Oxazole, oxadiazole, and indole derivatives for USP28 inhibition

Abstract

Provided herein are USP28 inhibitors, pharmaceutical compositions, methods for their preparation, and methods of their use in treatment and / or diagnosis.

Description

[Technical field]

[0001] This application claims priority to and the benefit of USSN 63 / 271,097, filed October 22, 2021, and is hereby incorporated by reference in its entirety for all purposes.

[0002] Provided herein are compounds and pharmaceutical compositions for inhibiting the deubiquitinating enzyme ubiquitin-specific peptidase 28 (USP28). The compounds and compositions are useful in methods for the treatment and prevention of diseases or conditions, including, but not limited to, cancer, inflammation, autoimmune diseases, and infectious diseases. [Background technology]

[0003] An important post-translational modification is ubiquitination, the process of attaching a target protein to ubiquitin. This is achieved by a covalent bond between the C-terminus of ubiquitin and a lysine residue of the target protein. When a protein is tagged with ubiquitin, the protein is usually marked for degradation. Recent studies show that ubiquitination also serves to regulate the subcellular localization of proteins, the activation and inactivation of proteins, and / or regulate protein-protein interactions.

[0004] Deubiquitinating enzymes (DUBs) play an important role in regulating the ubiquitination process by cleaving the covalent bond between ubiquitin and target proteins, thus reversing ubiquitination. Approximately 100 human DUBs have been identified, which are divided into two major classes: cysteine ​​proteases and metalloproteases. Among cysteine ​​proteases, the largest family is the ubiquitin-specific protease (USP / UBP) family, which consists of more than 50 proteases, including ubiquitin-specific peptidase 28 (USP28).

[0005] USP28 was first identified in a homology search of USP25 (Valero, et al. Genome Biol. 2001;2(10):research0043.1-research0043.10). Like USP25, USP28 contains a ubiquitin-associated domain and a ubiquitin-interacting motif in the N-terminal region. Since its identification, studies have shown that USP28 is involved in promoting oncoprotein stability, downregulating apoptosis, upregulating angiogenesis and metastasis, and maintaining cell cycle arrest and DNA repair (Wang et al. Cell Death and Disease 2018;9:186). For this reason, USP28 is involved in many diseases and disorders, including cancer, autoimmune diseases, inflammation, and infectious diseases.

[0006] For example, USP28 has been shown to be upregulated in non-small cell lung cancer, and high levels of USP28 are associated with poor disease prognosis. (Zhang et al., J. Cell. Mol. Med. 2015;19:799). USP28 is also often overexpressed in colon cancer (Diefenbacher et al., J. Clin. Invest. 2014;124:3407) and bladder cancer (Guo et al. Tumour Biol. 2014;35:4017). In breast cancer, USP28 is a deubiquitinase of the epigenetic regulator LSD1. Studies have shown that disruption of USP28 can lead to destabilization of LSD1, thereby inhibiting tumorigenesis. (Cao et al. Oncogene 2017;36:133).

[0007] Deubiquitinating enzymes, including USP25, are also involved in inflammation. For example, USP25 negatively regulates the proinflammatory protein interleukin 17 (IL-17). Overexpression of USP25 also inhibited IL-17-induced signaling (Zhong et al. Nat Immunol. 2012;13:1110-7). There is a need for additional therapies to inhibit USP28 and treat diseases caused by USP28 overexpression and / or dysfunction, including cancer, autoimmune diseases, inflammation, and infectious diseases. Small molecules targeting USP28 should provide safe, stable, and easy-to-administer therapeutic agents. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Valero,et al.Genome Biol.2001;2(10):research0043.1-research0043.10 [Non-Patent Document 2] Wang et al.Cell Death and Disease 2018;9:186 [Non-Patent Document 3] Zhang et al.,J.Cell.Mol.Med.2015;19:799 [Non-Patent Document 4] Diefenbacher et al.,J.Clin.Invest.2014;124:3407 [Non-Patent Document 5] Guo et al.Tumour Biol.2014;35:4017 [Non-Patent Document 6] Cao et al.Oncogene 2017;36:133 [Non-Patent Document 7] Zhong et al.Nat Immunol.2012;13:1110-7 Summary of the Invention

[0009] The present disclosure includes compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), and (III), or pharma- ceutically acceptable salts, diastereomers, or stereoisomers thereof. Additionally, subformulas of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), and (III), compositions comprising compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), and (III), and methods of making the compounds are provided herein. Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), and (III), and subformulas and embodiments thereof, are useful for inhibiting ubiquitin-specific peptidase 28 (USP28). In certain embodiments, the compounds can be used to treat diseases or conditions in which inhibition of USP28 provides a therapeutic benefit, including cancer, autoimmune diseases, inflammation, and infectious diseases.

[0010] In one aspect, there is provided a compound of formula (I) or (II), or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof: [ka] (In the formula, L 1 teeth, [ka] is selected from R 1 1, 2, 3, or 4 R 4a aryl substituted with a group; 1, 2, 3, or 4 R 4a cycloalkyl substituted with a group; 1, 2, 3, or 4 R 4a heteroaryl substituted with a group and one, two, three, or four R 4aand heterocycles substituted with R groups, wherein the heteroaryl and heterocycles contain at least one nitrogen, oxygen, or sulfur, and the nitrogen of the heterocycle is selected from the group consisting of R 4b is replaced by R 2 is optionally 1, 2, 3, or 4 R 5 aryl substituted with a group; optionally 1, 2, 3, or 4 R 5 heteroaryl substituted with a group; optionally 1, 2, 3, or 4 R 5 cycloalkyl substituted with a group; and optionally one, two, three, or four R 5 a heterocycle substituted with a group; R 3 is hydrogen or C 1-6 is alkyl, Each R 4a is independently 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkylaminoalkyl, C 1-6 Dialkylaminoalkyl, amino, hydroxy, cyano, nitro, halogen, -NR 6 R 7 , -CH2NR 6 R 7 , -C(O)NR 6 R 7 , -CH2C(O)NR 6 R 7 , -(CH2) a -O-(CH2) b R 8 , and -C(O)R 9 is selected from Each R 4b are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, cyano, -CHNR 6 R 7 , -C(O)NR6 R 7 , -CH2C(O)NR 6 R 7 , -(CH2) a -O-(CH2) b R 8 , and -C(O)R 9 is selected from Each R 5 If present, independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkylaminoalkyl, C 1-6 Dialkylaminoalkyl, amino, hydroxy, cyano, nitro, halogen, -NR 6 R 7 , -CH2NR 6 R 7 , -C(O)NR 6 R 7 , -CH2C(O)NR 6 R 7 , -(CH2) a -O-(CH2) b R 8 , and -C(O)R 9 is selected from R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, aryl, aryl C 1-6 Alkyl, Heteroaryl, HeteroarylC 1-6 Alkyl, heterocycle, and heterocycloC 1-6 alkyl, excluding hydrogen; R 6 and R 7 may independently optionally be one or two R 10 may be substituted with a group, Or, R 6 and R 7 can be joined together and optionally one or two R10 forming a heterocyclic or biheterocyclic ring substituted with a group, R 8 is hydroxy, cyano, halogen, C 1-6 Haloalkyl, -NR 6 R 7 , or -C(O)R 9 and R 9 is C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, aryl, aryloxy, arylC 1-6 Alkyl, aryloxy C 1-6 Alkyl, Heteroaryl, HeteroarylC 1-6 Alkyl, heterocycle, heterocycloC 1-6 Alkyl, or -NR 11 R 12 and R 10 are independently -C(O)R 9 , -COOH, amino, -NR 11 R 12 , -NR 11 C(O)R 12 , aryl, heteroaryl, aryl C 1-6 Alkyl and Heteroaryl C 1-6 alkyl; Or, two R's 10 The groups, when on the same carbon, can be taken together to form an oxo group, R 11 and R 12 are independently hydrogen and C 1-6 alkyl, X 1 is CH or N, a and b are integers independently selected from 1, 2, 3, and 4.

[0011] In one embodiment, there is provided a compound of formula (III) or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof: [ka] (In the formula, L 2 teeth, [ka] is selected from Y is NR 15 , C.R. 16 R 17 , or oxygen, R 15 is hydrogen, -C(O)R 9 , C 1-6 Alkyl, or C 3-6 is cycloalkyl, R 16 and R 17 are independently hydrogen, -C(O)R 9 , C 1-6 Alkyl, and C 3-6 cycloalkyl; R 1 and R 2 is as defined herein).

[0012] In one embodiment, the compound of formula (I) is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof. (In the formula, R 1 , R 5 , X 1 , and L 1 is as defined herein).

[0013] In one embodiment, the compound of formula (I) is a compound of formula (Ib): [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof. (In the formula, R 4a , R 4b , R 5, X 1 , and L 1 is as defined herein).

[0014] In certain embodiments, the compound of formula (I) is a compound of formula (Ic) or formula (Id): [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof. (In the formula, R 4a , R 5 , X 1 , and L 1 is as defined herein).

[0015] In one embodiment, the compound of formula (II) is a compound of formula (IIa): [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof. (In the formula, R 1 , R 5 , X 1 , and L 1 is as defined herein).

[0016] In one embodiment, the compound of formula (II) is a compound of formula (IIb): [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof. (In the formula, R 4a , R 4b , R 5 , X 1 , and L 1 is as defined herein).

[0017] In certain embodiments, the compound of formula (II) is a compound of formula (IIc) or (IId): [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof. (In the formula, R 4a , R 5 , X 1 , and L 1 is as defined herein).

[0018] In certain embodiments, the compounds are useful in methods for the treatment and prevention of diseases in which inhibition of USP28 is therapeutically beneficial, methods for the detection of diseases and conditions in which inhibition of USP28 is therapeutically beneficial, and methods for the diagnosis of diseases and conditions in which inhibition of USP28 is therapeutically beneficial.

[0019] In another aspect, a composition is provided that includes a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or (III). In some embodiments, the composition is a pharmaceutical composition. Any suitable pharmaceutical composition may be used. In a further aspect, a kit is provided herein that includes a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or (III), or an embodiment thereof, or a pharmaceutical composition thereof.

[0020] In another aspect, provided herein are methods of using the compounds or compositions described herein. In some embodiments, the methods are for treatment. In some embodiments, the methods are diagnostic methods. In some embodiments, the methods are analytical methods. In some embodiments, the compounds or compositions described herein are used to treat diseases or conditions in which inhibition of USP28 is therapeutically beneficial. In some aspects, the disease is cancer, including but not limited to non-small cell lung cancer, breast cancer, intestinal cancer, and bladder cancer. In some aspects, the disease is selected from inflammatory diseases, autoimmune diseases, and infectious diseases.

[0021] Also provided herein is the use of the compounds described herein and compositions thereof for the treatment of diseases or conditions in which inhibition of USP28 is therapeutically beneficial. Also provided herein is the use of the compounds described herein and compositions thereof for the treatment of cancer, including, but not limited to, non-small cell lung cancer, breast cancer, intestinal cancer, and bladder cancer.

[0022] Description of exemplary embodiments Described herein are USP28 inhibitors that are useful for the treatment of diseases or conditions in which inhibition of USP28 is of therapeutic benefit.

[0023] definition Unless otherwise defined, all technical terms, notations, and other scientific terms used herein shall have the meanings that they are commonly understood by those of ordinary skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ready reference. The techniques and procedures described or referred to herein are generally well understood and commonly used by those of ordinary skill in the art using conventional methodology. Where appropriate, procedures involving the use of commercially available kits and reagents are generally carried out according to manufacturer-defined protocols and conditions unless otherwise specified.

[0024] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0025] The term "about" denotes and encompasses the indicated value, as well as the range above and below that value. In certain embodiments, the term "about" denotes ±10%, ±5%, or ±1% of the specified value. In certain embodiments, the term "about" denotes the specified value ±1 standard deviation of that value. In certain embodiments, for example, on a logarithmic scale (e.g., pH), the term "about" denotes ±0.3, ±0.2, or ±0.1 of the specified value.

[0026] When referring to the compounds provided herein, the following terms have the following meanings unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In the event that there are multiple definitions for any term herein, the definition in this section shall prevail unless otherwise stated.

[0027] "Alkoxy" and "alkoxyl" refer to the group -OR" where R" is alkyl or cycloalkyl. Alkoxy groups, in certain embodiments, include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0028] The term "alkyl," as used herein, unless otherwise specified, refers to a saturated straight-chain or branched hydrocarbon. In certain embodiments, an alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, an alkyl group contains 1 to 10 carbon atoms (i.e., C1 to C6). 10 In certain embodiments, the alkyl is a lower alkyl, e.g., C 1-6and alkyl. In certain embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. In certain embodiments, "substituted alkyl" refers to an alkyl substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, the alkyl is unsubstituted.

[0029] The term "alkylene," as used herein, unless otherwise specified, refers to a divalent alkyl group, as defined herein. "Substituted alkylene" refers to an alkylene group substituted as described herein for alkyl. In some embodiments, the alkylene is unsubstituted.

[0030] In certain embodiments, "alkenyl" refers to an olefinically unsaturated hydrocarbon group, which may be straight-chained or branched, having up to about 11 carbon atoms, or from 2 to 6 carbon atoms (e.g., "lower alkenyl"), and having at least 1, or from 1 to 2 sites of olefinic unsaturation. "Substituted alkenyl" refers to an alkenyl group substituted as described herein for alkyl.

[0031] "Alkenylene" refers to a divalent alkenyl as defined herein. Lower alkenylene, for example, is C2-C6 alkenylene.

[0032] "Alkynyl" refers, in certain embodiments, to an acetylenically unsaturated hydrocarbon group having up to about 11 carbon atoms, or 2 to 6 carbon atoms (e.g., "lower alkynyl"), which may be straight-chained or branched, and having at least one, or 1 to 2 sites of acetylenic unsaturation. Non-limiting examples of alkynyl groups include acetylene (-C≡CH), propargyl (-CHC≡CH), and the like. "Substituted alkynyl" refers to an alkynyl group substituted as described herein for alkyl.

[0033] "Alkynylene" refers to a divalent alkynyl as defined herein. Lower alkenylene, for example, is C2-C6 alkynylene.

[0034] "Amino" refers to -NH2.

[0035] The term "alkylamino," as used herein, unless otherwise indicated, refers to the group -NHR", where R is, for example, C, as defined herein. 1-10 In certain embodiments, alkylamino is C 1-6 It is an alkylamino.

[0036] The term "dialkylamino," as used herein, unless otherwise indicated, refers to the group -NR"R", where each R" is independently a C alkyl group, as defined herein. 1-10 In certain embodiments, the dialkylamino is di-C 1-6 It is an alkylamino.

[0037] The term "aminoalkyl," as used herein, refers to an alkyl group, as described herein, substituted with an amino group.

[0038] The term "alkylaminoalkyl," as used herein, refers to an alkyl group, as described herein, substituted with an alkylamino group, as described herein.

[0039] The term "dialkylaminoalkyl," as used herein, refers to an alkyl group, as described herein, substituted with a dialkylamino group, as described herein.

[0040] The term "aryl" as used herein refers to phenyl, biphenyl, or naphthyl unless otherwise indicated. The term includes both substituted and unsubstituted moieties. The aryl group may be substituted with any of the described moieties, including, but not limited to, one or more moieties (e.g., in some embodiments, one, two, or three moieties) selected from the group consisting of halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, each moiety being independently unprotected or protected as necessary, as will be understood by those skilled in the art (e.g., Greene et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991); and the aryl in the arylamino and aryloxy substituents is not further substituted.

[0041] The term "arylalkyl," as used herein, refers to an "alkyl" group, as described herein, substituted with an "aryl" group, as described herein.

[0042] The term "arylamino," as used herein, unless otherwise indicated, refers to the group --NR'R", where R' is hydrogen or C1-C6 alkyl; and R" is aryl as defined herein.

[0043] The term "aryloxy," as used herein, unless otherwise indicated, refers to --OR, where R is aryl as defined herein.

[0044] The term "aryloxyalkyl," as used herein, unless otherwise indicated, refers to an alkyl group, as described herein, substituted with an --OR group, where R is aryl, as defined herein.

[0045] "Carboxyl" or "carboxy" refers to -C(O)OH or -COOH.

[0046] The term "cycloalkyl," as used herein, unless otherwise indicated, refers to a saturated cyclic hydrocarbon. In certain embodiments, a cycloalkyl group can be saturated, and / or bridged, and / or unbridged, and / or fused bicyclic groups. In certain embodiments, a cycloalkyl group contains 3 to 10 carbon atoms (i.e., C3 to C4). 10 In some embodiments, cycloalkyl is an alkyl group having 3 to 15 carbons (C 3-15 ), 3 to 10 carbons (C 3-10 ), 3 to 7 carbons (C 3-7 ), or having three to six carbons (C3-C6) (i.e., a "lower cycloalkyl"). In certain embodiments, a cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl.

[0047] The term "ester" as used herein refers to -C(O)OR, or -COOR, where R is alkyl as defined herein.

[0048] The term "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more independently selected halogen atoms (e.g., in some embodiments, 1, 2, 3, 4, or 5).

[0049] The term "halogen" or "halo" as used herein refers to chloro, bromo, iodo, or fluoro.

[0050] The term "heteroalkyl" refers to an alkyl, as defined herein, in which one or more carbon atoms are replaced with a heteroatom. As used herein, "heteroalkenyl" refers to an alkenyl, as defined herein, in which one or more carbon atoms are replaced with a heteroatom. As used herein, "heteroalkynyl" refers to an alkynyl, as defined herein, in which one or more carbon atoms are replaced with a heteroatom. Suitable heteroatoms include, but are not limited to, nitrogen (N), oxygen (O), and sulfur (S) atoms. Heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted. Examples of heteroalkyl moieties include, but are not limited to, aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl moieties also include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl. "Substituted heteroalkyl" refers to a heteroalkyl substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, the heteroalkyl group may contain one, two, three, or four heteroatoms. Those of skill in the art will recognize that a 4-membered heteroalkyl may generally contain one or two heteroatoms, a 5- or 6-membered heteroalkyl may generally contain one, two, or three heteroatoms, and a 7- to 10-membered heteroalkyl may generally contain one, two, three, or four heteroatoms.

[0051] The term "heterocyclic" or "heterocycle" refers to a monovalent, monocyclic, or polycyclic non-aromatic ring system in which one or more of the ring atoms are heteroatoms independently selected from oxygen (O), sulfur (S), and nitrogen (N) (e.g., the nitrogen or sulfur atom may be optionally oxidized and the nitrogen atom may be optionally quaternized), and the remaining ring atoms of the non-aromatic ring are carbon atoms. In certain embodiments, the heterocycle is a monovalent, monocyclic, or polycyclic fully saturated ring system. In certain embodiments, a heterocyclic group has 3-20, 3-15, 3-10, 3-8, 4-7, 4-11, or 5-6 ring atoms. The heterocycle may be attached to the core structure at any heteroatom or carbon atom that results in the formation of a stable compound. In certain embodiments, the heterocycle is a monocyclic, bicyclic (biheterocyclic), tricyclic (triheterocyclic), or tetracyclic (tetraheterocyclic) ring system, which may include fused or bridged ring systems, the nitrogen or sulfur atoms may be optionally oxidized, and / or the nitrogen atoms may be optionally quaternized. In some embodiments, heterocyclic radicals include 2,5-diazabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isothiazolidinyl, isothiazolidinyl, isothiocyan ... Examples of heterocyclic rings include, but are not limited to, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocycle may also be optionally substituted as described herein.In certain embodiments, the heterocycle is substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, the heterocycle may contain one, two, three, or four heteroatoms. Those of skill in the art will recognize that a 4-membered heterocycle may generally contain one or two heteroatoms, a 5- or 6-membered heterocycle may generally contain one, two, or three heteroatoms, and a 7- to 10-membered heterocycle may generally contain one, two, three, or four heteroatoms.

[0052] "Biheterocycle" refers to a heterocyclic ring system that forms two rings, where the rings have at least one atom in common. Biheterocycle groups can be fused, bridged, or spirocyclic.

[0053] "Heterocycloalkyl" refers to an alkyl group, as used herein, substituted with one or two heterocyclic groups, as used herein.

[0054] The term "heteroaryl" refers to a monovalent monocyclic aromatic and / or polycyclic aromatic group, in which at least one aromatic ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen within the ring. Each ring of the heteroaryl group may contain one or two oxygen atoms, one or two sulfur atoms, and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, a heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. A heteroaryl may be attached to the remainder of the molecule through a nitrogen atom or a carbon atom. In some embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, triazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted as described herein. "Substituted heteroaryl" refers to heteroaryl substituted as defined for aryl.

[0055] The term "heteroarylalkyl," as used herein, refers to an "alkyl" group, as described herein, substituted with a "heteroaryl" group, as described herein.

[0056] The term "hydroxyl" refers to --OH.

[0057] The term "hydroxyalkyl," as used herein, refers to an alkyl group, as described herein, substituted with a hydroxyl group.

[0058] The term "cyano" [ka] It is.

[0059] The term "nitro" refers to --NO.

[0060] The term "oxo" as used herein refers to a keto group (C=O). An oxo group that is a substituent of a non-aromatic carbon results in the conversion of -CH2- to -C=O. An oxo group that is a substituent of an aromatic carbon results in the conversion of -CH- to -C=O. When the substituent is oxo, two hydrogens of the atom are replaced. When an oxo group replaces an aromatic moiety, a corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted with an oxo group is pyridine. Those skilled in the art will appreciate that in some embodiments, such groups (e.g., pyridine) can exist in tautomeric forms (e.g., hydroxypyridine).

[0061] The term "protecting group" as used herein, unless otherwise specified, refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent further reaction of the oxygen, nitrogen, or phosphorus atom or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. (See, for example, Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Fourth Edition, 2006, which is incorporated herein by reference).

[0062] "Pharmaceutically acceptable salt" refers to any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions well known in the art.Such salts include (1) salts of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, and the like. carboxylic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid or (2) salts formed when an acidic proton present in the parent compound is (a) replaced with a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, including, but not limited to, ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0063] Pharmaceutically acceptable salts further include, by way of example and not limitation, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g., hydrochlorides, and hydrobromides, sulfates, phosphates, sulfamate, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, and the like. salts, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (mesylates), ethanesulfonates, 1,2-ethanedisulfonates, 2-hydroxyethanesulfonates, benzenesulfonates (besylates), 4-chlorobenzenesulfonates, 2-naphthalenesulfonates, 4-toluenesulfonates, camphorates, camphorsulfonates, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylates, glucoheptonates, 3-phenylpropionates, trimethylacetates, tert-butylacetates, lauryl sulfates, gluconates, glutamates, hydroxynaphthoates, salicylates, stearates, cyclohexylsulfamates, quinates, and muconates.

[0064] The term "substantially free" or "substantially absent" with respect to a composition refers to a composition that comprises at least 85%, or 90%, in certain embodiments, 95%, 98%, 99%, or 100% by weight; or, in certain embodiments, 95%, 98%, 99%, or 100% of a specified enantiomer or diastereomer of a compound. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of one of the two enantiomers. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of one of the two diastereomers. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of an enantiomer (i.e., a racemate, or a 50:50 mixture of the compound).

[0065] Similarly, the term "isolated" with respect to a composition refers to a composition that contains at least 85%, 90%, 95%, 98%, or 99% to 100% by weight of a compound, with the remainder containing other species, enantiomers or diastereomers.

[0066] "Solvate" refers to a compound provided herein or a salt thereof that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0067] "Isotopic composition" refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or abundance for a given atom. An atom that contains a natural isotopic composition may also be referred to herein as a "non-enriched" atom. Unless otherwise specified, the atoms of the compounds described herein are meant to represent any stable isotope of that atom. For example, unless otherwise specified, if a position is specifically designated as hydrogen (H), it is understood that the position has hydrogen at its natural isotopic composition.

[0068] "Isotopic enrichment" refers to the proportion of a given atom in a molecule that incorporates a certain amount of a particular isotope instead of the natural isotopic abundance of that atom. For example, deuterium (D) enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at that particular position. Since the distribution of naturally occurring deuterium is about 0.0156%, the deuterium enrichment at any position of a compound synthesized using a non-enriched starting material is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0069] "Isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound that includes at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0070] As used herein, "alkyl," "alkylene," "alkylamino," "dialkylamino," "cycloalkyl," "aryl," "arylene," "alkoxy," "amino," "carboxyl," "heterocycloalkyl," "heteroaryl," "carboxyl," and "amino acid" groups optionally contain deuterium (D) at one or more positions where a hydrogen (H) atom would be present, and the deuterium composition of the atom(s) is other than the natural isotopic composition.

[0071] In addition, the "alkyl", "alkylene", "alkylamino", "dialkylamino", "cycloalkyl", "aryl", "arylene", "alkoxy", "amino", "carboxyl", "heterocycloalkyl", "heteroaryl", "carboxyl", and "amino acid" groups used herein may contain amounts of carbon-13( 13 C) may be included.

[0072] As used herein, "EC 50" refers to a dose, concentration, or amount of a particular test compound that induces a dose-dependent response at 50% of the maximal expression of a particular response induced, elicited, or enhanced by the particular test compound.

[0073] As used herein, unless otherwise specified, "IC 50 The term "amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response."

[0074] As used herein, the terms "subject," "patient," and "host" are used interchangeably. The terms "subject" and "subjects" refer to animals, e.g., mammals, including non-primates (e.g., cows, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys, such as cynomolgus monkeys, chimpanzees, and humans), and in certain embodiments, humans. In certain embodiments, the subject is a farm animal (e.g., horses, cows, pigs, etc.), or a pet (e.g., dog or cat). In certain embodiments, the subject is a human.

[0075] As used herein, the term "therapeutic agent(s)" refers to any agent(s) that can be used in the treatment or prevention of a disorder, or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" includes the compounds provided herein. In certain embodiments, a therapeutic agent is an agent that is known or has been used or is currently being used to be useful in the treatment or prevention of a disorder, or one or more symptoms thereof.

[0076] "Therapeutically effective amount" means an amount of a compound or composition that, when administered to a subject for treating a condition, is sufficient to effect such treatment for the condition. A "therapeutically effective amount" can vary depending, inter alia, on the compound, the disease or disorder and its severity, as well as the age, weight, etc. of the subject to be treated.

[0077] "Treating" or "treatment" of any disease or disorder refers, in certain embodiments, to improving the disease or disorder present in a subject. In another embodiment, "treating" or "treatment" includes improving at least one physical parameter that may be difficult for a subject to distinguish. In yet another embodiment, "treating" or "treatment" includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physiological parameter), or both. In yet another embodiment, "treating" or "treatment" includes delaying or preventing the onset of a disease or disorder, or delaying or preventing the recurrence of a disease or disorder. In yet another embodiment, "treating" or "treatment" includes reducing or eliminating any of the disease or disorder, or delaying the progression of a disease or disorder, or one or more symptoms of a disease or disorder, or reducing the severity of a disease or disorder, or the severity of one or more symptoms of a disease or disorder.

[0078] As used herein, the term "prophylactic agent(s)" refers to any agent(s) that can be used in the prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term "prophylactic agent" includes the compounds provided herein. In certain other embodiments, the term "prophylactic agent" does not refer to the compounds provided herein. For example, a prophylactic agent is an agent that is known to be useful for preventing or hindering the onset, development, progression, and / or severity of a disorder, or that has been used or is currently being used to arrest the onset, development, progression, and / or severity of a disorder.

[0079] As used herein, the phrase "prophylactically effective amount" refers to an amount of a treatment (e.g., a prophylactic agent) sufficient to prevent or reduce the onset, recurrence, or onset of one or more symptoms associated with a disorder, or to enhance or improve the prophylactic effect(s) of another treatment (e.g., another prophylactic agent).

[0080] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), and (III) Provided herein are USP28 inhibitors useful for diseases in which inhibition of USP28 is therapeutically beneficial. Compounds can be prepared as described herein and used for treatment or diagnosis. In certain embodiments, the treatment is the treatment of cancer, including but not limited to non-small cell lung cancer, breast cancer, intestinal cancer, and bladder cancer. In certain embodiments, the treatment is the treatment of autoimmune diseases, including but not limited to inflammatory diseases of the intestine, ulcerative colitis, Crohn's disease, and rheumatoid arthritis. In certain embodiments, the treatment is the treatment of inflammation. In certain embodiments, the treatment is the treatment of infectious diseases, including but not limited to viral infections and bacterial infections. In certain embodiments, the treatment is the treatment of neurodegenerative diseases.

[0081] The embodiments described herein include the recited compounds, as well as pharma- ceutically acceptable salts, hydrates, solvates, stereoisomers, diastereomers, tautomers, and / or mixtures thereof.

[0082] In certain embodiments, L 1 teeth, [ka] In certain embodiments, L 1 teeth, [ka] In certain embodiments, L 1 teeth, [ka] and R 3 is C 1-6 In certain embodiments, L 1 teeth, [ka] In certain embodiments, L 1 teeth, [ka] In certain embodiments, L 1 teeth, [ka] In certain embodiments, L 1 teeth, [ka] and R 3 is C 1-6 In certain embodiments, L 1 teeth, [ka] In certain embodiments, L 1 teeth, [ka] In certain embodiments, L 1 teeth, [ka] In certain embodiments, L 1 teeth, [ka] In certain embodiments, L 1 teeth, [ka] It is.

[0083] In certain embodiments, R 1 is one R 4a In certain embodiments, R is an aryl substituted with a aryl group. 1 There are two R 4a In certain embodiments, R is an aryl substituted with a aryl group. 1 is -C(O)NR 6 R 7 In certain embodiments, R 1 is -C(O)N(C 1-6 In certain embodiments, R 1 is aryl substituted with -C(O)N(Me). In certain embodiments, R 1 is C 1-6 In certain embodiments, R is an aryl substituted with an alkyl. 1 is aryl substituted with methyl. In certain embodiments, R 1 is -CH2NR 6 R 7 In certain embodiments, R 1 is -CH2N(C 1-6 In certain embodiments, R 1 is aryl substituted with -CHN(Me). In certain embodiments, R 1 is -C(O)NR 6 R 7 aryl substituted with R 6 is hydrogen and R 7 Heterocyclo C 1-6 In certain embodiments, R 1 is -C(O)NR 6 R 7 aryl substituted with R 6 and R 7 can be joined together and optionally R 10 In certain embodiments, R 1 is -C(O)NR 6 R 7 aryl substituted with R 6 and R 7can be joined together and optionally R 10 In certain embodiments, R 1 -NR 6 R 7 In certain embodiments, R 1 is -N(C 1-6 In certain embodiments, R 1 is aryl substituted with -N(Me). In certain embodiments, R 1 is aryl substituted with -NH. In certain embodiments, R 1 is aryl substituted with -NHMe. In certain embodiments, R 1 is -(CH2) a -O-(CH2) b R 8 aryl substituted with R 8 is hydroxy. In certain embodiments, R 1 is -(CH2) a -O-(CH2) b R 8 wherein a is 1 and b is 2. In certain embodiments, R 1 is -(CH2) a -O-(CH2) b R 8 a is 1, b is 2, and R 8 is hydroxy. In certain embodiments, R 1 is -(CH2) a -O-(CH2) b R 8 and the second R 4a In one embodiment, R 4a The group is -C(O)NR 6 R 7 It is.

[0084] In certain embodiments, R 1 is one R 4a In certain embodiments, R is a cycloalkyl substituted with a cycloalkyl group. 1 There are two R 4aIn certain embodiments, R is a cycloalkyl substituted with a cycloalkyl group. 1 is -C(O)NR 6 R 7 In certain embodiments, R 1 is -C(O)N(C 1-6 In certain embodiments, R 1 is cycloalkyl substituted with -C(O)N(Me). In certain embodiments, R 1 is C 1-6 In certain embodiments, R is cycloalkyl substituted with alkyl. 1 is cycloalkyl substituted with methyl. In certain embodiments, R 1 is -CH2NR 6 R 7 In certain embodiments, R 1 is cycloalkyl substituted with -CHN(Me). In certain embodiments, R 1 -NR 6 R 7 In certain embodiments, R 1 is cycloalkyl substituted with -N(Me). In certain embodiments, R 1 is cycloalkyl substituted with -NH. In certain embodiments, R 1 is a cycloalkyl substituted with -NHMe.

[0085] In certain embodiments, R 1 is one R 4a In certain embodiments, R is a heteroaryl substituted with a aryl group. 1 There are two R 4a In certain embodiments, R is a heteroaryl substituted with a aryl group. 1 is -C(O)NR 6 R 7 In certain embodiments, R is a heteroaryl substituted with 1 is -C(O)N(C 1-6 In certain embodiments, R 1is heteroaryl substituted with -C(O)N(Me). In certain embodiments, R 1 is C 1-6 In certain embodiments, R is heteroaryl substituted with alkyl. 1 is heteroaryl substituted with methyl. In certain embodiments, R 1 is -CH2NR 6 R 7 In certain embodiments, R is a heteroaryl substituted with 1 is -CH2N(C 1-6 In certain embodiments, R 1 is heteroaryl substituted with -CHN(Me). In certain embodiments, R 1 is -C(O)NR 6 R 7 is heteroaryl substituted with R 6 is hydrogen and R 7 Heterocyclo C 1-6 In certain embodiments, R 1 is -C(O)NR 6 R 7 is heteroaryl substituted with R 6 and R 7 can be joined together and optionally R 10 In certain embodiments, R 1 is -C(O)NR 6 R 7 is heteroaryl substituted with R 6 and R 7 can be joined together and optionally R 10 In certain embodiments, R 1 -NR 6 R 7 In certain embodiments, R is a heteroaryl substituted with 1 is -N(C 1-6 In certain embodiments, R 1 is heteroaryl substituted with -N(Me). In certain embodiments, R 1is heteroaryl substituted with -NH. In certain embodiments, R 1 is heteroaryl substituted with -NHMe.

[0086] In certain embodiments, R 1 is one or two R 4a In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing one nitrogen. 1 is one or two R 4a In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing two nitrogen atoms. 1 is one or two R 4a In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing three nitrogen atoms. 1 is one or two R 4a In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing one nitrogen and one oxygen. 1 is one or two R 4a In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing one nitrogen and one sulfur. 1 is one or two R 4a In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing two nitrogen atoms and one sulfur. 1 is one or two R 4a In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing two nitrogen atoms and one oxygen atom. 1 is one or two R 4a In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing one oxygen and one sulfur. 1 is one or two R 4aIn certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing one sulfur. 1 is one or two R 4a A heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing one oxygen.

[0087] In certain embodiments, R 1 is one R 4a R is a heterocycloalkyl substituted with a 4b is hydrogen. In certain embodiments, R 1 There are two R 4a R is a heterocycloalkyl substituted with a 4b is hydrogen. In certain embodiments, R 1 is one R 4a R is a heterocycloalkyl substituted with a 4b is cyano. In certain embodiments, R 1 There are two R 4a R is a heterocycloalkyl substituted with a 4b is cyano. In certain embodiments, R 1 is C 1-6 Heterocycloalkyl substituted with haloalkyl; R 4b is hydrogen. In certain embodiments, R 1 is C 1-6 Heterocycloalkyl substituted with haloalkyl; R 4b is cyano. In certain embodiments, R 1 is C 1-6 Heterocycloalkyl substituted with alkyl, R 4b is hydrogen. In certain embodiments, R 1 is C 1-6 Heterocycloalkyl substituted with alkyl, R 4b is cyano. In certain embodiments, R 1 is heterocycloalkyl substituted with methyl; R 4b is cyano.

[0088] In certain embodiments, R 1 teeth, [ka] is selected from.

[0089] In certain embodiments, R 1 teeth, [ka] is selected from.

[0090] In certain embodiments, R 1 teeth, [ka] is selected from R 4a is -C(O)NR 6 R 7 , C 1-6 Alkyl, and -CHNR 6 R 7 is selected from R 6 and R 7 are independently hydrogen, C 1-6 Alkyl and Heteroaryl C 1-6 alkyl; Or, R 6 and R 7 can be joined together and optionally R 10 forming a heterocyclic or biheterocyclic ring substituted with R 10 -COOH, -NH2, -NHMe, and heteroaryl C 1-6 is selected from alkyl.

[0091] In certain embodiments, R 1 teeth, [ka] is selected from.

[0092] In certain embodiments, R 1 teeth, [ka] is selected from.

[0093] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] It is.

[0094] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 4b is cyano. In certain embodiments, R 4b is hydrogen. In certain embodiments, R 4b is cyano and R 4a is hydrogen. In certain embodiments, R 4b is cyano and R 4a is C 1-6 In some cases, R 4b is cyano and R 4a is methyl. In certain embodiments, R 4b is cyano and R 4a is C 1-6 In certain embodiments, R 4b is cyano and R 4a is CHF. In certain embodiments, R 4b is hydrogen and R 4a is methyl.

[0095] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] It is.

[0096] In certain embodiments, R 1 teeth, [ka] is selected from.

[0097] In certain embodiments, R 1 teeth, [ka] is selected from.

[0098] In certain embodiments, R 1 teeth, [ka] is selected from.

[0099] In certain embodiments, R 1 teeth, [ka] is selected from.

[0100] In certain embodiments, R 1 teeth, [ka] is selected from.

[0101] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] is selected from.

[0102] In certain embodiments, R 1 teeth, [ka] is selected from.

[0103] In certain embodiments, R 1 teeth, [ka] is selected from.

[0104] In certain embodiments, R 2 is one or two R 5 In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing one nitrogen. 2 is one or two R 5In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing two nitrogen atoms. 2 is one or two R 5 In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing one nitrogen and one oxygen. 2 is one or two R 5 In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing one nitrogen and one sulfur. 2 is one or two R 5 In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing two nitrogen atoms and one sulfur. 2 is one or two R 5 In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing two nitrogen atoms and one oxygen. 2 is one or two R 5 In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, the heteroaryl or heterocycle containing one oxygen and one sulfur. 2 is one or two R 5 In certain embodiments, R is a heteroaryl or heterocycle substituted with a group, wherein the heteroaryl or heterocycle contains one sulfur. 2 is one or two R 5 A heteroaryl or heterocycle substituted with a group, wherein the heteroaryl or heterocycle contains one oxygen.

[0105] In certain embodiments, R 2 is one R 5 In certain embodiments, R is an aryl substituted with a aryl group. 2 There are two R 5 In certain embodiments, R is an aryl substituted with a aryl group. 2 is aryl substituted with halogen. In certain embodiments, R 2is aryl substituted with chlorine. In certain embodiments, R 2 is C 1-6 In certain embodiments, R is an aryl substituted with an alkyl. 2 is aryl substituted with methyl. In certain embodiments, R 2 is C 1-6 In certain embodiments, R is an aryl substituted with haloalkyl. 2 is aryl substituted with CF. In certain embodiments, R 2 is C 1-6 In certain embodiments, R is an aryl substituted with alkoxy. 2 is aryl substituted with methoxy. In certain embodiments, R 2 is aryl substituted with cyano.

[0106] In certain embodiments, R 2 is one R 5 In certain embodiments, R is a heteroaryl substituted with a aryl group. 2 There are two R 5 In certain embodiments, R is a heteroaryl substituted with a aryl group. 2 is heteroaryl substituted with halogen. In certain embodiments, R 2 is heteroaryl substituted with chlorine. In certain embodiments, R 2 is C 1-6 In certain embodiments, R is heteroaryl substituted with alkyl. 2 is heteroaryl substituted with methyl. In certain embodiments, R 2 is C 1-6 In certain embodiments, R is heteroaryl substituted with haloalkyl. 2 is heteroaryl substituted with CF. In certain embodiments, R 2 is C 1-6 In certain embodiments, R is heteroaryl substituted with alkoxy. 2 is heteroaryl substituted with methoxy. In certain embodiments, R 2 is heteroaryl substituted with cyano.

[0107] In certain embodiments, R 2 teeth, [ka] It is.

[0108] In certain embodiments, R 2 teeth, [ka] is selected from.

[0109] In certain embodiments, R 2 teeth, [ka] It is.

[0110] In certain embodiments, R 2 teeth, [ka] It is.

[0111] In certain embodiments, R 2 is any one R 5 aryl substituted with R 1 is one R 4a In certain embodiments, R is a heterocycle substituted with a group. 2 is any one R 5 aryl substituted with R 1 is one R 4a In certain embodiments, R is an aryl substituted with a aryl group. 2 is any one R 5 aryl substituted with R 1 is one R 4a In certain embodiments, R is a heteroaryl substituted with a aryl group. 2is any one R 5 is a heteroaryl substituted with a group, 1 is one R 4a Groups each independently represent heteroaryl substituted with a heteroaryl group.

[0112] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] It is.

[0113] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] In certain embodiments, R 2 teeth, [ka] and R 1 teeth [ka] It is.

[0114] In certain embodiments, R 4a -NR 6 R7 , -CH2NR 6 R 7 or -C(O)NR 6 R 7 and R 6 and R 7 are joined together to form R 6 and R 7 In certain embodiments, the biheterocycle is a bridged heterocycle. In certain embodiments, the bridged heterocycle is a ring that is formed by bonding at least one oxygen, nitrogen, or sulfur ring including the nitrogen to which R is attached. 6 and R 7 In certain embodiments, the bridged heterocycle contains two nitrogen atoms, one of which is the nitrogen to which R is attached. 6 and R 7 is attached to the nitrogen atom. In certain embodiments, the bridged heterocycle is selected from quinuclidine, adamantane, 8-azabicyclo[3.2.1]octane, and 1,4-diazabicyclo[2.2.2]octane. In certain embodiments, R 4a -NR 6 R 7 , -CH2NR 6 R 7 or -C(O)NR 6 R 7 and R 6 and R 7 are joined together to form R 6 and R 7 In certain embodiments, the heterocycle contains at least one oxygen, nitrogen, or sulfur, including the nitrogen to which R is attached. In certain embodiments, the heterocycle contains one nitrogen and one oxygen. In certain embodiments, the heterocycle contains one nitrogen. In certain embodiments, the heterocycle contains two nitrogen atoms. In certain embodiments, the heterocycle contains three nitrogen atoms. In certain embodiments, R 6 and R 7 can be joined together and optionally R 10 In certain embodiments, R 6 and R 7 can be joined together and optionally R 10In certain embodiments, R 6 and R 7 can be joined together and optionally R 10 In certain embodiments, R 6 and R 7 can be joined together and optionally R 10 In certain embodiments, R 10 is COOH. In certain embodiments, R 10 is amino. In certain embodiments, R 10 is -NHMe. In certain embodiments, R 10 Heterocyclo C 1-6 In certain embodiments, heterocycloC is alkyl. 1-6 Alkyl is selected from pyrazole, imidazole, imidazoline, pyrazoline, imidazolidine, pyrazolidine, pyrrole, pyrroline, and pyrrolidine.

[0115] In certain embodiments, R 4a -NR 6 R 7 , -CH2NR 6 R 7 or -C(O)NR 6 R 7 and R 6 and R 7 are independently hydrogen and C 1-6 In certain embodiments, R 4a is -C(O)NR 6 R 7 and R 6 and R 7 are independently hydrogen and C 1-6 In certain embodiments, R 4a is -C(O)NR 6 R 7 and R 6 and R 7 Both are C 1-6 In certain embodiments, R 4a is -C(O)NR 6 R 7 and R6 and R 7 and R are both methyl. 4a is -C(O)NR 6 R 7 and R 6 is C 1-6 is alkyl, R 7 Heterocyclo C 1-6 In certain embodiments, R 4a is -C(O)NR 6 R 7 and R 6 is C 1-6 is alkyl, R 7 is heterocycloC alkyl. In certain embodiments, R 4a is -C(O)NR 6 R 7 and R 6 is methyl, R 7 is heterocycloC alkyl. In certain embodiments, R 4a is -C(O)NR 6 R 7 and R 6 is C 1-6 is alkyl, R 7 There are two R 10 HeterocycloC2 alkyl substituted with a group, 10 The groups taken together form an oxo group.

[0116] In certain embodiments, R 4a is -(CH2) a -O-(CH2) b R 8 where a is 1 and b is 1. In certain embodiments, R 4a is -(CH2) a -O-(CH2) b R 8 where a is 1 and b is 2. In certain embodiments, R 4a is -(CH2) a -O-(CH2) b R 8 where a is 1 and b is 3 or 4. In certain embodiments, R 4ais -(CH2) a -O-(CH2) b R 8 where a is 2 and b is 1. In certain embodiments, R 4a is -(CH2) a -O-(CH2) b R 8 wherein a is 2 and b is 2. In certain embodiments, R 4a is -(CH2) a -O-(CH2) b R 8 where a is 2 and b is 3 or 4. In certain embodiments, R 8 is OH. In certain embodiments, R 8 is COOH. In certain embodiments, R 8 is an amino.

[0117] In certain embodiments, R 6 and R 7 are joined together to form R 6 and R 7 In certain embodiments, R forms a heterocycle containing at least one oxygen, nitrogen, or sulfur, including the nitrogen to which R is attached. 6 and R 7 are joined together to form R 6 and R 7 In certain embodiments, R 6 and R 7 are linked to form a heterocycle containing two nitrogen atoms, one of which is R 6 and R 7 is the nitrogen to which is attached. In certain embodiments, R 6 and R 7 are joined together to form a heterocycle containing one nitrogen and one oxygen, the nitrogen being R 6 and R 7 is the nitrogen to which is attached. In certain embodiments, R 6 and R 7 are joined together to form R 6 and R 7In certain embodiments, R forms a biheterocycle containing at least one oxygen, nitrogen, or sulfur, including the nitrogen to which R is attached. 6 and R 7 are joined together to form R 6 and R 7 In certain embodiments, R 6 and R 7 are joined together to form a biheterocycle containing at least two nitrogen atoms, one of which is R 6 and R 7 is the nitrogen to which is attached. In certain embodiments, R 6 and R 7 are joined together to form a two-heterocycle containing one nitrogen and one oxygen, the nitrogen being R 6 and R 7 is the nitrogen to which it is bonded.

[0118] In certain embodiments, X 1 is N. In certain embodiments, X 1 is CH.

[0119] In certain embodiments of formula (III), L 2 teeth, [ka] In certain embodiments of formula (III), L 2 teeth, [ka] In certain embodiments of formula (III), L 2 teeth, [ka] It is.

[0120] In certain embodiments of Formula (III), Y is NR 15In certain embodiments of formula (III), Y is NR 15 and R 15 is -C(O)R 9 In certain embodiments of formula (III), Y is NR 15 and R 15 is -C(O)R 9 and R 9 is C 1-6 In certain embodiments of formula (III), Y is NR 15 and R 15 is -C(O)R 9 and R 9 In certain embodiments of formula (III), Y is NR 15 and R 15 is hydrogen. In certain embodiments of formula (III), Y is NR 15 and R 15 is C 1-6 In certain embodiments of formula (III), Y is NR 15 and R 15 is methyl. In certain embodiments of formula (III), Y is O. In certain embodiments of formula (III), Y is CR 16 R 17 In certain embodiments of formula (III), Y is CH2.

[0121] Non-limiting examples of formula (I) include: [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof.

[0122] Non-limiting examples of formula (II) include: [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof.

[0123] Non-limiting examples of formula (Ia) include: [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof.

[0124] Non-limiting examples of formula (Ib) include: [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof.

[0125] In certain embodiments of formula (Ib), R 4b In certain embodiments of formula (Ib), R 4b is hydrogen. In certain embodiments of formula (Ib), R 4a is methyl. In certain embodiments of Formula (Ib), R 4b is cyano and R 4a is methyl. In certain embodiments of Formula (Ib), R 5 is chloro.

[0126] Non-limiting examples of formula (Ic) or formula (Id) include: [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof.

[0127] In certain embodiments of Formula (Ic) or Formula (Id), R 10 is C(O)NR 6 R 7 In certain embodiments of formula (Ic) or formula (Id), R 10 is -CH2NR 6 R 7 In certain embodiments of formula (Ic) or formula (Id), R 10 is C 1-6In certain embodiments of Formula (Ic) or Formula (Id), R 10 is methyl.

[0128] Non-limiting examples of formulas (IIa) and (IIb) include: [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof.

[0129] Non-limiting examples of formula (IIb) include: [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof.

[0130] Non-limiting examples of formula (IIc) or formula (IId) include: [ka] or a pharma- ceutically acceptable salt, diastereomer, or stereoisomer thereof.

[0131] In certain embodiments of Formula (IIc) or Formula (IId), R 10 is -C(O)NR 6 R 7 In certain embodiments of Formula (IIc) or Formula (IId), R 10 is -CH2NR 6 R 7 In certain embodiments of Formula (IIc) or Formula (IId), R 10 is C 1-6 In certain embodiments of Formula (IIc) or Formula (IId), R 10 is methyl.

[0132] Non-limiting examples of formula (III) include: [ka] Examples include:

[0133] In certain embodiments, there is provided a compound in Table 1 below, or a pharmaceutical salt, diastereomer, stereoisomer, and / or mixture thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0134] optically active compound In certain embodiments, the compounds provided herein may have some chiral centers and may exist and be isolated in optically active racemic form. In certain embodiments, some compounds may exhibit polymorphism. Those skilled in the art will understand that the compounds provided herein may exist in any racemic, optically active, diastereomeric, polymorphic, or stereoisomeric form, and / or mixtures thereof. Those skilled in the art will also understand that such compounds described herein that have the useful properties described herein are within the scope of the present disclosure. Those skilled in the art will further understand how to prepare optically active forms of the compounds described herein, for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. Furthermore, most amino acids are chiral (i.e., designated L- or D-, with the L-enantiomer being the naturally occurring configuration) and can exist as separate enantiomers.

[0135] Examples of methods for obtaining optically active materials are known in the art and include at least the following: i) Physical separation of crystals - a technique in which macroscopic crystals of the individual enantiomers are manually separated. This technique can be used when crystals of the separate enantiomers are present (i.e. the material is a conglomerate and the crystals are visually distinct); ii) simultaneous crystallization - a technique in which the individual enantiomers are crystallized separately from a solution of the racemate only if the racemate is a conglomerate in the solid state; iii) Enzymatic resolution - a technique that exploits the different reaction rates of the enantiomers in the presence of an enzyme to achieve partial or complete separation of the racemate; iv) enzymatic asymmetric synthesis - a synthetic procedure that uses an enzymatic reaction in at least one step of the synthesis to obtain an enantiomerically pure or enriched synthetic precursor of a desired enantiomer; v) Chemical asymmetric synthesis - a synthetic technique in which a desired enantiomer is synthesized from an achiral precursor using a chiral catalyst or chiral auxiliary to create asymmetry (i.e., chirality) in the product; vi) Diastereomeric separation - a technique in which a racemate is treated with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to more distinct diastereomeric differences, and the chiral auxiliary is then removed to give each enantiomer. vii) First and second order asymmetric transformations - procedures in which racemic diastereomers are equilibrated in solution in favor of the diastereomer of the desired enantiomer, or kinetic or thermodynamic crystallization of the diastereomer of the desired enantiomer perturbs the equilibrium, so that essentially all of the material is eventually converted to the crystalline diastereomer of the desired enantiomer. The desired enantiomer is then derived from the diastereomer. viii) Kinetic Resolution- This technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) due to different rates of reaction of enantiomers with chiral or non-racemic reagents, or catalysts, under kinetic conditions. ix) Enantiospecific synthesis from non-racemic precursors - a synthetic approach in which the desired enantiomer is obtained from chiral starting materials and in which the stereochemical integrity is not or only minimally compromised during the synthesis; x) Chiral Liquid Chromatography - a technique in which the enantiomers of a racemate are separated in a liquid mobile phase by differential interactions with a stationary phase. The stationary phase can be made of a chiral substance or the mobile phase can contain additional chiral substances that cause different interactions. xi) Chiral gas chromatography - a technique in which columns containing a fixed non-racemic adsorbent phase are used to volatilize the racemate and separate the enantiomers by their different interactions in the gaseous mobile phase; xii) Chiral solvent extraction - a technique for separating enantiomers by kinetic or thermodynamic dissolution of one enantiomer in a specific chiral solvent; xiii) Transport across chiral membranes - a technique in which a racemate is placed in contact with a thin membrane barrier. The barrier usually separates two miscible fluids containing the racemate, and a driving force such as concentration or pressure difference causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[0136] In some embodiments, compositions of compounds of any of formulas (I)-(III) that are substantially free of the specified stereoisomer of the compound are provided herein. In certain embodiments, in the methods and compounds of the present disclosure, the compounds are substantially free of other diastereomers, including other diastereomer(s). In some embodiments, the compositions include at least 85%, 90%, 95%, 98%, or 99% to 100% by weight of the compound, with the remainder including other species or enantiomers. In some embodiments, compositions of compounds of any of formulas (I)-(III) that are substantially free of the specified enantiomer of the compound are provided herein. In certain embodiments, in the methods and compounds of the present disclosure, the compounds are substantially free of other enantiomers. In some embodiments, the compositions include at least 85%, 90%, 95%, 98%, or 99% to 100% by weight of the compound, with the remainder including other species or enantiomers.

[0137] isotopically enriched compounds Also provided herein are isotopically enriched compounds, including but not limited to, isotopically enriched compounds of any of Formulas (I)-(III).

[0138] Isotopic enrichment (e.g., deuteration) of pharmaceuticals to improve pharmacokinetic ("PK"), pharmacodynamic ("PD"), and / or toxicity profiles has previously been demonstrated for several classes of drugs. See, e.g., Lijinsky et al., Food Cosmet. Toxicol., 20:393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et al., Mutation Res. 308:33 (1994); Gordon et al., Drug Metab. Dispos., 15:589 (1987); Zello et al., Metabolism, 43:487 (1994); Gately et al., J. Nucl. Med., 27:388 (1986); Wade D, Chem. Biol. Interact. 117:191 (1999).

[0139] Isotopic enrichment of drugs can be used, for example, to (1) reduce or eliminate undesirable metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses required to achieve a desired effect, (4) decrease the dosage required to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and / or (6) decrease the production of harmful metabolites in specific tissues. Isotopic enrichment of drugs can also be used to make more effective and / or safer drugs for combination therapy, whether or not the combination therapy is intended.

[0140] Substitution of an atom with one of its isotopes will often result in a change in the reaction rate of a chemical reaction. This phenomenon is known as kinetic isotope effect ("KIE"). For example, if a C-H bond is broken during the rate-limiting step of a chemical reaction (i.e., the step with the highest transition state energy), substitution of its reactive hydrogen with a (heavier) isotope will cause a decrease in the reaction rate. The deuterium kinetic isotope effect ("DKIE") is the most common form of KIE. (See, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

[0141] The magnitude of the DKIE can be expressed as the ratio of the rate of a given reaction in which a C-H bond is broken to the rate of the same reaction in which deuterium is replaced with hydrogen and a C-D bond is broken. The DKIE can range from about 1 (no isotope effect) to very large numbers, e.g., 50 or more, meaning that the reaction can be 50 times slower or more when hydrogen is replaced with deuterium.

[0142] The substitution of tritium ("T") for hydrogen results in a much stronger bond than deuterium, giving a numerically larger isotope effect. 13 C, or 14 C; for sulfur 33 S, 34 S, or 36 S; for nitrogen 15 N; and oxygen 17 O, or 18 Isotopic substitution with other elements, including O, may result in similar kinetic isotope effects.

[0143] Animal bodies express a variety of enzymes for the purpose of clearing foreign substances, such as therapeutic drugs, from their circulatory system. Examples of such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases that react with these foreign substances and convert them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of carbon-hydrogen (CH) bonds to either carbon-oxygen (CO) or carbon-carbon (C=C) pi bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different PK / PD and acute and long-term toxicity profiles compared to the parent compound. For many drugs, such oxidation is rapid. Thus, these drugs often require multiple daily or high dose administration.

[0144] Thus, isotopic enrichment at specific positions of the compounds provided herein will produce detectable KIEs that affect the pharmacological, PK, PD, and / or toxicological profiles of the compounds provided herein compared to similar compounds having natural isotopic composition.

[0145] Compositions and Uses Pharmaceutical Compositions and Methods of Administration The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and disclosed herein. Any of the compounds provided herein can be provided in a suitable pharmaceutical composition and administered by a suitable route of administration.

[0146] The methods provided herein include administering a pharmaceutical composition comprising at least one compound provided herein and one or more compatible, pharma- ceutically acceptable carriers. In this context, the term "pharmaceutical acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and in certain embodiments, for use in humans. The term "carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle in which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Martin, EW, Remington's Pharmaceutical Sciences.

[0147] In clinical practice, the pharmaceutical compositions or compounds provided herein may be administered by any route known in the art. Exemplary administration routes include, but are not limited to, inhalation, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, oral, and subcutaneous routes. In some embodiments, the pharmaceutical compositions or compounds provided herein are administered parenterally. In some embodiments, the pharmaceutical compositions or compounds provided herein are administered orally.

[0148] The composition for parenteral administration may be an emulsion or a sterile solution. The parenteral composition may contain, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). These compositions may also contain wetting agents, isotonicity agents, emulsifying agents, dispersing agents, and stabilizing agents. Sterilization can be carried out in several ways, such as by using a bacteriological filter, by irradiation, or by heating. The parenteral composition can also be prepared in the form of a sterile solid composition that can be dissolved at the time of use in sterile water or any other injectable sterile medium.

[0149] In some embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic compounds.

[0150] A pharmaceutical composition may include one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art can select a suitable pharmaceutical excipient. Non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form is administered to a subject and the particular compound in the dosage form. A composition or single unit dosage form may also contain minor amounts of wetting agents, or emulsifying agents, or pH buffering agents, if desired. Thus, the pharmaceutical excipients provided below are illustrative and not limiting. Additional pharmaceutical excipients include, for example, those described in Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), which is incorporated herein by reference in its entirety.

[0151] In some embodiments, the pharmaceutical composition includes an antifoaming agent. Any suitable antifoaming agent may be used. In some aspects, the antifoaming agent is selected from alcohols, ethers, oils, waxes, silicones, surfactants, and combinations thereof. In some aspects, the antifoaming agent is selected from mineral oils, vegetable oils, ethylene bisstearamide, paraffin wax, ester wax, fatty alcohol wax, long chain fatty alcohols, fatty acid soaps, fatty acid esters, silicone glycols, fluorosilicones, polyethylene glycol-polypropylene glycol copolymers, polydimethylsiloxane-silicon dioxide, ethers, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethylhexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.

[0152] In some embodiments, the pharmaceutical composition comprises a co-solvent. Specific examples of co-solvents include ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol.

[0153] In some embodiments, the pharmaceutical composition comprises a buffer, specific examples of which include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.

[0154] In some embodiments, the pharmaceutical composition includes a carrier or filler. Specific examples of carriers or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.

[0155] In some embodiments, the pharmaceutical composition comprises a surfactant. Specific examples of surfactants include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene (glycol) succinate.

[0156] In some embodiments, the pharmaceutical composition comprises an anticoagulant. Specific examples of anticoagulants include calcium phosphate (tribasic), hydroxymethylcellulose, hydroxypropylcellulose, and magnesium oxide.

[0157] Other excipients that may be used with the pharmaceutical composition include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, release control agents, diluents, dispersants, solubility enhancers, emulsifiers, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizers, solvents, stabilizers, and sugars. Specific examples of each of these agents are described, for example, in Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), the entire contents of which are incorporated herein by reference.

[0158] In some embodiments, the pharmaceutical composition comprises a solvent. In some aspects, the solvent is a saline solution, such as sterile isotonic saline or a dextrose solution. In some aspects, the solvent is water for injection.

[0159] In some embodiments, the pharmaceutical composition is in particulate form, such as a microparticle or nanoparticle. The microparticles and nanoparticles can be formed from any suitable material, such as a polymer or lipid. In some aspects, the microparticle or nanoparticle is a micelle, liposome, or polymersome.

[0160] In some embodiments, furthermore, provided herein are anhydrous pharmaceutical compositions and dosage forms comprising the compounds since water can facilitate the degradation of some compounds.

[0161] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that contain at least one active ingredient that contains lactose and a primary or secondary amine can be anhydrous if substantial contact with steam and / or moisture is expected during manufacturing, packaging, and / or storage.

[0162] Anhydrous pharmaceutical compositions can be prepared and stored in such a way that anhydrous nature is maintained.Therefore, anhydrous compositions can be packaged using known materials to prevent exposure to water, so that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0163] The lactose-free compositions provided herein may contain excipients that are well known in the art and are listed, for example, in the United States Pharmacopoeia (USP) SP(XXI) / NF(XVI).In general, lactose-free compositions contain active ingredients, binders / fillers, and lubricants in pharma- ceutically compatible and pharma-ceutically acceptable amounts.Exemplary lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0164] Pharmaceutical compositions and dosage forms that contain one or more excipients that reduce the rate at which the compound decomposes are also provided. Such excipients, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants, such as ascorbic acid, pH buffers, or salt buffers.

[0165] Parenteral Dosage Forms In certain embodiments, parenteral dosage forms are provided. Parenteral dosage forms can be administered to subjects by various routes, including but not limited to subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration usually circumvents the subject's natural defense against contaminants, parenteral dosage forms are usually sterile or can be sterilized before administration to subjects. Examples of parenteral dosage forms include, but are not limited to, ready-to-inject solutions, dry products that are ready to be dissolved or suspended in a pharma- ceutically acceptable vehicle for injection, ready-to-inject suspensions, and emulsions.

[0166] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art.Examples include, but are not limited to, USP Water for Injection; aqueous vehicles, such as but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles, such as but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, such as but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0167] Excipients that increase the solubility of one or more of the antibodies disclosed herein can also be incorporated into the parenteral dosage form.

[0168] Oral dosage form In certain embodiments, oral dosage forms are provided.The compounds described herein can be formulated using any desired method, including formulating the compounds as solvent-free chemicals (e.g., powder, morphic form, amorphous form, or oil) or mixing the compounds with pharmaceutically acceptable excipients.The resulting pharmaceutically acceptable composition for oral delivery contains an effective amount of the compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

[0169] Representative dosage forms for oral administration include pills, tablets, capsules, gel capsules, solutions, suspensions, or emulsions. The dosage form may also be considered compartmentalized. For example, the dosage form may have different layers of material with different excipients or different excipient concentrations when it is a pill, tablet, or capsule. For example, enteric coated oral tablets may be used to enhance the bioavailability of the compound in the oral route of administration. The enteric coating would be a layer of excipients that allows the tablet to withstand gastric acid. In certain embodiments, the oral dosage form contains one or more additional active agents as described herein. In certain embodiments, the second active agent is administered separately from the compound of the present invention.

[0170] In another embodiment, one dosage form may be converted to another dosage form to favorably improve properties. For example, when preparing a solid pharma- ceutically acceptable composition, a suitable liquid formulation may be lyophilized. The solid may be reconstituted with a suitable carrier or diluent prior to administration. Oral pharmaceutical compositions may contain any amount of active compound that achieves the desired result, for example, 0.1 to 99% by weight (wt.%) of the compound, typically at least about 5% by weight of the compound.

[0171] Some embodiments contain at least about 10%, 15%, 20%, 25% to about 50%, or about 5% to about 75% by weight of the compound. Oral dosage forms can be administered as needed, for example, once daily (qd), twice daily (bid), three times daily (tid), four times daily (qid), once every two days (Q2d), once every three days (Q3d), or any dosing schedule that provides treatment for the disorders described herein.

[0172] Dosage and unit dosage forms In human therapy, the physician will determine the pharmacology which he considers most appropriate depending on the prophylactic or therapeutic treatment, as well as on the age, weight, condition and other factors specific to the subject to be treated.

[0173] In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibodies, or antigen-binding fragments thereof.

[0174] The amount of a compound or composition effective for preventing or treating a disorder or one or more symptoms thereof will vary depending on the nature and severity of the disease or condition, and the route by which the compound is administered. The frequency and dosage will also vary according to factors specific to each subject, depending on the specific treatment (e.g., therapeutic or prophylactic agent) administered, the severity of the disorder, disease, or condition, the route of administration, and the subject's age, weight, response, and past medical history. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0175] In certain embodiments, exemplary doses of the compositions include milligram or microgram amounts of compound per kilogram of subject or per sample weight (e.g., from about 10 micrograms per kilogram to about 50 milligrams per kilogram, from about 100 micrograms per kilogram to about 25 milligrams per kilogram, or from about 100 micrograms per kilogram to about 10 milligrams per kilogram). In certain embodiments, dosages of the compounds provided herein are 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg or more of the subject's body weight based on the weight of the compound administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject. In another embodiment, the dosage of a composition, or of a composition provided herein, administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is between 0.1 mg and 200 mg, 0.1 mg and 100 mg, 0.1 mg and 50 mg, 0.1 mg and 25 mg, 0.1 mg and 20 mg, 0.1 mg and 15 mg, 0.1 mg and 10 mg, 0.1 mg and 7.5 mg, 0.1 mg and 5 mg, 0.1 and 2.5 mg, 0.25 mg and 20 mg, 0. 25-15mg, 0.25-12mg, 0.25-10mg, 0.25mg-7.5mg, 0.25mg-5mg, 0.25mg-2.5mg, 0.5mg-20mg, 0.5-15mg, 0.5-12mg, 0.5-10mg, 0.5mg-7.5mg, 0.5mg-5mg, 0.5mg-2.5mg, 1mg-20mg, 1mg-15mg, 1mg-12mg, 1mg-10mg, 1mg-7.5mg, 1mg-5mg, or 1mg-2.5mg.

[0176] Dosage can be administered according to suitable schedule, for example, once, twice, three times or four times a week.In some cases, it may be necessary to use the dose of compound outside the range disclosed herein, as will be clear to those skilled in the art.Furthermore, it should be noted that the clinician or treating physician will know when and how to interrupt, adjust or terminate treatment depending on the subject's response.

[0177] As those skilled in the art will readily know, different therapeutically effective amounts may be applicable to different diseases and conditions.Similarly, amounts sufficient to prevent, manage, treat or improve such disorders, but insufficient to cause or reduce the adverse effects associated with the compounds provided herein, are also encompassed by the dosage and administration frequency schedules described herein.Furthermore, when a subject is administered multiple doses of the compositions provided herein, not all doses need to be the same.For example, the dosage administered to a subject may be increased to improve the preventive or therapeutic effect of the composition, or may be decreased to reduce one or more side effects experienced by a particular subject.

[0178] In certain embodiments, treatment or prophylaxis may be initiated with one or more loading doses, followed by one or more maintenance doses of a compound or composition provided herein.

[0179] In certain embodiments, a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the compound in the blood or serum of a subject. The steady-state concentration can be determined by measuring according to techniques available to those skilled in the art, or can be based on the subject's physical characteristics, such as height, weight, and age.

[0180] In certain embodiments, administration of the same composition may be repeated and administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0181] therapeutic use For therapeutic use, the compounds are administered to mammals, and in certain embodiments, humans, by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intraarticular, intrasynovial, intrathecal, or intratumoral routes, either intravenously as a bolus or by continuous infusion over a period of time, in a pharmacologic dosage form suitable for such dosage forms, as those known in the art and discussed herein. The compounds are also suitably administered by peritumoral, intralesional, or perilesional routes to exert local and systemic therapeutic effects. In certain embodiments, the compounds are administered to mammals, and in certain embodiments, humans, in a pharmacologic dosage form suitable for such oral dosage forms, as those known in the art and discussed herein. For example, the compounds of the present disclosure may be orally administered to humans in liquid or solid form. Solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity may be mixed with one or more pharma- ceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato denaturant, and the like. The granules are mixed with starch or tapioca, alginic acid, certain silicates, and sodium carbonate, e) dissolution retarders, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. A similar type of solid composition may also be used as a filler in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0182] The compounds provided herein may be useful for treating any disease or condition described herein (e.g., any disease or condition for which inhibition of USP28 is beneficial). In certain embodiments, the disease or condition is any disease or condition that benefits from inhibition of USP28. In one embodiment, the disease or condition is a disorder of abnormal cell proliferation mediated by USP28. Examples of proliferative disorders include, but are not limited to, benign tumors, neoplasms, tumors, cancer, autoimmune disorders, inflammatory diseases, graft-versus-host rejection, and fibrotic disorders. Abnormal cell proliferation, particularly hyperproliferation, can result from a variety of factors, including genetic mutations, infections, exposure to toxins, autoimmune disorders, and induction of benign or malignant tumors.

[0183] In one embodiment, the compounds described herein are administered in an effective amount to a host, including a human, to treat a tumor, cancer (such as solid, non-solid, diffuse, or hematological cancer), abnormal cell proliferation, an immune disorder, an inflammatory disease, a hematological disease, a bone marrow or lymphoproliferative disorder, such as B-cell or T-cell lymphoma, multiple myeloma, breast cancer, prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colon cancer, skin cancer, melanoma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder; an autoimmune disorder, such as lupus, Crohn's disease, Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, or reactive arthritis. In one embodiment, the compounds described herein are administered in an effective amount to a host, including a human, to treat an infectious disease (including a viral and / or bacterial infection), an inflammatory disease (including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis).

[0184] In some embodiments, the disease or condition is cancer. Non-limiting examples of cancer include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), ), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), neurilemmoma, liver cancer (e.g., For example, primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer), extragonadal germ cell tumors, ovarian germ cell tumors, low-grade ovarian tumors), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (eye) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), parathyroid cancer, These include adenocarcinoma, nasal cancer, paranasal sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, pediatric solid tumors (e.g., Wilms' tumor, pediatric kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma due to AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0185] Further non-limiting examples of cancers include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary tract cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma, breast carcinoma, medullary breast carcinoma), brain cancer (e.g., meningioma, Gliomas (e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), uterine cancer (e.g., uterine carcinoma, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's disease, adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familial eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC)), pharyngeal cancer (e.g., laryngeal carcinoma, pharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma)), hematopoietic cancer (e.g., leukemia, e.g., acute lymphocytic leukemia (ALL) - hereinafter also known as acute lymphoblastic leukemia or acute lymphocytic leukemia (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL);Lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (SCL), i.e., "Waldenstrom's macroglobulinemia"), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-associated T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the above leukemias / lymphomas;and multiple myeloma (MM)), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immune cell amyloidosis, kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., total lung cancer, pulmonary sarcoma, pulmonary fibrosis ... mastocytosis), myelodysplastic syndromes (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia of unknown etiology (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroendocrine carcinoma (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keloids, sarcomas ... latoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovium, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva);

[0186] In some embodiments, the cancer is a cancer that is sensitive to USP28 inhibition.

[0187] The cancer can be any cancer of any organ, such as a cancer selected from the group consisting of glioma, thyroid cancer, breast cancer, small cell lung cancer, non-small cell carcinoma, gastric cancer, colon cancer, gastrointestinal stromal cancer, pancreatic cancer, bile duct cancer, CNS cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cancer, anaplastic large cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof.

[0188] In certain embodiments, the cancer is a solid tumor. A solid tumor as used herein refers to an abnormal mass of tissue that does not usually contain cysts or liquid areas. Various types of solid tumors are named for the type of cells that form them. Examples of classes of solid tumors include, but are not limited to, sarcomas, carcinomas, and lymphomas, as described herein above. Further examples of solid tumors include, but are not limited to, squamous cell carcinoma, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma.

[0189] In some embodiments, the cancer is characterized by gene amplification and / or increased USP28, USP25, MYC, LSD1, NICD1, c-JUN, Notch-1, Claspin, CHK2, 53BP1, MDC1, and / or HIF-1α tumor expression compared to histomatch expression, and / or decreased expression of FBXW7.

[0190] In some embodiments, the disease or condition is an autoimmune disorder, non-limiting examples of which include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves' disease.

[0191] Further autoimmune disorders include inflammatory diseases of the intestine, ulcerative colitis, Crohn's disease, and polyarthritis, localized and systemic scleroderma, discoid lupus erythematosus, cutaneous lupus, cutaneous lupus erythematosus (including chilblain lupus erythematosus), lupus nephritis, discoid lupus, subacute cutaneous lupus erythematosus, dermatomyositis, polymyositis, idiopathic myxedema, Hashimoto's disease, Guillain-Barre syndrome, Graves' disease, Sjogren's syndrome, panarteritis nodosa, Autoimmune enteropathy, autoimmune oophoritis, chronic immune thrombocytopenic purpura, colitis, diabetes mellitus, pemphigus vulgaris, proliferative glomerulonephritis, Wiskott-Aldrich syndrome, autoimmune lymphoproliferative syndrome, chronic arthritis, inflammatory chronic rhinosinusitis, colitis, celiac disease, Barrett's esophagus, inflammatory gastritis, autoimmune nephritis, autoimmune vasculitis, autoimmune hepatitis, autoimmune carditis, autoimmune encephalitis, and autoimmune-mediated blood disorders.

[0192] In one embodiment, the autoimmune disorder is psoriasis, a benign disease of human skin generally characterized by thickened, scaly plaques. The disease is caused by increased proliferation of epidermal cells of unknown cause. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma. Other hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancer.

[0193] Vascular proliferative disorders include angiogenesis and angiogenesis disorders. Smooth muscle cell proliferation during plaque development in vascular tissues leads to, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation are involved in the formation of atherosclerotic lesions.

[0194] In some embodiments, the disease or condition is inflammatory disorder.Non-limiting examples of inflammatory disorder include rheumatoid arthritis, spondylitis degenerativeis, osteoarthritis, back pain, gout, postoperative or post-traumatic inflammation, bloating, neuralgia, laryngopharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), inflammation of metabolically important tissues such as liver, fat, pancreas, kidney and intestine, and proinflammatory conditions (for example, elevated levels of proinflammatory cytokines or inflammatory-like C-reactive protein markers in blood).

[0195] In some embodiments, the disease or condition is a neurological disorder (e.g., a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperactivity, mania, Morbus Parkinson, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis I, brain inflammation, Friedrich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), chronic wasting syndrome).

[0196] In certain embodiments, the disease or condition is a viral infection, including, but not limited to, AIDS / HIV (Acquired Immune Deficiency Syndrome), amebiasis, Avian Influenza (Bird Flu), Babesiosis, Avian Influenza (Bird Flu), Botulism, Brucellosis, Campylobacter infection, Chancroid, Chickenpox (Varicella), Chlamydia infection, Ciguatera poisoning, Coccidioidomycosis, Colorado Tick Fever, (2019 Novel Coronavirus) (COV), ID-19), cryptosporidiosis, cysticercosis, dengue fever, diphtheria, domoic acid poisoning (amnesic shellfish poisoning), Escherichia coli infection, Ebola virus (viral hemorrhagic fever, ehrlichiosis, influenza (influenza), gastroenteritis, viral rubella (rubella), giardiasis, glanders, gonorrhea (gonorrhea), Haemophilus influenzae serogroup B disease (Hib), hand, foot and mouth disease, hantavirus infection, hepatitis A, hepatitis B, hepatitis C, human immunodeficiency virus (H IV / AIDS), influenza (influenza), Lassa fever, Legionnaires' disease (Legionnaires' disease), Hansen's disease (Leprosy), leptospirosis, listeriosis, lymphogranuloma venereum (LGV), malaria, Marburg virus hemorrhagic fever, melioidosis, measles, meningitis, meningococcal disease, Middle East respiratory syndrome coronavirus (MERS-CoV), mumps, norovirus infection (Norwalk and Norwalk-like virus infections), nongonococcal urethritis, paralytic shellfish These include: poisoning, whooping cough (pertussis), pneumococcal infection, polio, psittacosis, rabies, relapsing fever, Rocky Mountain spotted fever, respiratory syncytial virus (RSV), salmonellosis, scombroid fish poisoning, bacterial dysentery, smallpox, syphilis, tetanus, toxoplasmosis, trichinosis (trichinosis), tuberculosis (TB), tularemia, typhoid fever, typhus, chickenpox (varicella), viral gastroenteritis and norovirus, West Nile virus, yellow fever, yersiniosis (Yersinia enterocolitica), and Zika virus.

[0197] In certain embodiments, a method of treatment is provided, comprising administering an effective amount of the compound provided herein or its pharma- ceutically acceptable salt.In certain embodiments, the method comprises administering to a subject in need thereof an effective amount of the compound described herein for treating a disease or condition in combination with a second agent effective for treating or preventing a disease or condition.In certain embodiments, the compound is in the form of a pharmaceutical composition or dosage form as described elsewhere herein.

[0198] In certain embodiments, the subject is a treatment-naive subject. In further embodiments, the subject has previously undergone treatment. For example, in certain embodiments, the subject has not responded to a single agent treatment regimen.

[0199] In certain embodiments, the subject is a subject who has discontinued other treatment due to one or more adverse events associated with the treatment. In certain embodiments, the subject is undergoing some other treatment and has discontinued the treatment prior to administration of the methods provided herein. In further embodiments, the subject is undergoing treatment and continues to undergo the treatment with administration of the compounds provided herein. The compounds described herein can be combined with other treatments for the treatment of disease or condition according to the judgment of the skilled artisan. In certain embodiments, the methods or compositions provided herein can be combined with reduced doses of other treatments for the treatment of disease or condition.

[0200] Diagnostic Uses In some embodiments, the compounds provided herein are used in diagnostic applications, which may be useful in diagnosing and / or prognosing a disease or condition (e.g., a metabolic disease or disorder).

[0201] In some diagnostic and prognostic applications or embodiments, the compounds may be labeled with a detectable moiety. Suitable detectable moieties include, but are not limited to, radioisotopes, fluorescent labels, and enzyme substrate labels. In another embodiment, the compounds need not be labeled, and the presence of the compound can be detected using a labeled antibody or antigen-binding fragment thereof that specifically binds to the compound.

[0202] kit In some embodiments, the compounds provided herein are provided in the form of a kit (i.e., a packaged combination of reagents in predetermined amounts with instructions for carrying out a procedure). In some embodiments, the procedure is a diagnostic assay. In certain embodiments, the procedure is a therapeutic procedure.

[0203] In some embodiments, the kit further comprises a solvent for reconstituting the compound, hi some embodiments, the compound is provided in the form of a pharmaceutical composition.

[0204] In some embodiments, the kit may include the compound or composition provided herein, any second agent or composition, and instructions that provide a healthcare provider with information on how to use to treat a disorder. The instructions may be provided in printed form, or in the form of an electronic medium such as a floppy disk, CD, or DVD, or in the form of a website address where such instructions can be obtained. A unit dose of the compound or composition provided herein, or the second agent or composition, may include a dosage that, when administered to a subject, can maintain a therapeutically or prophylactically effective plasma level of the compound or composition in the subject for at least one day. In some embodiments, the compound or composition may be included as a sterile aqueous pharmaceutical composition, or a dry powder (e.g., lyophilized) composition.

[0205] In some embodiments, suitable packaging is provided. As used herein, "packaging" includes solid matrix or materials that are conventionally used in systems and can hold the compounds provided herein and / or second agents suitable for administration to subjects within certain limits. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, plastic foil laminated envelopes, etc. When using e-beam sterilization techniques, packaging must be low enough density to allow sterilization of contents.

[0206] Preparation and synthesis procedures In some embodiments, the compounds described herein are prepared as outlined in Schemes 1-5. The synthesis of the compounds in this application is not limited to the general reaction schemes shown herein. For detailed synthesis of individual compounds, please see the Examples section. EXAMPLES

[0207] Preparation of compounds The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from Acros Organics (Pittsburgh, PA), Advanced ChemBlocks, Inc. (Burlingame, CA), Aldrich Chemical (Milwaukee, WI, e.g., Sigma Chemical and Fluka), AK Scientific (Union City, CA), AstaTech, Inc. (Bristol, PA), Aurum Pharmatech LLC (Franklin Park, NJ), Combi-Blocks, Inc. (San Diego, CA), Enamine (Monmouth Jct., NJ), Fisher Scientific Co. (Pittsburgh, PA), Frontier Scientific (Logan, UT), TCI America (Portland, OR), and VWR (Radnor, PA). Specific reactants and similar reactants are optionally identified through indexes of known chemical substances produced by the Chemical Abstract Service of the American Chemical Society; these indexes are available in most public and university libraries and online databases.

[0208] Suitable reference books detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing their preparation include, for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S.R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; “T.L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley Interscience, New York, 1992; R.C. Larock, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations”, 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; “Organic Functional Group Preparations”, 2nd Ed., Academic Press, New York, 1983; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes. Some compounds require the application of protecting groups. The need for such protection is within the skill of the art. For a general description of protecting groups and their use, see: T. W. Greene, PGM Nuts, and Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1999.

[0209] Analytical methods and instruments

[0210] Proton nuclear magnetic resonance (NMR) spectra were obtained at 400 or 600 MHz on Bruker or Varian spectrometers. NMR spectra are reported as chemical shift δ (ppm), multiplicity, coupling constant J (Hz), and integral relative to residual solvent signals. In some cases, tetramethylsilane (TMS) was used as an internal standard. Mass spectral data were measured using one of two systems: System A: Waters Acquity i-class ultra-performance liquid chromatography (UPLC) system equipped with an Acquity photodiode array detector, an Acquity evaporative light scattering detector (ELSD), and a Waters ZQ mass spectrometer. Data were acquired using Waters MassLynx 4.1 software, and purity was characterized at a UV wavelength of 220 nm, evaporative light scattering detection (ELSD) and electrospray positive ionization (ESI) (column: Acquity UPLC BEH C18 1.7μι 2.1×50 mm). System B: Agilent LC / MS consisting of a 1200 series LC and a 6140 quadrupole MS detector (column: Agilent USGYL01131, HPH-C18 2.7 μM, 2.1×50 mm). Solvent used: acetonitrile / water with 0.1% formic acid. Flow rate 0.7 mL / min. Preparative HPLC purification was performed at a flow rate of 15 mL / min with detection at UV wavelengths of 214 nm and 254 nm (column: Jupiter® 10 μM Proteo 90 Å, 250×21.2 mm A, solvent: acetonitrile / water with 0.1% modifiers such as trifluoroacetic acid, formic acid, or acetic acid). Purity of the compounds was checked by analytical HPLC (Waters Acquity UPLC H-Class instrument) at a flow rate of 0.5 mL / min (Acquity BEH C18, 50×2.1 mm column). [Table 2-1] [Table 2-2]

[0211] General scheme Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Reaction times and yields were not optimized. Example numbers and compound numbers are the same.

[0212] General scheme 1. [ka]

[0213] In step 1, hydroxylamine is used to generate 0 to 4 R 5 The 2-phenylacetonitrile intermediate 1-1 substituted with a group is converted to the corresponding N-hydroxy-2-phenylacetimidamide intermediate 1-2. In step 2, the N-hydroxy-2-phenylacetimidamide intermediate 1-2 is reacted with a carboxylic acid-containing compound 1-3 to provide the 1,2,4-oxadiazole compound of formula (I) 1-4.

[0214] General scheme 2. [ka]

[0215] In step 1, the ketone-containing intermediate 2-1 is treated with Br2 in the presence of acid to form intermediate 2-2, which is reacted with 2-phenylacetic acid to form intermediate 2-3. Then, in step 3, intermediate 2-3 is reacted with ammonium acetate to form the oxazole compound 2-4 of formula (II).

[0216] General scheme 3. [ka]

[0217] The 1,2,4-oxadiazole intermediate 3-1 is reacted with N2 under reaction conditions with bromoacetamide intermediate 3-2 to form the 1,2,4-oxadiazole compound 3-3 of formula (I).

[0218] General scheme 4. [ka]

[0219] First, the 1,2,4-oxadiazole intermediate 4-1 is subjected to appropriate conditions to introduce a linker terminating with a carboxylic acid. In the final step, intermediate 4-2 undergoes a condensation reaction with (2R,4R)-4-amino-2-methylpyrrolidine-1-carbonitrile to give compound 4-3 of formula (I).

[0220] General scheme 5. [ka]

[0221] In step 1, intermediate 5-1 is reacted with a halogen-substituted benzyl compound to give intermediate 5-2, which is then subjected to hydrolysis conditions to give intermediate 5-3. In step 3, intermediate 5-3 is reacted with succinimide to give intermediate 5-4, which is reacted with an appropriate amine to give compound 5-5 of formula (II).

[0222] Preparation of representative compounds Example 1. 2-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)acetamide (compound 3) [ka]

[0223] Step A. 2-(3-chlorophenyl)-N-hydroxyacetimidamide (3a) [ka]

[0224] To a solution of 2-(3-chlorophenyl)acetonitrile (0.5 g, 3.3 mmol) in EtOH (20 mL) was added K2CO3 (685 mg, 4.9 mmol) and NH2OH.HCl (343 mg, 4.9 mmol). The reaction was stirred at 80 °C for 18 h. Upon completion, the reaction was filtered and concentrated to give the crude title product (3a) (0.4 g) as a white solid, which was used in the next step without further purification. m / z (ESI, +ve ion) = 185.1 [M+H] + .

[0225] Step B. 4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenol (3b) [ka]

[0226] To a solution of 4-hydroxybenzoic acid (0.4 g, 2.9 mmol) in NMP (20 mL) was added CDI (563 mg, 3.4 mmol). After stirring at 50° C. for 1 h, 3a (515 mg, 2.8 mmol) was added and the reaction was stirred at 120° C. for 18 h. After completion, the mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether:EtOAc=1:1) to give the title product (3b) (106.1 mg, 13%) as a white solid. m / z (ESI, +ve ion)=287.1 [M+H] + .

[0227] Step C. 2-Bromo-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)acetamide (3c) [ka]

[0228] To a solution of tert-butyl (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylate (40 mg, 0.20 mmol) in DCM (2 mL) at 0° C., 2,2,6,6-tetramethylpiperidine (33 μL, 0.20 mmol) and bromoacetyl bromide (19 μL, 0.22 mmol) were added. After stirring at 0° C. for 30 min, 5 mL of water was added. The aqueous layer was separated from the reaction. To the organic layer was added TFA (1 mL) and the layers were stirred for 30 min and concentrated. The residue was redissolved in DCM (2 mL). DIPEA (0.1 mL, 0.57 mmol) was added, followed by cyanogen bromide (25 mg, 0.24 mmol). The mixture was stirred at 0° C. for 1 h and concentrated. The crude residue was purified by silica gel column chromatography (gradient elution, 50-80% EtOAc in hexanes) to give the title product (3c) (33 mg, 67%) as a colorless oil. m / z (ESI, +ve ion) = 248.1 [M+2+H] + .

[0229] Step D. 2-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)acetamide (3) [ka]

[0230] To a solution of 3b (3.4 mg, 0.012 mmol) in DMF (0.3 mL) was added K2CO3 (3.3 mg, 0.024 mmol) followed by a 0.1 M solution of 3c in DMF (0.12 mL, 0.012 mmol). The reaction was stirred at room temperature for 1.5 h and purified directly by reverse phase HPLC (CH3CN in water, 0.1% HOAc as modifier) ​​to give the title product (3) (4.2 mg, 77%) as a white solid. m / z (ESI, +ve ion) = 452.2 [M+H] + .

[0231] Compounds 1, 2, 4, 6, 7, 9, and 12 were synthesized using a procedure similar to that described for the synthesis of compound 3 in Example 1.

[0232] Example 2. (E)-3-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)acrylamide (Compound 5) [ka]

[0233] Step A. 3-(3-chlorobenzyl)-5-(4-iodophenyl)-1,2,4-oxadiazole (5a) [ka]

[0234] To a solution of 4-iodobenzoic acid (50 mg, 0.2 mmol) in NMP (2 mL) was added CDI (33 mg, 0.24 mmol). After stirring at 50 °C for 30 min, 3a (37 mg, 0.20 mmol) was added and the reaction was heated to 120 °C for 18 h. Upon completion, water (10 mL) was added and the reaction was extracted with EtOAc (20 mL). The organic layer was washed with H2O (10 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (petroleum: EtOAc = 1:2) to give the title product (5a) (20 mg, 18.6%) as a yellow solid. m / z (ESI, +ve ion) = 397.1 [M+H] + .

[0235] Step B. Ethyl (E)-3-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)acrylate (5b) [ka]

[0236] To a stirred solution of 5a (250 mg, 0.63 mmol) in DMF (10 mL) under N2, ethyl acrylate (63 mg, 0.63 mmol), Pd(OAc)2 (25 mg, 0.063 mmol), PPh3 (16.5 mg, 0.063 mmol), and Et3N (190 mg, 1.89 mmol) were added. The reaction was heated to 100 °C and stirred for 14 h. After completion, the resulting mixture was concentrated and purified by silica gel column chromatography (EtOAc:petroleum ether = 10:90) to give the title product (5b) (230 mg, 95%) as a yellow oil. m / z (ESI, +ve ion) = 369.0 [M+H] + .

[0237] Step C. (E)-3-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)acrylic acid (5c) [ka]

[0238] To a solution of 5b (200 mg, 0.54 mmol) in THF (4 mL) and water (4 mL) was added NaOH (55 mg, 2.75 mmol). The reaction mixture was stirred at 25° C. for 2 h and then diluted with EtOAc (20 mL) and ice water (20 mL). The organic layer was washed with water (10 mL×3), brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative TLC (DCM:MeOH=20:1) to give the title product (5c) (111.4 mg, 60%) as a white solid. m / z (ESI, -ve ion)=339.0 [MH] - .

[0239] Step D. (2R,4R)-4-Amino-2-methylpyrrolidine-1-carbonitrile (5d) [ka]

[0240] To a stirred solution of tert-butyl ((3R,5R)-5-methylpyrrolidin-3-yl)carbamate (100 mg, 0.050 mmol), DIPEA (0.13 mL, 0.75 mmol), and dichloromethane (1.0 mL) was added cyanogen bromide (58 mg, 0.055 mmol) in dichloromethane (0.5 mL) at 0° C. After stirring at room temperature for 25 min, the mixture was quenched with water (2.0 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 mL). The combined organic layers were dried over MgSO4, concentrated, and redissolved in HCl (3.0 mL, 4N in 1,4-dioxane). The reaction was stirred at room temperature for 1 h. A solid precipitated. The supernatant was decanted. To the remaining solid was added 1,4-dioxane (3 mL) and the reaction vial was sonicated and then concentrated. The same procedure was repeated with CH3CN (2 mL). The resulting solid was lyophilized to give the crude title product (5d) (HCl salt), which was used in the next step without further purification. m / z (ESI, +ve ion) = 126.3 [M+H] + .

[0241] Step E. (E)-3-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)acrylamide (5) [ka]

[0242] A solution of 5c (4.1 mg, 0.012 mmol), 5d (3 mg, crude), HATU (6.8 mg, 0.018 mmol), and DIPEA (0.0063 mL, 0.036 mmol) in DMF (0.3 mL) was stirred at room temperature for 3 h. The mixture was directly purified by reverse-phase HPLC (CH3CN in water, 0.1% HOAc as modifier) ​​to give the title product (5) (4.7 mg, 87%) as a white solid. m / z (ESI, +ve ion) = 448.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (d, J = 6.60 Hz, 1H), 8.12 (d, J = 8.31 Hz, 2H), 7.80 (d, J = 8.56 Hz, 2H), 7.28 - 7.59 (m, 5H), 6.77 (d, J = 15.89 Hz, 1 H), 4.38 (qt, J = 5.97, 2.90 Hz, 1H), 4.23 (s, 2H), 3.66 - 3.92 (m, 2H), 3.26 (dd, J = 9.90, 2.57 Hz, 1H), 2.01 (ddd, J = 12.90, 6.17, 2.93 Hz, 1H), 1.74 (ddd, J = 12.96, 8.80, 6.11 Hz, 1H), 1.26 (d, J = 6.11 Hz, 3H).

[0243] Example 3. N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)-2-(4-(3-(3-cyanobenzyl)-1,2,4-oxadiazol-5-yl)phenoxy)acetamide (Compound 8) [ka]

[0244] Step A. 3-((5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)benzonitrile (8b) [ka]

[0245] To a solution of 8a (prepared according to a similar procedure as 3b, 800 mg, 2.42 mmol) in NMP (15 mL) was added copper cyanide (649 mg, 7.25 mmol). The reaction was heated at 180° C. for 0.5 h. After cooling, the reaction mixture was filtered through a Celite pad. The filtrate was diluted with EtOAc (50 mL) and washed with brine (50 mL×3). The organic layer was dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether:EtOAc=2:1) ​​to give the title product (8b) (75 mg, 10.7%) as a yellow solid. m / z (ESI, +ve ion)=278.0 [M+H] + .

[0246] Step B N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)-2-(4-(3-(3-cyanobenzyl)-1,2,4-oxadiazol-5-yl)phenoxy)acetamide (8) [ka]

[0247] The title product (compound 8) was synthesized in a similar manner as described for the synthesis of compound 3 in step D of example 1. m / z (ESI, +ve ion) = 443.3 [M+H] + .

[0248] Example 4. 1-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)-3-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)urea (Compound 10) [ka]

[0249] Step A. 4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid (10a) [ka]

[0250] To a solution of 4-(aminomethyl)benzoic acid (0.5 g, 3.31 mmol) in 1,4-dioxane and water (1:1, 6 mL) was added (BOC)2O (0.938 g, 4.30 mmol) and NaOH (0.265 g, 6.62 mmol) at 0° C. The reaction mixture was stirred at 15° C. for 12 h. The solvent was then evaporated in vacuo to give the crude title product (10a), which was used in the next step without further purification. m / z (ESI, +ve ion)=196.1 [M+H] + .

[0251] Step B. tert-Butyl (4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)carbamate (10b) [ka]

[0252] A flask was charged with 10a (300 mg, 1.19 mmol) and CDI (202.2 mg, 1.43 mmol). NMP (5 mL) was added and the reaction was stirred at 50° C. for 0.5 h. Then 3a (329.55 mg, 1.785 mmol) was added and the reaction mixture was heated at 120° C. for 16 h. After cooling, the reaction was quenched with water (10 mL) and extracted with DCM (30 mL). The organic layer was washed with water (30 mL), dried, filtered and concentrated to give the crude title product (10b) (300 mg), which was used in the next step without further purification. m / z (ESI, +ve ion)=400.0 [M+H] + .

[0253] Step C. (4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine (10c) [ka]

[0254] TFA (2 mL) was added to a solution of 10b (300 mg, 0.75 mmol) in DCM. The reaction mixture was stirred at 15° C. for 2 h. The solvent was then evaporated in vacuo and the crude residue was purified by silica gel column chromatography (DCM / MeOH=10:1) to give the title product (10c) (85.5 mg, 37%) as a white solid. m / z (ESI, +ve ion)=300.1 [M+H] + .

[0255] Step D. tert-Butyl (2R,4R)-4-(3-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)ureido)-2-methylpyrrolidine-1-carboxylate (10d) [ka]

[0256] To a solution of tert-butyl (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylate (6.0 mg, 0.030 mmol) in DMF (0.3 mL) was added DIPEA (0.01 mL, 0.060 mmol) and CDI (4.9 mg, 0.030 mmol). The reaction was stirred at room temperature for 20 min (Solution A). To solution A was added 10c (6.0 mg, 0.020 mmol) and the resulting mixture was stirred overnight. However, the reaction showed incomplete conversion. Another solution A was prepared and added to the reaction. After stirring for 3 h, the reaction was purified by reverse phase HPLC (CH3CN in water, 0.1% HOAc used as modifier) ​​to give the title product (10d) (10.8 mg, quantitative) as a white solid. m / z (ESI, +ve ion) = 426.2 [M-Boc+H] + .

[0257] Step E. 1-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)-3-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)urea (10) [ka]

[0258] To a solution of 10d (10.8 mg, 0.02 mmol) in DCM (0.4 mL) was added TFA (0.4 mL) and the reaction was stirred at room temperature for 40 min. The reaction was concentrated under reduced pressure and redissolved in DCM (0.3 mL). DIPEA (0.01 mL, 0.060 mmol) was added followed by cyanogen bromide (2.5 mg, 0.024 mmol). The resulting mixture was stirred for 15 min and then purified by reverse phase HPLC (CH3CN in water, 0.1% HOAc as modifier) ​​to give the title product (10) (6.3 mg, 70%) as a white solid. m / z (ESI, +ve ion) = 451.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.00 - 8.06 (m, 2H), 7.43 - 7.50 (m, 3H), 7.30 - 7.41 (m, 3H), 6.52 (d, J = 6.60 Hz, 1H), 6.45 (t, J = 6.11 Hz, 1H), 4.30 (d, J=6.11 Hz, 2H), 4.21 (s, 2H), 4.09 - 4.17 (m, 1H), 3.78 (dt, J = 8.07, 6.36 Hz, 1H), 3.63 (dd, J = 9.78, 5.62 Hz, 1H), 3.15 (dd, J = 9.66, 3.30 Hz, 1H), 1.92 (ddd, J = 12.90, 6.42, 3.67 Hz, 1H), 1.65 (ddd, J = 12.84, 8.19, 6.11 Hz, 1H), 1.22 (d, J = 6.11 Hz, 3H).

[0259] Example 5. 2-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)propenamide (compound 11) [ka]

[0260] Step A. tert-Butyl 2-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenoxy)propanoate (11a) [ka]

[0261] To a solution of 3b (7.2 mg, 0.025 mmol) in DMF (0.3 mL) was added K2CO3 (6.9 mg, 0.050 mmol) and tert-butyl 2-bromopropanoate (6.3 mg, 0.030 mmol). The reaction was stirred at room temperature for 3 h and purified by reverse-phase HPLC (CH3CN in water with 0.1% HOAc as modifier) ​​to give the title product (11a) (10 mg, 96%) as a white solid.

[0262] Step B. 2-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenoxy)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)propenamide (11) [ka]

[0263] A solution of 11a (5 mg, 0.012 mmol) was dissolved in DCM (0.15 mL) and TFA (0.15 mL) was added. After stirring at room temperature for 2 h, the reaction was concentrated and redissolved in DMF (0.3 mL). DIPEA (0.0063 mL, 0.036 mmol), HATU (6.8 mg, 0.018 mmol), and 5d (3.3 mg, crude) were added and the reaction was stirred at room temperature for 10 min. The crude material was directly purified by reverse phase HPLC (CH3CN in water, 0.1% HOAc as modifier) ​​to give the title product (11) (4.0 mg, 68%) as a white solid. m / z (ESI, +ve ion) = 466.2 [M+H] + .

[0264] Example 6. (E)-3-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)-2-methylacrylamide (Compound 13) [ka]

[0265] Step A. (E)-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid (13a) [ka]

[0266] To a solution of ethyl 2-(diethoxyphosphoryl)propanoate (1.4 g, 5.88 mmol) in dry THF (20 mL) was added NaH (235 mg, 5.88 mmol, 60% dispersion in mineral oil) portionwise at 0° C. After stirring at 0° C. for 0.5 h, tert-butyl 4-formylbenzoate (1.0 g, 4.85 mmol) was added and the reaction was stirred at 20° C. for 4 h. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL×2), dried, filtered, concentrated and the crude residue was purified by silica gel column chromatography (petroleum ether:EtOAc=1:1) to give the title product (13a) (450 mg, 39.8%) as a white solid. m / z (ESI, +ve ion)=235.1 [M+H] + .

[0267] Step B. Ethyl (E)-3-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)-2-methylacrylate (13b) [ka]

[0268] To a solution of 13a (400 mg, 1.71 mmol) in NMP (5 mL) was added CDI (332 mg, 2.05 mmol). After stirring at 50° C. for 0.5 h, 3a (315 mg, 1.71 mmol) was added and the reaction was stirred at 120° C. for 2 h. The reaction was then diluted with EtOAc (30 mL) and washed with brine (30 mL×2). The organic layer was dried, filtered, concentrated and purified by silica gel column chromatography (petroleum ether:EtOAc=5:1) to give the title product (13b) (260 mg, 39.7%) as a yellow solid. m / z (ESI, +ve ion)=383.1 [M+H] + .

[0269] Step C. (E)-3-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)-2-methylacrylic acid (13c) [ka]

[0270] To a solution of 13b (130 mg, 0.34 mmol) in THF / H2O (5 mL, 1:1) was added NaOH (20 mg, 0.51 mmol). The reaction was stirred at 20° C. for 2 h, adjusted to pH=4 with 1N HCl, and extracted with EtOAc (20 mL). The organic layer was dried, filtered, concentrated, and the residue was purified by preparative TLC (petroleum ether:EtOAc=1:1) to give the title product (13c) (55 mg, 45.6%) as a white solid. m / z (ESI, -ve ion)=353.0 [MH] - .

[0271] Step D. (E)-3-(4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)-2-methylacrylamide (13) [ka]

[0272] The title product (13) was synthesized in a similar manner as described for the synthesis of compound 5 in step E of example 2. m / z (ESI, +ve ion) = 462.3 [M+H] + .

[0273] Example 7. (E)-3-(4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)acrylamide (Compound 14) [ka]

[0274] Step A. 1-(4-iodophenyl)propan-1-one (14a) [ka]

[0275] To a stirred solution of 1-(4-bromophenyl)propan-1-one (2 g, 9.39 mmol), CuI (0.179 g, 0.94 mmol), and KI (6.23 g, 37.6 mmol) in 1,4-dioxane (25 mL) at 20° C. under nitrogen atmosphere was added N1,N2-dimethylethane-1,2-diamine (0.17 g, 1.88 mmol). The reaction was heated to reflux for 24 h. After completion, the mixture was filtered. The filtrate was collected and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc:petroleum ether=1:6) to give the title product (14a) (2.1 g, 86%) as a white solid. m / z (ESI, +ve ion)=261.0 [M+H] + .

[0276] Step B. 2-Bromo-1-(4-iodophenyl)propan-1-one (14b) [ka]

[0277] To a solution of 14a (1 g, 3.85 mmol) in DCM (30 mL) was added Br2 (614.5 mg, 3.85 mmol) at 20 °C and stirred for 12 h. After completion, the mixture was quenched with saturated Na2SO3 (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc:petroleum ether = 1:8) to give the title product (14b) (450 mg, 34.6%) as a pale yellow solid. m / z (ESI, +ve ion) = 338.9 [M+H] + .

[0278] Step C. 1-(4-iodophenyl)-1-oxopropan-2-yl 2-(3-chlorophenyl)acetate ((14c) [ka]

[0279] To a stirred solution of 14b (400 mg, 1.18 mmol) and (3-chlorophenyl)acetic acid (201 mg, 1.18 mmol) in acetone (20 mL) at 20° C., DIPEA (457 mg, 3.54 mmol) was added. After stirring for 3 h, the reaction was concentrated and purified by silica gel column chromatography (EtOAc:petroleum ether=1:6) to give the title product (14c) (450 mg, 88%) as a colorless oil. m / z (ESI, +ve ion)=429.0 [M+H] + .

[0280] Step D. 2-(3-chlorobenzyl)-4-(4-iodophenyl)-5-methyloxazole (14d) [ka]

[0281] A solution of 14c (450 mg, 1.05 mmol) and NHOAc (405 mg, 5.26 mmol) in acetic acid (10 mL) was heated at 120° C. for 4 h. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated. The crude product was purified by silica gel column chromatography (EtOAc:petroleum ether=1:6) to give the title product (14d) (390 mg, 85%) as a white solid. m / z (ESI, +ve ion)=410.0 [M+H] + .

[0282] Step E. (E)-3-(4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenyl)acrylic acid (14e) [ka]

[0283] The title product (14e) was synthesized using a procedure similar to the synthesis of compound 5 described in Steps B and C of Example 2. m / z (ESI, +ve ion) = 354.0 [M+H] + .

[0284] Step F. (E)-3-(4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)acrylamide (14) [ka]

[0285] The title product (14) was synthesized using a procedure similar to that described for the synthesis of compound 5 in steps D-E of Example 2. m / z (ESI, +ve ion) = 461.3 [M+H] + .

[0286] Example 8. (E)-3-(4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenyl)-N-((3R,5R)-5-methylpyrrolidin-3-yl)acrylamide (Compound 15) [ka]

[0287] Step A. tert-Butyl (2R,4R)-4-((E)-3-(4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenyl)acrylamido)-2-methylpyrrolidine-1-carboxylate (15a) [ka]

[0288] A solution of 14e (24.7 mg, 0.07 mmol), tert-butyl (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylate (16.8 mg, 0.084 mmol), HATU (35 mg, 0.092 mmol), DIPEA (0.024 mL, 0.14 mmol) in DMF (0.5 mL) was stirred at room temperature for 1 h. The mixture was directly purified by reversed-phase HPLC (CH3CN in water, 0.1% HOAc as modifier) ​​to give the title product (15a) (24 mg, 64%) as a white solid. m / z (ESI, +ve ion) = 480.3 [M-tBu] + .

[0289] Step B. (E)-3-(4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenyl)-N-((3R,5R)-5-methylpyrrolidin-3-yl)acrylamide (15) [ka]

[0290] To a solution of 15a (21.4 mg, 0.04 mmol) in DCM (1 mL) was added TFA (1 mL). After stirring at room temperature for 50 min, the reaction was concentrated and lyophilized to give the title product (15) (18.8 mg, 86%, TFA salt) as a white solid. m / z (ESI, +ve ion) = 436.2 [M+H] + .

[0291] Compound 16 was synthesized from 3a and 4-(2-methoxy-2-oxoethyl)benzoic acid using a similar procedure for the synthesis of compound 13 described in steps B-D of Example 6. In the last step, T3P was used as the coupling reagent instead of HATU.

[0292] Compound 17 was synthesized using 3-iodobenzoic acid in a similar procedure as described for the synthesis of compound 5 in Example 2.

[0293] Example 9. 4-((4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)oxy)-N,N-dimethylbenzamide (Compound 18) [ka]

[0294] Step A. Methyl 4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)benzoate (18) [ka]

[0295] To a solution of 4-(methoxycarbonyl)benzoic acid (5.0 g, 27.8 mmol) in NMP (100 mL) was added CDI (5.0 g, 30.5 mmol). After heating at 50 °C for 2 h, 3a (5.1 g, 27.8 mmol) was added to the above solution. The mixture was stirred at 120 °C for 16 h. After cooling, the reaction was diluted with EtOAc (200 mL) and washed with H2O (500 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with H2O (100 mL x 2), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude residue, which was purified by silica gel column chromatography (EtOAc:petroleum ether = 1:5) to give the title product (18a) (4.9 g, 53.6%) as a white solid. m / z (ESI, +ve ion)=329.7[M+H] + .

[0296] Step B. (4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)phenyl)methanol (18b) [ka]

[0297] To a solution of 18a (2.0 g, 6.1 mmol) in THF (30 mL) was added 1 M diisobutylaluminum hydride (18.3 mL, 0.3 mmol) slowly at -78 °C. After stirring at the same temperature for 4 h, the reaction was quenched with 1N HCl to adjust pH = 4-5, and extracted with EtOAc (50 mL × 3). The organic layer was washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuum to give the crude residue, which was purified by silica gel column chromatography (petroleum ether: EtOAc = 1:1) to give the title product (18b) (1.2 g, 62.3%) as a white solid. m / z (ESI, +ve ion) = 301.7 [M+H] + .

[0298] Step C. 5-(4-(bromomethyl)phenyl)-3-(3-chlorobenzyl)-1,2,4-oxadiazole (18c) [ka]

[0299] To a solution of POBr3 (571 mg, 2.0 mmol) in DCM (10 mL) was added DMF (5.0 mL) at 0 °C. The mixture was stirred at 0 °C for 0.25 h, and then 18b (500 mg, 1.66 mmol) was added. After stirring at 0 °C for 1 h, the mixture was quenched with 5% aqueous NaHCO3 to adjust pH = 7-8, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with H2O (15 mL x 2), brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude residue, which was purified by reverse phase HPLC (70% CH3CN in H2O, with 0.05% formic acid as a modifier) ​​to give the title product (18c) (350 mg, 57.3%) as a white solid. m / z (ESI, +ve ion) = 365.0 [M+H] + .

[0300] Step D. 4-((4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)oxy)-N,N-dimethylbenzamide (18) [ka]

[0301] To a mixture of 4-hydroxy-N,N-dimethylbenzamide (9.1 mg, 0.055 mmol) and K2CO3 (22.8 mg, 0.17 mmol) in DMF (1.3 mL) was added 18c (20 mg, 0.055 mmol). The reaction was stirred at 50 °C for 2 h, diluted with H2O and EtOAc, and extracted with EtOAc (x3). The combined organic phases were washed with water, brine (x2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 1:1) to give the title product (18) (22 mg, 89%) as a white solid. m / z (ESI, +ve ion) = 448.1 [M+H] + . 1H NMR (600 MHz, CDCl3) δ ppm 8.14 (d, J = 8.07 Hz, 2H), 7.58 (d, J = 8.07 Hz, 2H), 7.39 - 7.43 (m, 3H), 7.21 - 7.33 (m, 3H), 6.98 (d, J = 8.44 Hz, 2H), 5.18 (s, 2H), 4.13 (s, 2H), 3.07 (br s, 6H).

[0302] Compound 19 was synthesized from 10c by a procedure similar to that described for the synthesis of compound 15 in Step A of Example 8.

[0303] Example 10. 1-(4-((4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)oxy)phenyl)-N,N-dimethylmethanamine (Compound 20) [ka]

[0304] Step A. 4-((4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)oxy)benzaldehyde (20a) [ka]

[0305] To a solution of 18b (200 mg, 0.55 mmol) and 4-hydroxybenzaldehyde (67 mg, 0.55 mmol) in DMF (10 mL) was added K2CO3 (152 mg, 1.1 mmol) at 25 °C. The reaction was heated to 55 °C and stirred for 1 h. After completion, the reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with H2O (50 mL x 2), brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude residue, which was purified by reverse phase HPLC (65% CH3CN in water with 0.05% formic acid as modifier) ​​to give the title product (20a) (150 mg, 67%) as a white solid. m / z (ESI, +ve ion) = 405.0 [M+H] + .

[0306] Step B. 1-(4-((4-(3-(3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)benzyl)oxy)phenyl)-N,N-dimethylmethanamine (20) [ka]

[0307] To a mixture of 20a (20 mg, 0.05 mmol), dimethylamine hydrochloride (2.7 mg, 0.06 mmol), and Et3N (15 mg, 0.15 mmol) in DCM (3 mL) was added NaBH(OAc)3 (16 mg, 0.075 mmol) at 0 °C under N2. After stirring at 0 °C for 1 h, the reaction was allowed to warm to room temperature and stirred for 12 h. Upon completion, the mixture was quenched with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with H2O (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude residue, which was purified by reverse phase HPLC (65% CH3CN in H2O, with 0.05% formic acid as a modifier) ​​to give the title product (20) (4.3 mg, 19.8%) as a white solid. m / z (ESI, +ve ion)=434.2[M+H] + . 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.39 (s, 1H), 7.10 - 7.35 (m, 5H), 7.03 (d, J = 8.7 Hz, 2H), 5.20 (s, 2H), 4.14 (s, 2H), 3.75 (s, 2H), 2.46 (s, 6H).

[0308] Example 11. 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)benzyl)oxy)-N,N-dimethylbenzamide (Compound 21) [ka]

[0309] Step A. (4-((benzyloxy)methyl)phenyl)methanol [ka]

[0310] A solution of [4-(hydroxymethyl)phenyl]methanol (50 g, 0.36 mol) in THF (350 mL) was cooled to 0° C., and sodium hydride (17.6 g, 0.44 mol, 60% dispersion in mineral oil) was added. After stirring at 0° C. for 1 h, TBAI (8.02 g, 21.7 mmol) and BnBr (51.4 mL, 0.43 mol) were added. The resulting mixture was stirred at 25° C. for 18 h, quenched with ice water (100 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (15 mL), brine (150 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude residue, which was purified by silica gel column chromatography (EtOAc:petroleum ether=1:10) to give the title product (21a) (38 g, 90%) as a yellow oil. m / z(ESI, +ve ion)=251.1[M+Na] + .

[0311] Step B. 4-((benzyloxy)methyl)benzaldehyde (21b) [ka]

[0312] To a mixture of 21a (20.0 g, 0.088 mol) in THF (250 mL) was added MnO2 (53 g, 0.61 mol) at 25 °C. The reaction was stirred at 70 °C for 4 h, cooled and filtered. The filtrate was concentrated in vacuo to give the title product (21b) (14.6 g, 74%) as a yellow oil, which was used in the next step without further purification. m / z (ESI, +ve ion) = 227.1 [M+H] + .

[0313] Step C. 1-(4-((benzyloxy)methyl)phenyl)propan-1-ol (21c) [ka]

[0314] To a mixture of 21b (14.5 g, 64.1 mmol) in anhydrous THF (70 mL) was added ethylmagnesium bromide (35.3 mL, 70.5 mmol) at 0 °C. After stirring at 0 °C for 1.5 h, the reaction was quenched with ice-cold saturated NH4Cl (200 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude residue. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 4:1) to give the title product (21c) (11.9 g, 85%) as a yellow oil. m / z (ESI, +ve ion) = 279.1 [M+Na] + .

[0315] Step D. 1-(4-((benzyloxy)methyl)phenyl)-2-hydroxypropan-1-one (21d) [ka]

[0316] To a solution of 21c (5.0 g, 19.5 mmol) in DMSO / dioxane (100 mL, 2:1) was added I2 (1.98 g, 7.8 mmol) at 25 °C. After stirring for 1 h, IBX (16.38 g, 58.5 mmol) was added and the reaction was heated at 80 °C for 24 h. After cooling, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (25 mL x 2). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (petroleum ether: EtOAc = 10:1) to give the title product (21d) (1.74 g, 29.7%) as a colorless oil. m / z (ESI, +ve ion) = 271.1 [M+H] + .

[0317] Step E. 1-(4-((benzyloxy)methyl)phenyl)-1-oxopropan-2-yl 2-(3-chlorophenyl)acetate (21e) [ka]

[0318] A solution of 21d (3.1 g, 11.4 mmol), (3-chlorophenyl)acetic acid (3.9 g, 22.8 mmol), 4-dimethylaminopyridine (1.4 g, 11.4 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.84 g, 14.8 mmol) in DCM (25 mL) was stirred at 25 °C for 5 h. The reaction was diluted with water and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (EtOAc:petroleum ether = 1:50) to give the title product (21e) (3 g, 56%) as a colorless oil. m / z (ESI, +ve ion) = 445.0 [M+Na] + .

[0319] Step F. 4-(4-((benzyloxy)methyl)phenyl)-2-(3-chlorobenzyl)-5-methyloxazole (21f) [ka]

[0320] To a stirred solution of 21e (2.3 g, 5.4 mmol) in acetic acid (40 mL) was added NHOAc (6.24 g, 81 mmol). The reaction was stirred at 120 °C for 2 h. After completion, the reaction was diluted with H0 (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over NaSO, filtered, concentrated and purified by silica gel column chromatography (EtOAc:petroleum ether = 1:20) to give the title product (21f) (1.6 g, 67%) as a white solid. m / z (ESI, +ve ion) = 404.1 [M+H] + .

[0321] Step G. (4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenyl)methanol (21 g) [ka]

[0322] To a stirred solution of 21f (1.5 g, 3.7 mmol) in DCM (20 mL) was added BCl3 (1 M in DCM, 7.5 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for another 2 h and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EtOAc:petroleum ether = 1:50) to give the title product (21g) (0.61 g, 49%) as a white solid. m / z (ESI, +ve ion) = 314.1 [M+H] + .

[0323] Step H. 4-(4-(bromomethyl)phenyl)-2-(3-chlorobenzyl)-5-methyloxazole (21h) [ka]

[0324] To a solution of 21g (1 g, 4.2 mol) in DCM (50 mL) was added PBr3 (0.57 g, 2.1 mol) dropwise at 0° C. After stirring at room temperature for 2 h, the reaction was concentrated to give the crude title product (21h) (1 g), which was used directly in the next step without further purification. m / z (ESI, +ve ion)=376.0 [M+H] + .

[0325] Step I. 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)benzyl)oxy)-N,N-dimethylbenzamide (21) [ka]

[0326] To a stirred solution of 4-hydroxy-N,N-dimethylbenzamide (7.9 mg, 0.048 mmol) in DMF (1 mL) was added K2CO3 (19.8 mg, 0.14 mmol) and 21h (18 mg, 0.048 mmol) at room temperature. The reaction was heated at 50 °C for 2 h. After cooling, the reaction was diluted with water and EtOAc and extracted with EtOAc (x3). The combined organic layers were washed with water, brine (x2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution, 20-90% EtOAc in hexanes) to give impure material which was purified again (gradient elution, 10-60% EtOAc in acetone) to give the title product (21) (15 mg, 68%) as a white solid. m / z (ESI, +ve ion) = 461.4 [M+H] + .

[0327] Example 12. 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)-N,N-dimethylbenzamide (Compound 22) [ka]

[0328] Step A. 4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenol (22b) [ka]

[0329] To a solution of 22a (420 mg, 1.34 mmol) in anhydrous DCM (5 mL) was added boron tribromide (1.68 g, 6.71 mmol) at -78 °C under nitrogen. The mixture was warmed to 20 °C and stirred for 3 h. After completion, the reaction was quenched with water (5 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried, filtered and concentrated to give a crude residue, which was purified by reverse phase HPLC (40-45% CH3CN in H2O, with 0.1% formic acid as modifier) ​​to give the title product (22b) (105 mg, 26%) as a white solid. m / z (ESI, +ve ion) = 300.1 [M+H] + .

[0330] Step B. tert-Butyl 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)benzoate (22c) [ka]

[0331] To a solution of 22b (50 mg, 0.17 mmol) in DMF (0.5 mL) was added Cs2CO3 (70.7 mg, 0.22 mmol) and tert-butyl 4-(bromomethyl)benzoate (49.8 mg, 0.18 mmol). After 1 h, additional Cs2CO3 (71 mg) and benzyl bromide (49.8 mg) were added and stirred for another 1 h before the addition was repeated. Upon completion, the reaction was quenched with saturated NH4Cl, extracted with EtOAc (x3), and washed with water and brine (x2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography (gradient elution, 0-20% EtOAc in hexanes) to afford the title product (22c) (73.6 mg, 90%) as a colorless gum. m / z (ESI, +ve ion)=490.2[M+H] + .

[0332] Step C. 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)benzoic acid (22d) [ka]

[0333] To a stirred solution of 22c (73.6 mg, 0.15 mmol) in DCM (2.5 mL) was added TFA (1 mL). After stirring at room temperature for 1 h, the reaction was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution, 1-5% MeOH in DCM) to give the title product (22d) (76 mg, quantitative) as an off-white solid. m / z (ESI, +ve ion) = 434.2 [M+H] + .

[0334] Step D. 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)-N,N-dimethylbenzamide (22) [ka]

[0335] To a stirred solution of 22d (35 mg, 0.081 mmol) and dimethylamine (0.048 mL, 0.097 mmol) in DMF (1.0 mL) were added DIPEA (0.042 mL, 0.24 mmol) and HATU (36.8 mg, 0.097 mmol). After stirring for 3 h, the reaction was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with water, brine (×2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution, 0.5-2.5% MeOH in DCM) to give the title product (22) (11.6 mg, 31%) as a white solid. m / z (ESI, +ve ion)=461.2 [M+H] + . 1 H NMR (600 MHz, CDCl3) δ ppm 7.53 - 7.61 (m, 2H), 7.43 - 7.51 (m, 4H), 7.35 (s, 1H), 7.22 - 7.30 (m, 3H), 7.00 - 7.04 (m, 2H), 5.13 (s, 2H), 4.08 (s, 2H), 3.13 (br s, 3H), 3.00 (s, 3H), 2.46 (s, 3H).

[0336] Example 13. 3-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (compound 23) [ka]

[0337] Step A. 3-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)-1-methyl-1H-pyrazole-5-carboxylic acid (23b) [ka]

[0338] To a cloudy solution of 23a (prepared in a similar manner as 22c, 66 mg, 0.15 mmol) in THF / water / MeOH (1.0 mL, 2:1:1) was added LiOH hydrate (12.3 mg, 0.29 mmol) at room temperature. After stirring for 1 h, the reaction was diluted with DCM and water, acidified with 1N HCl, and extracted with DCM (×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (gradient elution, 2-5% MeOH in DCM) to give the title product (23b) (61 mg, 95%) as a white solid. m / z (ESI, +ve ion)=438.3 [M+H] + .

[0339] Step B. 3-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (23) [ka]

[0340] The title compound (23) was synthesized from 23b in a similar manner to the synthesis of compound 22 described in step D of Example 12. m / z (ESI, +ve ion) = 465.1 [M+H] + . 1 H NMR (600 MHz, CDCl3) δ ppm 7.54 - 7.64 (m, 2H), 7.32 - 7.38 (m, 1H), 7.22 - 7.31 (m, 3H), 6.99 - 7.06 (m, 2H), 6.75 (s, 1H), 5.08 (s, 2H), 4.08 (s, 2H), 3.96 (s, 3H), 3.36 (s, 3H), 3.11 (s, 3H), 2.47 (s, 3H).

[0341] Compounds 24, 25, 26 (using methyl 2-(chloromethyl)pyrimidine-5-carboxylate), and 28 were synthesized using a procedure similar to that described for the synthesis of compound 23 in Example 13.

[0342] Example 14. (R)-4-(6-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)nicotinoyl)morpholine-2-carboxylic acid (Compound 27) [ka]

[0343] Step A. 2,5-Dioxopyrrolidin-1-yl 6-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)nicotinate (27b) [ka]

[0344] To a solution of 27a (267 mg, 0.61 mmol) and 1-hydroxypyrrolidine-2,5-dione (91.9 mg, 0.80 mmol) in DMF (3.1 mL) was added EDCI HCl at room temperature. After stirring for 3 h, additional 1-hydroxypyrrolidine-2,5-dione (36.7 mg) and EDCI (61 mg) were added and the reaction was stirred for an additional 20 min. The reaction was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with water, brine (×2), dried over Na2SO4, concentrated under reduced pressure and purified by silica gel column chromatography (gradient elution, 20-100% EtOAc in hexanes) to give the title product (27b) (304 mg, 93%) as an off-white solid. m / z (ESI, +ve ion)=532.2 [M+H] + .

[0345] Step B. (R)-4-(6-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)nicotinoyl)morpholine-2-carboxylic acid (27) [ka]

[0346] To a solution of (2R)-morpholine-2-carboxylate hydrochloride (15.8 mg, 0.094 mmol) in DMF (0.25 mL) was added DIPEA (0.049 mL, 0.28 mmol) at room temperature and the reaction was stirred for 10 min. A solution of 27b (20 mg, 0.038 mmol) in DMF (0.25 mL) was added and the resulting mixture was heated at 50 °C for 3 h. After cooling, the reaction was diluted with water and EtOAc, acidified with 1N HCl, and extracted with EtOAc (x3). The combined organic layers were washed with water, brine (x2), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (40-80% MeCN in water, 0.1% TFA as modifier) ​​to give the title product (27) (13.9 mg, 56%) as a white solid. m / z (ESI, +ve ion)=548.3[M+H] + . 1 H NMR (600 MHz, CD3OD) δ ppm 8.69 (br s, 1H), 7.97 - 8.03 (m, 1H), 7.75 (d, J = 8.07 Hz, 1H), 7.51 - 7.60 (m, 2H), 7.30 - 7.37 (m, 2H), 7.25 - 7.30 (m, 2H), 7.09 - 7.13 (m, 2H), 5.31 (s, 2H), 4.26 (br dd, J=8.44, 3.30 Hz, 1H) 4.12 (s, 2H), 3.94 - 4.08 (m, 2H), 3.69 - 3.83 (m, 2H), 3.51 - 3.64 (m, 2H), 2.45 (s, 3H).

[0347] Example 15. (3,8-diazabicyclo[3.2.1]octan-3-yl)(6-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)pyridin-3-yl)methanone (Compound 29) [ka]

[0348] Step A. tert-Butyl 3-(6-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (29) [ka]

[0349] The title compound 29a was synthesized from 27a and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate as described for the synthesis of compound 22 in step D of Example 12. m / z (ESI, +ve ion) = 629.2 [M+H] + .

[0350] Step B. tert-Butyl 3-(6-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (29) [ka]

[0351] To a stirred solution of 29a (24.5 mg, 0.039 mmol) in DCM at room temperature was added 4N HCl in 1,4-dioxane. After 2 h the product had formed as a sticky oil at the bottom of the reaction flask. The supernatant was decanted off. The oil was diluted with DCM and sonicated. The supernatant was removed and the remaining residue was lyophilized to give the title product (29) (18.3 mg, 83%) as a white solid. m / z (ESI, +ve ion) = 529.3 [M+H] + . 1H NMR (600 MHz, CD3OD) δ ppm 8.75 (d, J = 1.83 Hz, 1 H), 8.09 (dd, J = 8.07, 2.20 Hz, 1 H), 7.82 (d, J = 8.07 Hz, 1 H), 7.55 - 7.58 (m, 2 H), 7.23 - 7.38 (m, 4 H), 7.11 - 7.14 (m, 2 H), 5.34 (s, 2 H), 4.53 - 4.76 (m, 1 H), 3.94 - 4.32 (m, 5 H), 3.59 - 3.85 (m, 2 H), 2.46 (s, 3 H), 1.85 - 2.20 (m, 4H).

[0352] Example 16. 1-(4-(benzyloxy)phenyl)-1-oxopropan-2-yl 2-(1-methyl-1H-pyrazol-4-yl) acetate (compound 30) [ka]

[0353] Step A. 1-(4-(benzyloxy)phenyl)-1-oxopropan-2-yl 2-(1-methyl-1H-pyrazol-4-yl)acetate (30a) [ka]

[0354] A mixture of 1-(4-(benzyloxy)phenyl)-2-bromopropan-1-one (760 mg, 2.4 mmol), 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (334 mg, 2.4 mmol), and Cs2CO3 (470 mg, 1.4 mmol) in DMF (10 mL) was stirred at 20 °C for 4 h. After completion, the reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude title product (30a) (1.2 g) as a yellow oil, which was used in the next step without further purification. m / z (ESI, +ve ion) = 379.2 [M+H] + .

[0355] Step B. 1-(4-hydroxyphenyl)-1-oxopropan-2-yl 2-(1-methyl-1H-pyrazol-4-yl) acetate (30b) [ka]

[0356] The title compound was synthesized using a procedure similar to that described for the synthesis of compound 21 in steps F and G of Example 11. m / z (ESI, +ve ion) = 270.1 [M+H] + .

[0357] Step C. Methyl 6-((4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)methyl)oxazol-4-yl)phenoxy)methyl)nicotinate (30c) [ka]

[0358] The title compound (30c) was synthesized from 30b in a similar manner as described for the synthesis of compound 22 in step B of example 12. m / z (ESI, +ve ion) = 419.1 [M+H] + .

[0359] Step D. 1-(4-(benzyloxy)phenyl)-1-oxopropan-2-yl 2-(1-methyl-1H-pyrazol-4-yl)acetate (30) [ka]

[0360] The title compound (30) was synthesized from 30c in a similar procedure as described for the synthesis of compound 23 in Example 13. m / z (ESI, +ve ion) = 432.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.64 (d, J = 2.19 Hz, 1H), 7.94 (dd, J = 8.11, 1.97 Hz, 1H), 7.70 (d, J = 7.89 Hz, 1H), 7.49 - 7.60 (m, 3H), 7.42 (s, 1H), 7.05 - 7.12 (m, 2H), 5.27 (s, 2H), 3.97 (s, 2H), 3.85 (s, 3H), 3.13 (s, 3H), 3.04 (s, 3H), 2.45 (s, 3H).

[0361] Compound 31 was synthesized using a similar procedure to that for the synthesis of compound 30 described in Example 16, except that the benzyl group was removed by heating in TFA at 45° C. for 1 hour. m / z (ESI, +ve ion)=432.2 [M+H] + .

[0362] Compound 32 was synthesized using a procedure similar to that described for the synthesis of compound 27 in Example 14.

[0363] Example 17. 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)-3-((2-hydroxyethoxy)methyl)-N,N-dimethylbenzamide (Compound 33) [ka]

[0364] Step A. Methyl 5-bromo-2-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)benzoate (33) [ka]

[0365] To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (1.4 g, 4 mmol), 22b (1.35 g, 4 mmol) in DMF (10 mL) was added K2CO3 (1.24 g, 9 mmol) at 20 °C. After stirring at 45 °C for 16 h, the reaction was diluted with EtOAc (10 mL) and H2O (10 mL). The organic phase was separated and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc:petroleum ether = 1:5) to give the title product (33a) (1.8 g, 71.1%) as an oil. m / z (ESI, +ve ion) = 528.0 [M+H] + .

[0366] Step B. (5-Bromo-2-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)phenyl)methanol (33b) [ka]

[0367] To a solution of 33a (650 mg, 1.2 mmol) in THF (2 mL) was added lithium aluminum hydride (23.4 mg, 0.6 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h. After completion, the reaction was quenched by adding H2O (5 mL) at 0 °C. The mixture was filtered and the filtrate was extracted with EtOAc (5 mL × 3). The combined organic layers were dried, filtered, concentrated and purified by reverse phase HPLC (gradient elution, 0-50% CH3CN in H2O) to give the title product (33b) (450 mg, 69.5%) as a yellow oil. m / z (ESI, +ve ion) = 500.0 [M+H] + .

[0368] Step C. tert-Butyl 2-((5-bromo-2-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)benzyl)oxy)acetate (33c) [ka]

[0369] To a solution of 33b (450 mg, 0.9 mmol) in toluene (5 mL) was added NaOH (180 mg, 50% solution), tetrabutylammonium bromide (29 mg, 0.09 mmol), and tert-butyl 2-bromoacetate (352 mg, 1.8 mmol) at 0 °C. After stirring at 20 °C for 16 h, the reaction was quenched with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with H2O (2 mL), brine (2 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude residue, which was purified by reverse-phase HPLC (gradient elution, 0-40% CH3CN in H2O) to give the title product (33c) (370 mg, 63.6%) as an oil. m / z (ESI, +ve ion) = 636.0 [M+Na] + .

[0370] Step D. Methyl 3-((2-(tert-butoxy)-2-oxoethoxy)methyl)-4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)benzoate (33d) [ka]

[0371] To a solution of 33c (430 mg, 0.70 mmol) in MeOH / DMSO (2 mL, 1:1) at 20 °C was added Pd(dppf)Cl2 (114.5 mg, 0.14 mmol) and Et3N (800 mg, 7.0 mmol). The reaction was stirred at 80 °C under CO atmosphere for 16 h. After completion, the solvent was removed and the resulting residue was added with H2O (2 mL) and extracted with EtOAc (2 mL x 2). The combined organic layers were dried, filtered, concentrated and purified by preparative TLC (EtOAc:petroleum ether = 1:5) to give the title product (33d) (270 mg, 58.5%) as an oil. m / z (ESI, +ve ion) = 592.3 [M+H] + .

[0372] Step E. 2-((2-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)-5-(methoxycarbonyl)benzyl)oxy)acetic acid (33e) [ka]

[0373] To a solution of 33d (270 mg, 0.456 mmol) in DCM (2 mL) was added TFA (519 mg, 4.56 mmol) at 0° C. and the mixture was stirred at 20° C. for 2 h. After completion, the mixture was evaporated to give the crude title product (33e) (180 mg, 70%) as an oil, which was used in the next step without further purification. m / z (ESI, +ve ion)=536.2 [M+H] + .

[0374] Step F. Methyl 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)-3-((2-hydroxyethoxy)methyl)benzoate (33f) [ka]

[0375] To a solution of 33e (180 mg, 0.34 mmol) in THF (2 mL) was added BH3-Me2S (2N in THF, 0.5 mL, 1.0 mmol) at 0° C. After heating at 40° C. for 1 h, the reaction was cooled to 0° C. and quenched with MeOH (10 mL). The mixture was concentrated and the residue was purified by preparative TLC (EtOAc:petroleum ether=1:1) to give the title product (33f) (120 mg, 79.2%) as an oil. m / z (ESI, +ve ion)=522.2 [M+H] + .

[0376] Step G. 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)-3-((2-hydroxyethoxy)methyl)-N,N-dimethylbenzamide (33) [ka]

[0377] To a solution of dimethylamine hydrochloride (18 mg, 0.4 mmol) in toluene (2 mL) was added trimethylaluminum (0.2 mL, 0.4 mmol, 2 M in hexanes) at 0 °C. After stirring at 20 °C for 30 min, 33f (70 mg, 0.13 mmol) was added and the mixture was heated at 100 °C for 1 h. Upon completion, the mixture was cooled to 0 °C and 1N HCl (0.5 mL) was added. The reaction was concentrated and the crude residue was purified by reverse phase HPLC (gradient elution, 0-50% CH3CN in H2O) to give the title product (33) (16.4 mg, 22.6%) as a white solid. m / z (ESI, +ve ion) = 535.2 [M+H] + . 1H NMR (400 MHz, CD3OD) δ ppm 7.55-7.58 (m, 2H), 7.53 (d, J = 8.00 Hz, 2H), 7.38 (d, J = 8.00 Hz, 1H), 7.34 (s, 1H), 7.20 -7.27 (m, 3H), 7.02 (d, J = 8.00 Hz, 2H), 5.18 (s, 2H), 4.69 (s, 2H), 4.09 (s, 2H), 3.73 - 3.78 (m, 2H), 3.58 - 3.64 (m, 2H), 3.12 (s, 3H), 3.10 (s, 3H), 2.46 (s, 3H), 1.94 (br s, 1H).

[0378] Example 18. (S)-(3-aminopiperidin-1-yl)(6-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)pyridin-3-yl)methanone (Compound 34) [ka]

[0379] Step A. tert-Butyl (S)-(1-(6-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)nicotinoyl)piperidin-3-yl)carbamate (34a) [ka]

[0380] To a mixture of 27a (90 mg, 0.21 mmol), tert-butyl (3S)-piperidin-3-ylaminoformate (125 mg, 0.62 mmol) in DCM (5 ml) was added DIPEA (80 mg, 0.62 mmol), and T3P (172 mg, 0.27 mmol, 50% in EtOAc). The mixture was stirred at 25 °C for 2 h. The reaction was quenched by adding H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title product (34a) (110 mg), which was used in the next step without further purification. m / z (ESI, +ve ion) = 617.2 [M+H] + .

[0381] Step B. (S)-(3-aminopiperidin-1-yl)(6-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)phenoxy)methyl)pyridin-3-yl)methanone (34) [ka]

[0382] To a solution of 34a (120 mg, 0.19 mmol) in DCM (4 mL) was added TFA (1 mL) at 0° C. The reaction was stirred at 25° C. for 2 h. Then, H2O (50 mL) was added and the reaction was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude residue. The residue was purified by reverse phase HPLC (85% CH3CN in H2O, with 0.1% NH4OH as modifier) ​​to give the title product (34) (45 mg, 44.3%) as a white solid. m / z (ESI, +ve ion)=517.2 [M+H] +. H NMR (400 MHz, CD3OD) δ ppm 8.63 (d, J = 1.75 Hz, 1H), 7.93 (dd, J = 7.89, 2.19 Hz, 1H), 7.71 (d, J = 8.33 Hz, 1H), 7.56 (d, J = 8.77 Hz, 2H), 7.21 - 7.38 (m, 4H), 7.11 (br d, J = 14.47 Hz, 2H), 5.27 (s, 2H), 4.30 - 4.49 (m, 1H), 4.11 (s, 2H), 3.49 - 3.76 (m, 1H), 2.98 - 3.22 (m, 1H), 2.69 - 2.97 (m, 2H), 2.45 (s, 3H), 1.97 - 2.08 (m, 1H), 1.69 - 1.92 (m, 1H), 1.50 - 1.65 (m, 1H), 1.34 - 1.49 (m, 1H).

[0383] Using procedures similar to those described for the synthesis of compound 34 in Example 18, compounds 35, 36, 37, 38, 39, 40, and 41 were synthesized.

[0384] Example 19. (3S,5R)-1-cyano-5-methylpyrrolidin-3-yl (R)-1-acetyl-4-(5-(benzyloxy)-1H-indole-2-carbonyl)piperazine-2-carboxylate (Compound 42) [ka]

[0385] Step A. 1-(tert-butyl) 3-methyl (R)-4-acetylpiperazine-1,3-dicarboxylate (42a) [ka]

[0386] To a solution of 1-tert-butyl 3-methyl(3R)-piperazine-1,3-dicarboxylate (4 g, 16.4 mmol) in DCM (50 mL) at 0° C., Et3N (4.96 g, 49.1 mmol) was added, followed by dropwise addition of acetyl chloride (1.41 g, 18 mmol). The reaction was stirred at 0° C. for 6 h, diluted with H2O (10 mL), and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH=10:1) to give the title product (42a) (3.9 g, 77%) as a white solid. m / z (ESI, +ve ion)=287.1 [M+H] + .

[0387] Step B. Methyl (R)-1-acetylpiperazine-2-carboxylate (42b) [ka]

[0388] To a solution of 42a (2.65 g, 9 mmol) in THF (2 mL) was added 10 mL of HCl (2N in EtOAc). After stirring at 25° C. for 2 h, the reaction was concentrated to give the crude title product (42b) (1.9 g, 91%) as a white solid, which was used in the next step without further purification. m / z (ESI, +ve ion)=187.1 [M+H] + .

[0389] Step C. Methyl (R)-1-acetyl-4-(5-(benzyloxy)-1H-indole-2-carbonyl)piperazine-2-carboxylate (42c) [ka]

[0390] To a solution of 42b (300 mg, 1.05 mmol) in DMF (5 mL) was added EtN (424.2 mg, 4.2 mmol), T3P (50% in EtOAc, 1.6 g, 4.2 mmol) and 5-(benzyloxy)-1H-indole-2-carboxylic acid (360 mg, 1.45 mmol). The mixture was stirred at 25 °C for 4 h. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over NaSO4, filtered, concentrated and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (42c) (250 mg, 44.6%) as a white solid. m / z (ESI, +ve ion) = 436.1 [M+H] + .

[0391] Step D. (R)-1-Acetyl-4-(5-(benzyloxy)-1H-indole-2-carbonyl)piperazine-2-carboxylic acid (42d) [ka]

[0392] To a solution of 42c (250 mg, 0.57 mmol) in THF (5 mL) and HO (3 mL) was added NaOH (34.5 mg, 0.86 mmol). The reaction was stirred at 25° C. for 2 h, quenched with 1N HCl, adjusted to pH=4, and then extracted with EtOAc (5 mL×3). The combined organic layers were dried, filtered, and concentrated to give the crude title product (42d) (210 mg, 78.9%) as a white solid, which was used in the next step without further purification. m / z (ESI, +ve ion)=422.1 [M+H] + .

[0393] Step E. tert-Butyl (2R,4S)-4-((R)-1-acetyl-4-(5-(benzyloxy)-1H-indole-2-carbonyl)piperazine-2-carboxamide)-2-methylpyrrolidine-1-carboxylate (42e) [ka]

[0394] To a solution of 42d (120 mg, 0.28 mmol) in DCM (2 mL) was added EtN (84.84 mg, 0.84 mmol), HATU (319.2 mg, 0.84 mmol), and tert-butyl (2R,4S)-4-amino-2-methylpyrrolidine-1-carboxylate (56.08 mg, 0.28 mmol). The reaction was stirred at 25 °C for 4 h, diluted with DCM (5 mL x 2) and washed with H2O (5 mL x 2). The combined organic layers were dried, filtered, concentrated, and purified by reverse phase HPLC (CH3CN in H2O) to give the title product (42e) (50 mg, 34%) as a white solid. m / z (ESI, +ve ion) = 504.2 [M-Boc+H] + .

[0395] Step F. (R)-1-Acetyl-4-(5-(benzyloxy)-1H-indole-2-carbonyl)-N-((3S,5R)-5-methylpyrrolidin-3-yl)piperazine-2-carboxamide (42f) [ka]

[0396] To a solution of 42e (50 mg, 0.08 mmol) in THF (2 mL) was added HCl (2N in EtOAc, 0.1 mL). After stirring at 25° C. for 2 h, the reaction was concentrated and purified by reverse phase HPLC (CH3CN in H2O) to give the title product (42f) (40 mg, 95%) as a white solid. m / z (ESI, +ve ion)=504.2 [M+H] + .

[0397] Step G. (3S,5R)-1-Cyano-5-methylpyrrolidin-3-yl (R)-1-acetyl-4-(5-(benzyloxy)-1H-indole-2-carbonyl)piperazine-2-carboxylate (42) [ka]

[0398] To a solution of 42f (30 mg, 0.06 mmol) in DCM (0.5 mL) was added DIPEA (39 mg, 0.3 mmol) and BrCN (7 mg, 0.066 mmol). After stirring at 25 °C for 2 h, the reaction was diluted with HO (5 mL) and extracted with DCM (5 mL x 3). The combined organic phase was dried, filtered, concentrated and purified by preparative TLC (DCM:MeOH = 20:1) to give the title product (42) (8 mg, 24.2%) as a white solid. m / z (ESI, +ve ion) = 529.2 [M+H] + .

[0399] Example 20. (4-((1H-imidazol-2-yl)methyl)piperidin-1-yl)(4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)benzyl)oxy)phenyl)methanone (Compound 43) [ka]

[0400] Step A. Methyl 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)benzyl)oxy)benzoate (43a) [ka]

[0401] A solution of 21h (70 mg, 0.19 mmol), methyl 4-hydroxybenzoate (35 mg, 0.23 mmol), and potassium carbonate (53 mg, 0.38 mmol) in DMF (2 mL) was stirred at 55 °C for 1 h. After completion, the reaction was diluted with H2O (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (EtOAc:petroleum ether = 1:5) to give the title product (43a) (78 mg, 87%) as a white solid. m / z (ESI, +ve ion) = 448.1 [M+H] + .

[0402] Step B. 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)benzyl)oxy)benzoic acid (43b) [ka]

[0403] To a stirred solution of 43a (350 mg, 3.15 mmol) in MeOH (10 mL) was added a solution of sodium hydroxide (125 mg, 12.6 mmol) in HO (10 mL). The reaction mixture was heated at 50 °C for 2 h. After completion, in an ice bath, 1N HCl was added to the reaction to adjust pH = 5 and the reaction was extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (gradient elution, 20-30% EtOAc in petroleum ether) to give the title product (43b) (280 mg, 93%) as a white solid. m / z (ESI, +ve ion) = 434.1 [M+H] + .

[0404] Step C. 2,5-Dioxopyrrolidin-1-yl 4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)benzyl)oxy)benzoate (43c) [ka]

[0405] A solution of 43b (280 mg, 0.655 mmol), 1-hydroxypyrrolidine-2,5-dione (96 mg, 1.852 mmol) and DCC (173.2 mg, 0.84 mmol) in DCM (10 mL) was stirred at 20 °C for 2 h. After completion, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified on a silica gel column (EtOAc:petroleum ether = 1:6) to give the title product (43c) (160 mg, 70%) as a white solid. m / z (ESI, +ve ion) = 531.1 [M+H] + .

[0406] Step D. (4-((1H-imidazol-2-yl)methyl)piperidin-1-yl)(4-((4-(2-(3-chlorobenzyl)-5-methyloxazol-4-yl)benzyl)oxy)phenyl)methanone (43) [ka] To a stirred solution of 4-[(1H-imidazol-2-yl)methyl]piperidine dihydrochloride (8.1 mg, 0.034 mmol) in DMF (0.15 mL) was added DIPEA (0.015 mL, 0.085 mmol). After 10 min, 43c (15 mg, 0.028 mmol) in DMF (0.15 mL) was added. After stirring for 6 h, additional 4-[(1H-imidazol-2-yl)methyl]piperidine dihydrochloride (4 mg) and DIPEA (0.008 mL) were added and the mixture was heated at 40° C. overnight. The reaction was diluted with water, extracted with EtOAc (×3), and washed with water and brine (×2). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (gradient elution, 0-15% MeOH in DCM) to give the title product (43) (5 mg, 30%) as a white solid. m / z (ESI, +ve ion) = 581.3 [M+H] + . 1H NMR (600 MHz, CD3OD) δ ppm 7.58 - 7.70 (m, 2H), 7.52 (d, J = 8.44 Hz, 2H), 7.30 - 7.40 (m, 4H), 7.25 - 7.30 (m, 2H), 7.03 - 7.11 (m, 2H), 6.92 (s, 2H), 5.17 (s, 2H), 4.51 - 4.64 (m, 1H), 4.13 (s, 2H), 3.75 - 3.89 (m, 1H), 3.03 - 3.16 (m, 1H), 2.78 - 2.90 (m, 1H), 2.62 - 2.71 (m, 2H), 2.49 (s, 3H), 1.96 - 2.08 (m, 1H), 1.55 - 1.79 (m, 2H), 1.16 - 1.33 (m, 2H).

[0407] Compound 44 was synthesized similarly as described for the synthesis of compound 43 in Example 20.

[0408] Example 21. USP28 IC 50 Ubiquitin-Rhodamine 110 Assay to Determine

[0409] Each assay was performed in a final volume of 8 μl in assay buffer containing 10 mM HEPES pH 7.3 (1M, pH 7.3 solution, (VWR J848), 100 mM NaCl (5M, Corning 46-032-CV), 0.01% Triton® X-100 (Sigma #T8787), 3.5 mM DTT (1M, Sigma #43819) and 0.00375% BSA (10%, Calbiochem, #126609)). The pH of the assay buffer was adjusted to 7.5 using a DMSO buffer (Baker, #5000-03). Stock compounds were stored at -80°C as 25 mM in DMSO along with 20-point 2-fold serial dilutions of each. For dose response, stock compound plates were brought to room temperature on the day of the assay. 10 nl of the serial dilution series was pre-stamped onto an assay plate (black, high base, medium binding, Greiner #782076) to a final top screening concentration of 125 μM (final DMSO concentration = 0.5%). Enzyme (His6 The concentration of enzyme (USP28, BostonBiochem, #E-570) and incubation time were optimized. The final concentration of enzyme in the assay was 150 pM. The final substrate (Ub-Rho110, Ubiquitin-Rhodamine 110, UBP Bio, #M3020) concentration was 41 nM. 2 μl of 4X enzyme was added to the assay plate (pre-stamped with compounds) and incubated at room temperature for 2 hours. Then, 6 μl of 4X substrate was added to the assay plate and incubated at room temperature for 2 hours. Fluorescence was then read on an Envision (excitation 485 nm, emission 535 nm, Perkin Elmer).

[0410] The results are shown in Table 1 below. In the table, IC 50 Values ​​are ++++<0.05 μM<+++<0.5 μM<++<1 μM<+. Molecular weights are calculated using standard methods and mass spectrometry results are reported according to the examples above. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10]

[0411] Equivalent The above disclosure may encompass a number of different embodiments that have independent utility. While each of these embodiments has been disclosed, the specific embodiments disclosed and illustrated herein should not be considered in a limiting sense, since many variations are possible. The subject matter of the present embodiments includes all new and unobvious combinations and subcombinations of the various elements, features, functions, and / or properties disclosed herein. The following claims specifically point out certain combinations and subcombinations that are considered to be new and unobvious. Alternative embodiments, such as other combinations and subcombinations of features, functions, elements, and / or properties, may be claimed in this application, any application claiming priority to this application, or any related application. Such claims, whether directed to different or the same embodiments, and whether broader, narrower, equal or different in scope compared to the original claims, are deemed to be included within the subject matter of the present disclosure.

[0412] One or more features of any embodiment described in this specification or in any drawings may be combined with one or more features of any other embodiment described in this specification or in any drawings without departing from the scope of the disclosure.

[0413] All publications, patents, and patent applications cited in this specification are incorporated by reference herein as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of this disclosure that certain changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. A compound of formula (I), formula (II), or formula (III): 【Chemical 1】 or a pharmaceutically acceptable salt, diastereomer, or stereoisomer thereof (In the formula, L １ teeth, 【Chemistry 2】 is selected from L ２ teeth, 【Chemistry 3】 is selected from R １ is 1, 2, 3, or 4 R ４ａ aryl substituted with a group; one, two, three, or four R ４ａ cycloalkyl substituted with a group; 1, 2, 3, or 4 R ４ａ heteroaryl substituted with a group; and 1, 2, 3, or 4 R ４ａ and heterocyclic rings substituted with a group, wherein the heteroaryl and heterocyclic rings contain at least one nitrogen, oxygen, or sulfur, and the nitrogen of the heterocyclic ring is selected from the group consisting of R ４ｂ is replaced by R ２ optionally 1, 2, 3, or 4 R ５ aryl substituted with a group; optionally 1, 2, 3, or 4 R ５ heteroaryl substituted with a group; optionally 1, 2, 3, or 4 R ５ cycloalkyl substituted with a group, and optionally 1, 2, 3, or 4 R ５ a heterocycle substituted with a group; R ３ is hydrogen or C １－６ is alkyl, Each R ４ａ are independently １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Alkoxy, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, C １－６ Alkylaminoalkyl, C １－６ Dialkylaminoalkyl, amino, hydroxy, cyano, nitro, halogen, -NR ６ R ７ , -CH ２ NR ６ R ７ , —C(O)NR ６ R ７ , -CH ２ C(O)NR ６ R ７ , -(CH ２ ) ａ -O-(CH ２ ) ｂ R ８ , and -C(O)R ９ is selected from Each R ４ｂ are independently hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, cyano, -CH ２ NR ６ R ７ , —C(O)NR ６ R ７ , -CH ２ C(O)NR ６ R ７ , -(CH ２ ) ａ -O-(CH ２ ) ｂ R ８ , and -C(O)R ９ is selected from Each R ５ is, if present, independently １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Alkoxy, hydroxy C １－６ Alkyl, Amino C １－６ Alkyl, C １－６ Alkylaminoalkyl, C １－６ Dialkylaminoalkyl, amino, hydroxy, cyano, nitro, halogen, -NR ６ R ７ , -CH ２ NR ６ R ７ , —C(O)NR ６ R ７ , -CH ２ C(O)NR ６ R ７ , -(CH ２ ) ａ -O-(CH ２ ) ｂ R ８ , and -C(O)R ９ is selected from R ６ and R ７ are independently hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, aryl, aryl C １－６ Alkyl, heteroaryl, heteroaryl C １－６ Alkyl, heterocycle, and heterocycloC １－６ alkyl, excluding hydrogen; R ６ and R ７ independently optionally one or two R １０ may be substituted with a group, Or, R ６ and R ７ are bonded together and optionally one or two R １０ forming a heterocyclic or biheterocyclic ring substituted with a group, R ８ is hydroxy, cyano, halogen, C １－６ Haloalkyl, —NR ６ R ７ , or -C(O)R ９ and R ９ is C １－６ Alkyl, hydroxy, C １－６ Alkoxy, aryl, aryloxy, aryl C １－６ Alkyl, aryloxy C １－６ Alkyl, heteroaryl, heteroaryl C １－６ Alkyl, heterocycle, heterocyclo C １－６ alkyl, or —NR １１ R １２ and R １０ are independently —C(O)R ９ , —COOH, amino, —NR １１ R １２ , -NR １１ C(O)R １２ , aryl, heteroaryl, aryl C １－６ Alkyl and heteroaryl C １－６ alkyl; Or, two R's １０ groups, when on the same carbon, can be taken together to form an oxo group; R １１ and R １２ are independently hydrogen and C １－６ alkyl, R １５ is hydrogen, -C(O)R ９ , C １－６ Alkyl, or C ３－６ is cycloalkyl, R １６ and R １７ are independently hydrogen, —C(O)R ９ , C １－６ Alkyl, and C ３－６ cycloalkyl; Y is NR １５ , C.R. １６ R １７ , or oxygen, X １ is CH or N, a and b are integers independently selected from 1, 2, 3, and 4).

2. Formula (I): 【Chemistry 4】 10. The compound of claim 1, or a pharmaceutically acceptable salt, diastereomer, or stereoisomer thereof.

3. Formula (II): 【Chemistry 5】 10. The compound of claim 1, or a pharmaceutically acceptable salt, diastereomer, or stereoisomer thereof.

4. Formula (Ia) or Formula (Ib): 【Chemistry 6】 3. The compound of claim 2, or a pharmaceutically acceptable salt, diastereomer, or stereoisomer thereof.

5. Formula (Ic) or Formula (Id): 【Chemistry 7】 3. The compound of claim 2, or a pharmaceutically acceptable salt, diastereomer, or stereoisomer thereof.

6. Formula (IIa) or Formula (IIb): 【Chemistry 8】 4. The compound of claim 3, or a pharmaceutically acceptable salt, diastereomer, or stereoisomer thereof.

7. Formula (IIc) or Formula (IId); 【Chemistry 9】 4. The compound of claim 3, or a pharmaceutically acceptable salt, diastereomer, or stereoisomer thereof.

8. R １ But one R ４ａ The compound of claim 1 , wherein the compound is an aryl substituted with a group.

9. R １ But one R ４ａ The compound of claim 1 , which is a heteroaryl substituted with a group.

10. R １ But one R ４ａ a heterocycle substituted with a group, said heterocycle containing at least one nitrogen, said nitrogen being ４ｂ 2. The compound of claim 1 , substituted with:

11. The one R ４ａ The group is —NR ６ R ７ , -CH ２ NR ６ R ７ and —C(O)NR ６ R ７ 2. The compound of claim 1 selected from:

12. R ６ and R ７ are independently hydrogen, C １－６ Alkyl and heterocyclo C １－６ 12. The compound of claim 11, wherein the alkyl is selected from the group consisting of aryl, arylsulfonyl

13. R ６ and R ７ are bonded together and optionally R １０ 12. The compound of claim 11, wherein the compound forms a heterocycle substituted with

14. R １０ is COOH, amino, or NR １１ R １２ 14. The compound of claim 13, wherein:

15. R １１ and R １２ are independently hydrogen and C １－６ 15. The compound of claim 14, wherein the alkyl is selected from the group consisting of aryl, arylsulfonyl

16. R ４ｂ The compound of claim 10, wherein is cyano.

17. R ４ｂ The compound of claim 10, wherein is hydrogen.

18. R ２ However, optionally one R ５ The compound of claim 1 , wherein the compound is an aryl substituted with a group.

19. R ２ However, optionally one R ５ The compound of claim 1 , which is a heteroaryl substituted with a group.

20. R ２ However, optionally one R ５ The compound of claim 1 , which is a heterocycle substituted with a group.

21. A compound according to claim 1, wherein R 2 is an aryl optionally substituted with one R 5 group, a heteroaryl optionally substituted with one R 5 group, or a heterocycle optionally substituted with one R 5 group; The one R ５ The compound of claim 1 , wherein the group is a halogen.

22. The compound of claim 21, wherein said one R 5 group is chloro.

23. A compound according to claim 23, wherein R 2 is an aryl optionally substituted with one R 5 group, a heteroaryl optionally substituted with one R 5 group, or a heterocycle optionally substituted with one R 5 group; The one R ５ The group is C １～６ Alkyl, C １～６ Haloalkyl, C １～６ 2. The compound of claim 1, wherein the aryl group is selected from alkoxy and cyano.

24. L １ but, 【Chemistry 10】 2. The compound of claim 1 selected from:

25. L １ but, 【Chemistry 11】 2. The compound of claim 1 selected from:

26. L １ but, 【Chemistry 12】 2. The compound of claim 1 selected from:

27. X １ The compound of claim 1 , wherein is CH.

28. X １ The compound of claim 1 , wherein is N.

29. A compound of formula (Ia), (Ib), (Ic), (Id), (IIa), (IIb), (IIc), or (IId): 【Chemistry 13】 【change】 or a pharmaceutically acceptable salt, diastereomer, or stereoisomer thereof; R ５ The compound of claim 1 , wherein is chloro.

30. R ４ａ is -C(O)NR ６ R ７ , -NR ６ R ７ , or -CH ２ NR ６ R ７ 30. The compound of claim 29, wherein:

31. R ６ and R ７ are independently hydrogen, C １－６ Alkyl and heterocyclo C １－６ 30. The compound of claim 29, wherein the alkyl is selected from alkyl.

32. R ４ａ But C １－６ alkyl, and R ４ｂ 30. The compound of claim 29, wherein is cyano.

33. R ４ａ 33. The compound of claim 32, wherein is methyl.

34. R １ but, 【Chemistry 14】 is selected from R ４ａ is -C(O)NR ６ R ７ , C １－６ Alkyl, and —CH ２ NR ６ R ７ is selected from R ６ and R ７ are independently hydrogen, C １－６ Alkyl and heteroaryl C １－６ alkyl; Or, R ６ and R ７ are bonded together and optionally R １０ forming a heterocyclic or biheterocyclic ring substituted with R １０ -COOH, -NH ２ , —NHMe, and heteroaryl C １－６ 2. The compound of claim 1, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

35. R １ but, 【Chemistry 15】 2. The compound of claim 1 selected from:

36. R １ but, 【Chemistry 16】 2. The compound of claim 1 selected from:

37. L ２ but, 【Chemistry 17】 2. The compound of claim 1, wherein:

38. Y is NR １５ 2. The compound of claim 1, wherein:

39. R １５ But -C(O)R ９ 2. The compound of claim 1, wherein: 【Request 40】 【Chemical 18-1】 【Chemistry 18-2】 【Chemistry 18-3】 【Chemistry 18-4】 【Chemistry 18-5】 【Chemistry 18-6】 【Chemistry 18-7】 【Chemistry 18-8】 10. The compound of claim 1 selected from: or a pharmaceutically acceptable salt, diastereomer, or stereoisomer thereof.

41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 40 and a pharmaceutically acceptable carrier, excipient, or diluent.

42. A pharmaceutical composition for treating a disorder or condition in which inhibition of USP28 provides a therapeutic effect, the pharmaceutical composition comprising a compound according to any one of claims 1 to 40.

43. 43. The pharmaceutical composition of claim 42, wherein the disease or condition is cancer.

44. 44. The pharmaceutical composition of claim 43, wherein the cancer is selected from non-small cell lung cancer, breast cancer, intestinal cancer, and bladder cancer.

45. 43. The pharmaceutical composition of claim 42, wherein the disease or condition is an autoimmune disease, inflammation, or an infectious disease.

46. 41. A compound according to any one of claims 1 to 40 for use in the treatment of a disorder or condition in which inhibition of USP28 provides a therapeutic effect.

47. 41. Use of a compound according to any one of claims 1 to 40 in the preparation of a medicament for the treatment of a disorder or condition in which inhibition of USP28 provides a therapeutic effect.

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