LRRK2 inhibitors

Abstract

The present invention relates to compounds of formula (I) - inhibitors of LRRK2. The inhibitors described herein may be useful for treating diseases or disorders associated with LRRK2, such as Parkinson's disease (PD). In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit LRRK2, methods of treating diseases or disorders associated with LRRK2, and methods of synthesizing these compounds. JPEG2025511875000679.jpg55170

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to inhibitors of leucine-rich repeat kinase 2 (LRRK2). The inhibitors described herein may be useful in treating diseases or disorders associated with LRRK2, such as Parkinson's disease (PD). In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit LRRK2, methods for treating diseases or disorders associated with LRRK2, and methods for synthesizing these compounds. [Background technology]

[0002] (background) Parkinson's disease (PD), like many common age-related conditions, is known to have a significant genetic component. PD is a progressive neurodegenerative disorder that affects approximately 2% of people over the age of 60.

[0003] Multiple lines of evidence suggest that leucine-rich repeat kinase 2 (LRRK2) is a key factor in understanding the pathogenesis of PD. LRRK2 is a large, widely expressed, multidomain, and multifunctional protein. LRRK2 mutations are the primary cause of hereditary and sporadic PD. Recently, wild-type LRRK2 has also been considered a potential target for sporadic Parkinson's disease. LRRK2 mutations, particularly the most common mutation, Gly2019Ser, are found in patients with autosomal dominant Parkinson's disease and in patients with apparent sporadic Parkinson's disease, which is clinically indistinguishable from idiopathic Parkinson's disease. The discovery that pathogenic mutations in the LRRK2 gene increase LRRK2 kinase activity and that small-molecule LRRK2 kinase inhibitors can exert neuroprotective effects in preclinical PD models has placed LRRK2 at the center of disease-modifying efforts in PD. Increasing evidence highlights that LRRK2 regulates multiple processes in brain immune cells, microglia, and astrocytes, suggesting that dysregulation of LRRK2 activity in these cells due to genetic mutations may be directly related to the pathological mechanisms underlying PD. Recent studies have also suggested that LRRK2 is involved in the development of idiopathic PD, and therefore LRRK2 therapy (LRRK2 mutant and wild-type) may be beneficial for this common subtype of PD.

[0004] Treatment of Parkinson's disease requires comprehensive treatment, including drug therapy, surgery, rehabilitation therapy, and psychotherapy. Among these, drug therapy is the first-line and primary treatment. For example, deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for progressive PD, and the results of STN-DBS were not affected by the LRRK2 p.G2019S mutation. However, not all treatments can halt the progression of PD, let alone cure it. The primary goal of all treatments is to alleviate the motor and non-motor symptoms of PD. Therefore, the need for new drugs to reverse, prevent, or slow the progression of PD is one of the major goals of PD research. (overview)

[0005] A first aspect of the present invention is a compound of formula (I): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein V is selected from C and N; W is selected from C and N; one of V and W is N; bond V JPEG2025511875000003.jpg1140N is selected from a single bond and a double bond; Join W JPEG2025511875000004.jpg1140N is selected from a single bond and a double bond; However, when V is N, the bond V JPEG2025511875000005.jpg1140N is a single bond, W is a bond JPEG2025511875000006.jpg1140N is a double bond, W is C, and when V is C, the bond V JPEG2025511875000007.jpg1140N is a double bond, bond W JPEG2025511875000008.jpg1140N is a single bond, W is N; X is CR 7 and N; Y is C=O, CR 8 , and N; However, one of X and Y is N; join Y JPEG2025511875000009.jpg1140N is selected from a single bond and a double bond; r is an integer selected from 0 and 1; However, when Y is C=O, the bond Y JPEG2025511875000010.jpg1140N is a single bond, r is 1, and Y is CR 8 or N, when bond Y JPEG2025511875000011.jpg1140N is a double bond and r is 0; When Y is C=O or N, Z is CR 9 and N; Y is CR 8 When Z is CR 9 and; Q is CH2, NR 5 , selected from O, S, S(O), S(O)2; R 1 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 , and S(O)2R 12alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; or R 1 and R 2 together with the atoms to which they are attached and any intervening atoms, form C3-C 10 Forms a cycloalkyl, a 5-14 membered heterocycle, an aryl, or a heteroaryl, and the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 10 R 11 optionally substituted with one or more substituents independently selected from: R 3 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; or R 2 and R 3 together with the atoms to which they are attached and any intervening atoms, form C3-C 10 Forms a cycloalkyl, a 5-14 membered heterocycle, an aryl, or a heteroaryl, and the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 10 R 11 optionally substituted with one or more substituents independently selected from: R 4 is H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 , C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein alkyl, cycloalkyl or alkyl-alkoxy is selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Each R 5 is H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 and alkyl, cycloalkyl, or alkyl-alkoxy is independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Each R 6is halogen, OH, oxo, CN, CONR 10 R 11 , N.R. 10 R 11 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 , N.R. 10 C(O)R 11 , -S(O)2-C1-C6 alkyl, -C1-C6 alkanediyl-S(O)2-C1-C6 alkyl, wherein alkyl or alkoxy is independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Or two R's 6 together with the atom to which they are attached and any intervening atoms, form a 3-14 membered cycloalkyl, aryl, 3-14 membered heterocycle, or 5-10 membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 optionally substituted with one or more substituents independently selected from: R 7 , R 8 and R 9 are H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 and alkyl, alkoxy, cycloalkyl or alkylalkoxy is independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , S(O)2R 12optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; R 10 is H, C1-C6 alkyl, C3-C 10 Cycloalkyl, S(O)R 12 wherein alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 11 is H, C1-C6 alkyl, C3-C 10 cycloalkyl, wherein alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; or R 10 and R 11 together with the atom to which they are attached and any intervening atoms, form a 5- to 14-membered heterocycle, the heterocycle being optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 12 is selected from C1-C6 alkyl, —NH2, —NH(C1-C3 alkyl), or —N(C1-C3 alkyl)2, wherein alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, and 4; u is an integer selected from 0, 1, 2, 3, 4, 5, and 6; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro) or 11-14 membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C.

[0006] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0007] Another aspect of the present invention relates to a method for treating a disease or disorder associated with LRRK2, comprising administering to a patient in need of treatment for the disease or disorder associated with LRRK2 an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0008] Another aspect of the present invention relates to a method of inhibiting LRRK2, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0009] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting LRRK2.

[0010] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with LRRK2.

[0011] Another aspect of the present invention pertains to a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder disclosed herein.

[0012] Another aspect of the present invention relates to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0013] Another aspect of the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0014] The present invention further provides a method of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0015] The present invention provides inhibitors of LRRK2 that are therapeutic agents in the treatment of diseases and disorders.

[0016] The present invention further provides compounds and compositions with improved efficacy and safety profiles compared to known LRRK2 inhibitors. The present disclosure also provides agents with novel mechanisms of action against LRRK2 in the treatment of various types of diseases.

[0017] The present invention further provides a method of treating a disease or disorder associated with LRRK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0018] The present invention provides inhibitors of LRRK2 that are therapeutic agents in the treatment of diseases and disorders.

[0019] The present invention further relates to Parkinson's disease 8, autosomal dominant (PARK8); hereditary late-onset Parkinson's disease (LOPD); spinocerebellar atrophy; Klippel-Feil syndrome 1, autosomal dominant (KFS1); autosomal dominant cerebellar ataxia (SCA); Parkinson's disease, late-onset (PD); Parkinson's disease 2, autosomal recessive juvenile (PARK2); Parkinsonism; REM sleep behavior disorder; dementia with Lewy bodies (DLB); Lrrk2 Parkinson's disease; Parkinson's disease 3, autosomal dominant (PARK3); early-onset Parkinson's disease; multiple system atrophy Disease 1 (MSA1); Essential Tremor; Movement Disorder; Progressive Supranuclear Palsy 1 (PSNP1); Klippel-Feil Syndrome 1; Dementia; Parkinson's Disease 10 (PARK10); Tremor; Frontotemporal Dementia (FTD); Postencephalitic Parkinson's Disease; Vascular Parkinsonism; Aphasia; Parkinson's Disease 1, Autosomal Dominant (PARK1); Athetosis; Klippel-Feil Syndrome (KFS); Kufor-Rakeb Syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer's Disease 8 (AD8); Crohn's Disease; Rheumatoid Arthritis (RA); Alzheimer's Disease Zheimer's disease (AD); achromatopsia; Gaucher disease, type 1 (GD1); Parkinson's disease 15, autosomal recessive early-onset (PARK15); von Economo disease; Gerstmann-Sträussler disease (GSD); amyotrophic lateral sclerosis-Parkinson's disease / dementia complex 1 (ALS-PDC1); dystonia; sphingolipidosis; radial nerve lesions; toxic encephalopathy; sleep disorders; Pick's disease of the brain (PIDB); ocular glomerulopathy; Gaucher disease (GD); optic atrophy 7 (OPA7) with or without auditory neuropathy; ulnar nerve lesions; inflammatory bowel disease inflammatory bowel disease 4 (IBD4); inflammatory bowel disease; 3-methylglutaconic aciduria, type III (MGCA3); neurological disorders; amyotrophic lateral sclerosis 1 (ALS1); mitochondrial complex I deficiency, nuclear type 1 (MC1DN1), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0020] In some aspects, the disclosure provides compounds obtainable by or obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in General Procedures A, B, or C).

[0021] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein (e.g., the intermediates are selected from the intermediates described in Preparation Parts P1 to P44).

[0022] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0023] In some aspects, the present disclosure provides methods of preparing the compounds of the present disclosure, comprising one or more steps described herein.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular also includes the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. No reference cited herein is admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure will control.

[0025] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0026] (Detailed explanation) The present disclosure provides methods for treating, preventing, or ameliorating a disease or disorder associated with inhibition of LRRK2 by administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0027] Details of the present disclosure are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in practicing or testing the present disclosure, exemplary methods and materials are described here. Other features, objects, and advantages of the present disclosure will become apparent from the specification and claims. In this specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety. definition

[0028] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0029] In this disclosure, the term "and / or" means either "and" or "or" unless otherwise stated.

[0030] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For example, at any point along the chain, it can be bonded to a halogen atom, a hydroxyl group, or other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to include other functional groups, but does not necessarily have any additional functional groups. Suitable substituents for use in any substitution of the described groups include, but are not limited to, halogen, oxo, —OH, —CN, —COOH, —CHCN, —O—(C-C)alkyl, (C-C)alkyl, (C-C)alkoxy, (C-C)haloalkyl, (C-C)haloalkoxy, —O—(C-C)alkenyl, —O—(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, —OH, —OP(O )(OH), —OC(O)(C-C)alkyl, —C(O)(C-C)alkyl, —OC(O)O(C-C)alkyl, —NH, —NH((C-C)alkyl), —N((C-C)alkyl), —NHC(O)(C-C)alkyl, —C(O)NH(C-C)alkyl, —S(O)(C-C)alkyl, —S(O)NH(C-C)alkyl, and S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. As used herein, “optionally substituted” means substituted or unsubstituted, the meaning of which is described below.

[0031] As used herein, the term "substituted" means that a particular group or moiety has one or more suitable substituents, and the substituents may be linked to the particular group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl indicates that the cycloalkyl is linked to one atom of the aryl by a bond or by being fused to the aryl and sharing two or more common atoms.

[0032] As used herein, the term "unsubstituted" means that the particular group bears no substituents.

[0033] Unless otherwise defined, the term "aryl" refers to a cyclic, aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group can be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -O-P(O)(OH), -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH, -NH((C-C)alkyl), N((C-C)alkyl), -S(O)-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. Additionally, when containing two fused rings, aryl groups as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Examples of ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannurenyl, and the like.

[0034] Unless otherwise defined, "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. Polycyclic aromatic radicals can contain two or more fused rings and can further contain two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, "fused" refers to two rings that share two ring atoms. Unless otherwise specified, "spiro-fused" refers to two rings that share one ring atom. Heteroaryl, as defined herein, also refers to bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tricyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl, as defined herein, also refers to tetracyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radicals may be independently substituted with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl ... lo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyridinyl Furo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl Lysinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,

[0023] In addition, when containing two or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused with a saturated or partially unsaturated ring as described herein. In addition, when containing three or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings spiro-fused. Any saturated or partially unsaturated ring as described herein may be optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyra pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-onyl.

[0035] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0036] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0037] "Alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms including a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0038] "Alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. As defined herein, alkenyl can be straight-chain or branched.

[0039] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0040] The term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can be a C1-C6 alkylene. Alkylene can further be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-, and the like.

[0041] "Cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring containing 3-18 carbon atoms. Polycyclic cycloalkyls may be fused bicyclic cycloalkyls, bridged bicyclic cycloalkyls, or spiro-fused bicyclic cycloalkyls. Polycyclic cycloalkyls contain at least one non-aromatic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0042] A "heterocyclyl," "heterocycle," or "heterocycloalkyl" containing 3-24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P, or B, is monocyclic or polycyclic, and wherein the ring is not aromatic. The heterocycloalkyl ring structure may be substituted by one or more substituents, which may themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0043] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a system of linked p-orbitals with delocalized electrons, which may include lone pairs of electrons.

[0044] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0045] The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0046] As used herein, the term "cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, i.e., C≡N.

[0047] "Spirocycloalkyl" or "spirocyclyl" refers to a carbon-based bicyclic ring system in which both rings are connected through a single atom. The rings may be different in size and nature or may be identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, and spirodecane. One or both of the spiro rings may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spiro ring may be replaced with a heteroatom (e.g., O, N, S, or P). (C3-C 12 ) A spirocycloalkyl is a spiro ring containing 3 to 12 carbon atoms. One or more carbon atoms may be replaced with a heteroatom.

[0048] The terms "spiroheterocycloalkyl," "spiroheterocycle," or "spiroheterocyclyl" are understood to mean a spirocycle in which at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0049] The term "solvate" refers to a complex of varying stoichiometry formed by a solute and a solvent. For purposes of this disclosure, such solvents may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0050] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences may be in constitution (geometric isomers) or in ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0051] The present disclosure also provides isotopically labeled compounds of Formula I, such as 2 H and 14 C) are intended to be deuterated (i.e., 2 H or D) isotopes and carbon-14 (i.e., 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium, may offer certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced required dose), and therefore may be preferred in some circumstances. Isotopically labeled compounds of Formula I can generally be prepared by replacing non-isotopically labeled reagents with appropriate isotopically labeled reagents in accordance with procedures similar to those disclosed in the following schemes and / or examples.

[0052] The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, and hydrochloride. , hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, diacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0053] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0054] An "effective amount," when used in connection with a compound, is an amount effective to treat or prevent a disease in a subject as described herein.

[0055] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0056] The term "treating" with respect to a subject refers to improving at least one symptom of the subject's disorder. Treating includes curing, ameliorating, or at least partially ameliorating the disorder.

[0057] In this disclosure, the term "disorder" is used to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0058] The terms "administer," "administering," or "administration," as used in this disclosure, refer to either administering a disclosed compound, or a pharmaceutically acceptable salt or composition of a disclosed compound, directly to a subject, or administering a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt or composition of the compound, to a subject, allowing an equivalent amount of active compound to form in the subject's body.

[0059] The term "prodrug," as used in this disclosure, means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to a disclosed compound.

[0060] The term "salt" means a pharmaceutically acceptable salt.

[0061] The term "pharmaceutically acceptable salt" also refers to a salt of a composition of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0062] As used herein, "LRRK2 inhibitor" refers to a compound of Formula I and / or a composition comprising a compound of Formula I that inhibits LRRK2 kinase.

[0063] The amount of the compound of the composition described herein required to achieve a therapeutic effect can be empirically determined according to conventional procedures for a particular purpose. Generally, when administering a therapeutic agent (e.g., a compound of Formula I or a composition described herein (and / or an additional agent)) for therapeutic purposes, the therapeutic agent is given in a pharmacologically effective dose. A "pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce a desired physiological effect or achieve a desired result, particularly for treating a disorder or disease. As used herein, an effective amount includes, for example, an amount sufficient to delay the onset of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of symptoms of the disease), reduce or eliminate one or more symptoms or signs of a disorder or disease, and reverse symptoms of a disorder or disease. For example, administering a therapeutic agent to a subject suffering from cancer provides a therapeutic benefit not only if the underlying condition is eradicated or improved, but also if the subject reports a decrease in the severity or duration of symptoms associated with the disease, such as a decrease in tumor burden, a decrease in circulating tumor cells, or an increase in progression-free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is achieved. Compounds of the Disclosure

[0064] In one aspect, the disclosure provides compounds of formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, W, X, Y, Z, Q, m, n, r and u are as described herein.

[0065] For compounds of formula (I), R 1, R 2 , R 3 , R 4 , R 5 , R 6 , V, W, X, Y, Z, Q, m, n, r, and u can each be selected from groups described herein, where applicable; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, W, X, Y, Z, Q, m, n, r and u, any group described herein may be R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, W, X, Y, Z, Q, m, n, r and u may be combined with any group described herein.

[0066] In some embodiments, V is selected from C and N; W is selected from C and N; one of V and W is N; bond V JPEG2025511875000013.jpg1140N is selected from a single bond and a double bond; Join W JPEG2025511875000014.jpg1140N is selected from a single bond and a double bond; However, when V is N, the bond V JPEG2025511875000015.jpg1140N is a single bond, W is a bond JPEG2025511875000016.jpg1140N is a double bond, W is C, and when V is C, the bond V JPEG2025511875000017.jpg1140N is a double bond, bond W JPEG2025511875000018.jpg1140N is a single bond, W is N; X is CR 7and N; Y is C=O, CR 8 , and N; However, one of X and Y is N; join Y JPEG2025511875000019.jpg1140N is selected from a single bond and a double bond; r is an integer selected from 0 and 1; However, when Y is C=O, the bond Y JPEG2025511875000020.jpg1140N is a single bond, r is 1, and Y is CR 8 or N, when bond Y JPEG2025511875000021.jpg1140N is a double bond and r is 0; When Y is C=O or N, Z is CR 9 and N; Y is CR 8 When Z is CR 9 and; Q is selected from CH2, NH, O, S, S(O), S(O)2; R 1 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; or R 1 and R 2 together with the atoms to which they are attached and any intervening atoms, form C3-C 10 Forms a cycloalkyl, a 5-14 membered heterocycle, an aryl, or a heteroaryl, and the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 10 R 11 optionally substituted with one or more substituents independently selected from: R 3 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; or R 2 and R 3 together with the atoms to which they are attached and any intervening atoms, form C3-C 10 Forms a cycloalkyl, a 5-14 membered heterocycle, an aryl, or a heteroaryl, and the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 10 R 11 optionally substituted with one or more substituents independently selected from: R 4 is H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 , C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein alkyl, cycloalkyl or alkyl-alkoxy is selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Each R 5 is H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11and alkyl, cycloalkyl, or alkyl-alkoxy is independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Each R 6 is halogen, OH, oxo, CN, CONR 10 R 11 , N.R. 10 R 11 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 , N.R. 10 C(O)R 11 , -S(O)2-C1-C6 alkyl, -C1-C6 alkanediyl-S(O)2-C1-C6 alkyl, wherein alkyl or alkoxy is independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Or two R's 6 together with the atom to which they are attached and any intervening atoms, form a 3-14 membered cycloalkyl, aryl, 3-14 membered heterocycle, or 5-10 membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 optionally substituted with one or more substituents independently selected from: R 7 , R 8 and R 9 are H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR10 R 11 and alkyl, alkoxy, cycloalkyl or alkylalkoxy is independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , S(O)2R 12 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; R 10 is H, C1-C6 alkyl, C3-C 10 Cycloalkyl, S(O)R 12 wherein alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 11 is H, C1-C6 alkyl, C3-C 10 cycloalkyl, wherein alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; or R 10 and R 11 together with the atom to which they are attached and any intervening atoms, form a 5- to 14-membered heterocycle, the heterocycle being optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 12 is selected from C1-C6 alkyl, —NH2, —NH(C1-C3 alkyl), or —N(C1-C3 alkyl)2, wherein alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, and 4; u is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

[0067] In some embodiments, V is C or N. In some embodiments, V is C. In some embodiments, V is N.

[0068] In some embodiments, W is C or N. In some embodiments, W is C. In some embodiments, W is N.

[0069] In some embodiments, V is N and the bond V JPEG2025511875000022.jpg1140N is a single bond, and bond W JPEG2025511875000023.jpg1140N is a double bond and W is C.

[0070] In some embodiments, V is C and the bond V JPEG2025511875000024.jpg1140N is a double bond, and the bond W JPEG2025511875000025.jpg1140N is a single bond and W is N.

[0071] In some embodiments, X is CR 8 or N. In some embodiments, X is CR 8 In some embodiments, X is N.

[0072] In some embodiments, X is CR 8 is.

[0073] In some embodiments, X is N.

[0074] In some embodiments, Y is C=O, CR 9 In some embodiments, Y is C=O, or N. In some embodiments, Y is CR 9 In some embodiments, Y is N.

[0075] In some embodiments, Y is C=O.

[0076] In some embodiments, Y is CR 9 is.

[0077] In some embodiments, Y is N.

[0078] In some embodiments, Z is CH or N. In some embodiments, Z is CH. In some embodiments, Z is N.

[0079] In some embodiments, Z is CH.

[0080] In some embodiments, when Y is N, Z is also N.

[0081] In some embodiments, r is 0. In some embodiments, r is 1.

[0082] In some embodiments, r is 0.

[0083] In some embodiments, r is 1.

[0084] In some embodiments, when Y is C=O, the bond Y JPEG2025511875000026.jpg1140N is a single bond.

[0085] In some embodiments, Y is CR 9 or N, bond Y JPEG2025511875000027.jpg1140N is a double bond.

[0086] In some embodiments, when Y is C=O, the bond Y JPEG2025511875000028.jpg1140N is a single bond and r is 1.

[0087] In some embodiments, Y is CR 9 or N, bond Y JPEG2025511875000029.jpg1140N is a double bond and r is 0.

[0088] In some embodiments, R 1 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl.

[0089] In some embodiments, R 1 is hydrogen.

[0090] In some embodiments, R 1 is a halogen.

[0091] In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I.

[0092] In some embodiments, R 1 is F.

[0093] In some embodiments, R 1 is C1-C6 alkyl.

[0094] In some embodiments, R 1 is -CH3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is -CH2CH2CH3. In some embodiments, R 1 is -CH(CH3)2.

[0095] In some embodiments, R 1 is methyl.

[0096] In some embodiments, R 1 is -CHF. In some embodiments, R 1 is -CHF2. In some embodiments, R 1 is -CF3.

[0097] In some embodiments, R 1 is C1-C6 alkoxy.

[0098] In some embodiments, R 1 is —OCH. In some embodiments, R 1 is —OCH2CH3. In some embodiments, R 1 is —OCH2CH2CH3. In some embodiments, R 1 is -OCH(CH3)2.

[0099] In some embodiments, R 1 is -OMe.

[0100] In some embodiments, R 1 is methoxy.

[0101] In some embodiments, R 1 is -OCH(CH3)2.

[0102] In some embodiments, R 1 is iso-propoxy.

[0103] In some embodiments, R 1 is -OC(CH3)3.

[0104] In some embodiments, R 1 is -OCF3. In some embodiments, R 1 is -OCF2CF3.

[0105] In some embodiments, R 1 and R 2 together with the atom to which they are attached and any intervening atoms, form a 5- to 14-membered heterocycle, the heterocycle being selected from halogen, OH, ═O, CN, NH, C-C alkyl, C-C alkoxy, C-C alkyl-C-C alkoxy, C-C alkyl-NHC alkyl, and NR 10 R 11 and optionally substituted with one or more substituents independently selected from:

[0106] In some embodiments, R 1 and R 2 together with the atom to which they are attached and any intervening atoms, form a 5-membered heterocycle containing one heteroatom selected from O, N, and S.

[0107] In some embodiments, R 1 and R 2 together with the atoms to which they are attached and the intervening atoms form a 5-membered heterocyclic ring containing one heteroatom, -O.

[0108] In some embodiments, R 1 and R 2 together with the atom to which they are attached and any intervening atoms, form a 6-membered heterocycle containing one heteroatom selected from O, N, S.

[0109] In some embodiments, R 1 and R 2together with the atoms to which they are attached and the intervening atoms form a 6-membered heterocycle containing one heteroatom, -O.

[0110] In some embodiments, R 1 and R 2 together with the atoms to which they are bonded and the intervening atoms, [ka] Form.

[0111] In some embodiments, R 2 is H. In some embodiments, R 2 is halogen. In some embodiments, R 2 is halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 and C-C alkyl optionally substituted with one or more substituents independently selected from cycloalkyl, C-C alkenyl, C-C alkynyl, heterocycle, aryl, and heteroaryl. In some embodiments, R 2 is halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 and C-C alkoxy optionally substituted with one or more substituents independently selected from cycloalkyl, C-C alkenyl, C-C alkynyl, heterocycle, aryl, and heteroaryl. In some embodiments, R 2 is halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 C3-C optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl. 10 In some embodiments, R 2 is halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10C-C alkenyl optionally substituted with one or more substituents independently selected from cycloalkyl, C-C alkenyl, C-C alkynyl, heterocycle, aryl, and heteroaryl. In some embodiments, R 2 is halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 and C-C alkynyl optionally substituted with one or more substituents independently selected from cycloalkyl, C-C alkenyl, C-C alkynyl, heterocycle, aryl, and heteroaryl. 2 is halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 In some embodiments, R is a heterocycle, aryl, or heteroaryl optionally substituted with one or more substituents independently selected from cycloalkyl, C-C alkenyl, C-C alkynyl, heterocycle, aryl, and heteroaryl. 2 is NR 10 R 11 In some embodiments, R 2 is S(O)2R 12 is.

[0112] In some embodiments, R 2 is H.

[0113] In some embodiments, R 2 is C1-C6 alkyl.

[0114] In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is n-propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is butyl. In some embodiments, R 2is n-butyl. In some embodiments, R 2 is iso-butyl. In some embodiments, R 2 is sec-butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is hexyl.

[0115] In some embodiments, R 2 is C1-C6 alkyl substituted with one or more halogens.

[0116] In some embodiments, R 2 is C1-C6 alkyl substituted with one or more F.

[0117] In some embodiments, R 2 is -CHF. In some embodiments, R 2 is -CHF2. In some embodiments, R 2 is -CF3. In some embodiments, R 2 is -CF2CH3. In some embodiments, R 2 is —CH 2 CF 3 . In some embodiments, R 2 is -CFCF. In some embodiments, R 2 is -CF2CH(CH3)2.

[0118] In some embodiments, R 2 teeth, [ka] is.

[0119] In some embodiments, R 2 is C1-C6 alkyl substituted with one or more CN.

[0120] In some embodiments, R 2is —CHCN. In some embodiments, R 2 is —CH(CH)CN. In some embodiments, R 2 is -C(CH3)2CN.

[0121] In some embodiments, R 2 teeth, [ka] is.

[0122] In some embodiments, R 2 teeth, [ka] is.

[0123] In some embodiments, R 2 is C1-C6 alkoxy.

[0124] In some embodiments, R 2 is —OCH. In some embodiments, R 2 is —OCH2CH3. In some embodiments, R 2 is —OCH2CH2CH3. In some embodiments, R 2 is —OCH(CH). In some embodiments, R 2 is —OCH2CH2CH2CH3. In some embodiments, R 2 is —OCHCH(CH). In some embodiments, R 2 is —OCH(CH)CHCH. In some embodiments, R 2 is -OC(CH3)3.

[0125] In some embodiments, R 2 is -OCH(CH3)2.

[0126] In some embodiments, R 2 is iso-propoxy.

[0127] In some embodiments, R 2 is -OC(CH3)3.

[0128] In some embodiments, R 2 is tert-butoxy.

[0129] In some embodiments, R 2 is C1-C6 alkoxy substituted with one or more halogens.

[0130] In some embodiments, R 2 is -OCH2F. In some embodiments, R 2 is -OCHF. In some embodiments, R 2 is -OCF3. In some embodiments, R 2 is —OCF2CH3. In some embodiments, R 2 is —OCH 2 CF 3 . In some embodiments, R 2 is -OCF2CF3.

[0131] In some embodiments, R 2 teeth, [ka] is.

[0132] In some embodiments, R 2 teeth, [ka] is.

[0133] In some embodiments, R 2 is C3-C 10 It is a monocyclic cycloalkyl.

[0134] In some embodiments, R 2 is cyclopropyl. In some embodiments, R2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 2 is cycloheptyl.

[0135] In some embodiments, R 2 is a C3-C substituted with one or more halogens 10 It is a monocyclic cycloalkyl.

[0136] In some embodiments, R 2 is C3-C substituted with one or more F 10 It is a monocyclic cycloalkyl.

[0137] In some embodiments, R 2 is a C3-C substituted with one halogen 10 It is a monocyclic cycloalkyl.

[0138] In some embodiments, R 2 is C3-C substituted with one F 10 It is a monocyclic cycloalkyl.

[0139] In some embodiments, R 2 is cyclopropyl substituted with one F. In some embodiments, R 2 is cyclobutyl substituted with one F. In some embodiments, R 2 is cyclopentyl substituted with one F. In some embodiments, R 2 is cyclohexyl substituted with one F. In some embodiments, R 2 is cycloheptyl substituted with one F.

[0140] In some embodiments, R 2 teeth, [ka] is.

[0141] In some embodiments, R 2 is C3-C substituted with one or more CN 10 It is a monocyclic cycloalkyl.

[0142] In some embodiments, R 2 is C3-C substituted with one CN 10 It is a monocyclic cycloalkyl.

[0143] In some embodiments, R 2 is cyclopropyl substituted with one -CN. In some embodiments, R 2 is cyclobutyl substituted with one -CN. In some embodiments, R 2 is cyclopentyl substituted with one -CN. In some embodiments, R 2 is cyclohexyl substituted with one -CN. In some embodiments, R 2 is cycloheptyl substituted with one -CN.

[0144] In some embodiments, R 2 teeth, [ka] is.

[0145] In some embodiments, R 2 teeth, [ka] is.

[0146] In some embodiments, R 2 teeth, [ka] is.

[0147] In some embodiments, R 2 teeth, [ka] is.

[0148] In some embodiments, R 2 teeth, [ka] is.

[0149] In some embodiments, R 2 teeth, [ka] is.

[0150] In some embodiments, R 2 teeth, [ka] is.

[0151] In some embodiments, R 2 teeth, [ka] is.

[0152] In some embodiments, R 2 is C3-C 10 It is cycloalkoxy.

[0153] In some embodiments, R 2 is cyclopropoxy. In some embodiments, R 2 is cyclobutoxy. In some embodiments, R 2 is cyclopentoxy. In some embodiments, R 2 is cyclohexoxy. In some embodiments, R 2 is cycloheptoxy.

[0154] In some embodiments, R 2 teeth, [ka] is.

[0155] In some embodiments, R 2 teeth, [ka] is.

[0156] In some embodiments, R 2 teeth, [ka] is.

[0157] In some embodiments, R 2 teeth, [ka] is.

[0158] In some embodiments, R 2 is a C3-C substituted with one or more C1-C6 alkyls 10 It is cycloalkoxy.

[0159] In some embodiments, R 1 is a C3-C substituted with one C1-C6 alkyl 10 It is cycloalkoxy.

[0160] In some embodiments, R 2 is a C3-C substituted with one methyl 10 It is cycloalkoxy.

[0161] In some embodiments, R 2 teeth, [ka] is.

[0162] In some embodiments, R 2 teeth, [ka] is.

[0163] In some embodiments, R 2 teeth, [ka] is.

[0164] In some embodiments, R 2 teeth, [ka] is.

[0165] In some embodiments, R 2 teeth, [ka] is.

[0166] In some embodiments, R 2 teeth, [ka] is.

[0167] In some embodiments, R 2 teeth, [ka] is.

[0168] In some embodiments, R 2 teeth, [ka] is.

[0169] In some embodiments, R 2 teeth, [ka] is.

[0170] In some embodiments, R 2 teeth, [ka] is.

[0171] In some embodiments, R 2 teeth, [ka] is.

[0172] In some embodiments, R 2 teeth, [ka] is.

[0173] In some embodiments, R 2 is a heterocycle.

[0174] In some embodiments, R 2 is halogen, OH, =O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 A 3-10 membered heterocycle containing 1-3 heteroatoms selected from O, N, and S, optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0175] In some embodiments, R 2 is a 5-membered heterocycle containing S(O)2 and substituted with 1 to 4 substituents selected from OH, ═O, NH2, CN, C1-C6 alkyl.

[0176] In some embodiments, R 2 teeth, [ka] is.

[0177] In some embodiments, R 2 teeth, [ka] is.

[0178] In some embodiments, R 2 is a 5-membered heterocycle containing N and substituted with 1 to 4 substituents selected from OH, ═O, NH2, CN, C1-C6 alkyl.

[0179] In some embodiments, R 2 teeth, [ka] is.

[0180] In some embodiments, R 2 is heteroaryl.

[0181] In some embodiments, R 2 is halogen, OH=O, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 and heteroaryl optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0182] In some embodiments, R 2 is heteroaryl containing at least one heteroatom selected from N, O, S.

[0183] In some embodiments, R 2 is a 5-membered heteroaryl.

[0184] In some embodiments, R 2 is a 6-membered heteroaryl.

[0185] In some embodiments, R 2 is an O-containing 5-membered heteroaryl.

[0186] In some embodiments, R 2 is an N-containing 5-membered heteroaryl.

[0187] In some embodiments, R 2 is a 5-membered heteroaryl containing S.

[0188] In some embodiments, R 2 is a 5-membered heteroaryl containing O and N.

[0189] In some embodiments, R 2 is a 5-membered heteroaryl containing two N's.

[0190] In some embodiments, R 2 is a 5-membered heteroaryl containing S and N.

[0191] In some embodiments, R 2 is an O-containing 6-membered heteroaryl.

[0192] In some embodiments, R 2 is a 6-membered N-containing heteroaryl.

[0193] In some embodiments, R 2 is a 6-membered heteroaryl containing S.

[0194] In some embodiments, R 2 is a 6-membered heteroaryl containing O and N.

[0195] In some embodiments, R2 is a 6-membered heteroaryl containing two N's.

[0196] In some embodiments, R 2 is a 6-membered heteroaryl containing S and N.

[0197] In some embodiments, R 2 is heteroaryl substituted with -CH3.

[0198] In some embodiments, R 2 is heteroaryl substituted with halogen.

[0199] In some embodiments, R 2 is heteroaryl substituted with -CN.

[0200] In some embodiments, R 2 teeth, [ka] is.

[0201] In some embodiments, R 2 teeth, [ka] is.

[0202] In some embodiments, R 2 teeth, [ka] is.

[0203] In some embodiments, R 2 teeth, [ka] is.

[0204] In some embodiments, R2 is -NR 10 R 11 is.

[0205] In some embodiments, R 2 -NHS(O)2R 12 is.

[0206] In some embodiments, R 2 is -NHS(O)2R 12 and R 12 is C1-C6 alkyl optionally substituted with one or more halogens.

[0207] In some embodiments, R 2 is -NHS(O)2R 12 and R 12 is C1-C6 alkyl optionally substituted with one or more F.

[0208] In some embodiments, R 2 is -NHS(O)2CHF2.

[0209] In some embodiments, R 2 is -S(O)2R 12 is.

[0210] In some embodiments, R 2 is -S(O)2R 12 and R 12 is C1-C6 alkyl optionally substituted with one or more halogens.

[0211] In some embodiments, R 2 is -S(O)2CH3.

[0212] In some embodiments, R 2 and R 3together with the atom to which they are attached and any intervening atoms, form a 5- to 14-membered heterocycle, the heterocycle being selected from halogen, OH, ═O, CN, NH, C-C alkyl, C-C alkoxy, C-C alkyl-C-C alkoxy, C-C alkyl-NHC alkyl, and NR 10 R 11 and optionally substituted with one or more substituents independently selected from:

[0213] In some embodiments, R 2 and R 3 together with the atom to which they are attached and any intervening atoms, form a 5-membered heterocycle containing one heteroatom selected from O, N, and S.

[0214] In some embodiments, R 2 and R 3 together with the atoms to which they are attached and the intervening atoms form a 5-membered heterocyclic ring containing one heteroatom, -O.

[0215] In some embodiments, R 2 and R 3 together with the atom to which they are attached and any intervening atoms, form a 6-membered heterocycle containing one heteroatom selected from O, N, S.

[0216] In some embodiments, R 2 and R 3 together with the atoms to which they are attached and the intervening atoms form a 6-membered heterocycle containing one heteroatom, -O.

[0217] In some embodiments, R 2 and R 3 together with the atoms to which they are bonded and the intervening atoms, [ka] Form.

[0218] In some embodiments, R 3 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl.

[0219] In some embodiments, R 3 is H.

[0220] In some embodiments, R 3 is C1-C6 alkyl.

[0221] In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is n-propyl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is butyl. In some embodiments, R 3 is n-butyl. In some embodiments, R 3is isobutyl. In some embodiments, R 3 is sec-butyl. In some embodiments, R 3 is tert-butyl. In some embodiments, R 3 is pentyl. In some embodiments, R 3 is hexyl.

[0222] In some embodiments, R 3 is -CH3.

[0223] In some embodiments, R 4 is H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 , C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein alkyl, cycloalkyl or alkyl-alkoxy is selected from halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.

[0224] In some embodiments, R 4 is H.

[0225] In some embodiments, when V is C, R 4 is a halogen.

[0226] In some embodiments, R 4 is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is Br. In some embodiments, R 4 is I.

[0227] In some embodiments, when V is C, R 4 is CN.

[0228] In some embodiments, when V is N, R 4 is C(O)OC1-C6 alkyl.

[0229] In some embodiments, when V is N, R 4 is C(O)O-tert-butyl.

[0230] In some embodiments, R 5 is H, C1-C6 alkyl 、 C3-C 10 is selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, or heteroaryl, and alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle, aryl, or heteroaryl is selected from halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.

[0231] In some embodiments, R 5 is H.

[0232] In some embodiments, R 5 is C1-C6 alkyl.

[0233] In some embodiments, R 5 is CH3. In some embodiments, R 5 is C2H5. In some embodiments, R 5 is CH2CH2CH3. In some embodiments, R 5 is CH(CH). In some embodiments, R 5 is CH2CH2CH2CH3. In some embodiments, R 5 is CH2CH(CH3)2.

[0234] In some embodiments, R 5 is methyl.

[0235] In some embodiments, R 5 is ethyl.

[0236] In some embodiments, R 5 is isopropyl.

[0237] In some embodiments, R 5 is isobutyl.

[0238] In some embodiments, R 5 is C1-C6 alkyl substituted with one or more halogens.

[0239] In some embodiments, R 5 is C1-C6 alkyl substituted with one or more F.

[0240] In some embodiments, R 5 is -CHF2.

[0241] In some embodiments, R 5 is -CF3.

[0242] In some embodiments, R 5 is C3-C 10 It is cycloalkyl.

[0243] In some embodiments, R 5 is cyclopropyl.

[0244] In some embodiments, R 5 is cyclobutyl.

[0245] In some embodiments, R 5 is cyclopentyl.

[0246] In some embodiments, Q is CH. In some embodiments, Q is NR 5In some embodiments, Q is O. In some embodiments, Q is S. In some embodiments, Q is S(O). In some embodiments, Q is S(O).

[0247] In some embodiments, Q is one or two R 6 is CH2, optionally substituted with

[0248] In some embodiments, Q is CH2.

[0249] In some embodiments, Q is CHR 6 is.

[0250] In some embodiments, Q is C(R 6 )2.

[0251] In some embodiments, Q is O.

[0252] In some embodiments, Q is NR 5 is.

[0253] In some embodiments, Q is NH.

[0254] In some embodiments, Q is N(C1-C6 alkyl).

[0255] In some embodiments, Q is NCH3.

[0256] In some embodiments, Q is NCH(CH3)2.

[0257] In some embodiments, Q is N(C1-C6 halogenalkyl).

[0258] In some embodiments, Q is NCH2CF3.

[0259] In some embodiments, Q is N(C1-C6 hydroxyalkyl).

[0260] In some embodiments, Q is [ka] is.

[0261] In some embodiments, Q is S(O)2.

[0262] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0263] In some embodiments, m is 1.

[0264] In some embodiments, m is 2.

[0265] In some embodiments, m is 3.

[0266] In some embodiments, m is 4.

[0267] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0268] In some embodiments, n is 0.

[0269] In some embodiments, n is 1.

[0270] In some embodiments, n is 2.

[0271] In some embodiments, n is 3.

[0272] In some embodiments, n is 4.

[0273] In some embodiments, combinations of m and n are selected from the following table: JPEG2025511875000070.jpg24485

[0274] In some embodiments, m is 1 and n is 2.

[0275] In some embodiments, m is 1, n is 2, and Q is CH2.

[0276] In some embodiments, m is 1, n is 2, and Q is CHR 6 is.

[0277] In some embodiments, m is 1, n is 2, and Q is C(R 6 )2.

[0278] In some embodiments, m is 1, n is 2, and Q is C(CH3)2.

[0279] In some embodiments, m is 1, n is 2, and Q is [ka] is.

[0280] In some embodiments, m is 1, n is 2, and Q is [ka] is.

[0281] In some embodiments, m is 2 and n is 2.

[0282] In some embodiments, m is 2, n is 2, and Q is O.

[0283] In some embodiments, m is 2, n is 2, and Q is NR 5 is.

[0284] In some embodiments, m is 2, n is 2, and Q is S(O)2.

[0285] In some embodiments, m is 2, n is 2, and Q is CH2.

[0286] In some embodiments, m is 3 and n is 2.

[0287] In some embodiments, m is 3, n is 2, and Q is O.

[0288] In some embodiments, m is 3, n is 2, and Q is NR 5 is.

[0289] In some embodiments, m is 3, n is 2, and Q is NH.

[0290] In some embodiments, m is 3, n is 2, and Q is NCH3.

[0291] In some embodiments, m is 3, n is 2, and Q is NCH(CH3)2.

[0292] In some embodiments, m is 3, n is 2, and Q is NCH2CF3.

[0293] In some embodiments, m is 3, n is 2, and Q is [ka] is.

[0294] In some embodiments, m is 3, n is 2, and Q is CH2.

[0295] In some embodiments, m is 3, n is 2, and Q is CHCH3.

[0296] In some embodiments, m is 3, n is 2, and Q is C(CH3)2.

[0297] In some embodiments, m is 3, n is 2, and Q is CH(halogen).

[0298] In some embodiments, m is 3, n is 2, and Q is CHF.

[0299] In some embodiments, m is 3, n is 2, and Q is CH(OH).

[0300] In some embodiments, m is 3, n is 2, and Q is C(CH3)OH.

[0301] In some embodiments, m is 3, n is 2, and Q is S(O)2.

[0302] In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 5. In some embodiments, u is 6.

[0303] In some embodiments, u is 0.

[0304] In some embodiments, u is 1.

[0305] In some embodiments, u is 2.

[0306] In some embodiments, u is 3.

[0307] In some embodiments, u is 4.

[0308] In some embodiments, each R 6 is halogen, OH, oxo, CN, CONR 10 R 11 , N.R. 10 R 11 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 , N.R. 10 C(O)R 11 , -S(O)2-C1-C6 alkyl, -C1-C6 alkanediyl-S(O)2-C1-C6 alkyl, wherein alkyl or alkoxy is independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.

[0309] In some embodiments, R 6 is selected from halogen. 6 is OH. In some embodiments, R 6 is oxo. In some embodiments, R 6 is CN. In some embodiments, R 6 CONR 10 R 11 In some embodiments, R 6 is NR 10 R 11 In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is C1-C6 alkoxy. In some embodiments, R 6 is O-C1-C6 alkyl-C(O)NR 10 R 11 In some embodiments, R 6 is NR 10C(O)R 11 is.

[0310] In some embodiments, R 6 is a halogen.

[0311] In some embodiments, R 6 is F.

[0312] In some embodiments, R 6 is OH.

[0313] In some embodiments, R 6 is C1-C6 alkyl.

[0314] In some embodiments, R 6 is -CH3.

[0315] In some embodiments, R 6 is C1-C6 halogen alkyl.

[0316] In some embodiments, R 6 is -CF3.

[0317] In some embodiments, R 6 is -CH2Cl.

[0318] In some embodiments, R 6 is C1-C6 hydroxyalkyl.

[0319] In some embodiments, R 6 is -CHOH.

[0320] In some embodiments, R 6 teeth, [ka] is.

[0321] In some embodiments, R 6is C1-C6 alkyl-C1-C6 alkoxy.

[0322] In some embodiments, R 6 is -CH2-O-CH3.

[0323] In some embodiments, R 6 is -CH2-O-CH2CH3.

[0324] In some embodiments, two R 6 together with the atom to which they are attached and any intervening atoms, form a 3-14 membered cycloalkyl, aryl, 3-14 membered heterocycle, or 5-10 membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and optionally substituted with one or more substituents independently selected from:

[0325] In some embodiments, two geminal R 6 together with the atom to which they are attached and any intervening atoms, form a 3- to 14-membered cycloalkyl or a 3- to 14-membered heterocycle, and the cycloalkyl or heterocycle is selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and optionally substituted with one or more substituents independently selected from:

[0326] In some embodiments, two vicinal R 6together with the atom to which they are attached and any intervening atoms, form a 3-14 membered cycloalkyl, aryl, 3-14 membered heterocycle, or 5-10 membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and optionally substituted with one or more substituents independently selected from:

[0327] In some embodiments, two isolated R 6 together with the atom to which they are attached and any intervening atoms, form a 5-14 membered cycloalkyl or a 5-14 membered heterocycle, and the cycloalkyl or heterocycle is selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and optionally substituted with one or more substituents independently selected from:

[0328] In some embodiments, two R 6 together with the atoms to which they are bonded and the intervening atoms, [ka] Form.

[0329] In some embodiments, two R 6 together with the atoms to which they are bonded and the intervening atoms, [ka] Form.

[0330] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0331] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0332] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0333] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0334] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0335] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0336] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0337] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0338] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0339] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0340] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0341] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0342] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0343] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0344] In some embodiments, two R 6 together with the atoms to which they are bonded, [ka] Form.

[0345] In some embodiments, R 7 is H. In some embodiments, R 7 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is C-C alkyl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 7 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 C-C optionally substituted with one or more substituents independently selected from , cycloalkyl, and heterocycle. 10 In some embodiments, R 7 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is C-C alkoxy optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 7 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11In some embodiments, R is a C-C alkenyl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 7 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is a C-C alkynyl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 7 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is a heterocycle optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 7 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 aryl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 7 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heteroaryl optionally substituted with one or more substituents independently selected from heterocycle.

[0346] In some embodiments, R 7 is H.

[0347] In some embodiments, R 8 is H. In some embodiments, R 8 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is C-C alkyl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 8 is halogen, oxo, OH, NH2 , C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 C-C optionally substituted with one or more substituents independently selected from , cycloalkyl, and heterocycle. 10 In some embodiments, R 8 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is C-C alkoxy optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 8 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is a C-C alkenyl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 8 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is a C-C alkynyl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 8 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is a heterocycle optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 8 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 aryl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 8 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11, cycloalkyl, and heteroaryl optionally substituted with one or more substituents independently selected from heterocycle.

[0348] In some embodiments, R 8 is H.

[0349] In some embodiments, R 8 is halogen, oxo, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heterocycle.

[0350] In some embodiments, R 8 is C1-C6 alkyl.

[0351] In some embodiments, R 8 is -CH3.

[0352] In some embodiments, R 9 is H. In some embodiments, R 9 is halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is C-C alkyl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 9 is halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 C-C optionally substituted with one or more substituents independently selected from , cycloalkyl, and heterocycle. 10 In some embodiments, R 9 is halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11In some embodiments, R is C-C alkoxy optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 9 is halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is a C-C alkenyl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 9 is halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is a C-C alkynyl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 9 is halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 In some embodiments, R is a heterocycle optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 9 is halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 aryl optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle. 9 is halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , cycloalkyl, and heteroaryl optionally substituted with one or more substituents independently selected from heterocycle.

[0353] In some embodiments, R 9 is H.

[0354] In some embodiments, R 9 is C1-C6 alkyl.

[0355] In some embodiments, R 9 is -CH3.

[0356] In some embodiments, R 10 is H. In some embodiments, R 10 is C-C alkyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C-C alkyl, C-C alkoxy. In some embodiments, R 10 is a C3-C optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy 10 In some embodiments, R 10 is S(O)2R 12 is.

[0357] In some embodiments, R 10 is H.

[0358] In some embodiments, R 10 is C1-C6 alkyl.

[0359] In some embodiments, R 10 is methyl.

[0360] In some embodiments, R 10 is -S(O)2R 12 is.

[0361] In some embodiments, R 10 is —S(O)2C1-C6 alkyl.

[0362] In some embodiments, R 10 is -S(O)2CH3.

[0363] In some embodiments, R 10 is -S(O)2CHF2.

[0364] In some embodiments, R 11 is H. In some embodiments, R 11 is C-C alkyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C-C alkyl, C-C alkoxy. In some embodiments, R 11 is a C3-C optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy 10 It is cycloalkyl.

[0365] In some embodiments, R 11 is H.

[0366] In some embodiments, R 11 is C1-C6 alkyl.

[0367] In some embodiments, R 11 is methyl.

[0368] In some embodiments, R 12 is C1-C6 alkyl, -NH2, -NH(C1-C3 alkyl), or -N(C1-C3 alkyl)2, wherein alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy.

[0369] In some embodiments, R 12 is C1-C6 alkyl optionally substituted with one or more halogens.

[0370] In some embodiments, R 12 is -CHF2.

[0371] In some embodiments, the compound is of formula (II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0372] In some embodiments, the compound is of formula (I-II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein all variables are as defined herein.

[0373] In some embodiments, the compound is of formula (IO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0374] In some embodiments, the compound is of formula (IN): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0375] In some embodiments, the compound is of formula (IS): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0376] In some embodiments, the compound is of formula (II): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein X is CR 7 and N; Y is C=O, CR 8 , and N; However, one of X and Y is N; join Y JPEG2025511875000098.jpg1140N is selected from a single bond and a double bond; r is an integer selected from 0 and 1; However, when Y is C=O, the bond Y JPEG2025511875000099.jpg1140N is a single bond, r is 1, and Y is CR 8 or N, when bond Y JPEG2025511875000100.jpg1140N is a double bond and r is 0; When Y is C=O or N, Z is CR 9 and N; Y is CR 8 When Z is CR 9 and; Q is CH2, NR 5 , selected from O, S, S(O), S(O)2; R 1 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; or R 1 and R 2 together with the atoms to which they are attached and any intervening atoms, form C3-C 10 Forms a cycloalkyl, a 5-14 membered heterocycle, an aryl, or a heteroaryl, and the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 10 R 11 optionally substituted with one or more substituents independently selected from: R 3 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Monocyclic cycloalkyl, C3-C 10Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; or R 2 and R 3 together with the atoms to which they are attached and any intervening atoms, form C3-C 10 Forms a cycloalkyl, a 5-14 membered heterocycle, an aryl, or a heteroaryl, and the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 10 R 11 optionally substituted with one or more substituents independently selected from: R 4 is H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 , C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein alkyl, cycloalkyl or alkyl-alkoxy is selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Each R 5 is H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 and alkyl, cycloalkyl, or alkyl-alkoxy is independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Each R 6 is halogen, OH, oxo, CN, CONR 10 R 11 , N.R. 10 R 11 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 , N.R. 10 C(O)R 11 , -S(O)2-C1-C6 alkyl, -C1-C6 alkanediyl-S(O)2-C1-C6 alkyl, wherein alkyl or alkoxy is independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Or two R's 6 together with the atom to which they are attached and any intervening atoms, form a 3-14 membered cycloalkyl, aryl, 3-14 membered heterocycle, or 5-10 membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12optionally substituted with one or more substituents independently selected from: R 7 , R 8 and R 9 are H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 and alkyl, alkoxy, cycloalkyl or alkylalkoxy is independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , S(O)2R 12 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; R 10 is H, C1-C6 alkyl, C3-C 10 Cycloalkyl, S(O)R 12 wherein alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 11 is H, C1-C6 alkyl, C3-C 10 cycloalkyl, wherein alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; or R 10 and R 11 together with the atom to which they are attached and any intervening atoms, form a 5- to 14-membered heterocycle, the heterocycle being optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 12is selected from C1-C6 alkyl, —NH2, —NH(C1-C3 alkyl), or —N(C1-C3 alkyl)2, wherein alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, and 4; u is an integer selected from 0, 1, 2, 3, 4, 5, and 6; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings.

[0377] In some embodiments, the compound is of formula (II-QN): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, and a fragment [ka] teeth, [ka] [ka] [ka] [ka] is selected from.

[0378] In some embodiments, the compound is of formula (IIA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0379] In some embodiments, the compound is of formula (IIB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0380] In some embodiments, the compound is of formula (IIC): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0381] In some embodiments, the compound is of formula (IID): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0382] In some preferred embodiments, the compound is of formula (IID): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof; Q is CH2, NR 5 , selected from O, S, S(O), S(O)2; R 1 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, NR 10 R 11 , and S(O)2R12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; R 2 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; or R 1 and R 2 together with the atoms to which they are attached and any intervening atoms, form C3-C 10 Forms a cycloalkyl, a 5-14 membered heterocycle, an aryl, or a heteroaryl, and the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 10 R 11optionally substituted with one or more substituents independently selected from: R 3 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Monocyclic cycloalkyl, C3-C 10 Cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C2-C6 alkenyl-aryl, C2-C6 alkenyl-heteroaryl, C2-C6 alkynyl-aryl, C2-C6 alkynyl-heteroaryl, NR 10 R 11 , and S(O)2R 12 alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; or R 2 and R 3 together with the atoms to which they are attached and any intervening atoms, form C3-C 10 Forms a cycloalkyl, a 5-14 membered heterocycle, an aryl, or a heteroaryl, and the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from halogen, OH, oxo, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NHC1-C6 alkyl, and NR 10 R 11 optionally substituted with one or more substituents independently selected from: R 4 is H, OH, CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11, C(O)OC1-C6 alkyl, OC(O)C1-C6 alkyl, wherein alkyl, cycloalkyl or alkyl-alkoxy is selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Each R 5 is H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 and alkyl, cycloalkyl, or alkyl-alkoxy is independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Each R 6 is halogen, OH, oxo, CN, CONR 10 R 11 , N.R. 10 R 11 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-C3-C8 cycloalkoxy, O-C1-C6 alkyl-C(O)NR 10 R 11 , N.R. 10 C(O)R 11 , -S(O)2-C1-C6 alkyl, -C1-C6 alkanediyl-S(O)2-C1-C6 alkyl, wherein alkyl or alkoxy is independently selected from halogen, oxo, OH, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Or two R's 6together with the atom to which they are attached and any intervening atoms, form a 3-14 membered cycloalkyl, aryl, 3-14 membered heterocycle, or 5-10 membered heteroaryl, and the cycloalkyl, aryl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 optionally substituted with one or more substituents independently selected from: R 7 , R 8 and R 9 are H, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 Cycloalkyl, C1-C6 alkyl-C1-C6 alkoxy, C1-C6 alkyl-NR 10 R 11 and alkyl, alkoxy, cycloalkyl or alkylalkoxy is independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, NR 10 R 11 , S(O)2R 12 optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; R 10 is H, C1-C6 alkyl, C3-C 10 Cycloalkyl, S(O)R 12 wherein alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 11 is H, C1-C6 alkyl, C3-C 10 cycloalkyl, wherein alkyl or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; or R 10 and R 11together with the atom to which they are attached and any intervening atoms, form a 5- to 14-membered heterocycle, the heterocycle being optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R 12 is selected from C1-C6 alkyl, —NH2, —NH(C1-C3 alkyl), or —N(C1-C3 alkyl)2, wherein alkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, and 4; u is an integer selected from 0, 1, 2, 3, 4, 5, and 6.

[0383] In some preferred embodiments, the compound is of formula (IID-QN): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and [ka] teeth, [ka] [ka] [ka] [ka] is selected from.

[0384] In some embodiments, the compound is of formula (I-II-A): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0385] In some embodiments, the compound is of formula (I-II-B): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0386] In some embodiments, the compound is of formula (I-II-C): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0387] In some embodiments, the compound is of formula (I-II-D): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0388] In some embodiments, the compound is of formula (IIAM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0389] In some embodiments, the compound is of formula (IIBM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0390] In some embodiments, the compound is of formula (IICM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0391] In some embodiments, the compound is of formula (IIDI): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0392] In some embodiments, the compound is of formula (IIDM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0393] In some embodiments, the compound is of formula (IIDMH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0394] In some embodiments, the compound is of the formula (IIDMA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0395] In some embodiments, the compound is of formula (IIDM-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0396] In some embodiments, the compound is of formula (IIDM-1*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0397] In some embodiments, the compound is of formula (IIDM-1**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0398] In some embodiments, the compound is of formula (IIDO): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0399] In some embodiments, the compound is of the formula (IIDOH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0400] In some embodiments, the compound is of formula (IIDOA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0401] In some embodiments, the compound is of the formula (IIDOAH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0402] In some embodiments, the compound is of formula (IIDOA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0403] In some embodiments, the compound is of formula (IIDOA-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0404] In some embodiments, the compound is of formula (IIDOA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0405] In some embodiments, the compound is of the formula (IIDOA-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0406] In some embodiments, the compound is of formula (IIDOA-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0407] In some embodiments, the compound is of the formula (IIDO-3-AH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0408] In some embodiments, the compound is of the formula (IIDOB): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0409] In some embodiments, the compound is of the formula (IIDOBH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0410] In some embodiments, the compound is of the formula (IIDOB-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0411] In some embodiments, the compound is of the formula (IIDOB-1*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0412] In some embodiments, the compound is of the formula (IIDOB-1**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0413] In some embodiments, the compound is of the formula (IIDOB-1***): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0414] In some embodiments, the compound is of the formula (IIDOB-1****): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0415] In some embodiments, the compound is of formula (IIDOC): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0416] In some embodiments, the compound is of the formula (IIDOCH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0417] In some embodiments, the compound is of formula (IIDOC-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0418] In some embodiments, the compound is of the formula (IIDOC-1*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0419] In some embodiments, the compound is of the formula (IIDOC-1**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0420] In some embodiments, the compound is of the formula (IIDOD): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0421] In some embodiments, the compound is of the formula (IIDODH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0422] In some embodiments, the compound is of formula (IIDOD-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0423] In some embodiments, the compound is of the formula (IIDOD-1*): [ka]

[0424] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. In some embodiments, the compound is of formula (IIDOD-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0425] In some embodiments, the compound is of formula (IIDOE): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0426] In some embodiments, the compound is of formula (IIDOEH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0427] In some embodiments, the compound is of formula (IIDOE-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0428] In some embodiments, the compound is of formula (IIDOF): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0429] In some embodiments, the compound is of formula (IIDOFH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0430] In some embodiments, the compound is of formula (IIDOF-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0431] In some embodiments, the compound is of the formula (IIDOF-1*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0432] In some embodiments, the compound is of formula (IIDOF-1**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0433] In some embodiments, the compound is of formula (IIDOF-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0434] In some embodiments, the compound is of the formula (IIDOF-2*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0435] In some embodiments, the compound is of formula (IIDOF-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0436] In some embodiments, the compound is of formula (IIID-II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0437] In some embodiments, the compound is of formula (IIDZ): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0438] In some embodiments, the compound is of formula (IIDZH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0439] In some embodiments, the compound is of formula (IIDZ-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0440] In some embodiments, the compound is of formula (IIDZ-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0441] In some embodiments, the compound is of formula (IIDZ-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0442] In some embodiments, the compound is of formula (IIDZ-1-A): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0443] In some embodiments, the compound is of formula (IIDZ-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0444] In some embodiments, the compound is of formula (IIDZ-1-a*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0445] In some embodiments, the compound is of formula (IIDZ-1-a**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0446] In some embodiments, the compound is of formula (IIDD): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0447] In some embodiments, the compound is of the formula (IIDDH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0448] In some embodiments, the compound is of formula (IIDD-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0449] In some embodiments, the compound is of formula (IIDD-0-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0450] In some embodiments, the compound is of formula (IIDD-0-A): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0451] In some embodiments, the compound is of formula (IIDD-0-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0452] In some embodiments, the compound is of formula (IIDD-0-B): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0453] In some embodiments, the compound is of formula (IIDD-0-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0454] In some embodiments, the compound is of formula (IIDD-0-C): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0455] In some embodiments, the compound is of formula (IIDD-0-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0456] In some embodiments, the compound is of formula (IIDD-0-cc): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0457] In some embodiments, the compound is of formula (IIDD-0-ccc): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0458] In some embodiments, the compound is of formula (IIDD-0-D): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0459] In some embodiments, the compound is of formula (IIDD-0-d): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0460] In some embodiments, the compound is of formula (IIDD-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0461] In some embodiments, the compound is of formula (IIDD-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0462] In some embodiments, the compound is of formula (IIDD-1-A): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0463] In some embodiments, the compound is of formula (IIDD-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0464] In some embodiments, the compound is of formula (IIDD-1-B): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0465] In some embodiments, the compound is of formula (IIDD-1-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0466] In some embodiments, the compound is of formula (IIDD-1-C): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0467] In some embodiments, the compound is of formula (IIDD-1-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0468] In some embodiments, the compound is of formula (IIDD-1-cc): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0469] In some embodiments, the compound is of formula (IIDD-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0470] In some embodiments, the compound is of formula (IIDD-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0471] In some embodiments, the compound is of formula (IIDD-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0472] In some embodiments, the compound is of formula (IIDD-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0473] In some embodiments, the compound is of formula (IIDD-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0474] In some embodiments, the compound is of formula (IIDD-4-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0475] In some embodiments, the compound is of formula (IIID-III): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0476] In some embodiments, the compound is of formula (IIDP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0477] In some embodiments, the compound is of the formula (IIDPH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0478] In some embodiments, the compound is of formula (IIDP-0): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0479] In some embodiments, the compound is of formula (IIDP-0-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0480] In some embodiments, the compound is of formula (IIDP-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0481] In some embodiments, the compound is of formula (IIDP-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0482] In some embodiments, the compound is of formula (IIDP-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0483] In some embodiments, the compound is of formula (IIDP-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0484] In some embodiments, the compound is of formula (IIDP-2-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0485] In some embodiments, the compound is of formula (IIDP-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0486] In some embodiments, the compound is of formula (IIDP-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0487] In some embodiments, the compound is of formula (IIDP-3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0488] In some embodiments, the compound is of formula (IIDP-3-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0489] In some embodiments, the compound is of formula (IIDP-3-1-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0490] In some embodiments, the compound is of formula (IIDP-3-1-a-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0491] In some embodiments, the compound is of formula (IIDP-3-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein q is an integer selected from 1, 2, 3, 4, and 5; p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0492] In some embodiments, the compound is of formula (IIDP-3-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0493] In some embodiments, the compound is of formula (IIDP-3-2-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0494] In some embodiments, the compound is of formula (IIDP-3-2-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0495] In some embodiments, the compound is of formula (IIDP-3-2-a-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0496] In some embodiments, the compound is of formula (IIDP-3-2-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0497] In some embodiments, the compound is of formula (IIDP-3-2-bH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0498] In some embodiments, the compound is of formula (IIDP-3-2-b-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0499] In some embodiments, the compound is of formula (IIDP-3-2-b-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0500] In some embodiments, the compound is of formula (IIDP-3-2-b-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0501] In some embodiments, the compound is of formula (IIDP-3-2-b-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0502] In some embodiments, the compound is of formula (IIDP-3-2-b-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0503] In some embodiments, the compound is of formula (IIDP-3-2-b-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0504] In some embodiments, the compound is of formula (IIDP-3-2-b-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0505] In some embodiments, the compound is of formula (IIDP-3-2-b-4-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0506] In some embodiments, the compound is of formula (IIDP-3-2-b-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 Selected from; R 67 is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, and all other variables are as described herein.

[0507] In some embodiments, the compound is of formula (IIDP-3-2-b-5-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R 67 is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, and all other variables are as defined herein.

[0508] In some embodiments, the compound is of formula (IIDP-3-2-b-5-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0509] In some embodiments, the compound is of formula (IIDP-3-2-b-5-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0510] In some embodiments, the compound is of formula (IIDP-3-2-b-5-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0511] In some embodiments, the compound is of formula (IIDP-3-2-b-5-bH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0512] In some embodiments, the compound is of formula (IIDP-3-2-b-5-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0513] In some embodiments, the compound is of the formula (IIDP-3-2-b-5-cH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0514] In some embodiments, the compound is of formula (IIDP-3-2-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0515] In some embodiments, the compound is of formula (IIDP-3-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0516] In some embodiments, the compound is of formula (IIDP-3-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0517] In some embodiments, the compound is of formula (IIDP-3-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 wherein Ring H is a 3-8 membered saturated or partially unsaturated heterocyclyl containing 1-3 heteroatoms selected from N, O, S, and all other variables are as described herein.

[0518] In some embodiments, the compound is of formula (IIDP-3-4-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 wherein Ring H is a 3-8 membered saturated or partially unsaturated heterocyclyl containing 1-3 heteroatoms selected from N, O, S, and all other variables are as described herein.

[0519] In some embodiments, the compound is of formula (IIDP-3-4-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where w is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as described herein.

[0520] In some embodiments, the compound is of formula (IIDP-3-4-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where w is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as described herein.

[0521] In some embodiments, the compound is of formula (IIDP-3-4-a-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0522] In some embodiments, the compound is of formula (IIDP-3-4-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0523] In some embodiments, the compound is of formula (IIDP-3-4-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where x and y are integers independently selected from 1, 2, and 3, and all other variables are as described herein.

[0524] In some embodiments, the compound is of the formula (IIDP-3-4-bH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where x and y are integers independently selected from 1, 2, and 3, and all other variables are as described herein.

[0525] In some embodiments, the compound is of formula (IIDP-3-4-b-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0526] In some embodiments, the compound is of formula (IIDP-3-4-b-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0527] In some embodiments, the compound is of formula (IIDP-3-4-b-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0528] In some embodiments, the compound is of formula (IIDP-3-4-b-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0529] In some embodiments, the compound is of formula (IIDP-3-4-b-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0530] In some embodiments, the compound is of formula (IIDP-3-4-b-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0531] In some embodiments, the compound is of formula (IIDP-3-4-c): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where w is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as described herein.

[0532] In some embodiments, the compound is of the formula (IIDP-3-4-cH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where w is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as described herein.

[0533] In some embodiments, the compound is of formula (IIDP-3-4-c-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0534] In some embodiments, the compound is of formula (IIDP-3-4-c-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0535] In some embodiments, the compound is of formula (IIDP-3-4-c-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0536] In some embodiments, the compound is of formula (IIDP-3-4-c-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0537] In some embodiments, the compound is of formula (IIDP-3-4-c-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0538] In some embodiments, the compound is of formula (IIDP-3-4-c-2-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0539] In some embodiments, the compound is of formula (IIDP-3-4-c-2-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0540] In some embodiments, the compound is of the formula (IIDP-3-4-c-2-bH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0541] In some embodiments, the compound is of formula (IIDP-3-4-d): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3, p is an integer selected from 0, 1, and 2, and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0542] In some embodiments, the compound is of the formula (IIDP-3-4-dH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3, p is an integer selected from 0, 1, and 2, and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0543] In some embodiments, the compound is of formula (IIDP-3-4-d-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0544] In some embodiments, the compound is of formula (IIDP-3-4-d-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0545] In some embodiments, the compound is of formula (IIDP-3-4-d-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0546] In some embodiments, the compound is of formula (IIDP-3-4-d-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0547] In some embodiments, the compound is of formula (IIDP-3-4-d-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0548] In some embodiments, the compound is of the formula (IIDP-3-4-d-2-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0549] In some embodiments, the compound is of formula (IIDP-3-4-d-2-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0550] In some embodiments, the compound is of the formula (IIDP-3-4-d-2-bH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0551] In some embodiments, the compound is of formula (IIDP-3-4-e): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where w is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as described herein.

[0552] In some embodiments, the compound is of formula (IIDP-3-4-eH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where w is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as described herein.

[0553] In some embodiments, the compound is of formula (IIDP-3-4-e-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0554] In some embodiments, the compound is of formula (IIDP-3-4-e-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0555] In some embodiments, the compound is of formula (IIDP-3-4-e-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0556] In some embodiments, the compound is of formula (IIDP-3-4-e-1-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0557] In some embodiments, the compound is of formula (IIDP-3-4-e-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0558] In some embodiments, the compound is of formula (IIDP-3-4-e-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0559] In some embodiments, the compound is of formula (IIDP-3-4-e-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0560] In some embodiments, the compound is of the formula (IIDP-3-4-e-2-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0561] In some embodiments, the compound is of formula (IIDP-3-4-e-2-b): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0562] In some embodiments, the compound is of the formula (IIDP-3-4-e-2-bH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0563] In some embodiments, the compound is of formula (IIDP-3-4-f): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3, p is an integer selected from 0, 1, and 2, and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0564] In some embodiments, the compound is of the formula (IIDP-3-4-fH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein x and y are integers independently selected from 1, 2, and 3, p is an integer selected from 0, 1, and 2, and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0565] In some embodiments, the compound is of formula (IIDP-3-4-f-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0566] In some embodiments, the compound is of formula (IIDP-3-4-f-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0567] In some embodiments, the compound is of formula (IIDP-3-4-f-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0568] In some embodiments, the compound is of formula (IIDP-3-4-f-1-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0569] In some embodiments, the compound is of formula (IIDP-3-4-f-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0570] In some embodiments, the compound is of formula (IIDP-3-4-f-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 0, 1, and 2; and R 66 is halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 alkyl-C1-C6 alkoxy, S(O)2R 12 and all other variables are as described herein.

[0571] In some embodiments, the compound is of formula (IIDP-3-4-f-2-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0572] In some embodiments, the compound is of formula (IIDP-3-4-f-2-aH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0573] In some embodiments, the compound is of formula (IID-PP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0574] In some embodiments, the compound is of the formula (IID-PP-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0575] In some embodiments, the compound is of formula (IID-PP-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0576] In some embodiments, the compound is of formula (IID-PP-1-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0577] In some embodiments, the compound is of formula (IIDA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0578] In some embodiments, the compound is of formula (IIDAH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0579] In some embodiments, the compound is of formula (IIDA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0580] In some embodiments, the compound is of formula (IIDA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0581] In some embodiments, the compound is of formula (IIDA-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0582] In some embodiments, the compound is of formula (IIDA-3*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0583] In some embodiments, the compound is of formula (IIDA-3**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0584] In some embodiments, the compound is of formula (IIDA-3***): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0585] In some embodiments, the compound is of formula (IIDA-3****): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0586] In some embodiments, the compound is of formula (IIDA-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0587] In some embodiments, the compound is of formula (IIDA-4*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0588] In some embodiments, the compound is of formula (IIDA-4**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0589] In some embodiments, the compound is of formula (IIDA-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0590] In some embodiments, the compound is of formula (IIDA-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0591] In some embodiments, the compound is of formula (IIDA-6*): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0592] In some embodiments, the compound is of formula (IIDA-6**): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0593] In some embodiments, the compound is of formula (IIDA-6***): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0594] In some embodiments, the compound is of formula (IIDA-6****): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0595] In some embodiments, the compound is of formula (IIDA-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0596] In some embodiments, the compound is of formula (IIDA-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0597] In some embodiments, the compound is of formula (IIID-IV): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0598] In some embodiments, the compound is of formula (IIDT): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0599] In some embodiments, the compound is of the formula (IIIDTH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0600] In some embodiments, the compound is of formula (IID-TZ): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0601] In some embodiments, the compound is of formula (IID-TZ-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0602] In some embodiments, the compound is of formula (I-II-AM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0603] In some embodiments, the compound is of formula (I-II-BM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0604] In some embodiments, the compound is of formula (I-II-CM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0605] In some embodiments, the compound is of formula (I-II-DM): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0606] In some embodiments, the compound is of formula (IIAP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0607] In some embodiments, the compound is of formula (IIBP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0608] In some embodiments, the compound is of formula (IICP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0609] In some embodiments, the compound is of formula (IIDP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0610] In some embodiments, the compound is of formula (I-II-AP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0611] In some embodiments, the compound is of formula (I-II-BP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0612] In some embodiments, the compound is of formula (I-II-CP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0613] In some embodiments, the compound is of formula (I-II-DP): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0614] In some embodiments, the compound is of formula (IIAA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0615] In some embodiments, the compound is of formula (IIBA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0616] In some embodiments, the compound is of formula (IICA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0617] In some embodiments, the compound is of formula (IIDA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0618] In some embodiments, the compound is of formula (I-II-AA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0619] In some embodiments, the compound is of formula (I-II-BA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0620] In some embodiments, the compound is of formula (I-II-CA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0621] In some embodiments, the compound is of formula (I-II-DA): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where u is 0 or 1, and all other variables are as defined herein.

[0622] In some embodiments, the compound is of formula (IIA-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0623] In some embodiments, the compound is of formula (IIA-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0624] In some embodiments, the compound is of formula (IIA-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0625] In some embodiments, the compound is of formula (IIA-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0626] In some embodiments, the compound is of formula (IIA-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0627] In some embodiments, the compound is of formula (IIA-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0628] In some embodiments, the compound is of formula (IIA-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0629] In some embodiments, the compound is of formula (IIA-4-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0630] In some embodiments, the compound is of formula (IIA-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 1, 2, 3, and 4, and all other variables are as defined herein.

[0631] In some embodiments, the compound is of formula (IIA-5-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 1, 2, 3, and 4, and all other variables are as defined herein.

[0632] In some embodiments, the compound is of formula (IIB-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0633] In some embodiments, the compound is of formula (IIB-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0634] In some embodiments, the compound is of formula (IIC-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0635] In some embodiments, the compound is of formula (IIC-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0636] In some embodiments, the compound is of formula (IID-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0637] In some embodiments, the compound is of formula (IID-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0638] In some embodiments, the compound is of formula (IID-1-H-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0639] In some embodiments, the compound is of formula (IID-1-H-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0640] In some embodiments, the compound is of formula (IID-1-H-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0641] In some embodiments, the compound is of formula (IID-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0642] In some embodiments, the compound is of formula (IID-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0643] In some embodiments, the compound is of formula (IID-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where b is an integer selected from 1, 2, and 3, and all other variables are as defined herein.

[0644] In some embodiments, the compound is of formula (IID-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where b is an integer selected from 1, 2, and 3, and all other variables are as defined herein.

[0645] In some embodiments, the compound is of formula (IID-3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0646] In some embodiments, the compound is of formula (IID-3-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0647] In some embodiments, the compound is of formula (IID-3-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0648] In some embodiments, the compound is of formula (IID-3-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0649] In some embodiments, the compound is of formula (IID-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0650] In some embodiments, the compound is of formula (IID-4-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0651] In some embodiments, the compound is of formula (IID-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R S is H, halogen, CN, or CH3, and all other variables are as defined herein.

[0652] In some embodiments, the compound is of formula (IID-5-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R S is H, halogen, CN, or CH3, and all other variables are as defined herein.

[0653] In some embodiments, the compound is of formula (IID-6): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R S is H, halogen, CN, or CH3, and all other variables are as defined herein.

[0654] In some embodiments, the compound is of formula (IID-6-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R S is H, halogen, CN, or CH3, and all other variables are as defined herein.

[0655] In some embodiments, the compound is of formula (IID-7): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein L is CH, O, S, NH, and all other variables are as defined herein.

[0656] In some embodiments, the compound is of formula (IID-7-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein L is CH, O, S, NH, and all other variables are as defined herein.

[0657] In some embodiments, the compound is of formula (IID-7-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0658] In some embodiments, the compound is of formula (IID-7-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0659] In some embodiments, the compound is of formula (IID-8): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where L is CH, O, S, or NH, and all other variables are as defined herein.

[0660] In some embodiments, the compound is of formula (IID-8-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where L is CH, O, S, or NH, and all other variables are as defined herein.

[0661] In some embodiments, the compound is of formula (IID-7-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0662] In some embodiments, the compound is of formula (IID-7-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0663] In some embodiments, the compound is of formula (IID-9): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0664] In some embodiments, the compound is of formula (IID-9-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0665] In some embodiments, the compound is of formula (IID-9-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0666] In some embodiments, the compound is of formula (IID-9-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0667] In some embodiments, the compound is of formula (I-II-A-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R A is selected from H and C1-C3 alkyl, and all other variables are as defined herein.

[0668] In some embodiments, the compound is of formula (I-II-A-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R A is selected from H and C1-C3 alkyl, and all other variables are as defined herein.

[0669] In some embodiments, the compound is of formula (I-II-A-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0670] In some embodiments, the compound is of formula (I-II-A-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where p is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0671] In some embodiments, the compound is of formula (I-II-A-2-H-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0672] In some embodiments, the compound is of formula (I-II-A-2-H-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0673] In some embodiments, the compound is of formula (I-II-A-2-H-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0674] In some embodiments, the compound is of formula (I-II-A-2-H-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0675] In some embodiments, the compound is of formula (I-II-A-2-H-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0676] In some embodiments, the compound is of formula (I-II-A-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein ring A is heterocyclyl or heteroaryl, v is an integer selected from 0, 1, and 2, and each R Hare independently selected from halogen, OH, ═O, CN, C1-C6 alkyl, and all other variables are as defined herein.

[0677] In some embodiments, the compound is of formula (I-II-A-3-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein ring A is heterocyclyl or heteroaryl, v is an integer selected from 0, 1, and 2, and each R H are independently selected from halogen, OH, ═O, CN, C1-C6 alkyl, and all other variables are as defined herein.

[0678] In some embodiments, the compound is of formula (I-II-A-3-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0679] In some embodiments, the compound is of formula (I-II-A-3-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0680] In some embodiments, the compound is of formula (I-II-A-3-1-H'): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0681] In some embodiments, the compound is of formula (I-II-A-3-1-H"): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0682] In some embodiments, the compound is of formula (I-II-A-3-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0683] In some embodiments, the compound is of formula (I-II-A-3-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0684] In some embodiments, the compound is of formula (I-II-A-3-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0685] In some embodiments, the compound is of formula (I-II-A-3-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0686] In some embodiments, the compound is of formula (I-II-BH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0687] In some embodiments, the compound is of formula (I-II-CH): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0688] In some embodiments, the compound is of formula (I-II-D-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R A is selected from H and C1-C3 alkyl, and all other variables are as defined herein.

[0689] In some embodiments, the compound is of formula (I-II-D-1-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, and R A is selected from H and C1-C3 alkyl, and all other variables are as defined herein.

[0690] In some embodiments, the compound is of formula (I-II-D-1-H-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0691] In some embodiments, the compound is of formula (I-II-D-1-H-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0692] In some embodiments, the compound is of formula (I-II-D-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where p is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0693] In some embodiments, the compound is of formula (I-II-D-2-H): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where p is an integer selected from 1, 2, 3, 4, and 5, and all other variables are as defined herein.

[0694] In some embodiments, the compound is of formula (I-II-D-2-H-1): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0695] In some embodiments, the compound is of formula (I-II-D-2-H-2): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0696] In some embodiments, the compound is of formula (I-II-D-2-H-3): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0697] In some embodiments, the compound is of formula (I-II-D-2-H-4): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0698] In some embodiments, the compound is of formula (I-II-D-2-H-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0699] In some embodiments, the compound is one wherein the compound is of formula (IIAM), (IIBM), (IICM), (IIDM), (I-II-AM), (I-II-BM), (I-II-CM), or (I-II-DM): [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0700] In some embodiments, the compound is a compound of formula (IIAG), (IIBG), (IICG), or (IIDG): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0701] In some embodiments, the compound is a compound of formula (I-II-AG), (I-II-BG), (I-II-CG), or (I-II-DG): [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof. In some embodiments, the compound is a compound of formula (IIAA), (IIBA), (IICA), (IIDA), (I-II-AA), (I-II-BA), (I-II-CA), or (I-II-DA): [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, wherein u is 0 or 1, and all other variables are as defined herein.

[0702] In some preferred embodiments, the compound is Compound 27: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0703] In some preferred embodiments, the compound is Compound 50: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0704] In some preferred embodiments, the compound is Compound 59: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0705] In some preferred embodiments, the compound is Compound 62: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0706] In some preferred embodiments, the compound is Compound 65: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0707] In some preferred embodiments, the compound is Compound 70: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0708] In some preferred embodiments, the compound is Compound 74: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0709] In some preferred embodiments, the compound is Compound 78: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0710] In some preferred embodiments, the compound is Compound 79: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0711] In some preferred embodiments, the compound is Compound 81: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0712] In some preferred embodiments, the compound is Compound 82: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0713] In some preferred embodiments, the compound is Compound 88: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0714] In some preferred embodiments, the compound is Compound 92: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0715] In some preferred embodiments, the compound is Compound 121: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0716] In some preferred embodiments, the compound is Compound 122: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0717] In some preferred embodiments, the compound is compound 123: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0718] In some preferred embodiments, the compound is Compound 124: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0719] In some preferred embodiments, the compound is Compound 125: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0720] In some preferred embodiments, the compound is Compound 126: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0721] In some preferred embodiments, the compound is Compound 127: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0722] In some preferred embodiments, the compound is Compound 128: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0723] In some preferred embodiments, the compound is Compound 129: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0724] In some preferred embodiments, the compound is Compound 130: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0725] In some preferred embodiments, the compound is Compound 131: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0726] In some preferred embodiments, the compound is Compound 132: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0727] In some preferred embodiments, the compound is Compound 133: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0728] In some preferred embodiments, the compound is Compound 134: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

[0729] In some embodiments, the compound is selected from the compounds set forth in Table 1, and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0730] In some embodiments, the compound is selected from the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0731] In some embodiments, the compound is selected from the compounds set forth in Table 1, and pharmaceutically acceptable salts thereof.

[0732] In some embodiments, the compound is selected from prodrugs of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0733] In some embodiments, the compound is selected from the compounds listed in Table 1.

[0734] JPEG2025511875000467.jpg237170JPEG2025511875000468.jpg238170JPEG2025511875000469.jpg238170JPEG2025511875000470.jpg238170JPEG202 5511875000471.jpg227170JPEG2025511875000472.jpg227170JPEG2025511 875000473.jpg227170JPEG2025511875000474.jpg227170JPEG20255118750 00475.jpg227170JPEG2025511875000476.jpg227170JPEG2025511875000477.jpg227170JPEG2025511875000478.jpg227170JPEG2025511875000479.j pg227170JPEG2025511875000480.jpg227170JPEG2025511875000481.jpg227170JPEG2025511875000482.jpg227170JPEG2025511875000483.jpg227170

[0735] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 1.

[0736] In some embodiments, the compound is a lithium, sodium, potassium, calcium, or magnesium salt of any one of the compounds listed in Table 1.

[0737] In some embodiments, the compound is a salt of any acid listed in Table 2 with any one of the compounds listed in Table 1.

[0738] JPEG2025511875000484.jpg251170JPEG2025511875000485.jpg15170

[0739] In some embodiments, the compound is a salt of acetic acid and any one of the compounds listed in Table 1.

[0740] In some embodiments, the compound is a salt of adipic acid and any one of the compounds listed in Table 1.

[0741] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds listed in Table 1.

[0742] In some embodiments, the compound is a salt of hydrobromic acid and any of the compounds listed in Table 1.

[0743] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds listed in Table 1.

[0744] In some embodiments, the compound is a salt of citric acid and any one of the compounds listed in Table 1.

[0745] In some embodiments, the compound is a salt of glutamic acid and any of the compounds listed in Table 1.

[0746] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds listed in Table 1.

[0747] In some embodiments, the compound is a salt of formic acid and any one of the compounds listed in Table 1.

[0748] In some embodiments, the compound is a salt of sulfuric acid and any of the compounds listed in Table 1.

[0749] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0750] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, as well as prodrugs and pharmaceutically acceptable salts thereof.

[0751] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0752] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 1 and pharmaceutically acceptable salts thereof.

[0753] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0754] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents and by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0755] In some embodiments, the isotope derivative is a deuterium-labeled compound.

[0756] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0757] The term "isotopic derivative" as used herein refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of formula (I) is isotopically enriched or labeled with one or more isotopes compared to the corresponding compound of formula (I). In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P, and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., enriched or labeled with respect to one or more atoms selected from S). 2 H).

[0758] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0759] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0760] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds listed in Table 1 and pharmaceutically acceptable salts thereof.

[0761] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds listed in Table 1.

[0762] A deuterium-labeled compound is understood to contain deuterium atoms having an abundance of deuterium substantially greater than the natural abundance of deuterium, which is 0.015%.

[0763] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation in each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" refers to the ratio of deuterium abundance to the natural abundance of deuterium.

[0764] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein by substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[0765] Compounds of the present disclosure containing the above-mentioned deuterium atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 2 H) may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0766] In some embodiments, the compound is 18 F-labeled compound.

[0767] In some embodiments, the compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135I-labeled compounds, or any combination thereof.

[0768] In some embodiments, the compound is 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 S-labeled compounds, or any combination thereof.

[0769] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It will be appreciated that S-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds generally utilize S-labeled compounds in place of non-isotopic labeling reagents. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 S-labeled reagents can be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein.

[0770] the above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and 36 Compounds of the present disclosure containing one or more S atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. 18F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 S) substitution can confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0771] For the avoidance of doubt, when a group is qualified herein by "as described herein," it is to be understood that said group encompasses the broadest definition appearing first, as well as each and every specific definition associated with that group.

[0772] The various functional groups and substituents comprising the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound is less than 900, for example, less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600, for example, 550 daltons or less, for example, 500 daltons or less, for example, 450 daltons or less.

[0773] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0774] It will be understood that compounds of any one of the formulae disclosed herein, and any pharmaceutically acceptable salts thereof, include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of said compounds.

[0775] As used herein, the term "isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0776] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0777] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds with multiple chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. Substituents attached to the chiral center are ranked according to the rules of Cahn, Ingold, and Prelog ordering. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0778] As used herein, the term "geometric isomer" refers to diastereomers that exist due to hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, which indicate groups on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

[0779] It is understood that the compounds of the present disclosure may be represented as different chiral or geometric isomers, and when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude all isomeric forms, and it is understood that not all isomers have the same level of activity.

[0780] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It should also be understood that not all atropic isomers have the same level of activity.

[0781] As used herein, the term "atropic isomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers exist because of restricted rotation of large groups around a central bond, which prevents rotation. Such atropic isomers typically exist as mixtures, but recent advances in chromatographic techniques have made it possible to separate mixtures of two atropic isomers in selected cases.

[0782] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs when an aldehyde group (-CHO) of a sugar molecule reacts with one of the hydroxyl groups (-OH) of the same molecule to give a cyclic (ring-shaped) form, as shown in glucose.

[0783] It should be understood that the compounds of the present disclosure can be represented as different tautomers. When a compound has tautomeric forms, it should also be understood that all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form. It should be understood that certain tautomers may have a higher level of activity than other tautomers.

[0784] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called diastereomers, and stereoisomers that are not superimposable mirror images of each other are called enantiomers. When a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers can exist. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light and are called dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0785] The compounds of the present disclosure may have one or more asymmetric centers; such compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemates or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or resolution of racemates (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomer centers (E-isomers and Z-isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers and mixtures thereof that have inflammasome inhibitory activity.

[0786] The present disclosure also encompasses compounds of the disclosure as defined herein that contain one or more isotopic substitutions.

[0787] It should be understood that the compounds of any formula described herein include, if applicable, the compounds themselves, as well as their salts and solvates.For example, salts can be formed between an anion on the substituted compounds disclosed herein and a positively charged group (e.g., amino).Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0788] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on the substituted compounds disclosed herein and a negatively charged group (e.g., carboxylate). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing quaternary nitrogen atoms.

[0789] It is understood that compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc., and non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0790] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amount of solvent.Some compounds tend to trap a certain molar ratio of solvent molecules in crystalline solid state to form solvates.When the solvent is water, the solvate that is formed is a hydrate; when the solvent is alcohol, the solvate that is formed is an alcoholate.Hydrate is formed by the combination of one molecule of a substance with one or more molecules of water, with water retaining its molecular state as H2O.

[0791] As used herein, the term "analog" refers to a compound that is structurally similar to another but has a slightly different composition (for example, the replacement of one atom with an atom of a different element, or the replacement of one atom with the presence of a specific functional group, or the replacement of one functional group with another functional group).Thus, an analog is a compound that is similar or equivalent in function and appearance, but different in structure or origin from the reference compound.

[0792] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0793] As used herein, the term "bioisomer" refers to a compound resulting from the exchange of an atom or group of atoms with another, broadly similar atom or group of atoms. The purpose of bioisosteric substitution is to generate a new compound with similar biological properties to the parent compound. Bioisosteric substitution can be based on physicochemical or topology. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates and phosphonates. For example, see Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0794] It should also be understood that any one particular compound of formula disclosed herein can exist in solvated form and unsolvated form, for example, hydrated form.Suitable pharmaceutically acceptable solvate is, for example, hydrate such as hemihydrate, monohydrate, dihydrate or trihydrate.It should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[0795] It should also be understood that any one particular compound of the formula disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof that have inflammasome inhibitory activity.It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy.The water content of such crystalline materials can be measured by Karl Fischer analysis.

[0796] Compounds of any one of the formulae disclosed herein can exist in many different tautomeric forms, and a reference to a compound of formula (I) or (II) includes all such forms. For the avoidance of doubt, if a compound can exist in one of several tautomeric forms and only one is specifically described or illustrated, all others are nevertheless encompassed by formula (I) or (II). Examples of tautomeric forms include keto-, enol-, and enolate-forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acid-nitro. [ka]

[0797] Compounds of any one of the formulas disclosed herein containing an amine functional group can also form N-oxides. Herein, a reference to a compound of formula (I) or (II) containing an amine functional group also includes the N-oxide. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be generated by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid); see, for example, Advanced Organic Chemistry by Jerry March, 4th Edition, Wiley Interscience, pages 1977-1980. More specifically, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with metachloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0798] The compound of any one of the formulas disclosed herein can be administered in the form of a prodrug, which is broken down in the human or animal body to release the disclosed compound.Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compound of the present disclosure.When the compound of the present disclosure contains a suitable group or substituent to which a property-modifying group can be attached, a prodrug can be formed.Examples of prodrugs include derivatives of any one of the formulas disclosed herein that contain an alkyl or acyl substituent that can be cleaved in vivo on the ester or amide group.

[0799] Thus, the present disclosure includes those compounds of any of the above-defined formulas disclosed herein when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure also includes those compounds of any of the formulas disclosed herein produced by organic synthetic means, as well as such compounds produced in the human or animal body by metabolism of precursor compounds, and the compounds of any of the formulas disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[0800] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein are those that are based on sound medical judgment and are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0801] Suitable pharmaceutically acceptable prodrugs of compounds having a hydroxy group of any of the formulas disclosed herein are, for example, their in vivo cleavable esters or ethers. In vivo cleavable esters or ethers containing a hydroxy group of compounds of any of the formulas disclosed herein are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include C1-C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 C1-C groups such as alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups 10 Examples of the ring substituents of the phenylacetyl group and the benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0802] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group include, for example, an in vivo cleavable amide thereof, an amine such as ammonia, a C group such as methylamine, 1-4 alkylamines, (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amides formed with amino acids such as glycine or its esters.

[0803] Suitable pharmaceutically acceptable prodrugs of any compound of the formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C2 acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Examples of ring substituents for the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0804] The in vivo effects of a compound of any of the formulas disclosed herein may be exerted in part by one or more metabolites formed in the human or animal body after administration of a compound of any of the formulas disclosed herein. As mentioned above, the in vivo effects of a compound of any one of the formulas disclosed herein may also be exerted by metabolism of a precursor compound (prodrug). Compound synthesis method

[0805] The compounds of the invention may be made in a variety of ways, including standard chemistry. Suitable synthetic routes are illustrated in the schemes set out below.

[0806] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as defined in part by the synthetic schemes below. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. The presence of a stereocenter in a compound of formula (I) will be recognizable by those skilled in the art by the selection process and reaction conditions and sequences. Accordingly, the present invention (unless specified in the synthesis) encompasses both possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by separation of the final product or any convenient intermediate. Separation of the final product, an intermediate, or a starting material can be affected by any suitable method known in the art, see, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0807] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of compounds

[0808] The compounds of the present invention can be prepared in many ways well known to those skilled in the art of organic synthesis.For example, the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or modifications thereof that will be understood by those skilled in the art.Suitable methods include, but are not limited to, those methods described below.The compounds of the present invention can be synthesized according to the steps outlined in General Procedure A or B, involving assembly intermediates or compounds of different sequences.The starting materials are commercially available or can be prepared by any of the known procedures reported in the literature, or as shown below. General Procedure A

[0809] In general, compounds of formula (II) can be prepared using the sequence of reactions shown in Scheme 1: Scheme 1 [ka]

[0810] All reagents may be commercially available compounds themselves or synthetic products from commercially available reagents. These reagents may be prepared using one-step or multi-step synthetic methods, including but not limited to those described in the preparation section of this specification. General Procedure B

[0811] In general, compounds of formula (I-II) can be prepared using the sequence of reactions shown in Scheme 2: Scheme 2 [ka]

[0812] A specific, non-limiting example of this procedure is R 1 ', R 2 ', or R 3 The preparation of compounds of formula I-II where ' is Br can be mentioned.

[0813] All reagents may be commercially available compounds themselves or synthetic products from commercially available reagents. These reagents may be prepared using one-step or multi-step synthetic methods, including but not limited to those described in the preparation section of this specification. General Procedure C

[0814] In general, compounds of formula (I-II) can be prepared using the sequence of reactions shown in Scheme 3: Scheme 3 [ka] PG is a suitable protecting group.

[0815] All reagents may be commercially available compounds themselves or synthetic products from commercially available reagents. These reagents may be prepared using one-step or multi-step synthetic methods, including but not limited to those described in the preparation section of this specification.

[0816] It will be apparent to those skilled in the art that any of the compounds of formula (I) obtained according to procedures A, B or C above may be subject to further transformations and modifications leading to other compounds of formula (I). Biological assays

[0817] Once compounds designed, selected, and / or optimized by the above methods are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have the expected activity, binding activity, and / or binding specificity.

[0818] Furthermore, high-throughput screening can be used to speed up the analysis using such assays. As a result, it is possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay technologies, including but not limited to those described below.

[0819] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein. Pharmaceutical Composition

[0820] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each formula described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[0821] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts.

[0822] Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Solid carriers can be one or more substances that may also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is generally a finely divided solid, in admixture with the finely divided active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding capacity in appropriate proportions and compacted into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. In addition to the active ingredient, solid preparations may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0823] Liquid preparations suitable for oral administration include emulsions, syrups, elixirs, solutions, and aqueous suspensions. These include solid preparations intended to be converted to liquid preparations immediately prior to use. Emulsions may be prepared in solutions, such as aqueous propylene glycol solutions, and may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners. Aqueous suspensions may be prepared by dispersing the finely divided active ingredient in water with a viscous agent, such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agent.

[0824] The compounds of the present invention can be formulated for parenteral administration (e.g., injection, e.g., bolus injection or continuous infusion), and can be provided in unit dosage form in ampoules, pre-filled syringes, small-volume injections, or multi-dose containers containing added preservatives.The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous media, such as solutions in aqueous polyethylene glycol.Examples of oily or non-aqueous carriers, diluents, solvents, or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulating agents such as preservatives, wetting agents, emulsifiers or suspending agents, stabilizers, and / or dispersants.Alternatively, the active ingredient can be in powder form, obtained by aseptic isolation of sterile solids or by lyophilization from a solution that is to be constituted with a suitable vehicle, such as sterilized pyrogen-free water, before use.

[0825] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, etc. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0826] The formulation of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle.The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient.Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonicity agents, viscosity / suspension agents, buffering agents, and pH adjusting agents, and mixtures thereof.

[0827] Any suitable solubility enhancer can be used, including cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0828] Any suitable chelating agent can be used, and examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[0829] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts, such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0830] In some embodiments, exemplary preservatives include quaternary ammonium salts, such as those selected from the group consisting of benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0831] The aqueous vehicle may also contain a tonicity agent to adjust tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the tonicity agent is selected from the group consisting of glycols (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0832] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycols (Carbopols—e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0833] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to a target acceptable pH range. Therefore, it is not necessary to use both an acid and a base; depending on the formulation, the mixture can be adjusted to the desired pH range by simply adding either an acid or a base.

[0834] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffer (such as boric acid or a salt thereof including disodium tetraborate), citrate buffer (such as citric acid or a salt thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0835] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0836] Oral compositions typically contain an inert diluent or an edible pharmaceutically acceptable carrier. They can also be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be mixed with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is applied to the mouth, swished, and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose, a disintegrating agent such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, orange flavoring, and the like.

[0837] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0838] In some embodiments, the pharmaceutical compositions described herein can further comprise one or more additional pharmaceutically active agents.

[0839] The compositions of the disclosure may be in a form suitable for oral use (e.g., tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or granules, syrups or elixirs), topical use (e.g., as a cream, ointment, gel, aqueous or oily solution or suspension), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by inhalation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0840] The compositions of the present disclosure can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0841] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with an LRRK2-associated condition referred to herein.

[0842] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with an LRRK2-associated condition referred to herein.

[0843] The magnitude of a dose of a compound of formula (I) for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration, in accordance with well-known medical principles. How to use

[0844] In some aspects, the present disclosure provides a method of inhibiting LRRK2 (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0845] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0846] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0847] In some embodiments, the disease or disorder is associated with LRRK2. In some embodiments, the disease or disorder is a disease or disorder in which LRRK2 is implicated.

[0848] The compounds of the present invention are also useful for treating diseases associated with LRRK2. For example, diseases and conditions treatable according to the methods of the present invention include Parkinson's disease 8, autosomal dominant (PARK8); hereditary late-onset Parkinson's disease (LOPD); spinocerebellar atrophy; Klippel-Feil syndrome 1, autosomal dominant (KFS1); autosomal dominant cerebellar ataxia (SCA); Parkinson's disease, late-onset (PD); Parkinson's disease 2, autosomal recessive juvenile (PARK2); Parkinsonism; REM sleep behavior disorder; dementia with Lewy bodies (DLB); and LRRK2. Parkinson's disease 2; Parkinson's disease 3, autosomal dominant (PARK3); early-onset Parkinson's disease; multiple system atrophy 1 (MSA1); essential tremor; movement disorder; progressive supranuclear palsy 1 (PSNP1); Klippel-Feil syndrome 1; dementia; Parkinson's disease 10 (PARK10); tremor; frontotemporal dementia (FTD); postencephalitic Parkinson's disease; vascular parkinsonism; aphasia; Parkinson's disease 1, autosomal dominant (PARK1); athetosis; Klippel-Feil syndrome Weil syndrome (KFS); Kufor-Rakeb syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer's disease 8 (AD8); Crohn's disease; Rheumatoid arthritis (RA); Alzheimer's disease (AD); Achromatopsia; Gaucher disease, type 1 (GD1); Parkinson's disease 15, autosomal recessive early-onset (PARK15); von Economo disease; Gerstmann-Sträussler disease (GSD); Amyotrophic lateral sclerosis-Parkinson's disease / dementia complex 1 (ALS-PDC1) ; dystonia; sphingolipidosis; radial nerve lesions; toxic encephalopathy; sleep disorders; Pick's disease of the brain (PIDB); ocular glomerulopathy; Gaucher disease (GD); optic atrophy with or without auditory neuropathy 7 (OPA7); ulnar nerve lesions; inflammatory bowel disease 4 (IBD4); inflammatory bowel disease; 3-methylglutaconic aciduria, type III (MGCA3); neurological disorders; amyotrophic lateral sclerosis 1 (ALS1); mitochondrial complex I deficiency, nuclear type 1 (MC1DN1).

[0849] In some embodiments, the disease or disorder is Parkinson's disease (PD).

[0850] In some aspects, the present disclosure provides a method of treating or preventing Parkinson's disease (PD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0851] In some aspects, the present disclosure provides a method of treating Parkinson's disease (PD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0852] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting LRRK2 (e.g., in vitro or in vivo).

[0853] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[0854] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0855] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing Parkinson's disease (PD) in a subject in need thereof.

[0856] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating Parkinson's disease (PD) in a subject in need thereof.

[0857] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting LRRK2 (e.g., in vitro or in vivo).

[0858] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0859] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0860] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing Parkinson's disease (PD) in a subject in need thereof.

[0861] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating Parkinson's disease (PD) in a subject in need thereof.

[0862] The present disclosure provides compounds that function as inhibitors of LRRK2 (e.g., in vitro or in vivo). Accordingly, the present disclosure provides a method of inhibiting LRRK2 in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0863] In some embodiments, the inhibitor of LRRK2 is a compound of the present disclosure.

[0864] The efficacy of the compounds of the present disclosure can be determined by industry-accepted assays / disease models as described in the art and as found in the current general knowledge.

[0865] The present disclosure also provides a method of treating a disease or disorder in which LRRK2 is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0866] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human. Route of administration

[0867] The compounds of the present disclosure or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., to the desired site of action).

[0868] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, bandages, etc.); transmucosal (including, e.g., by patches, bandages, etc.); intranasal (e.g., nasal spray); ophthalmic (e.g., by eye drops); pulmonary (e.g., through the mouth or nose, e.g., using aerosols, e.g., inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral by injection, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, intradermal, intraarticular, subarachnoid, intrasternal, etc.; [Example]

[0869] General Synthetic Procedures and Examples of Compound Preparation. All reagents were commercially available and used without further purification. Yields refer to purified and spectroscopically pure compounds. Thin-layer chromatography (TLC) was performed on Merck TLC aluminum sheets silica gel 60 F. 254The NMR spectra were obtained using a plate and visualized by fluorescence quenching under UV light. Flash chromatography was performed using silica gel (Chromatorex, MB 70-40 / 75, 40-75 μm) purchased from Fuji Silysia Chemicals. 1 Recordings were performed on a Varian-400MR operating at 400 MHz relative to H. Chemical shifts are reported in ppm using the solvent resonance as an internal standard. Data are reported as follows: s = singlet, br = broad, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, coupling constants (Hz), and integrals. Purity data were recorded on a Waters e2695 Separations Module / 2998 PDA Detector HPLC system (Column: XBridge C18, 5 μm, 4.6 mm (ID) x 150 mm (L); Eluent: Mixture of mobile phases A and B; Mobile phase A: 100% acetonitrile; Mobile phase B: Pure water containing 0.1% formic acid and 10 mM NHOAc; Flow rate: 0.5 mL / min; Detection: UV, 254 nm).

[0870] Abbreviations used in the following examples and elsewhere in this specification are as follows: JPEG2025511875000490.jpg173113JPEG2025511875000491.jpg59170Building Block Synthesis Synthesis of 5-bromo-3-chloropyridazine (P2) [ka]

[0871] Preparation 1. Methyl 5-bromo-2-[(tert-butoxycarbonyl)amino]benzoate (P1). In a sealed tube, a mixture of 3,5-dichloropyridazine (3.4 g, 22.82 mmol, 1.0 equiv) and 30% ammonium hydroxide (34 mL) was stirred at 120 °C for 16 h. The resulting precipitate was collected by filtration and washed with water and diethyl ether to give P1 (2.54 g, 86% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6), δ: 8.49 (d, J = 2.4 Hz, 1H), 6.82 (br. s, 2H), 6.65 (d, J = 2.4 Hz, 1H).

[0872] Preparation of 2.5-bromo-3-chloropyridazine (P2). To a solution of P1 (2.92 g, 22.54 mmol, 1.0 equiv.) and tert-butyl nitrite (4.02 mL, 33.81 mmol, 1.5 equiv.) in acetonitrile (60 mL) was added copper(II) bromide (7.55 g, 33.81 mmol, 1.5 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 16 h, after which the reaction mixture was treated with water and extracted three times with ethyl acetate. The combined organic layer was washed with NaSO. 4(s) The mixture was dried at 77°C, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 5:1) to give P2 (2.04 g, 47% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 9.22 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H). Synthesis of 1-(5-(5-isopropoxy-1-trityl-1H-indazol-3-yl)pyridazin-3-yl)azetidin-3-ol (P8) [ka]

[0873] Preparation 3. 5-Isopropoxy-1H-indazole (P3). To a solution of 1H-indazol-5-ol (1.00 g, 7.46 mmol, 1.0 equiv) in DMF (10 mL) was added cesium carbonate (2.91 g, 8.95 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 15 minutes. 2-Iodopropane (0.89 mL, 8.95 mmol, 1.2 equiv) was added to the reaction, and the mixture was stirred at room temperature for 16 hours. The mixture was treated with water and extracted three times with ethyl acetate. The combined organic layers were washed with NaSO. 4(s) The mixture was dried at rt, filtered, and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (n-hexane: EtOAc 3:1) to give P3 (876 mg, 67% yield) as an orange solid. 1 H NMR (400 MHz, DMSO-d6), δ: 12.86 (br. s, 1H), 7.92-7.90 (m, 1H), 7.41 (d, J = 9.0 Hz,1H), 7.17 (d, J = 2.2 Hz, 1H), 6.96 (dd, J = 9.0, 2.2 Hz, 1H), 4.56 (septet, J = 6.0 Hz, 1H), 1.27 (d, J = 6.0 Hz, 6H).

[0874] Preparation 4. 3-Iodo-5-isopropoxy-1H-indazole (P4). To a solution of P3 (872 mg, 4.95 mmol, 1.0 equiv.) in acetonitrile (21 mL) was added potassium carbonate (1.37 g, 9.90 mmol, 2.0 equiv.) and iodine (1.88 g, 7.42 mmol, 1.5 equiv.). The solution was stirred at room temperature for 16 h, after which the mixture was diluted with saturated NaSO. 3(aq) The mixture was quenched with ethyl acetate and extracted three times with ethyl acetate. The combined organic layer was washed with NaSO 4(s) The extract was dried at rt, filtered, and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (n-hexane: EtOAc = 5:1) to give P4 (1.48 g, 99% yield) as an orange foam. 1H NMR (400 MHz, DMSO-d6), δ: 13.34 (br. s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 8.8, 2.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 4.63 (septet, J = 6.0 Hz, 1H), 1.28 (d, J = 6.0 Hz, 6H).

[0875] Preparation 5. 3-Iodo-5-isopropoxy-1-trityl-1H-indazole (P5). To a solution of 60% sodium hydride (235.12 mg, 5.88 mmol, 1.2 equiv) in mineral oil in anhydrous THF (10 mL) at 0 °C was added a solution of P4 (1.48 g, 4.90 mmol, 1.0 equiv) in anhydrous THF (11 mL). The reaction mixture was stirred at 0 °C for 30 min, and then TrCl (1.50 g, 5.39 mmol, 1.1 equiv) was added in one portion. The reaction mixture was allowed to warm slowly and stirred at room temperature for 16 h. The reaction was quenched with water and extracted three times with diethyl ether. The combined organic layers were washed with NaSO. 4(s) The extract was dried at 47°C, filtered, and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (n-hexane: EtOAc = 6:1) to give P5 (2.56 g, 96% yield) as an orange solid. 1 H NMR (400 MHz, CDCl3), δ: 7.32-7.28 (m, 2H), 7.28-7.26 (m, 3H), 7.26-7.24 (m, 5H), 7.22-7.19 (m, 6H), 6.74 (d, J = 2.6 Hz, 1H), 6.65 (dd, J = 9.4, 2.6 Hz, 1H), 6.22 (d, J = 9.4 Hz, 1H), 4.55 (septet, J = 6.0 Hz, 1H), 1.34 (d, J = 6.0 Hz, 6H).

[0876] Preparation 6. 5-Isopropoxy-3-(trimethylstannyl)-1-trityl-1H-indazole (P6). A solution of P5 (1.55 g, 2.85 mmol, 1.0 equiv.) and hexamethyldistannane (0.86 mL, 4.27 mmol, 1.5 equiv.) in 1,4-dioxane (26 mL) was degassed with argon for 10 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (263.2 mg, 0.228 mmol, 0.08 equiv.). The reaction mixture was stirred at 100 °C for 16 hours. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layer was washed with NaSO. 4(s) The mixture was dried at rt, filtered and concentrated in vacuo to give the product P6, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3), δ: 7.35-7.29 (m, 5H), 7.25-7.22 (m, 7H), 7.19 - 7.16 (m, 4H), 7.01 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 9.2, 2.4 Hz, 1H), 6.21 (d, J = 9.2 Hz, 1H), 4.46 (septet, J = 6.0 Hz, 1H), 1.33 (d, J = 6.0 Hz, 6H), 0.35 (s, 9H).

[0877] Preparation 7. 3-(6-chloropyridazin-4-yl)-5-isopropoxy-1-trityl-1H-indazole (P7). A solution of crude P6 (2.85 mmol, 1.0 equiv.) and 5-bromo-3-chloropyridazine (P2, 991.23 mg, 5.12 mmol, 1.8 equiv.) in anhydrous toluene (70 mL) was degassed with argon for 10 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (263.2 mg, 0.228 mmol, 0.08 equiv.), and the reaction mixture was stirred at 110 °C for 16 hours. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layers were washed with NaSO. 4(s) The extract was dried at 77°C, filtered, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (n-hexane: EtOAc = 20:1 to 10:1) to give P7 (660 mg, 44% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3), δ: 9.64 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.32-7.28 (m, 10H), 7.19-7.16 (m, 6H), 6.72 (dd, J = 9.4, 2.4 Hz, 1H), 6.40 (d, J = 9.4 Hz, 1H), 4.58 (septet, J = 6.0 Hz, 1H), 1.37 (d, J = 6.0 Hz, 6H).

[0878] Preparation 8. 3-(6-chloropyridazin-4-yl)-5-isopropoxy-1-trityl-1H-indazole (P8). To a solution of P7 (120.0 mg, 0.226 mmol, 1.0 equiv) in DMSO (1.1 mL) was added triethylamine (0.19 mL, 1.36 mmol, 6.0 equiv) and 3-hydroxyazetidine hydrochloride (74.3 mg, 0.678 mmol, 3.0 equiv). The reaction mixture was stirred at 120 °C for 16 h. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layer was washed with NaSO 4(s) The extract was dried at 47°C, filtered, and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (dichloromethane:MeOH=30:1) to give P8 (47 mg, 37% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 9.15 (d, J = 1.6 Hz, 1H), 7.30-7.27 (m, 10H), 7.21-7.17 (m, 6H), 6.94 (d, J = 2.2 Hz, 1H), 6.68 (dd, J = 9.2, 2.2 Hz, 1H), 6.35 (d, J = 9.2 Hz, 1H), 4.89-4.86 (m, 1H), 4.54 (septet, J = 6.0 Hz, 1H), 4.47-4.43 (m, 2H), 4.05-4.01 (m, 2H), 1.35 (d, J = 6.0 Hz, 6H). Synthesis of (R)-1-(5-(5-isopropoxy-1-trityl-1H-indazol-3-yl)pyridazin-3-yl)pyrrolidin-3-ol (P9) [ka]

[0879] Preparation 9. (R)-1-(5-(5-isopropoxy-1-trityl-1H-indazol-3-yl)pyridazin-3-yl)pyrrolidin-3-ol (P9) To a solution of P7 (120.0 mg, 0.23 mmol, 1.0 equiv) in DMSO (1.1 mL) was added triethylamine (0.2 mL, 1.36 mmol, 6.0 equiv) and (R)-pyrrolidin-3-ol (0.055 mL, 0.68 mmol, 3.0 equiv). The reaction mixture was stirred at 110 °C for 16 h. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layer was washed with NaSO 4(s) The residue was dried at 77°C, filtered, and concentrated in vacuo to give a residue that was purified by C-18 reverse-phase column chromatography (mobile phase A: water (containing NH4HCO3), mobile phase B: methanol, UV: 214 and 254 nm, flow rate: 30 mL / min, gradient: 3 to 90% (% B)) to give P9 (113 mg, 86% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 9.07 (d, J = 1.8 Hz, 1H), 7.32-7.24 (m, 10H), 7.20-7.14 (m, 6H), 7.03 (d, J = 1.8 Hz, 1H), 6.66 (dd, J = 9.2, 2.4 Hz, 1H), 6.33 (d, J = 9.2 Hz, 1H), 4.69-4.65 (m, 1H), 4.52 (septet, J = 6.0 Hz, 1H), 3.78-3.63 (m, 4H), 2.23 - 2.11 (m, 2H), 1.33 (d, J = 6.0 Hz, 6H). Synthesis of 5-isopropoxy-3-(6-(3-methylpyrrolidin-1-yl)pyridazin-4-yl)-1-trityl-1H-indazole (P10) [ka]

[0880] Preparation 10. 5-Isopropoxy-3-(6-(3-methylpyrrolidin-1-yl)pyridazin-4-yl)-1-trityl-1H-indazole (P10) To a solution of P7 (120.0 mg, 0.23 mmol, 1.0 equiv) in DMSO (1.1 mL) was added triethylamine (0.2 mL, 1.36 mmol, 6.0 equiv) and 3-methylpyrrolidine hydrochloride (82.4 mg, 0.678 mmol, 3.0 equiv). The reaction mixture was stirred at 120 °C for 24 h. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layer was washed with NaSO 4(s) The extract was dried at 47°C, filtered, and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (n-hexane: EtOAc = 2:1) to give P10 (66 mg, 50% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 9.06 (d, J = 1.8 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.31-7.27 (m, 8H), 7.22 -7.16 (m, 7H), 7.01 (d, J = 1.8 Hz, 1H), 6.68 (dd, J = 9.2, 2.2 Hz, 1H), 6.34 (d, J = 9.2 Hz, 1H), 4.54 (septet, J = 6.0 Hz, 1H), 3.81-3.74 (m, 1H), 3.73-3.66 (m, 1H), 3.57-3.50 (m, 1H), 3.15-3.09 (m, 1H), 2.49-2.40 (m, 1H), 2.23-2.15 (m, 1H), 1.72-1.66 (m, 1H), 1.35 (d, J = 6.0 Hz, 6H), 1.17 (d, J = 6.8 Hz, 3H). Synthesis of 4-(5-(5-isopropoxy-1-trityl-1H-indazol-3-yl)pyridazin-3-yl)morpholine (P11) [ka]

[0881] Preparation 11. 4-(5-(5-Isopropoxy-1-trityl-1H-indazol-3-yl)pyridazin-3-yl)morpholine (P11) To a solution of P7 (50.0 mg, 0.094 mmol, 1.0 equiv) in DMSO (0.50 mL) was added triethylamine (0.079 mL, 0.56 mmol, 6.0 equiv) and morpholine (0.025 mg, 0.28 mmol, 3.0 equiv). The reaction mixture was stirred at 110 °C for 16 h. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layer was washed with NaSO 4(s) The extract was dried at 47°C, filtered, and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (n-hexane: EtOAc = 2:1) to give P11 (40 mg, 73% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 9.19 (d, J = 1.6 Hz, 1H), 7.34-7.27 (m, 10H), 7.22-7.15 (m, 7H), 6.69 (dd, J = 9.2, 2.4 Hz, 1H), 6.36 (d, J = 9.6 Hz, 1H), 4.55 (septet, J = 6.0 Hz, 1H), 3.90-3.85 (m, 4H), 3.68-3.64 (m, 4H), 1.35 (d, J = 6.0 Hz, 6H). Synthesis of 5-isopropoxy-3-(6-(pyrrolidin-1-yl)pyridazin-4-yl)-1-trityl-1H-indazole (P12) [ka]

[0882] Preparation 12. 5-Isopropoxy-3-(6-(pyrrolidin-1-yl)pyridazin-4-yl)-1-trityl-1H-indazole (P12) To a solution of P7 (240.0 mg, 0.45 mmol, 1.0 equiv) in DMSO (2.0 mL) was added triethylamine (0.4 mL, 2.71 mmol, 6.0 equiv) and pyrrolidine (0.110 mL, 1.36 mmol, 3.0 equiv). The reaction mixture was stirred at 110 °C for 16 h. The solution was cooled to room temperature, treated with water, and extracted three times with ethyl acetate. The combined organic layer was washed with NaSO 4(s) The mixture was dried at rt, filtered, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (n-hexane: EtOAc = 1:1) to give P12 (205 mg, 80% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 9.07 (s, 1H), 7.34-7.29 (m, 6H), 7.26-7.15 (m, 10H), 7.04 (s, 1H), 6.68 (d, J = 9.4 Hz, 1H), 6.35 (d, J = 9.4 Hz, 1H), 4.54 (septet, J = 6.0 Hz, 1H), 3.58 (br. m, 4H), 2.10-2.04 (m, 4H), 1.35 (d, J = 6.0 Hz, 6H). Synthesis of 4-(6-chloro-3-methylpyridazin-4-yl)morpholine (P16) [ka]

[0883] Preparation 13. Phenylhydrazine carboxylate (P13). To a solution of diphenyl carbonate (15.0 g, 70.0 mmol) in DCM (230 mL) was added hydrazine hydrate (6.80 g, 140 mmol), which was stirred at room temperature overnight. The reaction was concentrated to remove the solvent. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate in n-hexane) to give P13 (5.5 g, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 8.73 (br. s, 1H), 7.38-7.34 (m, 2H), 7.21-7.16 (m, 1H), 7.06 (d, J = 7.6 Hz, 2H), 4.21 (br. s, 2H).

[0884] Preparation 14. Phenyl (E)-2-(3-oxobutan-2-ylidene)hydrazine-1-carboxylate (P14). To a solution of P13 (5.5 g, 36.1 mmol) in methanol (120 mL) was added 2,3-butanedione (3.40 g, 39.7 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated to give crude product P14 (7.9 g, 99%) as a white solid. 1 H NMR (400 MHz, DMSO-d6), δ: 11.13 (br. s, 1H), 7.46-7.42 (m, 2H), 7.30-7.23 (m, 2H), 2.32 (s, 3H), 1.96 (s, 3H).

[0885] Preparation 15. 6-Methyl-5-morpholinopyridazin-3(2H)-one (P15). To a solution of P14 (1.0 g, 4.5 mmol) in benzotrifluoride (9 mL) was added pivalic acid (1.10 mL, 13.6 mmol), magnesium sulfate (540 mg, 4.50 mmol), and morpholine (91 mg, 0.90 mmol). The reaction was stirred at 175 °C under microwave irradiation for 2 h. The reaction was filtered through a pad of Celite, washed with dichloromethane, and the filtrate was concentrated to remove the solvent. The residue was purified by silica gel chromatography (0–10% methanol in dichloromethane) to give P15 (400 mg, 45%) as a brown solid. 1 H NMR (400 MHz, CDCl3), δ: 11.00 (br. s, 1H), 6.17 (s, 1H), 3.84 (t, J = 4.6 Hz, 4H), 3.01 (t, J = 4.6 Hz, 4H), 2.31 (s, 3H).

[0886] Preparation 16. 4-(6-chloro-3-methylpyridazin-4-yl)morpholine (P16). A solution of 6-methyl-5-morpholinopyridazin-3(2H)-one (P15, 110 mg, 0.56 mmol) in POCl (5 mL) was refluxed overnight. The reaction was cooled and concentrated. The residue was diluted with ethyl acetate (100 mL) and washed with water (200 mL) and brine (200 mL). The organic layer was purified by filtration with NaSO. 4(s) The mixture was dried at rt, filtered and concentrated to give the crude product (P16, 90 mg, 75% yield). 1 H NMR (400 MHz, CDCl3), δ: 6.81 (s, 1H), 3.87 (t, J = 4.8 Hz, 4H), 3.08 (t, J = 4.8 Hz, 4H), 2.61 (s, 3H). Synthesis of 4-(6-(5-isopropoxy-1-trityl-1H-indazol-3-yl)-3-methylpyridazin-4-yl)morpholine (P17) [ka]

[0887] Preparation 17. 4-(6-(5-Isopropoxy-1-trityl-1H-indazol-3-yl)-3-methylpyridazin-4-yl)morpholine (P17). To a solution of P6 (400 mg, crude product) in dioxane (5.0 mL) at room temperature was added P16 (90 mg, 0.42 mmol) and Pd(PPh3)4 (50 mg, 0.04 mmol). The reaction was stirred overnight at 100 °C under an argon atmosphere. After it was cooled to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was concentrated. The residue was purified by preparative TLC (n-hexane: EtOAc = 1:1) to give P17 (40 mg, 19% yield). 1H NMR (400 MHz, CDCl3), δ: 8.20 (d, J = 2.4 Hz, 1H), 7.52 (s, 1H), 7.31-7.27 (m, 9H), 7.22-7.20 (m, 6H), 6.65 (dd, J = 2.8, 9.4 Hz, 1H), 6.23 (d, J = 9.4 Hz, 1H), 4.75-4.69 (m, 1H), 3.89-3.87 (m, 4H), 3.05-3.03 (m, 4H), 2.69 (s, 3H), 1.34 (d, J = 6.0 Hz, 6H). Synthesis of 3-bromo-5-isopropoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (P19) [ka]

[0888] Preparation 18. 3-Bromo-5-isopropoxy-1H-indazole (P18). To a solution of 5-isopropoxy-1H-indazole (P3, 3.0 g, 17 mmol) in DCM (30 mL) was added N-bromosuccinimide (3.32 g, 18.8 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The reaction was directly concentrated and purified by silica gel column chromatography (n-hexane: EtOAc = 1:1) to give P18 (4.11 g, 95% yield). 1 H NMR (400 MHz, CDCl3), δ: 10.37 (br. s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.10 (dd, J = 9.0, 2.4 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 4.62 (septet, J = 6.0 Hz, 1H), 1.38 (d, J = 6.0 Hz, 6H).

[0889] Preparation 19. 3-Bromo-5-isopropoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (P19). To a solution of P18 (4.11 g, 16.2 mmol) in DMF (40 mL) at 0 °C was added 60% NaH in mineral oil (780 mg, 19.4 mmol) under an argon atmosphere. The reaction was stirred at 0 °C for 1 h. To the reaction was added 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl, 3.42 mL, 19.4 mmol) at 0 °C. After the mixture was stirred at room temperature for 2 h, the solution was poured into water and extracted with EtOAc. The organic phase was evaporated under MgSO 4(s) The residue was purified by silica gel column (n-hexane:DCM=2:1) ​​to give P19 (4.75 g, 76% yield). 1 H NMR (400 MHz, CDCl3), δ: 7.46 (d, J = 9.0 Hz, 1H), 7.11 (dd, J = 9.0, 2.4 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 5.64 (s, 2H), 4.60 (septet, J = 6.0 Hz, 1H), 3.57-3.53 (m, 1H), 1.38 (d, J = 6.0 Hz, 6H), 0.89-0.85 (m, 2H), -0.06 (s, 9H). Synthesis of 4-(5-(5-isopropoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1,2,4-triazin-3-yl)morpholine (P24) [ka]

[0890] Preparation 20. 3-(Methylthio)-1,2,4-triazin-5(2H)-one (P20). To a solution of 3-mercapto-1,2,4-triazin-5(4H)-one (1.66 g, 12.8 mmol) in ethanol (83 mL) was added methyl iodide (1.60 mL, 25.6 mmol) and sodium hydroxide (620 mg, 15.5 mmol) at room temperature. The reaction was stirred at 40 °C overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic phase was evaporated under reduced pressure. 4(s)The residue was purified by silica gel column (methanol:DCM=20:1) to give P20 (556 mg, 31% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 7.58 (br. s, 1H), 2.46 (s, 3H).

[0891] Preparation 21. 3-Morpholino-1,2,4-triazin-5(4H)-one (P21). To a solution of P20 (190 mg, 1.33 mmol) in THF (7.0 mL) was added morpholine (340 mg, 3.98 mmol) at room temperature. The reaction was stirred under reflux overnight. After cooling to 0 °C for 30 min, the resulting solid was collected by filtration and washed with EtOAc. The filter cake was dried under high vacuum to give P21 (190 mg, 79% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 12.51 (br. s, 1H), 7.31 (s, 1H), 3.65-3.62 (m, 4H), 3.54-3.51 (m, 4H).

[0892] Preparation 22. 4-(5-chloro-1,2,4-triazin-3-yl)morpholine (P22). To a solution of triphenylphosphine (432 mg, 1.65 mmol) in dioxane (20 mL) was added N-chlorosuccinimide (220 mg, 1.65 mmol) at room temperature. After the mixture was stirred at room temperature for 30 minutes, P21 (100 mg, 0.55 mmol) was added, and the reaction mixture was stirred under reflux for 1 hour. The reaction was cooled to 0 °C, and triethylamine (110 mg, 1.10 mmol) was added. The mixture was stirred at 0 °C for an additional 1 hour. The reaction mixture was concentrated and purified by silica gel column chromatography (n-hexane: EtOAc = 3:1) to give P22 (100 mg, 91% yield). 1 H NMR (400 MHz, DMSO-d6), δ: 7.34 (s, 1H), 3.65-3.63 (m, 4H), 3.55-3.53 (m, 4H).

[0893] Preparation 23. 4-(5-(trimethylstannyl)-1,2,4-triazin-3-yl)morpholine (P23). To a solution of P22 (100 mg, 0.50 mmol) in dioxane (5.0 mL) at room temperature under an argon atmosphere were added hexamethylditin (250 mg, 0.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol). The reaction was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was concentrated to give P23 (100 mg, crude), which was used in the next step without purification.

[0894] Preparation 24. 4-(5-(5-Isopropoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1,2,4-triazin-3-yl)morpholine (P24). To a solution of P23 (100 mg) in dioxane (5.0 mL) at room temperature under an argon atmosphere was added P19 (211 mg, 0.55 mmol) and tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol). The reaction mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane: EtOAc = 3:1) to give P24 (30 mg, 12% yield). 1 H NMR (400 MHz, CDCl3), δ: 9.37 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.14 (dd, J = 2.2, 9.0 Hz, 1H), 5.78 (s, 2H), 4.57 (septet, J = 6.0 Hz, 1H), 4.05-4.02 (m, 4H), 3.89-3.87 (m, 4H), 3.61-3.57 (m, 2H), 1.41 (d, J = 6.0 Hz, 6H), 0.93-0.89 (m, 2H), -0.06 (s, 9H). Synthesis of 6-(5-isopropoxy-1-trityl-1H-indazol-3-yl)-2-methyl-4-morpholinopyridazin-3(2H)-one (P29) [ka]

[0895] Preparation 25. Methyl 4-bromo-6-chloropyridazin-3(2H)-one (P25). To a solution of sodium nitrite (7.94 g, 115 mol) in concentrated sulfuric acid (130 mL) was added a solution of 4-bromo-6-chloropyridazin-3-amine (20.00 g, 95.95 mol) in acetic acid (440 mL) in an ice bath. The mixture was stirred at room temperature until the solution became clear, and then water (660 mL) was added to the mixture. After stirring the solution at room temperature for 2 days, the precipitate was collected by filtration and washed with water to give P25 (15.00 g, 75%) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3), δ: 7.68 (s, 1H).

[0896] Preparation 26. 3-[6-(2,2,2-trifluoroethyl)quinazolin-4-yl]-3,9-diazaspiro[5.5]undecane (P26). To a solution of P25 (15.00 g, 71.62 mmol) and cesium carbonate (35.30 g, 108.0 mmol) in DMF (115 mL) was added iodomethane (6.70 mL, 108 mmol) in an ice bath. After stirring the reaction at room temperature overnight, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–30% EtOAc in n-hexane) to give P26 (9.79 g, 61%) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 7.62 (s, 1H), 3.80 (s, 3H).

[0897] Preparation 27. 6-Chloro-2-methyl-4-morpholinopyridazin-3(2H)-one (P27). To a solution of P26 (1.5 g, 6.71 mmol) in 1,4-dioxane (56 mL) was added morpholine (0.60 mL, 6.7 mmol), cesium carbonate (4.37 g, 13.4 mmol), and Xantphos (388 mg, 0.67 mmol). Argon was bubbled through the mixture for 15 min, tris(dibenzylideneacetone)dipalladium(0) (307 mg, 0.34 mmol) was added, and the solution was stirred at 80 °C overnight. The mixture was filtered through a pad of Celite. The filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-20% EtOAc in n-hexane) to give P27 (1.23 g, 80%) as an orange oil. 1 H NMR (400 MHz, CDCl3), δ: 6.23 (s, 1H), 3.84 (dd, J = 5.7, 4.0 Hz, 4H), 3.70 (s, 3H), 3.52 (dd, J = 5.7, 4.0 Hz, 4H).

[0898] Preparation 28. (1-Methyl-5-morpholino-6-oxo-1,6-dihydropyridazin-3-yl)boronic acid (P28). To a solution of P27 (1.20 g, 5.23 mmol) in 1,4-dioxane (60 mL) was added bis(pinacolato)diboron (6.63 g, 26.12 mmol) and potassium acetate (1.026 g, 10.45 mmol). Argon was bubbled through the mixture for 15 minutes. XPhos (500 mg, 1.05 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (382 mg, 0.52 mmol) were added to the mixture. Argon was bubbled through the solution for 15 minutes. After stirring the mixture at 50 °C for 16 hours, the solution was filtered through a pad of Celite, and the filtrate was concentrated to give crude product P28, which was used in the next step without further purification.

[0899] Preparation 29. 6-(5-Isopropoxy-1-trityl-1H-indazol-3-yl)-2-methyl-4-morpholinopyridazin-3(2H)-one (P29). To a solution of P28 (5.23 mmol) in DME (50 mL) was added P5 (2.37 g, 4.35 mmol) and potassium phosphate (2 M aqueous solution, 2.77 g, 13.1 mmol). Argon was bubbled through the mixture for 15 minutes. [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (356 mg, 0.44 mol) was added to the solution. After stirring the reaction at 90 °C overnight, the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0–30% EtOAc in n-hexane) to give 4.6 g of P29. 1 H NMR (400 MHz, CDCl3), δ: 7.79 (d, J = 2.4 Hz, 1H), 7.29-7.26 (m, 8H), 7.20-7.17 (m, 7H), 7.06 (s, 1H), 6.65 (dd, J = 9.2, 2.4 Hz, 1H)), 6.21 (d, J = 9.2 Hz, 1H), 4.59 (septet, J = 6.0 Hz, 1H), 3.88 (s, 3H), 3.88-3.84 (m, 4H), 3.43-3.40 (m, 4H), 1.37 (d, J = 6.0 Hz, 6H). Synthesis of 3-iodo-4-isopropoxy-1-trityl-1H-indazole (P32) [ka]

[0900] Preparation 30. 4-Isopropoxy-1H-indazole (P30). To a solution of 1H-indazol-4-ol (3.0 g, 22.3 mmol, 1.0 equiv.) in DMF (29 mL) was added 2-iodopropane (2.60 mL, 26.8 mmol, 1.2 equiv.) and cesium carbonate (8.71 g, 26.8 mmol, 1.2 equiv.). The reaction was stirred at room temperature for 16 hours. The reaction was treated with water and extracted three times with ethyl acetate. The combined organic layer was washed with NaSO. 4(s) The mixture was dried at rt, filtered, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (0–100% ethyl acetate in n-hexane) to give P30 (3.2 g, 87% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 9.99 (br. s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.29-7.25 (m, 1H), 7.04-7.01 (m, 1H), 6.50-6.48 (m, 1H), 4.75 (septet, J = 6.0 Hz, 1H), 1.43 (d, J = 6.0 Hz, 6H).

[0901] Preparation 31. 3-Iodo-4-isopropoxy-1H-indazole (P31). To a solution of P30 (3.2 g, 18.0 mmol, 1.0 equiv.) in acetonitrile (90 mL) was added potassium carbonate (4.9 g, 36.0 mmol, 2.0 equiv.) and iodine (6.8 g, 27.0 mmol, 1.5 equiv.). The reaction was stirred at room temperature for 16 h. The mixture was diluted with NaSO. 3(aq) The mixture was quenched with ethyl acetate and extracted three times with ethyl acetate. The combined organic layers were washed with NaSO 4(s) The mixture was dried at 77°C, filtered, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (0–50% ethyl acetate in n-hexane) to give P31 (2.0 g, 37% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3), δ: 10.28 (br. s, 1H), 7.29-7.25 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 4.73 (septet, J = 6.0 Hz, 1H)), 1.47 (d, J = 6.0 Hz, 6H).

[0902] Preparation 32. 3-Iodo-4-isopropoxy-1-trityl-1H-indazole (P32). To a solution of P31 (2.0 g, 6.6 mmol, 1.0 equiv) in THF (33 mL) was added sodium hydride (190 mg, 7.9 mmol, 1.2 equiv) and TrCl (2.0 g, 7.2 mmol, 1.1 equiv) at 0 °C. The reaction was stirred at room temperature for 16 h. The mixture was quenched with water and extracted three times with ether. The combined organic layer was diluted with NaSO 4(s) The mixture was dried at 77°C, filtered, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (0–50% ethyl acetate in n-hexane) to give P32 (3.3 g, 92% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3), δ: 7.25-7.23 (m, 8H), 7.21-7.17 (m, 7H), 6.84-6.80 (m, 1H), 6.34 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.67 (septet, J = 6.0 Hz, 1H), 1.45 (d, J = 6.0 Hz, 6H). Synthesis of 6-(4-isopropoxy-1-trityl-1H-indazol-3-yl)-2-methyl-4-morpholinopyridazin-3(2H)-one (P33) [ka]

[0903] Preparation 33. 6-(4-Isopropoxy-1-trityl-1H-indazol-3-yl)-2-methyl-4-morpholinopyridazin-3(2H)-one (P33). To a solution of (1-methyl-5-morpholino-6-oxo-1,6-dihydropyridazin-3-yl)boronic acid (P28, 2.20 mmol) in DME (20 mL) was added 3-iodo-4-isopropoxy-1-trityl-1H-indazole (P32, 1.00 g, 1.84 mmol) and potassium phosphate (2 M in HO, 2.75 mL, 5.51 mmol). Argon was bubbled through the mixture for 15 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (150 mg, 0.184 mmol) was added to the mixture, which was then degassed with argon. After stirring the mixture at 90 °C overnight, the solution was treated with EtOAc and filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-50% EtOAc in n-hexane) to give P33 (812 mg, 72%) as a brown solid. 1 H NMR (400 MHz, CDCl3), δ: 7.26-7.19 (m, 15H), 6.88 (dd, J = 8.4, 7.8 Hz, 1H), 6.79 (s, 1H), 6.42 (d, J = 7.8 Hz, 1H), 6.02 (d, J = 8.4 Hz, 1H), 4.766 (septet, J = 6.0 Hz, 1H), 3.89-3.82 (m, 7H), 3.47-3.39 (m, 4H), 1.34 (d, J = 6.0 Hz, 6H). Synthesis of 4-(2,7-diazaspiro[3.5]non-2-yl)-6-(2,2,2-trifluoroethyl)cinnoline (P35) [ka]

[0904] Preparation 34. 6-Bromo-1-(6-chloropyridazin-4-yl)-1H-indazole (P34). To a solution of 6-bromo-1H-indazole (100.0 mg, 0.508 mmol, 1.0 equiv) in DMF (1.0 mL) was added P2 (147.3 mg, 0.761 mmol, 1.5 equiv), copper(I) iodide (19.3 mg, 0.102 mmol, 0.2 equiv), and potassium phosphate tribasic (215.5 mg, 1.02 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 5 minutes and then at 130 °C for 16 hours. After cooling to room temperature, the solution was treated with water and extracted three times with DCM. The combined organic layers were washed with NaSO. 4(s) The mixture was dried at rt, filtered, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (n-hexane: EtOAc = 6:1 to 5:1) to give P34 (62 g, 39% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 9.78 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 0.8 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 8.4, 0.8 Hz, 1H), 7.52 (dd, J = 8.4, 1.6 Hz, 1H).

[0905] Preparation 35. 6-Bromo-1-(6-(pyrrolidin-1-yl)pyridazin-4-yl)-1H-indazole (P35). To a solution of P34 (62.0 mg, 0.20 mmol, 1.0 equiv) in DMSO (1.0 mL) was added triethylamine (0.17 mL, 1.20 mmol, 6.0 equiv) and pyrrolidine (0.05 mL, 0.60 mmol, 3.0 equiv). The solution was stirred at 110 °C for 16 h and, after cooling to room temperature, treated with water and extracted three times with DCM. The combined organic layer was diluted with NaSO. 4(s) The extract was dried at 77° C., filtered, and concentrated in vacuo to give a residue which was purified by silica gel chromatography (DCM:MeOH=50:1) to give P35 (58 mg, 84% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3), δ: 9.08 (d, J = 2.2 Hz, 1H), 8.23 ​​(s, 1H), 8.08 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 3.68-3.61 (m, 4H), 2.14-2.07 (m, 4H). Synthesis of 2-(1-(6-chloropyridazin-4-yl)-1H-indazol-6-yl)-2-methylpropanenitrile (P36) [ka]

[0906] Preparation 36. 2-(1-(6-chloropyridazin-4-yl)-1H-indazol-6-yl)-2-methylpropanenitrile (P36). To a solution of 2-(1H-indazol-6-yl)-2-methylpropanenitrile (185 mg, 1 mmol) and 3,5-dichloropyridazine (148 mg, 1 mmol) in 2 mL of DMF was added 40 mg of NaH (60% in mineral oil, 1 mmol) in one portion while stirring at room temperature. The reaction mixture was stirred at room temperature for 8 h and then poured into cold water (50 mL). The precipitate was filtered and dried under reduced pressure. Yield of P36: 150 mg (53%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min, retention time 1.52 min). MS (ESI) m / z: 298.5 [M + H] + . 1 H NMR (400 MHz, DMSO-d6), δ: 9.91 (d, J = 2.2 Hz, 1H), 8.66 (s, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.5, 1.5 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 1.80 (s, 6H). Synthesis of 1-(1-(6-chloropyridazin-4-yl)-1H-indazol-6-yl)cyclohexanecarbonitrile (P37) [ka]

[0907] Preparation 37. 1-[1-(6-chloropyridazin-4-yl)indazol-6-yl]cyclohexanecarbonitrile (P37). To a solution of 1-(1H-indazol-6-yl)cyclohexanecarbonitrile (225 mg, 1 mmol) and 3,5-dichloropyridazine (148 mg, 1 mmol) in 2 mL of DMF was added 40 mg of NaH (60% in mineral oil, 1 mmol) in one portion while stirring at room temperature. The reaction mixture was stirred at room temperature for 8 h and then poured into cold water (50 mL). The resulting precipitate was filtered and dried under reduced pressure. Yield of P37: 240 mg (71%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min, retention time 1.76 min). MS (ESI) m / z: 338.5 [M + H] + . 1 H NMR (400 MHz, DMSO-d6), δ: 9.91 (d, J = 2.2 Hz, 1H), 8.66 (s, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 2.21 (d, J = 12.9 Hz, 2H), 2.07-2.00 (m, 2H), 1.91-1.88 (d, 2H), 1.80-1.64 (m, 3H), 1.42-1.32 (m, 1H). Synthesis of 1-[1-(6-chloropyridazin-4-yl)indazol-6-yl]cyclopentanecarbonitrile (P38) [ka]

[0908] Preparation 38. 1-[1-(6-chloropyridazin-4-yl)indazol-6-yl]cyclopentanecarbonitrile (P38). To a solution of 1-(1H-indazol-6-yl)cyclopentanecarbonitrile (211 mg, 1 mmol) and 3,5-dichloropyridazine (148 mg, 1 mmol) in 2 mL of DMF was added 40 mg of NaH (60% in mineral oil, 1 mmol) in one portion while stirring at room temperature. The reaction mixture was stirred at room temperature for 8 h and then poured into cold water (50 mL). The resulting precipitate was filtered and dried under reduced pressure. The yield of P38 was 241 mg (74%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min, retention time 1.65 min). MS (ESI) m / z: 324.5 [M + H] + . 1 H NMR (400 MHz, DMSO-d6), δ: 9.90 (d, J = 2.2 Hz, 1H), 8.67 (s, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 2.60-2.55 (m, 2H), 2.29-2.21 (m, 2H), 1.98-1.95 (m, 4H). Synthesis of 1-[1-(6-chloropyridazin-4-yl)-1H-indazol-6-yl]-1H-pyrrole-2-carbonitrile (P42) [ka]

[0909] Preparation 39. 6-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (P39). To an ice-cold solution of 6-bromo-1H-indazole (10 g, 50.7 mmol) in DMF (50 mL) was added a 60% dispersion of NaH in mineral oil (2.2 g, 55 mmol) at 0 °C, and the reaction was stirred for 1 h. Next, SEM-Cl (10 mL, 9.42 g, 56.5 mmol) was added to the mixture. The resulting mixture was stirred at 0 °C for 1 h and then at ambient temperature overnight. The solvent was then evaporated in vacuo, and the residue was partitioned between DCM and water (100 mL each). The organic layer was separated, and the aqueous layer was extracted with DCM (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (gradient elution: 50-0% hexane / CHCl3) to give compound P39 (8.2 g, 49%). 1 H NMR (400 MHz, CDCl3), δ: 7.99 (s, 1H), 7.79 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 8.5, 1.3 Hz, 1H), 5.71 (s, 2H), 3.57 (dd, J = 25.9, 17.8 Hz, 2H), 1.00 - 0.80 (m, 2H), -0.05 (s, 9H).

[0910] Preparation 40. 1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)-1H-pyrrole-2-carbonitrile (P40). Compound P39 (1 g, 3.05 mmol), copper iodide (60 mg, 0.31 mmol), sodium iodide (0.96 g, 6.4 mmol), 2-cyanopyrrole (0.3 g, 3.2 mmol), and K3PO4 (1.4 g, 6.6 mmol) were weighed into a vial, a stir bar was added, and the vial was sealed and purged with nitrogen. 1,4-Dioxane (3 mL) was added, followed by trans-N,N'-dimethyl-1,2-diamine (0.04 mg, 0.032 g, 0.37 mmol). The mixture was heated to 110 °C overnight. The mixture was evaporated in vacuo and then diluted with DCM and water. The mixture was filtered through a hydrophobic frit and purified by column chromatography to give compound P40 (0.73 g, 67%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min, retention time 2.02 min). MS (ESI) m / z: 339.5 [M + H] + . 1 H NMR (400 MHz, CDCl3), δ: 8.10 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.33 (dd, J = 8.5, 1.6 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 7.05 (dd, J = 3.9, 1.4 Hz, 1H), 6.45 - 6.36 (m, 1H), 5.79 (s, 2H), 3.71 - 3.46 (m, 2H), 1.02 - 0.81 (m, 2H), -0.01 - -0.14 (m, 9H).

[0911] Preparation 41. 1-(1H-Indazol-6-yl)-1H-pyrrole-2-carbonitrile (P41). Compound P40 (0.4 g, 1.18 mmol) was dissolved in DCM (10 ml) and TFA (3.4 ml, 5.05 g, 44.2 mmol). The mixture was stirred at ambient temperature for 48 h and then evaporated under vacuum. The residue was treated with aqueous NaHCO3, and the product was extracted with ethyl acetate (2 x 10 ml). The combined organic layers were dried over MgSO4 and concentrated. Product P41 (0.2 g, 81%) was used further without further purification. LCMS (C18 column 20 x 2 mm, 2.5 μm, pore size 100 Å, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min, retention time 1.47 min). MS (ESI) m / z 209.4 [M + H] + . 1 H NMR (400 MHz, CDCl3), δ: 10.80 (br. s, 1H), 8.18 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.32 - 7.23 (m, 1H), 7.18 (dd, J = 2.3, 1.3 Hz, 1H), 7.09 - 7.02 (m, 1H), 6.46 - 6.37 (m, 1H).

[0912] Preparation 42. 1-[1-(6-chloropyridazin-4-yl)-1H-indazol-6-yl]-1H-pyrrole-2-carbonitrile (P42). To a solution of compound P41 (240 mg, 1.15 mmol) in anhydrous DMF (5 mL) was added a 60% dispersion of NaH in mineral oil (70.0 mg, 1.75 mmol) at 0 °C, and the reaction was stirred for 20 min. Next, 3,5-dichloropyridazine (0.2 mg, 1.34 mmol) was added to the mixture. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with water (10 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (gradient elution: 0–22% EtOAc / hexane) to give compound P42 (0.17 g, 45%). LCMS (C18 column 20 x 2 mm, 2.5 μm, 100 Å pore size, water-acetonitrile + 0.1% TFA, gradient 5-87%, 3 min, retention time 1.55 min). MS (ESI) m / z: 321.4 [M + H] + . Synthesis of 1-(1H-indazol-6-yl)cyclopropanecarbonitrile (P43) [ka]

[0913] Preparation 43. 1-(1H-indazol-6-yl)cyclopropanecarbonitrile (P43). To a solution of 6-bromo-1H-indazole (5.0 g, 25 mmol), cyclopropanecarbonitrile (2.6 g, 39 mmol), Pd2dba3 (1.2 g, 1.3 mmol), and NiXantPhos (1.4 g, 2.5 mmol) in THF / CPME (1:1 (v / v), 150 mL) was added LiHMDS (76 mL, 76 mmol, 1 M in THF) at 0 °C. The reaction was stirred at 80 °C for 30 min, after which the mixture was treated with NH4Cl(aq) and extracted with EtOAc. The organic layer was evaporated in water and the Na2SO4 4(s) The mixture was dried at 47° C., filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% EtOAc in n-hexane) to give P43 (2.95 g, 64%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 10.51 (br. s, 1H), 8.07 (s, 1H), 7.74 (dd, J = 8.6 Hz, 1H), 7.57 (s, 1H), 7.00 (d, J = 8.6 Hz, 1H), 1.81-1.78 (m, 2H), 1.51-1.47 (m, 2H); LRMS (ESI) m / z: C 11 Calculated for H9N3: 183.08; Found: 184.1 [M + H] + ; HPLC purity: 99.27%, t R = 14.56 minutes. Synthesis of 2-(1H-indazol-6-yl)-2-methylpropanenitrile (P44) [ka]

[0914] Preparation 44. 2-(1H-indazol-6-yl)-2-methylpropanenitrile (P44). To a solution of 6-bromo-1H-indazole (2.00 g, 10.2 mmol), isobutyronitrile (1.06 g, 15.3 mmol), Pd2dba3 (468 mg, 0.510 mmol), and NiXantPhos (564 mg, 1.02 mmol) in THF / CPME (1:1 (v / v), 60 mL) was added LiHMDS (30 mL, 30.45 mmol, 1 M in THF) at 0 °C. The reaction was stirred overnight at 80 °C, after which the mixture was diluted with NH4Cl (aq) The organic layer was treated with NaSO and extracted with EtOAc. 4(s) The mixture was dried at 47° C., filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% EtOAc in n-hexane) to give P44 (1.16 g, 62%) as a yellow oil. 1H NMR (400 MHz, CDCl3), δ: 10.34 (br. s, 1H), 8.08 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.26 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 1.80 (s, 6H) ; LRMS (ESI) m / z: C 11 H 11 Calculated for N3 185.10; Found, 186.2 [M + H] + ; HPLC purity: 94.14%, t R = 15.43 minutes. Synthesis of 2-cyclopropyl-6-(5-isopropoxy-1-trityl-1H-indazol-3-yl)-4-morpholinopyridazin-3(2H)-one (P48) [ka]

[0915] Preparation 45. 4-Bromo-6-chloro-2-cyclopropylpyridazin-3(2H)-one (P45). To a solution of P25 (1.50 g, 7.16 mmol) in 1,4-dioxane (10 mL) was added cyclopropylboronic acid (1.85 g, 21.5 mmol), pyridine (4.57 mL, 57.3 mmol), and triethylamine (5.00 mL, 35.8 mmol). Argon was bubbled through the mixture for 15 min, and copper(II) acetate (1.30 g, 7.16 mmol) was added and degassed with argon. After stirring the mixture at 80 °C for 30 min, the solution was treated with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–15% EtOAc in n-hexane) to give P45 (252 mg, 14%) as a white solid. 1H NMR (400 MHz, CDCl), δ: 7.57 (s, 1H), 4.11 (s, 1H), 1.13-1.12 (m, 2H), 1.05-1.04 (m, 2H); LCMS (ESI) m / z calculated for C7H6BrClN2O 247.94; found 248.6 [M + H] + .

[0916] Preparation 46. 6-Chloro-2-cyclopropyl-4-morpholinopyridazin-3(2H)-one (P46). To a solution of P45 (250 mg, 1.00 mmol) in 1,4-dioxane (10 mL) was added morpholine (0.087 mL, 1.00 mmol) and cesium carbonate (652 mg, 2.00 mmol). Argon was bubbled through the mixture for 15 min. Xantphos (57.9 mg, 0.100 mmol) and tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.050 mmol) were added to the mixture, which was then degassed with argon. After stirring the mixture at 80 °C overnight, the solution was filtered through a pad of Celite, and the filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–40% EtOAc in n-hexane) to give P46 (183 mg, 71%) as a yellow gum. 1 LCMS (ESI) m / z C 11 H 14 Calculated for ClN3O2 255.08; Found 255.9 [M + H] + .

[0917] Preparation 47. (1-Cyclopropyl-5-morpholino-6-oxo-1,6-dihydropyridazin-3-yl)boronic acid (P47). To a solution of P46 (180 mg, 0.704 mmol) in 1,4-dioxane (7.0 mL) was added bis(pinacolato)diboron (894 mg, 3.52 mmol) and potassium acetate (138 mg, 1.41 mmol). Argon was bubbled through the mixture for 15 min. XPhos (67 mg, 0.14 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52 mg, 0.070 mmol) were added to the mixture, and the solution was degassed with argon for 15 min. After stirring the mixture at 50 °C for 16 h, the solution was filtered through a pad of Celite, and the filtrate was concentrated to give crude product P47, which was used in the next step without further purification.

[0918] Preparation 48. 2-Cyclopropyl-6-(5-isopropoxy-1-trityl-1H-indazol-3-yl)-4-morpholinopyridazin-3(2H)-one (P48). To a solution of P47 (crude, 0.704 mmol) in 1,2-dimethoxyethane (7.0 mL) was added P5 (319 mg, 0.586 mmol) and potassium phosphate (2 M in HO, 0.80 mL, 1.8 mmol). The mixture was degassed with argon for 15 min. To the mixture was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex and DCM (48 mg, 0.059 mmol), and it was degassed again with argon. After stirring the mixture at 90 °C overnight, the solution was diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0–40% EtOAc in n-hexane) to give P48 (316 mg, 69%) as a brown solid. 1H NMR (400 MHz, CDCl3), δ: 7.72 (d, J = 2.4 Hz, 1H), 7.31-7.27 (m, 8H), 7.20-7.14 (m, 7H), 7.04 (s, 1H), 6.63 (dd, J = 9.2, 2.4 Hz, 1H), 6.21 (d, J = 9.2 Hz, 1H), 4.63-4.54 (m, 1H), 4.32-4.22 (m, 1H), 3.87-3.82 (m, 4H), 3.47-3.38 (m, 4H), 1.41 (s, 3H), 1.40 (s, 3H), 1.10-1.03 (m, 4H); LCMS (ESI) m / z C 40 H 39 Calculated for N5O3 637.31; Found 638.5 [M + H] + . Synthesis of 2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-4-morpholinopyridazin-3(2H)-one (P51) [ka]

[0919] Preparation 49. 5-(1-Methylcyclopropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (P49). To a solution of 5-(1-methylcyclopropoxy)-1H-indazole (1.9 g, 10.09 mmol) in acetonitrile (50 mL) was added iodine (3.5 g, 14 mmol), followed by potassium carbonate (1.5 g, 27 mmol) and iodine (3.84 g, 15.14 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated to remove the solvent. The residue was purified by silica gel column chromatography (0-50% ethyl ethanoate in n-hexane) to give P49 (1.8 g, 57%) as a yellow oil. 1H NMR (400 MHz, CDCl3), δ: 7.37 (d, J = 8.8 Hz, 1H), 7.12-7.09 (m, 1H), 7.05 (d, J = 2.4 Hz, 1H), 1.07-1.04 (m, 2H), 0.79-0.76 (m, 2H).

[0920] Preparation 50. 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (P50). A solution of P49 (2.2 g, 7.0 mmol), p-toluenesulfonic acid monohydrate (269 mg, 1.4 mmol), and 3,4-dihydro-2H-pyran (1.3 mL, 14.0 mmol) in toluene (345 mL) was stirred at 60 °C for 16 h. The mixture was treated with EtOAc and NaHCO 3(aq) The organic layer was washed with NaSO 4(s) The mixture was dried at 47°C, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-60% EtOAc in n-hexane) to give P50 (2.29 g, 82%) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.8 Hz, 1H), 7.10-7.07 (m, 1H), 7.00 (d, J = 2.0 Hz, 1H), 5.65-5.62 (m, 1H), 4.03-3.98 (m, 1H), 3.74-3.68 (m, 1H), 2.56-2.47 (m, 1H), 2.15-2.10 (m, 1H), 2.08-2.03 (m, 2H), 1.77-1.60 (m, 3H), 1.58 (s, 3H), 1.05-1.02 (m, 2H), 0.78-0.74 (m, 2H).

[0921] Preparation 51. 2-Methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-4-morpholinopyridazin-3(2H)-one (P51). To a solution of P28 (crude product, 1.74 mmol) in dimethoxyethane (15 mL) was added P50 (577 mg, 1.45 mmol) and potassium phosphate (2 M in water, 2.2 mL, 4.35 mmol). The mixture was degassed with argon for 15 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex and DCM (118 mg, 0.15 mmol) were added to the mixture, which was again degassed with argon. The mixture was stirred at 90 °C overnight. The mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was then concentrated in vacuo and purified by silica gel chromatography (0–100% EtOAc in n-hexane). The resulting solid was washed with methanol to give P51 (943 mg) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 8.05 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.29 (s, 1H), 7.10 (dd, J = 8.8, 2.4 Hz, 1H), 5.68 (dd, J = 9.4, 2.4 Hz, 1H), 4.10-3.84 (m, 8H), 3.77-3.72 (m, 1H), 3.54-3.52 (m, 4H), 2.65-2.55 (m, 1H), 2.13-2.05 (m, 2H), 1.80-1.72 (m, 3H), 1.61 (s, 3H), 1.09-1.05 (m, 2H), 0.76-0.72 (m, 2H). Synthesis of 2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-4-morpholinopyridazin-3(2H)-one (P60) [ka]

[0922] Preparation 52. 2-Bromo-4-cyclopropoxy-1-nitrobenzene (P52). To a solution of 60% sodium hydride in mineral oil (2.36 g, 59.1 mmol, 1.3 equiv.) in anhydrous DMF (100 mL) was added cyclopropanol (3.16 mL, 49.9 mmol, 1.1 equiv.) at 0° C. After stirring the reaction mixture at 0° C. for 30 minutes, 2-bromo-4-fluoro-1-nitrobenzene (10.0 g, 45.4 mmol, 1.0 equiv.) was added at 0° C. After stirring the reaction mixture at room temperature for 5 hours, the solution was diluted with HO at 0° C. The mixture was extracted with EtOAc and diluted with 1N HCl. (aq) The organic layer was washed with MgSO 4(s) The mixture was dried at 47°C, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (16% EtOAc in n-hexane) to give P52 (4.17 g, 35%) as a yellow liquid. 1 H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 2.8 Hz, 1H), 7.05 (dd, J = 9.2, 2.8 Hz, 1H), 3.83-3.79 (m, 1H), 0.91-0.79 (m, 4H).

[0923] Preparation 53. 4-Cyclopropoxy-2-methyl-1-nitrobenzene (P53). To a solution of P51 (4.45 g, 17.2 mmol, 1.0 equiv.) in 1,4-dioxane (170 mL) was added potassium carbonate (2.14 g, 34.5 mmol, 2.0 equiv.), cesium carbonate (2.52 g, 17.2 mmol, 1.0 equiv.), and 50% trimethylboroxine in THF (4.34 mL, 34.5 mmol, 2.0 equiv.). The reaction mixture was degassed with argon, and then tetrakis(triphenylphosphine)palladium(0) (895 mg, 1.72 mmol, 0.1 equiv.) was added. The reaction solution was stirred at 100 °C for 16 h, then filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was treated with water and extracted with EtOAc. The organic layer was evaporated in vacuo with MgSO 4 . 4(s)The mixture was dried at 47°C, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% EtOAc in n-hexane) to give P53 (2.54 g, 76%) as a yellow liquid. 1 H NMR (400 MHz, CDCl3), δ: 8.07 (d, J = 9.2 Hz, 1H), 6.97-6.91 (m, 2H), 3.82-3.78 (m, 1H), 3.41 (s, 3H), 0.88-0.77 (m, 4H).

[0924] Preparation 54. 4-Cyclopropoxy-2-methylaniline (P54). To a solution of Pd / C (139 mg, 10% w / w) in ethanol (75 mL) was added a solution of P52 (1.39 g, 7.19 mmol, 1.0 equiv) in ethanol (10 mL). After stirring the solution at room temperature under a hydrogen atmosphere for 16 h, the reaction solution was filtered through a pad of Celite and washed with solvent. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (16% EtOAc in n-hexane) to give P54 (920 mg, 78%) as a pink liquid. 1 H NMR (400 MHz, CDCl3), δ: 6.78-6.75 (m, 2H), 6.61 (d, J = 8.4 Hz, 1H), 3.68-3.63 (m, 1H), 3.30 (br. s, 2H), 2.16 (s, 3H), 0.73-0.70 (m, 4H).

[0925] Preparation 55. N-(4-cyclopropoxy-2-methylphenyl)acetamide (P55). To a solution of P53 (920 mg, 5.63 mmol, 1.0 equiv) in DCM (8.0 mL) was added triethylamine (0.864 mL, 6.20 mmol, 1.1 equiv) and acetic anhydride (0.586 mL, 6.20 mmol, 1.1 equiv) at 0 °C. After stirring the reaction solution at room temperature for 16 h, the solution was diluted with water and extracted with EtOAc. The organic layer was evaporated in MgSO 4(s)The mixture was dried at 47°C, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (16% EtOAc in n-hexane) to give P55 (1.06 g, 92%) as a white solid. 1 H NMR (400 MHz, CDCl3), δ: 7.43 (d, J = 8.4 Hz, 1H), 6.90-6.86 (m, 3H), 3.72-3.67 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 0.76-0.73 (m, 4H).

[0926] Preparation 56. 1-(5-Cyclopropoxy-1H-indazol-1-yl)ethan-1-one (P56). To a solution of P55 (1.06 g, 5.16 mmol, 1.0 equiv.) in toluene (60 mL) was added potassium acetate (760 mg, 7.75 mmol, 1.5 equiv.) and acetic anhydride (2.19 mL, 23.2 mmol, 4.5 equiv.) at room temperature. After heating the reaction solution to 80°C, isoamyl nitrite (2.76 mL, 20.6 mmol, 4.0 equiv.) was added to the solution. The reaction solution was stirred at 80°C for 16 hours. The solution was diluted with water and extracted with EtOAc. The organic layer was filtered and purified by evaporation of MgSO4. 4(s) The mixture was dried at 47°C, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (16% EtOAc in n-hexane) to give P56 (1.03 g, 92%) as an orange solid. 1 H NMR (400 MHz, CDCl3), δ: 8.32 (d, J = 9.2 Hz, 1H), 8.06 (s, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.21 (dd, J = 9.2, 2.4 Hz, 1H), 3.81-3.76 (m, 1H), 2.76 (s, 3H), 0.84-0.80 (m, 4H).

[0927] Preparation 57. 5-Cyclopropoxy-1H-indazole (P57). To a solution of P56 (1.03 g, 4.76 mmol, 1.0 equiv) in methanol (20 mL) was added 7N ammonia in methanol (3.40 mL, 23.8 mmol, 5.0 equiv). The reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give P57 (869 mg, 100%) as an orange solid, which was used in the next step without purification. 1 H NMR (400 MHz, CDCl3), δ: 8.00 (s, 1H), 7.40-7.37 (m, 2H), 7.07 (dd, J = 8.8, 2.4 Hz, 1H), 3.79-3.75 (m, 1H), 0.82-0.79 (m, 4H).

[0928] Preparation 58. 5-Cyclopropoxy-3-iodo-1H-indazole (P58). To a solution of P57 (869 mg, 4.98 mmol, 1.0 equiv.) in acetonitrile (25 mL) was added potassium carbonate (2.06 g, 14.9 mmol, 3.0 equiv.) and iodine (2.53 g, 9.97 mmol, 2.0 equiv.). After stirring the reaction at room temperature for 4 h, the mixture was diluted with water and extracted with EtOAc. The organic layer was purified by filtration using NaSO. 3(aq) Wash with MgSO 4(s) The mixture was dried at 77°C, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% EtOAc in n-hexane) to give P58 (1.25 g, 83%) as a yellow solid. 1 H NMR (400 MHz, CDCl3), δ: 10.32 (br. s, 1H), 7. 36 (dd, J = 10.0 Hz, 1H), 7.12-7.11 (m, 2H), 3.84-3.81 (m, 1H), 0.88-0.79 (m, 4H).

[0929] Preparation 59. 5-Cyclopropoxy-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (P59). To a solution of P58 (1.25 g, 4.16 mmol, 1.0 equiv.) in toluene (20 mL), 3,4-dihydropyran (700 mg, 8.33 mmol, 2.0 equiv.) and p-toluenesulfonic acid monohydrate (158 mg, 0.833 mmol, 0.2 equiv.) were added at room temperature. The reaction solution was stirred at 60 °C for 2 h, then diluted with water and extracted with EtOAc. The organic layer was filtered with MgSO 4 . 4(s) The mixture was dried at 47° C., filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% EtOAc in n-hexane) to give P59 (1.66 g, 100%) as a yellow oil. 1 H NMR (400 MHz, CDCl3), δ: 7.45 (d, J = 9.2 Hz, 1H), 7.11-7.06 (m, 2H), 5.64 (dd, J = 9.2, 2.8 Hz, 1H), 4.03-3.99 (m, 1H), 3.83-3.79 (m, 1H), 3.74-3.68 (m, 1H), 2.57-2.47 (m, 1H), 2.15-2.03 (m, 2H), 1.76-1.70 (m, 2H), 1.67-1.63 (m, 1H), 0.87-0.77 (m, 4H).

[0930] Preparation 60. 6-(5-Cyclopropoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-methyl-4-morpholinopyridazin-3(2H)-one (P60). A crude solution of (1-methyl-5-morpholino-6-oxo-1,6-dihydropyridazin-3-yl)boronic acid (P28, 0.468 mmol) was diluted with P59 (150 mg, 0.390 mmol, 1.0 equiv.), KPO 4(aq) (0.585 mL) and 1,2-dimethoxyethane (4.5 mL) were added at room temperature. The mixture was then heated under argon (g)The mixture was degassed at 400 K, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (31.8 mg, 0.039 mmol, 0.1 equiv.) was added. The reaction solution was stirred at 90 °C for 16 h, then filtered through a pad of Celite and washed with EtOAc. The filtrate was extracted with EtOAc. The organic layer was washed with water and MgSO 4(s) The mixture was dried at 47° C., filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc in n-hexane) to give P60 (41 mg, 23%) as a brown solid. 1 H NMR (400 MHz, CDCl3), δ: 8.09 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.13 (dd, J = 9.2, 2.8 Hz, 1H), 5.69 (dd, J = 9.6, 2.8 Hz, 1H), 4.11-4.07 (m, 1H), 3.91-3.89 (m, 7H), 3.85-3.81 (m, 1H), 3.79-3.73 (m, 1H), 3.55-3.53 (m, 4H), 2.86-2.57 (m, 1H), 2.19-2.16 (m, 1H), 2.07-2.04 (m, 1H) 1.81-1.76 (m, 2H), 1.67-1.66 (m, 1H), 0.84-0.82 (m, 4H). Synthesis of 4-((3aR,6aS)-3,3-dimethylhexahydro-1H-furo[3,4-b]pyrrol-1-yl)-2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridazin-3(2H)-one (P60) [ka]

[0931] Preparation 61. 6-Chloro-4-((3aR,6aS)-3,3-dimethylhexahydro-1H-furo[3,4-b]pyrrol-1-yl)-2-methylpyridazin-3(2H)-one (P61). To a solution of P26 (250 mg, 1.12 mmol) in anhydrous 1,4-dioxane (7.5 mL) was added (3aR,6aS)-3,3-dimethyl-1,2,3a,4,6,6a-hexahydrofuro[3,4-b]pyrrole (190 mg, 1.34 mmol), cesium carbonate (729 mg, 2.24 mmol), and Xantphos (64.7 mg, 0.11 mmol). The mixture was degassed with argon for 15 minutes. Tris(dibenzylideneacetone)dipalladium(0) (51 mg, 0.06 mmol) was added to the mixture, which was then degassed with argon. After stirring the mixture at 80 °C overnight, the solution was filtered through a pad of Celite. The filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% EtOAc in n-hexane) to give P61 (69 mg, 28%) as a yellow solid. 1 H NMR (400 MHz, CD3OD), δ: 6.09 (s, 1H), 4.85 (s, 2H), 3.93-3.89 (m, 1H), 3.80-3.71 (m, 2H), 3.66-3.64 (m, 1H), 3.61 (s, 3H), 3.28 (br. s, 1H), 2.59-2.53 (m, 1H), 1.13 (s, 3H), 1.12 (s, 3H); LCMS (ESI) m / z C 13 H 18 Calculated for ClN3O2 283.11; Found 284.1 [M + H] + .

[0932] Preparation 62. (5-((3aR,6aS)-3,3-Dimethylhexahydro-1H-furo[3,4-b]pyrrol-1-yl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)boronic acid (P62). To a solution of P61 (153 mg, 0.54 mmol) in anhydrous 1,4-dioxane (5.4 mL) was added bis(pinacolato)diboron (684 mg, 2.70 mmol), potassium acetate (106 mg, 1.08 mmol), and XPhos (5.1 mg, 0.11 mmol). Argon was bubbled through the mixture for 15 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (39 mg, 0.05 mmol) was added to the mixture, followed by argon bubbled through for 15 minutes. The mixture was stirred at 50 °C overnight, after which the solution was used in the next step without further purification. LCMS (ESI) m / z C 13 H 20 Calculated for BN3O4 293.15; Found 294.2 [M + H] + .

[0933] Preparation 63. 4-((3aR,6aS)-3,3-dimethylhexahydro-1H-furo[3,4-b]pyrrol-1-yl)-2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridazin-3(2H)-one (P63). A solution of P62 (crude product, 0.54 mmol), P50 (150 mg, 0.38 mmol), and potassium phosphate (242 mg, 1.14 mmol, 2 M aqueous solution) in 1,2-dimethoxyethane (3.8 mL) was degassed with argon for 15 min. To the mixture was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (33 mg, 0.04 mmol), and the mixture was degassed with argon for 15 min. The mixture was stirred at 90 °C overnight and then filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0–50% EtOAc in n-hexane) to give P63 (69 mg, 34%) as a yellow oil. 1H (399 MHz, CD3OD), δ: 8.07 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.07 (dd, J = 9.2, 2.4 Hz, 1H), 6.96 (s, 1H), 5.79-5.77 (m, 1H), 5.31 (br. s, 1H), 4.61 (br. s, 2H), 4.03-3.99 (m, 1H), 3.96-3.92 (m, 1H), 3.84 (s, 3H), 3.79-3.77 (m, 3H), 3.72-3.69 (m, 1H), 3.38 (br. s, 2H), 2.60-2.49 (m, 2H), 2.14-2.11 (m, 1H), 2.07-2.18 (m, 1H), 1.87-1.67 (m, 3H), 1.60 (s, 3H), 1.13-1.12 (m, 6H), 1.04-1.00 (m, 2H), 0.80-0.77 (m, 2H); LCMS (ESI) m / z C 29 H 37 Calculated for N5O4 519.28; Found 520.4 [M + H] + . Synthesis of 4-((2S,6R)-2,6-dimethylmorpholino)-2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridazin-3(2H)-one (P60) [ka]

[0934] Preparation 64. 6-Chloro-4-((2S,6R)-2,6-dimethylmorpholino)-2-methylpyridazin-3(2H)-one (P64). To a solution of P26 (1 g, 4.48 mmol) in anhydrous 1,4-dioxane (30 mL) was added cis-2,6-dimethylmorpholine (0.6 mL, 4.92 mmol), cesium carbonate (2.9 g, 8.96 mmol), and Xantphos (259 mg, 0.45 mmol). The mixture was degassed with argon for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (205 mg, 0.22 mmol) was added to the mixture, which was again degassed with argon. After stirring the mixture at 80 °C overnight, the solution was filtered through a pad of Celite. The filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–40% EtOAc in n-hexane) to give P64 (472 mg, 40%) as a yellow solid. 1 H NMR (400 MHz, CD3OD), δ: 6.22 (s, 1H), 4.12-4.09 (m, 2H), 3.84-3.76 (m, 2H), 3.70 (s, 3H), 2.50-2.45(m 2H), 1.22 (d, J = 6.0 Hz, 6H).

[0935] Preparation 65. (5-((2S,6R)-2,6-Dimethylmorpholino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)boronic acid (P65). To a solution of P64 (200 mg, 0.78 mmol) in anhydrous 1,4-dioxane (7.8 mL) was added bis(pinacolato)diboron (990 mg, 3.90 mmol), potassium acetate (153 mg, 1.56 mmol), and XPhos (75 mg, 0.16 mmol). The mixture was degassed with argon for 15 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57 mg, 0.08 mmol) was added to the mixture, which was then degassed with argon for 15 minutes. The mixture was stirred at 50 °C overnight, and the solution was used in the next step without further purification. LCMS (ESI) m / z C 13 H 20 Calculated for BN3O4 293.15; Found 294.2 [M + H] + .

[0936] Preparation 66. 4-((2S,6R)-2,6-Dimethylmorpholino)-2-methyl-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridazin-3(2H)-one (P66). The above crude solution of P65 (0.78 mmol), P50 (259 mg, 0.65 mmol), and potassium phosphate (413 mg, 1.95 mmol, 2 M aqueous solution) in 1,2-dimethoxyethane (6.5 mL) was degassed with argon for 15 min. To the mixture was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (64 mg, 0.08 mmol), and the mixture was degassed with argon for 15 min. The mixture was stirred at 90 °C overnight and then filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0–50% EtOAc in n-hexane) to give P66 (423 mg, 99%) as a yellow solid. 1 H (400 MHz, CDCl3), δ: 8.06 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.11 (dd, J = 9.2, 2.4 Hz, 1H), 6.98 (s, 1H), 5.69 (dd, J = 9.9, 2.6 Hz, 1H), 4.64 (br. s, 2H), 4.17-4.08 (m, 3H), 3.94-3.85 (m, 4H), 3.79- 3.73 (m, 2H), 2.53-2.44 (m, 2H), 2.06-2.00 (m, 4H), 1.61 (s, 3H), 1.29-1.28 (m, 6H), 1.10-1.08 (m, 2H), 0.76-0.73 (m, 2H). Synthesis of 2-cyclopropyl-4-((2S,6R)-2,6-dimethylmorpholino)-6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridazin-3(2H)-one (P69) [ka]

[0937] Preparation 67. 6-Chloro-2-cyclopropyl-4-((2S,6R)-2,6-dimethylmorpholino)pyridazin-3(2H)-one (P67). To a solution of P45 (300 mg, 1.20 mmol) in anhydrous 1,4-dioxane (8.6 mL) was added cis-2,6-dimethylmorpholine (148 μL, 1.20 m...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein V is selected from C and N; W is selected from C and N; one of V and W is N; bond V 【change】 N is selected from a single bond and a double bond; Join W 【change】 N is selected from a single bond and a double bond; However, when V is N, the bond V 【change】 N is a single bond, the bond W 【change】 N is a double bond, W is C, and when V is C, the bond V 【change】 N is a double bond, the bond W 【change】 N is a single bond, W is N; X is CR ７ and N; Y is C=O, CR ８ and N; provided that one of X and Y is N; bond Y 【change】 N is selected from a single bond and a double bond; r is an integer selected from 0 and 1; However, when Y is C═O, the bond Y 【change】 N is a single bond, r is 1, and Y is CR ８ or N, the bond Y 【change】 N is a double bond and r is 0; When Y is C=O or N, Z is CR ９ and N; Y is CR ８ When Z is CR ９ and Q is CH ２ , N.R. ５ ,O,S,S(O),S(O) ２ is selected from R １ is H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, heterocycle, aryl, heteroaryl, NR １０ R １１ , and S(O) ２ R １２ wherein said alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH ２ , C.N., C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ optionally substituted with one or more substituents independently selected from alkynyl, heterocycle, aryl, and heteroaryl; R ２ is H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Monocyclic cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, heterocycle, aryl, heteroaryl, C １ -C ６ Alkyl-aryl, C １ -C ６ Alkyl-heteroaryl, C ２ -C ６ Alkenyl-aryl, C ２ -C ６ Alkenyl-heteroaryl, C ２ -C ６ Alkynyl-aryl, C ２ -C ６ Alkynyl-heteroaryl, NR １０ R １１ , and S(O) ２ R １２ wherein said alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH ２ , C.N., C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ optionally substituted with one or more substituents independently selected from alkynyl, heterocycle, aryl, and heteroaryl; or R １ and R ２ are taken together with the atoms to which they are attached and any intervening atoms to form C ３ -C １０ Forms a cycloalkyl, a 5- to 14-membered heterocycle, an aryl, or a heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from the group consisting of halogen, OH, oxo, CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl-C １ -C ６ Alkoxy, C １ -C ６ Alkyl-NHC １ -C ６ Alkyl, and NR １０ R １１ optionally substituted with one or more substituents independently selected from R ３ is H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Monocyclic cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, heterocycle, aryl, heteroaryl, C １ -C ６ Alkyl-aryl, C １ -C ６ Alkyl-heteroaryl, C ２ -C ６ Alkenyl-aryl, C ２ -C ６ Alkenyl-heteroaryl, C ２ -C ６ Alkynyl-aryl, C ２ -C ６ Alkynyl-heteroaryl, NR １０ R １１ , and S(O) ２ R １２ wherein said alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is selected from halogen, OH, NH ２ , C.N., C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ optionally substituted with one or more substituents independently selected from alkynyl, heterocycle, aryl, and heteroaryl; or R ２ and R ３ are taken together with the atoms to which they are attached and any intervening atoms to form C ３ -C １０ Forms a cycloalkyl, a 5- to 14-membered heterocycle, an aryl, or a heteroaryl, wherein the cycloalkyl, heterocycle, aryl, or heteroaryl is selected from the group consisting of halogen, OH, oxo, CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl-C １ -C ６ Alkoxy, C １ -C ６ Alkyl-NHC １ -C ６ Alkyl, and NR １０ R １１ optionally substituted with one or more substituents independently selected from R ４ are H, OH, CN, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl-C １ -C ６ Alkoxy, C １ -C ６ Alkyl-NR １０ R １１ , C(O)OC １ -C ６ Alkyl, OC(O)C １ -C ６ alkyl, cycloalkyl or alkyl-alkoxy, wherein said alkyl, cycloalkyl or alkyl-alkoxy is selected from halogen, oxo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NR １０ R １１ optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Each R ５ is H, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl-C １ -C ６ Alkoxy, C １ -C ６ Alkyl-NR １０ R １１ wherein said alkyl, cycloalkyl or alkyl-alkoxy is independently selected from halogen, oxo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NR １０ R １１ optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Each R ６ is halogen, OH, oxo, CN, CONR １０ R １１ , N.R. １０ R １１ , C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl-C １ -C ６ Alkoxy, C １ -C ６ Alkyl-C ３ -C ８ Cycloalkoxy, O—C １ -C ６ Alkyl-C(O)NR １０ R １１ , N.R. １０ C(O)R １１ , -S(O) ２ -C １ -C ６ Alkyl, -C １ -C ６ Alkanediyl-S(O) ２ -C １ -C ６ alkyl, wherein the alkyl or alkoxy is selected from halogen, oxo, OH, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NR １０ R １１ optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; Or, two R ６ together with the atom to which they are attached and any intervening atoms, form a 3-14 membered cycloalkyl, aryl, 3-14 membered heterocycle, or 5-10 membered heteroaryl, wherein said cycloalkyl, aryl, heterocycle, or heteroaryl is selected from the group consisting of halogen, OH, CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Hydroxyalkyl, C １ -C ６ Alkyl-C １ -C ６ Alkoxy, S(O) ２ R １２ optionally substituted with one or more substituents independently selected from R ７ , R ８ and R ９ are H and C, respectively. １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C １ -C ６ Alkyl-C １ -C ６ Alkoxy, C １ -C ６ Alkyl-NR １０ R １１ wherein the alkyl, alkoxy, cycloalkyl or alkylalkoxy is independently selected from halogen, oxo, OH, CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, NR １０ R １１ , S(O) ２ R １２ optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, and heterocycle; R １０ is H, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, S(O) ２ R １２ alkyl or cycloalkyl is selected from halogen, oxo, OH, CN, C １ -C ６ Alkyl, C １ -C ６ optionally substituted with one or more substituents independently selected from alkoxy; R １１ is H, C １ -C ６ Alkyl, C ３ -C １０ cycloalkyl, wherein alkyl or cycloalkyl is selected from halogen, oxo, OH, CN, C １ -C ６ Alkyl, C １ -C ６ optionally substituted with one or more substituents independently selected from alkoxy; or R １０ and R １１ together with the atoms to which they are attached and any intervening atoms form a 5- to 14-membered heterocycle, said heterocycle being free of halogen, OH, CN, C １ -C ６ Alkyl, C １ -C ６ optionally substituted with one or more substituents independently selected from alkoxy; R １２ is C １ -C ６ Alkyl, —NH ２ , —NH(C １ -C ３ alkyl), or —N(C １ -C ３ alkyl) ２ wherein the alkyl is selected from halogen, oxo, OH, CN, C １ -C ６ Alkyl, C １ -C ６ optionally substituted with one or more substituents independently selected from alkoxy; m is an integer selected from 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, and 4; u is an integer selected from 0, 1, 2, 3, 4, 5, and 6; Aryl is a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings; Heterocyclyl is a saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro) or 11-14 membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms selected from O, N, S, P, Se, or B; Heteroaryl is a monovalent monocyclic or polycyclic aromatic radical having 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C.

2. The compound has the formula (II): 【Chemistry 2】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

3. The compound has the formula (IIA), IIB), (IIC), or (IID): 【Transformation 3】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

4. The compound has the formula (I-II): 【Chemistry 4】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

5. The compound has the formula (I-II-A), (I-II-B), (I-II-C), or (I-II-D): 【Transformation 5】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

6. The compound has the formula (IO): 【Transformation 6】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

7. The compound has the formula (I-N): 【Transformation 7】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

8. The compound has the formula (IC): 【Transformation 8】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

9. The compound has the formula (IS): 【Chemistry 9】 10. The compound of claim 1, which is: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

10. The compound has the formula (IOI): 【Chemistry 10】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

11. The compound has the formula (I-N-I): 【Chemistry 11】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

12. The compound has the formula (ICI): 【Chemistry 12】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

13. The compound has the formula (I-S-I): 【Chemistry 13】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

14. The compound has the formula (IO-II): 【Chemistry 14】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

15. The compound has the formula (IN-II): 【Chemistry 15】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

16. The compound has the formula (IC-II): 【Chemistry 16】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

17. The compound has the formula (IS-II): 【Chemistry 17】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

18. The compounds are of formula (I-I-D-I), (I-I-D-II), (I-I-D-III), or (I-I-D-IV): [Chemistry 18] 【Chemistry 19】 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

19. Fragment 【Chemistry 20】 teeth, 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 6. The compound of any one of claims 1, 2, 3, 4, or 5, selected from:

20. R ４ is H.

21. A compound selected from: or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

22. 10. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof, and a pharmaceutically acceptable carrier.

23. 23. The pharmaceutical composition of claim 22, further comprising one or more additional pharmaceutically active agents.

24. 23. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 22 in the preparation of a medicament for inhibiting LRRK2 in a cell, wherein said compound or said pharmaceutical composition is contacted with said cell.

25. 25. The use of claim 24, wherein the compound or the pharmaceutical composition is contacted in vitro or in vivo.

26. Use of a compound of claim 1 or a pharmaceutical composition of claim 22 in the preparation of a medicament for the treatment or prevention of a disease or disorder associated with LRRK2, wherein the compound or pharmaceutical composition is administered to a subject in need thereof.

27. The disease or disorder may be Parkinson's disease 8, autosomal dominant (PARK8); hereditary late-onset Parkinson's disease (LOPD); spinocerebellar atrophy; Klippel-Feil syndrome 1, autosomal dominant (KFS1); autosomal dominant cerebellar ataxia (SCA); Parkinson's disease, late-onset (PD); Parkinson's disease 2, autosomal recessive juvenile (PARK2); Parkinsonism; REM sleep behavior disorder; dementia with Lewy bodies (DLB); Lrrk2 Parkinson's disease; Parkinson's disease 3, Autosomal dominant (PARK3); Early-onset Parkinson's disease; Multiple system atrophy 1 (MSA1); Essential tremor; Movement disorder; Progressive supranuclear palsy 1 (PSNP1); Klippel-Feil syndrome 1; Dementia; Parkinson's disease 10 (PARK10); Tremor; Frontotemporal dementia (FTD); Postencephalitic Parkinson's disease; Vascular parkinsonism; Aphasia; Parkinson's disease 1, autosomal dominant (PARK1); Athetosis; Klippel-Feil syndrome (KFS); Klippel-Feil syndrome Klein syndrome (KRS); Leprosy 3 (LPRS3); Alzheimer's disease 8 (AD8); Crohn's disease; Rheumatoid arthritis (RA); Alzheimer's disease (AD); Achromatopsia; Gaucher disease, type I (GD1); Parkinson's disease 15, autosomal recessive early-onset (PARK15); von Economo disease; Gerstmann-Sträussler disease (GSD); Amyotrophic lateral sclerosis-Parkinson's disease / dementia complex 1 (ALS-PDC1); Dystonia; Sphingolipidosis; Radiculopathy 27. The use of claim 26, wherein the disease is selected from the group consisting of: osteopathic nerve lesions; toxic encephalopathy; sleep disorders; Pick's disease of the brain (PIDB); ocular glomerulopathy; Gaucher's disease (GD); optic atrophy 7 with or without auditory neuropathy (OPA7); ulnar nerve lesions; inflammatory bowel disease 4 (IBD4); inflammatory bowel disease; 3-methylglutaconic aciduria, type III (MGCA3); nervous system diseases; amyotrophic lateral sclerosis 1 (ALS1); mitochondrial complex I deficiency, nuclear type 1 (MC1DN1).

28. 27. The use of claim 26, wherein the disease or disorder is Parkinson's disease (PD).

29. 25. The use of claim 24, wherein the subject is a mammal.

30. 30. The use of claim 29, wherein the subject is a human.

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