Novel sulfonylurea compound

文档序号：538454 发布日期：2021-06-01 浏览：22次中文

阅读说明：本技术 新型磺酰脲化合物 (Novel sulfonylurea compound ) 是由 A·麦克劳德 J·香农 S·汤姆 J·卡里略阿雷古伊 T·阿拉尼恩于 2019-08-12 设计创作，主要内容包括：本发明涉及式(I)的化合物：其中A、B、X、Y、R～1、R～4和R～7如本说明书中所定义。本发明还涉及这类化合物的盐、溶剂合物和前药、包含这类化合物的药物组合物以及这类化合物尤其通过抑制NLRP3治疗和预防医学病症和疾病的用途。(The present invention relates to compounds of formula (I): a, B, X, Y, R therein 1 、R 4 And R 7 As defined in the specification. The invention also relates to salts, solvates and prodrugs of such compounds, pharmaceutical compositions comprising such compounds and the use of such compounds for the treatment and prevention of medical conditions and diseases, particularly by inhibition of NLRP 3.)

1. A compound of formula (I):

wherein:

a is phenyl or 5-or 6-membered heteroaryl, wherein A is substituted in the alpha position by B and in the beta position by R⁷Substituted and alpha' position by R⁴And wherein a is optionally additionally substituted;

b is phenyl, 5 or 6 membered heteroaryl or a 4 to 6 membered saturated heterocyclyl, wherein B is optionally substituted;

x is O, NH or N (CN);

y is O or S;

R¹is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo;

R⁴is monovalent and is linked to A at the alpha' position and is selected from C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl and phenyl, each optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: oxo, -OH, -O (C)₁-C₄Alkyl) and-O (C)₁-C₄Haloalkyl);

or R⁴Is divalent and is linked to A in the alpha 'and beta' positions and is selected from-CH₂CH₂CH₂-、-CH＝CHCH₂-、-CH₂CH＝CH-、-CH₂CH₂O-、-OCH₂CH₂-、-CH₂CH₂CH₂CH₂-and-CH-, both optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: oxo, -OH, -O (C)₁-C₄Alkyl) and-O (C)₁-C₄Haloalkyl);

R⁷is C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl radical, C₃-C₆Halocycloalkyl, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl) or halogen;

R²⁰is a bond, -NH-),-NMe-、C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R²¹is C₃-C₆Cycloalkyl, phenyl, 4-to 6-membered saturated heterocyclyl or 5-or 6-membered heteroaryl, all optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, -R²²-OH、-R²²-O(C₁-C₄Alkyl), -R²²-O(C₁-C₄Haloalkyl), -R)²²-NH₂、-R²²-NH(C₁-C₄Alkyl), -R²²-NH(C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Alkyl radical)₂、-R²²-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Haloalkyl groups)₂and-R²²-R²³；

R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and is

R²³Is C₃-C₆Cycloalkyl or 4 to 6 membered saturated heterocyclyl, each optionally substituted with halo.

2. The compound of claim 1, wherein B is optionally substituted pyridinyl.

3. The compound of claim 1 or 2, wherein the compound is of formula (IA):

wherein:

b is phenyl, 5-or 6-membered heteroaryl or 4-to 6-membered saturated heterocyclyl, wherein B is substituted with R²And wherein B is optionally additionally substituted;

x is O, NH or N (CN);

y is O or S;

R¹is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo;

R²is hydrogen, halo, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -R⁸-OH、-R⁸-O(C₁-C₄Alkyl), -R⁸-O(C₁-C₄Haloalkyl), -O-R¹⁰-OH、-O-R¹⁰-O(C₁-C₄Alkyl), -O-R¹⁰-O(C₁-C₄Haloalkyl), -R)⁸-NH₂、-R⁸-NH(C₁-C₄Alkyl), -R⁸-NH(C₁-C₄Haloalkyl), -R)⁸-N(C₁-C₄Alkyl radical)₂、-R⁸-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl), -R)⁸-N(C₁-C₄Haloalkyl groups)₂、-R¹¹、-OR¹¹or-O-R¹⁰-R¹¹；

R⁴Is monovalent and is linked to A at the alpha' position and is selected from C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl and phenyl, each optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: oxo, -OH, -O (C)₁-C₄Alkyl) and-O (C)₁-C₄Haloalkyl);

R⁷is C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl radical, C₃-C₆Halocycloalkyl, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl) or halogen;

R⁸is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R¹⁰is C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R¹¹is C₃-C₆Cycloalkyl or a 4-to 6-membered saturated heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally substituted with halo and/or is optionally substituted with one, two or three substituents independently selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₄Cycloalkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, phenyl, benzyl, -OH, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl), -NH₂、-NH(C₁-C₄Alkyl), -NH (C)₁-C₄Haloalkyl), -N (C)₁-C₄Alkyl radical)₂、-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl) and-N (C)₁-C₄Haloalkyl groups)₂；

R²⁰Is a bond, -NH-, -NMe-, C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and is

R²³Is C₃-C₆Cycloalkyl or 4 to 6 membered saturated heterocyclyl, each optionally substituted with halo.

4. A compound according to any one of claims 1 to 3, wherein B is pyridyl, R²Substituted, and optionally additionally substituted.

5. The compound of any one of claims 1 to 4, wherein A is phenyl or imidazolyl, wherein A is substituted with B at the alpha position and R at the beta position⁷Substituted and alpha' position by R⁴And wherein A is optionally additionally substitutedAnd (4) substitution.

6. The compound of any one of claims 1 to 5, wherein Y is O.

7. The compound of any one of claims 1 to 6, wherein

R⁴Is monovalent and is attached to a at the α' position and is selected from isopropyl, cyclopentyl, cyclohexyl, and phenyl;

or R⁴Is divalent and is linked to A in the alpha 'and beta' positions and is selected from-CH₂CH₂CH₂-、-CH₂CH₂O-and-OCH₂CH₂-。

8. The compound of any one of claims 1 to 7, wherein the compound is of formula (II):

wherein:

x is O, NH or N (CN);

R¹is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo;

R^2ais hydrogen, halo, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl), -O- (alkoxyalkyl), -OR⁹or-OCH₂-R⁹；

R³Is hydrogen or methyl;

R^4ais C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl or phenyl, each optionally substituted with halo;

R⁵is hydrogen; or

R^4aAnd R⁵Together form-CH₂CH₂CH₂-、-CH₂CH₂O-or-OCH₂CH₂-, are each optionally substituted by halo;

R⁶is hydrogen, halogen or cyano;

R⁷is C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl radical, C₃-C₆Halocycloalkyl or halogen;

R⁹is C₃-C₆Cycloalkyl or a 4-to 6-membered saturated heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally substituted with halo and/or is optionally substituted with one, two or three substituents independently selected from: c₁-C₄Alkyl radical, C₂-C₄Alkenyl, phenyl, benzyl, -OH, -O (C)₁-C₄Alkyl), -NH (C)₁-C₄Alkyl) and-N (C)₁-C₄Alkyl radical)₂；

R²⁰Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R²¹is C₃-C₆Cycloalkyl, phenyl, 4-to 6-membered saturated heterocyclyl or 5-or 6-membered heteroaryl, all optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, -R²²-OH、-R²²-O(C₁-C₄Alkyl), -R²²-O(C₁-C₄Haloalkyl), -R)²²-NH₂、-R²²-NH(C₁-C₄Alkyl), -R²²-NH(C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Alkyl radical)₂、-R²²-N(C₁-C₄Alkyl) (C₁-C₄Alkyl halidesRadical), -R²²-N(C₁-C₄Haloalkyl groups)₂and-R²²-R²³；

R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and is

R²³Is C₃-C₆Cycloalkyl or 4 to 6 membered saturated heterocyclyl, each optionally substituted with halo.

9. The compound of claim 8, wherein:

R⁵is hydrogen and R^4aIs isopropyl, cyclopentyl, cyclohexyl or phenyl;

or R^4aAnd R⁵Together form-CH₂CH₂CH₂-、-CH₂CH₂O-or-OCH₂CH₂-。

10. The compound of claim 8 or 9, wherein R⁶Is hydrogen or fluorine.

11. The compound of any one of claims 1 to 7, wherein the compound is of formula (III):

wherein:

x is O, NH or N (CN);

R¹is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo;

R^2bis hydrogen, halo, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O (C)₁-C₄Alkyl) or-O (C)₁-C₄Haloalkyl);

R³is hydrogen or methyl;

R^4bis C₁-C₄Alkyl or C₁-C₄A haloalkyl group;

R⁷is C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl radical, C₃-C₆Halocycloalkyl or halogen;

R²⁰is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and is

R²³Is C₃-C₆Cycloalkyl or 4 to 6 membered saturated heterocyclyl, each optionally substituted with halo.

12. The compound of claim 11, wherein R^4bIs isopropyl, sec-butyl, isobutyl or tert-butyl, all optionally substituted by halo.

13. The compound of any one of claims 1 to 12, wherein X is O.

14. The compound of any one of claims 1 to 13, wherein R¹Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NHMe, -NMe₂、-NHEt、-NEt₂or-NMeEt, each optionally substituted with halo; or R¹Is C₃-C₆Cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, thienyl, pyrazolyl or imidazolyl, all optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: c₁-C₃Alkyl, -R²²-OH、-R²²-O(C₁-C₃Alkyl), -R²²-NH(C₁-C₃Alkyl), -R²²-N(C₁-C₃Alkyl radical)₂and-R²²-R²³(ii) a Wherein R is²²Is a bond or C₁-C₄An alkylene group; and R is²³Is C₃-C₆Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

15. The compound of any one of claims 3 to 14, wherein R²Is hydrogen, halo, cyano, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, -R⁸-OH、-R⁸-O(C₁-C₃Alkyl), -R⁸-O(C₁-C₃Haloalkyl), -O-R¹⁰-OH、-O-R¹⁰-O(C₁-C₃Alkyl), -R¹¹、-OR¹¹or-O-R¹⁰-R¹¹(ii) a Wherein

R⁸Is a bond or-CH₂-；

R¹⁰Is C₁-C₃An alkylene group; and is

R¹¹Is cyclopropyl,Cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl, each optionally substituted with one or two substituents independently selected from: fluorine, C₁-C₃Alkyl radical, C₂-C₃Alkenyl, phenyl, benzyl, -OH, -O (C)₁-C₃Alkyl), -NH₂、-NH(C₁-C₃Alkyl) and-N (C)₁-C₃Alkyl radical)₂。

16. The compound of any one of claims 1 to 15, wherein R⁷Is methyl, ethyl, cyclopropyl or fluoro.

17. The compound of any one of claims 1 to 16, wherein the compound is selected from the group consisting of:

18. a pharmaceutically acceptable salt, solvate or prodrug of a compound of any one of claims 1 to 17.

19. A pharmaceutical composition comprising a compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt, solvate or prodrug of claim 18, and a pharmaceutically acceptable excipient.

20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition is an oral or topical pharmaceutical composition.

21. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or prodrug of claim 18, or a pharmaceutical composition of claim 19 or 20, for use in medicine.

22. The compound, pharmaceutically acceptable salt, solvate, prodrug or pharmaceutical composition of claim 21 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

23. The compound, pharmaceutically acceptable salt, solvate, prodrug or pharmaceutical composition of claim 21 or 22 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is selected from:

(i) inflammation;

(ii) (ii) an autoimmune disease;

(iii) cancer;

(iv) (ii) infection;

(v) central nervous system diseases;

(vi) metabolic diseases;

(vii) cardiovascular diseases;

(viii) respiratory diseases;

(ix) liver diseases;

(x) Renal disease;

(xi) Ocular diseases;

(xii) Skin diseases;

(xiii) Disorders of the lymphatic vessels;

(xiv) Psychological disorders;

(xv) Graft versus host disease;

(xvi) Induction of pain; and

(xvii) Any disease in which an individual carries germline or somatic non-silent mutations of NLRP3 has been identified.

24. The compound, pharmaceutically acceptable salt, solvate, prodrug or pharmaceutical composition of claim 21 or 22 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is selected from:

(i) coldness-imidacloprid associated periodic syndrome (CAPS);

(ii) muckle-weidi's syndrome (MWS);

(iii) familial Cold Autoinflammatory Syndrome (FCAS);

(iv) neonatal Onset Multisystem Inflammatory Disease (NOMID);

(v) familial Mediterranean Fever (FMF);

(vi) suppurative arthritis, pyoderma gangrenosum and acne syndrome (PAPA);

(vii) hyperimmune globulinemia D and periodic fever syndrome (HIDS);

(viii) tumor Necrosis Factor (TNF) receptor-related periodic syndrome (TRAPS);

(ix) systemic juvenile idiopathic arthritis;

(x) Adult Onset Still Disease (AOSD);

(xi) Recurrent polychondritis;

(xii) (iii) the Schnitler syndrome;

(xiii) A Switt syndrome;

(xiv) Behcet's disease;

(xv) Anti-synthetase syndrome;

(xvi) Interleukin 1 receptor antagonist Deficiency (DIRA); and

(xvii) A20 was underdosed at a single dose (HA 20).

25. A method of inhibiting NLRP3, comprising using a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or prodrug of claim 18, or a pharmaceutical composition of claim 19 or 20 to inhibit NLRP 3.

Technical Field

The present invention relates to compounds of formula (I); and to related salts, solvates, prodrugs and pharmaceutical compositions. The invention also relates to the use of such compounds for the treatment and prevention of medical conditions and diseases, especially by inhibiting NLRP 3.

Background

The NOD-like receptor (NLR) family of thermoprotein domain-containing protein 3(NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activity is a causative agent of genetic disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis.

NLRP3 is an intracellular signaling molecule that is capable of sensing many pathogen-, environmental-, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-related spot-like proteins containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form large aggregates, known as ASC blobs. The polymerized ASC in turn interacts with the cysteine protease caspase-1 to form a complex known as the inflammasome. This causes activation of caspase-1, which cleaves pro-inflammatory cytokines IL-1 β and precursor forms of IL-18 (referred to as pro-IL-1 β and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 also mediates an inflammatory cell death, known as cell apoptosis. ASC spots may also recruit and activate caspase-8, caspase-8 being able to process pre-IL-1 β and pre-IL-18 and trigger apoptotic cell death.

Caspase-1 cleaves both pro-IL-1 β and pro-IL-18 into their active forms, which are secreted from the cells. Active caspase-1 also cleaves cortin-D (gasdermin-D), triggering cell scorching. Caspase-1 also mediates the release of alarm molecules such as IL-33 and high mobility group box 1protein (HMGB 1) through control of the cell pyrophoric cell death pathway. Caspase-1 also cleaves intracellular IL-1R2, causing its degradation and release of IL-1 α. In human cells, caspase-1 may also control the processing and secretion of IL-37. A number of other caspase-1 substrates, such as cytoskeleton and components of the glycolytic pathway, promote caspase-1 dependent inflammation.

NLRP 3-dependent ASC spots are released into the extracellular environment where they can activate caspase-1, induce processing of caspase-1 substrates and spread inflammation.

Active cytokines derived from the activation of NLRP3 inflammasome are important drivers of inflammation and interact with other cytokine pathways to shape the immune response for infection and injury. For example, IL-1 β signaling induces the secretion of the proinflammatory cytokines IL-6 and TNF. IL-1. beta. and IL-18 act synergistically with IL-23 to induce the production of IL-17 by memory CD4 Th17 cells and γ δ T cells in the absence of T cell receptor involvement. IL-18 and IL-12 also act synergistically to induce IFN- γ production from memory T cells and NK cells, driving a Th1 response.

Genetic CAPS disease Muckle-Wells syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), and Neonatal Onset Multisystem Inflammatory Disease (NOMID) are caused by gain-of-function mutations in NLRP3, thus defining NLRP3 as a key component of the inflammatory process. NLRP3 is associated with the pathogenesis of a number of complex diseases, including in particular metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout.

The role of NLRP3 in central nervous system diseases is emerging and lung diseases are also shown to be affected by NLRP 3. In addition, NLRP3 plays a role in the progression of liver disease, kidney disease and aging. Using Nlrp3^-/-Mice defined multiple of these associations, but also gained in the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1 β signaling, causing cell death and inflammation.

Several small molecules have been shown to inhibit NLRP3 inflammasome. Glibenclamide (Glyburide) inhibits IL-1 β in response to activation of NLRP3 but not NLRC4 or NLRP1 at micromolar concentrations. Other previously characterized weak NLRP3 inhibitors include parthenolide (parthenolide), 3, 4-methylenedioxy-beta-nitrostyrene, and dimethyl sulfoxide (DMSO), but these agents have limited potency and are non-specific.

Current treatments for NLRP 3-related diseases include biologies targeting IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1. beta. antibody canamab and the soluble decoy IL-1 receptor linacept. These methods have demonstrated successful treatment of CAPS, and these biologic agents have been used in clinical trials for other IL-1 β related diseases.

Some diarylsulfonylurea-containing compounds have been identified as Cytokine Release Inhibitory Drugs (CRIDs) (Perregaux et al, J Pharmacol Exp Ther,299:187-197, 2001). CRIDs are a class of diarylsulfonylurea-containing compounds that inhibit the post-translational processing of IL-1 β. The post-translational processing of IL-1 β is accompanied by caspase-1 activation and cell death. CRID inhibits activated monocytes, leaving caspase-1 inactive and maintaining plasma membrane latency.

Certain sulfonylurea-containing compounds are also disclosed as inhibitors of NLRP3 (see, e.g., Baldwin et al, J.Med.chem.,59(5), 1691-one 1710,2016; and WO 2016/131098A 1, WO 2017/129897A 1, WO 2017/140778A 1, WO 2017/184623A 1, WO 2017/184624A 1, WO 2018/015445A 1, WO 2018/136890A 1, WO 2018/215818A 1, WO 2019/008025A 1, WO 2019/008029A 1, WO 2019/034686A 1, WO 2019/034688A 1, WO 2019/034690A 1, WO 2019/034692A 1, WO 2019/034693A 1, WO 2019/034696A 1, WO 2019/034697A 1, WO 2019/043610A 1, WO 2019/092170A 1, WO 2019/092171A 1 and WO 2019/092172A 1). In addition, WO 2017/184604 a1 and WO 2019/079119 a1 disclose a large number of sulfonamide-containing compounds as inhibitors of NLRP 3. Certain sulfinimide-containing compounds are also disclosed as inhibitors of NLRP3 (WO 2018/225018 a1, WO 2019/023145 a1, WO 2019/023147 a1, and WO 2019/068772 a 1).

There is a need to provide compounds having improved pharmacological and/or physiological and/or physicochemical properties and/or compounds which are suitable as alternatives to known compounds.

Definition of

In the context of this specification, a "hydrocarbyl" substituent group or hydrocarbyl portion of a substituent group includes only carbon and hydrogen atoms, but, unless otherwise specified, does not include any heteroatoms, such as N, O or S, in its carbon skeleton. The hydrocarbyl group/moiety may be saturated or unsaturated (including aromatic) and may be linear or branched, or be or include a cyclic group, wherein the cyclic group does not include any heteroatoms in its carbon backbone, such as N, O or S, unless otherwise specified. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and aryl groups/moieties and combinations of all of these groups/moieties. Typically, the hydrocarbyl group is C₁-C₂₀A hydrocarbyl group. More typically, the hydrocarbyl group is C₁-C₁₅A hydrocarbyl group. More typically, the hydrocarbyl group is C₁-C₁₀A hydrocarbyl group. "hydrocarbylene" is similarly defined as a divalent hydrocarbyl group.

An "alkyl" substituent group or alkyl portion of a substituent group can be linear (i.e., straight-chain) or branched. Examples of alkyl groups/moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and n-pentyl groups/moieties. The term "alkyl" excludes "cycloalkyl" unless otherwise indicated. Typically, alkyl is C₁-C₁₂An alkyl group. More typically, the alkyl group is C₁-C₆An alkyl group. "alkylene" is similarly defined as a divalent alkyl group.

An "alkoxyalkyl" substituent group or alkoxyalkyl moiety in a substituent group is a (alkyl) -O- (alkylene) -group. Typically, the alkoxyalkyl is (C)₁-C₆Alkyl) -O- (C₁-C₆Alkylene) -groups. More typically, the alkoxyalkyl is (C)₁-C₄Alkyl) -O- (C₁-C₆Alkylene) -groups. More typically, the alkoxyalkyl is (C)₁-C₃Alkyl) -O- (C₁-C₆Alkylene) -groups. Examples of alkoxyalkyl groups/moieties include methoxyalkyl and ethoxyAn alkyl group. Examples of the methoxyalkyl group include methoxy- (C)₁-C₆Alkylene) -, methoxy- (C)₁-C₄Alkylene) -and methoxy- (C)₁-C₃Alkylene) -. Examples of ethoxyalkyl groups include ethoxy- (C)₁-C₆Alkylene) -, ethoxy- (C)₁-C₄Alkylene) -and ethoxy- (C)₁-C₃Alkylene) -.

An "alkenyl" substituent group or alkenyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds. Examples of alkenyl groups/moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1, 3-butadienyl, 1, 3-pentadienyl, 1, 4-pentadienyl and 1, 4-hexadienyl groups/moieties. The term "alkenyl" does not include "cycloalkenyl," unless otherwise specified. Typically, alkenyl is C₂-C₁₂An alkenyl group. More typically, alkenyl is C₂-C₆An alkenyl group. "alkenylene" is similarly defined as a divalent alkenyl group.

An "alkynyl" substituent group or alkynyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds. Examples of alkynyl groups/moieties include ethynyl, propargyl, but-1-ynyl and but-2-ynyl groups/moieties. Typically, alkynyl is C₂-C₁₂Alkynyl. More typically, alkynyl is C₂-C₆Alkynyl. "Alkynylene" is similarly defined as a divalent alkynyl group.

A "cyclic" substituent group or cyclic moiety in a substituent group refers to any hydrocarbyl ring, wherein the hydrocarbyl ring may be saturated or unsaturated (including aromatic) and may include one or more heteroatoms, such as N, O or S, in its carbon backbone. Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl groups as discussed below. The cyclic group can be monocyclic, bicyclic (e.g., bridged, fused, or spiro) or polycyclic. Typically, the cyclic group is a 3 to 12 membered cyclic group, which means that it contains 3 to 12 ring atoms. More typically, the cyclic group is a 3 to 7 membered monocyclic group, which means that it contains 3 to 7 ring atoms.

A "heterocyclic" substituent group or heterocyclic moiety in a substituent group refers to a cyclic group or moiety that includes one or more carbon atoms and one or more (e.g., one, two, three, or four) heteroatoms, such as N, O or S, in the ring structure. Examples of heterocyclic groups include heteroaryl and non-aromatic heterocyclic groups as discussed below, such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thiacyclohexanyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl.

"cycloalkyl" substituent group or the cycloalkyl moiety in a substituent group refers to a saturated hydrocarbon ring containing, for example, 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless otherwise specified, cycloalkyl substituents or moieties may include monocyclic, bicyclic, or polycyclic hydrocarbon rings.

"cycloalkenyl" substituent group or cycloalkenyl moiety in a substituent group refers to a non-aromatic unsaturated hydrocarbon ring having one or more carbon-carbon double bonds and containing, for example, 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, and cyclohex-1, 3-dien-1-yl. Unless otherwise specified, cycloalkenyl substituent groups or moieties can include monocyclic, bicyclic, or polycyclic hydrocarbon rings.

An "aryl" substituent or an aryl moiety in a substituent means an aromatic hydrocarbon ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons, wherein all fused ring systems (excluding any ring systems formed as part of or by optional substituents) are aromatic. Examples of aryl groups/moieties include phenyl, naphthyl, anthryl and phenanthryl. The term "aryl" excludes "heteroaryl" unless otherwise indicated.

A "heteroaryl" substituent group or heteroaryl moiety in a substituent group refers to an aromatic heterocyclic group or moiety. The term "heteroaryl" includes monocyclic aromatic heterocycles and polycyclic fused aromatic heterocycles in which all fused ring systems (excluding any ring systems formed as part of or by optional substituents) are aromatic. Examples of heteroaryl groups/moieties include the following:

wherein G-O, S or NH.

For the purposes of this specification, where a combination of moieties refers to a group, such as arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last-mentioned moiety contains an atom which links the group to the rest of the molecule. An example of arylalkyl is benzyl.

For the purposes of this specification, in an optionally substituted group or moiety:

(i) each hydrogen atom may be optionally replaced with a monovalent substituent independently selected from the group consisting of: a halo group; -CN; -NO₂；-N₃；-R^β；-OH；-OR^β；-R^α-halo; -R^α-CN；-R^α-NO₂；-R^α-N₃；-R^α-R^β；-R^α-OH；-R^α-OR^β；-SH；-SR^β；-SOR^β；-SO₂H；-SO₂R^β；-SO₂NH₂；-SO₂NHR^β；-SO₂N(R^β)₂；-R^α-SH；-R^α-SR^β；-R^α-SOR^β；-R^α-SO₂H；-R^α-SO₂R^β；-R^α-SO₂NH₂；-R^α-SO₂NHR^β；-R^α-SO₂N(R^β)₂；-Si(R^β)₃；-O-Si(R^β)₃；-R^α-Si(R^β)₃；-R^α-O-Si(R^β)₃；-NH₂；-NHR^β；-N(R^β)₂；-N(O)(R^β)₂；-N⁺(R^β)₃；-R^α-NH₂；-R^α-NHR^β；-R^α-N(R^β)₂；-R^α-N(O)(R^β)₂；-R^α-N⁺(R^β)₃；-CHO；-COR^β；-COOH；-COOR^β；-OCOR^β；-R^α-CHO；-R^α-COR^β；-R^α-COOH；-R^α-COOR^β；-R^α-OCOR^β；-C(＝NH)R^β；-C(＝NH)NH₂；-C(＝NH)NHR^β；-C(＝NH)N(R^β)₂；-C(＝NR^β)R^β；-C(＝NR^β)NHR^β；-C(＝NR^β)N(R^β)₂；-C(＝NOH)R^β；-C(＝NOR^β)R^β；-C(N₂)R^β；-R^α-C(＝NH)R^β；-R^α-C(＝NH)NH₂；-R^α-C(＝NH)NHR^β；-R^α-C(＝NH)N(R^β)₂；-R^α-C(＝NR^β)R^β；-R^α-C(＝NR^β)NHR^β；-R^α-C(＝NR^β)N(R^β)₂；-R^α-C(＝NOH)R^β；-R^α-C(＝NOR^β)R^β；-R^α-C(N₂)R^β；-NH-CHO；-NR^β-CHO；-NH-COR^β；-NR^β-COR^β；-NH-COOR^β；-NR^β-COOR^β；-NH-C(＝NH)R^β；-NR^β-C(＝NH)R^β；-NH-C(＝NH)NH₂；-NR^β-C(＝NH)NH₂；-NH-C(＝NH)NHR^β；-NR^β-C(＝NH)NHR^β；-NH-C(＝NH)N(R^β)₂；-NR^β-C(＝NH)N(R^β)₂；-NH-C(＝NR^β)R^β；-NR^β-C(＝NR^β)R^β；-NH-C(＝NR^β)NHR^β；-NR^β-C(＝NR^β)NHR^β；-NH-C(＝NR^β)N(R^β)₂；-NR^β-C(＝NR^β)N(R^β)₂；-NH-C(＝NOH)R^β；-NR^β-C(＝NOH)R^β；-NH-C(＝NOR^β)R^β；-NR^β-C(＝NOR^β)R^β；-CONH₂；-CONHR^β；-CON(R^β)₂；-NH-CONH₂；-NR^β-CONH₂；-NH-CONHR^β；-NR^β-CONHR^β；-NH-CON(R^β)₂；-NR^β-CON(R^β)₂；-R^α-NH-CHO；-R^α-NR^β-CHO；-R^α-NH-COR^β；-R^α-NR^β-COR^β；-R^α-NH-COOR^β；-R^α-NR^β-COOR^β；-R^α-NH-C(＝NH)R^β；-R^α-NR^β-C(＝NH)R^β；-R^α-NH-C(＝NH)NH₂；-R^α-NR^β-C(＝NH)NH₂；-R^α-NH-C(＝NH)NHR^β；-R^α-NR^β-C(＝NH)NHR^β；-R^α-NH-C(＝NH)N(R^β)₂；-R^α-NR^β-C(＝NH)N(R^β)₂；-R^α-NH-C(＝NR^β)R^β；-R^α-NR^β-C(＝NR^β)R^β；-R^α-NH-C(＝NR^β)NHR^β；-R^α-NR^β-C(＝NR^β)NHR^β；-R^α-NH-C(＝NR^β)N(R^β)₂；-R^α-NR^β-C(＝NR^β)N(R^β)₂；-R^α-NH-C(＝NOH)R^β；-R^α-NR^β-C(＝NOH)R^β；-R^α-NH-C(＝NOR^β)R^β；-R^α-NR^β-C(＝NOR^β)R^β；-R^α-CONH₂；-R^α-CONHR^β；-R^α-CON(R^β)₂；-R^α-NH-CONH₂；-R^α-NR^β-CONH₂；-R^α-NH-CONHR^β；-R^α-NR^β-CONHR^β；-R^α-NH-CON(R^β)₂；-R^α-NR^β-CON(R^β)₂；-O-R^α-OH；-O-R^α-OR^β；-O-R^α-NH₂；-O-R^α-NHR^β；-O-R^α-N(R^β)₂；-O-R^α-N(O)(R^β)₂；-O-R^α-N⁺(R^β)₃；-NH-R^α-OH；-NH-R^α-OR^β；-NH-R^α-NH₂；-NH-R^α-NHR^β；-NH-R^α-N(R^β)₂；-NH-R^α-N(O)(R^β)₂；-NH-R^α-N⁺(R^β)₃；-NR^β-R^α-OH；-NR^β-R^α-OR^β；-NR^β-R^α-NH₂；-NR^β-R^α-NHR^β；-NR^β-R^α-N(R^β)₂；-NR^β-R^α-N(O)(R^β)₂；-NR^β-R^α-N⁺(R^β)₃；-N(O)R^β-R^α-OH；-N(O)R^β-R^α-OR^β；-N(O)R^β-R^α-NH₂；-N(O)R^β-R^α-NHR^β；-N(O)R^β-R^α-N(R^β)₂；-N(O)R^β-R^α-N(O)(R^β)₂；-N(O)R^β-R^α-N⁺(R^β)₃；-N⁺(R^β)₂-R^α-OH；-N⁺(R^β)₂-R^α-OR^β；-N⁺(R^β)₂-R^α-NH₂；-N⁺(R^β)₂-R^α-NHR^β；-N⁺(R^β)₂-R^α-N(R^β)₂(ii) a or-N⁺(R^β)₂-R^α-N(O)(R^β)₂(ii) a And/or

(ii) Any two hydrogen atoms attached to the same carbon or nitrogen atom may optionally be replaced with a pi-bonded substituent independently selected from the group consisting of: oxo (═ O), ═ S, ═ NH, or ═ NR^β(ii) a And/or

(iii) Any sulfur atom may be optionally substituted with one or two pi-bonded substituents independently selected from the group consisting of: oxo (═ O), ═ NH, or ═ NR^β(ii) a And/or

(iv) Any two hydrogen atoms attached to the same or different atoms may be optionally replaced within the same optionally substituted group or moiety by a bridging substituent independently selected from: -O-, -S-, -NH-, -N ═ N-, -N (R)^β)-、-N(O)(R^β)-、-N⁺(R^β)₂-or-R^α-；

Wherein each of-R^α-is independently selected from alkylene, alkenylene or alkynylene, wherein said alkylene, alkenylene or alkynylene contains 1 to 6 atoms in its backbone, wherein one or more carbon atoms within the backbone of said alkylene, alkenylene or alkynylene may optionally be replaced by one or more heteroatoms N, O or S, wherein one or more-CH within the backbone of said alkylene, alkenylene or alkynylene₂The radicals being optionally substituted by one or more-N (O) (R)^β) -or-N⁺(R^β)₂-group replacement, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo groups and/or-R^βSubstituted by groups; and is

Wherein each of-R^βIndependently selected from C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl or C₂-C₆Cyclic groups, or-R in which any two or three of them are bound to the same nitrogen atom^βMay form C together with the nitrogen atom to which they are attached₂-C₇A cyclic group, and wherein any-R^βOptionally via one or more C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₇Cycloalkyl radical, C₃-C₇Halocycloalkyl, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl), -O (C)₃-C₇Cycloalkyl), -O (C)₃-C₇Halocycloalkyl), -CO (C)₁-C₄Alkyl), -CO (C)₁-C₄Haloalkyl), -CO (C)₃-C₇Cycloalkyl), -CO (C)₃-C₇Halocycloalkyl), -COO (C)₁-C₄Alkyl), -COO (C)₁-C₄Haloalkyl), -COO (C)₃-C₇Cycloalkyl), -COO (C)₃-C₇Halocycloalkyl), halo, -OH, -NH₂-CN, -C ≡ CH, oxo (═ O), phenyl, halophenyl, or 4 to 6 membered heterocyclyl optionally substituted with halo.

Typically, the compounds of the invention contain at most one quaternary ammonium group, e.g., -N⁺(R^β)₃or-N⁺(R^β)₂-。

In the mention of-R^α-C(N₂)R^βIn the case of groups, the intention is:

typically, in an optionally substituted group or moiety:

(ii) Any two hydrogen atoms attached to the same carbon atom may be optionally replaced with a pi-bonded substituent independently selected from the group consisting of: oxo (═ O), ═ S, ═ NH, or ═ NR^β(ii) a And/or

(iii) Any two hydrogen atoms attached to the same or different atoms may be optionally replaced within the same optionally substituted group or moiety by a bridging substituent independently selected from: -O-, -S-, -NH-, -N (R)^β)-、-N⁺(R^β)₂-or-R^α-；

Wherein each of-R^α-is independently selected from alkylene, alkenylene or alkynylene, wherein said alkylene, alkenylene or alkynylene contains 1 to 6 atoms in its backbone, wherein one or more carbon atoms within the backbone of said alkylene, alkenylene or alkynylene may optionally be replaced by one or more heteroatoms N, O or S, wherein a single-CH within the backbone of said alkylene, alkenylene or alkynylene is₂The radical-may optionally be substituted by-N⁺(R^β)₂-group replacement, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo groupsand/or-R^βSubstituted by groups; and is

Typically, in an optionally substituted group or moiety:

Wherein each of-R^α-is independently selected from alkylene, alkenylene or alkynylene, wherein said alkylene, alkenylene or alkynylene contains 1 to 6 atoms in its backbone, wherein one or more carbon atoms within the backbone of said alkylene, alkenylene or alkynylene may optionally be replaced by one or more heteroatoms N, O or S, and wherein said alkylene, alkenylene or alkynylene may optionally be substituted by one or more halo groups and/or-R^βSubstituted by groups; and is

Wherein each of-R^βIndependently selected from C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl or C₂-C₆Cyclic groups, or-R in which any two of them are bound to the same nitrogen atom^βMay form C together with the nitrogen atom to which they are attached₂-C₆A cyclic group, and wherein any-R^βOptionally via one or more C₁-C₄Alkyl, halo, -OH, or 4-to 6-membered heterocyclyl.

Typically, a substituted group contains 1,2,3, or 4 substituents, more typically 1,2, or 3 substituents, more typically 1 or 2 substituents, and more typically 1 substituent.

Unless otherwise indicated, an optionally substituted groupRadicals or moieties (e.g. R)¹) Any of the divalent bridging substituents of (e.g. -O-, -S-, -NH-, -N (R))^β)-、-N(O)(R^β)-、-N⁺(R^β)₂-or-R^α-) can only be attached to the indicated group or moiety and not to a second group or moiety (e.g., R)²) Even though the second group or moiety may itself be optionally substituted.

The term "halo" includes fluoro, chloro, bromo and iodo.

Unless otherwise indicated, where a group is preceded by the term "halo", such as haloalkyl or halomethyl, it is understood that the group in question is substituted with one or more halo independently selected from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the corresponding group without the halo prefix. For example, a halomethyl group may contain one, two or three halo substituents. The haloethyl or halophenyl group may contain one, two, three, four or five halo substituents. Similarly, where a group is preceded by a particular halo group, it is understood that the group in question is substituted with one or more of the particular halo groups, unless otherwise indicated. For example, the term "fluoromethyl" refers to a methyl group substituted with one, two, or three fluoro groups.

Similarly, where a group is said to be "substituted with halo", unless otherwise indicated, it is understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the group referred to as being substituted by halo. For example, a methyl group substituted with a halo group may contain one, two, or three halo substituents. The ethyl group substituted with a halo group or the phenyl group substituted with a halo group may contain one, two, three, four or five halo substituents.

Unless otherwise indicated, any reference to an element shall be considered to refer to all isotopes of that element. Thus, for example, unless otherwise specified, any reference to hydrogen is considered to encompass all hydrogen isotopes including deuterium and tritium.

Unless otherwise indicated, any reference to a compound or group will be considered to refer to all tautomers of said compound or group.

In reference to a hydrocarbyl or other group including one or more heteroatoms N, O or S in the carbon backbone, or in reference to a carbon atom of the hydrocarbyl or other group being replaced with a N, O or S atom, it is intended that:

replacement;

-CH₂-is replaced by-NH-, -O-or-S-;

-CH₃is-NH₂-OH or-SH substitution;

-CH is replaced by-N;

CH₂substituted by NH, O or S; or

CH ≡ is replaced by N ≡;

with the proviso that the resulting group contains at least one carbon atom. For example, methoxy, dimethylamino, and aminoethyl are considered to be hydrocarbon groups that include one or more heteroatoms N, O or S in their carbon backbone.

-CH in the main chain referring to hydrocarbyl or other groups₂The radical-N (O) (R)^β) -or-N⁺(R^β)₂-in case of radical substitution, the intention is:

-CH₂-quiltReplacement; or

-CH₂-quiltAnd (4) replacement.

In the context of the present specification, unless otherwise indicated, C_x-C_yGroups are defined as containing from x to y carbonsA group of atoms. For example, C₁-C₄Alkyl is defined as an alkyl group containing 1 to 4 carbon atoms. Optional substituents and moieties are not included when calculating the total number of carbon atoms in a parent group substituted with an optional substituent and/or containing an optional moiety. For the avoidance of doubt, when C is calculated_x-C_yThe number of carbon atoms in the group, replacing a heteroatom, such as N, O or S, is counted as a carbon atom. For example, morpholinyl is considered to be C₆Heterocyclyl radical other than C₄A heterocyclic group.

For the purposes of this specification, where a first atom or group is said to be "directly connected" to a second atom or group, it is understood that the first atom or group is covalently bonded to the second atom or group, with no intervening atoms or groups present. Thus, for example, for the group- (C ═ O) N (CH)₃)₂In other words, each carbon atom of the methyl group is directly attached to a nitrogen atom and the carbon atom of the carbonyl group is directly attached to a nitrogen atom, but the carbon atom of the carbonyl group is not directly attached to a carbon atom of the methyl group.

For the avoidance of doubt, compounds or groups, e.g. R, are said¹Where there are from x to y atoms other than hydrogen, it is understood that the compound or group including any optional substituent generally contains from x to y atoms other than hydrogen. Such compounds or groups may contain a number of hydrogen atoms.

Disclosure of Invention

In a first aspect the present invention provides a compound of formula (I):

wherein:

b is phenyl, 5 or 6 membered heteroaryl or a 4 to 6 membered saturated heterocyclyl, wherein B is optionally substituted;

x is O, NH or N (CN);

y is O or S;

R¹is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo;

R⁷is C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl radical, C₃-C₆Halocycloalkyl, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl) or halogen;

R²⁰is a bond, -NH-, -NMe-, C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R²¹is C₃-C₆Cycloalkyl, phenyl, 4-to 6-membered saturated heterocyclyl or 5-or 6-membered heteroaryl, all optionally substituted with halo and/or optionally substituted with one or two substituents independently selected fromThe substituent (b): cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, -R²²-OH、-R²²-O(C₁-C₄Alkyl), -R²²-O(C₁-C₄Haloalkyl), -R)²²-NH₂、-R²²-NH(C₁-C₄Alkyl), -R²²-NH(C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Alkyl radical)₂、-R²²-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Haloalkyl groups)₂and-R²²-R²³；

R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and is

R²³Is C₃-C₆Cycloalkyl or 4 to 6 membered saturated heterocyclyl, each optionally substituted with halo.

A is phenyl or 5-or 6-membered heteroaryl, wherein A is substituted in the alpha position by B and in the beta position by R⁷Substituted and in the alpha' position (relative to A and R)¹(X) the point of attachment of (O) -NH-CY-NH-via R⁴And wherein a is optionally additionally substituted. In one embodiment, a is phenyl or a5 or 6 membered heteroaryl group comprising one, two or three nitrogen and/or oxygen and/or sulphur ring atoms, wherein a is substituted with B in the alpha position and R in the beta position⁷Substituted and alpha' position by R⁴And wherein a is optionally additionally substituted. In one embodiment, a is phenyl or a5 or 6 membered heteroaryl group comprising one or two nitrogen and/or oxygen ring atoms, wherein a is substituted with B in the alpha position and R in the beta position⁷Substituted and alpha' position by R⁴And wherein a is optionally additionally substituted. In one embodiment, a is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, whereinA is substituted in the alpha position by B and in the beta position by R⁷Substituted and alpha' position by R⁴And wherein a is optionally additionally substituted. In one embodiment, a is phenyl, pyrimidinyl, pyrazolyl, or imidazolyl, wherein a is substituted at the alpha position with B and at the beta position with R⁷Substituted and alpha' position by R⁴And wherein a is optionally additionally substituted. In one embodiment, a is phenyl or imidazolyl, wherein a is substituted with B at the alpha position and R at the beta position⁷Substituted and alpha' position by R⁴And wherein a is optionally additionally substituted.

A is optionally additionally substituted. In one embodiment, A is in the gamma position (relative to A and R)¹(X) the point of attachment of (O) -NH-CY-NH-is substituted by halogen or cyano. In one embodiment, a is substituted at the γ position with fluoro, chloro or cyano. In one embodiment, a is substituted with fluorine at the γ position.

B is phenyl, 5 or 6 membered heteroaryl or a 4 to 6 membered saturated heterocyclyl, wherein B is optionally substituted. In one embodiment, B is phenyl, or a5 or 6 membered heteroaryl comprising one, two or three nitrogen and/or oxygen and/or sulphur ring atoms, or a 4 to 6 membered saturated heterocyclyl comprising one or two nitrogen and/or oxygen and/or sulphur ring atoms, wherein B is optionally substituted. In one embodiment, B is phenyl, or a5 or 6 membered heteroaryl group comprising one or two nitrogen and/or oxygen ring atoms, or a 4 to 6 membered saturated heterocyclyl group comprising one nitrogen or oxygen ring atom, wherein B is optionally substituted. In one embodiment, B is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl, wherein B is optionally substituted. In one embodiment, B is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, or oxadiazolyl, wherein B is optionally substituted. In one embodiment, B is phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl, or thiazolyl, wherein B is optionally substituted. In one embodiment, B is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl, wherein B is optionally substituted. In one embodiment, B is phenyl or pyridyl, wherein B is optionally substituted. In one embodiment, B is optionally substituted pyridinyl. In one embodiment, B is optionally substituted pyridin-4-yl.

B is optionally substituted. In one embodiment, B is optionally via R²Substituted and optionally additionally substituted. In one embodiment, R²Is hydrogen, halo, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -R⁸-OH、-R⁸-O(C₁-C₄Alkyl), -R⁸-O(C₁-C₄Haloalkyl), -O-R¹⁰-OH、-O-R¹⁰-O(C₁-C₄Alkyl), -O-R¹⁰-O(C₁-C₄Haloalkyl), -R)⁸-NH₂、-R⁸-NH(C₁-C₄Alkyl), -R⁸-NH(C₁-C₄Haloalkyl), -R)⁸-N(C₁-C₄Alkyl radical)₂、-R⁸-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl), -R)⁸-N(C₁-C₄Haloalkyl groups)₂、-R¹¹、-OR¹¹or-O-R¹⁰-R¹¹(ii) a Wherein

R⁸Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R¹⁰is C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and is

R¹¹Is C₃-C₆Cycloalkyl or a 4-to 6-membered saturated heterocyclyl, wherein cycloalkyl or heterocyclyl is optionally substituted with halo and/or is optionally substituted with one, two or three substituents independently selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₄Cycloalkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, phenyl, benzyl, -OH, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl), -NH₂、-NH(C₁-C₄Alkyl), -NH (C)₁-C₄Haloalkyl), -N (C)₁-C₄Alkyl radical)₂、-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl) and-N (C)₁-C₄Haloalkyl groups)₂。

In one embodiment, R²Is hydrogen, halo, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -R⁸-OH、-R⁸-O(C₁-C₄Alkyl), -R⁸-O(C₁-C₄Haloalkyl), -O-R¹⁰-OH、-O-R¹⁰-O(C₁-C₄Alkyl), -O-R¹⁰-O(C₁-C₄Haloalkyl), -R)⁸-NH₂、-R⁸-NH(C₁-C₄Alkyl), -R⁸-NH(C₁-C₄Haloalkyl), -R)⁸-N(C₁-C₄Alkyl radical)₂、-R⁸-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl), -R)⁸-N(C₁-C₄Haloalkyl groups)₂、-R¹¹、-OR¹¹or-O-R¹⁰-R¹¹(ii) a Wherein

R⁸Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R¹⁰is C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and is

R¹¹Is C₃-C₆Cycloalkyl or a 4-to 6-membered saturated heterocyclyl group comprising one or two nitrogen and/or oxygen and/or sulphur ring atoms, wherein cycloalkyl or heterocyclyl group is optionally substituted by halo and/or is optionally substituted by one, two or three independentSubstituted with a substituent selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₄Cycloalkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, phenyl, benzyl, -OH, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl), -NH₂、-NH(C₁-C₄Alkyl), -NH (C)₁-C₄Haloalkyl), -N (C)₁-C₄Alkyl radical)₂、-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl) and-N (C)₁-C₄Haloalkyl groups)₂。

R⁸Is a bond, C₁-C₃Alkylene or C₁-C₃A haloalkylene group;

R¹⁰is C₁-C₃Alkylene or C₁-C₃A haloalkylene group; and is

R¹¹Is C₃-C₆Cycloalkyl or a 4-to 6-membered saturated heterocyclic group containing one nitrogen or oxygen ring atom, wherein cycloalkyl or heterocyclic group is optionally halogenatedSubstituted and/or optionally substituted with one, two or three substituents independently selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₄Cycloalkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, phenyl, benzyl, -OH, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl), -NH₂、-NH(C₁-C₄Alkyl), -NH (C)₁-C₄Haloalkyl), -N (C)₁-C₄Alkyl radical)₂、-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl) and-N (C)₁-C₄Haloalkyl groups)₂。

R⁸Is a bond or-CH₂-；

R¹⁰Is C₁-C₃An alkylene group; and is

R¹¹Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl, each optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: c₁-C₃Alkyl radical, C₁-C₃Haloalkyl, C₂-C₃Alkenyl radical, C₂-C₃Haloalkenyl, phenyl, benzyl, -OH, -O (C)₁-C₃Alkyl), -O (C)₁-C₃Haloalkyl), -NH₂、-NH(C₁-C₃Alkyl), -NH (C)₁-C₃Haloalkyl), -N (C)₁-C₃Alkyl radical)₂、-N(C₁-C₃Alkyl) (C₁-C₃Haloalkyl) and-N (C)₁-C₃Haloalkyl groups)₂。

In one embodiment, R²Is hydrogen, halo, cyano, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, -R⁸-OH、-R⁸-O(C₁-C₃Alkyl), -R⁸-O(C₁-C₃Haloalkyl), -O-R¹⁰-OH、-O-R¹⁰-O(C₁-C₃Alkyl), -R¹¹、-OR¹¹or-O-R¹⁰-R¹¹(ii) a Wherein

R⁸Is a bond or-CH₂-；

R¹⁰Is C₁-C₃An alkylene group; and is

R¹¹Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl, each optionally substituted with one or two substituents independently selected from: fluorine, C₁-C₃Alkyl radical, C₂-C₃Alkenyl, phenyl, benzyl, -OH, -O (C)₁-C₃Alkyl), -NH₂、-NH(C₁-C₃Alkyl) and-N (C)₁-C₃Alkyl radical)₂。

R⁸Is a bond or-CH₂-；

R¹⁰Is C₁-C₃An alkylene group; and is

R¹¹Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,Pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl, each optionally substituted with one or two substituents independently selected from: fluorine, methyl, -OH, -OMe, -NHMe and-NMe₂。

In one embodiment, when R¹¹In the case of pyrrolidinyl or piperidinyl, the pyrrolidinyl or piperidinyl group is substituted on the nitrogen ring atom.

B may be at the alpha, beta or gamma position (relative to the point of attachment of B to A) via R²And (4) substitution. In one embodiment, B is via R at the beta or gamma position²And (4) substitution. In one embodiment, B is via R in the beta position²And (4) substitution.

In one embodiment, B is pyridin-4-yl, in the beta position via R²Substituted, and optionally additionally substituted.

In one embodiment, B is optionally via R²Substituted and optionally further substituted with one or two substituents independently selected from: halo, C₁-C₃Alkyl, -O (C)₁-C₃Alkyl), -OH, -NH₂and-CN. In one embodiment, B is further substituted with one or two substituents independently selected from the group consisting of: fluorine, chlorine, methyl, ethyl, -OMe, -OEt, -OH, -NH₂and-CN. In one embodiment, B is further substituted with methyl.

X is O, NH or N (CN). In one embodiment, X is O or NH. In one embodiment, X is O.

Y is O or S. In one embodiment, Y is O.

R¹Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo; wherein R is²⁰Is a bond, -NH-, -NMe-, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; r²¹Is C₃-C₆Cycloalkyl, phenyl, 4-to 6-membered saturated heterocyclyl or 5-or 6-membered heteroaryl, all optionally substituted by haloAnd/or optionally substituted with one or two substituents independently selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, -R²²-OH、-R²²-O(C₁-C₄Alkyl), -R²²-O(C₁-C₄Haloalkyl), -R)²²-NH₂、-R²²-NH(C₁-C₄Alkyl), -R²²-NH(C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Alkyl radical)₂、-R²²-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Haloalkyl groups)₂and-R²²-R²³；R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and R is²³Is C₃-C₆Cycloalkyl or 4 to 6 membered saturated heterocyclyl, each optionally substituted with halo.

In one embodiment, R¹Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo; wherein R is²⁰Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; r²¹Is C₃-C₆Cycloalkyl, phenyl, 4-to 6-membered saturated heterocyclyl or 5-or 6-membered heteroaryl, all optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, -R²²-OH、-R²²-O(C₁-C₄Alkyl), -R²²-O(C₁-C₄Haloalkyl), -R)²²-NH₂、-R²²-NH(C₁-C₄Alkyl), -R²²-NH(C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Alkyl radical)₂、-R²²-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Haloalkyl groups)₂and-R²²-R²³；R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and R is²³Is C₃-C₆Cycloalkyl or 4 to 6 membered saturated heterocyclyl, each optionally substituted with halo.

In one embodiment, R¹Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₃Alkyl), -N (C)₁-C₃Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo; wherein R is²⁰Is a bond, C₁-C₃Alkylene or C₁-C₃A haloalkylene group; r²¹Is C₃-C₆Cycloalkyl or phenyl, or a 4-to 6-membered saturated heterocyclyl group comprising one or two nitrogen and/or oxygen and/or sulphur ring atoms, or a 5-or 6-membered heteroaryl group comprising one, two or three nitrogen and/or oxygen and/or sulphur ring atoms, each optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, -R²²-OH、-R²²-O(C₁-C₄Alkyl), -R²²-O(C₁-C₄Haloalkyl), -R)²²-NH₂、-R²²-NH(C₁-C₄Alkyl), -R²²-NH(C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Alkyl radical)₂、-R²²-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Haloalkyl groups)₂and-R²²-R²³；R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and R is²³Is C₃-C₆Cycloalkyl or a 4-to 6-membered saturated heterocyclic group containing one or two nitrogen and/or oxygen and/or sulfur ring atoms, are each optionally substituted with halo.

In one embodiment, R¹Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NHMe, -NMe₂、-NHEt、-NEt₂-NMeEt or-R²⁰-R²¹Each of which is optionally substituted with halo; wherein R is²⁰Is a bond or C₁-C₂An alkylene group; r²¹Is C₃-C₆Cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, or oxadiazolyl, all optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: cyano radicals, C₁-C₄Alkyl, -R²²-OH、-R²²-O(C₁-C₄Alkyl), -R²²-NH(C₁-C₄Alkyl), -R²²-N(C₁-C₄Alkyl radical)₂and-R²²-R²³；R²²Is a bond or C₁-C₄An alkylene group; and R is²³Is C₃-C₆Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

In one embodiment, R¹Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NHMe, -NMe₂、-NHEt、-NEt₂or-NMeEt, each optionally substituted with halo; or R¹Is C₃-C₆Cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolylOxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl or oxadiazolyl, all optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: cyano radicals, C₁-C₄Alkyl, -R²²-OH、-R²²-O(C₁-C₄Alkyl), -R²²-NH(C₁-C₄Alkyl), -R²²-N(C₁-C₄Alkyl radical)₂and-R²²-R²³(ii) a Wherein R is²²Is a bond or C₁-C₄An alkylene group; and R is²³Is C₃-C₆Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

In one embodiment, R¹Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NHMe, -NMe₂、-NHEt、-NEt₂or-NMeEt, each optionally substituted with halo; or R¹Is C₃-C₆Cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, thienyl, pyrazolyl or imidazolyl, all optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: c₁-C₃Alkyl, -R²²-OH、-R²²-O(C₁-C₃Alkyl), -R²²-NH(C₁-C₃Alkyl), -R²²-N(C₁-C₃Alkyl radical)₂and-R²²-R²³(ii) a Wherein R is²²Is a bond or C₁-C₄An alkylene group; and R is²³Is C₃-C₆Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

In one embodiment, R¹Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NHMe, -NMe₂、-NHEt、-NEt₂or-NMeEt; or R¹Is C₃-C₆Cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, phenyl, pyrrolidinyl, piperidinyl, and piperazinyl,Thienyl, pyrazolyl or imidazolyl, all optionally via C₁-C₃Alkyl, -R²²-OH、-R²²-O(C₁-C₃Alkyl), -R²²-NH(C₁-C₃Alkyl), -R²²-N(C₁-C₃Alkyl radical)₂or-R²²-R²³Substitution; wherein R is²²Is a bond or C₁-C₄An alkylene group; and R is²³Is C₃-C₆Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

In one embodiment, R¹Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NHMe, -NMe₂、-NHEt、-NEt₂or-NMeEt; or R¹Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, thienyl, pyrazolyl or imidazolyl, all optionally via C₁-C₃Alkyl, -R²²-OH、-R²²-O(C₁-C₃Alkyl), -R²²-NH(C₁-C₃Alkyl), -R²²-N(C₁-C₃Alkyl radical)₂or-R²²-R²³Substitution; wherein R is²²Is a bond or C₁-C₄An alkylene group; and R is²³Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl.

In one embodiment, R¹Is methyl, ethyl or-NMe₂(ii) a Or R¹Is cyclopropyl, phenyl, furyl or pyrazolyl, each optionally substituted by methyl, ethyl, isopropyl, CMe₂(OH) or cyclopropyl substitution.

In one embodiment, when R¹In the case of pyrrolidinyl, piperidinyl, pyrazolyl or imidazolyl, the pyrrolidinyl, piperidinyl, pyrazolyl or imidazolyl group is substituted on the nitrogen ring atom.

In one embodiment, a is phenyl substituted with B in the alpha position and R in the beta position⁷Substituted in the alpha' position by R⁴Substituted, and optionally additionally substituted; and R is¹Is methyl, ethyl or-NMe₂Or R is¹Is cyclopropyl, phenyl, furyl or pyrazolyl, each optionally substituted by methyl, ethyl, isopropyl, CMe₂(OH) or cyclopropyl substitution.

In another embodiment, A is imidazolyl substituted at the alpha position with B and at the beta position with R⁷Substituted in the alpha' position by R⁴Substituted, and optionally additionally substituted; and R is¹Is furyl or pyrazolyl, each optionally substituted by methyl, ethyl, isopropyl, CMe₂(OH) or cyclopropyl substitution.

In one embodiment, R⁴Is monovalent and is in the alpha' position (relative to A and R)¹(X) the point of attachment of (O) -NH-CY-NH-is attached to A and is selected from C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl and phenyl, each optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: oxo (═ O), -OH, -O (C)₁-C₄Alkyl) and-O (C)₁-C₄Haloalkyl). In one embodiment, R⁴Is monovalent and is linked to a at the α' position and is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl, all optionally substituted with halo and/or optionally substituted with one substituent selected from: oxo, -OH, -O (C)₁-C₄Alkyl) and-O (C)₁-C₄Haloalkyl). In one embodiment, R⁴Is monovalent and is attached to a at the α' position and is selected from isopropyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl, all optionally substituted with halo. In one embodiment, R⁴Is monovalent and is attached to a at the α' position and is selected from isopropyl, cyclopentyl, cyclohexyl, and phenyl, all optionally substituted with halo. In one embodiment, R⁴Is monovalent, andis linked to a at the α' position and is selected from isopropyl, cyclopentyl, cyclohexyl and phenyl. In one embodiment, R⁴Is isopropyl attached to a at the α' position.

In an alternative embodiment, R⁴Is divalent and is in the alpha 'and beta' positions (relative to A and R)¹(X) the point of attachment of (O) -NH-CY-NH-is attached to A and is selected from-CH₂CH₂CH₂-、-CH＝CHCH₂-、-CH₂CH＝CH-、-CH₂CH₂O-、-OCH₂CH₂-、-CH₂CH₂CH₂CH₂-and-CH-, both optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: oxo (═ O), -OH, -O (C)₁-C₄Alkyl) and-O (C)₁-C₄Haloalkyl). In one embodiment, R⁴Is divalent and is linked to A in the alpha 'and beta' positions and is selected from-CH₂CH₂CH₂-、-CH₂CH₂O-and-OCH₂CH₂-, are each optionally substituted by halo and/or optionally by one substituent selected from: oxo, -OH, -O (C)₁-C₄Alkyl) and-O (C)₁-C₄Haloalkyl). In one embodiment, R⁴Is divalent and is linked to A in the alpha 'and beta' positions and is selected from-CH₂CH₂CH₂-、-CH₂CH₂O-and-OCH₂CH₂-, are each optionally substituted by halo. In one embodiment, R⁴Is divalent and is linked to A in the alpha 'and beta' positions and is selected from-CH₂CH₂CH₂-、-CH₂CH₂O-and-OCH₂CH₂-. In one embodiment, R⁴to-CH of A in alpha 'and beta' positions₂CH₂CH₂-a group.

R⁷Is C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl radical, C₃-C₆Halocycloalkyl, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl) or halogen. In one embodiment, R⁷Is C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl radical, C₃-C₆Halocycloalkyl or halogen. In one embodiment, R⁷Is methyl, ethyl, halomethyl, haloethyl, cyclopropyl, halocyclopropyl or halogen. In one embodiment, R⁷Is methyl, ethyl, trifluoromethyl, cyclopropyl or fluoro. In one embodiment, R⁷Is methyl, ethyl, cyclopropyl or fluoro. In one embodiment, R⁷Is methyl.

The first aspect of the present invention also provides a compound of formula (IA):

wherein:

b is phenyl, 5-or 6-membered heteroaryl or 4-to 6-membered saturated heterocyclyl, wherein B is substituted with R²And wherein B is optionally additionally substituted;

x is O, NH or N (CN);

y is O or S;

R¹is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo;

R⁷is C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl radical, C₃-C₆Halocycloalkyl, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl) or halogen;

R⁸is a bond, C₁-C₄Alkylene or C₁-C₄HalogenatedAn alkylene group;

R¹⁰is C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R¹¹is C₃-C₆Cycloalkyl or a 4-to 6-membered saturated heterocyclyl, wherein cycloalkyl or heterocyclyl is optionally substituted with halo and/or is optionally substituted with one, two or three substituents independently selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₄Cycloalkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, phenyl, benzyl, -OH, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl), -NH₂、-NH(C₁-C₄Alkyl), -NH (C)₁-C₄Haloalkyl), -N (C)₁-C₄Alkyl radical)₂、-N(C₁-C₄Alkyl) (C₁-C₄Haloalkyl) and-N (C)₁-C₄Haloalkyl groups)₂；

R²⁰Is a bond, -NH-, -NMe-, C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R²¹is C₃-C₆Cycloalkyl, phenyl, 4-to 6-membered saturated heterocyclyl or 5-or 6-membered heteroaryl, all optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: cyano radicals, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Haloalkenyl, -R²²-OH、-R²²-O(C₁-C₄Alkyl), -R²²-O(C₁-C₄Haloalkyl), -R)²²-NH₂、-R²²-NH(C₁-C₄Alkyl), -R²²-NH(C₁-C₄Haloalkyl), -R)²²-N(C₁-C₄Alkyl radical)₂、-R²²-N(C₁-C₄Alkyl) (C₁-C₄Halogenated alkyl) compoundsR²²-N(C₁-C₄Haloalkyl groups)₂and-R²²-R²³；

R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and is

R²³Is C₃-C₆Cycloalkyl or 4 to 6 membered saturated heterocyclyl, each optionally substituted with halo.

A, B, X, Y, R described above for the compound of formula (I)¹、R²、R⁴、R⁷、R⁸、R¹⁰、R¹¹、R²⁰、R²¹、R²²And R²³The embodiments of (a) apply equally to the compounds of formula (IA).

The first aspect of the present invention also provides a compound of formula (II):

wherein:

x is O, NH or N (CN);

R¹is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo;

R^2ais hydrogen, halo, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl), -O- (alkoxyalkyl), -OR⁹or-OCH₂-R⁹；

R³Is hydrogen or methyl;

R^4ais C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl or phenyl, each optionally substituted with halo;

R⁵is hydrogen; or

R^4aAnd R⁵Together form-CH₂CH₂CH₂-、-CH₂CH₂O-or-OCH₂CH₂-, are each optionally substituted by halo;

R⁶is hydrogen, halogen or cyano;

R⁷is C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl radical, C₃-C₆Halocycloalkyl or halogen;

R⁹is C₃-C₆Cycloalkyl or a 4-to 6-membered saturated heterocyclyl, wherein cycloalkyl or heterocyclyl is optionally substituted with halo and/or is optionally substituted with one, two or three substituents independently selected from: c₁-C₄Alkyl radical, C₂-C₄Alkenyl, phenyl, benzyl, -OH, -O (C)₁-C₄Alkyl), -NH (C)₁-C₄Alkyl) and-N (C)₁-C₄Alkyl radical)₂；

R²⁰Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and is

R²³Is C₃-C₆Cycloalkyl or 4 to 6 membered saturated heterocyclyl, each optionally substituted with halo.

X, R described above for the compound of formula (I)¹、R⁷、R²⁰、R²¹、R²²And R²³The embodiments of (a) apply equally to the compounds of formula (II).

R^2aIs hydrogen, halo, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl), -O- (alkoxyalkyl), -OR⁹or-OCH₂-R⁹(ii) a Wherein R is⁹Is C₃-C₆Cycloalkyl or a 4-to 6-membered saturated heterocyclyl, wherein cycloalkyl or heterocyclyl is optionally substituted with halo and/or is optionally substituted with one, two or three substituents independently selected from: c₁-C₄Alkyl radical, C₂-C₄Alkenyl, phenyl, benzyl, -OH, -O (C)₁-C₄Alkyl), -NH (C)₁-C₄Alkyl) and-N (C)₁-C₄Alkyl radical)₂。

In one embodiment, R^2aIs hydrogen, halo, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O (C)₁-C₄Alkyl), -O (C)₁-C₄Haloalkyl), -O- (alkoxyalkyl), -OR⁹or-OCH₂-R⁹(ii) a Wherein R is⁹Is C₃-C₆Cycloalkyl or a 4-to 6-membered saturated heterocyclyl comprising one or two nitrogen and/or oxygen ring atoms, wherein cycloalkyl or heterocyclyl is optionally substituted with halo and/or is optionally substituted with one, two or three substituents independently selected from: c₁-C₄Alkyl radical, C₂-C₄Alkenyl, benzeneRadical, benzyl, -OH, -O (C)₁-C₄Alkyl), -NH (C)₁-C₄Alkyl) and-N (C)₁-C₄Alkyl radical)₂。

In one embodiment, R^2aIs hydrogen, cyano, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, -O (C)₁-C₃Alkyl), -O (C)₁-C₃Haloalkyl), -O- (alkoxyalkyl), -OR⁹or-OCH₂-R⁹(ii) a Wherein R is⁹Is C₃-C₆Cycloalkyl or a 4 to 6 membered saturated heterocyclyl comprising one nitrogen or oxygen ring atom, wherein cycloalkyl or heterocyclyl is optionally substituted with halo and/or is optionally substituted with one or two substituents independently selected from: c₁-C₃Alkyl, -OH, -O (C)₁-C₃Alkyl), -NH (C)₁-C₃Alkyl) and-N (C)₁-C₃Alkyl radical)₂。

In one embodiment, R^2aIs hydrogen, cyano, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, -O (C)₁-C₃Alkyl), -O (C)₁-C₃Haloalkyl), -O- (alkoxyalkyl), -OR⁹or-OCH₂-R⁹(ii) a Wherein R is⁹Is C₃-C₆Cycloalkyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl, each optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: c₁-C₃Alkyl, -OH, -O (C)₁-C₃Alkyl), -NH (C)₁-C₃Alkyl) and-N (C)₁-C₃Alkyl radical)₂。

In one embodiment, R^2aIs hydrogen, cyano, methyl, ethyl, n-propyl, isopropyl, halomethyl, haloethyl, -OMe, -OEt, -O- (halomethyl), -O- (haloethyl), -O- (methoxyalkyl) OR-OR⁹(ii) a Wherein R is⁹Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl,are each optionally substituted with one substituent selected from: methyl, ethyl, -OH, -OMe, -OEt, -NHMe, -NMe₂、-NHEt、-NEt₂and-NMeEt.

In one embodiment, when R⁹In the case of pyrrolidinyl or piperidinyl, the pyrrolidinyl or piperidinyl group is substituted on the nitrogen ring atom.

R³Is hydrogen or methyl. In one embodiment, R³Is hydrogen. In one embodiment, R³Is methyl.

In one embodiment of the compound of formula (II), R⁵Is hydrogen and R^4aIs C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl or phenyl, each optionally substituted with halo. In one embodiment, R^4aIs methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, all optionally substituted by halo. In one embodiment, R^4aIs isopropyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl, all optionally substituted by halo. In one embodiment, R^4aIs isopropyl, cyclopentyl, cyclohexyl or phenyl, all optionally substituted with halo. In one embodiment, R^4aIs isopropyl, cyclopentyl, cyclohexyl or phenyl. In one embodiment, R^4aIs isopropyl.

In an alternative embodiment of the compound of formula (II), R^4aAnd R⁵Together form-CH₂CH₂CH₂-、-CH₂CH₂O-or-OCH₂CH₂-, are each optionally substituted by halo. In one embodiment, R^4aAnd R⁵Together form-CH₂CH₂CH₂-、-CH₂CH₂O-or-OCH₂CH₂-. In one embodiment, R^4aAnd R⁵Together form-CH₂CH₂CH₂-。

R⁶Is hydrogen or halogenOr a cyano group. In one embodiment, R⁶Is hydrogen, fluorine, chlorine or cyano. In one embodiment, R⁶Is hydrogen or fluorine.

In one embodiment, the present invention provides a compound of formula (II) wherein:

x is O or NH;

R¹is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NHMe, -NMe₂、-NHEt、-NEt₂or-NMeEt, each optionally substituted with halo; or R¹Is C₃-C₆Cycloalkyl, phenyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, thienyl, pyrazolyl or imidazolyl, all optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: c₁-C₃Alkyl, -R²²-OH、-R²²-O(C₁-C₃Alkyl), -R²²-NH(C₁-C₃Alkyl), -R²²-N(C₁-C₃Alkyl radical)₂and-R²²-R²³；

R^2aIs hydrogen, cyano, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, -O (C)₁-C₃Alkyl), -O (C)₁-C₃Haloalkyl), -O- (alkoxyalkyl), -OR⁹or-OCH₂-R⁹；

R³Is hydrogen or methyl;

R^4ais isopropyl, cyclopentyl, cyclohexyl or phenyl;

R⁵is hydrogen; or

R^4aAnd R⁵Together form-CH₂CH₂CH₂-、-CH₂CH₂O-or-OCH₂CH₂-；

R⁶Is hydrogen, halogen or cyano;

R⁷is methyl, ethyl, cyclopropyl or fluoro;

R⁹is C₃-C₆A cycloalkyl group, a,Pyrrolidinyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl, each optionally substituted with halo and/or optionally substituted with one or two substituents independently selected from: c₁-C₃Alkyl, -OH, -O (C)₁-C₃Alkyl), -NH (C)₁-C₃Alkyl) and-N (C)₁-C₃Alkyl radical)₂；

R²²Is a bond or C₁-C₄An alkylene group; and is

R²³Is C₃-C₆Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

The first aspect of the present invention also provides a compound of formula (III):

wherein:

x is O, NH or N (CN);

R¹is C₁-C₄Alkyl radical, C₂-C₄Alkenyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂or-R²⁰-R²¹Each of which is optionally substituted with halo;

R^2bis hydrogen, halo, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O (C)₁-C₄Alkyl) or-O (C)₁-C₄Haloalkyl);

R³is hydrogen or methyl;

R^4bis C₁-C₄Alkyl or C₁-C₄A haloalkyl group;

R⁷is C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Cycloalkyl radical, C₃-C₆Halocycloalkyl or halogen;

R²⁰is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group;

R²²Is a bond, C₁-C₄Alkylene or C₁-C₄A haloalkylene group; and is

R²³Is C₃-C₆Cycloalkyl or 4 to 6 membered saturated heterocyclyl, each optionally substituted with halo.

X, R described above for the compound of formula (I)¹、R⁷、R²⁰、R²¹、R²²And R²³The embodiments of (a) apply equally to the compounds of formula (III).

R^2bIs hydrogen, halo, cyano, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O (C)₁-C₄Alkyl) or-O (C)₁-C₄Haloalkyl). In one embodiment, R^2bIs hydrogen, cyano, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, -O (C)₁-C₃Alkyl) or-O (C)₁-C₃Haloalkyl). In one embodimentIn the scheme, R^2bIs hydrogen, C₁-C₃Alkyl, -O (C)₁-C₃Alkyl) or-O (C)₁-C₃Haloalkyl). In one embodiment, R^2bIs hydrogen, methyl, trifluoromethyl or-OMe. In one embodiment, R^2bIs hydrogen or-OMe.

R³Is hydrogen or methyl. In one embodiment, R³Is hydrogen. In one embodiment, R³Is methyl.

R^4bIs C₁-C₄Alkyl or C₁-C₄A haloalkyl group. In one embodiment, R^4bIs methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, all optionally substituted by halo. In one embodiment, R^4bIs isopropyl, sec-butyl, isobutyl or tert-butyl, all optionally substituted by halo. In one embodiment, R^4bIs isopropyl optionally substituted with halo. In one embodiment, R^4bIs isopropyl.

In one embodiment, the present invention provides a compound of formula (III) wherein:

x is O or NH;

R^2bIs hydrogen, cyano, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, -O (C)₁-C₃Alkyl) or-O (C)₁-C₃Haloalkyl);

R³is hydrogen or methyl;

R^4bis C₁-C₄Alkyl or C₁-C₄A haloalkyl group;

R⁷is methyl, ethyl, cyclopropyl or fluoro;

R²²is a bond or C₁-C₄An alkylene group; and is

R²³Is C₃-C₆Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

In one aspect of any of the above embodiments, R¹Containing from 1 to 30 atoms other than hydrogen. More typically, R¹Containing from 1 to 25 atoms other than hydrogen. More typically, R¹Containing 1 to 20 atoms other than hydrogen. More typically, R¹Containing 1 to 16 atoms other than hydrogen.

In an aspect of any of the above embodiments, A, B, R⁴And R⁷Together containing from 11 to 50 atoms other than hydrogen. More typically A, B, R⁴And R⁷Together containing from 12 to 45 atoms other than hydrogen. More typically A, B, R⁴And R⁷Together containing from 13 to 40 atoms other than hydrogen. Most typically A, B, R⁴And R⁷Together containing from 14 to 35 atoms other than hydrogen.

In one aspect of any of the above embodiments, the compound of formula (I), (IA), (II) or (III) has a molecular weight of 250 to 2,000 Da. Typically, the compound of formula (I), (IA), (II) or (III) has a molecular weight of 300 to 1,000 Da. Typically, the compound of formula (I), (IA), (II) or (III) has a molecular weight of 310 to 800 Da. More typically, the compound of formula (I), (IA), (II) or (III) has a molecular weight of 320 to 650 Da.

A second aspect of the invention provides a compound selected from the group consisting of:

a third aspect of the invention provides a pharmaceutically acceptable salt, solvate or prodrug of any of the compounds of the first or second aspects of the invention.

The compounds of the invention can be used in the form of their free bases and in the form of their acid addition salts. For the purposes of the present invention, "salts" of the compounds of the present invention include acid addition salts. The acid addition salts are preferably pharmaceutically acceptable non-toxic addition salts formed with suitable acids including, but not limited to, inorganic acids such as hydrohalic acids (e.g., hydrofluoric, hydrochloric, hydrobromic or hydroiodic) or other inorganic acids (e.g., nitric, perchloric, sulfuric or phosphoric); or organic acids, for example organic carboxylic acids (for example propionic acid, butyric acid, glycolic acid, lactic acid, mandelic acid, citric acid, acetic acid, benzoic acid, salicylic acid, succinic acid, malic acid or malic acid, tartaric acid, fumaric acid, maleic acid, hydroxycitric acid, mucic acid or galactaric acid, gluconic acid, pantothenic acid or pamoic acid), organic sulfonic acids (for example methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluene-p-sulfonic acid, naphthalene-2-sulfonic acid or camphorsulfonic acid) or amino acids (for example ornithine, glutamic acid or aspartic acid). The acid addition salts may be mono-, di-, tri-or poly-acid addition salts. Preferred salts are the addition salts of hydrohalic acids, sulfuric acid, phosphoric acid or organic acids. Preferred salts are the hydrochloric acid addition salts.

Where the compounds of the present invention include quaternary ammonium groups, the compounds are typically used in the form of their salts. The counter ion of the quaternary ammonium group can be any pharmaceutically acceptable non-toxic counter ion. Examples of suitable counterions include the conjugate bases of protic acids discussed above with respect to acid addition salts.

The compounds of the invention may also be used both in their free acid form and in their acid addition salt form. For purposes of the present invention, "salts" of the compounds of the present invention include salts formed between a protic acid functionality (e.g., a carboxylic acid group) of the compounds of the present invention and a suitable cation. Suitable cations include, but are not limited to, lithium, sodium, potassium, magnesium, calcium, and ammonium. The salts may be mono-, di-, tri-or poly-salts. The salt is preferably a mono-or dilithium, sodium, potassium, magnesium, calcium or ammonium salt. More preferably, the salt is a mono-or disodium salt or a mono-or dipotassium salt.

Preferably, any salt is a pharmaceutically acceptable non-toxic salt. However, in addition to pharmaceutically acceptable salts, other salts are included in the present invention as they may be useful as intermediates in the purification or preparation of other, e.g., pharmaceutically acceptable, salts, or may be useful in the identification, characterization or purification of the free acid or base.

The compounds and/or salts of the present invention may be anhydrous or in the form of hydrates (e.g., hemihydrate, monohydrate, dihydrate or trihydrate) or other solvates. Such other solvates may be formed with common organic solvents including, but not limited to, alcoholic solvents such as methanol, ethanol or isopropanol.

In some embodiments of the invention, a therapeutically inactive prodrug is provided. Prodrugs are compounds which are converted, completely or in part, to the compounds of the present invention when administered to a subject, e.g., a human. In most embodiments, prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to active drug molecules to exert a therapeutic effect. Any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, or stability of the compound, or to otherwise alter the properties of the compound. Typical examples of prodrugs include compounds having biologically labile protecting groups on the functional moiety of the active compound. Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated and/or dephosphorylated to yield the active compound. The invention also encompasses salts and solvates of such prodrugs as described above.

The compounds, salts, solvates and prodrugs of the invention may contain at least one chiral center. Thus, the compounds, salts, solvates and prodrugs may exist in at least two isomeric forms. The present invention encompasses racemic mixtures of the compounds, salts, solvates, and prodrugs of the invention as well as enantiomerically enriched and substantially enantiomerically pure isomers. For the purposes of the present invention, a "substantially enantiomerically pure" isomer of a compound comprises less than 5% by weight of the other isomer of the same compound, more typically less than 2%, and most typically less than 0.5%.

The compounds, salts, solvates, and prodrugs of the invention may contain any stable isotope, including (but not limited to)¹²C、¹³C、¹H、²H(D)、¹⁴N、¹⁵N、¹⁶O、¹⁷O、¹⁸O、¹⁹F and¹²⁷i, and any radioisotope, including (but not limited to)¹¹C、¹⁴C、³H(T)、¹³N、¹⁵O、¹⁸F、¹²³I、¹²⁴I、¹²⁵I and¹³¹I。

the compounds, salts, solvates and prodrugs of the invention may be in any polymorphic or amorphous form.

A fourth aspect of the invention provides a pharmaceutical composition comprising a compound of the first or second aspects of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, and a pharmaceutically acceptable excipient.

Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Aulton's pharmaceuticals-The Design and Manufacture of pharmaceuticals", M.E.Aulton and K.M.G.Taylor, Churchill Livingstone Elsevier, 4 th edition, 2013.

Pharmaceutically acceptable excipients that may be used in the pharmaceutical compositions of the present invention, including adjuvants, diluents or carriers, are excipients commonly used in the pharmaceutical formulation art and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat.

In one embodiment, the pharmaceutical composition of the fourth aspect of the invention additionally comprises one or more other active agents.

In another embodiment, the pharmaceutical composition of the fourth aspect of the invention may be provided as part of a kit of parts, wherein the kit of parts comprises the pharmaceutical composition of the fourth aspect of the invention and one or more further pharmaceutical compositions, wherein the one or more further pharmaceutical compositions each comprise a pharmaceutically acceptable excipient and one or more further active agents.

A fifth aspect of the invention provides a compound of the first or second aspects of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in medicine and/or for use in the treatment or prevention of a disease, disorder or condition. Typically, the use comprises administering the compound, salt, solvate, prodrug or pharmaceutical composition to a subject. In one embodiment, the use comprises co-administration of one or more additional active agents.

As used herein, the term "treatment" refers equally to curative and ameliorative or palliative therapy. The term includes obtaining a beneficial or desired physiological result that may or may not be clinically established. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, prevention of symptoms, diminishment of extent of disease, stabilization (i.e., not worsening) of the condition, delay or slowing of progression/worsening of the condition/symptom, amelioration or palliation of the condition/symptom, and remission (whether partial or complete), whether detectable or undetectable. As used herein, the term "alleviate" and variations thereof means to reduce the extent and/or undesirable manifestations of a physiological condition or symptom, and/or slow or prolong the time course of progression, as compared to not administering a compound, salt, solvate, prodrug, or pharmaceutical composition of the invention. As used herein with respect to a disease, disorder or condition, the term "prevention" refers to prophylactic or preventative therapy as well as therapy that reduces the risk of developing a disease, disorder or condition. The term "preventing" includes both avoiding the onset of a disease, disorder or condition and delaying the onset of a disease, disorder or condition. Avoidance of occurrence, delay of onset, or reduced risk of any statistically significant (p ≦ 0.05) as measured by controlled clinical trials may be considered prevention of the disease, disorder, or condition. Subjects that can be prevented include subjects at increased risk of a disease, disorder, or condition, as identified by genetic or biochemical markers. Typically, genetic or biochemical markers are appropriate for the disease, disorder or condition in question, and may include, for example, inflammatory biomarkers, such as C-reactive protein (CRP) and monocyte chemotactic protein 1(MCP-1) in the case of inflammation; total cholesterol, triglycerides, insulin resistance and C-peptide in case of NAFLD and NASH; and more generally IL-1 β and IL-18 in the context of a disease, disorder or condition that is responsive to inhibition of NLRP 3.

A sixth aspect of the invention provides the use of a compound of the first or second aspect or a pharmaceutically effective salt, solvate or prodrug of the third aspect in the manufacture of a medicament for the treatment or prophylaxis of a disease, disorder or condition. Typically, treatment or prevention comprises administering a compound, salt, solvate, prodrug or drug to the subject. In one embodiment, the treatment or prevention comprises co-administration of one or more additional active agents.

A seventh aspect of the invention provides a method of treatment or prophylaxis of a disease, disorder or condition, which method comprises the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, thereby treating or preventing the disease, disorder or condition. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents. Typically, administration is to a subject in need thereof.

An eighth aspect of the invention provides a compound of the first or second aspects of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in the treatment or prevention of a disease, disorder or condition in a subject, wherein the subject has a germline or somatic non-silent mutation of NLRP 3. The mutation may be, for example, a gain-of-function mutation or other mutation that causes an increase in NLRP3 activity. Typically, the use comprises administering to the subject the compound, salt, solvate, prodrug or pharmaceutical composition. In one embodiment, the use comprises co-administration of one or more additional active agents. The use may further comprise diagnosing an individual with a germline or somatic non-silent mutation of NLRP3, wherein the compound, salt, solvate, prodrug or pharmaceutical composition is administered to the individual based on a positive diagnosis of the mutation. Typically, the NLRP3 mutation in an individual may be identified by any suitable genetic or biochemical means.

A ninth aspect of the invention provides the use of a compound of the first or second aspect or a pharmaceutically effective salt, solvate or prodrug of the third aspect in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition in a subject, wherein the subject has a germline or somatic non-silent mutation of NLRP 3. The mutation may be, for example, a gain-of-function mutation or other mutation that causes an increase in NLRP3 activity. Typically, treating or preventing comprises administering to the subject a compound, salt, solvate, prodrug or drug. In one embodiment, the treatment or prevention comprises co-administration of one or more additional active agents. Treatment or prevention may also include diagnosing an individual with a germline or somatic non-silent mutation of NLRP3, wherein the compound, salt, solvate, prodrug or drug is administered to the individual based on a positive diagnosis of the mutation. Typically, the NLRP3 mutation in an individual may be identified by any suitable genetic or biochemical means.

A tenth aspect of the invention provides a method of treating or preventing a disease, disorder or condition, the method comprising the steps of: diagnosing an individual with a germline or somatic non-silent mutation of NLRP 3; and administering to a diagnostically positive individual an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, thereby treating or preventing the disease, disorder or condition. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents. Typically, administration is to a subject in need thereof.

In general embodiments, the disease, disorder or condition may be a disease, disorder or condition of the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, hepatic system, metabolic system, respiratory system, central nervous system, may be cancer or other malignant disease, and/or may be caused by or associated with a pathogen.

It is understood that these general implementations, defined according to the broad class 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 above general embodiments. One non-limiting example is type I diabetes, which is an autoimmune disease and disease of the endocrine system.

In one embodiment of the fifth, sixth, seventh, eighth, ninth or tenth aspect of the invention, the disease, disorder or condition is responsive to NLRP3 inhibition. As used herein, the term "NLRP 3 inhibition" refers to a complete or partial reduction in the level of activity of NLRP3 and includes, for example, inhibition of active NLRP3 and/or inhibition of activation of NLRP 3.

There is evidence that NLRP 3-induced IL-1 and IL-18 play a role in inflammatory responses that are associated with or caused by a number of different disorders (Menu et al, Clinical and Experimental Immunology,166:1-15,2011; Strowig et al, Nature,481: 278-.

Genetic diseases in which NLRP3 has been proposed to play a role include sickle cell disease (Vogel et al, Blood,130 (suppl 1):2234,2017) and Valosin Containing Protein disease (Nalbandian et al, Inflammation,40(1):21-41,2017).

NLRP3 has been associated with a number of auto-inflammatory diseases including Familial Mediterranean Fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), hyper-immunoglobulinemia D and periodic fever syndrome (HIDS), suppurative arthritis, pyoderma gangrenosum and acne (PAPA), Switter's syndrome (Sweet's syndrome), Chronic Nonbacterial Osteomyelitis (CNO) and acne vulgaris (Cook et al, Eur J Immunol,40: 595-. In particular, NLRP3 mutations have been found to cause a group of rare auto-inflammatory diseases called CAPS (Ozaki et al, J Inflammation Research,8:15-27,2015; Schroder et al, Cell,140:821-832, 2010; and Menu et al, Clinical and Experimental Immunology,166:1-15,2011). CAPS is a genetic disease characterized by recurrent fever and inflammation and consists of three autoinflammatory disorders that form a clinical continuum. These diseases are, in order of increasing severity, Familial Cold Autoinflammatory Syndrome (FCAS), Mu-Weldii syndrome (MWS) and chronic infant neurocutaneous joint syndrome (CINCA; also known as neonatal onset multiple system inflammatory disease, NOMID), and all have been shown to be caused by a functionally acquired mutation of the NLRP3 gene, which leads to increased secretion of IL-1 β.

A number of autoimmune diseases have been shown to involve NLRP3, including, in particular, multiple sclerosis, type 1 diabetes (T1D), psoriasis, Rheumatoid Arthritis (RA), Behcet's disease, Schnitz's syndrome, macrophage activation syndrome (Masters, Clin Immunol,147(3):223 228, 2013; Braddock et al, Nat Rev Drug Disc,3:1-10,2004; Inoue et al, Immunogloy, 139:11-18,2013; Coll et al, Nat Med,21(3): 248; 2015; Scott et al, Clin Exp Rheumatol,34(1):88-93,2016; and Guo et al, Clin Exp (2): 194), lupus 2018), 20120165, (20129) lupus erythematosus (3165, 29, 3165; lupus erythematosus et al,3, 2013165; lupus erythematosus, 3, 3165; lupus erythematosus et al, (3165, 20111-3176, 29, 3165; lupus erythematosus, 3, multiple sclerosis (Xu et al, J Cell Biochem,120(4): 5160-.

NLRP3 has also been shown to play a role in a number of pulmonary diseases including Chronic Obstructive Pulmonary Disease (COPD), asthma (including steroid resistant asthma and eosinophilic asthma), asbestosis and silicosis (De Nardo et al, Am J Pathol,184:42-54,2014; Lv et al, Jbiol Chem,293(48):18454,2018; and Kim et al, Am J Respir Crit Care Med,196(3): 283-.

NLRP3 has also been suggested to play a role in a number of central nervous system disorders, including Parkinson's Disease (PD), Alzheimer's Disease (AD), dementia, Huntington's disease, cerebral malaria, Brain damage caused by pneumococcal meningitis (Walsh et al, Nature Reviews,15:84-97,2014; and Dempsey et al, Brain Behav Immun,61:306-, brain Res Bull,146: 320-.

NRLP3 activity has also been shown to be associated with a variety of metabolic diseases, including type 2 diabetes (T2D), atherosclerosis, obesity, gout, pseudogout, metabolic syndrome (Wen et al, Nature Immunology,13: 352-.

It is also proposed that NLRP3 acts via IL-1 β in: atherosclerosis, myocardial infarction (van Hout et al, Eur Heart J,38(11):828-, doi:10.1056/NEJMoa1707914, 2017).

Other diseases that have been shown to involve NLRP3 include:

ocular diseases, such as wet and dry age-related macular degeneration (Doyle et al, Nature Medicine,18: 791-;

liver diseases, including nonalcoholic steatohepatitis (NASH) (Henao-Meija et al, Nature,482: 179. sup. 185,2012), hepatic ischemia-reperfusion injury (Yu et al, Transplantation,103(2): 353. sup. 362,2019), fulminant hepatitis (Pourcet et al, Gastroenterology,154(5): 1449. sup. 1464, E20,2018), liver fibrosis (Zhang et al, Parasit Vectors,12(1):29,2019), and liver failure (Wang et al, Hepatol Res,48(3): E194-E202,2018);

renal diseases, including renal calcinosis (Anders et al, Kidney Int,93(3):656-669,2018), renal fibrosis (including chronic crystal nephropathy) (Ludwig-Portugall et al, Kidney Int,90(3):525-39,2016) and renal hypertension (Krishnan et al, Br JPharmacol,173(4):752-65, 2016);

-conditions associated with diabetes, including diabetic encephalopathy (Zhai et al, Molecules,23(3):522,2018), diabetic retinopathy (Zhang et al, Cell Death Dis,8(7): e2941,2017) and diabetic hypoadiponectin-emia (Zhang et al, Biochimica et Biophysica Acta (BBA) -Molecular Basis of Disease,1863(6): 1556-;

inflammatory responses in the lung and skin (Primiano et al, J Immunol,197(6): 2421. sup. 33,2016), including pulmonary ischemia-reperfusion injury (Xu et al, Biochemical and Biophysical Research Communications,503(4): 3031. sup. 3037,2018), epithelial-mesenchymal transition (EMT) (Li et al, Experimental Research,362(2): 489. sup. 497,2018), contact hypersensitivity (e.g. bullous pemphigoid (Fan et al, J Dermatol Sci,83(2): 116. sup. 23,2016)), atopic dermatitis (Niebuhr et al, Allergy,69(8): 1058. sup. 67,2014), hidradenitis suppurativa (Alhan et al, J Amacad, Dermatory, 60, Jatroph 4. sup. 539, J25. sup. J.: 3588, J25, J. sup. 12, J. sup. J. 12, J. sup. 12, J. sup. 12, J. sup. 12, J. sup. Puff, J. acidal, J. 12, J. acidal;

inflammatory reactions in the joints (Braddock et al, Nat Rev Drug Disc,3:1-10,2004) and osteoarthritis (Jin et al, PNAS,108(36):14867-14872, 2011);

amyotrophic lateral sclerosis (Gugliandolo et al, Inflammation,41(1):93-103,2018);

cystic fibrosis (Ianitti et al, Nat Commun,7:10791,2016);

stroke (Walsh et al, Nature Reviews,15:84-97,2014);

chronic kidney disease (Granata et al, PLoS One,10(3): e0122272,2015);

-sjogren's disease syndrome (Syndrome) (Vakrakou et al, Journal of Autoimmitude, 91:23-33,2018);

sickle cell disease (Vogel et al, Blood,130 (supplement 1):2234,2017); and

colitis and inflammatory bowel disease, including ulcerative colitis and Crohn's disease (Braddock et al, Nat Rev Drug Disc,3:1-10,2004; Neudecker et al, J Exp Med,214(6): 1737-.

Gene excision of NLRP3 has been shown to avoid HSD (high glucose diet), HFD (high fat diet) and HSFD induced obesity (Pavillard et al, Oncotarget,8(59): 99740-.

It has been found that NLRP3 inflammasome is activated in response to oxidative stress, sunburn (Hasegawa et al, Biochemical and Biophysical Research Communications,477(3): 329-.

NLRP3 is also shown to be related to: inflammatory hyperalgesia (Dolunay et al, Inflammation,40: 366-.

Inflammasomes, in particular NLRP3, have also been proposed as targets for regulation by a variety of pathogens, including bacterial pathogens such as Staphylococcus aureus (Staphylococcus aureus) (Cohen et al, Cell Reports,22(9): 2431-; viruses, such as DNA viruses (Amsler et al, Future Virol,8(4): 357-; fungal pathogens, such as Candida albicans (Tucey et al, mSphere,1(3), pi i: e00074-16,2016); and other Pathogens, such as Toxoplasma gondii (T. gondii) (Gov et al, J Immunol,199(8): 2855-. NLRP3 has been shown to be required for effective control of viral, bacterial, fungal and helminth pathogen infections (Strowig et al Nature 481: 278-.

NLRP3 is also associated with the pathogenesis of many cancers (Menu et al Clinical and Experimental Immunology,166:1-15,2011; and Masters, Clin Immunol,147(3): 223-. For example, several previous studies have suggested a role for IL-1 β in cancer aggressiveness, growth and metastasis, and inhibition of IL-1 β with canakinumab in randomized, double-blind, placebo-controlled trials has been shown to reduce lung cancer incidence and overall cancer mortality (Ridker et al, Lancet, S0140-6736(17)32247-X, 2017). Inhibition of NLRP3 inflammasome or IL-1. beta. has also been shown to inhibit proliferation and migration of lung cancer cells in vitro (Wang et al, Oncol Rep,35(4):2053-64,2016). The role of NLRP3 inflammasome in myelodysplastic syndrome has been proposed (Basiorka et al, Blood,128(25):2960-, breast Cancer (Guo et al, Scientific Reports,6:36107,2016), inflammation-induced tumors (Allen et al, J Exp Med,207(5): 1045-. Activation of the NLRP3 inflammasome was also shown to mediate chemoresistance of tumor cells to 5-fluorouracil (5-fluorouracil) (Feng et al, J Exp Clin Cancer Res,36(1):81,2017), and activation of the NLRP3 inflammasome in peripheral nerves contributes to chemotherapy-induced neuropathic Pain (Jia et al, Mol Pain,13:1-11,2017).

(i) inflammation, including inflammation that occurs as a result of an inflammatory disorder (e.g., an autoinflammatory disease), inflammation that occurs as a result of a symptom of a non-inflammatory disorder, inflammation that occurs as a result of infection, or inflammation secondary to trauma, injury, or autoimmunity;

(ii) autoimmune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti-synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune gland failure, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpa sture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki' disease, lupus erythematosus (including Systemic Lupus Erythematosus (SLE)), Multiple Sclerosis (MS) (including Primary Progressive Multiple Sclerosis (PPMS), Secondary Progressive Multiple Sclerosis (SPMS) and relapsing-remitting multiple sclerosis (RRMS)), myasthenia gravis, ocular clonus-myoclonus syndrome (OMS), optic neuritis, oddi's thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, Rheumatoid Arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Reiter's syndrome, sjogren's syndrome ((s) ((r)'s syndrome) syndrome), systemic sclerosis (a systemic connective tissue disorder), Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, systemic alopecia, behcet's disease, Chagas' disease, familial autonomic spiritMenstrual abnormalities, endometriosis, Hidradenitis Suppurativa (HS), interstitial cystitis, neuromuscular stiffness, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, senitler syndrome, macrophage activation syndrome, Blau syndrome, leukoderma or vulvar pain;

(iii) cancers including lung, pancreatic, gastric, myelodysplastic syndromes, leukemias (including Acute Lymphocytic Leukemia (ALL) and Acute Myelogenous Leukemia (AML)), adrenal, anal, basal and squamous cell skin, bile duct, bladder, bone, brain and spinal cord tumors, breast, cervical, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal, endometrial, esophageal, Ewing family of tumors (Ewing family of tumors), eye, gall bladder, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, gliomas, Hodgkin lymphoma (Hodgkin lymphoma), Kaposi's sarcoma (Kaposi's sarcoma), kidney, larynx and hypopharynx cancers, liver, lung carcinoid tumors, lung tumors, colon, stomach, colon, rectum, and larynx tumors, Lymphoma (including cutaneous T-cell lymphoma), malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer (Merkel cell skin cancer), multiple myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymus cancer, thyroid cancer (including undifferentiated thyroid cancer), uterine sarcoma, vaginal cancer, vulval cancer, waldenstrom's macroglobulinemia, and Wilms tumor (Wilms tunour);

(iv) infections, including viral infections (e.g., from influenza virus, Human Immunodeficiency Virus (HIV), alphaviruses (e.g., chikungunya virus and Ross river virus), flaviviruses (e.g., Dengue virus (Dengue virus) and Zika virus), herpes viruses (e.g., Epstein Barr virus, cytomegalovirus, varicella-zoster virus and KSHV), poxviruses (e.g., vaccinia virus (Modified vaccinia virus Ankara) and myxoma virus), adenoviruses (e.g., adenovirus 5) or papilloma virus), bacterial infections (e.g., from Staphylococcus aureus, Helicobacter pylori (Helicobacter pylori), Bacillus anthracis (Bacillus anthracis), Bordetella pertussis (Bordetella pertussis), Burkholderia-like (Burkholderia rhinovirus), Corynebacterium diphtheria (Corynebacterium), Clostridium tetanium), Klebsiella pneumoniae (Clostridium), Clostridium (Clostridium), Rheumatobacter) viruses (Clostridium), herpes viruses (Clostridium), and Bacillus spp) Clostridium botulinum (Clostridium botulinum), Streptococcus pneumoniae (Streptococcus pneumniae), Streptococcus pyogenes (Streptococcus pyogenes), Listeria monocytogenes (Listeria monocytogenes), Haemophilus influenzae (Hemophilus influenzae), Pasteurella multocida (Pasteurella mulida), Bacillus dysenteriae (Shigella dysseneria), Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium leprae (Mycobacterium leprae), Mycoplasma pneumoniae (Mycoplasma pneumniae), Mycoplasma hominus (Mycoplasma hominis), Neisseria meningitidis (Neisseria meningitidis), Neisseria gonorrhoeae (Neisseria gonorrhoeae), Salmonella rickettii (Rickettsia rickettii), Salmonella typhimurium (Klebsiella pneumoniae), Salmonella typhimurium (Salmonella typhimurium), Salmonella typhimurium (Salmonella pneumoniae), Salmonella typhi-pneumoniae (Salmonella typhi-la pneumoniae), Salmonella typhi-la pneumoniae (Salmonella typhi-la-pneumoniae), Salmonella typhi-la-pneumoniae (Salmonella-typhi), Salmonella-typhi, Salmonella-typhi, and Salmonella-typhi (i), and (Salmonella-typhi, Borrelia burgdorferi (Borrelia burgdorferi) or Yersinia pestis (Yersinia pestis)), fungal infections (e.g. from Candida (Candida) or Aspergillus species), protozoal infections (e.g. from plasmodium, Babesia (Babesia), Giardia (Giardia), Entamoeba (Entamoeba), leishmania or trypanosoma), helminth infections (e.g. from schistosoma, ascaris, cestodes or trematodes) and prion infections;

(v) central nervous system diseases such as parkinson's disease, alzheimer's disease, dementia, motor neuron disease, huntington's disease, cerebral malaria, brain injury caused by pneumococcal meningitis, intracranial aneurysm, intracerebral hemorrhage, sepsis-related encephalopathy, postoperative cognitive dysfunction, early stage brain injury, traumatic brain injury, and amyotrophic lateral sclerosis;

(vi) metabolic diseases, such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout;

(vii) cardiovascular diseases such as hypertension, ischemia, reperfusion injury (including post-MI ischemia reperfusion injury), stroke (including ischemic stroke), transient ischemic attack, myocardial infarction (including recurrent myocardial infarction), heart failure (including congestive heart failure and ejection fraction retention heart failure), cardiac hypertrophy and fibrosis, embolism, aneurysm (including abdominal aortic aneurysm), and pericarditis (including Dressler's syndrome);

(viii) respiratory diseases including Chronic Obstructive Pulmonary Disease (COPD), asthma (e.g., allergic asthma, eosinophilic asthma, and steroid resistant asthma), asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis;

(ix) liver diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), including advanced fibrosis stages F3 and F4, Alcoholic Fatty Liver Disease (AFLD), Alcoholic Steatohepatitis (ASH), hepatic ischemia-reperfusion injury, fulminant hepatitis, liver fibrosis and liver failure;

(x) Renal diseases, including chronic kidney disease, oxalate kidney disease, nephrocalcinosis, glomerulonephritis, diabetic nephropathy, renal fibrosis (including chronic crystal nephropathy), and renal hypertension;

(xi) Eye diseases including ocular epithelial eye disease, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infections, diabetic retinopathy, optic nerve damage, dry eye and glaucoma;

(xii) Skin diseases including dermatitis (e.g., contact dermatitis and atopic dermatitis), contact hypersensitivity, sunburn, skin lesions, Hidradenitis Suppurativa (HS), other cystic skin diseases, and acne conglobata;

(xiii) Lymphatic disorders such as lymphangitis and Castleman's disease;

(xiv) Psychological disorders, such as depression and psychological stress;

(xv) Graft versus host disease;

(xvi) Touch-induced pain, including mechanical touch-induced pain;

(xvii) Conditions associated with diabetes including diabetic encephalopathy, diabetic retinopathy and diabetic hypoadiponectin; and

(xviii) Any disease in which an individual carries germline or somatic non-silent mutations of NLRP3 has been identified.

In one embodiment, the disease, disorder or condition is selected from:

(i) cancer;

(ii) (ii) infection;

(iii) central nervous system diseases;

(iv) cardiovascular diseases;

(v) liver diseases;

(vi) ocular diseases; or

(vii) Skin diseases.

More typically, the disease, disorder or condition is selected from:

(i) cancer;

(ii) (ii) infection;

(iii) central nervous system diseases; or

(iv) Cardiovascular diseases.

In one embodiment, the disease, disorder or condition is selected from:

(i) acne conglobata;

(ii) atopic dermatitis;

(iii) alzheimer's disease;

(iv) amyotrophic lateral sclerosis;

(v) age-related macular degeneration (AMD);

(vi) undifferentiated thyroid carcinoma;

(vii) coldness-imidacloprid associated periodic syndrome (CAPS);

(viii) contact dermatitis;

(ix) cystic fibrosis;

(x) Congestive heart failure;

(xi) Chronic kidney disease

(xii) Crohn's disease;

(xiii) Familial Cold Autoinflammatory Syndrome (FCAS);

(xiv) Huntington's disease;

(xv) Heart failure;

(xvi) Ejection fraction retention type heart failure;

(xvii) Ischemia reperfusion injury;

(xviii) Juvenile idiopathic arthritis;

(xix) Myocardial infarction;

(xx) Macrophage activation syndrome;

(xxi) Myelodysplastic syndrome;

(xxii) Multiple myeloma;

(xxiii) Motor neuron disease;

(xxiv) Multiple sclerosis;

(xxv) Moore-weidi syndrome;

(xxvi) Nonalcoholic steatohepatitis (NASH);

(xxvii) Neonatal Onset Multisystem Inflammatory Disease (NOMID);

(xxviii) Parkinson's disease;

(xxix) Sickle cell disease;

(xxx) Systemic juvenile idiopathic arthritis;

(xxxi) Systemic lupus erythematosus;

(xxxii) Traumatic brain injury;

(xxxiii) Transient ischemic attack;

(xxxiv) Ulcerative colitis; or

(xxxv) Containing valosin.

In another exemplary embodiment of the invention, the disease, disorder or condition is inflammation. Examples of inflammation that may be treated or prevented according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the invention include inflammatory reactions that are associated with or caused by:

(i) skin disorders, such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema or alopecia;

(ii) joint disorders such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis, or reiter's disease);

(iii) muscular disorders, such as polymyositis or myasthenia gravis;

(iv) gastrointestinal disorders such as inflammatory bowel disease (including crohn's disease and ulcerative colitis), colitis, gastric ulcers, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome or food-related allergies that may have a role away from the intestine (such as migraine, rhinitis or eczema);

(v) respiratory system disorders, such as Chronic Obstructive Pulmonary Disease (COPD), asthma (including eosinophilic asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic or dust asthma and in particular chronic or intractable asthma, such as late asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, purulent rhinitis (rhinitis pumlenta), dry rhinitis, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis (e.g. hay fever) and vasomotor rhinitis), sinusitis, Idiopathic Pulmonary Fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis or idiopathic interstitial pneumonia;

(vi) vascular disorders, such as atherosclerosis, behcet's disease, vasculitis, or wegener's granulomatosis;

(vii) autoimmune disorders, such as systemic lupus erythematosus, sjogren's syndrome, systemic sclerosis, hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or graves ' disease;

(viii) eye disorders such as uveitis, allergic conjunctivitis, or vernal conjunctivitis;

(ix) neurological disorders, such as multiple sclerosis or encephalomyelitis;

(x) Infection or infection-related conditions, such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (type a, type b or type c or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue fever, leishmaniasis, streptococcal myositis, mycobacterium tuberculosis, mycobacterium intracellularis, pneumocystis carinii (pnemocystis carinii), orchitis/epididymitis, legionella, Lyme disease (Lyme disease), influenza a, setan-bal virus infection, viral encephalitis/aseptic meningitis or pelvic inflammatory disease;

(xi) Renal disorders such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia, renal syndrome, renal fibrosis including chronic crystal nephropathy, or renal hypertension;

(xii) Lymphatic vessel disorders, such as castleman's disease;

(xiii) Immune system or disorders involving the immune system such as hyper IgE syndrome, leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease;

(xiv) Liver disorders, such as chronic active hepatitis, nonalcoholic fatty liver disease (NASH), alcohol-induced hepatitis, nonalcoholic fatty liver disease (NAFLD), Alcoholic Fatty Liver Disease (AFLD), Alcoholic Steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, liver fibrosis, or liver failure;

(xv) Cancers, including those listed above;

(xvi) Burns, wounds, trauma, bleeding or stroke;

(xvii) (ii) radiation exposure;

(xviii) Obesity; and/or

(xix) Pain, such as inflammatory hyperalgesia.

In one embodiment of the fifth, sixth, seventh, eighth, ninth or tenth aspect of the invention, the disease, disorder or condition is an autoinflammatory disease, such as, for example, cryopyrin-associated periodic syndrome (CAPS), muckle-vehich syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), Familial Mediterranean Fever (FMF), neonatal-onset multiple system inflammatory disease (NOMID), Tumor Necrosis Factor (TNF) receptor-associated periodic syndrome (TRAPS), hyper-immunoglobulin-emia D and periodic fever syndrome (HIDS), interleukin 1 receptor antagonist antibody Deficiency (DIRA), magerid syndrome (Majeed syndrome), suppurative arthritis, pyoderma gangrenosum and acne syndrome (PAPA), adult-onset stele disease (AOSD), a20 single underdose (HA20), Pediatric Granulomatous Arthritis (PGA), and, PLCG 2-related antibody deficiency and immune disorders (PLAID), PLCG 2-related autoinflammatory antibody deficiency and immune disorders (aploid), or sideroblastic anemia (SIFD) with B-cell immunodeficiency, periodic fever and developmental delay.

Thus, examples of diseases, disorders or conditions that may be responsive to NLRP3 inhibition and that may be treated or prevented according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the invention are listed above. Some of these diseases, disorders or conditions are mediated substantially or entirely by NLRP3 inflammasome activity and IL-1 β and/or IL-18 induced by NLRP 3. Thus, such diseases, disorders or conditions may be particularly responsive to inhibition of NLRP3 and are particularly suitable for treatment or prevention according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the invention. Examples of such diseases, disorders or conditions include cryopyrin-associated periodic syndrome (CAPS), muckle-weidi's syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), neonatal onset multiple system inflammatory disease (NOMID), Familial Mediterranean Fever (FMF), suppurative arthritis, pyoderma gangrenosum and acne syndrome (PAPA), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), Tumor Necrosis Factor (TNF) receptor-associated periodic syndrome (TRAPS), systemic juvenile idiopathic arthritis, Adult Onset Stele Disease (AOSD), recurrent polychondritis, senitlerian syndrome, scutt syndrome, behcet disease, anti-synthetase syndrome, interleukin 1 receptor antagonist Defect (DIRA), and a20 single underdose (HA 20).

Furthermore, some of the diseases, disorders or conditions mentioned above arise due to mutations of NLRP3 that cause, inter alia, an increase in NLRP3 activity. Thus, such diseases, disorders or conditions may be particularly responsive to inhibition of NLRP3 and are particularly suitable for treatment or prevention according to the fifth, sixth, seventh, eighth, ninth or tenth aspects of the invention. Examples of such diseases, disorders or conditions include coldness-imidacloprid associated periodic syndrome (CAPS), muckle-weidi syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FCAS), and Neonatal Onset Multisystem Inflammatory Disease (NOMID).

An eleventh aspect of the invention provides a method of inhibiting NLRP3, the method comprising inhibiting NLRP3 using a compound of the first or second aspects of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention.

In one embodiment of the eleventh aspect of the invention, the method comprises the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, in combination with one or more other active agents.

In one embodiment of the eleventh aspect of the invention, the method is performed ex vivo or in vitro, for example to analyze the effect of NLRP3 inhibition on cells.

In another embodiment of the eleventh aspect of the invention, the method is performed in vivo. For example, the method may comprise the steps of: administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, thereby inhibiting NLRP 3. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents. Typically, administration is to a subject in need thereof.

Alternatively, the method of the eleventh aspect of the invention may be a method of inhibiting NLRP3 in a non-human animal subject, the method comprising the steps of: administering the compound, salt, solvate, prodrug or pharmaceutical composition to the non-human animal subject, and optionally subsequently disabling or sacrificing the non-human animal subject. Typically, such methods further comprise the step of analyzing one or more tissue or fluid samples from the optionally mutilated or sacrificed non-human animal subject. In one embodiment, the method further comprises the step of co-administering an effective amount of one or more additional active agents.

A twelfth aspect of the invention provides a compound of the first or second aspects of the invention, or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in inhibiting NLRP 3. Typically, the use comprises administering the compound, salt, solvate, prodrug or pharmaceutical composition to a subject. In one embodiment, the compound, salt, solvate, prodrug, or pharmaceutical composition is co-administered with one or more other active agents.

A thirteenth aspect of the invention provides the use of a compound of the first or second aspects of the invention, or a pharmaceutically effective salt, solvate or prodrug of the third aspect of the invention, in the manufacture of a medicament for the inhibition of NLRP 3. Typically, the inhibiting comprises administering the compound, salt, solvate, prodrug or drug to the subject. In one embodiment, the compound, salt, solvate, prodrug, or drug is co-administered with one or more other active agents.

In any embodiment of any of the fifth to thirteenth aspects of the invention that includes the use or co-administration of one or more additional active agents, the one or more additional active agents may include, for example, one, two or three different additional active agents.

One or more additional active agents may be used or administered before, simultaneously, sequentially or after each other and/or the compound of the first or second aspect of the invention, the pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, or the pharmaceutical composition of the fourth aspect of the invention. Where one or more additional active agents are administered concurrently with a compound of the first or second aspect of the invention or a pharmaceutically acceptable salt, solvate or prodrug of the third aspect of the invention, a pharmaceutical composition of the fourth aspect of the invention may be administered, wherein the pharmaceutical composition additionally comprises one or more additional active agents.

In one embodiment of any of the fifth to thirteenth aspects of the invention, which comprises the use or co-administration of one or more further active agents, the one or more further active agents are selected from:

(i) a chemotherapeutic agent;

(ii) an antibody;

(iii) an alkylating agent;

(iv) an antimetabolite;

(v) an anti-angiogenic agent;

(vi) plant bases and/or terpenoids;

(vii) a topoisomerase inhibitor;

(viii) an mTOR inhibitor;

(ix) stilbene compounds;

(x) STING agonists;

(xi) A cancer vaccine;

(xii) An immunomodulator;

(xiii) (ii) an antibiotic;

(xiv) An antifungal agent;

(xv) An anti-helminthic agent; and/or

(xvi) Other active agents.

It is to be understood that these general embodiments, defined in terms of the broad class of active agents, are not mutually exclusive. In this regard, any particular active agent may be classified according to more than one of the above general embodiments. One non-limiting example is udeluzumab (ureluab), an antibody that is an immunomodulator in the treatment of cancer.

In some embodiments, the one or more chemotherapeutic agents are selected from abiraterone acetate (abiraterone acetate), altretamine (altretamine), amsacrine (amsacrine), anhydrovinblastine (anhydrovinblastine), orlistatin (auristatin), azathioprine (azathioprine), adriamycin (adriamycin), bexarotene (bexarotene), bicalutamide (bicalutamide), BMS 184476, bleomycin (bleomycin), N-dimethyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-tert-butanamide, cisplatin (cistatin), carboplatin (carboplatin), carboplatin cyclophosphamide (carboplatin), chlorambucil (lomycin), polycystin (polycystine), candida albicans (carmustine), candida (carmustine), candida albicans (carmustine), and mixtures thereof, Cytarabine (cytarabine), docetaxel (docetaxel), docetaxel (doxetaxel), doxorubicin (doxorubicin), dacarbazine (dacarbazine, DTIC), actinomycin D (dactinomycin), daunorubicin (daunorubicin), decitabine (decitabine), dolastatin (dolastatin), etoposide (etoposide), etoposide phosphate (etoposide phosphate), enzalutamide (enzutamide, MDV3100), 5-fluorouracil (5-fluoroouracil), fludarabine (fludarabine), flutamide (flutamide), gemcitabine (gemcitabine), hydroxyurea (hydroxyurea) and hydroxyureane (hydrourecananes), ibarotenone (ibarotene), isoxathiuracin (flutamide), gemcitabine (gentamicin), tetrahydrofolate (thioglucamine), methotrexate (mitomycin (C), methotrexate (D-D), D-D (D-D), D-D, D-D, D-D, D-, Mitoxantrone (mitoxantrone), melphalan (melphalan), mitobutrine (mivobulin), 3',4' -didehydro-4 '-deoxy-8' -iso-vinblastine, nilutamide (nilutamide), oxaliplatin (oxaliplatin), onapristone (onapristone), prednimustine (prednimustine), procarbazine (procarbazine), paclitaxel (paclitaxel), platinum-containing anticancer agents, 2,3,4,5, 6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, prednimustine (prednimustine), procarbazine (procarbazine), rhizomycin (rhizoxin), serteretenef, streptozocin (streptozocin), estramustine phosphate (tramsfungine), tretinoin (tretinoin), paclitaxel (taxol), topotecan (taxol), paclitaxel), oxaliplatin (oxaliplatin), onapristone (onapristone), ponin (onapristinane (prednimustine), prednimustine (procarbazine), procarbazine (pravastatin), paclitaxel (paclitaxel), neomycin (triptonidine), neomycin (tretinoside (paclitaxel), neomycin (tretinomycin), neomycin (paclitaxel), neomycin, Tegafur/uracil, vincristine (vinchristine), vinblastine (vinblastine), vinorelbine (vinorelbine), vindesine (vindesine), vindesine sulfate and/or vinflunine (vinflunine).

Alternatively or additionally, the one or more chemotherapeutic agents may be selected from the group consisting of CD59 complement fragments, fibronectin fragments, gro-beta (CXCL2), heparinase, heparin polyhexose fragments, human chorionic gonadotropin (hCG), interferon alpha, interferon beta, interferon gamma, interferon inducible protein (IP-10), interleukin-12, kringle 5 (plasminogen fragment), metalloproteinase inhibitor (TIMP), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16kD fragment, multiple-ferutin-related protein (PRP), retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-beta (TGF-beta), Angiostatin, angiostatic factor (calreticulin fragment) and/or cytokine (including interleukin, such as interleukin-2 (IL-2) or IL-10).

In some embodiments, the one or more antibodies may comprise one or more monoclonal antibodies. In some embodiments, the one or more antibodies are selected from the group consisting of abciximab (abciximab), adalimumab (adalimumab), alemtuzumab (alemtuzumab), alemtuzumab (atlizumab), basiliximab (basiliximab), belimumab (belimumab), bevacizumab (bevacizumab), weibutuximab (bretuximab vedottin), canakinumab (canakinumab), cetuximab (cevatuzumab), polyethylene glycol-bound certolizumab (cetuximab pegol), dallizumab (daclizumab), dinolizumab (denosumab), eculizumab (eculizumab), efuzumab (efuzumab), gemtuzumab (gemtuzumab), golimab (golimab), ibritumumab (iruzumab), ibritumomab (rituximab), rituximab (8584), zelimumab (CD-8584), rituximab (zezumab-d), yamazumab (zepinuzumab), gemtuzumab (gemtuzumab), gemtuzumab (zepinolizumab), gemtuzumab (zepinyli (zepinolizumab), geminivu (CD (zepinolizumab), yae (CD) and (, Panitumumab (panitumumab), ranibizumab (ranibizumab), rituximab (rituximab), tocilizumab (tocilizumab), tositumomab (tositumomab), and/or trastuzumab (trastuzumab).

In some embodiments, the one or more alkylating agents may include an agent capable of alkylating a nucleophilic functional group under conditions present in a cell including, for example, a cancer cell. In some embodiments, the one or more alkylating agents are selected from cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin. In some embodiments, alkylating agents may function by weakening cell function by forming covalent bonds with amino, carboxyl, sulfhydryl, and/or phosphate groups in biologically important molecules. In some embodiments, the alkylating agent may act by modifying the DNA of the cell.

In some embodiments, the one or more antimetabolites may comprise an agent capable of affecting or preventing RNA or DNA synthesis. In some embodiments, the one or more antimetabolites are selected from azathioprine and/or mercaptopurine.

In some embodiments, the one or more anti-angiogenic agents are selected from endostatin, angiogenin inhibitors, angiostatin (a plasminogen fragment), basement membrane collagen-derived anti-angiogenic factors (tumstatin, angiostatin, or profilin), anti-angiogenic antithrombin III, and/or cartilage-derived inhibitory factor (CDI).

In some embodiments, one or more plant bases and/or terpenoids may prevent microtubule function. In some embodiments, the one or more plant alkaloids and/or terpenoids are selected from vinca alkaloids, podophyllotoxins, and/or taxanes. In some embodiments, the one or more vinca alkaloids may be derived from vinca (Madagascar periwinkle), hedera (Catharanthus roseus) (formerly known as rhinum), and may be selected from vincristine, vinblastine, vinorelbine, and/or vindesine. In some embodiments, the one or more taxanes are selected from the group consisting of taconazole (taxol), paclitaxel, docetaxel, and/or ortataxel. In some embodiments, the one or more podophyllotoxins are selected from etoposide and/or teniposide.

In some embodiments, the one or more topoisomerase inhibitors are selected from type I topoisomerase inhibitors and/or type II topoisomerase inhibitors, and may interfere with transcription and/or replication of DNA by interfering with DNA supercoiling. In some embodiments, the one or more type I topoisomerase inhibitors may comprise camptothecin, which may be selected from irinotecan (exatecan), irinotecan, lurtotecan (lurtotecan), topotecan, BNP 1350, CKD 602, DB 67(AR67), and/or ST 1481. In some embodiments, the one or more type II topoisomerase inhibitors can include epipodophyllotoxins, which can be selected from amsacrine, etoposide (etoposid), etoposide phosphate, and/or teniposide.

In some embodiments, the one or more mTOR (target protein of rapamycin, also known as a mechanistic target of rapamycin) inhibitors are selected from rapamycin, everolimus (everolimus), temsirolimus (temsirolimus), and/or deforolimus (deforolimus).

In some embodiments, the one or more stilbenes are selected from resveratrol (resveratrol), piceatannol (piceatannol), pinosylvin (pinosylvin), pterostilbene (pterostilbene), alpha-viniferin (alpha-viniferin), ampelopsin a (ampelopsin a), ampelopsin e (ampelopsin e), dipteronesin C, dipteronesin F, epsilon-weivin (epsilon-viniferin), campylosin a (flexuosol a), kaempferin (lignin H), pimeliol d (hemsleyanoes d), hoprenol (hopepanoel), trans-dipteronesin B, piceatannoside (trigenin), piceatannon (piceatannoid) and/or dionin a.

In some embodiments, one or more agonists of STING (interferon gene stimulating protein, also known as transmembrane protein (TMEM)173) may comprise cyclic dinucleotides, such as cAMP, cGMP, and cGAMP, and/or modified cyclic dinucleotides that may include one or more of the following modification characteristics: 2'-O/3' -O linkages, phosphorothioate linkages, adenine and/or guanine analogs and/or 2'-OH modifications (e.g. protection of 2' -OH with methyl or protection with-F or-N)₃Instead of 2' -OH).

In some embodiments, the one or more cancer vaccines are selected from HPV vaccines, hepatitis b vaccines, Oncophage, and/or Provenge.

In some embodiments, the one or more immune modulators may comprise an immune checkpoint inhibitor. Immune checkpoint inhibitors may target immune checkpoint receptors or combinations of receptors including, for example: CTLA-4, PD-1, PD-L1, T-cell immunoglobulin and mucin 3(TIM 1 or HAVCR 1), galectin 9, phosphatidylserine, lymphocyte activation gene 3 protein (LAG 1), MHC class I, MHC class II, 4-1BB, 4-1L, OX 1, OX40 1, GITR, GITRL, CD1, TNFRSF 1, TL 11, CD40 1, HVEM, LIGHT, BTLA, CD160, CD1, CD244, CD1, ICOS, ICOSL, B1-H1, VISTA, TMIGD 1, HHLA 1, TMIGD 1, CD1, a hemophilin (including NL 1), a member of the PVR family, TIG, killer, immunoglobulin-like receptor, SIRIL-like receptor, NKIgG 1, NKCD 1, CD 1.

In some embodiments, the immune checkpoint inhibitor is selected from among udersumab, PF-05082566, MEDI6469, TRX518, valreulumab (varliumab), CP-870893, pembrolizumab (PD1), nivolumab (PD1), alemtuzumab (formerly MPDL3280A) (PD-L1), MEDI4736(PD-L1), avilumab (PD-L1), PDR001(PD1), BMS-986016, MGA271, lireulumab, IPH2201, imatuzumab (ematumab), INCB024360, grussolitib (galinisertib), urotuzumab (ulomb), b140, kt bavituximab, CC-90002, bevacizumab, and/or MNRP 1685A.

In some embodiments, the one or more antibiotics are selected from amikacin (amikacin), gentamicin (gentamicin), kanamycin (kanamycin), neomycin (neomycin), netilmicin (netilmicin), tobramycin (tobramycin), paromomycin (paromomycin), streptomycin (streptamycin), spectinomycin (spectinomycin), geldanamycin (geldanamycin), herbimycin (herbimycin), rifaximin (rifaximin), loracarbef (loracarbef), ertapenem (apenem), donepezil (doripenem), imipenem (imipenem), cilastatin (cilastatin), meropenem (meropenem), cefadroxil (cefaclor), cefaclin (cefaclin), cefaclor (cefaclor), cefaclor (cefaclor, Cefditoren (cefditoren), cefoperazone (cefepime), cefotaxime (cefetaxime), cefpodoxime (cefpodoxime), ceftazidime (cefradime), ceftibuten (cefbuperazine), ceftizoxime (cefepime), ceftriaxone (cefatrixone), cefepime (cefepime), ceftaroline (cefatrione fossa), cefbiprofecol (cefuroxime), teicoplanin (teicoplanin), vancomycin (vancomycin), telavancin (telavancin), dalbavancin (dalbavancin), orivaccin (orivatincin), clindamycin (clindamycin), linomycin (clindamycin), daptomycin (azithromycin), tetracycline (clarithromycin), erythromycin (erythromycin), erythromycin (erythromycin), erythromycin (erythromycin) and erythromycin (erythromycin) or (erythromycin (, Raltitrazolide (radizolid), tedizolid (torezolid), amoxicillin (amoxicillin), ampicilin (ampicilin), azlocillin (azlocillin), carbenicillin (carbenicillin), cloxacillin (cloxacillin), dicloxacillin (dicloxacillin), flucloxacillin (flucloxacillin), mezlocillin (mezlillin), methicillin (methicillin), nafcillin (nafcillin), oxacillin (oxacillin), penicillin G (penicillin G), penicillin V (penicillin V), piperacillin (piperacillin), temocillin (temocillin), ticarcillin (ticarcillin), kalium clavulanate (calvatulanate), ampicilin (amancillin), sulbactam (bbacibactam), ciprofloxacin (ticarcillin), ciprofloxacin (doxoracin), carbenicillin (ticarcillin), ciprofloxacin (clavulanate (clavulan), ciprofloxacin (clavulanate (clavicilin), ciprofloxacin (bacicilin), ciprofloxacin (clavulanate (b), ciprofloxacin (doxoracin), ciprofloxacin (b) (clavulan (b) (clavulan), ciprofloxacin (b) and (antibiotic (, Levofloxacin (levofloxacin), lomefloxacin (lomefloxacin), moxifloxacin (moxifloxacin), nalidixic acid (nalidixic acid), norfloxacin (norfloxacin), ofloxacin (ofloxacin), trovafloxacin (trovafloxacin), grepafloxacin (grepafloxacin), sarfloxacin (sparfloxacin), temafloxacin (temafloxacin), mafenide (mafenide), sulphanilamide (sulfacetamide), sulfadiazine (sulfadiazine), silver sulfadiazine (silver sulfadiazine), sulfadimethoxine (sulfadimethoxine), sulfamethoxazole (sulfadimethoxine), sulfadimethenamide (sulfafenamide), sulfasalazine (sulfasalazine), sulfadoxine (sulfadoxine), sulfadoxine (trimethopine), trimethopine (cloxacine (clocycline), sulfadoxine (cloxacine (tetracycline), sulfadoxine (cloxacine), sulfadoxine (cloxacine), cloxacine (clo, Ethambutol (ethambutol), ethionamide (ethionamide), isoniazid (isoniazid), pyrazinamide (pyrazinamide), rifampicin (rifampicin), rifabutin (rifabutin), rifapentine (rifapentine), streptomycin (streptomycin), arsinamine (arsfenamine), chloramphenicol (chloremycin), fosfomycin (fosfomycin), fusidic acid (fusidic acid), metronidazole (metronidazole), mupirocin (mupirocin), flatamycin (flatamycin), quinupristin (prothromycin), quinupristin (quinupristin), dalfopristin (dalloprolitin), thiamphenicol (thiamphenicol), tigecycline (tigecycline), tinidazole (tinidazole), trimethoprim (trimethoprim) and/or teibadine (teibadine).

In some embodiments, the one or more antibiotics may include one or more cytotoxic antibiotics. In some embodiments, the one or more cytotoxic antibiotics are selected from the group consisting of actinomycin, anthracenedione, anthracycline, thalidomide (thalidomide), dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and/or clofazimine (chlorezimine). In some embodiments, the one or more actinomycin is selected from actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B. In some embodiments, the one or more anthracenediones are selected from mitoxantrone (mitoxantrone) and/or pixantrone (pixantrone). In some embodiments, the one or more anthracyclines are selected from bleomycin, doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin (epirubicin), idarubicin, mitomycin (mitomycin), mithramycin (plicamycin), and/or valrubicin.

In some embodiments, the one or more antifungal agents are selected from the group consisting of bifonazole (bifonazole), butoconazole (butoconazole), clotrimazole (clotrimazole), econazole (econazole), ketoconazole (ketoconazole), luliconazole (luliconazole), miconazole (miconazole), omoconazole (omoconazole), oxiconazole (oxiconazole), sertaconazole (sertaconazole), sulconazole (sulconazole), tioconazole (tioconazole), abaconazole (albaconazole), efaconazole (efinaconazole), itraconazole (efaconazole), eponazole (eponazole), fluconazole (fluconazole), isazol (itraconazole), fluconazole (amoxicillin), amoxicillin (amoxicillin), sulconazole (ibuprofen (amoxicillin), sulconazole (sulconazole), sulconazole (amoxicillin (nafcillin), sulconazole (sulconazole), sulconazole (amoxicillin (nafcillin (amoxicillin), sulconazole (sulconazole), sulconazole (sulbactam (sulconazole), sulbactin (sulbactam (sulbactin (sulbactam), sulbactam (, Benzoic acid, ciclopirox (ciclopirox), flucytosine (flucytosine), 5-flucytosine (5-flucytosine), griseofulvin (griseofulvin), chlorophenol ether (haloprogin), tolnaftate (tolnaftate), undecylenic acid and/or balsam of Peru (balsam of Peru).

In some embodiments, the one or more anti-gut agents are selected from the group consisting of benzimidazole (including albendazole), mebendazole, thiabendazole, fenbendazole, triclabendazole and flubendazole), abamectin (abamectin), diethylcarbamazine (diethylcarbamazine), ivermectin (ivermectin), suramin (suramin), quinacrid (pyrantel pamoate), levotetramisole (levamisole), salicylanilide (salicide) including bezoar (nicamide) and hydroxychlorozamide (oxyclozanide) and/or nitazoxanide (nitazoxanide).

In some embodiments, the additional active agent is selected from growth inhibitors, anti-inflammatory agents (including non-steroidal anti-inflammatory agents), anti-psoriatic agents (including anthralin and derivatives thereof), vitamins and vitamin derivatives (including retinoids and VDR receptor ligands), corticosteroids, ion channel blockers (including potassium channel blockers), immune system modulators (including cyclosporine (cyclosporine), FK 506, and glucocorticoids), luteinizing hormone releasing hormone agonists (e.g., leuprolide (leuprolide), goserelin (goserelin), triptorelin (triptorelin), histrelin (histrelin), bicalutamide (bicalutamide), flutamide (flutamide), and/or nilutamide (nilutamide)), and/or hormones (including estrogens).

In any of the fifth to thirteenth aspects of the invention, the subject may be any human or other animal, unless otherwise specified. Typically, the subject is a mammal, more typically a human or domesticated mammal, such as a cow, pig, lamb, sheep, goat, horse, cat, dog, rabbit, mouse, and the like. Most typically, the subject is a human.

Any of the drugs employed in the present invention may be administered orally, parenterally (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial, and epidural), airway (aerosol), rectally, vaginally, ocularly, or topically (including transdermal, buccal, mucosal, sublingual, and ocular surfaces).

Typically, the mode of administration selected is that which is most appropriate for the condition, disease or disorder to be treated or prevented. Where one or more additional active agents are administered, the mode of administration may be the same or different from that of the compounds, salts, solvates, prodrugs or pharmaceutical compositions of the present invention.

For oral administration, the compounds, salts, solvates or prodrugs of the invention are generally provided in the form of tablets, capsules, hard or soft gelatin capsules, caplets, lozenges or troches, as powders or granules or as aqueous solutions, suspensions or dispersions.

Oral tablets may contain the active ingredient in admixture with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preserving agents. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose. Corn starch and alginic acid are suitable disintegrants. The binder may include starch and gelatin. The lubricant, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract. The tablet may also be an effervescent tablet and/or a fast dissolving tablet.

Oral capsules include hard gelatin capsules wherein the active ingredient is mixed with a solid diluent; and soft gelatin capsules wherein the active ingredient is mixed with water or an oil, for example peanut oil, liquid paraffin or olive oil.

The oral powder or granules may be provided in a sachet or a tub. An aqueous solution, suspension or dispersion may be prepared by adding water to a powder, granule or tablet.

Any form suitable for oral administration may optionally include sweetening agents, such as sugars, flavoring agents, coloring agents and/or preserving agents.

Formulations for rectal administration may be presented as suppositories with suitable bases including, for example, cocoa butter or salicylates.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

For parenteral use, the compounds, salts, solvates or prodrugs of the invention are generally provided as sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride or dextrose. Aqueous suspensions according to the invention may include suspending agents, for example cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent, for example lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate. The compounds of the invention may also be presented as liposomal formulations.

For ophthalmic administration, the compounds, salts, solvates or prodrugs of the invention are generally provided in a form suitable for topical administration, for example as eye drops. Suitable forms may include ophthalmic solutions, gel-forming solutions, sterile powders for reconstitution, ophthalmic suspensions, ophthalmic ointments, ophthalmic emulsions, ophthalmic gels, and ophthalmic inserts. Alternatively, the compounds, salts, solvates or prodrugs of the invention may be provided in a form suitable for other types of ocular administration, for example, as an intraocular formulation (including as a lavage fluid, as an intraocular, intravitreal or juxtascleral injection formulation, or as an intravitreal implant), as a package or corneal shield, as an intracameral, subconjunctival or retrobulbar injection formulation, or as an iontophoretic formulation.

For transdermal and other topical applications, the compounds, salts, solvates, or prodrugs of the invention are generally provided in the form of an ointment, poultice (cataplasm), paste, powder, dressing, cream, plaster, or patch.

Suitable suspensions and solutions may be used in an inhaler for gas-line (aerosol) administration.

The dosage of the compounds, salts, solvates or prodrugs of the invention will, of course, vary with the disease, disorder or condition to be treated or prevented. In general, suitable dosages will range from 0.01 to 500mg per kg of recipient body weight per day. The desired dose may be provided at appropriate intervals, for example, once every other day, once a day, twice a day, three times a day, or four times a day. The desired dose may be administered, for example, in unit dosage forms containing from 1mg to 50g of active ingredient per unit dosage form.

For the avoidance of doubt, to the extent feasible, any embodiment of a given aspect of the invention may exist in combination with any other embodiment of the same aspect of the invention. Additionally, to the extent practicable, it should be appreciated that any preferred, exemplary, or optional embodiment of any aspect of the invention should also be considered a preferred, exemplary, or optional embodiment of any other aspect of the invention.

example-Synthesis of Compounds

Unless otherwise indicated, all solvents, reagents and compounds were purchased and used without further purification.

Abbreviations

2-MeTHF 2-methyltetrahydrofuran

Ac₂O acetic anhydride

AcOH acetic acid

aq solution of aq

B₂Pin₂Bis (pinacolato) diboron, also known as 4,4,4',4',5,5,5',5' -octamethyl

-2,2' -bis (1,3, 2-dioxaborolan)

Boc tert-butyloxycarbonyl group

br broad peak

Cbz carboxybenzyl radical

CDI 1, 1-carbonyl-diimidazoles

conc concentration

d double peak

DABCO 1, 4-diazabicyclo [2.2.2] octane

DCE 1, 2-dichloroethane, also known as ethylene dichloride

DCM dichloromethane

DIPEA N, N-diisopropylethylamine, also known as Henschel base (Hunig's base)

DMA dimethyl acetamide

DMAP 4-dimethylaminopyridine, also known as N, N-dimethylpyridin-4-amine

DME dimethoxyethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide

eq or equv equivalent

(ES⁺) Electrospray ionization, positive ion mode

Et Ethyl group

EtOAc ethyl acetate

EtOH ethanol

h hours

HATU 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ]

Pyridinium 3-oxide hexafluorophosphate

HPLC high performance liquid chromatography

LC liquid chromatography

m multiplet

m-CPBA 3-chloroperoxybenzoic acid

Me methyl group

MeCN acetonitrile

MeOH methanol

(M+H)⁺Protonated molecular ions

MHz megahertz

min for

MS mass spectrometry

Ms methanesulfonyl, also known as methanesulfonyl

MsCl methanesulfonyl chloride, also known as methanesulfonyl chloride

MTBE methyl tert-butyl ether, also known as tert-butyl methyl ether

m/z mass to charge ratio

NaO^tSodium Bu tert-butoxide

NBS 1-bromopyrrolidine-2, 5-dione, also known as N-bromosuccinimide

NCS 1-chloropyrrolidine-2, 5-dione, also known as N-chlorosuccinimide

NMP N-methylpyrrolidine

NMR Nuclear magnetic resonance (Spectroscopy)

Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium (0)

PdCl₂(dppf) [ [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride, also known as Pd (dppf) Cl₂

PE Petroleum Ether

Ph phenyl

PMB p-methoxybenzyl, also known as 4-methoxybenzyl

Preparative HPLC preparative high performance liquid chromatography

Preparative TLC preparative thin layer chromatography

PTSA para-toluenesulfonic acid

q quartet peak

RP inverse

RT Room temperature

s single peak

sat saturation

SCX solid supported cation exchange resin

sept heptad

t triplet peak

T3P propyl phosphoric anhydride

TBME Tert-butyl methyl Ether, also known as methyl Tert-butyl Ether

TEA Triethylamine

TFA 2,2, 2-trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

wt% weight percent or percent by weight

Xphos 2-dicyclohexylphosphino-2 ',4', 6 ' -triisopropylbiphenyl

Experimental methods

Nuclear magnetic resonance

NMR spectra were recorded at 300, 400 or 500 MHz. Unless otherwise indicated, spectra were measured at 298K and referenced against solvent resonance. Chemical shifts are reported in parts per million. The spectra were recorded using one of the following machines:

bruker Avance III spectrophotometer, at 400MHz, equipped with a BBO 5mm liquid probe,

bruker 400MHz spectrophotometer using ICON-NMR under the control of the TopSpin program,

bruker Avance III HD spectrophotometer, at 500MHz, equipped with Bruker5mm SmartProbe^TM，

An Agilent VNMRS 300 instrument equipped with a 7.05Tesla magnet from Oxford instruments, indirect detection probes and a direct drive console including a PFG module, or

The Agilent MercuryPlus 300 instrument, equipped with a 7.05Tesla magnet from Oxford instruments, a 4-core self-disposable probe and Mercury plus console.

LC-MS

LC-MS method: ShimadZU LCMS-2020, Agilent 1200LC/G1956A MSD and Agilent 1200\ G6110A, Agilent 1200LC and Agilent6110MSD were used. Mobile phase: a: 0.025% NH in water₃·H₂O (v/v); b: and (3) acetonitrile. Column: kinetex EVO C182.1X 30mm, 5 μm.

Preparative reverse phase HPLC universal method

Acidic preparative HPLC (x-y% MeCN in water): waters X-Select CSH column C18, 5 μm (19X 50mm), flow rate 28mL min^-16.5 min with H containing 0.1% v/v formic acid₂Gradient elution was performed with O-MeCN and UV detection at 254 nm. Gradient information: 0.0-0.2 min, x% MeCN; from 0.2 to 5.5 minutes, ramping from x% MeCN to y% MeCN; 5.5-5.6 minutes, ramping from y% MeCN to 95% MeCN; 5.6-6.5 minutes, held at 95% MeCN.

Acidic preparative HPLC (x-y% MeOH in water): waters X-Select CSH column C18, 5 μm (19X 50mm), flow rate 28mL min^-1Eluted with a 10mM aqueous formic acid-MeOH gradient over 7.5 min, using UV detection at 254 nm. Gradient information: 0.0-1.5 min, x% MeOH; 1.5-6.8 minutes, ramping from x% MeOH to y% MeOH; 6.8-6.9 min, ramping from y% MeOH to 95% MeOH; 6.9-7.5 min, held at 95% MeOH.

Basic preparative HPLC (x-y% MeCN in water): waters X-Bridge Prep column C18, 5 μm (19X 50mm), flow rate 28mL min^-1Over 6.5 minutes with 10mM NH₄HCO₃MeCN gradient elution, UV detection at 254 nm. Gradient information: 0.0-0.2 min, x% MeCN; from 0.2 to 5.5 minutes, ramping from x% MeCN to y% MeCN; 5.5-5.6 minutes, ramping from y% MeCN to 95% MeCN; 5.6-6.5 minutes, held at 95% MeCN.

Synthesis of intermediates

Intermediate L1:(4- (dimethylamino) pyridin-1-ium-1-carbonyl) (methylsulfonyl) amide

A solution of methanesulfonamide (1.7g, 17.87mmol) and DMAP (4.37g, 35.7mmol) in MeCN (25mL) was stirred at room temperature for 10 min. Diphenyl carbonate (4.21g, 19.66mmol) was then added and the reaction stirred at room temperature for 5 days. The precipitate was filtered off, washed with MTBE and dried in vacuo to give the title compound as a white solid (1.67g, 38%).

¹H NMR(CDCl₃)δ9.07(d,J＝7.4Hz,2H),6.74(d,J＝7.5Hz,2H),3.35(s,6H),3.20(s,3H)。

The following intermediates were prepared according to the general procedure for intermediate L1:

intermediate L7:4- (2-hydroxypropan-2-yl) furan-2-sulphonamide

Step A:furan-3-carboxylic acid ethyl ester

To a mixture of furan-3-carboxylic acid (50g, 446.10mmol, 1 equiv.) in EtOH (500mL) was added H dropwise at 25 deg.C₂SO₄(89.29g, 892.20mmol, 98% purity in solution, 2 equiv.). The reaction mixture was then heated to 75 ℃ and stirred for 2.5 hours. The mixture was poured into ice water (200mL) and extracted with EtOAc (3X 200 mL). The organic phase was washed with 20% NaHCO₃Washed with aqueous solution (2X 200mL) over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound as a yellow oil (50g, 80%).

¹H NMR(400MHz,CDCl₃) δ 8.01(d,1H),7.43(t,1H),6.75(t,1H),4.31(q,2H) and 1.35(s, 3H).

And B:4- (ethoxycarbonyl) furan-2-sulfonic acid

In N₂Next, chlorosulfonic acid (46.77g, 401.39mmol, 1.25 equiv.) was added dropwise to a mixture of ethyl furan-3-carboxylate (45g, 321.12mmol, 1 equiv.) in DCM (500mL) at-10 deg.C. After 15 minutes, the reaction mixture was stirred at 20 ℃ for 24 hours. The reaction mixture was then filtered and the filter cake was dried under vacuum to give a solution ofTitle compound (55g, 78%) as white solid.

¹H NMR(400MHz,D₂O) Δ 8.19(s,1H),7.10(s,1H),4.27(q,2H) and 1.27(t, 3H).

And C:5- (chlorosulfonyl) furan-3-carboxylic acid ethyl ester

In N₂Pyridine (20.74g, 262.26mmol, 1.05 equiv.) is then added dropwise to a mixture of 4- (ethoxycarbonyl) furan-2-sulfonic acid (55g, 249.77mmol, 1 equiv.) in DCM (350mL) at-10 ℃. After 15 minutes, PCl was added₅(54.61g, 262.26mmol, 1.05 eq.) and the resulting mixture was stirred for a further 15 minutes. The reaction mixture was then allowed to warm to 20 ℃ and stirred for 12 hours. The mixture was quenched with water (200mL) and extracted with DCM (2X 200 mL). The combined organic phases were then washed with brine (100mL) over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound as a yellow oil (35g, 59%) which was used in the next step without further purification.

Step D:5-sulfamoylfuran-3-carboxylic acid ethyl ester

NH at 0 ℃₃(15psi) was bubbled through a solution of ethyl 5- (chlorosulfonyl) furan-3-carboxylate (35g, 146.66mmol, 1 eq.) in DCM (300mL) for 15 minutes. The reaction mixture was then stirred at 20 ℃ for 45 minutes. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by wet milling with DCM (200 mL). The mixture was filtered and the filter cake was dried in vacuo to give the title compound as a white solid (24g, 75%).

¹H NMR(400MHz,DMSO-d₆) δ 8.63(s,1H),7.93(s,2H),7.12(s,1H),4.27(q,2H) and 1.28(t, 3H).

Step E:4- (2-hydroxypropan-2-yl) furan-2-sulphonamide

At-10 ℃ under N₂To a mixture of ethyl 5-sulfamoylfuran-3-carboxylate (24g, 109.48mmol, 1 eq) in THF (500mL) was added dropwise MeMgBr (3M, 164.22mL, 4.5 eq) over a period of 30 min. The mixture was stirred at 0 ℃ for 30 minutes, then warmed to 20 ℃ and stirred for 12 hours. The mixture was slowly poured into ice water (300mL) and extracted with EtOAc (2X 300 mL). The organic phase was washed with brine (100mL) over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by wet milling with a mixture of n-hexane: EtOAc (v: v 20:1, 300 mL). The mixture was filtered and the filter cake was dried in vacuo to give the title compound as a white solid (22g, 97% yield, 99.3% purity on LCMS).

¹H NMR(400MHz,DMSO-d₆) δ 7.68(s,1H),7.65(br s,2H),6.94(s,1H), and 1.38(s, 6H).

Intermediate L8:1-cyclopropyl-1H-pyrazole-3-sulfonamides

Step A:1-cyclopropyl-3-nitro-1H-pyrazoles

To a solution of cyclopropylboronic acid (36.77g, 428.04mmol, 1.1 equiv.) in DCE (500mL) at 25 deg.C was added 3-nitro-1H-pyrazole (44g, 389.12mmol, 1 equiv.), 2-bipyridine (60.77g, 389.12mmol, 1 equiv.), and Na₂CO₃(64.59g, 609.44mmol, 1.57 equiv.). The mixture was stirred at 25 ℃ for 30 minutes. Then Cu (OAc) is added₂(70.68g, 389.12mmol, 1 eq.) and the reaction mixture was heated to 70 ℃ and stirred for 15.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO)₂Petroleum ether, ethyl acetate, or a mixture thereof,30:1 to 3:1) to give an impure product (26.7 g). The impure product was dissolved in pyrrolidine (10mL) and the resulting mixture was stirred at 70 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyrrolidine. The residue is washed with H₂O (33mL) was diluted and the pH adjusted to 5-6 with 1M aqueous HCl. The mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (2X 33mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave the title compound as a yellow oil (17.7g, 30%).

¹H NMR(400MHz,CDCl₃) δ 7.54(d,1H),6.84(d,1H),3.73-3.67(m,1H),1.24-1.22(m,2H) and 1.13-1.07(m, 2H).

And B:1-cyclopropyl-1H-pyrazol-3-amines

To a solution of 1-cyclopropyl-3-nitro-1H-pyrazole (36g, 235.08mmol, 1 eq) in EtOH (400mL) was added NH₄Cl (62.87g, 1.18mol, 5 equivalents) in H₂Solution in O (150 mL). The reaction mixture was then heated to 60 ℃ and iron powder (39.38g, 705.24mmol, 3 equiv.) was added portionwise. The reaction mixture was stirred at 60 ℃ for 16 hours. The reaction mixture was then concentrated under reduced pressure. The residue is washed with H₂O (500mL) was diluted and the mixture was extracted with EtOAc (3X 500 mL). The combined organic layers were washed with brine (2X 250mL) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO)₂Ethyl acetate, 30:1 to 1:1) to give the title compound as a yellow oil (20g, 69%).

¹H NMR(400MHz,CDCl₃) Δ 7.14(d,1H),5.11(d,1H),3.57(br s,2H),3.38-3.32(m,1H),0.99-0.95(m,2H) and 0.90-0.87(m, 2H).

LCMS:m/z 124.2(M+H)⁺(ES⁺)。

And C:1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride

To 1-cyclopropyl-1H-pyrazol-3-amine (19g, 154.28mmol, 1 eq) in MeCN (500mL) and H at 0 deg.C₂To a solution in O (50mL) was added a concentrated HCl solution (50mL, 36 wt% aqueous). Then slowly adding NaNO₂(12.77g, 185.13mmol, 1.2 eq.) in H₂Solution in O (50 mL). The resulting solution was stirred at 0 ℃ for 40 minutes. AcOH (50mL), CuCl was added₂(10.37g, 77.14mmol, 0.5 equiv.) and CuCl (763mg, 7.71mmol, 0.05 equiv.). Then the SO is brought to 0 DEG C₂Gas (15psi) was bubbled into the resulting mixture for 20 minutes. The resulting reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue is washed with H₂O (250mL) was diluted and extracted with EtOAc (3X 250 mL). The combined organic layers were washed with brine (2X 150mL) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO)₂Ethyl acetate, 1:0 to 1:1) to give the title compound as a yellow oil (14g, 44%).

¹H NMR(400MHz,CDCl₃) δ 7.62(d,1H),6.83(d,1H),3.78-3.72(m,1H),1.28-1.24(m,2H) and 1.16-1.12(m, 2H).

Step D:1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazole-3-sulfonamide

To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride (28g, 135.49mmol, 1 eq) in THF (300mL) was added TEA (27.42g, 270.99mmol, 2 eq) and bis (4-methoxybenzyl) amine (34.87g, 135.49mmol, 1 eq). The reaction mixture was stirred at 25 ℃ for 1 hour with H₂O (500mL) was diluted and extracted with EtOAc (3X 500 mL). The combined organic layers were washed with brine (2X 500mL) and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (0.5% NH)₃.H₂O-MeCN) and concentrating the collected elution solution under reduced pressure to remove most of the MeCN. The mixture was then extracted with EtOAc (3 × 1L). The combined organic layers were washed with brine (2X 500mL) and Na₂SO₄Drying, filtration and concentration under reduced pressure gave the title compound (30g, 52% yield, 99.8% purity on HPLC).

¹H NMR(400MHz,CDCl₃) δ 7.49(d,1H),7.08-7.06(m,4H),6.79-6.77(m,4H),6.62(d,1H),4.32(s,4H),3.80(s,6H),3.68-3.64(m,1H),1.15-1.13(m,2H) and 1.09-1.06(m, 2H).

LCMS:m/z 428.2(M+H)⁺(ES⁺)。

Step E:1-cyclopropyl-1H-pyrazole-3-sulfonamides

To a mixture of 1-cyclopropyl-N, N-bis (4-methoxybenzyl) -1H-pyrazole-3-sulfonamide (1g, 2.34mmol, 1 eq) in DCM (10mL) was added TFA (15.40g, 135.06mmol, 57.74 eq). The mixture was stirred at 25 ℃ for 12 hours. Most of the solvent was evaporated and the residue was redissolved in MeOH (30 mL). A solid formed and the reaction mixture was filtered. The filtrate was concentrated in vacuo and the residue wet-milled with a mixture of petroleum ether and EtOAc (30mL, 20:1) to give the title compound as a white solid (430mg, 88% yield, 90% purity on LCMS).

¹H NMR(DMSO-d₆) Δ 7.92(s,1H),7.38(br s,2H),6.55(s,1H),3.84-3.78(m,1H) and 1.10-0.98(m, 4H).

Intermediate L9:1-methyl-3- [ methyl (sulfamoyl) amino]Pyrrolidine as a therapeutic agent

To N, 1-dimethyl pyridineThioamide (4.04g, 42.04mmol, 1.2 equiv.) was added in one portion to a solution of pyrrolidin-3-amine (4g, 35.03mmol, 1 equiv.) in 1, 2-dimethoxyethane (80 mL). The reaction mixture was heated to 90 ℃ and under N₂Stirred for 12 hours. The reaction mixture was then concentrated in vacuo. The residue was purified by column chromatography (SiO)₂EtOAc: EtOH, 20:1 to 5:1) to give the title compound as a brown oil (3.5g, 43% yield, 83% purity on LCMS).

¹H NMR(400MHz,DMSO-d₆) δ 6.65(s,2H),4.31-4.23(m,1H),2.62(s,3H),2.61-2.56(m,2H),2.41-2.36(m,1H),2.20(s,3H),2.18-2.12(m,1H),2.05-1.98(m,1H) and 1.78-1.71(m, 1H).

LCMS:m/z 194.0(M+H)⁺(ES⁺)。

Intermediate L10:benzene sulfenamides

To a solution of methylsulphinate (500mg, 3.20mmol, 1 equiv) in THF (10mL) at-78 deg.C was added LiHMDS (1M, 4.80mL, 1.5 equiv). The reaction mixture was stirred at-78 ℃ for 2 hours. Then NH is added₄Cl (342mg, 6.40mmol, 2 equiv.) in H₂O (5mL), and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was quenched with water (20mL) and extracted with ethyl acetate (3X 20 mL). Subjecting the organic layer to anhydrous Na₂SO₄Drying, filtration and concentration gave the title compound as a white solid (400mg, 89%).

¹H NMR(400MHz,CDCl₃) δ 7.78-7.74(m,2H),7.54-7.51(m,3H) and 4.36(br s, 2H).

LCMS:m/z 141.9(M+H)⁺(ES⁺)。

Intermediate L11:methane sulfinamides

Ammonia gas (15psi) was bubbled into THF (10mL) at-78 deg.C for 10 minutes. Oxalyl chloride (39.18mmol, 3.4mL, 2 equiv.) is added to a solution of sodium methanesulfinate (2g, 19.59mmol, 1 equiv.) in THF (20mL) at 0 ℃ under nitrogen. The mixture was stirred at 0 ℃ for 1 hour. Then dropping the mixture into the above NH at 0 deg.C₃In THF solution. The resulting mixture was stirred at 20 ℃ for 12 hours. A solid was formed. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (0.9g, crude) as a yellow solid.

¹H NMR(400MHz,CDCl₃) δ 4.30(br s,2H) and 2.66(s, 3H).

Intermediate R1:5-bromo-6-methyl-2, 3-dihydro-1H-inden-4-amine

Step A:n- (6-bromo-4-nitro-2, 3-dihydro-1H-inden-5-yl) acetamide

Nitric acid (150mL, 2350mmol) was slowly added to sulfuric acid (150mL) cooled to 0 ℃ while maintaining the temperature below 20 ℃. The mixture was stirred for 10 minutes and added dropwise to a stirred mixture of N- (6-bromo-2, 3-dihydro-1H-inden-5-yl) acetamide (58g, 228mmol) in AcOH (300mL) and sulfuric acid (150mL), maintaining the temperature below 30 ℃. The reaction mixture was stirred at room temperature for 4 hours, then poured onto ice/water (4.5L total volume, 2.5kg ice) and allowed to stand at room temperature for 18 hours. The solid was filtered, washed with water (2.5L) and dried to give the title compound (55g, 80%) as an ochre powder.

¹H NMR(DMSO-d6)δ9.99(s,1H),7.85(s,1H),3.01-2.88(m,4H),2.07(p,J＝7.5Hz,2H),2.00(s,3H)。

LCMS m/z 299.0/301.0(M+H)⁺(ES⁺)。

And B:n- (6-methyl-4-nitro-2, 3-dihydro-1H-inden-5-yl) acetamide

N- (6-bromo-4-nitro-2, 3-dihydro-1H-inden-5-yl) acetamide (30g, 100mmol), 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboran (14.02mL, 100mmol) and K₂CO₃(34.7g, 251mmol) in dioxane (500mL) and H₂Mixture in O (140mL) with N₂Degassing for 15 minutes. Adding PdCl₂(dppf)-CH₂Cl₂Adduct (4.10g, 5.01 mmol). The reaction mixture was heated at 100 ℃ for 16 h, diluted with brine (300mL), and extracted with EtOAc (2X 800 mL). The organic layer was dried (MgSO₄) And evaporated. The residue was wet-milled with EtOAc/isohexane (1:1 mixture, 400mL) and the resulting solid was filtered, washed with hexane, and dried in vacuo to give the title compound as a brown solid (15.33g, 56%).

¹H NMR(DMSO-d6)δ9.65(s,1H),7.41(s,1H),2.98-2.87(m,4H),2.20(s,3H),2.07-2.03(m,2H),1.99(s,3H)。

LCMS m/z 235.2(M+H)⁺(ES⁺)。

And C:6-methyl-4-nitro-2, 3-dihydro-1H-inden-5-amine

N- (6-methyl-4-nitro-2, 3-dihydro-1H-inden-5-yl) acetamide (15.33g, 65.4mmol) was suspended in a mixture of EtOH (126mL) and concentrated aqueous HCl (126 mL). The mixture was heated to reflux, overnight and concentrated in vacuo. The residue was basified by adding 2m naoh aqueous solution (500mL) portion by portion. The aqueous layer was extracted with DCM (5X 200mL) and dried (MgSO)₄) And concentrated in vacuo to give the title compound (15.18g, 84%) as a brown solid.

¹H NMR(DMSO-d6)δ7.21(s,1H),6.61(s,2H),3.16(t,J＝7.5Hz,2H),2.76(t,J＝7.6Hz,2H),2.16(s,3H),2.00-1.94(m,2H)。

LCMS m/z 193.4(M+H)⁺(ES⁺)。

Step D:5-bromo-6-methyl-4-nitro-2, 3-dihydro-1H-indene

A solution of 6-methyl-4-nitro-2, 3-dihydro-1H-inden-5-amine (4.9g, 20.39mmol) and isoamyl nitrite (3mL, 22.33mmol) in MeCN (400mL) was heated to 55 deg.C, and CuBr was added₂(4.56g, 20.39 mmol). The reaction mixture was heated to 70 ℃ and stirred for 1 hour. The reaction mixture was cooled to room temperature and 1M HCl (200mL) was added. The reaction mixture was extracted with DCM (3X 200 mL). The organic phase was concentrated in vacuo and the crude product was purified by flash chromatography (0-20% EtOAc/isohexane) to give the title compound as a pale yellow solid (3.2g, 60%).

¹H NMR(DMSO-d6)δ7.50(s,1H),2.94-2.86(m,4H),2.41(s,3H),2.09(p,J＝7.6Hz,2H)。

LCMS m/z 279.2(M+Na)⁺(ES⁺)。

Step E:5-bromo-6-methyl-2, 3-dihydro-1H-inden-4-amine

Stirring 5-bromo-6-methyl-4-nitro-2, 3-dihydro-1H-indene (8.42g, 32.9mmol), saturated NH₄A mixture of aqueous Cl (50mL) and iron powder (7.34g, 132mmol) in EtOH/water (3:2, 80mL) was stirred at 80 ℃ for 2 hours. After cooling to room temperature, the reaction was diluted with EtOAc (20mL) and filteredThe pad is filtered. The filtrate was diluted with water (10 mL). The layers were separated and the organic layer was dried (MgSO₄) And concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc/isohexane) to give the title compound as a pink solid (6.52g, 75%).

¹H NMR(DMSO-d6)δ6.48(s,1H),4.94(br s,2H),2.73(t,J＝7.5Hz,2H),2.68(t,J＝7.4Hz,2H),2.24(s,3H),2.02-1.95(m,2H)。

LCMS m/z 226/228(M+H)⁺(ES⁺)。

Intermediate R2: 2-bromo-5-cyclopropyl-4-fluoroaniline

Step A:3-cyclopropyl-4-fluoroaniline

3-bromo-4-fluoroaniline (5g, 26.3mmol), cyclopropylboronic acid (2.7g, 31.4mmol) and K₂CO₃(11g, 80mmol) of a mixture in dioxane (100mL) and water (20mL) with N₂Degassing for 10 minutes. Adding PdCl₂(dppf) (0.96g, 1.312mmol) and the reaction mixture was heated at 80 ℃ for 16 h. Additional cyclopropylboronic acid (2.7g, 26.3mmol) and additional PdCl were added₂(dppf) (0.96g, 26.3mmol) and the reaction mixture was heated at 80 ℃ for 48 h. The reaction mixture was then cooled to room temperature and partitioned between EtOAc (100mL) and water (100 mL). The organic phase was washed with saturated brine (2X 100mL) and dried (MgSO)₄) And concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc/isohexane) to give the title compound as a brown solid (1.87g, 42%).

¹H NMR(DMSO-d₆)δ6.79-6.71(m,1H),6.35-6.28(m,1H),6.12(dd,J＝7.0,2.7Hz,1H),4.78(s,2H),1.96-1.88(m,1H),0.94-0.86(m,2H),0.61-0.55(m,2H)。

LCMS m/z 152.1(M+H)+(ES+)。

And B:2-bromo-5-cyclopropyl-4-fluoroaniline

3-cyclopropyl-4-fluoroaniline (1.37g, 8.07mmol) and NBS (1.4g, 7.87mmol) in MeCN (20mL) were stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (0-40% EtOAc/hexanes) to give the title compound as a light tan solid (1.04g, 52%).

¹H NMR(DMSO-d₆)δ7.18(d,J＝9.7Hz,1H),6.40(d,J＝7.4Hz,1H),5.00(s,2H),1.91(tt,J＝8.5,5.2Hz,1H),0.97-0.90(m,2H),0.63-0.58(m,2H)。

LCMS m/z 229.9/231.9(M+H)+(ES+)。

Intermediate R3: 2-bromo-4-fluoro-5- (trifluoromethoxy) aniline

4-fluoro-3- (trifluoromethoxy) aniline (1g, 5.13mmol) and NBS (1g, 5.62mmol) in MeCN (50mL) were stirred at room temperature for 3 hours. The volatiles were evaporated. The crude product was diluted with DCM (50mL), water (100mL) and saturated Na₂S₂O₃Washed with aqueous solution (100mL) and dried (MgSO)₄) And concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc/isohexane) to give the title compound as a brown oil (1.25g, 88%).

¹H NMR(DMSO-d₆)δ7.62(d,J＝9.9Hz,1H),6.94-6.87(m,1H),5.53(s,2H)。

LCMS m/z 273/275(M+H)⁺(ES⁺)。

Intermediate R4:2-bromo-5-ethyl-4-fluoroaniline

3-Ethyl-4-fluoroaniline (1.06g, 7.62mmol) and NBS (1.4g, 7.87mmol) in MeCN (25mL) were stirred at room temperature for 3 hours. The volatiles were evaporated. The crude product was diluted with DCM (50mL), water (100mL) and saturated Na₂S₂O₃Washed with aqueous solution (100mL) and dried (MgSO)₄) And concentrated in vacuo. Will be coarseThe product was purified by flash chromatography on silica gel (0-40% EtOAc/isohexane) followed by another flash chromatography on silica gel (0-50% EtOAc/isohexane) to give the title compound as a brown oil (1.39g, 75%).

¹H NMR(DMSO-d₆)δ7.19(d,J＝9.4Hz,1H),6.70(d,J＝7.3Hz,1H),5.12(s,2H),2.47(q,J＝7.4Hz,2H),1.12(t,J＝7.5Hz,3H)。

LCMS m/z 218/220(M+H)⁺(ES⁺)。

Intermediate R5:4-bromo-3-methyl-2- ((1-methylpiperidin-4-yl) oxy) pyridine

1-Methylpiperidin-4-ol (0.67g, 5.79mmol) was added to KO at room temperature^tA mixture of Bu (0.89g, 7.89mmol) in THF (5 mL). The reaction mixture was stirred for 1 hour and then cooled in an ice bath. A solution of 4-bromo-2-fluoro-3-methylpyridine (1g, 5.26mmol) in THF (5mL) was added. The mixture was allowed to warm to room temperature, stirred for 2 days, and then partitioned between EtOAc (20mL) and water (20 mL). The aqueous phase was extracted with EtOAc (20 mL). The organic phases were combined and dried (MgSO)₄) And concentrated in vacuo. The crude product was purified by flash chromatography (0-10% (0.7M ammonia/MeOH)/DCM) to give the title compound as an anhydrous oil (1.30g, 86%).

¹H NMR(DMSO-d6)δ7.85(dd,J＝5.4,0.8Hz,1H),7.19(d,J＝5.4Hz,1H),5.02(tt,J＝8.1,4.0Hz,1H),2.59-2.52(m,2H),2.26-2.20(m,5H),2.17(s,3H),1.97-1.86(m,2H),1.74-1.62(m,2H)。

LCMS m/z 285.1/287.1(M+H)⁺(ES⁺)。

The following intermediates were prepared according to the general procedure for intermediate R5:

intermediate R7:5-bromo-6-cyclopropyl-2, 3-dihydro-1H-inden-4-amine

Step A:n- (6-cyclopropyl-4-nitro-2, 3-dihydro-1H-inden-5-yl) acetamide

Make N₂Bubbling through stirred N- (6-bromo-4-nitro-2, 3-dihydro-1H-inden-5-yl) acetamide (intermediate R1, step A) (1g, 3.34mmol), cyclopropylboronic acid (0.35g, 4.01mmol) and K₂CO₃(1.39g, 10.03mmol) in dioxane (35ml) and water (10ml) over 10 minutes. Adding PdCl₂(dppf) (0.122g, 0.167 mmol). The reaction mixture was then heated at 80 ℃ for 4h, cooled to room temperature, and partitioned between EtOAc (100mL) and water (100 mL). The organic layer was dried (MgSO₄) And evaporated. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/isohexane) to give the title compound as a yellow solid (120mg, 13%).

¹H NMR(DMSO-d6)δ9.76(s,1H),7.09(s,1H),2.98-2.88(m,4H),2.09-1.94(m,6H),1.00-0.89(m,2H),0.68-0.60(m,2H)。

LCMS m/z 261.2(M+H)⁺(ES⁺)。

And B:6-cyclopropyl-4-nitro-2, 3-dihydro-1H-inden-5-amine

N- (6-cyclopropyl-4-nitro-2, 3-dihydro-1H-inden-5-yl) acetamide (120mg, 0.461mmol) was suspended in H₂O (2 mL). Concentrated HCl (2mL) was added slowly as the reaction mixture was cooled in an ice bath. The reaction mixture was then stirred at 110 ℃ for 16 hours and cooled to 0 ℃ on ice. Will be provided withThe reaction mixture was basified by adding 50 wt% aqueous NaOH solution in portions (added in 10mL increments, about 50 mL). The aqueous mixture was extracted with DCM (5X 200 mL). The combined organic layers were dried (MgSO)₄) And concentrated in vacuo to give the title compound (107mg, 51%) as a brown solid.

¹H NMR(DMSO-d6)δ7.14(s,1H),6.76(s,2H),3.16(t,J＝7.3Hz,2H),2.76(t,J＝7.6Hz,2H),1.97(p,J＝7.4Hz,2H),1.76-1.65(m,1H),0.96-0.90(m,2H),0.59-0.47(m,2H)。

LCMS m/z 219.4M+H)⁺(ES⁺)。

And C:5-bromo-6-cyclopropyl-4-nitro-2, 3-dihydro-1H-indene

A solution of 6-cyclopropyl-4-nitro-2, 3-dihydro-1H-inden-5-amine (106mg, 0.487mmol) and isoamyl nitrite (72 μ L, 0.536mmol) in MeCN (7mL) was heated to 55 ℃. Then adding CuBr₂(109mg, 0.487mmol) and the reaction mixture was heated to 70 ℃ and stirred for 1 hour. The reaction mixture was then allowed to cool to room temperature. 1M HCl (10mL) was added and the reaction mixture was extracted with DCM (3X 20 mL). The combined organic phases were concentrated in vacuo to give the title compound, which was used as crude material in the next step.

Step D:5-bromo-6-cyclopropyl-2, 3-dihydro-1H-inden-4-amine

A stirred mixture of 5-bromo-6-cyclopropyl-4-nitro-2, 3-dihydro-1H-indene (104mg, 0.369mmol), saturated aqueous ammonium chloride (0.5mL) and iron powder (82mg, 1.474mmol) in EtOH: water (3:2, 1mL) was stirred at 80 ℃ for 2 hours. The reaction mixture was then cooled to room temperature, diluted with EtOAc (20mL) and passedThe pad is filtered. The filtrate was diluted with water (10mL) and the organic layer was collected and dried (MgSO)₄) And concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc/isohexane) to give the title compound as a pink solid (17mg, 11%).

LCMS m/z 252/254(M+H)⁺(ES⁺)。

Intermediate R8: 6-methyl-5- (pyridin-4-yl) -2, 3-dihydro-1H-inden-4-amine

Make N₂Bubbling through stirred 5-bromo-6-methyl-2, 3-dihydro-1H-inden-4-amine (intermediate R1) (200mg, 0.885mmol), pyridin-4-ylboronic acid (120mg, 0.973mmol), and K₂CO₃(367mg, 2.65mmol) in a mixture of dioxane (30mL) and water (5mL) over 5 minutes. Adding PdCl₂(dppf) (32.4mg, 0.044mmol) and the reaction mixture was heated at 80 ℃ for 20 h. The reaction mixture was then cooled to room temperature and partitioned between EtOAc (100mL) and water (50 mL). The organic layer was dried (MgSO₄) Evaporation and purification of the residue by flash chromatography on silica gel (0-40% EtOAc/isohexane) gave the title compound as a yellow oil (40mg, 20%).

¹H NMR(DMSO-d6)δ8.67-8.62(m,2H),7.21-7.17(m,2H),6.47(s,1H),4.14(s,2H),2.79(t,J＝7.5Hz,2H),2.65(t,J＝7.3Hz,2H),2.00(p,J＝7.4Hz,2H),1.87(s,3H)。

LCMS m/z 225.1(M+H)⁺(ES⁺)。

The following intermediates were prepared according to the general procedure for intermediate R8:

intermediate R13:5- (2-Cyclopropoxypyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine

Step A:4-bromo-2-cyclopropoxypyridines

To a mixture of cyclopropanol (1g, 17.22mmol) and 4-bromo-2-fluoropyridine (1.2mL, 11.68mmol) in NMP (13mL) was added potassium tert-butoxide (1.9g, 16.93mmol) portionwise. The resulting mixture was stirred at room temperature under nitrogen for 30 minutes. The reaction mixture was then diluted with EtOAc (50mL), washed with water (30mL) and brine (30mL), dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound as a brown oil (2.27g, 83%).

¹H NMR(DMSO-d6)δ8.12(d,J＝5.4Hz,1H),7.28(dd,J＝5.4,1.7Hz,1H),7.16(d,J＝1.6Hz,1H),4.21(tt,J＝6.2,3.0Hz,1H),0.80-0.74(m,2H),0.70-0.66(m,2H)。

LCMS m/z 214/216(M+H)⁺(ES⁺)。

And B:5- (2-Cyclopropoxypyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine

To a solution of 4-bromo-2-cyclopropoxypyridine (189mg, 0.885mmol) in dioxane (5mL) was added B₂Pin₂(247mg, 0.973mmol), followed by the addition of potassium acetate (347mg, 3.54mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (36mg, 0.044 mmol). Degassing the reaction (N)₂5 minutes), evacuated and charged with N₂Backfilled (× 3) and stirred at 90 ℃ for 2 hours. The reaction mixture was then allowed to cool to room temperature. A solution of 5-bromo-6-methyl-2, 3-dihydro-1H-inden-4-amine (intermediate R1) (200mg, 0.885mmol) in dioxane (3mL) was added, followed by potassium carbonate (367mg,2.65mmol) in water (1.5 mL). The reaction mixture was stirred at 90 ℃ for 16 h, diluted with brine (10mL) and extracted with DCM (2X 20 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash chromatography (0-60% EtOAc/isohexane) to give the title compound as a yellow oil (135mg, 52%).

¹H NMR(DMSO-d6)δ8.26(d,J＝5.1Hz,1H),6.81(dd,J＝5.1,1.3Hz,1H),6.63(d,J＝1.2Hz,1H),6.45(s,1H),4.22(tt,J＝6.3,3.1Hz,1H),4.16(s,2H),2.78(t,J＝7.5Hz,2H),2.64(t,J＝7.3Hz,2H),2.02-1.95(m,2H),1.88(s,3H),0.81-0.68(m,4H)。

LCMS m/z 281.2(M+H)+(ES+)。

The following intermediates were prepared according to the general procedure for intermediate R13:

intermediate R25:5- (2-methoxypyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine

Step A:2-methoxy-4- (6-methyl-4-nitro-2, 3-dihydro-1H-inden-5-yl) pyridine

5-bromo-6-methyl-4-nitro-2, 3-dihydro-1H-indene (intermediate R1, step D) (218mg, 0.851mmol), (2-methoxypyridin-4-yl) boronic acid (156mg, 1.021mmol) in dioxane (2.5ml) and K₂CO₃A mixture of (353mg, 2.55mmol) in water (0.5mL) was treated with N₂Degassing for 15 minutes. Then Pd (dppf) Cl is added₂DCM (35mg, 0.043 mmol). The reaction mixture was heated to 80 ℃ for 2h, cooled to room temperature and partitioned between EtOAc (10mL) and water (5 mL). The organic layer was washed with water (10mL) and brine (10mL) and dried (MgSO)₄) And evaporated to give the title compound (186mg, 63%) which was used in the next step without purification.

¹H NMR(DMSO-d6)δ8.24(d,J＝5.2Hz,1H),7.50(s,1H),6.88-6.81(m,1H),6.67(d,J＝2.0Hz,1H),3.89(s,3H),3.03-2.92(m,4H),2.18-2.03(m,5H)。

LCMS m/z 285.0(M+H)⁺(ES⁺)。

And B:5- (2-methoxypyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine

A mixture of 2-methoxy-4- (6-methyl-4-nitro-2, 3-dihydro-1H-inden-5-yl) pyridine (186mg, 0.536mmol) and 5% Pd/C (type 87L, 58.5% humidity) (55mg, 10.72. mu. mol) in EtOH (2mL) was hydrogenated at 1 bar (bar) for 6H. Then the reaction mixture is passed throughFiltration and evaporation gave the title compound (120mg, 77%) which was used without purification.

¹H NMR(DMSO-d6)δ8.24(d,J＝5.2Hz,1H),6.77(dd,J＝5.2,1.5Hz,1H),6.58(s,1H),6.45(s,1H),4.16(s,2H),3.89(s,3H),2.78(t,J＝7.5Hz,2H),2.64(t,J＝7.4Hz,2H),1.99(p,J＝7.4Hz,2H),1.88(s,3H)。

LCMS m/z 255.1(M+H)⁺(ES⁺)。

The following intermediates were prepared according to the general procedure for intermediate R25:

intermediate R27:4- (4-isothiocyanato-6-methyl-2, 3-dihydro-1H-inden-5-yl) -2- ((1-methylpiperidin-4-yl) oxy) pyridine

Triphosgene (0.077g, 0.260mmol) in THF (1mL) was added dropwise to ice-cold 6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-amine (intermediate R26) (0.129g, 0.4mmol) and Et₃A solution of N (0.112mL, 0.800mmol) in THF (5mL) was stirred at room temperature for 3 hours. The reaction mixture was filtered, washed with THF, concentrated in vacuo and azeotropically dried with toluene (3 × 1 mL). The crude product was used without further purification.

The following intermediates were prepared according to the general procedure for intermediate R27:

intermediate R29:5- (2-ethoxypyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine

Step A:5- (2-Fluoropyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine

4-bromo-2-fluoropyridine (1.170g, 6.65mmol), KOAc (2.60g, 26.5mmol) and B₂Pin₂(1.685g, 6.63mmol) and PdCl₂(dppf)-CH₂Cl₂Solution of adduct (0.271g, 0.332mmol) in 1, 4-dioxane (20mL) in N₂The mixture was heated at 100 ℃ for 2 hours. The reaction mixture was then cooled to room temperature and a solution of 5-bromo-6-methyl-2, 3-dihydro-1H-inden-4-amine (intermediate R1) (1.5g, 6.63mmol) in 1, 4-dioxane (5mL) was added followed by K₂CO₃(3.67g, 26.5mmol) in water (2.5 mL). The reaction mixture was heated at 100 ℃ for 2h, diluted with EtOAc (75mL), and washed with water (100mL) and brine (100 mL). The organic phase was separated and dried (MgSO)₄) And evaporated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc/isohexane) to give the title compound as a white solid (940mg, 55%).

¹H NMR(CDCl₃)δ8.32(d,J＝5.0Hz,1H),7.12(dt,J＝5.2,1.6Hz,1H),6.88(s,1H),6.66(s,1H),3.36(s,2H),2.93(t,J＝7.5Hz,2H),2.72(t,J＝7.4Hz,2H),2.14(p,J＝7.5Hz,2H),2.00(s,3H)。

LCMS m/z 243.2(M+H)⁺(ES⁺)。

And B:5- (2-ethoxypyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine

5- (2-Fluoropyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine (100mg, 0.413mmol) was dissolved in THF (2 mL). EtONa (42mg, 0.617mmol) was added and the reaction mixture was stirred at room temperature for 18 h. Additional EtONa (42mg, 0.617mmol) was added and the reaction mixture was stirred for 4 h. The reaction mixture was then partitioned between EtOAc (20mL) and water (10 mL). The organic layer was separated, washed with water (10mL), dried (phase separator) and concentrated in vacuo to give the title compound (121mg, quantitative yield).

¹H NMR(DMSO-d6)δ8.21(d,J＝5.2Hz,1H),6.74(dd,J＝5.2,1.4Hz,1H),6.54(s,1H),6.45(s,1H),4.34(q,J＝7.0Hz,2H),4.14(s,2H),2.78(t,J＝7.5Hz,2H),2.64(t,J＝7.3Hz,2H),1.99(p,J＝7.5Hz,2H),1.88(s,3H),1.35(t,J＝7.1Hz,3H)。

LCMS m/z 269.2(M+H)+(ES+)。

The following intermediates were prepared according to the general procedure for intermediate R29:

intermediate R31:5- (2- (cyclohexyloxy) pyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine

Mixing KO with water^tBu (0.132g, 1.176mmol) was added to THF (3mL) containing cyclohexanol (0.163mL, 1.568 mmol). The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0 ℃.5- (2-Fluoropyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine (intermediate R29, step A) (0.200g, 0.784mmol) was added and the reaction mixture was stirred at room temperature for 18H. The reaction mixture was then partitioned between EtOAc (20mL) and water (10 mL). The organic layer was washed with water (10mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by flash chromatography (0-25% EtOAc/isohexane) to give the title compound as a thick anhydrous oil (0.177g, 61%).

¹H NMR(DMSO-d6)δ8.19(d,J＝5.1Hz,1H),6.71(dd,J＝5.1,1.4Hz,1H),6.49(s,1H),6.44(s,1H),5.04-4.96(m,1H),4.12(s,2H),2.77(t,J＝7.5Hz,2H),2.64(t,J＝7.3Hz,2H),2.04-1.94(m,4H),1.88(s,3H),1.78-1.69(m,2H),1.59-1.52(m,1H),1.51-1.33(m,4H),1.30-1.22(m,1H)。

LCMS m/z 323.3(M+H)⁺(ES⁺)。

The following intermediates were prepared according to the general procedure for intermediate R31:

intermediate R33: 4-fluoro-6-isopropyl-2- (2-methoxypyridin-4-yl) -3-methylaniline

Step A:4-fluoro-5-methyl-2- (prop-1-en-2-yl) aniline

2-bromo-4-fluoro-5-methylaniline (10.00g, 49.0mmol), 4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (11mL, 58.8mmol), Pd (OAc)₂(440mg, 1.960mmol), tricyclohexylphosphine (21.2g, 76mmol) and K₃PO₄(28.1g, 132mmol) of a mixture in dioxane (120mL) and water (30mL) with N₂And (4) degassing. The reaction mixture was then heated at 100 ℃ for 18 hours. The solvent was evaporated and the residue partitioned between isohexane (500mL) and water (300 mL). The organic layer was washed with water (200mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-40% EtOAc/isohexane) to give the title compound as a brown oil (9.09g, 99%).

¹H NMR(DMSO-d₆)δ6.70(d,J＝10.6Hz,1H),6.52(d,J＝7.3Hz,1H),5.24-5.20(m,1H),5.01-4.98(m,1H),4.59(br s,2H),2.09(s,3H),1.98(s,3H)。

And B:4-fluoro-2-isopropyl-5-methylaniline

A mixture of 4-fluoro-5-methyl-2- (prop-1-en-2-yl) aniline (13.33g, 81mmol) and 5% Pd/C (type 87L, 58.5% humidity) (1.66g, 0.324mmol) in EtOAc (145mL) was hydrogenated at 3 bar for 16 h. Then the reaction mixture is passed throughFiltration and concentration in vacuo afforded the title compound as a dark green oil (11.95g, 79%).

¹H NMR(DMSO-d₆)δ6.74(d,J＝11.4Hz,1H),6.50(d,J＝7.3Hz,1H),5.07(s,2H),2.92(hept,J＝6.7Hz,1H),2.08(s,3H),1.11(d,J＝6.8Hz,6H)。

LCMS m/z 168.1(M+H)+(ES+)。

And C:2-bromo-4-fluoro-6-isopropyl-3-methylaniline

NBS (12.08g, 67.9mmol) was added to a solution of 4-fluoro-2-isopropyl-5-methylaniline (11.95g, 67.9mmol) in DCM (180 mL). The reaction mixture was stirred at room temperature for 20 minutes, then washed with water (200mL) and 10% Na₂S₂O₃The aqueous solution (200mL) was washed, dried (phase separator) and concentrated in vacuo to give the crude product (14.6 g). 5g of the crude product was purified by flash chromatography on silica gel (0-20% EtOAc/isohexane) to give the title compound as a red-orange oil (3.26g, 19%).

¹H NMR(DMSO-d₆)δ6.89(d,J＝11.0Hz,1H),4.87(s,2H),3.06(sept,J＝6.7Hz,1H),2.20(d,J＝2.4Hz,3H),1.14(d,J＝6.7Hz,6H)。

LCMS m/z 246.1/248.1(M+H)⁺(ES⁺)。

Step D:4-fluoro-6-isopropyl-2- (2-methoxypyridin-4-yl) -3-methylaniline

(2-methoxypyridin-4-yl) boronic acid (200mg, 1.308mmol), 2-bromo-4-fluoro-6-isopropyl-3-methylaniline (322mg, 1.308mmol), potassium carbonate (723mg, 5.23mmol) and PdCl₂(dppf.) DCM (53mg, 0.065mmol) was dissolved in 1, 4-dioxane (6mL) and water (3 mL). Degassing the reaction mixture (N)₂5 minutes) and evacuated andand with N₂Backfill (× 3). The reaction mixture was then stirred at 100 ℃ for 3 hours. The reaction mixture was diluted with EtOAc (20mL) and washed with brine (2X 20 mL). The organic extract was dried (phase separator) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/isohexane) to give the title compound as a brown oil (276mg, 73%).

¹H NMR(DMSO-d₆)δ8.28(d,J＝5.1Hz,1H),6.88(d,J＝11.3Hz,1H),6.81(dd,J＝5.2,1.4Hz,1H),6.65(s,1H),3.99(s,2H),3.90(s,3H),3.03-2.96(m,1H),1.79(d,J＝2.1Hz,3H),1.15(d,J＝6.7Hz,6H)。

LCMS(m/z 275.1(M+H)+(ES+)。

The following intermediates were prepared according to the general procedure for intermediate R33:

intermediate R39:4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-amine

Step A:2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole

To a solution of NaH (9.74g, 243.59mmol, 60 wt% in mineral oil, 1 eq.) in DMF (200mL) was added 2-methyl-1H-imidazole (20g, 243.59mmol, 1 eq.) in portions at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 minutes. Then (2- (chloromethoxy) ethyl) trimethylsilane (48.73g, 292.31mmol, 1.2 equiv.) was added. The resulting mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was quenched with ice water (300mL), diluted with ethyl acetate (1L), and saturated NH₄Aqueous Cl solution (3X 30)0mL) and brine (3X 300 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Ethyl acetate, 5:1 to 1:1) to give the title compound as a yellow oil (40g, 76% yield, 98% purity on LCMS).

¹H NMR(400MHz,CDCl₃) δ 6.90(s,2H),5.18(s,2H),3.47(t,2H),2.43(s,3H),0.89(t,2H) and 0.01(s, 9H).

LCMS:m/z 213.0(M+H)⁺(ES⁺)。

And B:4-bromo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole

To a solution of 2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (20g, 94.18mmol, 1 eq) in DMF (200mL) was added NBS (16.76g, 94.18mmol, 1 eq) at-20 ℃. The reaction mixture was then stirred at-20 ℃ for 2 hours. The reaction mixture was saturated with Na₂SO₃Quench with aqueous solution (100mL), dilute with EtOAc (200mL), and saturate NH₄Aqueous Cl (3X 100mL) and brine (3X 100 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Ethyl acetate, 10:1 to 5:1) to give the title compound as a yellow oil (13.5g, 41% yield, 84% purity on LCMS).

¹H NMR(400MHz,CDCl₃) δ 6.88(s,1H),5.25(s,2H),3.55(t,2H),2.42(s,3H),0.91(t,2H) and 0.02(s, 9H).

LCMS:m/z 292.9(M+H)⁺(ES⁺)。

And C:2-methyl-4- (prop-1-en-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole

4-bromo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (10g, 28.84mmol, 1 eq.), 4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (5.33g, 31.72mmol, 1.1 eq.), Pd (dppf) Cl₂(1.06g, 1.44mmol, 0.05 eq.) and Na₂CO₃(6.11g, 57.68mmol, 2 equiv.) in dioxane (100mL) and H₂Solution in O (20mL) in N₂The mixture was stirred at 100 ℃ for 12 hours. The reaction mixture was diluted with water (100mL) and extracted with ethyl acetate (3X 100 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Ethyl acetate, 5:1 to 1:1) to give the title compound as a yellow oil (7g, 96%).

¹H NMR(400MHz,CDCl₃) δ 6.88(s,1H),5.23(s,2H),5.20(s,1H),5.14(s,1H),3.52(t,2H),2.48(s,3H),2.08(s,3H),0.93(t,2H) and 0.01(s, 9H).

LCMS:m/z 253.0(M+H)⁺(ES⁺)。

Step D:4-isopropyl-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole

In N₂To a solution of 2-methyl-4- (prop-1-en-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (7.18g, 28.44mmol, 1 eq) in MeOH (100mL) was added Pd/C (700mg, 10 wt% supported on activated carbon). The suspension is degassed under vacuum and treated with H₂And (5) purifying for several times. Mixing the mixture in H₂(15psi) at 25 ℃ for 12 hours. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (8g, 99% yield, 90% purity on LCMS).

¹H NMR(400MHz,CDCl₃) δ 6.66(s,1H),5.15(s,2H),3.49(t,2H),2.95-2.84(m,1H),2.43(s,3H),1.26(d,6H),0.91(t,2H) and 0.02(s, 9H).

LCMS:m/z 255.2(M+H)⁺(ES⁺)。

Step E:4-isopropyl-2-methyl-1H-imidazole

To a solution of 4-isopropyl-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (8g, 31.44mmol, 1 eq) in DCM (80mL) at 25 ℃ was added TFA (123.20g, 1.08mol, 34.37 eq). The mixture was then stirred at 25 ℃ for 12 hours. The reaction mixture was washed with ice water (10mL) and saturated NaHCO₃Aqueous solution (300mL) was quenched. The mixture was extracted with ethyl acetate (2X 100 mL). The combined organic layers were washed with brine (2X 200mL) and dried over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Ethyl acetate: methanol, 1:0 to 20:1) to give the title compound as a yellow oil (3.7g, 95%).

¹H NMR(400MHz,CDCl₃) δ 6.71(s,1H),2.99-2.93(m,1H),2.53(s,3H) and 1.27(d, 6H).

LCMS:m/z 125.3(M+H)⁺(ES⁺)。

Step F:4- (4-isopropyl-2-methyl-1H-imidazol-1-yl) pyridine

To a solution of 4-isopropyl-2-methyl-1H-imidazole (1.4g, 11.27mmol, 1 equiv.) and 4-iodopyridine (1.85g, 9.02mmol, 0.8 equiv.) in DMF (14mL) was added Cu₂O (81mg, 563.68. mu. mol, 0.05 eq.) and Cs₂CO₃(7.35g, 22.55mmol, 2 equiv.). The reaction mixture was stirred at 100 ℃ for 15 hours. The reaction mixture is then treated with ethyl acetateEster (50mL) diluted and saturated NH₄Aqueous Cl (3X 30mL) and brine (3X 30 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Ethyl acetate, 5:1 to 0:1) to give the title compound as a yellow solid (600mg, 26% yield, 97% purity on LCMS).

¹H NMR(400MHz,CDCl₃) δ 8.73(dd,2H),7.27(dd,2H),6.77(s,1H),2.93-2.86(m,1H),2.48(s,3H) and 1.29(d, 6H).

LCMS:m/z 202.0(M+H)⁺(ES⁺)。

Step G:4- (4-isopropyl-2-methyl-5-nitro-1H-imidazol-1-yl) pyridine

To 4- (4-isopropyl-2-methyl-1H-imidazol-1-yl) pyridine (400mg, 1.93mmol, 1 eq) in H at 0 deg.C₂SO₄(71.33mmol, 3.88mL, 98% purity in solution, 37 equivalents) to which HNO was added₃(5.78mmol, 400. mu.L, 65% purity in aqueous solution, 3 equivalents). The reaction mixture was then stirred at 25 ℃ for 12 hours. The reaction mixture was quenched with ice water (20mL) and saturated NaHCO₃Adjusting the pH value of the aqueous solution to 8-9. The mixture was extracted with ethyl acetate (3X 20 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The yellow solid was purified by column chromatography (SiO)₂Ethyl acetate, 2:1 to 1:1) to give the title compound as a yellow solid (400mg, 84%).

¹H NMR(400MHz,CDCl₃) Δ 8.83(d,2H),7.22(d,2H),3.75-3.69(m,1H),2.25(s,3H) and 1.36(d, 6H).

LCMS:m/z 247.1(M+H)⁺(ES⁺)。

Step H:4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-amine

A mixture of 4- (4-isopropyl-2-methyl-5-nitro-1H-imidazol-1-yl) pyridine (400mg, 1.62mmol, 1 eq) and Pd/C (40mg, 10 wt% on activated carbon) in MeOH (20mL) at 20 deg.C in H₂Hydrogenation at (15psi) for 1 hour. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was dissolved in THF (10mL) and adjusted to pH 3-4 with 4 mhz cl/dioxane. The resulting mixture was concentrated in vacuo to give the title compound (400mg, 97%, HCl salt) as a yellow solid, which was used in the next step without further purification.

¹H NMR(400MHz,DMSO-d₆) δ 15.02(s,1H),8.99(d,2H),7.90(d,2H),3.25-3.15(m,1H),2.45(s,3H) and 1.27(d, 6H).

LCMS:m/z 217.1(M+H)⁺(ES⁺)。

Intermediate R40:4-isopropyl-1- (2-methoxypyridin-4-yl) -2-methyl-1H-imidazol-5-amine

Step A:4- (4-isopropyl-2-methyl-1H-imidazol-1-yl) -2-methoxypyridine

4-isopropyl-2-methyl-1H-imidazole (intermediate R39, step E) (1g, 6.44mmol, 1 equiv.), 4-iodo-2-methoxypyridine (1.51g, 6.44mmol, 1 equiv.), Cu₂O (922mg, 6.44mmol, 1 eq.) and Cs₂CO₃A reaction mixture of (4.20g, 12.88mmol, 2 equiv.) in DMF (10mL) was stirred at 100 ℃ for 12 h. The reaction mixture was then filtered. The filtrate was poured into water (20mL) and extracted with ethyl acetate (3X 30 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Ethyl acetate, 5:1 to 1:1) to give the title compound as a yellow oil (700mg, 47%).

¹H NMR(400MHz,CD₃OD) Δ 8.25(d,1H),7.03(d,1H),6.98(s,1H),6.84(s,1H),3.96(s,3H),2.87-2.80(m,1H),2.46(s,3H) and 1.26(d, 6H).

LCMS:m/z 232.2(M+H)⁺(ES⁺)。

And B:4- (4-isopropyl-2-methyl-5-nitro-1H-imidazol-1-yl) -2-methoxypyridine

To 4- (4-isopropyl-2-methyl-1H-imidazol-1-yl) -2-methoxypyridine (0.7g, 3.03mmol, 1 eq) in H at 0 deg.C₂SO₄(12.88g, 98 wt% in aqueous solution, 131.32mmol, 43.39 equivalents) to the solution was added HNO₃(829mg, 9.08mmol, 69 wt% in water, 3 equivalents). The reaction mixture was then stirred at 25 ℃ for 2 hours. The reaction mixture was poured into ice water (40mL) and adjusted to pH 8-9 with NaOH solid. The mixture was then extracted with ethyl acetate (3X 50 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Ethyl acetate, 5:1 to 3:1) to give the title compound as a yellow solid (600mg, 67% yield, 94% purity on LCMS).

¹H NMR(400MHz,CD₃OD) Δ 8.33(d,1H),6.99(dd,1H),6.90(d,1H),4.00(s,3H),3.76-3.68(m,1H),2.25(s,3H) and 1.34(d, 6H).

LCMS:m/z 277.0(M+H)⁺(ES⁺)。

And C:4-isopropyl-1- (2-methoxypyridin-4-yl) -2-methyl-1H-imidazol-5-amine

In N₂To a solution of 4- (4-isopropyl-2-methyl-5-nitro-1H-imidazol-1-yl) -2-methoxypyridine (200mg,723.88 μmol, 1 eq) in MeOH (5mL) was added Pd/C (20mg, 10 wt% on activated carbon). The suspension is degassed under vacuum and treated with H₂And (5) purifying for several times. The mixture was heated at 25 ℃ under H₂Stir (15psi) for 2 hours. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (178mg, 100%) which was used directly in the next step.

¹H NMR(400MHz,CDCl₃) δ 8.30(d,1H),6.81(dd,1H),6.65(d,1H),4.01(s,3H),3.65-3.57(m,1H),2.26(s,3H) and 1.37(d, 6H).

Intermediate R41:

(6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamic acid phenyl ester

Step A:4-bromo-2- ((1-methylpiperidin-4-yl) oxy) pyridine

To a solution of KOtBu (41.13g, 366.51mmol, 1.5 equiv.) in THF (500mL) at 20 deg.C was added 1-methylpiperidin-4-ol (33.77g, 293.20mmol, 1.2 equiv.). The reaction mixture was stirred for 1 hour. 4-bromo-2-fluoropyridine (43g, 244.34mmol, 1 eq) was then added at 0 ℃. The reaction mixture was stirred at 20 ℃ for 12 hours and then poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (2X 500 mL). The combined organic phases were washed with brine (2X 500mL) over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂Containing 0.1% NH₃.H₂O, DCM: methanol 1:0 to 10:1) to give the title compound as a yellow solid (61g, 92%).

¹H NMR(400MHz,DMSO-d₆) Δ 8.05(d,1H),7.18(dd,1H),7.06(s,1H),4.98-4.93(m,1H),2.62-2.59(m,2H),2.16-2.11(m,5H)1.94-1.91(m,2H) and 1.66-1.62(m, 2H).

LCMS:m/z 273.0(M+H)⁺(ES⁺)。

And B:2- ((1-methylpiperidin-4-yl) oxy) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

In N₂To a mixture of 4-bromo-2- ((1-methylpiperidin-4-yl) oxy) pyridine (20g, 73.76mmol, 1 eq) and 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (24.35g, 95.89mmol, 1.3 eq) in dioxane (200mL) was added PdCl in one portion₂(dppf) (3.24g, 4.43mmol, 0.06 equiv.) and KOAc (34.24g, 348.88mmol, 4.73 equiv.). The reaction mixture was then heated to 100 ℃ for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% NH)₃.H₂O-MeCN) to give the title compound as a brown oil (22.5g, 96%).

¹H NMR(400MHz,DMSO-d₆) δ 8.17-8.12(m,1H),7.08-7.03(m,1H),6.93-6.88(m,1H),5.05-4.90(m,1H),3.92-3.86(m,2H),2.73-2.66(m,2H),2.22(s,3H),1.95-1.90(m,2H),1.69-1.63(m,2H) and 1.06(s, 12H).

LCMS:m/z 319.0(M+H)⁺(ES⁺)。

And C:

6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-amine

In N₂5-bromo-6-methyl-2, 3-dihydro-1H-inden-4-amine (intermediate R1) (40g, 176.90mmol, 1 equiv.) and 2- ((1-methylpiperidin-4-yl) oxy) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (78.81g, 247.66mmol, 1.4 equiv.) in dioxane (500mL) and H₂The mixture in O (100mL) was added in one portionK₂CO₃(73.35g, 530.71mmol, 3 equiv.) and PdCl₂(dppf) (7.77g, 10.61mmol, 0.06 equiv.). The reaction mixture was then stirred at 100 ℃ for 12 hours. The reaction mixture was quenched with water (500mL) and extracted with EtOAc (3X 500 mL). The combined organic phases were washed with brine (500mL) over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was diluted with DCM (300mL) and extracted with HCl (3X 100mL, 3M). The combined aqueous phases were saturated with Na₂CO₃The aqueous solution was adjusted to pH 8 and then extracted with DCM (3X 200 mL). The combined organic phases were washed with brine (200mL) over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂PE EtOAc 1:0 to 5:1, then DCM 1:0 to 10:1 MeOH containing 0.1% NH₃.H₂O) to yield the title compound as a brown gum (50g, 80% yield, 95.6% purity on HPLC).

¹H NMR(400MHz,DMSO-d₆) δ 8.20(d,1H),6.72(dd,1H),6.50(s,1H),6.44(s,1H),5.02-4.97(m,1H),4.13(s,2H),2.77(t,2H),2.67-2.61(m,4H),2.17(s,3H),2.16-2.11(m,2H),2.02-1.94(m,4H),1.87(s,3H) and 1.72-1.64(m, 2H).

LCMS:m/z 338.2(M+H)⁺(ES⁺)。

Step D:

(6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamic acid phenyl ester

To a solution of 6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-amine (1g, 2.96mmol, 1 eq) and phenyl chloroformate (463mg, 2.96mmol, 1 eq) in DCM (20mL) at 0 ℃ was added TEA (300mg, 2.96mmol, 1 eq). The reaction mixture was then stirred at 25 ℃ for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% TFA-MeCN in water) to give the title compound as a yellow solid (350mg, 20% yield, 95% purity on LCMS, TFA salt).

¹H NMR(400MHz,DMSO-d₆) δ 9.70-9.60(m,1H),9.19(s,1H),8.25(t,1H),7.36-7.34(m,2H),7.23-7.16(m,2H),6.90-6.81(m,3H),6.68-6.62(m,1H),5.36-5.19(m,1H),3.39-3.14(m,4H),2.97-2.91(m,2H),2.87-2.79(m,5H),2.38-2.33(m,1H),2.27-2.16(m,1H),2.06(d,6H) and 1.90-1.78(m, 1H).

LCMS:m/z 458.1(M+H)⁺(ES⁺)。

Preparation examples

Example 1:n- ((6-methyl-5- (2-methylpyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) methanesulfonamide

6-methyl-5- (2-methylpyridin-4-yl) -2, 3-dihydro-1H-inden-4-amine (intermediate R9) (35mg, 0.147mmol) was added to a suspension of (4- (dimethylamino) pyridin-1-ium-1-carbonyl) (methylsulfonyl) amide (intermediate L1) (36mg, 0.148mmol) in acetonitrile (1 mL). The reaction mixture was stirred at 60 ℃ for 1 hour. The volatiles were evaporated and the crude product was dissolved in DMSO (1mL) and filtered. The crude product was purified by basic preparative HPLC (10-40% MeCN in water) to give the title compound as a white solid (7mg, 13%).

¹H NMR (DMSO-d6) δ 8.48(d, J ═ 5.1Hz,1H),7.11(s,1H),7.04(s,1H),6.96(d, J ═ 5.1Hz,1H),3.30(s,3H),3.02(s,3H),2.91(t, J ═ 7.4Hz,2H),2.75(t, J ═ 7.3Hz,2H),2.04-1.97(m, 5H). No two exchangeable protons are observed.

LCMS m/z 360.2(M+H)⁺(ES⁺)。

The following examples were prepared according to the general procedure of example 1:

example 40:n- ((5- (2-methoxypyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-yl) carbamoyl) methanesulfonamide, sodium salt

5- (2-Methoxypyridin-4-yl) -6-methyl-2, 3-dihydro-1H-inden-4-amine (intermediate R25) (148mg, 0.582mmol) was added to a suspension of (4- (dimethylamino) pyridin-1-ium-1-carbonyl) (methylsulfonyl) amide (intermediate L1) (142mg, 0.582mmol) in MeCN (2 mL). The reaction mixture was stirred at 60 ℃ for 1 hour. The volatiles were evaporated and the crude product was dissolved in DMSO (2mL) and filtered. The crude material was purified by basic preparative HPLC to give the free acid, which was treated with 0.5M NaOH (474 μ L, 0.237mmol) and lyophilized to give the title compound as a white solid (83mg, 87%).

¹H NMR(DMSO-d6)δ8.15(dd,J＝5.2,0.7Hz,1H),6.95(s,1H),6.75(dd,J＝5.2,1.4Hz,1H),6.63-6.54(m,2H),3.87(s,3H),2.86(t,J＝7.4Hz,2H),2.79(t,J＝7.5Hz,2H),2.58(s,3H),2.04-1.89(m,5H)。

LCMS m/z 376.2(M+H)⁺(ES⁺)。

Example 41:1- (2- (dimethylamino) ethyl) -N- ((6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -1H-pyrazole-3-sulfonamide

To a stirred solution of 1- (2- (dimethylamino) ethyl) -1H-pyrazole-3-sulfonamide (22mg, 0.1mmol) in THF (2mL) was added 2M sodium tert-butoxide (0.055mL, 0.11mmol) in THF at room temperature. The resulting mixture was stirred at room temperature for 1 hour. A solution of 4- (4-isocyanato-6-methyl-2, 3-dihydro-1H-inden-5-yl) -2- ((1-methylpiperidin-4-yl) oxy) pyridine (intermediate R27) (36.3mg, 0.1mmol) in THF (1mL) was then added and the reaction mixture was stirred at room temperature overnight. The volatiles were evaporated and the crude product was dissolved in DMSO (1mL) and purified by basic preparative HPLC (10-40% MeCN in water) to give the title compound as a solid (5mg, 9%).

¹H NMR (DMSO-d6) δ 8.13(d, J ═ 5.3Hz,1H),7.79(s,1H),7.25(s,1H),7.02(s,1H),6.67(d, J ═ 5.3Hz,1H),6.53(s,1H),6.47-6.40(m,1H),5.13-5.04(m,1H),4.23(t, J ═ 6.6Hz,2H),2.96-2.89(m,2H),2.85(t, J ═ 7.4Hz,2H),2.66(t, J ═ 6.6Hz,2H),2.62-2.56(m,4H),2.41(s,3H),2.19(s,6H),2.10-2.03(m,2H), 1.90 (s,1H), 1.87 (m,1H), 2.73(m, 2.87). No exchangeable proton was observed.

LCMS m/z 582.3(M+H)⁺(ES⁺)。

The following examples were prepared according to the general procedure of example 41:

example 46:4- (2-hydroxypropan-2-yl) -N- ((4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-yl) carbamoyl) furan-2-sulfonamide, ammonium salt

Step A:((4- (2-hydroxypropan-2-yl) furan-2-yl) sulfonyl) (4-isopropylpyridin-1-ium-1-carbonyl) amide

A solution of 4- (2-hydroxypropan-2-yl) furan-2-sulfonamide (intermediate L7) (100mg, 487.26. mu. mol, 1 eq.) and N, N-lutidine-4-amine (119mg, 974.51. mu. mol, 2 eq.) in MeCN (2mL) was stirred at 25 ℃ for 30 minutes. Diphenyl carbonate (115mg, 535.98. mu. mol, 1.1 eq.) was then added. The reaction mixture was stirred at 25 ℃ for 12 hours. The reaction mixture, a red solution (theoretical amount: 172.19mg in 2mL MeCN), was used directly in the next step.

And B:

4- (2-hydroxypropan-2-yl) -N- ((4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-yl) carbamoyl) furan-2-sulfonamide, ammonium salt

To a solution of 4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-amine (intermediate R39) (100mg, 395.66 μmol, 1 eq, HCl salt) in MeCN (1mL) was added a solution of ((4- (2-hydroxyprop-2-yl) furan-2-yl) sulfonyl) (4-isopropylpyridin-1-ium-1-carbonyl) amide in MeCN (theoretical amount: 140mg, 1.6mL, 395.66 μmol, 1 eq). The reaction mixture was stirred at 70 ℃ for 1 hour. The reaction mixture was then purified by reverse phase preparative HPLC (column: Waters Xbridge C18, 150mm X25 mm X5 μm; mobile phase [ A: water (0.05% ammonium hydroxide v/v); B: MeCN ]; B%: 1% -20%, 10min) to give the title compound (9.52mg, two steps 5% yield, 99% purity on LCMS, ammonium salt) as a white solid.

¹H NMR(400MHz,DMSO-d₆+D₂O) Δ 8.71(s,2H),7.51-7.40(m,3H),6.72-6.65(s,1H),2.85-2.81(m,1H),2.33(s,3H),1.37(s,6H) and 1.17(s, 6H).

LCMS:m/z 448.1(M+H)⁺(ES⁺)。

Example 47:1-cyclopropyl-N- ((4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-yl) carbamoyl) -1H-pyrazole-3-sulfonamide

Step A:((1-cyclopropyl-1H-pyrazol-3-yl) sulfonyl) (4- (dimethylamino) pyridin-1-ium-1-carbonyl) amide

A mixture of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (intermediate L8) (150mg, 801.20. mu. mol, 1 eq.) and N, N-lutidine-4-amine (196mg, 1.60mmol, 2 eq.) in MeCN (3mL) was stirred at 25 ℃ for 30 min. Diphenyl carbonate (189mg, 881.32. mu. mol, 1.1 eq.) was then added. The resulting mixture was stirred at 25 ℃ for 12 hours. The reaction mixture became cloudy and some solids precipitated out. The suspension was filtered and the filter cake was collected to give the title compound as an off-white solid (95mg, 35%).

¹H NMR(DMSO-d₆) δ 8.10(d,2H),7.92(d,1H),6.59-6.56(m,3H),3.84-3.75(m,1H),2.95(s,6H) and 1.07-0.99(m, 4H).

And B:

1-cyclopropyl-N- ((4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-yl) carbamoyl) -1H-pyrazole-3-sulfonamide

To a solution of 4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-amine (intermediate R39) (107mg, 424.89 μmol, 1.5 equivalents, HCl salt) in MeCN (4mL) was added ((1-cyclopropyl-1H-pyrazol-3-yl) sulfonyl) (4- (dimethylamino) pyridin-1-ium-1-carbonyl) amide (95mg, 283.26 μmol, 1 equivalent). The reaction mixture is stirred under N₂Then, the mixture was stirred at 70 ℃ for 45 minutes. The reaction mixture was then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% NH)₃.H₂O-MeCN), then purified by reverse phase preparative HPLC (column: waters Xbridge, 150 mm. times.25 mm. times.5 μm; mobile phase [ a: water (0.05% ammonium hydroxide v/v); b: MeCN](ii) a B%: 1% -20%, 10min) to give the title compound as a white solid (11.61mg, two steps 9% yield, 98% purity on HPLC).

¹H NMR(400MHz,DMSO-d₆) δ 8.65-8.62(m,2H),7.89(s,1H),7.79(d,1H),7.34-7.31(m,2H),6.47(s,1H),3.83-3.81(m,1H),2.67-2.64(m,1H),2.20(s,3H) and 1.10-1.02(m, 10H).

LCMS:m/z 430.1(M+H)⁺(ES⁺)。

Example 48:4- (2-hydroxypropan-2-yl) -N- ((4-isopropyl-1- (2-methoxypyridin-4-yl) -2-methyl-1H-imidazol-5-yl) carbamoyl) furan-2-sulfonamide

A mixture of 4-isopropyl-1- (2-methoxypyridin-4-yl) -2-methyl-1H-imidazol-5-amine (intermediate R40) (178mg, 722.67. mu. mol, 1 eq.) and ((4- (2-hydroxypropan-2-yl) furan-2-yl) sulfonyl) (4-isopropylpyridin-1-ium-1-carbonyl) amide (example 46, step A) (255mg, 722.67. mu. mol, 1 eq.) in MeCN (5mL) in N₂The mixture was stirred at 70 ℃ for 2 hours. The reaction mixture was directly subjected to reverse phase flash chromatography (0.1% NH)₃·H₂O-MeCN), then purified by reverse phase preparative HPLC (column: xtimate C18, 150mm × 25mm × 5 μm; mobile phase [ a: water (0.05% ammonium hydroxide v/v); b: MeCN](ii) a B%: 0% -24%, 10min) to give the title compound as a white solid (24.92mg, two steps 7% yield, 100% purity on LCMS).

¹H NMR(400MHz,DMSO-d₆) δ 8.27-8.19(m,1H),7.68-7.45(m,1H),7.39(s,1H),7.04-6.77(m,2H),6.65-6.53(m,1H),4.93(s,1H),3.87(s,3H),2.80-2.69(m,1H),2.22(s,3H),1.33(s,6H) and 1.10(s, 6H).

LCMS:m/z 478.3(M+H)⁺(ES⁺)。

Example 49:1- (5-isopropyl-2-methyl-3- (4-pyridyl) imidazol-4-yl) -3- (methyl- (1-methylpyrrolidin-3-yl) sulfamoyl) urea

Step A:(4- (dimethylamino) pyridin-1-ium-1-carbonyl) (N-methyl-N- (1-methylpyrrolidin-3-yl) sulfamoyl) amide

A solution of N, N-lutidine-4-amine (366mg, 3.00mmol, 2 equiv.) and 1-methyl-3- [ methyl (sulfamoyl) amino ] pyrrolidine (intermediate L9) (0.29g, 1.50mmol, 1 equiv.) in MeCN (8mL) was stirred at 20 ℃ for 30 min. Diphenyl carbonate (353mg, 1.65mmol, 1.1 equiv) was then added. The resulting mixture was stirred at 20 ℃ for 12 hours. The mixture (theoretical amount: 0.53g, crude) was used directly in the next step.

And B:1- (5-isopropyl-2-methyl-3- (4-pyridyl) imidazol-4-yl) -3- (methyl- (1-methylpyrrolidin-3-yl) sulfamoyl) urea

To a mixture of 4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-amine (intermediate R39) (0.2g, 791.32. mu. mol, 1 eq, HCl salt) in MeCN (1mL)A solution of (4- (dimethylamino) pyridin-1-ium-1-carbonyl) (N-methyl-N- (1-methylpyrrolidin-3-yl) sulfamoyl) amide (the reaction mixture of step A) in MeCN (8mL) was added. Heating the resulting mixture to 70 ℃ and under N₂Stirred for 30 minutes. The reaction mixture was then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% NH)₃.H₂O-MeCN), then further purified by preparative HPLC (column: waters Xbridge C18, 150 mm. times.25 mm. times.5 μm; mobile phase [ a: water (10mM NH)₄HCO₃)，B：MeCN](ii) a B%: 1% -15%, 10min) to give the title compound as a white solid (25.13mg, two steps 7% yield, 100% purity on LCMS).

¹H NMR(400MHz,CD₃OD) δ 8.70(d, J ═ 6.0Hz,2H),7.50-7.48(m,2H),4.48-4.44(m,1H),3.30-2.92(m,5H),2.74(s,3H),2.63(s,3H),2.29(s,3H),2.15-1.98(m,2H),1.27(d, J ═ 6.8Hz, 6H). 2 × NH was lost.

LCMS:m/z 436.1(M+H)⁺(ES⁺)。

Example 50:n- ((4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-yl) carbamoyl) benzenesulfonamide

Step A:(4- (dimethylamino) pyridin-1-ium-1-carbonyl) (phenylsulfonyl) amide

A solution of benzenesulfonamide (125mg, 795.22. mu. mol, 1 eq.) and N, N-lutidine-4-amine (194mg, 1.59mmol, 2 eq.) in MeCN (3mL) was stirred at 25 ℃ for 30 min. Diphenyl carbonate (187mg, 874.74. mu. mol, 1.1 eq.) was then added. The resulting mixture was stirred at 25 ℃ for 12 hours. The reaction mixture (theoretical amount: 242mg, crude) was used directly in the next step.

And B:n- ((4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-yl) carbamoyl) benzenesulfonamide

To a solution of 4-isopropyl-2-methyl-1- (pyridin-4-yl) -1H-imidazol-5-amine (197mg, 780.00 μmol, 1 eq, HCl salt) (intermediate R39) in MeCN (2mL) was added a solution of (4- (dimethylamino) pyridin-1-ium-1-carbonyl) (phenylsulfonyl) amide (the reaction mixture of step a) in MeCN (3 mL). The resulting mixture is stirred under N₂Then, the mixture was stirred at 70 ℃ for 45 minutes. The reaction mixture was then concentrated and the residue was purified by reverse phase flash chromatography (0.1% NH)₃.H₂O-MeCN) and then purified by preparative HPLC (column: xtimate C18, 150mm × 25mm × 5 μm; mobile phase [ a: water (0.05% ammonium hydroxide v/v), B: MeCN](ii) a B%: 0% -30%, 10min) to give the title compound as a white solid (17.42mg, two steps 6% yield, 99.8% purity on HPLC).

¹H NMR(400MHz,DMSO-d₆) δ 8.60-8.45(m,2H),7.70-7.47(m,6H),7.26-6.90(m,2H),2.68-2.65(m,1H),2.19(s,3H) and 1.09(d, 6H). 1 × NH is lost.

LCMS:m/z 400.1(M+H)⁺(ES⁺)。

Example 51:n- ((6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) benzene imidosulfonamide

Step A:

n- ((6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) benzene sulfinamide

To a solution of benzenesulfinamide (intermediate L10) (50mg, 354.13. mu. mol, 1 eq) in THF (1mL) was added t-BuONa (102mg, 1.06mmol, 3 eq) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 30 minutes. Then (6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamic acid methyl ester is addedPhenyl ester of acid (intermediate R41) (202mg, 354.13. mu. mol, 1 eq., TFA salt). The resulting mixture was stirred at 25 ℃ for 5 hours. The reaction mixture was then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% NH)₃.H₂O-MeCN) to give the title compound as a white solid (120mg, 59% yield, 88% purity on LCMS).

¹H NMR(400MHz,DMSO-d₆) δ 9.57-9.27(m,1H),8.31-8.17(m,1H),7.71-7.42(m,5H),7.24-7.07(m,1H),6.82-6.65(m,1H),6.51(s,1H),5.11-4.93(m,1H),3.48-3.41(m,2H),2.99-2.68(m,5H),2.24-1.96(m,11H) and 1.89-1.61(m, 2H). 1 × NH is lost.

LCMS:m/z 505.3(M+H)⁺(ES⁺)。

And B:

n- ((6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) benzene imidosulfonamide

To a solution of N- ((6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) benzenesulfonamide (0.1g, 198.16. mu. mol, 1 eq) in THF (1mL) was added 1-chloro-1H-benzo [ d][1,2,3]Triazole (27mg, 178.34 μmol, 0.9 equiv.). The reaction mixture was stirred at 25 ℃ for 30 minutes. The reaction mixture was then added to NH at-70 deg.C₃In THF solution (5 mL); by reaction of NH₃Bubbling into THF for 5 minutes to give NH₃In THF. After the addition, the mixture was stirred at-70 ℃ for 30 minutes. The reaction mixture was then concentrated in vacuo. The residue was purified by preparative TLC (SiO)₂DCM: methanol, 10:1) and then purified by preparative HPLC (column: phenomenex luna C18, 150mm × 25mm × 10 μm; mobile phase [ a: water (0.1% TFA); b: MeCN](ii) a B%: 22% -42%, 10min) to give the title compound as a white solid (21.45mg, 17% yield, 100% purity on LCMS, TFA salt).

¹H NMR(400MHz,CDCl₃) δ 8.22-8.10(m,1H),8.02-7.80(m,2H),7.68-7.46(m,3H),7.10(d,1H),6.83-6.62(m,2H),5.45-5.21(m,1H),3.93-3.40(m,2H),3.38-3.01(m,2H),3.00-2.71(m,7H),2.49-2.19(m,4H) and 2.17-1.96(m, 5H). 3 x NHs was lost.

LCMS:m/z 520.1(M+H)⁺(ES⁺)。

Example 52:n- ((6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) methanesulfonamide

Step A:n- ((6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) methanesulfonamide

Sodium tert-butoxide (134mg, 1.40mmol, 1.6 equiv.) was added to a mixture of methanesulfonamide (intermediate L11) (103mg, 1.31mmol, 1.5 equiv.) in THF (2mL) at 20 ℃. The reaction mixture was stirred at 20 ℃ for 30 minutes. Phenyl (6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamate (intermediate R41) (400mg, 874.20 μmol, 1 eq) was then added at 20 ℃ and the resulting mixture was stirred for 30 minutes at 20 ℃. The reaction mixture was poured into ice water (30 mL). The aqueous phase was extracted with ethyl acetate (3X 20 mL). The combined organic phases were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% NH)₃.H₂O-MeCN) to give the title compound as a white solid (150mg, 26% yield, 68% purity on LCMS).

¹H NMR(400MHz,CDCl₃) Δ 8.17(d,1H),7.14(d,1H),6.71-6.65(m,1H),6.54(d,1H),5.08-5.04(m,1H),2.97(t,2H),2.87(t,2H),2.75-2.73(m,2H),2.64(s,3H),2.33-2.27(m,5H),2.15-2.07(m,7H) and 1.86-1.73(m, 2H). 2 x NHs are missing.

LCMS:m/z 443.4(M+H)⁺(ES⁺)。

And B:n- ((6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) methanesulfonamide

To a solution of N- ((6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) methanesulfonamide (250mg, 564.88. mu. mol, 1 eq) in THF (5mL) at 20 ℃ was added 1-chloro-1H-benzo [ d][1,2,3]Triazole (78mg, 508.39. mu. mol, 0.9 equiv.). The reaction mixture was stirred at 20 ℃ for 30 minutes. The reaction mixture was then added to NH at-78 deg.C₃A THF solution; by reaction of NH₃Gas (15psi) was bubbled into THF (5mL) for 5 minutes to give NH₃In THF. The resulting mixture was stirred at-78 ℃ for 20 minutes, then warmed to 20 ℃ and stirred for 2 hours. The reaction mixture was then concentrated in vacuo. The residue was passed through preparative HPLC (column: Xtimate C18, 150mm X40 mm X10 μm; mobile phase [ A: water (0.05% ammonium hydroxide v/v); B: MeCN;)](ii) a B%: 19% -49%, 10min) to give the title compound as a yellow solid (2.19mg, 1% yield, 99.8% purity on LCMS).

¹H NMR(400MHz,CD₃OD) Δ 8.12(d,1H),7.09(s,1H),6.82(d,1H),6.69(s,1H),5.14-5.12(m,1H),3.21(s,3H),3.03-3.01(m,2H),2.95(t,2H),2.88(t,2H),2.83-2.57(m,2H),2.55(s,3H) and 2.14-1.92(m, 9H). 3 x NHs was lost.

LCMS:m/z 458.3(M+H)⁺(ES⁺)。

Example 53:1- (N-cyano-S-methyl-sulfamoyl) -3- (6-methyl-5- (2- ((1-methyl-4-piperidinyl) oxy) -4-pyridinyl) indan-4-yl) urea

Cyanogen bromide (14mg, 131.12. mu. mol, 2 equiv.) is added to a mixture of N- ((6-methyl-5- (2- ((1-methylpiperidin-4-yl) oxy) pyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) methanesulfonamide (example 52) (30mg, 65.56. mu. mol, 1 equiv.) and triethylamine (27mg, 262.24. mu. mol, 4 equiv.) in DMF (1mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 12h, then quenched with water (0.5mL) and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 75mm X30 mm X3 μm; mobile phase [ A: water (0.1% TFA), B: MeCN ]; B%: 20% -30%, 7 min) to give the title compound as a yellow oil (21.8mg, 54% yield, 97.6% purity on HPLC, TFA salt).

¹H NMR(400MHz,DMSO-d6+D₂O) delta 8.16(t,1H),7.09(s,1H),6.79(t,1H),6.63(d,1H),5.27-5.13(m,1H),3.48-3.45(m,1H),3.35-3.32(m,1H),3.27-3.12(m,5H),2.88(t,2H),2.81-2.75(m,5H),2.34-2.30(m,1H),2.18-2.13(m,1H),3.05-1.96(m,6H) and 1.83-1.75(m, 1H). 2 x NHs are missing.

LCMS:m/z 483.2(M+H)⁺(ES⁺)。

Example-biological study

NLRP3 and cell apoptosis

It is well known that activation of NLRP3 causes apoptosis of cells and that this feature plays an important role in the manifestation of clinical Disease (Yan-gan Liu et al, Cell Death & Disease,2017,8(2), e 2579; Alexander Wree et al, Hepatology,2014,59(3), 898-. Therefore, it is expected that NLRP3 inhibitors will block cellular apoptosis and release of pro-inflammatory cytokines (e.g., IL-1 β) from cells.

THP-1 cells: culture and preparation

Reacting THP-1Cells (ATCC # TIB-202) were grown in RPMI (Gibco #11835) containing L-glutamine, supplemented with 1mM sodium pyruvate (Sigma # S8636) and penicillin (100 units/ml)/streptomycin (0.1mg/ml) in 10% Fetal Bovine Serum (FBS) (Sigma # F0804) (Sigma # P4333). Cells were passaged and grown to confluence (about 10) as usual⁶Individual cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (FBS-free). Cells were then counted and checked for viability with trypan blue (Sigma # T8154) ((r))>90%). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma # L4524) to give a Final Assay Concentration (FAC) of 1. mu.g/ml. 40 μ l of the final formulation was aliquoted into each well of a 96-well plate. The plates thus prepared were used for screening compounds.

Cell apoptosis assay for THP-1 cells

The following protocol was followed step by step for compound screening.

1. THP-1 cells (25,000 cells/well) were seeded in 40. mu.l RPMI medium (no FBS) containing 1.0. mu.g/ml LPS in 96-well black-wall clear-bottom cell culture plates coated with poly-D-lysine (VWR #734-

2. Add 5. mu.l of compound (8-point semilog dilution, maximum dose 10. mu.M) or vehicle (DMSO 0.1% FAC) to appropriate wells

3. At 37 deg.C, 5% CO₂Incubation for 3 hours

4. Add 5. mu.l nigericin (Sigma # N7143) (FAC 5. mu.M) to all wells

5. At 37 deg.C, 5% CO₂Incubation for 1 hour

6. At the end of the incubation period, the plates were rotated at 300 × for 3 minutes and the supernatant removed

7. Then 50. mu.l resazurin (Sigma # R7017) (100. mu.M resazurin in FAC FBS-free RPMI medium) was added and incubated at 37 ℃ and 5% CO₂Incubate the plate for 1-2 hours

8. Plates were read at Ex 560nm and Em 590nm in an Envision reader

9. Will IC₅₀Data fitting to a non-linear regression equation (l)Slope of reaction change for og inhibitors 4 parameters)

96 well plate map

THP IC is shown in Table 1 below₅₀The results of the cell apoptosis assay are summarized.

Human whole blood IL-1 beta Release assay

For systemic delivery, the ability to inhibit NLRP3 when the compound is present in the bloodstream is important. To this end, the NLRP3 inhibitory activity of a number of compounds in human whole blood was studied according to the following protocol.

Human whole blood was obtained from healthy donors from a volunteer donor panel in heparin lithium tubes.

1. Mu.l of whole blood containing 1. mu.g/ml LPS was plated in 96-well clear-bottomed cell culture plates (Corning #3585)

2. Add 10. mu.l of compound (8-point semilog dilution, maximum dose 10. mu.M) or vehicle (DMSO 0.1% FAC) to appropriate wells

3. At 37 deg.C, 5% CO₂Incubation for 3 hours

4. Add 10. mu.l nigericin (Sigma # N7143) (10. mu.M FAC) to all wells

5. At 37 deg.C, 5% CO₂Incubation for 1 hour

6. At the end of the incubation period, the plates were spun at 300 Xg for 5 minutes to pellet the cells, and 20. mu.l of the supernatant was removed and added to a 96-well v-plate for IL-1. beta. assay (note: these plates containing supernatant could be stored at-80 ℃ for later analysis)

7. IL-1. beta. measurement according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 kit AL220F-5000)

8. Will IC₅₀Data fitting to nonlinear regression equation(Log inhibitor vs. reaction Change slope 4 parameters)

HWB IC in Table 1 below₅₀The results of the human whole blood assay are summarized.

For comparison, three compounds outside the scope of the claims are included in table 1:

table 1: NLRP3 inhibitory activity (≦ 0.25 μ M ═ + + + +++, ≦ 0.5 μ M ═++++, ≦ 1 μ M ═+++, ≦ 2 μ M ═++++++, ≦ 5 μ M ═++++, ≦ 10 μ M ═ 10 μ M ═ inactive ', not determined ═ ND').

As is apparent from the results presented in table 1, surprisingly, the compounds of the present invention show high levels of NLRP3 inhibitory activity in cell apoptosis assays and in particular in human whole blood assays, despite structural differences compared to prior art compounds.

It will be appreciated that the invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is limited only by the following claims.

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