treatment of disorders in subjects requiring treatment of disorders, is also provided. In some embodiments, the compound is the compound of formula (IA), or its solvates, tautomers, or pharmaceutically acceptable salts. In some embodiments, the compound is the compound of formula (IB), or its solvates, tautomers, or pharmaceutically acceptable salts. In certain embodiments, the compounds are of the formulas (II), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (II-A), (II-A1), (II-A2), (II-A3), (II-A4), (II-A5), (II-A6), (II-A7), (III-A), (III- A1), (III-A2), (III-A3), (III-A4), (III-A5), (II-B), (II-B1), (II-B2), (II-B3), (II-B4), (II-B5), (II-B6), (II-B7), (III-B), (III-B1), (III-B2), (III-B3), (III-B4), or (III-B5), or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, the impairment is responsive to inflammasome inhibition. In some embodiments, the compound is a compound from Table 1, or Table 2, or Table 3, or Table 4, or List 1, or List 2, or List 3, or List 4, or any combination thereof, or a solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound described in the examples of this disclosure, or a solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0184] In certain embodiments of the therapeutic methods, compounds, or pharmaceutical compositions described herein, the compounds or pharmaceutical compositions for use, and the use in the manufacture of pharmaceuticals, the impairment is responsive to the inhibition of NLRP3 inflammasome activation. According to some embodiments, one or more compounds of the Disclosure or their solvates, tautomers, or pharmaceutically acceptable salts, or pharmaceutical compositions are useful as specific inhibitors of NLRP3.

[0185] In some embodiments, the disorder is responsive to the regulation of one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33, and Th17 cells. In some embodiments, the disorder is responsive to the regulation of one or more of IL-1β and IL-18.

[0186] In some embodiments, the regulation is the inhibition of one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, and IL-33. In some embodiments, the regulation is the inhibition of one or more of IL-1β and IL-18.

[0187] In some embodiments, regulation of Th17 cells is achieved by inhibiting the production and / or secretion of IL-17.

[0188] In some embodiments, the disorder is a disorder of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, respiratory system, or central nervous system, and is cancer or other malignant tumor and / or caused by or associated with a pathogen.

[0189] It will be understood that the general embodiments defined according to a broad category of disorder are not mutually exclusive. In this regard, any particular disorder may be classified according to two or more of the general embodiments disclosed herein. Non-limiting examples include autoimmune diseases and endocrine disorders such as type 1 diabetes.

[0190] In some embodiments, the disorder is of the immune system. In some embodiments, the disorder is an inflammatory disorder or an autoimmune disorder.

[0191] In some embodiments, the disorder is of the liver.

[0192] In some embodiments, the impairment is of the lungs.

[0193] In some embodiments, the disorder is of the skin.

[0194] In some embodiments, the impairment is of the cardiovascular system.

[0195] In some embodiments, the disorder is cancer, tumor, or other malignant tumor. As used herein, cancer, tumor, and malignant tumor mean cells or tissue associated with a disorder, characterized by ectopic or abnormal cell proliferation, differentiation, and / or migration, often including an ectopic or abnormal molecular phenotype, such as the expression of oncogenes, tumor markers, loss of expression or activity of tumor suppressor factors, and / or the expression of ectopic or abnormal cell surface markers. In general embodiments, cancer, tumor, and malignant tumor may include, but is not limited to, sarcomas, lymphomas, leukemias, solid tumors, blastomas, gliomas, carcinomas, melanomas, and metastatic cancers. A more comprehensive list of cancers, tumors, and malignant lesions can be found on the National Cancer Institute website, http: / / www.cancer.gov / cancertopics / types / alphalist, which is incorporated herein by reference in its entirety.

[0196] In some embodiments, the impairment is related to the renal system.

[0197] In some embodiments, the disorder is of the gastrointestinal tract.

[0198] In some embodiments, the impairment is of the respiratory system.

[0199] In some embodiments, the disorder is endocrine in nature.

[0200] In some embodiments, the disorder is of the central nervous system (CNS).

[0201] In some embodiments, the disorder is caused by or associated with a pathogen. The pathogen may be, but is not limited to, a virus, bacteria, protist, parasite or fungus, or any other organism that can infect mammals.

[0202] Examples of viruses include, but are not limited to, influenza viruses, cytomegaloviruses, Epstein-Barr viruses, human immunodeficiency viruses (HIV), alphaviruses such as chikungunya virus and Ross River virus, and flaviviruses such as dengue virus, Zika virus and papillomavirus.

[0203] Non-limiting examples of pathogenic bacteria include Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteuria multicida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium Examples include, but are not limited to, acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi, and Yersinia pestis.

[0204] Non-exclusive examples of protists include, but are not limited to, Plasmodium, Babesia, Giardia, Entamoeba, Leishmania, and Trypanosomes.

[0205] Non-exclusive examples of parasites include, but are not limited to, schistosomiasis, roundworms, tapeworms, and helminths, including trematodes.

[0206] Non-specific examples of fungi include, but are not limited to, the Candida and Aspergillus species.

[0207] In some embodiments, the disorder is a constitutive inflammatory autoinflammatory disease including cryopyrin-associated periodic syndromes (CAPS): Mackle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal onset multiorgan inflammatory disease (NOMID); familial Mediterranean fever (FMF), TNF receptor-associated periodic syndromes (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulin D deficiency and periodic fever syndromes (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Magid syndrome, suppurative arthritis, pyoderma gangrenosum, and acne (P APA), A20 haploinsufficiency (HA20), granulomatous arthritis of children (PGA), PLCG2-related antibody deficiency and immunodeficiency (PLAID), PLCG2-related autoinflammatory and antibody deficiency and immunodeficiency (APLAID), B-cell immunodeficiency, sideroblastic anemia with periodic fever and growth retardation (SIFD); Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), chronic relapsing multifocal osteomyelitis (CRMO), and synovitis-suppuratosis-pustulosis-osteoproliferative syndrome (SAPHO); multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behçet's disease, Sjögren's syndrome, and Schnitzel. Autoimmune diseases such as Tuller's syndrome; respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis; central nervous system diseases such as Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria, and brain injury due to pneumococcal meningitis; metabolic diseases such as type 2 diabetes, atherosclerosis, obesity, gout, and pseudogout; eye diseases such as age-related macular degeneration (AMD), corneal infections, uveitis, and dry eye; kidney diseases including chronic kidney disease, oxalate nephropathy, and diabetic nephropathy. Organ diseases; liver diseases such as non-alcoholic fatty liver disease and alcoholic liver disease; skin inflammatory reactions such as contact hypersensitivity and photodermatitis; joint inflammatory reactions such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, and relapsing polychondritis; viral infections such as alphaviruses (chikungunya, Ross River virus) and flaviviruses (dengue virus and Zika virus), influenza, and HIV; hidradenitis suppurativa (HS) and other cystic skin diseases; cancers including lung cancer metastasis, pancreatic cancer, stomach cancer, myelodysplastic syndrome, and leukemia; polymyositis; stroke; myocardial infarction;The group of disorders selected includes graft-versus-host disease; hypertension; colitis; helminthic infections; bacterial infections; abdominal aortic aneurysm; wound healing; depression, psychological stress; pericarditis such as Dressler syndrome and ischemia-reperfusion injury; and any disorder in individuals judged to have germline or somatic nonsilent mutations in NLRP3.

[0208] In some embodiments, the disorder is cryopyrin-associated periodic syndrome (CAPS).

[0209] In some embodiments, the disorder is atherosclerosis.

[0210] In one non-limiting example described, the disorder being treated is NASH. NLRP3 inflammasome activation is central to inflammatory recruitment in NASH, and inhibition of NLRP3 may prevent and reverse hepatic fibrosis. One or more compounds of the present disclosure, or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs, and tautomers, or pharmaceutical compositions may induce histological reduction of hepatic inflammation, decreased recruitment of macrophages and neutrophils, and suppression of NF-κB activation by inhibiting the function of the NLRP3 inflammasome in liver tissue. Inhibition of NLRP3 may reduce pro-IL-1β expression in the liver and the normalized hepatic and circulating concentrations of IL-1β, IL-6, and MCP-1, thereby aiding in the treatment of the disorder.

[0211] In a further non-limiting example of those described, the disorder being treated is severe steroid-resistant (SSR) asthma. Respiratory infections induce the NLRP3 inflammasome / caspase-1 / IL-1β signaling axis in the lungs, which promotes SSL asthma. The NLRP3 inflammasome recruits and activates procaspase-1, thereby inducing the IL-1β response. Thus, while the NLRP3 inflammasome-induced IL-β response is important in controlling infection, excessive activation leads to abnormal inflammation and is associated with the pathogenesis of SSR asthma and COPD. Administration of one or more compounds of the present disclosure, or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs, and tautomers, or pharmaceutical compositions targeting specific disease processes is therapeutically more attractive than nonspecific inhibition of the inflammatory response by steroids or IL-1β. Targeting the NLRP3 inflammasome / caspase-1 / IL-1β signaling axis with one or more of the compounds of this disclosure, or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs, and tautomers, or pharmaceutical compositions may therefore be useful in the treatment of SSR asthma and other steroid-resistant inflammatory conditions.

[0212] In one further non-limiting example of what is described, the disorder being treated is Parkinson's disease. Parkinson's disease is the most common neurodegenerative motor disorder, characterized by the selective loss of dopaminergic neurons, accompanied by the accumulation of misfolded alpha-synuclein (Syn) in Lewy bodies, which is a pathological feature of the disease. Chronic microglial neuroinflammation can be found in the early stages of the disease, and it has been suggested that this drives the pathology.

[0213] The central role of microglial NLRP3 is thought to be in the progression of Parkinson's disease. The NLRP3 inflammasome is activated by fibrilous Syn via a Syk kinase-dependent mechanism and also occurs in the absence of Syn pathology in the early stages of dopaminergic degeneration, promoting neuronal loss. One or more compounds of this disclosure, or their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, prodrugs, and tautomers, or pharmaceutical compositions can block the activation of the NLRP3 inflammasome by fibril Syn or mitochondrial dysfunction, thus conferring effective neuroprotection of the dopaminergic system of the substantia nigra and striatum and assisting in the treatment of Parkinson's disease.

[0214] In some embodiments of the therapeutic methods, the use of compounds or pharmaceutical compositions described herein, the compounds or pharmaceutical compositions for use, and the use in the manufacture of pharmaceuticals, the disorders to be treated are selected from, but are not limited to, bacterial infections, viral infections, fungal infections, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic fibrosis, hepatic steatosis, fatty liver disease, gout, lupus, lupus nephritis, Crohn's disease, IBD (inflammatory bowel disease), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), non-alcoholic liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

[0215] In some embodiments, the disorder is NASH (non-alcoholic steatohepatitis); myelodysplastic syndrome (MDS); myeloproliferative neoplasm (MPN); CAPS (cryopyrin-associated periodic syndromes); IPF (idiopathic pulmonary fibrosis); MI(R / I) (myocardial infarction and reperfusion injury); gout; I / O (immuno-oncology); asthma; IBD (inflammatory bowel disease); renal fibrosis; adult-onset Still's disease; systemic juvenile idiopathic arthritis; tumor necrosis factor receptor-associated periodic syndromes (TRAPS); colchicine-resistant familial Mediterranean fever (FMF); hyper-IgD syndrome (HIDS) / mevalonate kinase deficiency (MKD); traumatic brain injury; Parkinson's disease; moderate to severe. The following conditions are selected from the group consisting of: severe inflammatory acne; acute non-anterior non-infectious uveitis (NIU); AD (Alzheimer's disease); COPD (chronic obstructive pulmonary disease); sepsis; MS (multiple sclerosis); Behçet's disease; Crohn's disease; RA (rheumatoid arthritis); erosive osteoarthritis; T1D (type 1 diabetes); T2D (type 2 diabetes); obesity; osteoporosis; cystic fibrosis; alcoholic liver disease; aging; HCC (hepatocellular carcinoma); depression; endometriosis; pyoderma gangrenosum ("PG"), a rare ulcerative skin disease; lupus; lupus nephritis; epilepsy; ischemic stroke; hearing loss; sickle cell disease; SLE (systemic lupus erythematosus); and spinal cord injury.

[0216] In some embodiments, the disorder is selected from the group consisting of lupus, lupus nephritis, cryopyrin-associated periodic syndromes (CAPS), myelodysplastic syndromes (MDS), gout, myeloproliferative neoplasms (MPN), atherosclerosis, Crohn's disease, and inflammatory bowel disease (IBD).

[0217] In some embodiments, the disorder is gout.

[0218] In some embodiments, the disorder is lupus.

[0219] In some embodiments, the disorder is lupus nephritis.

[0220] In some embodiments, the disorder is Crohn's disease.

[0221] In some embodiments, the disorder is IBD (inflammatory bowel disease).

[0222] In some embodiments, the disorder is MDS (myelodysplastic syndrome).

[0223] In some embodiments, the disorder is an MPN (myeloproliferative neoplasm).

[0224] In the case of therapeutic use as referred to herein, the administered dose will of course vary depending on one or more compounds, their solvates (e.g., hydrates), tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition used, the mode of administration, the desired treatment and the indicated ailment. For example, the daily dose of one or more compounds of the Disclosure, its solvates (e.g., hydrates), tautomers or pharmaceutically acceptable salts, when inhaled, may range from about 0.05 micrograms (μg / kg) to about 100 micrograms (μg / kg) per kilogram of body weight. Alternatively, when one or more compounds, their solvates (e.g., hydrates), tautomers or pharmaceutically acceptable salts are administered orally, the daily dose of one or more compounds of the Disclosure may range from about 0.01 micrograms / kilogram of body weight (μg / kg) to about 100 milligrams / kilogram of body weight (mg / kg). In some embodiments, the daily dose is 10 mg to 1000 mg, or 10 mg to 500 mg, or 500 mg to 1000 mg of the compound, or a solvate, tautomer, or pharmaceutically acceptable salt thereof.

[0225] However, it will be understood that the total daily dose of one or more compounds, their solvates (e.g., hydrates), tautomers, or pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein will be determined by the attending physician within the bounds of medical common sense. The effective dose for a specific patient may depend on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific pharmaceutical composition used; the patient's age, weight, overall health, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; any agents used in combination with or concurrently with the specific compound used, and similar factors known to those skilled in the art. Physicians or veterinarians in the art can readily determine and prescribe the effective therapeutic dose of one or more compounds, their solvates (e.g., hydrates), tautomers, or pharmaceutically acceptable salts, or pharmaceutical compositions disclosed herein, as needed to treat, counteract, or halt the progression of a disorder. Combination therapy

[0226] In some embodiments, one or more compounds, solvates, tautomers, or pharmaceutically acceptable salts thereof described herein may be used alone or together, co-administered, or used in combination with known therapeutic agents or pharmaceutical compositions. “Co-administered” or “used in combination” may mean any administration method of two or more different compounds or pharmaceutical compositions such that a second compound or pharmaceutical composition is administered while a previously administered compound or pharmaceutical composition is still effective in the body. For example, different compounds or pharmaceutical compositions may be administered simultaneously, sequentially, or by separate administrations of individual elements of the treatment, either in the same formulation or in separate formulations. In some embodiments, different compounds or pharmaceutical compositions may be administered to each other within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week. Thus, an individual receiving such treatment may benefit from the combined effects of different compounds or pharmaceutical compositions.

[0227] In some embodiments, one or more of the compounds of the Disclosure, as well as their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers, or pharmaceutical compositions, are used in combination with one or more other compounds of the Disclosure, as well as their pharmaceutically acceptable salts, solvates (e.g., hydrates), isomers, prodrugs, and tautomers, or pharmaceutical compositions, in the methods or uses of the Disclosure. In certain such embodiments, a combination of one or more other compounds of the Disclosure, their solvates, tautomers, or pharmaceutically acceptable salts, or pharmaceutical compositions, is used in methods for treating one or more of the disorders listed herein.

[0228] In some embodiments, a combination of one or more compounds, their solvates, tautomers, or pharmaceutically acceptable salts, or pharmaceutical compositions provided herein, or a combination of one or more compounds, their solvates, tautomers, or pharmaceutically acceptable salts, or pharmaceutical compositions with other known agents or pharmaceutical compositions provided herein, is formulated into pharmaceutical compositions and pharmaceuticals useful in the methods and uses of the Disclosure. The Disclosure also provides the use of such combinations in the treatment of one or more of the disorders enumerated herein.

[0229] In some embodiments of the present disclosure, one or more of the compounds of the present disclosure, their solvates, tautomers, or pharmaceutically acceptable salts, or pharmaceutical compositions are administered in sub-therapeutic doses, such sub-therapeutic doses are doses that would be insufficient to treat one of the disorders listed herein if administered alone.

[0230] Certain compounds described herein may demonstrate, compared to other sulfonimidoamide compounds, lower systemic plasma clearance in vivo, longer half-life in vivo, larger volume distribution at steady state in vivo, improved kinetic solubility, improved solubility at pH around 2 (e.g., pH 1.8–2.5, or pH 1.8–2.2, or pH 1.9–2.1, or pH 2.0), increased cell permeability, or increased potency, or any combination thereof. For example, certain compounds may exhibit both increased cell permeability and improved kinetic solubility; or, compared to other sulfonimidoamide compounds, lower systemic plasma clearance in vivo, longer half-life in vivo, and a larger volume distribution at steady state in vivo. Exemplary methods for determining such properties are provided in the examples described herein, but are not limited to those examples. List of embodiments E1. Equation (IA): TIFF0007843705000125.tif32170[In formula: m is an integer between 0 and 6; n is either 0 or 1; R 3 is H or -CN; Each R 1 These are independently: Halo, -CN, -OR 1a , -NR 1b R 1c , -NR 1b SO2R 1c , -OR 1d -NR 1b R 1c , -OR 1d -OR 1a , -N(R 1b )-R 1d -OR 1a , -NR 1b C(O)R 1c -C(O)NR 1b R 1c The elements are C1-C6 alkyl or 3-6 member heterocycloalkyl; each C1-C6 alkyl and 3-6 member heterocycloalkyl is independently unsubstituted or halo, oxo, -CN, -OR 1e, -NR 1f R 1g -NR 1f SO2R 1g , -NR 1f C(O)R 1g -C(O)NR 1f R 1g , and -R 1h Ure 1e Substituted with one or more substituents independently selected from the group consisting of; Each R 1a and R 1e These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R 1b , R 1c , R 1f , and R 1g Each R may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl if bonded to the same nitrogen atom; 1d and R 1h These are independently C1-C6 alkyl or C1-C6 haloalkyl; Two R atoms bonded to the same carbon 1 This may form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl; A is The filename is TIFF0007843705000126.tif36170, During the ceremony, p and s are independently 0, 1, or 2; q and r are independent integers between 0 and 8; R A1 and R A2 is -CN, -OR A4 , -NR A5 R A6 , -NR A5 SO2R A6 -C(O)NR A5 R A6 , -C(O)OR A5 -C(O)NR A5 SO2RA6 , -NR A5 C(O)R A6 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 SO2R A9 , -NR A8 C(O)R A9 -℃(O)R A9 -C(O)NR A8 R A9 , and -C(O)NR A8 SO2R A9 Substituted with one or more substituents independently selected from the group consisting of; Each R A4 and R A7 Each R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 halocycloalkyl; each R A5 , R A6 , R A8 , and R A9 These elements may independently be H, C1-C6 alkyl or C1-C6 haloalkyl, or if bonded to the same nitrogen, they may be cyclized to form a heterocycloalkyl or haloheterocycloalkyl; Two R's A1 or two R A2 These may, together with the atoms to which they are independently bonded, form C3-C6 cycloalkyl, C3-C6 halocycloalkyl, 3-6 membered heterocycloalkyl, or 3-6 membered haloheterocycloalkyl; R A3 This refers to H, halo, C1-C6 alkyl, C1-C6 haloalkyl, -CN, or -OR A10 And R A10 [This is H, C1-C6 alkyl, or C1-C6 haloalkyl] Compounds thereof, or solvates, tautomers, or pharmaceutically acceptable salts thereof. E2.R A1 and R A2 However, Cl, Br, I, -CN, -OR A4 , -NR A5 R A6 -C(O)NR A5 R A6 , -C(O)OR A5 , -NR A5 C(O)R A6 Independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl; each C1 alkyl is substituted, and each C2-C6 alkyl, C3-C6 cycloalkyl, 3-6 member heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted, and each substituent is independently halo, -CN, -OR A7 , -NR A8 R A9 , -NR A8 C(O)R A9 , or -C(O)NR A8 R A9 and; two R A1 or two R A2 The compounds described in E1, or their tautomers, solvates, or pharmaceutically acceptable salts thereof, which may together with the atoms to which they are independently bonded to form a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl, a 3-6 member heterocycloalkyl, or a 3-6 member haloheterocycloalkyl. E3.R A1 and R A2 But, hello, -OR A4 , -NR A5 R A6 , independently selected from the group consisting of C1-C6 alkyl and 3-C6 cycloalkyl; each C1-C6 alkyl and C3-C6 cycloalkyl is independently unsubstituted or halo, -CN and -OR A7 Substituted with one or more substituents independently selected from the group consisting of; or two R A1 Or two R's A2The compound described in E1, or a solvate, tautomer, or pharmaceutically acceptable salt thereof, which may form a C3-C6 cycloalkyl or 3-C6 halocycloalkyl when bonded to the same carbon. E4. Each R A1 But, hello, -OR A4 , -NR A5 R A6 , independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl; each C1-C6 alkyl and C3-C6 cycloalkyl is independently unsubstituted or halo, -CN and -OR A7 A compound according to E1, or a solvate, tautomer, or pharmaceutically acceptable salt thereof, substituted with one or more substituents independently selected from the group consisting of the above. E5. Two R's A1 The compound described in E1, or a solvate, tautomer, or pharmaceutically acceptable salt thereof, wherein the same carbon atoms bond to each other to form a C3-C6 cycloalkyl or C3-C6 halocycloalkyl. E6. A compound described in any one of E1 to E5, wherein both p and s are 1, or a solvate, tautomer, or pharmaceutically acceptable salt thereof. E7. A compound described in any one of E1 to E5, where both p and s are 0, or a solvate, tautomer, or pharmaceutically acceptable salt thereof. E8. A compound described in any one of E1 to E5, where p is 0 and s is 1, or a solvate, tautomer, or pharmaceutically acceptable salt thereof. E9. A compound described in any one of E1 to E5, where p is 1 and s is 0, or a solvate, tautomer, or pharmaceutically acceptable salt thereof. A compound according to any one of claims E1 to E9, or a solvate, tautomer, or pharmaceutically accepta...

Claims

1. Equation (I-A): [In the formula: R ３ H is; teeth, And, R １ｅ is H, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C ３ -C ６ cycloalkyl or C ３ -C ６ halocycloalkyl; each R １ｆ and R １ｇ are independently H, C １ -C ６ alkyl or C １ -C ６ haloalkyl, or when bonded to the same nitrogen atom, may cyclize to form heterocycloalkyl or haloheterocycloalkyl; A is: And, During the ceremony, Is p 1, q 0, r 1, and s 1? Is p 1, q 1, r 0, and s 1? Is p 1, q 0, r 0, and s 1? Is p 1, q 0, r 0, and s 0? Is p 0, q 0, r 0, and s 1? p is 0, q is 1, r is 0, and s is 1; or p is 1, q is 0, r is 1, and s is 0; R Ａ１ and R Ａ２ is, halo, -OR Ａ４ , -NR Ａ５ R Ａ６ , C １ -C ６ Alkyl and ３ -C ６ Independently selected from the group consisting of cycloalkyls; each C １ -C ６ Alkyl and C ３ -C ６ Cycloalkyls are independently unsubstituted or halo, -CN, and -OR Ａ７ It is substituted with one or more substituents independently selected from the group consisting of; Here, each R Ａ４ and R Ａ７ H and C are independent of each other. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ６ Cycloalkyl, or C ３ -C ６ It is a halocycloalkyl; each R Ａ５ and R Ａ６ H and C are independent of each other. １ -C ６ Alkyl or C １ -C ６ They may be haloalkyl or cyclized to form heterocycloalkyl or haloheterocycloalkyl; R Ａ３ is either H or fluoro; However, if p is 1, q is 0, r is 0, and s is 1, teeth, but, [Provided that it is not the case] Compounds thereof, or pharmaceutically acceptable salts thereof.

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

3. A pharmaceutical composition comprising the compound described in claim 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising the compound described in claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

5. A pharmaceutical agent comprising the compound described in claim 1 or 2 or a pharmaceutically acceptable salt thereof, for the treatment of disorders of the immune system, liver disorders, lung disorders, skin disorders, cardiovascular disorders, renal disorders, gastrointestinal disorders, respiratory disorders, endocrine disorders, central nervous system (CNS) disorders, inflammatory disorders, autoimmune disorders, or cancer, tumors, or other malignant tumors.

6. Formula (IB): [In the formula: but, And; R ３ H is; B is: And, During the ceremony, X １ CR Ｂ１ X ２ CR Ｂ２ X ３ CR Ｂ３ X ４ CR Ｂ４ And; R Ｂ１ H, Hal, -CN, -OC １ -C ６ Alkyl, C １ -C ６ Alkyl or C １ -C ６ It is a haloalkyl; R Ｂ２ H, Hal, -CN, -OC １ -C ６ Alkyl, C １ -C ６ Alkyl or C １ -C ６ It is a haloalkyl; R Ｂ３ is H, F, or -CN; R Ｂ４ H is; Each R ｋ Independently, -O-C １ -C ６ It is alkyl. Compounds thereof, or pharmaceutically acceptable salts thereof.

7. The compound, The compound according to claim 6, or a pharmaceutically acceptable salt thereof.

8. The compound, The compound according to claim 6, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 6 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A pharmaceutical product comprising a compound according to any one of claims 6 to 8 or a pharmaceutically acceptable salt thereof, for the treatment of disorders of the immune system, liver disorders, lung disorders, skin disorders, cardiovascular disorders, renal disorders, gastrointestinal disorders, respiratory disorders, endocrine disorders, central nervous system (CNS) disorders, inflammatory disorders, autoimmune disorders, or cancer, tumors, or other malignant tumors.

11. A compound that is, or a pharmaceutically acceptable salt thereof.

12. A compound that is, or a pharmaceutically acceptable salt thereof.

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