Heterocyclic amide and urea compounds as JAK2 inhibitors

Abstract

The present disclosure provides heterocyclic amide and urea compounds, and compositions thereof, useful for inhibition of JAK2.

Description

[0001] Related applications

[0002] This application claims priority to and the benefit of U.S. Application No. 63 / 395,992, filed August 8, 2022, the entire contents of which are hereby incorporated by reference. Background Art

[0003] 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 is associated with a variety of diseases, including cancer and other proliferative diseases, as well as immune system diseases. For example, essentially all BCR-ABL1 negative myeloproliferative neoplasms are associated with mutations that activate JAK2. Specifically, JAK2 V617F It is the most common mutation in myeloproliferative neoplasms, occurring in approximately 70% of all patients and up to 95% of patients with polycythemia vera. (Vainchenker, W., Kralovics, R. Blood 2017, 129(6):667-79). Even less common mutations (such as those in MPL and CALR) have been shown to affect JAK2 activation, thereby initiating and / or driving disease progression. (Vainchenker, W. et al., F1000 Research 2018, 7(F1000 Faculty Rev):82). In addition, polymorphisms in JAK2 are associated with various autoimmune and inflammatory diseases, 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 is also associated with atopic dermatitis. (Rodrigues, MA and Torres, TJDerm. Treat. 2019, 31(1):33-40).

[0004] JAK (eg, JAK2) inhibitors are classified based on their binding mode. All currently approved JAK inhibitors are type I inhibitors, which are those inhibitors that block catalysis by binding to the ATP binding site in the active conformation of the kinase domain (Vainchenker, W. et al.). However, it was observed that type I inhibitors increased the phosphorylation of the JAK2 activation loop and may produce acquired resistance in some 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, and therefore can avoid the hyperphosphorylation observed by type I inhibitors (Wu, SC et al., Cancer Cell July 13, 2015, 28 (1): 29-41). Summary of the Invention

[0005] The present disclosure provides compounds that can be used to inhibit JAK2. In some embodiments, provided compounds are particularly useful for treating and / or preventing diseases, disorders, or conditions associated with JAK2.

[0006] In some embodiments, the present disclosure provides compounds of Formula A:

[0007]

[0008] 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.

[0009] In some embodiments, the present disclosure provides compounds of Formula I:

[0010]

[0011] 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

[0012] Compounds and Definitions

[0013] Compounds of the present disclosure include those compounds summarized above and are further illustrated by the categories, subclasses and species disclosed herein. Unless otherwise indicated, the following definitions as used herein shall apply. For the purposes of the present disclosure, chemical elements are identified according to the periodic table of the elements (CAS version, Handbook of Chemistry and Physics, 75th edition). In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0014] Unless otherwise indicated, the structures depicted herein are intended to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are considered as part of this disclosure. Therefore, single stereochemical isomers of the provided compounds, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are within the scope of this disclosure. For example, in some cases, Table 1 shows one or more stereoisomers of the compound, and unless otherwise indicated, represents each individual stereoisomer and / or as a mixture. Unless otherwise indicated, all tautomeric forms of the provided compounds are within the scope of this disclosure.

[0015] Unless otherwise indicated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures having the present invention (including replacement of hydrogen with deuterium or tritium, or with 13 C or 14 Compounds in which C is enriched in carbon (replacing carbon) are within the scope of the present disclosure.

[0016] Aliphatic: The term "aliphatic" refers to an optionally substituted straight (i.e., unbranched) or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocycle" or "cycloaliphatic") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-12 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms (e.g., C 1-6 In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C 1-5In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C 1-4 In other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C 1-3 ), and in other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C 1-2 Suitable aliphatic groups include, but are not limited to, substituted or unsubstituted straight or branched chain alkyls, alkenyls, alkynyls, and hybrids thereof. In some embodiments, "aliphatic" refers to an optionally substituted straight (i.e., unbranched) or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, and has a single point of attachment to the rest of the molecule.

[0017] Alkyl: The term "alkyl" when used alone or as part of a larger moiety refers to a group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C 1-12 、C 1-10 、C 1-8 、C 1-6 、C 1-4 、C 1-3 or C 1-2 ) is an optionally substituted straight or branched chain saturated hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. The term "alkylene," as used herein, alone or in combination, refers to an optionally substituted divalent saturated straight or branched chain hydrocarbon, such as methylene (-CH2-).

[0018] Carbocyclyl: As used herein, the terms "carbocyclyl," "carbocycle," and "carbocyclic ring" refer to a saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring system having 3 to 14 members as described herein, wherein the 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 or an optionally substituted C5-C8 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic. 10Bicyclic hydrocarbons having a single point of attachment to the rest of the molecule. The term "cycloalkyl" refers to an optionally substituted saturated ring system having from about 3 to about 10 ring carbon atoms. In some embodiments, the cycloalkyl has 3-6 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0019] Alkenyl: The term "alkenyl" when used alone or as part of a larger moiety refers to a group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 、C 2-10 、C 2-8 、C 2-6 、C 2-4 or C 2-3 ) is an optionally substituted straight or branched hydrocarbon chain. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0020] Alkynyl: The term "alkynyl" when used alone or as part of a larger moiety refers to a group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C 2-12 、C 2-10 、C 2-8 、C 2-6 、C 2-4 or C 2-3 ) is an optionally substituted straight or branched chain hydrocarbon group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0021] Aryl: The term "aryl" refers to a group having a total of 6 to 14 ring members (e.g., C 6-14 ) monocyclic and bicyclic ring systems, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" is used interchangeably with the term "aryl ring". In some embodiments, "aryl" refers to an aromatic ring system, which includes (but is not limited to) phenyl, naphthyl, anthracenyl, etc., which may bear one or more substituents. Unless otherwise specified, "aryl" is a hydrocarbon.

[0022] Heteroaryl: The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy") refer to monocyclic or bicyclic groups having 5 to 10 ring atoms (e.g., a 5- to 6-membered monocyclic heteroaryl or a 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 pi electrons shared in the cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. Exemplary heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, 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 "heteroar-" 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, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, 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," any of which includes rings that are optionally substituted.

[0023] Heteroatom: As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen.

[0024] 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 heterocyclic moiety or a 10- to 16-membered polycyclic (i.e., containing three or more rings) moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more (e.g., one to four) heteroatoms as defined above. The term "nitrogen," when used with respect to the ring atoms of a heterocycle, includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(as in N-substituted pyrrolidinyl). The heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazepine, thiazepine, morpholinyl, and thiomorpholinyl. The heterocyclic group may be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, more preferably monocyclic or bicyclic. Bicyclic heterocycles also include groups in which the heterocycle 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 heterocycle can also be a spirocyclic system (e.g., a 6- to 11-membered spirocyclic bicyclic heterocycle having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three, or four heteroatoms)).

[0025] Partially Unsaturated: As used herein, the term "partially unsaturated" when referring to a ring moiety means a ring moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties as defined herein.

[0026] 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, for example, for experimental, diagnostic, preventive, 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 susceptible to one or more conditions or disorders. In some embodiments, the patient or subject exhibits one or more symptoms of a condition or disorder. In some embodiments, the patient or subject has been diagnosed as having one or more conditions or disorders. In some embodiments, the patient or subject is receiving or has received a therapy to diagnose and / or treat a disease, condition, or disorder.

[0027] 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" or not, means that one or more hydrogens of the designated 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 according to the structure (e.g., means at least and means at least ). Unless otherwise indicated, a group that is "optionally substituted" may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent at each position may be the same or different. The substituent combinations contemplated by the present invention are preferably those that can form stable or chemically feasible compounds. As used herein, the term "stable" means that for one or more purposes provided herein, the compound does not undergo substantial changes when subjected to conditions that allow it to be produced, detected, and in certain embodiments, recovered, purified, and used. The group described as "substituted" preferably has 1 to 4 substituents, more preferably 1 or 2 substituents. The group described as "optionally substituted" may be unsubstituted or "substituted" as described above.

[0028] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o 、-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ; -(CH2) 0-4 Ph, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substituted; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o)C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(C H2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o ,-(CH2) 0- 4OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2)0-4 S(O)(NH)R o ; -(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;-SiR o 3;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring) or a 3- to 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 o Together with its central atoms, it forms a 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0029] R o (or two independent occurrences of R o Suitable monovalent substituents on the ring formed by the ring and its middle atom are independently halogen, -(CH2) 0-2 R · 、-(halogen R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2、-O(halogen R · )、-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- 2SH, -(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, in the case of "halo" in front, is substituted only with one or more halogens, and is independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0030] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0 ("oxo"), =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2- 3O-or-S(C(R * 2)) 2-3 S-, where each independent occurrence of R * is selected from hydrogen, C 1-6 an aliphatic group or an unsubstituted 3- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to the ortho-substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6an aliphatic or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0031] R * Suitable substituents on the aliphatic group include halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, in the case of "halo" in the preceding case, is substituted only with one or more halogens, and is independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0032] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include Each of these are independently hydrogen, C 1-6 an aliphatic group or an unsubstituted 3- to 6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of Together with its central atoms, it forms an unsubstituted 3- to 12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0033] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, in the case of "halo" in the preceding case, is substituted only with one or more halogens, and is independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1Ph or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0034] Treatment: As used herein, the term "treat" (and "treatment" or "treating") refers to any administration of a therapy that partially or completely alleviates, ameliorates, alleviates, suppresses, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, this treatment may be for subjects who do not exhibit signs of the relevant disease, disorder, and / or condition and / or subjects who exhibit only early signs of the disease, disorder, and / or condition. Alternatively or additionally, this treatment may be for subjects who exhibit one or more established signs of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be for subjects who have been diagnosed with the relevant disease, disorder, and / or condition.

[0035] The provided compounds

[0036] In some embodiments, the present disclosure provides compounds of Formula A:

[0037]

[0038] or a pharmaceutically acceptable salt thereof, wherein:

[0039] X is -C(R 6 )2-、-N(R 7 )-or-O-;

[0040] Each R 6 are independently hydrogen or optionally substituted C 1-6 an aliphatic group, or

[0041] Two R's 6 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0042] R 7 is hydrogen or optionally substituted C 1-6 aliphatic groups;

[0043] Ring A is an optionally substituted group selected from the group consisting of phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0044] Ring B is an optionally substituted group selected from the group consisting of a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 10- to 16-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0045] Ring C is an optionally substituted group selected from the group consisting of phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-4 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 1-3 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;

[0046] L is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;

[0047] R 8 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 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- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0048] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0049] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0050] Each R c are independently halogen, -CN, -OR or optionally substituted C 1-6 aliphatic group, and / or

[0051] Two R's c Group and / or R c and R 6 Group and / or R c and R 7 The groups, taken together with the atoms to which they are attached, form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring, and / or

[0052] Two R's c The group, together with the atom to which it is attached, combines to form an oxo group;

[0053] When valence permits, p is 0, 1, 2, 3, 4, or 5;

[0054] When valence permits, q is 0, 1, 2, 3, 4, or 5;

[0055] When valence permits, s is 0, 1, 2, 3, 4, or 5;

[0056] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6Aliphatic group, C 3-7 cycloaliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a phenyl group, and a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0057] 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; and

[0058] Each R' is independently an optionally substituted 1-6 Aliphatic group and C 3-7 Cycloaliphatic groups.

[0059] In some embodiments, the present disclosure provides compounds of Formula B:

[0060]

[0061] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring C, L, p, q, s, R a 、R b 、R c and X are as defined above for Formula A and described in classes and subclasses herein, both individually and in combination; and

[0062] Ring B1 is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur,

[0063] wherein Ring B1 is optionally fused to Ring B2; and

[0064] Ring B2, when present, is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur,

[0065] wherein at least one of Ring B1 and Ring B2 is aromatic; and

[0066] At least one of ring B1 and ring B2 contains a heteroatom.

[0067] In some embodiments, the present disclosure provides a compound of Formula C:

[0068]

[0069] 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 are as defined above for Formula A and described in classes and subclasses herein, both individually and in combination; and

[0070] W is CH, CR w or N;

[0071] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0072] Two R's w The group and the atoms to which it is attached form a group consisting of 0-4 R b a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group; and

[0073] r is 0, 1, 2 or 3.

[0074] In some embodiments, the present disclosure provides compounds of Formula D:

[0075]

[0076] 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 are as defined above for Formula A and described both individually and in combination in classes and subclasses herein.

[0077] In some embodiments, the present disclosure provides compounds of Formula E:

[0078]

[0079] or a pharmaceutically acceptable salt thereof, wherein ring C, L, p, s, R a 、R c 、R 8 and X are as defined above for Formula A and described in classes and subclasses herein, both individually and in combination; and

[0080] W is CH, CR w or N;

[0081] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0082] Two R's w The group and the atoms to which it is attached form a group consisting of 0-4 R b a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group; and

[0083] r is 0, 1, 2 or 3.

[0084] In some embodiments, the present disclosure provides compounds of Formula A, wherein:

[0085] X is -C(R 6 )2-、-N(R 7 )-or-O-;

[0086] Each R 6 is hydrogen, or

[0087] Two R's 6 The group, together with the atoms to which it is attached, forms a 3-membered carbon ring;

[0088] R 7C 1-6 alkyl;

[0089] Ring A is selected from phenyl and a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0090] Ring B is selected from 5- to 6-membered monocyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0091] Ring C is an optionally substituted group selected from the group consisting of phenyl, a 6-membered saturated or partially unsaturated monocyclic carbocyclyl, a 5-membered saturated or partially unsaturated bicyclic carbocyclyl, a 5-membered to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 7-membered to 8-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0092] L is a covalent bond or -CH2-;

[0093] R 8 is optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0094] Each R a is independently optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0095] Each R b are independently halogen, -CN, -OR, -N(R)2, -C(O)N(R)2, -N(R)C(O)R', -N(R)C(O)N(R)2, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0096] Each R c are independently halogen, -OR or optionally substituted C 1-6 Alkyl, and / or

[0097] Two R's c Group and / or R c and R7 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring;

[0098] p is 0, 1, 2, or 3;

[0099] q is 0, 1, 2, or 3;

[0100] s is 0, 1, 2, or 3;

[0101] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 Alkyl, C 3-7 cycloalkyl and 3- to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0102] Each R' is independently an optionally substituted 1-6 Alkyl and C 3-7 Cycloalkyl groups.

[0103] In some embodiments, the present disclosure provides compounds of formula A, wherein Ring A, Ring B, L, R a 、R b 、R c 、R 8 , q, p, s, and X are as defined above for Formula A and described in classes and subclasses herein, both individually and in combination; and wherein Ring C comprises a N atom as the point of attachment to Ring B and is an optionally substituted group selected from the group consisting of 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.

[0104] In some embodiments, the present disclosure provides compounds of Formula I:

[0105]

[0106] or a pharmaceutically acceptable salt thereof, wherein:

[0107] X is -C(R 6 )2-、-N(R 7 )-or-O-;

[0108] Each Y is -C(R 4 )2-;

[0109] Each Z is -C(R 5 )2-;

[0110] n is 0, 1, or 2;

[0111] m is 0, 1, or 2,

[0112] Provided that at least one of n or m is 1 or 2;

[0113] Each R 1 、R 2 、R 3 、R 4 and R 5 are independently hydrogen, halogen, -CN, -OR or optionally substituted C 1-6 aliphatic group, and / or

[0114] Two R's 1 Group and / or two R 2 Group and / or two R 4 Group and / or two R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring, and / or

[0115] Two R's 1 Group and / or two R 2 Group and / or two R 4 Group and / or two R 5 The group, together with the atom to which it is attached, forms an oxo group, and / or

[0116] 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 6Group and / or R 5 and R 7 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring;

[0117] Each R 6 are independently hydrogen or optionally substituted C 1-6 an aliphatic group, or

[0118] Two R's 6 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0119] R 7 is hydrogen or optionally substituted C 1-6 aliphatic groups;

[0120] Ring A is an optionally substituted group selected from the group consisting of phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0121] Ring B is an optionally substituted group selected from the group consisting of a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 10- to 16-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0122] L is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;

[0123] R 8 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 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- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0124] Each R aare 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0125] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0126] When valence permits, p is 0, 1, 2, 3, 4, or 5;

[0127] When valence permits, q is 0, 1, 2, 3, 4, or 5;

[0128] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 3-7 cycloaliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a phenyl group, and a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0129] 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; and

[0130] Each R' is independently an optionally substituted 1-6 Aliphatic group and C 3-7 Cycloaliphatic groups.

[0131] In some embodiments, the present disclosure provides compounds of Formula I, wherein:

[0132] X is -C(R 6 )2-or-N(R 7 )-;

[0133] Each Y is -C(R 4 )2-;

[0134] Each Z is -C(R 5 )2-;

[0135] n is 0, 1, or 2;

[0136] m is 0, 1, or 2,

[0137] Provided that at least one of n or m is 1 or 2;

[0138] Each R 1 、R 2 、R 3 、R 4 and R 5 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 aliphatic group, and / or

[0139] Two R's 1 Group and / or two R 2 Group and / or two R 4 Group and / or two R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring, and / or

[0140] Two R's 1 Group and / or two R 2 Group and / or two R 4 Group and / or two R 5 The group, together with the atom to which it is attached, forms an oxo group, and / or

[0141] R 1 and R 2 Group and / or R 1 and R 3Group 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 group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0142] Each R 6 are independently hydrogen or optionally substituted C 1-6 an aliphatic group, or

[0143] Two R's 6 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0144] R 7 is hydrogen or optionally substituted C 1-6 aliphatic groups;

[0145] Ring A is an optionally substituted group selected from the group consisting of phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0146] Ring B is an optionally substituted group selected from the group consisting of a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10- to 16-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0147] L is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;

[0148] R 8 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 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- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0149] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0150] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0151] When valence permits, p is 0, 1, 2, 3, 4, or 5;

[0152] When valence permits, q is 0, 1, 2, 3, 4, or 5;

[0153] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 3-7 cycloaliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a phenyl group, and a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0154] 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; and

[0155] Each R' is independently an optionally substituted 1-6 Aliphatic group and C 3-7 Cycloaliphatic groups.

[0156] In some embodiments, the present disclosure provides compounds of Formula I, wherein:

[0157] X is -C(R 6 )2-、-N(R 7 )-or-O-;

[0158] Each Y is -C(R 4 )2-;

[0159] Each Z is -C(R 5 )2-;

[0160] n is 1 or 2;

[0161] m is 1;

[0162] Each R 1 、R 2 、R 3 、R 4 and R 5 are independently hydrogen, halogen, -OR or optionally substituted C 1-6 Alkyl, and / or

[0163] R 1and 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, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring;

[0164] Each R 6 are independently hydrogen, or

[0165] Two R's 6 The group, together with the atoms to which it is attached, forms a 3-membered carbon ring;

[0166] R 7 C 1-6 alkyl;

[0167] Ring A is selected from phenyl and a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0168] Ring B is selected from 5- to 6-membered monocyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8- to 10-membered bicyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0169] L is a covalent bond or -CH2-;

[0170] R 8 is optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0171] Each R a is independently optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0172] Each R b are independently halogen, -CN, -OR, -N(R)2, -C(O)N(R)2, -N(R)C(O)R', -N(R)C(O)N(R)2, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0173] p is 0, 1, 2, or 3;

[0174] q is 0, 1, 2, or 3;

[0175] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 Alkyl, C 3-7 cycloalkyl and 3- to 7-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

[0176] Each R' is independently an optionally substituted 1-6 Alkyl and C 3-7 Cycloalkyl groups.

[0177] In some embodiments, the present disclosure provides compounds of Formula IA:

[0178]

[0179] 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 are as defined above for Formula I and described both individually and in combination in classes and subclasses herein.

[0180] In some embodiments, the present disclosure provides compounds of Formula IB:

[0181]

[0182] 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 are as defined above for Formula I and described both individually and in combination in classes and subclasses herein.

[0183] In some embodiments, the present disclosure provides compounds of Formula IC:

[0184]

[0185] 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 are as defined above for Formula I and described both individually and in combination in classes and subclasses herein.

[0186] In some embodiments, the present disclosure provides compounds of Formula ID:

[0187]

[0188]

[0189] 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 are as defined above for Formula I and described both individually and in combination in classes and subclasses herein.

[0190] In some embodiments, the present disclosure provides compounds of Formula II:

[0191]

[0192] or a pharmaceutically acceptable salt thereof, wherein ring A, L, m, n, p, q, R a 、R b 、R 1 、R 2 、R 3 、R 8 , X, Y, and Z are as defined above for Formula I and described in classes and subclasses herein, both individually and in combination; and

[0193] Ring B1 is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur,

[0194] wherein Ring B1 is optionally fused to Ring B2; and

[0195] Ring B2, when present, is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur,

[0196] wherein at least one of Ring B1 and Ring B2 is aromatic; and

[0197] At least one of ring B1 and ring B2 contains a heteroatom.

[0198] In some embodiments, the present disclosure provides compounds of Formula III:

[0199]

[0200] or a pharmaceutically acceptable salt thereof, wherein ring A, L, m, n, p, R a 、R 1 、R 2 、R 3 、R 8 , X, Y, R, R', and Z are as defined above for Formula I and described in classes and subclasses herein, both individually and in combination; and

[0201] W is CH, CR w or N;

[0202] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0203] Two R's w The group and the atoms to which it is attached form a group consisting of 0-4 R b a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group; and

[0204] r is 0, 1, 2 or 3.

[0205] In some embodiments, the present disclosure provides compounds of Formula IV:

[0206]

[0207] or a pharmaceutically acceptable salt thereof, wherein 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 above for Formula I and are described herein in classes and subclasses both individually and in combination.

[0208] In some embodiments, the present disclosure provides compounds of Formula V:

[0209]

[0210] or a pharmaceutically acceptable salt thereof, wherein 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 above for Formula I and are described herein in classes and subclasses both individually and in combination.

[0211] In some embodiments, the present disclosure provides compounds of Formula VI:

[0212]

[0213] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, p, q, R a 、R b 、R 8 and X are as defined above for Formula A1 and described in classes and subclasses herein, both individually and in combination; and wherein each R 1 、R 2 、R 3 、R 4 and R 5 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 Aliphatic group.

[0214] In some embodiments, the present disclosure provides compounds of formula A, wherein Ring A, Ring B, L, R a 、R b 、Rc 、R 8 , q, p, s, and X are as defined above for formula A and described in classes and subclasses herein, both individually and in combination; and wherein Ring C comprises a carbon atom as the point of attachment to Ring B and is an optionally substituted group selected from the group consisting of 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.

[0215] In some embodiments, the present disclosure provides compounds of Formula VII:

[0216]

[0217] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, p, q, R a 、R b 、R 8 and X are as defined above for Formula A2 and described in classes and subclasses herein, both individually and in combination; and wherein each R 1 、R 2 、R 4 and R 5 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 Aliphatic group.

[0218] In some embodiments, the present disclosure provides compounds of Formula VIII:

[0219]

[0220] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, p, q, R a 、R b 、R 8 and X are as defined above for Formula A2 and described in classes and subclasses herein, both individually and in combination; and wherein 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 Aliphatic group.

[0221] In some embodiments, the present disclosure provides compounds of Formula IX:

[0222]

[0223] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, p, q, R a 、R b 、R 8 and X are as defined above for Formula A2 and described in classes and subclasses herein, both individually and in combination; and wherein each R 1 、R 2 、R 3 、R 4 and R 5 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 Aliphatic group.

[0224] In some embodiments, the present disclosure provides compounds of Formula X:

[0225]

[0226] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, p, q, R a 、R b 、R 8 and X are as defined above for Formula A2 and described both individually and in combination in classes and subclasses herein.

[0227] In some embodiments, the present disclosure provides compounds of Formula XI:

[0228]

[0229] or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, L, p, q, R a 、R b 、R 8 and X are as defined above for Formula A2 and described in classes and subclasses herein, both individually and in combination; and

[0230] Each R 2 、R 3 、R 4 、R 5 and R 9 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 aliphatic group, and / or

[0231] Two R's 2 Group and / or two R 3 Group and / or two R 4 Group and / or two R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring, and / or

[0232] R9 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 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, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring.

[0233] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula 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-.

[0234] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, and Formula E, ring C is selected from phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 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, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl. In some embodiments, ring C is selected from 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl and 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl. In some embodiments, Ring C is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0235] In some embodiments, Ring C comprises an N atom as the point of attachment to Ring B and 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. In some such embodiments, Ring C is

[0236] In some embodiments, ring C comprises 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, 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 comprises 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 comprises a C atom as the point of attachment to Ring B and is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, Ring C is

[0237] In some embodiments, Ring C is phenyl. In some embodiments, Ring C is

[0238] In some embodiments, ring C is a 3-membered to 7-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, ring C is a 5-membered 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

[0239] In some embodiments, Ring C is a 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclyl. In some embodiments, Ring C is a 5- to 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

[0240] In some embodiments, ring C is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 6- to 7-membered saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 3-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 4-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 6-membered saturated monocyclic heterocyclic group having 1-2 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 heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 7-membered saturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is an azepane ring. In some embodiments, ring C is

[0241] In some embodiments, ring C is a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group 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 heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 7- to 8-membered saturated bicyclic heterocyclic group 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 heterocyclic group 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 heterocyclic group 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 heterocyclic group 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 heterocyclic group 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 heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is

[0242] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, and Formula E, each R c are independently halogen, -CN, -OR or optionally substituted C 1-6 an aliphatic group, 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 atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring. c are independently halogen, -CN, -OR or optionally substituted C 1-6 an aliphatic group, 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 atoms to which they are attached, are combined to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring.

[0243] 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 In some embodiments, each R c In some embodiments, each R c is -OR (e.g., -OCH3 or -OCHF2). In some embodiments, each R c is optionally substituted C 1-6 Alkyl (eg, methyl).

[0244] In some embodiments, both R c The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring. c The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring. c The groups are combined with the atoms to which they are attached to form a C3-C6 cycloalkyl group. cThe group is combined with the atoms to which it is attached to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. c The radicals, together with the atoms to which they are attached, are combined to form a 3- to 6-membered saturated heterocyclic radical having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0245] In some embodiments, R c and R 6 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring. c and R 6 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring. c and R 6 The groups, together with the atoms to which they are attached, are combined to form a C3-C6 cycloalkyl group. c and R 6 The group is combined with the atoms to which it is attached to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. c and R 6 The radicals, together with the atoms to which they are attached, are combined to form a 3- to 6-membered saturated heterocyclic radical having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0246] In some embodiments, R c and R 7 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring. c and R 7 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 6-membered saturated or partially unsaturated ring. c and R 7 The group is combined with the atoms to which it is attached to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. c and R 7 The radicals, together with the atoms to which they are attached, are combined to form a 3- to 6-membered saturated heterocyclic radical having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0247] In some embodiments, only one pair combines to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring, wherein the pair is selected from two R c Group, Rc and R 6 Group and R c and R 7 group.

[0248] In some embodiments, two R c The group is combined with the carbon atom to which it is attached to form an oxo group. In some embodiments, only one pair of R c The groups combine to form an oxo group.

[0249] In some embodiments of any of Formula A, Formula B, Formula C, Formula D, and Formula 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.

[0250] In some embodiments of any of Formula I, Formula II, Formula III, Formula IV, and Formula 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.

[0251] In some embodiments of any of Formula I, Formula II, Formula III, Formula IV, and Formula 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.

[0252] In some embodiments of any of Formula I, Formula II, Formula III, Formula IV, and Formula 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.

[0253] In some embodiments of any one of Formula I, IA, IB, IC, ID, II, III, IV, V, VI, VII, and IX, each R 1 、R 2 、R 3 、R4 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 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 Alkyl (eg, methyl).

[0254] In some embodiments of any of Formula VIII and Formula XI, each R1 、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 For hydrogen.

[0255] In some embodiments of any one of Formula 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 group; or two R 1 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; or two R 1 The group and the atom to which it is attached are combined to form an oxo group; 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 5The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring. 1 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 aliphatic group; or two R 1 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; or two R 1 The group and the atom to which it is attached are combined to form an oxo group; 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, form a 3- to 8-membered saturated or partially unsaturated ring. 1 are independently hydrogen, -CN or optionally substituted C 1-6 aliphatic group; or two R 1 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; or two R 1 The group and the atom to which it is attached are combined to form an oxo group; 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, 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 Aliphatic group.

[0256] In some embodiments, R 1 In some embodiments, R 1 is halogen (eg, fluorine). In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is optionally substituted C 1-6 Aliphatic groups (e.g., optionally substituted C 1-6 In some embodiments, R 1 It is a methyl group.

[0257] In some embodiments, both R 1 The groups, together with the atoms to which they are attached, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 1 The groups are combined with the atoms to which they are attached to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group. 1 The groups are combined with the atoms to which they are attached to form a C3-C6 cycloalkyl group. 1 The group is combined with the atoms to which it is attached to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 The radicals, together with the atoms to which they are attached, are combined to form a 3- to 6-membered saturated heterocyclic radical having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0258] In some embodiments, both R 1 The group, together with the atom to which it is attached, forms an oxo group.

[0259] In some embodiments of any one of Formula 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 group; or two R 2 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; or two R 2 The group and the atom to which it is attached are combined to form an oxo group; or R 1 and R 2 Group and / or R 9 and R 2 Group and / or R 2 and R3 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, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring. 2 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 aliphatic group; or two R 2 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; or two R 2 The group and the atom to which it is attached are combined to form an oxo group; 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, form a 3- to 8-membered saturated or partially unsaturated ring. 2 are independently hydrogen, -CN or optionally substituted C 1-6 aliphatic group; or two R 2 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; or two R 2 The group and the atom to which it is attached are combined to form an oxo group; 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, 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 R2 is hydrogen, and the other R 2 is halogen, -CN or optionally substituted C 1-6 Aliphatic group.

[0260] In some embodiments, R 2 In some embodiments, R 2 is halogen (eg, fluorine). In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 is optionally substituted C 1-6 Aliphatic groups (e.g., optionally substituted C 1-6 In some embodiments, R 2 It is a methyl group.

[0261] In some embodiments, both R 2 The groups, together with the atoms to which they are attached, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 2 The groups are combined with the atoms to which they are attached to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group. 2 The groups are combined with the atoms to which they are attached to form a C3-C6 cycloalkyl group. 2 The group is combined with the atoms to which it is attached to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 The radicals, together with the atoms to which they are attached, are combined to form a 3- to 6-membered saturated heterocyclic radical having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0262] In some embodiments, both R 2 The group, together with the atom to which it is attached, forms an oxo group.

[0263] In some embodiments of any one of Formula I, IA, IB, IC, ID, II, III, IV, V, VI, VIII, IX, and XI, R 3 is hydrogen, halogen, -CN, -OR or optionally substituted C 1-6 aliphatic group; or R 1 and R 3 Group or R 9 and R 3 Group or R 2 and R 3 Group or R3 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, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring. 3 is hydrogen, halogen, -CN or optionally substituted C 1-6 aliphatic group; 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, form a 3- to 8-membered saturated or partially unsaturated ring. 3 is hydrogen, -CN or optionally substituted C 1-6 aliphatic group; 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, form a 3- to 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 Aliphatic group.

[0264] In some embodiments, R 3 In some embodiments, R 3 is halogen (eg, fluorine). In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3is optionally substituted C 1-6 Aliphatic groups (e.g., optionally substituted C 1-6 In some embodiments, R 3 It is a methyl group.

[0265] In some embodiments of any one of Formula I, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula XI, each R 4 are independently hydrogen, halogen, -CN, -OR or optionally substituted C 1-6 an aliphatic group; and / or two R 4 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; and / or two R 4 The group, together with the atom to which it is attached, forms an oxo group; 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, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring. 4 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 an aliphatic group; and / or two R 4 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; and / or two R 4 The group, together with the atom to which it is attached, forms an oxo group; and / or R 1 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 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring. 4 is hydrogen, halogen (such as fluorine), -O(C 1-6 alkyl) (e.g., -OCH3), -O(C 1-6haloalkyl) (e.g. -OCHF2) or C 1-6 In some embodiments, each R 4 is hydrogen, halogen (such as fluorine) or C 1-6 In some embodiments, each R 4 In some embodiments, each R 4 is halogen (e.g., fluorine). In some embodiments, each R 4 C 1-6 In some embodiments, one R 4 is hydrogen, and the other R 4 is halogen (such as fluorine), -O(C 1-6 alkyl) (e.g., -OCH3), -O(C 1-6 haloalkyl) (e.g. -OCHF2) or C 1-6 Alkyl (eg, methyl).

[0266] In some embodiments, R 4 In some embodiments, R 4 is halogen (eg, fluorine). In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 -O(C 1-6 alkyl) (e.g., -OCH3) or -O(C 1-6 In some embodiments, R 4 is optionally substituted C 1-6 Aliphatic groups (e.g., optionally substituted C 1-6 In some embodiments, R 4 C 1-6 Alkyl (eg, methyl).

[0267] In some embodiments, both R 4 The groups, together with the atoms to which they are attached, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4 The groups are combined with the atoms to which they are attached to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group. 4 The groups are combined with the atoms to which they are attached to form a C3-C6 cycloalkyl group. 4The group is combined with the atoms to which it is attached to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 The radicals, together with the atoms to which they are attached, are combined to form a 3- to 6-membered saturated heterocyclic radical having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0268] In some embodiments, both R 4 The group, together with the atom to which it is attached, forms an oxo group.

[0269] In some embodiments of any one of Formula 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 an aliphatic group; and / or two R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; and / or two R 5 The group, together with the atom to which it is attached, forms an oxo group; 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, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring. 5 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 an aliphatic group; and / or two R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; and / or two R 5 The group, together with the atom to which it is attached, forms an oxo group; 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 5The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring. 5 is hydrogen, halogen (such as fluorine), -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 5 is hydrogen, halogen (such as fluorine) or C 1-6 In some embodiments, each R 5 In some embodiments, each R 5 is halogen (e.g., fluorine). In some embodiments, each R 5 C 1-6 In some embodiments, one R 5 is hydrogen, and the other R 5 is halogen (such as fluorine), -O(C 1-6 alkyl) (e.g., -OCH3), -O(C 1-6 haloalkyl) (e.g. -OCHF2) or C 1-6 Alkyl (eg, methyl).

[0270] In some embodiments, R 5 In some embodiments, R 5 is halogen (eg, fluorine). In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 -O(C 1-6 alkyl) (e.g., -OCH3) or -O(C 1-6 In some embodiments, R 5 is optionally substituted C 1-6 Aliphatic groups (e.g., optionally substituted C 1-6 In some embodiments, R 5 C 1-6 Alkyl (eg, methyl).

[0271] In some embodiments, both R 5 The groups, together with the atoms to which they are attached, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 5 The groups are combined with the atoms to which they are attached to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group.5 The groups are combined with the atoms to which they are attached to form a C3-C6 cycloalkyl group. 5 The group is combined with the atoms to which it is attached to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5 The radicals, together with the atoms to which they are attached, are combined to form a 3- to 6-membered saturated heterocyclic radical having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0272] In some embodiments, both R 5 The group, together with the atom to which it is attached, forms an oxo group.

[0273] In some embodiments of any of Formula VIII and Formula XI, R 9 is hydrogen, halogen, -CN, -OR or optionally substituted C 1-6 aliphatic group; 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, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring. 9 is hydrogen, halogen, -CN or optionally substituted C 1-6 aliphatic group; 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, form a 3- to 8-membered saturated or partially unsaturated ring. 9 is hydrogen, -CN or optionally substituted C 1-6 aliphatic group; 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 9and R 5 The groups, together with the atoms to which they are attached, form a 3- to 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 Aliphatic group.

[0274] In some embodiments, R 9 In some embodiments, R 9 is halogen (eg, fluorine). In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 is optionally substituted C 1-6 Aliphatic groups (e.g., optionally substituted C 1-6 In some embodiments, R 9 It is a methyl group.

[0275] In some embodiments of any one of Formula 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 R6 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, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 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 5Group 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 5 The groups, together with the atoms to which they are attached, form an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic group (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 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6In 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 5 The group is combined with the atoms to which it is attached to form an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclic group (e.g., a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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 R4 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 group is combined with the atoms to which it is attached to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., a 3- to 6-membered saturated heterocyclic group). In some embodiments, only one pair is combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a carbocyclic or heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein 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 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 4group; and R 9 and R 5 In some embodiments, only one pair combines to form a 3- to 8-membered saturated or partially unsaturated ring (i.e., a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein 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 group; and R 4 and R 5 group.

[0276] In some embodiments, R 1 and R 2 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 1 and R 2 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 1 and R 2 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0277] In some embodiments, R 1 and R 3The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 1 and R 3 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 1 and R 3 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0278] In some embodiments, R 1 and R 4 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 1 and R 4 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 1 and R 4 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0279] In some embodiments, R 1 and R 5 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 and R 5The groups, together with the atoms to which they are attached, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 1 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 1 and R 5 The group is combined with the atoms to which it is attached to form a 5-membered saturated or partially unsaturated carbocyclic group (e.g., a C5 cycloalkyl group). 1 and R 5 The group, together with the atoms to which it is attached, is combined to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group (e.g., a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 and R 5 The group, together with the atoms to which it is attached, forms a 5-membered saturated or partially unsaturated heterocyclic group (eg, a 5-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0280] In some embodiments, R 2 and R 3 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 2 and R 3 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 2 and R 3 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0281] In some embodiments, R 2 and R 4The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 2 and R 4 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 2 and R 4 The group is combined with the atoms to which it is attached to form a 5-membered saturated or partially unsaturated carbocyclic group (e.g., a C5 cycloalkyl group). 2 and R 4 The group, together with the atoms to which it is attached, is combined to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group (e.g., a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 and R 4 The group, together with the atoms to which it is attached, forms a 5-membered saturated or partially unsaturated heterocyclic group (eg, a 5-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0282] In some embodiments, R 2 and R 5 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 2 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 2 and R 5 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0283] In some embodiments, R 3 and R 4 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 3 and R 4 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 3 and R 4 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0284] In some embodiments, R 3 and R 5 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 5 The groups, together with the atoms to which they are attached, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 3 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 3 and R 5 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0285] In some embodiments, R 3 and R 6 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R3 and R 6 The groups, together with the atoms to which they are attached, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 3 and R 6 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 3 and R 6 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0286] In some embodiments, R 3 and R 7 The group, together with the atoms to which it is attached, is combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (ie, a heterocyclyl group 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a heterocyclyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 3 and R 7 The group, together with the atoms to which it is attached, is combined to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group (e.g., a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 and R 7 The group, together with the atoms to which it is attached, is combined to form a 4-membered saturated or partially unsaturated heterocyclic group (e.g., a 4-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 and R 7 The group is combined with the atoms to which it is attached to form a 5-membered saturated or partially unsaturated heterocyclic group (e.g., a 5-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclic group is optionally substituted by one or more C 1-6 In some embodiments, R 3 and R 7 The group, together with the atoms to which it is attached, forms a 5-membered saturated or partially unsaturated heterocyclic group (eg, a 5-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0287] In some embodiments, R4 and R 5 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 4 and R 5 The group, together with the atoms to which it is attached, forms a 6-membered saturated or partially unsaturated carbocyclic group (e.g., a 6-membered saturated carbocyclic group). 4 and R 5 The group, together with the atoms to which it is attached, is combined to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group (e.g., a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 and R 5 The group, together with the atoms to which it is attached, is combined to form a 5- to 7-membered saturated or partially unsaturated heterocyclic group (e.g., a 5- to 7-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 and R 5 The group, together with the atoms to which it is attached, forms a 7-membered saturated or partially unsaturated heterocyclic group (eg, a 7-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0288] In some embodiments, R 4 and R 6 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4 and R 6 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6In some embodiments, R 4 and R 6 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0289] In some embodiments, R 4 and R 7 The group, together with the atoms to which it is attached, is combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (ie, a heterocyclyl group 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a heterocyclyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4 and R 7 The group, together with the atoms to which it is attached, is combined to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group (e.g., a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 4 and R 7 The group, together with the atoms to which it is attached, is combined to form a 6-membered saturated or partially unsaturated heterocyclic group (eg, a 6-membered saturated heterocyclic group such as morpholine) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0290] In some embodiments, R 5 and R 6 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 5 and R 6 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 5 and R 6 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0291] In some embodiments, R 5 and R 7 The group, together with the atoms to which it is attached, is combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (ie, a heterocyclyl group 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a heterocyclyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 5 and R 7 The group, together with the atoms to which it is attached, is combined to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group (e.g., a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5 and R 7 The group, together with the atoms to which it is attached, is combined to form a 6-membered saturated or partially unsaturated heterocyclic group (eg, a 6-membered saturated heterocyclic group such as morpholine) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0292] In some embodiments, R 1 and R 9 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 1 and R 9 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 1 and R 9 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0293] In some embodiments, R 2 and R 9 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2 and R 9 The groups, together with the atoms to which they are attached, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 2 and R 9 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 2 and R 9 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0294] In some embodiments, R 3 and R 9 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 3 and R 9 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 3 and R 9 The group, together with the atoms to which it is attached, forms a 6-membered saturated or partially unsaturated carbocyclic group (e.g., a 6-membered saturated carbocyclic group). 3 and R 9 The group, together with the atoms to which it is attached, is combined to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group (e.g., a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3 and R 9 The group, together with the atoms to which it is attached, forms a 6-membered saturated or partially unsaturated heterocyclic group (eg, a 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0295] In some embodiments, R 4 and R 9The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a 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, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 4 and R 9 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 4 and R 9 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0296] In some embodiments, R 5 and R 9 The groups, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring (i.e., a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 9 The groups, together with the atoms to which they are attached, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 5 and R 9 The group and the atoms to which it is attached are combined to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group (e.g., C 3-6 In some embodiments, R 5 and R 9 The group, together with the atoms to which it is attached, forms a 3- to 6-membered saturated or partially unsaturated heterocyclic group (eg, a 3- to 6-membered saturated heterocyclic group) having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0297] In some embodiments of any of Formula I, Formula II, Formula III, Formula IV, and Formula V, a portion Selected from: In some embodiments, part Selected from: In some embodiments, part for In some embodiments, part for In some embodiments, part Selected from In some embodiments, part Selected from In some embodiments, part Selected from (That is, when R 3 With R 7 When combined to form a 4-membered ring), (That is, when R 3 With R 7 When combined to form a 5-membered ring), (That is, when R 3 With R 7 When combined to form a 5-membered ring substituted with a methyl group), (That is, when R 3 With R 7 When combined to form a 5-membered ring) and (That is, when R 4 With R 7 In some embodiments, part of Selected from (That is, when R 3 With R 7 when combined to form a 5-membered ring).

[0298] In some embodiments of Formula VI, the moiety for

[0299] In some embodiments of Formula VII, the moiety for

[0300] In some embodiments of Formula VIII, the moiety for

[0301] In some embodiments of Formula IX, the moiety for

[0302] In some embodiments of Formula XI, the moiety for

[0303] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula 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 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring. 6 In some embodiments, R 6 In some embodiments, R 6 is optionally substituted C 1-6 Aliphatic groups (e.g., optionally substituted C 1-6 In some embodiments, two R 6 The groups, together with the atoms to which they are attached, are combined to form a 3- to 8-membered saturated or partially unsaturated ring (ie, a carbocyclyl or heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 6 The groups are combined with the atoms to which they are attached to form a 3- to 6-membered saturated or partially unsaturated carbocyclic group. 6 The group and the atoms to which it is attached combine to form a C 3-6 In some embodiments, two R 6 The group is combined with the atoms to which it is attached to form a 3- to 6-membered saturated or partially unsaturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 6 The radicals, together with the atoms to which they are attached, are combined to form a 3- to 6-membered saturated heterocyclic radical having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0304] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, R 7 is optionally substituted C 1-6 In some embodiments, R 7 is optionally substituted C 1-6 In some embodiments, R 7 C 1-6 In some embodiments, R 7 is optionally substituted C 1-4In some embodiments, R 7 For hydrogen.

[0305] In some embodiments of any one of Formula 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- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 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 the group consisting of phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an optionally substituted group selected from the group consisting of phenyl and a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is phenyl or a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0306] In some embodiments, Ring A is phenyl.

[0307] In some embodiments, Ring A is a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5- to 6-membered monocyclic heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-membered monocyclic heteroaryl group 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 group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is pyridyl or pyridonyl.

[0308] In some embodiments, Ring A is an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an 8-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 9-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0309] 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.

[0310] In some embodiments, Ring A is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 3-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 4-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 5-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0311] In some embodiments, Ring A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 7-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an 8-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 9-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0312] In some embodiments, ring A(i) is optionally substituted on a substitutable carbon atom with one or more groups independently selected from the group consisting of oxo, halogen, -(CH2) 0-4 R o 、-CN、-OR o 、-O(CH2) 1-4 R o 、-SR o 、-N(R o )2、-NO2、-C(O)R o、-C(O)OR o 、-C(O)NR o 2. -OC(O)R o 、-OC(O)NR o 2. -OC(O)OR o 、-OS(O)2R o 、-OS(O)2NR o 2. -N(R o )C(O)R o 、-N(R o )S(O)2R o 、-S(O)2R o 、-SO2NR o 2 and -S(O)2OR o , and (ii) is optionally substituted on the substitutable nitrogen atom with one or more groups selected from: In some embodiments, ring A(i) is optionally substituted on a substitutable carbon atom by one or more independently selected from oxo, -(CH2) 0-4 R o and -N(R o ) 2 group substituted; and (ii) on the substitutable nitrogen atom, optionally by one or more selected from substituted by a group.

[0313] In some embodiments of any one of Formula 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 In some embodiments, L is a straight or branched hydrocarbon chain. In some embodiments, L is a methylene group (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-.

[0314] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, R 8 is halogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6cycloaliphatic, an optionally substituted 3- to 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- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 7- to 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 optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is optionally substituted C 1-6 aliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl or an optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is optionally substituted C 1-6 alkyl or an optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0315] In some embodiments, R 8 In some embodiments, R 8 Not hydrogen.

[0316] In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 For chlorine.

[0317] In some embodiments, R 8 is optionally substituted C 1-6 In some embodiments, R 8 is an optionally substituted linear or branched C 1-6 Aliphatic (ie, optionally substituted non-cyclic C 1-6 In some embodiments, R 8 is C optionally substituted by one or more halogens (eg, fluorine) 1-6 In some embodiments, R 8is optionally substituted C 1-6 In some embodiments, R 8 is C optionally substituted by one or more halogens (eg, fluorine) 1-6 In some embodiments, R 8 For unsubstituted C 1-6 In some embodiments, R 8 C 1-6 Haloalkyl (eg, -CF3).

[0318] In some embodiments, R 8 is optionally substituted C 3-6 In some embodiments, R 8 is optionally substituted C 3-6 In some embodiments, R 8 is an optionally substituted C3 cycloaliphatic group. 8 is an optionally substituted C4 cycloaliphatic group (eg, cyclobutane optionally substituted with one or more -OH groups). 8 is an optionally substituted C5 cycloaliphatic group. 8 is an optionally substituted C6 cycloaliphatic group.

[0319] In some embodiments, R 8 is an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 4- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is a 4- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more C 1-6 In some embodiments, R 8 is an optionally substituted 3-membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 4-membered saturated monocyclic heterocyclyl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 5-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 8 is an optionally substituted tetrahydrofuranyl. 8is an optionally substituted 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 8 is optionally substituted tetrahydropyranyl, piperidinyl or piperazinyl. 8 is optionally substituted piperidinyl or piperazinyl.

[0320] In some embodiments, R 8 is an optionally substituted phenyl. 8 is not optionally substituted phenyl.

[0321] In some embodiments, R 8 is an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 5-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0322] In some embodiments, R 8 is an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 8 is an optionally substituted 7- to 10-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0323] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, -R 8 (i.e., L is a covalent bond). In some embodiments, For-(C 1-3 Alkylene)-R 8 (i.e. L is C 1-3 In some embodiments, For-(C 1-2 Alkylene)-R 8 (i.e. L is C 1-2 In some embodiments, -CH2-R 8 (i.e., L is a C1 hydrocarbon chain). In some embodiments, -CH2CH2-R 8 (i.e., L is a C2 straight hydrocarbon chain). In some embodiments, -CH2CH2CH2-R 8 (i.e., L is a C3 straight hydrocarbon chain). In some embodiments, -C(CH3)2-R 8 (i.e. L is a C3 branched hydrocarbon chain).

[0324] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, each R a are independently halogen, -CN, -OR, -O(CH2) 1-4 R, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0325] In some embodiments, R a In some embodiments, R a In some embodiments, R a For chlorine.

[0326] In some embodiments, R a -CN, -OR, -O(CH2) 1-4 In some embodiments, R a -CN, -OR or -O(CH2) 1-4 R.

[0327] In some embodiments, R a is optionally substituted C 1-6 In some embodiments, R a is an optionally substituted linear or branched C1-6 Aliphatic (ie, optionally substituted non-cyclic C 1-6 In some embodiments, R a is optionally substituted C 1-6 In some embodiments, R a is C optionally substituted by one or more halogens (eg, fluorine) 1-6 In some embodiments, R a is optionally substituted C 1-4 In some embodiments, R a is C optionally substituted by one or more halogens (eg, fluorine) 1-4 In some embodiments, R a C 1-4 In some embodiments, R a For unsubstituted C 1-4 In some embodiments, R a is -CH3, -CF3 or -C(CH3)3. In some embodiments, R a It is -CH3 or -CF3.

[0328] In some embodiments, R a is optionally substituted C 3-6 In some embodiments, R a is optionally substituted C 3-6 In some embodiments, R a is optionally substituted cyclopropyl.

[0329] In some embodiments, R a is an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. a is an optionally substituted 3- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0330] In some embodiments, R a is optionally substituted phenyl.

[0331] In some embodiments, R a is an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0332] In some embodiments of any of Formula 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.

[0333] In some embodiments of any of Formula A, Formula B, Formula C, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, a portion for In some embodiments, part Selected from: In some embodiments, part Selected from: In some embodiments, part Selected from: In some embodiments, part Selected from: In some embodiments, part Selected from: In some embodiments, part Selected from: In some embodiments, part Selected from:

[0334] In some embodiments of any one of Formula 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 the group consisting of a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is selected from the group consisting of a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0335] In some embodiments, Ring B is a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5- to 6-membered monocyclic heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 5- to 6-membered monocyclic heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 6-membered monocyclic heteroaryl group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is pyridyl or pyrazinyl.

[0336] In some embodiments, Ring B is an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an 8-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is a 9-membered bicyclic heteroaryl group 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]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, isothiazolo[5,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[4,3-b]pyridinyl, 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, pyrazolo[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.

[0337] In some embodiments, Ring B is a 10- to 16-membered polycyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0338] In some embodiments, Ring B(i) is optionally substituted on a substitutable carbon atom with one or more groups independently selected from the group consisting of oxo, halogen, R o 、-CN、-OR o 、-SR o 、-N(R o )2、-NO2、-C(O)R o 、-C(O)OR o 、-C(O)NR o 2. -OC(O)R o 、-OC(O)NR o 2. -OC(O)OR o 、-OS(O)2R o、-OS(O)2NR o 2. -N(R o )C(O)R o 、-N(R o )C(O)NR o 2. -N(R o )S(O)2R o 、-S(O)2R o 、-SO2NR o 2 and -S(O)2OR o , and (ii) is optionally substituted on the substitutable nitrogen atom with one or more groups selected from: In some embodiments, Ring B(i) is optionally substituted on a substitutable carbon atom with one or more groups independently selected from: R o 、-N(R o )2、-C(O)NR o 2. -N(R o )C(O)R o and -N(R o )C(O)NR o 2, and (ii) optionally on the substitutable nitrogen replace.

[0339] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, each R b are independently halogen, -CN, -OR, -N(R)2, -C(O)N(R)2, -N(R)C(O)R', -N(R)C(O)N(R)2, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. b independently halogen, -CN, -OR, -N(R)2, -C(O)N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, optionally substituted C 1-6 aliphatic or optionally substituted C 3-6 In some embodiments, each R b are independently halogen, -OR, -N(R)2, -N(R)C(O)R', -N(R)C(O)N(R)2, optionally substituted C 1-6aliphatic or optionally substituted C 3-6 In some embodiments, each R b are independently halogen, -OR, -N(R)2, -N(H)C(O)R', -N(H)C(O)N(R)2, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl or an optionally substituted 3- to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. b are independently halogen, -OR, -N(R)2, -N(H)C(O)R', -N(H)C(O)N(R)2, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 In some embodiments, each R b are independently halogen, -N(R)2, optionally substituted C 1-6 aliphatic or optionally substituted C 3-6 Cycloaliphatic group.

[0340] In some embodiments, R b In some embodiments, R b In some embodiments, R b For chlorine.

[0341] In some embodiments, R b -CN, -OR, -O(CH2) 1-4 In some embodiments, R b It 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.

[0342] In some embodiments, R b It is -CN.

[0343] In some embodiments, R b In some embodiments, R b is -OR, where R b R is optionally substituted C1-6 aliphatic, optionally substituted C 3-7 cycloaliphatic or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. b is -OR, where R b R is optionally substituted C 1-6 Aliphatic groups (eg, methyl, -CH2CH2OCH3, -CH2(1,4-dioxane), in some embodiments, R b is -OR, where R b R is optionally substituted C 3-7 In some embodiments, R b is -OR, where R b R is an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur (eg, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl).

[0344] In some embodiments, R b is -N(R)2. In some embodiments, R b is -N(R)2, where R b Each R is independently hydrogen or optionally substituted C 1-6 Aliphatic groups (e.g., optionally substituted C 1-6 In some embodiments, R b It is -NHCH3 or -N(CH3)2.

[0345] In some embodiments, R b is -C(O)N(R)2. In some embodiments, R b -C(O)N(R)2, where R b Each R is independently hydrogen or optionally substituted C 1-6 Aliphatic groups (e.g., optionally substituted C 1-6 In some embodiments, R b It is -C(O)N(CH3)2.

[0346] 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-N(H)C(O)(C 1-6 In some embodiments, R b is -N(H)C(O)CH3. In some embodiments, R b is -N(H)C(O)(optionally substituted C 3-6 In some embodiments, R b -N(H)C(O)(C 3-6 In some embodiments, R b It is -N(H)C(O)(cyclopropyl).

[0347] In some embodiments, R b is -N(R)C(O)N(R)2. In some embodiments, R b is -N(H)C(O)N(R)2. In some embodiments, R b is -N(H)C(O)N(optionally substituted C 1-6 In some embodiments, R b -N(H)C(O)N(C 1-6 In some embodiments, R b In some embodiments, R b It is -N(H)C(O)N(CH3)2.

[0348] In some embodiments, R b is optionally substituted C 1-6 In some embodiments, R b is an optionally substituted linear or branched C 1-6 Aliphatic (ie, optionally substituted non-cyclic C 1-6 In some embodiments, R b is optionally substituted C 1-6 In some embodiments, R b is optionally substituted C 1-4 In some embodiments, R b For unsubstituted C 1-4 Alkyl (eg, methyl).

[0349] In some embodiments, R b is optionally substituted C 3-6 In some embodiments, R b is optionally substituted C 3-6 In some embodiments, R b In some embodiments, R bIn some embodiments, R b is optionally replaced by -O(C 1-6 In some embodiments, R b In some embodiments, R b It is cyclohexyl.

[0350] In some embodiments, R b is an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. b is an optionally substituted 3- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. b is an optionally substituted 5-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. b is an optionally substituted 6-membered saturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. b is optionally substituted piperidinyl, tetrahydropyranyl or morpholinyl (e.g. optionally substituted with C 1-6 Alkyl or -C(O)(C 1-6 alkyl) substituted piperidinyl, tetrahydropyranyl or morpholinyl).

[0351] In some embodiments, R b is optionally substituted phenyl.

[0352] In some embodiments, R b is an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0353] In some embodiments of any of Formula 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.

[0354] In some embodiments of any of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, a portion Selected from: In some embodiments, part Selected from: In some embodiments, part Selected from: In some embodiments, part Selected from: In some embodiments, part Selected from:

[0355]

[0356] In some embodiments, part for in:

[0357] Ring B1 is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur,

[0358] wherein Ring B1 is optionally fused to Ring B2; and

[0359] Ring B2, when present, is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0360] It should be understood that ring B1 and ring B2 are together surrounded by q R b Therefore, unless otherwise stated, the substituent R b It may be linked to Ring B1, Ring B2, or both Ring B1 and Ring B2.

[0361] It is also 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.

[0362] In some embodiments of any one of Formula A, Formula B, Formula D, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, Ring B1 is a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0363] In some embodiments, Ring B1 is phenyl. In some embodiments, when Ring B1 is phenyl, Ring B2 contains at least one heteroatom.

[0364] In some embodiments, Ring B1 is a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is a 5-membered monocyclic heteroaryl group 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 group 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.

[0365] In some embodiments, Ring B1 is C 5-6 In some embodiments, when Ring B1 is C 5-6 When ring B1 is C 5-6 When cycloaliphatic, ring B2 is aromatic.

[0366] In some embodiments, Ring B1 is a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when Ring B1 is a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group 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 heterocyclic group 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 heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0367] In some embodiments, Ring B1 optionally fused to Ring B2 is selected from the group consisting of:

[0368]

[0369] In some embodiments of any one of Formula A, B, D, I, IA, IB, IC, ID, II, IV, V, VI, VII, VIII, IX, X, and XI, Ring B2 is a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0370] In some embodiments, Ring B2 is absent.

[0371] In some embodiments, Ring B2 is phenyl. In some embodiments, when Ring B2 is phenyl, Ring B1 contains at least one heteroatom.

[0372] In some embodiments, Ring B2 is a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B2 is a 5-membered monocyclic heteroaryl group having 1-3 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 group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is pyrimidine or pyrazine.

[0373] In some embodiments, Ring B2 is C 5-6 In some embodiments, when Ring B2 is C 5-6 When ring B1 is cycloaliphatic, ring B2 contains at least one heteroatom. 5-6 When cycloaliphatic, ring B1 is aromatic.

[0374] In some embodiments, Ring B2 is a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when Ring B2 is a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ring B1 is aromatic. In some embodiments, Ring B2 is a 5-membered saturated or partially unsaturated monocyclic heterocyclic group 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 heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0375] In some embodiments, Ring B2, when present and fused to Ring B1, is selected from the group consisting of:

[0376]

[0377] In some embodiments, both Ring B1 and Ring B2 are 5- to 6-membered monocyclic heteroaryl groups 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 heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Ring B2, when present, is a 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B1 is a 5-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B1 is fused to Ring B2; and Ring B2 is a 6-membered monocyclic heteroaryl group 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, when 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, when 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; 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, when present, is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0378] In some embodiments, part for in:

[0379] W is CH, CR w or N;

[0380] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0381] Two R's w The group and the atoms to which it is attached form a group consisting of q R b a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group; and

[0382] r is 0, 1, 2 or 3.

[0383] In some embodiments of any one of Formula 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.

[0384] In some embodiments of any one of Formula A, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, each R w independently halogen, -CN, -N(R)2, -C(O)N(R)2, -N(R)C(O)R', -N(R)C(O)OR, -N(R)C(O)N(R)2, 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)2, 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)2. In some embodiments, each R w are independently -N(R)C(O)R' or -N(R)C(O)N(R)2.

[0385] In some embodiments, R w In some embodiments, R w In some embodiments, R w For chlorine.

[0386] In some embodiments, Rw -CN, -OR, -O(CH2) 1-4 In some embodiments, R w It 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.

[0387] In some embodiments, R w In some embodiments, R w is -OR, where R w R is optionally substituted C 1-6 Aliphatic groups (e.g., optionally substituted C 1-6 In some embodiments, R w It is -OCH3.

[0388] 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 -N(H)C(O)(C 1-6 In some embodiments, R w is -N(H)C(O)CH3. In some embodiments, R w is -N(H)C(O)(optionally substituted C 3-6 In some embodiments, R w -N(H)C(O)(C 3-6 In some embodiments, R w It is -N(H)C(O)(cyclopropyl).

[0389] In some embodiments, R w is -N(R)C(O)N(R)2. In some embodiments, R w is -N(H)C(O)N(R)2. In some embodiments, R wis -N(H)C(O)N(optionally substituted C 1-6 In some embodiments, R w -N(H)C(O)N(C 1-6 In some embodiments, R w In some embodiments, R w It is -N(H)C(O)N(CH3)2.

[0390] In some embodiments, R w is optionally substituted C 1-6 In some embodiments, R w is an optionally substituted linear or branched C 1-6 Aliphatic (ie, optionally substituted non-cyclic C 1-6 In some embodiments, R w is optionally substituted C 1-6 In some embodiments, R w is optionally substituted C 1-4 In some embodiments, R w For unsubstituted C 1-4 Alkyl (eg, methyl).

[0391] In some embodiments, R w is optionally substituted C 3-6 In some embodiments, R w is optionally substituted C 3-6 In some embodiments, R w In some embodiments, R w In some embodiments, R w In some embodiments, R w It is cyclohexyl.

[0392] In some embodiments, R w is an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. w is an optionally substituted 3- to 6-membered saturated monocyclic heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0393] In some embodiments, R w is optionally substituted phenyl.

[0394] In some embodiments, R wis an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0395] In some embodiments, both R w The group and the atoms to which it is attached form a group consisting of q R b In some embodiments, two R w The group and the atoms to which it is attached form a group consisting of q R b In some embodiments, two R w The group and the atoms to which it is attached form a group consisting of q R b In some embodiments, the two R w The group and the atoms to which it is attached form a group consisting of q R b In some embodiments, two R w The group and the atoms to which it is attached form a group consisting of q R b A 6-membered aromatic ring substituted with a moiety (eg, pyrimidine or pyrazine).

[0396] In some embodiments of any of Formula 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 does not exceed 5. In some embodiments, q + r does not exceed 4.

[0397] In some embodiments, part for:

[0398] (i) Among them, W, R w and r is as defined above for Formula III and described in classes and subclasses herein, both individually and in combination; or

[0399] (ii) Among them, ring B2, R b and q are as defined above for Formula II and described both individually and in combination in classes and subclasses herein; and:

[0400] Ring B1 is a 5-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0401] In some embodiments, part for:

[0402] (i) Among them, W, R w and r is as defined above for Formula III and described in classes and subclasses herein, both individually and in combination; or

[0403] (ii) Among them, ring B2, R b and q are as defined above for Formula II and described both individually and in combination in classes and subclasses herein;

[0404] Ring B1 is a 5-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0405] Ring B1 is fused to ring B2.

[0406] In some embodiments, part for:

[0407] (i) Among them, W, R w and r is as defined above for Formula III and described in classes and subclasses herein, both individually and in combination; or

[0408] (ii) where R b and q are as defined above for Formula II and described both individually and in combination in classes and subclasses herein;

[0409] Ring B1 is a 5-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0410] Ring B1 is fused to Ring B2; and

[0411] Ring B2 is a 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0412] In some embodiments of any one of Formula 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 hydrogen, optionally substituted C 1-6an aliphatic group or an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R is independently hydrogen or an optionally substituted C 1-6 In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1-6 In some embodiments, R is an optionally substituted linear or branched C 1-6 Aliphatic (ie, optionally substituted non-cyclic C 1-6 In some embodiments, R is an optionally substituted C 1-6 Alkyl (eg, methyl, -CHF2, -CH2CH2OCH3, or -CH2(1,4-dioxane)). In some embodiments, R is C optionally substituted with one or more halogens (eg, fluorine). 1-6 Alkyl, -O(C 1-6 In some embodiments, R is an optionally substituted C 3-7 In some embodiments, R is an optionally substituted C 3-7 In some embodiments, R is an optionally substituted 3 yuan to 7 yuan saturated or partially unsaturated monocyclic heterocyclic radical with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur. In some embodiments, R is an optionally substituted 4 yuan to 6 yuan saturated monocyclic heterocyclic radical (such as tetrahydrofuranyl or tetrahydropyranyl) with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 5 yuan to 6 yuan monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur. In some embodiments, two R form together when connected to the same nitrogen-atoms an additional heteroatomic 3 yuan to 7 yuan saturated or partially unsaturated monocyclic heterocyclic radical with 0-1 independently selected from nitrogen, oxygen and sulphur.

[0413] In some embodiments of any of Formula 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 optionally substituted C 1-6 Alkyl or optionally substituted C 3-7 In some embodiments, R' is an optionally substituted C 1-6 In some embodiments, R' is an optionally substituted linear or branched C 1-6Aliphatic (ie, optionally substituted non-cyclic C 1-6 In some embodiments, R' is an optionally substituted C 1-6 In some embodiments, R' is an unsubstituted C 1-6 In some embodiments, R' is an optionally substituted C 3-7 In some embodiments, R' is an optionally substituted C 3-7 Cycloalkyl (eg, cyclopropyl).

[0414] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, R 7 is optionally substituted C 1-6 aliphatic group; and when R 8 When it is hydrogen, p is 1, 2, 3, 4 or 5 when the valence permits.

[0415] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, R 7 is optionally substituted C 1-6 aliphatic; Ring A is an optionally substituted group selected from the following: phenyl and a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; and when R 8 When it is hydrogen, p is 1, 2, 3, 4 or 5 when the valence permits.

[0416] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, R 7 is optionally substituted C 1-6 Aliphatic group; R a and R 8 is not optionally substituted phenyl; and when R 8 When it is hydrogen, p is 1, 2, 3, 4 or 5 when the valence permits.

[0417] In some embodiments of any of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, and Formula V, the compound is not:

[0418]

[0419]

[0420] In some embodiments of any one of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI, R a or At least one of them is C 1-4 Haloalkyl (eg, -CF3).

[0421] In some embodiments of any of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, and Formula V, the compound is not:

[0422]

[0423]

[0424] In some embodiments of any of Formula A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, when the moiety for and Ring B1 is a 5-membered monocyclic heteroaryl group 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 group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0425] In some embodiments of any of Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, and Formula V, the compound is not:

[0426]

[0427] In some embodiments, the present disclosure provides a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0428] Table 1.

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459] In some embodiments, the present disclosure encompasses the following recognition: provided compounds (for example) exhibit certain desirable properties compared to other known compounds. For example, in some embodiments, provided compounds are more potent than other known compounds in one or more biochemical or cell assays (for example, the JAK2 binding assay or SET2-pSTAT5 cell assay described herein) and / or have one or more other properties that make them more suitable for drug development, such as 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 profiles (for example, based on the assays described in the subsequent Examples). In some embodiments, provided compounds exhibit certain desirable properties in one or more assays described herein (for example) compared to other known compounds.

[0460] In some embodiments, the compounds provided are provided and / or utilized in salt form (e.g., pharmaceutically acceptable salt form). Unless otherwise indicated, references to the compounds provided herein should be understood to include references to their salts. Pharmaceutically acceptable salt forms are known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[0461] It should be understood that throughout this disclosure, unless otherwise indicated, references to compounds of Formula I are intended to also include compounds of Formula I, IA, IB, IC, ID, II, III, IV, and V, as well as species of compounds of such formulae disclosed herein. It should also be understood that throughout this disclosure, unless otherwise indicated, references to compounds of Formula A are intended to also include compounds of Formula B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI, as well as species of compounds of such formulae disclosed herein.

[0462] Preparation of provided compounds

[0463] The provided compounds can generally be prepared by the methods described in the subsequent schemes and examples. In some embodiments, the provided compounds (e.g., compounds of Formula I, wherein X is -C(R 6 )2-):

[0464]

[0465] Among them, 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 are as defined above for Formula I and are described in the categories and subcategories herein in both individual and combined forms. Therefore, in some embodiments, compound A.3 is prepared by a method comprising the following: intermediate A.1 is contacted with intermediate A.2 in the presence of a suitable coupling agent (e.g., HATU or POCl 3 ) and / or a suitable base (DIPEA or pyridine). In some embodiments, compound A.1 is provided in a protected form (e.g., wherein the substituents on ring B are protected, for example, through a suitable protecting group such as Boc). In some embodiments, after coupling of intermediate A.1 with intermediate A.2, the resulting compound undergoes 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 via an amide coupling reaction (e.g., using acetyl chloride or acetic anhydride).

[0466] In some embodiments, provided compounds (eg, compounds of Formula I, wherein X is -N(R 7 )-):

[0467]

[0468] Among them, 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 are as defined above for Formula I and are described in the categories and subcategories herein, both individually and in combination. Thus, in some embodiments, compound B.3 is prepared by a method 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., wherein the nitrogen atom of ring B is protected, for example, by a suitable protecting group such as SEM). In some embodiments, after coupling intermediate B.1 with intermediate B.2, the resulting compound undergoes a deprotection step under suitable conditions (e.g., acidic conditions, such as TFA).

[0469] In some embodiments, provided compounds (eg, compounds of Formula A, wherein X is -N(R 7 )-or-O-):

[0470]

[0471] Among them, ring A, ring B, ring C, L, p, q, s, R a 、R b 、R c and R 8 As defined above for Formula I and described in classes and subclasses herein, both individually and in combination; and X is -N(R 7 )- or -O-. Thus, in some embodiments, compound C.3 is prepared by a method 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., wherein the nitrogen atom of ring B is protected, for example, with a suitable protecting group such as SEM). In some embodiments, after coupling intermediate C.1 with intermediate C.2, the resulting compound undergoes a deprotection step under suitable conditions (e.g., acidic conditions such as TFA).

[0472] In some embodiments, provided compounds (e.g., compounds of Formula A, wherein X is -C(R 6 )2-):

[0473]

[0474] Among them, ring A, ring B, ring C, L, p, q, s, R a 、R b 、R c 、R 6 and R 8As defined above for formula I and described in the categories and subclasses herein in both individual and combined ways. Therefore, in some embodiments, compound D.3 is prepared by a method comprising the following: intermediate D.1 is contacted with intermediate D.2 in the presence of a suitable coupling agent (e.g., HATU or POCl 3 ) and / or a suitable base (DIPEA or pyridine). In some embodiments, compound D.1 is provided in a protected form (e.g., wherein the substituent on ring B is protected, for example, through a suitable protecting group such as Boc). In some embodiments, after intermediate D.1 is coupled with intermediate D.2, the resulting compound undergoes 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 via an amide coupling reaction (e.g., using acetyl chloride or acetic anhydride).

[0475] Composition

[0476] The disclosure also provides compositions comprising compounds provided herein and one or more other components. In some embodiments, the compositions provided include and / or deliver compounds described herein (e.g., compounds of formula A, B, C, D, E, I, IA, IB, IC, ID, II, III, IV, V, VI, VII, VIII, IX, X, and XI).

[0477] In some embodiments, the composition provided is a pharmaceutical composition, which includes and / or delivers a compound provided herein (e.g., Formula A, Formula B, Formula C, Formula D, Formula E, Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI compounds) and further includes a pharmaceutically acceptable carrier. Pharmaceutical compositions generally contain an active agent (e.g., compound described herein) that effectively achieves the desired therapeutic effect while avoiding adverse side effects or minimizing the amount thereof. In some embodiments, the pharmaceutical composition provided includes a compound described herein and one or more fillers, disintegrants, lubricants, glidants, antiadhesives, and / or antistatic agents. The pharmaceutical composition provided can be in various forms, including oral dosage forms, topical creams, topical patches, iontophoretic forms, suppositories, nasal sprays, and / or inhalants, eye drops, intraocular injection forms, storage forms, and injectable and infusible solutions. Methods for preparing pharmaceutical compositions are well known in the art.

[0478] In some embodiments, the compound provided is formulated in unit dosage form for ease of administration and uniform dosage. As used herein, the expression "unit dosage form" refers to a physical discrete unit of an active agent (e.g., compound described herein) for administration to a subject. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, the unit dosage form contains the entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, it is necessary or expected that multiple unit dosage forms will need to be administered to achieve the desired effect. The unit dosage form can, for example, be a liquid pharmaceutical composition containing a predetermined amount of one or more active agents, a solid pharmaceutical composition (e.g., tablets, capsules, 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, etc.

[0479] Provided compositions can be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or condition described herein.

[0480] use

[0481] The present disclosure provides the uses of the compounds and compositions set forth herein. In some embodiments, the compounds and compositions provided can be used in medicine (e.g., as therapy). In some embodiments, the compounds and compositions provided can be used as analytical tools and / or control compounds in, for example, bioassays in research.

[0482] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with JAK2.

[0483] In some embodiments, the compounds provided are useful as JAK2 inhibitors. In some embodiments, the compounds provided are useful as type II JAK2 inhibitors. In some embodiments, the present disclosure provides methods for inhibiting JAK2 in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods for inhibiting JAK2 in a biological sample comprising contacting the sample with a provided compound or composition.

[0484] JAK (e.g., JAK2) is associated with a variety of 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). Therefore, in some embodiments, the present disclosure provides a method for treating a disease, disorder, or condition associated with JAK2 in a subject in need thereof, comprising administering to the subject a compound or composition provided. In some embodiments, the disease, disorder, or condition is associated with overexpression of JAK2.

[0485] 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.

[0486] In some embodiments, present disclosure provides a method for treating hematological malignancies, which includes applying provided compound or composition to a subject in need. In some embodiments, hematological malignancies are leukemias (such as chronic lymphocytic leukemia, acute lymphoblastic leukemia, T cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia or acute monocytic leukemia). In some embodiments, hematological malignancies are lymphomas (such as Burkitt's lymphoma, Hodgkin's lymphoma or non-Hodgkin's lymphoma). In some embodiments, non-Hodgkin's lymphoma is B cell lymphoma. In some embodiments, non-Hodgkin's lymphoma is NK / T cell lymphoma (such as cutaneous T cell lymphoma). In some embodiments, hematological malignancies are myeloma (such as multiple myeloma). In some embodiments, the hematological malignancy is a myeloproliferative neoplasm (eg, polycythemia vera, essential thrombocytopenia, or myelofibrosis). In some embodiments, the hematological malignancy is myelodysplastic syndrome.

[0487] In some embodiments, the present disclosure provides methods of treating inflammatory diseases, disorders, or conditions, such as acute respiratory syndrome, hyperinflammatory and / or cytokine storm syndrome (including those associated with COVID-19), or atopic dermatitis, comprising administering to a subject in need thereof a provided compound or composition.

[0488] In some embodiments, the compound or composition provided is administered as part of a combination therapy. As used herein, the term "combination therapy" refers to those situations in which a subject is exposed to two or more treatment or prevention regimens (e.g., two or more therapeutic agents or preventive agents) simultaneously. In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "dosages" of the first regimen are administered before any dose of the second regimen); in some embodiments, such agents are administered with overlapping dosing regimens. In some embodiments, the "administration" of the combination therapy may involve administering one or more agents or medication procedures to subjects receiving other agents or medication procedures in the combination. For clarity, combination therapy does not require that individual agents be administered together with a single composition (or even must be administered simultaneously), but in some embodiments, two or more agents or their active parts may be administered together with a combination composition.

[0489] For example, in some embodiments, provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., anticancer therapy and / or therapy to address one or more side effects of this anticancer therapy, or otherwise providing palliative care). Exemplary additional therapies include BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib), 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 showed good efficacy in a mouse model of myeloproliferative neoplasms (Jutzi, JS et al., HemaSphere 2018, 2(3), http: / / dx.doi.org / 10.1097 / HS9.00000000000000054). It has been shown that CXCR2 activity regulates signaling pathways involved in tumor growth, angiogenesis and / or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl 4), S616-S628).

[0490] Exemplary embodiments

[0491] The following numbered embodiments, while not limiting, illustrate certain aspects of the present disclosure:

[0492] 1. A compound of formula I:

[0493]

[0494] or a pharmaceutically acceptable salt thereof, wherein:

[0495] X is -C(R 6 )2-or-N(R 7 )-;

[0496] Each Y is -C(R 4 )2-;

[0497] Each Z is -C(R 5 )2-;

[0498] n is 0, 1, or 2;

[0499] m is 0, 1, or 2,

[0500] Provided that at least one of n and m is 1 or 2;

[0501] Each R 1 、R 2 、R 3 、R 4 and R 5 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 aliphatic group, and / or

[0502] Two R's 1 Group and / or two R 2 Group and / or two R 4 Group and / or two R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring, and / or

[0503] Two R's 1 Group and / or two R 2 Group and / or two R 4 Group and / or two R 5 The group, together with the atom to which it is attached, forms an oxo group, and / or

[0504] 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 group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0505] Each R 6 are independently hydrogen or optionally substituted C 1-6an aliphatic group, or

[0506] Two R's 6 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0507] R 7 is hydrogen or optionally substituted C 1-6 aliphatic groups;

[0508] Ring A is an optionally substituted group selected from the group consisting of phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0509] Ring B is an optionally substituted group selected from the group consisting of a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 10- to 16-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0510] L is a covalent bond or a divalent C 1-3 straight or branched hydrocarbon chain;

[0511] R 8 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 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- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0512] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0513] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0514] When valence permits, p is 0, 1, 2, 3, 4, or 5;

[0515] When valence permits, q is 0, 1, 2, 3, 4, or 5;

[0516] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 Aliphatic group, C 3-7 cycloaliphatic, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, a phenyl group, and a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0517] 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; and

[0518] Each R' is independently an optionally substituted 1-6 Aliphatic group and C 3-7 Cycloaliphatic groups.

[0519] 2. The compound according to embodiment 1, wherein ring B is an optionally substituted group selected from the following: a 5-membered to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8-membered to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0520] 3. The compound according to embodiment 1 or 2, wherein part for in:

[0521] W is CH, CR w or N;

[0522] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0523] Two R's w The group and the atoms to which it is attached form a group consisting of q R b a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group; and

[0524] r is 0, 1, 2 or 3.

[0525] 4. The compound according to embodiment 3, wherein W is CH.

[0526] 5. The compound according to embodiment 3, wherein W is N.

[0527] 6. The compound of any one of embodiments 1-5, wherein r is 1.

[0528] 7. The compound according to embodiment 6, wherein R w are independently -N(R)C(O)R' or -N(R)C(O)N(R)2.

[0529] 8. The compound of any one of embodiments 1-5, wherein r is 2.

[0530] 9. The compound according to embodiment 8, wherein two R w The group and the atoms to which it is attached form a group consisting of q R b A 5- to 6-membered partially unsaturated or aromatic ring substituted with a radical.

[0531] 10. The compound according to embodiment 9, wherein each R b are independently halogen, -N(R)2, optionally substituted C 1-6 aliphatic or optionally substituted C 3-6 Cycloaliphatic group.

[0532] 11. The compound of any one of embodiments 1-10, wherein the compound is not:

[0533]

[0534]

[0535] 12. The compound according to embodiment 1 or 2, wherein part for in:

[0536] Ring B1 is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur,

[0537] wherein Ring B1 is optionally fused to Ring B2; and

[0538] Ring B2, when present, is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0539] 13. The compound according to embodiment 12, wherein Ring B1 is a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0540] 14. The compound according to embodiment 13, wherein Ring B1 is a 5-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0541] 15. The compound according to embodiment 13, wherein Ring B1 is a 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0542] 16. The compound of any one of embodiments 12-15, wherein Ring B1 is fused to Ring B2.

[0543] 17. The compound of any one of embodiments 12-16, wherein Ring B2 is a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0544] 18. The compound of any one of embodiments 12-15, wherein Ring B1 is not fused to Ring B2.

[0545] 19. The compound of any one of embodiments 1-18, wherein the compound is not:

[0546]

[0547] 20. A compound as described in any one of embodiments 1-19, wherein part for:

[0548] (i) in:

[0549] W is CH, CR w or N;

[0550] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0551] Two R's w The group and the atoms to which it is attached form a group consisting of q R b a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group; and

[0552] r is 0, 1, 2 or 3; or

[0553] (ii) in:

[0554] Ring B1 is a 5-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur,

[0555] wherein Ring B1 is optionally fused to Ring B2; and

[0556] Ring B2, when present, is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0557] 21. A compound as described in any one of embodiments 1-20, wherein each R b are independently halogen, -OR, -N(R)2, -N(R)C(O)R', -N(R)C(O)N(R)2, optionally substituted C 1-6 aliphatic or optionally substituted C 3-6 Cycloaliphatic group.

[0558] 22. The compound of any one of embodiments 1-21, wherein q is 0 or 1.

[0559] 23. A compound as described in any one of embodiments 1-22, wherein X is -C(R 6 )2-.

[0560] 24. A compound as described in any one of embodiments 1-23, wherein each R 6 For hydrogen.

[0561] 25. A compound as described in any one of embodiments 1-23, wherein two R 6 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring.

[0562] 26. A compound as described in any one of embodiments 1-22, wherein X is -N(R 7 )-.

[0563] 27. A compound as described in any one of embodiments 1-22 and 26, wherein R 7 is optionally substituted C 1-6 Aliphatic group.

[0564] 28. The compound according to embodiment 27, wherein R 7 C 1-6 alkyl.

[0565] 29. The compound of any one of embodiments 1-28, wherein n is 1.

[0566] 30. The compound of any one of embodiments 1-29, wherein m is 1.

[0567] 31. A compound as described in any one of embodiments 1-30, wherein each R 1 、R 2 、R 3 、R 4 and R 5 are independently hydrogen, halogen, -CN or optionally substituted C 1-6 Aliphatic group.

[0568] 32. The compound of embodiment 31, wherein 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 Aliphatic group.

[0569] 33. The compound of embodiment 32, wherein each R 1 、R 2 、R 3 、R 4 and R 5 For hydrogen.

[0570] 34. The compound of any one of embodiments 1-30, wherein one of the following occurs:

[0571] (i) Two Rs 1 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0572] (ii) Two Rs 2 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0573] (iii) Two Rs 4 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring; and

[0574] (iv) Two Rs 5 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring.

[0575] 35. The compound of any one of embodiments 1-30 and 34, wherein one of the following occurs:

[0576] (i) Two Rs 1 The group, together with the atom to which it is attached, combines to form an oxo group;

[0577] (ii) Two Rs 2 The group, together with the atom to which it is attached, combines to form an oxo group;

[0578] (iii) Two Rs 4 The group, taken together with the atom to which it is attached, forms an oxo group; and

[0579] (iv) Two Rs 5 The group, together with the atom to which it is attached, forms an oxo group.

[0580] 36. The compound of any one of embodiments 1-30 and 34-35, wherein one of the following occurs:

[0581] (i)R 1 and R 2 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0582] (ii)R 1 and R 3 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0583] (iii)R 1 and R 4 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0584] (iv)R 1 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0585] (v)R 2 and R 3 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0586] (vi)R 2 and R 4 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0587] (vii)R 2 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0588] (viii)R 3 and R 4 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0589] (ix)R 3 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0590] (x)R 3 and R 6 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring;

[0591] (xi)R 3 and R 7 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring; and

[0592] (xii)R 4 and R 5 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring.

[0593] 37. The compound of any one of embodiments 1-36, wherein ring A is phenyl or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0594] 38. The compound of embodiment 37, wherein ring A is phenyl.

[0595] 39. The compound as described in embodiment 37, wherein ring A is a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0596] 40. The compound of any one of embodiments 1-39, wherein L is a covalent bond.

[0597] 41. A compound as described in any of embodiments 1-39, wherein L is -CH2-.

[0598] 42. A compound as described in any one of embodiments 1-41, wherein R 8 is halogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 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- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0599] 43. The compound according to embodiment 42, wherein R 8 is optionally substituted C 1-6 an aliphatic group or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0600] 44. A compound as described in any one of embodiments 1-43, wherein each R a are independently halogen, -CN, -OR, -O(CH2) 1-4 R, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic or an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0601] 45. The compound of embodiment 44, wherein each R a is optionally substituted C 1-6 Aliphatic group.

[0602] 46. ​​The compound of embodiment 45, wherein each R a is C optionally substituted by one or more halogens (eg, fluorine) 1-6 alkyl.

[0603] 47. The compound of any one of embodiments 1-46, wherein p is 0 or 1.

[0604] 48. A compound as described in any one of embodiments 1-47, wherein part Selected from:

[0605] 49. A compound as described in any one of embodiments 1-48, wherein R a and At least one of them is C 1-4 Halogenated alkyl.

[0606] 50. The compound of any one of embodiments 1-49, wherein the compound is not:

[0607]

[0608]

[0609] 51. A compound as described in any one of embodiments 1-50, wherein when R 8 When it is hydrogen, p is not 0.

[0610] 52. The compound of any one of embodiments 1-51, wherein the compound is of formula IA:

[0611]

[0612] or a pharmaceutically acceptable salt thereof.

[0613] 53. The compound of any one of embodiments 1-51, wherein the compound is of formula IB:

[0614]

[0615] or a pharmaceutically acceptable salt thereof.

[0616] 54. The compound of any one of embodiments 1-51, wherein the compound is of formula IC:

[0617]

[0618] or a pharmaceutically acceptable salt thereof.

[0619] 55. The compound of any one of embodiments 1-51, wherein the compound is of formula ID:

[0620]

[0621] or a pharmaceutically acceptable salt thereof.

[0622] 56. The compound of any one of embodiments 1-55, wherein the compound is of formula II:

[0623]

[0624] or a pharmaceutically acceptable salt thereof, wherein:

[0625] Ring B1 is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur,

[0626] wherein Ring B1 is optionally fused to Ring B2; and

[0627] Ring B2, when present, is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur,

[0628] wherein at least one of Ring B1 and Ring B2 is aromatic; and

[0629] At least one of ring B1 and ring B2 contains a heteroatom.

[0630] 57. The compound of any one of embodiments 1-55, wherein the compound is of formula III:

[0631]

[0632] or a pharmaceutically acceptable salt thereof, wherein:

[0633] W is CH, CR w or N;

[0634] 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or

[0635] Two R's w The group and the atoms to which it is attached form a group consisting of 0-4 R b a 5- to 6-membered partially unsaturated or aromatic ring substituted with a group; and

[0636] r is 0, 1, 2 or 3.

[0637] 58. The compound of any one of embodiments 1-57, wherein the compound is of formula IV:

[0638]

[0639] or a pharmaceutically acceptable salt thereof.

[0640] 59. The compound of any one of embodiments 1-57, wherein the compound is of formula V:

[0641]

[0642] or a pharmaceutically acceptable salt thereof.

[0643] 60. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0644] 61. A pharmaceutical composition comprising the compound according to any one of the preceding embodiments or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0645] 62. A method of inhibiting JAK2 in a subject, the method comprising administering a compound of any one of embodiments 1-60 or a composition of embodiment 61.

[0646] 63. A method of treating a disease, condition, or disorder 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.

[0647] 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.

[0648] 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.

[0649] 66. The method of embodiment 65, wherein the hematological malignancy is a leukemia or a lymphoma.

[0650] 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.

[0651] 68. The method of embodiment 67, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis.

[0652] Example

[0653] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods illustrate the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to those skilled in the art are applicable to all compounds as described herein and their respective subclasses and species.

[0654] Chiral HPLC and SFC methods

[0655] The following exemplary chiral HPLC and SFC methods were used to synthesize the provided compounds, as indicated below:

[0656] Method A: Column: CHIRALCEL OX-H (250 mm*20 mm, 5 μm); Mobile phase: (A) liquid CO2, (B) 0.1% diethylamine (DEA) in propan-2-ol:methanol (50:50); Flow rate: 80 mL / min.

[0657] Method B: Column: CHIRALCEL OJ-H (250 mm*21 mm, 5 μm); Mobile phase: (A) liquid CO 2 , (B) 0.1% DEA in propan-2-ol:MeCN (50:50); Flow rate: 80 mL / min.

[0658] Method C: Column: CHIRALPAK IG (250 mm*21 mm, 5 μm); Mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in propan-2-ol:MeCN (70:30); Flow rate: 20 mL / min.

[0659] Method D: Column: CHIRALCEL IC (250 mm*21 mm, 5 μm); Mobile phase: (A) liquid CO 2 , (B) 0.1% DEA in propan-2-ol:MeCN (50:50); Flow rate: 80 mL / min.

[0660] Method E: Column: CHIRALPAK IC (250 mm*21 mm, 5 μm); Mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in propan-2-ol:MeCN (70:30); Flow rate: 20 mL / min.

[0661] Method F: Column: CHIRALPAK IG (250 mm*21 mm, 5 μm); Mobile phase: (A) liquid CO 2 , (B) 0.1% DEA in propan-2-ol:MeCN (50:50); Flow rate: 80 mL / min.

[0662] Method G: Column: CHIRALPAK IH (250 mm*21 mm, 5 μm); Mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in propan-2-ol:MeCN (50:50); Flow rate: 20 mL / min.

[0663] Method H: Column: CHIRALPAK AD-H (250 mm*21 mm, 5 μm); Mobile phase: (A) liquid CO 2 , (B) 0.1% DEA in propan-2-ol:MeCN (50:50); Flow rate: 80 mL / min.

[0664] Method I: Column: CHIRALPAK IH (250 mm*21 mm, 5 μm); Mobile phase: (A) liquid CO2, (B) 0.1% DEA in propan-2-ol:MeCN (50:50); Flow rate: 80 mL / min

[0665] Method J: CHIRALPAK IB-N (250 mm*21 mm, 5 μm); mobile phase: (A) liquid CO 2 , (B) 0.1% DEA in propan-2-ol:MeCN (50:50); flow rate: 80 mL min .

[0666] Method K: CHIRALPAK IB-N (250 mm*21 mm, 5 μm); mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in propan-2-ol:MeCN (70:30); flow rate: 20 mL / min.

[0667] Method L: Column: CHIRALCEL OX-H (250 mm*20 mm, 5 μm); Mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in propan-2-ol:MeCN (70:30); Flow rate: 20 mL / min.

[0668] Method M: Column: CHIRALPAK AD-H (250 mm*21 mm, 5 μm); Mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in propan-2-ol:MeCN (50:50); Flow rate: 20 mL / min.

[0669] Preparation of intermediates

[0670] Preparation of intermediate H-1: 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

[0671]

[0672] Synthesis of compound H-1. To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1 g, 5 mmol, 1.0 equivalent) in DMF (10 mL) was added sodium hydride (0.728 g.15 mmol, 3 equivalents) at 0 ° C and stirred for 45 min. 2-(trimethylsilyl)ethoxychloromethane (1.25 g, 7.5 mmol, 1.5 equivalents) was added dropwise to the mixture and stirred at room temperature for 1 h. The reaction mixture was carefully quenched with cold 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 10% ethyl acetate in hexane to give H-1 (1 g, 60%). MS (ES): m / z 328.1 and 330.1 [M+H] + .

[0673] The following intermediates were prepared by following the procedure of H-1:

[0674]

[0675] Preparation of intermediate H-4: 2-bromo-6-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

[0676]

[0677] Synthesis of compound H-4.1. A mixture of 3,5-dibromopyrazine-2-amine (3.0 g, 11.86 mmol, 1.0 equivalent), triethylamine (4.95 mL, 35.35 mmol, 3.0 equivalent) and cuprous iodide (0.225 g, 1.185 mmol, 0.1 equivalent) in THF (60 mL) was degassed by bubbling with argon gas for 5 min. Bis(triphenylphosphine)palladium(II) chloride (0.866 g, 1.185 mmol, 0.1 equivalent) and ethynylcyclopropane (0.822 g, 12.45 mmol, 1.05 equivalent) were added and degassed with argon for another 5 min. The reaction mixture was stirred at room temperature for 3 h. The reaction 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 8% ethyl acetate in hexanes to afford H-4.1 (1.2 g, 42.5%). MS (ES): m / z 238.03 and 239.80 [M+H] + .

[0678] 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 h. It was poured into a 5N aqueous hydrochloric acid 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 20% ethyl acetate in hexanes to give H-4.2 (0.90 g, 75%). MS (ES): m / z 238.12 and 240.1 [M+H] + .

[0679] Synthesis of Compound H-4. Compound H-4 was prepared from H-4.2 following the procedure described in the synthesis of H-1. The product was purified by filtration using 7.7% ethyl acetate in hexane. MS (ES): m / z 368.20 and 369.5 [M+H] + .

[0680] Preparation of intermediate H-6: 2-bromo-7-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

[0681]

[0682] Synthesis of compound H-6.1. To a solution of 3,5-dibromopyrazine-2-amine (29g, 114.2mmol, 1.0 equivalent) in THF (100mL) was added bis(trimethylsilyl)amide lithium solution (1M in THF, 140mL, 142.0mmol, 1.2 equivalents) at room temperature and stirred for 2h. Allyl bromide (27.9g, 229.0mmol, 2.0 equivalents) was added dropwise to the solution and stirred for 16h. The reaction mixture was slowly quenched with aqueous ammonium chloride 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 2.0% ethyl acetate in hexanes to afford H-6.1 (18 g, 54%). MS (ES): m / z 293.91 and 295.91 [M+H] + .

[0683] Synthesis of compound H-6.2. A mixture of H-6.1 (6 g, 3.1 mmol, 1 equivalent), triethylamine (5.188 g, 42.8 mmol, 2.5 equivalents), sodium formate (0.279 g, 4.10 mmol, 0.2 equivalents), palladium (II) acetate (0.460 g, 2.0 mmol, 0.1 equivalents) and tetrabutylammonium bromide (0.992 g, 3.0 mmol, 0.15 equivalents) 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 11% ethyl acetate in hexanes to afford H-6.2 (0.620 g, 14%). MS (ES): m / z 212.03 and 214.03 [M+H] + .

[0684] Synthesis of Compound H-6. Compound H-6 was prepared from H-6.2 following the procedure described in the synthesis of H-1. The product was purified by HPLC with 10% ethyl acetate in hexane. MS (ES): m / z 342.2 and 344.24 [M+H] + .

[0685] Preparation of intermediate H-7: 2-bromo-6-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

[0686]

[0687] The synthesis of compound H-7.1. A mixture of 3,5-dibromopyrazine-2-amine (3g, 11.6mmol, 1.0 equivalent), triethylamine (1.43g, 14.24mmol, 1.2 equivalents), cuprous iodide (0.113g, 0.59mmol, 0.05 equivalents) and 1,1-bis(triphenylphosphine)palladium chloride (II) (0.417g, 0.59mmol, 0.05 equivalents) in THF (40mL) was degassed by argon gas flow through 10min. Trimethyl(prop-2-yn-1-yl)silane (1.6g, 14.24mmol, 1.2 equivalents) was added, and the reaction mixture was stirred at room temperature for 16h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 12% ethyl acetate in hexanes to give H-7.1 (3.0 g, 89%). MS (ES): m / z 284.16 and 286.16 [M+1] + .

[0688] 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 h. The reaction mixture was diluted with ethyl acetate, washed with water and then 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%). It was used in the next step without purification. MS (ES): m / z 212.13 and 214.13 [M + 1] + .

[0689] Synthesis of Compound H-7. Compound H-7 was prepared from H-7.2 following the procedure described in the synthesis of H-1. The product was purified by silica gel flash column chromatography ( The product was purified by 10% ethyl acetate in hexane. MS (ES): m / z 342.07 and 344.07 [M+1] + .

[0690] Preparation of intermediate H-8: 6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine

[0691]

[0692] 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 h. Concentrated under reduced pressure. The product was purified by silica gel flash column chromatography ( The residue was purified with 15% ethyl acetate in hexanes to give H-8.1 (2.74 g, 87%). MS (ES): m / z 198.03 and 200.02 [M+H] + .

[0693] Synthesis of Compound H-8. Compound H-8 was prepared from H-8.1 following the procedure described in the synthesis of H-1. The product was purified by 6.0% ethyl acetate in hexanes. MS (ES): m / z 328.1 and 330.1 [M+H] + .

[0694] Preparation of intermediate H-9: 2-bromo-7-fluoro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

[0695]

[0696] Synthesis of compound H-9.1 To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (3.5 g, 17.67 mmol, 1.0 equivalent) in acetonitrile (40 mL) and acetic acid (15 mL) was added Selectfluor (6.2 g, 17.67 mmol, 1.0 equivalent) dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h and at 80 ° C for 8 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 25% ethyl acetate in hexanes to give H-9.1 (1.0 g, 26%). MS (ES): m / z [M+H] + .

[0697] Synthesis of compound H-9. Compound H-9 was prepared from H-9.1 following the procedure described for the synthesis of H-1. The product was used without purification. MS (ES): m / z [M+H] + .

[0698] Preparation of intermediate H-10: 2-bromo-7-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

[0699]

[0700] 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 equivalent) in DMF (40 mL) was added N-iodosuccinimide (4.43 g, 19.69 mmol, 1.5 equivalents) in small portions at 0 ° C. The reaction mixture was stirred at 25 ° C for 16 h. It was transferred to 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] + .

[0701] Synthesis of compound H-10.2. To a solution of H-10.1 (3.0 g, 9.25 mmol, 1.0 equiv) in DMF (30 mL) cooled to 0 ° C. was added sodium hydride (60 wt% in mineral oil, 0.399 g, 27.75 mmol, 3.0 equiv). The mixture was stirred for 30 min. 2-(Trimethylsilyl)ethoxychloromethane (1.6 mL, 13.87 mmol, 1.5 equiv) was added and stirred at room temperature for 1 h. It 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] + .

[0702] Synthesis of compound H-10. A mixture of H-10.2 (2.8 g, 6.18 mmol, 1.0 equivalent), cyclopropylboronic acid (2.6 g, 30.90 mmol, 5.0 equivalent) and cesium carbonate (6.0 g, 18.54 mmol, 3.0 equivalent) in acetonitrile (30 mL) was degassed by bubbling with argon gas for 10 min. [1,1'-bis(diphenylphosphino)ferrocene] palladium (II) chloride (0.451 g, 0.618 mmol, 0.1 equivalent) was added and degassed for 5 min. The reaction mixture was stirred at 90 ° C for 2 h. It was cooled to room temperature, transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 12% ethyl acetate in hexanes to give H-10 (0.7 g, 58.33%). MS (ES): m / z 368.14 and 370.16 [M+H] + .

[0703] Preparation of intermediate H-11: 5-bromo-N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-amine

[0704]

[0705] Synthesis of compound H-11.1. To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-amine (0.8g, 3.75mmol, 1.0 equivalent) in THF (20mL) was added formaldehyde (3.3g, 112.6mmol, 30 equivalents) and acetic acid (0.29mL, 4.87mmol, 1.3 equivalents). The reaction mixture was stirred at 0°C for 15min, and sodium cyanoborohydride (0.801g, 12.75mmol, 3.4 equivalents) was added. It was stirred at room temperature for 16h, transferred to a 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 4.0% methanol in DCM to give H-11.1 (0.5 g, 56%). MS (ES): m / z: 241.18 and 243.20 [M+H] + .

[0706] Synthesis of Compound H-11. Compound H-11 was prepared from H-11.1 following the procedure described in the synthesis of H-1. The product was purified by silica gel flash column chromatography ( The product was purified by filtration using 3.1% methanol in DCM. MS (ES): m / z 371.29 and 373.29 [M+H] - .

[0707] Preparation of intermediate H-13: 5-bromo-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine

[0708]

[0709] Synthesis of compound H-13.1. To a solution of methyl 5-bromo-2-chloronicotinate (5.0 g, 19.96 mmol, 1.0 equivalent) in ethanol (80 mL) was added hydrazine hydrate (7.0 g, 139.73 mmol, 7.0 equivalents), and the reaction mixture was stirred at 80 ° C for 16 h. It was allowed to cool 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] + .

[0710] 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 h. 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 silica gel flash column chromatography (45% ethyl acetate in hexane) to give H-13.2 (1.30 g, 40%). MS (ES): m / z 333.16 and 335.1 [M + H] + .

[0711] Synthesis of compound H-13. To a solution of H-13.2 (1.3 g, 3.89 mmol, 1 eq.) in DMF (12 mL) was added sodium hydride (60%, 0.186 g, 4.67 mmol, 1.20 eq.) at 0 ° C. The mixture was stirred at 0 ° C. for 10 min, followed by the addition of iodomethane (0.662 g, 4.67 mmol, 1.20 eq.). It was stirred for 1.5 h, 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 40% ethyl acetate in hexanes to give H-13 (0.78 g, 58%). MS (ES): m / z: 348.12 and 350.12 [M+H] + .

[0712] Preparation of intermediate H-15: 2-bromo-6-(methoxymethyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

[0713]

[0714] Synthesis of compound H-15.1. To a solution of H-7 (1.8 g, 5.26 mmol, 1.0 eq.) in 1,4-dioxane (20 mL) was added selenium dioxide (0.727 g, 55.55 mmol, 4.0 eq.) in portions at 0°C. The reaction mixture was stirred at 130°C for 16 h. The mixture was filtered through a pad of Celite® and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and purified by flash column chromatography on silica gel ( The residue was purified with 25% ethyl acetate in hexanes to give H-15.1 (1.2 g, 64%), MS (ES): m / z 357.1 and 359.1 [M+H] + .

[0715] 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 several portions at 0 ° C. The reaction mixture was stirred at room temperature for 6 h. The mixture was quenched with saturated ammonium chloride 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 30% ethyl acetate in hexanes to give H-15.2 (0.80 g, 66%). MS (ES): m / z 359.15 and 361.1 [M+H] + .

[0716] Synthesis of compound H-15. To a solution of H-15.2 (0.800 g, 2.23 mmol, 1.0 equivalent) in THF (10 mL) was added sodium hydride (0.065 g, 3.35 mmol, 1.5 equivalents) at 0 ° C. and stirred at 0 ° C. for 15 min. Iodomethane (0.4 mL, 6.69 mmol, 3.0 equivalents) was added to the mixture, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched with saturated ammonium chloride 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 15% ethyl acetate in hexanes to give H-14 (0.50 g, 60.24%). MS (ES): m / z 374.12 and 376.12 [M+H] + .

[0717] 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

[0718]

[0719] Synthesis of compound H-16.1. To 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (10 g, 46.29 mmol, 1.0 equivalent) was added thionyl chloride (100 mL) and a catalytic amount of DMF (0.5 mL) at 0 ° C. The reaction mixture was stirred at 80 ° C for 16 h. It was concentrated and azeotroped with toluene, and the resulting acid chloride was dissolved in DCM (100 mL). It was cooled to 0 ° C, and a mixture of methylhydrazine (2.4 mL, 46.29 mmol, 1.0 equivalent), sodium hydroxide (7.4 g, 185 mmol, 4.0 equivalent) and water (15 mL) was added. The reaction mixture was stirred at 80 ° C for 30 min. The mixture was diluted with 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 5.0% methanol in DCM to afford H-16.1 (3.0 g, 25%). MS (ES): m / z 264.3 and 266.3 [M+H] + .

[0720] Synthesis of compound H-16.2. To a stirred solution of compound H-16.1 (3.0 g, 11.36 mmol, 1 equivalent) in 1-pentanol (30 mL) was added sodium carbonate (1.2 g, 11.36 mmol, 1.0 equivalent). The reaction mixture was stirred at 140 ° C for 48 h under argon. It was allowed to cool 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] + .

[0721] Synthesis of Compound H-16. Compound H-16 was prepared from H-16.2 following the procedure described in the synthesis of H-1. The product was purified by silica gel flash column chromatography ( The product was purified by HPLC with 3.0% methanol in DCM. MS (ES): m / z 358.1 and 360.1 [M+H] - .

[0722] Preparation of intermediate H-17: N-(3-bromopyrazolo[1,5-a]pyrazin-6-yl)-N-methylcyclopropanecarboxamide

[0723]

[0724] Synthesis of compound H-17.1. To a solution of 2-bromopyrazine (432.0 g, 2720 mmol, 1.0 equivalent) in DCM (5180 mL) was added O-(mesitylenesulfonyl)hydroxylamine (701.9 g, 3260 mmol, 1.2 equivalents) at 0 ° C. The reaction mixture was stirred at room temperature for 1 h. It was transferred to diethyl ether. The precipitated solid was collected by filtration and dried under vacuum. Trimethylamine (372.2 g, 3685 mmol, 2.0 equivalents) was added to a solution of the solid in DMF (2160 mL), followed by ethyl propiolate (361.16 g, 3685 mmol, 2.0 equivalents) at 0 ° C. The reaction mixture was stirred at room temperature for 48 h. It was transferred to brine and extracted with ethyl acetate. The combined organic layer was washed with an 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 in hexanes) to afford H-17.1 (20 g, 2.7%). MS (ES): m / z 270.1 and 272.1 [M+H] + .

[0725] Synthesis of compound H-17.2. A mixture of H-17.1 (1.5 g, 4.95 mmol, 1.0 equivalent), N-methylcyclopropanecarboxamide (1.3 g, 14.85 mmol, 3.0 equivalent) and cesium carbonate (4.8 g, 14.85 mmol, 3.0 equivalent) in 1,4-dioxane (10 mL) was degassed by bubbling with argon gas for 10 min. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.572 g, 0.99 mmol, 0.2 equivalent) and tris(dibenzylideneacetone)dipalladium(0) (0.452 g, 0.495 mmol, 0.1 equivalent) were added and degassed for 5 min. The reaction mixture was stirred at 110 ° C for 1 h. It was cooled to room temperature, transferred to 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 with 3.1% methanol in DCM to give J-17.2 (0.75 g, 54%). MS (ES): m / z: 289.12 [M+H] + .

[0726] Synthesis of compound H-17.3. To a solution of H-17.2 (0.75 g, 2.59 mmol, 1.0 equivalent) 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 equivalents) in several portions. The reaction mixture was stirred at room temperature for 1 h. The mixture was extracted with ethyl acetate. The aqueous layer was separated, adjusted to pH 2 using 1.5N 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] + .

[0727] Synthesis of compound H-17. To a solution of H-17.3 (0.50 g, 1.92 mmol, 1.0 equivalent) in DMF (3.0 mL) was added sodium bicarbonate (0.482 g, 5.74 mmol, 3.0 equivalents) and N-bromosuccinimide (0.375 g, 2.11 mmol, 1.1 equivalents), and the mixture was stirred at room temperature for 6 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 30% ethyl acetate in hexanes to give H-17 (0.28 g, 49%). MS (ES): m / z 295.01 [M+H] + .

[0728] Preparation of intermediate H-18: 5-bromo-3-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine

[0729]

[0730] Synthesis of compound H-18.1. To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (5.0 g, 22.22 mmol, 1.0 equivalent) in THF (100 mL) was added triethylamine (3.5 mL, 24.44 mmol, 1.1 equivalent) and p-toluenesulfonyl chloride (4.2 g, 22.22 mmol, 1.0 equivalent). The mixture was stirred at room temperature for 12 h. 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] + .

[0731] Synthesis of compound H-18.2. To a solution of H-18.1 (3.2 g, 8.42 mmol, 1.0 equivalent) in DCM (50 mL) was added 3-chloroperoxybenzoic acid (3.1 g, 18.52 mmol, 2.2 equivalents) in portions over a period of 30 min at 0 ° C. The mixture was stirred at room temperature for 2 h, and 10% aqueous sodium sulfite solution and saturated aqueous sodium bicarbonate solution were added and stirred for 6 h. It was diluted with DCM, and the solid was 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 in hexane) to give H-18.2 (0.395 g, 13%). MS (ES): m / z 367.1 and 369.1 [M + H] + .

[0732] Synthesis of compound H-18. To a solution of H-18.2 (0.395 g, 1.07 mmol, 1.0 equivalent) in methanol (15 mL) and THF (15 mL) was added (trimethylsilyl) diazomethane (2.1 mL, 4.28 mmol, 4.0 equivalent) at 0 ° C. The reaction mixture was stirred at room temperature for 4 h. Another portion of (trimethylsilyl) diazomethane (2.1 mL, 4.28 mmol, 4.0 equivalent) was added dropwise and stirred for 12 h. It was quenched with acetic acid (0.006 mL, 0.107 mmol, 0.1 equivalent), 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] + .

[0733] Preparation of intermediate H-19: 5-bromo-N-methyl-1H-pyrazolo[3,4-b]pyridin-3-amine

[0734]

[0735] Synthesis of compound H-19.1. Thionyl chloride (500 mL) and a catalytic amount of DMF (4.0 mL) were added to compound 5-bromo-2-hydroxynicotinic acid (50 g, 229.35 mmol, 1.0 equivalent) at 0 ° C. The reaction mixture was stirred at 80 ° C for 16 h. It was concentrated and azeotroped with toluene. The resulting acid chloride was dissolved in DCM (500 mL) and cooled to 0 ° C, and a solution of methylamine in methanol (8.02 g, 229.35 mmol, 1.0 equivalent), sodium hydroxide (37.0 g, 917.41 mmol, 4.0 equivalent) and water (150 mL) were added. The reaction mixture was stirred at 80 ° C for 30 min. The mixture was diluted with 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 5.0% methanol in DCM to give H-19.1 (32.0 g, 56%). MS (ES): m / z 249.6 and 251.6 [M+H] + .

[0736] 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) was added Lawesson's reagent (207 g, 256.52 mmol, 2.0 equiv) and stirred at 40 ° C for 24 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 29% ethyl acetate in hexanes to give H-19.2 (16.3 g, 48%). MS (ES): m / z 265.2 and 267.2 [M+H] + .

[0737] Synthesis of compound H-19.3. To a solution of H-19.2 (16.3 g, 61.38 mmol, 1.0 equivalent) in dimethyl sulfoxide (200 mL) was added hydrazine hydrate (9.2 g 184 mmol, 3.0 equivalent) and stirred at 80 ° C for 24 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 50% ethyl acetate in hexanes to give H-19.3 (8.6 g, 62%). MS (ES): m / z 227.1 and 229.1 [M+H] + .

[0738] Synthesis of compound H-19. To a solution of H-19.3 (0.68 g, 2.99 mmol, 1.0 equivalent), triethylamine (0.90 g, 8.98 mmol, 3.0 equivalent) and 4-dimethylaminopyridine (0.72 g, 5.98 mmol, 3.0 equivalent) in DCM (8.0 mL) was added di-tert-butyl dicarbonate (1.95 g, 8.98 mmol, 3.0 equivalent) and stirred at room temperature for 24 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 20% ethyl acetate in hexanes to give H-19 (0.32 g, 25%). MS (ES): m / z 427.2 and 429.2 [M+H] + .

[0739] Preparation of intermediate H-20: 6-bromo-1,3-bis(4-methoxybenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[0740]

[0741] 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 equivalent) in DMF (10 mL) was added sodium hydride (60% in mineral oil) (0.441 g, 10.28 mmol, 2.2 equivalents) in several portions at 0 ° C and stirred for 15 min. 4-methoxybenzyl chloride (1.6 g, 10.28 mmol, 2.2 equivalents) was added and stirred at room temperature for 2 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 40% ethyl acetate in hexanes to give H-20 (0.80 g, 38%). MS (ES): m / z 454.3 and 456.11 [M+H] + .

[0742] Preparation of intermediate H-21: 5-bromo-1-(4-methoxybenzyl)-3-(oxetan-3-yloxy)-1H-pyrazolo[3,4-b]pyridine

[0743]

[0744] Synthesis of compound H-21. To a solution of H-13.2 (1.0 g, 2.99 mmol, 1.0 equivalent) in DMF (10 mL) was added sodium hydride (0.129 g, 8.97 mmol, 3.0 equivalents) at 0 ° C. The mixture was stirred for 30 min, and 3-iodooxetane (0.658 g, 3.58 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at 100 ° C for 2 h. It was transferred to 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-21 (0.659 g, 56%). MS (ES): m / z 390.03 and 392.01 [M + H] + .

[0745] Preparation of intermediate H-22: (R)-3-((1,4-dioxan-2-yl)methoxy)-5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine

[0746]

[0747] Synthesis of compound H-22.1. To a solution of (S)-(1,4-dioxane-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) was added methanesulfonyl chloride (0.5 mL, 6.60 mmol, 1.3 equiv) at 0 ° C., and the reaction mixture was stirred at room temperature for 6 h. It was transferred to 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] + .

[0748] Synthesis of compound H-22. To a solution of H-13.2 (0.70 g, 2.08 mmol, 1.0 equivalent) in DMF (3.0 mL) was added sodium hydride (0.089 g, 6.24 mmol, 3.0 equivalents) at 0 ° C. The mixture was stirred for 30 min, and H-22.1 (0.491 g, 2.50 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at 60 ° C for 2 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 3.0% methanol in DCM to give H-22 (0.50 g, 55%). MS (ES): m / z 434.1 and 436.04 [M+H] +.

[0749] Preparation of intermediate H-22: 5-bromo-1-(4-methoxybenzyl)-3-(2-methoxyethoxy)-1H-pyrazolo[3,4-b]pyridine

[0750]

[0751] Synthesis of compound H-23. To a solution of H-13.2 (1.0 g, 2.99 mmol, 1.0 equivalent) in DMF (10.0 mL) was added sodium hydride (60% in mineral oil) (0.141 g, 3.59 mmol, 1.2 equivalents) at 0 ° C. and stirred for 15 min. 1-bromo-2-methoxyethane (0.49 g, 3.59 mmol, 1.2 equivalents) was added and stirred at room temperature for 2 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 40% ethyl acetate in hexanes to give H-23 (0.620 g, 53%). MS (ES): m / z 392.16 and 394.17 [M+H] + .

[0752] Preparation of intermediate H-24: 5-bromo-1-(4-methoxybenzyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazolo[3,4-b]pyridine

[0753]

[0754] 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 min. The mixture was quenched with water (30 mL) and extracted with DCM (50 mL). The combined organic layers were 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] + .

[0755] 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) was added sodium hydride (0.129 g, 9.0 mmol, 3.0 equiv) at 0 ° C. The mixture was stirred for 30 min. H-24.1 (0.81 g, 4.50 mmol, 1.5 equiv) was added to the mixture, and the reaction mixture was stirred at room temperature for 2 h. It was transferred to 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-24 (0.48 g, 38%). MS (ES): m / z 418.20 and 420.20 [M + H] + .

[0756] 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

[0757]

[0758] Synthesis of compound H-25. Compound H-25 was prepared following the procedure described in the synthesis of H-16. MS (ES): m / z 428.2 and 430.2 [M+H] + .

[0759] 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

[0760]

[0761] Synthesis of compound H-26.1. To a solution of 3-(benzyloxy)cyclobutan-1-one (5.0 g, 28.40 mmol, 1.0 equivalent) in methanol (50 mL) was added sodium borohydride (1.29 g, 34.05 mmol, 1.2 equivalents) at 0 ° C. The resulting reaction mixture was stirred at room temperature for 0.5 h. The mixture was quenched with water (100 mL) and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the substance. The product was purified by flash column chromatography on silica gel ( The residue was purified with 28% ethyl acetate in hexanes to give H-26.1 (5.0 g, 99%). MS (ES): m / z 179.23 [M+H] + .

[0762] Synthesis of compound H-26.2. Methanesulfonyl chloride (4.5 mL, 58.35 mmol, 2.0 equivalents) was added to a solution of H-26.1 (5.0 g, 29.175 mmol, 1.0 equivalents) and triethylamine (16.2 mL, 116.7 mmol, 4.0 equivalents) in DCM (52 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM. The combined organic layer was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the substance. The product was then purified by flash column chromatography on silica gel ( This material was purified with 35% ethyl acetate in hexanes to afford H-26.2 (5.0 g, 63%). MS (ES): m / z 257.32 [M+H] - .

[0763] 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. Concentrated under reduced pressure to give H-26.3 (3.71 g, 99%). MS (ES) m / z 193.26 [M+H] + .

[0764] 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 equivalent) in DCM (40 mL) and DMF (1 mL) was added thionyl chloride (4 mL) at 0 ° C. The mixture was stirred at 40 ° C for 1 h. Concentrated under reduced pressure. The obtained acid chloride was dissolved in DCM (58 mL), and 1M sodium hydroxide solution (29 mL) and H-26.3 (3.7 g, 19.27 mmol, 1.0 equivalent) were added at 0 ° C. The mixture was stirred at 50 ° C for 15 min. The mixture was quenched with water (200 mL) and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel ( The residue was purified with 14% ethyl acetate in hexanes to give H-26.4 (1.8 g, 23%). MS (ES): m / z 411.70 [M+H] + .

[0765] Synthesis of compound H-26.5. A mixture of H-26.45 (1.8 g, 4.39 mmol, 1 eq.) and sodium carbonate (1.39 g, 13.17 mmol, 3 eq.) in 1-pentanol (18 mL) was stirred at 140 ° C. for 2 days. Concentrated under reduced pressure to give the substance. The product was purified by silica gel flash column chromatography ( The residue was purified with 52% ethyl acetate in hexanes to give H-26.5 (1.6 g, 98%). MS (ES): m / z 374.2 and 376.2 [M+H] + .

[0766] Synthesis of Compound H-26. Compound H-26 was prepared from H-26.5 following the procedure described in the synthesis of H-1. The product was purified by 30% ethyl acetate in hexane. MS (ES): m / z 504.3 and 505.2 [M+H] + .

[0767] 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

[0768]

[0769] Synthesis of Compound H-27.1. Compound H-27.1 was prepared from 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine following the procedure described for the synthesis of H-1. The product was purified by silica gel flash column chromatography ( The product was purified by 30% ethyl acetate in hexane. MS (ES): m / z 453.1 and 455.0 [M+H] + .

[0770] 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 a stream of argon through for 20 min. Tetrakis(triphenylphosphine)palladium(0) (0.073 g, 0.44 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 ° C for 2 h. The mixture was filtered through a pad of Celite® and rinsed with ethyl acetate. Water was added to the filtrate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel ( The residue was purified with 30% ethyl acetate in hexanes to give H-27 (1.68 g, 75%). MS (ES): m / z 509.2 and 511.2 [M+H] + .

[0771] Preparation of intermediate H-28: 4-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)morpholine

[0772]

[0773] Synthesis of compound H-28.1. Compound 2-bromo-5H-pyrrolo[2,3-b]pyrazine (2.0 g, 10.101 mmol, 1.0 equivalent) 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 h. The reaction mixture was poured into ice-water. A precipitate was formed and aged for 30 min. The precipitate was collected by filtration and 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] - .

[0774] 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) was added sodium hydride (60% in mineral oil) (0.394 g, 9.87 mmol, 1.5 equiv) in several portions at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min, and 2-(trimethylsilyl)ethoxychloromethane (1.206 g, 7.238 mmol, 1.1 equiv) was added. It was stirred at room temperature for 1 h, transferred to ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The product was purified by flash column chromatography on silica gel ( The residue was purified with 10% ethyl acetate in hexanes to give H-28.2 (1.2 g, 49%), MS (ES): m / z 373.2 and 375.2 [M+H] + .

[0775] Synthesis of compound H-28.3: A mixture of compound H-28.2 (1.2 g, 3.214 mmol, 1.0 eq), ethanol (28.8 mL), water (9.6 mL), ammonium chloride (0.859 g, 16.07 mmol, 5 eq) and iron powder (0.897 g, 16.07 mmol, 5 eq) was stirred at 80 °C for 90 min. The reaction mixture was filtered through a pad of Celite®. The filtrate was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 2.5% methanol in DCM to afford H-28.3 (0.795 g, 72%). MS (ES): m / z 343.1 and 345.1 [M+H] + .

[0776] Synthesis of compound H-28. To a solution of H-28.3 (0.795 g, 2.315 mmol, 1.0 equivalent) in acetonitrile (8 mL) was added potassium carbonate (0.966 g, 6.945 mmol, 3.0 equivalents), followed by 1-bromo-2-(2-bromoethoxy)ethane (0.536 g, 2.315 mmol, 1.0 equivalents). The reaction mixture was stirred at 150 ° C for 16 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 3.1% methanol in DCM to give H-28 (0.210 g, 22%). MS (ES): m / z 414.39 [M+H] + .

[0777] Preparation of intermediate trans-H-29: trans-6-(2-((tert-butyldiphenylsilyl)oxy)cyclobutyloxy)-3-iodopyrazolo[1,5-a]pyrazine

[0778]

[0779] 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 silica containing ferric chloride (0.050 g, 0.5% w / w). The reaction mixture was stirred at room temperature for 1.5 h. Concentrated under reduced pressure. The product was purified by silica gel flash column chromatography ( The residue was purified with 11% ethyl acetate in hexanes) to afford H-29. 1H NMR (CDCl3, 400MHz): δ5.02-5.00(m,1H), 2.88-2.78(m,2H), 2.49-2.43(m,1H), 1.93-1.88(m,1H).

[0780] Synthesis of compound H-29.2. To compound H-29.1 (2.2 g, 25.55 mmol, 1.0 equivalent) was added triethylamine (5.16 g, 51.1 mmol, 2.0 equivalent) and stirred at room temperature for 10 min, followed by addition of tert-butyldiphenylsilyl chloride (14.05 g, 51.1 mmol, 2.0 equivalent). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was poured onto brine 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 5% ethyl acetate in hexanes to afford H-29.2. MS (ES): m / z 325.6 [M+H] + .

[0781] Synthesis of compound 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 several portions at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min. It was poured onto ice-water, stirred 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 product was purified by flash column chromatography on silica gel ( The residue was purified by 8%-15% ethyl acetate in 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] + .

[0782] 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) was added sodium hydride (60% in mineral oil) (2.3 g, 159 mmol, 3.0 equiv) at 0 ° C., followed by 2-bromo-5-iodopyrazine (15 g, 53.0 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 1 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 30% ethyl acetate in hexanes to give trans-H-29.4 (13 g, 46%). MS (ES): m / z 531.2 [M+H] + .

[0783] Synthesis of compound trans-H-29.5. A mixture of trans-H-29.42 (13 g, 24.52 mmol, 1.0 equivalent) and N, N-diisopropylethylamine (10 mL, 73.58 mmol, 3.0 equivalent) in DMF (130 mL) was degassed by bubbling with argon gas for 10 min. Copper (I) iodide (0.232 g, 1.226 mmol, 0.05 equivalent) and bis (triphenylphosphine) palladium (II) dichloride (0.859 g, 1.226 mmol, 0.05 equivalent). The reaction mixture was degassed for 15 min, and ethynyltrimethylsilane (10 mL, 73.56 mmol, 3.0 equivalent) was added. It was stirred at 120 ° C for 16 h, 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 2.0% methanol in DCM to give trans-H-29.5 (9.0 g, 76%). MS (ES): m / z: 502.1 [M+H] + .

[0784] 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-(mesitylenesulfonyl)hydroxylamine (4.6 g, 21.55 mmol, 1.2 equiv) at 0 ° C. The reaction mixture was stirred at room temperature for 16 h. 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 transferred to 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 in hexane) to give trans-H-29.6 (1.3 g, 16%). MS (ES): m / z 444.19 [M + H] - .

[0785] Synthesis of compound trans-H-29. To a solution of trans-H-29.6 (1.3 g, 2.93 mmol, 1.0 equivalent) in acetonitrile (15 mL) was added N-iodosuccinimide (0.716 g, 1.25 mmol, 1.5 equivalents) at 0 ° C. The reaction mixture was stirred at room temperature for 6 h. Concentrated under reduced pressure. Water was added to the residue 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 10% ethyl acetate in hexanes to give trans-H-29 (0.84 g, 65%). MS (ES): m / z 570.10 [M+H] + .

[0786] Preparation of intermediate trans-H-31: N-(5-bromo-4-methoxypyridin-2-yl)cyclopropanecarboxamide

[0787]

[0788] Synthesis of compound H-31.1. To a solution of 4-methoxypyridine-2-amine (5.0 g, 40.32 mmol, 1.0 equivalent) in acetonitrile (200 mL) was added N-bromosuccinimide (7.17 g, 40.32 mmol, 1.0 equivalent) at 0 ° C. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum pressure to remove acetonitrile. The resulting residue was dissolved in DCM and washed with saturated bicarbonate solution. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel ( The residue was purified with 15% ethyl acetate in hexanes to give H-31.1 (3.1 g, 38%). MS (ES): m / z 204.04 [M+H] + .

[0789] Synthesis of compound H-31. To a solution of H-31.1 (1.6 g, 40.32 mmol, 1.0 equivalent) in acetonitrile (200 mL) was added cyclopropanecarbonyl chloride (1.639 g, 15.763 mmol, 2.0 equivalents) at 0 ° C., followed by triethylamine (7.17 g, 40.32 mmol, 1.0 equivalents) and 4-dimethylaminopyridine (0.009 g, 0.079 mmol, 0.01 equivalents). The mixture was stirred at room temperature for 1 h. It was poured onto 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 30% ethyl acetate in hexanes to give H-31 (1.0 g, 47%). MS (ES): m / z 272.11 [M+H] + .

[0790] Preparation of intermediate H-33: benzyl (2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)(methyl)carbamate

[0791]

[0792] 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) was added saturated aqueous sodium carbonate solution (20 mL) at 0 ° C and stirred for 10 min. To the mixture was added benzyl chloroformate (50% in toluene, 3.9 mL, 11.66 mmol, 2 equiv) at 0 ° C. The reaction mixture was stirred for 30 min. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 5% methanol in DCM to give H-31.1 (2.2 g, 79%). MS (ES): m / z 477.28 and 479.28 [M+H] + .

[0793] Synthesis of compound H-33. To a solution of compound H-33.1 (2.2 g, 4.61 mmol, 1.0 equivalent) in DMF (20 mL) was added sodium hydride (0.36 g, 9.2 mmol, 2 equivalents) at 0 ° C. and stirred for 30 min. Iodomethane (1.3 g, 9.2 mmol, 2 equivalents) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 30 min. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 22% ethyl acetate in hexanes to afford H-33 (1.9 g, 84%). MS (ES): m / z 491.46 and 493.4 [M+H] + .

[0794] Preparation of intermediate H-35: 5-bromo-3-(4-methylpiperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine

[0795]

[0796] Synthesis of compound H-35. A mixture of H-27.1 (2.0 g, 4.45 mmol, 1.0 equivalent), 1-methylpiperazine (0.663 g, 6.63 mmol, 1.5 equivalents), cesium carbonate (1.13 g, 13.27 mmol, 3.0 equivalents), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.767 g, 1.327 mmol, 0.3 equivalents) and tris(dibenzylideneacetone)dipalladium(0) (0.32 g, 0.88 mmol, 0.2 equivalents) in 1,4-dioxane (20 mL) was purged with argon for 10 min. The reaction mixture was stirred at 120 ° C for 2 h. It was transferred 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 1.8% methanol in DCM to afford H-35 (0.900 g, 50%). MS (ES): m / z 426.4 and 428.4 [M+H] + .

[0797] Preparation of intermediate H-36: 5-bromo-3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine

[0798]

[0799] Synthesis of compound H-36.1. To a solution of H-13 (2.0 g, 5.74 mmol, 1.0 equivalent) in DCM (30 mL) was added trifluoroacetic acid (5 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 3 h. The mixture was washed with saturated aqueous 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 1.8% methanol in DCM to afford H-36.1 (1.2 g, 92%). MS (ES): m / z 228.1 and 230.1 [M+H] + .

[0800] Synthesis of Compound H-36. Compound H-36 was prepared from H-36.1 following the procedure described in the synthesis of H-1. The product was purified by 18% ethyl acetate in hexane. MS (ES): m / z 358.21 and 360.2 [M+H] + .

[0801] Preparation of intermediate H-37: 5-bromo-3-(2-methoxyethoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine

[0802]

[0803] 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) was added sodium hydride (60%) (1.0 g, 20.94 mmol, 2.0 equiv) at 0 ° C and stirred for 15 min. 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 h. It was transferred to 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 in hexane) to give H-37.1 (2.90 g, 66%). MS (ES): m / z 394.2 and 396.2 [M + H] + .

[0804] Synthesis of compound H-37.2. To a solution of H-37.1 (1.8 g, 4.59 mmol, 1.0 equivalent) in DCM (20 mL) was added trifluoromethanesulfonic acid (5 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 3 h. The mixture was washed with saturated sodium bicarbonate and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel ( The residue was purified with 2.1% methanol in DCM to afford H-37.2 (0.98 g, 78%). MS (ES): m / z 274.1 and 276.1 [M+H] + .

[0805] Synthesis of Compound H-37. Compound H-37 was prepared from H-37.2 following the procedure described in the synthesis of H-1. The product was purified by 32% ethyl acetate in hexane. MS (ES): m / z 404.3 and 406.3 [M+H] + .

[0806] 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

[0807]

[0808] Synthesis of compound H-38.1. To a solution of H-22 (2.0 g, 4.61 mmol, 1.0 equivalent) in DCM (20 mL) was added trifluoromethanesulfonic acid (5 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 3 h. The mixture was washed with saturated sodium bicarbonate 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 2.2% methanol in DCM to afford H-38.1 (1.1 g, 76%). MS (ES): m / z 314.1 and 316.1 [M+H] + .

[0809] Synthesis of Compound H-38. Compound H-38 was prepared from H-38.1 following the procedure described in the synthesis of H-1. The product was purified by 30% ethyl acetate in hexane. MS (ES): m / z 444.5 and 446.5 [M+H] + .

[0810] Preparation of intermediate H-39: 5-bromo-3-((tetrahydrofuran-3-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine

[0811]

[0812] Synthesis of compound H-39.1. To a solution of H-13.2 (3.5 g, 10.47 mmol, 1.0 equivalent) in DMF (35 mL) was added sodium hydride (60 wt%, 1.0 g, 20.94 mmol, 2.0 equivalents) at 0 ° C and stirred for 15 min. Tetrahydrofuran-3-yl methanesulfonate (2.09 g, 12.57 mmol, 1.2 equivalents) was added to the mixture and stirred at room temperature for 1 h. It was transferred to 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 in hexane) to give H-39.1 (2.70 g, 64%). MS (ES): m / z 404.2 and 406.2 [M + H] + .

[0813] Synthesis of compound H-39.2. To a solution of H-39.1 (2.0 g, 4.95 mmol, 1.0 equivalent) in DCM (20 mL) was added trifluoroacetic acid (5 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 3 h. The mixture was washed with saturated aqueous 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 2.2% methanol in DCM to afford H-39.2 (1.3 g, 92%). MS (ES): m / z 284.1 and 286.1 [M+H] + .

[0814] Synthesis of Compound H-39. Compound H-39 was prepared from H-39.2 following the procedure described in the synthesis of H-1. The product was purified by filtration using 28% ethyl acetate in hexane. MS (ES): m / z 414.2 and 416.2 [M+H] + .

[0815] Preparation of intermediate H-40: 5-bromo-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

[0816]

[0817] 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 equivalent) in fuming HNO3 (33 mL) was stirred at 0°C for 1 h. 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] + .

[0818] Synthesis of Compound H-40. Compound H-40 was prepared from H-40.1 following the procedure described in the synthesis of H-1. The product was purified by 30% ethyl acetate in hexane. MS (ES): m / z 373.42 [M+H] + .

[0819] Preparation of intermediate L-1: N-benzyl-3,3-difluoro-N-methylpiperidin-4-amine

[0820]

[0821] Synthesis of compound L-1.1. To a solution of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (5g, 21.25mmol, 1.0 equivalent) in DCM (100mL) was added benzylamine (3.41g, 31.88mmol, 1.5 equivalents) and sodium triacetoxyborohydride (18g, 85.02mmol, 4.0 equivalents). The reaction mixture was stirred at room temperature for 16h. It was transferred 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 30% ethyl acetate in hexanes to give L-1.1 (3.9 g, 56%). MS (ES): m / z 327.1 [M+H] + .

[0822] Synthesis of compound L-1.2. To a solution of L-1.1 (3.8 g, 11.62 mmol, 1.0 equivalent) and paraformaldehyde (3.48 g, 116.2 mmol, 10 equivalents) in methanol (75 mL) was added sodium cyanoborohydride (3.65 g, 58.10 mmol, 5.0 equivalents). The reaction mixture was stirred at room temperature for 16 h. It was transferred 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 product was purified by flash column chromatography on silica gel ( The residue was purified by 28% ethyl acetate in hexanes to give (±)-22.2 (3.1 g, 78%). MS (ES): m / z 341.1 [M+H] + .

[0823] Synthesis of compound L-1. To a solution of L-1.2 (3.1 g, 2.71 mmol, 1.0 equivalent) 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 h. It was transferred to a 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 4% methanol in DCM to give L-1 (1.6 g, 73%). MS (ES): m / z 241.1 [M+H] + .

[0824] Preparation of intermediate L-2: N-benzyl-N-methylazepan-4-amine

[0825]

[0826] Synthesis of compound L-2.1. To a solution of tert-butyl 4-oxoazepane-1-carboxylate (2.0 g, 9.38 mmol, 1.0 equivalent), N-benzylmethylamine (1.36 g, 11.26 mmol, 1.2 equivalents) and acetic acid (0.619 g, 10.32 mmol, 1.2 equivalents) in DCM (20 mL) was added sodium triacetoxyborohydride (2.98 g, 14.08 mmol, 1.5 equivalents) at 0 ° C and stirred at room temperature for 20 h. It was transferred to a saturated sodium bicarbonate solution (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 product was purified by flash column chromatography on silica gel ( The residue was purified with 2.8% methanol in DCM to give L-2.1 (1.9 g, 64%). MS (ES): m / z: 319.2 [M+H] + .

[0827] Synthesis of compound L-2. To a solution of L-2.1 (1.8 g, 5.66 mmol, 1.0 equivalent) in DCM (20 mL) was added trifluoroacetic acid (10 mL) at 0 ° C and stirred for 1.5 h. It was transferred to 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 wet grinding with diethyl ether to obtain L-2 (1.17 g, 95%). MS (ES): m / z: 219.2 [M + H] + .

[0828] Preparation of intermediate L-3: benzyl ((1S,4S,5R)-2-azabicyclo[2.2.1]hept-5-yl)(methyl)carbamate

[0829]

[0830] Synthesis of compound L-3.1. To a solution of triethylamine (5.9 g, 42.65 mmol, 0.9 equiv.) and hydroxylamine hydrochloride (3.6 g, 52.13 mmol, 1.1 equiv.) was added compound 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (10 g, 47.39 mmol, 1.0 equiv.) in ethanol (0.619 g, 10.32 mmol, 1.2 equiv.) at 0 ° C. The reaction mixture was stirred at 80 ° C for 2 h. Concentrated under reduced pressure. The residue was wet-triturated with water, filtered and dried to give L-3.1 (7.0 g, 65%). MS (ES): m / z: 227.13 [M + H] + .

[0831] 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 eq), 10% methanolic ammonia (80 mL) and Raney nickel (5.0 g) was shaken in a Paar shaker under 40 bar of hydrogen for 8 h. The reaction mixture was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure. The product was purified by silica gel flash column chromatography ( The residue was separated from 2-propanol to afford 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] + .

[0832] Synthesis of compound L-3.4. To a solution of L-3.2 (2.1 g, 9.90 mmol, 1.0 equivalent) and sodium bicarbonate (2.5 g, 29.71 mmol, 3.0 equivalent) in THF (40 mL) and water (20 mL) was added benzyl chloroformate (1.4 mL, 9.90 mmol, 1.0 equivalent) at 0 ° C. The reaction mixture was stirred at room temperature for 6 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 18% ethyl acetate in hexanes to give L-3.4 (1.6 g, 47%). MS (ES): m / z: 347.19 [M+H] + .

[0833] Synthesis of compound L-3.5. To a solution of L-3.4 (1.6 g, 4.62 mmol, 1.0 equivalent) in DMF (15 mL) was added sodium hydride (60 wt%, 0.182 g, 6.93 mmol, 1.5 equivalents) in several portions and stirred at 0 ° C for 15 min. To the mixture was added iodomethane (0.6 mL, 13.86 mmol, 3.0 equivalents), and the mixture was warmed to room temperature and stirred for 2 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 15% ethyl acetate in hexanes to give L-3.5 (1.0 g, 60%). MS (ES): m / z 361.20 [M+H] + .

[0834] Synthesis of compound L-3. To a solution of L-3.5 (0.6 g, 1.66 mmol, 1.0 equivalent) in DCM (1.2 mL) was added trifluoroacetic acid (0.6 mL). The reaction mixture was stirred at room temperature for 1 h. It was transferred to a 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] + .

[0835] Preparation of Intermediate L-4: tert-Butyl (3,3-dimethylpiperidin-4-yl)(methyl)carbamate

[0836]

[0837] Synthesis of compound L-4.1 To a solution of 1-benzylpiperidin-4-one (5.0 g, 26.45 mmol, 1.0 equivalent) in THF (40 mL) was added sodium hydride (1.0 g, 38.17 mmol, 1.5 equivalents) at 0 ° C and stirred for 30 min. Iodomethane (1.97 mL, 31.74 mmol, 1.2 equivalents) was added dropwise to the mixture. It was stirred at room temperature for 12 h, transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 15% ethyl acetate in hexanes to give L-4.1 (1.62 g, 28%). MS (ES): m / z 218.15 [M+H] + .

[0838] Synthesis of compound L-4.2. To a solution of L-4.1 (1.62 g, 7.46 mmol, 1.0 equivalent) in methanol (20 mL) was added methylamine hydrochloride (5.0 g, 74.6 mmol, 10 equivalents) and potassium hydroxide (4.1 g, 74.6 mmol, 10 equivalents). The mixture was stirred at room temperature for 6 h, and sodium cyanoborohydride (0.470 g, 7.46 mmol, 1.0 equivalents) was added several times. The reaction mixture was stirred at room temperature for 12 h. It was transferred to 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] + .

[0839] 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 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 h. It was transferred to ice-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-4.3 (0.830 g, 53%). MS (ES): m / z 333.25 [M + H] + .

[0840] Synthesis of compound L-4: A mixture of compound L-4.3 (0.83 g, 2.50 mmol, 1.0 eq) and 10% palladium hydroxide on carbon (0.1 g) in methanol (20 mL) was stirred under hydrogen (1 atm) at room temperature for 2 h. The reaction mixture was filtered through a Celite pad 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] + .

[0841] Preparation of intermediate L-5: N-benzyl-N-methylpiperidin-4-amine hydrochloride

[0842]

[0843] Synthesis of compound L-5.1. To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10.03 mmol, 1.0 equivalent) in DCM (20 mL) was added N-benzylmethylamine (1.45 g, 12.04 mmol, 1.2 equivalents) and stirred at room temperature for 6 h. Sodium triacetoxyborohydride (2.1 g, 10.03 mmol, 1.0 equivalents) was added to the mixture in several portions. The reaction mixture was stirred at room temperature for 16 h. It was transferred to 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-5.1 (0.8 g, 26%). MS (ES): m / z 305.22 [M+H] + .

[0844] Synthesis of compound L-5. To a solution of L-5.1 (0.8 g, 2.63 mmol, 1.0 equiv) in DCM (0.8 mL) was added 4.0 M hydrochloric acid in dioxane (0.8 mL). The reaction mixture was stirred at room temperature for 2 h. It was 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]+ .

[0845] Preparation of intermediate L-6: N-benzyl-N,3,3-trimethylpiperidin-4-amine

[0846]

[0847] 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 equivalent) in DCM (100 mL) was added benzylamine (3.10 g, 29.7 mmol, 1.5 equivalents) and sodium triacetoxyborohydride (16.7 g, 79.2 mmol, 4.0 equivalents). The reaction mixture was stirred at room temperature for 16 h. It was transferred 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 30% ethyl acetate in hexanes to give L-6.1 (3.1 g, 49%). MS (ES): m / z 319.23 [M+H] + .

[0848] Synthesis of compound L-6.2. To a solution of L-6.1 (3.1 g, 9.73 mmol, 1.0 equivalent) in THF (30 mL) was added sodium hydride (0.467 g, 19.46 mmol, 2.0 equivalents) at -10 ° C., followed by dropwise addition of iodomethane (2.0 g, 14.59 mmol, 1.5 equivalents). The reaction mixture was stirred at room temperature for 6 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 28% ethyl acetate in hexanes to give L-6.2 (2.5 g, 77%). MS (ES): m / z 333.49 [M+H] + .

[0849] Synthesis of compound L-6. To a solution of L-6.2 (2.5 g, 10.7 mmol, 1.0 equivalent) in DCM (25 mL) was added dioxane (25 mL) containing 4.0 M hydrochloric acid. The reaction mixture was stirred at room temperature for 3 h. It was transferred to a 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 3% methanol in DCM to give L-6 (1.8 g). MS (ES): m / z 233.37 [M+H] + It was used without purification.

[0850] Preparation of intermediate L-7: Benzyl 3-methyl-1,8-diazaspiro[4.5]decane-1-carboxylate

[0851] Synthesis of compound L-7.1. To a solution of tert-butyl 4-nitropiperidine-1-carboxylate (10 g, 43.47 mmol, 1.0 equivalent) in THF (100 mL) was added methyl methacrylate (8.7 g, 86.95 mmol, 2.0 equivalents) and tetra-n-butylammonium fluoride (52.16 mL, 52.16 mmol, 1.2 equivalents) at 0 ° C. The mixture was stirred at 80 ° C for 16 h. It was transferred 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 at 80 ° C for 16 h under hydrogen (20 psi). Via The reaction mixture was filtered through a pad of Celite® and washed with DCM containing 50% methanol. The filtrate was concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel ( The residue was purified with 2.0% methanol in DCM to afford L-7.1 (7.0 g, 55%). MS (ES): m / z 269.18 [M+H] + .

[0852] Synthesis of compound L-7.2. Borane dimethyl sulfide (19.8 g, 261.19 mmol, 10 equivalents) was added to a solution of L-7.1 (7.0 g, 26.10 mmol, 1.0 equivalents) in THF (70 mL) at 0 ° C and stirred at 80 ° C for 5 h. The reaction mixture was cooled to 0 ° C and quenched by adding methanol and stirred for 10 min. 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] + .

[0853] Synthesis of compound L-7.3. To a solution of L-7.2 (1.3 g, 5.11 mmol, 1.0 equivalent) in DCM (20 mL) was added saturated bicarbonate solution (10 mL) and benzyl chloroformate (0.9 mL, 6.13 mmol, 1.2 equivalents). The reaction mixture was stirred at room temperature for 6 h. It was transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 16% ethyl acetate in hexanes to give L-7.3 (1.0 g, 50%). MS (ES): m / z 389.24 [M+H] + .

[0854] Synthesis of compound L-7. To a solution of L-7.3 (1.0 g, 2.57 mmol, 1.0 equivalent) in DCM (10 mL) was added trifluoroacetic acid (5.0 mL). The reaction mixture was stirred at room temperature for 2 h. It was concentrated under reduced pressure. Water and a saturated bicarbonate solution were added to the residue 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-7 (0.68 g, 92%). MS (ES): m / z 289.18 [M+H] + .

[0855] Preparation of intermediate L-8: benzyl methyl(2-azaspiro[3.3]hept-6-yl)carbamate

[0856]

[0857] 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 equivalent) in THF (20 mL) and water (20 mL) was added sodium bicarbonate (1.9 g, 23.55 mmol, 2.0 equivalents) at 0 ° C. Benzyl chloroformate (1.9 mL, 11.77 mmol, 1.0 equivalents) was added dropwise, and the reaction mixture was stirred at room temperature for 2 h. It was transferred to a saturated sodium bicarbonate solution (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 product was purified by flash column chromatography on silica gel ( The residue was purified with 15% ethyl acetate in hexanes to give L-8.1 (2.0 g, 49%). MS (ES): m / z: 347.19 [M+H] + .

[0858] Synthesis of compound L-8.2. To a solution of L-8.1 (2.0 g, 5.78 mmol, 1.0 equivalent) in THF (20 mL) was added sodium hydride (60 wt%, 0.228 g, 8.67 mmol, 1.5 equivalents) at 0 ° C and stirred for 15 min. To the mixture was added iodomethane (1.0 mL, 17.34 mmol, 3.0 equivalents). It was stirred at room temperature for 2 h, transferred to 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 product was purified by flash column chromatography on silica gel ( The residue was purified with 10% ethyl acetate in hexanes to give L-8.2 (1.5 g, 72%). MS (ES): m / z 361.20 [M+H] + .

[0859] Synthesis of compound L-8. To a solution of L-8.2 (1.5 g, 4.16 mmol, 1.0 equivalent) in DCM (30 mL) was added trifluoroacetic acid (10 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to remove excess trifluoroacetic acid and azeotroped with DCM to give L-8 (1.0 g, 93%). MS (ES): m / z: 261.15 [M + H] + .

[0860] Preparation of intermediate cis-L-9: cis-methyl(3-methylpiperidin-4-yl)carbamic acid tert-butyl ester

[0861]

[0862] Synthesis of compound L-9.1. To a solution of 1-benzyl-3-methylpiperidin-4-one (15 g, 73.89 mmol, 1.0 equivalent) in methanol (500 mL) was added ammonium acetate (56.8 g, 738.9 mmol, 10 equivalents) at 0 ° C and stirred at room temperature for 4 h. Sodium cyanoborohydride (2.32 g, 36.91 mmol, 0.5 equivalents) was added to the mixture, and the reaction mixture was stirred at room temperature for 3 h. Concentrated under reduced pressure. Water was added to the residue, basified with 10% ammonia solution (pH 9) and extracted with chloroform. The combined organic layers were 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] + .

[0863] Synthesis of compound cis-L-9.2 and trans-L-9.2. To a solution of L-9.1 (16 g, 78.43 mmol, 1.0 equivalent) in DCM (100 mL) was added trimethylamine (2.23 mL, 15.56 mmol, 0.2 equivalent) and di-tert-butyl dicarbonate (17 mL, 78.43 mmol, 1 equivalent) at 0 ° C. The reaction mixtu...

Claims

1. A compound of formula I: 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-; Each Z is -C(R 5 )2-; 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 aliphatic group, and / or Two R's 1 Group and / or two R 2 Group and / or two R 4 Group and / or two R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring, and / or Two R's 1 Group and / or two R 2 Group and / or two R 4 Group and / or two R 5 The group, together with the atom to which it is attached, forms an oxo group, 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 group, together with the atoms to which it is attached, forms 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 group, or Two R's 6 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; R 7 is hydrogen or optionally substituted C 1-6 aliphatic group; Ring A is an optionally substituted group selected from the group consisting of phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring B is an optionally substituted group selected from a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 10- to 16-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; L is a covalent bond or a divalent C 1-3 Straight or branched hydrocarbon chain; R 8 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 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- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 7- to 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted phenyl, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted phenyl, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; When valence permits, p is 0, 1, 2, 3, 4, or 5; When valence permits, q is 0, 1, 2, 3, 4, or 5; Each R is independently hydrogen or an optionally substituted group selected from the following: 1-6 Aliphatic group, C 3-7 cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, phenyl, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R 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; and Each R' is independently an optionally substituted 1-6 Aliphatic and C 3-7 Cycloaliphatic groups.

2. The compound of claim 1, wherein the moiety for: (i) in: 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or Two R's w The group and the atoms to which it is attached combine to form q R b A 5- to 6-membered partially unsaturated or aromatic ring substituted with a radical; and r is 0, 1, 2 or 3; or (ii) in: Ring B1 is a 5-membered or 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Ring B1 is fused to Ring B2; and Ring B2 is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, And wherein the compound is not:

3. The compound of claim 1, wherein Ring B is an optionally substituted group selected from the group consisting of a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

4. The compound according to claim 1 or 2, wherein the moiety for in: 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or Two R's w The group and the atoms to which it is attached combine to form q R b A 5- to 6-membered partially unsaturated or aromatic ring substituted with a radical; and r is 0, 1, 2 or 3.

5. The compound of claim 4, wherein W is CH. The compound as claimed in claim 4 , wherein W is N.

7. The compound of any one of claims 4 to 6, wherein r is 1 or 2.

8. The compound of claim 7, wherein R w are independently -OR, -N(R)C(O)R' or -N(R)C(O)N(R)2.

9. The compound of any one of claims 4 to 6, wherein r is 2.

10. The compound as claimed in claim 9, wherein two R w The group and the atoms to which it is attached combine to form q R b A 5- to 6-membered partially unsaturated or aromatic ring substituted with a radical.

11. The compound of claim 10, wherein each R b are independently halogen, -CN, -OR, -N(R)2, -N(R)C(O)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 heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

12. The compound of claim 1, wherein the moiety for in: Ring B1 is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Ring B1 is optionally fused to Ring B2; and Ring B2, when present, is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 Cycloaliphatic or 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 13 . The compound according to claim 12 , wherein Ring B 1 is a 5- to 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

14. The compound according to claim 13, wherein Ring B1 is a 5-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

15. The compound of claim 13, wherein Ring B1 is a 6-membered monocyclic heteroaryl group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

16. The compound of any one of claims 12 to 15, wherein Ring B1 is fused to Ring B2.

17. The compound of any one of claims 12 to 16, wherein Ring B2 is a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

18. A compound as described in any one of claims 1 to 17, wherein each R b are independently halogen, -CN, -OR, -N(R)2, -C(O)N(R)2, -N(R)C(O)R', -N(R)C(O)N(R)2, optionally substituted C 1-6 an aliphatic or optionally substituted C 3-6 Cycloaliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

19. The compound of any one of claims 1 to 18, wherein q is 0 or 1.

20. The compound of any one of claims 1-19, wherein X is -C(R 6 )2-.

21. A compound as described in any one of claims 1 to 20, wherein each R 6 For hydrogen.

22. A compound as described in any one of claims 1 to 20, wherein two R 6 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring.

23. A compound as described in any one of claims 1-19, wherein X is -N(R 7 )-.

24. A compound as described in any one of claims 1-19 and 23, wherein R 7 is optionally substituted C 1-6 Aliphatic group.

25. The compound of claim 24, wherein R 7 C 1-6 alkyl.

26. The compound of any one of claims 1-25, wherein n is 1 or 2.

27. The compound of claim 26, wherein n is 1.

28. The compound of any one of claims 1-27, wherein m is 1.

29. A compound as described in any one of claims 1-28, wherein each R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen, halogen, -CN, -OR or optionally substituted C 1-6 Aliphatic group.

30. The compound of claim 29, wherein 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 Aliphatic group.

31. The compound of claim 30, wherein each R 1 , R 2 , R 3 , R 4 and R 5 For hydrogen.

32. The compound of any one of claims 1-31, wherein one of the following occurs: (i) Two Rs 1 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (ii) Two Rs 2 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (iii) Two Rs 4 The group, together with the atoms to which it is attached, forms a 3- to 8-membered saturated or partially unsaturated ring; or (iv) Two Rs 5 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring.

33. A compound as described in any one of claims 1-28 and 32, wherein one of the following occurs: (i) Two Rs 1 The group, together with the atom to which it is attached, combines to form an oxo group; (ii) Two Rs 2 The group, together with the atom to which it is attached, combines to form an oxo group; (iii) Two Rs 4 The group, together with the atom to which it is attached, forms an oxo group; or (iv) Two Rs 5 The group, together with the atom to which it is attached, forms an oxo group.

34. A compound as described in any one of claims 1-28 and 32-33, wherein one of the following occurs: (i)R 1 and R 2 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (ii) R 1 and R 3 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (iii) R 1 and R 4 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (iv) R 1 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (v)R 2 and R 3 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (vi)R 2 and R 4 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (vii) R 2 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (viii) R 3 and R 4 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (ix)R 3 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (x)R 3 and R 6 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (xi)R 3 and R 7 The group, together with the atoms to which it is attached, forms an optionally substituted 3- to 8-membered saturated or partially unsaturated ring; (xii)R 4 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (xiii)R 4 and R 6 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (xiv)R 4 and R 7 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (xv)R 5 and R 6 The group, together with the atoms to which it is attached, forms a 3- to 8-membered saturated or partially unsaturated ring; or (xvi)R 5 and R 7 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring.

35. The compound of claim 34, wherein one of the following occurs: (i)R 1 and R 5 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; (ii) R 3 and R 7 The group, together with the atoms to which it is attached, forms an optionally substituted 3- to 8-membered saturated or partially unsaturated ring; (iii) R 4 and R 5 The group, together with the atoms to which it is attached, forms a 3- to 8-membered saturated or partially unsaturated ring; or (iv) R 4 and R 7 The groups, together with the atoms to which they are attached, form a 3- to 8-membered saturated or partially unsaturated ring.

36. The compound of any one of claims 1-35, wherein Ring A is phenyl or a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

37. The compound of claim 36, wherein Ring A is phenyl.

38. The compound of claim 36, wherein Ring A is a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

39. The compound of any one of claims 1-38, wherein L is a covalent bond.

40. The compound of any one of claims 1-38, wherein L is -CH2-.

41. A compound as described in any one of claims 1-40, wherein R 8 is halogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 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- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

42. The compound of claim 41, wherein R 8 is optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 Cycloaliphatic or optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

43. A compound as described in any one of claims 1-42, wherein each R a are independently halogen, -CN, -OR, -O(CH2) 1-4 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 heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

44. The compound of claim 43, wherein each R a is optionally substituted C 1-6 Aliphatic group.

45. The compound of claim 44, wherein each R a is C optionally substituted by one or more halogens (eg fluorine) 1-6 alkyl.

46. ​​The compound of any one of claims 1-45, wherein p is 0 or 1.

47. A compound as described in any one of claims 1 to 46, wherein part Selected from:

48. A compound as described in any one of claims 1-47, wherein R a and At least one of them is C 1-4 Halogenated alkyl.

49. The compound of any one of claims 1-48, wherein the compound is not:

50. The compound of any one of claims 1-49, wherein when R 8 When it is hydrogen, p is not 0.

51. The compound of any one of claims 1-50, wherein the compound is a compound of formula IA: or a pharmaceutically acceptable salt thereof.

52. The compound of any one of claims 1 to 50, wherein the compound is a compound of formula IB: or a pharmaceutically acceptable salt thereof.

53. The compound of any one of claims 1-50, wherein the compound is a compound of formula IC: or a pharmaceutically acceptable salt thereof.

54. The compound of any one of claims 1-50, wherein the compound is a compound of formula ID: or a pharmaceutically acceptable salt thereof.

55. The compound of any one of claims 1 to 54, wherein the compound is a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein: Ring B1 is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Ring B1 is optionally fused to Ring B2; and Ring B2, when present, is phenyl, a 5- to 6-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, C 5-6 cycloaliphatic or a 5- to 6-membered saturated or partially unsaturated monocyclic heterocyclic group having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein at least one of Ring B1 and Ring B2 is aromatic; and At least one of ring B1 and ring B2 contains a heteroatom.

56. The compound of any one of claims 1 to 54, wherein the compound is a compound of formula III: or a pharmaceutically acceptable salt thereof, wherein: 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or Two R's w The group and the atoms to which it is attached together form a group consisting of 0-4 R b A 5- to 6-membered partially unsaturated or aromatic ring substituted with a radical; and r is 0, 1, 2 or 3.

57. The compound of any one of claims 1 to 56, wherein the compound is a compound of formula IV: or a pharmaceutically acceptable salt thereof.

58. The compound of any one of claims 1-56, wherein the compound is a compound of formula V: or a pharmaceutically acceptable salt thereof.

59. A compound of formula A: or a pharmaceutically acceptable salt thereof, wherein: X is -C(R 6 )2-、-N(R 7 )-or-O-; Each R 6 are independently hydrogen or optionally substituted C 1-6 aliphatic group, or Two R's 6 The group and the atoms to which it is attached are combined to form a 3- to 8-membered saturated or partially unsaturated ring; R 7 is hydrogen or optionally substituted C 1-6 aliphatic group; Ring A is an optionally substituted group selected from the group consisting of phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring B is an optionally substituted group selected from a 5- to 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8- to 10-membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 10- to 16-membered polycyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring C is an optionally substituted group selected from the group consisting of phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic group, a 5- to 8-membered saturated or partially unsaturated bicyclic carbocyclic group, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L is a covalent bond or a divalent C 1-3 Straight or branched hydrocarbon chain; R 8 is hydrogen, halogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 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- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or an optionally substituted 7- to 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted phenyl, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted phenyl, or optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R c are independently halogen, -CN, -OR or optionally substituted C 1-6 aliphatic group, and / or Two R's c Group and / or R c and R 6 Group and / or R c and R 7 The group, together with the atoms to which it is attached, forms an optionally substituted 3- to 8-membered saturated or partially unsaturated ring, and / or Two R's c The group, together with the atom to which it is attached, combines to form an oxo group; When valence permits, p is 0, 1, 2, 3, 4, or 5; When valence permits, q is 0, 1, 2, 3, 4, or 5; When valence permits, s is 0, 1, 2, 3, 4, or 5; Each R is independently hydrogen or an optionally substituted group selected from the following: 1-6 Aliphatic group, C 3-7 cycloaliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, phenyl, and 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R 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; and Each R' is independently an optionally substituted 1-6 Aliphatic and C 3-7 Cycloaliphatic groups.

60. The compound of claim 59, wherein the compound is a compound of formula E: or a pharmaceutically acceptable salt thereof, wherein: 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)SO2R', -SO2R', -SO2N(R)2, -SO3R', optionally substituted C 1-6 aliphatic, optionally substituted C 3-6 cycloaliphatic, an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, an optionally substituted phenyl, or an optionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or Two R's w The group and the atoms to which it is attached together form a group consisting of 0-4 R b A 5- to 6-membered partially unsaturated or aromatic ring substituted with a radical; and r is 0, 1, 2 or 3.

61. The compound of claim 59 or 60, wherein Ring C comprises a nitrogen atom as the point of attachment to Ring B and is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 6- to 10-membered saturated or partially unsaturated bicyclic heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

62. The compound of claim 61, wherein ring C is 63. The compound of claim 59 or 60, wherein ring C comprises a carbon atom as the point of attachment to ring B.

64. The compound of claim 63, wherein ring C is 65. A compound as described in any one of claims 59-64, wherein each R c are independently halogen, -CN, -OR or optionally substituted C 1-6 an aliphatic group, and / or two R c Group and / or R c and R 6 Group and / or R c and R 7 The radicals, together with the atoms to which they are attached, are combined to form an optionally substituted 3- to 8-membered saturated or partially unsaturated ring.

66. A compound as described in any one of claims 59-65, wherein s is 0, 1 or 2.

67. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

68. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

69. A method of inhibiting JAK2 in a subject, the method comprising administering a compound of any one of claims 1-67 or a composition of claim 68.

70. A method of treating a disease, disorder or condition associated with JAK2, the method comprising administering to a subject in need thereof a compound of any one of claims 1-67 or a composition of claim 68.

71. A method of treating cancer, comprising administering to a subject in need thereof a compound of any one of claims 1-67 or a composition of claim 68.

72. A method of treating a hematological malignancy, the method comprising administering to a subject in need thereof a compound of any one of claims 1-67 or a composition of claim 68.

73. The method of claim 72, wherein the hematological malignancy is a leukemia or a lymphoma.

74. A method of treating a myeloproliferative neoplasm comprising administering to a subject in need thereof a compound of any one of claims 1-67 or a composition of claim 68.

75. The method of claim 74, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis.

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