Heterocyclic amide and urea compounds as JAK2 inhibitors

Abstract

The present disclosure provides heterocyclic amide and urea compounds and compositions thereof useful for inhibiting JAK2. The present disclosure provides compounds useful for inhibiting JAK2. In some embodiments, the provided compounds are useful, inter alia, for treating and / or preventing diseases, disorders, or conditions associated with JAK2. In some embodiments, the present disclosure provides compounds of formula A, or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring C, L, p, q, s, R a , R b , R c , R 8 , and X are as defined herein.

Description

[Technical Field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Patent Application No. 63 / 395,992, filed August 8, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase involved in the JAK-STAT signaling pathway, which plays a role in cellular processes such as immunity, cell division, and cell death. Dysfunction of the JAK-STAT pathway has been shown to be involved in a variety of diseases, including cancer and other proliferative disorders and disorders of the immune system. For example, essentially all BCR-ABL1-negative myeloproliferative neoplasms are associated with mutations that activate JAK2. In particular, JAK2V617F is the most common mutation in myeloproliferative neoplasms, occurring in approximately 70% of all patients and up to 95% of patients with polycythemia vera (PVA). (Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79). Even relatively rare mutations, such as those in MPL and CALR, have been shown to activate JAK2, thereby initiating and / or driving disease progression. (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82). Furthermore, JAK2 polymorphisms have been implicated in various autoimmune diseases and inflammatory conditions, such as psoriasis and inflammatory bowel disease. (O'Shea, JJ et al., Ann. Rheum. Dis. 2013 Apr, 72:ii111-ii115). Increased signaling through JAK2 and other members of the JAK family has also been associated with atopic dermatitis. (Rodrigues, MA and Torres, TJ Derm. Treat. 2019, 31(1):33-40). JAK (e.g., JAK2) inhibitors are classified based on their binding mode. All currently approved JAK inhibitors are type I inhibitors, which bind to the ATP-binding site in the active conformation of the kinase domain, thereby blocking catalytic activity (Vainchenker, W. et al.). However, increased phosphorylation of the JAK2 activation loop has been observed with type I inhibitors, which may lead to acquired resistance in certain patients (Meyer SC, Levine, RL Clin. Cancer Res. 2014, 20(8):2051-9). On the other hand, type II inhibitors bind to the ATP-binding site in the inactive conformation of the kinase domain, thereby avoiding the hyperphosphorylation observed with type I inhibitors (Wu, SC et al. Cancer Cell 2015 Jul 13, 28(1):29-41). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79 [Non-patent document 2] Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82 [Non-patent document 3] O'Shea, JJ et al., Ann. Rheum. Dis. 2013 Apr, 72:ii111-ii115 [Non-patent document 4] Rodrigues, MA and Torres, TJ Derm. Treat. 2019, 31(1):33-40 [Non-patent document 5] Meyer SC, Levine, RL Clin. Cancer Res. 2014, 20(8):2051-9 [Non-patent document 6] Wu, SC et al. Cancer Cell 2015 Jul 13, 28(1):29-41 Summary of the Invention

[0004] The present disclosure provides compounds useful for inhibiting JAK2. In some embodiments, the provided compounds are useful, inter alia, for treating and / or preventing diseases, disorders, or conditions associated with JAK2.

[0005] In some embodiments, the present disclosure provides a compound of formula A: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring C, L, p, q, s, R a , R b , R c , R 8 , and X are as defined herein.

[0006] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, m, n, p, q, R a , R b , R 1 , R 2 , R 3 , R 8 , X, Y, and Z are as defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0007] Compounds and Definitions Compounds of the present disclosure include those broadly described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise stated. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Further, the general principles of organic chemistry are identified in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0008] Unless otherwise specified, a structure depicted herein is intended to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, and all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the present disclosure. Accordingly, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the provided compounds, are within the scope of the present disclosure. For example, in some cases, Table 1 depicts one or more stereoisomers of a compound, and unless otherwise specified, each stereoisomer is represented individually and / or as a mixture. Unless otherwise specified, all tautomeric forms of the provided compounds are within the scope of the present disclosure.

[0009] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C-enriched carbon or 14Compounds having the subject structures including the replacement of carbons with C-enriched carbons are within the scope of this disclosure.

[0010] Aliphatic: The term "aliphatic" refers to a linear (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic" or "cycloaliphatic") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C 1-6 In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1-5 In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C 1-4 In yet other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms (e.g., C 1-3 ), in still other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C 1-2 ). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof. In some embodiments, "aliphatic" refers to a linear (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation and has one point of attachment to the rest of the molecule.

[0011] Alkyl: The term “alkyl” used alone or as part of a larger moiety refers to an alkyl group having 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms (unless otherwise specified) (e.g., C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2), saturated, optionally substituted, straight-chain or branched hydrocarbon radical. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. As used herein, alone or in combination, the term "alkylene" refers to a divalent, saturated, optionally substituted, straight-chain or branched hydrocarbon radical, such as methylene (-CH-).

[0012] Carbocyclyl: As used herein, the terms "carbocyclyl," "carbocycle," and "carbocyclic ring" refer to a saturated or partially unsaturated cycloaliphatic monocyclic, bicyclic, or polycyclic ring system having 3 to 14 members, as described herein, which aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, "carbocyclyl" (or "cycloaliphatic") refers to an optionally substituted monocyclic C3-C8 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the remainder of the molecule, or an optionally substituted C5-C6 hydrocarbon. 10 It refers to a bicyclic hydrocarbon. The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, the cycloalkyl group has 3 to 6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0013] Alkenyl: The term “alkenyl,” used alone or as part of a larger moiety, refers to an alkyl group having at least one double bond and having 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (unless otherwise specified) (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ), which means an optionally substituted straight or branched hydrocarbon chain. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0014] Alkynyl: The term “alkynyl,” used alone or as part of a larger moiety, refers to an alkyl group having at least one triple bond and having 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (unless otherwise specified) (e.g., C 2-12 , C 2-10 , C 2-8 , C 2-6 , C 2-4 , or C 2-3 ), means an optionally substituted straight or branched chain hydrocarbon group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0015] Aryl: The term "aryl" refers to an alkyl group having a total of 6 to 14 ring members (e.g., C 6-14 ) refers to monocyclic and bicyclic ring systems in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used synonymously with the term "aryl ring." In some embodiments, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Unless otherwise specified, "aryl" groups are hydrocarbons.

[0016] Heteroaryl: The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy," refer to a monocyclic or bicyclic ring group having 5 to 10 ring atoms, having 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms (e.g., a 5- or 6-membered monocyclic heteroaryl or a 9- or 10-membered bicyclic heteroaryl). Exemplary heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzisoxazolyl. As used herein, the terms "heteroaryl" and "heteroara" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings (i.e., bicyclic heteroaryl rings having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, and benzisoxazolyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include rings that are optionally substituted.

[0017] Heteroatom: As used herein, the term "heteroatom" means nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0018] Heterocycle: As used herein, the terms "heterocycle," "heterocyclyl," and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 6- to 10-membered bicyclic, or 10- to 16-membered polycyclic (i.e., containing three or more rings) moiety that is either saturated or partially unsaturated and that, in addition to carbon atoms, has one or more, e.g., 1 to 4, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(In the case of N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group can be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, and more preferably monocyclic or bicyclic. Bicyclic heterocyclic rings also include groups in which a heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. The bicyclic or polycyclic heterocyclic ring may be a spirocyclic ring system (e.g., a 6- to 11-membered spirocyclic bicyclic heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) as defined above).

[0019] Partially unsaturated: As used herein, the term "partially unsaturated" with respect to a ring moiety means a ring moiety that contains at least one double or triple bond between ring atoms. The term "partially unsaturated," as defined herein, is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties.

[0020] Patient or Subject: As used herein, the term "patient" or "subject" refers to any organism to which a provided composition is or can be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient or subject suffers from or is prone to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject is undergoing or has undergone a particular therapy to diagnose and / or treat a disease, disorder, or condition.

[0021] Substituted or optionally substituted: As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent (i.e., as described below for optionally substituted groups). "Substituted" applies to one or more hydrogens that are explicit or implicit from the structure (e.g., [ka] At least [ka] means, [ka] At least [ka] (meaning "substituted" or "optionally substituted"). Unless otherwise specified, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituents can be the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that remains substantially unchanged when subjected to conditions that permit the compound's production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes provided herein. Groups described as "substituted" preferably have one to four substituents, more preferably one or two substituents. Groups described as "optionally substituted" can be unsubstituted or "substituted" as described above.

[0022] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are, independently, halogen; -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°; optionally substituted with R° -(CH2) 0-4 Ph; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 Ph; optionally substituted with R° -CH=CHPh; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)(NH)R°;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;-SiR°3;-(C 1-4 linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, two independent occurrences of R° together with the intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be optionally substituted as defined below.

[0023] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with the intervening atoms) are independently halogen, —(CH) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and C 1-4Aliphatic, -CH2Ph, -O(CH2) 0-1 or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0024] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include ═O ("oxo"), ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, where R is an independent * Each occurrence of C may be substituted as defined below, hydrogen 1-6 The "optionally substituted" group is selected from an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of the "optionally substituted" group include -O(CR * 2) 2-3 O-, where an independent R * Each occurrence of C may be substituted as defined below, hydrogen 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0025] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0026] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, optionally substituted C as defined below 1-6 an aliphatic or unsubstituted 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent R † The occurrences of, taken together with the intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] R † Suitable substituents on the aliphatic groups are, independently, halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] Treat: As used herein, the term "treat" (also "treatment" or "treating") refers to the administration of a therapy that partially or completely alleviates, improves, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, characteristics, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be treatment of a subject who does not exhibit symptoms of the associated disease, disorder, and / or condition and / or who exhibits only early symptoms of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be treatment of a subject who exhibits one or more established symptoms of the associated disease, disorder, and / or condition. In some embodiments, treatment may be treatment of a subject who has been diagnosed with the associated disease, disorder, and / or condition.

[0029] Provided compounds In some embodiments, the present disclosure provides a compound of formula A: [ka] or a pharmaceutically acceptable salt thereof, wherein: X is -C(R 6 )2-, -N(R 7 )-, or -O-, Each R 6are independently hydrogen or optionally substituted C 1-6 aliphatic, or The Two R's 6 the groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; R 7 is hydrogen or an appropriately substituted C 1-6 is aliphatic, Ring A is an optionally substituted group selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted group selected from a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 10- to 16-membered polycyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is an optionally substituted group selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent C 1-3a linear or branched hydrocarbon chain, R 8 is hydrogen, halogen, optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur; an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R a are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R b are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R c are independently halogen, —CN, —OR, or optionally substituted C 1-6 is aliphatic, and / or The Two R's c group, and / or R c and R 6 group, and / or R c and R 7 groups, taken together with the atom(s) to which they are attached, form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring; and / or The Two R's c groups, when combined with the atoms to which they are attached, form oxo; p is 0, 1, 2, 3, 4, or 5, as permitted by valence; q is 0, 1, 2, 3, 4, or 5, as valence permits; s is 0, 1, 2, 3, 4, or 5, as permitted by valence; Each R is independently hydrogen or C 1-6 Aliphatic and C 3-7 an optionally substituted group selected from cycloaliphatic, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently C 1-6Aliphatic and C 3-7 is an optionally substituted group selected from cycloaliphatic groups.

[0030] In some embodiments, the present disclosure provides a compound of formula B: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, L, p, q, s, R a , R b , R c and X, alone or in combination, are as defined above for formula A and as described in classes and subclasses herein; Ring B1 is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6 a cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B1 is optionally fused to ring B2; Ring B2, if present, is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6 a cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; At least one of ring B1 and ring B2 is aromatic; At least one of ring B1 and ring B2 contains a heteroatom.

[0031] In some embodiments, the present disclosure provides a compound of formula C: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, L, p, s, R a , R b , R c , R 8, R, R', and X, alone or in combination, are as defined above for Formula A and as described in classes and subclasses herein; W is CH, CR w , or N, Each R w are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's w The groups, in combination with the atoms to which they are attached, can consist of 0 to 4 R b forming a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group, r is 0, 1, 2, or 3.

[0032] In some embodiments, the present disclosure provides a compound of formula D: [ka] or a pharmaceutically acceptable salt thereof, wherein ring B, ring C, L, p, q, s, R a , R b , R c , R 8 and X, alone or in combination, are as defined above for formula A and as described in classes and subclasses herein.

[0033] In some embodiments, the present disclosure provides a compound of formula E: [ka] or a pharmaceutically acceptable salt thereof, wherein rings C, L, p, s, R a , R c , R 8 and X, alone or in combination, are as defined above for formula A and as described in classes and subclasses herein; W is CH, CR w , or N, Each R w are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's w The groups, in combination with the atoms to which they are attached, can consist of 0 to 4 R b forming a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group, r is 0, 1, 2, or 3.

[0034] In some embodiments, the disclosure provides a compound of formula A, wherein: X is -C(R 6 )2-, -N(R 7 )-, or -O-, Each R 6 is hydrogen, or The Two R's 6 groups, together with the atoms to which they are attached, combine to form a three-membered carbocyclic ring; R 7 is C 1-6 is alkyl, Ring A is selected from phenyl and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is an optionally substituted group selected from phenyl, a 6-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5-membered saturated or partially unsaturated bicyclic carbocyclyl, a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or -CH2-; R 8 is replaced appropriately by C 1-6 Aliphatic, optionally substituted C 3-6 cycloaliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R a are independently optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 cycloaliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R bare independently selected from halogen, —CN, —OR, —N(R), —C(O)N(R), —N(R)C(O)R′, —N(R)C(O)N(R), optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 cycloaliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R c are independently halogen, —OR, or optionally substituted C 1-6 is alkyl, and / or The Two R's c group, and / or R c and R 7 groups, together with the atom(s) to which they are attached, combine to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; s is 0, 1, 2, or 3; Each R is independently hydrogen or C 1-6 Alkyl and C 3-7 an optionally substituted group selected from cycloalkyl and a 3- to 7-membered saturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently C 1-6 Alkyl and C 3-7 cycloalkyl is an optionally substituted group selected from cycloalkyl.

[0035] In some embodiments, the present disclosure provides a compound of formula A, wherein ring A, ring B, L, R a , R b , R c , R 8, q, p, s, and X, alone or in combination, are as defined above for Formula A and as described in classes and subclasses herein; and Ring C is an optionally substituted group selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing an N atom as the point of attachment to Ring B and having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0036] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: X is -C(R 6 )2-, -N(R 7 )-, or -O-, Each Y is -C(R 4 )2- and Each Z is -C(R 5 )2- and n is 0, 1, or 2; m is 0, 1, or 2; provided that at least one of n or m is 1 or 2; Each R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 is aliphatic, and / or The Two R's 1 group, and / or two R 2 group, and / or two R 4 group, and / or two R 5 groups, together with the atom(s) to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; and / or The Two R's 1 group, and / or two R2 group, and / or two R 4 group, and / or two R 5 groups, taken together with the atoms to which they are attached, form oxo; and / or R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 group, and / or R 3 and R 4 group, and / or R 3 and R 5 group, and / or R 3 and R 6 group, and / or R 3 and R 7 group, and / or R 4 and R 5 group, and / or R 4 and R 6 group, and / or R 4 and R 7 group, and / or R 5 and R 6 group, and / or R 5 and R 7 the groups, taken together with the atoms to which they are attached, combine to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring; Each R 6 are independently hydrogen or optionally substituted C 1-6 aliphatic, or The Two R's 6 the groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; R 7 is hydrogen or an appropriately substituted C 1-6 is aliphatic, Ring A is an optionally substituted group selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted group selected from a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 10- to 16-membered polycyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent C 1-3 a linear or branched hydrocarbon chain, R 8 is hydrogen, halogen, optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur; an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R a are independently halogen, -CN, -OR, -O(CH2) 1-4R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R b are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; p is 0, 1, 2, 3, 4, or 5, as permitted by valence; q is 0, 1, 2, 3, 4, or 5, as valence permits; Each R is independently hydrogen or C 1-6 Aliphatic and C 3-7an optionally substituted group selected from cycloaliphatic, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently C 1-6 Aliphatic and C 3-7 is an optionally substituted group selected from cycloaliphatic groups.

[0037] In some embodiments, the disclosure provides a compound of formula I, wherein: X is -C(R 6 )2- or -N(R 7 )- and Each Y is -C(R 4 )2- and Each Z is -C(R 5 )2- and n is 0, 1, or 2; m is 0, 1, or 2; provided that at least one of n or m is 1 or 2; Each R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 is aliphatic, and / or The Two R's 1 group, and / or two R 2 group, and / or two R 4 group, and / or two R 5 groups, together with the atom(s) to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; and / or The Two R's 1group, and / or two R 2 group, and / or two R 4 group, and / or two R 5 groups, taken together with the atoms to which they are attached, form oxo; and / or R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 group, and / or R 3 and R 4 group, and / or R 3 and R 5 group, and / or R 3 and R 6 group, and / or R 3 and R 7 group, and / or R 4 and R 5 the groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; Each R 6 are independently hydrogen or optionally substituted C 1-6 aliphatic, or The Two R's 6 the groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; R 7 is hydrogen or an appropriately substituted C 1-6 is aliphatic, Ring A is an optionally substituted group selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted group selected from a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10- to 16-membered polycyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent C 1-3 a linear or branched hydrocarbon chain, R 8 is hydrogen, halogen, optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur; an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R a are independently halogen, -CN, -OR, -O(CH2) 1-4R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R b are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; p is 0, 1, 2, 3, 4, or 5, as permitted by valence; q is 0, 1, 2, 3, 4, or 5, as valence permits; Each R is independently hydrogen or C 1-6 Aliphatic and C 3-7an optionally substituted group selected from cycloaliphatic, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently C 1-6 Aliphatic and C 3-7 is an optionally substituted group selected from cycloaliphatic groups.

[0038] In some embodiments, the disclosure provides a compound of formula I, wherein: X is -C(R 6 )2-, -N(R 7 )-, or -O-, Each Y is -C(R 4 )2- and Each Z is -C(R 5 )2- and n is 1 or 2, m is 1, Each R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, —OR, or optionally substituted C 1-6 is alkyl, and / or R 1 and R 5 group, and / or R 3 and R 7 group, and / or R 4 and R 5 group, and / or R 4 and R 7 the groups, taken together with the atoms to which they are attached, combine to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring; Each R 6are independently hydrogen, or The Two R's 6 groups, together with the atoms to which they are attached, combine to form a three-membered carbocyclic ring; R 7 is C 1-6 is alkyl, Ring A is selected from phenyl and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is selected from a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or -CH2-; R 8 is replaced appropriately by C 1-6 Aliphatic, optionally substituted C 3-6 cycloaliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R a are independently optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 cycloaliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R b are independently selected from halogen, —CN, —OR, —N(R), —C(O)N(R), —N(R)C(O)R′, —N(R)C(O)N(R), optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 cycloaliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; Each R is independently hydrogen or C 1-6 Alkyl and C 3-7 an optionally substituted group selected from cycloalkyl and a 3- to 7-membered saturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently C 1-6 Alkyl and C 3-7 cycloalkyl is an optionally substituted group selected from cycloalkyl.

[0039] In some embodiments, the present disclosure provides a compound of formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, p, q, R a , R b , R 1 , R 2 , R 3 , R 5 , R 8 and X, alone or in combination, are as defined above for Formula I and as described in classes and subclasses herein.

[0040] In some embodiments, the present disclosure provides a compound of formula IB: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, p, q, R a , R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and X, alone or in combination, are as defined above for Formula I and as described in classes and subclasses herein.

[0041] In some embodiments, the present disclosure provides a compound of formula IC: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, p, q, R a , R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and X, alone or in combination, are as defined above for Formula I and as described in classes and subclasses herein.

[0042] In some embodiments, the present disclosure provides a compound of formula ID: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, p, q, R a , R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and X, alone or in combination, are as defined above for Formula I and as described in classes and subclasses herein.

[0043] In some embodiments, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, L, m, n, p, q, R a , R b , R 1 , R 2 , R 3 , R 8 , X, Y, and Z, alone or in combination, are as defined above for Formula I and as described in classes and subclasses herein; Ring B1 is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6a cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B1 is optionally fused to ring B2; Ring B2, if present, is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6 a cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; At least one of ring B1 and ring B2 is aromatic; At least one of ring B1 and ring B2 contains a heteroatom.

[0044] In some embodiments, the present disclosure provides a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, L, m, n, p, R a , R 1 , R 2 , R 3 , R 8 , X, Y, R, R', and Z, alone or in combination, are as defined above for Formula I and as described in classes and subclasses herein; W is CH, CR w , or N, Each R w are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's w The groups, in combination with the atoms to which they are attached, can consist of 0 to 4 R b forming a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group, r is 0, 1, 2, or 3.

[0045] In some embodiments, the present disclosure provides a compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, m, n, p, q, R a , R b , R 1 , R 2 , R 3 , R 8 , X, Y, and Z, alone or in combination, are as defined above for Formula I and as described in classes and subclasses herein.

[0046] In some embodiments, the present disclosure provides a compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein rings B, L, m, n, p, q, R a , R b , R 1 , R 2 , R 3 , R 8 , X, Y, and Z, alone or in combination, are as defined above for Formula I and as described in classes and subclasses herein.

[0047] In some embodiments, the present disclosure provides a compound of formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, p, q, R a , R b , R 8 and X, alone or in combination, are as defined above for Formula A1 and as described in classes and subclasses herein; and each R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 It is aliphatic.

[0048] In some embodiments, the present disclosure provides a compound of formula A, wherein ring A, ring B, L, R a , R b , R c , R 8 , q, p, s, and X, alone or in combination, are as defined above for Formula A and as described in classes and subclasses herein; and Ring C contains a carbon atom as the point of attachment to Ring B and is an optionally substituted group selected from phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 5-8 membered saturated or partially unsaturated bicyclic carbocyclyl, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0049] In some embodiments, the present disclosure provides a compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, p, q, R a , R b , R 8and X, alone or in combination, are as defined above for formula A2 and as described in classes and subclasses herein; and each R 1 , R 2 , R 4 , and R 5 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 It is aliphatic.

[0050] In some embodiments, the present disclosure provides a compound of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, p, q, R a , R b , R 8 and X, alone or in combination, are as defined above for formula A2 and as described in classes and subclasses herein; and each R 1 , R 2 , R 3 , R 4 , R 5 , and R 9 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 It is aliphatic.

[0051] In some embodiments, the present disclosure provides a compound of formula IX: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, p, q, R a , R b , R 8 and X, alone or in combination, are as defined above for formula A2 and as described in classes and subclasses herein; and each R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 It is aliphatic.

[0052] In some embodiments, the present disclosure provides a compound of formula X: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, p, q, R a , R b , R 8 and X, alone or in combination, are as defined above for formula A2 and as described in classes and subclasses herein.

[0053] In some embodiments, the present disclosure provides a compound of formula XI: [ka] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, L, p, q, R a , R b , R 8 and X, alone or in combination, are as defined above for formula A2 and as described in classes and subclasses herein; Each R 2 , R 3 , R 4 , R 5 , and R 9 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 is aliphatic, and / or The Two R's 2 group, and / or two R 3 group, and / or two R 4 group, and / or two R 5 the groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; and / or R 9 and R 2 group, and / or R 9 and R 3 group, and / or R 9 and R 4 group, and / or R 9 and R 5 group, and / or R2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 group, and / or R 3 and R 4 group, and / or R 3 and R 5 group, and / or R 3 and R 6 group, and / or R 3 and R 7 group, and / or R 4 and R 5 group, and / or R 4 and R 6 group, and / or R 4 and R 7 group, and / or R 5 and R 6 group, and / or R 5 and R 7 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring.

[0054] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, X is -C(R 6 )2- or -N(R 7 In some embodiments, X is —C(R 6 )2-. In some embodiments, X is -N(R 7 )-. In some embodiments, X is -O-.

[0055] In some embodiments of any of Formulas A, B, C, D, and E, Ring C is an optionally substituted group selected from phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is selected from phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl. In some embodiments, Ring C is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl and a 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl. In some embodiments, Ring C is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0056] In some embodiments, Ring C contains an N atom as the point of attachment to Ring B and is selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, Ring C is [ka] is.

[0057] In some embodiments, ring C contains a C atom as the point of attachment to ring B and is an optionally substituted group selected from phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C contains a C atom as the point of attachment to ring B and is selected from phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl. In some embodiments, Ring C contains a C atom as the point of attachment to Ring B and is selected from 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, Ring C is [ka] is.

[0058] In some embodiments, Ring C is phenyl. In some embodiments, Ring C is [ka] is.

[0059] In some embodiments, ring C is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring C is a 5- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring C is a 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring C is a 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring C is a 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring C is a 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring C is a cyclohexane or cyclohexene ring. In some embodiments, ring C is a 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring C is [ka] is.

[0060] In some embodiments, ring C is a 5-8 membered saturated or partially unsaturated bicyclic carbocyclyl. In some embodiments, ring C is a 5-6 membered saturated bicyclic carbocyclyl. In some embodiments, ring C is a 5 membered saturated bicyclic carbocyclyl. In some embodiments, ring C is a 6 membered saturated or partially unsaturated bicyclic carbocyclyl. In some embodiments, ring C is a 7 membered saturated or partially unsaturated bicyclic carbocyclyl. In some embodiments, ring C is an 8 membered saturated or partially unsaturated bicyclic carbocyclyl. In some embodiments, ring C is [ka] is.

[0061] In some embodiments, ring C is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 6- to 7-membered saturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 3-membered saturated or partially unsaturated monocyclic heterocyclyl having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 4-membered saturated or partially unsaturated monocyclic heterocyclyl having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 6-membered saturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a piperidine ring. In some embodiments, ring C is a 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 7-membered saturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is an azepane ring. In some embodiments, ring C is [ka] is.

[0062] In some embodiments, ring C is a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 7- to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 7- to 8-membered saturated bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 6-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 7-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is an 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 9-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is [ka] is.

[0063] In some embodiments of any of Formulas A, B, C, D, and E, each R c are independently halogen, —CN, —OR, or optionally substituted C 1-6 Aliphatic and / or two R c group, and / or R c and R 6 group, and / or R c and R 7The groups, together with the atom(s) to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring. In some embodiments, each R c are independently halogen, —CN, —OR, or optionally substituted C 1-6 Aliphatic and / or two R c group, and / or R c and R 6 group, and / or R c and R 7 The groups, together with the atom(s) to which they are attached, combine to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring.

[0064] In some embodiments, each R c are independently halogen, —CN, —OR, or optionally substituted C 1-6 In some embodiments, each R c are independently halogen, —CN, —OR, or optionally substituted C 1-6 In some embodiments, each R c is halogen. In some embodiments, each R c In some embodiments, each R c is —OR (e.g., —OCH or —OCHF). In some embodiments, each R c is replaced appropriately by C 1-6 It is alkyl (eg, methyl).

[0065] In some embodiments, two R c The groups, together with the atom(s) to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring. In some embodiments, two R c The groups, together with the atom(s) to which they are attached, combine to form an optionally substituted 3-6 membered saturated or partially unsaturated ring. In some embodiments, two R cThe groups, together with the atom(s) to which they are attached, combine to form a C-C cycloalkyl. In some embodiments, two R c The groups combine together with the atom(s) to which they are attached to form a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R c The groups combine together with the atom(s) to which they are attached to form a 3-6 membered saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0066] In some embodiments, R c and R 6 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring. In some embodiments, R c and R 6 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring. In some embodiments, R c and R 6 The groups, together with the atoms to which they are attached, combine to form a C-C cycloalkyl. In some embodiments, R c and R 6 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R c and R 6 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0067] In some embodiments, R c and R 7The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring. In some embodiments, R c and R 7 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring. In some embodiments, R c and R 7 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R c and R 7 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0068] In some embodiments, only one pair combines to form an optionally substituted 3-8 membered saturated or partially unsaturated ring, and the pair is c Group, R c and R 6 groups, as well as R c and R 7 is selected from the group

[0069] In some embodiments, two R on the same carbon atom c In some embodiments, R c Only one pair of groups combines to form oxo.

[0070] In some embodiments of any of Formulas A, B, C, D, and E, s is 0, 1, 2, 3, or 4. In some embodiments, s is 0, 1, 2, or 3. In some embodiments, s is 0, 1, or 2. In some embodiments, s is 0 or 1. In some embodiments, s is 1, 2, 3, 4, or 5. In some embodiments, s is 1, 2, or 3. In some embodiments, s is 1 or 2. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, s is 5.

[0071] In some embodiments of any of Formulas I, II, III, IV, and V, n is 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0072] In some embodiments of any of Formulas I, II, III, IV, and V, m is 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0073] In some embodiments of any of Formulas I, II, III, IV, and V, n is 0 and m is 1. In some embodiments, n is 0 and m is 2. In some embodiments, n is 1 and m is 0. In some embodiments, n is 1 and m is 1. In some embodiments, n is 1 and m is 2. In some embodiments, n is 2 and m is 0. In some embodiments, n is 2 and m is 1. In some embodiments, n is 2 and m is 2.

[0074] In some embodiments of any of Formulas I, IA, IB, IC, ID, II, III, IV, V, VI, VII, and IX, each R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 In some embodiments, each R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 In some embodiments, each R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 In some embodiments, each R 1 , R 2 , R 3 , R 4 , and R 5 is independently hydrogen or halogen. In some embodiments, each R 1 , R 2 , R 3 , R 4 , and R 5 is hydrogen. In some embodiments, each R 1 , R 2 , R 3 , and R 4 is hydrogen, and each R 5 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 In some embodiments, each R 1 , R 2 , R 3 , and R 4 is hydrogen, and each R 5 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 In some embodiments, each R 1, R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, -CN, -O(C 1-6 alkyl) (e.g., -OCH3), -O(C 1-6 haloalkyl) (e.g., -OCHF2), or C 1-6 It is alkyl (eg, methyl).

[0075] In some embodiments of either of Formulas VIII and XI, each R 1 , R 2 , R 3 , R 4 , R 5 , and R 9 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 In some embodiments, each R 1 , R 2 , R 3 , R 4 , R 5 , and R 9 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 In some embodiments, each R 1 , R 2 , R 3 , R 4 , R 5 , and R 9 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 In some embodiments, each R 1 , R 2 , R 3 , R 4 , R 5 , and R 9 is independently hydrogen or halogen. In some embodiments, each R 1 , R 2 , R 3 , R 4 , R 5 , and R 9 is hydrogen.

[0076] In some embodiments of any of Formulas I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, and IX, each R 1 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 Aliphatic or two R 1 The groups, together with the atoms to which they are attached, may combine to form a 3- to 8-membered saturated or partially unsaturated ring, or two R 1 The groups combine with the atoms to which they are attached to form oxo or R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring. In some embodiments, each R 1 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 Aliphatic or two R 1 The groups, together with the atoms to which they are attached, may combine to form a 3- to 8-membered saturated or partially unsaturated ring, or two R 1 The groups combine with the atoms to which they are attached to form oxo or R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring. 1 are independently hydrogen, —CN, or optionally substituted C 1-6 Aliphatic or two R 1The groups, together with the atoms to which they are attached, may combine to form a 3- to 8-membered saturated or partially unsaturated ring, or two R 1 The groups combine with the atoms to which they are attached to form oxo or R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring. 1 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 In some embodiments, each R 1 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 In some embodiments, each R 1 In some embodiments, one R 1 is hydrogen, and the other R 1 is halogen, -CN, -OR, or optionally substituted C 1-6 In some embodiments, one R 1 is hydrogen, and the other R 1 is halogen, -CN, or optionally substituted C 1-6 It is aliphatic.

[0077] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is halogen (e.g., fluoro). In some embodiments, R 1 is -CN. In some embodiments, R 1 is -OR. In some embodiments, R 1 is replaced appropriately by C 1-6 Aliphatic (e.g., optionally substituted C 1-6 In some embodiments, R 1is methyl.

[0078] In some embodiments, two R 1 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, two R 1 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, two R 1 The groups, together with the atoms to which they are attached, combine to form a C-C cycloalkyl. In some embodiments, two R 1 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 1 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0079] In some embodiments, two R 1 The groups combine with the atoms to which they are attached to form an oxo.

[0080] In some embodiments of any of Formulas I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, and XI, each R 2 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 Aliphatic or two R 2 The groups, together with the atoms to which they are attached, may combine to form a 3- to 8-membered saturated or partially unsaturated ring, or two R 2 The groups combine with the atoms to which they are attached to form oxo or R 1and R 2 group, and / or R 9 and R 2 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring. In some embodiments, each R 2 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 Aliphatic or two R 2 The groups, together with the atoms to which they are attached, may combine to form a 3- to 8-membered saturated or partially unsaturated ring, or two R 2 The groups combine with the atoms to which they are attached to form oxo or R 1 and R 2 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring. 2 are independently hydrogen, —CN, or optionally substituted C 1-6 Aliphatic or two R 2 The groups, together with the atoms to which they are attached, may combine to form a 3- to 8-membered saturated or partially unsaturated ring, or two R 2 The groups combine with the atoms to which they are attached to form oxo or R 1 and R 2 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5The groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring. 2 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 In some embodiments, each R 2 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 In some embodiments, each R 2 In some embodiments, one R 2 is hydrogen, and the other R 2 is halogen, -CN, -OR, or optionally substituted C 1-6 In some embodiments, one R 2 is hydrogen, and the other R 2 is halogen, -CN, or optionally substituted C 1-6 It is aliphatic.

[0081] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halogen (e.g., fluoro). In some embodiments, R 2 is -CN. In some embodiments, R 2 is -OR. In some embodiments, R 2 is replaced appropriately by C 1-6 Aliphatic (e.g., optionally substituted C 1-6 In some embodiments, R 2 is methyl.

[0082] In some embodiments, two R 2 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, two R 2The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, two R 2 The groups, together with the atoms to which they are attached, combine to form a C-C cycloalkyl. In some embodiments, two R 2 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 2 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0083] In some embodiments, two R 2 The groups combine with the atoms to which they are attached to form an oxo.

[0084] In some embodiments of any of Formulas I, IA, IB, IC, ID, II, III, IV, V, VI, VIII, IX, and XI, R 3 is hydrogen, halogen, -CN, -OR, or an optionally substituted C 1-6 aliphatic or R 1 and R 3 group or R 9 and R 3 group or R 2 and R 3 group or R 3 and R 4 group or R 3 and R 5 group or R 3 and R 6 group or R 3 and R 7 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring. In some embodiments, R 3 is hydrogen, halogen, -CN, or optionally substituted C 1-6aliphatic or R 1 and R 3 group or R 2 and R 3 group or R 3 and R 4 group or R 3 and R 5 group or R 3 and R 6 group or R 3 and R 7 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring. 3 is hydrogen, -CN, or an optionally substituted C 1-6 aliphatic or R 1 and R 3 group or R 2 and R 3 group or R 3 and R 4 group or R 3 and R 5 group or R 3 and R 6 group or R 3 and R 7 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring. 3 is hydrogen, halogen, -CN, -OR, or optionally substituted C 1-6 In some embodiments, R 3 is hydrogen, halogen, -CN, or optionally substituted C 1-6 It is aliphatic.

[0085] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is halogen (e.g., fluoro). In some embodiments, R 3 is -CN. In some embodiments, R 3 is -OR. In some embodiments, R 3 is replaced appropriately by C 1-6 Aliphatic (e.g., optionally substituted C1-6 In some embodiments, R 3 is methyl.

[0086] In some embodiments of any of Formulas I, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, and XI, each R 4 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 Aliphatic and / or two R 4 groups, together with the atom(s) to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring, and / or two R 4 The groups, when combined with the atoms to which they are attached, form oxo, and / or R 1 and R 4 group, and / or R 9 and R 4 group, and / or R 2 and R 4 group, and / or R 3 and R 4 group, and / or R 4 and R 5 group, and / or R 4 and R 6 group, and / or R 4 and R 7 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring. In some embodiments, each R 4 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 Aliphatic and / or two R 4 groups, together with the atom(s) to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring, and / or two R 4 The groups, when combined with the atoms to which they are attached, form oxo, and / or R 1 and R 4 group, and / or R 2 and R 4 group, and / or R 3and R 4 group, and / or R 4 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring. 4 is hydrogen, halogen (e.g., fluoro), -O(C 1-6 alkyl) (e.g., -OCH3), -O(C 1-6 haloalkyl) (e.g., -OCHF2), or C 1-6 In some embodiments, each R 4 is hydrogen, halogen (e.g., fluoro), or C 1-6 In some embodiments, each R 4 is hydrogen. In some embodiments, each R 4 is halogen (e.g., fluoro). In some embodiments, each R 4 is C 1-6 In some embodiments, one R 4 is hydrogen, and the other R 4 is a halogen (e.g., fluoro), -O(C 1-6 alkyl) (e.g., -OCH3), -O(C 1-6 haloalkyl) (e.g., -OCHF2), or C 1-6 It is alkyl (eg, methyl).

[0087] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is halogen (e.g., fluoro). In some embodiments, R 4 is -CN. In some embodiments, R 4 is -OR. In some embodiments, R 4 is -O(C 1-6 alkyl) (e.g., -OCH3) or -O(C 1-6 haloalkyl) (e.g., —OCHF). In some embodiments, R 4 is replaced appropriately by C 1-6Aliphatic (e.g., optionally substituted C 1-6 In some embodiments, R 4 is C 1-6 It is alkyl (eg, methyl).

[0088] In some embodiments, two R 4 The groups, together with the atom(s) to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, two R 4 The groups combine with the atom(s) to which they are attached to form a 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, two R 4 The groups, together with the atom(s) to which they are attached, combine to form a C-C cycloalkyl. In some embodiments, two R 4 The groups combine together with the atom(s) to which they are attached to form a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 4 The groups combine together with the atom(s) to which they are attached to form a 3-6 membered saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0089] In some embodiments, two R 4 The groups combine with the atoms to which they are attached to form an oxo.

[0090] In some embodiments of any of Formulas I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, and XI, each R 5 are independently hydrogen, halogen, —CN, —OR, or optionally substituted C 1-6 Aliphatic and / or two R 5groups, together with the atom(s) to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring, and / or two R 5 The groups, when combined with the atoms to which they are attached, form oxo, and / or R 1 and R 5 group, and / or R 9 and R 5 group, and / or R 2 and R 5 group, and / or R 3 and R 5 group, and / or R 4 and R 5 group, and / or R 5 and R 6 group, and / or R 5 and R 7 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring. In some embodiments, each R 5 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 Aliphatic and / or two R 5 groups, together with the atom(s) to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring, and / or two R 5 The groups, when combined with the atoms to which they are attached, form oxo, and / or R 1 and R 5 group, and / or R 2 and R 5 group, and / or R 3 and R 5 group, and / or R 4 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring. 5 is hydrogen, halogen (e.g., fluoro), -O(C 1-6 alkyl) (e.g., -OCH3), -O(C 1-6 haloalkyl) (e.g., -OCHF2), or C 1-6In some embodiments, each R 5 is hydrogen, halogen (e.g., fluoro), or C 1-6 In some embodiments, each R 5 is hydrogen. In some embodiments, each R 5 is halogen (e.g., fluoro). In some embodiments, each R 5 is C 1-6 In some embodiments, one R 5 is hydrogen, and the other R 5 is a halogen (e.g., fluoro), -O(C 1-6 alkyl) (e.g., -OCH3), -O(C 1-6 haloalkyl) (e.g., -OCHF2), or C 1-6 It is alkyl (eg, methyl).

[0091] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is halogen (e.g., fluoro). In some embodiments, R 5 is -CN. In some embodiments, R 5 is -OR. In some embodiments, R 5 is -O(C 1-6 alkyl) (e.g., -OCH3) or -O(C 1-6 haloalkyl) (e.g., —OCHF). In some embodiments, R 5 is replaced appropriately by C 1-6 Aliphatic (e.g., optionally substituted C 1-6 In some embodiments, R 5 is C 1-6 It is alkyl (eg, methyl).

[0092] In some embodiments, two R 5The groups, together with the atom(s) to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, two R 5 The groups combine with the atom(s) to which they are attached to form a 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, two R 5 The groups, together with the atom(s) to which they are attached, combine to form a C-C cycloalkyl. In some embodiments, two R 5 The groups combine together with the atom(s) to which they are attached to form a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 5 The groups combine together with the atom(s) to which they are attached to form a 3-6 membered saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0093] In some embodiments, two R 5 The groups combine with the atoms to which they are attached to form an oxo.

[0094] In some embodiments of either of Formulas VIII and XI, R 9 is hydrogen, halogen, -CN, -OR, or an optionally substituted C 1-6 aliphatic or R 1 and R 9 group or R 2 and R 9 group or R 3 and R 9 group or R 9 and R 4 group or R 9 and R 5The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring. In some embodiments, R 9 is hydrogen, halogen, -CN, or optionally substituted C 1-6 aliphatic or R 1 and R 9 group or R 2 and R 9 group or R 3 and R 9 group or R 9 and R 4 group or R 9 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring. 9 is hydrogen, -CN, or an optionally substituted C 1-6 aliphatic or R 1 and R 9 group or R 2 and R 9 group or R 3 and R 9 group or R 9 and R 4 group or R 9 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring. 9 is hydrogen, halogen, -CN, -OR, or optionally substituted C 1-6 In some embodiments, R 9 is hydrogen, halogen, -CN, or optionally substituted C 1-6 It is aliphatic.

[0095] In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is halogen (e.g., fluoro). In some embodiments, R 9 is -CN. In some embodiments, R 9 is -OR. In some embodiments, R9 is replaced appropriately by C 1-6 Aliphatic (e.g., optionally substituted C 1-6 In some embodiments, R 9 is methyl.

[0096] In some embodiments of any of Formulas I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, and XI, R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 group, and / or R 3 and R 4 group, and / or R 3 and R 5 group, and / or R 3 and R 6 group, and / or R 3 and R 7 group, and / or R 4 and R 5 group, and / or R 4 and R 6 group, and / or R 4 and R 7 group, and / or R 5 and R 6 group, and / or R 5 and R 7 group, and / or R 1 and R 9 group, and / or R 2 and R 9 group, and / or R 3 and R 9 group, and / or R 9 and R 4 group, and / or R 9 and R 5The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 group, and / or R 3 and R 4 group, and / or R 3 and R 5 group, and / or R 3 and R 6 group, and / or R 3 and R 7 group, and / or R 4 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 group, and / or R 3 and R 4group, and / or R 3 and R 5 group, and / or R 3 and R 6 group, and / or R 3 and R 7 group, and / or R 4 and R 5 group, and / or R 4 and R 6 group, and / or R 4 and R 7 group, and / or R 5 and R 6 group, and / or R 5 and R 7 group, and / or R 1 and R 9 group, and / or R 2 and R 9 group, and / or R 3 and R 9 group, and / or R 9 and R 4 group, and / or R 9 and R 5 The groups, taken together with the atoms to which they are attached, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 group, and / or R 3 and R 4 group, and / or R 3 and R 5 group, and / or R 3 and R 6 group, and / or R 3 and R7 group, and / or R 4 and R 5 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 group, and / or R 3 and R 4 group, and / or R 3 and R 5 group, and / or R 3 and R 6 group, and / or R 3 and R 7 group, and / or R 4 and R 5 group, and / or R 4 and R 6 group, and / or R 4 and R 7 group, and / or R 5 and R 6 group, and / or R 5 and R 7 group, and / or R 1 and R 9 group, and / or R 2 and R 9 group, and / or R 3 and R 9 group, and / or R 9 and R 4 group, and / or R 9 and R 5The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-6 membered saturated or partially unsaturated heterocyclyl (e.g., a 3-6 membered saturated heterocyclyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 group, and / or R 3 and R 4 group, and / or R 3 and R 5 group, and / or R 3 and R 6 group, and / or R 3 and R 7 group, and / or R 4 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a 3-6 membered saturated heterocyclyl). In some embodiments, only one pair joins to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., a carbocyclyl or a heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and this pair is not joined by R 1 and R 2 Group, R 1 and R 3 Group, R 1 and R 4 Group, R 1 and R 5 Group, R 2 and R 3 Group, R 2 and R 4 Group, R2 and R 5 Group, R 3 and R 4 Group, R 3 and R 5 Group, R 3 and R 6 Group, R 3 and R 7 Group, R 4 and R 5 Group, R 4 and R 6 Group, R 4 and R 7 Group, R 5 and R 6 Group, R 5 and R 7 Group, R 1 and R 9 Group, R 2 and R 9 Group, R 3 and R 9 Group, R 9 and R 4 groups, as well as R 9 and R 5 In some embodiments, only one pair joins to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the pair is selected from R 1 and R 2 Group, R 1 and R 3 Group, R 1 and R 4 Group, R 1 and R 5 Group, R 2 and R 3 Group, R 2 and R 4 Group, R 2 and R 5 Group, R 3 and R 4 Group, R 3 and R 5 Group, R 3 and R 6 Group, R 3 and R 7 groups, as well as R 4 and R 5 is selected from the group

[0097] In some embodiments, R 1 and R 2 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 2 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 2 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 1 and R 2 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0098] In some embodiments, R 1 and R 3 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 3 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1and R 3 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 1 and R 3 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0099] In some embodiments, R 1 and R 4 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 4 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 4 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 1 and R 4 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, R 1 and R 5The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 5 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 1 and R 5 The groups, together with the atoms to which they are attached, combine to form a 5-membered saturated or partially unsaturated carbocyclyl (e.g., C cycloalkyl). In some embodiments, R 1 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl (e.g., a 3-6 membered saturated heterocyclyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 and R 5 The groups, together with the atoms to which they are attached, combine to form a 5-membered saturated or partially unsaturated heterocyclyl (e.g., a 5-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0101] In some embodiments, R 2 and R 3The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 and R 3 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 and R 3 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 2 and R 3 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0102] In some embodiments, R 2 and R 4 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 and R 4 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 and R 4 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C3-6 In some embodiments, R 2 and R 4 The groups, together with the atoms to which they are attached, combine to form a 5-membered saturated or partially unsaturated carbocyclyl (e.g., C cycloalkyl). In some embodiments, R 2 and R 4 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl (e.g., a 3-6 membered saturated heterocyclyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 and R 4 The groups, together with the atoms to which they are attached, combine to form a 5-membered saturated or partially unsaturated heterocyclyl (e.g., a 5-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0103] In some embodiments, R 2 and R 5 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 and R 5 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 2 and R 5The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0104] In some embodiments, R 3 and R 4 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 4 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 4 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 3 and R 4 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0105] In some embodiments, R 3 and R 5 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 5The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 5 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 3 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0106] In some embodiments, R 3 and R 6 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 6 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 6 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 3 and R 6The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0107] In some embodiments, R 3 and R 7 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 7 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 3 and R 7 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl (e.g., a 3-6 membered saturated heterocyclyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3 and R 7 The groups, together with the atoms to which they are attached, combine to form a 4-membered saturated or partially unsaturated heterocyclyl (e.g., a 4-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3 and R 7 The groups, together with the atoms to which they are attached, combine to form a 5-membered saturated or partially unsaturated heterocyclyl (e.g., a 5-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the heterocyclyl may contain one or more C 1-6 In some embodiments, R 3 and R 7The groups, together with the atoms to which they are attached, combine to form a 5-membered saturated or partially unsaturated heterocyclyl (e.g., a 5-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0108] In some embodiments, R 4 and R 5 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4 and R 5 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 4 and R 5 The groups, together with the atoms to which they are attached, combine to form a 6-membered saturated or partially unsaturated carbocyclyl (e.g., a 6-membered saturated carbocyclyl). 4 and R 5 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl (e.g., a 3-6 membered saturated heterocyclyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 and R 5The groups, together with the atoms to which they are attached, combine to form a 5-7 membered saturated or partially unsaturated heterocyclyl (e.g., a 5-7 membered saturated heterocyclyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 and R 5 The groups, together with the atoms to which they are attached, combine to form a 7-membered saturated or partially unsaturated heterocyclyl (e.g., a 7-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0109] In some embodiments, R 4 and R 6 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4 and R 6 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4 and R 6 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 4 and R 6 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0110] In some embodiments, R 4 and R 7The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4 and R 7 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4 and R 7 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl (e.g., a 3-6 membered saturated heterocyclyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 4 and R 7 The groups combine together with the atoms to which they are attached to form a 6-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a 6-membered saturated heterocyclyl such as morpholine).

[0111] In some embodiments, R 5 and R 6 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 6 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 6The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 5 and R 6 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0112] In some embodiments, R 5 and R 7 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 7 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 5 and R 7 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl (e.g., a 3-6 membered saturated heterocyclyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 5 and R 7 The groups combine together with the atoms to which they are attached to form a 6-membered saturated or partially unsaturated heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a 6-membered saturated heterocyclyl such as morpholine).

[0113] In some embodiments, R 1 and R 9The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 9 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 9 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 1 and R 9 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0114] In some embodiments, R 2 and R 9 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 and R 9 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 and R 9 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C3-6 In some embodiments, R 2 and R 9 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0115] In some embodiments, R 3 and R 9 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 9 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 9 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 3 and R 9 The groups, together with the atoms to which they are attached, combine to form a 6-membered saturated or partially unsaturated carbocyclyl (e.g., a 6-membered saturated carbocyclyl). 3 and R 9 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl (e.g., a 3-6 membered saturated heterocyclyl) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3 and R 9The groups, together with the atoms to which they are attached, combine to form a 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0116] In some embodiments, R 4 and R 9 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4 and R 9 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4 and R 9 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 4 and R 9 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0117] In some embodiments, R 5 and R 9 The groups, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 9The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 9 The groups, taken together with the atoms to which they are attached, form a 3- to 6-membered saturated or partially unsaturated carbocyclyl (e.g., C 3-6 In some embodiments, R 5 and R 9 The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated heterocyclyl (e.g., a 3- to 6-membered saturated heterocyclyl) having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0118] In some embodiments of any of Formulas I, II, III, IV, and V, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] (i.e., R 3 R 7 When bonded to form a four-membered ring), [ka] (i.e., R 3 R 7 When bonded to form a five-membered ring), [ka] (i.e., R 3 R 7 and combine to form a five-membered ring substituted with methyl groups), [ka] (i.e., R 3 R 7 When bonded to form a five-membered ring, [ka] (i.e., R 4 R 7 and form a 6-membered ring). [ka] part is, [ka] (i.e., R 3 R 7 and form a five-membered ring).

[0119] In some embodiments of Formula VI, [ka] part is, [ka] is.

[0120] In some embodiments of Formula VII, [ka] part is, [ka] is.

[0121] In some embodiments of Formula VIII, [ka] part is, [ka] is.

[0122] In some embodiments of Formula IX, [ka] part is, [ka] is.

[0123] In some embodiments of Formula XI, [ka] part is, [ka] is.

[0124] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, each R 6 are independently hydrogen or optionally substituted C 1-6 In some embodiments, each R 6 is hydrogen or two R 6 In some embodiments, the groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring. 6 is hydrogen. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is replaced appropriately by C 1-6 Aliphatic (e.g., optionally substituted C 1-6 In some embodiments, two R 6 The groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring (i.e., carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, two R 6The groups, together with the atoms to which they are attached, combine to form a 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, two R 6 The groups, together with the atoms to which they are attached, combine to form C 3-6 In some embodiments, two R 6 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 6 The groups, together with the atoms to which they are attached, combine to form a 3-6 membered saturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0125] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, R 7 is replaced appropriately by C 1-6 In some embodiments, R 7 is replaced appropriately by C 1-6 In some embodiments, R 7 is C 1-6 In some embodiments, R 7 is replaced appropriately by C 1-4 In some embodiments, R 7 is hydrogen.

[0126] In some embodiments of any of Formulas A, B, C, I, IA, IB, IC, ID, II, III, VI, VII, VIII, IX, X, and XI, ring A is an optionally substituted group selected from a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7-10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted group selected from phenyl, a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an optionally substituted group selected from phenyl and a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is phenyl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0127] In some embodiments, ring A is phenyl.

[0128] In some embodiments, ring A is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-6 membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is pyrazolyl. In some embodiments, ring A is a 6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is pyridyl or pyridonyl.

[0129] In some embodiments, ring A is an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0130] In some embodiments, ring A is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring A is a 3-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring A is a 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring A is a 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring A is a 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring A is a 7-membered saturated or partially unsaturated monocyclic carbocyclyl.

[0131] In some embodiments, ring A is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 3-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 4-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0132] In some embodiments, ring A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 7-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is an 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 9-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is a 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0133] In some embodiments, ring A is selected from the group consisting of (i) oxo, halogen, -(CH) at any substitutable carbon atom;0-4 R°, -CN, -OR°, -O(CH2) 1-4 R o , —SR°, —N(R°)2, —NO2, —C(O)R°, —C(O)OR°, —C(O)NR°2, —OC(O)R°, —OC(O)NR°2, —OC(O)OR°, —OS(O)2R°, —OS(O)2NR°2, —N(R°)C(O)R°, —N(R°)S(O)2R°, —S(O)2R°, —SO2NR°2, and —S(O)2OR°; and (ii) at a substitutable nitrogen atom, —R † , -NR † 2. -C(O)R † , -C(O)OR † , -S(O)2R † , and -S(O)NR † 2. In some embodiments, Ring A is optionally substituted with one or more groups selected from (i) oxo, —(CH) 0-4 and (ii) at a substitutable nitrogen atom, -R † and optionally substituted with one or more groups selected from:

[0134] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, L is a covalent bond. In some embodiments, L is a divalent C 1-3 In some embodiments, L is a divalent C 1-2 It is a straight or branched hydrocarbon chain. In some embodiments, L is methylene (i.e., -CH2-). In some embodiments, L is -CH2CH2-. In some embodiments, L is -CH2CH2CH2-. In some embodiments, L is -C(CH3)2-. In some embodiments, L is a covalent bond or -CH2-.

[0135] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, R 8 is halogen, optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 In some embodiments, R is an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted phenyl, an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is replaced appropriately by C 1-6 Aliphatic, optionally substituted C 3-6 In some embodiments, R is a cycloaliphatic or optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is replaced appropriately by C 1-6 In some embodiments, R is an aliphatic or optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is replaced appropriately by C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is replaced appropriately by C 1-6 alkyl, or an optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0136] In some embodiments, R 8is hydrogen. In some embodiments, R 8 is not hydrogen.

[0137] In some embodiments, R 8 is halogen. In some embodiments, R 8 is fluoro. In some embodiments, R 8 is chloro.

[0138] In some embodiments, R 8 is replaced appropriately by C 1-6 In some embodiments, R 8 is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R 8 is C optionally substituted with one or more halogens (e.g., fluoro) 1-6 In some embodiments, R 8 is replaced appropriately by C 1-6 In some embodiments, R 8 is C optionally substituted with one or more halogens (e.g., fluoro) 1-6 In some embodiments, R 8 is the unsubstituted C 1-6 In some embodiments, R 8 is C 1-6 Haloalkyl (e.g., -CF3).

[0139] In some embodiments, R 8 is replaced appropriately by C 3-6 In some embodiments, R 8 is replaced appropriately by C 3-6 In some embodiments, R 8 is an optionally substituted C cycloaliphatic. In some embodiments, R 8is an optionally substituted C4 cycloaliphatic (e.g., cyclobutane optionally substituted with one or more —OH). In some embodiments, R 8 is an optionally substituted C5 cycloaliphatic. In some embodiments, R 8 is an optionally substituted C6 cycloaliphatic.

[0140] In some embodiments, R 8 is an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is an optionally substituted 4-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is a 4- to 6-membered saturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and one or more C 1-6 Optionally substituted with alkyl or -OH. In some embodiments, R 8 is an optionally substituted 3-membered saturated monocyclic heterocyclyl having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is an optionally substituted 4-membered saturated monocyclic heterocyclyl having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is an optionally substituted 5-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is optionally substituted tetrahydrofuranyl. In some embodiments, R 8 is an optionally substituted 6-membered saturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is optionally substituted tetrahydropyranyl, piperidinyl, or piperazinyl. In some embodiments, R 8is optionally substituted piperidinyl or piperazinyl.

[0141] In some embodiments, R 8 is optionally substituted phenyl. In some embodiments, R 8 is not optionally substituted phenyl.

[0142] In some embodiments, R 8 is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is an optionally substituted 5-6 membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is an optionally substituted 5-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is an optionally substituted 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0143] In some embodiments, R 8 is an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 8 is an optionally substituted 7-10 membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0144] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, [ka] -R 8(i.e., L is a covalent bond). In some embodiments, [ka] is -(C 1-3 alkylene)-R 8 (i.e., L is C 1-3 In some embodiments, [ka] is -(C 1-2 alkylene)-R 8 (i.e., L is C 1-2 In some embodiments, [ka] is -CH2-R 8 (i.e., L is a C1 hydrocarbon chain). In some embodiments, [ka] is -CH2CH2-R 8 (i.e., L is a C2 linear hydrocarbon chain). In some embodiments, [ka] is -CH2CH2CH2-R 8 (i.e., L is a C3 linear hydrocarbon chain). In some embodiments, [ka] is -C(CH3)2-R 8 (i.e., L is a C3 branched hydrocarbon chain).

[0145] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, each R aare independently halogen, -CN, -OR, -O(CH2) 1-4 R, C substituted as appropriate 1-6 Aliphatic, optionally substituted C 3-6 It is a cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0146] In some embodiments, R a is halogen. In some embodiments, R a is fluoro. In some embodiments, R a is chloro.

[0147] In some embodiments, R a are -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R), -NO, -C(O)R', -C(O)OR, -C(O)N(R), -OC(O)R', -OC(O)N(R), -OC(O)OR, -OSOR, -OSOR(R), -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R), -N(R)SOR', -SOR', -SOR(R), or -SOR'. In some embodiments, R a is -CN, -OR, or -O(CH2) 1-4 It's R.

[0148] In some embodiments, R a is replaced appropriately by C 1-6 In some embodiments, R a is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R a is replaced appropriately by C 1-6 In some embodiments, R a is C optionally substituted with one or more halogens (e.g., fluoro) 1-6 In some embodiments, R ais replaced appropriately by C 1-4 In some embodiments, R a is C optionally substituted with one or more halogens (e.g., fluoro) 1-4 In some embodiments, R a is C 1-4 haloalkyl (e.g., —CF). In some embodiments, R a is the unsubstituted C 1-4 alkyl (e.g., methyl or tert-butyl). In some embodiments, R a is —CH, —CF, or —C(CH). In some embodiments, R a is -CH3 or -CF3.

[0149] In some embodiments, R a is replaced appropriately by C 3-6 In some embodiments, R a is replaced appropriately by C 3-6 In some embodiments, R a is optionally substituted cyclopropyl.

[0150] In some embodiments, R a is an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R a is an optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0151] In some embodiments, R a is optionally substituted phenyl.

[0152] In some embodiments, R a is an optionally substituted 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0153] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0154] In some embodiments of any of Formulas A, B, C, I, IA, IB, IC, ID, II, III, VI, VII, VIII, IX, X, and XI, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] is selected from.

[0155] In some embodiments of any of Formulas A, D, E, I, IA, IB, IC, ID, IV, V, VI, VII, VIII, IX, X, and XI, Ring B is an optionally substituted group selected from a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is selected from a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0156] In some embodiments, ring B is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 5-6 membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 6-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is pyridinyl or pyrazinyl.

[0157] In some embodiments, ring B is an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is an 8-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B is a 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 3H-imidazo[4,5-b]pyridyl, pyrazolo[1,5-a]pyrimidyl, isothiazolo[5,4-b]pyridyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[4,3-b]pyridyl, 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-onyl, 1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-onyl, imidazo[1,5-a]pyrimidinyl, pyrazole[1,5-a]pyrazinyl, or pyrrolo[1,2-b]pyridazinyl. In some embodiments, Ring B is a 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0158] In some embodiments, Ring B is a 10-16 membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0159] In some embodiments, Ring B is (i) optionally substituted at a substitutable carbon atom with one or more groups independently selected from oxo, halogen, R°, —CN, —OR°, —SR°, —N(R°), —NO, —C(O)R°, —C(O)OR°, —C(O)NR°, —OC(O)R°, —OC(O)NR°, —OC(O)OR°, —OS(O)R°, —OS(O)NR°, —N(R°)C(O)R°, —N(R°)C(O)NR°, —N(R°)S(O)R°, —S(O)R°, —SONR°, and —S(O)OR°; and (ii) at a substitutable nitrogen atom with —R † , -NR † 2. -C(O)R † , -C(O)OR † , -S(O)2R † , and -S(O)NR † In some embodiments, Ring B is optionally substituted (i) at a substitutable carbon atom with one or more groups independently selected from R°, —N(R°)2, —C(O)NR°2, —N(R°)C(O)R°, and —N(R°)C(O)NR°2, and (ii) at a substitutable nitrogen with —R † is substituted as appropriate.

[0160] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, each R b are independently selected from halogen, —CN, —OR, —N(R), —C(O)N(R), —N(R)C(O)R′, —N(R)C(O)N(R), optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6In some embodiments, each R is an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. b are independently selected from halogen, —CN, —OR, —N(R), —C(O)N(R), —N(R)C(O)R′, —N(R)C(O)OR, —N(R)C(O)N(R), optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 In some embodiments, each R b are independently selected from halogen, —OR, —N(R), —N(R)C(O)R′, —N(R)C(O)N(R), optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 In some embodiments, each R b are independently selected from halogen, —OR, —N(R), —N(H)C(O)R′, —N(H)C(O)N(R), optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted 3-6 membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R b are independently selected from halogen, —OR, —N(R), —N(H)C(O)R′, —N(H)C(O)N(R), optionally substituted C 1-6 Alkyl, or optionally substituted C 3-6 In some embodiments, each R b are independently selected from halogen, —N(R), optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 It is cycloaliphatic.

[0161] In some embodiments, R b is halogen. In some embodiments, R b is fluoro. In some embodiments, R b is chloro.

[0162] In some embodiments, R b are -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R), -NO, -C(O)R', -C(O)OR, -C(O)N(R), -OC(O)R', -OC(O)N(R), -OC(O)OR, -OSOR, -OSOR(R), -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R), -N(R)SOR', -SOR', -SOR(R), or -SOR'. In some embodiments, R b is -CN, -OR, -N(R)2, -C(O)N(R)2, -N(R)C(O)R', or -N(R)C(O)OR, -N(R)C(O)N(R)2.

[0163] In some embodiments, R b is -CN.

[0164] In some embodiments, R b is -OR. In some embodiments, R b is -OR, where R b R is an optionally substituted C 1-6 Aliphatic, optionally substituted C 3-7 In some embodiments, R is a cycloaliphatic or optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. b is -OR, where R b R is an optionally substituted C 1-6 aliphatic (e.g., methyl, -CHCHOCH, -CH(1,4-dioxane). In some embodiments, R b is -OR, where R b R is an optionally substituted C 3-7 In some embodiments, R is cycloaliphatic (e.g., cyclobutyl optionally substituted with one or more —OH). b is -OR, where R bR is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[0165] In some embodiments, R b is -N(R). In some embodiments, R b is -N(R)2, where R b Each R is independently hydrogen or an optionally substituted C 1-6 Aliphatic (e.g., optionally substituted C 1-6 In some embodiments, R b is -NHCH3 or -N(CH3)2.

[0166] In some embodiments, R b is —C(O)N(R). In some embodiments, R b is -C(O)N(R)2, where R b Each R is independently hydrogen or an optionally substituted C 1-6 Aliphatic (e.g., optionally substituted C 1-6 In some embodiments, R b is -C(O)N(CH3)2.

[0167] In some embodiments, R b is —N(R)C(O)R′. In some embodiments, R b is —N(H)C(O)R′. In some embodiments, R b is -N(H)C(O) (optionally substituted C 1-6 In some embodiments, R b is -N(H)C(O)(C 1-6 In some embodiments, R b is —N(H)C(O)CH. In some embodiments, R b is -N(H)C(O) (optionally substituted C 3-6In some embodiments, R b is -N(H)C(O)(C 3-6 In some embodiments, R b is —N(H)C(O)(cyclopropyl).

[0168] In some embodiments, R b is —N(R)C(O)N(R). In some embodiments, R b is —N(H)C(O)N(R). In some embodiments, R b is -N(H)C(O)N (optionally substituted C 1-6 aliphatic). In some embodiments, R b is -N(H)C(O)N(C 1-6 In some embodiments, R b In some embodiments, R b is -N(H)C(O)N(CH3)2.

[0169] In some embodiments, R b is replaced appropriately by C 1-6 In some embodiments, R b is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R b is replaced appropriately by C 1-6 In some embodiments, R b is replaced appropriately by C 1-4 alkyl (e.g., methyl or -CH2OCH3). In some embodiments, R b is the unsubstituted C 1-4 It is alkyl (eg, methyl).

[0170] In some embodiments, R b is replaced appropriately by C 3-6 In some embodiments, R b is replaced appropriately by C 3-6In some embodiments, R b is cyclopropyl. In some embodiments, R b is cyclobutyl. In some embodiments, R b is -O(C 1-6 In some embodiments, R b is cyclopentyl. In some embodiments, R b is cyclohexyl.

[0171] In some embodiments, R b is an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is an optionally substituted 3-6 membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is an optionally substituted 5-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is an optionally substituted 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R b is optionally substituted piperidinyl, tetrahydropyranyl, or morpholinyl (e.g., C 1-6 Alkyl or -C(O)(C 1-6 piperidinyl, tetrahydropyranyl, or morpholinyl optionally substituted with alkyl).

[0172] In some embodiments, R b is optionally substituted phenyl.

[0173] In some embodiments, R b is an optionally substituted 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0174] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, q is 0, 1, or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5.

[0175] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] In some embodiments, [ka] part is, [ka] [ka] is selected from.

[0176] In some embodiments, [ka] part is, [ka] where: Ring B1 is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6 a cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B1 is optionally fused to ring B2; Ring B2, if present, is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6 It is a cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0177] Ring B1 and ring B2 together form q R b It is understood that the substituent R b may be bonded to ring B1, ring B2, or both ring B1 and ring B2.

[0178] It will also be understood that at least one of Ring B1 and Ring B2 contains a heteroatom and at least one of Ring B1 and Ring B2 is aromatic.

[0179] In some embodiments of any of Formulas A, B, D, I, IA, IB, IC, ID, II, IV, V, VI, VII, VIII, IX, X, and XI, Ring B1 is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0180] In some embodiments, Ring B1 is phenyl. In some embodiments, when Ring B1 is phenyl, Ring B2 contains at least one heteroatom.

[0181] In some embodiments, Ring B1 is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is pyrazole. In some embodiments, Ring B1 is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is pyridine, pyridazine, pyrimidine, or pyrazine. In some embodiments, Ring B1 is pyridine or pyrazine.

[0182] In some embodiments, ring B1 is C 5-6 In some embodiments, ring B1 is C 5-6 When ring B2 is cycloaliphatic, it contains at least one heteroatom. 5-6 When cycloaliphatic, ring B2 is aromatic.

[0183] In some embodiments, Ring B1 is a 5-6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when Ring B1 is a 5-6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ring B2 is aromatic. In some embodiments, Ring B1 is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0184] In some embodiments, ring B1, optionally fused to ring B2, is [ka] is selected from the group consisting of:

[0185] In some embodiments of any of Formulas A, B, D, I, IA, IB, IC, ID, II, IV, V, VI, VII, VIII, IX, X, and XI, Ring B2 is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0186] In some embodiments, ring B2 is absent.

[0187] In some embodiments, ring B2 is phenyl. In some embodiments, when ring B2 is phenyl, ring B1 contains at least one heteroatom.

[0188] In some embodiments, ring B2 is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B2 is a 5-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B2 is pyrrole, pyrazole, imidazole, pyrazolidin-3-one, imidazolidin-2-one, or isothiazole. In some embodiments, ring B2 is pyrrole, pyrazole, or imidazole. In some embodiments, ring B2 is a 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B1 is pyrimidine or pyrazine.

[0189] In some embodiments, ring B2 is C 5-6 In some embodiments, ring B2 is C 5-6 When cycloaliphatic, ring B1 contains at least one heteroatom. In some embodiments, ring B2 is C 5-6 When cycloaliphatic, ring B1 is aromatic.

[0190] In some embodiments, ring B2 is a 5-6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B1 is aromatic when ring B2 is a 5-6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B2 is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0191] In some embodiments, ring B2, when present and fused to ring B1, is: [ka] is selected from the group consisting of:

[0192] In some embodiments, ring B1 and ring B2 are both 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B1 is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring B2, if present, is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring B1 is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring B1 is fused to ring B2, and ring B2 is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring B2, if present, is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring B2, if present, is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, (i) ring B1 is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring B1 is fused to ring B2, and ring B2 is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or (ii) ring B1 is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and ring B2, if present, is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0193] In some embodiments, [ka] part is, [ka] where: W is CH, CR w , or N, Each R w are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's w The groups, together with the atoms to which they are attached, combine to form q R b forming a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group, r is 0, 1, 2, or 3.

[0194] In some embodiments of any of Formulas A, C, D, E, I, IA, IB, IC, ID, III, IV, V, VI, VII, VIII, IX, X, and XI, W is CH. In some embodiments, W is CR w In some embodiments, W is N.

[0195] In some embodiments of any of Formulas A, C, D, E, I, IA, IB, IC, ID, III, IV, V, VI, VII, VIII, IX, X, and XI, each Rw are independently selected from halogen, —CN, —N(R), —C(O)N(R), —N(R)C(O)R′, —N(R)C(O)OR, —N(R)C(O)N(R), optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 In some embodiments, each R w are independently —N(R)C(O)R′, —N(R)C(O)N(R), optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 In some embodiments, each R w is independently —OR, —N(R)C(O)R′, or —N(R)C(O)N(R). In some embodiments, each R w is independently —N(R)C(O)R′ or —N(R)C(O)N(R)2.

[0196] In some embodiments, R w is halogen. In some embodiments, R w is fluoro. In some embodiments, R w is chloro.

[0197] In some embodiments, R w are -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R), -NO, -C(O)R', -C(O)OR, -C(O)N(R), -OC(O)R', -OC(O)N(R), -OC(O)OR, -OSOR, -OSOR(R), -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R), -N(R)SOR', -SOR', -SOR(R), or -SOR'. In some embodiments, R w is -CN, -N(R)2, -C(O)N(R)2, -N(R)C(O)R', or -N(R)C(O)OR, -N(R)C(O)N(R)2.

[0198] In some embodiments, R w is -OR. In some embodiments, Rw is -OR, where R w R is an optionally substituted C 1-6 Aliphatic (e.g., optionally substituted C 1-6 In some embodiments, R w is -OCH3.

[0199] In some embodiments, R w is —N(R)C(O)R′. In some embodiments, R w is —N(H)C(O)R′. In some embodiments, R w is -N(H)C(O) (optionally substituted C 1-6 In some embodiments, R w is -N(H)C(O)(C 1-6 In some embodiments, R w is —N(H)C(O)CH. In some embodiments, R w is -N(H)C(O) (optionally substituted C 3-6 In some embodiments, R w is -N(H)C(O)(C 3-6 In some embodiments, R w is —N(H)C(O)(cyclopropyl).

[0200] In some embodiments, R w is —N(R)C(O)N(R). In some embodiments, R w is —N(H)C(O)N(R). In some embodiments, R w is -N(H)C(O)N (optionally substituted C 1-6 aliphatic). In some embodiments, R w is -N(H)C(O)N(C 1-6 In some embodiments, R w In some embodiments, R w is -N(H)C(O)N(CH3)2.

[0201] In some embodiments, R w is replaced appropriately by C 1-6 In some embodiments, R w is an optionally substituted linear or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R w is replaced appropriately by C 1-6 In some embodiments, R w is replaced appropriately by C 1-4 In some embodiments, R w is the unsubstituted C 1-4 It is alkyl (eg, methyl).

[0202] In some embodiments, R w is replaced appropriately by C 3-6 In some embodiments, R w is replaced appropriately by C 3-6 In some embodiments, R w is cyclopropyl. In some embodiments, R w is cyclobutyl. In some embodiments, R w is cyclopentyl. In some embodiments, R w is cyclohexyl.

[0203] In some embodiments, R w is an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R w is an optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0204] In some embodiments, R w is optionally substituted phenyl.

[0205] In some embodiments, R w is an optionally substituted 5-6 membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0206] In some embodiments, two R w The groups, together with the atoms to which they are attached, combine to form q R b In some embodiments, two R w The groups, together with the atoms to which they are attached, combine to form q R b In some embodiments, two R w The groups, together with the atoms to which they are attached, combine to form q R b In some embodiments, two R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 w The groups, together with the atoms to which they are attached, combine to form q R b In some embodiments, two R w The groups, together with the atoms to which they are attached, combine to form q R b The aryl group forms a six-membered aromatic ring (eg, pyrimidine or pyrazine) substituted with the aryl group.

[0207] In some embodiments of any of Formulas A, C, D, E, I, IA, IB, IC, ID, III, IV, V, VI, VII, VIII, IX, X, and XI, r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 1 or 2. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, q + r is 5 or less. In some embodiments, q + r is 4 or less.

[0208] In some embodiments, [ka] part is, [ka] [In the formula, W, R w and r, alone or in combination, are as defined above for formula III and as described in classes and subclasses herein; or [ka] [In the formula, ring B2, R b and q, alone or in combination, are as defined above for Formula II and as described in classes and subclasses herein; Ring B1 is a 5-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0209] In some embodiments, [ka] part is, [ka] [In the formula, W, R w and r, alone or in combination, are as defined above for formula III and as described in classes and subclasses herein; or [ka] [In the formula, ring B2, R b and q, alone or in combination, are as defined above for Formula II and as described in classes and subclasses herein; Ring B1 is a 5-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B1 is fused to ring B2.

[0210] In some embodiments, [ka] part is, [ka] [In the formula, W, R w and r, alone or in combination, are as defined above for formula III and as described in classes and subclasses herein; or [ka] [In the formula, R b and q, alone or in combination, are as defined above for Formula II and as described in classes and subclasses herein; Ring B1 is a 5-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B1 is fused to ring B2, Ring B2 is a 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0211] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, each R is independently selected from hydrogen, optionally substituted C 1-6 In some embodiments, each R is independently hydrogen or an optionally substituted C 1-6 In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is an optionally substituted linear or branched C1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R is optionally substituted C 1-6 In some embodiments, R is alkyl (e.g., methyl, -CHF, -CHCHOCH, or -CH(1,4-dioxane)). In some embodiments, R is C optionally substituted with one or more halogens (e.g., fluoro). 1-6 Alkyl, -O(C 1-6 alkyl), or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted C 3-7 In some embodiments, R is optionally substituted C 3-7 In some embodiments, R is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 4- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R, when attached to the same nitrogen atom, combine to form a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0212] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, each R′ is independently an optionally substituted C 1-6 Alkyl or optionally substituted C 3-7In some embodiments, R' is optionally substituted C 1-6 In some embodiments, R' is an optionally substituted straight or branched C 1-6 Aliphatic (i.e., optionally substituted acyclic C 1-6 In some embodiments, R' is optionally substituted C 1-6 In some embodiments, R' is an unsubstituted C 1-6 In some embodiments, R' is optionally substituted C 3-7 In some embodiments, R' is an optionally substituted C 3-7 It is cycloalkyl (eg, cyclopropyl).

[0213] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, R 7 is replaced appropriately by C 1-6 It is aliphatic and R 8 When is hydrogen, p is 1, 2, 3, 4, or 5, as valences allow.

[0214] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, R 7 is replaced appropriately by C 1-6 aliphatic, ring A is an optionally substituted group selected from phenyl and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and R 8 When is hydrogen, p is 1, 2, 3, 4, or 5, as valences allow.

[0215] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, R 7 is replaced appropriately by C 1-6It is aliphatic and R a and R 8 is not an optionally substituted phenyl, R 8 When is hydrogen, p is 1, 2, 3, 4, or 5, as valences allow.

[0216] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, and V, the compound is [ka] isn't it.

[0217] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, R a or [ka] At least one of the 1-4 Haloalkyl (e.g., -CF3).

[0218] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, and V, the compound is [ka] [ka] isn't it.

[0219] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, [ka] The part [ka] and ring B1 is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, then ring B2 is present. In some such embodiments, ring B2 is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0220] In some embodiments of any of Formulas A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, and V, the compound is [ka] isn't it.

[0221] In some embodiments, the disclosure provides a compound selected from Table 1, or a pharmaceutically acceptable salt 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

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

[0222] In some embodiments, the present disclosure encompasses the recognition that provided compounds exhibit certain desirable characteristics, e.g., when compared to other known compounds. For example, in some embodiments, provided compounds are more potent in one or more biochemical or cellular assays (e.g., the JAK2 binding assay or the SET2-pSTAT5 cellular assay described herein) than other known compounds, and / or have one or more other characteristics that make them more suitable for drug discovery, e.g., better selectivity over other kinases, and / or better ADME (absorption, distribution, metabolism, and excretion) properties, including, but not limited to, better permeability, cytotoxicity, hepatocyte stability, solubility, and / or plasma protein binding profile (e.g., based on the assays described in the Examples below). In some embodiments, provided compounds exhibit certain desirable characteristics, e.g., when compared to other known compounds, in one or more assays described herein.

[0223] In some embodiments, the provided compounds are provided and / or utilized in the form of a salt (e.g., a pharmaceutically acceptable salt). Reference to a compound provided herein is understood to include a reference to its salt unless otherwise specified. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977).

[0224] It will be understood that throughout this disclosure, unless otherwise indicated, a reference to a compound of Formula I is intended to include species of compounds of Formulas I, IA, IB, IC, ID, II, III, IV, and V, and such formulae disclosed herein. It will also be understood that throughout this disclosure, unless otherwise indicated, a reference to a compound of Formula A is intended to include species of compounds of Formulas B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, and such formulae disclosed herein.

[0225] Preparation of the provided compounds The provided compounds can generally be made by the processes described in the schemes and examples below. In some embodiments, the provided compounds (e.g., X is -C(R 6 Compounds of formula I, wherein 2-) are prepared according to the following scheme: [ka] In the formula, ring A, ring B, L, m, n, p, q, R a , R b , R 1 , R 2 , R 3 , R 6 , R 8, Y, and Z, alone or in combination, are as defined above for Formula I and as described in classes and subclasses herein. Thus, in some embodiments, compound A.3 is prepared by a process comprising contacting intermediate A.1 with intermediate A.2 in the presence of a suitable coupling agent (e.g., HATU or POCl) and / or a suitable base (DIPEA or pyridine). In some embodiments, compound A.1 is provided in a protected form (e.g., a form in which a substituent on ring B is protected with a suitable protecting group, such as, for example, Boc). In some embodiments, after coupling intermediate A.1 with intermediate A.2, the resulting compound is subjected to a deprotection step under suitable conditions (e.g., acidic conditions such as TFA or HCl). In some embodiments, after the deprotection step, the resulting compound is further functionalized by an amide coupling reaction (e.g., with acetyl chloride or acetic anhydride).

[0226] In some embodiments, provided compounds (e.g., where X is —N(R 7 Compounds of formula I, wherein - is prepared according to the following scheme: [ka] In the formula, ring A, ring B, L, m, n, p, q, R a , R b , R 1 , R 2 , R 3 , R 7 , R 8, Y, and Z, alone or in combination, are as defined above for Formula I and as described in classes and subclasses herein. Thus, in some embodiments, compound B.3 is prepared by a process comprising contacting intermediate B.1 with intermediate B.2 in the presence of a suitable coupling agent (e.g., carbonyldiimidazole or triphosgene) and / or a suitable base (DIPEA or triethylamine). In some embodiments, compound B.1 is provided in a protected form (e.g., with the nitrogen atom of ring B protected with a suitable protecting group, such as SEM). In some embodiments, after coupling intermediate B.1 with intermediate B.2, the resulting compound is subjected to a deprotection step under suitable conditions (e.g., acidic conditions, such as TFA).

[0227] In some embodiments, provided compounds (e.g., where X is —N(R 7 Compounds of formula A, where - is - or -O-, are prepared according to the following scheme: [ka] In the formula, ring A, ring B, ring C, L, p, q, s, R a , R b , R c , and R 8 is as defined above for Formula I and as described in classes and subclasses herein, alone or in combination; X is —N(R 7 )- or -O-. Thus, in some embodiments, compound C.3 is prepared by a process comprising contacting intermediate C.1 with intermediate C.2 in the presence of a suitable coupling agent (e.g., carbonyldiimidazole or triphosgene) and / or a suitable base (DIPEA or triethylamine). In some embodiments, compound C.1 is provided in a protected form (e.g., with the nitrogen atom of ring B protected with a suitable protecting group, such as SEM). In some embodiments, after coupling intermediate C.1 with intermediate C.2, the resulting compound is subjected to a deprotection step under suitable conditions (e.g., acidic conditions, such as TFA).

[0228] In some embodiments, provided compounds (e.g., where X is —C(R 6 Compounds of formula A, wherein 2-) are prepared according to the following scheme: [ka] In the formula, ring A, ring B, ring C, L, p, q, s, R a , R b , R c , R 6 , and R 8 are as defined above for Formula I and as described in classes and subclasses herein, either alone or in combination. Thus, in some embodiments, compound D.3 is prepared by a process comprising contacting intermediate D.1 with intermediate D.2 in the presence of a suitable coupling agent (e.g., HATU or POCl) and / or a suitable base (DIPEA or pyridine). In some embodiments, compound D.1 is provided in a protected form (e.g., a form in which a substituent on ring B is protected with a suitable protecting group, such as, for example, Boc). In some embodiments, after coupling intermediate D.1 with intermediate D.2, the resulting compound is subjected to a deprotection step under suitable conditions (e.g., acidic conditions such as TFA or HCl). In some embodiments, after the deprotection step, the resulting compound is further functionalized by an amide coupling reaction (e.g., with acetyl chloride or acetic anhydride).

[0229] composition The present disclosure also provides compositions comprising the compounds provided herein together with one or more other ingredients. In some embodiments, the provided compositions comprise and / or provide a compound described herein (e.g., a compound of Formula A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI).

[0230] In some embodiments, provided compositions are pharmaceutical compositions that contain and / or deliver a compound provided herein (e.g., a compound of Formula A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI) and further comprise a pharmaceutically acceptable carrier. Pharmaceutical compositions typically contain an amount of an active agent (e.g., a compound described herein) effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions contain a compound described herein and one or more fillers, disintegrants, lubricants, glidants, antiadhesive agents, and / or antistatic agents, etc. Provided pharmaceutical compositions can be in a variety of forms, including oral dosage forms, topical creams, topical patches, iontophoretic forms, suppositories, nasal sprays and / or inhalers, eye drops, intraocular injection forms, depot forms, and injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art.

[0231] In some embodiments, provided compounds are formulated in unit dosage forms for ease of administration and uniformity of dosage. As used herein, the phrase "unit dosage form" refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, a unit dosage form contains an entire single dose of a drug. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is necessary or anticipated to be necessary to achieve the intended effect. A unit dosage form can be, for example, a liquid pharmaceutical composition containing a predetermined amount of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, capsule, etc.) containing a predetermined amount of one or more active agents, a sustained-release formulation containing a predetermined amount of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents.

[0232] The provided compositions can be administered using any amount and any dosage form effective to treat or lessen the severity of any disease or disorder described herein.

[0233] use The present disclosure provides uses of the compounds and compositions described herein. In some embodiments, the provided compounds and compositions are useful in medicine (e.g., as therapeutics). In some embodiments, the provided compounds and compositions are useful in research, for example, as analytical tools and / or control compounds in biological assays.

[0234] In some embodiments, the present disclosure provides methods of administering a provided compound or composition to a subject in need thereof, hi some embodiments, the present disclosure provides methods of administering a provided compound or composition to a subject suffering from or susceptible to a JAK2-associated disease, disorder, or condition.

[0235] In some embodiments, provided compounds are useful as JAK2 inhibitors. In some embodiments, provided compounds are useful as type II JAK2 inhibitors. In some embodiments, the present disclosure provides a method of inhibiting JAK2 in a subject, comprising administering a provided compound or composition. In some embodiments, the present disclosure provides a method of inhibiting JAK2 in a biological sample, comprising contacting the sample with a provided compound or composition.

[0236] JAKs (e.g., JAK2) have been shown to be involved in various diseases, disorders, and conditions, such as myeloproliferative neoplasms (Vainchenker, W. et al., F1000 Research 2018, 7 (F1000 Faculty Rev): 82), atopic dermatitis (Rodrigues, MA and Torres, TJ Derm. Treat. 2019, 31(1), 33-40), and acute respiratory syndrome, hyperinflammation, and / or cytokine storm syndrome (The Lancet. doi:10.1016 / S0140-6736(20)30628-0). Accordingly, in some embodiments, the present disclosure provides methods of treating a JAK2-associated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a provided compound or composition. In some embodiments, the disease, disorder, or condition is associated with overexpression of JAK2.

[0237] In some embodiments, the present disclosure provides a method of treating cancer comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides a method of treating a proliferative disease comprising administering a provided compound or composition to a subject in need thereof.

[0238] In some embodiments, the present disclosure provides a method of treating a hematological malignancy, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the hematological malignancy is a leukemia (e.g., chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or acute monocytic leukemia). In some embodiments, the hematological malignancy is a lymphoma (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma). In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma. In some embodiments, the non-Hodgkin's lymphoma is an NK / T-cell lymphoma (e.g., cutaneous T-cell lymphoma). In some embodiments, the hematological malignancy is a myeloma (e.g., multiple myeloma). In some embodiments, the hematological malignancy is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis). In some embodiments, the hematological malignancy is a myelodysplastic syndrome.

[0239] In some embodiments, the present disclosure provides methods of treating an inflammatory disease, disorder, or condition (e.g., acute respiratory syndrome, hyperinflammation, and / or cytokine storm syndrome (including those associated with COVID-19) or atopic dermatitis) comprising administering a provided compound or composition to a subject in need thereof.

[0240] In some embodiments, provided compounds or compositions are administered as part of a combination therapy. As used herein, the term "combination therapy" refers to a situation in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously. In some embodiments, the regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered before any doses of a second regimen). In some embodiments, the agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administering one or more agent(s) or modality(s) in combination to a subject receiving other agent(s) or modality(s). For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even necessarily simultaneously), although in some embodiments, two or more agents or their active portions may be administered together in a combined composition.

[0241] For example, in some embodiments, provided compounds or compositions are administered to a subject who is receiving or has received one or more additional therapies (e.g., anti-cancer therapies and / or therapies to address one or more side effects of such anti-cancer therapies or otherwise provide palliative care). Exemplary additional therapies include BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mibebrexit), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors. Useful combinations of JAK2 inhibitors with BCL2, HDAC, BET, and proteasome inhibitors have been demonstrated in cells derived from patients with cutaneous T-cell lymphoma (Yumeen, S., et al., Blood Adv. 2020, 4(10), 2213-2226). The combination of a JAK2 inhibitor and an LSD1 inhibitor demonstrated good efficacy in a mouse model of myeloproliferative neoplasms (Jutzi, JS, et al., HemaSphere 2018, 2(3), http: / / dx.doi.org / 10.1097 / HS9.0000000000000054). CXCR2 activity has been shown to modulate signaling pathways, including the JAK-STAT3 pathway, that are involved in tumor growth, angiogenesis, and / or metastasis (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl. 4), S616-S628).

[0242] Illustrative Embodiments The following numbered embodiments are illustrative, but non-limiting, of certain aspects of the present disclosure. 1. Compounds of Formula I: [ka] or a pharmaceutically acceptable salt thereof [wherein: X is -C(R 6 )2- or -N(R 7 )- and Each Y is -C(R 4 )2- and Each Z is -C(R 5 )2- and n is 0, 1, or 2; m is 0, 1, or 2; provided that at least one of n and m is 1 or 2; Each R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 is aliphatic, and / or The Two R's 1 group, and / or two R 2 group, and / or two R 4 group, and / or two R 5 groups, together with the atom(s) to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; and / or The Two R's 1 group, and / or two R 2 group, and / or two R 4 group, and / or two R 5 groups, taken together with the atoms to which they are attached, form oxo; and / or R 1 and R 2 group, and / or R 1 and R 3 group, and / or R 1 and R 4 group, and / or R 1 and R 5 group, and / or R 2 and R 3 group, and / or R 2 and R 4 group, and / or R 2 and R 5 group, and / or R 3 and R 4 group, and / or R 3 and R 5 group, and / or R 3 and R 6 group, and / or R 3 and R7 group, and / or R 4 and R 5 the groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; Each R 6 are independently hydrogen or optionally substituted C 1-6 aliphatic, or The Two R's 6 the groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; R 7 is hydrogen or an appropriately substituted C 1-6 is aliphatic, Ring A is an optionally substituted group selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B is an optionally substituted group selected from a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10- to 16-membered polycyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L is a covalent bond or a divalent C 1-3 a linear or branched hydrocarbon chain, R 8 is hydrogen, halogen, optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur; an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R a are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R b are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; p is 0, 1, 2, 3, 4, or 5, as permitted by valence; q is 0, 1, 2, 3, 4, or 5, as valence permits; Each R is independently hydrogen or C 1-6 Aliphatic and C 3-7 an optionally substituted group selected from cycloaliphatic, 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R's, when attached to the same nitrogen atom, together form an optionally substituted 3- to 7-membered saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R' is independently C 1-6 Aliphatic and C 3-7 an optionally substituted group selected from cycloaliphatic groups. 2. The compound of embodiment 1, wherein Ring B is an optionally substituted group selected from a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3. A compound according to embodiment 1 or 2, [ka] part is, [ka] where: W is CH, CR w , or N, Each R w are independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's w The groups, together with the atoms to which they are attached, combine to form q R b forming a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group, The compound wherein r is 0, 1, 2, or 3. 4. The compound of embodiment 3, wherein W is CH. 5. The compound of embodiment 3, wherein W is N. 6. The compound of any one of embodiments 1-5, wherein r is 1. 7. R w is independently —N(R)C(O)R′ or —N(R)C(O)N(R)2. 8. The compound of any one of embodiments 1-5, wherein r is 2. 9. The Two R's wThe groups, together with the atoms to which they are attached, combine to form q R b The compound of embodiment 8, wherein the compound forms a 5-6 membered partially unsaturated or aromatic ring substituted with a group. 10. Each R b are independently selected from halogen, —N(R), optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6 The compound of embodiment 9, which is cycloaliphatic. 11. A compound according to any one of embodiments 1 to 10, [ka] Not the compound. 12. A compound according to embodiment 1 or 2, [ka] part is, [ka] where: Ring B1 is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6 a cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B1 is optionally fused to ring B2; Ring B2, if present, is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6 The compound is a cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 13. Compounds according to embodiment 12, wherein Ring B1 is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 14. Compounds according to embodiment 13, wherein Ring B1 is a 5-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 15. Compounds according to embodiment 13, wherein Ring B1 is a 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 16. The compound of any one of embodiments 12-15, wherein ring B1 is fused to ring B2. 17. Compounds according to any one of embodiments 12-16, wherein Ring B2 is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 18. The compound of any one of embodiments 12-15, wherein ring B1 is not fused to ring B2. 19. A compound according to any one of embodiments 1 to 18, [ka] Not the compound. 20. A compound according to any one of embodiments 1 to 19, [ka] part is, [ka] [In the formula, W is CH, CR w , or N, Each R w are independently halogen, -CN, -OR, -O(CH2) 1-4R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's w The groups, together with the atoms to which they are attached, combine to form q R b forming a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group, r is 0, 1, 2, or 3], or [ka] [In the formula, Ring B1 is a 5-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B1 is optionally fused to ring B2; Ring B2, if present, is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6 a cycloaliphatic, or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. twenty one. Each R b are independently selected from halogen, —OR, —N(R), —N(R)C(O)R′, —N(R)C(O)N(R), optionally substituted C 1-6 Aliphatic or optionally substituted C 3-6The compound of any one of embodiments 1-20, which is cycloaliphatic. twenty two. The compound of any one of embodiments 1-21, wherein q is 0 or 1. twenty three. X is -C(R 6 23. The compound of any one of embodiments 1-22, wherein R is 1 or 2. twenty four. Each R 6 The compound of any one of embodiments 1-23, wherein is hydrogen. twenty five. The Two R's 6 Embodiment 24. Compounds according to any one of embodiments 1 to 23, wherein the groups, together with the atoms to which they are attached, combine to form a 3-8 membered saturated or partially unsaturated ring. 26. X is -N(R 7 )-. 27. R 7 is replaced appropriately by C 1-6 The compound of any one of embodiments 1-22 and 26, which is aliphatic. 28. R 7 is C 1-6 The compound of embodiment 27, wherein the aryl is alkyl. 29. The compound of any one of embodiments 1-28, wherein n is 1. 30. The compound of any one of embodiments 1-29, wherein m is 1. 31. Each R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 The compound of any one of embodiments 1-30, which is aliphatic. 32. Each R 1 , R 2 , R 3 , and R4 is hydrogen, and each R 5 are independently hydrogen, halogen, —CN, or optionally substituted C 1-6 The compound of embodiment 31, which is aliphatic. 33. Each R 1 , R 2 , R 3 , R 4 , and R 5 The compound of embodiment 32, wherein 34. A compound according to any one of embodiments 1 to 30, (i) Two Rs 1 groups, together with the atom(s) to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (ii) Two Rs 2 groups, together with the atom(s) to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (iii) Two Rs 4 the groups, together with the atom(s) to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; and (iv) Two Rs 5 Groups that combine with the atom(s) to which they are attached to form a 3- to 8-membered saturated or partially unsaturated ring The compound, wherein one of 35. A compound according to any one of embodiments 1 to 30 and 34, (i) Two Rs 1 groups combined with the atoms to which they are attached to form oxo; (ii) Two Rs 2 groups combined with the atoms to which they are attached to form oxo; (iii) Two Rs 4 groups, together with the atoms to which they are attached, combine to form oxo; and (iv) Two Rs 5groups combine with the atoms to which they are attached to form oxo The compound, wherein one of 36. A compound according to any one of embodiments 1 to 30 and 34 to 35, (i)R 1 and R 2 groups, taken together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (ii)R 1 and R 3 groups, taken together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (iii)R 1 and R 4 groups, taken together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (iv)R 1 and R 5 groups, taken together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (v)R 2 and R 3 groups, taken together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (vi)R 2 and R 4 groups, taken together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (vii)R 2 and R 5 groups, taken together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (viii)R 3 and R 4 groups, taken together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (ix)R 3 and R 5groups, taken together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (x)R 3 and R 6 groups, taken together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; (xi)R 3 and R 7 the groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring; and (xii)R 4 and R 5 Groups, together with the atoms to which they are attached, combine to form a 3- to 8-membered saturated or partially unsaturated ring The compound, wherein one of 37. Compounds according to any one of embodiments 1-36, wherein Ring A is phenyl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 38. The compound of embodiment 37, wherein Ring A is phenyl. 39. Compounds according to embodiment 37, wherein Ring A is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 40. The compound of any one of embodiments 1-39, wherein L is a covalent bond. 41. The compound of any one of embodiments 1-39, wherein L is -CH2-. 42. R 8 is halogen, optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6The compound of any one of embodiments 1-41, which is an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted phenyl; an optionally substituted 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 7-10 membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 43. R 8 is replaced appropriately by C 1-6 Compounds according to embodiment 42, which are aliphatic or optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 44. Each R a are independently halogen, -CN, -OR, -O(CH2) 1-4 R, C substituted as appropriate 1-6 Aliphatic, optionally substituted C 3-6 The compound of any one of embodiments 1-43, which is cycloaliphatic or optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 45. Each R a is replaced appropriately by C 1-6 The compound of embodiment 44, which is aliphatic. 46. Each R a is C optionally substituted with one or more halogens (e.g., fluoro) 1-6 The compound of embodiment 45, wherein the aryl is alkyl. 47. The compound of any one of embodiments 1-46, wherein p is 0 or 1. 48. [ka] part is, [ka] 48. The compound of any one of embodiments 1-47, selected from: 49. R a and [ka] At least one of the 1-4 The compound of any one of embodiments 1-48, wherein the compound is haloalkyl. 50. A compound according to any one of embodiments 1 to 49, [ka] [ka] Not the compound. 51. R 8 The compound of any one of embodiments 1-50, wherein p is not 0 when is hydrogen. 52. 52. The compound of any one of embodiments 1-51, having formula IA: [ka] or a pharmaceutically acceptable salt thereof. 53. 52. The compound of any one of embodiments 1-51, wherein the compound has formula IB: [ka] or a pharmaceutically acceptable salt thereof. 54. 52. The compound of any one of embodiments 1-51, having formula IC: [ka] or a pharmaceutically acceptable salt thereof. 55. 52. The compound of any one of embodiments 1 to 51, comprising the compound of formula ID: [ka] or a pharmaceutically acceptable salt thereof. 56. 56. The compound of any one of embodiments 1-55, comprising Formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein Ring B1 is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6 a cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B1 is optionally fused to ring B2; Ring B2, if present, is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; 5-6 a cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; At least one of ring B1 and ring B2 is aromatic; At least one of ring B1 and ring B2 contains a heteroatom. 57. 56. The compound of any one of embodiments 1-55, comprising Formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH, CR w , or N, Each R ware independently halogen, -CN, -OR, -O(CH2) 1-4 R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)S02R', -S02R', -S02N(R)2, -S03R', and optionally substituted C 1-6 Aliphatic, optionally substituted C 3-6 an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from cycloaliphatic, nitrogen, oxygen, and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's w The groups, in combination with the atoms to which they are attached, can consist of 0 to 4 R b forming a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group, r is 0, 1, 2, or 3]. 58. 58. The compound of any one of embodiments 1-57, comprising Formula IV: [ka] or a pharmaceutically acceptable salt thereof. 59. 58. The compound of any one of embodiments 1-57, wherein the compound has formula V: [ka] or a pharmaceutically acceptable salt thereof. 60. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof. 61. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 62. A method of inhibiting JAK2 in a subject, comprising administering a compound of any one of embodiments 1-60 or a composition of embodiment 61. 63. A method for treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof a compound of any one of embodiments 1-60 or a composition of embodiment 61. 64. A method of treating cancer, comprising administering to a subject in need thereof a compound of any one of embodiments 1-60 or a composition of embodiment 61. 65. A method of treating a hematological malignancy, comprising administering to a subject in need thereof a compound of any one of embodiments 1-60 or a composition of embodiment 61. 66. 66. The method of embodiment 65, wherein the hematological malignancy is leukemia or lymphoma. 67. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof a compound of any one of embodiments 1-60 or a composition of embodiment 61. 68. 68. The method of embodiment 67, wherein said myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis. [Example]

[0243] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods illustrate the synthesis of specific compounds of the present disclosure, it will be understood that the following general methods, and other methods known to those of skill in the art, can be applied to all compounds described herein and each subclass and species of these compounds.

[0244] Chiral HPLC and SFC methods The following exemplary chiral HPLC and SFC methods were used in the synthesis of the compounds provided below:

[0245] Method A: Column: CHIRALCEL OX-H (250 mm*20 mm, 5 μm); Mobile phase: (A) liquid CO2, (B) 0.1% diethylamine (DEA) / propan-2-ol:methanol (50:50); Flow rate: 80 mL / min.

[0246] Method B: Column: CHIRALCEL OJ-H (250 mm*21 mm, 5 μm); Mobile phase: (A) liquid CO2, (B) 0.1% DEA / propan-2-ol:MeCN (50:50); Flow rate: 80 mL / min.

[0247] Method C: Column: CHIRALPAK IG (250 mm*21 mm, 5 μm); Mobile phase: (A) 0.1% DEA / n-hexane, (B) 0.1% DEA / propan-2-ol:MeCN (70:30); Flow rate: 20 mL / min.

[0248] Method D: Column: CHIRALCEL IC (250 mm*21 mm, 5 μm); Mobile phase: (A) liquid CO 2 , (B) 0.1% DEA / propan-2-ol:MeCN (50:50); Flow rate: 80 mL / min.

[0249] Method E: Column: CHIRALPAK IC (250 mm*21 mm, 5 μm); Mobile phase: (A) 0.1% DEA / n-hexane, (B) 0.1% DEA / propan-2-ol:MeCN (70:30); Flow rate: 20 mL / min.

[0250] Method F: Column: CHIRALPAK IG (250mm*21mm, 5μm); Mobile phase: (A) liquid CO2, (B) 0.1% DEA / propan-2-ol:MeCN (50:50); flow rate: 80mL / min.

[0251] Method G: Column: CHIRALPAK IH (250 mm*21 mm, 5 μm); Mobile phase: (A) 0.1% DEA / n-hexane, (B) 0.1% DEA / propan-2-ol:MeCN (50:50); Flow rate: 20 mL / min.

[0252] Method H: Column: CHIRALPAK AD-H (250mm*21mm, 5μm); Mobile phase: (A) liquid CO2, (B) 0.1% DEA / propan-2-ol:MeCN (50:50); flow rate: 80mL / min.

[0253] Method I: Column: CHIRALPAK IH (250 mm*21 mm, 5 μm); Mobile phase: (A) liquid CO 2 , (B) 0.1% DEA / propan-2-ol:MeCN (50:50); Flow rate: 80 mL / min.

[0254] Method J: CHIRALPAK IB-N (250mm*21mm, 5μm); Mobile phase: (A) liquid CO2, (B) 0.1% DEA / propan-2-ol:MeCN (50:50); flow rate: 80mL / min.

[0255] Method K: CHIRALPAK IB-N (250mm*21mm, 5μm); Mobile phase: (A) 0.1%DEA / n-hexane, (B) 0.1%DEA / propan-2-ol:MeCN (70:30); Flow rate: 20mL / min.

[0256] Method L: Column: CHIRALCEL OX-H (250 mm*20 mm, 5 μm); Mobile phase: (A) 0.1% DEA / n-hexane, (B) 0.1% DEA / propan-2-ol:MeCN (70:30); Flow rate: 20 mL / min.

[0257] Method M: Column: CHIRALPAK AD-H (250mm*21mm, 5um); Mobile phase: (A) 0.1% DEA / n-hexane, (B) 0.1% DEA / propan-2-ol:MeCN (50:50); Flow rate: 20mL / min.

[0258] Preparation of intermediates Preparation of Intermediate H-1: 2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine [ka] Synthesis of Compound H-1. To a DMF solution (10 mL) of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1 g, 5 mmol, 1.0 equiv.) was added sodium hydride (0.728 g, 15 mmol, 3 equiv.) at 0° C. and stirred for 45 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (1.25 g, 7.5 mmol, 1.5 equiv.) was added dropwise to the mixture and stirred at room temperature for 1 hour. The reaction mixture was carefully quenched with cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate / hexane) to give H-1 (1 g, 60%). MS (ES): m / z 328.1 and 330.1 [M+H] + .

[0259] The following intermediates were prepared according to the procedure of H-1. [Table 3]

[0260] Preparation of Intermediate H-4: 2-Bromo-6-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine [ka] Synthesis of Compound H-4.1. A mixture of 3,5-dibromopyrazin-2-amine (3.0 g, 11.86 mmol, 1.0 equiv.), triethylamine (4.95 mL, 35.35 mmol, 3.0 equiv.), and copper iodide (0.225 g, 1.185 mmol, 0.1 equiv.) in THF (60 mL) was degassed by bubbling a stream of argon through it for 5 minutes. Palladium(II) bis(triphenylphosphine) dichloride (0.866 g, 1.185 mmol, 0.1 equiv.) and ethynylcyclopropane (0.822 gm, 12.45 mmol, 1.05 equiv.) were added, and the mixture was degassed with argon for an additional 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 8% ethyl acetate / hexanes) to give H-4.1 (1.2 g, 42.5%). MS (ES): m / z 238.03 and 239.80 [M+H] + .

[0261] Synthesis of Compound H-4.2. To a solution of H-4.1 (1.2 g, 5.04 mmol, 1.0 equiv.) in tert-butanol (15 mL) was added potassium tert-butoxide (1.24 g, 11.09 mmol, 2.2 equiv.). The reaction mixture was stirred at 60° C. for 2 hours. It was poured into 5N aqueous hydrogen chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate / hexane) to give H-4.2 (0.90 g, 75%). MS (ES): m / z 238.12 and 240.1 [M+H] + .

[0262] Synthesis of Compound H-4. Compound H-4 was prepared from H-4.2 according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 7.7% ethyl acetate / hexane). MS (ES): m / z 368.20 and 369.5 [M+H] + .

[0263] Preparation of Intermediate H-6: 2-Bromo-7-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine [ka] Synthesis of Compound H-6.1. To a solution of 3,5-dibromopyrazin-2-amine (29 g, 114.2 mmol, 1.0 equiv.) in THF (100 mL), a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 140 mL, 142.0 mmol, 1.2 equiv.) was added at room temperature and stirred for 2 hours. Allyl bromide (27.9 g, 229.0 mmol, 2.0 equiv.) was added dropwise to the solution and stirred for 16 hours. The reaction mixture was slowly quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% ethyl acetate / hexane) to give H-6.1 (18 g, 54%). MS (ES): m / z 293.91 and 295.91 [M+H] + .

[0264] Synthesis of Compound H-6.2. A mixture of H-6.1 (6 g, 3.1 mmol, 1 equiv.), triethylamine (5.188 g, 42.8 mmol, 2.5 equiv.), sodium formate (0.279 g, 4.10 mmol, 0.2 equiv.), palladium(II) acetate (0.460 g, 2.0 mmol, 0.1 equiv.), and tetrabutylammonium bromide (0.992 g, 3.0 mmol, 0.15 equiv.) in DMF (6 mL) was purged with argon. The flask was sealed, and the reaction mixture was stirred at 100 °C for 16 h. It was cooled to room temperature, poured into water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 11% ethyl acetate / hexanes) to give H-6.2 (0.620 g, 14%). MS (ES): m / z 212.03 and 214.03 [M+H] + .

[0265] Synthesis of Compound H-6. Compound H-6 was prepared from H-6.2 according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate / hexane). MS (ES): m / z 342.2 and 344.24 [M+H] + .

[0266] Preparation of Intermediate H-7: 2-Bromo-6-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine [ka] Synthesis of Compound H-7.1. A mixture of 3,5-dibromopyrazin-2-amine (3 g, 11.6 mmol, 1.0 equiv.), triethylamine (1.43 g, 14.24 mmol, 1.2 equiv.), copper iodide (0.113 g, 0.59 mmol, 0.05 equiv.), and 1,1-bis(triphenylphosphine)palladium(II) chloride (0.417 g, 0.59 mmol, 0.05 equiv.) in THF (40 mL) was degassed by bubbling a stream of argon through it for 10 minutes. Trimethyl(prop-2-yn-1-yl)silane (1.6 g, 14.24 mmol, 1.2 equiv.) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate / hexanes) to give H-7.1 (3.0 g, 89%). MS (ES): m / z 284.16 and 286.16 [M+1] + .

[0267] Synthesis of Compound H-7.2. To a solution of H-7.1 (3 g, 10.55 mmol, 1.0 equiv.) in THF (40 mL) was added 1 M potassium tert-butoxide in THF (21.12 mL, 21.12 mmol, 2.0 equiv.). The reaction mixture was stirred at 60° C. for 2 hours. It was diluted with ethyl acetate, washed with water, and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give H-7.2 (1.1 g, 49%), which was used in the next step without purification. MS (ES): m / z 212.13 and 214.13 [M+1] + .

[0268] Synthesis of Compound H-7. Compound H-7 was prepared from H-7.2 according to the procedure described in the synthesis of H-1. The product was purified by silica gel flash column chromatography (CombiFlash®, 10% ethyl acetate / hexane) on silica gel. MS (ES): m / z 342.07 and 344.07 [M+1] + .

[0269] Preparation of Intermediate H-8: 6-Bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine [ka] Synthesis of Compound H-8.1. To a solution of 5-bromopyridine-2,3-diamine (3.0 g, 15.95 mmol, 1.0 equiv.) in formic acid (1.1 mL) was added triethoxymethane (48 mL). The reaction mixture was stirred at 90° C. for 4 hours. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate / hexane) to give H-8.1 (2.74 g, 87%). MS (ES): m / z 198.03 and 200.02 [M+H] + .

[0270] Synthesis of Compound H-8. Compound H-8 was prepared from H-8.1 according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 6.0% ethyl acetate / hexane). MS (ES): m / z 328.1 and 330.1 [M+H] + .

[0271] Preparation of Intermediate H-9: 2-Bromo-7-fluoro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine [ka] Synthesis of Compound H-9.1. Selectfluor (6.2 g, 17.67 mmol, 1.0 equiv.) was added dropwise to a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (3.5 g, 17.67 mmol, 1.0 equiv.) in acetonitrile (40 mL) and acetic acid (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then at 80° C. for 8 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 25% ethyl acetate / hexane) to give H-9.1 (1.0 g, 26%). MS (ES): m / z [M+H] + .

[0272] Synthesis of Compound H-9. Compound H-9 was prepared from H-9.1 according to the procedure described in the synthesis of H-1. This product was used without purification. MS (ES): m / z [M+H] + .

[0273] Preparation of Intermediate H-10: 2-Bromo-7-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine [ka] Synthesis of Compound H-10.1. To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (3.0 g, 15.15 mmol, 1.0 equiv.) in DMF (40 mL) was added N-iodosuccinimide (4.43 g, 19.69 mmol, 1.5 equiv.) in small portions at 0° C. The reaction mixture was stirred at 25° C. for 16 hours. It was then poured into ice water. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give H-10.1 (3.0 g, 62%). MS (ES): m / z 323.9 and 326.0 [M+H] + .

[0274] Synthesis of Compound H-10.2. To a DMF solution (30 mL) of H-10.1 (3.0 g, 9.25 mmol, 1.0 equiv.) cooled to 0 °C, sodium hydride (60 wt% in mineral oil, 0.399 g, 27.75 mmol, 3.0 equiv.) was added. The mixture was stirred for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (1.6 mL, 13.87 mmol, 1.5 equiv.) was added and stirred at room temperature for 1 hour. The mixture was transferred to ice water. The solid was collected by filtration and dried under vacuum to give H-10.2 (2.8 g, 67%). MS (ES): m / z 454.06 and 456.04 [M+H] + .

[0275] Synthesis of Compound H-10. A mixture of H-10.2 (2.8 g, 6.18 mmol, 1.0 equiv.), cyclopropylboronic acid (2.6 g, 30.90 mmol, 5.0 equiv.), and cesium carbonate (6.0 g, 18.54 mmol, 3.0 equiv.) in acetonitrile (30 mL) was degassed by bubbling a stream of argon through it for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.451 g, 0.618 mmol, 0.1 equiv.) was added and degassed for 5 minutes. The reaction mixture was stirred at 90 °C for 2 hours. It was cooled to room temperature, poured into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate / hexane) to give H-10 (0.7 g, 58.33%). MS (ES): m / z 368.14 and 370.16 [M+H] + .

[0276] Preparation of Intermediate H-11: 5-Bromo-N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-amine [ka] Synthesis of Compound H-11.1. To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine (0.8 g, 3.75 mmol, 1.0 equiv.) in THF (20 mL) was added formaldehyde (3.3 g, 112.6 mmol, 30 equiv.) and acetic acid (0.29 mL, 4.87 mmol, 1.3 equiv.). The reaction mixture was stirred at 0° C. for 15 minutes, and sodium cyanoborohydride (0.801 g, 12.75 mmol, 3.4 equiv.) was added. The mixture was stirred at room temperature for 16 hours, transferred to a saturated solution of sodium bicarbonate, and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 4.0% methanol / DCM) to give H-11.1 (0.5 g, 56%). MS (ES): m / z: 241.18 and 243.20 [M+H] + .

[0277] Synthesis of Compound H-11. Compound H-11 was prepared from H-11.1 according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.1% methanol / DCM). MS (ES): m / z 371.29 and 373.29 [M+H] + .

[0278] Preparation of Intermediate H-13: 5-Bromo-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine [ka] Synthesis of Compound H-13.1. To a solution of methyl 5-bromo-2-chloronicotinate (5.0 g, 19.96 mmol, 1.0 equiv.) in ethanol (80 mL) was added hydrazine hydrate (7.0 g, 139.73 mmol, 7.0 equiv.), and the reaction mixture was stirred at 80° C. for 16 hours. It was then cooled to 10° C. The precipitated solid was collected by filtration, rinsed with ethanol and water, and dried under vacuum to give H-13.1 (2.10 g, 49%). MS (ES): m / z 214.02 and 216.01 [M+H] + .

[0279] Synthesis of Compound H-13.2. To a solution of H-13.1 (2.10 g, 9.81 mmol, 1.0 equiv.) in dimethyl sulfoxide (25.0 mL) was added sodium hydroxide (0.581 g, 14.72 mmol, 1.5 equiv.) at 0 °C, followed by 4-methoxybenzyl chloride (2.3 g, 14.72 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 2 hours. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (45% ethyl acetate / hexane) to give H-13.2 (1.30 g, 40%). MS (ES): m / z 333.16 and 335.1 [M+H] + .

[0280] Synthesis of Compound H-13. To a solution of H-13.2 (1.3 g, 3.89 mmol, 1 equiv.) in DMF (12 mL) at 0° C., sodium hydride (60%, 0.186 g, 4.67 mmol, 1.20 equiv.) was added. The mixture was stirred at 0° C. for 10 minutes, followed by the addition of methyl iodide (0.662 g, 4.67 mmol, 1.20 equiv.). The mixture was stirred for 1.5 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 40% ethyl acetate / hexane) to give H-13 (0.78 g, 58%). MS (ES): m / z: 348.12 and 350.12 [M+H] + .

[0281] Preparation of Intermediate H-15: 2-Bromo-6-(methoxymethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine [ka] Synthesis of Compound H-15.1. To a solution of H-7 (1.8 g, 5.26 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL) at 0° C., selenium dioxide (0.727 g, 55.55 mmol, 4.0 equiv.) was added in portions. The reaction mixture was stirred at 130° C. for 16 hours. It was filtered through a pad of Celite®, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 25% ethyl acetate / hexane) to give H-15.1 (1.2 g, 64%). MS (ES): m / z 357.1 and 359.1 [M+H] + .

[0282] Synthesis of Compound H-15.2. To a solution of H-15.1 (1.2 g, 3.37 mmol, 1.0 equiv.) in methanol (15 mL) was added sodium borohydride (0.192 g, 5.05 mmol, 1.5 equiv.) in small portions at 0° C. The reaction mixture was stirred at room temperature for 6 hours. It was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane) to give H-15.2 (0.80 g, 66%). MS (ES): m / z 359.15 and 361.1 [M+H] + .

[0283] Synthesis of Compound H-15. To a solution of H-15.2 (0.800 g, 2.23 mmol, 1.0 equiv.) in THF (10 mL) at 0° C., sodium hydride (0.065 g, 3.35 mmol, 1.5 equiv.) was added in small portions and stirred at 0° C. for 15 minutes. Methyl iodide (0.4 mL, 6.69 mmol, 3.0 equiv.) was added to the mixture, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate / hexane) to give H-14 (0.50 g, 60.24%). MS (ES): m / z 374.12 and 376.12 [M+H] + .

[0284] Preparation of Intermediate H-16: 5-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one [ka] Synthesis of Compound H-16.1. To 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (10 g, 46.29 mmol, 1.0 equiv.) at 0° C. was added thionyl chloride (100 mL) and a catalytic amount of DMF (0.5 mL). The reaction mixture was stirred at 80° C. for 16 hours. The mixture was concentrated and azeotroped with toluene, and the resulting acid chloride was dissolved in DCM (100 mL). The mixture was cooled to 0° C., and a mixture of methylhydrazine (2.4 mL, 46.29 mmol, 1.0 equiv.), sodium hydroxide (7.4 g, 185 mmol, 4.0 equiv.), and water (15 mL) was added. The reaction mixture was stirred at 80° C. for 30 minutes. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5.0% methanol / DCM) to give H-16.1 (3.0 g, 25%). MS (ES): m / z 264.3 and 266.3 [M+H] + .

[0285] Synthesis of Compound H-16.2. To a stirred solution of compound H-16.1 (3.0 g, 11.36 mmol, 1 equiv.) in 1-pentanol (30 mL) was added sodium carbonate (1.2 g, 11.36 mmol, 1.0 equiv.). The reaction mixture was stirred at 140° C. for 48 h under argon. It was cooled to room temperature and acidified with acetic acid. Most of the solvent was removed under reduced pressure, and the residue was purified by flash chromatography (ethyl acetate-methanol 9:1) to give H-16.2 (1.0 g, 38%). MS (ES): m / z 288.01 and 300.01 [M+H] + .

[0286] Synthesis of Compound H-16. Compound H-16 was prepared from H-16.2 according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol / DCM). MS (ES): m / z 358.1 and 360.1 [M+H] + .

[0287] Preparation of Intermediate H-17: N-(3-Bromopyrazolo[1,5-a]pyrazin-6-yl)-N-methylcyclopropanecarboxamide [ka] Synthesis of Compound H-17.1. To a solution of 2-bromopyrazine (432.0 g, 2720 mmol, 1.0 equiv.) in DCM (5180 mL) was added O-(mesitylsulfonyl)hydroxylamine (701.9 g, 3260 mmol, 1.2 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. It was transferred into diethyl ether. The precipitated solid was collected by filtration and dried under vacuum. To a solution of the solid in DMF (2160 mL) was added trimethylamine (372.2 g, 3685 mmol, 2.0 equiv.), followed by ethyl propionate (361.16 g, 3685 mmol, 2.0 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 48 hours. It was transferred into brine and extracted with ethyl acetate. The combined organic layers were washed with aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (4% ethyl acetate / hexanes) to give H-17.1 (20 g, 2.7%). MS (ES): m / z 270.1 and 272.1 [M+H] + .

[0288] Synthesis of Compound H-17.2. A mixture of H-17.1 (1.5 g, 4.95 mmol, 1.0 equiv.), N-methylcyclopropanecarboxamide (1.3 g, 14.85 mmol, 3.0 equiv.), and cesium carbonate (4.8 g, 14.85 mmol, 3.0 equiv.) in 1,4-dioxane (10 mL) was degassed by bubbling a stream of argon through it for 10 minutes. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.572 g, 0.99 mmol, 0.2 equiv.) and tris(dibenzylideneacetone)dipalladium(0) (0.452 g, 0.495 mmol, 0.1 equiv.) were added and degassed for 5 minutes. The reaction mixture was stirred at 110 °C for 1 hour. It was cooled to room temperature, poured into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.1% methanol / DCM) to give J-17.2 (0.75 g, 54%). MS (ES): m / z: 289.12 [M+H] + .

[0289] Synthesis of Compound H-17.3. To a solution of H-17.2 (0.75 g, 2.59 mmol, 1.0 equiv.) in methanol (3.0 mL), THF (3.0 mL), and water (2.0 mL) was added lithium hydroxide (0.163 g, 3.89 mmol, 1.5 equiv.) in small portions. The reaction mixture was stirred at room temperature for 1 hour. It was extracted with ethyl acetate. The aqueous layer was separated, adjusted to pH 2 using 1.5 N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give H-17.3 (0.50 g, 74%). MS (ES): m / z 261.09 [M+H] + .

[0290] Synthesis of Compound H-17. To a DMF solution (3.0 mL) of H-17.3 (0.50 g, 1.92 mmol, 1.0 equiv.), sodium bicarbonate (0.482 g, 5.74 mmol, 3.0 equiv.) and N-bromosuccinimide (0.375 g, 2.11 mmol, 1.1 equiv.) were added, and the mixture was stirred at room temperature for 6 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane) to give H-17 (0.28 g, 49%). MS (ES): m / z 295.01 [M+H] + .

[0291] Preparation of Intermediate H-18: 5-Bromo-3-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] Synthesis of Compound H-18.1. To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (5.0 g, 22.22 mmol, 1.0 equiv.) in THF (100 mL) was added triethylamine (3.5 mL, 24.44 mmol, 1.1 equiv.) and p-toluenesulfonyl chloride (4.2 g, 22.22 mmol, 1.0 equiv.). The mixture was stirred at room temperature for 12 hours. It was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. DCM-diethyl ether was added to the residue, and the solid was collected by filtration, rinsed with hexane, and dried under vacuum to give H-18.1 (3.2 g, 50%). MS (ES): m / z 379.1 and 380.1 [M+H] + .

[0292] Synthesis of Compound H-18.2. To a solution of H-18.1 (3.2 g, 8.42 mmol, 1.0 equiv.) in DCM (50 mL) at 0 °C, 3-chloroperbenzoic acid (3.1 g, 18.52 mmol, 2.2 equiv.) was added in small portions over 30 minutes. The mixture was stirred at room temperature for 2 hours, and then 10% aqueous sodium sulfite and saturated aqueous sodium bicarbonate were added and stirred for 6 hours. The mixture was diluted with DCM, and the solids were removed by filtration. The filtrate was extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (35% ethyl acetate / hexane) to give H-18.2 (0.395 g, 13%). MS (ES): m / z 367.1 and 369.1 [M+H] + .

[0293] Synthesis of compound H-18. To a solution of H-18.2 (0.395 g, 1.07 mmol, 1.0 equiv) in methanol (15 mL) and THF (15 mL) at 0 °C, (trimethylsilyl)diazomethane (2.1 mL, 4.28 mmol, 4.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 4 h. An additional portion of (trimethylsilyl)diazomethane (2.1 mL, 4.28 mmol, 4.0 equiv) was added dropwise and stirred for 12 h. This was quenched with acetic acid (0.006 mL, 0.107 mmol, 0.1 equiv), and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30% ethyl acetate-hexane) to give H-18 (0.205 g, 50%). MS(ES): m / z 379.1 and 381.03 [M+H] + .

[0294] Preparation of Intermediate H-19: 5-Bromo-N-methyl-1H-pyrazolo[3,4-b]pyridin-3-amine [ka] Synthesis of Compound H-19.1. To the compound 5-bromo-2-hydroxynicotinic acid (50 g, 229.35 mmol, 1.0 equiv.) at 0° C. was added thionyl chloride (500 mL) and a catalytic amount of DMF (4.0 mL). The reaction mixture was stirred at 80° C. for 16 hours. The mixture was concentrated and azeotroped with toluene. The resulting acid chloride was dissolved in DCM (500 mL), cooled to 0° C., and a solution of methylamine in methanol (8.02 g, 229.35 mmol, 1.0 equiv.), sodium hydroxide (37.0 g, 917.41 mmol, 4.0 equiv.), and water (150 mL) were added. The reaction mixture was stirred at 80° C. for 30 minutes. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5.0% methanol / DCM) to give H-19.1 (32.0 g, 56%). MS (ES): m / z 249.6 and 251.6 [M+H] + .

[0295] Synthesis of Compound H-19.2. To a solution of H-19.1 (32.0 g, 128.26 mmol, 1.0 equiv.) in THF (400.0 m), Lawesson's reagent (207 g, 256.52 mmol, 2.0 equiv.) was added and stirred at 40° C. for 24 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 29% ethyl acetate / hexane) to give H-19.2 (16.3 g, 48%). MS (ES): m / z 265.2 and 267.2 [M+H] + .

[0296] Synthesis of Compound H-19.3. To a solution of H-19.2 (16.3 g, 61.38 mmol, 1.0 equiv.) in dimethyl sulfoxide (200 mL), hydrazine hydrate (9.2 g, 184 mmol, 3.0 equiv.) was added and stirred at 80° C. for 24 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 50% ethyl acetate / hexane) to give H-19.3 (8.6 g, 62%). MS (ES): m / z 227.1 and 229.1 [M+H] + .

[0297] Synthesis of compound H-19. To a DCM solution (8.0 mL) of H-19.3 (0.68 g, 2.99 mmol, 1.0 equiv.), triethylamine (0.90 g, 8.98 mmol, 3.0 equiv.), and 4-dimethylaminopyridine (0.72 g, 5.98 mmol, 3.0 equiv.), di-tert-butyl dicarbonate (1.95 g, 8.98 mmol, 3.0 equiv.) was added and stirred at room temperature for 24 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 20% ethyl acetate / hexane) to give H-19 (0.32 g, 25%). MS (ES): m / z 427.2 and 429.2 [M+H] + .

[0298] Preparation of Intermediate H-20: 6-Bromo-1,3-bis(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one [ka] Synthesis of Compound H-20. To a solution of 6-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.0 g, 4.67 mmol, 1.0 equiv.) in DMF (10 mL) at 0° C., sodium hydride (60% in mineral oil) (0.441 g, 10.28 mmol, 2.2 equiv.) was added in small portions and stirred for 15 minutes. 4-Methoxybenzyl chloride (1.6 g, 10.28 mmol, 2.2 equiv.) was added and stirred at room temperature for 2 hours. This mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 40% ethyl acetate / hexane) to give H-20 (0.80 g, 38%). MS(ES): m / z 454.3 and 456.11 [M+H] + .

[0299] Preparation of Intermediate H-21: 5-Bromo-1-(4-methoxybenzyl)-3-(oxetan-3-yloxy)-1H-pyrazolo[3,4-b]pyridine [ka] Synthesis of Compound H-21. To a solution of H-13.2 (1.0 g, 2.99 mmol, 1.0 equiv.) in DMF (10 mL) at 0° C., sodium hydride (0.129 g, 8.97 mmol, 3.0 equiv.) was added. The mixture was stirred for 30 minutes, and 3-iodooxetane (0.658 g, 3.58 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 100° C. for 2 hours. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give H-21 (0.659 g, 56%). MS (ES): m / z 390.03 and 392.01 [M+H] + .

[0300] Preparation of Intermediate H-22: (R)-3-((1,4-dioxan-2-yl)methoxy)-5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine [ka] Synthesis of Compound H-22.1. To a solution of (S)-(1,4-dioxan-2-yl)methanol (0.60 g, 5.08 mmol, 1.0 equiv.) and triethylamine (1.4 mL, 10.16 mmol, 2.0 equiv.) in DCM (10 mL) at 0° C., methanesulfonyl chloride (0.5 mL, 6.60 mmol, 1.3 equiv.) was added, and the reaction mixture was stirred at room temperature for 6 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give H-22.1 (0.7 g, 70%). MS (ES): m / z 197.04 [M+H] + .

[0301] Synthesis of Compound H-22. To a DMF solution (3.0 mL) of H-13.2 (0.70 g, 2.08 mmol, 1.0 equiv.) at 0° C. was added sodium hydride (0.089 g, 6.24 mmol, 3.0 equiv.). The mixture was stirred for 30 minutes, and H-22.1 (0.491 g, 2.50 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 60° C. for 2 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.0% methanol / DCM) to give H-22 (0.50 g, 55%). MS (ES): m / z 434.1 and 436.04 [M+H] + .

[0302] Preparation of Intermediate H-22: 5-Bromo-1-(4-methoxybenzyl)-3-(2-methoxyethoxy)-1H-pyrazolo[3,4-b]pyridine [ka] Synthesis of Compound H-23. To a DMF solution (10.0 mL) of H-13.2 (1.0 g, 2.99 mmol, 1.0 equiv.), sodium hydride (60% in mineral oil) (0.141 g, 3.59 mmol, 1.2 equiv.) was added in small portions at 0° C. and stirred for 15 minutes. 1-Bromo-2-methoxyethane (0.49 g, 3.59 mmol, 1.2 equiv.) was added and stirred at room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 40% ethyl acetate / hexane) to give H-23 (0.620 g, 53%). MS (ES): m / z 392.16 and 394.17 [M+H] + .

[0303] Preparation of Intermediate H-24: 5-Bromo-1-(4-methoxybenzyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazolo[3,4-b]pyridine [ka] Synthesis of Compound H-24.1. To a solution of tetrahydro-2H-pyran-4-ol (2.0 g, 19.60 mmol, 1.0 equiv.), trimethylamine (8.4 mL, 58.8 mmol, 3.0 equiv.) in DCM (20 mL) was added methanesulfonyl chloride (2.26 mL, 29.4 mmol, 1.5 equiv.) at 0° C. The mixture was stirred at room temperature for 30 minutes. It was quenched with water (30 mL) and extracted with DCM (50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give H-24.1 (2.2 g, 100%). MS (ES): m / z 181.05 [M+H] + .

[0304] Synthesis of Compound H-24. To a solution of H-13.2 (1.0 g, 3.00 mmol, 1.0 equiv.) in DMF (10 mL) at 0 °C, sodium hydride (0.129 g, 9.0 mmol, 3.0 equiv.) was added. The mixture was stirred for 30 minutes. To this mixture, H-24.1 (0.81 g, 4.50 mmol, 1.5 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give H-24 (0.48 g, 38%). MS (ES): m / z 418.20 and 420.20 [M+H] + .

[0305] Preparation of Intermediate H-25: 5-Bromo-2-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one [ka] Synthesis of Compound H-25. Compound H-25 was prepared according to the procedure described in the synthesis of H-16. MS (ES): m / z 428.2 and 430.2 [M+H] + .

[0306] Preparation of Intermediate H-26: trans-2-(3-(benzyloxy)cyclobutyl)-5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one [ka] Synthesis of Compound H-26.1. To a solution of 3-(benzyloxy)cyclobutan-1-one (5.0 g, 28.40 mmol, 1.0 equiv.) in methanol (50 mL) at 0° C. was added sodium borohydride (1.29 g, 34.05 mmol, 1.2 equiv.) in portions. The resulting reaction mixture was stirred at room temperature for 0.5 hours. It was quenched with water (100 mL) and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the material. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 28% ethyl acetate / hexane) to give H-26.1 (5.0 g, 99%). MS (ES): m / z 179.23 [M+H] + .

[0307] Synthesis of Compound H-26.2. To a solution of H-26.1 (5.0 g, 29.175 mmol, 1.0 equiv.) and triethylamine (16.2 mL, 116.7 mmol, 4.0 equiv.) in DCM (52 mL) was added methanesulfonyl chloride (4.5 mL, 58.35 mmol, 2.0 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was quenched with water (100 mL) and extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the material. This was then purified by flash column chromatography on silica gel (CombiFlash®, 35% ethyl acetate / hexanes) to give H-26.2 (5.0 g, 63%). MS (ES): m / z 257.32 [M+H] + .

[0308] Synthesis of compound H-26.3. To a solution of H-26.2 (5.0 g, 19.53 mmol, 1.0 equiv.) in ethanol (50 mL) was added hydrazine (1.25 g, 30.26 mmol, 2.0 equiv.) at room temperature. The reaction mixture was stirred at 95 °C for 6 h. It was concentrated under reduced pressure to give H-26.3 (3.71 g, 99%). MS (ES) m / z 193.26 [M+H] + .

[0309] Synthesis of Compound H-26.4. To a solution of 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (4.2 g, 19.27 mmol, 1.0 equiv.) in DCM (40 mL) and DMF (1 mL) at 0° C. was added thionyl chloride (4 mL). The mixture was stirred at 40° C. for 1 hour. It was then concentrated under reduced pressure. The resulting acyl chloride was dissolved in DCM (58 mL), and 1 M sodium hydroxide solution (29 mL) and H-26.3 (3.7 g, 19.27 mmol, 1.0 equiv.) were added at 0° C. The mixture was stirred at 50° C. for 15 minutes. It was quenched with water (200 mL) and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 14% ethyl acetate / hexanes) to give H-26.4 (1.8 g, 23%). MS (ES): m / z 411.70 [M+H] + .

[0310] Synthesis of Compound H-26.5. A mixture of H-26.45 (1.8 g, 4.39 mmol, 1 equiv.) and sodium carbonate (1.39 g, 13.17 mmol, 3 equiv.) in 1-pentanol (18 mL) was stirred at 140° C. for 2 days. The mixture was concentrated under reduced pressure to give the material. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 52% ethyl acetate / hexanes) to give H-26.5 (1.6 g, 98%). MS (ES): m / z 374.2 and 376.2 [M+H] + .

[0311] Synthesis of Compound H-26. Compound H-26 was prepared from H-26.5 according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane). MS (ES): m / z 504.3 and 505.2 [M+H] + .

[0312] Preparation of Intermediate H-27: tert-butyl 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Synthesis of Compound H-27.1. Compound H-27.1 was prepared from 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane). MS (ES): m / z 453.1 and 455.0 [M+H] + .

[0313] Synthesis of Compound H-27. A mixture of H-27.1 (2.0 g, 4.4 mmol, 1.0 equiv.), (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (1.2 g, 17.05 mmol, 1.5 equiv.), and potassium carbonate (1.52 g, 11.02 mmol, 2.50 equiv.) in 1,4-dioxane (15.0 mL) and water (5 mL) was degassed by bubbling with argon for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.073 g, 0.44 mmol, 0.1 equiv.) was added and degassed for 5 minutes. The reaction mixture was stirred at 100° C. for 2 hours. It was filtered through a pad of Celite® and rinsed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane) to give H-27 (1.68 g, 75%). MS (ES): m / z 509.2 and 511.2 [M+H] + .

[0314] Preparation of Intermediate H-28: 4-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)morpholine [ka] Synthesis of Compound H-28.1. Compound 2-bromo-5H-pyrrolo[2,3-b]pyrazine (2.0 g, 10.101 mmol, 1.0 equiv.) was slowly added to concentrated sulfuric acid (14 mL) at 0° C., followed by fuming nitric acid (0.8 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water. A precipitate formed and was allowed to stand for 30 minutes. The precipitate was collected by filtration, washed with water (200 mL), and dried under vacuum to give H-28.1 (1.9 g, 78%). MS (ES): m / z 243.07 and 245.07 [M+H] + .

[0315] Synthesis of Compound H-28.2. To a solution of H-28.1 (1.6 g, 6.58 mmol, 1.0 equiv.) in DMF (16 mL) at 0° C., sodium hydride (60% in mineral oil) (0.394 g, 9.87 mmol, 1.5 equiv.) was added portionwise. The reaction mixture was stirred at 0° C. for 30 minutes, and 2-(trimethylsilyl)ethoxymethyl chloride (1.206 g, 7.238 mmol, 1.1 equiv.) was added. The mixture was stirred at room temperature for 1 hour, poured into ice water, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate / hexane) to give H-28.2 (1.2 g, 49%). MS (ES): m / z 373.2 and 375.2 [M+H] + .

[0316] Synthesis of Compound H-28.3. A mixture of compound H-28.2 (1.2 g, 3.214 mmol, 1.0 equiv.), ethanol (28.8 mL), water (9.6 mL), ammonium chloride (0.859 g, 16.07 mmol, 5 equiv.), and iron powder (0.897 g, 16.07 mmol, 5 equiv.) was stirred at 80° C. for 90 minutes. The reaction mixture was filtered through a pad of Celite®. The filtrate was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.5% methanol / DCM) to give H-28.3 (0.795 g, 72%). MS (ES): m / z 343.1 and 345.1 [M+H] + .

[0317] Synthesis of Compound H-28. To a solution of H-28.3 (0.795 g, 2.315 mmol, 1.0 equiv.) in acetonitrile (8 mL) was added potassium carbonate (0.966 g, 6.945 mmol, 3.0 equiv.), followed by 1-bromo-2-(2-bromoethoxy)ethane (0.536 g, 2.315 mmol, 1.0 equiv.). The reaction mixture was stirred at 150° C. for 16 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3.1% methanol / DCM) to give H-28 (0.210 g, 22%). MS (ES): m / z 414.39 [M+H] + .

[0318] Preparation of intermediate trans-H-29: trans-6-(2-((tert-butyldiphenylsilyl)oxy)cyclobutoxy)-3-iodopyrazolo[1,5-a]pyrazine [ka] Synthesis of compound H-29.1. To a solution of 1,2-bis((trimethylsilyl)oxy)cyclobut-1-ene (10 g, 43.39 mmol, 1.0 equiv) in acetone:water (20:1, 50 mL) was added ferric chloride in silica (0.050 g, 0.5% w / w). The reaction mixture was stirred at room temperature for 1.5 hours. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 11% ethyl acetate / hexanes) to give H-29. 1 H NMR (CDCl3, 400 MHz): δ 5.02-5.00 (m, 1H), 2.88-2.78 (m, 2H), 2.49-2.43 (m, 1H), 1.93-1.88 (m, 1H).

[0319] Synthesis of Compound H-29.2. Compound H-29.1 (2.2 g, 25.55 mmol, 1.0 equiv.) was added with triethylamine (5.16 g, 51.1 mmol, 2.0 equiv.) and stirred at room temperature for 10 minutes, followed by the addition of tert-butyldiphenylchlorosilane (14.05 g, 51.1 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into brine and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5% ethyl acetate / hexane) to give H-29.2. MS (ES): m / z 325.6 [M+H] + .

[0320] Synthesis of compounds trans-H-29.3 and cis-H-29.3. To a solution of H-29.2 (2.2 g, 6.78 mmol, 1.0 equiv.) in methanol (15 mL) was added sodium borohydride (0.501 g, 13.56 mmol, 2.0 equiv.) in small portions at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. It was poured into ice water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 8-15% ethyl acetate / hexanes) to give trans-H-29.3 (MS(ES): m / z 327.1 [M+H]). + ) and cis-H-29.3 (MS(ES): m / z 327.1 [M+H] + ) was obtained.

[0321] Synthesis of compound trans-H-29.4. To a solution of trans-H-29.3 (29 g, 79.5 mmol, 1.5 equiv.) in DMF (150 mL) at 0° C. was added sodium hydride (60% in mineral oil) (2.3 g, 159 mmol, 3.0 equiv.), followed by 2-bromo-5-iodopyrazine (15 g, 53.0 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature for 1 hour. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexanes) to give trans-H-29.4 (13 g, 46%). MS (ES): m / z 531.2 [M+H] + .

[0322] Synthesis of compound trans-H-29.5. A mixture of trans-H-29.42 (13 g, 24.52 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (10 mL, 73.58 mmol, 3.0 equiv.) in DMF (130 mL) was degassed by bubbling with argon for 10 minutes. Copper(I) iodide (0.232 g, 1.226 mmol, 0.05 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (0.859 g, 1.226 mmol, 0.05 equiv.) were added. The reaction mixture was degassed for 15 minutes, and ethynyltrimethylsilane (10 mL, 73.56 mmol, 3.0 equiv.) was added. The mixture was stirred at 120 °C for 16 hours, poured into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% methanol / DCM) to give trans-H-29.5 (9.0 g, 76%). MS (ES): m / z: 502.1 [M+H] + .

[0323] Synthesis of compound trans-H-29.6. To a solution of trans-H-29.5 (9.0 g, 17.96 mmol, 1.0 equiv) in DCM (90 mL) was added O-(mesitylsulfonyl)hydroxylamine (4.6 g, 21.55 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. It was then concentrated under reduced pressure. The residue was dissolved in DMF (100 mL), and potassium carbonate (8.02 g, 58.13 mmol, 2.0 equiv) was added. The reaction mixture was stirred at room temperature for 16 h. It was then transferred into brine and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (6.0% ethyl acetate / hexane) to give trans-H-29.6 (1.3 g, 16%). MS (ES): m / z 444.19 [M+H] + .

[0324] Synthesis of compound trans-H-29. To a solution of trans-H-29.6 (1.3 g, 2.93 mmol, 1.0 equiv.) in acetonitrile (15 mL) was added N-iodosuccinimide (0.716 g, 1.25 mmol, 1.5 equiv.) in small portions at 0° C. The reaction mixture was stirred at room temperature for 6 hours. It was then concentrated under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate / hexane) to give trans-H-29 (0.84 g, 65%). MS (ES): m / z 570.10 [M+H] + .

[0325] Preparation of intermediate trans-H-31: N-(5-bromo-4-methoxypyridin-2-yl)cyclopropanecarboxamide [ka] Synthesis of Compound H-31.1. To a solution of 4-methoxypyridin-2-amine (5.0 g, 40.32 mmol, 1.0 equiv.) in acetonitrile (200 mL) was added N-bromosuccinimide (7.17 g, 40.32 mmol, 1.0 equiv.) in small portions at 0° C. The reaction mixture was stirred at room temperature for 1 hour. It was concentrated under vacuum to remove acetonitrile. The resulting residue was dissolved in DCM and washed with saturated bicarbonate solution. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate / hexane) to give H-31.1 (3.1 g, 38%). MS (ES): m / z 204.04 [M+H] + .

[0326] Synthesis of Compound H-31. To a solution of H-31.1 (1.6 g, 40.32 mmol, 1.0 equiv.) in acetonitrile (200 mL) was added cyclopropanecarbonyl chloride (1.639 g, 15.763 mmol, 2.0 equiv.) at 0° C., followed by the addition of triethylamine (7.17 g, 40.32 mmol, 1.0 equiv.) and 4-dimethylaminopyridine (0.009 g, 0.079 mmol, 0.01 equiv.). The mixture was stirred at room temperature for 1 hour. It was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane) to give H-31 (1.0 g, 47%). MS(ES): m / z 272.11 [M+H] + .

[0327] Preparation of Intermediate H-33: Benzyl (2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(methyl)carbamate [ka] Synthesis of Compound H-33.1. To a solution of H-28.3 (2 g, 5.83 mmol, 1.0 equiv.) in dioxane (30 mL), saturated aqueous sodium carbonate (20 mL) was added at 0° C. and stirred for 10 minutes. Benzyl chloroformate (50% in toluene, 3.9 mL, 11.66 mmol, 2 equiv.) was added to the mixture at 0° C. The reaction mixture was stirred for 30 minutes. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 5% methanol / DCM) to give H-31.1 (2.2 g, 79%). MS (ES): m / z 477.28 and 479.28 [M+H] + .

[0328] Synthesis of Compound H-33. To a solution of compound H-33.1 (2.2 g, 4.61 mmol, 1.0 equiv.) in DMF (20 mL), sodium hydride (0.36 g, 9.2 mmol, 2 equiv.) was added portionwise and stirred at 0° C. for 30 minutes. Methyl iodide (1.3 g, 9.2 mmol, 2 equiv.) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 22% ethyl acetate / hexane) to give H-33 (1.9 g, 84%). MS (ES): m / z 491.46 and 493.4 [M+H] + .

[0329] Preparation of Intermediate H-35: 5-Bromo-3-(4-methylpiperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine [ka] Synthesis of compound H-35. A mixture of H-27.1 (2.0 g, 4.45 mmol, 1.0 equiv.), 1-methylpiperazine (0.663 g, 6.63 mmol, 1.5 equiv.), cesium carbonate (1.13 g, 13.27 mmol, 3.0 equiv.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.767 g, 1.327 mmol, 0.3 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (0.32 g, 0.88 mmol, 0.2 equiv.) in 1,4-dioxane (20 mL) was purged with argon for 10 minutes. The reaction mixture was stirred at 120 °C for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1.8% methanol / DCM) to give H-35 (0.900 g, 50%). MS (ES): m / z 426.4 and 428.4 [M+H]+ .

[0330] Preparation of Intermediate H-36: 5-Bromo-3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine [ka] Synthesis of Compound H-36.1. To a solution of H-13 (2.0 g, 5.74 mmol, 1.0 equiv.) in DCM (30 mL) was added trifluoroacetic acid (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was washed with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 1.8% methanol / DCM) to give H-36.1 (1.2 g, 92%). MS (ES): m / z 228.1 and 230.1 [M+H] + .

[0331] Synthesis of Compound H-36. Compound H-36 was prepared from H-36.1 according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 18% ethyl acetate / hexane). MS (ES): m / z 358.21 and 360.2 [M+H] + .

[0332] Preparation of Intermediate H-37: 5-Bromo-3-(2-methoxyethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine [ka] Synthesis of Compound H-37.1. To a solution of H-13.2 (3.5 g, 10.47 mmol, 1.0 equiv.) in DMF (35 mL) at 0 °C, sodium hydride (60%) (1.0 g, 20.94 mmol, 2.0 equiv.) was added and stirred for 15 minutes. 1-Bromo-2-methoxyethane (1.73 g, 12.57 mmol, 1.2 equiv.) was added to the mixture and stirred at room temperature for 1 hour. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (18% ethyl acetate / hexane) to give H-37.1 (2.90 g, 66%). MS (ES): m / z 394.2 and 396.2 [M+H] + .

[0333] Synthesis of Compound H-37.2. To a solution of H-37.1 (1.8 g, 4.59 mmol, 1.0 equiv) in DCM (20 mL) was added trifluoromethanesulfonic acid (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was washed with saturated sodium bicarbonate, and the aqueous portion was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.1% methanol / DCM) to give H-37.2 (0.98 g, 78%). MS (ES): m / z 274.1 and 276.1 [M+H] + .

[0334] Synthesis of Compound H-37. Compound H-37 was prepared from H-37.2 according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 32% ethyl acetate / hexane). MS (ES): m / z 404.3 and 406.3 [M+H] + .

[0335] Preparation of Intermediate H-38: (R)-3-((1,4-dioxan-2-yl)methoxy)-5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine [ka] Synthesis of Compound H-38.1. To a solution of H-22 (2.0 g, 4.61 mmol, 1.0 equiv.) in DCM (20 mL) was added trifluoromethanesulfonic acid (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was washed with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.2% methanol / DCM) to give H-38.1 (1.1 g, 76%). MS (ES): m / z 314.1 and 316.1 [M+H] + .

[0336] Synthesis of Compound H-38. Compound H-38 was prepared from H-38.1 according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane). MS (ES): m / z 444.5 and 446.5 [M+H] + .

[0337] Preparation of Intermediate H-39: 5-Bromo-3-((tetrahydrofuran-3-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine [ka] Synthesis of Compound H-39.1. To a solution of H-13.2 (3.5 g, 10.47 mmol, 1.0 equiv.) in DMF (35 mL) at 0° C., sodium hydride (60% by weight, 1.0 g, 20.94 mmol, 2.0 equiv.) was added and stirred for 15 minutes. Tetrahydrofuran-3-yl methanesulfonate (2.09 g, 12.57 mmol, 1.2 equiv.) was added to the mixture and stirred at room temperature for 1 hour. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (15% ethyl acetate / hexane) to give H-39.1 (2.70 g, 64%). MS (ES): m / z 404.2 and 406.2 [M+H] + .

[0338] Synthesis of Compound H-39.2. To a solution of H-39.1 (2.0 g, 4.95 mmol, 1.0 equiv) in DCM (20 mL) was added trifluoroacetic acid (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was washed with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.2% methanol / DCM) to give H-39.2 (1.3 g, 92%). MS (ES): m / z 284.1 and 286.1 [M+H] + .

[0339] Synthesis of Compound H-39. Compound H-39 was prepared from H-39.2 according to the procedure described for the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 28% ethyl acetate / hexane). MS (ES): m / z 414.2 and 416.2 [M+H] + .

[0340] Preparation of Intermediate H-40: 5-Bromo-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine [ka] Synthesis of Compound H-40.1. A solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 50.76 mmol, 1.0 equiv) in fuming HNO3 (33 mL) was stirred at 0 °C for 1 hour. It was poured into ice water. The precipitated solid was collected by filtration, rinsed with water, and dried under vacuum to give H-40.1 (8.0 g, 65%). MS (ES): m / z 243.23 [M+H] + .

[0341] Synthesis of Compound H-40. Compound H-40 was prepared from H-40.1 according to the procedure described in the synthesis of H-1. The product was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane). MS (ES): m / z 373.42 [M+H] + .

[0342] Preparation of Intermediate L-1: N-benzyl-3,3-difluoro-N-methylpiperidin-4-amine [ka] Synthesis of Compound L-1.1. To a solution of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (5 g, 21.25 mmol, 1.0 equiv.) in DCM (100 mL) were added benzylamine (3.41 g, 31.88 mmol, 1.5 equiv.) and sodium triacetoxyborohydride (18 g, 85.02 mmol, 4.0 equiv.). The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane) to give L-1.1 (3.9 g, 56%). MS (ES): m / z 327.1 [M+H] + .

[0343] Synthesis of Compound L-1.2. To a solution of L-1.1 (3.8 g, 11.62 mmol, 1.0 equiv.) and paraformaldehyde (3.48 g, 116.2 mmol, 10 equiv.) in methanol (75 mL) was added sodium cyanoborohydride (3.65 g, 58.10 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 28% ethyl acetate / hexane) to give (±)-22.2 (3.1 g, 78%). MS (ES): m / z 341.1 [M+H] + .

[0344] Synthesis of Compound L-1. To a solution of L-1.2 (3.1 g, 2.71 mmol, 1.0 equiv.) in methanol (31 mL) was added hydrochloric acid (4.0 M in dioxane, 30 mL). The reaction mixture was stirred at room temperature for 3 hours. It was transferred into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 4% methanol / DCM) to give L-1 (1.6 g, 73%). MS (ES): m / z 241.1 [M+H] + .

[0345] Preparation of Intermediate L-2: N-benzyl-N-methylazepan-4-amine [ka] Synthesis of Compound L-2.1. To a DCM solution (20 mL) of tert-butyl 4-oxoazepane-1-carboxylate (2.0 g, 9.38 mmol, 1.0 equiv.), N-benzylmethylamine (1.36 g, 11.26 mmol, 1.2 equiv.), and acetic acid (0.619 g, 10.32 mmol, 1.2 equiv.), sodium triacetoxyborohydride (2.98 g, 14.08 mmol, 1.5 equiv.) was added at 0° C. and stirred at room temperature for 20 hours. The mixture was transferred to a saturated solution of sodium bicarbonate (50 mL) and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.8% methanol / DCM) to give L-2.1 (1.9 g, 64%). MS(ES): m / z: 319.2 [M+H] + .

[0346] Synthesis of Compound L-2. To a DCM solution (20 mL) of L-2.1 (1.8 g, 5.66 mmol, 1.0 equiv.) was added trifluoroacetic acid (10 mL) at 0° C. and stirred for 1.5 hours. This was transferred into an ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to give L-2 (1.17 g, 95%). MS (ES): m / z: 219.2 [M+H] + .

[0347] Preparation of intermediate L-3: benzyl ((1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-yl)(methyl)carbamate [ka] Synthesis of Compound L-3.1. To a solution of trimethylamine (5.9 g, 42.65 mmol, 0.9 eq) and hydroxylamine hydrochloride (3.6 g, 52.13 mmol, 1.1 eq) at 0 °C, compound tert-butyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (10 g, 47.39 mmol, 1.0 eq) in ethanol (0.619 g, 10.32 mmol, 1.2 eq) was added. The reaction mixture was stirred at 80 °C for 2 hours. It was then concentrated under reduced pressure. The residue was triturated with water, filtered, and dried to give L-3.1 (7.0 g, 65%). MS (ES): m / z: 227.13 [M+H] + .

[0348] Synthesis of Compounds L-3.2 and L-3.3. A mixture of compound L-3.1 (7.0 g, 30.83 mmol, 1.0 equiv.), 10% methanolic ammonia (80 mL), and Raney nickel (5.0 g) in a Paar shaker was shaken under 40 bar of hydrogen for 8 hours. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2-propanol) to give L-3.2 (2.1 g, 32%) (MS(ES): m / z 214.16 [M+H]). + ) and L-3.3 (3.3 g, 50%) (MS (ES): m / z 214.16 [M + H] + ) was obtained.

[0349] Synthesis of Compound L-3.4. To a solution of L-3.2 (2.1 g, 9.90 mmol, 1.0 equiv.) and sodium bicarbonate (2.5 g, 29.71 mmol, 3.0 equiv.) in THF (40 mL) and water (20 mL) at 0 °C, benzyl chloroformate (1.4 mL, 9.90 mmol, 1.0 equiv.) was added dropwise. The reaction mixture was stirred at room temperature for 6 hours. It was poured into water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 18% ethyl acetate / hexane) to give L-3.4 (1.6 g, 47%). MS (ES): m / z: 347.19 [M+H] + .

[0350] Synthesis of Compound L-3.5. To a solution of L-3.4 (1.6 g, 4.62 mmol, 1.0 equiv.) in DMF (15 mL), sodium hydride (60% by weight, 0.182 g, 6.93 mmol, 1.5 equiv.) was added portionwise and stirred at 0° C. for 15 minutes. Methyl iodide (0.6 mL, 13.86 mmol, 3.0 equiv.) was added to the mixture, and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate / hexane) to give L-3.5 (1.0 g, 60%). MS (ES): m / z 361.20 [M+H] + .

[0351] Synthesis of Compound L-3. To a solution of L-3.5 (0.6 g, 1.66 mmol, 1.0 equiv.) in DCM (1.2 mL) was added trifluoroacetic acid (0.6 mL). The reaction mixture was stirred at room temperature for 1 hour. It was transferred to saturated sodium bicarbonate solution and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give L-3 (0.421 g, 97%). MS (ES): m / z 261.15 [M+H] + .

[0352] Preparation of Intermediate L-4: tert-butyl (3,3-dimethylpiperidin-4-yl)(methyl)carbamate [ka] Synthesis of Compound L-4.1. To a solution of 1-benzylpiperidin-4-one (5.0 g, 26.45 mmol, 1.0 equiv.) in THF (40 mL) at 0° C., sodium hydride (1.0 g, 38.17 mmol, 1.5 equiv.) was added and stirred for 30 minutes. To this mixture, iodomethane (1.97 mL, 31.74 mmol, 1.2 equiv.) was added dropwise. This mixture was stirred at room temperature for 12 hours, poured into water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate / hexane) to give L-4.1 (1.62 g, 28%). MS (ES): m / z 218.15 [M+H] + .

[0353] Synthesis of Compound L-4.2. To a solution of L-4.1 (1.62 g, 7.46 mmol, 1.0 equiv.) in methanol (20 mL) was added methylamine hydrochloride (5.0 g, 74.6 mmol, 10 equiv.) and potassium hydroxide (4.1 g, 74.6 mmol, 10 equiv.). The mixture was stirred at room temperature for 6 hours, and sodium cyanoborohydride (0.470 g, 7.46 mmol, 1.0 equiv.) was added in small portions. The reaction mixture was stirred at room temperature for 12 hours. It was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give L-4.2 (1.1 g, 64%). MS (ES): m / z 233.19 [M+H] + .

[0354] Synthesis of Compound L-4.3. To a solution of L-4.2 (1.1 g, 4.74 mmol, 1.0 equiv.) in DCM (10 mL) was added triethylamine (1.3 mL, 11.85 mmol, 2.5 equiv.), followed by the addition of di-tert-butyl dicarbonate (1.4 mL, 11.85 mmol, 1.5 equiv.) at 0° C. The mixture was stirred at room temperature for 1 hour. It was then poured into ice water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give L-4.3 (0.830 g, 53%). MS (ES): m / z 333.25 [M+H] + .

[0355] Synthesis of Compound L-4. A mixture of compound L-4.3 (0.83 g, 2.50 mmol, 1.0 equiv.) and 10% palladium hydroxide on carbon (0.1 g) in methanol (20 mL) was stirred under hydrogen (1 atm) at room temperature for 2 hours. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give L-4 (0.55 g, 91%). MS (ES): m / z 243.2 [M+H] + .

[0356] Preparation of Intermediate L-5: N-Benzyl-N-methylpiperidin-4-amine Hydrochloride [ka] Synthesis of Compound L-5.1. To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10.03 mmol, 1.0 equiv.) in DCM (20 mL) was added N-benzylmethylamine (1.45 g, 12.04 mmol, 1.2 equiv.) and stirred at room temperature for 6 hours. To this mixture was added sodium triacetoxyhydroborate (2.1 g, 10.03 mmol, 1.0 equiv.) in small portions. The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give L-5.1 (0.8 g, 26%). MS (ES): m / z 305.22 [M+H] + .

[0357] Synthesis of compound L-5. To a DCM solution (0.8 mL) of L-5.1 (0.8 g, 2.63 mmol, 1.0 equiv.), 4.0 M hydrochloric acid in dioxane (0.8 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. It was then concentrated under reduced pressure. The residue was azeotroped with DCM to give L-5 (0.65 g). MS (ES): m / z 205.14 [M+H] + .

[0358] Preparation of Intermediate L-6: N-Benzyl-N,3,3-trimethylpiperidin-4-amine [ka] Synthesis of Compound L-6.1. To a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (4.5 g, 19.80 mmol, 1.0 equiv.) in DCM (100 mL) were added benzylamine (3.10 g, 29.7 mmol, 1.5 equiv.) and sodium triacetoxyborohydride (16.7 g, 79.2 mmol, 4.0 equiv.). The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 30% ethyl acetate / hexane) to give L-6.1 (3.1 g, 49%). MS (ES): m / z 319.23 [M+H] + .

[0359] Synthesis of Compound L-6.2. To a solution of L-6.1 (3.1 g, 9.73 mmol, 1.0 equiv.) in THF (30 mL) was added sodium hydride (0.467 g, 19.46 mmol, 2.0 equiv.) at −10° C., followed by dropwise addition of methyl iodide (2.0 g, 14.59 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 6 hours. It was poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 28% ethyl acetate / hexane) to give L-6.2 (2.5 g, 77%). MS (ES): m / z 333.49 [M+H] + .

[0360] Synthesis of Compound L-6. To a DCM solution (25 mL) of L-6.2 (2.5 g, 10.7 mmol, 1.0 equiv.), 4.0 M hydrochloric acid in dioxane (25 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. It was transferred into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 3% methanol / DCM) to give L-6 (1.8 g). MS (ES): m / z 233.37 [M+H] + This was used without further purification.

[0361] Preparation of Intermediate L-7: Benzyl 3-methyl-1,8-diazaspiro[4.5]decane-1-carboxylate [ka] Synthesis of Compound L-7.1. To a solution of tert-butyl 4-nitropiperidine-1-carboxylate (10 g, 43.47 mmol, 1.0 equiv.) in THF (100 mL) at 0° C., methyl methacrylate (8.7 g, 86.95 mmol, 2.0 equiv.) and tetra-n-butylammonium fluoride (52.16 mL, 52.16 mmol, 1.2 equiv.) were added. The mixture was stirred at 80° C. for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was added to ethanol (100 mL) and Raney nickel (10 g) in an autoclave and stirred under hydrogen (20 psi) at 80° C. for 16 hours. The reaction mixture was filtered through a pad of Celite® and washed with 50% methanol in DCM. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 2.0% methanol / DCM) to give L-7.1 (7.0 g, 55%). MS (ES): m / z 269.18 [M+H] + .

[0362] Synthesis of Compound L-7.2. To a solution of L-7.1 (7.0 g, 26.10 mmol, 1.0 equiv.) in THF (70 mL), borane dimethyl sulfide (19.8 g, 261.19 mmol, 10 equiv.) was added at 0° C. and stirred at 80° C. for 5 hours. The reaction mixture was cooled to 0° C. and quenched by adding methanol and stirred for 10 minutes. It was poured into water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give L-7.2 (1.3 g, 20%). MS (ES): m / z 255.20 [M+H] + .

[0363] Synthesis of Compound L-7.3. To a solution of L-7.2 (1.3 g, 5.11 mmol, 1.0 equiv.) in DCM (20 mL) was added saturated bicarbonate solution (10 mL) and benzyl chloroformate (0.9 mL, 6.13 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature for 6 hours. It was poured into ice water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 16% ethyl acetate / hexane) to give L-7.3 (1.0 g, 50%). MS (ES): m / z 389.24 [M+H] + .

[0364] Synthesis of Compound L-7. To a solution of L-7.3 (1.0 g, 2.57 mmol, 1.0 equiv.) in DCM (10 mL) was added trifluoroacetic acid (5.0 mL). The reaction mixture was stirred at room temperature for 2 hours. It was concentrated under reduced pressure. To the residue, water and a saturated solution of bicarbonate were added and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give L-7 (0.68 g, 92%). MS (ES): m / z 289.18 [M+H] + .

[0365] Preparation of Intermediate L-8: Benzylmethyl (2-azaspiro[3.3]heptan-6-yl)carbamate [ka] Synthesis of Compound L-8.1. To a solution of tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (2.5 g, 11.77 mmol, 1.0 equiv.) in THF (20 mL) and water (20 mL) was added sodium bicarbonate (1.9 g, 23.55 mmol, 2.0 equiv.) at 0 °C. Benzyl chloroformate (1.9 mL, 11.77 mmol, 1.0 equiv.) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was transferred to a saturated solution of sodium bicarbonate (50 mL) and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 15% ethyl acetate / hexane) to give L-8.1 (2.0 g, 49%). MS(ES): m / z: 347.19 [M+H] + .

[0366] Synthesis of Compound L-8.2. To a solution of L-8.1 (2.0 g, 5.78 mmol, 1.0 equiv.) in THF (20 mL) at 0° C., sodium hydride (60% by weight, 0.228 g, 8.67 mmol, 1.5 equiv.) was added and stirred for 15 minutes. To this mixture was added methyl iodide (1.0 mL, 17.34 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 2 hours, poured into ice water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 10% ethyl acetate / hexane) to give L-8.2 (1.5 g, 72%). MS (ES): m / z 361.20 [M+H] + .

[0367] Synthesis of compound L-8. To a solution of L-8.2 (1.5 g, 4.16 mmol, 1.0 equiv.) in DCM (30 mL) at 0 °C, trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. It was concentrated using DCM to remove excess trifluoroacetic acid and the azeotrope, yielding L-8 (1.0 g, 93%). MS (ES): m / z: 261.15 [M+H]+ .

[0368] Preparation of intermediate cis-L-9: cis-tert-butyl methyl (3-methylpiperidin-4-yl)carbamate [ka] Synthesis of Compound L-9.1. To a solution of 1-benzyl-3-methylpiperidin-4-one (15 g, 73.89 mmol, 1.0 equiv.) in methanol (500 mL), ammonium acetate (56.8 g, 738.9 mmol, 10 equiv.) was added at 0° C. and stirred at room temperature for 4 hours. Sodium cyanoborohydride (2.32 g, 36.91 mmol, 0.5 equiv.) was added to the mixture, and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was basified (pH 9) using 10% ammonia solution and extracted with chloroform. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give L-9.1 (16 g, 99%). MS (ES: m / z 205.16 [M+H] + .

[0369] Synthesis of Compounds cis-L-9.2 and trans-L-9.2. To a solution of L-9.1 (16 g, 78.43 mmol, 1.0 equiv.) in DCM (100 mL) was added trimethylamine (2.23 mL, 15.56 mmol, 0.2 equiv.) and di-tert-butyl dicarbonate (17 mL, 78.43 mmol, 1 equiv.) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1.5 hours. It was quenched with water (60 mL) and extracted with DCM (200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 12% ethyl acetate / hexane) to give the distinct isomers cis-L-9.2 (5.3 g, 22%) (MS(ES): m / z 305.2 [M+H] + ) and trans-L-9.2 (2.0 g, 8%) (MS(ES): m / z 305.2 [M+H] + ) was obtained.

[0370] Synthesis of compound cis-L-9.3. To a solution of cis-L-9.2 (5.3 g, 17.43 mmol, 1.0 equiv.) in DMF (40 mL) at 0° C., sodium hydride (60%) (1.046 g, 26.151 mmol, 1.5 equiv.) was added and stirred for 30 minutes. To this mixture, iodomethane (3.35 mL, 51.9 mmol, 3.0 equiv.) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash®, 25% ethyl acetate / hexane) to give cis-L-9.3 (2.0 g, 36%). MS (ES): m / z 319.23 [M+H] + .

[0371] Synthesis of compound cis-L-9. A mixture of cis-L-9.3 (2.0 g, 6.28 mmol, 1.0 equiv.) and 10% palladium on carbon (1.0 g) in methanol (20 mL) was stirred under hydrogen for 3 hours. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to give cis-L-9 (1.3 g, 93%). MS (ES): m / z 229.18 [M+H] + .

[0372] Preparation of intermediate trans-L-9: trans-tert-butyl methyl (3-methylpiperidin-4-yl)carbamate [ka] Synthesis of compound trans-L-9. Compound trans-L-9 was prepared from trans-L-9.2 according to the procedure described for the synthesis of cis-L-9. MS(ES): m / z 229.34 [M+H].

[0373] Preparation of intermediate trans-L-10: trans-tert-butyl (3-fluoropiperidin-4-yl)(methyl)carbamate [ka] Synthesis of compounds cis-L-10.1 and trans-L-10.1. To a solution of benzyl 3-fluoro-4-oxopiperidine-1-carboxylate (10 g, 39.84 mmol, 1.0 equiv.) in methanol (100 mL) at 0 °C, acetic acid (5.0 mL) and 1 M methylamine in methanol (60 mL) were added dropwise, followed by the dropwise addition of sodium cyanoborohydride (3.7 g, 59.76 mmol, 1.5 equiv.). The reaction mi...

Claims

1. Compounds of formula IB: 【Chemical 325】 or a pharmaceutically acceptable salt thereof [in the formula, X is -N(R 7)- or -C(R ６ ) ２ - and Ring A is selected from a 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and phenyl. L represents a covalent bond or divalent C １－３ It is a linear or branched hydrocarbon chain. R ８ C is a halogen, substituted or unsubstituted C １－６ Aliphatic, substituted, or unsubstituted C ３－６ A substituted or unsubstituted 3-6 member saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from cyclic aliphatic, nitrogen, oxygen, and sulfur, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Each R ａ is, independently, halogen, -CN, -OR, -O(CH ２ ), １－４ R, -SR, -N(R) ２ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R, -OSO ２ N(R) ２ , -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R) ２ , -N(R)SO ２ R', -SO ２ R', -SO ２ N(R) ２ , -SO ３ R', a substituted or unsubstituted C １－６ aliphatic, a substituted or unsubstituted C ３－６ cycloaliphatic, a substituted or unsubstituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 【Chemical 316】 teeth, 【Chemical 317】 And in the formula, W is CH, CR w, or N. Each R w is independently a halogen, -CN, -OR, -O(CH2)1-4R, -SR, -N(R)2, -NO2, -C(O)R', -C(O)OR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R, -OSO2N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, -N(R)SO2R', -SO2R', -SO2N(R)2, -SO3R', substituted or unsubstituted C1-6 aliphatic, substituted or unsubstituted C3-6 A substituted or unsubstituted 3-6 member saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from cyclic aliphatic, nitrogen, oxygen, and sulfur, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or The two Rw groups, together with the atom to which they are bonded, form a 5-6 member partially unsaturated or aromatic ring substituted with q Rb groups. r is 0, 1, 2, or 3. Each R ｂ These are, independently, halogen, -CN, -OR, -O(CH ２ ) １－４ R, -SR, -N(R) ２ , -NO ２ , -C(O)R', -C(O)OR, -C(O)N(R) ２ , -OC(O)R', -OC(O)N(R) ２ , -OC(O)OR, -OSO ２ R, -OSO ２ N(R) ２ , -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R) ２ , -N(R)SO ２ R', -SO ２ R', -SO ２ N(R) ２ , -SO ３ R', substituted or unsubstituted C １－６ Aliphatic, substituted, or unsubstituted C ３－６ A substituted or unsubstituted 3-6 member saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from cyclic aliphatic, nitrogen, oxygen, and sulfur, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, p is 0, 1, 2, 3, 4, or 5, as long as the valence allows. q is 0, 1, 2, 3, 4, or 5, as long as the valence allows it. Each R1, R2, R3, R4, and R5 is independently hydrogen, halogen, -CN, -OR, or substituted or unsubstituted C1-6 aliphatic, and / or Two R1 groups, and / or two R2 groups, and / or two R4 groups, and / or two R5 groups, together with the atom(s) they are bonded to, form a 3- to 8-membered saturated or partially unsaturated ring, and / or Two R1 groups, and / or two R2 groups, and / or two R4 groups, and / or two R5 groups, combine with the atoms to which they are bonded to form an oxo, and / or R1 and R2 units, and / or R1 and R3 units, and / or R1 and R4 units, and / or R1 and R5 units, and / or R2 and R3 units, and / or R2 and R4 units, and / or R2 and R5 units, and / or R3 and R4 units, and / or R3 and R5 units, and / or R3 and R6 units, and / or R3 and R7 units, and / or R4 and R5 units, and / or R4 and R7 units, and / or R5 and R6 units, and / or R5 and R7 units The groups, together with the atoms to which they are bonded, form substituted or unsubstituted 3- to 8-membered saturated or partially unsaturated rings. Each R 6 is independently hydrogen, or a substituted or unsubstituted C 1-6 aliphatic, or The two R6 groups, together with the atom to which they are bonded, form a 3- to 8-membered saturated or partially unsaturated ring. R7 is a substituted or unsubstituted C1-6 aliphatic molecule. Each R is independently either hydrogen or C １－６ Aliphatic and C ３－７ A substituted or unsubstituted group selected from a cyclic aliphatic, a 3-7 member saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a phenyl, a 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or When bonded to the same nitrogen atom, the two R atoms combine to form a substituted or unsubstituted 3-7 member saturated or partially unsaturated ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. Each R' is independent of C １－６ Aliphatic and C ３－７ A substituted or unsubstituted group selected from cyclic aliphatic groups, wherein the compound is 【Chemistry 336】 Not the aforementioned compound or any pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein W is CH.

3. The compound according to claim 1, wherein W is N.

4. The compound according to claim 1, wherein r is 2.

5. Two R's ｗ The groups, together with the atoms they are bonded to, form q R groups. ｂ The compound according to claim 4, which forms a 5-6 membered partially unsaturated or aromatic ring substituted with a group.

6. Each R ｂ These are, independently, halogen, -CN, -OR, and -N(R). ２ , -N(R)C(O)R', substituted or unsubstituted C １－６ Aliphatic, substituted, or unsubstituted C ３－６ The compound according to claim 5, which is a cyclic aliphatic, or a substituted or unsubstituted 3-6 member saturated or partially unsaturated monocyclic heterocycline having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

7. X is -N(R ７ The compound according to claim 1, wherein the compound is:

8. R ７ is C １－６ The compound according to claim 7, wherein it is alkyl.

9. Each R １ , R ２ , R ３ , and R ４ is hydrogen, and each R ５ These are, independently, hydrogen, halogen, -CN, -OR, or substituted or unsubstituted C １－６ The compound according to claim 1, which is aliphatic.

10. The compound according to claim 1, (i) R １ and R ５ The groups, together with the atoms to which they are bonded, form a saturated or partially unsaturated ring with 3 to 8 members. (ii) R ３ and R ７ The groups, together with the atoms to which they are bonded, form a substituted or unsubstituted 3- to 8-membered saturated or partially unsaturated ring. (iii) R ４ and R ５ The groups, together with the atoms to which they are bonded, form a saturated or partially unsaturated ring with 3 to 8 members, or (iv)R ４ and R ７ The group, together with the atom to which it is bonded, forms a saturated or partially unsaturated ring with 3 to 8 members. The compound in which one of the following occurs.

11. The compound according to claim 1, wherein ring A is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

12. The compound according to claim 1, wherein L is a covalent bond.

13. R ８ C is either substituted or non-substituted. １－６ Aliphatic, substituted, or unsubstituted C ３－６ The compound according to claim 1, which is a cyclic aliphatic, or a substituted or unsubstituted 3-6 member saturated or partially unsaturated monocyclic heterocycline having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

14. Each R ａ These are, independently, halogen, -CN, -OR, -O(CH ２ ) １－４ R, substituted or unsubstituted C １－６ Aliphatic, substituted, or unsubstituted C ３－６ The compound according to claim 1, which is a cyclic aliphatic, or a substituted or unsubstituted 3-6 member saturated or partially unsaturated monocyclic heterocycline having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

15. Each R ａ C is either substituted or non-substituted. １－６ The compound according to claim 14, which is aliphatic.

16. Each R ａ This is a C1-6 alkyl group that is unsubstituted or substituted with one or more halogens. １－６ The compound according to claim 15, wherein it is alkyl.

17. The compound according to claim 16, wherein each R a is an unsubstituted C1-6 alkyl or a C1-6 alkyl substituted with one or more fluoropolymers.

18. The compound according to claim 1, wherein p is 0 or 1. 【Request Item 19】 【Chemistry 320】 part is, 【Chemistry 321】 A compound according to claim 1, selected from the following.

20. The compound according to claim 6, wherein q is 1. 【Request Item 21】 【Chemistry 337】 part is, 【Chemical 338】 A compound according to claim 1, selected from the following.

22. The compound according to claim 1, wherein each R is independently hydrogen or a substituted or unsubstituted C1-6 aliphatic.

23. The compound according to claim 1, wherein each R5 is hydrogen.

24. The compound according to claim 13, wherein R8 is a substituted or unsubstituted C1-6 aliphatic.

25. The compound according to claim 18, wherein p is 1.

26. The compound according to claim 1, wherein each R2 is hydrogen. 【Request Item 27】 【Chemistry 339-1】 【Chemistry 339-2】 【Chemistry 339-3】 【Chemistry 339-4】 【Chemistry 339-5】 【Chemistry 339-6】 【Chemistry 339-7】 【Chemistry 339-8】 【Chemistry 339-9】 【Chemistry 339-10】 【Chemistry 339-11】 【Chemistry 339-12】 【Chemistry 339-13】 【Chemistry 339-14】 【Chemistry 339-15】 【Chemistry 339-16】 【Chemistry 339-17】 【Chemistry 339-18】 【Chemistry 339-19】 【Chemistry 339-20】 【Chemistry 339-21】 【Chemistry 339-22】 【Chemistry 339-23】 【Chemistry 339-24】 【Chemistry 339-25】 【Chemistry 339-26】 【Chemistry 339-27】 【Chemistry 339-28】 【Chemistry 339-29】 【Chemistry 339-30】 【Chemistry 339-31】 【Chemistry 339-32】 【Chemistry 339-33】 【Chemistry 339-34】 【Chemistry 339-35】 【Chemistry 339-36】 A compound selected from, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. A composition for inhibiting JAK2 in a target, comprising a compound according to any one of claims 1 to 27.

30. A composition for treating a disease, disorder, or condition related to JAK2, comprising a compound according to any one of claims 1 to 27.

31. A composition for treating cancer, comprising a compound according to any one of claims 1 to 27.

32. A composition for treating hematological malignancies, comprising a compound according to any one of claims 1 to 27.

33. The composition according to claim 32, wherein the hematological malignancy is leukemia or lymphoma.

34. A composition for treating myeloproliferative neoplasms, comprising a compound according to any one of claims 1 to 27.

35. The composition according to claim 34, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis.

36. The composition according to claim 34, wherein the myeloproliferative neoplasm is myelofibrosis.

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