RU2792143C2 - Chemical compounds as interleukin-1 inhibitors - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (Ib) or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein X¹ is O; R ¹ is chosen from the group consisting of ring structures (a), where

is a single bond; each A is independently CR^5a or N; each A ² is independently C(R^5a ) ₂, NR ^5a or O and at least one A ² is NR ^5a or O; R ² is a structure chosen from (b), X² is N or CR^5b ; R³ and R⁴ are H; each R^5a is independently H, halogen, -OH, -CN, SR ⁶, -OR⁶, -NHR⁶, -NR⁶ R⁷, C₁-C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, monocyclic heterocyclyl or -CH₂ -C₃ -C₈ cycloalkyl; where C₁-C ₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃-C₈ cycloalkyl, monocyclic heterocyclyl and -CH₂-C ₃ -C ₈ cycloalkyl are optionally substituted with halogen, C₁ -C₆ alkyl, -OR⁶, -NH₂, NH(C₁ -C₆ alkyl) or N(C -C₆ alkyl)₂ ; or two R^5a together with the atoms to which they are attached may form a C₃ -C₈ cycloalkyl or monocyclic heterocyclyl; wherein the monocyclic heterocyclyl contains 1-3 heteroatoms chosen from the group consisting of N, S, P and O; where C₃ -C₈ cycloalkyl or monocyclic heterocyclyl is optionally substituted with halogen, C₁ -C₆ alkyl, -OR⁶, -NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) ₂ ; or two geminal R ^5a may form an oxo group; each R^5b is independently H, halogen, -OH, -CN, -SR⁶, -OR⁶, NHR⁶, -NR⁶ R⁷, or C₁-C ₆ alkyl; where C₁ -C ₆ alkyl is optionally substituted with halogen, -OR ⁶, -NH ₂, -NH(C₁-C₆ alkyl) or -N(C₁-C ₆ alkyl)₂; R⁶ and R⁷ are independently at each occurrence H, C₁-C ₈ alkyl, C ₂ -C ₈ alkenyl, or C₂-C ₈ alkynyl; where C₁-C₆ alkyl, C₂-C ₈ alkenyl and C₂-C ₆ alkynyl are optionally substituted with halogen, C₁-C₆ alkyl, -OH, -OC_1-C₆ alkyl, -NH₂, -NH(C₁-C₆ alkyl) or -N(C₁-C ₆ alkyl)₂; or R⁶ and R⁷ together with the atom to which they are attached may form a monocyclic heterocyclyl containing 1-3 heteroatoms chosen from the group consisting of N, S, P and O; and n is an integer from 0 to 5. The invention also relates to specific sulfonylurea compounds listed in the claims. The invention relates to a pharmaceutical composition for inhibiting the activation of the NLRP3 inflammasome, containing a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate or tautomer thereof, and a pharmaceutically acceptable carrier.

EFFECT: sulfonylurea derivatives inhibiting the activation of the NLRP3 inflammasome.

44 cl, 6 dwg, 5 tbl, 89 ex

or

Description

[0001] This application claims priority over U.S. Provisional Application No. 62/449,431, filed January 23, 2017, and U.S. Provisional Application No. 62/492,813, filed May 1, 2017, the contents of which are incorporated herein in their entirety by reference .

Technical field

[0002] This invention relates to novel sulfonylurea and sulfonylurea compounds and related compounds and their use in the treatment of a disease or condition susceptible to modulation of cytokines such as IL-1β and IL-18, modulation of NLRP3, or inhibition of the activation of NLRP3 or its related components. inflammatory process.

State of the art

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

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

[0005] Caspase-1 cleaves pro-IL-1β and pro-IL-18 to their active forms, which are released from the cell. Active caspase-1 also cleaves gasdermin-D to induce pyroptosis. By controlling the pyroptotic pathway of cell death, caspase-1 also releases alarmin molecules such as IL-33 and the high mobility group 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and allowing the release of IL-1α. In human cells, caspase-1 can also control the processing and secretion of IL-37. A number of other caspase-1 substrates, such as components of the cytoskeletal pathway and glycolysis, may contribute to caspase-1-dependent inflammation.

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

[0007] Active cytokines derived from NLRP3 inflammasome activation are important factors in inflammation and interact with other cytokine pathways to generate an immune response to infection and injury. For example, IL-1β signaling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 interact with IL-23 to cause production of IL-17 by memory CD4 Th17 cells and γδ T cells in the absence of interaction with T cell receptors. IL-18 and IL-12 also synergize to induce the production of IFN-γ from memory T cells and NK cells, causing a Th1 response.

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

[0009] The inherited diseases of CAPS, Muckle-Wales syndrome (MWS), familial cold auto-inflammatory syndrome, and neonatal multisystem inflammatory disease are caused by gain-of-function mutations in NLRP3, which define NLRP3 as a critical component of the inflammatory process. NLRP3 is also involved in the pathogenesis of a number of complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0010] The role of NLRP3 appears in diseases of the central nervous system, and diseases of the lung have been shown to affect NLRP3. In addition, NLRP3 plays a role in the development of liver and kidney diseases and aging. Many of these associations have been identified using mice with constitutive NLRP3 activation, but there is also an understanding of specific NLRP3 activation in these diseases. In type 2 diabetes, islet amyloid polypeptide deposition in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0011] There is a need to provide compounds with improved pharmacological and/or physiological and/or physicochemical properties, and/or those that provide a useful alternative to known compounds.

The essence of the invention

[0012] The present invention provides compounds that are effective in inhibiting an inflammasome, such as the NLRP3 inflammasome. The compounds are also effective in modulating interleukins. The disclosed compounds have desirable molecular weights, physicochemical properties, and lipophilicity, which are characteristics that help achieve therapeutic efficacy and reduce liability for unintended side effects.

[0013] This invention provides compounds of formula I:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O, S,

R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkenyl, optionally substituted C ₁ -C ₆ alkynyl, -(CH ₂ ) _m -O-(CH ₂ ) _m - CH ₃ ,

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ⁵ or N;

A ¹ is NR ⁵ , O, S or C(O);

each A ² is independently CR ⁵ , C(R ⁵ ) ₂ , N, NR ⁵ , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ⁵ ;

R ³ and R ⁴ are H;

each R ⁵ is independently H, D, halogen, OH, CN, NO ₂ , SR ⁶ , OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ - -S (O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; or

two R ⁵ together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O; or

two geminal R ⁵ can form an oxo group;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or a heteroaryl containing 13 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ⁵ , O, S or S(O) ₂ .

[0014] This invention provides compounds of formula Ia:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O, S,

R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkenyl, optionally substituted C ₁ -C ₆ alkynyl, -(CH ₂ ) _m -O-(CH ₂ ) _m - CH ₃ ,

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

;R ² is

;

X ² is N or CR ^5b ;

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S( O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ ,

-S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , - NR ⁶ S(O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; or

two R ^5b together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or a heteroaryl containing 13 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[0015] This invention provides compounds of formula Ib:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O, S,

R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkenyl, optionally substituted C ₁ -C ₆ alkynyl, -(CH ₂ ) _m -O-(CH ₂ ) _m - CH ₃ ,

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b ;

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S (O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ ; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ ,

-S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , - NR ⁶ S(O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl , heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, halogen, C ₁ - C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[0016] This invention provides compounds of formula Ic:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O, S,

R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkenyl, optionally substituted C ₁ -C ₆ alkynyl, -(CH ₂ ) _m -O-(CH ₂ ) _m - CH ₃ ,

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b ;

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ² - -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S( O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ ,

-NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ ,

-S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , - NR ⁶ S(O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl , heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, halogen, C ₁ - C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[0017] This invention provides compounds of formula Id:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O, S,

R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkynyl, -(CH ₂ ) _m -O-(CH ₂ ) _m -CH ₃ ,

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

R ² is

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S (O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₁ alkyl) ₂ ; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ ,

-S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , - NR ⁶ S(O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl , heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, halogen, C ₁ - C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[0018] This invention provides compounds of formula Ie:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O or S;

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a1 or N;

each A ² is independently CR ^5a2 , C(R ^5a2 ) ₂ , N, NR ^5a2 , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b1 ;

each R ^b10 , R ^b11 , R ^b12 , R ^b13 , R ^b14 and R ^b15 independently represents H, -OH or oxo;

R ³ and R ⁴ are H;

each R ^5a1 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

each R ^5a2 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O ) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ ,

-S(O) ₂ -R ⁶ , -COR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S(O ) ₂ R ⁶ ; or

two geminal R ^5a2 can form an oxo group;

R ^5b1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl, optionally substituted with D, halogen, -CN,

-OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, NO ₂ ,

-SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ ,

-NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; And

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or a heteroaryl containing 13 heteroatoms selected from the group consisting of N, S, P and O;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a2 , O, S or S(O) ₂ .

[0019] This invention provides compounds of the formula If:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O or S;

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a1 or N;

each A ² is independently CR ^5a2 , C(R ^5a2 ) ₂ , N, NR ^5a2 , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b1 ;

R ³ and R ⁴ are H;

each R ^5a1 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

each R ^5a2 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O ) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ ,

-S(O) ₂ -R ⁶ , -COR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S(O ) ₂ R ⁶ ; or

two geminal R ^5a2 can form an oxo group;

R ^5b1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, -NO ₂ ,

-SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or

-N(C ₁ -C ₆ alkyl) ₂ ; or

two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ ,

-NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; And

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a2 , O, S or S(O) ₂ .

[0020] The present invention provides compounds of formula Ig:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O or S;

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a1 or N;

each A ² is independently CR ^5a2 , C(R ^5a2 ) ₂ , N, NR ^5a2 , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b1 ;

R ³ and R ⁴ are H;

each R ^5a1 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

each R ^5a2 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -C(O)R ⁶ ,

-S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -S(O) ₂ -R ⁶ ; -COR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two geminal R ^5a2 can form an oxo group;

R ^5b1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl, optionally substituted with D, halogen, -CN,

-OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, -NO ₂ ,

-SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or

-N(C ₁ -C ₆ alkyl) ₂ ; or

two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ ,

-NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; And

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a2 , O, S or S(O) ₂

[0021] This invention provides compounds of formula Ih:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O or S;

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a1 or N;

each A ² is independently CR ^5a2 , C(R ^5a2 ) ₂ , N, NR ^5a2 , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b1 ;

R ³ and R ⁴ are H;

each R ^5a1 is independently H, D, halogen, -OH, -CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ - C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

each R ^5a2 is independently H, D, halogen, OH, -CN, -NO ₂ , -SR ⁶ , OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O )2R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH ₂ -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O)2R ⁶ ;

and at least R ^5a2 represents -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl or heterocyclyl containing N; where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ and heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ - With ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C( O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O)2R ⁶ ;

R ^5b1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl, optionally substituted with D, halogen, -CN,

-OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, NO ₂ ,

-SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or

-N(C ₁ -C ₆ alkyl) ₂ ; or

two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ ,

-NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; And

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a2 , O, S or S(O) ₂ .

[0022] This invention provides a pharmaceutical composition comprising a compound of this invention and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers, and a pharmaceutically acceptable carrier, diluent, and/or excipient.

[0023] The present invention provides a method for treating or preventing a disease, disorder, or condition, comprising the step of administering an effective amount of a compound of the present invention and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers thereof, to treat or prevent the disease, disorder, or condition in a subject in need.

[0024] This invention provides a compound of this invention and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers thereof, or a pharmaceutical composition of this invention for use in the treatment or prevention of a disease, disorder or condition in a subject in need thereof.

[0025] This invention provides the use of a compound of this invention and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers thereof for the treatment or prevention of a disease, disorder or condition in a subject in need thereof.

[0026] This invention provides the use of a compound of this invention and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.

[0027] In certain embodiments, the disease, disorder, or condition is responsive to inflammasome inhibition.

[0028] In certain embodiments, the disease, disorder, or condition is responsive to inhibition of NLRP3 inflammasome activation.

[0029] In certain embodiments, the disease, disorder or condition is a disease, disorder or condition of the immune system, liver, lung, skin, cardiovascular system, renal system, gastrointestinal tract, respiratory system, endocrine system, central nervous system system, or is a cancer or other malignancy, or is caused by or associated with a pathogenic microorganism.

[0030] The present invention provides a method for modulating the activity of a biological target, comprising the step of exposing the biological target to a compound of the present invention and pharmaceutically acceptable salts thereof.

[0031] The biological target can be selected from the group consisting of NLRP3 inflammasome, IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33, and Th17 cells .

BRIEF DESCRIPTION OF GRAPHICS

[0032] In FIG. 1 shows the inhibition of IL-1β production in peripheral blood mononucleocytes (PBMCs) following treatment with Compound 1, Compound 2, or Compound 3.

[0033] In FIG. 2 shows inhibition of IL-1β and IL-18 production but not TNFα production in Kupffer cells (KS) following treatment with Compound 1, Compound 4, or Compound 5.

[0034] In FIG. 3 shows the modulation of IL-1β in the tested LPS and ATP model by Compound 1 and Compound 2.

[0035] In FIG. 4 shows the modulation of TNFα in the test LPS and ATP model by Compound 1 and Compound 2.

[0036] In FIG. 5 shows the modulation of IL-1β in the tested LPS and ATP model by Compound 3.

[0037] In FIG. 6 shows inhibition of caspase 1 activation (conversion of pro-caspase 1 to active caspase 1) as a result of treatment with Compound 1, Compound 4 or Compound 2.

DETAILED DESCRIPTION OF THE INVENTION

[0038] Used above and throughout this description, the following terms, unless otherwise indicated, should be understood as having the following meanings. If the term is absent, the meaning determines the generally accepted term known to a person skilled in the art.

[0039] In the context of this document, the terms "including", "consisting of" and "comprising" are used in their open, non-limiting sense.

[0040] Singular forms are used herein to refer to one or more than one (i.e., at least one) grammatical entity. For example, "element" means one element or more than one element.

[0041] The term "and/or" is used herein to mean "and" or "or" unless otherwise indicated.

[0042] To give a more concise description, some quantitative expressions given in this document are not quantified by the term "about". It is understood that, whether the term "about" is used explicitly or not, each value given in this document is intended to indicate an actual setpoint, as well as to refer to an approximation to such a setpoint that would reasonably be inferred from the knowledge of one of ordinary skill in the art, including equivalents and approximations due to experimental and/or measurement conditions for such a given value. Whenever a yield is given as a percentage, that yield refers to the weight of the item for which the yield is given relative to the maximum amount of the same item that can be produced under specific stoichiometric conditions. Concentrations that are given as a percentage refer to mass ratios unless otherwise indicated.

[0043] A "patient" is a mammal, such as a human, a mouse, a rat, a guinea pig, a dog, a cat, a horse, a cow, a pig, or a non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey. "Patient" includes both humans and animals.

[0044] The term "inhibitor" refers to a molecule, such as a compound, drug, enzyme, or hormone, that blocks or otherwise interferes with a particular biological activity.

[0045] The terms "effective amount" or "therapeutically effective amount" when used in combination with a compound refer to a sufficient amount of the compound to provide the desired biological result. Such a result may be a reduction in the intensity and/or alleviation of the signs, symptoms or causes of a disease or any other desired change in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound described herein necessary to provide a clinically significant reduction in the symptoms of a disease. An appropriate "effective amount" in any particular case can be determined by one of ordinary skill in the art using routine experimentation. Thus, the expression "effective amount" usually refers to the amount for which the active substance has a therapeutic effect. In this case, the active substance is an inflammasome inhibitor.

[0046] In the context of this document, the terms "treat" or "treatment" are synonymous with the term "prevent" and are intended to mean delaying the development of diseases, preventing the development of diseases, and/or reducing the severity of such symptoms that will or are expected to develop. Thus, these terms include alleviating existing symptoms of a disease, preventing additional symptoms, improving or preventing underlying causes of symptoms, inhibiting a disorder or disease, e.g. disease or disorder, or cessation or amelioration of the symptoms of the disease or disorder.

[0047] the Term "disorder" is used in this description to refer to and is used interchangeably with the terms disease, condition or disease, unless otherwise indicated.

[0048] By "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material that is not biologically or otherwise undesirable - the material can be administered to an individual without causing any substantially undesirable biological effects or without interacting in an adverse manner with any of the components composition in which it is contained.

[0049] The term "carrier" as used herein encompasses carriers, excipients, and diluents, and means a material, composition, or carrier medium such as a liquid or solid excipient, diluent, excipient, solvent, or encapsulating material involved in the transfer or transport of a pharmaceutical agent from one organ or body part to another organ or body part of the subject. Excipients should be selected based on compatibility and properties of the release profile of the desired dosage form. Illustrative examples of carrier materials include, for example, binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, spray-dried dispersions, and the like.

[0050] The term "pharmaceutically compatible carrier materials" may include, for example, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch and the like. See, for example, Hoover, John E., Remington Pharmaceutical Sciences, Mack Publishing Co., Easton, PA 1975.

[0051] In the context of this document, the term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class of mammals: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the invention according to this invention, the mammal is a human.

[0052] This description also includes "prodrugs" of the compounds. The term "prodrug" means a compound that is converted in vivo by metabolic means (eg, hydrolysis) to the described compound or active ingredient. Prodrugs can be obtained by methods known to the person skilled in the art. These techniques typically modify suitable functional groups, eg hydroxy, amino, carboxy, etc., groups on a given compound. However, from these modified functional groups, the original functional groups are regenerated by conventional manipulations or in vivo. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of the hydroxy or amino functional groups in the compounds of this invention, amides (e.g., trifluoroacetylamino, acetylamino and the like) and the like. Because prodrugs are known to enhance numerous desirable properties of pharmaceuticals (eg, solubility, bioavailability, manufacturing, transport, pharmacodynamics, etc.), the compounds of this invention can be delivered in prodrug form. Prodrugs, for example, may be orally bioavailable even if the parent drug is not. Thus, this description is intended to cover the prodrugs of the currently claimed compounds, their modes of delivery, and compositions containing them. Generally speaking, prodrugs are derivatives of drugs as such, which, after administration, are converted or metabolized into physiologically active species. The transformation may be spontaneous, such as hydrolysis in a physiological environment, or may be catalyzed by an enzyme. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolysed, esterified, alkylated, dealkylated, acylated, deacylated, phosphorylated and/or dephosphorylated to provide the active compound.

[0053] The term "IC ₅₀ ", as used herein, refers to concentrations at which a measurable activity, phenotype, or response, such as growth or proliferation of cells, such as tumor cells, is inhibited by 50%. IC ₅₀ values can be estimated from a suitable dose-response curve, eg visually or using a suitable curve or statistical software. More specifically, IC ₅₀ values can be determined using non-linear regression analysis.

[0054] The terms "administered", "administration" or "administration" as used herein refer either to the direct administration of a described compound or a pharmaceutically acceptable salt of a described compound or composition to a subject, or to the administration of a prodrug derivative or analogue of a compound or a pharmaceutically acceptable a salt of a compound or composition to a subject that can form an equivalent amount of the active compound in the body of the subject, including an animal in need of treatment, by bringing such an individual into contact with or otherwise exposing such an individual, such a compound.

[0055] In the context of this document, "alkyl" means a saturated chain with a straight or branched chain, having from 1 to 10 carbon atoms. Typical saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2 -pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl , t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like, and longer alkyl groups such as heptyl and octyl and the like. The alkyl group may be unsubstituted or substituted. Alkyl groups containing three or more carbon atoms may be straight or branched. In the context of this document, "lower alkyl" means alkyl having from 1 to 6 carbon atoms.

[0056] In the context of this document, "alkenyl" includes a straight or branched hydrocarbon chain containing 2-12 carbon atoms. The "alkenyl" group contains at least one double bond. The double bond of the alkenyl group may be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include, but are not limited to, ethyleneyl, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene )-pentenyl and the like. The alkenyl group may be unsubstituted or substituted. Alkenyl, as defined herein, may also be branched or straight.

[0057] As used herein, "alkynyl" includes a straight or branched unsaturated hydrocarbon chain containing 2-12 carbon atoms. The "alkynyl" group contains at least one triple bond. The triple bond of the alkynyl group may be unconjugated or conjugated to another unsaturated group. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, 4-butyl-2-hexynyl, and the like. The alkynyl group may be unsubstituted or substituted.

[0058] The term "hydroxyl" or "hydroxy" means an OH group;

[0059] As used herein, the term "alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms, containing a terminal "O" in the chain, i.e. -O (alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0060] It should also be noted that any carbon, as well as heteroatom with unsaturated valences in the text, schemes, examples and tables in this document, is assumed to have a sufficient number of hydrogen atoms to saturate the valences.

[0061] In the context of this document, references to hydrogen may also refer to substitution by deuterium, if necessary. As used herein, the term "deuterium" means a stable isotope of hydrogen having an odd number of protons and neutrons.

[0062] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0063] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted with one or more halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0064] As used herein, the term "haloalkoxy" refers to an alkoxy group as defined herein that is substituted with one or more halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0065] As used herein, the term "cyano" means a substituent having a carbon atom bonded to a nitrogen atom in a triple bond, i.

[0066] As used herein, the term "amino" means a substituent containing at least one nitrogen atom. Specifically, NH ₂ , -NH(alkyl) or alkylamino, -N(alkyl) ₂ or dialkylamino, amide, carboxamide, urea and sulfamide substituents are included in the term "amino".

[0067] Unless specifically defined otherwise, the term "aryl" refers to cyclic aromatic hydrocarbon groups that have from 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. If the aromatic rings of the aryl group contain two aromatic rings (bicyclic, etc.), they can be connected at one point (for example, biphenyl) or condensed (for example, naphthyl). The aryl group may optionally be substituted with one or more substituents, for example 1 to 5 substituents, at any point of attachment. The substituents may themselves be optionally substituted. In addition, if they contain two fused rings, the aryl groups as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Illustrative examples of these aryl group ring systems include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0068] Unless specifically defined otherwise, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic radical with 5-18 ring atoms, or a polycyclic aromatic radical containing one or more ring heteroatoms selected from N, O or S, the remaining ring atoms are C. Heteroaryl, as defined herein, also means a bicyclic heteroaromatic group in which the heteroatom is selected from N, O, or S. The aromatic radical is independently optionally substituted with one or more substituents as described herein. The substituents may themselves be optionally substituted. Examples include, but are not limited to, benzothiophene, furyl, thienyl, pyrrolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, isothiazolyl, thiazolyl, thiadiazolyl , thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[ 2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, benzimidazolyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyrinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3- a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2 -b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ ² -pyrrolo[2, 1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b] [1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1, 5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c] [1, 2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5 -b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3 ,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl and their derivatives. Additionally, when containing two fused rings, the heteroaryl groups as defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring.

[0069] In the context of this document, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic, fused or spiro-polycyclic carbocycle having from 3 to 18 carbon atoms per ring. the cycloalkyl ring or carbocycle may be optionally substituted with one or more substituents, eg 1 to 5 substituents, at any point of attachment. The substituents may themselves be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, decahydronaphthalenyl, octahydro-1H- indenyl, cyclopentenyl, cyclohexenyl, cyclohexa-1,4-dienyl, cyclohexa-1,3-dienyl, 1,2,3,4-tetrahydronaphthalenyl, octahydropentalenyl, Za, 4,5,6,7,7a-hexahydro-1H- indenyl, 1,2,3,3a-tetrahydropentalenyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2,2,1]hept-2-enyl, bicyclo[2,2,2]octanyl, 6-methylbicyclo[3,1,1]heptanyl, 2,6,6-trimethylbicyclo[3,1,1] heptanyl and its derivatives.

[0070] As used herein, the term "cycloalkenyl" refers to a partially saturated, monocyclic, fused, or spiro-polycyclic carbocycle having 3 to 18 carbon atoms per ring and containing at least one double bond. the cycloalkenyl ring may optionally be substituted with one or more substituents, for example 1 to 5 substituents, at any attachment point. The substituents may themselves be optionally substituted.

[0071] In the context of this document, the term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated and non-aromatic monocyclic or fused or spiro, polycyclic, ring structure of 4-18 carbon atoms containing carbon and heteroatoms taken from oxygen, nitrogen or sulfur, and moreover, the delocalized n-electrons (aromaticity) are not distributed between the ring carbon or heteroatoms. The heterocycloalkyl or heterocyclyl ring structure may be substituted with one or more substituents. The substituents may themselves be optionally substituted. Examples of heterocycloalkyl or heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl-S-thiomorpholinyl β-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinil, tropanil, homotropanil, dihydrothiophen-2(3H)-onyl, tetrahydrothiophene-1,1-dioxide, 2,5-dihydro-1H-pyrrolyl, imidazolidin-2-one, pyrrolidine -2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2-one, isothiazolidin-1,1-dioxide, 4,5-dihydro-1H-imidazolyl, 4,5-dihydrooxazolyl, oxiranil, pyrazolidinyl, 4H-1,4-thiazinyl, thiomorpholinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrazinyl, 1,3-oxazinan-2-one, tetrahydro-2H-thiopyran-1, 1-dioxide, 7-oxabicyclo[2.2.1]heptanyl, 1,2-thiazepan-1,1-dioxide, octahydro-2H-quinolisinyl, 1,3-diazabicyclo[2.2.2]octanyl, 2, 3-dihydrobenzo[b][1,4] dioxin, 3-azabicyclo[3,2,1]octanyl, 8- azaspiro[4,5]decane, 8-oxa-3-azabicyclo[3,2,1]octanyl, 2-azabicyclo[2,2,1]heptane, 2,8-diazaspiro[5,5]undecanil, 2- azaspiro[5,5]undecanil, 3-azaspiro[5,5]undecanil, decahydroisoquinolinyl, 1-oxa-8-azaspiro[4,5]decanyl, 8-azabicyclo[3,2,1]octanyl, 1,4' -bipiperidinyl, azepanil, 8-oxa-3-azabicyclo[3,2,1]octanyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydroimidazo[ 1,2-a]pyridinyl, 1,4-diazepanyl, phenoxathiinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 4- (piperidin-4-yl)morpholinyl, 3-azaspiro[5,5]undecanyl, decahydroquinolinyl, piperazin-2-one, 1-(pyrrolidin-2-ylmethyl)pyrrolidinyl, 1,3'-bipyrrolidinyl and 6,7,8 ,9-tetrahydro-1H,5H-pyrazolo[1,2-a][1,2]diazepinyl.

[0072] The numeric ranges used herein are intended to include consecutive integers. For example, a range expressed as "0 to 5" would include 0, 1, 2, 3, 4, and 5.

[0073] In the context of this document, the term "substituted" means that the specified group or fragment has one or more suitable substituents, and the substituents can connect to the specified group or fragment in one or more positions. For example, aryl substituted with cycloalkyl may indicate that the cycloalkyl is bonded to one aryl atom via a bond or fused to an aryl and has two or more atoms in common.

[0074] In the context of this document, the term "unsubstituted" means that the specified group has no substituents.

[0075] The term "optionally substituted" is intended to mean that a given chemical moiety (eg, an alkyl group) can (but need not) bind other substituents (eg, heteroatoms). For example, an alkyl group that is optionally substituted may be a fully saturated alkyl chain (ie, a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents other than hydrogen. For example, at any point in the chain, it may be linked to a halogen atom, a hydroxy group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have any additional functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, oxo, -halo, C ₁ -C ₆ alkyl, C 1 -C ₆ alkoxy, C _{1 -C 6} haloalkyl, C ₁ -C ₆ haloalkoxy, -OC ₁ -C ₆ alkenyl, -OC ₁ -C ₆ alkynyl, -C ₁ -C ₆ alkenyl, -C ₁ -C ₆ alkynyl, -OH, CN (cyano), -CH ₂ CN, -OP (O) (OH ) ₂ , -C (O) OH, -OC (O) C ₁ -C ₆ alkyl, -C (O) C ₁ -C ₆ alkyl, -C (O) -C ₀ -C ₆ alkylenyl-cycloalkyl, - C (O) -C ₀ -C ₆ alkylenyl-heterocycloalkyl, -C (O) -C ₀ -C ₆ alkylenyl-aryl, -C (O) -C ₀ -C ₆ alkylenyl-heteroaryl, -OC (O) OS ₁ -C ₆ alkyl, NH ₂ , NH (C ₁ -C ₆ alkyl), H (C ₁ -C ₆ alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)NH cycloalkyl, -C(O)N(C ₁ -C ₆ alkyl)cyclo alkyl, -C(O)NHheterocycloalkyl , -C(O)N(C ₁ -C ₆ alkyl)heterocycloalkyl, -C(O)NHaryl, -C(O)N(C ₁ -C ₆ alkyl)aryl, -C(O)NHheteroaryl, -C( O) N (C ₁ -C ₆ alkyl) heteroaryl, -S (O) ₂ -C ₁ -C ₆ alkyl, -S (O) ₂ -C ₁ -C ₆ haloalkyl, -S (O) ₂ -cycloalkyl, -S(O) ₂ -heterocycloalkyl, -S(O) ₂ - aryl, - S (O) ₂ -heteroaryl -C ₀ -C ₆ alkylenyl-S (O) ₂ NH ₂ , -S (O) ₂ NHC ₁ -C ₆ alkyl, -S (O) ₂ N (C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ NHcycloalkyl, -S(O) ₂ NHheterocycloalkyl, -S(O) ₂ NHaryl, -S(O) ₂ NHheteroaryl, -NHS(O) ₂ C ₁ -C ₆ alkyl, -N (C ₁ -C ₆ alkyl) S (O) ₂ (C ₁ -C ₆ alkyl), -NHS (O) ₂ aryl, -N (C ₁ -C ₆ alkyl) S (O) ₂ aryl, -NHS ( O) ₂ heteroaryl, -N(C ₁ -C ₆ alkyl)S(O) ₂ heteroaryl, -NHS(O) ₂ cycloalkyl, -N(C ₁ -C ₆ alkyl)S(O) ₂ cycloalkyl, -NHS( O) ₂ heterocycloalkyl, -N (C ₁ -C ₆ alkyl) S (O) ₂ heterocycloalkyl, -N (C ₁ -C ₆ alkyl) S (O) ₂ aryl, -C ₀ -C ₆ alkylenyl-aryl, - C ₀ -C ₆ alkylenyl-heteroaryl, -C ₀ -C ₆ alkylenyl-cycloalkyl, -C ₀ -C ₆ alkylenyl-heterocycloalkyl, -O-aryl, -NH-aryl N(C ₁ -C ₆ alkyl) aryl. The substituents may themselves be optionally substituted. When a multifunctional fragment is shown, the point of attachment to the core is indicated by a line, for example, (cycloalkyloxy)alkyl- means that alkyl is the point of attachment to the core, while cycloalkyl is attached to alkyl through an oxy group. "Optionally substituted" also refers to "substituted" or "unsubstituted" in the meanings described above.

[0076] As used herein, the term "oxa" refers to the "-O-" group.

[0077] As used herein, the term "oxo" refers to the group "=O".

[0078] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents, for the purposes of this disclosure, may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Solvates in which water is the solvent molecule are commonly referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing varying amounts of water.

[0079] The term "salt(s)", as used herein, means acid salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of the formula contains both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") can be formed and included in the term "salt(s)" as used in this document. Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also suitable. Salts of compounds of the formula can be obtained, for example, by reacting a compound of the formula with an amount of acid or base, such as an equivalent amount, in a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0080] In another embodiment of this invention, the compounds of formula (I) are enantiomers. In some embodiments, the compounds are the (S)-enantiomer. In other embodiments, the compounds are the (R)-enantiomer. In yet other embodiments of the invention, the compounds of formula (I) may be (+) or (-) enantiomers.

[0081] It should be understood that all isomeric forms are included in this description, including mixtures thereof. If the compound contains a double bond, the substituent may have the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have the cis or trans configuration. It is also intended that all tautomeric forms be included.

[0082] Compounds of various formulas and their salts, solvates, esters, and their prodrugs may exist in their tautomeric form (eg, as an amide or imino ester). All such tautomeric forms are considered in this document as part of this description.

[0083] Compounds of different formulas may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of various formulas, as well as mixtures thereof, including racemic mixtures, are intended to form part of this invention. In addition, this description covers all geometric and positional isomers. For example, if a compound of various formulas includes a double bond or a fused ring, both the cis and trans forms, as well as mixtures, are included within the scope of this invention. Each compound described herein includes all enantiomers that correspond to the general structure of the compound. The compounds may be in racemic or enantiomerically pure form, or in any other form in terms of stereochemistry. The results of the analysis may reflect the data collected for the racemic form, enantiomerically pure form, or any other form in terms of stereochemistry.

[0084] Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as, for example, chromatography and/or fractional crystallization. Enantiomers can be separated by converting an enantiomeric mixture to a diastereomeric mixture by reacting with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to corresponding pure enantiomers. In addition, some of the compounds of various formulas may be atropisomers (eg, substituted biaryls) and are considered part of this description. Enantiomers can also be separated using a chiral HPLC column.

[0085] It is also possible that the compounds of formula (I) may exist in different tautomeric forms, and all such forms are included within the scope of this invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in this description.

[0086] All stereoisomers (e.g., geometric isomers, optical isomers, and the like) of the compounds of this invention (including salts, solvates, esters, and prodrugs of compounds, as well as salts, solvates, and esters of prodrugs), such as those that may to exist due to the presence of asymmetric carbon atoms at various substituents, including enantiomeric forms (which can exist even in the absence of asymmetric carbon atoms), rotamer forms, atropisomers and diastereomeric forms are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4 -pyridyl and 3-pyridyl). (For example, if the compound of various formulas includes a double bond or a fused ring, both cis and trans forms, as well as mixtures are included in the scope of this invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in this specification.) Individual stereoisomers of the compounds of this invention may, for example, be substantially free of other isomers, or may be mixed, for example, as racemates or with all or other selected stereoisomers. The chiral centers of this invention may be in the S or R configuration as defined by R ⁷ PAC 1974.

[0087] This description also covers isotopically labeled compounds of this invention that are identical to those listed here, but except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number other than atomic mass or mass numbers commonly found in nature. Examples of isotopes that can be included in the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H (or D), ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively.

[0088] Certain isotopically labeled compounds of various formulas (eg, those labeled with ³ H and ¹⁴ C) are useful in tissue distribution and/or substrate distribution assays. Particularly preferred isotopes of tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) due to their ease of production and detection. Additionally, substitution with heavier isotopes such as deuterium (i.e. ² H) may provide some therapeutic benefit as a result of higher metabolic stability (e.g., increased in vivo half-life or reduced doses required), and therefore, in some situations may be preferred. Isotopically labeled compounds of various formulas can usually be obtained by following methods similar to those described in the schemes and/or in the examples below, replacing the non-isotopically labeled reagent with a suitable isotopically labeled reagent.

[0089] In some embodiments, the compounds contain at least one deuterium atom. For example, in the compound of this invention, one or more hydrogen atoms may be replaced or replaced by deuterium. In some embodiments of the invention, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms.

[0090] the Compounds of formula (I) can form salts, which are also included in the scope of this invention. Reference to a compound of formula herein is intended to include reference to its salts, unless otherwise indicated.

[0091] Provided herein are the compounds described herein and pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers or tautomers thereof, and pharmaceutical compositions containing one or more of the compounds described herein, or pharmaceutically acceptable compounds thereof. salts, enantiomers, hydrates, solvates, prodrugs, isomers or tautomers.

[0092] In this description, reference to formula (1b) includes reference to formula (1b)-1 and similarly for formula (Ic), (Id) and (Ig). In this specification, reference to, for example, formula 1b-1g includes reference to formula (1b)-1, (Ic)-1, (Id)-1, (1g)-1 and (Ih)-1

Connections

[0093] The present invention provides a compound having the structure of formula (I),

and their pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers and tautomers, wherein X ¹ , R ¹ , R ² , R ³ and R ⁴ are as described above.

[0094] The present invention provides a compound having the structure of formula (Ia),

and their pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers and tautomers, wherein X ¹ , R ¹ , R ² , R ³ and R ⁴ are as described above.

[0095] The present invention provides a compound having the structure of formula (Ib),

and their pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers and tautomers, wherein X ¹ , R ¹ , R ² , R ³ and R ⁴ are as described above.

[0096] In certain embodiments of the invention, this invention provides a compound having the structure of formula (Ib), which is formula (Ib)-1:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O, S,

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b ;

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ - -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S( O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ ,

-S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , - NR ⁶ S(O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl , heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, halogen, C ₁ - With ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[0097] The present invention provides a compound having the structure of formula (Ic),

and their pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers and tautomers, wherein X ¹ , R ¹ , R ² , R ³ and R ⁴ are as described above.

[0098] In certain embodiments of the invention, this invention provides a compound having the structure of formula (Ic), which is formula (Ic)-1:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O, S,

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b ;

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S (O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ ,

-NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S (O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₂ - C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl , heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, halogen, C ₁ - C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[0099] The present invention provides a compound having the structure of formula (Id),

and their pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers and tautomers, wherein X ¹ , R ¹ , R ² , R ³ and R ⁴ are as described above.

[00100] In certain embodiments, the invention provides a compound having the structure of formula (Id) which is formula (Id)-1:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O, S,

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

R ₂ is

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ -NR ⁶ S(O) ₂ R ⁷ , -S( O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ ,

-NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 13 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or N(C ₁ - With ₆ alkyl) ₂ ; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ ,

-S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , - NR ⁶ S(O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl , heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, halogen, C ₁ - C ₆ alkyl, -OH, -O-C ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[00101] The present invention provides a compound having the structure of formula (Ie),

and their pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers and tautomers, wherein X ¹ , R ¹ , R ² , R ³ and R ⁴ are as described above.

[00102] The present invention provides a compound having the structure of formula (If),

and their pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers and tautomers, wherein X ¹ , R ¹ , R ² , R ³ and R ⁴ are as described above.

[00103] The present invention provides a compound having the structure of formula (Ig),

and their pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers and tautomers, wherein X ¹ , R ¹ , R ² , R ³ and R ⁴ are as described above. The compounds of formula (If) do not contain a basic amino group in the substituent R ¹ . The sulfonylurea moiety in the compounds of formula (1g) displays pka values for these compounds in the range of 5.2-6.2, characterizing them as weak organic acids. Compounds of this structure may exhibit low volumes of distribution in vivo and may exhibit high plasma protein binding.

[00104] In specific embodiments, the invention provides a compound having the structure of formula (Ig) which is formula (Ig)-1:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O or S;

R ¹ is selected from the group consisting of

R ² is

X ² is N or CR ^5b1 ;

R ³ and R ⁴ are H;

R ^5a1a is H, D, halogen, OH, CN, -NO ₂ -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ ,

-NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ ,

-NH ₂ , -NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f are independently selected from H, D, halo, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -C(O)R ⁶ . -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or

-CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , -NS(O) ₂ R ⁶ ; or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f that are geminal, together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ ,

-S(O) ₂ -R ⁶ ; -COR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , or -NS(O) ₂ R ⁶ ; or

two geminal R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f can form an oxo group;

R ^5b1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl, optionally substituted with D, halogen, -CN,

-OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, NO ₂ ,

-SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or

-N(C ₁ -C ₆ alkyl) ₂ ; or

two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ ,

-NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; And

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or a heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O.

[00105] The present invention provides a compound having the structure of formula (Ih),

and their pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers and tautomers, wherein X ¹ , R ¹ , R ² , R ³ and R ⁴ are as described above. The compounds of formula (Ih) contain a basic amino group. The inclusion of a basic amino group in a compound of formula (Ih) which also has an acidic sulfonylurea moiety can be expected to exist as a zwitterion having a net charge of zero. Zwitterionic compounds may have different physicochemical properties than weak organic acids. Notably, in vivo volumes of distribution may be increased as well as reduced plasma protein binding. In specific embodiments of the invention of formula Ih, one or two R ^5a2 represent -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl or heterocyclyl containing N; where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ , and heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ - With ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C( O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ . In specific embodiments of formula Ih, one R ^5a2 is -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, or heterocyclyl containing N; where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ , and heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ - With ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C( O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ .

[00106] In certain embodiments of the invention, this invention provides a compound having the structure of formula (Ih), which is formula (Ih)-1:

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers or tautomers,

Where:

X ¹ represents O or S;

R ¹ is selected from the group consisting of

R ² is

X ² is N or CR ^5b1 ;

R ³ and R ⁴ are H;

R ^5a1a is H, D, halogen, OH, CN, -NO ₂ -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ ,

-NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ ,

-NH ₂ , -NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

each R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f are independently selected from H, -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl and heterocyclyl containing N; where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ and heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ - With ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C( O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ ;

R ^5b 1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl, optionally substituted with D, halogen, -CN,

-OR ⁶ , -NH ₂ , NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, -NO ₂ ,

-SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or

-N(C ₁ -C ₆ alkyl) ₂ ; or

two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ ,

-NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; And

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or a heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O.

или

затем по меньшей мере один А² представляет собой N, NR⁵, О, S или S(O)₂. В конкретных вариантах реализации изобретения формулы Ia-Id, где R¹ представляет собой

или

затем по меньшей мере один А² представляет собой N, NR^5a, О, S или S(O)₂.[00107] In specific embodiments of the invention of formula I, where R ¹ represents

or

then at least one A ² is N, NR ⁵ , O, S or S(O) ₂ . In specific embodiments of the invention of formula Ia-Id, where R ¹ represents

or

then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

В определенных вариантах реализации изобретения X¹ представляет собой

[00108] In certain embodiments, in the formulas described herein, X ¹ is O. In certain embodiments, X ¹ is S. In certain embodiments, X ¹ is

In certain embodiments of the invention, X ¹ is

В конкретных вариантах реализации изобретения формулы I, R² представляет собой

В конкретных вариантах реализации изобретения формулы Ia-Id, R² представляет собой

В конкретных вариантах реализации R² представляет собой

В конкретных вариантах реализации R² представляет собой

[00109] In certain embodiments, in the formulas described herein, R ² is

In specific embodiments of the invention of formula I, R ² represents

In specific embodiments of the invention of formula Ia-Id, R ² is

In particular embodiments, R ² is

In particular embodiments, R ² is

[00110] In certain embodiments of the formula described herein, R ² represents

[00111] In certain embodiments of the formula IR ⁵ is H, D, halogen, CN, OR ⁶ or C ₁ -C ₆ alkyl. In certain embodiments of the invention, R ⁵ represents H, halogen or C ₁ -C ₆ alkyl. In certain embodiments of the invention R ⁵ represents H, halogen or methyl. In certain embodiments of the invention R ⁵ represents H, fluorine, chlorine or methyl. In certain embodiments, R ⁵ is H. In certain embodiments, R ⁵ is halogen. In certain embodiments of the invention, R ⁵ is fluoro. In certain embodiments of the invention R ⁵ represents chlorine. In certain embodiments of the invention, R ⁵ is methyl.

[00112] In specific embodiments of formulas Ia-Id, R ^5b is H, D, halogen, CN, -OR ⁶ or C ₁ -C ₆ alkyl. In certain embodiments of the invention R ^5b represents H, halogen or C ₁ -C ₆ alkyl. In certain embodiments of the invention R ^5b represents H, halogen or methyl. In certain embodiments of the invention R ^5b represents H, fluorine, chlorine or methyl. In certain embodiments, R ^5b is H. In certain embodiments, R ^5b is halogen. In certain embodiments of the invention, R ^5b is fluoro. In certain embodiments of the invention R ^5b represents chlorine. In certain embodiments of the invention, R ^5b is methyl.

В конкретных вариантах реализации изобретения формулы Ia-Id R² представляет собой

В определенных вариантах реализации изобретения n равен нулю, одному или двум.[00113] In specific embodiments of Formula I, R ² is

In specific embodiments of the invention of formula Ia-Id R ² is

In certain embodiments of the invention, n is zero, one, or two.

[00114] In particular embodiments of formula I, each R ⁵ is independently H, halogen, OH, CN, -NO ₂ , -OR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₃ -C ₈ cycloalkyl. In certain embodiments of the invention, each R ⁵ is independently selected from the group consisting of H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, and -CN.

[00115] In particular embodiments of Formula Ia-Id, each R ^5b is independently H, halo, OH, CN, -NO ₂ , -OR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₃ -C ₈ cycloalkyl. In certain embodiments of the invention, each R ^5b is independently selected from the group consisting of H, halo, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, and -CN.

В конкретных вариантах реализации изобретения формулы Ia-Id, R² представляет собой

В конкретных вариантах реализации изобретения формулы I, R² представляет собой

В конкретных вариантах реализации изобретения формулы Ia-Id, R² представляет собой

[00116] In specific embodiments of Formula I, R ² is

In specific embodiments of the invention of formula Ia-Id, R ² is

In specific embodiments of the invention of formula I, R ² represents

In specific embodiments of the invention of formula Ia-Id, R ² is

,

,

,

и

. В определенных вариантах реализации изобретения, где R² выбирают из группы, состоящей из

,

и

.[00117] In certain embodiments, in the formulas described herein, R ² is selected from the group consisting of

,

,

,

And

. In certain embodiments of the invention, where R ² is selected from the group consisting of

,

And

.

.In particular embodiments, R ² is

.

где по меньшей мереодин из R^5b2, R^5b3, R^5b4, R^5b5 и R^5b6 представляет собой C₁-С₆алкил или С₃-С₈циклоалкил, причем C₁-С₆алкил и С₃-С₈циклоалкил необязательно замещены D, галогеном, -CN, -OR⁶, -NH₂, -NH(C₁-С₆алкилом) или -N(С₁-С₆алкилом)₂. В определенных вариантах реализации изобретения по меньшей мере один из R^5b2, R^5b3, R^5b4, R^5b5 и R^5b6 представляет собой C₁-С₆алкил или С₃-С₈циклоалкил, где C₁-С₆алкил и С₃-С₈циклоалкил необязательно замещены галогеном.[00118] In certain embodiments of formulas Ie-Ih, R ² is

where at least one of R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 is C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, with C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl optional substituted with D, halo, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ . In certain embodiments of the invention, at least one of R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 is C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl are optionally substituted with halogen.

[00119] In certain embodiments of the formulas described herein, R ¹ is an optionally substituted C ₁ -C ₆ alkyl. In certain embodiments of the invention, R ¹ is C ₁ -C ₆ alkyl. In certain embodiments of the invention, R ¹ is C ₁ -C ₃ alkyl. In certain embodiments of the invention, R ¹ is methyl. In certain embodiments of the invention, R ¹ is an optionally substituted C ₁ -C ₆ alkenyl. In certain embodiments of the invention, R ¹ is an optionally substituted C ₁ -C ₆ alkynyl. In certain embodiments of the invention, R ¹ is -(CH ₂ ) _m -O-(CH ₂ ) _m -CH ₃ , each m is independently an integer from one to 4.

[00120] In certain embodiments of the formulas described herein, R ¹ is selected from the group consisting of

[00121] In certain embodiments, in the formulas described herein, R ¹ is

,

,

или

[00122] In certain embodiments, in the formulas described herein, R ¹ is

,

,

or

,

,

или

[00123] In certain embodiments, in the formulas described herein, R ¹ is

,

,

or

,

,

или

.[00124] In certain embodiments, in the formulas described herein, R ¹ is

,

,

or

.

[00125] In certain embodiments, in the formulas described herein, R ¹ is

[00126] In certain embodiments, in the formulas described herein, R ¹ is

В конкретных вариантах реализации R¹ представляет собой

В некоторых вариантах реализации R¹ представляет собой

.[00127] In certain embodiments, in the formulas described herein, R ¹ is

In particular embodiments, R ¹ is

In some embodiments, R ¹ is

.

представляют собой одинарные связи в кольце, содержащем А², образуя таким образом насыщенное кольцо. В определенных вариантах реализации изобретения от одной до двух

представляют собой двойные связи в кольце, содержащем А², образуя таким образом ненасыщенное кольцо.[00128] In certain embodiments, in the formulas described herein,

are single bonds in the ring containing A ² , thus forming a saturated ring. In certain embodiments of the invention, one to two

are double bonds in the ring containing A ² , thus forming an unsaturated ring.

[00129] In specific embodiments of Formula I, A is CR ⁵ . In specific embodiments of the invention of formulas Ia-Id And represents CR ^5a . In certain embodiments of the formulas described herein, A is N.

[00130] In specific embodiments of Formula I, A ¹ is NR ⁵ . In specific embodiments of the invention of formulas Ia-Id And ¹ represents NR ^5a . In certain embodiments, in the formulas described herein, A ¹ is O. In certain embodiments, in the formulas described herein, A ¹ is S. In certain embodiments, in the formulas described herein, A ¹ is C(O).

[00131] In certain embodiments, in the formulas described herein, each A ² is independently CH ₂ or O. In certain embodiments, each A ² is CH ₂ .

[00132] In particular embodiments of Formula I, one A is CR ⁵ and the other A is N. In certain embodiments, each A ² is independently C(R ⁵ ) ₂ , NR ⁵ , or O.

[00133] In specific embodiments of Formulas Ia-Id, one A is CR ^5a and the other A is N. In certain embodiments, each A ² is independently C(R ^5a ) ₂ , NR ^5a , or O.

[00134] In particular embodiments of formula I, R ⁵ is independently H, D, halogen, OH, CN, -NO ₂ -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S( O) ₂ N(R ⁶ ) ₂ - -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S( O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ - C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH _{2 -C 3} -C ₈ cycloalkyl. In certain embodiments of the invention, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[00135] In particular embodiments of Formula Ia, each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S (O) ₂ N(R ⁶ ) ₂ - -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S (O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl. In certain embodiments of the invention, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[00136] In particular embodiments of Formula Ia, each R ^5b is independently H, D, halogen, OH, CN, NO ₂ , SR ⁶ , OR ⁶ , NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl. In certain embodiments of the invention, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[00137] In specific embodiments of the invention of formula I, two R ⁵ together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O. In certain embodiments of the invention C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[00138] In specific embodiments of the invention of formulas Ia-Id, two R ^5a together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O. In certain embodiments of the invention C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted. In certain embodiments, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OH, -NH ₂ , NH(C ₁ -C ₆ alkyl), or N(C ₁ -C ₆ alkyl) ₂ . In certain embodiments, the two R ^5a , together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl, optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH( C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ .

[00139] In certain embodiments, in the formulas described herein, two geminal R ⁵ can form an oxo group. In specific embodiments of the invention of formula Ia-Id, the two geminal R ^5a may form an oxo group.

[00140] In specific embodiments of formulas Ib-Id, each R ^5a is independently H, D, halogen, OH, CN, NO ₂ , SR ⁶ , OR ⁶ , NHR ⁶ , -NR ⁶ R ⁷ , -S(O ) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S( O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH _{2 -C 3} -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ . In certain embodiments, R ^5a is C ₁ -C ₆ alkyl optionally substituted with D, halo, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , NH(C ₁ -C ₆ alkyl), or N(C ₁ -C ₆ alkyl) ₂ . In certain embodiments, R ^5a is heterocyclyl optionally substituted with D, halo, C ₁ -C ₆ alkyl, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl), or -N(C ₁ -C ₆ alkyl) ₂ .

[00141] In specific embodiments of the invention of formulas Ib-Id, two R ^5a together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 13 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ - With ₆ alkyl) ₂ . In certain embodiments, the two R ^5a , together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl, optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH( C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ .

[00142] In specific embodiments of Formula Ib-Id, the two geminal R ^5a may form an oxo group.

[00143] In specific embodiments of formulas Ib-Id, each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ -SR ⁶ , -OR ⁶ , -NHR ⁶ , NR ⁶ R ⁷ , -S (O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S(O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ .

[00144] In specific embodiments of Formula I, each R ⁵ is independently H, -NHR ⁶ or NR ⁶ R ⁷ . In certain embodiments of the invention, each A ² is independently C(R ⁵ ) ₂ or O; and each R ⁵ is independently H, -NHR ⁶ or -NR ⁶ R ⁷ .

[00145] In particular embodiments of formulas Ia-Id, each R ^5a is independently H, -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, or heterocyclyl containing N, where C ₁ -C ₆ alkyl is substituted -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ and the heterocyclyl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ . In certain embodiments of the invention, each A ² is independently C(R ^5a ) ₂ or O; and each R ^5a is independently H, -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, or heterocyclyl containing N, where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ and heterocyclyl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ .

[00146] In certain embodiments of the formulas described herein, R ¹ is selected from the group consisting of

where R ^5a1a represents H, D, halo, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ; And

R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f are independently selected from H, -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl or heterocyclyl containing N, where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ and wherein heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ .

[00147] In certain embodiments of the formulas described herein, R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P, and O. In certain embodiments, the implementation of the invention C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted.

[00148] In certain embodiments of the formulas described herein, R ⁶ and R ⁷ together with the atom to which they are attached, can form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S , P and O. In certain embodiments of the invention heterocyclyl or heteroaryl is optionally substituted.

[00149] In specific embodiments of the invention of formulas Ib-Id, R ⁶ and R ⁷ independently represent, in each case, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, halogen, C ₁ - With ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ . In certain embodiments, R ⁶ is C ₁ -C ₆ alkyl optionally substituted with D, halo, C ₁ -C ₆ alkyl, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl), or -N( C ₁ -C ₆ alkyl) ₂ . In certain embodiments, R ⁷ is C ₁ -C ₆ alkyl optionally substituted with D, halo, C ₁ -C ₆ alkyl, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl), or -N( C ₁ -C ₆ alkyl) ₂ .

где каждый R^b10, R^b11, R^b12, R^b13, R^b14 и R^b15 независимо представляет собой Н, -ОН или оксо. В определенных вариантах реализации изобретения один из R^b10, R^b11, R^b12, R^b13, R^b14 и R^b15 представляет собой -ОН или оксо и остальные представляют собой Н. В определенных вариантах реализации изобретения один из R^b10, Rbu, R^b12, R^b13, R^b14 и R^b15 представляет собой -ОН и остальные представляют собой Н. В определенных вариантах реализации изобретения один из R^b10, R^b11, R^b12, R^b13, R^b14 и R^b15 представляет собой оксо и остальные представляют собой Н.[00150] As described above for formula Ie, R ² may be

where each R ^b10 , R ^b11 , R ^b12 , R ^b13 , R ^b14 and R ^b15 independently represents H, -OH or oxo. In certain embodiments, one of R ^b10 , R ^b11 , R ^b12 , R ^b13 , R ^b14 and R ^b15 is -OH or oxo and the remainder is H. In certain embodiments one of R ^b10 , Rbu, R ^b12 , R ^b13 , R ^b14 and R ^b15 is -OH and the rest are H. In certain embodiments, one of R ^b10 , R ^b11 , R ^b12 , R ^b13 , R ^b14 and R ^b15 is oxo and the rest are N.

[00151] As described above for Formula Ie-Ih, X ¹ is O or S. In specific embodiments of Formula Ie-Ig, X ¹ is O. In certain embodiments, X ¹ is S.

или

[00152] As described above for formula Ie-Ih, R ² is

or

[00153] In particular embodiments of formula Ie-Ih, R ² is

[00154] As described above for the formula Ie-Ih X ² is N or CR ^5b1 . In specific embodiments of the invention of formula Ie-Ih X ² is CR ^5b1 . In specific embodiments of the invention, X ² is N.

[00155] As described above for formula Ie-Ih, R ^5b1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ .

[00156] In specific embodiments of formula Ie-Ih, R ^5b1 is H, halogen, or C ₁ -C ₆ alkyl. In certain embodiments of the invention R ^5b1 represents H, halogen or methyl. In certain embodiments of the invention R ^5b1 represents H, fluorine, chlorine or methyl. In certain embodiments, R ^5b1 is H. In certain embodiments, R ^5b1 is halogen. In certain embodiments of the invention, R ^5b1 is fluoro. In certain embodiments of the invention R ^5b1 represents chlorine. In certain embodiments of the invention, R ^5b1 is methyl. In particular embodiments of formula Ie-Ih, R ^5b1 is an optionally substituted C ₁ -C ₆ alkyl. In certain embodiments of the invention R ^5b1 represents C ₁ -C ₆ alkyl, optionally substituted with halogen. In certain embodiments of the invention, R ^5b1 is -OR ⁶ . In certain embodiments of the invention, R ^5b1 represents -OH.

В конкретных вариантах реализации R² представляет собой

[00157] In particular embodiments of formula Ie-Ih, R ² is

In particular embodiments, R ² is

[00158] In particular embodiments of formula Ie-Ih, R ² is

[00159] As described above for formula Ie-Ih, each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, -NO ₂ -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached may form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl , aryl or heteroaryl is optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ .

[00160] In certain embodiments of Formula Ie-Ih, each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 is independently H, D, halogen, OH, CN, -NO ₂ , -OR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₃ -C ₈ cycloalkyl. In certain embodiments of the invention, each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 is independently selected from the group consisting of H, D, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl and -CN. In certain embodiments of the invention, at least one of R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 is not hydrogen. In certain embodiments of the invention, one of R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 is -OR ⁶ . In certain embodiments of the invention, one of R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 is —OH.

В конкретных вариантах реализации изобретения формулы Ie-Ih R² представляет собой

[00161] In particular embodiments of formula Ie-Ih, R ² is

In specific embodiments of the invention of the formula Ie-Ih R ² is

В определенных вариантах реализации изобретения, где R² выбирают из группы, состоящей из

В конкретных вариантах реализации R² представляет собой

[00162] In specific embodiments of the invention of formula Ie-Ih R ² is selected from the group consisting of

In certain embodiments of the invention, where R ² is selected from the group consisting of

In particular embodiments, R ² is

[00163] In specific embodiments of the invention of formula Ie-Ih, two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ . In certain embodiments of the invention, two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl, where C ₃ -C ₈ cycloalkyl and heterocyclyl optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ .

В определенных вариантах реализации изобретения каждый R^5b2 и R^5b4 выбирают из группы, состоящей из Н, D, галогена, C₁-С₆алкила, С₃-С₈циклоалкила и -CN.[00164] In particular embodiments of formula Ie-Ih, R ² is

In certain embodiments of the invention, each R ^5b2 and R ^5b4 is selected from the group consisting of H, D, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl and -CN.

[00165] In particular embodiments of formula Ie-Ih, R ² is

[00166] As described above for formula Ie-Ih R ¹ is selected from the group consisting of

при этом

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо.

wherein

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring.

представляют одинарную связь. В конкретных вариантах реализации изобретения формулы Ie-Ih

представляет двойную связь. В определенных вариантах реализации изобретения

представляют собой одинарные связи в кольце, содержащем А², образуя таким образом насыщенное кольцо.[00167] In specific embodiments of the invention of the formula Ie-Ih

represent a single bond. In specific embodiments of the invention of the formula Ie-Ih

represents a double bond. In certain embodiments of the invention

are single bonds in the ring containing A ² , thus forming a saturated ring.

[00168] In particular embodiments of formula Ie-Ih, R ¹ is

In certain embodiments of the invention, R ¹ is

или

or

[00169] As described above for formula Ie-Ih, each A is independently CR ^5a1 or N; and each A ² is independently CR ^5a2 , C(R ^5a2 ) ₂ , N, NR ^5a2 , O, S or S(O) ₂ .

[00170] In specific embodiments of Formula Ie-Ih, one A is CR ^5a1 and the other A is N. In certain embodiments, each A ² is independently C(R ^5a2 ) ₂ , NR ^5a2 or O.

[00171] As described above for formula Ie-Ih, each R ^5a1 is independently H, D, halogen, OH, CN, NO ₂ , SR ⁶ , -OR 6 , -NHR ⁶ , ^{-NR 6 R 7} , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ .

[00172] In specific embodiments of formula Ie-Ih, each R ^5a1 is independently H, halogen, OH,

-OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or heterocyclyl, where C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ ,

-NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ .

[00173] As described above for formula Ie-Ih, each R ^5a2 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ . -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ - C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ ,

-S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or two geminal R ^5a2 may form an oxo group;

[00174] In specific embodiments of formulas Ie, If, and Ig, each R ^5a2 is independently H, halogen, OH, -OR ⁶ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, or heterocyclyl; where C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ .

[00175] In particular embodiments of Formulas Ie, If, and Ih, each R ^5a2 is independently H, halo, OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or heterocyclyl; where C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or NR ⁶ C(O)R ⁶ .

[00176] In specific embodiments of formulas Ie, If, and Ih, each R ^5a2 is independently H,

-NHR ⁶ or C ₁ -C ₆ alkyl; where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ . In certain embodiments of the invention, each R ^5a2 is independently H or a heterocyclyl containing N; wherein the heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ .

[00177] In particular embodiments of formula Ie, If, each A ² is independently C(R ^5a2 ) ₂ or O; and each R ^5a2 is independently H, -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, or heterocyclyl containing N; where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH (C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) ₂ and heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O )R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ .

[00178] In specific embodiments of formulas Ie-Ih, two geminal R ^5a2 may form an oxo group.

[00179] In particular embodiments of formulas Ie-If, R ¹ is selected from the group consisting of

where R^5a1a is H, D, halogen, OH, CN, -NO₂, -SR⁶, -OR⁶, -NHR⁶, -NR⁶R⁷,

-NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f are independently selected from H, D, halo, OH, CN, -NO2-SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ . -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ - C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f that are geminal, together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ ,

-NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ ,

-NR ⁶ C(O)NR ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or

two geminal R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f can form an oxo group.

[00180] In specific embodiments of the invention, formula Ie-Ig R ¹ is selected from the group consisting of

where R ^5a1a represents H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ ,

-NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)0R ⁶ or -NR ⁶ C(O)R ⁶ ;

R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f are selected from H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -C(O)R ⁶ , - S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ ;; or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f that are geminal, together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ ,

-S(O) ₂ -R ⁶ ; -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two geminal R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f can form an oxo group.

[00181] In specific embodiments of the invention, the formulas Ie-If and Ih R ¹ are selected from the group consisting of

where R ^5a1a represents H, D, halo, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ; And

R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f are independently selected from H, -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl or heterocyclyl containing N; where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ and heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ - With ₆ alkyl, -OR ⁶ , -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ ,

-NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ .

В определенных вариантах реализации изобретения один А представляет собой CR^5a1 и другой А представляет собой N. В определенных вариантах реализации изобретения каждый А² независимо представляет собой C(R^5a2)₂, NR^5a2 или О. В определенных вариантах реализации изобретения, где каждый R^5a2 независимо представляет собой Н, галоген, ОН, -OR⁶, -NHR⁶, -NR⁶R⁷, C₁-С₆алкил, С₃-С₈циклоалкил, гетероциклил, арил, гетероарил или -СН₂-С₃-С₈циклоалкил. В определенных вариантах реализации изобретения, где два R^5a2 вместе с атомами, к которым они присоединены, могут образовывать С₃-С₈циклоалкил или гетероциклил.[00182] In certain embodiments, in the formulas described herein, R ¹ is

In certain embodiments, one A is CR ^5a1 and the other A is N. In certain embodiments, each A ² is independently C(R ^5a2 ) ₂ , NR ^5a2 , or O. In certain embodiments, where each R ^5a2 is independently H, halogen, OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, or -CH ₂ -C ₃ -C ₈ cycloalkyl. In certain embodiments of the invention, where two R ^5a2 together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

который представляет собой формулу

где:[00183] In certain embodiments, in the formulas described herein, R ¹ is

which is the formula

Where:

A ^2ab is selected from CR ^5a2 , C(R ^5a2a )(R ^5a2b ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2cd is selected from CR ^5a2 , C(R ^5a2c )(R ^5a2d ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2ef is selected from CR ^5a2 , C(R ^5a2e )(R ^5a2f ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2gh is selected from CR ^5a2 , C(R ^5a2g )(R ^5a2h ), N, NR ^5a2 , O, S or S(O) ₂ ;

each R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h independently represent H, D, halo, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , - NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or

two geminal R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h can form an oxo group.

[00184] In certain embodiments, in the formulas described herein, R ¹ is

where R ^5ala is H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ ,

-NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

R ^5a2c and R ^5a2d are each independently H, D, halogen, OH, CN, -NO ₂ , SR ⁶ , OR ⁶ ,

-NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ ,

-NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2c and R ^5a2d together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2c and R ^5a2d may form an oxo group.

[00185] In certain embodiments of the invention, each R ^5a2c and R ^5a2d independently represents H, halogen, OH,

-OR ⁶ , -NHR ⁶ , NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl. In certain embodiments of the invention, each R ^5a2c and R ^5a2d independently represents H, halogen, OH,

OR ⁶ , NHR ⁶ or -NR ⁶ R ⁷ . In certain embodiments, one of R ^5a2c and R ^5a2d is H and the other is independently halogen, OH, -OR ⁶ , -NHR ⁶ , or -NR ⁶ R ⁷ . In certain embodiments of the invention, R ^5a2c and R ^5a2d , together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

где[00186] In certain embodiments, in the formulas described herein, R ¹ is

Where

^R5a2a and ^R5a2b ; each independently are H, D, halogen, OH, CN, -NO ₂ , SR ⁶ , OR ⁶ ,

-NHR ⁶ , NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ ,

-NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2a and R ^5a2b together with the atoms to which they are attached may form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2a and R ^5a2b may form an oxo group.

[00187] In certain embodiments of the invention, each R ^5a2a and R ^5a2b independently represents H, halogen, OH, -OR ⁶ ,

-NHR ⁶ , NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl. In certain embodiments of the invention, each R ^5a2a and R ^5a2b independently represents H, halogen, OH,

-OR ⁶ , -NHR ⁶ or NR ⁶ R ⁷ . In certain embodiments, one of R ^5a2a and R ^5a2b is H and the other is independently halogen, OH, -OR ⁶ , NHR ⁶ , or -NR ⁶ R ⁷ . In certain embodiments of the invention, R ^5a2a and R ^5a2b , together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

где[00188] In certain embodiments, in the formulas described herein, R ¹ is

Where

R ^5a2e and R ^5a2f are each independently H, D, halogen, OH, CN, -NO ₂ ,

-SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or

-CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ ,

-NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2e and R ^5a2f together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2e and R ^5a2f may form an oxo group.

[00189] In certain embodiments of the invention, each R ^5a2e and R ^5a2f independently represents H, halogen, OH, -OR ⁶ ,

-NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ picloalkyl, heterocyclyl, aryl, heteroaryl or -CH _{2 -C 3} -C ₈ cycloalkyl. In certain embodiments of the invention, each R ^5a2e and R ^5a2f independently represents H, halogen, OH,

-OR ⁶ , -NHR ⁶ or -NR ⁶ R ⁷ . In certain embodiments, one of R ^5a2e and R ^5a2f is H and the other is independently halogen, OH, -OR ⁶ , -NHR ⁶ , or -NR ⁶ R ⁷ . In certain embodiments of the invention, R ^5a2e and R ^5a2f , together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

где[00190] In certain embodiments, in the formulas described herein, R ¹ is

Where

R^5a2c and R^5a2d, each independently, are H, D, halogen, OH, CN, -NO₂, -SR⁶, -OR⁶,

-NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ ,

-NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2c and R ^5a2d together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ ; or

R ^5a2c and R ^5a2d may form an oxo group.

[00191] In certain embodiments of the invention, each R ^5a2c and R ^5a2d independently represents H, halogen, OH, -OR ⁶ ,

-NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH _{2 -C 3} -C ₈ cycloalkyl. In certain embodiments of the invention, each R ^5a2c and R ^5a2d independently represents H, halogen, OH,

OR ⁶ , NHR ⁶ or -NR ⁶ R ⁷ . In certain embodiments, one of R ^5a2c and R ^5a2d is H and the other is independently halogen, OH, -OR ⁶ , -NHR ⁶ , or NR ⁶ R ⁷ . In certain embodiments of the invention, R ^5a2c and R ^5a2d , together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

[00192] In certain embodiments, in the formulas described herein, R ¹ is selected from the group consisting of

представляет собой связь с остальным соединением.and

represents a link to the rest of the compound.

причем

представляет собой связь с остальным соединением.[00193] In certain embodiments of the formulas described herein, R ¹ is selected from the group consisting of

and

represents a link to the rest of the compound.

причем

представляет собой связь с остальным соединением.[00194] In certain embodiments of the formulas described herein, R ¹ is selected from the group consisting of

and

represents a link to the rest of the compound.

В определенных вариантах реализации изобретения один А представляет собой CR^5a1 и другой А представляет собой N. В определенных вариантах реализации изобретения каждый А² независимо представляет собой C(R^5a2)₂, NR^5a2 или О. В определенных вариантах реализации изобретения, где каждый R^5a2 независимо представляет собой Н, галоген, ОН, -OR⁶, -NHR⁶, NR⁶R⁷, C₁-С₆алкил, С₃-С₈циклоалкил, гетероциклил, арил, гетероарил или -СН₂-С₃-С₈циклоалкил. В определенных вариантах реализации изобретения, где два R^5a2 вместе с атомами, к которым они присоединены, могут образовывать С₃-С₈циклоалкил или гетероциклил.[00195] In certain embodiments, in the formulas described herein, R ¹ is

In certain embodiments, one A is CR ^5a1 and the other A is N. In certain embodiments, each A ² is independently C(R ^5a2 ) ₂ , NR ^5a2 , or O. In certain embodiments, where each R ^5a2 independently represents H, halogen, OH, -OR ⁶ , -NHR ⁶ , NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, or -CH ₂ -C ₃ - C ₈ cycloalkyl. In certain embodiments of the invention, where two R ^5a2 together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

который представляет собой формулу

где[00196] In certain embodiments, in the formulas described herein, R ¹ is

which is the formula

Where

A ^2ab is selected from CR ^5a2 , C(R ^5a2a )(R ^5a2b ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2cd is selected from CR ^5a2 , C(R ^5a2c )(R ^5a2d ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2ef is selected from CR ^5a2 , C(R ^5a2e )(R ^5a2f ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2gh is selected from CR ^5a2 , C(R ^5a2g )(R ^5a2h ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2ij is selected from CR ^5a2 , C(R ^5a2i )(R ^5a2j ), N, NR ^5a2 , O, S or S(O) ₂ ;

each R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g , R ^5a2h , R ^5a2i and R ^5a2j are independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ ,

-C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, or - CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g , R ^5a2h , R ^5a2i and R ^5a2j together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ ,

-NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or

two geminal R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g , R ^5a2h , R ^5a2i and R ^5a2j can form an oxo group.

[00197] In certain embodiments of the invention in the formulas described herein, R ¹ is

В определенных вариантах реализации изобретения один А представляет собой CR^5a1 и другой А представляет собой N. В определенных вариантах реализации изобретения каждый А² независимо представляет собой C(R^5a2)₂, NR^5a2 или О. В определенных вариантах реализации изобретения, где каждый R^5a2 независимо представляет собой Н, галоген, ОН, OR⁶, NHR⁶, -NR⁶R⁷, C₁-С₆алкил, С₃-С₈циклоалкил, гетероциклил, арил, гетероарил или -СН₂-С₃-С₈циклоалкил. В определенных вариантах реализации изобретения, где два R^5a2 вместе с атомами, к которым они присоединены, могут образовывать С₃-С₈циклоалкил или гетероциклил.[00198] In certain embodiments, in the formulas described herein, R ¹ is

In certain embodiments, one A is CR ^5a1 and the other A is N. In certain embodiments, each A ² is independently C(R ^5a2 ) ₂ , NR ^5a2 , or O. In certain embodiments, where each R ^5a2 independently represents H, halogen, OH, OR ⁶ , NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, or -CH ₂ -C ₃ -C ₈ cycloalkyl. In certain embodiments of the invention, where two R ^5a2 together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

который представляет собой формулу

где[00199] In certain embodiments of the invention in the formulas described herein, R ¹ is

which is the formula

Where

A ^2ab is selected from C(R ^5a2a )(R ^5a2b ), NR ^5a2 , O, S or S(O) ₂ ;

A ^2cd is selected from C(R ^5a2c )(R ^5a2d ), NR ^5a2 , O, S or S(O) ₂ ;

A ^2ef is selected from C(R ^5a2e )(R ^5a2f ), NR ^5a2 , O, S or S(O) ₂ ;

each R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f are independently H, D, halogen, OH, CN,

-NO ₂ , -SR ⁶ , -OR ⁶ , NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O )NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or

-CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ ,

-NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ ; or

the two geminal R ^5a2a , R ^5a2b , R ^5a2c , -R ^5a2d , -R ^5a2e and R ^5a2f can form an oxo group.

[00200] In certain embodiments of the invention in the formulas described herein, R ¹ is

В определенных вариантах реализации изобретения один А представляет собой CR^5a1 и другой А представляет собой N. В определенных вариантах реализации изобретения каждый А² независимо представляет собой C(R^5a2)₂, NR^5a2 или О. В определенных вариантах реализации изобретения, где каждый R^5a2 независимо представляет собой Н, галоген, ОН, OR⁶, NHR⁶, NR⁶R⁷, C₁-С₆алкил, С₃-С₈циклоалкил, гетероциклил, арил, гетероарил или -СН₂-С₃-С₈циклоалкил. В определенных вариантах реализации изобретения, где два R^5a2 вместе с атомами, к которым они присоединены, могут образовывать С₃-С₈циклоалкил или гетероциклил.[00201] In certain embodiments, in the formulas described herein, R ¹ is

In certain embodiments, one A is CR ^5a1 and the other A is N. In certain embodiments, each A ² is independently C(R ^5a2 ) ₂ , NR ^5a2 , or O. In certain embodiments, where each R ^5a2 independently represents H, halogen, OH, OR ⁶ , NHR ⁶ , NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl. In certain embodiments of the invention, where two R ^5a2 together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

который представляет собой формулу

где[00202] In certain embodiments of the invention in the formulas described herein, R ¹ is

which is the formula

Where

A ^2ab is selected from CR ^5a2 , C(R ^5a2a )(R ^5a2b ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2cd is selected from CR ^5a2 , C(R ^5a2c )(R ^5a2d ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2ef is selected from CR ^5a2 , C(R ^5a2e )(R ^5a2f ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2gh is selected from CR ^5a2 , C(R ^5a2g )(R ^5a2h ), N, NR ^5a2 , O, S or S(O) ₂ ;

each R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h independently represent H, D, halo, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , - NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ ,

-C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, or - CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or

-NR ⁶ S(O) ₂ R ⁶ , or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ or

two geminal R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h can form an oxo group.

[00203] The present invention provides a compound of formula Ie-If, wherein

X ¹ is O;

R ¹ is selected from the group consisting of

представляет одинарную связь;Where

represents a single bond;

each A ² is independently C(R ^5a2 ) ₂ or O;

X ² is CR ^5b1 ;

each R ^5a1 is independently H or C ₁ -C ₆ alkyl; where C ₁ -C ₆ alkyl is optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or NR ⁶ C(O)R ⁶ ;

each R ^5a2 is independently H, halogen, OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl or heterocyclyl; where C ₁ -C ₆ alkyl and heterocyclyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C (O)OR ⁶ or -NR ⁶ C(O)R ⁶ ; or

two R ^5a2 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ or -S(O) ₂ -R ⁶ ; or

two geminal R ^5a2 can form an oxo group;

R ^5b1 represents H, D, halogen or C ₁ -C ₆ alkyl;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, -CN, -OR ⁶ , C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 HR ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with halogen or C ₁ -C ₆ alkyl; And

R ⁶ and R ⁷ independently represent, at each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkynyl or aryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkynyl and aryl, optionally substituted with D, halogen or C ₁ -C ₆ alkyl.

[00204] In certain embodiments of the invention, the compound has the formula:

[00205] In certain embodiments of the invention, the compound has the formula:

[00206] In certain embodiments of Formula (I), X ¹ is

is O and R ² is

[00207] In certain embodiments of Formula (I), X ¹ is O and R ¹ is

и R² представляет собой

[00208] In certain embodiments of Formula (I), R ¹ is

and R ² is

[00209] In some embodiments, this invention provides a compound of formula (I):

having one, two or three of the following:

a) X is O;

b) R ¹ is

c) R ² is

d) X ² is CH or CF.

[00210] In some embodiments, this invention provides a compound of formula (I):

having one, two or three of the following:

a) X is O;

b) R ¹ is

c) R ² is

d) X ² is CH.

[00211] In some embodiments, this invention provides a compound of formula (I):

having one, two or three of the following:

a) X is S;

b) R ¹ is

c) R ² is

d) X ² is CH.

[00212] In some embodiments, this invention provides a compound of formula (I):

having one, two or three of the following:

a) X is O;

b) R ¹ is methyl;

c) R ² is

d) X ² is CH.

[00213] In some embodiments, this invention provides a compound of formula (I):

having one, two or three of the following:

a) X is S;

b) R ¹ is methyl;

c) R ² is

d) X ² is CH.

[00214] In some embodiments, this invention provides a compound of formula (I):

having one, two or three of the following:

a) X is O;

b) R ¹ is

c) R ² is

d) X ² is CH.

[00215] In some embodiments, this invention provides a compound of formula Ie-If,

having one, two or three of the following:

a) X is O;

b) R ¹ is

c) one of R ^5a2c and R ^5a2d is H and the other is independently halogen, OH, -OR ⁶ , -NHR ⁶ or -NR ⁶ R ⁷ ;

d) R ² is

e) X ² is CH or CF.

[00216] In some embodiments, this invention provides a compound of formula (I):

having one, two or three of the following:

a) X is O;

b) R ¹ is

c) R ² is

[00217] In certain embodiments, this invention provides

N-((1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-3-sulfonamide and pharmaceutically acceptable salts thereof.

[00218] In certain embodiments, this invention provides

N-((1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl)methanesulfonamide and pharmaceutically acceptable salts thereof.

[00219] In certain embodiments, this invention provides

and its pharmaceutically acceptable salts.

[00220] In certain embodiments, this invention provides

and its pharmaceutically acceptable salts.

[00221] In certain embodiments, this invention provides

and its pharmaceutically acceptable salts.

[00222] In certain embodiments, this invention provides

and its pharmaceutically acceptable salts.

[00223] In certain embodiments, this invention provides

and its pharmaceutically acceptable salts.

[00224] In certain embodiments, this invention provides

and its pharmaceutically acceptable salts.

[00225] In certain embodiments, this invention provides

and its pharmaceutically acceptable salts.

[00226] In certain embodiments, this invention provides

and its pharmaceutically acceptable salts.

[00227] In certain embodiments of the invention, this invention relates to a compound and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers selected from the group consisting of:

[00228] In certain embodiments of the invention, this invention relates to a compound and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers selected from the group consisting of:

[00229] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00230] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00231] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00232] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00233] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00234] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00235] In certain embodiments, the invention provides the following compounds and pharmaceutically acceptable salts thereof:

[00236] In certain embodiments, the invention provides the following compounds and pharmaceutically acceptable salts thereof:

[00237] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00238] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00239] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00240] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00241] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00242] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers

[00243] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00244] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00245] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00246] In certain embodiments, the invention provides the following compounds and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers:

[00247] Unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having this structure, except for the replacement of a hydrogen atom with deuterium or tritium, or the replacement of a carbon atom with ¹³ C or ¹⁴ C, or the replacement of a nitrogen atom with ¹⁵ N, or the replacement of an oxygen atom with ¹⁷ O or ¹⁸ O, are within the scope of this description. Such isotopically labeled compounds are useful as research or diagnostic tools.

Methods of treatment

[00248] The described compounds (for example, compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig and Ih) and their pharmaceutically acceptable salts have activity as pharmaceutical agents, as discussed in this document.

[00249] The present invention provides a method for treating or preventing a disease, disorder or condition, comprising the step of administering an effective amount of a compound of the present invention and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers thereof to treat or prevent the disease, disorder or condition in a subject in need.

[00250] This invention provides a compound of this invention and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers thereof, or a pharmaceutical composition of this invention for use in the treatment or prevention of a disease, disorder or condition in a subject in need thereof.

[00251] This invention provides the use of a compound of this invention and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers thereof for the treatment or prevention of a disease, disorder or condition in a subject in need thereof.

[00252] This invention provides the use of a compound of this invention and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.

[00253] In certain embodiments, the disease, disorder, or condition is responsive to inhibition of inflammasome activation. In specific embodiments of the invention, the disease, disorder or condition is responsive to inhibition of NLRP3 inflammasome activation.

[00254] According to this embodiment, the compound of this invention, or a pharmaceutically effective salt, solvate, or prodrug thereof, is a specific inhibitor of NLRP3.

[00255] In additional embodiments, the disease, disorder, or condition is responsive to modulation 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 certain embodiments of the invention, the disease, disorder or condition is responsive to the modulation of one or more IL-1β and IL-18.

[00256] In one embodiment, the modulation 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 one embodiment, the modulation is the inhibition of one or more of IL-1β and IL-18.

[00257] In one embodiment, the modulation of Th17 cells is to inhibit the production and/or secretion of IL-17.

[00258] In a general embodiment, the disease, disorder or condition is a disease, disorder or condition of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, respiratory system, central nervous system, is cancer or other malignant neoplasms and/or caused by or associated with a pathogen.

[00259] It is understood that these general embodiments of the invention, defined in accordance with the broad categories of diseases, disorders and conditions, are not mutually exclusive. In this regard, any particular disease, disorder, or condition may be classified according to more than one of the aforementioned general embodiments. A non-limiting example is type I diabetes, which is an autoimmune and endocrine disorder.

[00260] In one embodiment, the disease, disorder or condition is associated with the immune system. In specific embodiments, the disease, disorder, or condition is an inflammatory disease, disorder, or condition, or an autoimmune disease, disorder, or condition.

[00261] In one embodiment, the disease, disorder, or condition is associated with the liver.

[00262] In one embodiment, the disease, disorder, or condition is associated with the lungs.

[00263] In one embodiment, the disease, disorder, or condition is associated with the skin.

[00264] In one embodiment, the disease, disorder, or condition is associated with the cardiovascular system.

[00265] In one embodiment, the disease, disorder, or condition is a cancer, tumor, or other malignancy. As used herein, cancers and malignancies referring to diseases, disorders or conditions or cells or tissues associated with diseases, disorders or conditions characterized by aberrant or abnormal cell proliferation, differentiation and/or migration, often accompanied by aberrant or abnormal a molecular phenotype that includes one or more genetic mutations or other genetic changes associated with tumorigenesis, expression of tumor markers, loss of tumor suppressor expression or activity, and/or aberrant or abnormal expression of a cell surface marker. In general embodiments, various cancers, tumors, and malignancies may include, but are not limited to, sarcomas, lymphomas, leukemias, solid tumors, blastomas, gliomas, carcinomas, melanomas, and metastatic cancers. A more complete list of cancers and malignancies can be found at the National Cancer Institute website http://www.cancer.gov/cancertopics/types/alphalist, which is incorporated herein by reference in its entirety.

[00266] In one embodiment, the disease, disorder, or condition is associated with the renal system.

[00267] In one embodiment, the disease, disorder, or condition is associated with the gastrointestinal tract.

[00268] In one embodiment, the disease, disorder, or condition is associated with the respiratory system.

[00269] In an additional embodiment of the invention, the disease, disorder or condition is associated with the endocrine system.

[00270] In one embodiment, the disease, disorder, or condition is associated with the central nervous system (CNS).

[00271] In one embodiment, the disease, disorder, or condition is caused by or associated with a pathogen. The pathogen may be a virus, bacterium, protist, worm or fungus, or any other organism capable of infecting a mammal, but not limited to.

[00272] Non-limiting examples of viruses include influenza virus, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus (HIV), alpha virus such as Chikungunya and Ross River virus, flaviviruses such as dengue virus, Zika virus, and papilloma virus, although not limited to them.

[00273] 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, Pasteureiium tuberculosis, mycobacteria, Shigella Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi и Yersinia pestis , although not limited to them.

[00274] Non-limiting examples of protists include, but are not limited to, Plasmodium, Babesia, Giardia, Entamoeba, Leishmania, and Trypanosomes.

[00275] Non-limiting examples of worms include worms, including but not limited to shale, roundworms, tapeworms, and flukes.

[00276] Non-limiting examples of fungi include, but are not limited to, Candida and Aspergillus species.

[00277] In specific embodiments, the disease, disorder, or condition is selected from the group consisting of constitutive inflammation, including cryopyrin-associated periodic syndromes (CAPS): Mackle-Wales syndrome (MWS), familial cold auto-inflammatory syndrome (FCAS), and multisystem inflammatory disease of neonatal age (NOMID); including autoinflammatory diseases: familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), interleukin 1 receptor antagonist deficiency (DIRA), syndrome Majida, pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated auto-inflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD); Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (S ARNO); autoimmune diseases including multiple sclerosis (PC), type 1 diabetes, psoriasis, rheumatoid arthritis, Behçet's disease, Sjögren's syndrome and Schnitzler's syndrome; respiratory diseases, including idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, and cystic fibrosis; diseases of the central nervous system, including Parkinson's disease, Alzheimer's disease, motor neurone disease, Huntington's disease, cerebral malaria, and brain damage from pneumococcal meningitis; metabolic diseases, including type 2 diabetes, atherosclerosis, obesity, gout, pseudo-gout; eye diseases, including ocular epithelial diseases, age-related macular degeneration (AMD), corneal infection, uveitis, and dry eyes; kidney diseases, including chronic kidney disease, oxalate nephropathy and diabetic nephropathy; liver disease, including non-alcoholic steatohepatitis and alcoholic liver disease; inflammatory reactions in the skin, including contact hypersensitivity and sunburn; inflammatory reactions in the joints, including osteoarthritis, systemic juvenile idiopathic arthritis, adult Still's disease, relapsing polychondritis; viral infections, including alpha virus (Chikungunya, Ross River) and flavivirus (Dengue and Zika virus), influenza, HIV; purulent hidradenitis (HS) and other cystic skin diseases; cancers including lung cancer metastases, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia; polymyositis; stroke myocardial infarction; graft-versus-host disease; hypertension; colitis; helminth infections; bacterial infection; aneurysms of the abdominal aorta; wound treatment; depression, psychological stress; pericarditis, including Dressler's syndrome, ischemic reperfusion injury, and any disease in which a person is determined to have a germline or somatic non-silent mutation in NLRP3.

[00278] In one non-limiting example of those described, the disease, disorder, or condition being treated is NASH. NLRP3-inflammasome activation is central to inflammatory recruitment in NASH, and inhibition of NLRP3 can both prevent and reverse liver fibrosis. The compounds of this invention, by interrupting the function of NLRP3 inflammasomes in liver tissue, can cause a histological reduction in liver inflammation, a decrease in macrophage and neutrophil recruitment, and suppression of NF-κB activation. Inhibition of NLRP3 can reduce hepatic expression of npo-IL-1β and normalized hepatic and circulating levels of IL-1β, IL-6 and MCP-1, thereby contributing to the treatment of the disease.

[00279] In another non-limiting example of reported cases, the disease, disorder, or condition being treated is severe steroid-resistant (SSR) asthma. Respiratory infections induce the NLRP3/caspase-1/IL-Iβ inflammasome signaling axis in the lungs, which contributes to SSR asthma. The NLRP3 inflammasome recruits and activates pro-caspase-1 to induce IL-1β responses. Therefore, NLRP3 inflammasome-induced IL-β responses are important for infection control, however, excessive activation leads to aberrant inflammation and is associated with the pathogenesis of asthma SSR and COPD. Administration of compounds of this invention that target specific disease processes are more therapeutically attractive than non-specific inhibition of inflammatory responses by steroids or IL-1β. Therefore, targeting the NLRP3/caspase-l/IL-1β inflammasome signaling axis with be useful in the treatment of SSR asthma and other steroid-resistant inflammatory conditions.

[00280] In another non-limiting example of the diseases described, the disease, disorder, or condition being treated is Parkinson's disease. Parkinsonism is the most common neurodegenerative movement disorder and is characterized by a selective loss of dopaminergic neurons accompanied by an accumulation of misfolded α-synuclein (Syn) in Lewy bodies, which are pathological features of the disease. Chronic microglial neuroinflammation appears early in the disease and is thought to lead to pathology.

[00281] A central role for microglial NLRP3 has been postulated in the progression of Parkinson's disease. The NLRP3 inflammasome is activated by fibrillar Syn via a Syk kinase-dependent mechanism and also occurs in the absence of Syn pathology in the early stages of dopaminergic degeneration and leads to neuronal loss. The compounds of this invention can block the activation of the NLRP3 inflammasome by Syn fibrillar or mitochondrial dysfunction and thus provide effective neuroprotection of the nigrostriatal dopaminergic system and help in the treatment of Parkinson's disease.

[00282] In certain embodiments, the method treats or prevents a disease or disorder, including, but not limited to, bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, liver fibrosis, hepatic steatosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

[00283] In certain embodiments, the disease, disorder, or condition is selected from the group consisting of NASH (non-alcoholic steatohepatitis); 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; onset of Still's disease in adults; systemic juvenile idiopathic arthritis; tumor necrosis factor receptor-associated periodic syndrome (TRAPS); colchicine-resistant familial Mediterranean fever (FMF), hyper-IgD syndrome (HIDS)/mevalonate kinase deficiency (MKD); traumatic brain injury; Parkinson's disease; inflammatory acne of moderate or severe degree; acute non-anterior non-infectious uveitis (NIU); AD (Alzheimer's disease); COPD (chronic obstructive pulmonary disease); sepsis; MS (multiple sclerosis); Behçet'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 skin ulcer; lupus nephritis; epilepsy; ischemic attack; deafness; sickle cell anemia; SLE (systemic lupus erythematosus); and spinal cord injury.

[00284] For the aforementioned therapeutic uses, the dosage administered will, of course, vary depending on the compound used, the route of administration, the treatment desired, and the disorder in question. For example, a daily inhalation dose of a compound of this invention may range from about 0.05 micrograms per kilogram of body weight (μg/kg) to about 100 micrograms per kilogram of body weight (μg/kg). Alternatively, if the compound is administered orally, the daily dose of the compound of this invention may range from about 0.01 micrograms per kilogram of body weight (μg/kg) to about 100 milligrams per kilogram of body weight (mg/kg).

Pharmaceutical compositions

[00285] The described compounds (for example, compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig and Ih) and their pharmaceutically acceptable salts can be used alone, but they are usually administered in the form of a pharmaceutical composition in which a disclosed compound/salt (eg, compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig and Ih and their salts) (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical preparations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", M.E. Aulton, Churchill Livingstone, 1988, which is hereby incorporated by reference in its entirety.

[00286] Depending on the route of administration, the pharmaceutical composition will be from about 0.05 to about 99% wt. (percent by weight), more specifically from about 0.05 to about 80% wt., even more specifically from about 0.10 to about 70% wt. and even more specifically from about 0.10 to about 50% wt. active ingredient, all weight fractions being calculated based on the total weight of the composition.

[00287] This invention also relates to a pharmaceutical composition containing the described compound (for example, a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig and Ih) or a pharmaceutically acceptable salt thereof, as defined above, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

[00288] This description further provides a method for preparing a pharmaceutical composition of this invention, which includes mixing the described compound (for example, compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig and Ih) or its pharmaceutically acceptable salt, as defined above, with a pharmaceutically acceptable adjuvant, diluent or carrier.

[00289] Pharmaceutical compositions can be administered topically (for example, to the skin or to the lungs and/or respiratory tract) in the form of, for example, creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols, and dry powder compositions, for example, inhaler formulations, known as Turbuhaler®; or systemically, for example by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile injectable solution, suspension or emulsion (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories.

[00290] Dry powder formulations and pressurized HFA aerosols of the compounds of this invention (including pharmaceutically acceptable salts) may be administered by oral or nasal inhalation. For inhalation, the compound is desirably completely separated. The finely divided compound preferably has a mass median diameter of less than 10 micrometers (μm) and can be suspended in the propellant mixture with a dispersant such as C ₈ -C ₂₀ fatty acid or its salt (for example, oleic acid), acid), bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.

[00291] The compounds of this invention may also be administered by dry powder inhalation. The inhalation may be a single or multiple dose inhalation and may be a dry powder inhalation actuated by the breath.

[00292] One possibility is to mix the finely divided compound of this invention with a carrier material, such as a mono-, di-, or polysaccharide, sugar alcohol, or other polyol. Suitable carriers are sugars, eg lactose, glucose, raffinose, melesitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively, the finely divided compound may be coated with another substance. The powder mixture may also be dispensed into hard gelatin capsules, each containing the desired dose of the active compound.

[00293] Another possibility is to process the fine powder into spheres that break during the inhalation procedure. This spheronized powder can be filled into the drug reservoir of a multi-disc inhaler, such as known as the Turbuhaler®, in which a dosing device measures the desired dose, which is then inhaled by the patient. With this system, the active ingredient, with or without a carrier substance, is delivered to the patient.

[00294] Another possibility is to treat the compound as an amorphous dispersion in a polymer matrix such as hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMCAS). As the name suggests, spray-dried dispersions (SDDs) are prepared by dissolving the drug and polymer in an organic solvent, spraying the resulting solution into droplets, and evaporating to dried solids. SDDs are generally suitable for use with a variety of final oral dosage forms, including capsules and tablets.

[00295] For oral administration, the compound of this invention may be mixed with an adjuvant or carrier, eg lactose, sucrose, sorbitol, mannitol; starch, for example potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatin or polyvinylpyrrolidone; and/or a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin and the like, and then compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talc and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a highly volatile organic solvent.

[00296] For the preparation of soft gelatin capsules, the compound of this invention can be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using each of the tablet excipients mentioned above. Also, liquid or semi-solid compositions of the compound of this invention may be placed in hard gelatin capsules.

[00297] Oral liquid preparations may be in the form of syrups or suspensions, eg solutions, containing a compound of this invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain colorants, flavors, saccharin and/or carboxymethyl cellulose as a thickener, or other excipients known to those skilled in the art.

Combination Therapy

[00298] The compounds of this invention (i.e., compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig and Ih and their pharmaceutically acceptable salts) can also be administered in combination with other compounds used to treat the above conditions.

[00299] The present invention therefore further relates to a combination therapy in which a compound of the present invention or a pharmaceutical composition or composition containing a compound of the present invention is administered simultaneously or sequentially or as a combination preparation with another therapeutic agent or agents for the treatment of one or more of the listed states.

Methods for the synthesis of compounds

[00300] the Compounds of this invention can be obtained in various ways, including standard chemical methods. One suitable synthesis route is depicted in the scheme below.

[00301] Compounds of this invention (e.g., a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih), or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, isomer, or tautomer thereof, may be prepared by methods known in the art of organic synthesis, as set forth in part in the following synthesis scheme. In the scheme described below, it is well understood that protective groups for sensitive or reactive groups are used where necessary, in accordance with general principles or chemistry. Protective group transformations are carried out according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, incorporated herein in its entirety by links). These groups are removed at a convenient stage in the synthesis of the compound using methods that are obvious to those skilled in the art. The methods of selection, as well as the conditions for placing the mixture and the order in which they are performed, should correspond to the preparation of the described compounds (for example, compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig and Ih).

[00302] Those skilled in the art will appreciate whether a stereocenter exists in compounds of formula (I). Accordingly, this description includes both possible stereoisomers (unless indicated in the synthesis) and includes not only racemic compounds, but also individual enantiomers and/or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it may be prepared by stereospecific synthesis or resolution of the final product or any suitable intermediate. The separation of the final product, intermediate, or starting material can be influenced by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" E.L. Eliel, S.H. Wilen and L N. Mander (Wiley-Interscience, 1994), which is hereby incorporated by reference in its entirety.

[00303] The compounds described herein can be obtained from commercially available starting materials or synthesized using known organic, inorganic and/or enzymatic processes.

Getting connections

[00304] The compounds of this invention can be prepared by a number of methods well known to those skilled in the art of organic synthesis. By way of example, the compounds of this invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Illustrative methods include, but are not limited to, the methods described below. Compounds of this invention can be synthesized following the steps outlined in Scheme 1. Starting materials are either commercially available or prepared according to known methods described in the literature or as illustrated in the schemes.

[00305] Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih can be prepared according to the general procedures described in Scheme 1. In method A, the described compounds (e.g., compounds of formula I, Ia, Ib , Ic, Id, Ie, If, Ig and 1h) are readily available by the reaction of a sulfonyl isocyanate or isothiocyanate (Compound A-1) and an amine (Compound A-2). In certain embodiments of the invention, Compound A-2 is treated with a base in a suitable solvent. Then, compound A-1 is added to compound A-2. The reaction is carried out in a suitable solvent (eg tetrahydrofuran or dichloromethane) at room temperature to reflux.

[00306] With reference to Scheme 1 in method B, compounds of formula (I) are readily available by the reaction of an isocyanate or isothiocyanate (Compound B-1) and a sulfonamide (Compound B-2). In certain embodiments of the invention, Compound B-2 is treated with a base in a suitable solvent. Compound B-1 is then added to compound B-2. The reaction is carried out in a suitable solvent (eg tetrahydrofuran or dichloromethane) at room temperature to reflux.

Scheme 1

Illustrative examples of embodiments of the invention

[00307] Embodiment I-1. Compound of Formula I:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof. Where:

или

X ¹ represents O, S,

or

R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkenyl, optionally substituted C ₁ -C ₆ alkynyl, (CH ₂ ) _m -O-(CH ₂ ) _m -CH ₃ ,

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ⁵ or N;

A ¹ is NR ⁵ , O, S or C(O);

each A ² is independently CR ⁵ , C(R ⁵ ) ₂ , N, NR ⁵ , O, S or S(O) ₂ ;

или

R ² is

or

X ² is N or CR ⁵ ;

R ³ and R ⁴ are H;

each R ⁵ is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ - -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S(O )R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; or

two R ⁵ together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 13 heteroatoms selected from the group consisting of N, S, P and O; or

two geminal R ⁵ can form an oxo group;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ⁵ , O, S or S(O) ₂ .

[00308] Embodiment I-2. The compound of Embodiment I-1, wherein X ¹ is O.

[00309] Embodiment I-3. Compound of Embodiment I-1, wherein X ¹ is S.

[00310] Embodiment I-4. The compound according to any one of embodiments of the invention from I-1 to I-3, where R ² represents

[00311] Embodiment I-5. The compound according to any one of embodiments of the invention from I-1 to I-3, where R ² represents

представляют собой одинарные связи в кольце, содержащем А², образуя таким образом насыщенное кольцо.[00312] Embodiment I-6. A compound according to any of the embodiments of the invention from I-1 to I-5, characterized in that

are single bonds in the ring containing A ² , thus forming a saturated ring.

[00313] Embodiment I-7. The compound according to any one of embodiments of the invention from I-1 to I-5, where R ¹ represents

[00314] Embodiment I-8. The compound of Embodiment I-7 wherein each A ² is independently CH ₂ or O.

[00315] Embodiment I-9. The compound according to any one of embodiments of the invention from I-1 to I-5, where R ¹ represents

[00316] Embodiment I-10. The compound according to any one of embodiments of the invention from I-1 to I-5, where R ¹ represents methyl.

[00317] Embodiment I-11. A compound according to any one of embodiments I-1 to I-9, wherein the compound has the formula:

[00318] Embodiment I-12. The compound of Embodiment I-1, which is

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonamide.

[00319] Embodiment I-13. The compound of Embodiment I-1, which is

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide.

[00320] Embodiment I-14. The compound of Embodiment I-1, which is selected from the group consisting of

[00321] Embodiment I-15. A pharmaceutical composition containing a compound according to any of the embodiments of the invention from I-1 to I-14 and a pharmaceutically acceptable carrier.

[00322] Embodiment I-16. A method of treating or preventing a disease, disorder, or condition, comprising the step of administering an effective amount of a compound according to any one of embodiments I-1 to I-14, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate isomer or tautomer thereof, to treat or prevent the disease, or states.

[00323] Embodiment I-17. The method of embodiment I-16 wherein the disease, disorder, or condition is responsive to inflammasome inhibition.

[00324] Embodiment I-18. The method of embodiment I-16 or I-17, wherein the disease, disorder, or condition is one that responds to inflammasome NLRP3 activation.

[00325] Embodiment I-19. The method of embodiment I-16 or I-17, wherein the disease, disorder, or condition is responsive to modulation of one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL -37, IL-22, IL-33 and Th17 cells.

[00326] Embodiment I-20. The method according to any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the immune system.

[00327] Embodiment I-21. The method of any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is an inflammatory disease or condition, or an autoimmune disease or condition.

[00328] Embodiment I-22. The method of any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is a liver disease, disorder, or condition.

[00329] Embodiment I-23. The method of any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the lung.

[00330] Embodiment I-24. The method of any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the skin.

[00331] Embodiment I-25. The method according to any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the cardiovascular system.

[00332] Embodiment I-26. The method according to any one of embodiments of the invention from I-16 to I-19, characterized in that the disease, disorder or condition is a cancer, tumor or other malignant neoplasms.

[00333] Embodiment I-27. The method according to any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the renal system.

[00334] Embodiment I-28. The method according to any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the gastrointestinal tract.

[00335] Embodiment I-29. The method of any one of embodiments I-16 to I-19 wherein the disease, disorder, or condition is a disease, disorder, or condition of the respiratory system.

[00336] Embodiment I-30. The method according to any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the endocrine system.

[00337] Embodiment I-31. The method according to any one of embodiments I-16 to I-19, wherein the disease, disorder, or condition is a disease, disorder, or condition of the central nervous system (CNS).

[00338] Embodiment I-32. The method according to any one of the embodiments of the invention from I-16 to I-19, characterized in that the disease, disorder or condition is selected from the group consisting of constitutive inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS) , familial cold auto-inflammatory syndrome (FCAS), multisystem inflammatory disease of neonatal age (NOMID), auto-inflammatory diseases, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) , hyperimmunoglobulinemia D, intermittent fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majid syndrome, pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (HA20), granulomatous arthritis in children (PGA), deficiency PLCG2-associated antibodies and immune dysregulation (PLAID), PLCG2-associated auto-inflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delays (SIFD), Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, syndrome osteitis (SAPHO), autoimmune diseases including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome, Schnitzler's syndrome, respiratory diseases, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) , steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, central nervous system disease, Parkinson's disease, Alzheimer's disease, motor neuron disease, Huntington's disease, cerebral malaria, traumatic brain injury from pneumococcal meningitis, metabolic disease, type 2 diabetes, atherosclerosis, obesity, gout, pseudo-gout, eye disease, ocular epithelial disease, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, kidney disease, chronic kidney disease, oxalate nephropathy, diabetic nephropathy, liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, inflammatory reactions in the skin, contact hypersensitivity, sunburn, inflammatory joint reactions, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, viral infections, alpha virus infection, Chikungunya virus infection, Ross River virus infection, flavivirus infection, Dengue virus infection, Zika virus infection, influenza, HIV infection, hidradenitis suppurativa (HS), cyst-causing skin disease, cancer, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia, polymyositis, stroke, myocardial infarction, graft versus master, hype arthritis, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis, Dressler's syndrome, ischemic reperfusion injury, and any disease in which a person is determined to have a germline or somatic non-silent mutation in NLRP3.

[00339] Embodiment I-33. The method according to embodiment I-15, wherein the disorder is selected from the group consisting of bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver, liver fibrosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[00340] Embodiment I-34. The method of embodiment I-33, wherein the disorder is non-alcoholic steatohepatitis (NASH).

[00341] Embodiment I-35. The method according to any one of the embodiments of the invention from I-16 to I-34, characterized in that the treatment or prevention of the disease, disorder or condition is carried out on a mammal.

[00342] Embodiment I-36. The method of embodiment I-35, wherein the mammal is a human.

[00343] Embodiment I-37. A method for modulating the activity of a biological target, comprising the step of exposing the biological target to a compound according to any one of embodiments of the invention from I-1 to I-14, or a pharmaceutically effective salt, solvate, or prodrug thereof.

[00344] Embodiment I-38. The method according to embodiment I-37, wherein the biological target can be selected from the group consisting of NLRP3 inflammasome, IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33 and Th17 cells.

[00345] Embodiment I-39. The use of a compound according to any one of embodiments I-1 to I-14 in the treatment of a disease, disorder, or condition that responds to inflammasome inhibition.

[00346] Embodiment I-40. A compound according to any one of embodiments I-1 to I-14 for use in the manufacture of a medicament for the treatment of a disease, disorder or condition that responds to inflammasome inhibition.

[00347] Embodiment II-1. Compound of formula Ia:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof. Where:

или

X ¹ represents O, S,

or

R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkenyl, optionally substituted C ₁ -C ₆ alkynyl, -(CH ₂ ) _m -O-(CH ₂ ) _m - CH _3,

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

или

R ² is

or

X ² is N or CR ^5b ;

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ - , -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , C(O)NR ⁶ R ⁷ , NR ⁶ S(O) ₂ R ⁷ , -S(O) R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl , C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 13 heteroatoms selected from the group consisting of N, S, P and O; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ - -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S( O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; or

two R ^5b together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 13 heteroatoms selected from the group consisting of N, S, P and O;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or a heteroaryl containing 13 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[00348] An embodiment of the invention P-2. Compound of formula Ib:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof. Where:

или

X ¹ represents O, S,

or

R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkenyl, optionally substituted C ₁ -C ₆ alkynyl, -(CH ₂ ) _m -O-(CH ₂ ) _m - CH ₃ ,

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

или

R ² is

or

X ² is N or CR ^5b ;

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ - , -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , C(O)NR ⁶ R ⁷ , NR ⁶ S(O) ₂ R ⁷ , -S(O) R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl , C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S (O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₂ - C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl , heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, halogen, C ₁ - C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or a heteroaryl containing 13 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[00349] Embodiment II-3. Formula 1 compound with:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof. Where:

или

X ¹ represents O, S,

or

R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkenyl, optionally substituted C ₁ -C ₆ alkynyl, -(CH ₂ ) _m -O-(CH ₂ ) _m - CH ₃ ,

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b ;

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ - -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S( O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ - -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S( O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl , heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, halogen, C ₁ - With ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) g; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[00350] Embodiment II-4. Compound Formula Id:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof. Where:

или

X ¹ represents O, S,

or

R ¹ is selected from the group consisting of optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₁ -C ₆ alkynyl, -(CH ₂ ) _m -O-(CH ₂ ) _m -CH ₃ ,

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a or N;

A ¹ is NR ^5a , O, S or C(O);

each A ² is independently CR ^5a , C(R ^5a ) ₂ , N, NR ^5a , O, S or S(O) ₂ ;

R ² is

R ³ and R ⁴ are H;

each R ^5a is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ - -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S( O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5a together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , NH(C ₁ -C ₆ alkyl) or -N(C ₁ - With ₆ alkyl) ₂ ; or

two geminal R ^5a can form an oxo group;

each R ^5b is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -S(O) ₂ N(R ⁶ ) ₂ -, -S(O) ₂ R ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ R ⁷ , -NR ⁶ S(O) ₂ R ⁷ , -S (O)R ⁶ , -S(O)NR ⁶ R ⁷ , -NR ⁶ S(O)R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₂ - C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl , heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, halogen, C ₁ - C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

each m is independently an integer from one to 4; And

n is an integer from zero to 5;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a , O, S or S(O) ₂ .

[00351] Embodiment II-5. The compound according to any one of embodiments of the invention from II-1 to II-4, where R ¹ is selected from the group consisting of:

[00352] Embodiment II-6. A compound according to any of the embodiments of the invention from II-1 to II-5, where X ¹ is O.

[00353] Embodiment II-7. The compound according to any of the embodiments of the invention from II-1 to II-5, where X ¹ represents S.

[00354] Embodiment II-8. The compound according to any of the embodiments of the invention from II-1 to II-3 and from II-5 to II-7, where R ² represents

[00355] Embodiment II-9. The compound according to any of the embodiments of the invention from II-1 to II-3 and from II-5 to II-7, where R ² represents

представляют собой одинарные связи в кольце, содержащем А², образуя таким образом насыщенное кольцо.[00356] Embodiment II-10. The compound according to any of the embodiments of the invention from II-1 to II-9, characterized in that

are single bonds in the ring containing A ² , thus forming a saturated ring.

[00357] Embodiment II-11. The compound according to any of the embodiments of the invention from II-1 to II-10, where R ¹ represents

[00358] Embodiment II-12. The compound of Embodiment II-11 wherein each A ² is independently CH ₂ or O.

[00359] Embodiment II-13. The compound according to any of the embodiments of the invention from II-1 to II-10, where R ¹ represents

[00360] Embodiment II-14. The compound according to any of the embodiments of the invention from II-1 to II-10, where R ¹ represents

[00361] Embodiment II-15. The compound according to any of the embodiments of the invention from II-1 to II-10, where R ¹ represents

[00362] Embodiment II-16. A compound according to any of the embodiments of the invention from II-1 to II-15, where R ¹ represents methyl.

[00363] Embodiment II-17. The compound according to any of the embodiments of the invention from II-1 to II-3 and II-5 to II-16, characterized in that the compound has the formula:

[00364] Embodiment II-18. The compound of Embodiment II-1, which is

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-3-sulfonamide or a pharmaceutically acceptable salt thereof.

[00365] Embodiment II-19. The compound of Embodiment II-1, which is

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide or a pharmaceutically acceptable salt thereof.

[00366] Embodiment II-20. The compound of Embodiment II-1, which is

or a pharmaceutically acceptable salt thereof.

[00367] Embodiment II-21. The compound of Embodiment II-1, which is

or a pharmaceutically acceptable salt thereof.

[00368] Embodiment II-22. The compound of Embodiment II-1, which is selected from the group consisting of

[00369] Embodiment II-23. The compound of Embodiment II-1, which is selected from the group consisting of

[00370] Embodiment II-24. The compound according to any one of the embodiments of the invention from II-1 to II-4, which is selected from the group consisting of

[00371] Embodiment II-25. A pharmaceutical composition containing a compound according to any of the embodiments of the invention from II-1 to II-24 and a pharmaceutically acceptable carrier.

[00372] Embodiment II-26. A method of treating or preventing a disease, disorder or condition, comprising the step of administering an effective amount of a compound according to any one of embodiments II-1 to II-24, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate isomer or tautomer thereof, to treat or prevent the disease, or states.

[00373] Embodiment II-27. The method of embodiment II-25, wherein the disease, disorder, or condition is responsive to inflammasome inhibition.

[00374] Embodiment II-28. The method of embodiment II-26 or II-27, wherein the disease, disorder, or condition is one that responds to inflammasome NLRP3 activation.

[00375] Embodiment II-29. The method of embodiment II-26 or II-27, wherein the disease, disorder, or condition is responsive to modulation of one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL -37, IL-22, IL-33 and Th17 cells.

[00376] Embodiment II-30. The method according to any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the immune system.

[00377] Embodiment II-31. The method of any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is an inflammatory disease or condition, or an autoimmune disease or condition.

[00378] Embodiment II-32. The method according to any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the liver.

[00379] Embodiment II-33. The method according to any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the lung.

[00380] Embodiment II-34. The method of any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the skin.

[00381] Embodiment II-35. The method according to any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the cardiovascular system.

[00382] Embodiment II-36. The method according to any one of embodiments of the invention from II-26 to II-29, characterized in that the disease, disorder or condition is a cancer, tumor or other malignant neoplasms.

[00383] Embodiment II-37. The method according to any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the renal system.

[00384] Embodiment II-38. The method according to any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the gastrointestinal tract.

[00385] Embodiment II-39. The method of any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the respiratory system.

[00386] Embodiment II-40. The method according to any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the endocrine system.

[00387] Embodiment II-41. The method according to any one of embodiments II-26 to II-29, wherein the disease, disorder, or condition is a disease, disorder, or condition of the central nervous system (CNS).

[00388] Embodiment II-42. The method according to any one of the embodiments of the invention from II-26 to II-29, characterized in that the disease, disorder or condition is selected from the group consisting of constitutive inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS) , familial cold auto-inflammatory syndrome (FCAS), multisystem inflammatory disease of neonatal age (NOMID), auto-inflammatory diseases, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) , hyperimmunoglobulinemia D, intermittent fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majid syndrome, pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (HA20), granulomatous arthritis in children (PGA), deficiency PLCG2-associated antibodies and immune dysregulation (PLAID), PLCG2-associated auto-inflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delays (SIFD), Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO), autoimmune diseases including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome, Schnitzler's syndrome, respiratory diseases, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) ), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, central nervous system disease, Parkinson's disease, Alzheimer's disease, motor neurone disease, Huntington's disease, cerebral malaria, traumatic brain injury from pneumococcal meningitis, metabolic disease, type 2 diabetes, atherosclerosis , obesity, gout, pseudo-gout, eye diseases and, ocular epithelial disease, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, kidney disease, chronic kidney disease, oxalate nephropathy, diabetic nephropathy, liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, inflammatory reactions in the skin, contact hypersensitivity, sunburn, inflammatory joint reactions, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, viral infections, alpha virus infection, Chikungunya virus infection, Ross River virus infection, flavivirus infection, viral infection Dengue, Zika virus infection, influenza, HIV infection, hidradenitis suppurativa (HS), cyst-causing skin diseases, cancer, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia, polymyositis, stroke, myocardial infarction, disease " graft versus host, gi pertonia, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis, Dressler's syndrome, ischemic reperfusion injury, and any disease in which a person is determined to have a germline or somatic non-silent mutation in NLRP3.

[00389] Embodiment II-43. The method according to embodiment II-26, wherein the disorder is selected from the group consisting of bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver, liver fibrosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[00390] Embodiment II-44. The method of embodiment II-43 wherein the disorder is non-alcoholic steatohepatitis (NASH).

[00391] Embodiment II-45. The method according to any one of embodiments of the invention from II-26 to II-44, characterized in that the treatment or prevention of the disease, disorder or condition is carried out on a mammal.

[00392] Embodiment II-46. The method of embodiment II-45, wherein the mammal is a human.

[00393] Embodiment II-47. A method for modulating the activity of a biological target, comprising the step of exposing the biological target to a compound according to any of the embodiments of the invention from II-1 to II-24 or a pharmaceutically effective salt, solvate or prodrug thereof.

[00394] Embodiment II-48. The method of embodiment II-47, wherein the biological target may be selected from the group consisting of NLRP3 inflammasome, IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33 and Th17 cells.

[00395] Embodiment II-49. The use of a compound according to any of the embodiments of the invention from II-1 to II-24 in the treatment of a disease, disorder or condition that responds to inflammasome inhibition.

[00396] Embodiment II-50. A compound according to any one of embodiments II-1 to II-24 for use in the manufacture of a medicament for the treatment of a disease, disorder or condition that responds to inflammasome inhibition.

[00397] Embodiment III-1. Compound Formula If:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof.

Where:

X ¹ represents O or S;

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a1 or N;

each A ² is independently CR ^5a2 , C(R ^5a2 ) ₂ , N, NR ^5a2 , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b1 ;

R ³ and R ⁴ are H;

each R ^5a1 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

each R ^5a2 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O ) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or

two geminal R ^5a2 can form an oxo group;

R ^5b1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, -NO ₂ , -SR ⁶ , -OR 6 , -NHR ⁶ , -NR ^{6 R 7} , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; And

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a2 , O, S or S(O) ₂ .

[00398] Embodiment III-2. A compound according to claim 1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein:

X ¹ is O;

R ¹ is selected from the group consisting of

представляет одинарную связь;Where

represents a single bond;

each A ² is independently C(R ^5a2 ) ₂ or O;

X ² is CR ^5b1 ;

each R ^5a1 is independently H or C ₁ -C ₆ alkyl; where C ₁ -C ₆ alkyl is optionally substituted with D, halo, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O )OR ⁶ or NR ⁶ C(O)R ⁶ ;

each R ^5a2 is independently H, halogen, OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl or heterocyclyl; where C ₁ -C ₆ alkyl and heterocyclyl are optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , NH(C ₁ -C ₆ alkyl), M(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O )OR ⁶ or -NR ⁶ C(O)R ⁶ ; or

two R ^5a2 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ or -S(O) ₂ -R ⁶ ; or

two geminal R ^5a2 can form an oxo group;

R ^5b1 represents H, D, halogen or C ₁ -C ₆ alkyl;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, -CN, -OR ⁶ , C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl, optionally substituted with D, halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached may form C ₃ -C ₈ cycloalkyl, heterocyclyl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl or heteroaryl is optionally substituted halogen or C ₁ -C ₆ alkyl; And

R ⁶ and R ⁷ independently represent, at each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkynyl or aryl; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkynyl and aryl, optionally substituted with D, halogen or C ₁ -C ₆ alkyl.

[00399] Embodiment III-3. Compound of formula Ig:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof,

Where:

X ¹ represents O or S;

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a1 or N;

each A ² is independently CR ^5a2 , C(R ^5a2 ) ₂ , N, NR ^5a2 , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b1 ;

R ³ and R ⁴ are H;

each R ^5a1 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

each R ^5a2 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O) OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -S(O) ₂ -R ⁶ ; -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two geminal R ^5a2 can form an oxo group;

R ^5b1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, -NO ₂ , -SR ⁶ , -OR 6 , -NHR ⁶ , -NR ^{6 R 7} , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; And

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a2 , O, S or S(O) ₂ .

[00400] Embodiment III-4. Compound of formula Ih:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof,

Where:

X ¹ represents O or S;

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a1 or N;

each A ² is independently CR ^5a2 , C(R ^5a2 ) ₂ , N, NR ^5a2 , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b1 ;

R ³ and R ⁴ are H;

each R ^5a1 is independently H, D, halogen, -OH, -CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ - C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

each R ^5a2 is independently H, D, halogen, OH, -CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S( O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ ; or

where at least one R ^5a2 represents -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl or heterocyclyl containing N, where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ and wherein the heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ , -NR ⁶ C( O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ ;

R ^5b1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, -NO ₂ , -SR ⁶ , -OR 6 , -NHR ⁶ , -NR ^{6 R 7} , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; And

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a2 , O, S or S(O) ₂ .

[00401] Embodiment III-5. Compound of formula Ie:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof,

Where:

X ¹ represents O or S;

R ¹ is selected from the group consisting of

представляет собой одинарную или двойную связь при условии, что кольцо, содержащее один или более А², представляет собой неароматическое кольцо;Where

is a single or double bond, provided that the ring containing one or more A ² is a non-aromatic ring;

each A is independently CR ^5a1 or N;

each A ² is independently CR ^5a2 , C(R ^5a2 ) ₂ , N, NR ^5a2 , O, S or S(O) ₂ ;

R ² is

X ² is N or CR ^5b1 ;

each R ^b10 , R ^b11 , R ^b12 , R ^b13 , R ^b14 and R ^b15 independently represents H, -OH or oxo;

R ³ and R ⁴ are H;

each R ^5a1 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

each R ^5a2 is independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O ) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ ; or

two geminal R ^5a2 can form an oxo group;

R ^5b1 is H, D, halogen, -CN, -OR ⁶ or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, -C(O)NR ⁶ , -C(O)OR ⁶ ; where C ₁ -C ₆ alkyl and C ₃ -C ₈ cycloalkyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ;

each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 independently represents H, D, halogen, OH, -CN, -NO ₂ , -SR ⁶ , -OR 6 , -NHR ⁶ , -NR ^{6 R 7} , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl or C ₂ -C ₆ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₃ -C ₈ cycloalkyl and C ₂ -C ₆ alkynyl are optionally substituted with D, halogen, -CN, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

two adjacent R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl, where C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with halogen, -CN, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; And

R ⁶ and R ⁷ are independently, in each occurrence, H, D, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl or heteroaryl; moreover, heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O; where C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or

R ⁶ and R ⁷ together with the atom to which they are attached may form a heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O;

with the proviso that when the ring containing A and/or A ¹ is imidazole, then at least one A ² is N, NR ^5a2 , O, S or S(O) ₂ .

[00402] Embodiment III-6. A compound according to any one of embodiments III-1 and III-3 to III-5, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein X ¹ is O.

[00403] Embodiment III-7. A compound according to any one of embodiments III-1 to III-6, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ² is

[00404] Embodiment III-8. The compound of Embodiment III-7, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein X ² is CR ^5b1 .

[00405] Embodiment III-9. The compound of Embodiment III-8, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ^5b1 is H, halogen, or C ₁ -C ₆ alkyl.

[00406] Embodiment III-10. The compound of Embodiment III-8, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ^5b1 is H, fluorine, chlorine, or methyl.

[00407] Embodiment III-11. A compound according to any one of embodiments III-1 to III-10, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ² is

[00408] Embodiment III-12. A compound according to any one of embodiments III-1 to III-10, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ² is

[00409] Embodiment III-13. A compound according to any one of embodiments III-1 to III-6, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ² is

[00410] Embodiment III-14. The compound of Embodiment III-13, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 is independently H, D, halogen, OH , CN, -NO ₂ , -OR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl or C ₃ -C ₈ cycloalkyl.

[00411] Embodiment III-15. A compound according to any one of embodiments III-1 to III-13, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ² is

[00412] Embodiment III-16. The compound of Embodiment III-15, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein each R ^5b2 , R ^5b3 , R ^5b4 , R ^5b5 and R ^5b6 is independently selected from the group consisting of H, D , halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl and -CN.

[00413] Embodiment III-17. A compound according to any one of embodiments III-1 to III-16, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ² is selected from the group consisting of

[00414] Embodiment III-18. A compound according to any one of embodiments III-1 to III-17, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ² is selected from the group consisting of

[00415] Embodiment III-19. A compound according to any one of embodiments III-1 to III-18, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ² is

[00416] Embodiment III-20. A compound according to any one of embodiments III-1 to III-13, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ² is

[00417] Embodiment III-21. The compound of Embodiment III-20, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein each R ^5b2 and R ^5b4 is selected from the group consisting of H, D, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl and -CN.

[00418] Embodiment III-22. The compound according to any of the embodiments of the invention from III-20 and III-21 or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer, where R ² represents

[00419] Embodiment III-23. A compound according to any one of embodiments III-1 to III-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

[00420] Embodiment III-24. A compound according to any one of embodiments III-1 to III-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

[00421] Embodiment III-25. A compound according to any of embodiments III-1 to III-24, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein one A is CR ^5a1 and the other A is N.

[00422] Embodiment III-26. A compound according to any of embodiments III-1 to III-25, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein each A ² is independently C(R ^5a2 ) ₂ , NR ^5a2 , or O.

[00423] Embodiment III-27. The compound of Embodiment III-26 wherein each R ^5a2 is independently H, -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, or heterocyclyl containing N, wherein C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ and heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ , -NR ⁶ C( O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ .

[00424] Embodiment III-28. The compound of Embodiment III-27, wherein R ¹ is selected from the group consisting of

where R ^5a1a represents H, D, halo, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ; And

R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f are independently selected from H, -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl or heterocyclyl containing N, where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ and heterocyclyl is optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ , - NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ .

[00425] Embodiment III-29. A compound according to any one of embodiments III-1 to III-23, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

[00426] Embodiment III-30. The compound of Embodiment III-29, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein one A is CR ^5a1 and the other A is N.

[00427] Embodiment III-31. A compound according to any of embodiments III-29 to III-30, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein each A ² is independently C(R ^5a2 ) ₂ , NR ^5a2 , or O.

[00428] Embodiment III-32. A compound according to any of embodiments III-29 to III-30, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein each R ^5a2 is independently H, halogen, OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, or -CH ₂ -C ₃ -C ₈ cycloalkyl.

[00429] Embodiment III-33. A compound according to any one of embodiments III-20 to III-32, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein two R ^5a2 together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

который представляет собой формулу

где[00430] Embodiment III-34. A compound according to any one of embodiments III-1 to III-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

which is the formula

Where

A ^2ab is selected from CR ^5a2 , C(R ^5a2a )(R ^5a2b ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2cd is selected from CR ^5a2 , C(R ^5a2c )(R ^5a2d ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2ef is selected from CR ^5a2 , C(R ^5a2e )(R ^5a2f ), N, NR ^5a2 , O, S or S(O) ₂ ; And

A ^2gh is selected from CR ^5a2 , C(R ^5a2g )(R ^5a2h ), N, NR ^5a2 , O, S or S(O) ₂ ;

each R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h independently represent H, D, halo, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , - NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; wherein the heterocyclyl contains 13 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ ; or

two geminal R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h can form an oxo group.

где[181] Embodiment III-35. The compound of Embodiment III-34, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

Where

where R ^5a1a represents H, D, halo, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ or -NR ⁶ C(O)R ⁶ ;

^R5a2c and ^R5a2d ; each independently are H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2c and R ^5a2d together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ ; or

R ^5a2c and R ^5a2d may form an oxo group.

[00432] Embodiment III-36. The compound of Embodiment III-35, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ^5a2c and R ^5a2d are each independently H, halogen, OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl.

[00433] Embodiment III-37. A compound according to any of embodiments III-35 to III-36, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R ^5a2c and R ^5a2d together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

где[00434] Embodiment III-38. The compound of Embodiment III-34, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

Where

R ^5a2a and R ^5a2b are each independently H, D, halogen, OH, CN, -NO _{2 ,} -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2a and together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ ; or

R ^5a2a and R ^5a2b may form an oxo group.

[00435] Embodiment III-39. The compound of Embodiment III-38, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ^5a2a and R ^5a2b are each independently H, halogen, OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl.

[00436] Embodiment III-40. A compound according to any of embodiments III-38 to III-39, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R ^5a2a and R ^5a2b together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

где[00437] Embodiment III-41. The compound of Embodiment III-33, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

Where

R ^5a2e and R ^5a2f are each independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2e and R ^5a2f together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ ; or

R ^5a2e and R ^5a2f may form an oxo group.

[00438] Embodiment III-42. The compound of Embodiment III-41, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ^5a2e and R ^5a2f are each independently H, halogen, OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl.

[00439] Embodiment III-43. A compound according to any one of embodiments III-41 to III-42, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R ^5a2e and R ^5a2f together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

где[184] Embodiment III-44. A compound according to an embodiment of the invention from III-34, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

Where

R ^5a2c and R ^5a2d are each independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

R ^5a2c and R ^5a2d together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ ; or

R ^5a2c and R ^5a2d may form an oxo group.

[00441] Embodiment III-45. The compound of Embodiment III-44, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ^5a2c and R ^5a2d are each independently H, halogen, OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl.

[00442] Embodiment III-46. A compound according to any of embodiments III-44 to III-45, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, wherein R ^5a2c and R ^5a2d together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl.

[00443] Embodiment III-47. The compound of Embodiment III-29, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is selected from the group consisting of

[00444] Embodiment III-48. The compound of Embodiment III-29, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is selected from the group consisting of

[186] Embodiment III-49. The compound of Embodiment III-29, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is selected from the group consisting of

[00446] Embodiment III-50. A compound according to any one of embodiments III-1 to III-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

[00447] Embodiment III-51. The compound of Embodiment III-50, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein one A is CR ^5a1 and the other A is N.

[00448] Embodiment III-52. A compound according to any of embodiments III-50 to III-51, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein each A ² is independently C(R ^5a2 ) ₂ , NR ^5a2 , or O.

который представляет собой формулу

где[00449] Embodiment III-53. A compound according to any one of embodiments III-1 to III-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

which is the formula

Where

A ^2ab is selected from CR ^5a2 , C(R ^5a2a )(R ^5a2b ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2cd is selected from CR ^5a2 , C(R ^5a2c )(R ^5a2d ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2ef is selected from CR ^5a2 , C(R ^5a2e )(R ^5a2f ), N, NR ^5a2 , O, S or S(O) ₂ ; And

A ^2gh is selected from CR ^5a2 , C(R ^5a2g )(R ^5a2h ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2ij is selected from CR ^5a2 , C(R ^5a2i )(R ^5a2j ), N, NR ^5a2 , O, S or S(O) ₂ ;

each R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g , R ^5a2h , R ^5a2i and R ^5a2j are independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g , R ^5a2h , R ^5a2i and R ^5a2j together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ ; or

two geminal R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g , R ^5a2h , R ^5a2i and R ^5a2j can form an oxo group.

[00450] Embodiment III-54. The compound of Embodiment III-50, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

[00451] Embodiment III-55. A compound according to any one of embodiments III-1 to III-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

[00452] Embodiment III-56. The compound of Embodiment III-55, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein one A is CR ^5a1 and the other A is N.

[00453] Embodiment III-57. A compound according to any of embodiments III-55 to III-56, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein each A ² is independently C(R ^5a2 ) ₂ , NR ^5a2 , or O.

который представляет собой формулу

где[00454] Embodiment III-58. A compound according to any one of embodiments III-1 to III-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

which is the formula

Where

A ^2ab is selected from C(R ^5a2a )(R ^5a2b ), NR ^5a2 , O, S or S(O) ₂ ;

A ^2cd is selected from C(R ^5a2c )(R ^5a2d ), NR ^5a2 , O, S or S(O) ₂ ;

A ^2ef is selected from C(R ^5a2e )(R ^5a2f ), NR ^5a2 , O, S or S(O) ₂ ; And

each R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f are independently H, D, halogen, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ , or -NR ⁶ S(O) ₂ R ⁶ ; or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ ; or

two geminal R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e and R ^5a2f can form an oxo group.

[189] Embodiment III-59. The compound of Embodiment III-55, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

[00456] Embodiment III-60. A compound according to any one of embodiments III-1 to III-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

[00457] Embodiment III-61. The compound of Embodiment III-60, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein one A is CR ^5a1 and the other A is N.

[00458] Embodiment III-62. A compound according to any of embodiments III-60 to III-61, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein each A ² is independently C(R ^5a2 ) ₂ , NR ^5a2 , or O.

который представляет собой формулу

где[00459] Embodiment III-63. A compound according to any one of embodiments III-1 to III-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein R ¹ is

which is the formula

Where

A ^2ab is selected from CR ^5a2 , C(R ^5a2a )(R ^5a2b ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2cd is selected from CR ^5a2 , C(R ^5a2c )(R ^5a2d ), N, NR ^5a2 , O, S or S(O) ₂ ;

A ^2ef is selected from CR ^5a2 , C(R ^5a2e )(R ^5a2f ), N, NR ^5a2 , O, S or S(O) ₂ ; And

A ^2gh is selected from CR ^5a2 , C(R ^5a2g )(R ^5a2h ), N, NR ^5a2 , O, S or S(O) ₂ ;

each R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h independently represent H, D, halo, OH, CN, -NO ₂ , -SR ⁶ , -OR ⁶ , - NHR ⁶ , -NR ⁶ R ⁷ , -C(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)OR ⁶ , -C(O)NR ⁶ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₄ -C ₈ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, heteroaryl and -CH ₂ -C ₃ -C ₈ cycloalkyl optionally substituted with D, -CN, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , - NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , NR ⁶ C(O)NR ⁶ , -NR ⁶ C(O)R ⁶ or -NR ⁶ S(O) ₂ R ⁶ or

two R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or heterocyclyl; moreover, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ -R ⁶ , -COR ⁶ , NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)NR ⁶ or -NR ⁶ S (O) ₂ R ⁶ or

two geminal R ^5a2a , R ^5a2b , R ^5a2c , R ^5a2d , R ^5a2e , R ^5a2f , R ^5a2g and R ^5a2h can form an oxo group.

представляют собой одинарные связи в кольце, содержащем А², образуя таким образом насыщенное кольцо.[00460] Embodiment III-64. A compound according to any one of embodiments III-1 to III-63, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, wherein

are single bonds in the ring containing A ² , thus forming a saturated ring.

[00461] Embodiment III-65. A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, selected from the group consisting of

[00462] Embodiment III-66. A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, selected from the group consisting of

[00463] Embodiment III-61. A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, selected from the group consisting of and

[00464] Embodiment III-68. A compound or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer thereof, selected from the group consisting of

[00465] Embodiment III-69. A pharmaceutical composition containing a compound according to any of the embodiments of the invention from III-1 to III-68 or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer or tautomer and a pharmaceutically acceptable carrier.

[00466] Embodiment III-70. A method of treating or preventing a disease, disorder, or condition that responds to inflammasome inhibition, comprising administering an effective amount of a compound according to any of embodiments III-1 to III-68, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof to thereby treat or prevent a disease or condition in a subject in need thereof.

[00467] Embodiment III-71. The method of embodiment III-70, wherein the disease, disorder, or condition is one that responds to inflammasome NLRP3 activation.

[00468] Embodiment III-72. The method of embodiment III-70 or III-71, wherein the disease, disorder, or condition is responsive to modulation of one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL -37, IL-22, IL-33 and Th17 cells.

[00469] Embodiment III-73. The method of embodiment III-70 or III-71, wherein the disease, disorder, or condition is responsive to modulation of one or more of IL-1β and IL-18.

[00470] Embodiment III-74. The method according to any one of embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the immune system.

[00471] Embodiment III-75. The method according to any one of embodiments III-70 to III-73, wherein the disease, disorder, or condition is an inflammatory disease or condition, or an autoimmune disease or condition.

[00472] Embodiment III-16. The method according to any one of embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the liver.

[00473] Embodiment III-77. The method according to any one of embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the lung.

[00474] Embodiment III-78. The method according to any one of embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the skin.

[00475] Embodiment III-79. The method according to any one of embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the cardiovascular system.

[00476] Embodiment III-80. The method according to any of the embodiments of the invention from III-70 to III-73, characterized in that the disease, disorder or condition is a cancer, tumor or other malignant neoplasms.

[00477] Embodiment III-81. The method according to any one of embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the renal system.

[00478] Embodiment III-82. The method according to any one of embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the immune system

[00479] Embodiment III-83. The method according to any of embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the respiratory system.

[00480] Embodiment III-84. The method according to any of the embodiments of the invention from III-70 to III-73, characterized in that the disease, disorder or condition is a disease, disorder or condition of the endocrine system.

[00481] Embodiment III-85. The method according to any one of embodiments III-70 to III-73, wherein the disease, disorder, or condition is a disease, disorder, or condition of the central nervous system (CNS).

[00482] Embodiment III-86. The method according to any one of the embodiments of the invention from III-70 to III-73, characterized in that the disease, disorder or condition is selected from the group consisting of constitutive inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS) , familial cold auto-inflammatory syndrome (FCAS), multisystem inflammatory disease of neonatal age (NOMID), auto-inflammatory diseases, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) , hyperimmunoglobulinemia D, intermittent fever syndrome (HIDS), interleukin-1 receptor antagonist deficiency (DIRA), Majid syndrome, pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), A20 haploinsufficiency (HA20), granulomatous arthritis in children (PGA), deficiency PLCG2-associated antibodies and immune dysregulation (PLAID), PLCG2-associated auto-inflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delays (SIFD), Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO), autoimmune diseases including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjögren's syndrome, Schnitzler's syndrome, respiratory diseases, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) ), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, central nervous system disease, Parkinson's disease, Alzheimer's disease, motor neurone disease, Huntington's disease, cerebral malaria, traumatic brain injury from pneumococcal meningitis, metabolic disease, type 2 diabetes, atherosclerosis , obesity, gout, pseudo-gout, eye pain ocular epithelial disease, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, kidney disease, chronic kidney disease, oxalate nephropathy, diabetic nephropathy, liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, inflammatory reactions in the skin, contact hypersensitivity, sunburn, inflammatory joint reactions, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, viral infections, alpha virus infection, Chikungunya virus infection, Ross River virus infection, flavivirus infection, viral infection Dengue, Zika virus infection, influenza, HIV infection, hidradenitis suppurativa (HS), cyst-causing skin diseases, cancer, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia, polymyositis, stroke, myocardial infarction, disease " graft versus host, hypertension, colitis, helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis, Dressler's syndrome, ischemic reperfusion injury, and any disease in which a person is determined to have a germline or somatic non-silent mutation in NLRP3.

[00483] Embodiment III-87. The method of embodiment III-86 wherein the disorder is selected from the group consisting of bacterial infection, viral infection, fungal infection, inflammatory bowel disease, celiac disease, colitis, intestinal hyperplasia, cancer, metabolic syndrome, obesity, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver, liver fibrosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[00484] Embodiment III-88. The method of embodiment III-87 wherein the disorder is non-alcoholic steatohepatitis (NASH).

[00485] Embodiment III-89. The method according to any of the embodiments of the invention from III-70 to III-88, characterized in that the treatment or prevention of a disease, disorder or condition is carried out on a small-nourisher.

[00486] Embodiment III-90. The method of embodiment III-89, wherein the mammal is a human.

[00487] Embodiment III-91. A method for modulating the activity of a biological target, comprising the step of exposing the biological target to a compound according to any one of embodiments III-1 to III-68 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[00488] Embodiment III-92. Method according to embodiment III-91, wherein the biological target can be selected from the group consisting of NLRP3 inflammasome, IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL-22, IL-33 and Th17 cells.

[00489] Embodiment III-93. The method of embodiment III-91, wherein the biological target may be selected from the group consisting of IL-1β and IL-18.

[00490] Embodiment III-94. A method for inhibiting inflammasome activation, comprising the step of exposing a biological target to a compound according to any one of embodiments III-1 to III-68 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof.

[00491] Embodiment III-95. The method of embodiment III-94, wherein the inflammasome is an NLRP3 inflammasome.

[00492] Embodiment III-96. The method of embodiment III-94 or III-95, wherein the inflammasome inhibition is associated with one or more of IL-6, IL-1β, IL-17, IL-18, IL-1α, IL-37, IL -22, IL-33 and Th17 cells.

[00493] Embodiment III-97. The method of embodiment III-96 wherein the inhibition of the inflammasome is associated with one or more of IL-1β and IL-18.

[00494] Embodiment III-98. Use of a compound according to any of embodiments III-1 to III-68, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, for the treatment of a disease, disorder, or condition that responds to inflammasome inhibition.

[00495] Embodiment III-99. A compound according to any of embodiments III-1 to III-68, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, for use in the manufacture of a medicament for the treatment of a disease, disorder, or condition that responds to inflammasome inhibition.

Examples

[00496] The following examples are provided to illustrate this description and should not be construed as limiting it. In these examples, all parts and percentages are by weight unless otherwise indicated. The conventions in the examples are shown below.

Symbols

Example 1: Synthesis of Compound 1 -b][1,3]oxazine-3-sulfonamide)

[00497] N,N-dimethylpyridin-4-amine (0.517 mmol, 0.063 g) was dissolved in THF (1.5 ml) and then a solution of di-tert-butyl dicarbonate (0.492 mmol, 0.113 ml) in THF (1, 5 ml). After stirring for several minutes, a solution of 1,2,3,5,6,7-hexahydro-8-indacen-4-amine (0.492 mmol, 0.085 g) in THF (1 ml) was added and the mixture was allowed to stir for 30 min. At the same time, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (0.492 mmol, 100 mg) in THF (1 ml) was treated with sodium hydride (0.492 mmol, 0.018 g) and left to mix for 30 minutes. At the same time, the two solutions were mixed and allowed to stir for 18 hours.

[00498] The reaction mixture was then quenched with sat. NH ₄ Cl (10 ml) and diluted with EtOAc (10 ml). The layers were separated and aq. the layer was extracted with EtOAc (10 ml). The combined organic extracts were then washed with water (10 ml) and concentrated. The resulting solid was suspended in MeOH (5 ml), filtered and the filtrate was purified using preparative HPLC (10-40% MeCN:10 mm aq. NH ₃ ). The purified fractions were combined and concentrated to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonamide (Compound 1) (3.5 mg, 1.768%) as a white solid. [M+N] ⁺ found 403.

[00499] ¹ H NMR (400 MHz; MeOD): δ 7.67 (s, 1H), 6.93 (d, J=0.9 Hz, 1H), 6.93 (d, J=0.9 Hz, 1H), 4.42 (t, J=5.3 Hz, 2H), 4.42 (t, J=5.3 Hz, 2H), 4.16 (t, J=6.2 Hz, 2H), 4.16 (t, J=6.2 Hz, 2H), 2.86 (t, J=7.4 Hz, 4H), 2.86 (t, J=7.4 Hz, 4H) , 2.74-2.71 (m, 4H), 2.74-2.71 (m, 4H), 2.31-2.25 (m, 3H), 2.31-2.25 (m, 3H), 2.08-2.00 (m, 6H), 2.08-2.00 (m, 6H).

Getting TCPC

[00500] A solution of 2,4,6-trichlorophenol (50 g, 250 mmol) and pyridine (20.5 ml, 250 mmol) in ether (800 ml) was cooled to -78° C. under N ₂ . On cooling, the mixture forms solids. SO ₂ Cl ₂ (21 ml, 250 mmol) was slowly added to the mixture. The reaction mixture was then stirred at room temperature. pace, during the night. The reaction mixture was filtered through a pad of celite and washed with ether (300 ml). The ether solution was concentrated below 40°C. The residue was purified by silica gel column chromatography (hexane~PE) to give TCPC (55 g, 75% yield) as a colorless oily liquid.

[00501] ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.45 (s, 2H).

Stage 1

[00502] 1,2-Dihydro-pyrazol-3-one (4.0 g, 47.6 mmol) and K ₂ CO ₃ (23.0 g, 166.7 mmol) were heated to 130° C. in DM FA ( 80 ml). 1,3-dibromopropane (11.6 g, 57.1 mmol) was added and the mixture was heated for 3 hours and then concentrated. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml) and the layers were separated. The aqueous layer was extracted with EA (50 ml) and the combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=1/2) to give 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (3.0 g, yield: 51%) as a yellow oily liquid.

[00503] ¹ H NMR (400 MHz; CDCl ₃ ): δ = 7.31 (d, J=2.0 Hz, 1H), 5.48 (d, J=2.0 Hz, 1H), 4, 28 (t, J=5.2 Hz, 2H), 4.18 (t, J=6.2 Hz, 2H), 2.29-2.22 (m, 2H).

[00504] NBS (4.4 g, 24.7 mmol) was added in portions to a solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (3.0 g, 24.3 mmol) in MeCN (40 ml) at 0°C and the reaction mixture was stirred for 2 hours at room temperature. The mixture was filtered and purified with a reverse phase column (5%-95% MeCN in H ₂ O) to give 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (3.6 g, yield: 74%) as a yellow solid.

[00505] ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.30 (s, 1H), 4.36 (t, J=5.2 Hz, 2H), 4.17 (t, J=6 .2 Hz, 2H), 2.30-2.24 (m, 2H).

Stage 3

[00506] To a solution of 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.8 g, 8.9 mmol) in dry THF (15 ml) slowly added n-BuLi in hexane (2.5 M, 3.5 ml, 8.9 mmol) at -78° C. under N ₂ atmosphere. After stirring with cooling for 20 min, ZnCl ₂ in ether (1 M, 8.9 ml, 8.9 mmol) was added slowly at the same temperature. The ice bath was removed and the reaction mixture was stirred at room temperature. temp, over 1 h. TCPC (2.6 g, 8.9 mmol) was then added at 0° C. and stirred at room temperature. temp, for 1 h. The reaction was quenched with a saturated solution of NH ₄ Cl (10 ml) and divided between water (80 ml) and EA (80 ml). The organic layer was washed with brine (80 ml), dried over Na ₂ SO ₄ and concentrated to give crude 2,4,6-trichloro-phenyl ester 6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazine-3-sulfonic acid as a yellow oily liquid, which was used directly in the next step without further purification. Stage 4

[00507] 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid 2,4,6-trichloro-phenyl ester mixture (crude, ~8.9 mmol) , NH ₄ OH (10 ml) and THF (10 ml) were stirred at 60°C during the night. The reaction mixture was concentrated under reduced pressure to 10 ml of remaining liquid. The remaining solution was acidified with 1 N HCl to pH=5 and partitioned between EA (10 ml) and water (50 ml). The aqueous layer was purified using a reverse phase column (MeCN/H ₂ O) to give 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide (650 mg, yield: 36% over 2 steps) as a light yellow solid.

[00508] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.47 (s, 1H), 7.09 (br. s, 2H), 4.40 (t, J=5.2 Hz , 2H), 4.25 (t, J=6.0 Hz, 2H), 2.22-2.14 (m, 2H). MS: m/z 203.9 (M+H ⁺ ).

Stage 5

[00509] MeONa was added to a solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide (120 mg, 0.6 mmol) in THF (10 mL) (40 mg, 0.7 mmol) and stirred at room temperature. pace, for 20 min to obtain a suspension of sodium salt.

[00510] In another flask to a solution of 1,2,3,5,6,7-hexahydro-8-indacen-4-ylamine (110 mg, 0.6 mmol) and TEA (120 mg, 1.2 mmol) in THF (10 ml), triphosgene (120 mg, 0.4 mmol) was added in one portion and stirred at room temperature. temp, in an N2 atmosphere for 20 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature. pace for 20 min. Thereafter, the reaction solution was partitioned between EA (60 ml) and water (60 ml). The aqueous phase was acidified to pH = 5 conc. HCl and extracted with EA (60 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated until the disappearance of a white solid. The resulting solid was collected by filtration and dried to give N-((1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonamide (57 mg, yield: 22%) as a white solid.

[00511] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.46 (br. s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.42 (t, J=5.2 Hz, 2H), 4.25 (t, J=5.8 Hz, 2H), 2.79 (t, J=7.6 Hz , 4H), 2.60 (t, J=7.6 Hz, 4H), 2.22-2.18 (m, 2H), 1.99-1.92 (m, 4H). MS: m/z 403.0 (M+H ⁺ ).

Example 2 Synthesis of Compound 2 N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide:

[00512] To a solution of methanesulfonamide (95 mg, 1.0 mmol) in THF (5 ml) was added NaH (60%, 45 mg, 1.1 mmol) and stirred at room temperature for 10 min to obtain a suspension of the sodium salt.

[00513] To a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (173 mg, 1.0 mmol) and TEA (0.5 ml, 3.5 mmol) in THF (10 ml) triphosgene (120 mg, 0.4 mmol) was added in one portion and the mixture was stirred at room temperature under N ₂ for 20 minutes. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature for 30 minutes. Thereafter, the reaction solution was partitioned between ethyl acetate (50 ml) and water (100 ml). The aqueous phase was filtered and acidified to pH = 5 aq. HCl (1N). The resulting solid was collected by filtration and dried to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide (130 mg, yield: 44%) as white solid.

[00514] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.19 (br. s, 1H), 8.13 (s, 1H), 6.96 (s, 1H), 3.26 (s, 3H), 2.82 (t, J=7.2 Hz, 4H), 2.71 (t, J=7.2 Hz, 4H), 2.03-1.94 (m, 4H) . MS: m/z 295.0 (M+H ⁺ ).

Example 3: Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indyacen-4-yl)carbamothioyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonamide

[00515] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamothioyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfone amide a is illustrated below.

Stage 1

[00516] To a solution of 1,2,3,5,6,7-hexahydro-p-indacen-4-ylamine (350 mg, 2 mmol) in THF (20 ml) was added thiophosgene (233 mg, 2 mmol) and TEA (612 mg, 6 mmol). The reaction mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was diluted in saturated NaHCO ₃ (50 ml) and the aqueous phase was extracted with EA (50 ml × 3). The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 4-isothiocyanato-1,2,35,6,7-hexahydro-s-indacene as a crude product which was used in the next step without further purification.

Stage 2

[00517] 4- isothiocyanato-1,2,3,5,6,7-hexahydro-s-indacene (64.5 mg, 0.3 mmol) and NaH (60% in mineral oil, 24 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 2 hours (reaction progress was monitored by LCMS) and quenched with H ₂ O (20 ml). The mixture was acidified with 1 M HCl to pH = 3 and was extracted with EA (20 ml × 3). The organic phase was combined, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by preparative HPLC to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamothioyl)-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazine-3-sulfonamide (30 mg, yield: 24.2%) as a white solid.

[00518] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.62 (s, 1H), 7.21-6.96 (m, 2H), 4.40-4.35 (m, 2H), 4.11-4.08 (m, 2H), 2.80 (t, J=7.2 Hz, 4H), 2.63-2.58 (m, 4H), 2.19-2 .16 (m, 2H), 1.98-1.91 (m, 4H). MS: m/z 417.0 (M-H ⁺ ).

Example 4 Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine -3-sulfonamide:

[00519] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine -3-sulfonamide is illustrated below.

Stage 1

[00520] To a solution of 3-bromo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine (1 g, 5 mmol) in dry THF (10 mL) was slowly added n-BuLi in hexane ( 2.5 M, 2 ml, 5 mmol) at -78° C. under N2. After stirring with cooling for 20 min, ZnCl ₂ in ether (1 M, 5 ml, 5 mmol) was added slowly at the same temperature. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. Then TCPC (1.8 g, 5 mmol) was added and the reaction solution was stirred at room temperature for 1 h. The reagents were partitioned between water (80 ml) and EA ( 80 ml). The organic layer was washed with brine (80 ml), dried over Na ₂ SO ₄ and concentrated to give crude 2,4,6-trichloro-phenyl ester 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine -3-sulfonic acid as a yellow gel, which was used directly in the next step without further purification.

Stage 2

[00521] 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-3-sulfonic acid 2,4,6-trichloro-phenyl ester mixture (crude, ~5 mmol), NH ₃ ⋅H ₂ O (15 ml) and THF (15 ml) were stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure. The remaining solution was acidified with 1 N HCl to pH=5 and partitioned between EA (15 ml) and water (70 ml). The aqueous phase was purified using a reverse phase column to give 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-3-sulfonic acid amide (270 mg, yield: 27% over 2 steps) as yellow solid.

[00522] ¹ H NMR (400 MHz, DMSO-d6): δ = 7.62 (s, 1H), 7.15 (br. s, 2H), 4.08 (t, J=6.0 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 1.98-1.92 (m, 2H), 1.83-1.77 (m, 2H). MS: m/z 201.9 (M+H ⁺ ).

Stage 3

[00523] This step is similar to the method for the synthesis of n-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonamide (Example 1).

[00524] NMR (400 MHz, DMSO-d6): δ = 10.54 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 6.94 (s, 1H) , 4.09 (t, J=5.6 Hz, 2H), 2.97 (t, J=6.4 Hz, 2H), 2.78 (t, J=7.6 Hz, 4H), 2 .57 (t, J=7.6 Hz, 4H), 1.98-1.90 (m, 6H), 1.82-1.78 (m, 2H). MS: m/z 401.0 (M+H ⁺ ).

Example 5 Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5',7'-dihydrospiro[oxetane-3,6'-pyrazolo[ 5,1-b][1,3]oxazine]-3,-sulfonamide

[00525] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5',7'-dihydrospiro[oxetan-3,6'-pyrazolo[ 5,1-b][1,3]oxazine]-3'-sulfonamide is illustrated below.

[00526] The title compound was prepared using the general synthetic method N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (Example 1).

[00527] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.77 (s, 1H), 7.51 (s, 1H), 6.85 (s, 1H), 4.59 (s , 2H), 4.50 (d, J=6.0 Hz, 2H), 4.43 (d, J=6.4 Hz, 2H), 4.38 (s, 2H), 2.76 (t , J=7.2 Hz, 4H), 2.60 (t, J=6.4 Hz, 4H), 1.94-1.90 (m, 4H). MS: m/z 445.0 (M+H ⁺ ).

Example 6: Synthesis of N-((2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

[00528] The synthesis of N-((2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[00529] 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (0.123 mmol, 0.025 g) was suspended in THF (1 ml) and cooled to 0°C. NaH (0.123 mmol, 2.95 mg) was added and the mixture was allowed to stir for 5 minutes. Then 2-isocyanato-1,3-diisopropylbenzene (0.123 mmol, 0.026 ml) was added and the mixture was left to stir at room temperature for 2 hours. At the same time, the reaction mixture was quenched with water and the organic solvent was evaporated. The reaction mixture was then acidified with HCl and the white precipitate was filtered off, washed with water and dried to give N-((2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonamide (38 mg, 76%). ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 10.60 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.24 (t, J= 1.1 Hz, 1H), 7.12 (d, J=1.1 Hz, 2H), 4.46-4.44 (m, 2H), 4.11 (dd, J=7.5, 4 .7 Hz, 2H), 2.91 (t, J=6.9 Hz, 2H), 2.23-2.20 (m, 2H), 1.13-1.01 (m, 12H). MS: m/z 407 (M+H ⁺ ).

Example 7 Synthesis of N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

[00530] The synthesis of N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[00531] 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (0.105 mmol, 0.021 g) was dissolved in THF (2 ml) and treated with NaH (0.105 mmol, 4.21 mg) at 0C. After a few minutes, 5-chloro-2-isocyanato-1,3-diisopropylbenzene (0.105 mmol, 25 mg) was added and the mixture was allowed to stir over the weekend. The reaction mixture was then quenched with water and the solvent volume was reduced to ~1/3 of the original volume. The reaction mixture was then acidified with 1 M HCl and the finely crystalline precipitate was filtered off, washed with water and dried to give N-((4-chloro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonamide (23.7 mg, 51.1%). ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 10.70 (s, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.15 (s, 2H) , 4.45 (dd, J=5.4, 4.8 Hz, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.62-3.59 (m, 3H), 2.93-2.86 (m, 2H), 2.24-2.20 (m, 2H), 1.78-1.75 (m, 3H), 1.11-1.01 (m, 13H ). MS: m/z 442 (M+H ⁺ ).

Example 8: Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazine-3-sulfonamide

[00532] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00533] To a suspension of PPh ₃ (252.0 g, 961.5 mmol) in acetonitrile (600 ml) was added dropwise a solution of Br ₂ (49.3 ml, 961.5 mmol) in acetonitrile (200 ml) at 0° C, then 2,2-dimethyl-propane-1,3-diol (50.0 g, 480.8 mmol) was added. The reaction mixture was heated to 85°C and boiled under reflux for 16 hours. The solvent was removed in vacuo. The residual solid was washed (PE/EA=3/1, 300 ml) and filtered. The filtrate was concentrated and distilled to give 1,3-dibromo-2,2-dimethyl-propane (45.0 g, yield: 41%) as a colorless oily liquid.

[00534] 1 H NMR (300 MHz, CDCl ₃ ): δ = 3.42 (s, 4H), 1.18 (s, 6H).

Stage 2

[00535] 1,2-Dihydro-pyrazol-3-one (25.0 g, 297.6 mmol) and K ₂ CO ₃ (144.0 g, 1041.7 mmol) were heated to 120° C. in DM FA ( 700 ml). 1,3-Dibromo-2,2-dimethyl-propane (82.0 g, 357.1 mmol) was added and the mixture was heated for 24 hours. The solvent was removed in vacuo. The residue was divided between EA/H ₂ O (200 ml/500 ml) and the layers were separated. The aqueous layer was extracted with EA (200 ml) and the combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was cooled to 5°C and washed with PE (100 ml) to give 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (14.0 g, yield : 31%) as a yellow solid.

[00536] ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.32 (s, 1H), 5.48 (s, 1H), 3.87 (s, 2H), 3.84 (s, 2H ), 1.13 (s, 6H).

Stage 3-5

[00537] These three steps are similar to the general method for the synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazine-3-sulfonamide (Example 1).

Stage 6

[00538] To a suspension of 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide (400 mg, 1.7 mmol) in THF (10 ml) was added MeONa (190 mg, 3.5 mmol) and the mixture was stirred at room temperature for 20 minutes. to obtain a suspension of sodium salt.

[00539] In another flask to a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (300 mg, 1.7 mmol) and TEA (530 mg, 5.2 mmol) in THF (15 ml) was added triphosgene (210 mg, 0.7 mmol) in one portion and the mixture was stirred at room temperature under N ₂ for 20 minutes. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature for 16 hours. Thereafter, the reaction solution was partitioned between EA (50 ml) and water (150 ml). The aqueous phase was filtered and passed N ₂ for 5 min, then acidified to pH=5 conc. HCl. The formed solid was dissolved, then MeCN (50 ml) was added. And the mixture was concentrated to remove MeCN at 40°C. The resulting solid was collected by filtration and dried to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (320 mg, yield: 43%) as a white solid.

[00540] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.49 (s, 1H), 7.90 (s, 1H), 7.64 (s, 1H), 6.93 (s , 1H), 4.14 (s, 2H), 3.88 (s, 2H), 2.78 (t, J=7.2 Hz, 4H), 2.58 (t, J=7.2 Hz , 4H), 1.98-1.90 (m, 4H), 1.02 (s, 6H). MS: m/z 431.0 (M+H+).

Example 9 Synthesis of 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide

[00541] Another method for the synthesis of 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide is illustrated below.

Stage 1

[00542] 6,6-Dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (3.0 g, 19.7 mmol) was added portionwise to ClSO ₃ H (25 ml) at 0°C. After stirring at 80° C. for 16 hours, the reaction mixture was added dropwise to ice water (250 ml) and extracted with EA (100 ml×3). The combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was cooled to 5°C and washed with PE/EA (5/1, 30 ml) to give 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 3-sulfonyl chloride (2.4 g, yield: 49%) as a yellow solid.

[00543] ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.79 (s, 1H), 4.16 (s, 2H), 3.90 (s, 2H), 1.20 (s, 6H ). Stage 2

[00544] To a solution of 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride (2.2 g, 8.8 mmol) in THF (18 ml) was added NH ₃ ⋅H ₂ O (10 ml). After stirring at 60° C. for 1 hour, the reaction mixture was concentrated to dryness. The residue was diluted with MeOH (20 ml) and acidified with aq. HCl (2 N) to pH=5. The resulting solution was purified using a reverse phase column (0% - 60% MeCN in H ₂ O) to obtain the amide 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonic acid (1.6 g, yield: 79%) as a yellow solid.

Example 10 Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazine-3-sulfonamide

[00545] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00546] TsOH (3 .6 g, 0.019 mol) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE/EA=50/1) to obtain 2-(2-bromo-1-bromomethyl-ethoxy)-tetrahydro-pyran (34 g, yield: 60%) as a colorless oily liquid.

[00547] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 4.80-4.79 (m, 1H), 4.04-3.90 (m, 2H), 3.72-3, 52 (m, 5H), 1.87-1.55 (m, 6H).

Stage 2

[00548] A mixture of 2-(2-bromo-1-bromomethyl-ethoxy)-tetrahydro-pyran (17 g, 56.3 mmol), 1,2-dihydro-pyrazol-3-one (4 g, 47 mmol) and K ₂ CO ₃ (23 g, 165 mmol) in DM FA (250 ml) was stirred at 100° C. overnight. The solvent was removed under reduced pressure. The residue was partitioned between EA (200 ml) and water (200 ml). The aqueous phase was extracted with EA (200 ml). The organic layers were combined, washed with water (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (EA) to give 6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (4.9 g , yield: 46%) as a yellow oily liquid.

[00549] ¹ H NMR (300 MHz, DMSO-d6): δ = 7.34 (s, 1H), 5.51 (s, 1H), 4.89-4.83 (m, 1H), 4, 36-4.24 (m, 4H), 3.93-3.88 (m, 1H), 3.59-3.54 (m, 1H), 1.79-1.69 (m, 3H), 1.65-1.51 (m, 4H). MS: m/z 224.9 (M+H ⁺ ).

Stage 3

[00550] To a solution of 6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (5.1 g, 22.8 mmol) in MeCN, two portions were added NBS at 0°C in an atmosphere of N ₂ . The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between EA (100 ml) and water (200 ml). The organic layer was washed with water (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give 3-bromo-6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine (5.6 g, yield: 81%) as a yellow solid.

[00551] ¹ H NMR (300 MHz, DMSO-d6): δ = 7.33 (s, 1H), 4.88-4.82 (m, 1H), 4.48-4.18 (m, 5H ), 3.88-3.75 (m, 1H), 3.58-3.53 (m, 1H), 1.84-1.51 (m, 7H). MS: m/z 303.0 (M+H ⁺ ).

Stage 4

[00552] To a solution of 3-bromo-6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (2 g, 6.6 mmol) in dry THF (20 ml) was added slowly n-BuLi in hexane (2.5 M, 2.6 ml, 6.6 mmol) at -78° C. under N ₂ atmosphere. After stirring with cooling for 20 min, ZnCl ₂ in ether (1 M, 6.6 ml, 6.6 mmol) was added slowly at the same temperature. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. TCPC (2 g, 6.6 mmol) was then added and the mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between water (100 ml) and EA ( 100 ml). The organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated to give crude 2,4,6-trichloro-phenyl ester 6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid as a yellow gel, which was used directly in the next step without further purification.

Stage 5

[00553] 6-(Tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 2,4,6-trichlorophenyl ether mixture -sulfonic acid (crude, ~6.6 mmol), NH ₄ OH (20 ml) and THF (20 ml) were stirred at 60°C during the night. The reaction mixture was concentrated under reduced pressure to 10 ml of remaining liquid. The remaining solution was acidified with 1 N HCl to pH=5 and extracted with EA (100 ml x 5). The organic layers were combined, dried over Na ₂ SO ₄ and concentrated to give crude amide 6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonic acid as a yellow gel, which was used directly in the next step without further purification. MS: m/z 304.1 (M+H ⁺ ).

Stage 6

[00554] To a solution of 6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide (crude, 6, 6 mmol) in THF/H ₂ O/EtOH (50 ml/10 ml/50 ml) was added conc. HCl (10 ml) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase column (MeCN/H ₂ O) to give 6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide ( 290 mg, yield: 21% over 3 steps) as a white solid.

[00555] ¹ H NMR (300 MHz, DMSO-d6): δ = 7.48 (s, 1H), 7.11 (br. s, 2H), 5.65 (br. s, 1H), 4, 30-4.20 (m, 4H), 3.96-3.92 (m, 1H). MS: m/z 220.1 (M+H ⁺ ).

Stage 7

[00556] To a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (63.1 mg, 0.365 mmol) and TEA (0.203 ml, 1.1 mmol) in THF (5 ml), triphosgene (43.7 mg, 0.146 mmol) was added and the mixture was stirred for 10 minutes at room temperature. In another round bottom flask to a solution of 6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide (80 mg, 0.365 mmol) in THF (5 ml ) was added MeONa (21.7 mg, 0.401 mmol) and the mixture was stirred for 20 minutes at room temperature. The resulting 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene was filtered to remove the resulting precipitate, and the filtrate was added to another flask containing the sulfonamide salt. The progress of the reaction was monitored by TLC and quenched by adding water (30 ml) after 20 minutes. The aqueous phase was washed with EA (20 ml) and later filtered. The filtrate was acidified to pH=3~4. The resulting solid was collected by filtration to give N-((1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl)-6-hydroxy-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide (15 mg, yield: 10%) as a white solid.

[00557] ¹ H NMR (400 MHz, DMSO-d6): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 5.67 (s, 1H), 4.34 (s, 3H), 4.24 (dd, J=4.0, 3.2 Hz, 1H), 3.96 (d, J=12 .4 Hz, 1H), 2.78 (t, J=7.2 Hz, 4H), 2.60 (t, J=7.6 Hz, 4H), 1.98-1.93 (m, 4H ). MS: m/z 419.1 (M+H ⁺ ).

Example 11: Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5,6,7,8-tetrahydropyrazolo[5,1-b][ 1,3]oxazepine-3-sulfonamide

[00558] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5,6,7,8-tetrahydropyrazolo[5,1-b][ 1,3]oxazepine-3-sulfonamide illustrated below

Stage 1

[00559] 1,2-Dihydro-pyrazol-3-one (3.0 g, 35.7 mmol) and K ₂ CO ₃ (17.0 g, 125.0 mmol) were heated to 130° C. in DMF (100 ml). 1,4-dnbromo-butane (9.3 g, 42.9 mmol) was added and the mixture was heated for 16 hours. The solvent was removed in vacuo. The residue was divided between EA/H ₂ O (50 ml/80 ml) and the layers were separated. The aqueous layer was extracted with EA (50 ml) and the combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give 5,6,7,8-tetrahydro-4-oxa-1,8a-diaza-azulene (1.3 g, yield: 27%) in form of a colorless oily liquid.

[00560] ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.24 (d, J=1.5 Hz, 1H), 5.69 (d, J=1.5 Hz, 1H), 4, 25-4.20 (m, 2H), 4.06 (t, J=5.1 Hz, 2H), 2.07-2.03 (m, 2H), 1.91-1.84 (m, 2H). Stage 2-5

[00561] These four steps are similar to the general procedure for the synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazine-3-sulfonamide (Example 3).

[00562] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.60 (s, 1H), 7.94 (s, 1H), 7.60 (s, 1H), 6.94 (s , 1H), 4.22-4.16 (m, 4H), 2.79 (t, J=7.6 Hz, 4H), 2.5 8 (t, J=7.2 Hz, 4H), 2.03-1.90 (m, 6H), 1.80-1.70 (m, 2H). MS: m/z 417.0 (M+H ⁺ ).

Example 12 Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonamide

[00563] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00564] 1,2-Dihydro-pyrazol-3-one (2.0 g, 23.8 mmol) and K ₂ CO ₃ (11.5 g, 83.3 mmol) were heated to 120° C. in DM FA ( 60 ml). Added 1,3-dibromo-butane (6.2 g, 28.6 mmol) and the mixture was heated for 16 hours. The solvent was removed in vacuo. The residue was divided between EA/H ₂ O (50 ml/80 ml) and the layers were separated. The aqueous layer was extracted with EA (50 ml) and the combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 5/1 to 1/1) to give 7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1 .3 g, yield: 40%) as a yellow oily liquid and 5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (500 mg, yield: 15%) as a yellow solid.

[00565] 7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.32 (d, J =2.0 Hz, 1H), 5.45 (d, J=1.6 Hz, 1H), 4.36-4.31 (m, 2H), 4.24-4.18 (m, 1H) , 2.34-2.27 (m, 1H), 2.02-1.94 (m, 1H), 1.59 (d, J=6.0 Hz, 3H).

[00566] 5-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine: ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.30 (d, J =1.6Hz, 1H), 5.45(d, J=2.0Hz, 1H), 4.38-4.30(m, 1H), 4.25-4.20(m, 1H) , 4.15-4.08 (m, 1H), 2.19-2.03 (m, 2H), 1.46 (d, J=6.4 Hz, 3H).

Stage 2-5

[00567] These four steps are similar to the general procedure for the synthesis of N-((1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazine-3-sulfonamide (Example 1).

[00568] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.47 (s, 1H), 7.91 (s, 1H), 7.64 (s, 1H), 6.94 (s , 1H), 4.53-4.32 (m, 3H), 2.79 (t, J=7.2 Hz, 4H), 2.58 (t, J=7.2 Hz, 4H), 2 .38-2.31 (m, 1H), 1.99-1.91 (m, 5H), 1.45 (d, J=6.0 Hz, 3H). MS: m/z 417.0 (M+H ⁺ ).

Example 13: Synthesis of 6-fluoro-N-((1,2,3,5,6,7-hexahydro-s-nedacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazine-3-sulfonamide

[00569] Synthesis of 6-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00570] To a solution of 6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide (100 mg, 0.46 mmol) in DCM (5 ml) was added DAST (148 mg, 0.92 mmol) at -78°C in an atmosphere of N ₂ . The reaction mixture was then stirred at room temperature overnight. The reaction mixture was quenched with H ₂ O (20 ml) and partitioned between DCM (40 ml) and water (20 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified using a reverse phase column (MeCN/H ₂ O) to give 6-fluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide ( 18 mg, yield: 18%) as a white solid. MS: m/z 222.1 (M+H ⁺ ).

Stage 2

[00571] This step is similar to the method for the synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonamide (Example 1).

[00572] ¹ H NMR (400 MHz, DMSO-d6): δ = 10.58 (s, 1H), 8.00 (s, 1H), 7.69 (s, 1H), 6.93 (s, 1H), 5.58 (d, J=44.0 Hz, 1H), 4.75(t, J=12.0 Hz, 1H), 4.59-4.37 (m, 3H), 2, 78 (t, J=7.2 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 1.97-1.90 (m, 4H). MS: m/z 421.0 (M+H ⁺ ).

Example 14 Synthesis of 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-sulfonamide

[00573] Synthesis of 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-sulfonamide is illustrated below.

Stage 1

[00574] To a solution of 3-bromo-6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (4.6 g, 15 .2 mmol) in THF/H ₂ O/EtOH (50 ml/10 ml/50 ml) was added conc. HCl. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated. The residue was treated with saturated NaHCO ₃ solution. The solid formed was collected by filtration to give 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (2.76 g, yield: 84%) as white solid.

[00575] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 7.36 (s, 1H), 5.59 (br. s, 1H), 4.28-4.18 (m, 4H) , 3.95-3.90 (m, 1H).

Stage 2

[00576] To a solution of 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (1.2 g, 5.5 mmol) in DMF (12 ml) NaH (60% in mineral oil, 263 mg, 6.6 mmol) was added. The reaction mixture was stirred at room temperature for 1 h under N ₂ . MeI (940 mg, 6.6 mmol) was then added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (60 ml) and extracted with EA (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified using a reverse phase column (MeCN/H ₂ O) to give 3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1 g , yield: 78%) as a white solid.

[00577] ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.34 (s, 1H), 4.53-4.48 (m, 1H), 4.27-4.18 (m, 3H) , 3.94-3.93 (m, 1H), 3.49 (s, 3H). MS: m/z 232.9 (M+H+).

Stage 3~5

[00578] These steps are similar to the general method for the synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonamide Example 1).

[00579] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.47 (s, 1H), 7.91 (s, 1H), 7.62 (s, 1H), 6.93 (s , 1H), 4.65 (d, J=11.6 Hz, 1H), 4.37 (d, J=11.2 Hz, 1H), 4.24-4.22 (m, 2H), 4 .06 (s, 1H), 3.34 (overlapped, 3H), 2.78 (t, J=7.6 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 1 .98-1.91 (m, 4H). MS: m/z 433.0 (M+H ⁺ ).

Example 15 Synthesis of 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-sulfonamide

[00580] Synthesis of 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-sulfonamide is illustrated below.

[00581] The title compound was prepared using the general synthetic method N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (Example 1).

[00582] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.51 (s, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.94 (s , 1H), 4.60-4.56 (m, 1H), 4.13-4.08 (m, 2H), 2.79 (t, J=7.2 Hz, 4H), 2.59 ( t, J=6.8 Hz, 4H), 2.28-2.24 (m, 1H), 1.98-1.93 (m, 5H), 1.38 (d, J=6.0 Hz , 3H). MS: m/z 417.0 (M+H ⁺ ).

Example 16: Synthesis of N-((8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazine-3-sulfonamide

[00583] Synthesis of N-((8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00584] 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (2.332 mmol, 404 mg) and NCS (2.332 mmol, 0.311 g) were mixed in DCM (5 ml) and allowed to stir during the night. The mixture was then partitioned between water (20 ml) and DCM (20 ml). The layers were separated and aq. the layer was extracted with DCM (20 ml). The combined organic layers were then dried over Na ₂ SO ₄ , filtered and concentrated to yield 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (2.332 mmol, 404 mg) as a brown solid, which was used without purification. MS: m/z 209 (M+H ⁺ ).

Stage 2

[00585] N,N-dimethylpyridin-4-amine (0.481 mmol, 0.059 g) was dissolved in THF (1.5 ml) and then a solution of di-tert-butyl dicarbonate (0.481 mmol, 0.111 ml) in THF (1.5 ml) was added slowly 5 ml). After stirring for several minutes, a solution of 8-chloro-1,2,3,5,6,7-hexahydro-s-indacene-4-amine (0.481 mmol, 100 mg) in THF (1 ml) was added and the mixture was allowed to stir within 30 min. At the same time, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (0.481 mmol, 0.098 g) in THF (1 ml) was treated with sodium hydride (0.481 mmol , 0.012 g) and left to mix for 30 minutes. At the same time, the two solutions were mixed and allowed to stir for 18 hours.

[00586] The reaction mixture was then quenched with sat. NH4Cl (10 ml) and diluted with EtOAc (40 ml). The layers were separated and aq. the layer was extracted with EtOAc (30 ml). The combined organic extracts were then washed with water (20 ml) and concentrated. The resulting solid was suspended in MeOH:water (10:1, 10 ml), the reddish solid was filtered off and discarded. The filtrate was concentrated and purified by preparative HPLC (10-40% MeCN:10 mM aq. NH3). Purified fractions were combined and concentrated to give N-((8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide (5.8 mg, 2.76%) as a white solid.

[00587] ¹ H-NMR (400 MHz; DMSO-d ₆ ): δ 7.88-7.85 (m, 1H), 7.55 (s, 1H), 4.42-4.39 (m, 2H), 4.11-4.08 (m, 2H), 2.85-2.82 (m, 4H), 2.71 (t, J=7.4 Hz, 4H), 2.22-2 .16 (m, 2H), 2.04-1.97 (m, 4H). MS: m/z 437 (M+H ⁺ ).

Example 17: Synthesis of 4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5 -a]pyridine-3-sulfonamide

[00588] Synthesis of 4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5 -a]pyridine-3-sulfonamide is illustrated below.

Stage 1

[00589] To a solution of 4-bromo-2H-pyrazole-3-carboxylic acid ethyl ester (8.0 g, 36.4 mmol) in DMF (80 ml) was added K ₂ CO ₃ (10 g, 72.8 mmol) and 4-bromobutyric acid ethyl ester (10 g, 54.8 mmol), then the suspension was stirred overnight. The reaction mixture was quenched by the addition of EA (200 ml) and water (200 ml). The organic layer was separated. The aqueous layer was extracted with EtOAc (200 ml). The organic layers were combined and washed with water (300 ml×3), brine (300 ml) and dried over Na ₂ SO ₄ . The solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=10/1) to give 4-bromo-2-(3-ethoxycarbonyl-propyl)-2H-pyrazole-3-carboxylic acid ethyl ester (6.7 g, yield: 55 .4%) as a colorless oily liquid. MS: m/z 332.8 (M+H ⁺ ).

Stage 2

[00590] NaH (1 .2 g, 30.3 mmol) at 0°C and then the mixture was heated to boiling overnight. When the reaction was complete, the reaction mixture was quenched with saturated aqueous NH ₄ Cl (20 ml). The aqueous phase was extracted with EA (100 ml x 2). The extracts were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated to give 3-bromo-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-5 ethyl ester -carboxylic acid (5.2 g, yield: 90%) as a white solid. MS: m/z 286.9 (M+H ⁺ ).

Stage 3

[00591] To a solution of 3-bromo-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (5.2 g, 15.7 mmol) in DMSO (200 ml) and water (5 ml) was added NaCl (5.5 g, 94 mmol) and the mixture was heated to 150°C for 2 hours. After cooling to room temperature, the reagents were diluted with EA (200 ml) and water (200 ml). The organic layer was separated. The aqueous layer was extracted with EtOAc (200 ml). The combined organic layers were washed with water (300 ml×3), brine (300 ml) and dried over Na ₂ SO ₄ . The solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=5/1) to give 3-bromo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridin-4-one (2.6 g, yield: 66%) as a white solid.

[00592] ¹ H NMR (400 MHz, DMSO-d6): δ = 7.55 (s, 1H), 4.40 (t, J=6.0 Hz, 2H), 2.72 (t, J= 6.4 Hz, 2H), 2.36-2.40 (m, 2H).

Stage 4

[00593] To a solution of 3-bromo-6,7-dihydro-5H-pyrazolo[1,5-a]pyridin-4-one (1.6 g, 7.36 mmol) in MeOH (20 ml) was added _{NaBH -} (l.4 g, 12.8 mmol) at 0°C and the mixture was stirred at room temperature for 2 hours. When the reaction was complete, the reactants were evaporated to remove the MeOH. The residue was partitioned between EA (50 ml) and water (50 ml). The organic layer was separated. The aqueous layer was extracted with EtOAc (50 ml). The combined organic layers were washed with brine (30 ml) and dried over Na ₂ SO ₄ . The solution was concentrated to give 3-bromo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-4-ol (1.4 g, yield: 88%) as a white solid. MS: m/z 216.9 (M+H ⁺ ).

Stage 5

[00594] To a solution of 3-bromo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-4-ol (1.4 g, 6.5 mmol) in DCM (30 ml) was added DAST (2.1 g, 13 mmol) at -60°C. The solution was allowed to slowly warm to room temperature and stirred at room temperature for 2 hours. When the reaction was complete, DCM (50 ml) and water (50 ml) were added to the mixture. The organic layer was separated. The aqueous layer was extracted with DCM (50 ml). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=5/1) to give 3-bromo-4-fluoro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine (830 mg, yield: 59%) as a yellow oily liquid.

[00595] ¹ H NMR (400 MHz, DMSO-d6): δ = 7.50 (s, 1H), 5.60 (dt, J=51.2, 2.8 Hz, 1H), 4.28- 4.32(m, 1H), 3.87-3.94(m, 1H), 2.26-2.40(m, 2H), 1.92-2.00(m, 2H).

Stage 6

[00596] To a solution of 3-bromo-4-fluoro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine (0.5 g, 2.3 mmol) in dry THF (5 ml) n-BuLi in hexane (0.92 ml, 2.3 mmol, 2.5 M) was added slowly at -78° C. under N ₂ . After stirring at that temperature for 20 min, ZnCl ₂ in ether ( 2.3 ml, 2.3 mmol, 1 M) at the indicated temperature. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. TCPC (0.68 g, 2.3 mmol) was added to the mixture at 0° C. and the mixture was allowed to stir at room temperature for 1 h. The reaction was quenched with saturated solution NH ₄ Cl (2 ml) and partitioned between water (20 ml) and EA (20 ml). The organic layer was washed with brine (80 ml), dried over Na ₂ SO ₄ and concentrated to give crude 2,4,6-trichloro-phenyl ester 6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazine-3-sulfonic acid as a yellow oily liquid. The crude product was dissolved in THF (5 ml) and NH ₃ ⋅H ₂ O (5 ml) was added, then heated to 60° C. overnight. When the reaction was completed, the reaction solution was concentrated to remove the solvent. The residue was acidified with 1 N HCl to pH=5 and partitioned between EA (20 ml) and water (20 ml). The organic layer was separated. The aqueous layer was extracted with EtOAc (20 ml). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give 4-fluoro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-3-sulfonic acid amide (0.17 g, yield: 34%) as a yellow solid. MS: m/z 220.0 (M+H ⁺ ).

Stage 7

[00597] To a solution of 4-fluoro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-3-sulfonic acid amide (75 mg, 0.34 mmol) in THF (2 ml) was added MeONa (22 mg, 0.41 mmol) and the mixture was stirred at room temperature for 20 minutes. to obtain a suspension of sodium salt.

[00598] In another flask to a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (59 mg, 0.34 mmol) and TEA (69 mg, 0.68 mmol) in THF (3 mL), triphosgene (141 mg, 0.14 mmol) was added in one portion and the mixture was stirred at room temperature under N ₂ for 20 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature for 1 hour. After that, the reaction solution was partitioned between EA (15 ml) and water (15 ml). The aqueous phase was separated and acidified to pH=5 with 1M HCl. The resulting solid was collected by filtration and air dried to give 4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6, 7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonamide (45 mg, yield: 31.4%) as a white solid.

[00599] ¹ H NMR (400 MHz, DMSO-d6): δ = 10.67 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 6.93 (s, 1H), 6.08 (d, J=49.2 Hz, 1H), 4.35-4.37 (m, 1H), 4.05-4.08 (m, 1H), 2.78 (t , J=6.8 Hz, 4H), 2.55 (t, J=6.8 Hz, 4H), 1.92-2.29 (m, 8H). MS: m/z 419.0 (M+H ⁺ ).

Example 18

[00600] Synthesis of ((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)((1,2,3,5,6,7-hexahydro -s-indacen-4-yl)carbamoyl)amide sodium is illustrated below.

Stage 1:

[00601] 1,2-Dihydro-pyrazol-3-one (53.0 g, 630.9 mmol) and K ₂ CO ₃ (305.0 g, 2210.1 mmol) were heated to 130° C. in DMF (1 l). 1,3-dibromopropane (140.0 g, 693.1 mmol) was added and the mixture was heated for 8 hours and then concentrated. The residue was partitioned between EA (200 ml) and water (500 ml) and the layers were separated. The aqueous layer was extracted with EA (150 ml x 8) and the combined organic layer was washed with brine (300 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=3/1) to give 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (32.0 g, yield: 41%) as a yellow oily liquid.

[00602] ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.31 (d, J=2.0 Hz, 1H), 5.48 (d, J=2.0 Hz, 1H), 4, 28 (t, J=5.2 Hz, 2H), 4.18 (r, J=6.2 Hz, 2H), 2.29-2.22 (m, 2H).

Stage 2:

[00603] 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (64.0 g, 516.1 mmol) was added dropwise to ClSO ₃ H (380 ml) at 0° WITH. After stirring at 80°C for 16 hours, the reaction mixture was added dropwise to a mixture of ice-water/EA (4 l/1.5 l). The two layers were separated and the aqueous layer was extracted with EA (300 ml x 2). The organic layers were washed with brine (500 ml), dried over Na ₂ SO ₄ and concentrated. The residue was washed with PE (200 ml) to give 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride (73.0 g, yield: 63%) as a yellow solid substances.

Stage 3:

[00604] NH ₃ ⋅H ₂ O (180 ml). After stirring at 60°C for 16 hours, the reaction mixture was concentrated to dryness. The residue was washed with aq. HCl (0.2 M, 110 ml), H ₂ O (40 ml) and dried to give 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide (52.0 g, yield: 78%) as a yellow solid.

[00605] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 7.47 (s, 1H), 7.08 (s, 2H), 4.40 (t, J=5.1 Hz, 2H ), 4.10 (t, J=6.0 Hz, 2H), 2.23-2.15 (m, 2H).

Stage 4:

[00606] To a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (15.0 g, 87 mmol) and TEA (13.3 ml, 95.4 mmol) in THF (300 ml) triphosgene (8.5 g, 28.6 mmol) was added in one portion at 0~5°C and the mixture was stirred at 70°C under N ₂ atmosphere for 1 hour. The reaction mixture was then filtered through diatomaceous earth. The filter press cake was then washed with 30 ml of PE. The filtrate was concentrated to dryness and dissolved in 100 ml n-hexane. The mixture was filtered through a pad of silica gel. The filtrate was concentrated to dryness to give 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (14.6 g, yield: 84%) as a pink oily liquid.

[00607] A suspension of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide (14.3 g, 70.4 mmol) in MeOH (500 mL) was stirred at 80° C. until a clear solution was obtained, then MeONa (3.8 g, 70.4 mmol) was added and the mixture was stirred for 5 min. The solution was concentrated to dryness and the residue co-evaporated with MeCN (100 ml). The remaining solid was suspended in MeCN (320 ml) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (14.6 g, 73.3 mmol) was added. The mixture was stirred for 16 hours at room temperature and filtered. The filter press cake was triturated with EtOH (250 ml), PE/EA (5/1, 250 ml) to give the product. The product was dissolved in H ₂ O (200 ml) and concentrated to dryness to give ((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)((1, 2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide sodium (24.5 g, yield: 82%) as a white solid.

[00608] ¹ H NMR (400 MHz, D ₂ O): δ = 7.64 (s, 1H), 7.02 (s, 1H), 4.40 (t, J=5.2 Hz, 2H) , 4.11 (t, J=6.0 Hz, 2H), 2.83 (t, J=7.2 Hz, 4H), 2.66 (t, J=7.2 Hz, 4H), 2 .28-2.22 (m, 2H), 2.04-1.96 (m, 4H). MS: m/z 403.1 (M+H ⁺ ).

Example 19

[00609] Synthesis of 1-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl))-3-(2,3-dihydro-pyrazolo[5,1-b]oxazole -7-sulfonyl)-urea is illustrated below.

Stage 1

[00610] To a solution of 1,2-dihydro-pyrazol-3-one (500 mg, 5.9 mmol) in MeCN (50 ml) was added 1,2-dibromo-ethane (3.3 g, 17.6 mmol) and K ₂ CO ₃ (2.4 g, 17.6 mmol). After stirring at reflux overnight, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC (MeCN in H ₂ O, 5% to 95%) to give 2,3-dihydro-pyrazolo[5,1-b]oxazole (260 mg, 40%) as a yellow solid substances.

[00611] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.27 (s, 1H), 5.37 (d, J=1.6 Hz, 1H), 5.06 (t, J = 8.0 Hz, 2H), 4.23 (t, J=8.0 Hz, 2H).

Stage 2

[00612] 2,3-Dihydro-pyrazolo[5,1-b]oxazole (1 g, 9.1 mmol) was dissolved in ClSO ₃ H (20 ml). After heating at 80°C overnight, the reaction mixture was added dropwise to a mixture of EA (150 ml), NH ₃ ⋅H ₂ O (20 ml) and H ₂ O (150 ml). After stirring at room temperature, the reaction mixture was concentrated in vacuo. The residue was suspended in MeOH (30 ml), stirred for 0.5 h and the mixture was filtered. The filtrate was evaporated in vacuo and the residue was purified by reverse phase HPLC (MeCN in water, 0% to 60%) to give 2,3-dihydro-pyrazolo[5,1-b]oxazole-7-sulfonic acid amide (60 mg, 4%) as a yellow solid.

Stage 3 - Getting E

[00613] To a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (55 mg, 0.32 mmol) in THF (10 ml) mmol) and TEA (48 mg, 0.48 mmol). After stirring at room temperature for 2 hours, the reaction mixture was filtered. The filtrate was evaporated in vacuo. The residue was then dissolved in THF (5 ml). Then 2,3-dihydro-pyrazolo[5,1-b]oxazole-7-sulfonic acid amide (60 mg, 0.32 mmol) and NaOMe (35 mg, 0.64 mmol) were added to the mixture. After stirring at room temperature for 3 hours, the reaction mixture was quenched with H ₂ O (10 ml), acidified with 3 N HCl to pH=3 and extracted with EA (10 ml×3). The organic phase was combined, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by preparative HPLC to give 1-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl))-3-(2,3-dihydro-pyrazolo[5.1 -b]oxazole-7-sulfonyl)-urea (6 mg, 5%) as a white solid.

[00614] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.52 (br s, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 6.91 (s, 1H), 5.21 (t, J=8.0 Hz, 2H), 4.32 (t, J=8.0 Hz, 2H), 2.78 (t, J=7.2 Hz , 4H), 2.62 (t, J=7.2 Hz, 4H), 1.98-1.91 (m, 4H). MS: m/z 389.0 (M+H ⁺ ).

Example 20

[00615] Synthesis of (R)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-hydroxy-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazin-3-sulfonamide and (S)-N-((l,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) -6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00616] To a solution of ura-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (530 mg, 2.4 mmol) and pyridine (382 mg , 4.8 mmol) in THF (10 ml) was added TBSOTf (702 mg, 2.7 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with H ₂ O (20 ml) and acidified to pH=5 with 1 N HCl. The residue was purified by reverse phase HPLC (MeCN/H ₂ O) to give 6-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonamide (330 mg, yield: 41%) as a white solid. MS: m/z 334.1 (M+H ⁺ ).

Stage 2

[00617] Pau-6-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (420 mg, 1.3 mmol ) separated by chiral preparative HPLC to give two isomers (S)-6-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonamide (180 mg, yield: 42%) as a white solid; (R)-6-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (200 mg, yield: 46%) as a white solid.

Stage 3

[00618] To a solution of (S)-6-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (180 mg, 0.5 mmol) in THF (4 ml) was added conc. HCl (4 ml). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (MeCN/H ₂ O) to give (S)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- sulfonamide (115 mg, yield: 97%) as a white solid. MS: m/z 220.1 (M+H ⁺ ).

[00619] (R)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was prepared using a similar procedure.

Stage 4

[00620] (S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-hydroxy-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide was synthesized as in Preparation A herein to give the desired product (50 mg, yield: 23%) as a white solid.

[00621] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s , 1H), 5.66 (d, J=2.4 Hz, 1H), 4.34 (s, 3H), 4.24 (dd, J=4.0, 3.2 Hz, 1H), 3 .96 (d, J=12.4 Hz, 1H), 2.78 (t, J=7.2 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 1.98 -1.91 (m, 4H). MS: m/z 419.0 (M+H ⁺ ).

[00622] (R)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-hydroxy-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide was prepared using a similar procedure.

[00623] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.45 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s , 1H), 5.66 (d, J=3.2 Hz, 1H), 4.34 (s, 3H), 4.27-4.23 (m, 1H), 3.96 (d, J= 13.6 Hz, 1H), 2.78 (t, J=7.2 Hz, 4H), 2.61 (t, J=7.2 Hz, 4H), 1.98-1.91 (m, 4H). MS: m/z 419.0 (M+H ⁺ ).

Example 21

[00624] Synthesis of rac-6-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00625] To a solution of rac-tert-butyl-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (1.0 g, 3.2 mmol) in DCM (5 ml) was added TFA (5 ml) and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated to dryness to give crude rac-3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6-amine as a yellow solid, which was used directly in the next step without further purification. MS: m/z 218.0 (M+H ⁺ ).

Stage 2

[00626] To a solution of rac-3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6-amine (crude, ~3.2 mmol) in MeOH (10 ml) HCHO (30%, 3.2 g, 31.5 mmol) was added. The mixture was stirred for 2 hours at room temperature, then NaBH ₃ CN (2.0 g, 31.5 mmol) was added. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was purified by reverse phase HPLC (0%-95% MeCN in H ₂ O) to give rac-3-bromo-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine-6-amine (410 mg, yield: 53%) as a solid.

[00627] ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.33 (s, 1H), 4.45-4.44 (m, 1H), 4.30-4.24 (m, 2H) , 4.18-4.11 (m, 1H), 3.00-2.97 (m, 1H), 2.40 (s, 6H). MS: m/z 245.9 (M+H ⁺ ).

Stage 3 - Getting B

[00628] To a solution of rac-3-bromo-N,N-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6-amine (400 mg, 1.6 mmol) in dry THF (5 ml) was added slowly n-BuLi (2.5 M in hexane, 0.7 ml, 1.6 mmol) at -78° C. under N2 atmosphere. After stirring with cooling for 20 min, ZnCl ₂ (1Mb ether, 1.6 ml, 1.6 mmol) was slowly added at the same temperature. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour. TCPC (479 mg, 1.6 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between water (30 ml) and EA ( 30 ml). The organic layer was washed with brine (30 ml), dried over Na ₂ SO ₄ and concentrated to give crude rac-2,4,6-trichlorophenyl-6-(dimethylamino)-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazine-3-sulfonate as a yellow gel, which was used in the next step without purification.

Stage 4 - Getting C

[00629] A mixture of rac-2,4,6-trichlorophenyl-6-(dimethylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate (crude, - 1.6 mmol), NH ₄ OH (10 ml) and THF (10 ml) were stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure to 10 ml of remaining liquid. The remaining solution was acidified with 1 N HCl to pH=5. The residue was purified by reverse phase HPLC (0%-95% MeCN in H ₂ O) to give

[00630] Rac-2,4,6-trichlorophenyl-6-(dimethylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate (66 mg, yield : 16% over two steps) as a white solid. Alternatively, the solution may be concentrated to dryness and purified by flash chromatography.

[00631] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.47 (s, 1H), 7.13 (br. s, 2H), 4.95-4.41 (m, 2H) , 4.23-4.13(m, 2H), 2.89-2.86(m, 1H), 2.26(s, 6H).

Stage 5 - Getting A

[00632] To a solution of rac-2,4,6-trichlorophenyl 6-(dimethylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate (66 mg, 0.3 mmol) in THF (5 ml) was added MeONa (18 mg, 0.3 mmol) and the mixture was stirred at room temperature for 20 min to obtain a suspension of the sodium salt.

[00633] In another flask to a solution of 1,2,3,5,6,7-hexahydro-8-indacen-4-ylamine (47 mg, 0.3 mmol) and TEA (55 mg, 0.5 mmol) in THF (5 ml) was added triphosgene (33 mg, 0.1 mmol) in one portion and the mixture was stirred at room temperature under N ₂ for 20 minutes. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature for 20 minutes. Thereafter, the reaction solution was partitioned between EA (20 ml) and water (20 ml). The aqueous phase was acidified to pH=5 with 1 N HCl. The resulting solid was collected by filtration and dried to give rac-6-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7- dihydro-5H-pyrazolo[5D-b][1,3]oxazine-3-sulfonamide (27 mg, yield: 22%) as a white solid.

[00634] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.41 (s, 1H), 7.33 (s, 1H), 6.76 (s, 1H), 4.37-4 .22 (m, 2H), 4.11-4.09 (m, 1H), 4.03-4.01 (m, 1H), 2.83-2.82 (m, 1H), 2.74 (t, J=7.2 Hz, 4H), 2.64 (t, J=7.6 Hz, 4H), 2.25 (s, 6H), 1.93-1.86 (m, 4H) . MS: m/z 446.0 (M+H ⁺ ).

Example 22

[00635] Synthesis of (S)-6-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide and (R)-6-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00636] Rac-6-(dimethylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (110 mg, 0.4 mmol) was separated using a chiral preparative HPLC to give (S)-6-(dimethylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (41 mg, yield: 42%) in as a white solid and (R)-6-(dimethylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (36 mg, yield: 37%) as a white solid.

Stage 2

[00637] (S)-6-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was synthesized as in Preparation A to give the desired product (14 mg, yield: 18%) as a white solid.

[00638] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.47 (br. s, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 6.90 (s, 1H), 4.46-4.43 (m, 2H), 4.24-4.12 (m, 2H), 2.92-2.91 (m, 1H), 2.80 (t , J=7.2 Hz, 4H), 2.64 (t, J=7.2 Hz, 4H), 2.25 (s, 6H), 1.93-1.90 (m, 4H). MS: m/z 446.0 (M+H ⁺ ).

[00639] (R)-6-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was synthesized in a similar manner to give the product as a white solid (15 mg, yield: 22%).

[00640] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.91 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.54-4 .45 (m, 2H), 4.25-4.15 (m, 2H), 2.93-2.91 (m, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.62-2.54 (m, 4H), 2.27 (s, 6H), 1.99-1.92 (m, 4H). MS: m/z 446.0 (M+H ⁺ ).

Example 23

[00641] Synthesis of (R)-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]oxazin-3-sulfonamide and (S)-N-((l,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-sulfonamide is illustrated below.

Stage 1

[00642] Rac-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (460 mg) was separated using a chiral column to give two isomers:

[00643] (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5D-b][1,3]oxazine-3-sulfonamide (peak 1, 91 mg) and (S)-6-methoxy -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (peak 2, 116 mg).

Stage 2

[00644] (R)-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-sulfonamide was synthesized using Preparation A to give the desired product (44 mg, yield: 31%) as a white solid.

[00645] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.48 (br. s, 1H), 7.92 (br. s, 1H), 7.62 (s, 1H), 6 .93 (s, 1H), 4.63 (d, J=11.6 Hz, 1H), 4.36 (d, J=11.6 Hz, 1H), 4.27-4.19 (m, 2H), 4.06 (s, 1H), 3.34 (overlapped, 3H), 2.78 (t, J=7.2 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 1.99-1.93 (m, 4H). MS: m/z 433.0 (M+H ⁺ ).

[00646] (S)-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-sulfonamide was prepared using a similar procedure.

[00647] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.51 (s, 1H), 7.98 (s, 1H), 7.62 (s, 1H), 6.93 (s , 1H), 4.64 (d, J=11.6 Hz, 1H), 4.37 (d, J=12.0 Hz, 1H), 4.24-4.22 (m, 2H), 4 .05 (s, 1H), 3.34 (overlapped, 3H), 2.78 (t, J=7.6 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 1 .98-1.91 (m, 4H). MS: m/z 433.0 (M+H ⁺ ).

Example 24

[00648] Synthesis of (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-methoxy-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazin-3-yl)sulfonyl)amide and (S)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl )((6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium is illustrated below.

Stage 1

[00649] To a solution of rac-6-((tetrahydro-2H-pyran-2-yl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (36 g, 0.161 mol) in MeOH (200 ml) and H ₂ O (50 ml) was added conc. HCl (50 ml). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The residue was treated with saturated NaHCO ₃ (pH=8) and purified by reverse phase HPLC (0%-50% MeCN in H ₂ O) to give rac-6,7-dihydro-5H-pyrazolo[5D-b][ 1,3]oxazin-6-ol (27 g, crude yield: quantitative) as a yellow solid.

[00650] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 7.21 (s, 1H), 5.56 (s, 1H), 5.43 (s, 1H), 4.23-4 .15 (m, 4H), 3.94-3.89 (m, 1H).

Stage 2

[00651] To a solution of rac-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (10 g, 71.4 mmol) in dry DMF (150 ml) was added NaH (60%, 4.3 g, 107 mmol) at 0° C. under N ₂ atmosphere. After stirring at room temperature for 1 h, MeI (15.2 g, 107 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight, poured into water (100 ml) and filtered. The filter press cake was dried to give rau-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (5.5 g, yield: 50%) as a yellow solid substances.

[00652] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ = 7.21 (s, 1H), 5.44 (s, 1H), 4.44-4.40 (m, 1H), 4 .23-4.10 (m, 3H), 3.96 (s, 1H), 3.34 (overlapped, 3H).

Stage 3

[00653] Rac-6-Methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (5.5 g) was separated using a chiral column to give two isomers:

[00654] (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (peak 1, 2.4 g) as a white solid and (S )-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (peak 2, 2.5 g) as a white solid.

Stage 4

[00655] To a solution of (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (2.4 g, 15.6 mmol) in MeCN was added in portions NBS (2.78 g, 15.6 mmol) under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was purified by reverse phase HPLC (MeCN/H ₂ O) to give (R)-3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine (2.6 g, yield: 72%).

[00656] ¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.33 (s, 1H), 4.52-4.48 (m, 1H), 4.32-4.20 (m, 3H) , 3.93-3.92 (m, 1H), 3.49 (s, 3H).

[00657] (S)-3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine was prepared using a similar procedure.

Stage 5

[00658] (R)-2,4,6-trichlorophenyl-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate was synthesized using Preparation B , which gave the product as a yellow oil, which was used in the next step without further purification.

[00659] (5)-2,4,6-Trichlorophenyl-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate was prepared using a similar procedure .

Stage 6

[00660] (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was synthesized as in Preparation C to give the desired product (800 mg, yield: 32% over 2 steps) as a yellow solid. MS: m/z 234.0 (M+H ⁺ ).

[00661] (S)-6-Methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was prepared using a similar procedure.

Stage 7 - Getting D

[00662] To a solution of (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (800 mg, 3.43 mol) in THF (10 ml) was added MeONa (370 mg, 6.86 mmol). The mixture was stirred at room temperature for 30 minutes to give a sodium salt slurry.

[00663] In another flask to a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (891 mg, 5.1 mol) and TEA (1.5 g, 15.3 mmol ) in THF (20 ml) triphosgene (611 mg, 2.1 mmol) was added in one portion. After stirring at room temperature under N ₂ for 30 minutes, the reaction mixture was filtered. The filtrate was added to the above sodium salt suspension and the reaction mixture was stirred at room temperature overnight. Thereafter, the reaction solution was partitioned between EA (50 ml) and water (80 ml). The aqueous phase was purified by reverse phase HPLC (MeCN/H ₂ O) to give (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)(( Sodium 6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide (250 mg, yield: 16%) as a yellow solid.

[00664] ¹ H NMR (400 MHz, D ₂ O): δ=7.52 (s, 1H), 6.88 (s, 1H), 4.51 (d, J=12.0 Hz, 1H) , 4.16-4.11 (m, 3H), 4.02-4.00 (m, 1H), 3.30 (s, 3H), 2.68 (t, J=7.2 Hz, 4H ), 2.51 (t, J=7.6 Hz, 4H), 1.90-1.81 (m, 4H). MS: m/z 433.1 (M+H ⁺ ).

[00665] (S)-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)((6-methoxy-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium was obtained using a similar method.

[00666] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.47 (br. s, 1H), δ=7.39 (s, 1H), 6.78 (s, 1H), 4 .49 (dt, J=8.0 Hz, 2.0 Hz, 1H), 4.23-4.15 (m, 2H), 4.14-4.08 (m, 1H), 3.99- 3.95 (m, 1H), 3.34 (s, 3H), 2.75 (t, J=7.2 Hz, 4H), 2.65 (t, J=7.2 Hz, 4H), 1.96-1.86 (m, 4H). MS: m/z 433.1 (M+H ⁺ ).

Example 25

[00667] Synthesis of (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-methoxy-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium is illustrated below.

[00668] A solution of 1,2-dihydro-pyrazol-3-one (50.0 g, 600 mmol) in pyridine (300 ml) was heated to 95°C. To the solution was slowly added a solution of acetic anhydride (61.2 g, 600 mmol) in pyridine (100 ml) over 0.5 hour. The reaction mixture was heated for an additional 1 h at 95°C. The reaction mixture was concentrated in vacuo to give a dark red oil which was triturated with MeOH (150 ml) and filtered to give 1-acetyl-1,2-dihydro-pyrazol-3-one (54.0 g, yield: 71% ) as a white solid. ¹ H NMR (300 MHz, DMSO-A): δ=10.92 (s, 1H), 8.08 (s, 1H), 5.96 (s, 1H), 2.45 (overlapped, 3H).

Stage 2

[00669] A mixture of 1-acetyl-1,2-dihydro-pyrazol-3-one (34.7 g, 280 mol) and PPh ₃ (24.9 g, 420 mol) in THF (400 ml) was cooled to 0° C in an N ₂ atmosphere. DIAD (84.8 g, 420 mmol) was slowly added to the mixture. The reaction mixture was stirred for an additional 1 hour at 0° C., then (R)-oxiran-2-ylmethanol (25.2 g, 340 mmol) was added slowly. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EA=10/1) to give (R)-1-acetyl-2-(oxiran-2-ylmethyl)-1H-pyrazol-3(2H)- she (34.8 g, yield: 68%) as a white solid.

[00670] ¹ H NMR (400 MHz, CDCl ₃ ): δ=8.06 (d, J=2.8 Hz, 1H), 6.00 (d, J=3.2 Hz, 1H), 4, 55 (dd, J=12.0, 3.2 Hz, 1H), 4.20 (dd, J=12.0, 3.2 Hz, 1H), 3.39 (k, J=3.2 Hz , 1H), 2.92 (t, J=4.4 Hz, 1H), 2.76 (dd, J=4.4, 2.4 Hz, 1H), 2.57 (s, 3H).

Stage 3

[00671] To a solution of (R)-1-acetyl-2-(oxiran-2-ylmethyl)-1H-pyrazol-3(2H)-one (34.8 g, 190 mmol) in AcOH (34.2 g, 570 mmol) and THF (200 ml), LiCl (13.1 g, 310 mmol) was added at room temperature. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was partitioned between EA (200 ml) and water (200 ml). The organic layer was washed with sat. NaHCO ₃ (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give crude (R)-1-acetyl-2-(3-chloro-2-hydroxypropyl)-1H-pyrazole -3(2H)-one as a colorless oily liquid, which was used directly in the next step without further purification.

[00672] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=8.25 (d, J=2.7 Hz, 1H), 6.23 (d, J=3.0 Hz, 1H), 5.59 (br. s, 1H), 4.24-4.19 (m, 2H), 4.07-4.04 (m, 1H), 3.75-3.62 (m, 2H), 2.50 (overlapped, 3H). MS: m/z 219.4 (M+H ⁺ ).

Stage 4

[00673] A mixture of (R)-1-acetyl-2-(3-chloro-2-hydroxypropyl)-1H-pyrazol-3(2H)-one (crude, 190 mmol) and K ₂ CO ₃ (78.7 g , 570 mmol) in DMF (400 ml) was stirred at 135° C. overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EA) to give (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (12.8 g, yield: 48 %) as a white solid.

[00674] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.21 (d, J=1.6 Hz, 1H), 5.51 (d, J=3.2 Hz, 1H), 5.44 (d, J=1.6 Hz, 1H), 4.24-4.13 (m, 4H), 3.92 (d, J=12.4 Hz, 1H).

Stage 5

[00675] To a solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (12.8 g, 91.4 mmol) in MeCN (200 ml) NBS (17.9 g, 100.6 mmol) was added in two portions at 0° C. under N ₂ atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between EA (200 ml) and water (200 ml). The organic layer was washed with sat. NaHCO ₃ (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with EA (50 ml) and filtered to give (R)-3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (11.3 g, yield: 57%) as a white solid. MS: m/z 219.3 (M+H ⁺ ).

Stage 6

[00676] To a solution of (R)-3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (12.2 g, 55.7 mmol) in DMF (60 ml) was added NaH (60% in mineral oil, 2.7 g, 66.8 mmol). The reaction mixture was stirred at room temperature for 1 h under N ₂ . MeI (9.5 g, 66.8 mmol) was then added. After stirring at room temperature for 2 hours, the reaction mixture was poured into water (200 ml) and extracted with EA (100 ml×2). The organic layer was washed with water (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was triturated with MeOH/H ₂ O (2/1, 100 ml) and filtered to give (R)-3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine (9.5 g, yield: 73%) as a white solid. MS: m/z 233.3 (M+H ⁺ ).

Stage 7

[00677] (R)-2,4,6-trichlorophenyl 6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate was synthesized using Preparation B, which gave the product as a yellow oily liquid which was used directly in the next step without further purification.

[00678] (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was synthesized as in Preparation C to give the desired product (2.6 g, yield: 27% over 2 steps) as a white solid.

[00679] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=7.47 (s, 1H), 7.08 (s, 2H), 4.58-4.54 (m, 1H), 4 .32-4.18 (m, 3H), 4.01 (d, J=1.2 Hz, 1H), 3.35 (overlapped, 3H).

Stage 8

[00680] To a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (15.0 g, 87 mmol) and TEA (13.3 ml, 95.4 mmol) in THF (30 ml) triphosgene (8.5 g, 28.6 mmol) was added in one portion at 0° C. and the mixture was stirred at 70° C. under N ₂ for 1 hour. The reaction mixture was then filtered through diatomaceous earth. The filter press cake was washed with 30 ml of PE. The filtrate was concentrated to dryness and dissolved in 100 ml n-hexane. The mixture was filtered through a pad of silica gel. The filtrate was concentrated to dryness to give 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (14.1 g, yield: 81%) as a pink oily liquid.

[00681] A suspension of (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (1.6 g, 6.9 mmol) in MeOH (30 ml) was stirred at 80° C. until a clear solution was obtained, then MeONa (372.6 mg, 6.9 mmol) was added and the mixture was stirred for 30 minutes. The solution was concentrated to dryness and the residue co-evaporated with MeCN (30 ml). The remainder of the solid was suspended in MeCN (30 ml) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (1.4 g, 7.2 mmol) was added. The mixture solution was stirred for 16 hours at room temperature and filtered. The filter cake was triturated with PE/EA (5/1, 40 mL) to give (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)(( Sodium 6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide (2.4 g, yield: 80%) as white solid substances.

[00682] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.42 (s, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 4.50 (d , J=12.0 Hz, 1H), 4.21-4.08 (m, 3H), 3.95 (s, 1H), 3.34 (overlap, 3H), 2.76 (t, J= 6.8 Hz, 4H), 2.67 (t, J=6.8 Hz, 4H), 1.94-1.88 (m, 4H). MS: m/z 433.1 (M+H ⁺ ).

Example 26

[00683] Synthesis of (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-methoxy-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium is illustrated below.

[00684] To a solution of (R)-3-chloropropane-1,2-diol (61.0 g, 552.0 mmol) in pyridine (450 ml) was added TsCl (105.2 g, 552.0 mmol) in portions at 0°C. After stirring at room temperature for 1 h, the reaction was quenched with H ₂ O (10 ml) and concentrated. The residue was poured into aq. HCl (2 N, 200 ml) and extracted with DCM (300 ml x 3). The combined organic layer was washed with sat. NaHCO ₃ (300 ml), dried over Na ₂ SO ₄ and concentrated to give (R)-3-chloro-2-hydroxypropyl-4-methylbenzenesulfonate (121.8 g, crude, yield: 76%) as a yellow oily liquid .

Stage 2

[00685] A mixture of (R)-3-chloro-2-hydroxypropyl-4-methylbenzenesulfonate (121.8 g, 461.4 mmol), CH ₃ I (43 ml, 690.4 mmol) and Ag ₂ O (128, 0 g, 551.7 mmol) in DCM (1 L) was refluxed at 45° C. for 24 hours. Added another portion of CH ₃ I (28.7 ml, 460.8 mmol) and the reaction mixture was refluxed for an additional 24 hours. Ag ₂ O was removed by filtration and the filtrate was concentrated by purifying with a silica gel column (PE/EA=8/1) to give (R)-3-chloro-2-methoxypropyl-4-methylbenzenesulfonate (77.0 g, yield: 60 %) as a yellow oily liquid.

[00686] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.79 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 4, 15-4.08 (m, 2H), 3.64-3.50 (m, 3H), 3.38 (s, 3H), 2.44 (s, 3H).

Stage 3-4

[00687] A mixture of (R)-3-chloro-2-methoxypropyl-4-methylbenzenesulfonate (26.2 g, 94.2 mmol), 1-acetyl-1,2-dihydro-pyrazol-3-one (11.9 g, 94.2 mmol) and K ₂ CO ₃ (39.0 g, 282.6 mmol) in DMF (350 ml) were stirred at 50°C for 16 hours. Added N ₂ About (35 ml) and the reaction mixture was stirred at 130°C for an additional 3 hours. K ₂ CO ₃ was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE/EA=2/1) to obtain (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (13, 8 g, contains some DMF and an unknown by-product, yield: 95%) as a white solid.

[00688] ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.33 (d, J=2.0 Hz, 1H), 5.50 (d, J=2.4 Hz, 1H), 4, 40-4.34 (m, 1H), 4.32-4.23 (m, 2H), 4.17 (dd, J=11.6, 1.6 Hz, 1H), 3.92-3, 89 (m, 1H), 3.48 (s, 3H).

Stage 5

[00689] To a solution of (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (13.8 g, 89.6 mmol) in DCM (150 ml) was added dropwise ClSO ₃ H (13.1 ml, 197.1 mmol) at 0°C. After stirring at room temperature for 16 hours, pyridine (15.8 ml, 197.1 mmol) was added dropwise at 0°C and then PCl ₃ (41.0 g, 197.1 mmol) was added in portions at 0°C . The reaction mixture was stirred at room temperature for 1 h, poured into ice water (200 ml) and extracted with EA (100 ml x 3). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated to give (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonyl chloride (16.7 g, crude, yield: 74%) as a yellow solid.

Stage 6

[00690] To a solution of (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride (16.7 g, 66.3 mmol) in THF (100 ml) was added NH ₃ .H ₂ O (42 ml). After stirring at 60°C for 2 hours, the reaction mixture was concentrated to about 20 ml. The remainder of the suspension was acidified with aq. HCl (1 N) to pH=3 and filtered. The filter press cake was washed with H ₂ O (50 ml) and triturated with MeOH (20 ml) to give (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonamide (10.7 g, yield: 69%) as a white solid.

[00691] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.49 (s, 1H), 7.12 (s, 2H), 4.59 (td, J=11.6, 2, 4 Hz, 1H), 4.32 (d, J=12.0 Hz, 1H), 4.27-4.17 (m, 2H), 4.04-4.02 (m, 1H), 3, 35 (s, 3H).

Stage 7

[00692] (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-methoxy-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazin-3-yl)sulfonyl)amide was synthesized as described in Step 8 in the previous example to obtain the desired product (2.4 g, yield: 80%) as a white solid.

Example 27

[00693] An alternative synthesis of (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[00694] To a solution of (R)-3-bromo-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.0 g, 4.3 mmol) in dry THF (10 ml) was added slowly n-BuLi in hexane (2.5 M, 2.1 ml, 5.2 mmol) at -78° C. under N ₂ atmosphere. After stirring with cooling for 1 h, (BnS) ₂ (1.6 g, 6.5 mmol) was added slowly at the same temperature. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH ₄ Cl solution (5 ml) and partitioned between water (20 ml) and EA (20 ml). The organic layer was washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/1) to obtain (R)-3-(benzylthio)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazine (760 mg, yield: 63%) as a yellow oily liquid. MS: m/z 277.4 (M+H ⁺ ).

Stage 2

[00695] To a solution of (R)-3-(benzylthio)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (750 mg, 2.7 mmol) NCS (1.5 g, 10.9 mmol) was added in AcOH/H ₂ O (3 ml/1 ml) in two portions at 0° C. under N ₂ atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between EA (20 ml) and water (20 ml). The organic layer was washed with sat. NaHCO ₃ (20 ml) and brine (20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give crude (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine-3-sulfonyl chloride as a yellow oily liquid, which was used directly in the next step without further purification.

Stage 3

[00696] (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was synthesized as in Preparation C to give the desired product (280 mg, yield: 44% over 2 steps) as a white solid.

[00697] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.48 (s, 1H), 7.11 (s, 2H), 4.61-4.56 (m, 1H), 4 .34 (d, J=11.6 Hz, 1H), 4.26-4.16 (m, 2H), 4.03 (d, J=1.2 Hz, 1H), 3.35 (s, 3H). MS: m/z 233.8 (M+H ⁺ ).

Example 28

[00698] Synthesis of rac-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-sulfonamide is illustrated below.

[00699] To a solution of 2-methyl-propane-1,3-diol (1 g, 11.1 mmol) and TEA (4.5 g, 44.4 mmol) in THF (30 ml), 8 g, 24.4 mmol) under ice-cooling under N ₂ . The reaction mixture was stirred at room temperature for 1 hour and filtered. The filtrate was concentrated to give a colorless oily liquid. A mixture of this oily liquid, 1,2-dihydro-pyrazol-3-one (993 mg, 11.1 mmol) and K ₂ CO ₃ (6.1 g, 44.4 mmol) in DMF (40 ml) was heated to 80 °C for 12 hours. The reaction mixture was cooled and partitioned between EA (100 ml) and water (200 ml) and the layers were separated. The organic layer was washed with water (80 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give rac-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (500 mg, yield : 33%) as a white solid.

[00700] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.31 (s, 1H), 5.47 (s, 1H), 4.27-4.23 (m, 2H), 3.87 -3.68 (m, 2H), 2.47-2.45 (m, 1H), 1.23-1.09 (m, 3H). MS: m/z 139.0 (M+H ⁺ ).

Stage 2~3

[00701] A solution of rac-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (500 mg, 3.6 mmol) in chlorosulfonic acid (5 ml) was stirred at 80°C during the night. The reaction mixture was dissolved in EA (60 ml) and slowly added to water (100 ml). The organic layer was washed with brine (60 ml), dried over Na ₂ SO ₄ and concentrated. The residue was dissolved in THF (15 ml) and ammonia (5 ml) was added. The mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated, acidified with 1 N HCl and purified by reverse phase HPLC (MeCN/H ₂ O) to give the amide rac-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3]oxazine-3-sulfonic acid (450 mg, yield: 58% over 2 steps) as a white solid.

[00702] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=7.46 (s, 1H), 7.11 (br. s, 2H), 4.43-4.38 (m, 1H) , 4.21-4.15 (m, 1H), 4.06-3.99 (m, 1H), 3.76-3.69 (m, 1H), 2.42-2.34 (m, 1H), 1.02-1.00 (m, 3H).

Stage 4

[00703] Rac-H-((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-sulfonamide was synthesized using Preparation A to give the desired product (29.7 mg, yield: 18%) as a white solid.

[00704] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.49 (s, 1H), 7.92 (s, 1H), 7.62 (s, 1H), 6.93 (s , 1H), 4.48-4.45 (m, 1H), 4.44-4.18 (m, 1H), 4.08 (t, J=11.4 Hz, 1H), 3.77- 3.72 (m, 1H), 2.78 (t, J=7.6 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 2.40 (overlapped, 1H), 1.98-1.91 (m, 4H), 1.01 (d, J=6.4 Hz, 3H). MS: m/z 417.0 (M+H ⁺ ).

Example 29

[00705] Synthesis of (S)-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]oxazin-3-sulfonamide and (R)-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-sulfonamide is illustrated below.

[00706] Rac-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (350 mg) was separated by chiral preparative HPLC to give (S) -6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (242 mg as diethylamine salt) and (R)-6-methyl-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (240 mg as diethylamine salt)

Stage 2

[00707] (R)-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-sulfonamide was synthesized as in Preparation A to give the desired product (112 mg, yield: 37%) as a white solid.

[00708] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.45 (br s, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.48-4.45 (m, 1H), 4.44-4.18 (m, 1H), 4.08 (t, J=11.4 Hz, 1H), 3, 77-3.72 (m, 1H), 2.78 (t, J=7.6 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 2.40 (overlapped, 1H ), 1.98-1.91 (m, 4H), 1.00 (d, J=6.4 Hz, 3H). MS: m/z 417.1 (M+H ⁺ ).

[00709] (S)-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-sulfonamide was prepared using a similar procedure.

[00710] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.45 (s, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.93 (s , 1H), 4.48-4.44 (m, 1H), 4.22-4.18 (m, 1H), 4.11-4.06 (m, 1H), 3.77-3.72 (m, 1H), 2.78 (t, J=7.2 Hz, 4H), 2.60 (t, J=6.8 Hz, 4H), 2.42-2.38 (m, 1H) , 1.98-1.92 (m, 4H), 1.00 (d, J=6.8 Hz, 3H). MS: m/z 417.1 (M+H ⁺ ).

Example 30

[00711] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[ 5,1-b][1,3]oxazine]-3'-sulfonamide is illustrated below.

[00712] To a solution of (1-hydroxymethyl-cyclopropyl)-methanol (1.53 g, 15 mmol) and TEA (6.1 g, 60 mmol) in THF (45 ml), MsCl (3.8 g, 33 mmol) when cooled with ice in an atmosphere of N ₂ . After stirring at room temperature for 1 hour, the reaction mixture was partitioned between EA (500 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried over (Na ₂ SO ₄ ) and concentrated to give a colorless oily liquid. A mixture of this oily liquid, 1,2-dihydro-pyrazol-3-one (1.3 g, 15 mmol) and K ₂ CO ₃ (8.3 g, 60 mmol) in DMF (60 ml) was heated to 80°C during the night. The reaction mixture was cooled and partitioned between EA (120 ml) and water (300 ml). The organic layer was washed with water (100 ml) and brine (80 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by reverse phase HPLC (MeCN/H ₂ O) to give 5',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine] (380 mg , yield: 17%) as a white solid.

[00713] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.33 (d, J=1.8 Hz, 1H), 5.52 (d, J=1.8 Hz, 1H), 3, 99 (s, 4H), 0.81-0.49 (m, 4H). MS: m/z 151.0 (M+H ⁺ ).

Stage 2

[00714] NBS (960 mg, 5 mmol) was added in portions to a solution of 5',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine] (380 mg, 5 .3 mmol) in MeCN (15 ml). After stirring at room temperature for 1 hour, the reaction mixture was partitioned between EA (60 ml) and water (60 ml). The organic layer was washed with brine (60 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give 3'-bromo-5',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3] oxazine] (380 mg, yield: 66%) as a yellow solid.

[00715] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.33 (s, 1H), 4.07 (s, 2H), 3.98 (s, 2H), 0.86-0.81 (m, 4H). MS: m/z 230.9 (M+H ⁺ ).

Stage 3

[00716] 2,4,6-trichlorophenyl-5',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonate was synthesized using Preparation B to give the product as a yellow oil which was used in the next step without further purification.

Stage 4

[00717] 5',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonamide was synthesized as in Preparation C to give the desired product (105 mg , yield: 27% over 2 steps) as a white solid.

[00718] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.49 (s, 1H), 7.12 (br. s, 2H), 4.20 (s, 2H), 4.00 (s, 2H), 0.78 (s, 4H).

Stage 5

[00719] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5',7'-dihydrospiro[cyclopropane-1,6'-pyrazolo [ 5,1-b][1,3]oxazine]-3'-sulfonamide was synthesized using Preparation A to give the desired product (54 mg, yield: 34%) as a white solid.

[00720] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.53 (s, 1H), 8.01 (s, 1H), 7.62 (s, 1H), 6.94 (s , 1H), 4.25 (s, 2H), 4.01 (s, 2H), 2.79 (t, J=7.2 Hz, 4H), 2.60 (t, J=7.2 Hz , 4H), 1.99-1.93 (m, 4H), 0.78 (s, 4H). MS: m/z 429.0 (M+H ⁺ ).

Example 31

[00721] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-tosyl-5',7'-dihydrospiro[azetidine-3,6 '-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonamide is illustrated below.

[00722] To a solution of [3-bromomethyl-1-(toluene-4-sulfonyl)-azetidin-3-yl]methanol (4 g, 12 mmol) in DCM (60 ml) was added CBr ₄ 19.2 mmol) and PPh ₃ (5.2 g, 19.2 mmol) at 0°C. After stirring at room temperature for 16 hours, the reaction mixture was partitioned between DCM (200 ml) and H ₂ O (200 ml). The aqueous layer was extracted with DCM (200 ml). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=5/1) to give 3,3-bis-bromomethyl-1-(toluene-4-sulfonyl)-azetidine (3.8 g, yield: 79%) as yellow solid. MS: m/z 395.9 (M+H ⁺ ).

Stage 2

[00723] To a solution of 3,3-bis-bromomethyl-1-(toluene-4-sulfonyl)-azetidine (4.2 g, 10.6 mmol) and 1,2-dihydro-pyrazol-3-one (0. 89 g, 10.6 mmol) in DMF (50 ml) was added K ₂ CO ₃ (3.7 g, 26.5 mmol). After stirring at 130°C for 16 hours, the reaction mixture was cooled and extinguished by adding EA (100 ml) and water (100 ml). The organic layer was separated. The aqueous layer was extracted with EtOAc (100 ml). The organic layers were combined, washed with brine (80 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give 1-tosyl-5',7'-dihydrospiro[azetidine-3,6'-pyrazolo[5,1-b][1,3]oxazine ] (1.4 g, yield: 42%) as a white solid. MS: m/z 320 (M+H ⁺ ).

Stage 3

[00724] NBS (0.64 g, 3.6 mmol) was added in portions to a solution of 1-tosyl-5',7'-dihydrospiro[azetidine-3,6'-pyrazolo[5,1-b][1,3 ]oxazine] (1 g, 0.33 mmol) in MeCN (10 ml) at 0°C and the reaction mixture was stirred for 2 hours at room temperature. The mixture was filtered and the filtrate was purified by reverse phase HPLC (5%-95% MeCN in H ₂ O) to give 3'-bromo-1-tosyl-5',7'-dihydrospiro[azetidine-3,6'-pyrazolo [5,1-b][1,3]oxazine] (1.16 g, yield: 83%) as a yellow solid. MS: m/z 398 (M+H ⁺ ).

Stage 4

[00725] 2,4,6-trichlorophenyl 1-tosyl-5',7'-dihydrospiro[azetidine-3,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonate was synthesized using Preparation B which gave the product as a yellow oily liquid.

[00726] 1-Tosyl-5',7'-dihydrospiro[azetidine-3,6'-pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonamide was synthesized as in Preparation C to give the desired product (140 mg, yield: 32%) as a light yellow solid. MS: m/z 399.1 (M+H ⁺ ).

Stage 5

[00727] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-tosyl-5',7'-dihydrospiro[azetidine-3,6' -pyrazolo[5,1-b][1,3]oxazine]-3'-sulfonamide was synthesized using Preparation A and further purified by preparative HPLC to give the desired product (24 mg, yield: 22%) as white solid.

[00728] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.52 (s, 1H), 7.90 (s, 1H), 7.74 (d, J=8.0 Hz, 2H ), 7.62 (s, 1H), 7.53 (d, J=8.0 Hz, 2H), 6.94 (s, 1H), 4.24 (s, 2H), 4.00 (s , 2H), 3.68 (s, 4H), 2.80 (t, J=7.2 Hz, 4H), 2.55 (t, J=6.8 Hz, 4H), 2.46 (s , 3H), 1.91-1.98 (m, 4H). MS: m/z 598.2 (M+H ⁺ ).

Example 32

[00729] Synthesis of 6-amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazine-3-sulfonamide is illustrated below.

[00730] Boc ₂ O (14 .4 g, 65.9 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water (80 ml) and EA (80 ml). The organic layer was washed with brine (80 ml), dried over Na ₂ SO ₄ and concentrated to give crude tert-butyl-(1,3-dihydroxypropan-2-yl)carbamate as a white solid, which was used directly in the next step without additional cleaning.

Stage 2

[00731] To a solution of tert-butyl-(1,3-dihydroxypropan-2-yl)carbamate (crude, ~21.0 mmol) and TEA (8.5 g, 84.0 mmol) in dry THF (30 mL) added MsCl (5.3 g, 46.0 mmol) and at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give 2-((tert-butoxycarbonyl)amino)propane-1,3-diyldimethanesulfonate (3.9 g, yield: 53%) as a white solid .

[00732] ¹ H NMR (300 MHz, CDCl ₃ ): δ=5.11 (d, J=7.5 Hz, 1H), 4.36-4.22 (m, 5H), 3.07 (s , 6H), 1.44 (s, 9H).

Stage 3

[00733] A mixture of 2-((tert-butoxycarbonyl)amino)propan-1,3-diyldimethanesulfonate (3.9 g, 11.2 mmol), 1,2-dihydro-pyrazol-3-one (945 mg, 11. 2 mmol) and K ₂ CO ₃ (5.4 g, 39.3 mmol) in DMF (30 ml) was heated to 80°C for 12 hours. The reaction mixture was cooled and partitioned between EA (150 ml) and water (200 ml). The organic layer was washed with water (80 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give tert-butyl-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (975 mg, yield: 13%) as a white solid.

[00734] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.37 (d, J=1.2 Hz, 1H), 5.55 (d, J=1.5 Hz, 1H), 5, 14-5.04 (m, 1H), 4.43-4.12 (m, 5H), 1.46 (s, 9H). MS: m/z 240.1 (M+H ⁺ ).

Stage 4

[00735] To a solution of tert-butyl-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (610 mg, 2.6 mmol) in MeCN, NBS (454 mg, 2.6 mmol) was added in two portions at 0° C. under N ₂ atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between EA (20 ml) and water (20 ml). The organic layer was washed with water (20 ml) and brine (20 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give t-butyl (3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6- yl)carbamate (640 mg, yield: 79%) as a white solid. MS: m/z 318.0 (M+H ⁺ ).

Stage 5

[00736] 2,4,6-trichlorophenyl 6-((tert-butoxycarbonyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate was synthesized using Preparation B which gave the product as a yellow gel which was used directly in the next step without further purification.

Stage 6

[00737] A mixture of 2,4,6-trichlorophenyl-6-((tert-butoxycarbonyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate ( crude, ~1.9 mmol), NH ₄ OH (20 ml) and THF (20 ml) were stirred at 60°C during the night. The reaction mixture was concentrated under reduced pressure to 10 ml of remaining liquid. The remaining solution was acidified with 1 N HCl to pH=5 and extracted with EA (20 ml x 2). The organic layers were combined, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=40/1) to give t-butyl (3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6- yl)carbamate (80 mg, yield: 13% over 2 steps) as a yellow semi-solid. MS: m/z 317.0 (M-H ⁺ ).

Stage 7

[00738] tert-Butyl-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate was synthesized using Preparation A to give the desired product (28 mg, yield: 22%) as a white solid.

Stage 8

[00739] To a solution of tert-butyl-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (28 mg, 0.05 mmol) in DCM (5 ml) TFA (5 ml) was added and the mixture was stirred at room temperature in within 20 min. The reaction mixture was concentrated to dryness and the residue was triturated with EA to give the TFA salt of 6-amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (5.4 mg, yield: 23%) as a white solid.

[00740] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.15 (br s, 1H), 7.54 (s, 1H), 6.88 (s, 1H), 4.32 -4.30(m, 1H), 4.21-4.16(m, 1H), 4.11-4.01(m, 1H), 3.81-3.75(m, 1H), 3 .47 (overlapped, 1H), 2.77 (t, J=7.2 Hz, 4H), 2.67-2.62 (m, 4H), 1.97-1.92 (m, 4H). MS: m/z 418.2 (M+H ⁺ ).

Example 33

[00741] Synthesis of ((6-(((tert-butoxycarbonyl)amino)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)( Sodium (1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide is illustrated below.

[00742] A mixture of 1,2-dihydro-pyrazol-3-one (10.42 g, 0.124 mol) and K ₂ CO ₃ (42.8 g, 0.31 mol) in DMF (700 ml) was heated to 100° WITH. 3-Chloro-2-chloromethyl-propene (15.5 g, 0.124 mol) was added and the mixture was stirred at 100° C. for 16 hours. The solvent was removed in vacuo. The residue was partitioned between EA (200 ml) and H ₂ O (500 ml). The aqueous layer was extracted with EtOAc (200 ml). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give 6-methylene-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.7 g, yield : 10%) as a yellow oily liquid.

[00743] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.34 (s, 1H), 5.51 (s, 1H), 5.39 (s, 2H), 4.80 (s, 2H ), 4.63 (s, 2H). MS: m/z 137.1 (M+H ⁺ ).

Stage 2

[00744] To a solution of 6-methylene-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.7 g, 12.5 mmol) in THF (20 mL) was added BH ₃ /Me ₂ S (10M, 5 ml, 50 mmol) at 0°C. After stirring at room temperature for 16 hours, a solution of NaOH (3 M, 50 ml, 150 mmol) and H ₂ O ₂ (30%, 5.7 g, 50 mmol) was slowly added to the reaction mixture. After stirring at 80°C for 2 hours, the reaction mixture was cooled. Saturated aqueous Na ₂ SO ₃ solution (50 ml) was added to the reaction mixture. After stirring at room temperature for 0.5 h, the resulting mixture was extracted with EA (100 ml x 3). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated to give (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)- methanol (1.3 g, yield: 68%) as a yellow oily liquid.

[00745] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.31 (d, J=1.8 Hz, 1H), 5.49 (d, J=1.8 Hz, 1H), 4, 37 (dd, J=11.4, 3 Hz, 1H), 4.28-4.12 (m, 2H), 4.07-4.00 (m, 1H), 3.77 (d, J= 6.6 Hz, 2H), 2.58-2.50 (m, 1H).

Stage 3

[00746] To a solution of (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)-methanol (2.05 g, 13.3 mmol) in THF (30 ml) DPPA (7.3 g, 26.6 mmol) and DBU (6.1 g, 39.9 mmol) were added at room temperature. The suspension was stirred at 60°C for 16 hours. The reaction mixture was quenched by the addition of EA (100 ml) and water (100 ml). The organic layer was separated. The aqueous layer was extracted with EtOAc (100 ml). The organic layer was washed with water and brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give 6-azidomethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.24 g, yield : 62%) as a yellow oily liquid. MS: m/z 180.3 (M+H ⁺ ).

Stage 4

[00747] To a solution of 6-azidomethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.24 g, 16.9 mmol) in MeOH (20 mL) was added Boc ₂ O (3 g, 13.8 mmol) and Pd/C (5%, 0.2 g). The mixture was stirred under H ₂ (balloon atmosphere) at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give a crude product which was used directly in the next step without further purification. MS: m/z 254.0 (M+H ⁺ ).

Stage 5

[00748] NBS (1.3 g, 24.7 mmol) was added portionwise to a solution of tert-butyl-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6- yl)methyl)carbamate (crude, 6.9 mmol) in MeCN (20 ml) at 0°C and the reaction mixture was stirred for 2 hours at room temperature. The mixture was filtered and purified by reverse phase HPLC (5%-95% MeCN in H ₂ O) to give t-butyl-((3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazin-6-yl)methyl)carbamate (1.62 g, yield: 71%) as a yellow solid. MS: m/z 331.9 (M+H ⁺ ).

Stage 6

[00749] 2,4,6-trichlorophenyl-6-(((tert-butoxycarbonyl)amino)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- the sulfonate was synthesized using Preparation B to give the product as a yellow oil which was used directly in the next step without further purification.

Stage 7

[00750] tert-Butyl-((3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)carbamate was synthesized as in Preparation C to give the desired product (80 mg, yield: 33% over 2 steps) as a light yellow solid. MS: m/z 333.4 (M+H ⁺ ).

Stage 8

[00751] ((6-(((tert-butoxycarbonyl)amino)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)(( 1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide was synthesized as in Preparation D to give the desired product (27 mg, yield: 21%) as a white solid.

[00752] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.35 (s, 1H), 7.31 (s, 1H), 7.11 (s, 1H), 6.75 (s , 1H), 4.31 (d, J=5.6 Hz, 1H), 4.10-3.98 (m, 2H), 3.78 (dd, J=10.0, 2.0 Hz, 1H), 3.07-3.04 (m, 2H), 2.74 (t, J=7.2 Hz, 4H), 2.64 (t, J=7.2 Hz, 4H), 2, 40-2.3 (m, 1H), 1.93-1.86 (m, 4H), 1.39 (s, 9H). MS: m/z 532.2 (M+H ⁺ ).

Example 34

[00753] Synthesis of rac-N-((3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)acetamide is illustrated below.

[00754] To a solution of rac-tert-butyl-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)carbamate (crude, ~1.05 mmol) in DCM (3 ml) was added TFA (1 ml). Then the solution was stirred at room temperature for 2 hours, the solution was concentrated and dissolved with Ac ₂ O (3 ml). After stirring at reflux for 3 hours, the reaction solution was quenched by adding EA (20 ml) and water (10 ml). The organic layer was separated. The aqueous layer was extracted with EtOAc (10 ml). The organic layers were combined and washed with brine (10 ml) and dried over Na ₂ SO ₄ . The solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give rac-N-acetyl-N-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 6-yl)methyl)acetamide (90 mg, yield: 31%) as a yellow oily liquid. MS: m/z 238.4 (M+H ⁺ ).

Stage 2

[00755] To a solution of rac-N-acetyl-N-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)acetamide (90 mg, 0 .38 mmol) in DCM (2 ml) was added dropwise ClSO ₃ H (0.075 ml, 1.14 mmol) at 0°C. After stirring at room temperature for 16 hours, pyridine (0.092 ml, 1.14 mmol) was added dropwise to the reaction mixture at 0° C., followed by addition of PCl ₅ (237 mg, 1.14 mmol) in portions. The reaction mixture was stirred at room temperature for 1 h, poured into ice water (2 ml) and extracted with EA (10 ml x 3). The combined organic layer was washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated to give a crude product which was used directly in the next step without further purification. Stage 3

[00756] To a solution of rac-6-((N-acetylacetamido)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride (crude, ~0.387 mmol ) in THF (3 ml) was added NH ₃ .H ₂ O (3 ml). After stirring at 60°C for 2 hours, the reaction mixture was concentrated to about 1 ml. The remainder of the suspension was acidified with aq. HCl (1 N) to pH=3 and filtered. The filtrate was purified by reverse phase HPLC (MeCN/H ₂ O) to give rac-N-((3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 6-yl)methyl)acetamide (67 mg, yield: 64%) as a white solid.

[00757] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.02 (br. s, 1H), 7.37 (s, 1H), 6.65 (br. s, 2H), 4 .40-4.30 (m, 1H), 4.17-4.04 (m, 2H), 3.85-3.73 (m, 1H), 3.10-3.00 (m, 2H) , 2.50 (overlapped, 1H), 1.76 (s, 3H).

Stage 4

[00758] Rac-N-((3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)acetamide was synthesized as in Preparation D to give the desired product (34 mg, yield: 48%) as a white solid.

[00759] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.47 (s, 1H), 8.07 (t, J=6 Hz, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.93 (s, 1H), 4.48 (d, J=8.8 Hz, 1H), 4.26-4.14 (m, 2H), 3.93 -3.85 (m, 1H), 3.23-3.08 (m, 2H), 2.79 (t, J=7.2 Hz, 4H), 2.59 (t, J=6.8 Hz, 4H), 2.50 (overlap, 1H), 2.10-1.90 (m, 4H), 1.83 (s, 3H). MS: m/z 474.2 (M+H ⁺ ).

Example 35

[00760] Synthesrau-6-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[00761] To a solution of urac-tert-butal-((3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)carbamate (110 mg, 0.33 mmol) in MeOH (2 ml) was added HCl/dioxane (4 M, 1 ml, 4 mmol) at 0°C. After stirring at room temperature for 2 hours, the solution was concentrated to give crude rac-6-(aminomethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide hydrochloride , which was directly used in the next step without further purification. Stage 2

[00762] To a solution of rac-6-(aminomethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide hydrochloride (crude, 0.33 mmol) in MeOH (2 ml) was added HCHO (1.5 ml) and NaCNBH ₃ (20.8 mg, 0.33 mmol). After stirring at room temperature for 3 hours, the reaction mixture was filtered and the filtrate was purified by reverse phase HPLC (MeCN/H ₂ O) to give rac-6-((dimethylamino)methyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (50 mg, yield: 59%) as a white solid. MS: m/z 261.1 (M+H ⁺ ).

Stage 3

[00763] Rac-6-((dimethylamino)methyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was synthesized as in Preparation D to give the desired product (27 mg, yield: 21%) as a white solid.

[00764] ¹ H NMR (400 MHz, DMSO-d ₆ +CD ₃ CD): δ=7.37 (s, 1H), 7.32 (s, 1H), 6.75 (s, 1H), 4 .37 (dd, J=6.8, 2.8 Hz, 1H), 4.10-4.00 (m, 2H), 3.80-3.75 (m, 1H), 2.74 (t , J=7.2 Hz, 4H), 2.64 (t, J=7.2 Hz, 4H), 2.47-2.43 (m, 1H), 2.23 (d, J=7, 2 Hz, 2H), 2.14 (s, 6H), 1.95-1.85 (m, 4H). MS: m/z 460.1 (M+H ⁺ ).

Example 36

[00765] Synthesis of rac-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methoxymethyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[00766] To a solution of rac-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)-methanol (0.6 g, 3.9 mmol) in THF (10 ml) was added NaH (187 mg, 4.7 mmol) followed by the addition of MeI (667 mg, 4.7 mmol) at 0°C. After stirring overnight, the reaction mixture was quenched by the addition of EA (20 ml) and water (20 ml). The organic layer was separated. The aqueous layer was extracted with EtOAc (20 ml). The organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give rau-6-methoxymethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (270 mg, yield: 41%) as a yellow solid. MS: m/z 169.3 (M+H ⁺ ).

Stage 2

[00767] NBS (256 mg, 1.44 mmol) was added in portions to a solution of 6-methoxymethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (230 mg, 1.37 mmol) in MeCN (5 ml) at 0°C and the reaction mixture was stirred for 2 hours at room temperature. The mixture was filtered and the filtrate was purified by reverse phase HPLC (5%-95% MeCN in H ₂ O) to give 3-bromo-6-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b ][1,3]oxazine (220 mg, yield: 65%) as a yellow oily liquid. MS: m/z 247.3 (M+H ⁺ ).

Stage 3

[00768] 2,4,6-trichlorophenyl 6-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate was synthesized using Preparation B to give product as a yellow oily liquid which was used directly in the next step without further purification.

Stage 4

[00769] 6-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was synthesized as in Preparation C to give the desired product (25 mg, yield: 13% over 2 steps) as a light yellow solid.

Stage 5

[00770] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methoxymethyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonamide was synthesized as in Preparation D to give the desired product (9 mg, yield: 20%) as a white solid.

[00771] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.46 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.93 (s , 1H), 4.51 (dd, J=10.8, 2.8 Hz, 1H), 4.29 (dd, J=11.2, 7.2 Hz, 1H), 4.51 (dd, J=12.4, 5.2 Hz, 1H), 4.51 (dd, J=12.4, 7.2 Hz, 1H), 3.43 (d, J=3.6 Hz, 2H), 3.25 (s, 3H), 2.79 (t, J=7.2 Hz, 4H), 2.61-2.58 (m, 5H), 1.99-1.92 (m, 4H) . MS: m/z 446.8 (M+H ⁺ ).

Example 37

[00772] Synthesis of rac-6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[00773] To a solution of rac-3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (700 mg, 3.2 mmol) in DMF (10 ml) NaH (60% in mineral oil, 192 mg, 4.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 h under N ₂ . Iodoethane (549 mg, 3.5 mmol) was then added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (60 ml) and extracted with EA (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by reverse phase HPLC (MeCN/H ₂ O) to give rac-3-bromo-6-ethoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine ( 640 mg, yield: 81%) as a white solid.

[00774] MS: m/z 248.9 (M+H ⁺ ).

Stage 2

[00775] 2,4,6-trichlorophenyl-6-ethoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate was synthesized using Preparation B to give the product as a yellow oily liquid, which was used directly in the next step without further purification.

Stage 3

[00776] Solution of rac-2,4,6-trichlorophenyl-6-ethoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate (crude) and NH ₃ .H ₂ O (8.4 ml) in THF (8.4 ml) was stirred at 60°C for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC (MeCN/H ₂ O) to give rac-6-ethoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide ( 222.0 mg, yield: 35%) as a white solid.

[00777] MS: m/z 247.9 (M+H ⁺ ).

Stage 4 - Getting F

[00778] To a solution of rac-6-ethoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (116 mg, 0.47 mmol) in THF (8 0 ml) was added MeONa (28 mg, 0.52 mmol) and the mixture was stirred at room temperature for 20 min to obtain a suspension of the sodium salt.

[00779] In another flask to a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (81 mg, 0.47 mmol) and TEA (142 mg, 1.4 mmol) in THF (10 ml) was added triphosgene (56.0 mg, 0.19 mmol) in one portion and the mixture was stirred at room temperature under N ₂ for 20 minutes. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and the mixture was stirred at room temperature for 20 minutes. Thereafter, the reaction solution was partitioned between EA (60 ml) and water (60 ml). The aqueous phase was acidified to pH=5 conc. HCl and extracted with EA (60 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated until the disappearance of a white solid. The resulting solid was collected by filtration and dried to give rac-6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (68 mg, yield: 32%) as a white solid.

[00780] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.48 (s, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 6.93 (s , 1H), 4.58 (d, J=11.6 Hz, 1H), 4.36 (d, J=11.6 Hz, 1H), 4.27-4.24 (m, 1H), 4 .18-4.15 (m, 2H), 3.61-3.56 (m, 2H), 2.79 (t, J=7.2 Hz, 4H), 2.60 (t, J=7 .2 Hz, 4H), 1.99-1.91 (m, 4H), 1.09 (t, J=7.2 Hz, 3H). MS: m/z 447.0 (M+H ⁺ ).

Example 38

[00781] Synthesis of (R)-6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide and (S)-6-ethoxy-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-sulfonamide is illustrated below.

[00782] Rac-6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonamide (222 mg) was separated by chiral preparative HPLC to give (R)-6-ethoxy-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonamide (20 mg) as a white solid and (S)-6-ethoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonamide (20 mg) as a white solid.

Stage 2

[00783] (R)-6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide was synthesized as described in Preparation F to give the desired product (5.0 mg, yield: 14%) as a white solid.

[00784] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.47 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.93 (s , 1H), 4.58 (d, J=10.0 Hz, 1H), 4.36 (d, J=11.2 Hz, 1H), 4.27-4.24 (m, 1H), 4 .18-4.15 (m, 2H), 3.59 (k, J=7.2 Hz, 2H), 2.79 (t, J=7.6 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 1.99-1.91 (m, 4H), 1.09 (t, J=6.8 Hz, 3H). MS: m/z 447.1 (M+H ⁺ ).

[00785] (S)-6-ethoxy-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide was prepared using a similar procedure.

[00786] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.47 (s, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 6.93 (s , 1H), 4.59 (d, J=11.6 Hz, 1H), 4.37 (d, J=11.6 Hz, 1H), 4.27-4.23 (m, 1H), 4 .17-4.15 (m, 2H), 3.53 (k, J=7.2 Hz, 2H), 2.78 (t, J=7.2 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 1.98-1.91 (m, 4H), 1.08 (t, J=7.2 Hz, ZN). MS: m/z 447.1 (M+H ⁺ ).

Example 39

[00787] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-isopropoxy-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazine-3-sulfonamide is illustrated below.

[00788] To a solution of dimethylmalonate (5.0 g, 38.0 mmol) and TEA (7.7 g, 76.0 mmol) in MeCN (80 ml) was added 4-acetamidobenzenesulfonyl azide (9.1 g, 38.0 mmol ) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was partitioned between water (80 ml) and EA (80 ml). The organic layer was washed with brine (80 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=10/1) to obtain dimethyl 2-diazomalonate (3.9 g, yield: 53%) as a yellow oily liquid.

Stage 2

[00789] To a solution of dimethyl-2-diazomalonate (3.4 g, 21.5 mmol) and Rh ₂ (Ac) ₄ (36 mg, 0.2 mmol) in DCM (10 ml) was added i-PrOH (132 0 g, 0.2 mol) and the reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was concentrated to dryness.

The residue was purified by silica gel column chromatography (PE/EA=10/1) to obtain dimethyl 2-isopropoxymalonate (3.7 g, yield: 90%) as a colorless oily liquid.

[00790] ¹ H NMR (300 MHz, CDCl ₃ ): δ=4.60 (s, 1H), 3.81-3.74 (m, 7H), 1.26 (d, J=6.0 Hz , 6H).

Stage 3

[00791] To a solution of dimethyl-2-isopropoxymalonate (3.7 g, 19.4 mmol) in dry THF (30 ml) was added LiBH ₄ (2 M in THF, 19.4 ml, 38.7 mol) at 0° C and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with H ₂ O (20 ml) and the mixture was dried over MgSO ₄ . The reaction mixture was filtered and the filtrate was concentrated to dryness to give 2-isopropoxypropane-1,3-diol (2.5 g, yield: 96%) as a colorless oily liquid.

[00792] ¹ H NMR (300 MHz, CDCl ₃ ): δ=3.72-3.50 (m, 6H), 1.26 (t, J=5.4 Hz, 2H), 1.22 (d , J=6.0 Hz, 6H).

Stage 4

[00793] To a solution of 2-isopropoxypropane-1,3-diol (2.5 g, 18.7 mmol) and TEA (5.7 g, 56.0 mmol) in dry THF (30 ml) 7 g, 41.0 mmol) at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was filtered. The filtrate was concentrated to dryness to give crude 2-isopropoxypropane-1,3-diyldimethanesulfonate as a white solid, which was used directly in the next step without further purification.

Stage 5

[00794] A mixture of 2-isopropoxypropan-1,3-diyldimethanesulfonate (crude, ~18.7 mmol), 1,2-dihydro-pyrazol-3-one (1.6 g, 18.7 mmol) and K ₂ CO ₃ (7.7 g, 56.0 mmol) in DMF (40 ml) was heated to 100°C for 16 hours. The reaction mixture was cooled and partitioned between EA (150 ml) and water (200 ml) and the layers were separated. The organic layer was washed with water (80 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/2) to give 6-isopropoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (2.1 g, yield : 88%) as a white solid.

[00795] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.33 (s, 1H), 5.49 (s, 1H), 4.31-3.84 (m, 5H), 3.84 -3.80 (m, 1H), 1.22-118 (m, 6H). MS: m/z 183.3 (M+H ⁺ ).

Stage 6

[00796] NBS (1 .5 g, 8.6 mmol) at 0° C. under N ₂ . The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was partitioned between EA (40 ml) and water (40 ml). The organic layer was washed with water (40 ml) and brine (40 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give 3-bromo-6-isopropoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1, 2 g, yield: 75%) as a yellow solid. MS: m/z 261.2 (M+H ⁺ ).

Stage 7

[00797] 2,4,6-trichlorophenyl-6-isopropoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonate was synthesized using Preparation B to give the product as a yellow gel, which was used directly in the next step without further purification.

[00798] 6-isopropoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was synthesized as in Preparation C to give the desired product (110 mg, yield: 22% in 2 steps) as a yellow solid. MS: m/z 262.3 (M+H ⁺ ).

Stage 8

[00799] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-isopropoxy-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonamide was synthesized using Preparation A to give the desired product (18 mg, yield: 10%) as a white solid.

[00800] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.47 (br. s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.49-4.46 (m, 1H), 4.37 (d, J=12.0 Hz, 1H), 4.28-4.24 (m, 2H), 4. 09-4.06 (m, 1H), 3.87-3.81 (m, 1H), 2.77 (t, J=8.0 Hz, 4H), 2.61 (overlapped, 4H), 1 .97-1.91 (m, 4H), 1.09-1.05 (m, 6H). MS: m/z 461.1 (M+H ⁺ ).

Example 40

[00801] Synthesis of rac-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(methylamino)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium is illustrated below.

[00802] To a solution of 2-aminopropane-1,3-diol (10.0 g, 0.1 mol) in EtOH (100 ml) was added di-tert-butyl dicarbonate (24.0 g, 0.1 mol). The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to dryness in vacuo to obtain t-butyl (1,3-dihydroxypropan-2-yl)carbamate (21.0 g, yield: 100%) as a white solid.

Stage 2

[00803] To a solution of tert-butyl (1,3-dihydroxypropan-2-yl)carbamate (21.0 g, 0.1 mol) and TEA (23.0 g, 0.2 mol) in dry CH ₂ Cl ₂ (200 ml) was added MsCl (26.0 g, 0.2 mol) at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was filtered. The filtrate was concentrated to dryness to give crude 2-((tert-butoxycarbonyl)amino)propane-1,3-diyldimethanesulfonate (37.0 g, yield: 97%) as a white solid, which was used directly in the next step without further purification.

Stage 3

[00804] 2-((tert-Butoxycarbonyl)amino)propan-1,3-diyldimethanesulfonate (37.3g, 0.11mol), 1H-pyrazol-3(2H)-one (9.0g, 0. 11 mol) and K ₂ CO ₃ (30.0 g, 0.22 mol) in DMF (300 ml) were heated at 120°C for 16 hours. After concentration, the residue was partitioned between EA (300 ml) and water (500 ml). The aqueous layer was extracted with EA (300 ml). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give rac-tert-butyl-(6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazin-6-yl)carbamate (8.8 g, yield: 34%) as a yellow solid. MS: m/z 240.0 (M+H ⁺ ).

Stage 4

[00805] NBS (6.5 g, 37.0 mmol) was added in portions to a solution of rac-tert-butyl-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6 -yl)carbamate (8.8 g, 37.0 mmol) in MeCN (100 ml) at 0°C and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (PE/EA=5/1) to give rac-tert-butyl-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -6-yl)carbamate (2.5 g, yield: 21%) as a yellow solid. MS: m/z 319.9 (M+H ⁺ ).

Stage 5

[00806] To a solution of rac-tert-butyl-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (900 mg, 2, 8 mmol) in DMF (10 ml) was added NaH (60% in mineral oil, 226 mg, 5.7 mmol). The reaction mixture was stirred at room temperature for 1 h under N ₂ . Iodomethane (2.0 g, 14.2 mmol) was then added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (60 ml) and extracted with EA (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by reverse phase HPLC (MeCN/H ₂ O) to give rac-tert-butyl-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -6-yl)(methyl)carbamate (550 mg, yield: 59%) as a yellow solid.

[00807] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.36 (s, 1H), 4.6 (br, 1H), 4.38-4.29 (m, 4H), 2.82 (d, J=3.6 Hz, 3H), 1.50 (s, 9H). MS: m/z 333.9 (M+H ⁺ ).

Stage 6

[00808] Rac-2,4,6-trichlorophenyl-6-((tert-butoxycarbonyl)(methyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- The 3-sulfonate was synthesized using Preparation B to give the product as a yellow oil which was used directly in the next step without further purification.

Stage 7

[00809] Rac-2,4,6-trichlorophenyl-6-((tert-butoxycarbonyl)(methyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine solution -3-sulfonate (crude) and NH ₃ .H ₂ O (3.0 ml) in THF (5.0 ml) were stirred at 60°C for 16 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=25/1) to give t-butyl-methyl(3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazin-6-yl)carbamate (26.0 mg, yield: 8%, 2 steps) as a colorless oily liquid.

[00810] ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.64 (s, 1H), 5.14 (br. 2H), 4.68 (br. 1H), 4.53-4.44 (m, 2H), 4.38-4.26 (m, 2H), 2.84 (s, 3H), 1.48 (s, 9H). MS: m/z 276.9 (M-56+H ⁺ ).

Stage 8

[00811] tert-Butyl-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate was synthesized as in Preparation D to give the desired product (40 mg, yield: 95%) as a white solid. MS: m/z 476.0 (M-55 ^- ).

Stage 9

[00812] To a solution of tert-butyl-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (40 mg, 0.08 mmol) in CH ₂ Cl ₂ (2 ml) TFA (0.6 ml) was added ) and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated in vacuo to remove the solvent. The residue was treated with 2 M NaOH solution to pH>13. The resulting solution was purified by reverse phase HPLC (MeCN/H ₂ O) to give rac-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6- sodium (methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide (25.0 mg, 78%) as a white solid.

[00813] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.33 (s, 1H), 7.30 (s, 1H), 6.75 (s, 1H), 4.25-4 .10 (m, 3H), 3.83-3.79 (m, 1H), 3.07 (m, 1H), 2.77-2.73 (m, 4H), 2.67-2.63 (m, 4H), 2.33 (s, 3H), 1.92-1.88 (m, 4H). MS: m/z 432.1 (M+H ⁺ ).

Example 41

[00814] Synthesis of (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(methylamino)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium and (S)-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)((6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium is illustrated below.

[00815] Rac-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide (400 mg, 1.2 mmol) was separated by chiral preparative HPLC to give (S)-N-((1,2,3,5,6 ,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (240 mg, yield: 60%) as a white solid and (S)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (150 mg, yield: 37%) as a white solid.

Stage 2:

[00816] (R)-tert-Butyl-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate was synthesized as in Preparation D to give the desired product (200 mg, yield: 52%) as a white solid .

[00817] (S)-tert-butyl-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate was prepared using a similar procedure.

Stage 3

[00818] To a solution of (R)-tert-butyl-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (250 mg, 0.75 mmol) in CH ₂ Cl ₂ (5 ml) was added TFA ( 2 ml) and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated in vacuo to remove the solvent. The residue was treated with 2 M NaOH solution to pH>13. The resulting solution was purified by reverse phase HPLC (MeCN/H ₂ O) to give (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)(( 6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium (130 mg, 30%) as a white solid.

[00819] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.50 (s, 1H), 7.38 (s, 1H), 6.8 (s, 1H), 4.28 (dd , J=10.8 Hz, 2.4 Hz, 1H), 4.20-4.10 (m, 2H), 3.85 (dd, J=11.6 Hz, 4.8 Hz, 1H), 3.14-3.06 (m, 1H), 2.76 (t, J=7.2 Hz, 4H), 2.64 (t, J=7.2 Hz, 4H), 2.33 (s , 3H), 1.97-1.86 (m, 4H). MS: m/z 432.1 (M+H ⁺ ).

[00820] (S)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(methylamino)-6,7-dihydro-5H-pyrazolo Sodium [5,1-b][1,3]oxazin-3-yl)sulfonyl)amide was prepared using a similar procedure.

[00821] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.35 (s, 1H), 7.30 (s, 1H), 6.75 (s, 1H), 4.27-4 .21 (m, 1H), 4.17-4.12 (m, 1H), 4.08-4.05 (m, 1H), 3.84-3.77 (m, 1H), 3.11 -3.03 (m, 1H), 2.76 (t, J=8.0 Hz, 4H), 2.65 (t, J=7.6 Hz, 4H), 2.33-2.27 ( m, 3H), 1.97-1.83 (m, 4H). MS: m/z 432.1 (M+H ⁺ ).

Example 42

[00822] Synthesis of (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(methylamino)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide is illustrated below.

[00823] A mixture of 1-acetyl-1,2-dihydro-pyrazol-3-one (10.0 g, 0.79 mmol), (S)-oxiran-2-ylmethanol (7.0 g, 95 mmol) and PPh ₃ (31.0 g, 118.5 mmol) in THF (100 ml) was cooled to 0° C. under N ₂ atmosphere. DIAD (23.3 ml, 118.5 mmol) in THF (25 ml) was slowly added to the mixture. The reaction mixture was stirred for an additional 1 hour at 0°C. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EA=10/1) to give (S)-1-acetyl-2-(oxiran-2-ylmethyl)-1H-pyrazol-3(2H)- she (10.1 g, yield: 70%) as a white solid.

[00824] ¹ H NMR (400 MHz, CDCl ₃ ): δ=8.07 (d, J=2.8 Hz, 1H), 6.00 (d, J=2.8 Hz, 1H), 4, 56-4.51 (m, 1H), 4.21-4.15 (m, 1H), 3.41-3.34 (m, 1H), 2.93-2.89 (m, 1H), 2.77-2.74 (m, 1H), 2.58 (s, 3H). Stage 2

[00825] To a solution of (S)-1-acetyl-2-(oxiran-2-ylmethyl)-1H-pyrazol-3(2H)-one (55.0 g, 300 mmol) in AcOH (52 ml, 900 mmol ) and THF (250 ml) LiCl.H ₂ O (29.0 g, 480 mmol) was added in portions at 0°C. The reaction mixture was then stirred at room temperature overnight. After removal of AcOH and THF in vacuo, the residue was partitioned between EA (200 ml) and water (200 ml). The aqueous layer was extracted with EA (50 ml x 4). The combined organic layer was washed with saturated NaHCO ₃ and brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give crude (S)-1-acetyl-2-(3-chloro-2-hydroxypropyl)-1H -pyrazol-3(2H)-one (59.0 g, 90%) as a colorless oily liquid, which was used directly in the next step without further purification.

[00826] ¹ H NMR (400 MHz, CDCl ₃ ): δ=8.07 (d, J=3.2 Hz, 1H), 6.00 (d, J=3.2 Hz, 1H), 4, 41 (d, J=4.8 Hz, 2H), 4.28-4.20 (m, 1H), 3.78-3.64 (m, 2H), 2.58 (s, 3H).

Stage 3

[00827] Mixture of (S)-1-acetyl-2-(3-chloro-2-hydroxypropyl)-1H-pyrazol-3(2H)-one (65.4 g, 0.3 mol), K ₂ CO ₃ (82.8 g, 0.6 mol) and KI (9.96 g, 60 mmol) in DMF (500 ml) were stirred at 130° C. overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EA) to give (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (27.6 g, yield: 66 %) as a white solid.

[00828] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.22 (d, J=2.0 Hz, 1H), 5.44 (d, J=2.0 Hz, 1H), 4.28-4.09 (m, 4H), 3.94-3.87 (m, 1H).

Stage 4

[00829] To a solution of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (28.0 g, 0.2 mol) in pyridine (200 ml) methanesulfonyl chloride (23.0 g, 0.2 mol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to dryness in vacuo and the residue was partitioned between EA (300 ml) and water (500 ml). The aqueous layer was extracted with EtOAc (300 ml). The combined organic layer was washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness in vacuo to give (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazin-6-yl methanesulfonate (44.0 g, yield: 99%) as a white solid, which was used directly in the next step without further purification.

Stage 5

[00830] A mixture of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl methanesulfonate (44.0 g, 0.2 mol) and NaN ₃ ( 26.0 g, 0.4 mol) in dry DMF (300 ml) was stirred at 120° C. for 2 hours. The mixture was then directly used in the next step without further purification.

Stage 6

[00831] Solution of (R)-6-azido-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (crude solution in DMF), Boc ₂ O (44 g, 0. 2 mol) and Pd/C (3.0 g) in MeOH (300 ml) was stirred at room temperature under nitrogen (50 psi) for 16 hours. The reaction mixture was filtered and concentrated to dryness in vacuo. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give (R)-tert-butyl-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-6 -yl)carbamate (30 g, 63%) as a white solid.

Stage 7

[00832] NBS (10.7 g, 60.0 mmol) was added in portions to a solution of (R)-tert-butyl-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -6-yl)carbamate (14.0 g, 60.0 mmol) in MeCN (200 ml) at 0°C and the reaction mixture was stirred for 2 hours at room temperature. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/2) to give (R)-tert-butyl-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazin-6-yl)carbamate (20.5 g, crude) as a yellow solid. MS: m/z 320.0 (M+H ⁺ ).

Stage 8

[00833] To a solution of (R)-tert-butyl-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (20.5 g, 64.4 mmol) in DMF (150 ml) was added NaH (60% in mineral oil, 5.2 g, 130.0 mmol). The reaction mixture was stirred at room temperature for 1 h under N ₂ . Iodomethane (46.0 g, 320.0 mmol) was then added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (300 ml) and extracted with EA (300 ml). The organic layer was washed with water (150 ml), brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=3/1) to obtain (R)-tert-butyl-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazin-6-yl)(methyl)carbamate (18 g, yield: 90%) as a white solid. MS: m/z 334.0 (M+H ⁺ ).

Stage 9

[00834] (R)-2,4,6-trichlorophenyl-6-((tert-butoxycarbonyl)(methyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonate was synthesized using Preparation B to give the product as a yellow oil which was used in the next step without purification.

Stage 10

[00835] A solution of (R)-2,4,6-trichlorophenyl-6-((tert-butoxycarbonyl)(methyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonate (crude) and NH ₃ .H ₂ O (12.0 ml) in THF (50.0 ml) were stirred at 60°C for 16 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=25/1) to give (R)-tert-butyl-methyl(3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazin-6-yl)carbamate (1.8 g, yield: 25%, 2 steps) as a yellow solid. MS: m/z 333.1 (M+H ⁺ ).

Stage 11

[00836] (R)-tert-Butyl-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate was synthesized as in Preparation D to give the desired product (230 mg, yield: 96%) as a yellow solid .

Stage 12

[00837] To a solution of (R)-tert-butyl-(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (230 mg, 0.43 mmol) in CH ₂ Cl ₂ (2 ml) was added TFA ( 0.6 ml) and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated in vacuo to remove the solvent. The residue was treated with 2 M NaOH solution to pH>13. The resulting solution was purified by reverse phase HPLC (0%-50% MeCN in H ₂ O) to give (s)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl )carbamoyl)((6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium (150.0 mg, 80% ) as a white solid.

[00838] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.41 (s, 1H), 7.33 (s, 1H), 6.76 (s, 1H), 4.26 (d, J =9.2 Hz, 1H), 4.19-4.07 (m, 2H), 3.84-3.80 (m, 1H), 3.09 (br., 1H), 2.75 (t , J=7.2 Hz, 4H), 2.66 (t, J=7.2 Hz, 4H), 2.34 (s, 3H), 1.94-1.87 (m, 4H). MS: m/z 432.1 (M+H ⁺ ).

Example 43

[00839] Synthesis of rac-6-(ethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[00840] These three steps are similar to the general synthesis method for ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(methylamino)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium.

Stage 4

[00841] Rac-tert-butyl-ethyl (3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate was synthesized as described in Preparation F to give the desired product (100 mg, yield: 64%) as a white solid. MS: m/z 546.3 (M+H ⁺ )

Stage 5

[00842] To a solution of urac-tert-butyl-ethyl (3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (100 mg, 0.2 mmol) in CH ₂ Cl ₂ (2 ml) TFA (1 ml) was added and the mixture stirred at room temperature for 30 min. The mixture was then concentrated to remove the solvent. The residue was co-evaporated with CH ₂ Cl ₂ (5 mL×3) and then purified by reverse phase HPLC [0%-95% MeCN in H ₂ O (0.1% NH ₃ .H ₂ O)] to give rac -6-(ethylamino)-H-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonamide (60 mg, 73%) as a white solid.

[00843] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.91 (s, 1H), 7.62 (s, 1H), 6.93 (s, 1H), 4.41 (dd , J=11.2, 2.4 Hz, 1H), 4.31 (dd, J=10.8, 4.8 Hz, 1H), 4.24 (dd, J=12.8, 4.4 Hz, 1H), 3.95 (dd, J=12.8, 4.4 Hz, 1H), 3.33 (overlapped, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.68-2.58 (m, 6H), 2.00-1.91 (m, 4H), 1.01 (t, J=7.2 Hz, 3H). MS: m/z 446.1 (M+H ⁺ ).

Example 44

[00844] Synthesis of (R)-6-(ethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide hydrochloride and (S)-6-(ethylamino)-N-((1,2,3,5,6,7-hexahydro-s -indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-sulfonamide hydrochloride is illustrated below.

[00845] Rac-tert-butyl-ethyl (3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (120 mg) was separated with chiral preparative HPLC to obtain

[00846] (R)-tert-Butyl-ethyl(3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (peak 1, 52 mg) and (S)-tert-butyl-ethyl(3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (peak 2, 48 mg).

Stage 2

[00847] This step is similar to the general procedure for the synthesis of rac-6-(ethylamino)-H-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide.

Stage 3

[00848] To a solution of (R)-tert-butyl-ethyl(3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (40 mg, 0.1 mmol) in CH ₂ Cl ₂ (2 ml) TFA (1 ml) was added ) and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated to remove the solvent. The residue was co-evaporated with CH ₂ Cl ₂ (5 ml x 3) and then neutralized to pH=8 sat. _NaHC03 . The resulting solution was acidified to pH=5 aq. HCl (2 N) and then purified by reverse phase HPLC [0%-95% MeCN in H ₂ O] to give (R)-6-(ethylamino)-N-((1,2,3,5, 6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide hydrochloride (15 mg, 22% ) as a white solid.

[00849] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=7.74 (s, 1H), 7.52 (s, 1H), 6.88 (s, 1H), 4.38-4 .33 (m, 1H), 4.24-4.17 (m, 2H), 3.92-3.85 (m, 1H), 3.32 (overlap, 1H), 2.77 (t, J =7.2 Hz, 4H), 2.64-2.59 (m, 6H), 2.00-1.89 (m, 4H), 1.00 (t, J=7.2 Hz, 3H) . MS: m/z 446.1 (M+H ⁺ ).

[00850] (S)-6-(ethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide hydrochloride was prepared using a similar procedure.

[00851] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.89 (s, 1H), 7.60 (s, 1H), 6.93 (s, 1H), 4.41 (dd , J=10.8, 2.4 Hz, 1H), 4.31 (dd, J=10.8, 5.2 Hz, 1H), 4.24 (dd, J=12.4, 4.4 Hz, 1H), 3.95 (dd, J=12.4, 4.4Hz, 1H), 3.00 (overlapped, 1H), 2.78 (t, J=7.6Hz, 4H), 2.63-2.58 (m, 6H), 1.97-1.93 (m, 4H), 1.01 (t, J=7.2 Hz, 3H). MS: m/z 446.1 (M+H ⁺ ).

Example 45

[00852] Synthesis of (R)-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(methylamino)-6,7- sodium dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide is illustrated below.

[00853] To a solution of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (3.0 g, 17.3 mmol) in THF/H ₂ O/HBF ₄ (45 ml/ 7 ml/22 ml) was added dropwise a solution of NaNO ₂ (1.3 g, 18.2 mmol) in H ₂ O (3 ml) at -10° C. under N ₂ atmosphere. After stirring with cooling for 2 hours, the cooling bath was removed and the reaction mixture was partitioned between water (100 ml) and EA (100 ml). The organic layer was washed with sat. NaHCO ₃ (50 ml), brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel (PE) column chromatography to obtain 4-fluoro-1,2,3,5,6,7-hexahydro-s-indacene (1.4 g, yield: 46%) as a white solid.

[00854] ¹ H NMR (300 MHz, CDCl ₃ ): δ=6.88 (s, 1H), 2.92-2.87 (m, 8H), 2.17-2.07 (m, 4H) .

Stage 2

[00855] To a solution of 4-fluoro-1,2,3,5,6,7-hexahydro-s-indacene (1.4 g, 8.0 mmol) in MeCN (20 ml) was added NO ₂ BF ₄ in two portions (1.3 g, 9.8 mmol) at 0° C. under N ₂ . The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was partitioned between EA (100 ml) and water (100 ml). The organic layer was washed with water (20 ml) and brine (20 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel flash column chromatography (0% ~ 45% EA in PE) to give 4-fluoro-s-nitro-1,2,3,5,6,7-hexahydro-s-indacene (1, 4 g, yield: 80%) as a white solid.

[00856] ¹ H NMR (400 MHz, CDCl ₃ ): δ=3.30 (t, J=6.8 Hz, 4H), 2.95 (t, J=7.6 Hz, 4H), 2, 22-2.13 (m, 4H).

Stage 3

[00857] 10% Pd/C (200 mg). After stirring at room temperature under a balloon of hydrogen overnight, the reaction mixture was filtered. The filtrate was evaporated in vacuo to dryness and the residue was purified by silica gel flash column chromatography (0%~45% EA in PE) to give 8-fluoro-1,2,3,5,6,7-hexahydro-s-indacene- 4-amine (1.1 g, yield: 91%) as a white solid.

[00858] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=4.42 (s, 2H), 2.75 (t, J=7.6 Hz, 4H), 2.62 (t, J = 7.6 Hz, 4H), 2.05-1.97 (m, 4H). MS: m/z 192.4 (M+H ⁺ ).

Stage 4

[00859] (R)-tert-butyl-(3-(N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate was synthesized as in Preparation D to give the desired product (1.8 g, yield: 72% ) as a yellow solid. MS: m/z 550.2 (M+H ⁺ ).

Stage 5

[00860] To a solution of (R)-tert-butyl-(3-(N-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl )-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (1.8 g, 3.3 mmol) in CH ₂ Cl ₂ ( 8 ml) was added TFA (8 ml) and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated in vacuo to remove the solvent. The residue was treated with 2 N aq. NaOH up to pH>13. The resulting solution was purified by reverse phase HPLC (MeCN/H ₂ O) to give (R)-((8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)((6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium (1.2 g, 80%) as a yellow solid.

[00861] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.42 (s, 1H), 7.32 (s, 1H), 4.28-4.24 (m, 1H), 4 .16 (k, J=4.8 Hz, 1H), 4.09 (k, J=6.0 Hz, 1H), 3.82 (k, J=5.2 Hz, 1H), 3.08 (br, 1H), 2.78 (t, J=7.6 Hz, 4H), 2.71 (t, J=7.6 Hz, 4H), 2.33 (s, 3H), 1.99 -1.93 (m, 4H). MS: m/z 450.1 (M+H ⁺ ).

Example 46

[00862] Synthesis of (R)-N-((8-fluoro-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-sulfonamide is illustrated below.

[00863] To a solution of (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide (80 mg, 0.34 mmol) in THF (10 ml) was added MeONa (54 mg, 1.0 mmol) and the mixture was stirred at room temperature for 30 min to obtain a suspension of the sodium salt.

[00864] In another flask to a solution of 8-fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (66 mg, 0.34 mmol) and TEA (102 mg, 1 mmol ) in THF (10 mL), triphosgene (40 mg, 0.14 mmol) was added in one portion and the mixture was stirred at room temperature under N ₂ for 30 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature overnight. Thereafter, the reaction solution was partitioned between EA (10 ml) and water (5 ml). The aqueous phase was acidified to pH=5 with 1 N HCl. The resulting solid was collected by filtration and dried to give (R)-N-((8-fluoro-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-sulfonamide (27 mg, yield: 17.6%) as a white solid.

[00865] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.55 (br. s, 1H), 7.91 (br. s, 1H), 7.61 (s, 1H), 4 .62 (d, J=11.6 Hz, 1H), 4.35 (d, J=11.6 Hz, 1H), 4.18-4.27 (m, 2H), 4.06 (s, 1H), 3.35 (s, 3H), 2.82 (t, J=7.2 Hz, 4H), 2.64 (t, J=7.6 Hz, 4H), 1.98-2, 05 (m, 4H) MS: m/z 450.8 (M+H ⁺ ).

Example 47

[00866] Synthesis of (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(prop-2-yn-1-yloxy)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium is illustrated below.

[00867] To a solution of rac-N,N-dibenzyl-6-(3-hydroxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3- sulfonamide (840 mg, 2.1 mmol) in DMF (10 ml) was added NaH (60% in mineral oil, 126.0 mg, 3.2 mmol). The reaction mixture was stirred at room temperature for 1 h under N ₂ . Then 3-bromoprop-1-yne (273.0 mg, 2.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 ml) and extracted with EA (20 ml). The organic layer was washed with water (10 ml) and brine (10 ml), dried over Na ₂ SO ₄ and concentrated to dryness to give rac-N,N-dibenzyl-6-(prop-2-yn-1-yloxy)-6 ,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (580 mg, yield: 63%) as a yellow solid.

[00868] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.63 (s, 1H), 7.25-7.16 (m, 10H), 4.52-4.17 (m, 11H) , 2.55 (s, 1H). MS: m/z 438.1 (M+H ⁺ ).

Stage 2

[00869] To a stirred solution of rac-N,N-dibenzyl-6-(prop-2-yn-1-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonamide (115 mg, 0.3 mmol) in CH ₂ Cl ₂ (3.0 ml) was added conc. H ₂ SO ₄ (16 drops, 0.32 ml) and stirred at 0°C for 10 min. The reaction solution was concentrated. The residue was neutralized with saturated NaHCO ₃ solution. The mixture was then filtered off the solid and the filtrate was purified by reverse phase HPLC (MeCN/H ₂ O) to give rac-6-(prop-2-u-1-yloxy)-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazine-3-sulfonamide (23.0 mg, yield: 34%) as a yellow solid.

[00870] MS: m/z 258.0 (M+H ⁺ ).

Stage 3

[00871] Rac-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(prop-2-yn-1-yloxy)-6.7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide was synthesized as in Preparation D to give the desired product (20.0 mg, yield: 49%) as white solid.

[00872] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.86 (br. s, 1H), 7.85 (s, 1H), 6.92 (s, 1H), 4.63 -4.59 (m, 1H), 4.40-4.25 (m, 6H), 3.52 (t, J=2.4 Hz, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.62 (t, J=7.2 Hz, 4H), 1.99-1.92 (m, 4H). MS: m/z 457.1 (M+H ⁺ ).

Example 48

[00873] Synthesis of rac-((6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide is illustrated below.

[00874] To a solution of rac-tert-butyl-((3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)carbamate (0, 3 g, 0.9 mmol) in THF (3 ml) was added NaH (60%, 108 mg, 2.7 mmol) followed by the addition of MeI (639 mg, 4.5 mmol) at 0°C. After stirring at room temperature for 16 hours, the suspension was quenched by the addition of EA (20 ml) and water (10 ml). The organic layer was separated. The aqueous layer was extracted with EtOAc (10 ml). The organic layers were combined, washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give rac-tert-butyl-((3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-6-yl)methyl)(methyl)carbamate (290 mg, yield: 93%) as a yellow oily liquid.

Stage 2

[00875] Rac-2,4,6-trichlorophenyl-6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonate was synthesized using Preparation B to give the product as a yellow oil which was used in the next step without purification.

Stage 3

[00876] Rac-tert-butyl-methyl((3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)carbamate was synthesized as in Preparation C to give the desired product (60 mg, yield: 16% over 2 steps) as a light yellow solid. MS: m/z 369.4 (M+Na ⁺ ).

Stage 4

[00877] ((6-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl )((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide was synthesized as in Preparation D to give the desired product (28 mg, yield: 31%) as white solid.

[00878] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.33 (s, 1H), 7.31 (s, 1H), 6.75 (s, 1H), 4.28 (d , J=10.4 Hz, 1H), 4.10-4.0 (m, 2H), 3.80-3.73 (m, 1H), 3.25-3.15 (m, 2H), 2.80 (s, 3H), 2.74 (t, J=7.2 Hz, 4H), 2.64 (t, J=7.2 Hz, 4H), 2.50 (overlapped, 1H), 1.95-1.85 (m, 4H), 1.41-1.31 (m, 9H). MS: m/z 546.2 (M+H ⁺ ).

Example 49

[00879] Synthesis of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-((methylamino)methyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium is illustrated below.

[00880] To a solution of rac-((6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide sodium (15 mg, 0.03 mmol) in CH ₂ Cl ₂ (2 ml ) TFA (0.6 ml) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated in vacuo to remove the solvent. A 2N NaOH solution was added to the residue until pH>13. The resulting solution was purified by reverse phase HPLC (MeCN/H ₂ O) to give rac-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6- sodium ((methylamino)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide (10 mg, 80%) as a white solid .

[00881] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.36 (s, 1H), 6.77 (s, 1H), 4.39 (dd, J=11.2 Hz, 2 .8 Hz, 1H), 4.20-4.1 (m, 2H), 3.83 (dd, J=12.4 Hz, 7.6 Hz, 1H), 3.42 (m, 5H), 3.16-3.11 (m, 1H), 2.75 (t, J=7.2 Hz, 4H), 2.66 (t, J=7.2 Hz, 4H), 1.96-1 .86 (m, 4H). MS: m/z 446.1 (M+H ⁺ ).

Example 50

[00882] Synthesis of (R)-6-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide and (S)-6-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[00883] To a solution of dimethyl-2-ethylmalonate (1.8 g, 9.6 mmol) in THF (10 ml) was added dropwise LiBH ₂ (2 M in THF, 9.6 ml, 19.2 mmol) at 0 °С in N ₂ atmosphere. The reaction mixture was stirred at room temperature for 16 hours and then poured into water (40 ml). The resulting solution was concentrated to about 5 ml and mixed with EA (50 ml). The mixture was stirred vigorously for 5 minutes, dried with MgSO ₄ and concentrated to give 2-ethylpropane-1,3-diol (970 mg, yield: 97%) as a colorless oily liquid.

Stage 2

[00884] To a solution of 2-ethylpropane-1,3-diol (970 mg, 9.3 mol) and Et ₃ N (2.4 g, 23.8 mmol) in dry THF (20 ml) 2 g, 19.3 mmol) at 0°C. After stirring at room temperature for 30 minutes, the reaction mixture was filtered. The filtrate was concentrated to dryness to give crude 2-ethylpropane-1,3-diyldimethanesulfonate as a yellow oil.

Stage 3

[00885] A mixture of 2-ethylpropane-1,3-diyldimethanesulfonate (crude), 1H-pyrazol-3(2H)-one (750 mg, 8.9 mmol) and K ₂ CO ₃ (4.3 g, 31.2 mmol) in DMF (40 ml) was heated at 100°C for 16 hours. The reaction mixture was partitioned between EA/H ₂ O (80 ml/200 ml) and the layers were separated. The aqueous layer was extracted with EA (80 ml×3) and the combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=3/1) to give rac-6-ethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (650 mg, yield : 48%) as a colorless oily liquid.

[00886] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.32 (d, J=1.5 Hz, 1H), 5.48 (d, J=1.5 Hz, 1H), 4, 34-4.26 (m, 2H), 3.95-3.87 (m, 1H), 3.81-3.73 (m, 1H), 2.30-2.19 (m, 1H), 1.60-1.40 (m, 2H), 1.05 (t, J=7.5 Hz, 3H).

Stage 4

[00887] Rac-6-ethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (650 mg, 4.3 mmol) was added dropwise to ClSO ₃ H (4 ml ) at 0°C. After stirring at 80°C for 2 hours, the reaction mixture was added dropwise to a mixture of ice water/EA (30 ml/20 ml). The two layers were separated and the aqueous layer was extracted with EA (10 ml x 2). The combined organic layer was washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated to give crude rac-6-ethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonyl chloride as a yellow solid.

Stage 5

[00888] To a solution of crude rac-6-ethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride in THF (3 ml) was added NH ₃ .H ₂ O (1 ml). After stirring at 60° C. for 1 hour, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH (3 ml) and acidified with aq. HCl (1 N) to pH=3. The residue was purified by reverse phase HPLC (0% - 95% MeCN in H ₂ O) to give rac-6-ethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonamide (200 mg, yield: 20%, two steps) as a yellow solid.

[00889] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.48 (s, 1H), 7.08 (s, 2H), 4.48-4.44 (m, 1H), 4 .21 (dd, J=12.4, 5.6 Hz, 1H), 4.12-4.07 (m, 1H), 3.81-3.75 (m, 1H), 2.24-2 .17 (m, 1H), 1.47-1.32 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

Stage 6

[00890] Rac-6-ethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (200 mg) was separated by chiral HPLC to give two isomers:

[00891] (R)-6-ethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (peak 1, 80 mg) and (S)-6 -ethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (peak 2, 83 mg).

Stage 7

[00892] (S)-6-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide was synthesized using Preparation A to give the desired product (53 mg, yield: 34%) as a white solid.

[00893] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.48 (br. s, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H), 4.51 (d, J=2.8 Hz, 1H), 4.48-4.15 (m, 2H), 3.82-3.77 (m, 1H), 2, 78 (t, J=7.2 Hz, 4H), 2.60 (t, J=6.8 Hz, 4H), 2.20-1.98 (m, 1H), 1.97-1.91 (m, 4H), 1.45-1.11 (m, 2H), 0.96 (t, J=7.6 Hz, ZN). MS: m/z 431.1 (M+H ⁺ ).

[00894] (R)-6-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide was prepared using a similar procedure.

[00895] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.46 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.93 (s , 1H), 4.50 (dd, J=10.8, 3.2 Hz, 1H), 4.24-4.13 (m, 2H), 3.83-3.78 (m, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.59 (t, J=7.2 Hz, 4H), 2.21-2.19 (m, 1H), 1.99-1 .92 (m, 4H), 1.42-1.35 (m, 2H), 0.95 (t, J=7.2 Hz, ZN). MS: m/z 431.1 (M+H ⁺ ).

Example 51

[00896] Synthesis of 6-(3-fluoroazetidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00897] 2,4,6-trichlorophenyl ether 6-(tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- sulfonic acid was synthesized using Preparation B, which gave the product as a yellow gel, which was used in the next step without purification.

Stage 2

[00898] 6-(Tetrahydro-pyran-2-yloxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 2,4,6-trichloro-phenyl ester mixture -sulfonic acid (crude, ~6.6 mmol), dibenzylamine (2.5 g, 12.0 mmol) and THF (20 ml) were stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure to 10 ml of remaining liquid. The remaining solution was acidified with aq. HCl (1 N) to pH=5 and extracted with EA (100 ml x5). The organic layers were combined, dried over Na ₂ SO ₄ and concentrated to give N,N-dibenzyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazine-3-sulfonamide (1.5 g, yield: 51%) as a yellow solid.

[00899] MS: m/z 484.2 (M+H ⁺ ).

Stage 3

[00900] To a solution of N,N-dibenzyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-sulfonamide (6.1 g, 12.6 mmol) in THF/H ₂ O/EtOH (50 ml/10 ml/50 ml) was added conc. HCl (10 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (MeCN/H ₂ O) to give N,N-dibenzyl-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 3-sulfonamide (4.0 g, yield: 80%) as a white solid. MS: m/z 400.1 (M+H ⁺ ).

Stage 4

[00901] N,N-dibenzyl-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide solution (3.4 g, 8.5 mmol ) and Dess-Martin periodinane (7.2 g, 17.0 mmol) in CH ₂ Cl ₂ (50.0 ml) was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=1:2) to give N,N-dibenzyl-6-oxo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 3-sulfonamide (3.0 g, yield: 91%) as a yellow solid.

Stage 5

[00902] To a stirred solution of N,N-dibenzyl-6-oxo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (397.0 mg, 1. 0 mmol) and 3-fluoroazetidine hydrochloride (224.0 mg, 2.0 mmol) in MeOH (10.0 ml) was added sodium triacetoxyborohydride (424.0 mg, 2.0 mmol) at room temperature. After stirring at room temperature for 30 minutes, sodium cyanotrihydroborate (126 mg, 2.0 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=5/1) to give N,N-dibenzyl-6-(3-fluoroazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonamide (160 mg, yield: 35%) as a yellow solid.

Stage 6

[00903] To a solution of N,N-dibenzyl-6-(3-fluoroazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide ( 140 mg, 0.3 mmol) in CH ₂ Cl ₂ (3.0 ml) was added conc. H ₂ SO ₄ (16 drops, 0.32 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated. The residue was neutralized with saturated NaHCO ₃ solution and filtered. The filtrate was purified by reverse phase HPLC (0%-95% MeCN in H ₂ O) to give 6-(3-fluoroazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonamide (60.0 mg, yield: 71%) as a yellow solid.

Stage 7

[00904] 6-(3-fluoroazetidin-1-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide was synthesized as described in Preparation F to give the desired product (11.0 mg, yield: 11%) as a white solid.

[00905] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.48 (br. s, 1H), 7.87 (s, 1H), 7.58 (s, 1H), 6.93 (s, 1H), 5.20-5.17 (m, 0.5H), 5.06-5.03 (m, 0.5H), 4.32 (k, J=6.0 Hz, 2H ), 4.17 (dd, J=12.8, 4.0 Hz, 1H), 3.89 (d, J=13.2 Hz, 1H), 3.65-3.60 (m, 2H) , 3.28 (overlapped, 2H), 3.09 (d, J=4.0 Hz, 1H), 2.79 (t, J=7.6 Hz, 4H), 2.61 (t, J= 7.6 Hz, 4H), 1.99-1.94 (m, 4H). MS: m/z 476.1 (M+H ⁺ ).

Example 52

[00906] Synthesis of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(pyrrolidin-1-yl)-6,7-dihydro-5H- sodium pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide is illustrated below.

Stage 1

[00907] To a solution of 6-oxo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid dibenzylamide (750 mg, 1.9 mmol) and pyrrolidine (270 mg, 3.8 mmol) in MeOH (18 ml) was added AcOH to pH=6. NaBH(OAc) ₃ (810 mg, 3.8 mmol) was then added and the reaction mixture was stirred at room temperature for 3 hours. NaBH ₃ CN (240 mg, 3.8 mmol) was added and the reaction mixture was stirred at room temperature for an additional 16 hours. The reaction solution was concentrated to about 6 ml and then purified by reverse phase HPLC (0%-95% MeCN in H ₂ O) to give dibenzylamide 6-pyrrolidin-1-yl-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazine-3-sulfonic acid (290 mg, yield: 34%) as a gummy yellow solid. MS: m/z 453.1 (M+H ⁺ )

Stage 2

[00908] This step is similar to the general procedure for the synthesis of 6-(3-fluoroazetidin-1-yl)-H-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide.

Stage 3

[00909] To a suspension of 6-pyrrolidin-1-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid amide (50 mg, 0.2 mmol) in THF (2 ml) was added MeONa (35 mg, 0.6 mmol) and the mixture was stirred at room temperature for 20 min to obtain a suspension of the sodium salt.

[00910] In another flask to a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (30 mg, 0.2 mmol) and TEA (50 mg, 0.5 mmol) in THF (3 ml) was added triphosgene (20 mg, 0.1 mmol) in one portion and the mixture was stirred at room temperature under N ₂ for 20 minutes. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension. After stirring at room temperature for 16 hours, the reaction solution was partitioned between EA (10 ml) and water (30 ml). N ₂ was bubbled through the aqueous phase for 5 min and then purified by reverse phase HPLC (0%-95% MeCN in H ₂ O) to give ((1,2,3,5,6,7-hexahydro-s -indacen-4-yl)carbamoyl)((6-(pyrrolidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl) sodium amide (10 mg, yield: 12%) as a white solid.

[00911] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.86 (s, 1H), 7.60 (s, 1H), 6.92 (s, 1H), 4.50-4 .40 (m, 2H), 4.27 (dd, J=12.8, 4.0 Hz, 1H), 4.13 (dd, J=12.8, 4.0 Hz, 1H), 2, 94-2.91 (m, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.68-2.58 (m, 8H), 2.00-1.91 (m, 4H), 1.70-1.60 (m, 4H). MS: m/z 472.1 (M+H ⁺ ).

Example 53

[00912] ((6-(Azetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)((1,2, 3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide sodium

[00913] The title compound was prepared using the general synthetic procedure ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(pyrrolidin-1-yl) -6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium.

[00914] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.42 (s, 1H), 7.33 (s, 1H), 6.77 (s, 1H), 4.15-4 .02 (m, 3H), 3.75 (dd, J=12.8, 1.6 Hz, 1H), 3.20 (t, J=6.8 Hz, 4H), 2.84-2, 80 (m, 1H), 2.75 (t, J=7.2 Hz, 4H), 2.66 (t, J=7.2 Hz, 4H), 1.97-1.87 (m, 6H ). MS: m/z 458.1 (M+H ⁺ ).

Example 54

[00915] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00916] To a stirred solution of TiCl ₄ (0.5 ml, excess) and methylmagnesium bromide (1.0 ml, excess) in THF (5.0 ml) was added N,N-dibenzyl-6-oxo-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (140.0 mg, 0.4 mmol) at -78°C under N ₂ atmosphere. The mixture was then filtered and the filtrate was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=25/1) to give N,N-dibenzyl-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide (55 mg, yield: 38%) as a white solid.

Stage 2

[00917] To a stirred solution of N,N-dibenzyl-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b[1,3]oxazine-3-sulfonamide (55 mg, 0 .1 mmol) in CH ₂ Cl ₂ (3.0 ml) was added conc. H ₂ SO ₄ (8 drops, 0.16 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated. The residue was neutralized with saturated NaHCO ₃ solution. The mixture was then filtered and the filtrate was purified by reverse phase HPLC (MeCN/H ₂ O) to give 6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonamide (26.0 mg, yield: 87%) as a white solid. Stage 3

[00918] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide was synthesized as described in Preparation F to give the desired product (7.0 mg, yield: 15%) as a white solid.

[00919] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.4 (s, 1H), 7.89 (s, 1H), 7.62 (s, 1H), 6.93 (s , 1H), 5.45 (s, 1H), 4.18 (s, 2H), 4.04 (d, J=12.4 Hz, 1H), 3.91 (d, J=12.0 Hz , 1H), 2.79 (t, J=7.2 Hz, 4H), 2.61 (t, J=7.2 Hz, 4H), 1.99-1.92 (m, 4H), 1 .25 (s, 3N). MS: m/z 433.1 (M+H ⁺ ).

Example 55

[00920] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[00921] To a solution of N,N-dibenzyl-6-hydroxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (35 mg, 0 08 mmol) in DMF (3 ml) was added NaH (60% in mineral oil, 6.4 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 1 h under N ₂ . Iodomethane (60 mg, 0.4 mmol) was then added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 ml) and extracted with EA (20 ml). The organic layer was washed with water (10 ml) and brine (10 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by reverse phase HPLC (MeCN/H ₂ O) to give N,N-dibenzyl-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1, 3]oxazine-3-sulfonamide (30 mg, yield: 83%) as a yellow oily liquid.

[00922] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.58 (s, 1H), 7.29-7.26 (m, 5H), 7.18-7.15 (m, 5H) , 4.34 (s, 4H), 4.21 (s, 3H), 4.16 (s, 2H), 2.67 (s, 2H), 1.38 (s, 3H).

[00923] MS: m/z 428.0 (M+H ⁺ ).

Stage 2

[00924] To a stirred solution of N,N-dibenzyl-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (25 mg, 0.06 mmol) in CH ₂ Cl ₂ (3.0 ml) was added conc. H ₂ SO ₄ (8 drops, 0.16 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated. The residue was neutralized with saturated NaHCO ₃ solution. The mixture was then filtered and the filtrate was purified by reverse phase HPLC (MeCN/H ₂ O) to give 6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonamide (6.0 mg, yield: 35%) as a yellow solid.

[00925] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.57 (s, 1H), 4.09 (s, 3H), 3.89 (q, J=10.4 Hz, 2H ), 3.66 (k, J=10.0 Hz, 2H), 1.24 (s, 3H).

[00926] MS: m/z 247.9 (M+H ⁺ ).

Stage 3

[00927] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxy-6-methyl-6,7-dihydro-5H-pyrazolo[ 5,1-b][1,3]oxazine-3-sulfonamide was synthesized as in Preparation D to give the desired product (7.0 mg, yield: 73%) as a white solid.

[00928] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.42 (s, 1H), 6.80 (s, 1H), 4.15 (s, 3H), 4.01 (s , 2H), 2.75 (t, J=7.2 Hz, 4H), 2.60 (t, J=8.4 Hz, 4H), 2.58 (overlapped, 2H), 1.92-1 .88 (m, 4H), 1.20 (s, 3H). MS: m/z 447.1 (M+H ⁺ ).

Example 56

[00929] Synthesis of rac-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(3-methoxyazetidin-1-yl)-6,7- sodium dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide is illustrated below.

Stage 1

[00930] To a stirred solution of N,N-dibenzyl-6-oxo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (794 mg, 2.0 mmol ) and azetidin-3-ol hydrochloride (440.0 mg, 4.0 mmol) in MeOH (30.0 ml) was added sodium triacetoxyborohydride (848.0 mg, 4.0 mmol) at room temperature. The mixture was then stirred at room temperature for 30 minutes. Sodium cyanotrihydroborate (252.0 mg, 4.0 mmol) was added to the mixture and stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=5/1) to give rac-N,N-dibenzyl-6-(3-hydroxyazetidin-1-yl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (340 mg, yield: 37%) as a yellow solid. MS: m/z 455.2 (M+H ⁺ ).

Stage 2

[00931] To a solution of rac-N,N-dibenzyl-6-(3-hydroxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3- sulfonamide (105 mg, 0.2 mmol) in DMF (3 ml) was added NaH (60% in mineral oil, 14.0 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 1 h under N ₂ . Iodomethane (39.0 mg, 0.3 mmol) was then added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 ml) and extracted with EA (20 ml). The organic layer was washed with water (10 ml) and brine (10 ml), dried over Na ₂ SO ₄ and concentrated to dryness to give rac-N,N-dibenzyl-6-(3-methoxyazetidin-1-yl)-6.7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (120 mg, crude) as a yellow oily liquid.

[00932] MS: m/z 469.1 (M+H ⁺ ).

Stage 3

[00933] To a stirred solution of rac-N,N-dibenzyl-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonamide (120 mg, 0.3 mmol) in CH ₂ Cl ₂ (3.0 ml) was added conc. H ₂ SO ₄ (16 drops, 0.32 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated. The residue was neutralized with saturated NaHCO ₃ solution. The solid was then filtered from the mixture and the filtrate was purified by reverse phase HPLC (MeCN/H ₂ O) to give rac-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5, 1-b][1,3]oxazine-3-sulfonamide (52.0 mg, yield: 70%) as a white solid. MS: m/z 289.1 (M+H ⁺ ).

Stage 4

[00934] Rac-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(3-methoxyazetidin-1-yl)-6,7-dihydro -5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide was synthesized as in Preparation D to give the desired product (10.0 mg, yield: 11%) as a white solid substances.

[00935] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.85 (br s, 1H), 7.57 (s, 1H), 6.92 (s, 1H), 4.30 -4.28(m, 2H), 4.17-4.12(m, 1H), 3.91-3.84(m, 2H), 3.52(t, J=7.2Hz, 2H ), 3.14 (s, 3H), 3.01-2.94 (m, 3H), 2.79 (t, J=7.2 Hz, 4H), 2.62 (t, J=7, 2 Hz, 4H), 1.99-1.92 (m, 4H). MS: m/z 488.2 (M+H ⁺ ).

Example 57

[00936] Synthesis of (R)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-(3-methoxyazetidin-1-yl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium and (S)-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)((6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl )sulfonyl)amide sodium is illustrated below.

Stage 1

[00937] Rac-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (150 mg) was separated with chiral preparative HPLC to give (R)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (65 mg ) as a white solid and (S)-6-(3-methoxyazetidin-1-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide ( 60 mg) as a white solid.

Stage 2

[00938] (R)-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)((6-(3-methoxyazetidin-1-yl)-6.7 -dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide was synthesized as in Preparation D to give the desired product (54.0 mg, yield: 48%) as white solid.

[00939] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.37 (br. s, 1H), 7.30 (s, 1H), 6.75 (s, 1H), 4.13 -4.08 (m, 3H), 3.96-3.92 (m, 1H), 3.79-3.76 (m, 1H), 3.55-3.53 (m, 2H), 3 .14 (s, 3H), 2.98-2.94 (m, 2H), 2.87 (br, 1H), 2.75 (t, J=6.8 Hz, 4H), 2.66 ( t, J=6.8 Hz, 4H), 1.92-1.89 (m, 4H). MS: m/z 488.2 (M+H ⁺ ).

[00940] (S)-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)((6-(3-methoxyazetidin-1-yl)-6.7 sodium -dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide was prepared using a similar procedure.

[00941] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.39 (br.s, 1H), 7.30 (s, 1H), 6.76 (s, 1H), 4.12 -4.06(m, 3H), 3.95-3.92(m, 1H), 3.79-3.76(m, 1H), 3.55-3.52(m, 2H), 3 .14 (s, 3H), 2.98-2.92 (m, 2H), 2.88 (br, 1H), 2.75 (t, J=7.2 Hz, 4H), 2.66 ( t, J=7.2 Hz, 4H), 1.95-1.87 (m, 4H). MS: m/z 488.2 (M+H ⁺ ).

Example 58

[00942] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][ 1,4]oxazine-2-sulfonamide is illustrated below.

Stage 1

[00943] To a solution of 2-bromoethanol (3.8 g, 30.0 mmol) and DHP (2.5 g, 30.0 mmol) in DCM (50 ml), TsOH (380.0 mg, 2, 2 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified on a silica gel column (PE/EA=50/1) to obtain 2-(2-bromoethoxy)tetrahydro-2H-pyran (5.6 g, yield: 89%) as a colorless oily liquid.

[00944] ¹ H NMR (400 MHz, CDCl ₃ ): δ=4.68 (t, J=3.2 Hz, 1H), 4.05-3.99 (m, 1H), 3.92-3 .86 (m, 1H), 3.80-3.74 (m, 1H), 3.54-3.49 (m, 3H), 1.85-1.71 (m, 3H), 1.65 -1.53 (m, 3H).

Stage 2

[00945] Conc. H ₂ SO ₄ (2.0 ml). The resulting mixture was stirred at 65° C. overnight. The mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (DCM/MeOH=50/1) to give methyl 3-nitro-1H-pyrazole-5-carboxylate (1.42 g, yield: 83%) as a yellow solid.

[00946] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=15.24 (br. s, 1H), 7.54 (s, 1H), 3.90 (s, 3H).

Stage 3

[00947] To a solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (1.7 g, 10.0 mmol) in NMP (20 ml) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (2 .6 g, 13.0 mmol) followed by the addition of K ₂ CO ₃ (1.7 g, 13.0 mmol). The resulting mixture was stirred at 80°C for 16 hours. Then K ₂ CO ₃ was filtered off. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (PE/EA=2/1) to give methyl 3-nitro-1-(2-((tetrahydro-2H-pyran-2-yl)oxy) ethyl)-1H-pyrazole-5-carboxylate (2.8 g, yield: 94%) as a yellow oily liquid.

[00948] ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.39 (s, 1H), 4.92 (t, J=7.2 Hz, 2H), 4.57 (s, 1H), 4.11-4.07 (m, 1H), 3.98 (overlap, 1H), 3.96 (s, 3H), 3.84-3.80 (m, 1H), 3.64-3, 60 (m, 1H), 3.49-3.46 (m, 1H), 1.67-1.46 (m, 6H).

Stage 4

[00949] To a solution of methyl 3-nitro-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole-5-carboxylate (2.5 g, 8.4 mmol ) in dry THF (50 ml) was added LiBH ₄ (6.3 ml, 2.0 M in THF) at 0°C. The resulting mixture was stirred from 0°C to room temperature for 3 hours. The reaction mixture was then quenched by the addition of MeOH (4 ml). The mixture was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (PE/EA=1/1) to give (3-nitro-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl )-1H-pyrazol-5-yl)methanol (2.2 g, yield: 96%) as a yellow oily liquid.

[00950] ¹ H NMR (300 MHz, CDCl ₃ ): δ=6.88 (s, 1H), 4.69 (t, J=6.3 Hz, 2H), 4.57-4.49 (m , 3H), 4.21-4.16 (m, 1H), 3.92-3.85 (m, 1H), 3.77-3.65 (m, 2H), 3.51-3.42 (m, 2H), 1.72-1.48 (m, 6H).

Stage 5

[00951] To a stirred solution of (3-nitro-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-5-yl)methanol (2.0 g, 7, 5 mmol), pyridine (593 mg, 7.5 mmol) and perbromomethane (5.0 g, 15.0 mmol) in dry Et ₂ O (30 ml) triphenylphosphine (3.9 g, 15.0 mmol) was added at 0°C. The resulting mixture was stirred from 0°C to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered off the solid and the solvent was concentrated in vacuo to dryness to give a yellow gum, which was purified by silica gel column chromatography (PE/EA=1/1) to give 5-(bromomethyl)-3-nitro-1-(2-( (tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole (1.5 g, yield: 60%) as a yellow oily liquid.

[00952] ¹ H NMR (400 MHz, CDCl ₃ ): δ=6.89 (s, 1H), 4.69 (t, J=16.0 Hz, 2H), 4.57-4.48 (m , 3H), 4.16-4.10 (m, 1H), 3.84-3.77 (m, 1H), 3.64-3.57 (m, 1H), 3.48-3.43 (m, 1H), 1.72-1.45 (m, 6H).

Stage 6:

[00953] To a solution of 5-(bromomethyl)-3-nitro-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole (1.5 g, 4.5 mmol ) in THF (5 ml) was added conc. HCl (1.0 ml) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was neutralized with saturated NaHCO ₃ solution and extracted with EA (60 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated to dryness in vacuo to give a yellow gum which was purified by silica gel column chromatography (PE/EA=1/1) to give 2 -(5-(bromomethyl)-3-nitro-1H-pyrazol-1-yl)ethanol (1.0 g, yield: 91%) as a yellow oily liquid.

Stage 7

[00954] NaH (60%, 197 mg, 4.92 mmol). After stirring at room temperature under N ₂ for 4 hours, the reaction mixture was partitioned between water (50 ml) and EA (50 ml). The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=4/1) to give 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (300 mg, yield: 40 %) as a white solid.

[00955] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=6.88 (s, 1H), 4.82 (s, 2H), 4.23 (t, J=4.8 Hz, 2H ), 4.12 (t, J=4.8 Hz, 2H).

Stage 8

[00956] To a solution of 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (300 mg, 1.78 mmol) in MeOH (10 mL) was added Pd/C (10% wet, 100 mg). The reaction mixture was stirred at room temperature under H ₂ (1 atm) for 3 hours and filtered. The filtrate was concentrated to give 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-amine (250 mg, yield: quantitative) as a yellow gum. MS: m/z 277.0 (M-56+H ⁺ ).

[00957] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=5.20 (s, 1H), 4.63-4.55 (m, 4H), 3.98-3.94 (m, 2H), 3.79-3.75 (m, 2H).

Stage 9

[00958] To a solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-amine (250 mg, 1.8 mmol) in MeCN/H ₂ O (12 mL/ 1 ml) was added conc. HCl (2.7 ml) and AcOH (1.1 ml). The mixture was then cooled to 0° C. and a solution of NaNO ₂ (149 mg, 2.2 mmol) in H ₂ O (1 ml) was added slowly. After stirring at 0° C. for 30 min, CuCl ₂ (121 mg, 0.9 mmol) and CuCl (9 mg, 0.09 mmol) were added. Then, SO ₂ was passed through the reaction solution for 10 minutes. The reaction mixture was partitioned between water (50 ml) and EA (50 ml). The organic layer was washed with brine (40 ml), dried over Na ₂ SO ₄ and concentrated to give crude 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonyl chloride, which was directly used in the next step.

Stage 10

[00959] Ammonia ( 5 ml). The mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated, acidified with 2 N HCl to pH=5 and purified by reverse phase HPLC (MeCN/H ₂ O) to give 6,7-dihydro-4H-pyrazolo[5,1-c][1,4] oxazine-2-sulfonamide (100 mg, yield: 27% over 2 steps) as a white solid.

[00960] 1 H NMR (300 MHz, DMSO-d ₆ ): δ=7.42 (s, 2H), 6.39 (s, 1H), 4.80 (s, 2H), 4.17-4, 14 (m, 2H), 4.08 (t, J=4.8 Hz, 2H).

Stage 11

[00961] N-((1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1 ,4]oxazine-2-sulfonamide was synthesized using Preparation A to give the desired product (60 mg, yield: 30%) as a white solid.

[00962] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.86 (br. s, 1H), 8.05 (s, 1H), 6.95 (s, 1H), 6.59 (s, 1H), 4.81 (s, 2H), 4.19 (t, J=4.8 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 2.79 (t, J=7.2 Hz, 4H), 2.60 (t, J=7.2 Hz, 4H), 1.97-1.94 (m, 4H). MS: m/z 403.0 (M+H ⁺ ).

Example 59

[00963] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dihydro-2H-imidazo[5,1-b][ 1,3]oxazine-8-sulfonamide is illustrated below.

Stage 1

[00964] To a solution of 3-bromo-1-propanol (4 g, 28.8 mmol) in DCM (50 ml) was added TsOH (496 mg, 2.88 mmol) and 3,4-2H-dihydropyran (7.2 g, 86.2 mmol) at 0°C. The mixture was stirred at room temperature overnight. The reaction mixture was poured into H ₂ O (100 ml). The mixture was extracted with DCM (70 ml x2). The combined extracts were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel (PE) column chromatography to obtain 2-(3-bromo-propoxy)-tetrahydro-pyran (838 mg, yield: 57%) as a red solid.

[00965] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=4.60-4.56 (m, 1H), 3.77-3.72 (m, 2H), 3.61-3, 56 (m, 2H), 3.47-3.42 (m, 2H), 2.07-2.03 (m, 2H), 1.70-1.61 (m, 2H), 1.51- 1.45 (m, 4H).

Stage 2

[00966] A solution of 5-bromo-1H-imidazole (6.6 g, 44.9 mmol) in ClSO ₃ H (30 ml) was stirred at 180° C. under N ₂ for 2 hours. The reaction mixture was poured into ice water (70 ml) and filtered. The filter press cake was washed with H ₂ O (30 ml) and dried to give 5-bromo-1H-imidazole-4-sulfonyl chloride (7 g, yield: 63%) as a yellow solid.

Stage 3

[00967] TEA (4.5 ml, 32.6 mmol) and dibenzylamine (3.2 g, 16.3 mmol) at room temperature. After stirring at room temperature overnight, the reaction mixture was poured into H ₂ O (100 ml) and extracted with EA (50 ml ×2). The combined EA was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/1) to obtain 5-bromo-1H-imidazole-4-sulfonic acid dibenzylamide (1.4 g, yield: 21%) as a red solid.

[00968] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=7.96 (s, 1H), 7.25-7.19 (m, 6H), 7.12-7.05 (m, 4H), 4.36 (s, 4H).

Stage 4

[00969] To a solution of 5-bromo-1H-imidazole-4-sulfonic acid dibenzylamide (1.4 g, 3.2 mmol) in DMF (20 ml) was added K ₂ CO ₃ (883 mg, 6.4 mmol), 2-(3-bromo-propoxy)-tetrahydropyran (856 mg, 3.8 mmol) at room temperature and the mixture was stirred at 80° C. with N ₂ overnight. The reaction mixture was added silica gel and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EA=3/1 to 1/1) to give 5-bromo-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-imidazol-4 dibenzylamide -sulfonic acid (1.6 g, yield: 69%) as a red oily liquid.

[00970] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=8.08 (s, 1H), 7.23-7.20 (m, 6H), 7.13-7.10 (m, 4H), 4.55-4.52 (m, 1H), 4.36 (s, 4H), 4.12 (t, J=6.9 Hz, 2H), 3.72-3.64 (m , 2H), 3.40-3.30 (m, 2H), 2.02-1.95 (m, 2H), 1.80-1.59 (m, 2H), 1.50-1.40 (m, 4H).

Stage 5

[00971] To a solution of 5-bromo-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-imidazole-4-sulfonic acid dibenzylamide (1.6 g, 3.0 mmol) in THF ( 10 ml) added MeOH (5 ml), water. HCl (6 ml, 6 N) at room temperature and stirred at room temperature for 1 h. The reaction mixture was poured into H ₂ O (50 ml) and neutralized to pH=7 sat. _NaHC03 . The resulting mixture was extracted with EA (30 ml×2). The combined EA was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated to give 5-bromo-1-(3-hydroxy-propyl)-1H-imidazole-4-sulfonic acid dibenzylamide (1.4 g, crude ) as a red oily liquid.

Stage 6

[00972] NaH (60 %, 145 mg, 3.6 mmol) and the mixture was stirred at 80° C. under N ₂ for 4 hours. The reaction mixture was poured into H ₂ O (100 ml) and extracted with EA (50 ml ×3). The combined EA layer was washed with H ₂ O (60 ml x2), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by preparative HPLC (NH ₄ HCO ₃ ) to give 3,4-dihydro-2H-imidazo[5,1-b][1,3]oxazine-8-sulfonic acid dibenzylamide (176 mg, yield: 16%) in form of a colorless oily liquid.

[00973] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=7.42 (s, 1H), 7.23-7.18 (m, 6H), 7.15-7.12 (m, 4H), 4.34 (t, J=5.1 Hz, 2H), 4.26 (s, 4H), 4.08 (t, J=6.3 Hz, 2H), 2.10-2, 06 (m, 2H).

Stage 7

[00974] Conc. . H ₂ SO ₄ (12 drops) at 0°C and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into sat. NaHCO ₃ (20 ml) and then concentrated to remove DCM. The resulting solution was neutralized to pH=7 and filtered. The filtrate was purified by reverse phase HPLC (20% MeCN in H ₂ O) to give 3,4-dihydro-2H-imidazo[5,1-b][1,3]oxazine-8-sulfonic acid amide (60 mg , yield: 62%) as a white solid.

[00975] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=7.32 (s, 1H), 6.87 (s, 2H), 4.33 (t, J=5.7 Hz, 2H ), 4.07 (t, J=6.3 Hz, 2H), 2.09-2.05 (m, 2H).

Stage 8

[00976] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dihydro-2H-imidazo[5,1-b][1 ,3]oxazine-8-sulfonamide was synthesized as described in Preparation E to give the desired product (8 mg, yield: 8%) as a white solid.

[00977] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=7.98 (s, 1H), 7.40 (s, 1H), 6.91 (s, 1H), 4.33 (t , J=2.4 Hz, 2H), 4.06 (t, J=2.4 Hz, 2H), 2.80 (t, J=3.0 Hz, 4H), 2.60 (t, J =2.4 Hz, 4H), 2.07-2.05 (m, 2H), 1.98-1.92 (m, 4H). MS: m/z 403.1 (M+H ⁺ ).

Example 60

[00978] Synthesis of N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5 -a]pyrazine-2-sulfonamide is illustrated below.

Stage 1

[00979] To a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (100 mg, 0.58 mmol) in DMF (10 ml) was added tert-butyl-(2-bromoethyl) carbamate (197 mg, 0.58 mmol) 88 mmol) and K ₂ CO ₃ (240 mg, 1.74 mmol). Then the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=3/1) to give methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-nitro-1H-pyrazole-5-carboxylate (166 mg, 80%) as a yellow solid.

[00980] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.57 (s, 1H), 6.96 (t, J=6.0 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.41-3.36 (m, 2H), 1.26 (s, 9H).

Stage 2

[00981] To a solution of methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-nitro-1H-pyrazole-5-carboxylate (166 mg, 0.46 mmol) in dioxane (5 ml) was added HCl (1.15 ml, 4.6 mmol, 4 M in dioxane). The reaction mixture was then stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo. The residue was added to a suspension of DM FA (10 ml) and K ₂ CO ₃ (127 mg, 0.92 mmol). The reaction mixture was stirred at 80° C. overnight and the progress of the reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=50/1 ~ 10/1) to give 2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (65 mg, 68 %) as a yellow solid.

[00982] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.61 (s, 1H), 7.43 (s, 1H), 4.46 (t, J=6.0 Hz, 2H ), 3.72-3.65 (m, 2H).

Stage 3

[00983] Iron powder ( 1.8 g, 33.0 mmol), NH ₄ Cl (1.76 g, 33.0 mmol) and H ₂ O (10 ml). The reaction mixture was stirred at 80° C. under N ₂ overnight and the progress of the reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM/MeOH=10/1) to give 2-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.76 g, 76% ) as a yellow solid.

[00984] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.01 (s, 1H), 5.80 (s, 1H), 4.88 (s, 2H), 3.98 (t , J=5.6 Hz, 2H), 3.54-3.45 (m, 2H).

Stage 4

[00985] To a suspension of CuCl (0.204 g, 2.1 mmol) in H ₂ O (265 ml) was added SOCl ₂ (44.85 ml, 0.618 mol) dropwise at 0°C with vigorous stirring. The solution was stirred at room temperature overnight to give a light yellow solution. Separately, to a solution of 2-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.62 g, 4.1 mmol) in conc. HCl (4 ml) was added dropwise with a solution of NaNO ₂ (0.33 g, 4.8 mmol) in H ₂ O (2 ml) at -10°C. The resulting dark orange solution was stirred at -10°C for 30 minutes and then added to a solution (10.6 ml) of copper (I) chloride from the first stage at -5°C for 5 minutes. The reaction mixture was stirred at -5°C for 1 h and was extracted with EA (10 ml × 3). The organic layer was concentrated in vacuo to give a yellow solid. The solid was dissolved in THF (20 ml), followed by the addition of a solution of NH ₃ (10 ml, 28% wt.) dropwise at 0°C. The reaction mixture was stirred for 2 hours at 0° C. and then concentrated in vacuo. The resulting solid was purified by silica gel column chromatography (DCM/MeOH=10/1) to give 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide (0.2 g, 23%) as a white solid.

[00986] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.46 (s, 1H), 7.59 (s, 2H), 6.94 (s, 1H), 4.39 (t , J=5.2 Hz, 2H), 3.70-3.63 (m, 2H).

Stage 5

[00987] N-((1,2,3,5,6,7-Hexahydro-5-indacen-4-yl)carbamoyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-2-sulfonamide was synthesized as described in Preparation F to give the desired product (8.3 mg, 4.3%) as a white solid.

[00988] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.37 (s, 1H), 7.81 (s, 1H), 7.11 (s, 1H), 6.92 (s , 1H), 6.85 (s, 1H), 4.33 (t, J=6.0 Hz, 2H), 3.65-3.61 (m, 2H), 2.76 (t, J= 7.2 Hz, 4H), 2.63 (t, J=6.8 Hz, 4H), 1.96-1.88 (m, 4H). MS: m/z 414.1 (M-H ⁺ ).

Example 61

[00989] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazine-2-sulfonamide is illustrated below.

Stage 1

[00990] To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (5.0 g, 31.8 mmol) and 2-(methylamino)ethanol (3.58 g, 47.7 mmol) in DCM (50 ml) was added dropwise SOCl ₂ (11.5 ml, 159 mmol) and DMF (4 drops) at -5°C for 10 min. The reaction mixture was then stirred at 50° C. overnight. The reaction mixture was concentrated in vacuo. The residue was added in DMF (50 ml) and TEA (13.3 ml, 95.4 mmol). The reaction mixture was then stirred at 60° C. overnight. After the solvent was removed in vacuo, the residue was purified by silica gel column chromatography (DCM/MeOH=50/1 ~ 10/1) to obtain 5-methyl-2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazine-4( 5H)-one (4.66 g, 75%) as a yellow solid.

[00991] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.42 (s, 1H), 4.53 (t, J=6.0 Hz, 2H), 3.87 (t, J =6.8 Hz, 2H), 3.03 (s, 3H).

Stage 2

[00992] Powder was added to a solution of 5-methyl-2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (700 mg, 3.6 mmol) in EtOH (20 ml) iron (1.0 g, 17.9 mmol), NH ₄ Cl (0.96 g, 17.9 mmol) and H ₂ O (7 ml). The reaction mixture was stirred at 80° C. under N ₂ overnight and the progress of the reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM/MeOH=50/1~10/1) to give 2-amino-5-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.44 g, 73%) as a yellow solid.

[00993] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=5.80 (s, 1H), 4.85 (br. s, 2H), 4.08 (t, J=6.0 Hz , 2H), 3.87 (t, J=6.4 Hz, 2H), 2.95 (s, 3H).

Stage 3

[00994] To a suspension of CuCl (0.204 g, 2.1 mmol) in H ₂ O (265 ml) was added SOCl ₂ (44.85 ml, 0.618 mol) dropwise at -5°C with vigorous stirring. The solution was stirred at room temperature overnight to give a light yellow solution. Separately, to a solution of 2-amino-5-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (100 mg, 0.6 mmol) in conc. HCl (0.97 ml) was added dropwise with a solution of NaNO ₂ (50 mg, 0.72 mmol) in H ₂ O (2 ml) at -10°C. The resulting dark orange solution was stirred at -10°C for 30 minutes and then added to the above solution (1.6 ml) of copper (I) chloride at -5°C for 5 minutes. The reaction mixture was stirred at -5°C for 1 h and was extracted with EA (10 ml × 3). The organic layer was concentrated in vacuo to give a yellow solid. The solid was added with THF (5 ml) followed by the addition of NH ₃ (3 ml, 28% wt.) dropwise at -5°C. The reaction mixture was stirred for 2 hours at 0° C. then concentrated in vacuo. The resulting solid was purified by silica gel column chromatography (DCM/MeOH=10/1) to give 5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide (42 mg, 30%) as a yellow solid.

[00995] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.60 (s, 2H), 6.93 (s, 1H), 4.46 (t, J=6.0 Hz, 2H ), 3.87 (t, J=6.4 Hz, 2H), 3.01 (s, 3H).

Stage 4

[00996] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrazine-2-sulfonamide was synthesized as described in Preparation E to give the desired product (21.8 mg, 12%) as a white solid.

[00997] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.70 (s, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 6.82 (s , 1H), 4.39 (t, J=6.0 Hz, 2H), 3.78 (t, J=6.4 Hz, 2H), 3.34 (s, 3H), 2.76 (t , J=7.2 Hz, 4H), 2.64 (t, J=7.2 Hz, 4H), 1.96-1.86 (m, 4H). MS: m/z 430.0 (M+H ⁺ ).

Example 62

[00998] Synthesis of N-((1,2,3,5,6,7-hexahydro-5-indacen-4-yl)carbamoyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5 -a]pyrazine-3-sulfonamide is illustrated below.

Stage 1

[00999] To a solution of 4-nitro-1H-pyrazole-5-carboxylic acid (1.0 g, 6.4 mmol) in MeOH (30 ml) was added TsOH (52 mg, 0.3 mmol). The reaction mixture was then stirred at 65° C. overnight. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=40/1~10/1) to obtain methyl 4-nitro-1H-pyrazole-5-carboxylate (1.0 g, 91%) as a white solid.

[001000] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.90 (s, 1H), 3.88 (s, 3H).

Stage 2

[001001] To a solution of 4-nitro-1H-pyrazole-5-carboxylate (3.0 g, 17.5 mmol) in MeOH (100 ml) was added (Boc) ₂ O (4.2 g, 19.25 mmol) and Pd/C (300 mg, 10% wt.). Then the reaction mixture was stirred at 40°C overnight in an atmosphere of N ₂ and the progress of the reaction was monitored using LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=2/1~1/1) to obtain methyl 4-((tert-butoxycarbonyl)amino)-1H-pyrazole-5-carboxylate (2.52 g, 60%) as a white solid.

Stage 3

[001002] To a solution of methyl 4-((tert-butoxycarbonyl)amino)-1H-pyrazole-5-carboxylate (4.2 g, 17.4 mmol) in DMF (50 ml) was added tert-butyl-(2- bromoethyl) carbamate (5.8 g, 26.1 mmol) and K ₂ CO ₃ (7.2 g, 52.2 mmol). The reaction mixture was then stirred at 80° C. overnight and the progress of the reaction monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=3/1) to give methyl-4-((tert-butoxycarbonyl)amino)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole- 5-carboxylate (1.26 g, 19%) as a yellow oily liquid.

[001003] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.16 (s, 1H), 7.80 (s, 1H), 6.81 (t, J=6.8 Hz, 1H ), 4.40 (t, J=6.4 Hz, 2H), 3.86 (s, 3H), 3.29-3.22 (m, 2H), 1.46 (s, 9H), 1 .33 (s, 9H).

Stage 4

[001004] To a solution of methyl 4-((tert-butoxycarbonyl)amino)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylate (1.26 g, 3.3 mmol) in DCM (20 ml) was added CF ₃ CO ₂ H (2.4 ml, 33 mmol). The reaction mixture was then stirred at room temperature overnight and the progress of the reaction monitored by LCMS. The reaction mixture was concentrated in vacuo. The residue was added to a suspension of DMF (20 ml) and K ₂ CO ₃ (1.36 mg, 9.9 mmol). The reaction mixture was stirred at 80° C. overnight and the progress of the reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1~10/1) to give 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (354 mg, 71 %) as a white solid.

[001005] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.75 (br. s, 1H), 7.00 (s, 1H), 4.68 (br. s, 2H), 4 .08 (d, J=5.6 Hz, 2H), 3.55-3.47 (m, 2H).

Stage 5

[001006] To a suspension of CuCl (0.204 g, 2.1 mmol) in H ₂ O (265 ml) was added SOCl ₂ (44.85 ml, 0.618 mol) dropwise at 0°C with vigorous stirring. The solution was stirred at room temperature overnight to give a light yellow solution. Separately, to a solution of 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (155 mg, 1.02 mmol) in conc. HCl (1 ml) was added dropwise with a solution of NaNO ₂ (84.4 mg. 1.23 mmol) in H ₂ O (2 ml) at -10°C. The resulting dark orange solution was stirred at -10°C for 30 minutes and then added to the above solution (2.65 ml) of copper(I) chloride at -5°C over 5 minutes. The reaction mixture was stirred at -5°C for 1 h and then was extracted with EA (10 ml × 3). The organic layer was concentrated in vacuo to give a yellow solid. The solid was dissolved in THF (5 ml), followed by the addition of NH ₃ (4 ml, 28% wt.) dropwise at 0°C. The reaction mixture was stirred for 2 hours at 0° C. and then concentrated in vacuo. The resulting solid was purified by preparative TLC (DCM/MeOH=10/1) to give 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-sulfonamide (5 mg, 2. 2%) as a yellow solid.

Stage 6

[001007] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-3-sulfonamide was synthesized as described in Preparation E to give the desired product (1.1 mg, 5.8%) as a yellow solid.

[001008] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.64 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 6.87 (s , 1H), 4.38 (d, J=5.6 Hz, 2H), 3.65-3.59 (m, 2H), 2.77 (t, J=6.8 Hz, 4H), 2 .57 (t, J=7.2 Hz, 4H), 1.97-1.87 (m, 4H). MS: m/z 416.1 (M+H ⁺ ).

Example 63

[001009] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazine-3-sulfonamide is illustrated below.

Stage 1

[001010] To a solution of 4-nitro-1H-pyrazole-5-carboxylic acid (1.0 g, 6.4 mmol) and 2-(methylamino)ethanol (0.55 g, 7.3 mmol) in toluene (5 ml) added dropwise SOCl ₂ (20 ml) and DMF (3 drops) at -5°C for 10 min. The reaction mixture was then stirred at 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved in DMF (20 ml) and TEA (2.7 ml, 19.3 mmol). The reaction mixture was then stirred at 60° C. overnight and the progress of the reaction monitored by LCMS. After the solvent was removed in vacuo, the residue was purified by silica gel column chromatography (PE/EA=3/1~1/1) to give 5-methyl-3-nitro-6,7-dihydropyrazolo[1,5-a]pyrazine-4( 5H)-one (0.7 g, 56%) as a yellow solid.

[001011] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.34 (s, 1H), 4.47 (t, J=5.6 Hz, 2H), 3.85 (t, J =6.4 Hz, 2H), 3.05 (s, 3H).

Stage 2

[001012] Powder was added to a solution of 5-methyl-3-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (3.52 g, 18 mmol) in EtOH (75 ml) iron (5.04 g, 90 mmol), NH ₄ Cl (4.82 g, 90 mmol) and H ₂ O (25 ml). The reaction mixture was stirred at 80° C. under N ₂ overnight and the progress of the reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM/MeOH=10/1) to give 3-amino-5-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2.58 g, 86%) as a yellow solid.

[001013] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.01 (s, 1H), 4.76 (s, 2H), 4.16 (t, J=6.0 Hz, 2H ), 3.66 (t, J=6.4 Hz, 2H), 2.94 (s, 3H).

Stage 3

[001014] SOCl ₂ (20 ml) was added dropwise to water (70 ml) at -5°C. The solution was stirred at 5° C. for 1 hour and at room temperature for 1 hour. CuCl (0.16 g) was added to give a yellow solution. Stirred at room temperature for 5 min then cooled to -10°C. Separately, to a solution of 3-amino-5-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (358 mg, 2.2 mmol) in conc. HCl (2.0 ml) was added dropwise with a solution of NaNO ₂ (180 mg, 2.62 mmol) in H ₂ O (1.6 ml) at -10°C. The resulting dark orange solution was stirred at -10°C for 30 minutes and then added to the above solution (5.7 ml) of copper (I) chloride at -5°C for 5 minutes. The reaction mixture was stirred at -5°C for 1 h and then was extracted with EA (5 ml × 3). The organic layer was concentrated in vacuo to give a yellow solid. The solid was dissolved in THF (5 ml), followed by the addition of a solution of NH ₃ (3 ml, 28% wt.) dropwise at -5°C. The reaction mixture was stirred for 2 hours at 0° C. and then concentrated in vacuo. The resulting solid was purified by preparative TLC (DCM/MeOH=10/1) to give 5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-sulfonamide (30 mg, 6%) as a yellow solid.

[001015] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.86 (s, 1H), 7.18 (s, 2H), 4.48 (t, J=6.0 Hz, 2H ), 3.87 (t, J=6.4 Hz, 2H), 3.06 (s, 3H).

Stage 4

[001016] NaH (6.24 mg, 0.156 mmol, 60% dispersion in paraffin oil) in DMSO (2 mL) was stirred at 70°C for 30 minutes. Then 5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-sulfonamide (30 mg, 0.13 mmol) was added to a solution of NaH in DMSO (2 ml) at -5°C and stirred at -5°C for 30 min. Separately, triphosgene (15.4 mg, 0.14 mmol) in THF (5 ml) 0.052 mmol) and TEA (0.1 ml) at -5°C. Then the reaction mixture was stirred at -5°C for 30 min and the progress of the reaction was monitored by TLC. This reagent was filtered off and the filtrate was added to the above suspension of ((5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)sulfonyl)amide at -5°C . The reaction mixture was stirred at room temperature overnight and the progress of the reaction was monitored by LCMS. This reaction mixture was then washed with a saturated solution of aqueous NH ₄ Cl (5 ml × 3). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4-oxo-4,5,6 ,7-tetrahydropyrazolo[1,5-a]pyrazine-3-sulfonamide (12.8 mg, 25%) as a white solid.

[001017] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.27 (br. s, 1H), 7.91 (s, 1H), 6.90 (s, 1H), 4.47 (t, J=5.6 Hz, 2H), 3.83 (t, J=6.0 Hz, 2H), 3.06 (s, 3H), 2.77 (t, J=6.8 Hz , 4H), 2.55 (t, J=7.6 Hz, 4H), 1.99-1.88 (m, 4H). MS: m/z 430.1 (M+H ⁺ ).

Example 64

[001018] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine -3-sulfonamide is illustrated below.

Stage 1

[001019] 1.3 -dibromopropane (26.3 g, 0.1 mmol). After stirring at 110°C for 5 hours, the reaction mixture was filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (DCM/MeOH=100/1) to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (5.3 g, yield: 36%) as a white solid .

[001020] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.18 (s, 1H), 5.26 (s, 1H), 4.22-4.00 (m, 3H), 3.26 -3.22 (m, 2H), 2.11-2.03 (m, 2H).

Stage 2

[001021] NaH (60% in mineral oil, 1, 5 g, 36.6 mmol). The reaction mixture was stirred at room temperature for 1 h under N ₂ . Boc ₂ O (8.0 g, 36.6 mmol) was then added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (60 ml) and extracted with EA (50 ml x2). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH=100/1) to give tert-butyl 6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (4.4 g, yield: 81 %) as a white solid.

[001022] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.37 (s, 1H), 6.28 (s, 1H), 4.21-4.16 (m, 2H), 3.86 -3.80 (m, 2H), 2.20-2.15 (m, 2H), 1.57 (s, 9H). MS: m/z 224.4 (M+H ⁺ ).

Stage 3

[001023] NBS (4.2 g, 23.5 mmol) was added in portions to a solution of tert-butyl 6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (4.4 g, 19 .6 mmol) in MeCN (20 ml) at 0°C and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (40 ml) and extracted with EA (40 ml x2). The organic layer was washed with water (40 ml) and brine (40 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give tert-butyl 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (4.1 g , yield: 69%) as a yellow solid. MS: m/z 304.3 (M+H ⁺ ).

Stage 4

[001024] tert-Butyl 3-((2,4,6-trichlorophenoxy)sulfonyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate was synthesized using Preparation B to give product as a yellow oily liquid which was used in the next step without purification.

Stage 5

[001025] tert-Butyl 3-((2,4,6-trichlorophenoxy)sulfonyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate mixture (crude, ~1.85 mmol), NH ₄ OH (5 ml) and THF (20 ml) were stirred at 60°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The remaining solution was acidified with aq. HCl (1 N) to pH=5 and partitioned between EA (60 ml) and water (60 ml). The organic layer was washed with water (60 ml), brine (60 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give tert-butyl-3-sulfamoyl-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (100 mg, yield : 18% over 2 steps) as a white solid.

[001026] ¹ H NMR (300 MHz, CDCl ₃ ): δ=7.80 (s, 1H), 5.54 (br. s, 2H), 4.23 (t, J=6.3 Hz, 2H ), 3.96 (t, J=6.0 Hz, 2H), 2.23-2.19 (m, 2H), 1.57 (s, 9H). MS: m/z 303.1 (M+H ⁺ ).

Stage 6

[001027] To a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (68.7 mg, 0.397 mmol) and TEA (0.16 ml, 1.2 mmol) in THF (5 ml) triphosgene (47.2 mg, 0.16 mmol) was added. The reaction mixture was stirred for 20 minutes at room temperature. In another round bottom flask, MeONa (23 .6 mg, 0.436 mmol) and the mixture was stirred for 20 minutes at room temperature. The resulting 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene was filtered to remove the resulting precipitate, and the filtrate was added to another flask containing the sulfonamide salt. The reaction mixture was quenched by adding water (30 ml) after 30 minutes. The aqueous phase was extracted with EA (20 ml) and filtered. The filtrate was acidified to pH=3~4 and extracted with EA (20 ml×2) to give t-butyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacene-4- yl)carbamoyl)sulfamoyl)-6,7-dihydropyrazolo[1,5-a]pyrimidine-4(5H)-carboxylate (32 mg, yield: 16%) as a white solid.

Stage 7

[001028] To a solution of tert-butyl-3-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7-dihydropyrazolo[1 ,5-a]pyrimidine-4(5H)-carboxylate (32 mg, 0.064 mmol) in DCM (2 ml) was added TFA (1 ml) and the solution was stirred for 30 minutes at room temperature. The progress of the reaction was monitored by LCMS and the reaction mixture was concentrated to dryness in vacuo. The residue was purified by preparative HPLC (NH ₃ ⋅H ₂ O) to give N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6 ,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-sulfonamide (11.6 mg, yield: 45%) as a white solid.

[001029] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ=8.01 (s, 1H), 7.39 (s, 1H), 6.92 (s, 1H), 6.42 (s , 1H), 3.96 (t, J=5.6 Hz, 2H), 3.25-3.23 (m, 2H), 2.79 (t, J=7.6 Hz, 4H), 2 .60 (t, J=7.2 Hz, 4H), 1.97-1.91 (m, 6H). MS: m/z 402.0 (M+H ⁺ ).

Example 65

[001030] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine Trifluoroacetic acid-2-sulfonamide is illustrated below.

Stage 1

[001031] Conc. H ₂ SO ₄ (2.0 ml). The resulting mixture was stirred at 65°C overnight. The mixture was then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (DCM/MeOH=50/1) to give methyl 3-nitro-1H-pyrazole-5-carboxylate (1.42 g, yield: 83%) as a yellow solid.

[001032] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=15.24 (br. s, 1H), 7.54 (s, 1H), 3.90 (s, 3H).

Stage 2

[001033] To a solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (342 mg, 2.0 mmol) in acetone (40 ml) was added 1,2-dibromethane (412 mg, 2.2 mmol) followed by addition of K ₂ CO ₃ (828 mg, 6.0 mmol). The resulting mixture was stirred at the boil under reflux for 2 hours. Then K ₂ CO ₃ was filtered off. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (DCM/MeOH=50/1) to give methyl 1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (430 mg, yield: 77%) as a yellow solid.

[001034] ¹ H NMR (400 MHz, CDCl ₃ ): δ=7.42 (s, 1H), 5.08 (t, J=6.4 Hz, 2H), 3.97 (s, 3H), 3.78 (t, J=6.4 Hz, 2H).

Stage 3

[001035] To a solution of 1-(2-bromoethyl)-3-nitro-1H-pyrazole-5-carboxylate (278 mg, 1.0 mmol) in dry THF (20 ml) was added LiBH ₄ (2 ml, M in THF) at 0°C. The resulting mixture was stirred from 0°C to room temperature for 3 hours. The reaction mixture was then quenched by the addition of MeOH (4 ml). The mixture was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (DCM/MeOH=100/1) to give (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (122 mg , yield: 49%) as a white solid.

[001036] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=6.99 (s, 1H), 5.69 (t, J=5.6 Hz, 1H), 4.66 (t, J =6.0 Hz, 2H), 4.61 (d, J=5.6 Hz, 2H), 3.91 (t, J=6.4 Hz, 2H).

Stage 4

[001037] [2-(2-Bromo-ethyl)-5-nitro-2H-pyrazol-3-yl]-methanol mixture (3.0 g, 12.0 mmol), PBr ₃ (4.9 g, 18 .0 mmol) and CH ₂ Cl ₂ (50 ml) were stirred at 45°C for 3 hours. The reaction mixture was neutralized with sat. NaHCO ₃ and extracted with CH ₂ Cl ₂ (60 ml) and the combined organic layer washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to dryness to give 1-(2-bromo-ethyl)-5 -bromomethyl-3-nitro-1H-pyrazole (2.2 g, yield: 58%) as a light yellow solid.

[001038] ¹ H NMR (300 MHz, CDCl ₃ ): δ=6.93 (s, 1H), 4.63 (t, J=3.8 Hz, 2H), 4.53 (s, 2H), 3.86 (t, J=4.2 Hz, 2H).

Stage 5

[001039] A mixture of 1-(2-bromo-ethyl)-5-bromomethyl-3-nitro-1H-pyrazole (1.5 g, 4.8 mmol), NH ₃ ⋅H ₂ O (8 ml) and MeOH ( 10 ml) was stirred at 50°C for 16 hours in a sealed tube. The reaction mixture was concentrated to dryness in vacuo to give 2-nitro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (700 mg, yield: 87%) as a white solid.

[001040] MS: m/z 169.0 (M+H ⁺ ).

Stage 6

[001041] 2-nitro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine mixture (700 mg, 4.2 mmol), CbzCl (700 mg, 4.2 mmol), K ₂ CO ₃ (1.2 g, 8.4 mmol) and CH ₃ CN (20 ml) were stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by silica gel column chromatography (PE/EA=5/1 to 1/1) to give 2-nitro-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid benzyl ester (900 mg, yield: 69%) as a yellow solid.

Stage 7

[001042] 2-nitro-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid benzyl ester mixture (710 mg, 2.4 mmol), Fe (658 mg, 11.8 mmol), NH ₄ Cl (637 mg, 11.8 mmol), H ₂ O (10 ml) and EtOH (20 ml) were stirred at 80°C for 16 hours. The reaction mixture was filtered through a pad of celite and washed with CH ₂ Cl ₂ (30 ml). The filtrate solution was concentrated to dryness to give 2-amino-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid benzyl ester (639 mg, yield: 98%) as a yellow oily liquid.

Stage 8

[001043] A solution of benzyl 2-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (639 mg, 2.4 mmol) in MeCN (8 ml) at 0°C was treated conc. HCl (3.0 ml) in H ₂ O (1.2 ml) followed by the addition of an aqueous solution of NaNO ₂ (198 mg, 2.9 mmol) was dissolved in H ₂ O (0.9 ml). The resulting solution was stirred at 0°C for 45 min. AcOH (1.2 ml), CuCl ₂ (162 mg, 1.2 mmol) and CuCl (12 mg, 0.12 mmol) were successively added to the above mixture and SO ₂ gas was purged for 25 min at 0°C. After stirring for 1 h at 0°C, the reaction mixture was poured into ice water (100 ml) and extracted with EA (40 ml×3). The combined organic layer was dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give benzyl 2-(chlorosulfonyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (crude) as yellow oily liquid. This material was used directly in the next step without further purification.

Stage 9

[001044] NH ₃ H ₂ O (3 ml). After stirring at room temperature for 20 minutes, the reaction mixture was concentrated, diluted with MeOH (5 ml) and acidified with aq. HCl (1 N) to pH=5. The resulting solution was purified by reverse phase HPLC (0%-50% MeCN in H ₂ O) to give benzyl 2-sulfamoyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate ( 122 mg, yield: 15%, two steps) as a white solid.

[001045] MS: m/z 337.0 (M+H ⁺ ).

Stage 10

[001046] Benzyl 2-sulfamoyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate solution (102 mg, 0.3 mmol), Boc ₂ O (73 mg, 0.33 mmol) and Pd/C (20 mg) in MeOH (10 ml) was stirred at room temperature in an atmosphere of hydrogen (50 psi) for 16 hours. The reaction mixture was filtered and concentrated to dryness in vacuo. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH=40/1) to give tert-butyl-2-sulfamoyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (106 mg, yield: 96%) as a yellow solid.

[001047] MS: m/z 303.0 (M+H ⁺ ).

Stage 11

[001048] tert-Butyl-2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7-dihydropyrazolo[1,5 -a]pyrazine-5(4H)-carboxylate was synthesized as described in Preparation F to give the desired product (108 mg, crude) as a yellow solid.

[001049] MS: m/z 502.1 (M+H ⁺ ).

Stage 12:

[001050] To a solution of tert-butyl-2-(N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)-6,7-dihydropyrazolo[1 ,5-a]pyrazine-5(4H)-carboxylate (68 mg, crude) in CH ₂ Cl ₂ (1 ml) was added TFA (0.5 ml) and the mixture was stirred at room temperature for 30 minutes. The resulting solution was purified by reverse phase HPLC (0%-50% MeCN in H ₂ O) to give the TFA salt N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl )carbamoyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide (7.9 mg, 15%) as a white solid.

[001051] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.01 (s, 1H), 6.93 (s, 1H), 6.50 (s, 1H), 4.05 (t , J=4.8 Hz, 2H), 3.93 (s, 2H), 3.17 (t, J=5.2 Hz, 2H), 2.79 (t, J=7.2 Hz, 4H ), 2.61 (t, J=7.6 Hz, 4H), 1.99-1.94 (m, 4H). MS: m/z 401.9 (M+H ⁺ ).

Example 66

[001052] Synthesis of H-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5 -a]pyrazine-2-sulfonamide is illustrated below.

Stage 1

[001053] To a solution of tert-butyl-2-sulfamoyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (60 mg, 0.2 mmol) in CH ₂ Cl ₂ (1 ml ) was added TFA (2 ml) and the mixture was stirred at room temperature for 30 minutes. The resulting solution was purified by reverse phase HPLC (0%-50% MeCN in H ₂ O) to give the TFA salt of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide (50 mg, crude) as a brown solid. MS: m/z 202.9 (M+H ⁺ ).

Stage 2

[001054] Formaldehyde (40 mg, 1.3 mmol) and sodium cyanoborohydride (14 mg, 0.2 mmol). After stirring at room temperature for 2 hours. The reaction mixture was concentrated and purified on a reverse phase column (0%-50% MeCN in H ₂ O) to give 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-sulfonamide ( 17 mg, yield: 32% as white solid.

[001055] MS: m/z 217.0 (M+H ⁺ ).

Stage 3:

[001056] N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine-2-sulfonamide was synthesized using Preparation A to give the desired product (9.6 mg, yield: 29%) as a white solid.

[001057] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.80 (s, 1H), 8.02 (s, 1H), 6.94 (s, 1H), 6.55 (s , 1H), 4.16 (t, J=5.6 Hz, 2H), 3.62 (s, 2H), 2.89 (t, J=5.8 Hz, 2H), 2.79 (t , J=7.2 Hz, 4H), 2.60 (t, J=6.8 Hz, 4H), 2.40 (s, 3H), 1.99-1.93 (m, 4H). MS: m/z 416.1 (M+H ⁺ ).

Example 67

[001058] Synthesis of 4,4-difluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyridine-3-sulfonamide is illustrated below.

Stage 1

[001059] I ₂ (58 mg , 0.23 mmol) and propane-1,3-dithiol (276 mg, 2.57 mmol), then the mixture was stirred at room temperature overnight. The reaction mixture was then partitioned between DCM (20 ml) and water (20 ml). The organic layer was separated and the aqueous layer was extracted with DCM (20 ml). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give 3'-bromo-6',7'-dihydro-5'H-spiro[[1,3]dithian-2,4'-pyrazolo[ 1,5-a]pyridine] (530 mg, yield: 75%) as a white solid.

Stage 2

[001060] To a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (1.61 g, 5.6 mmol) in DCM (5 ml) was added HF. .4 ml, 18.6 mmol) and 3'-bromo-6',7'-dihydro-5'H-spiro[[1,3]dithian-2,4'-pyrazolo[1,5-a]pyridine ] (430 mg, 1.4 mmol) at -70°C. After stirring at room temperature for 1 hour, the reaction mixture was partitioned between DCM (20 ml) and water (20 ml). The organic layer was separated and the aqueous layer was extracted with DCM (20 ml). The combined organic layers were combined, washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=5/1) to give 3-bromo-4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (260 mg, yield: 57%) as a yellow oily liquid. MS: m/z 236.9 (M+H ⁺ ).

Stage 3

[001061] To a solution of 3-bromo-4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.26 g, 1.1 mmol) in dry THF (5 mL) slowly added n-BuLi in hexane (0.44 ml, 1.1 mmol, 2.5 M) at -78°C in an atmosphere of N ₂ . After stirring at the same temperature for 20 minutes, ZnCl2 in ether (1.1 ml, 1.1 mmol, 1 M) was slowly added at the same temperature. The ice bath was removed and the reaction mixture was stirred at room temperature. temp. for 1 h. TCPC (0.33 g, 1.1 mmol) was added to the mixture at 0° C. and the mixture was stirred at room temperature. pace. within 1 h. The reaction was extinguished with a saturated solution of NH ₄ Cl (2 ml) and divided between water (20 ml) and EA (20 ml). The organic layer was washed with brine (80 ml), dried over Na ₂ SO ₄ and concentrated to give crude 2,4,6-trichlorophenyl-4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a ]pyridine-3-sulfonate as a yellow oily liquid The crude product was dissolved in THF (5 ml) and NH ₃ .H ₂ O (5 ml) was added to the solution. After stirring at 60°C overnight, the reaction mixture was concentrated to remove the solvent. The residue was acidified with 1 N HCl to pH=5 and partitioned between EA (20 ml) and water (20 ml). The organic layer was separated and the aqueous layer was extracted with EA (20 ml). The combined organic layers were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=2/1) to give 4,4-difluoro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-sulfonamide (50 mg, yield: 19% over 2 steps) as a yellow solid. MS: m/z 238 (M+H ⁺ ).

Stage 4

[001062] 4,4-Difluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4,5,6,7-tetrahydropyrazolo[1, 5-a]pyridine-3-sulfonamide was synthesized using Preparation A to give the desired product (26 mg, yield: 28%) as a white solid.

[001063] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.65 (br s, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 6.93 (s, 1H), 4.28 (t, J=5.6 Hz, 2H), 2.78 (t, J=6.8 Hz, 4H), 2.60 (t, J=6.8 Hz , 4H), 2.50 (overlapped, 2H), 2.20-2.11 (m, 2H), 1.99-1.91 (m, 4H). MS: m/z 437.0 (M+H ⁺ ).

Example 68

[001064] Synthesis of N-((8-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-sulfonamide is illustrated below.

[001065] N-((8-fluoro-1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonamide was synthesized using Preparation A to give the desired product (210 mg, yield: 61%) as a white solid.

[001066] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.51 (br. s, 1H), 7.91 (s, 1H), 7.60 (s, 1H), 4.45 (t, J=5.2 Hz, 2H), 4.11 (t, J=6.4 Hz, 2H), 2.82 (t, J=7.6 Hz, 4H), 2.64 (t , J=6.8 Hz, 4H), 2.22-2.17 (m, 2H), 2.05-1.98 (m, 4H). MS: m/z 421.1 (M+H ⁺ ).

Example 69

[001067] Synthesis of N-((8-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-sulfonamide is illustrated below.

Stage 1

[001068] To a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (1 g, 5.78 mmol) in DCM (20 mL) was added NBS (1.03 g, 5 .78 mmol) at 0°C and the mixture was stirred at 0°C for 2 hours. The reaction mixture was poured into H ₂ O (30 ml) and extracted with EA (50 ml ×2). The combined EA was washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EA=50/1) to give 8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (838 mg, yield: 57% ) as a red solid.

[001069] ¹ H NMR (300 MHz, CDCl ₃ ): δ=3.48 (br. s, 2H), 2.91 (t, J=7.5 Hz, 4H), 2.81 (t, J =6.9 Hz, 4H), 2.19-2.06 (m, 4H).

Stage 2

[001070] To a solution of 8-bromo-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (200 mg, 0.79 mmol) in dioxane (8 ml) and H ₂ O ( 2 ml) was added methylboronic acid (52 mg, 0.87 mmol), K ₂ CO ₃ (327 mg, 2.37 mmol) and Pd(PPh ₃ ) ₄ (45 mg, 0.039 mmol) at room temperature and stirred at 100 °С in N ₂ atmosphere during the night. The reaction mixture was filtered through silica gel and then purified by preparative HPLC (NH ₃ ⋅H ₂ O) to give 8-methyl-1,2,3,5,6,7-hexahydro-s-indacen-4-amine (26 mg , yield: 18%) as a white solid.

Stage 3

[001071] N-((8-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-sulfonamide was synthesized as described in Preparation E to give the desired product (14 mg, yield: 24%) as a white solid.

[001072] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.41 (s, 1H), 7.81 (s, 1H), 7.60 (s, 1H), 4.44 (t , J=4.8 Hz, 2H), 4.11 (t, J=5.6 Hz, 2H), 2.74 (t, J=6.8 Hz, 4H), 2.69-2.58 (m, 4H), 2.21-2.17 (m, 2H), 2.08 (s, 3H), 2.00-1.92 (m, 4H). MS: m/z 417.0 (M+H ⁺ ).

Example 70

[001073] Synthesis of (R)-((4-chloro-2,6-diisopropylphenyl)carbamoyl)((6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-yl)sulfonyl)amide sodium is illustrated below.

Stage 1

[001074] To a solution of 2,6-diisopropyl-phenylamine (2.4 g, 13.5 mmol) in DMF (20 mL) was added NCS (1.9 g, 14.2 mmol) in one portion. After stirring at room temperature for 16 hours, the reaction mixture was poured into water (100 ml) and extracted with EA (50 ml×2). The combined organic layer was washed with brine (50 ml×2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE/EA=50/1) to obtain 4-chloro-2,6-diisopropyl-phenylamine (2.0 g, yield: 70%) as a red oily liquid.

Stage 2

[001075] (R)-((4-chloro-2,6-diisopropylphenyl)carbamoyl)((6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 3-yl)sulfonyl)amide was synthesized as described in Preparation E to give the desired product (50 mg, yield: 51%) as a white solid.

[001076] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.38 (s, 1H), 7.33 (s, 1H), 7.00 (s, 2H), 4.49-4 .45 (m, 1H), 4.18-4.08 (m, 3H), 4.00-3.90 (m, 1H), 3.34 (s, 3H), 3.20-3.05 (m, 2H), 1.05-1.03 (m, 12H). MS: m/z 471.0 (M+H ⁺ ).

Example 71

[001077] Synthesis of N-((8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[001078] N,N-dimethylpyridin-4-amine (0.657 mmol, 0.080 g) was dissolved in THF (1.5 ml) and then a solution of di-tert-butyl dicarbonate (0.626 mmol, 0.144 ml) in THF (1, 5 ml). After stirring for several minutes, a solution of 8-chloro-1,2,3,5,6,7-hexahydro-s-indacene-4-amine (0.626 mmol, 130 mg) in THF (1 ml) was added and the mixture was allowed to stir within 30 min. At the same time, 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (0.626 mmol, 0.145 g) in THF (1 ml) was treated sodium hydride (0.626 mmol, 0.023 g) and allowed to stir for 30 minutes. At the same time, the two solutions were mixed and allowed to stir for 18 hours.

[001079] The reaction mixture was then quenched with sat. NH ₄ Cl (10 ml) and diluted with EtOAc (10 ml). The layers were separated and aq. the layer was extracted with EtOAc (10 ml). The combined organic extracts were then washed with water (10 ml) and concentrated. The resulting solid was suspended in MeOH (5 ml), filtered and purified by preparative HPLC (10-40% MeCN: 10 mM aq. NH4OH). Purified fractions were combined and concentrated to give N-((8-chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6,6-dimethyl-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (4 mg, 1.374%) as a white solid.

[001080] ¹ H-NMR (400 MHz; MeOD): δ 7.68 (s, 1H), 4.08 (s, 2H), 3.86 (s, 3H), 2.90-2.87 ( m, 4H), 2.80-2.76 (m, 4H), 2.09-2.02 (m, 5H), 1.11 (s, 6H). MS: m/z 465.0 (M+H ⁺ ).

Example 72

[001081] Synthesis of N-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 3-sulfonamide is illustrated below.

[001082] 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (100 mg, 0.492 mmol) was dissolved in MeOH (4 ml) at 80°C. Sodium methoxide (0.106 g, 0.492 mmol) was then added and the mixture was stirred for 30 minutes. The solvent was then evaporated and 7-isocyanato-2,2-dimethyl-2,3-dihydrobenzofuran (0.093 g, 0.492 mmol) in MeCN (4 mL) was added and the mixture was left stirring overnight. At the same time the reaction mixture was filtered and filtered and washed with EtOAc and dried to give N-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide (108.5 mg, 56.19%) as a creamy solid. MS: m/z 393 (M+H ⁺ ).

Example 73

[001083] Synthesis of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-methyl-6,7-dihydro-5H-pyrazolo[5,1 -b][1,3]oxazine-3-sulfonamide is illustrated below.

[001084] 2-methyl-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine-3-sulfonamide was prepared in a manner analogous to 6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3-sulfonamide except using the appropriate 3-methyl-3-pyrazolin-5-one as starting material.

[001085] 2-Methyl-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide (80 mg, 0.368 mmol), 4-isocyanato-1,2,3 ,5,6,7-hexahydro-s-indacene (0.073 g, 0.368 mmol) and sodium hydride (13.595 mg, 0.368 mmol) were mixed in DMF (5 ml) and left to stir overnight. The reaction mixture was then quenched with water and the white solid was filtered off. The filtrate was concentrated and the residue was suspended in acetone (10 ml), filtered and washed with acetone to dryness, yielding N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2 -methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (51.4 mg, 33.51%) as a light brown solid. MS: m/z 417 (M+H ⁺ ).

Example 74

[001086] The synthesis of N-((4-cyano-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[001087] To a solution of 4-amino-3,5-diisopropylbenzonitrile (300 mg, 1.48 mmol) in anhydrous THF (10 ml) was added Et3N (0.41 ml, 2.97 mmol) followed by triphosgene (220 mg , 0.74 mmol) at room. pace. The reaction mixture was heated at 60°C for 1 h before cooling to room. pace. and partitioned between EtOAc (30 ml) and water (20 ml). The aqueous phase was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with water (20 ml), brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield a yellow solid (210 mg, 62%).

[001088] The solid (100 mg, 0.44 mmol) was dissolved in anhydrous DMF (1 mL). To this solution was added 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (90 mg, 0.44 mmol) followed by addition of NaH (60% in mineral oil, 17 mg, 0.44 mmol) at room. pace. The reaction mixture was stirred for 1 h before the addition of MeOH (3 ml). The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (MeOH/DCM 0 to 5%) to give N-((4-cyano-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide (36.3 mg, 19%) as a white solid. MS: m/z 432 (M+H ⁺ ).

Example 75

[001089] The synthesis of N-((4-chloro-2,6-dicyclopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

[001090] To a solution of 4-chloro-2,6-dicyclopropaniline (180 mg, 0.87 mmol) in anhydrous THF (10 mL) was added Et3N (0.24 mL, 1.73 mmol) followed by triphosgene (130 mg , 0.43 mmol) at room. pace. The reaction mixture was heated at 60°C for 1 h before cooling to room. temp, and divided between EtOAc (30 ml) and water (20 ml). The aqueous phase was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with water (20 ml), brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield a light yellow solid (170 mg, 84%).

[001091] The solids (100 mg, 0.49 mmol) were dissolved in anhydrous DMF (1 mL). To this solution was added 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (115 mg, 0.49 mmol) followed by addition of NaH (60% in mineral oil, 20 mg, 0.49 mmol) at room. pace. The reaction mixture was stirred at rt. pace. for 1 h before the addition of MeOH (3 ml). The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography (MeOH/DCM 0 to 5%) to give N-((4-chloro-2,6-dicyclopropylphenyl)carbamoyl)-6,7-dihydro-5H -pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (37.7 mg, 17%) as a white solid. MS: m/z 437 (M+H ⁺ ).

Example 76

[001092] Synthesis of N-((3,5-dicyclopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

[001093] To a solution of 3,5-dicyclopropylaniline (200 mg, 1.15 mmol) in anhydrous THF (10 ml) was added Et ₃ N (0.27 ml, 2.0 mmol) followed by the addition of triphosgene (120 mg, 0 .39 mmol) at room. pace. The reaction mixture was stirred for 2 hours to remove the THF. The resulting residue was suspended in a mixture of hexanes (50 ml), insoluble solids were removed by vacuum filtration, and the mixture of hexanes was removed under reduced pressure to yield a clear oily liquid.

[001094] The resulting oily liquid was then dissolved in anhydrous DMF (2 ml). To this solution was added 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (80 mg, 0.39 mmol) followed by NaH (60% in mineral oil, 20 mg, 0.49 mmol) at room. pace. The reaction mixture was stirred for 1 hour before MeOH (5 ml) was added. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography (MeOH/DCM 0 to 10%) to give N-((3,5-dicyclopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazine-3-sulfonamide (90 mg, 57%) as a white solid. MS: m/z 403 (M+H ⁺ ).

Example 77

[001095] Synthesis of N-((7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazine-3-sulfonamide is illustrated below.

[001096] Et ₃ N (0.17 ml, 1.2 mmol) followed by the addition of triphosgene (60 mg, 0.20 mmol) at room. pace. The reaction mixture was heated at 60°C for 1 h before cooling to room. pace. and partitioned between EtOAc (30 ml) and water (20 ml). The aqueous phase was extracted with EtOAc (2×10 ml). The combined organic extracts were washed with water (20 ml), brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield a yellow oily liquid.

[001097] The resulting oily liquid was then dissolved in anhydrous DMF (1 ml). To this solution was added 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (50 mg, 0.25 mmol) followed by addition of NaH (60% in mineral oil, 16 mg, 0.41 mmol) at room. pace. The reaction mixture was stirred for 1 hour before MeOH (5 ml) was added. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (MeOH/DCM 0 to 10%) to give N-((7-chloro-5-cyclopropyl-2,3-dihydro-1H-inden-4- yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (60 mg, 57%) as a light yellow substance. MS: m/z 437 (M+H ⁺ ).

Example 78

[001098] Synthesis of N-((1,2,3,4-tetrahydroacridin-9-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- sulfonamide is illustrated below.

[001099] Et ₃ N (0.17 ml, 1.2 mmol) was added to a solution of 1,2,3,4-tetrahydroacridine-9-amine (200 mg, 1.01 mmol) in anhydrous THF (10 ml) with subsequent addition of triphosgene (150 mg, 0.49 mmol) at room. pace. The reaction mixture was heated at 60°C for 2 hours before cooling to room. pace. Removed THF and the resulting residue was suspended in a mixture of hexanes (50 ml), insoluble solids were removed by vacuum filtration and the mixture of hexanes was removed under reduced pressure to yield a yellow oily liquid.

[001100] The resulting oily liquid was then dissolved in anhydrous DMF (1 ml). To this solution was added 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (50 mg, 0.25 mmol) followed by addition of NaH (60% in mineral oil, 20 mg, 0.49 mmol) at room. pace. The reaction mixture was stirred for 1 h before the addition of Meon (1 ml). The residue was purified by preparative HPLC (MeCN/water/0.1% formic acid) to give N-((1,2,3,4-tetrahydroacridin-9-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo [5,1-b][1,3]oxazine-3-sulfonamide (1.8 mg, 2%) as solids. MS: m/z 428 (M+H ⁺ ).

Example 79

[001101] Synthesis of ((6-(aminomethyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)((1,2,3,5 ,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sodium amide and ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6- Sodium ((2,2,2-trifluoroacetamido)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide is illustrated below.

Stage 1:

[001102] (6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methanamine (crude, ~1.2 mmol) was dissolved in TFAA (3 mL). The solution was then heated at reflux for 3 hours, quenched by addition of EA (20 ml) and water (10 ml). The organic layer was separated. The aqueous layer was extracted with EA (10 ml×3). The organic layers were mixed and washed with brine (10 ml) and dried over anhydrous Na ₂ SO ₄ . The solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=1/1) to give N-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl) -2,2,2-trifluoroacetamide (140 mg, yield: 47%) as a yellow solid. MS: m/z 250.2 (M+H ⁺ ).

Stage 2:

[001103] To a solution of N-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)-2,2,2-trifluoroacetamide (140 mg, 0.56 mmol) in DCM (3 ml) was added dropwise ClSO ₃ H (0.11 ml, 1.68 mmol) at 0°C. After stirring at room temperature for 16 hours, pyridine (0.14 ml, 1.68 mmol) was added dropwise at 0°C and then PCl ₅ (350 mg, 1.68 mmol) was added in portions at 0°C. the mixture was stirred at room temperature for 1 h, poured into ice water (2 ml) and extracted with EA (10 ml×3). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to give a crude product which was used directly in the next step without further purification.

Stage 3:

[001104] To a solution of 6-((2,2,2-trifluoroacetamido)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride (crude, ~ 0.56 mmol) in THF (3 ml) was added NH ₃ .H ₂ O (3 ml). After stirring at 60°C for 2 hours, the reaction mixture was concentrated to about 1 ml. The remaining suspension was acidified with 1 M aq. HCl to pH=3 and filtered. The filtrate was purified using a reverse phase column (MeCN/H ₂ O) to give 2,2,2-trifluoro-N-((3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazin-6-yl)methyl)acetamide (120 mg, yield: 65%) as a yellow solid.

[001105] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.58 (s, 1H), 4.51 (dd, J=11.2, 2.8 Hz, 1H), 4.32 -4.23 (m, 2H), 3.96 (dd, J=12.4, 3.2 Hz, 1H), 3.44 (d, J=7.2 Hz, 2H), 2.73- 2.64 (m, 1H).

Stage 4:

[001106] To a suspension of N-((3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)methyl)acetamide (60 mg, 0.18 mmol) in DMSO (2 ml) was added MeONa (10.7 mg, 0.2 mmol) and the mixture was stirred at room temperature for 20 min to obtain a suspension of the sodium salt. In another flask to a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (38 mg, 0.22 mmol) and TEA (54 mg, 0.54 mmol) in THF (2 ml) triphosgene (24 mg, 0.80 mmol) was added in one portion and the mixture was stirred at room temperature under N ₂ for 20 min. The reaction mixture was then filtered. The filtrate was added to the above sodium salt suspension and stirred at room temperature for 16 hours. After this suspension was filtered, the filtrate was purified using a reverse phase column (MeCN/H ₂ O) to obtain ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)(( 6-((2,2,2-trifluoroacetamido)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium (44 mg, yield: 44%) as a white solid.

[001107] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=9.69 (t, J=5.6 Hz, 1H), 7.53 (br. s, 1H), 7.41 (s , 1H), 6.80 (s, 1H), 4.37 (dd, J=10.8, 2.8 Hz, 1H), 4.19-4.11 (m, 2H), 3.88 ( dd, J=12.0, 7.6 Hz, 1H), 3.30-3.25 (m, 2H), 2.75 (t, J=7.2 Hz, 4H), 2.66-2 .59 (m, 5H), 1.95-1.85 (m, 4H). MS: m/z 528.1 (M+H ⁺ ).

Stage 5:

[001108] To a solution of ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((6-((2,2,2-trifluoroacetamido)methyl)-6, 7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide sodium (7 mg, 0.01 mmol) in DMSO (1 ml) was added aqueous NaOH (0. 5 ml, 1 mmol, 2 M) and the mixture was stirred at room temperature for 48 hours. After that, the suspension was filtered and the filtrate was purified using a reverse phase column (MeCN/H ₂ O) to obtain ((6-(aminomethyl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3 ]oxazin-3-yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide (4.9 mg, yield: 84%) as white solid.

[001109] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.45 (br s, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 4.37 (dd, J=10.8, 3.2 Hz, 1H), 4.13-4.02 (m, 2H), 3.82 (dd, J=12.4, 8.0 Hz, 1H), 2.74 (t, J=6.8 Hz, 4H), 2.68-2.57 (m, 6H), 2.30-2.12 (m, 1H), 1.94-1.85 ( m, 4H). MS: m/z 432.1 (M+H ⁺ ).

Example 80

[001110] Synthesis of (R)-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)((6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine -3-yl)sulfonyl)amide is illustrated below.

Stage 1

[001111] To a solution of 2,6-dibromo-4-fluoroaniline (2.0 g, 7.4 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)- 1,3,2-dioxaborolane (3.37 g, 20.1 mmol), Cs ₂ CO ₃ (7.23 g, 22.2 mmol) and H ₂ O (4 ml) in dioxane (40 ml) were added Pd (dppf)Cl ₂ (0.54 g, 0.74 mmol) in N ₂ . The reaction mixture was stirred at 100° C. overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=10/1) to give 4-fluoro-2,6-di(prop-1-en-2-yl)aniline (1.10 g, 78%) as a brown oily liquid.

[001112] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=6.72 (d, J=9.6 Hz, 2H), 5.29 (t, J=1.6 Hz, 2H), 5.01 (d, J=1.2 Hz, 2H), 4.24 (s, 2H), 2.01 (s, 6H).

Stage 2

[001113] Pd/C (0. 11 g, 10% wt.). The reaction mixture was degassed and passed H ₂ three times. Stirred at room temperature overnight under H ₂ from a balloon and the progress of the reaction was monitored by LCMS. The mixture was filtered. The filtrate was concentrated in vacuo to give 4-fluoro-2,6-diisopropylaniline (1.05 g, 94%) as a brown oil.

[001114] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=6.67 (d, J=10.0 Hz, 2H), 4.44 (br. s, 2H), 3.07-3 .01 (m, 2H), 1.16-1.10 (m, 12H).

Stage 3

[001115] To a solution of (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (55 mg, 0.25 mmol) in THF (5 ml) was added MeONa (15 mg, 0.28 mmol) at -5°C. The reaction mixture was then stirred at -5°C for 30 minutes. Separately, to a solution of 4-fluoro-2,6-diisopropylaniline (45 mg, 0.23 mmol) in THF (5 ml) was added triphosgene (27 mg, 0.092 mmol) and TEA (47 mg, 0.46 mmol) at - 5°C. The reaction mixture was then stirred at -5°C for 30 minutes. The indicated reagent was filtered and to a suspension of (R)-((6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)sulfonyl)amide from the first stage added the filtrate at -5°C. The reaction mixture was stirred at room temperature overnight. After removal of the solvent in vacuo, the residue was purified by preparative HPLC to give (R)-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)((6-methoxy-6,7-dihydro-5H-pyrazolo[5.1 -b][1,3]oxazin-3-yl)sulfonyl)amide sodium (28.2 mg, 27%) as a white solid.

[001116] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.65 (s, 1H), 7.57 (s, 1H), 6.91 (d, J=9.6 Hz, 2H ), 4.63 (d, J=11.6 Hz, 1H), 4.31 (d, J=11.6 Hz, 1H), 4.22 (d, J=1.6 Hz, 2H), 4.06 (s, 1H), 3.36 (s, 3H), 2.96-2.86 (m, 2H), 1.05 (s, 12H). MS: m/z 455.1 (M+H ⁺ ).

Example 81

[001117] Synthesis of (R)-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)((6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazin-3-yl)sulfonyl)amide sodium

Stage 1

[001118] To a solution of (R)-tert-butyl-methyl(3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate (375 mg , 1.13 mmol) in THF (10 ml) was added MeONa (165 mg, 3.06 mmol) at -5°C. The reaction mixture was then stirred at -5°C for 30 minutes. Separately, to a solution of 4-fluoro-2,6-diisopropylaniline (200 mg, 1.02 mmol) in THF (5 ml) was added triphosgene (121 mg, 0.41 mmol) and TEA (0.28 ml, 2.04 mmol) at -5°C. Then the reaction mixture was stirred at -5°C for 30 min and the progress of the reaction was monitored by TLC. This reagent was filtered off and the filtrate was added at -5°C to a suspension of (R)-((6-((tert-butoxycarbonyl)(methyl)amino)-6,7-dihydro-5H-pyrazolo[5,1-b][ 1,3]oxazin-3-yl)sulfonyl)amide sodium from the first stage. The reaction mixture was stirred at room temperature overnight. After removal of the solvent in vacuo, the residue was purified by flash column chromatography to give (R)-tert-butyl-(3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (237 mg, 43%) as a yellow solid.

Stage 2

[001119] To a solution of (R)-tert-butyl-(3-(N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)sulfamoyl)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-6-yl)(methyl)carbamate (100 mg, 0.18 mmol) in DCM (2 ml) was added CF ₃ CO ₂ H (5 ml). The reaction mixture was then stirred at room temperature for 20 minutes. The mixture was podslushivaet 4 M aqueous NaOH to pH=12 at -5°C. The aqueous layer was concentrated in vacuo. The residue was purified by flash column chromatography to give (R)-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)((6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazin-3-yl)sulfonyl)amide sodium (23.6 mg, 23%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ=7.67 (s, 1H), 7.57 (s, 1H), 6.92 (d, J=10.0 Hz, 2H), 4 .40-4.28 (m, 2H), 4.22 (dd, J=12.4, 4.4 Hz, 1H), 3.94 (dd, J=12.8, 4.4 Hz, 1H ), 3.21-3.16 (m, 1H), 2.95-2.85 (m, 2H), 2.34 (s, 3H) 1.09-1.00 (m, 12H). MS: m/z 454.2 (M+H+). Example 82

[001120] The synthesis of N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide is illustrated below.

Stage 1

[001121] MeONa (73 mg, 1.35 mmol) and DMSO (1 ml) at -5°C. The reaction mixture was then stirred at -5°C for 30 minutes. Separately, to a solution of 4-fluoro-2,6-diisopropylaniline (100 mg, 0.45 mmol) in THF (5 ml) was added triphosgene (53 mg, 0.18 mmol) and TEA (0.13 ml, 0.90 mmol) at -5°C. The reaction mixture was then stirred at -5°C for 30 minutes. This reagent was filtered off and the filtrate was added at -5°C to the suspension of ((6,7-dihydro-5H-pyrazolo[5,1-6][1,3]oxazin-3-yl)sulfonyl)amide from the first stage. The reaction mixture was stirred at room temperature overnight. After removal of the solvent in vacuo, the residue was purified by preparative HPLC to give N-((4-fluoro-2,6-diisopropylphenyl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazine-3-sulfonamide (103.5 mg, 54%) as a white solid.

[001122] ¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.52 (br. s, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 6.89 (d, J=10.0 Hz, 2H), 4.39 (t, J=4.8 Hz, 2H), 4.08 (t, J=6.4 Hz, 2H), 3.00-2 .90 (m, 2H), 2.24-2.14 (m, 2H), 1.04 (s, 12H). MS: m/z 424.8 (M+H ⁺ ).

Biological research methods Symbols

PBMC: peripheral blood mononuclear cells

KC: Kupffer cells

FBS: fetal bovine serum

LPS: lipopolysaccharides

NLRP3 activation and inhibition assays

[001123] Some of the following assays were used to determine the inhibitory activity of compounds on the NLRP3 inflammasome using the common inflammasome activation stimulant, nigericin.

Biological example 1: Cell culture

[001124] Fresh human peripheral blood mononuclear cells (PBMCs), consisting of lymphocytes (T, B and NK cells), monocytes and dendritic cells, were isolated from human peripheral blood from healthy donors. The cells were obtained through the IRB-approved donor program iXCells Biotechnologies, where all donors were tested for bacterial and viral infections. Cells were purified from peripheral blood using Ficoll gradient centrifugation.

[001125] Human Kupffer cells (KC), specialized liver macrophages residing in the space of Disse, were obtained by gradient isolation from liver samples collected posthumously by Samsara Sciences. The cells were obtained through the IRB-approved Samsara Sciences donor program, and all donors tested negative for bacterial and viral infections.

Biological Example 2: NLRP3 Inflammasome Activation Assays

[001126] Fresh or cryopreserved PBMCs were plated in a 96-well V-bottomed plate at 0.5-1x10 ⁵ cells per well and incubated overnight at 37°C with 5% CO ₂ in RPMI 1640 supplemented with GlutaMAX, 4.5 g/L D-glucose, 10% fetal bovine serum (FBS), 100 mM sodium pyruvate, 1% penicillin/streptomycin, 10 mM HEPES, and 0.05 mM β-mercaptoethanol. Freshly isolated or cryopreserved SC cells were seeded in 96-well flat bottom plates at 0.6-1.5×10 ⁵ cells/well and incubated overnight at 37°C, 5% CO ₂ in RPMI 1640 medium supplemented with GlutaMAX, FBS, 1% Penicillin/Streptomycin and 10 mM HEPES. The next day, cells were primed with 100 ng/ml lipopolysaccharides (LPS; Sigma Aldrich) in RPMI 1640 without FBS for 3 hours. After the priming step, medium was removed and PBMCs were pre-incubated with serial concentrations of test compounds (0.00017-10 μM) or carrier medium (DMSO) for 30 min in FBS-free medium before adding NLRP3 activator. The cells were then stimulated with 10 μM nigericin (Sigma Aldrich; InvivoGen) for 1.5 hours. The plates were centrifuged at 1500 rpm for 3 minutes to pellet the cells and the supernatant was transferred to new plates for subsequent experiments.

Measurement of cytokines/assessment of NLRP3 inflammasome activity

[001127] For ELISA assays, cells were seeded in 96-well plates. After the study, the supernatants were removed and the levels of mature IL-1β, IL 18 and TNFα (Quantikine ELISA systems, R&D) were measured in cell-conditioned medium by ELISA according to the manufacturer's instructions.

results

[001128] The results of some compounds are shown below.

Biological Example 3: CTG Assay (CellTitre-Glo)

[001129] Viability of compound-treated cells is measured using the CellTiter-Glo® assay (Promega, Madison, Wisconsin), which measures the ATP content of the cells, which is proportional to the number of live cells per well. This was a drug selectivity and specificity study to establish that the decrease in IL-1β levels in cells stimulated with LPS and nigericin and treated with the compounds is not due to cytotoxicity, but rather due to inhibition of the inflammasome pathway. Compounds that inhibit NRLP3 inflammasome activation ultimately increase the viability of LPS and nigericin-stimulated cells by blocking NLRP3-mediated pyroptosis, which would otherwise lead to cell lysis.

Biological example 4: TNF-α

[001130] TNFα levels in cells stimulated with LPS and nigericin are measured by the HTRF method (Cisbio, Bedford, MA). The selective pathways of the compound's inflammatory pathway do not inhibit TNFα production, which depends solely on LPS stimulation and proceeds along the TLR4/NFkB pathway. The measurement of TNF-alpha production also serves as a technical study of drug selectivity and specificity to eliminate compounds that interfere with HTRF reagents. Thus, compounds that inhibit both IL-1β and TNFα levels have been tested to either be insensitive to inflammasomes or interfere with HTRF reading.

Additional tests

[001131] Some of the following assays were used.

Biological example 5: Stability of human microsomes (Eh)

[001132] Test article and positive control stock solutions were prepared at a concentration of 10 mM using DMSO as diluents. All stock solutions were then diluted to working concentrations at 0.25 mM with 70% acetonitrile. The cofactor used in this study was the NADPH regenerating system, consisting of 6.5 mM NADP, 16.5 mM G-6-P, 3 U/ml G-6-PD. The quenching agent consisted of acetonitrile containing tolbutamide and propranolol (serving as an internal standard). The incubation mixes contain 0.5 mg/ml liver microsomal protein and 1 µM test device/positive control in 100 mM potassium phosphate buffer.

[001133] 0-minute samples were prepared by adding an 80 µl aliquot of each incubation mixture to 300 µl of quench reagent to precipitate proteins. Samples were shaken and then a 20 μl aliquot of NADPH regenerating system was added. The reaction mixture was initiated by adding 80 μl of NADPH regeneration system to 320 μl of each incubation mixture. The final incubation conditions are reached in 400 µl: 0.5 mg/ml microsomal protein, 1 µM test device/positive control, 1.3 mM NADP, 3.3 mM glucose-6-phosphate, 0.6 U/ml glucose- 6-phosphate dehydrogenase. The mixtures were incubated in a water bath at 37°C with gentle shaking. An aliquot of 100 µl of each mixture was removed after 10, 30, 90 minutes on a clean 96-well plate that contained 300 µl of quench reagent to precipitate proteins and centrifuged (4000 × g, 10 min). 80 µl of the supernatant was withdrawn into 96-well assay plates pre-filled with 160 µl of ultrapure water and then analyzed by LC-MS/MS. is 20.7 ml / min / kg. Eh values<0.3 indicate compounds with favorable metabolic stability.

Biological example 6: Lipophilicity:

[001134] Lipophilicity reported by logD was calculated using ChemAxon's LogD plugin for some compounds, as shown in the table below.

[001135] In recent years, many publications have been published that link the clinical success of drug candidates with their physical qualities. For example, the degree of lipophilicity may be a factor in the success of drug candidates. In "Lipophilicity in Drug Discovery" (Waring, Expert Opinion on Drug Discovery Volume 5, 2010 - Issue 3 pp. 235-248, which is incorporated herein by reference), the author's analysis showed that the optimal lipophilicity for small molecule drugs, measured with using logD, is somewhere between 1 and 3. Design connections outside this range can lead to unintended commitments (i.e. ADMET, promiscuous). Care should be taken when adding non-polar atoms during major drug discovery optimization to identify quality molecules that can successfully advance in clinical trials.

[001136] For example, pyrazolo-oxazine described herein may offer advantages in terms of lipophilicity. For example, compared to an analog with a similar number of non-polar atoms, a cyclic saturated ring saves ~0.7 log units of clogD.

[001137] In addition, the oxazine ring also offers a backbone with a polar atom, resulting in a clogD of 1.8. This may allow further development with other substituents, such as non-polar substituents, without going beyond the ideal range described herein.

results

[001138] The results of some compounds are shown below and in FIG. 1 and 2. PBMC IL-1β IC50 and KC IL-1β IC50 are described above. A<100 nM, B 100 nM - 1 μM, C 1 - 10 μM, D>10 μM

Biological Example 7: Effect of Treatment on Cytokine Production Following LPS/ATP Injection in C57BL/6 Mice

Short description:

[001139] The therapeutic effect of compounds 1 and 2 on NLRP3-dependent release of IL-1β and TNFα cytokines was studied in an in vivo LPS/ATP model under study. Peritoneal lavage levels of IL-1β in LPS plus ATP-treated mice were >98% reduced compared to vehicle-treated animals after single oral administration of Compound 1 at 1.5 and 5 mg/kg and Compound 2 at a dose of 1 and 2 5 mg/kg at 3.5 hours. IL-1β release was reduced >79% at 0.5 mg/kg Compound 1 and >57% at 0.25 mg/kg Compound 2 after a single oral dose at 3.5 hours relative to vehicle treated animals. There were no significant changes in TNFα levels in either group compared to vehicle treated animals.

Research objectives:

[001140] The purpose of this study was to determine the effect of treatment with compounds 1 and 2 on the production of cytokines after injection of LPS/ATP in female C57BL/6 mice.

Experimental plan and methods:

[001141] The main parameters of the study are shown in Table 1.

[001142] Mice were acclimatized at the facility at least 7 days before the start of the study.

[001143] On Day-1, mice were weighed and grouped in Table 2 (see below) in a balanced manner to achieve the same average group weight at baseline.

[001144] All mice received a single dose of treatment or vehicle per hour minus 1.

[001145] At hour 0, all mice were intraperitoneally injected with 1 μg of ultrapure lipopolysaccharide (LPS, InvivoGen, San Diego, CA) in 0.5 ml of PBS.

[001146] At 2 hours (two hours after LPS injection), all mice were intraperitoneally injected with 0.5 ml of 80 mm ATP disodium salt (Sigma, pH adjusted to 7.2 before injection).

[001147] At 2.5 hours (30 minutes after ATP administration and 3.5 hours after compound administration), blood from all mice was collected by retroorbital bleeding into K2 EDTA tubes and plasma was prepared and stored at 80°C. Samples were sent to the customer or customer's supplier, selected within 7 days of completion of the study.

[001148] Immediately after blood sampling, each mouse was euthanized, the abdomen was flushed with 3 ml ice-cold PBS containing 25 U/ml heparin sodium, a protease inhibitor cocktail (complete™ ULTRA tablets, Sigma, Roche) and 10% FBS. Approximately 1 ml of lavage was collected, centrifuged to remove cells and the supernatant was stored at -80°C.

[001149] The vehicle for compound 1 was PBS and for compound 2 0.5% methylcellulose was used. Compound powders were stored at 4°C. All compounds were already obtained. The compounds were weighed and first ground with a mortar and pestle, then ground with a small amount of carrier medium. The solution was then washed several times with carrier medium to remove all material and achieve the correct concentration. The final solution was shaken to create a homogeneous mixture.

Analysis for cytokines:

[001150] Murine IL-1β and TNFα concentrations in peritoneal lavage samples were determined using the Becton Dickinson CBA assay kit (Franklin Lake, NJ) according to the manufacturer's protocol. One analysis was performed on each sample.

Statistical analysis:

[001151] Cytokine concentrations were compared using Student's t-test.

Results:

[001152] The effect of Compound 1 and Compound 2 treatment on IL-1β cytokine production was evaluated in an LPS/ATP injection model. Female C57BL/6 mice were orally administered either Compound 1 at 0.5, 1.5 and 5 mg/kg or Compound 2 at 0.25, 1 and 2.5 mg/kg and relative amounts of IL-1β (pg/ml ) was determined using the Becton Dickinson CBA assay kit. Peritoneal lavage levels of IL-1β in LPS plus ATP treated mice were >98% reduced compared to vehicle treated animals after single oral administration of Compound 1 at 1.5 and 5 mg/kg and Compound 2 at dose 1 and 2 5 mg/kg at time 3.5 hours (Tables 3 and 4, Fig. 3).

[001153] IL-1β release was reduced >79% at 0.5 mg/kg Compound 1 and >57% at 0.25 mg/kg Compound 2 after a single oral dose at 3.5 hours relative to vehicle treated animals environment. There were no significant changes in TNFα levels in either group compared to vehicle treated animals (Tables 3 and 4, Fig. 4).

[001154] The effect of Compound 3 treatment on IL-1β cytokine production was evaluated in an LPS/ATP injection model. Compound 3 was orally administered to female C57BL/6 mice at doses of 0.25, 1 and 2.5 mg/kg and relative amounts of IL-1β (pg/ml) were determined using the Becton Dickinson CBA assay kit. Peritoneal lavage levels of IL-1β in LPS plus ATP treated mice were >96% reduced compared to vehicle treated animals after a single oral dose of Compound 2 at 1 and 2.5 mg/kg at time 3 .5 hours (Tables 5, Fig. 5).

Conclusions:

[001155] The effect of treatment with Compound 1 and Compound 2 on NLRP3-dependent release of the cytokine IL-1β was investigated in an in vivo LPS/ATP model under investigation. Peritoneal lavage levels of IL-1β in LPS plus ATP treated mice were >98% reduced compared to vehicle treated animals after single oral administration of Compound 1 at 1.5 and 5 mg/kg and Compound 2 at dose of 1 and 2.5 mg/kg at 3.5 hours. IL-1β release was reduced >79% at 0.5 mg/kg Compound 1 and >57% at 0.25 mg/kg Compound 2 after a single oral dose at 3.5 hours relative to vehicle treated animals. There were no significant changes in TNFα levels in any of the groups compared to vehicle treated animals.

Biological Example 8 Inhibition of Caspase-1 Activity

Materials and methods

cell culture

[001156] Bone marrow cells were harvested from freshly harvested mouse bones from 16 Black 6 mice, 4 bones each (2 shins and 2 thighs). Bones were delivered fresh in complete BMDM medium: RPMI 1640 medium, GlutaMAX™ supplement, 1% essential amino acids, 1% penicillin/streptomycin, 10 mM HEPES, 0.05 mM β-ME, 20 ng/mL GM-CSF, and 10% FBS. The top and bottom were cut off with scissors and a 25G needle was used to thoroughly wash the cells from each bone with complete BMDM medium. The cells were passed through a 100 µm sieve before centrifugation at 250G. CD14 ⁺ cells were isolated by magnetic negative screening using the EasySep Mouse Monocyte Isolation Kit (StemCell Technologies) according to the manufacturer's instructions. Approximately 2 ml of cells were subjected to 3 independent purification procedures. The total number of cells was approximately 12.7 million. CD14 ⁺ cells were seeded into 96-well plates at 25,000 cells/well. The complete BMDM medium was changed every 3 days. The experiments were carried out on the 9th day after sowing. Inflammasome activation

[001157] Bone marrow-derived macrophages (BMDM) were pre-incubated with DMSO or compounds at the indicated concentrations for 30 minutes, after which they were stimulated with LPS at 100 ng/ml. Cells were incubated at 37°C in an atmosphere of 5% CO ₂ for 3 hours. The cells were then stimulated with 10 μM nigericin and incubated at 37° C., 5% CO ₂ for 90 minutes. At the end of the incubation period, supernatants were collected and analyzed for cytokines. Cells were either harvested for Western blot analysis or tested for viability using CellTiter-Glo (Promega). Western blotting

[001158] Cell samples from 96-well plates were prepared by in situ cell lysis with 50 μl of 4x NuPAGE LDS sample buffer (Fisher) + 5% β-mercaptoethanol. The plates were placed on a shaker plate at 700 rpm for one hour and then sonicated for 10 minutes. Cell lysates were transferred to a PCR plate and heated to 95°C for 5 min. Samples were processed on NuPAGE bis-Tris gels (Fisher) and transferred to PVDF membranes using the iBlot 2 system (Fisher). The PVDF membranes were blocked in Azure Blot Wash Buffer (Azure Biosystems) + 5% low fat milk powder for less than 5 minutes. The membranes were tested with the following primary antibodies: pro-caspase-1+p10+p12 [EPR16883] (Abeam), β-actin (Sigma), NLRP3 [Cryo-2] (Adipogen). All antibody incubations were performed in Azure Blot wash buffer + 5% skimmed milk powder. Secondary antibodies were purchased from Azure Biosystems. The membranes were washed for at least 3×5 minutes after each antibody incubation with Azure Blot wash buffer. The membranes were visualized using Azure C300 (Azure Biosystems)

results

Western blotting

[001159] Stimulation of BMDM with LPS followed by the addition of nigericin results in the activation of the NLRP3 inflammasome, which in turn initiates the activation of pro-caspase-1. During autocatalytic cleavage, pro-caspase p45 is cleaved into p10 and p20 fragments. The decrease in the intensity of the p45 band and the appearance of the p10 band on the attached Western blots indicate successful activation of pro-caspase-1 upon stimulation with LPS and nigericin. In the presence of 10 μm of Compounds 1, 4 and 2, pro-caspase-1 activation is blocked, as indicated by intact p45 bands and the absence of p10 bands (FIG. 6). Biological Example 9: Pharmacokinetics in mice

[001160] Solutions for intravenous administration were administered at a dose of 1 mg/kg and prepared by dissolving the study device in the preparations shown below. Suspensions or solutions for oral dosing were administered at a dose of 10 mg/kg and were prepared by dissolving the study device in the preparations shown below. Blood samples were collected in tubes containing either K2EDTA or sodium heparin and kept refrigerated on ice block or wet ice immediately after collection and during processing. After centrifugation, the resulting plasma samples were stored in a freezer at -80°C until analysis. Pharmacokinetic parameters were determined after measuring compound plasma concentrations using standard bioanalytical methods at time points ranging from 0 to 24 hours.

EQUIVALENTS

[001161] While the invention has been described in connection with the specific embodiments set forth above, many alternatives, modifications, and other variations thereof will be apparent to those skilled in the art. All such alternatives, modifications and variations are intended to be within the spirit and scope of this invention.

Claims (125)

1. Compound of formula (Ib):

or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein: X ¹ is O; R ¹ is selected from the group consisting of:

Where

is a single bond; each A is independently CR ^5a or N; each A ² is independently C(R ^5a ) ₂ , NR ^5a or O and at least one A ² is NR ^5a or O; R ² is

X ² is N or CR ^5b ; R ³ and R ⁴ are H; each R ^5a is independently H, halogen, -OH, -CN, SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ ; or two R ^5a, together with the atoms to which they are attached, can form C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl; wherein the monocyclic heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl is optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , NH(C ₁ -C ₆ alkyl) or N(C ₁ -C ₆ alkyl) ₂ ; or two geminal R ^5a can form an oxo group; each R ^5b is independently H, halogen, -OH, -CN, -SR ⁶ , -OR ⁶ , NHR ⁶ , -NR ⁶ R ⁷ , or C ₁ -C ₆ alkyl; where C ₁ -C ₆ alkyl is optionally substituted with halogen, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; R ⁶ and R ⁷ are independently at each occurrence H, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, or C ₂ -C ₈ alkynyl; where C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl and C ₂ -C ₆ alkynyl are optionally substituted with halogen, C ₁ -C ₆ alkyl, -OH, -OC ₁ -C ₆ alkyl, -NH ₂ , -NH( C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or R ⁶ and R ⁷ together with the atom to which they are attached may form a monocyclic heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O; And n is an integer from 0 to 5. 2. A compound according to claim 1, wherein the compound is a compound of formula (I):

or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein: X ¹ is O; R ¹ is selected from the group consisting of:

Where

is a single bond; each A is independently CR ⁵ or N; each A ² is independently C(R ⁵ ) ₂ , NR ⁵ or O and at least one A ² is NR ⁵ or O; R ² is

X ² is N or CR ⁵ ; R ³ and R ⁴ are H; each R ⁵ is independently H, halogen, -OH, -CN, -SR ⁶ , -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , or C ₁ -C ₆ alkyl; R ⁶ and R ⁷ are independently at each occurrence H, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, or C ₂ -C ₈ alkynyl; or R ⁶ and R ⁷ together with the atom to which they are attached may form a monocyclic heterocyclyl containing 1-3 heteroatoms selected from the group consisting of N, S, P and O; And n is an integer from 0 to 5. 3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein one A is CR ^5a and the other A is N. 4. A compound according to claim 1 or 3, or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein each R ^5a is independently H, -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, or a monocyclic heterocyclyl containing N , where C ₁ -C ₆ alkyl is substituted with -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ and where monocyclic heterocyclyl is optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ . 5. The compound according to p. 1 or its pharmaceutically acceptable salt, solvate or tautomer, where R ¹ represents

where R ^5a1a represents H; R ^5a2c and R ^5a2d are each independently H, halogen, -OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl , C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or R ^5a2c and R ^5a2d together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl; wherein the monocyclic heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl is optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or R ^5a2c and R ^5a2d may form an oxo group. 6. A compound according to claim 5 or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein each R ^5a2c and R ^5a2d is independently H, halogen, -OH, -OR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl , C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl or -CH ₂ -C ₃ -C ₈ cycloalkyl. 7. A compound according to claim 5, or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein R ^5a2c and R ^5a2d together with the atoms to which they are attached form a C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl. 8. The compound according to p. 1 or its pharmaceutically acceptable salt, solvate or tautomer, where R ¹ represents

where R ^5a2a and R ^5a2b are each independently H, halogen, -OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or R ^5a2a and R ^5a2b together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl; wherein the monocyclic heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl is optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or R ^5a2a and R ^5a2b may form an oxo group. 9. A compound according to claim 8 or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein each R ^5a2a and R ^5a2b is independently H, halogen, -OH, -OR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl , C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl or -CH ₂ -C ₃ -C ₈ cycloalkyl. 10. A compound according to claim 8, or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein R ^5a2a and R ^5a2b together with the atoms to which they are attached form a C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl. 11. The compound according to p. 1 or its pharmaceutically acceptable salt, solvate or tautomer, where R ¹ represents

where R ^5a2e and R ^5a2f are each independently H, halogen, -OH, -OR ⁶ , -NHR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl or -CH ₂ -C ₃ -C ₈ cycloalkyl; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl and -CH ₂ -C ₃ -C ₈ cycloalkyl are optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or R ^5a2e and R ^5a2f together with the atoms to which they are attached can form C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl; wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O; where C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl is optionally substituted with halogen, C ₁ -C ₆ alkyl, -OR ⁶ , -NH ₂ , -NH(C ₁ -C ₆ alkyl) or -N(C ₁ -C ₆ alkyl) ₂ ; or R ^5a2e and R ^5a2f may form an oxo group. 12. The compound of claim 11, or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein each R ^5a2e and R ^5a2f is independently H, halogen, -OH, -OR ⁶ , -NR ⁶ R ⁷ , C ₁ -C ₆ alkyl , C ₃ -C ₈ cycloalkyl, monocyclic heterocyclyl or -CH ₂ -C ₃ -C ₈ cycloalkyl. 13. A compound according to claim 11, or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein R ^5a2e and R ^5a2f together with the atoms to which they are attached form a C ₃ -C ₈ cycloalkyl or monocyclic heterocyclyl. 14. Connection according to any one of paragraphs. 1-13 or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein R ² is

15. The compound of claim 14, or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein X ² is CR ^5b and R ^5b is H, fluorine, chlorine or methyl. 16. Connection according to any one of paragraphs. 1-13 or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein R ² is

17. Connection according to any one of paragraphs. 1 or 3-13 or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein R ² is

18. The compound according to claim 17, or a pharmaceutically acceptable salt, solvate or tautomer thereof, where R ² is

and each R ^5b is independently selected from the group consisting of H, halo, -OH, -CN, -OR ⁶ or C ₁ -C ₆ alkyl. 19. Connection according to any one of paragraphs. 1-4 or 14-18 or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein R ¹ is

20. Connection according to any one of paragraphs. 1 or 14-19 or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein R ¹ is selected from the group consisting of:

21. Connection according to any one of paragraphs. 1, 2 or 14-19 or a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein R ¹ is selected from the group consisting of

22. Connection, while the connection is:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 23. Connection, while the connection is:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 24. Connection, while the connection is:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 25. Connection, while the connection is:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 26. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 27. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 28. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 29. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 30. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 31. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 32. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 33. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 34. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 35. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 36. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 37. Connection:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 38. Pharmaceutical composition for inhibiting the activation of the NLRP3 inflammasome, containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-37 or a pharmaceutically acceptable salt, solvate or tautomer thereof and a pharmaceutically acceptable carrier. 39. A pharmaceutical composition for inhibiting the activation of the NLRP3 inflammasome, containing a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate or tautomer thereof. 40. A method of treating a disease, disorder or condition in a subject in need of such treatment, wherein the method involves administering an effective amount of a compound according to any one of paragraphs. 1-37 or a pharmaceutically acceptable salt, solvate or tautomer thereof to a subject in need thereof, characterized in that the disease, disorder, or condition responds to inhibition of NLRP3 inflammasome activation. 41. The method of claim. 40, characterized in that the disease, disorder or condition is a disease, disorder or condition of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, respiratory system, central nervous system, is a cancer or other malignancy, or is caused by or associated with a pathogen. 42. The method of claim 40, wherein the disease, disorder, or condition is an inflammatory or autoimmune disease, disorder, or condition. 43. The method of claim 40, wherein the disease, disorder, or condition is selected from the group consisting of constitutive inflammation, cryopyrin-associated periodic syndromes (CAPS), Mackle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) , multisystem inflammatory disease of neonatal age (NOMID), autoinflammatory diseases, familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), deficiency interleukin-1 receptor antagonist (DIRA), Majid syndrome, pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), haploinsufficiency A20 (HA20), granulomatous arthritis in children (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell dysimmunodeficiency, periodic fevers, developmental delays (SIFD), Sweet's syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO), autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, psoriasis, rheumatoid arthritis, Behcet's disease, Sjogren's syndrome, Schnitzler's syndrome, respiratory disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, central nervous system disease, Parkinson's disease, Alzheimer's disease, motor neurone disease, Huntington's disease, cerebral malaria, traumatic brain injury from pneumococcal meningitis, metabolic disease, type 2 diabetes, atherosclerosis, obesity, gout, pseudogout, eye disease , diseases of the eye epithelium, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, kidney disease, chronic kidney disease, oxalate nephropathy, diabetic nephropathy, liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, inflammatory reactions in the skin, contact hypersensitivity, sunburn, inflammatory reactions in joints, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, viral infections, alpha virus infection, Chikungunya virus infection, Ross River virus infection, flavivirus infection, dengue virus infection, Zika virus infection, influenza, HIV infection, hidradenitis suppurativa (HS), cyst-causing skin disease, cancer, lung cancer metastasis, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukemia, polymyositis, stroke, myocardial infarction, graft versus host disease, hypertension, colitis , helminth infection, bacterial infection, abdominal aortic aneurysm, wound healing, depression, psychological stress, pericarditis, Dressler's syndrome, ischemic reperfusion injury, and any disease in which a person is determined to have a germline or somatic non-silent mutation in NLRP3. 44. The method of claim. 40, characterized in that the disease, disorder or condition is selected from the group consisting of cryopyrin-associated periodic syndromes (CAPS), atherosclerosis, gout, pseudogout, rheumatoid arthritis, systemic juvenile idiopathic arthritis, non-alcoholic steatohepatitis, infarction myocardial infarction, Parkinson's disease, Alzheimer's disease, multiple sclerosis and type 1 diabetes.

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