Heteroaryl compounds useful as TYK2 inhibitors

Abstract

The present disclosure provides compounds useful as TYK2 inhibitors for treating autoimmune disorders.

Description

HETEROARYL COMPOUNDS USEFUL AS TYK2 INHIBITORS BACKGROUND

[0001] Tyrosine Kinase 2 (TYK2) is a non-receptor tyrosine kinase involved in both adaptive and innate immune responses. It is a member of the Janus kinase (JAK) family, which also includes JAK1, JAK2, and JAK3. These kinases are associated with cytokine receptors and mediate the tyrosine phosphorylation of these receptors. This process recruits and activates STAT transcription factors, regulating gene expression crucial for diverse cellular functions and human physiology.

[0002] More than 50 cytokines, growth factors and hormones are known to utilize the JAK-STAT signaling pathway to perform their roles in cell differentiation, metabolism, survival, homeostasis, and immune response. TYK2, which is ubiquitously expressed and particularly active in immune cells, transduces signals downstream from various cytokine receptor families, including type I IFNAR, IL-6R, IL-10R, IL-12R, IL-13R, and IL-23R. Consequently, TYK2 coordinates a broad range of cellular responses, significantly impacting cytokine functions (Hu, X. (2021). The JAK / STAT signaling pathway: from bench to clinic. In Signal Transduction and Targeted Therapy (Vol. 6, Issue 1). Springer Nature, https: / / doi.org / 10.1038 / s41392-021-00791-1).SUMMARY

[0003] The present disclosure provides the recognition that the modulation of TYK2 plays a role in many cellular responses. In some embodiments, the present disclosure provides a compound of formula I:Ior a pharmaceutically acceptable salt thereof, wherein each of V1, V2, X1, R1, R2, R3, and n is as defined herein.

[0004] In particular, the present disclosure provides compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in inhibiting the TYK2 pathway. Insome embodiments, the present disclosure provides methods of inhibiting TYK2, the method comprising contacting a biological sample or administering to a subject a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0005] In certain embodiments, the present disclosure provides a method of treating a TYK2 -mediated disease, disorder, or condition, the method comprising administering to a subject a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, a TYK2 -mediated disease, disorder, or condition is an autoimmune disorder that comprises neurological involvement such as, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis, and psoriatic arthritis, among others.DETAILED DESCRIPTIONDefinitions

[0006] Compounds provided herein include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0007] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

[0008] As used herein, the term “carbocyclic” means a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring comprises a cyclic C3-C6 hydrocarbon.

[0009] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2 / / -pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in

[0010] The term “halogen” means F, Cl, Br, or I.

[0011] The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0012] The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 1471 electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. A heteroaryl group may be mono- or bicyclic. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examplesinclude indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4Z / -quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”.

[0013] As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (asin 3,4-dihydro-2 / / -pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in

[0014] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. A heterocyclyl group may be mono- or bicyclic, bridged or spirocyclic. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 377-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring.

[0015] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0016] As described herein, compounds of the 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. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0017] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o 4R0; -(CH2)o 4OR0; -0(CH2)o-4R°, -O-(CH2)0 4C(O)OR°; -(CH2)O 4CH(ORO)2; -(CH2)O-4SR°; -(CH2)o-4Ph, which may be substituted with R°; -(CH2)o40(CH2)o i Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O-4N(R°)2; -(CH2)O4N(R°)C(O)RO; -N(R°)C(S)R°; -(CH2)O-4N(RO)C(O)NRO2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR&; - N(R°)N(R°)C(O)R°; -N(R°)N(R0)C(0)NR02; -N(R°)N(R°)C(O)OR°; -(CH2)o4C(O)R°; -C(S)R°; -(CH2)O 4C(O)ORO; -(CH2)O4C(O)SRO; -(CH2)o-4C(0)OSiR°3; -(CH2)o4OC(O)R°; -OC(0)(CH2)O4SRO, SC(S)SR°; -(CH2)O4SC(O)R°; -(CH2)O4C(O)NRO2; -C(S)NRO2; -C(S)SR°; SC(S)SR°, -(CH2)0 4OC(O)NRO2; -C(O)N(OR°)R°; C(O)C(O)R°; C(O)CH2C(O)RO;C(NOR°)R°; -(CH2)o4SSR°; -(CH2)o4S(O)2R°; -(CH2)o4S(O)2OR°; -(CH2)o4OS(O)2R°; -S(O)2NR°2; -(CH2)O 4S(O)RO: -N(RO)S(O)2NR°2; N(RO)S(O)2R°; N(0R°)R°; C(NH)NRO2; P(O)2RO; -P(O)R°2; -OP(O)RO2; -OP(O)(OR°)2; SiR°3; -(C1-4 straight or branched alkylene)O-N(R°)2; or -(C1-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -0(CH2)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono-or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0018] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o-2OH, -(CH2)o2OR*, -(CH2)o2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)0 2C(O)R*, -(CH2)o2C(O)OH, -(CH2)o2C(O)OR*, -(CH2)O2SR*, -(CH2)O2SH, -(CH2)O-2NH2, -(CH2)O2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* - (Ci— 4 straight or branched alkylene)C(O)OR*, or-SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0019] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S- wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0020] Suitable substituents on the aliphatic group of R* include halogen, - R*, -(haloR*), -OH, -OR’, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci -4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0021] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -RJ, -NR+2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf, -C(O)CH2C(O)RT, -wherein each R' is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R', taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0022] Suitable substituents on the aliphatic group of R' are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C i 4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0023] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate,cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0024] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0025] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. In certain embodiments, a group described herein as a “heteroaryl” ring may be drawn in its tautomeric form. Such tautomeric forms of heteroaryl rings are encompassed by the definition of “heteroaryl” as if they were drawn in the fully aromatic tautomeric state. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0026] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits the target protein kinase with measurable affinity. In certain embodiments, an inhibitorhas an IC50 and / or binding constant of less about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0027] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in TYK2 activity between a sample comprising a compound of the present disclosure, or composition thereof, and TYK2, and an equivalent sample comprising TYK2, in the absence of said compound, or composition thereof.Compounds and Compositions

[0028] In some embodiments, the present disclosure provides a compound of Formula I:Ior a pharmaceutically acceptable salt thereof, wherein:V1is N and V2is C, or V2is N and V1is C;X1is C-H orN;Ring A is a 6-membered heteroaryl ring having 0-2 nitrogen atoms in addition to V1or V2; R1is -C(O)Y or an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Yis -Ra, -ORa, or -NHRa;R2is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 0-3 instances of Rb;R3is halogen, -CN, -OR, -N(R)2, C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc;Rais hydrogen, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 - to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral;Ralis Ci-6 aliphatic or -OR;Rbis -CN, -OR, -N(R)2, an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9- membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9- membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:two instances of Rb, together with the atoms to which they are attached, may cyclize to form a 5- to 6-membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-2 instances of Rb*; Rb* is -OR or optionally substituted Ci-6 aliphatic, wherein two instances of Rb* attached to the same carbon atom may cyclize to form a 4- to 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur; Rcis halogen, -CN, -OR, -N(R)2, Ci-6 aliphatic optionally substituted with halogen, -C(O)R, or a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R is hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andn is 0-2.

[0029] In some embodiments, the present disclosure provides a compound of Formula F:I’or a pharmaceutically acceptable salt thereof, wherein:V1is N and V2is C, or V2is N and V1is C;X1is C-H orN;Ring A is a 6-membered heteroaryl ring having 0-2 nitrogen atoms in addition to V1or V2;R1is -C(O)Y or an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Y is -Ra, -ORa, -NHRa, or -C(O)NHRa;R2is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 0-3 instances of Rb;R3is halogen, -CN, -OR, -N(R)2, C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 8-membered bridged bicyclic carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc;Rais hydrogen, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 - to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral;Ralis Ci-6 aliphatic, halogen, or -OR;RxR bbis halogen, -CN, -ORW, 'Ry, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 6- to 8-membered bridged bicyclic carbocyclic ring, a 3- to 8-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 11-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:two instances of Rb, together with the atoms to which they are attached, may cyclize to form a 5- to 6-membered saturated carbocyclic ring, a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-3 instances of Rb*;Rb* is halogen, -OR, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein two instances of Rb* attached to the same carbon atom may cyclize to form a 3 - to 6- membered saturated carbocyclic ring or a 3- to 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur;Rcis halogen, oxo, -CN, -OR, -N(R)2, Ci-6 aliphatic optionally substituted with 1-3 halogen, - C(O)R, -CO2R, or a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rwis hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 8-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rxis hydrogen or Ci-6 aliphatic;Ryis hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9- membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 8-membered fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 8- membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R is hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andn is 0-2.

[0030] In some embodiments, a compound of Formula T has the structure of Formula IT:IIor a pharmaceutically acceptable salt thereof, wherein:V1is N and V2is C, or V2is N and V1is C;X1is C-H orN;Ring A is a 6-membered heteroaryl ring having 0-2 nitrogen atoms in addition to V1or V2; R2is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 0-3 instances of Rb;R3is halogen, -CN, -OR, -N(R)2, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc;Rais hydrogen, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 - to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral;Ralis Ci-6 aliphatic or -OR;Rbis -CN, -OR, -N(R)2, an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9- membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9- membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rcis halogen, -CN, -OR, -N(R)2, Ci-6 aliphatic, -C(O)R, or a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R is hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andn is 0-2.

[0031] In some embodiments, a compound of Formula I’ has the structure of Formula II’:II’or a pharmaceutically acceptable salt thereof, wherein:V1is N and V2is C, or V2is N and V1is C;X1is C-H orN;Ring A is a 6-membered heteroaryl ring having 0-2 nitrogen atoms in addition to V1or V2;R2is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 0-3 instances of Rb;R3is halogen, -CN, -OR, -N(R)2, C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 8-membered bridged bicyclic carbocyclic ring, phenyl, a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc;Rais hydrogen, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 - to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral;Ralis Ci-6 aliphatic, halogen, or -OR;RxR bbis halogen, -CN, -ORW, 'Ry, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 6- to 8-membered bridged bicyclic carbocyclic ring, a 3- to 8-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 11-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:two instances of Rb, together with the atoms to which they are attached, may cyclize to form a 5- to 6-membered saturated carbocyclic ring, a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-3 instances of Rb*;Rb* is halogen, -OR, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein two instances of Rb* attached to the same carbon atom may cyclize to form a 3 - to 6- membered saturated carbocyclic ring or a 3- to 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur;Rcis halogen, oxo, -CN, -OR, -N(R)2, Ci-6 aliphatic optionally substituted with 1-3 halogen, - C(O)R, -CO2R, or a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rwis hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 8-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rxis hydrogen or Ci-6 aliphatic;Ryis hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9- membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 8-membered fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 8- membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R is hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andn is 0-2.

[0032] As defined generally above, V1is N and V2is C, or V2is N and V1is C. In some embodiments, V1is C and V2is N. In some embodiments, V1is N and V2is C.

[0033] As defined generally above, X1is C-H or N. In some embodiments, V1is C, V2is N, and X1is C-H. In some embodiments, V1is C, V2is N, and X1is N. In some embodiments, V1is N, V2is C, and X1is C-H. In some embodiments, V1is N, V2is C, and X1is N.

[0034] As defined generally above, Ring A is a 6-membered heteroaryl ring having 0-2 nitrogen atoms in addition to V1or V2. In some embodiments, Ring A is a 6-membered heteroaryl ring having 0 nitrogen atoms in addition to V1or V2. In some embodiments, Ring A is a 6-membered heteroaryl ring having 1 nitrogen atom in addition to V1or V2. In some embodiments, Ring A is a 6-membered heteroaryl ring having 2 nitrogen atoms in addition to V1or V2.

[0035] In some embodiments, the compound is selected from a compound of any of formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h:or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the compound is selected from a compound of any of formulae I-a-z, I-b-z, I-c-z, I-d-z, I-e-z, I-f-z, I-g-z, I-h-z, I-j-z, and I-k-z:or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the compound is selected from a compound of any of formulae I-a-z-A, I-c-z-A, I-e-z-A, I-f-z-A, I-g-z-A, and I-h-z-A:or a pharmaceutically acceptable salt thereof.

[0038] It will be appreciated that the embodiments described herein for formula I apply equally to any of formulae I-a, I-a-z, I-a-z-A, I-b, I-b-z, I-c, I-c-z, I-c-z-A, I-d, I-d-z, I-e, I-e-z, I-e-z- A, I-f, I-f-z, I-f-z-A, I-g, I-g-z, I-g-z-A, I-h, I-h-z, and I-h-z-A.

[0039] As defined generally above, R1is -C(O)Y or an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is -C(O)Y.

[0040] In some embodiments, R1is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R1is an optionally substituted 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0041] In some embodiments, R1is selected from

[0043] As defined generally above for Formula I, Y is -Ra, -ORa, or -NHRa. As defined generally above for Formula I’, Y is -Ra, -ORa, -NHRa, or -C(O)NHRa. In some embodiments, Y is -Ra. In some embodiments, Y is -ORa. In some embodiments, Y is -C(O)NHRa. In someembodiments, Y is -NHRa. In some embodiments, R1is selected fromando oIn some embodiments, R1is selected fromuHY o 'K-

[0044] As defined generally above, R2is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 0-3 instances of Rb. In some embodiments, R2is unsubstituted. In some embodiments, R2is substituted with 1-3 instances of Rb. In some embodiments, R2is substituted with 2-3 instances of Rb. In some embodiments, R2is substituted with 1-2 instances of Rb. In some embodiments, R2is substituted with 1 instance of Rb. In some embodiments, R2is substituted with 2 instances of Rb. In some embodiments, R2is substituted with 3 instances of Rb.

[0045] In some embodiments, R2is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2is a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2is a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 1 instance of Rb. In some embodiments, R2is a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 2 instances of Rb. In some embodiments, R2is a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 3 instances of Rb.

[0046] In some embodiments, R2is selected from

[0047] In some embodiments, R2is a 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R2is a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R2is a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R2is a 6-membered heteroaryl ring having 1-2 nitrogen atoms, wherein R2is substituted with 2 instances of Rb. In some embodiments, R2is a 6-membered heteroaryl ring having 1-2 nitrogen atoms, wherein R2is substituted with 3 instances of Rb. In some embodiments, R2is a 6-membered heteroaryl ring having 1-2 nitrogen atoms, wherein R2is substituted with 1-3 instances of Rb.

[0048] In some embodiments, R2is selected from

[0049] In some embodiments, R2is selected from

[0050] In some embodiments, R2is a 6-membered heteroaryl ring having 1-3 nitrogen atoms, wherein R2is substituted with 0-3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5 - to 6-membered saturated carbocyclic ring, a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-3 instances of Rb*.

[0051] In some embodiments, R2is pyridyl substituted with 0-3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic ring, a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-3 instances of Rb*.

[0052] In some embodiments, R2is pyridyl substituted with 0-3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic ring or a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0053] In some embodiments, R2is pyridyl substituted with 0-3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0054] In some embodiments, R2is pyridyl substituted with 3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic ring or a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-3 instances of Rb*.

[0055] In some embodiments, R2is selected from:

[0056] In some embodiments, R2is pyridyl substituted with 3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0057] In some embodiments, R2is selected from:

[0058] In some embodiments, R2is pyridyl substituted with 3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic ring.

[0059] In some embodiments, R2is pyridyl substituted with 3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0060] In some embodiments, R2is selected from

[0061] In some embodiments, R2is pyridyl substituted with 3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic ring, a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-3 instances of Rb*.

[0062] In some embodiments, R2is selected from

[0064] In some embodiments, R2is a 6-membered heteroaryl ring having 1-3 nitrogen atoms, wherein R2is substituted with 0-3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5 - to 6-membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-2 instances of Rb*, wherein two instances of Rb* attached to the same carbon atom cyclize to form a 4- to 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur.

[0065] In some embodiments, R2is pyridyl substituted with 3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 2 instances of Rb*, wherein two instances of Rb* attached to the same carbon atom cyclize to form a 4- to 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur.

[0066] In some embodiments, R2is pyridyl substituted with 3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 2 instances of Rb*, wherein two instances of Rb* attached to the same carbon atom cyclize to form a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur.

[0067] In some embodiments, R2is pyridyl substituted with 3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 2 instances of Rb*, wherein two instances of Rb* attached to the same carbon atom cyclize to form a 5 -membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur.

[0068] In some embodiments, R2is pyridyl substituted with 3 instances of Rb, wherein two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 2 instances of Rb*, wherein two instances of Rb* attached to the same carbon atom cyclize to form a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur.

[0069] In some embodiments, R2is selected from

[0070] In some embodiments, R2is selected from

[0071] In some embodiments, R2is selected from

[0072] As defined generally above for Formula I, R3is halogen, -CN, -OR, -N(R)2, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc. As defined generally above for Formula F, R3is halogen, -CN, -OR, -N(R)2, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 8-membered bridged bicyclic carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc. In some embodiments, R3is unsubstituted. In some embodiments, R3is substituted with 1-3 instances of Rc. In some embodiments, R3is substituted with 2-3 instances of Rc. In some embodiments, R3is substituted with 1-2 instances of Rc. In some embodiments, R3is substituted with 1 instance of Rc. In some embodiments, R3is substituted with 2 instances of Rc. In some embodiments, R3is substituted with 3 instances of Rc.

[0073] In some embodiments, R3is halogen (e.g., fluoro or chloro).

[0074] In some embodiments, R3is -CN.

[0075] In some embodiments, R3is -OR.

[0076] In some embodiments, R3is -N(R)2.

[0077] In some embodiments, R3is Ci-6 aliphatic substituted with 0-3 instances of Rc. In some embodiments, R3is Ci-4 aliphatic substituted with 0-3 instances of Rc. In some embodiments, R3is C1-3 aliphatic substituted with 0-3 instances of Rc. In some embodiments, R3is C1-3 aliphatic substituted with 1 instance of Rc. In some embodiments, R3is C1-3 aliphatic substituted with 2 instances of Rc. In some embodiments, R3is C1-3 aliphatic substituted with 3 instances of Rc. In some embodiments. R3is -CH3, -CH2-RC, -CH(RC)2, -C(RC)3, -CH2CH3, or -C=C-RC.

[0078] In some embodiments, R3is a 3- to 6-membered saturated carbocyclic ring substituted with 0-3 instances of Rc. In some embodiments, R3is a 3-membered saturated carbocyclic ring substituted with 0-3 instances of Rc. In some embodiments, R3is a 3-membered saturated carbocyclic ring. In some embodiments, R3is a 3-membered saturated carbocyclic ring substituted with 1-2 instances of Rc. In some embodiments, R3is a 3-membered saturated carbocyclic ring substituted with 1 instance of Rc. In some embodiments, R3is a 3-membered saturated carbocyclic ring substituted with 2 instances of Rc.

[0079] In some embodiments, R3is a 4-membered saturated carbocyclic ring substituted with 0-3 instances of Rc. In some embodiments, R3is a 4-membered saturated carbocyclic ring. In some embodiments, R3is a 4-membered saturated carbocyclic ring substituted with 1-2 instances of Rc. In some embodiments, R3is a 4-membered saturated carbocyclic ring substituted with 1 instance of Rc. In some embodiments, R3is a 4-membered saturated carbocyclic ring substituted with 2 instances of Rc.

[0080] In some embodiments, R3is a 5-membered saturated carbocyclic ring substituted with 0-3 instances of Rc. In some embodiments, R3is a 5-membered saturated carbocyclic ring. In some embodiments, R3is a 5-membered saturated carbocyclic ring substituted with 1-2 instances of Rc. In some embodiments, R3is a 5-membered saturated carbocyclic ring substituted with 1 instance of Rc. In some embodiments, R3is a 5-membered saturated carbocyclic ring substituted with 2 instances of Rc.

[0081] In some embodiments, R3is a 6-membered saturated carbocyclic ring substituted with 0-3 instances of Rc. In some embodiments, R3is a 6-membered saturated carbocyclic ring. In some embodiments, R3is a 6-membered saturated carbocyclic ring substituted with 1-2instances of Rc. In some embodiments, R3is a 6-membered saturated carbocyclic ring substituted with 1 instance of Rc. In some embodiments, R3is a 6-membered saturated carbocyclic ring substituted with 2 instances of Rc.

[0082] In some embodiments, R3is a 5- to 8-membered bridged bicyclic carbocyclic ring substituted with 0-3 instances of Rc. In some embodiments, R3is a 5- to 8-membered bridged bicyclic carbocyclic ring substituted with 1-2 instances of Rc. In some embodiments, R3is a 5-to 8-membered bridged bicyclic carbocyclic ring substituted with 1 instance of Rc.

[0083] In some embodiments, R3is a 5-membered bridged bicyclic carbocyclic ring substituted with 0-3 instances of Rc. In some embodiments, R3is a 5-membered bridged bicyclic carbocyclic ring substituted with 1-2 instances of Rc. In some embodiments, R3is a 5-membered bridged bicyclic carbocyclic ring substituted with 1 instance of Rc.

[0084] In some embodiments, R3is a 6-membered bridged bicyclic carbocyclic ring substituted with 0-3 instances of Rc. In some embodiments, R3is a 6-membered bridged bicyclic carbocyclic ring substituted with 1-2 instances of Rc. In some embodiments, R3is a 6-membered bridged bicyclic carbocyclic ring substituted with 1 instance of Rc.

[0085] In some embodiments, R3is a 7-membered bridged bicyclic carbocyclic ring substituted with 0-3 instances of Rc. In some embodiments, R3is a 7-membered bridged bicyclic carbocyclic ring substituted with 1-2 instances of Rc. In some embodiments, R3is a 7-membered bridged bicyclic carbocyclic ring substituted with 1 instance of Rc.

[0086] In some embodiments, R3is a 8-membered bridged bicyclic carbocyclic ring substituted with 0-3 instances of Rc. In some embodiments, R3is a 8-membered bridged bicyclic carbocyclic ring substituted with 1-2 instances of Rc. In some embodiments, R3is a 8-membered bridged bicyclic carbocyclic ring substituted with 1 instance of Rc.

[0087] In some embodiments, R3is phenyl substituted with 0-3 instances of Rc. In some embodiments, R3is phenyl. In some embodiments, R3is phenyl substituted with 1-3 instances of Rc. In some embodiments, R3is phenyl substituted with 2-3 instances of Rc. In some embodiments, R3is phenyl substituted with 1-2 instances of Rc.

[0088] In some embodiments, R3is a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 3-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances ofRc. In some embodiments, R3is a 3-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 3-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc.

[0089] In some embodiments, R3is a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with 1-3 instances of Rc. In some embodiments, R3is a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc.

[0090] In some embodiments, R3is a 5-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc.

[0091] In some embodiments, R3is a 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc. In some embodiments, R3is a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with 1-3 instances of Rc. In some embodiments, R3is a 6-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. Insome embodiments, R3is a 6-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 6-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc. In some embodiments, R3is a 6-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-3 instances of Rc.

[0092] In some embodiments, R3is a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 7-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 7-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-3 instances of Rc. In some embodiments, R3is a 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc.

[0093] In some embodiments, R3is a 8-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 8-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-3 instances of Rc. In some embodiments, R3is a 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc.

[0094] In some embodiments, R3is a 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 9-membered bridged bicyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-3 instances of Rc. In some embodiments, R3is a 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc.

[0095] In some embodiments, R3is a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 6-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 6-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 6-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 6-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-3 instances of Rc. In some embodiments, R3is a 6-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc.

[0096] In some embodiments, R3is a 7-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-3 instances of Rc. In some embodiments, R3is a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc.

[0097] In some embodiments, R3is a 8-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3instances of Rc. In some embodiments, R3is a 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-3 instances of Rc. In some embodiments, R3is a 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc.

[0098] In some embodiments, R3is a 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-3 instances of Rc. In some embodiments, R3is a 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 1-2 instances of Rc.

[0099] In some embodiments, R3is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0-3 instances of Rc. In some embodiments, R3is furanyl, pyrazolyl, isoxazolyl, oxazolyl,

[0100] In some embodiments, R3is selected from halogen (e.g., fluoro or chloro), -CH3, -CH2CH3, -CN, -OR, -N(R)2,

[0101] In some embodiments, R3is selected from halogen (e.g., fluoro or chloro), -CH3, - CD3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C =CH, -CN, -OR, -N(R)2,

[0102] In some embodiments, R3is selected from

[0104] As defined generally above, Rais hydrogen, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral. In some embodiments, Rais unsubstituted. In some embodiments, Rais substituted with 1-2 instances of Ral. In some embodiments, Rais substituted with 1 instance of Ral. In some embodiments, Rais substituted with 2 instances of Ral.

[0105] In some embodiments, Rais hydrogen. In some embodiments, Rais Ci-6 aliphatic. In some embodiments, Rais Ci-4 aliphatic. In some embodiments, Rais C1-2 aliphatic. In some embodiments, Rais -CH3, -CH2CH3, or -CH2OCH3.

[0106] In some embodiments, Rais a 3- to 6-membered saturated carbocyclic ring. In some embodiments, Rais a 3- to 4-membered saturated carbocyclic ring. In some embodiments, Rais a 5- to 6-membered saturated carbocyclic ring. In some embodiments, Rais cyclopropyl.

[0107] In some embodiments, Rais phenyl.

[0108] In some embodiments, Rais a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a 3- to 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais dioxanyl.

[0109] In some embodiments, Rais a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a 5-membered heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a 5-membered heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen,and sulfur. Tn some embodiments, Rais a 5-membered heteroaryl ring having 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, ortriazolyl.

[0110] In some embodiments, Rais a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, Rais pyridyl or pyrimidinyl.

[0111] In some embodiments, Rais a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a 9-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a 9-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a 9-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais benzoxazolyl.

[0112] In some embodiments, Rais selected from

[0113] In some embodiments, Rais selected from

[0114] In some embodiments, Y is selected from

[0115] In some embodiments, Y is selected from

[0116] As defined generally above, Ralis Ci-6 aliphatic, halogen, or -OR. In some embodiments, Ralis Ci-6 aliphatic. In some embodiments, Ralis C 1-4 aliphatic. In some embodiments, Ralis C1-2 aliphatic. In some embodiments, Ralis -CH3 or -CH2CH3. In some embodiments, Ralis halogen. In some embodiments, Ralis fluoro.

[0117] In some embodiments, Ralis -OR. In some embodiments, Ralis -OR, wherein the R group of Rlais -CH3.

[0118] As defined generally above for Formula I, Rbis -CN, -OR, -N(R)2, an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 3- to 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: two instances of Rb, together with the atoms to which they are attached, cyclize to form a 5- to 6-membered saturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-2 instances of Rb*.Rx

[0119] As defined generally above for Formula I’, Rb» is halogen, -CN, -ORW,an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 6- to 8-membered bridged bicyclic carbocyclic ring, a 3- to 8-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 11-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two instances of Rb, together with the atoms to which they are attached, may cyclize to form a 5- to 6-membered saturated carbocyclic ring, a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-3 instances of Rb*.

[0120] In some embodiments, Rbis halogen. In some such embodiments, Rbis fluoro or chloro. In some embodiments, Rbis -CN. In some embodiments, Rbis -OR (e.g., -OCH3). In some embodiments, Rbis -N(R)2.

[0121] In some embodiments, Rbis optionally substituted C1-6 aliphatic. In some embodiments, Rbis -CH3, -CH2CH3, or CH(CH3)2. In some embodiments, Rbis C1-6 aliphatic optionally substituted with halogen, cyano, or -(CH2)o-40R°. In some embodiments, Rbis C1-6 aliphatic optionally substituted with halogen, cyano, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rbis C1-6 aliphatic optionally substituted with halogen, cyano, or -OR°. In some embodiments, Rbis C1-6 aliphatic optionally substituted with halogen, cyano, -R°, or -OR°. In some embodiments, Rbis C1-4 aliphatic optionally substituted with halogen, cyano, or-(CH2)o-4OR0. In some embodiments, Rbis C1-4 aliphatic optionally substituted with halogen, cyano, -(CH2)o-4R°, or -(CH2)O-40R°. In some embodiments, Rbis C1-4 aliphatic optionally substituted with halogen, cyano, or -OR0. In some embodiments, Rbis C1-4 aliphatic optionally substituted with halogen, cyano, -R°, or -OR°. In some embodiments, Rbis C1-2 aliphatic optionallysubstituted with halogen, cyano, or-(CH2)o-40R°. In some embodiments, Rbis C1-2 aliphatic optionally substituted with halogen, cyano, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rbis C1-2 aliphatic optionally substituted with halogen, cyano, or -OR°. In some embodiments, Rbis C1-2 aliphatic optionally substituted with halogen, cyano, -R°, or -OR°. In some embodiments of any of the foregoing, R° is C1-4 aliphatic or a 3- to 6-membered saturated carbocyclic or heterocyclic ring optionally substituted with halogen, -OR’, or -R’, wherein R’ is -CH3.

[0122] In some embodiments, Rbis an optionally substituted 3- to 6-membered saturated carbocyclic ring. In some embodiments, Rbis an optionally substituted 3- to 6-membered saturated carbocyclic ring optionally substituted with halogen, cyano, (CH2)o-4R°, or (CH2)o-4OR0. In some embodiments, Rbis an optionally substituted 3- to 6-membered saturated carbocyclic ring optionally substituted with halogen, cyano, -R°, or -OR0. In some embodiments of any of the foregoing, R° is -H or -CH3.

[0123] In some embodiments, Rbis an optionally substituted 3-membered saturated carbocyclic ring. In some embodiments, Rbis cyclopropyl. In some embodiments, Rbis a 3-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -(CH2)o-4OR0. In some embodiments, Rbis a 3-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -OR0. In some embodiments of any of the foregoing, R° is -CH3.

[0124] In some embodiments, Rbis an optionally substituted 4-membered saturated carbocyclic ring. In some embodiments, Rbis cyclobutyl. In some embodiments, Rbis a 4-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or-(CH2)o-40R°. In some embodiments, Rbis a 4-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR0. In some embodiments of any of the foregoing, R° is -H or -CH3.

[0125] In some embodiments, Rbis an optionally substituted 5-membered saturated carbocyclic ring. In some embodiments, Rbis cyclopentyl. In some embodiments, Rbis a 5-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or-(CH2)O-40R°. In some embodiments, Rbis a 5-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR°. In some embodiments of any of the foregoing, R° is -H or -CH3.

[0126] In some embodiments, Rbis an optionally substituted 6-membered saturated carbocyclic ring. In some embodiments, Rbis cyclohexyl. In some embodiments, Rbis a 6-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or-(CH2)O-40R°. In some embodiments, Rbis a 6-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR0. In some embodiments of any of the foregoing, R° is -H or -CH3.

[0127] In some embodiments, Rbis an optionally substituted 6- to 8-membered bridged bicyclic carbocyclic ring. In some embodiments, Rbis a substituted 6- to 8-membered bridged bicyclic carbocyclic ring optionally substituted with halogen or -(CH2)o-40R°. In some embodiments, Rbis a substituted 6- to 8-membered bridged bicyclic carbocyclic ring optionally substituted with halogen or -OR°. In some embodiments of any of the foregoing, R° is -H or -CH3.

[0128] In some embodiments, Rbis an optionally substituted 6-membered bridged bicyclic carbocyclic ring. In some embodiments, Rbis a substituted 6-membered bridged bicyclic carbocyclic ring optionally substituted with halogen or -(CH2)o-40R°. In some embodiments, Rbis a substituted 6-membered bridged bicyclic carbocyclic ring optionally substituted with halogen or -OR°. In some embodiments of any of the foregoing, R° is -H or -CH3.

[0129] In some embodiments, Rbis an optionally substituted 7-membered bridged bicyclic carbocyclic ring. In some embodiments, Rbis a substituted 7-membered bridged bicyclic carbocyclic ring optionally substituted with halogen or -(CH2)o-40R°. In some embodiments, Rbis a substituted 7-membered bridged bicyclic carbocyclic ring optionally substituted with halogen or -OR0. In some embodiments of any of the foregoing, R° is -H or -CH3.

[0130] In some embodiments, Rbis an optionally substituted 8-membered bridged bicyclic carbocyclic ring. In some embodiments, Rbis a substituted 8-membered bridged bicyclic carbocyclic ring optionally substituted with halogen or -(CH2)o-40R°. In some embodiments, Rbis a substituted 8-membered bridged bicyclic carbocyclic ring optionally substituted with halogen or -OR0. In some embodiments of any of the foregoing, R° is -H or -CH3.

[0131] In some embodiments, Rbis optionally substituted phenyl.

[0132] In some embodiments, Rbis an optionally substituted 3- to 8-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 3- to 8-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-40R°, -(CH2)o-4C(0)R°, or -(CH2)o-4C(0)N(R°)2. In some embodiments, Rbis a 3- to 8-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR°, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or Ci-6 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-4 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic.

[0133] In some embodiments, Rbis a 3-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-4OR°, -(CH2)o-4C(0)R°, or -(CH2)o-4C(0)N(R0)2. In some embodiments, Rbis a 3-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR0, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or Ci-6 aliphatic optionally substituted with halogen (e g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-4 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic.

[0134] In some embodiments, Rbis a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-40R°, -(CH2)o-4C(0)R°, or -(CH2)o-4C(0)N(R°)2. In some embodiments, Rbis a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR°, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or C1-6 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR", wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-4 aliphatic optionally substituted with halogen (e.g., fluoro)or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic.

[0135] In some embodiments, Rbis a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-4OR°, -(CH2)o-4C(0)R°, or -(CH2)o-4C(0)N(R°)2. In some embodiments, Rbis a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR0, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen, Ci-6 aliphatic optionally substituted with halogen (e.g., fluoro), or a 3- to 4-membered saturated carbocyclic ring optionally substituted with -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or Ci-4aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic.

[0136] In some embodiments, Rbis a 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-4OR°, -(CH2)o-4C(0)R°, or -(CH2)o-4C(0)N(R°)2. In some embodiments, Rbis a 6-membered saturated heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR°, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or C1-6 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or Ci-4aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is Ci-2aliphatic.

[0137] In some embodiments, Rbis a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-4OR°, -(CH2)o-4C(0)R°, or -(CH2)o-4C(0)N(R°)2. In some embodiments, Rbis a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR0, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or C1-6 aliphatic optionally substituted with halogen (e g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In someembodiments, R° is hydrogen or C1-4 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR’, wherein R* is C1-2 aliphatic. In some embodiments, Rbis a 6-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-40R°, -(CH2)o-4C(0)R°, or -(CH2)0-4C(O)N(R°)2.

[0138] In some embodiments, Rbis a 6-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR0, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or C1-6 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-4 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic.

[0139] In some embodiments, Rbis a 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-40R°, -(CH2)o-4C(0)R0, or -(CH2)o-4C(0)N(R°)2. In some embodiments, Rbis a 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR0, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or C i-6 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR, wherein R is C1-2 aliphatic. In some embodiments, R° is hydrogen or Ci-4aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is Ci-2aliphatic.

[0140] In some embodiments, Rbis a 7-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)0-4OR°, -(CH2)0-4C(O)R°, or -(CH2)0-4C(O)N(R°)2. In some embodiments, Rbis a 7-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR°, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or Ci-6 aliphaticoptionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-4 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic.

[0141] In some embodiments, Rbis a 7-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-40R°, -(CH2)o-4C(0)R°, or -(CH2)o-4C(0)N(R°)2. In some embodiments, Rbis a 7-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR0, -C(O)R°, or-C(O)N(R°)2. In some such embodiments, R° is hydrogen or C1-6 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-4 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic.

[0142] In some embodiments, Rbis an 8-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-40R°, -(CH2)o-4C(0)R°, or -(CH2)o-4C(O)N(R°)2. In some embodiments, Rbis an 8-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR0, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or C1-6 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C 1 1 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic.

[0143] In some embodiments, Rbis an 8-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-40R°, -(CH2)o-4C(0)R°, or -(CH2)o-4C(0)N(R0)2. In some embodiments, Rbis an 8-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR0, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or Ci-6 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-4 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic.

[0144] In some embodiments, Rbis an 8-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -(CH2)o-4R°, -(CH2)o-40R°, -(CH2)o-4C(0)R°, or -(CH2)o-4C(0)N(R°)2. In some embodiments, Rbis an 8-membered saturated heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR°, -C(O)R°, or -C(O)N(R°)2. In some such embodiments, R° is hydrogen or C i-6 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR, wherein R is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-4 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic. In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro) or -OR*, wherein R* is C1-2 aliphatic.

[0145] In some embodiments, Rbis an optionally substituted 6- to 9-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 6- to 9-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rbis a 6- to 9-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rbis a 6- to 9-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -OR°, or-R°. In some embodiments, R° is C1-4 aliphatic. In some such embodiments, R° is -CH3.

[0146] In some embodiments, Rbis an optionally substituted 6-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 6-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted withhalogen, -(CH2)o-4R°, or -(CH2)o-40R°. Tn some embodiments, Rbis a 6-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -OR°, or -R°. In some embodiments, R° is C1-4 aliphatic. In some such embodiments, R° is -CH3.

[0147] In some embodiments, Rbis an optionally substituted 7-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 7-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rbis a 7-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -OR°, or -R°. In some embodiments, R° is C1-4 aliphatic. In some such embodiments, R° is -CH3.

[0148] In some embodiments, Rbis an optionally substituted 8-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an 8-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rbis an 8-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -OR°, or -R°. In some embodiments, R° is C1-4 aliphatic. In some such embodiments, R° is -CH3.

[0149] In some embodiments, Rbis an optionally substituted 8-membered fused bicyclic heterocyclic ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an 8-membered fused bicyclic heterocyclic ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rbis an 8-membered fused bicyclic heterocyclic ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -OR°, or -R°. In some embodiments, R° is C aliphatic. In some such embodiments, R° is -CH3.

[0150] In some embodiments, Rbis an optionally substituted 9-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an 9-membered fused bicyclic heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rbis an 9-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -OR°, or -R°. In some embodiments, R° is Ci-4 aliphatic. In some such embodiments, R° is -CH3.

[0151] In some embodiments, Rbis an optionally substituted 9-membered fused bicyclic heterocyclic ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an 9-membered fused bicyclic heterocyclic ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)o-4R°, or (CH2)o-40R°. In some embodiments, Rbis an 9-membered fused bicyclic heterocyclic ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -OR°, or -R°. In some embodiments, R° is C1-4 aliphatic. In some such embodiments, R° is -CH3.

[0152] In some embodiments, Rbis an optionally substituted 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with -(CH2)o-4R°.

[0153] In some embodiments, Rbis an optionally substituted 6-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 6-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with - (CH2)O-4R° or -(CH2)o-40R°. In some embodiments, Rbis a 6-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with -R° or -OR°. In some such embodiments, R° is hydrogen or C1-6 aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, R° is hydrogen or C1-4 aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro).

[0154] In some embodiments, Rbis an optionally substituted 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 7-membered bridged bicyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with - (CH2)O-4R°. In some embodiments, Rbis a 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with -R°. In some such embodiments, R° is hydrogen or Ci-6 aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, R° is hydrogen or C i 4 aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, R° is hydrogen or Ci-2 aliphatic optionally substituted with halogen (e.g., fluoro).

[0155] In some embodiments, Rbis an optionally substituted 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with -(CH2)o-4R°. In some embodiments, Rbis an 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with -R°. In some such embodiments, R° is hydrogen or Ci-6 aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, R° is hydrogen or Ci-4 aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen (e.g., fluoro).

[0156] In some embodiments, Rbis an optionally substituted 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with - (CH )O-4R°. In some embodiments, Rbis a 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with -R°. In some such embodiments, R° is hydrogen or C1-6 aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, R° is hydrogen or CH aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, R° is hydrogen or Ci-2 aliphatic optionally substituted with halogen (e.g., fluoro).

[0157] In some embodiments, Rbis an optionally substituted 6- to 11 -membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 6- to 11-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionallysubstituted with oxo, halogen, or -(CH2)o-40R°. Tn some embodiments, Rbis a 6- to 11-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -OR°. In some embodiments, Rbis a 6- to 11 -membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -(CH2)o-40R°. In some embodiments, Rbis a 6- to 11-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -OR°. In some embodiments of any of the foregoing, R° is hydrogen or C1-2 aliphatic (e.g., -CH3).

[0158] In some embodiments, Rbis a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -(CH2)o-40R°. In some embodiments, Rbis a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -OR°. In some embodiments, Rbis a 6-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -(CH2)o-40R°. In some embodiments, Rbis a 6-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -OR°. In some embodiments, Rbis a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -(CH2)o-40R°. In some embodiments, Rbis a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -OR0. In some embodiments, Rbis an 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -(CH2)o-40R°. In some embodiments, Rbis an 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -OR°. In some embodiments, Rbis a 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo, halogen, or -(CH2)o-40R°. In some embodiments, Rbis a 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur optionally substituted with oxo, halogen, or -OR0. In some embodiments of any of the foregoing, R° is C1-2 aliphatic (e.g., -CH3).

[0159] In some embodiments, Rbis an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an optionally substituted 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, Rbis a 6-membered heteroaryl ring having 1-2 nitrogen atoms optionally substituted with halogen or-(CH2)O-40R°. In some embodiments, Rbis a 6-membered heteroaryl ring having 1-2 nitrogen atoms optionally substituted with halogen or -OR°. In some embodiments, Rbis a 6-membered heteroaryl ring having 1-2 nitrogen atoms optionally substituted with halogen or -OR0, wherein R° is hydrogen or C1-2 aliphatic (e.g., -CH3).

[0160] In some embodiments, Rbis selected from

[0161] In some embodiments, Rbis selected from

[0162] As defined generally above for Formula I, Rb* is -OR or optionally substituted Ci-6 aliphatic, wherein two instances of Rb* attached to the same carbon atom may cyclize to form a 4- to 6-membered saturated heterocyclic ring. As defined generally above for Formula I’, Rb* is halogen, -OR, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein two instances of Rb* attached to the same carbon atom may cyclize to form a 3- to 6-membered saturated carbocyclic ring or a 3- to 6-membered saturatedheterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. It will be appreciated that when two instances of Rbor two instances of Rb* cyclize to form a ring, the group Rbor Rb* is first selected from the options set forth for that group, and then, if valency permits, the two groups may cyclize to form a ring as described above. In some embodiments, Rb* is -OR. In some embodiments, Rb* is optionally substituted Ci-6 aliphatic. In some embodiments, Rb* is optionally substituted C1-4 aliphatic. In some embodiments, Rb* is optionally substituted C1-2 aliphatic.

[0163] In some embodiments, Rb* is halogen.

[0164] In some embodiments, Rb* is an optionally substituted C1-6 aliphatic. In some embodiments, Rb* is C1-6 aliphatic optionally substituted with a 3- to 6-membered saturated carbocyclic ring. In some embodiments, Rb* is C1-6 aliphatic optionally substituted with -(CH2)o-4R0. In some embodiments, Rb* is Ci-6 aliphatic optionally substituted with -R°. In some embodiments of the foregoing, R° is a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur or a 3- to 6-membered saturated carbocyclic ring which is optionally substituted with halogen or -(CH2)o-20R*. In some embodiments of the foregoing, R° is a 3- to 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur or a 3- to 4-membered saturated carbocyclic ring which is optionally substituted with halogen, -(CH2)o-2R* or -(CH2)o-20R*. In some embodiments, Rb* is C1-6 aliphatic optionally substituted with -R°, wherein R° is a 3- to 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur or a 3- to 4-membered saturated carbocyclic ring which is optionally substituted with halogen or -(CH2)o-20R* (e.g., -OCH3). In some embodiments of any of the foregoing, R* is Ci- 2 alkyl (e.g., -CH3).

[0165] In some embodiments, Rb* is an optionally substituted 3- to 6-membered saturated carbocyclic ring. In some embodiments, Rb* is a 3- to 6-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rb* is a 3- to 6-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR°. In some embodiments, Rb* is a 3-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or (CH2)o-40R°. In some embodiments, Rb* is a 3-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR°. In some embodiments, Rb* is a 4-membered saturated carbocyclic ring optionally substituted withhalogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rb* is a 4-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR0. In some embodiments, Rb* is a 5-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)O-40R°. In some embodiments, Rb* is a 5-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR0. In some embodiments, Rb* is a 6-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Rb* is a 6-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR°. In some embodiments of any of the foregoing, R° is hydrogen or C1-2 aliphatic optionally substituted with -OH, -OR* or -(halo)OR’, wherein R* is C1-2 aliphatic (e.g., -CH3).

[0166] In some embodiments, Rb* is an optionally substituted 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rb* is a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)o-4R°, -(CH2)o-4C(0)R°, or -(CH2)o-40R°. In some embodiments, Rb* is a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -R°, -C(O)R°, or -OR°. In some embodiments, Rb* is a 4-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)O-4R°, -(CH2)O-4C(0)R°, or -(CH2)o-40R°. In some embodiments, Rb* is a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -R°, -C(O)R°, or -OR°. In some embodiments, Rb* is a 5-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)o-4R°, -(CH2)o-4C(0)R°, or -(CH2)O-40R°. In some embodiments, Rb* is a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -R°, -C(O)R°, or -OR°. In some embodiments, Rb* is a 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -(CH2)o-4R°, -(CH2)o-4C(0)R°, or -(CH2)O-40R°. In some embodiments, Rb* is a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, -R°, -C(O)R°, or -OR°. Insome embodiments of any of the foregoing, R° is hydrogen or C1-2 aliphatic optionally substituted with -OH, -OR* or -(halo)OR*, wherein R* is C1-2 aliphatic (e.g., -CH3).

[0167] In some embodiments, Rb* is an optionally substituted 7- to 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an optionally substituted 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rb* is an optionally substituted 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0168] In some embodiments, Rb* is selected from

[0169] As defined generally above for Formula F, Rwis hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 8-membered bridged bicyclic heterocyclic ring. In some embodiments, Rwis hydrogen.

[0170] In some embodiments, Rwis an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 3- to 6-membered saturatedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 8-membered bridged bicyclic heterocyclic ring.

[0171] In some embodiments, Rwis optionally substituted Ci-6 aliphatic. In some embodiments, Rwis optionally substituted C1-3 aliphatic. In some embodiments, Rwis C1-3 aliphatic optionally substituted with halogen, cyano, -(CH2)o-40R°, or -(CH2)o-4R°. In some embodiments, Rwis C1-3 aliphatic optionally substituted with halogen, cyano, -OR°, or -R°. In some embodiments of any of the foregoing, R° is hydrogen, C1-2 aliphatic, a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0172] In some embodiments, Rwis an optionally substituted 3- to 6-membered saturated carbocyclic ring. In some embodiments, Rwis a 3- to 6-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -(CH2)o-40R°. In some embodiments, Rwis a 3- to 6-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -OR°. In some embodiments, Rwis a 3-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -(CH2)o-40R°. In some embodiments, Rwis a 3-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -OR°. In some embodiments, Rwis a 4-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -(CH2)O-40R°. In some embodiments, Rwis a 4-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -OR°. In some embodiments, Rwis a 5-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -(CH2)o-40R°. In some embodiments, Rwis a 5-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -OR°. In some embodiments, Rwis a 6-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -(CH2)o-40R°. In some embodiments, Rwis a 6-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -OR°. In some embodiments of any of the foregoing, R° is hydrogen or C1-2 aliphatic.

[0173] In some embodiments, Rwis an optionally substituted 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis a 3- to 6-membered saturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with - (CH2)O-4R° or -(CH2)O-40R°. In some embodiments, Rwis a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with -R° or -OR0. In some embodiments, Rwis a 3-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with -(CH2)o-4R° or -(CH2)o-40R°. In some embodiments, Rwis a 3-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with -R° or -OR°. In some embodiments, Rwis a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with -(CH2)o-4R° or -(CH2)o-40R°. In some embodiments, Rwis a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with -R° or -OR0. In some embodiments, Rwis a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with -(CH2)o-4R° or -(CH2)o-40R°. In some embodiments, Rwis a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with -R° or -OR0. In some embodiments, Rwis a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with -(CH2)o-4R° or -(CH2)o-40R°. In some embodiments, Rwis a 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with -R° or -OR°. In some embodiments of any of the foregoing, R° is C1-2 aliphatic (e.g., -CH3).

[0174] In some embodiments, Rwis an optionally substituted 7- to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0175] In some embodiments, Rwis an optionally substituted 6- to 8-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 6-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0176] As defined generally above for Formula I’, Rxis hydrogen or Ci-6 aliphatic. In some embodiments, Rxis hydrogen. In some embodiments, Rxis Ci-6 aliphatic. In some embodiments, Rxis Ci-4 aliphatic. In some embodiments, Rxis C1-2 aliphatic (e g., -CH3).

[0177] As defined generally above for Formula I’, Ryis hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 8-membered bridged bicyclic heterocyclic ring.

[0178] In some embodiments, Ryis hydrogen. In some embodiments, Ryis an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 8-membered bridged bicyclic heterocyclic ring.

[0179] In some embodiments, Ryis optionally substituted C1-6 aliphatic. In some embodiments, Ryis optionally substituted C1-4 aliphatic. In some embodiments, Ryis optionally substituted C1-2 aliphatic. In some embodiments, Ryis -CH3. In some embodiments, Ryis C1-2 aliphatic optionally substituted with -(CH2)o-40R° or -(CH2)o-4R°. In some embodiments, Ryis C1-2 aliphatic optionally substituted with -OR0or -R°. In some embodiments of any of the foregoing, R° is a 3- to 4-membered saturated carbocyclic ring or a 3 - to 4-membered saturatedheterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. Tn some embodiments, R° is optionally substituted with halogen or (halo)R*, wherein R* is C1-2 aliphatic.

[0180] In some embodiments, Ryis an optionally substituted 3- to 6-membered saturated carbocyclic ring. In some embodiments, Ryis a 3- to 6-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Ryis a 3- to 6-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR°. In some embodiments, Ryis a 3-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Ryis a 3-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR0. In some embodiments, Ryis a 4-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or-(CH2)O-40R°. In some embodiments, Ryis a 4-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR0. In some embodiments, Ryis a 5-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Ryis a 5-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR0. In some embodiments, Ryis a 6-membered saturated carbocyclic ring optionally substituted with halogen, -(CH2)(MR°, or -(CH2)o-40R°. In some embodiments, Ryis a 6-membered saturated carbocyclic ring optionally substituted with halogen, -R°, or -OR°. In some embodiments of any of the foregoing, R° is hydrogen or C1-2 aliphatic optionally substituted with halogen.

[0181] In some embodiments, Ryis an optionally substituted 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Ryis a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -R°, or -OR°. In some embodiments, Ryis a 3 -membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -(CH2)o-4R°, or-(CH2)o-4OR0. In some embodiments, Ryis a 3-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -R°, or -OR0. In some embodiments, Ryis a 4-membered saturated heterocyclic ring having 1heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, - (CH2)o-4R°, or -(CH2)O-40R°. In some embodiments, Ryis a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -R°, or -OR°. In some embodiments, Ryis a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -(CH2)o-4R0, or -(CH2)o-40R°. In some embodiments, Ryis a 5-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -R°, or -OR°. In some embodiments, Ryis a 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, (CH2)o-4R°, or-(CH2)o-4OR0. In some embodiments, Ryis a 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -R°, or -OR°. In some embodiments of any of the foregoing, R° is C1-2 aliphatic optionally substituted with halogen or -(CH2)o-20R*, wherein R* is C1-2 aliphatic (e.g., -CH3).

[0182] In some embodiments, Ryis an optionally substituted 7- to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis a 7- to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Ryis a 7-to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -R°, or -OR°. In some embodiments, Ryis a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, - (CH2)O-4R°, or-(CH2)o-40R°. In some embodiments, Ryis a 7-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -R°, or -OR°. In some embodiments, Ryis a 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -(CH2)o-4R°, or-(CH2)o-4OR0. In some embodiments, Ryis a 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -R°, or -OR°. In some embodiments, Ryis a 9-membered spirocyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -(CH2)o-4R°, or -(CH2)o-40R°. In some embodiments, Ryis a 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, oxo, -R°, or -OR°. In some embodiments of any of the foregoing, R° is C1-2 aliphatic optionally substituted with halogen

[0183] In some embodiments, Ryis an optionally substituted 6- to 8-membered fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis an optionally substituted 6-membered fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis an optionally substituted 7-membered fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis an optionally substituted 8-membered fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0184] In some embodiments, Ryis an optionally substituted 5- to 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ryis a 5- to 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen. In some embodiments, Ryis a 5-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen. In some embodiments, Ryis a 6-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen. In some embodiments, Ryis a 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen. In some embodiments, Ryis an 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen.

[0185] In some embodiments, R2is selected from

[0186] In some embodiments, R2is selected from90 k03 kS£

[0187] As defined generally above for Formula I, Rcis halogen, -CN, -OR, -N(R)2, Ci-6 aliphatic optionally substituted with halogen, -C(O)R, or a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. As defined generally above for Formula F, Rcis halogen, oxo, -CN, -OR, -N(R)2, Ci-6aliphatic optionally substituted with 1-3 halogen, -C(O)R, -CO2R, or a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rcis halogen (e.g., fluoro or chloro). In some embodiments, Rcis -CN. In some embodiments, Rcis -OR (e.g., -OH, -OCH3, -OCD3, or -OCH2CH3). In some embodiments, Rcis. In some embodiments, Rcis -N(R)z (e.g., -NH2, -NHCH3, or -N(CH3)2). In some embodiments, Rcis C1-6aliphatic. In some embodiments, Rcis C1-4 aliphatic. In some embodiments, Rcis C1-2 aliphatic. In some embodiments, Rcis -CH3, CH2CH3, or -CH(CH3)2. In some embodiments, Rcis Ci-6 aliphatic optionally substituted with halogen. In some embodiments, Rcis C1-4 aliphatic optionally substituted with halogen. In some embodiments, Rcis C1-2 aliphatic optionally substituted with halogen. In some embodiments, Rcis -CHF2, -CF3, or -CH2CF3.

[0188] In some embodiments, Rcis -C(O)R. In some such embodiments, Rcis -C(O)CH3.

[0189] In some embodiments, Rcis a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rcis a 3- to 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Rcis a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rcis oxetanyl.

[0190] In some embodiments, Rcis oxo.

[0191] In some embodiments, Rcis -CO2R. In some such embodiments, Rcis -CO2CH3.

[0192] As defined generally above, R is hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0193] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from C1-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0194] In some embodiments, R is an optionally substituted Ci-6 aliphatic. In some embodiments, R is an optionally substituted Ci-4 aliphatic. In some embodiments, R is an optionally substituted C1-2 aliphatic. In some embodiments, R is -CH3, -CD3, -CH2CH3, or -CH(CH3)2. In some embodiments, R is -CH2F, -CHF2, or -CF3.

[0195] In some embodiments, R is an optionally substituted 3- to 6-membered saturated carbocyclic ring. In some embodiments, R is an optionally substituted 3- to 4-membered saturated carbocyclic ring. In some embodiments, R is an optionally substituted 5- to 6-membered saturated carbocyclic ring. In some embodiments, R is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0196] In some embodiments, R is an optionally substituted phenyl.

[0197] In some embodiments, R is an optionally substituted 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 3- to 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, or piperazinyl.

[0198] In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0199] In some embodiments, a compound of Formula I is selected from those in Table A.

[0200] Table A.1-82 1-83 1-84I-391 I-392 I-393I-403 I-404 I-405I-428 I-429I-4271-762 1-761-7601-832 1-833 1-8341-934 1-935 1-936-988I-1075 I-1076 I-1077I-11141-1180 1-1181 1-1182I-1395 I-1394I-1393I-1465 I-1466 I-1467I-1477 I-1478 I-1479-1663 1-1664 1-16651-1753 1-1754 1-17551-1924 1-1925 1-19261-2008 1-2009 1-2010-2047 1-2048 1-2049-2062 1-2063 1-2064-2077 1-2078 1-2079-2101 1-2102 1-21031-2128 1-2129 1-21301-2170 1-2171 1-2172I-2302I-2310I-2350 I-2351 I-2352Pharmaceutically Acceptable Compositions

[0201] According to another embodiment, the present disclosure provides a composition comprising a compound provided herein or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this disclosure is such that is effective to measurably inhibit TYK2, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions provided herein is such that is effective to measurably inhibit TYK2, in a biological sample or in a patient. In certain embodiments, a composition provided herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a patient. It will be appreciated that reference to the inhibition of TYK2, or treatment of a TYK2 -mediated disease, also encompasses the inhibition of any gain-of-function TYK2 mutants or treatment of any gain-of-function TYK2-mediated diseases.

[0202] The terms “patient” or “subject” are used interchangeably and mean an animal, preferably a mammal, and most preferably a human.

[0203] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0204] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound provided herein that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.

[0205] As used herein, the term “inhibitorily active metabolite or residue thereof’ means that a metabolite or residue thereof is also an inhibitor of TYK2.

[0206] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0207] For this purpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0208] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose anddried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0209] Alternatively, pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0210] Pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0211] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0212] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0213] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0214] Pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0215] Most preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration.

[0216] The amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0217] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.

[0218] Compounds and compositions described herein are generally useful for the inhibition of protein kinase activity of one or more enzymes.

[0219] The activity of a compound utilized in this disclosure as an inhibitor of TYK2, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity and / or the subsequent functional consequences, or ATPase activity of activated TYK2. Alternate in vitro assays quantitate the ability of the inhibitor to bind to TYK2. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with TYK2 bound to known radioligands.Uses of Compounds and Compositions

[0220] Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP or GTP to a tyrosine residue located on a protein substrate. Receptor tyrosine kinases act to transmit signals from the outside of a cell to the inside by activating secondary messaging effectors via a phosphorylation event. A variety of cellular processes are promoted by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival.

[0221] Studies on TYK2 deficiency in humans and mice have demonstrated the crucial role of TYK2 in modulating IL-12, IL-23, and type I interferons (e.g., IFNa), as well as subsequent cellular responses (Dendrou, C. A. et al. (2016). Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity, http: / / stm.sciencemag.org / ; Ishizaki, M. et al. (2011). Involvement of tyrosine kinase-2 in both the IL-12 / Thl and IL-23 / Thl7 axes in vivo. Journal of Immunology (Baltimore, Md.: 1950), 187(\), 181-189. https: / / doi.org / 10.4049 / JIMMUNOL.1003244.) The heterodimeric cytokines IL-12 and IL-23, which share a common p40 subunit, are essential for the differentiation and development of Thl and Thl7 cells, respectively (Teng, M. et al. (2015). IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nature Medicine 201521:7, 21(7), 719-729. https: / / doi.org / 10.1038 / nm.3895). Thl cells play a primary role in cell-mediated immunity against intracellular pathogens by secreting IFNy, which activates macrophages and stimulates cytotoxic T cell activity. Conversely, IL-23 is crucial for the survival and expansion of Thl7 cells, which produce IL-17 along with other pro-inflammatory cytokines such as IL-6 and TNFa. These Thl7 cells are instrumental in mediating immune responses against extracellular bacteria and fungi, as well as in driving chronic inflammation and autoimmunity. Type I interferons activate immune cells, such as macrophages and natural killer cells, and enhance the antigen-presentation capacity of dendritic cells. They signal through the type I interferon receptor (IFNAR), which is expressed on many cell types, triggering antiviral, antiproliferative, and immunomodulatory pathways (Hall, J. C., & Rosen, A. (2010). Type I interferons: crucial participants in disease amplification in autoimmunity. Nature Reviews Rheumatology 20106:1, 6(1), 40-49. https: / / doi.org / 10.1038 / nrrheum.2009.237). IFN-a plays a key role in driving autoimmunity by activating immune cells, increasing antigen presentation, and promoting theproduction of autoantibodies (Fernandez-Ruiz, R., & Niewold, T. B. (2022). Type I TFNs in Autoimmunity. The Journal of Investigative Dermatology, 142(3 PtB), 793.https: / / doi. org / 10.1016 / J. JID.2021.11.031).

[0222] Dysregulated cytokine-JAK-STAT signaling is linked with numerous autoimmune disorders, inflammatory diseases, and malignancies. Abnormal elevations of cytokines such as IL-12, IL-23, and IFN-a or aberrant activation of their pathways can lead to excessive immune responses, chronic inflammation, and tissue damage, contributing to the pathogenesis of diseases like psoriasis, psoriatic arthritis, inflammatory bowel disease (especially Crohn’s Disease), systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, spondyloarthritis, type 1 diabetes, Sjogren’s syndrome, and scleroderma (Femandez-Ruiz & Niewold, 2022; Teng et al., 2015).

[0223] In line with the observations in diseases where TYK2-dependent cytokines and receptors are upregulated, human genetic studies have demonstrated that TYK2 mutations and polymorphisms are associated with autoimmune diseases and immune-mediated cancers. TYK2 variants have been linked to systemic lupus erythematosus (Sigurdsson, S.et al. (2005).Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. American Journal of Human Genetics, 76(3), 528-537. https: / / doi.org / 10.1086 / 428480), psoriasis, inflammatory bowel disease (Ellinghaus, D. et al. (2012). Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. American Journal of Human Genetics, 90(4), 636-647. https: / / doi. Org / 10.1016 / J. AJHG.2012.02.020 / ATTACHMENT / 7ADD3DD0-614A-4023-8430-FAC7F7FB61FA / MMC1. PDF), and rheumatoid arthritis (Eyre, S. (2012). High density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nature Genetics, 44(12), 1336. https: / / doi.org / 10.1038 / NG.2462). Both germline and somatic TYK2 GOF mutations are linked to acute lymphoblastic leukemia, while oncogenic TYK2 fusions leading to constitutive activation have been identified in primary hematological malignancies (Wbss, K. et al. (2019). Tyk2: An upstream kinase of stats in cancer. In Cancers (Vol. 11, Issue 11). MDPI AG. https: / / doi.org / 10.3390 / cancerslllll728). Hyperactive TYK.2 mutants can drive malignant transformation both in vitro and in vivo (Woess, K. et al. (2023). Oncogenic TYK2 P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4 / 6 kinase blockade.Haematologica, 108(4), 993-1005. https: / / doi.org / 10.3324 / haematol.2021.279848). Conversely,human TYK2 loss-of-function (LOF) variants confer protection against autoimmunity but increase susceptibility to intracellular pathogens (Couturier, N. et al. (2011). Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility. Brain, 134(3), 693-703. https: / / doi.org / 10.1093 / BRAIN / AWR010; Wu, P. et al. (2020). ATYK2 Gene Mutation c.2395G> A Leads to TYK2 Deficiency: A Case Report and Literature Review. Frontiers in Pediatrics, 8. https: / / doi.org / 10.3389 / FPED.2020.00253). TYK2-deficient mice have shown resistance to experimental models of colitis, psoriasis, and multiple sclerosis (Ishizaki et al., 2011; Oyamada, A. et al. (2009). Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis. The Journal of Immunology, 753(11), 7539-7546. https: / / doi.org / 10.4049 / jimmunol.0902740).

[0224] The common TYK2 variant rs34536443 (P1104A), located in the JH1 kinase domain, leads to a loss of catalytic enzyme activity, likely due to the stabilization of inactive conformations (Lesgidou, N. (2018). Insights on the alteration of functionality of a tyrosine kinase 2 variant: a molecular dynamics study. Bioinformatics, 34(11), i781— i786. https: / / doi.org / 10.1093 / BIOINFORMATICS / BTY556). Importantly, this single amino acid change does not affect the protein’s expression or its scaffolding capacity (Couturier et al., 2011; Dendrou et al., 2016). This polymorphism has displayed protective effects against at least ten different autoimmune conditions in diverse populations (Dendrou et al., 2016; Yuan, S. et al. (2023). Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases. EBioMedicine, 89. https: / / doi. Org / 10.1016 / j.ebiom.2023.104488). Genetic meta-analyses involving 116,732 individuals genotyped and phenotype through the UK Biobank have revealed significant homozygous effects in Crohn's disease (OR=0.094), ankylosing spondylitis (OR=0.095), multiple sclerosis (OR=0.307), psoriasis (OR=0.158), and ulcerative colitis (OR=0.188), without causing significant perturbations in immune profiles or increased infection-related hospitalizations (Dendrou et al., 2016). The rs34536443 variant represents the most significant genetic protection against the development of multiple sclerosis outside of the HLA region (Jensen, L. T. et al. (2023). Allosteric TYK2 inhibition: redening autoimmune disease therapy beyond JAK1-3 inhibitors. http: / / creativecommons. Org / licenses / by / 4.0 / ). Similarly, homozygous mice carrying the orthologous missense mutation (P1124A) are protected against MOG-induced experimental autoimmune encephalomyelitis (EAE) (Dendrou et al., 2016).

[0225] These findings collectively support the potential of selective TYK2 inhibitors in treating numerous autoimmune diseases. Moreover, while TYK2 is recognized for its role in tumor surveillance, emerging data suggest an oncogenic potential, making TYK2 inhibitors also promising for cancer treatment (Woess et al., 2023).

[0226] The JAKs consist of seven homology domains (JH), organized into four functional domains. The tandem architecture of the structurally similar JH1 and JH2 domains is a hallmark of JAKs. The JH1 kinase domain, which is catalytically active, features a conserved ATP binding site, while the JH2 pseudokinase domain plays a regulatory role over the kinase domain's activity. Classical inhibitors of JAK1, 2, and 3 target the JH1 domain, which contains the ATP catalytic site and is highly conserved among many kinases. Severe safety concerns raised from clinical development and post-approval surveillance studies of first-generation, non-selective inhibitors highlight the importance of selective inhibition (Salinas, C. A. et al. (2023). Evaluation of VTE, MACE, and Serious Infections Among Patients with RA Treated with Baricitinib Compared to TNFi: A Multi -Database Study of Patients in Routine Care Using Disease Registries and Claims Databases. Rheumatology and Therapy, 10(f), 201-223. https: / / doi. Org / 10.1007 / S40744-022-00505-l / FIGURES / 3; Ytterberg, S. R. et al. (2022).Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. New England Journal of Medicine, 386(4), 316-326.https: / / doi. org / 10.1056 / NEJMO A2109927 / SUPPL FILE / NEJMO A2109927_D ATA-SHARING. PDF). Targeting the JH2 domain with allosteric inhibitors has enabled the development of selective functional TYK2 inhibitors that do not block JAK1, 2, and 3, paving the way for their potential use in treating numerous autoimmune diseases and cancers.

[0227] In some embodiments, the present disclosure provides a method of treating a TYK2 -mediated disease, disorder, or condition, the method comprising administering to a subject a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, a TYK2-mediated disease, disorder, or condition is an autoimmune disease, an inflammatory disease, a cancer, a neurodegenerative disease, or transplantation rejection. In some embodiments, a TYK2-mediated disease is a disease that has an inflammatory component such as Alzheimer’s disease, ALS, and Parkinson’s disease.

[0229] In some embodiments, a cancer is a cancer associated with TYK2 gain-of-function. Such cancers include hematological malignancies such as leukemias and lymphomas(e g., acute large cell lymphoma, T-cell acute lymphoblastic lymphoma, acute myeloid leukemia, anaplastic large cell lymphoma, etc.)

[0230] In some embodiments, a TYK2-mediated disease, disorder, or condition is an autoimmune disease. In some embodiments, an autoimmune disease is a disease that is associated with or comprises neurological involvement. In some embodiments, a disease that is associated with or comprises neurological involvement is SLE, rheumatoid arthritis, or psoriatic arthritis.

[0231] In some embodiments, an autoimmune disease is a CNS demyelinating disease. In some such embodiments, a CNS demyelinating disease is acute disseminated encephalomyelitis, myelin oligodendrocyte glycoprotein antibody-associated disease, Neuromyelitis Optica Spectrum Disorder (NMOSD), Schilder's Disease, Marburg's multiple sclerosis, Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS), or Hashimoto’s Encephalopathy. Acute disseminated encephalomyelitis is a rare, often monophasic autoimmune demyelinating disease that follows infections or vaccinations, affecting the brain and spinal cord and causing widespread inflammation and demyelination. Myelin Oligodendrocyte Glycoprotein Antibody -Associated Disease is an autoimmune disorder with demyelination in the CNS, often affecting the optic nerves and spinal cord. Unlike NMOSD, it involves antibodies against myelin oligodendrocyte glycoprotein (MOG). NMOSD primarily affects the optic nerves and spinal cord, leading to optic neuritis and transverse myelitis. It is associated with antibodies against aquaporin-4.Schilder's Disease is a rare form of progressive multiple sclerosis that primarily affects children and young adults, causing extensive demyelination in the cerebral white matter. Marburg’s multiple sclerosis is an aggressive and fulminant form of multiple sclerosis that progresses rapidly and can be fatal within months. CLIPPERS is a rare CNS demyelinating disorder involving the brainstem, cerebellum, and pons, leading to ataxia, dizziness, and gait instability. Hashimoto’s Encephalopathy is a rare condition associated with autoimmune thyroiditis (Hashimoto's disease) and presents with CNS demyelination, causing confusion, seizures, and cognitive impairment.

[0232] In some embodiments, an autoimmune disease is a demyelinating condition associated with or comprising both central nervous system (CNS) and peripheral nervous system (PNS) involvement. In some such embodiments, a demyelinating condition associated with orcomprising both CNS and PNS involvement is Neuro-Beh^et's disease, systemic lupus erythematosus (SLE) with neuropsychiatric involvement, or sarcoidosis with neurological involvement (Neurosarcoidosis). Behcet's disease is a rare, chronic, and systemic inflammatory disorder that affects blood vessels and tissues in many parts of the body. The neural form involves CNS demyelination and inflammation, causing neurological symptoms such as headaches, balance problems, and vision impairment. SLE with neuropsychiatric involvement can cause demyelination in both the CNS and PNS, leading to cognitive changes, seizures, and peripheral neuropathy. Sarcoidosis can cause demyelinating lesions in the CNS or PNS, leading to symptoms such as cranial nerve palsies, myelopathy, or peripheral neuropathy.

[0233] In some embodiments, an autoimmune disease is a neurological disease associated with one or more of Thl / IL-12, Thl7 / IL-17, IL-23 and type I INF signaling. In some embodiments, a neurological disease associated with one or more of Thl / IL-12, Thl7 / IL-17, IL-23 and type I INF signaling is chronic viral encephalitis, encephalopathy, Rasmussen’s Encephalitis, autoimmune encephalomyelitis, including anti -NMD A receptor encephalitis, anti-LGI1 encephalitis, anti-GABA(A) receptor encephalitis, anti-GABA(B) receptor encephalitis, anti-CASPR2 encephalitis, anti-AMPA receptor encephalitis, Stiff Person Syndrome, Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease, or clinically isolated syndrome (CIS). Rasmussen’s Encephalitis is a rare, chronic inflammatory neurological disorder characterized by severe, progressive damage to one hemisphere of the brain, leading to intractable seizures, cognitive decline, and loss of motor function on one side of the body (hemiparesis). The condition typically affects children but can also occur in adults. The collection of diseases such as autoimmune encephalomyelitis, including anti -NMD A receptor encephalitis, anti-LGIl encephalitis, anti-GABA(A) receptor encephalitis, anti-GABA(B) receptor encephalitis, anti-CASPR2 encephalitis, anti-AMPA receptor encephalitis, Stiff Person Syndrome, Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease is a group of neurological disorders in which the body’s immune system mistakenly attacks healthy brain cells. CIS is a neurological disorder that refers to a first episode of neurological symptoms caused by inflammation and demyelination in the CNS, which lasts at least 24 hours. CIS is often considered a possible early stage of multiple sclerosis (MS), although not all individuals with CIS will go on to develop multiple sclerosis.

[0234] In some embodiments, an autoimmune disease is a PNS demyelinating disease. In some embodiments, a PNS demyelinating disease is Guillain-Barre syndrome, including acute inflammatory demyelinating polyneuropathy (AIDP), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Multifocal Motor Neuropathy, or Anti -MAG Peripheral Neuropathy. Guillain-Barre syndrome and AIDP are acute autoimmune diseases where the immune system attacks the myelin of peripheral nerves, causing ascending paralysis and, in some cases, respiratory failure. CIDP is a chronic inflammation and demyelination, leading to progressive weakness, sensory loss, and impaired motor function. CIDP is considered the chronic counterpart of Guillain-Barre Syndrome (GBS), progresses over months or even years. Multifocal Motor Neuropathy is a rare autoimmune disorder affecting peripheral motor nerves, leading to asymmetric muscle weakness without significant sensory loss.

[0235] In some embodiments, an autoimmune disease is a neuromuscular disorder. In some embodiments, a neuromuscular disease is myasthenia gravis, which is an autoimmune disease caused by autoantibodies that attack acetylcholine receptors or muscle-specific kinase at the neuromuscular junction.

[0236] In some embodiments, an autoimmune disease is a STAT3 / TYK2 -related CNS disease. In some embodiments, a STAT3 / TYK2-related CNS disease is Dentatorubro-pallidoluysian Atrophy (DRPLA), Neuronal Intranuclear Hyaline Inclusion Disease (NIHID), Down's Syndrome, Hallervorden- Spatz disease, prion diseases, cortocobasal degeneration, dementia pugilistica, diffuse neurofibrillary tangles, Gerstmann-Straussler-Scheinker disease, Jakob-Creutzfeldt disease, Niemann-Pick disease type 3, subacute sclerosing panencephalitis, Spinocerebellar Ataxias, Pick's disease, or dentatorubral-pallidoluysian atrophy.

[0237] In some embodiments, an autoimmune disease is a TDP-43 related CNS disease. In some embodiments, a TDP-43 related CNS disease is amyotrophic lateral sclerosis (ALS), ALS-FTLD (frontotemporal lobar degeneration), MSP (Multiple system proteinopathy), FTLD (frontotemporal lobar degeneration), Alzheimer’s disease, Dementia with Lewy bodies, Parkinson’s disease, Huntington’s disease, LATE (limbic-predominant age-related TDP-43 encephalopathy ) / CARTS (cerebral age-related TDP-43 with sclerosis), CTE ( chronic traumatic encephalopathy), Perry disease, FOSMN (facial onset sensory and motor neuronopathy), sIBM (sporadic inclusion body myositis), PSP (Progressive Supranuclear Palsy), CBD (Corticobasal degeneration), or AGD (argyrophilic grain dementia).

[0238] In some embodiments, a TYK2-mediated disease, disorder, or condition is an inflammatory disease.

[0239] In some embodiments, a TYK2-mediated disease, disorder, or condition is a cancer.EXAMPLES

[0240] Example 1.1. KdELECT Competition Binding Assays

[0241] The KdELECT competition assays (Eurofms DiscoverX, San Diego, CA) were employed to assess the dissociation constant (Kd) of compounds with the JH1 kinase catalytic domain or JH2 pseudokinase damain in TYK2 or JAK1-3. In these assays, the test compound competes with an immobilized ligand to bind to a DNA-tagged kinase domain. Compounds that do not bind to the target kinase domain have no effect on the amount of kinase captured by its ligand on the solid surface. Conversely, compounds that bind to the kinase domain inhibit the protein’s binding to the immobilized ligand, thereby reducing the amount of kinase captured on the solid surface. The amount of kinase bound to the immobilized ligand is quantified by amplifying the DNAtags using quantitative PCR (qPCR). A dose-response curve is generated by plotting the qPCR signal intensity as a function of the test compound concentration.

[0242] Binding constants (Kds) were calculated using a standard dose-response curve with the Hill equation:

[0244] The Hill Slope was set to -1. Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.

[0245] Briefly, the JH1 or JH2 protein segments were either expressed on T7 phage coat and tagged with a qPCR detection amplicon or produced in HEK 293 cells as a fusion with the DNA binding domain ofNFkB, and subsequently tagged with a qPCR detection amplicon. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Thetest compound was prepared as 111 x stocks in 100% DMSO and directly diluted into the assay wells. All reactions performed in polypropylene 384-well plate with a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 pM non- biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Results are presented in Table 1.

[0246] Table 1.

[0247] Activity: A < 1 nM; 1 nM < B < 50 nM, C > 50 nM

[0248] Example 1.2. MDCK-MDR1 Assay

[0249] MDCK-MDR1 assay was used to evaluate the permeability and transport of drugs across cellular barriers.

[0250] Preparation ofMDCK-MDRl Cells

[0251] Prior to seeding MDCK-MDR1 cells into a 96-well HTS Transwell plate, 50 pL of cell culture medium was added to each Transwell insert and 25 mL to the reservoir. The plates were incubated at 37 °C with 5% CO2 for 1 hour. The cells were diluted to 1.56 x 106cells / mLwith culture medium, and 50 pL of the cell suspension was dispensed into the fdter wells. The cells were cultured for 3-8 days at 37 °C with 5% CO2 and 95% relative humidity, with the medium replaced every other day, starting no later than 24 hours after initial plating.

[0252] Assessment of Cell Monolayer Integrity

[0253] The medium was removed from both the Transwell inserts and the reservoirs and replaced with pre-warmed fresh culture medium. Transepithelial electrical resistance (TEER) across the cell monolayer was measured using a Millicell Epithelial Volt-Ohm measuring system (Millipore, USA). After measurement, the plates were returned to the incubator. The TEER value was calculated by multiplying the TEER measurement (ohms) by the membrane area (cm2). A TEER value greater than 42 ohm«cm2indicated a well-qualified MDCK-MDR1 monolayer.

[0254] Assay Procedures

[0255] Stock solutions of the test compounds and positive control solutions (metoprolol, prazosin, and imatinib) were prepared at 10 mM in DMSO. The MDCK-MDR1 plates were removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), followed by a 30-minute incubation at 37 °C. Stock solutions of test compounds and controls were diluted to 0.2 mM in DMSO and further diluted in HBSS to a final concentration of 1 pM, with a DMSO concentration of 0.5% in the system.

[0256] To determine the rate of drug transport in the apical-to-basolateral direction, 75 pL of 1 pM working solutions of test and control compounds were added to the Transwell inserts (apical compartment), and 235 pL of HBSS was added to the receiver plate wells (basolateral compartment). The assay was performed in duplicate.

[0257] For the basolateral-to-apical drug transport assay, 235 pL of the 1 pM working solutions were added to the basolateral compartment, and the Transwell inserts (apical compartment) were filled with 75 pL of HBSS. Time 0 samples were collected by transferring 50 pL of the working solution to a 96-deepwell plate, followed by the addition of 200 pL of cold methanol containing appropriate internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac).

[0258] The plates were incubated at 37 °C for 2 hours. After incubation, 50 pL samples from both donor and receiver sides were transferred to a new 96-well plate, followed by the addition of four volumes of cold methanol containing internal standards. The samples were vortexed for 5 minutes, and centrifuged at 3,220 g for 40 minutes. An aliquot of the supernatantwas then mixed with an equal volume of ultrapure water. The resulting samples were analyzed by LC-MS / MS.

[0259] Lucifer Yellow Leakage Test

[0260] Lucifer Yellow stock solution was prepared in water and diluted with HBSS (10 mM HEPES, pH 7.4) to a final concentration of 100 pM. 100 pL of this solution was added to each Transwell insert (apical compartment), and 300 pL of HBSS was added to the receiver plate (basolateral compartment). After 30 minutes of incubation at 37 °C, 80 pL samples were collected from the apical and basolateral wells. Lucifer Yellow fluorescence was measured at 485 nm excitation and 530 nm emission to monitor monolayer integrity.

[0261] Data Analysis

[0262] The apparent permeability coefficient (Papp) was calculated using the following equation:

[0263] Papp—( Ax[drug] acceptor) / (Area^Time < [drug] initial, donor)where VA was the volume in the acceptor well and Area was the membrane surface area (0.143 cm2).

[0264] The efflux ratio was determined using the equation:

[0265] PffluX RatiO=Papp(B-A) Papp(A-B)where PapP(B^A) indicated permeability in the basolateral -to-apical direction, and PaPP(A-> B) indicated permeability in the apical-to-basolateral direction.

[0266] The recovery percentage was calculated as follows:

[0267] ReCOVery%=(VA [drUg]acceptor+ VDX[drug] r) / (VDx[drug] initial, donor) where VA was the acceptor well volume, and VD was the donor well volume.

[0268] Lucifer Yellow leakage was calculated using the equation:

[0269] %LY leakage = 100x[LY]acceptor 0.3 / ([LY]donor 0.1-[LY]aCceptor 0.3)

[0270] A leakage percentage of <1% was deemed acceptable, indicating a well-qualified MDCK-MDR1 monolayer. Results are presented in Table 2.

[0271] Table 2.

[0272] Efflux ratio (ER): A < 3; B > 3

[0273] Example 1.3. Plasma Protein Binding Assay

[0274] Test and control compounds (ketoconazole as the positive control) were prepared in DMSO to a working solution of 200 pM, subsequently diluted in plasma to a final concentration of 1 pM with 0.5% DMSO. Dialysis membranes were conditioned sequentially in ultrapure water, 20% ethanol, and dialysis buffer. Equilibrium dialysis was conducted by adding 150 pL of plasma to each cell of a dialysis setup, dialyzed against an equal volume of PBS buffer at 37°C and 5% CO2 at 100 rpm for 6 hours. Post-dialysis, 50 pL samples from both buffer andplasma chambers were analyzed. Samples were prepared by adding 400 pL of quench solution (acetonitrile with internal standards: 200 nM labetalol, 100 nM tolbutamide, 100 nM ketoprofen) to precipitate proteins and liberate compounds, then vortexed and centrifuged. The supernatant was diluted and analyzed via LC-MS / MS. Stability tests were conducted similarly, with incubation periods of 0 and 6 hours. Data were analyzed using Excel to determine concentrations and calculate percentages of free, bound, and recovered compounds, along with stability at 6 hours based on peak area ratios. Results are presented in Table 3.

[0275] Table 3.

[0276] Mouse PPB: A < 98%; B > 98%

[0277] Example 1.4. Brain Tissue Binding Assay

[0278] The frozen brain tissue homogenate was thawed in a 37°C water bath. The test compound stock solution was diluted to 200 pM in DMSO, spiked into the homogenate, with a final concentration of 1 pM. Propranolol served as a positive control. Dialysis membranes were prepared by soaking in ultrapure water, 20% ethanol and dialysis buffer. The dialysis apparatus was assembled, with 150 pL of the homogenate in each cell dialyzed against an equal volume of 100 mM PBS buffer (pH 7.4) for 6 hours at 37°C, 100 rpm, with 5% CO2. After incubation, 50 pL samples were collected from both the buffer and brain tissue homogenate. For analysis, 50 pL of brain tissue homogenate was added to the buffer samples, and PBS was supplemented to the brain homogenate samples. Proteins were precipitated using acetonitrile containing internal standards (200 nM Labetalol, 200 nM Imipramine and 2 pM Ketoplofen). Samples were vortexed, centrifuged, and supernatants were analyzed by LC-MS / MS. The percentage of bound compound was determined based on peak area ratios from the two chambers.

[0279] Example 1.5. Brain Kpuu Measurement

[0280] A pharmacokinetic study was performed using male SD rat (n=3) to determine brain and plasma exposure of test compounds. The compounds were administered as IV Infusion of 3 mg / kg over 6 hours at a rate of 0.833 mL / kg.hr. The sample was formulated in 20%DMSO,60% PEG400, 20% (2O%HP-0-CD) at a concentration of 0.6 mg / mL. The plasma sampling was done at 2, 4, 5 and 6 hours while the brain sampling was done at 6 hr. Blood was processed to plasma and subjected to ultrafiltration to isolate unbound drug, while brain tissue was weighed, homogenized in PBS, and similarly filtered to separate the unbound fraction. Concentrations of unbound drug in both plasma and brain homogenates were quantified using LC-MS / MS. The unbound partition coefficient (Kpuu) was calculated by dividing the concentration of unbound drug in the brain by that of unbound concentration in the plasma. Results are presented in Table 4.

[0281] Table 4.

[0282] Rat steady state Kpuu: A> 0.1; B < 0.1

[0283] Example 1.6. IFNa-induced TYK2 phosphoSTAT5 Activity

[0284] Human peripheral blood mononuclear cells resuspended in 50 pl of RPMI 1640 medium with 10% FBS were seeded at 200,000 cells per well in a 96-well plate. Test compounds were prepared in 10 rnM DMSO and serially diluted using a TEC AN EV0200. 50nL of the diluted compounds were added to assay plates, incubated at 37°C with 5% CO2 for 1 hour, followed by the addition of 50 pL IFNa (SinoBiological) at the final concentration of 50 ng / mL and a further 15-minute incubation. After centrifugation, 100 pL of media was aspirated, and cells were lysed with 40 pL of lx lysis buffer containing 1 x HALT protease and phosphatase inhibitor cocktail and agitation at 4°C for 20 minutes. 20 uL of lysate supernatant was transferred to a 384-well plate, and the AlphaLlSA protocol for AlphaLlSA SureFire Ultra p-STAT5 (Tyr694 / 699) HV Assay Kit (Revvity, ALSU-PST5-B10K) was followed according to the manufacture’s instruction.

[0285] Inhibition data (duplicates) were calculated by comparison to vehicle control wells for 0% inhibition and non-stimulated control wells for 100% inhibition. Dose response curves were then generated to determine the concentration required to suppress 50% of cellularresponse (IC50) as derived by non-linear regression analysis using GraphPad Prism. Results are presented in Table 5.

[0286] Table 5.IC50: A< 100 nM; 100 nM < B < 1000 nM; C > 1000 nM

[0287] Example 1.7. JAK Cellular Functional Selectivity Assays

[0288] LL-6-induced JAK1 phosphoSTAT3 (pSTAT3), GM-CSF-induced JAK2 pSTAT5, and IL-2-induced JAK1 / 3 pSTAT5 activity assay were performed to assess the JAK cellular selectivity of compounds.

[0289] In human IL-6-pSTAT3 assay, TF1 cells resuspended in 40 pL of DMEM with 1% FBS were plated at 50,000 cells / well in a 384-well plate and incubated at 37°C and 5% CO2 for overnight. Test compounds were prepared in 10 mM DMSO and serially diluted using a TEC ANEV0200. 40nL of the diluted compounds were added to assay plates, incubated at 37°C with 5% CO2 for 1 hour, followed by the addition of 10 pL IL-6 (R& D) at the final concentration of 5 ng / mL, and a further 15-minute incubation. After centrifugation, approximately 40 pL of media was aspirated, and cells were lysed with 10 pL 2x lysis buffer containing 2* HALT protease and phosphatase inhibitor cocktail and agitation at 4°C for 20 minutes. For MSD detection, the standard MSD plate was coated with anti-STAT3 antibody [9D8] (Abeam, abl 19352) in 1:500 dilution and incubated overnight at 4°C with shaking. Following washing, 40 pL of 5% BSA blocking buffer was added to each well and plates were shaken for 1 hour at room temperature. After another round of washing, 20 pL of sample lysates are added to the wells and shaken for 1 hour at room temperature. Following washing, the detection antibody phospho-Stat3 (Tyr705) (D3A7) XP Rabbit mAb (CST, #9145) was added in 1: 300 dilution, and incubated for 1 hour with shaking. After a final wash, 25 pL of anti-rabbit goat antibody with SULFO-TAG labeled (MSD, R32AB-1) was added for detection and reading according to MSD standard protocol.

[0290] For the human GM-CSF-pSTAT5 assay, TF1 cells resuspended in 40 pL of RPMI 1640 Medium with 1% FBS were seeded at 50,000 cells per well in a 384-well plate. The cells were incubated overnight at 37°C with 5% CO2. 40 nL of diluted compounds were added to the assay plates. Following 1 hour of incubation, 10 pL of GM-CSF (R& D) was added at the final concentration of 1 ng / mL, and cells were incubated for an additional 15 minutes. After centrifugation, approximately 40 pL of the medium was aspirated, cells were lysed with 10 pL of 2x lysis buffer containing 2x HALT protease and phosphatase inhibitor cocktail, and lysates were agitated at 4°C for 20 minutes. Then an AlphaLISA protocol for AlphaLISA SureFire Ultra p-STAT5 (Tyr694 / 699) HV Assay Kit (Revvity, ALSU-PST5-B10K) was followed according to the manufacture’s instruction.

[0291] For the human IL-2-pSTAT5 assay, human peripheral blood mononuclear cells resuspended in 50 pl of RPMI 1640 medium with 10% FBS were seeded at 200,000 cells per well in a 96-well plate. 50nL of the diluted compounds were added to assay plates, incubated at 37°C with 5% CO2 for 1 hour, followed by the addition of 50 pL IL -2 (R& D) at the final concentration of 80 ng / mL and a further 10-minute incubation. After centrifugation, 100 pL of media was aspirated, and cells were lysed with 40 pL of lx lysis buffer containing 1* HALT protease and phosphatase inhibitor cocktail and agitation at 4°C for 20 minutes. 20 uL of lysate supernatant was transferred to a 384-well plate, and the AlphaLISA protocol for AlphaLISASureFire Ultra p-STAT5 (Tyr694 / 699) HV Assay Kit (Revvity, ALSU-PST5-B10K) was followed according to the manufacture’s instruction. Results are presented in Table 6.

[0292] Table 6.

[0293] IC50: A< 1 uM; 1 uM < B < 10 uM; C > 10 uM

[0294] Example 2. Synthesis of Exemplary Compounds

[0295] Compounds of Formula I wherein X1=CH, V2=N and V1=C and wherein Ring A further comprises 0 or 1 additional N atoms can be prepared according to general scheme below:wherein Group G is a stannane or boronate residue (e.g., G= Sn(Alk)s or alternatively G=B(0H)2 or G=B(0Alk)2). Ring A and groups R1, R2, R3are defined above. LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, bromo or iodo).

[0296] Step 1: Step 1 is a reaction of the starting 6-membered aminohetereocycle with alkyl 2-oxopropanoate possessing a suitable leaving group (e.g., ethyl 3-bromo-2-oxopropanoate). In cases where the leaving group LG is hydrolyzed during the reaction workup, it is then re-constituted by reacting the intermediate with suitable halogenating reagent (e.g., phosphorous oxychloride).

[0297] Step 2: The alkyl ester intermediate is next hydrolyzed to carboxylic acid using a strong base (e.g., lithium hydroxide) and further subjected to Curtius rearrangement (e.g., using diphenylphosphoryl azide in the presence of suitable base e.g., tri ethylamine in a solvent containing alcohol, e.g., tert-butanol) followed by hydrolysis of the resulting carbamate using strong acid (e.g., trifluoroacetic acid).

[0298] Step 3: The amino intermediate is next converted to amide (e.g., using acyl halide or acid anhydride in the presence of suitable base e.g., tri ethyl amine). Alternatively, the amino intermediate is derivatized as carbamate (e.g., using alkyl chloroformate in the presence of suitable base e.g., triethylamine). Alternatively, the intermediate is converted to a urea (e.g., using methyl isocyanate). Alternatively, the intermediate is coupled with a heteroaromatic halide in a Buchwald-Hartwig cross coupling reaction (e.g., using palladium catalyst e.g., EPhos Pd G4 in the presence of suitable base e.g., sodium phenoxide).

[0299] Step 4: The coupling reagent R2-G is prepared from corresponding aryl halide by treatment with alkylstannane (e.g., hexamethylditin in the presence of suitable palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium(0))). The reagent R2-G is reacted with the intermediate in the presence of suitable palladium catalyst (e.g., bis(tri-tert-butylphosphine)palladium(O)). Alternatively, the coupling reagent R2-G is prepared from corresponding aryl halide by treatment with borylating reagent (e.g., bis(pinacolato)diboron) in the presence of palladium catalyst (e.g., [l, T-bis(diphenylphosphino)ferrocene]palladium(II) dichloride) in the presence of suitable base (e.g., potassium acetate). The reagent R2-G is reacted with the intermediate in the presence of suitable palladium catalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)) and base (e.g., sodium carbonate).

[0300] Compounds of Formula I wherein X1=CH, V2=N and V1=C and wherein Ring A further comprises 0 or 1 additional N atoms can be prepared according to general scheme below:wherein: Group G is a stannane or boronate residue (e.g., G= Sn(Alk)a or alternatively G=B(0H)2 or G=B(0Alk)2). Ring A and groups R1, R2, R3are defined above. LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, bromo or iodo).

[0301] Step 1: Step l is a reaction of the starting 6-membered aminohetereocycle with alkyl 2-oxopropanoate possessing a suitable leaving group (e.g., ethyl 3-bromo-2-oxopropanoate). In cases where the leaving group LG is hydrolyzed during the reaction workup, it is then re-constituted by reacting the intermediate with suitable halogenating reagent (e.g., phosphorous oxychloride).

[0302] Step 2: The coupling reagent R2-G is prepared from corresponding aryl halide by treatment with alkylstannane (e.g., hexamethylditin in the presence of suitable palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium(0))). The reagent R2-Gis reacted with the intermediate in the presence of suitable palladium catalyst (e.g., bis(tri-tert-butylphosphine)palladium(O)). Alternatively, the coupling reagent R2-G is prepared from corresponding aryl halide by treatment with borylating reagent (e.g., bis(pinacolato)diboron) in the presence of palladium catalyst (e.g., [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride) in the presence of suitable base (e.g., potassium acetate). The reagent R2-G is reacted with the intermediate in the presence of suitable palladium catalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)) and base (e.g., sodium carbonate).

[0303] Step 3: The alkyl ester intermediate is next hydrolyzed to carboxylic acid using a strong base (e.g., lithium hydroxide) and further subjected to Curtius rearrangement (e.g., using diphenylphosphoryl azide in the presence of suitable base e.g., tri ethylamine in a solvent containing alcohol, e.g., tert-butanol) followed by hydrolysis of the resulting carbamate using strong acid (e.g., trifluoroacetic acid).

[0304] Step 4: The amino intermediate is next converted to amide (e.g., using acyl halide or acid anhydride in the presence of suitable base e.g., triethylamine). Alternatively, the amino intermediate is derivatized as carbamate (e.g., using alkyl chloroformate in the presence of suitable base e.g., tri ethyl amine). Alternatively, the intermediate is converted to a urea (e.g., using methyl isocyanate). Alternatively, the intermediate is coupled with a heteroaromatic halide in a Buchwald-Hartwig cross coupling reaction (e.g., using palladium catalyst e.g., EPhos Pd G4 in the presence of suitable base e.g., sodium phenoxide).

[0305] Compounds of Formula I wherein X1=CH, V1=N and V2=C and wherein Ring A further comprises 0 or 1 additional N atom can be prepared according to general scheme below:.wherein Group G is a stannane or boronate residue (e.g., G= Sn(Alk)? or alternatively G=B(OH)2 or G=B(OAlk)2). Ring A and groups R1, R2, R3are defined above. LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, bromo or iodo).

[0306] Step 1: The starting material is reacted with carbanion generated from acetonitrile using suitable base (e.g., sodium bis(trimethylsilyl)amide).

[0307] Step 2: The intermediate is reacted with an aminating reagent (e.g., 2-[(aminooxy )sulfonyl]- 1,3,5-trimethylbenzene).

[0308] Step 3: The intermediate is cyclized by exposure to a suitable base (e.g., tri ethylamine).

[0309] Step 4: The amino intermediate is next converted to amide (e.g., using acyl halide or acid anhydride in the presence of suitable base e.g., triethylamine). Alternatively, the amino intermediate is derivatized as carbamate (e.g., using alkyl chloroformate in the presence of suitable base e.g., tri ethyl amine). Alternatively, the intermediate is converted to a urea (e.g., using methyl isocyanate). Alternatively, the intermediate is coupled with a heteroaromatic halidein a Buchwald-Hartwig cross coupling reaction (e.g., using palladium catalyst e.g., EPhos Pd G4 in the presence of suitable base e.g., sodium phenoxide).

[0310] Step 5: The coupling reagent R2-G is prepared from corresponding aryl halide by treatment with alkyl stannane (e.g., hexamethylditin in the presence of suitable palladium catalyst (e.g., tetrakis(triphenylphosphine)palladium(0))). The reagent R2-G is reacted with the intermediate in the presence of suitable palladium catalyst (e.g., bis(tri-tert-butylphosphine)palladium(O)). Alternatively, the coupling reagent R2-G is prepared from corresponding aryl halide by treatment with borylating reagent (e.g., bis(pinacolato)diboron) in the presence of palladium catalyst (e.g., [l, T-bis(diphenylphosphino)ferrocene]palladium(II) dichloride) in the presence of suitable base (e.g., potassium acetate). The reagent R2-G is reacted with the intermediate in the presence of suitable palladium catalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)) and base (e.g., sodium carbonate).

[0311] Compounds of Formula I wherein X1=CH, V1=N and V2=C and wherein Ring A further comprises 0 or 1 additional N atom can be prepared according to general scheme below:wherein Group G is a stannane or boronate residue (e.g., G= SnfAlkp or alternatively G=B(OH)2 or G=B(OAlk)2). Ring A and groups R1, R2, R3are defined above. LG is a suitable leaving group (e g., halogen, e.g., fluoro, chloro, bromo or iodo).

[0312] Step 1: Alkyl 3-nitro-lH-pyrazole-5-carboxylate is reacted with halomethyl ketone in the presence of suitable base (e.g., potassium carbonate).

[0313] Step 2: The intermediate is cyclized using ammonium salt (e.g., ammonium acetate).

[0314] Step 3: The hydroxyl group is converted to a suitable leaving group using halogenating reagent (e.g., phosphorous oxychloride).

[0315] Step 4: The nitro intermediate is reduced to amine using suitable reducing agent (e.g., iron powder in acetic acid).

[0316] Step 5: The amino intermediate is next converted to amide (e.g., using acyl halide or acid anhydride in the presence of suitable base e.g., triethylamine). Alternatively, the amino intermediate is derivatized as carbamate (e.g., using alkyl chloroformate in the presence of suitable base e.g., triethylamine). Alternatively, the intermediate is converted to a urea (e.g., using methyl isocyanate). Alternatively, the intermediate is coupled with a heteroaromatic halide in a Buchwald-Hartwig cross coupling reaction (e.g., using palladium catalyst e g., EPhos Pd G4 in the presence of suitable base e.g., sodium phenoxide).

[0317] Step 6: The coupling reagent R2-G is prepared from corresponding aryl halide by treatment with alkylstannane (e.g., hexamethylditin in the presence of suitable palladium catalyst (e g., tetrakis(triphenylphosphine)palladium(0))). The reagent R2-G is reacted with the intermediate in the presence of suitable palladium catalyst (e.g., bis(tri-tert-butylphosphine)palladium(O)). Alternatively, the coupling reagent R2-G is prepared from corresponding aryl halide by treatment with borylating reagent (e.g., bis(pinacolato)diboron) in the presence of palladium catalyst (e.g., [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride) in the presence of suitable base (e.g., potassium acetate). The reagent R2-G is reacted with the intermediate in the presence of suitable palladium catalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)) and base (e.g., sodium carbonate).

[0318] Compounds of Formula I wherein X1=CH, V1=N and V2=C and wherein Ring A further comprises 0 or 1 additional N atom can be prepared according to the general scheme below:wherein Group G is a stannane or boronate residue (e.g., G= Sn(Alk)s or alternatively G=B(0H)2 or G=B(0Alk)2). Ring A and groups R1, R2, R3are defined above. LG is a suitable leaving group (e.g., halogen, e.g., fluoro, chloro, bromo or iodo).

[0319] Step 1: 3-Nitro-lH-pyrazole-5-carboxylate is reacted with protected 2-aminoacetaldehyde or 2-amino-l-ethan-l-one or substituted 2-amino-l-ethan-l-one in the presence of suitable coupling agent (e.g., carbonyldiimidazole).

[0320] Step 2: The protecting group is removed by treatment with suitable acid (e.g., hydrochloric acid) and the intermediate undergoes cyclization.

[0321] Step 3: The material is treated with a halogenating reagent (e.g., phosphorus oxychloride) what leads to dehydration and concomitant aromatization and conversion of the hydroxyl group into a leaving group (e.g., chloride).

[0322] Step 4: The nitro intermediate is reduced to amine using suitable reducing agent (e g., iron powder in acetic acid).

[0323] Step 5: The amino intermediate is next converted to amide (e.g., using acyl halide or acid anhydride in the presence of suitable base e.g., triethylamine). Alternatively, the amino intermediate is derivatized as carbamate (e.g., using alkyl chloroformate in the presence of suitable base e.g., tri ethyl amine). Alternatively, the intermediate is converted to a urea (e.g., using methyl isocyanate). Alternatively, the intermediate is coupled with a heteroaromatic halidein a Buchwald-Hartwig cross coupling reaction (e.g., using palladium catalyst e.g., EPhos Pd G4 in the presence of suitable base e.g., sodium phenoxide).

[0324] Step 6: The coupling reagent R2-G is prepared from corresponding aryl halide by treatment with alkyl stannane (e.g., hexamethylditin in the presence of suitable palladium catalyst (e g., tetrakis(triphenylphosphine)palladium(0))). The reagent R2-G is reacted with the intermediate in the presence of suitable palladium catalyst (e.g., bis(tri-tert-butylphosphine)palladium(O)). Alternatively, the coupling reagent R2-G is prepared from corresponding aryl halide by treatment with borylating reagent (e.g., bis(pinacolato)diboron) in the presence of palladium catalyst (e.g., [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride) in the presence of suitable base (e.g., potassium acetate). The reagent R2-G is reacted with the intermediate in the presence of suitable palladium catalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)) and base (e.g., sodium carbonate).

[0325] GENERAL PROCEDURES:

[0326] Procedure A

[0327] The solution of the carboxylic acid (6.00 mmol, 1.0 eq) in dichloroethane (36 m ) was stirred at 80 °C for 4 h. The reaction mixture was evaporated under reduced pressure, diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

[0328] Procedure B

[0329] To a stirred solution of aryl halide (5.49 mmol, 1.0 eq) in 1,4-dioxane (28 mL) was added hexamethylditin (2.87 g, 8.75 mmol, 1.6 eq). The reaction mixture was degassed by bubbling a stream of argon for 5 min. Tetrakis(triphenylphosphine)palladium(0) (0.315 g, 0.27 mmol, 0.05 eq) was added, and the solution was again degassed for 5 min. The reaction mixture was stirred at 100 °C for 16 h and then cooled to an ambient temperature. The reaction mixture was diluted with 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.

[0330] Procedure Cl

[0331] To a stirred solution of the aryl halide (8.35 mmol, 1.0 eq) in N, N-dimethylformamide (40 mL) was added the aryltrimethylstannyl coupling partner (16.69 mmol, 2.0 eq). The reaction mixture was degassed by bubbling through a stream of argon for 5 min.Bis(tri-t-butylphosphine)palladium(0) (0.426 g, 0.83 mmol, 0.1 eq) was added and the solution was again degassed for 5 min. The solution was stirred at 100 °C for 6 h. The reaction mixture was cooled to an ambient temperature, diluted with 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.

[0332] Procedure C2

[0333] To a stirred solution of aryl halide (0.872 mmol, 1.0 eq) in N, N-dimethylformamide (3 mL) was added the aryltrimethylstannyl coupling partner (1.05 mmol, 1.2 eq). The reaction mixture was degassed by bubbling through a stream of argon for 5 min.Bis(triphenylphosphine)palladium(II) dichloride (61 mg, 0.087 mmol, 0.1 eq) was added and the solution was again degassed for 5 minutes. The reaction mixture was heated at 100 °C for 4 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure.

[0334] Procedure D

[0335] To a stirred solution of carboxylic ester (1.05 mmol, 1.0 eq) in methanol (3 mL) and tetrahydrofuran (3 mL) was added lithium hydroxide monohydrate (0.11 g, 2.63 mmol, 2.5 eq) in water (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was evaporated under reduced pressure, diluted with cold water and acidified with 2N hydrochloric acid until pH ~ 4. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound.

[0336] Procedure E

[0337] A solution of diphenylphosphoryl azide (0.131 g, 1.48 mmol, 1.2 eq) and triethylamine (0.048 g, 0.48 mmol, 1.2 eq) was added to a stirred solution of the carboxylic acid (0.40 mmol, 1.0 eq) in toluene (3 mL) and tert-butanol (3 mL). The reaction mixture was stirred at 125 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with saturated aq. 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.

[0338] Procedure F

[0339] To a stirred solution of tert-butyl carbamate (0.060 g, 0.14 mmol, 1.0 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (0.25 mL) at 0 °C. The temperature wasraised to room temperature and the solution was stirred for 4 h. The reaction mixture was evaporated under reduced pressure, diluted with saturated aq. 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.

[0340] Procedure G

[0341] To a stirred solution of amine (0.03 g, 0.09 mmol, 1.0 eq) in tetrahydrofuran (2 mb) was added N, N-diisopropylethylamine (0.036 g, 0.28 mmol, 3.0 eq) and acetic anhydride (0.02 g, 0.19 mmol, 2.0 eq) in tetrahydrofuran at 0 °C. The temperature was raised to 60 °C and the solution was stirred for 4 h. The reaction mixture was cooled to room temperature, diluted with 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.

[0342] Procedure Hl

[0343] To a stirred solution of aryl fluoride (24.27 mmol, 1.0 eq) and amine or amine hydrochloride (36.41 mmol, 1.5 eq) in dimethylsulfoxide (50 mL), was added potassium carbonate (6.69 g, 48.54 mmol, 2.0 eq). The reaction mixture was heated at 90 °C for 2 h. Next, the reaction mixture was diluted with 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.

[0344] Procedure H2

[0345] To a stirred solution of aryl fluoride (1.94 mmol, 1.0 eq) in dimethyl sulfoxide (5 mL), was added cesium carbonate (1.27 g, 3.88 mmol, 2.0 eq) and the amine or amine hydrochloride (2.91 mmol, 1.5 eq). The reaction mixture was heated at 90 °C for 2 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure.

[0346] Procedure H3

[0347] To a stirred solution of aryl fluoride (2.84 mmol, 1.0 eq) in dimethyl sulfoxide (5 mL) was added amine or amine hydrochloride (3.41 mmol, 1.2 eq) and N, N-diisopropylethylamine (1.84 g, 14.21 mmol, 5.0 eq). The solution was stirred at 120 °C for 2 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

[0348] Procedure H4

[0349] To a stirred solution aryl fluoride (11.36 mmol, 1.0 eq) in N-methylpyrrolidone (40 mL) was added potassium carbonate (3.14 g, 22.73 mmol, 2.0 eq) at 0 °C followed by addition of amine (17.05 mmol, 1.5 eq) and the reaction was further stirred at 150 °C for 6 h. Next, the reaction was diluted with cold water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

[0350] Procedure H5

[0351] To a stirred solution of aryl fluoride (1.36 mmol, 1.0 eq) in N, N-dimethylformamide (2.0 mL) was added potassium carbonate (377.2 mg, 2.73 mmol, 2.0 eq) and the amine or amine hydrochloride (1.77 mmol, 1.3 eq). The reaction mixture was heated at 90 °C for 2 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

[0352] Procedure II

[0353] To a stirred solution the nitro compound (2.35 mmol, 1.0 eq) in ethanol (2.5 mL) was added acetic acid (2.5 mL) and iron powder (0.394 g, 7.06 mmol, 3.0 eq). The reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was cooled to room temperature, evaporated under reduced pressure, diluted with saturated aq. 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.

[0354] Procedure 12

[0355] Iron powder (1.02 g, 18.21 mmol, 5.0 eq) and ammonium chloride (0.97 g, 18.21 mmol, 5.0 eq) was added to a stirred solution of the nitro compound (3.64 mmol, 1.0 eq) in ethanol (10 mL) and water (5 mL). The reaction mixture was stirred at 90 °C for 4 h. Next, the reaction mixture was filtered through small pad of celite, the filtrate was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure.

[0356] Procedure J

[0357] To a stirred solution of amine (0.94 mmol, 1.0 eq) in N, N-dimethylformamide (5 mL) was added sodium hydride (68.10 mg, 2.84 mmol, 3.0 eq, 60% dispersion in oil) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, followed by the addition of iodomethane(1.34 g, 9.45 mmol, 10.0 eq) at 0 °C. The reaction mixture was then allowed to warm at room temperature and was further stirred for 16 h. Next, the reaction mixture was diluted with 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.

[0358] Note: The assignment of stereochemistry of enantiomers is arbitrary unless otherwise stated.

[0359] Example 2.1. Synthesis of N-(7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidin-2-yl)acetamide (1-125)

[0360] Synthesis of 4-(6-bromo-4-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile. To a stirred solution of 2-bromo-6-fluoro-4-methyl-pyridine (5.00 g, 26.31 mmol, 1.0 eq) in tetrahydrofuran (50 mb), was added tetrahydropyran-4-carbonitrile (2.92 g, 26.31 mmol, 1.0 eq). The resulting solution was cooled to -20 °C and sodium bis(trimethylsilyl)amide(35% solution in tetrahydrofuran, 41.25 mL, 78.94 mmol, 1.5 eq) was added and the solution was stirred at -20 °C for 4 h. The reaction mixture was diluted with aq. 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 residue was purified by flash column chromatography on silica gel (Combiflash, 15% ethyl acetate in hexane) to afford the title compound (4.40 g, off white solid). MS (ES): / z 281.1 [M+H]+.

[0361] Synthesis of 4-(6-bromo-4-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid. To a stirred solution of 4-(6-bromo-4-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (3.00 g, 10.67 mmol, 1.0 eq) in ethanol (60 mL), was added solution of sodium hydroxide (25% solution in water, 30 mL) at 0 °C. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was evaporated, diluted with cold water and treated with a solution of 2N hydrochloric acid until pH ~ 4. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound (1.80 g, white solid). MS (ES): z 300.0 [M+H]+.

[0362] Synthesis of 2-bromo-4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridine.4-(6-Bromo-4-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid (1.80 g, 6.00 mmol, 1.0 eq) was subjected to the conditions described in the General Procedure A. The crude material was purified by flash column chromatography on silica gel (Combiflash, 45% ethyl acetate in hexane) to afford the title compound (1.40 g, off white solid). MS (ES): m / z 256.1 [M+H]+.

[0363] Synthesis of 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6- (trimethylstannyl)pyridine.2-Bromo-4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridine (1.40 g, 5.49 mmol, 1.0 eq) was subjected to the conditions described in the General Procedure B to afford the title compound (1.80 g, light brown oil), which was used in the next step without further purification. MS (ES): m z 341.2 [M+H]+.

[0364] Synthesis of ethyl 5-hydroxy-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate. To a stirred solution of 2-chloro-6-methylpyrimidin-4-amine (10.00 g, 69.65 mmol, 1.0 eq) and ethyl 3-bromo-2-oxopropanoate (33.96 g, 174.13 mmol, 2.5 eq) in ethanol (200 mL) was added acetic acid (41.99 g, 699.15 mmol, 10 eq) at 0 °C. The reaction mixture was heated at 90 °C for 16 h. The reaction mixture was then cooled to room temperature and evaporated under reduced pressure. The residue was diluted with saturated aq. sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodiumsulfate, concentrated under reduced pressure and triturated with n-pentane to afford the title compound (8.00 g, off white solid). MS (ES): m'z 222.2 [M+H]+.

[0365] Synthesis of ethyl 5-chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate.To a stirred solution of ethyl 5-hydroxy-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (8.00 g, 36.16 mmol, 1.0 eq) in phosphorus (V) oxychloride (160 mL) was added N. N-diisopropylethylamine (80 mL) at 0 °C. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature, evaporated under reduced pressure, diluted with saturated aq. 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 residue was purified by flash column chromatography on silica gel (Combiflash, 65% ethyl acetate in hexane) to afford the title compound (2.50 g, brown solid). MS (ES): m / z 240.2 [M+H]+.

[0366] Synthesis of ethyl 7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylate. Ethyl 5-chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (2.00 g, 8.35 mmol, 1.0 eq) and 4-methyl-2-(tetrahydro-2EI-pyran-4-yl)-6-(trimethylstannyl)pyridine (5.68 g, 16.69 mmol, 2.0 eq) were subjected to the conditions described in the General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 45% ethyl acetate in hexane) to afford the title compound (1.30 g, light yellow solid). MS (ES): m / z 381.0 [M+H]+.

[0367] Synthesis of 7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid. Ethyl 7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylate (0.40 g, 1.05 mmol, 1.0 eq) was subjected to the conditions described in the General Procedure D to afford the title compound (0.24 g, off white solid). MS (ES): m'z 353.2 [M+H]+.

[0368] Synthesis of tert-butyl (7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidin-2-yl)carbamate. 7-Methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid (0.140 g, 0.40 mmol, 1.0 eq) was subjected to the conditions described in the General Procedure E. The residue was purified by flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford the title compound (0.070 g, light yellow solid). MS (ES): m / z 424.4 [M+H]+.

[0369] Synthesis of 7-methyl-5-(4-inethyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidin-2-amine. Tert-butyl (7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidin-2-yl)carbamate (0.060 g, 0.14 mmol, 1.0 eq) was subjected to the conditions described in the General Procedure F. The residue was triturated with ethyl acetate and n-pentane to afford the title compound (0.030 g, light yellow solid). MS (ES): m / z 324.3 [M+H]+.

[0370] Synthesis of 1-125.7-Methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidin-2-amine (0.03 g, 0.09 mmol, 1.0 eq) was subjected to the conditions described in the General Procedure G. The residue was triturated with ethyl acetate and n-pentane to afford compound 1-125 (0.010 g, light yellow solid). MS (ES): m / z 366.4 [M+H]+; 'H NMR(DMSO-d6, 400MHz): 8 10.78 (s, 1H), 9.35 (s, 1H), 8.12 (s, 1H), 7.41 (s, 2H), 4.02 (dd, J = 12.3, 8.8 Hz, 2H), 3.55 - 3.47 (m, 2H), 3.08 - 3.04 (m, 1H), 2.54 (s, 3H), 2.46 (s, 3H), 2.10 (s, 3H), 1.96 - 1.91 (m, 4H).

[0371] Example 2.2. Synthesis of N,7-dimethyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxamide (1-387)

[0372] Synthesis of 7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carbonyl azide. To a stirred solution of 7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid (0.35 g, 0.99 mmol, 1.0 equiv) in 1,4-dioxane (3.5 mL), was added solution of triethylamine (0.131 g, 1.29 mmol, 1.3 equiv) and diphenylphosphoryl azide (0.355 g, 1.29 mmol, 1.3 equiv) in 1,4-dioxane at 0 °C. The temperature was raised to room temperature and the solution was stirred for 6 h. The reaction mixture was diluted with saturated aq. sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and triturated with n-pentane to afford the title compound (0.400 g, yellow oil), which was used in the next step without further purification. MS (ES): m / z 378.4 [M+H]+.

[0373] Synthesis of T-387. To a stirred solution of 7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carbonyl azide (0.400 g, 1.06 mmol, 1.0 equiv) in toluene (8 mL), was added acetic acid (0.127 g, 2.12 mmol, 2.0 equiv) and 4-dimethylaminopyridine (0.013 g, 0.11 mmol, 0.1 equiv) at room temperature. The temperature of the reaction mixture was raised to 110 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with saturated aq. sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, fdtered, concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.8% methanol in dichloromethane) to afford compound 1-387 (0.022 g, light yellow solid). MS (ES): m / z 366.3 [M+H]+. 'HNMR (DMSO-d6, 400 MHz): 59.46 (s, 1H), 8.51 (d, J= 5.0 Hz, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 4.03 - 4.00 (m, 2H), 3.53 (td, J= 11.3, 3.3 Hz, 2H), 3.19 - 3.05 (m, 1H), 2.81 (d, J= 4.7 Hz, 3H), 2.58 (s, 3H), 2.48 (s, 3H), 1.94 - 1.80 (m, 4H).

[0374] Example 2.3. Synthesis of N-(5-(6-(4-cyanotetrahydro-2H-pyran-4-yl)-4-methylpyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)acetamide (1-235)

[0375] Synthesis of 4-(4-methyl-6-(trimethylstannyl)pyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile. 4-(6-Bromo-4-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (1.50 g, 5.34 mmol, 1.0 eq) was subjected to the conditions described in the General Procedure B to afford the title compound (1.20 g, brown oil), which was used in the next step without further purification. MS (ES): m / z 367.2 [M+H]+.

[0376] Synthesis of ethyl 5-(6-(4-cyanotetrahydro-2H-pyran-4-yl)-4-methylpyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate. Ethyl 5-chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (1 g, 4.17 mmol, 1.0 eq) and 4-(4-methyl-6-(trimethylstannyl)pyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (3.05 g, 8.35 mmol, 2.0 eq) were subjected to the conditions described in the General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford the title compound (0.75 g, light yellow solid). MS (ES): m / z 406.2 [M+H]+.

[0377] Synthesis of 5-(6-(4-cyanotetrahydro-2H-pyran-4-yl)-4-methylpyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid. Ethyl 5-(6-(4-cyanotetrahydro-2H-pyran-4-yl)-4-methylpyri din-2 -yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (0.420 g, 1.04 mmol, 1.0 eq) was subjected to the conditions described in the General Procedure D to afford the title compound (0.21 g, off white solid). MS (ES): m / z 378.2 [M+H]+.

[0378] Synthesis of tert-butyl (5-(6-(4-cyanotetrahydro-2H-pyran-4-yl)-4-methylpyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate. 5-(6-(4-Cyanotetrahydro-2H-pyran-4-yl)-4-methylpyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid (0.190 g, 0.50 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E. The residue was purified by flash column chromatography on silica gel (Combiflash, 85% ethyl acetate in hexane) to afford the title compound (0.095 g, light yellow solid). MS (ES): m / z 449.4 [M+H]+.

[0379] Synthesis of 4-(6-(2-amino-7-methylimidazo[l,2-c]pyrimidin-5-yl)-4-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile. Tert-butyl (5-(6-(4-cyanotetrahydro-2H-pyran-4-yl)-4-methylpyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate (0.095 g, 0.21 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F. The residue was triturated with ethyl acetate and n-pentane to afford the title compound (0.040 g, light yellow solid). MS (ES): m / z 349.3 [M+H]+.

[0380] Synthesis of compound 1-235. 4-(6-(2-Amino-7-methylimidazo[l,2-c]pyrimidin-5-yl)-4-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (0.04 g, 0.11 mmol, 1.0 eq) wassubjected to the conditions described in General Procedure G. The residue was triturated with ethyl acetate and n-pentane to afford compound 1-235 (0.012 g, light yellow solid). MS (ES): m / z 391.3 [M+H]+;XH NMR (DMSO-d6, 400 MHz): 8 10.84 (s, 1H), 9.27 (s, 1H), 8.32 (s, 1H), 7.77 (s, 1H), 7.45 (s, 1H), 4.06 (td, J= 9.5, 5.2 Hz, 2H), 3.74 (td, J= 11.6, 2.8 Hz, 2H), 2.56 (d, J = 3.8 Hz, 6H), 2.43 -2.32 (m, 4H), 2.11 (s, 3H).

[0381] Example 2.4. Synthesis of N-(5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl) pyridin-2-yl)-7-methylimidazo [1,2-c] pyrimidin-2-yl) acetamide (1-38)

[0382] Synthesis of 6-bromo-2-fluoropyridin-3-ol. To a stirred solution of 2-fluoropyridin-3-ol (25.00 g, 221.23 mmol, 1.0 eq) and sodium acetate (18.14 g, 221.23 mmol, 1.0 eq) in acetic acid (250 mL), was added bromine (17.67 g, 221.23 mmol, 1.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with aq. ammonium chloride solution and extracted with ethyl acetate. The combined organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford the title compound (36.0 g, off white solid). MS (ES): m / z 189.9 [M-H]+.

[0383] Synthesis of 6-bromo-2-fluoro-3-methoxypyridine. To a stirred solution of 6-bromo-2-fluoropyri din-3 -ol (26.00 g, 136.16 mmol, 1.0 eq) in N, N-dimethylformamide (260 mL), was added potassium carbonate (37.58 g, 272.33 mmol, 2.0 eq) at room temperature. The resulting reaction mixture was cooled to 0 °C. Methyl iodide (19.32 g, 136.16 mmol, 1 eq) was added to the reaction mixture and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 15% ethyl acetate in hexane) to afford the title compound (15.0 g, white solid).NMR (CDCh, 400 MHz): 57.41 - 7.17 (m, 2H), 3.90 (s, 3H).

[0384] Synthesis of 4-(6-bromo-3-methoxypyridin-2-yI)tetrahydro-2H-pyran-4-carbonitrile. To a stirred solution of 6-bromo-2-fluoro-3-methoxypyridine (3.00 g, 14.63 mmol, 1.0 eq) in tetrahydrofuran (30 mL), was added tetrahydro-2H-pyran-4-carbonitrile (1.62 g, 14.63 mmol, 1.0 eq) at room temperature. The resulting reaction mixture was cooled to -20 °C. Sodium bis(trimethylsilyl)amide (35% solution in tetrahydrofuran, 9.7 mL, 17.56 mmol, 1.2 eq) was added and the solution was stirred at -20 °C for 4 h. The reaction mixture was diluted with aq. ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford the title compound (3.80 g, off white solid). MS (ES): m / z 297.2 [M+H]1.

[0385] Synthesis of 4-(6-bromo-3-methoxypyridin-2-yI)tetrahydro-2H-pyran-4-carboxylic acid. To a stirred solution of 4-(6-bromo-3-methoxypyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (3.30 g, 11.14 mmol, 1.0 eq) in ethanol (33 mL), was added hydrochloric acid (12N in water, 66 mL) at 0 °C. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with cold water. The precipitate was filtered, washed with water anddried under vacuum to afford the title compound (1.10 g, white solid). MS (ES): m / z 315.9 [M+H]+.

[0386] Synthesis of 6-bromo-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyridine.4-(6-Bromo-3-methoxypyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid (1.10 g, 3.49 mmol, 1.0 eq) was subjected to the conditions described in General Procedure A. The residue was purified by flash column chromatography on silica gel (Combiflash, 50% ethyl acetate in hexane) to afford the title compound (0.50 g, white solid). MS (ES): m / z 272.1 [M+H]+.

[0387] Synthesis of 3-methoxy-2-(tetrahydro-2H-pyran-4-yl)-6- (trimethylstannyl)pyridine. 6-Bromo-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyridine (0.50 g, 1.84 mmol, 1.0 eq) was subjected to the conditions described in General Procedure B to afford the title compound (0.41 g, brown oil), which was used in the next step without further purification. MS (ES): m / z 357.9 [M+H]+.

[0388] Synthesis of ethyl 5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate. 3-Methoxy-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (0.19 g, 0.79 mmol, 1.0 eq) and ethyl 5-chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (0.41 g, 1.11 mmol, 1.4 eq) were subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 55% ethyl acetate in hexane) to afford the title compound (0.36 g, light yellow solid). MS (ES): m / z 396.6 [M+H]+.

[0389] Synthesis of 5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid. Ethyl 5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (0.36 g, 0.90 mmol, 1.0 eq) was subjected to the conditions described in General Procedure D to afford the title compound (0.18 g, white solid). MS (ES): m / z 368.9 [M+H]+.

[0390] Synthesis of tert-butyl (5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate. 5-(5-Methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid (0.180 g, 0.48 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E. The residue was purified by flash column chromatography on silica gel (Combiflash, 75% ethyl acetate in hexane) to afford the title compound (0.045 g, light yellow solid). MS (ES): m / z 440.1 [M+H]+.

[0391] Synthesis of 5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine. Tert-butyl (5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate (0.045 g, 0.10 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F to afford the title compound (0.032 g, brown oil) as a trifluoroacetate salt, which was used in the next step without further purification. MS (ES): m / z 340.0 [M+H]+.

[0392] Synthesis of compound 1-38. 5-(5-Methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine (0.03 g, 0.06 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G. The residue was triturated with ethyl acetate and n-pentane to afford compound 1-38 (0.011 g, light yellow solid). MS (ES): m / z 382.1 [M+H]+; ’H NMR (DMSO-d6, 400 MHz): 8 10.75 (s, 1H), 9.36 (s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 7.66 (d, J= 8.8 Hz, 1H), 7.34 (s, 1H), 4.05 - 3.96 (m, 2H), 3.96 (s, 3H), 3.52 (td, J = 11.8, 2.0 Hz, 2H), 3.50 - 3.35 (m, 1H), 2.53 (s, 3H), 2.10 (s, 3H), 2.08 - 1.94 (m, 2H), 1.81 (d, J = 12.4 Hz, 2H).

[0393] Example 2.5. Synthesis of N-(5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)acetamide (1-63)

[0394] Synthesis of 4-(6-bromo-3-methoxypyridin-2-yl)morpholine. 6-Bromo-2-fluoro-3 -methoxypyridine (5.00 g, 24.27 mmol, 1.0 eq) and morpholine (3.17 g, 36.41 mmol, 1.5 eq) were subjected to the conditions described in General Procedure Hl to afford the title compound (3.50 g, off white solid). MS (ES): m / z T / >.\ [M+H]+.

[0395] Synthesis of 4-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)morpholine.4-(6- Bromo-3-methoxypyridin-2-yl)morpholine (1.00 g, 3.67 mmol, 1.0 eq) was subjected to the conditions described in General Procedure B to afford the title compound (1.30 g, light brown oil), which was used in the next step without further purification. MS (ES): m / z 359.1 [M+H]+.

[0396] Synthesis of ethyl 5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate. Ethyl 5-chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (0.67 g, 2.80 mmol, 1.0 eq) and 4-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)morpholine (1.3 g, 3.64 mmol, 1.3 eq) were subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford the title compound (0.200 g, light yellow solid). MS (ES): m / z 398.0 [M+H]+.

[0397] Synthesis of 5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid. Ethyl 5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (0.20 g, 0.50 mmol, 1.0 eq) was subjected to the conditions described in General Procedure D to afford the title compound (0.200 g, off white solid). MS (ES): m / z 370.2 [M+H]+.

[0398] Synthesis of tert-butyl (5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate. 5-(5-Methoxy-6-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid (0.20 g, 0.54 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford the title compound (0.090 g, light yellow solid). MS (ES): m / z 441.3 [M+H]+.

[0399] Synthesis of 5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine. Tert-butyl (5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate (0.09 g, 0.20 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F to afford the title compound (0.090 g, light brownoil) as tri fluoroacetate salt, which was used in the next step without further purification. MS (ES): m / z 341.2 [M+H]+.

[0400] Synthesis of compound 1-63. 5-(5-Methoxy-6-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine (0.09 g, 0.20 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G. The residue was triturated with ethyl acetate and n-pentane to afford compound 1-63 (0.039 g, light yellow solid). MS (ES): m / z 383.3 [M+H]+; 'H NMR (DMSO-d6, 400MHz): 8 10.77 (s, 1H), 9.47 (s, 1H), 8.15 (d, J= 8.4 Hz, 1H), 7.54 - 7.52 (m, 1H), 7.30 (s, 1H), 3.93 (d, J= 1.7 Hz, 3H), 3.83 - 3.77 (m, 4H), 3.50 (t, J= 4.7 Hz, 4H), 2.50 (s, 3H), 2.10 (s, 3H).

[0401] Example 2.6. Synthesis of N-(5-(5-methoxy-6-(l,4-oxazepan-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)acetamide (1-70)

[0402] Synthesis of 4-(6-bromo-3-methoxypyridin-2-yl)-l,4-oxazepane. 6-Bromo-2-fluoro-3-methoxypyridine (4.00 g, 19.51 mmol, 1.0 eq) and 1,4-oxazepane (1.97 g, 19.51 mmol, 1.0 eq) were subjected to the conditions described in General Procedure Hl. The residue was purified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford the title compound (2.7 g, colorless oil). MS (ES): m / z 287.1 [M+H]+.

[0403] Synthesis of 4-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)-l,4-oxazepane.4-(6-Bromo-3-methoxypyridin-2-yl)-l,4-oxazepane (1 g, 3.90 mmol, 1.0 eq) was subjected to the conditions described in General Procedure B to afford the title compound (1.0 g, brown oil), which was used in the next step without further purification. MS (ES): m / z 372.1 [M+H]+.

[0404] Synthesis of ethyl 5-(5-methoxy-6-(l,4-oxazepan-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate. Ethyl 5-chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (1.00 g, 4.18 mmol, 1.5 eq) and 4-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)-l,4-oxazepane (1.00 g, 2.69 mmol, 1.0 eq was subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 2.8% methanol in dichloromethane) to afford the title compound (1.2 g, yellow solid). MS (ES): m / z 412.6 [M+H]+.

[0405] Synthesis of 5-(5-methoxy-6-(l,4-oxazepan-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid. Ethyl 5-(5-methoxy-6-(l,4-oxazepan-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (1.2 g, 2.91 mmol, 1.0 eq) was subjected to the conditions described in General Procedure D to afford the title compound (0.700 g, yellow solid). MS (ES): m / z 384.30 [M+H]+.

[0406] Synthesis of tert-butyl (5-(5-methoxy-6-(l,4-oxazepan-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate. 5-(5-Methoxy-6-(l,4-oxazepan-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid (0.700 g, 1.83 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E. The residue was purified by flash column chromatography on silica gel (Combiflash, 3% methanol in dichloromethane) to afford the title compound (0.300 g, yellow solid). MS (ES): m / z 455.5 [M+H]+.

[0407] Synthesis of 5-(5-methoxy-6-(l,4-oxazepan-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine. Tert-butyl (5-(5-methoxy-6-(l,4-oxazepan-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate (0.150 g, 0.33 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F to afford the title compound (0.100 g, brown oil) as a trifluoroacetate salt, which was used in next step without further purification. MS (ES): m / z 355.33 [M+H]+.

[0408] Synthesis of compound 1-70. 5-(5-Methoxy-6-(l,4-oxazepan-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine (0.100 g, 0.22 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G. The residue was triturated with ethyl acetate and n-pentane to afford compound 1-70 (0.040 g, light yellow solid). MS (ES): m / z 397.5 [M+H]+; 'H NMR (DMSO-d6, 400 MHz): 5 10.75 (s, 1H), 9.26 (s, 1H), 7.92 (d, J= 8.2 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 3.90 (s, 3H), 3.83 - 3.79 (m, 6H), 3.69 - 3.67 (m, 2H), 2.56 (s, 3H), 2.09 (s, 3H), 1.97 (p, J= 5.6 Hz, 2H).

[0409] Example 2.7. Synthesis of N-(7-methyl-5-(6-morpholinopyridin-2-yl)imidazo[l,2-c]pyrimidin-2-yl)acetamide (1-151)

[0410] Synthesis of 4-(6-bromopyridin-2-yl)morpholine. To a stirred solution of 2,6-dibromopyridine (2.00 g, 8.44 mmol, 1.0 eq) and morpholine (0.736 g, 8.44 mmol, 1.0 eq) in N, N-dimethylformamide (40 mL), was added cesium carbonate (2.75 g, 8.44 mmol, 1.0 eq). The reaction mixture was stirred at 120 °C for 5 h and cooled to ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 30% ethyl acetate in hexane) to afford the title compound (1.50 g, orange solid). MS (ES): m / z 243.2 [M+H]+.

[0411] Synthesis of 4-(6-(trimethylstannyl)pyridin-2-yl)morpholine. 4-(6- Bromopyridin-2-yl)morpholine (1.00 g, 4.11 mmol, 1.0 eq) was subjected to the conditions described in General Procedure B to afford the title compound (1.5 g, brown oil) which was used in the next step without further purification. MS (ES): m / z 329.2 [M+H]+.

[0412] Synthesis of ethyl 7-methyl-5-(6-morpholinopyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylate. 5-Chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (1.00 g, 4.17 mmol, 1.0 eq) and 4-(6-(trimethylstannyl)pyridin-2-yl)morpholine (2.73 g, 8.35 mmol, 2.0 eq) were subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 50% ethyl acetate in hexane) to afford the title compound (0.900 g, light yellow solid) MS (ES): m / z 368.5 [M+H]+.

[0413] Synthesis of 7-methyl-5-(6-morpholinopyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid. 7-Methyl-5-(6-morpholinopyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylate (0.900 g, 2.45 mmol, 1.0 eq) was subjected to the conditions described in General Procedure D to afford the title compound (0.330 g, off white solid). MS (ES): m / z 340.3 [M+H]+.

[0414] Synthesis of tert-butyl (7-methyl-5-(6-morpholinopyridin-2-yl)imidazo[l,2-c]pyrimidin-2-yl)carbamate. 7-Methyl-5-(6-morpholinopyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid (0.300 g, 0.88 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E. The residue was purified by flash column chromatography on silica gel (Combiflash, 90% ethyl acetate in hexane) to afford the title compound (0.140 g, light yellow solid). MS (ES): m / z 411.3 [M+H]+.

[0415] Synthesis of 7-methyl-5-(6-morpholinopyridin-2-yl)imidazo[l,2-c]pyrimidin- 2-amine. Tert-butyl (7-methyl-5-(6-morpholinopyridin-2-yl)imidazo[l,2-c]pyrimidin-2-yl)carbamate (0.140 g, 0.34 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F. The residue was triturated with ethyl acetate and n-pentane to afford the title compound (0.070 g, light yellow solid). MS (ES): m / z 311.3 [M+H]+.

[0416] Synthesis of compound 1-151. 7-Methyl-5-(6-morpholinopyridin-2-yl)imidazo[l,2-c]pyrimidin-2-amine (0.060 g, 0.19 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G. The residue was purified by flash column chromatography on silica gel (Combiflash, 95% ethyl acetate in hexane) to afford compound I-151 (0.032 g, light yellow solid). MS (ES): m / z 353.2 [M+H]+. 'H NMR (DMSO-d6, 400 MHz):8 10.80 (s, 1H), 9.31 (s, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.77 (d, J= 7.4 Hz, 1H), 7.37 (s, 1H), 7.11 (d, J= 8.3 Hz, 1H), 3.79 (t, J= 4.8 Hz, 4H), 3.63 (t, J= 4.8 Hz, 4H), 2.53 (s, 3H), 2.09 (s, 3H).

[0417] Example 2.8. Synthesis of N-(5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-a]pyridin-2-yl)acetamide (1-386)

[0418] Synthesis of ethyl 5-bromoimidazo[l,2-a]pyridine-2-carboxylate. To a stirred solution of 6-bromopyridin-2-amine (5.00 g, 28.90 mmol, 1.0 eq) and ethyl 3-bromo-2-oxopropanoate (6.20 g, 31.79 mmol, 1.1 eq) in ethanol (100 mL). The reaction mixture was heated at 90 °C for 3 h. The reaction mixture was cooled to room temperature. The precipitate was filtered, washed with diethyl ether and dried under vacuum and triturated with n-pentane to afford the title compound (8.00 g, off white solid). MS (ES): m / z 269.2 [M+H]+.

[0419] Synthesis of 5-bromoimidazo[l,2-a]pyridine-2-carboxylic acid. Ethyl 5-bromoimidazo[l,2-a]pyridine-2-carboxylate (8.00 g, 29.73 mmol, 1.0 eq) was subjected to the conditions described in General Procedure D with reaction time shortened to 3 h. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound (5.00 g, white solid). MS (ES): m / z 241.08 [M+H]+.

[0420] Synthesis of tert-butyl (5-bromoimidazo[l,2-a]pyridin-2-yl)carbamate. 5-Bromoimidazo[l,2-a]pyridine-2-carboxylic acid (1.50 g, 6.25 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E with reaction time shortened to 2 h. The residue was purified by flash column chromatography on silica gel (Combiflash, 25% ethyl acetate in hexane) to afford the title compound (0.900 g, off white solid). MS (ES): m / z 256.10 [M-56],

[0421] Synthesis of 5-bromoimidazo[l,2-a]pyridin-2-amine. Tert-butyl (5-bromoimidazo[l,2-a]pyridin-2-yl)carbamate (0.500 g, 1.60 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F to afford the title compound (0.450 g, brown oil) as a trifluoroacetate salt, which was used in next step without further purification. MS (ES): m / z 212 [M+H]+.

[0422] Synthesis of N-(5-bromoimidazo[l,2-a]pyridin-2-yl)acetamide. 5-Bromoimidazo[l,2-a]pyridin-2-amine (0.450 g, 1.38 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G. The residue was purified by flash column chromatography on silica gel (Combiflash, 30% ethyl acetate in hexane) to afford the title compound (0.250 g, off white solid). MS (ES): m / z 254.03 [M+H]+.

[0423] Synthesis of compound 1-386. N-(5-Bromoimidazo[l,2-a]pyridin-2-yl)acetamide (0.250 g, 0.98 mmol, 1.0 eq) and 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (0.669 g, 1.97 mmol, 2.0 eq) were subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 3.5% methanol in dichloromethane) to afford compound 1-386 (0.030 g, light yellow solid). MS (ES): m / z 351.36 [M+H]+; 'H NMR (DMSO-d6, 400 MHz): δ 10.67 (s, 1H), 8.80 (s, 1H), 7.61 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.35 -7.25 (m, 3H), 3.96 (dt, J = 11.1, 3.1 Hz, 2H), 3.50 - 3.43 (m, 2H), 3.04-2.96 (m, 1H), 2.37 (s, 3H), 2.05 (s, 3H), 1.88 (h, J = 4.1 Hz, 4H).

[0424] Example 2.9. Synthesis of N-(7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)py ridin-2-yI)imidazo [1,2-a] pyridin-2-yl)acetamide (I- 140)

[0425] Synthesis of ethyl 5-bromo-7-methylimidazo[l,2-a]pyridine-2-carboxylate. To a stirred solution of 6-bromo-4-methylpyridin-2-amine (5.00 g, 26.73 mmol, 1.0 eq) in ethanol (100 mL) was added ethyl 3-bromo-2-oxopropanoate (5.73 g, 29.41 mmol, 1.1 eq). The reaction mixture was heated at 90 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 35% ethyl acetate in hexane) to afford the title compound (5.2 g, off white solid). 'H NMR (DMSO-d6, 400 MHz): δ 8.29 (s, 1H), 7.49 (s, 1H), 7.33 (s, 1H), 4.32 (q, J= 7.1 Hz, 2H), 2.37 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0426] Synthesis of 5-bromo-7-methylimidazo[l,2-a]pyridine-2-carboxylic acid. 5-Bromo-7-methylimidazo[l,2-a]pyridine-2-carboxylate (5.2g, 18.43 mmol, 1.0 eq) was subjected to the conditions described in General Procedure D to afford the title compound (2.5 g, white solid). MS (ES): m / z 255.1 [M+H]+.

[0427] Synthesis of tert-butyl (5-bromo-7-methylimidazo[l,2-a]pyridin-2-yl)carbamate. 5-Bromo-7-methylimidazo[l,2-a]pyridine-2-carboxylic acid (2.50 g, 9.80 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E. The residue waspurified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford the title compound (0.900 g, off white solid). MS (ES): m / z 326.20 [M+H]+.

[0428] Synthesis of 5-bromo-7-methylimidazo[l,2-a]pyridin-2-amine. Tert-butyl (5-bromo-7-methylimidazo[l,2-a]pyridin-2-yl)carbamate (0.50 g, 1.53 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F to afford the title compound (0.500 g, brown oil) as a trifluoroacetic salt, which was used in next step without further purification MS (ES): m / z 227 [M+H]+.

[0429] Synthesis of N-(5-bromo-7-methylimidazo[l,2-a]pyridin-2-yl)acetamide. 5-Bromo-7-methylimidazo[l,2-a]pyridin-2-amine (0.50 g, 1.55 mmol, 1.0 eq was subjected to the conditions described in General Procedure G. The residue was purified by flash column chromatography on silica gel (Combiflash, 40% ethyl acetate in hexane) to afford the title compound (0.300 g, off white solid). MS (ES): m / z 267.77 [M+H]+.

[0430] Synthesis of compound 1-140. N-(5-Bromo-7-methylimidazo[l,2-a]pyridin-2-yl)acetamide (0.150 g, 0.63 mmol, 1.0 eq) and 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (0.259 g, 1.97 mmol, 1.2 eq) were subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 3.9% methanol in dichloromethane) to afford compound 1-140 (0.030 g, off white solid). MS (ES): m / z 365.5 [M+H]+; ¹H NMR (DMSO-d6, 400 MHz): δ 10.59 (s, 1H), 8.68 (s, 1H), 7.61 (s, 1H), 7.31 (d, J= 10.7 Hz, 2H), 7.13 (s, 1H), 3.98 (d, J= 12.3 Hz, 2H), 3.49 (dt, J = 13.4, 7.6 Hz, 2H), 2.99 - 2.97 (m, 1H), 2.41 (s, 6H), 2.04 (s, 3H), 1.86 (h, J= 4.4 Hz, 4H).

[0431] Example 2.10. Synthesis of N-(6-methyl-4-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)pyrazolo[l,5-a]pyrazin-2-yl)acetamide (1-64)

[0432] Synthesis of (E)-N-benzyl-l,l-dimethoxypropan-2-imine. Sodium sulfate (7.24 g, 50.79 mmol, 0.2 eq) was added to a stirred solution of benzyl amine (32.65 g, 304.75 mmol, 1.2 eq) in heptane (300 mL) and l,l-dimethoxypropan-2-one (30.00 g, 253.96 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (40 g, light yellow oil), which was used in the next step without further purification.

[0433] Synthesis of N-benzyl-l,l-dimethoxypropan-2-amine. To a stirred solution (E)-N-benzyl-l,l-dimethoxypropan-2-imine (40.00 g, 192.99 mmol, 1.0 eq) in methanol (400 mL), was added sodium borohydride (8.03 g, 212.29 mmol, 1.1 eq) portion wise at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was evaporated under reduced pressure, diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 3% Methanol in dichloromethane) to afford the title compound (35 g, brown liquid). ¹H NMR (CDCl₃, 400 MHz): δ 7.33 (dt, J= 4.2, 2.1 Hz, 4H), 7.30 - 7.21 (m, 1H), 4.16 -4.15 (m, 1H), 3.91 (d, J= 13.2 Hz, 1H), 3.72 (d, J= 13.0 Hz, 1H), 3.45 - 3.32 (m, 6H), 2.91 -2.79 (m, 1H), 1.12 (dt, J = 7.0, 2.2 Hz, 3H).

[0434] Synthesis of l,l-dimethoxypropan-2-amine. To a stirred solution of N-benzyl-l,l-dimethoxypropan-2-amine (35.00 g, 137.24 mmol, 1.0 eq) in methanol (350 mL) was added palladium (3.50 g, 10% on carbon) at room temperature. The reaction mixture was stirred under 50 psi hydrogen pressure in autoclave at room temperature for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (25 g, brown viscous oil). ¹H NMR (CDCl₃, 400 MHz): δ 3.98 (d, J= 6.0 Hz, 1H), 3.44 - 3.40 (m, 6H), 3.02 (p, J = 6.4 Hz, 1H), 1.11 (d, J= 6.6 Hz, 3H).

[0435] Synthesis of N-(l,l-dimethoxypropan-2-yl)-3-nitro-lH-pyrazole-5-carboxamide. To a stirred solution of 3-nitro-lH-pyrazole-5-carboxylic acid (20.00 g, 127.32 mmol, 1.0 eq) in tetrahydrofuran (200 mL) was added l, T-carbonyldiimidazole (30.97 g, 190.98 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at 50 °C for 1 h, cooled to room temperature followed by addition of l,l-dimethoxypropan-2-amine (16.69 g, 140.05 mmol, 1.1 eq). The reaction mixture was stirred at 50 °C for 5 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combi flash, 30% ethyl acetate in hexane) to afford the title compound (16 g, white solid). 'H NMR (DMSO-d6, 400 MHz): δ 14.78 (s, 1H), 8.62 (d, J= 8.5 Hz, 1H), 7.72 (s, 1H), 4.30 (d, J = 5.5 Hz, 1H), 4.23 -4.10 (m, 1H), 3.33 (d, J= 14.6 Hz, 6H), 1.23 - 1.07 (m, 3H).

[0436] Synthesis of 7-hydroxy-6-methyl-2-nitro-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one. To a stirred solution of N-(l,l-dimethoxypropan-2-yl)-3-nitro-lH-pyrazole-5-carboxamide (5.00 g, 19.36 mmol, 1.0 eq) in 5M aq. hydrochloric acid (50 mL) was for 16 h. The reaction mixture was diluted with saturated aq. sodium carbonate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 50% ethyl acetate in hexane) to afford the title compound (3.7 g, off white solid). MS (ES): m / z 213 [M+H]+.

[0437] Synthesis of 4-chloro-6-methyl-2-nitropyrazolo[l,5-a]pyrazine. To a stirred solution of 7-hydroxy-6-methyl-2-nitro-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one (3.7g, 17.44 mmol, 1.0 eq) in phosphorus oxychloride (74 mL) was added N, N-diisopropylethylamine (37 mL) at 0 °C. The reaction mixture was heated at 100 °C for 3 h. The reaction mixture wascooled to room temperature, evaporated under reduced pressure, diluted with saturated aq. sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford the title compound (2.0 g, off white solid). 'H NMR (DMSO-d6, 400 MHz): δ 8.89 (s, 1H), 7.85 (s, 1H), 2.48 (d, J= 1.1 Hz, 3H).

[0438] Synthesis of 4-chloro-6-methylpyrazolo[l,5-a]pyrazin-2-amine.4-Chloro-6-methyl-2-nitropyrazolo[l,5-a]pyrazine (0.500 g, 2.35mmol, 1.0 eq) was subjected to the conditions described in General Procedure I1. The residue was purified by flash column chromatography on silica gel (Combiflash, 30% ethyl acetate in hexane) to afford the title compound (0.300 g, brown solid). MS (ES): m / z 183.1 [M+H]+.

[0439] Synthesis of N-(4-chloro-6-methylpyrazolo[1,5-a]pyrazin-2-yl)acetamide. 4-Chloro-6-methylpyrazolo[l,5-a]pyrazin-2-amine (0.300 g, 1.64 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G with reaction time extended to 16 h. The residue was purified by flash column chromatography on silica gel (Combi flash, 30% ethyl acetate in hexane) to afford the title compound (0.200 g, white solid). MS (ES): m / z 225.1 [M+H]+.

[0440] Synthesis of compound 1-64. N-(4-Chloro-6-methylpyrazolo[l,5-a]pyrazin-2-yl)acetamide (0.150 g, 0.667 mmol, 1.0 eq) and 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (0.454 g, 1.34 mmol, 2.0 eq) were subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 50% ethyl acetate in hexane) to afford compound 1-64 (0.052 g, light yellow solid). MS (ES): m / z 366.2 [M+H]+; ’H NMR (DMSO-d6, 400 MHz): δ 10.91 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.28 (s, 1H), 4.00 (dt, J= 11.1, 3.3 Hz, 2H), 3.57 - 3.45 (m, 2H), 3.04 - 3.00 (m, 1H), 2.51 (s, 3H), 2.42 (s, 3H), 2.11 (d, J= 3.2 Hz, 3H), 1.92 (ddt, J = 9.6, 7.0, 3.7 Hz, 4H).

[0441] Example 2.11. Synthesis of N-(6-methyl-4-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)pyrazolo[l,5-a]pyridin-2-yl)acetamide (1-97)

[0442] Synthesis of 0-(mesitylsulfonyl)hydroxylamine. Tert-butyl((mesitylsulfonyl)oxy)carbamate (5.00 g, 15.85 mmol, 1.0 eq) was added in trifluoroacetic acid (40 mL) at 0 °C and the resulting mixture was stirred at the same temperature for 1 h. The reaction mixture was poured into ice-cold water. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound (4.10 g, white solid), which was used in the next step without further purification.

[0443] Synthesis of 2-(3-bromo-5-methylpyridin-2-yl)acetonitrile. To a stirred solution of 3-bromo-2-fluoro-5-methylpyridine (10.00 g, 52.63 mmol, 1.0 eq) in toluene (200 mL), was added sodium bis(trimethylsilyl)amide (35% solution in tetrahydrofuran, 41.25 mL, 78.94 mmol, 1.5 eq) at 0 °C and the solution was stirred at 0 °C for 15 min. Acetonitrile (2.60 g, 63.15 mmol, 1.2 eq) was added at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was diluted with aq. 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 residue was purified by flash column chromatography on silica gel (Combiflash, 15% ethyl acetate in hexane) to afford the title compound (3.80 g, brown solid). ’HNMR (DMSO-d6, 400 MHz): δ 8.41 (s, 1H), 8.00 (s, 1H), 4.27 (s, 2H), 2.30 (s, 3H).

[0444] Synthesis of l-amino-3-bromo-2-(cyanomethyl)-5-methylpyridin-l-ium 2,4,6-trimethylbenzenesulfonate salt. To a stirred solution of 2-(3-bromo-5-methylpyridin-2-yl)acetonitrile (3.80 g, 18.00 mmol, 1.0 eq) in dichloromethane (38 mL) was added O-(mesitylsulfonyl)hydroxylamine (3.88 g, 18.00 mmol, 1.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The precipitate was filtered, washed with hexane and dried under vacuum to afford the title compound (0.700 g, white solid), which was used in the next step without further purification.

[0445] Synthesis of 4-bromo-6-methylpyrazolo[l,5-a]pyridin-2-amine. To a stirred solution of l-amino-3-bromo-2-(cyanomethyl)-5-methylpyridin-l-ium 2,4,6-trimethylbenzenesulfonate salt (0.625 g, 1.47 mmol, 1.0 eq) in methanol (6 mL) was added potassium carbonate (0.406 g, 2.94 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford the title compound (0.140 g, brown solid). MS (ES): m / z 226.0 [M+H]+.

[0446] Synthesis of N-(4-bromo-6-methylpyrazolo[l,5-a]pyridin-2-yl)acetamide. 4-Bromo-6-methylpyrazolo[l,5-a]pyridin-2-amine (0.120 g, 0.530 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F with reaction time shorten to 1 h. The residue was triturated with n-pentane to afford the title compound (0.080 g, brown solid).!H NMR (DMSO-d6, 400 MHz): 8 10.84 (s, 1H), 8.43 (s, 1H), 7.43 (s, 1H), 6.80 (s, 1H), 2.26 (s, 3H), 2.07 (s, 3H).

[0447] Synthesis of compound 1-97. N-(4-Bromo-6-methylpyrazolo[l,5-a]pyridin-2-yl)acetamide (0.070 g, 0.26 mmol, 1.0 eq) and 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (0.177 g, 0.522 mmol, 2.0 eq) were subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 2.5% methanol in dichloromethane) to afford compound 1-97 (0.040 g, off white solid). MS (ES): m / z 365.2 [M+H]+; 'HNMR (DMSO-d6, 400 MHz): δ 10.70 (s, 1H), 8.43 (s, 1H), 7.63 (s, 1H), 7.59 (d, J= 1.4 Hz, 1H), 7.39 (s, 1H), 7.17 (s, 1H), 4.00 -3.97 (m,2H), 3.49 (td, J= 11.0, 5.5 Hz, 2H), 3.05 - 2.96 (m, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 2.07 (s, 3H), 1.89 - 1.85 (m, 4H).

[0448] Example 2.12. Synthesis of N-(6-cyclopropyl-4-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)pyrazolo[l,5-a]pyrazin-2-yl)acetamide (1-286)

[0449] Synthesis of ethyl l-(2-cyclopropyl-2-oxoethyl)-3-nitro-lH-pyrazole-5-carboxylate. To a stirred solution of ethyl 3-nitro-lH-pyrazole-5-carboxylate (1.00 g, 5.40 mmol, 1.0 eq) in acetone (10 mL), was added potassium carbonate (0.84 g, 5.97 mmol, 1.1 eq). The resulting reaction mixture was cooled to 0 °C. To the reaction was added 2-bromo-l-cyclopropylethan-l-one (0.88 g, 5.40 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 15% ethyl acetate in hexane) to afford the title compound (0.90 g, light yellow solid). MS (ES): m / z 268.2 [M+H]+.

[0450] Synthesis of 6-cyclopropyl-2-nitropyrazolo[l,5-a]pyrazin-4(5H)-one. To a stirred solution of ethyl l-(2-cyclopropyl-2-oxoethyl)-3-nitro-lH-pyrazole-5-carboxylate (0.9 g, 3.37 mmol, 1.0 eq) in acetic acid (21.6 mL), was added ammonium formate (5.19 g, 67.39 mmol, 20.0 eq) at 0 °C. The reaction mixture was stirred at 120 °C for 48 h. The reaction mixture was evaporated under reduced pressure, diluted with cold water and the precipitate was filtered,washed with water and dried under vacuum to afford the title compound (0.38 g, light yellow solid). MS (ES): m / z 219.1 [M-H]+.

[0451] Synthesis of 4-chloro-6-cyclopropyl-2-nitropyrazolo[l,5-a]pyrazine. To a stirred solution of 6-cyclopropyl-2-nitropyrazolo[l,5-a]pyrazin-4(5H)-one (0.38 g, 1.73 mmol, 1.0 eq) in phosphorus oxychloride (7.6 mL) was added N, N-diisopropylethylamine (3.8 mL) at 0 °C. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature, evaporated under reduced pressure, diluted with saturated aq. sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 65% ethyl acetate in hexane) to afford the title compound (0.32 g, light yellow solid).1H NMR (DMSO-d6, 400 MHz): δ 8.97 (s, 1H), 7.82 (s, 1H), 2.22 -2.18 (m, 1H), 1.11 - 0.89 (m, 4H).

[0452] Synthesis of 4-chloro-6-cyclopropylpyrazolo[l,5-a]pyrazin-2-amine. 4-Chloro-6-cyclopropyl-2-nitropyrazolo[l,5-a]pyrazine (0.320 g, 1.45 mmol, 1.0 eq) was subjected to the conditions described in General Procedure I1. The residue was purified by flash column chromatography on silica gel (Combiflash, 30% ethyl acetate in hexane) to afford the title compound (0.20 g, yellow solid). MS (ES): m / z 209.1 [M+H]+.

[0453] Synthesis of N-(4-chloro-6-cyclopropyIpyrazolo[1,5-a]pyrazin-2-yl)acetamide. 4-Chloro-6-cyclopropylpyrazolo[l,5-a]pyrazin-2-amine (0.2 g, 0.96 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G with the reaction time extended to 16 h. The residue was purified by flash column chromatography on silica gel (Combiflash, 30% ethyl acetate in hexane) to afford the title compound (0.14 g, off white solid). MS (ES): m / z 251.0 [M+H]+.

[0454] Synthesis of compound 1-286. N-(4-Chloro-6-cyclopropylpyrazolo[l,5-a]pyrazin-2-yl)acetamide (0.07 g, 0.279 mmol, 1.0 eq) and 3-methoxy-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (0.198 g, 0.55 mmol, 2.0 eq) were subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford compound 1-286 (0.070 g, light yellow solid). MS (ES): m / z 408.5 [M+H]+; ¹H NMR (DMSO-d6, 400 MHz): δ 10.87 (s, 1H), 8.59 (d, J= 1.0 Hz, 1H), 8.27 (d, J= 8.7 Hz, 1H), 8.00 (s, 1H), 7.59 (d, J= 8.8 Hz, 1H), 4.04 -3.96 (m, 2H), 3.92 (s, 3H), 3.52 (td, J= 11.8, 1.9 Hz, 2H), 3.47 - 3.35 (m, 1H), 2.19 (tt, J= 8.2,4.9 Hz, 1H), 2.12 (s, 3H), 2.00 (qd, J= 12.5, 4.3 Hz, 2H), 1.84 - 1.75 (m, 2H), 1.07 - 0.92 (m, 4H).

[0455] Example 2.13. Synthesis of N-(6-cyclopropyl-4-(5-methoxy-6-morpholinopyridin-2-yl)pyrazolo[l,5-a]pyrazin-2-yl)acetamide (1-287)

[0456] Synthesis of compound 1-287. N-(4-Chloro-6-cyclopropylpyrazolo[l,5-a]pyrazin-2-yl)acetamide (0.07 g, 0.280 mmol, 1.0 eq) and 4-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)morpholine (0.2 g, 0.56 mmol, 2.0 eq) were subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford compound I-287 (0.060 g, light yellow solid). MS (ES): m / z 408.9 [M+H]+; 'H NMR (DMSO-d6, 400 MHz): 8 10.89 (s, 1H), 8.55 (s, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.46 (d, J= 8.4 Hz, 1H), 3.89 (s, 3H), 3.79 (t, J= 4.6 Hz, 4H), 3.46 (d, J= 5.1 Hz, 4H), 2.16 (s, 1H), 2.10 (s, 3H), 1.02 - 0.93 (m, 4H).

[0457] Example 2.14. Synthesis of N-(4-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-6-methylpyrazolo[l,5-a]pyrazin-2-yl)acetamide (1-288)

[0458] Synthesis of compound 1-288. N-(4-Chloro-6-methylpyrazolo[l,5-a]pyrazin-2-yl)acetamide (0.125 g, 0.558 mmol, 1.0 eq) and 3-methoxy-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (0.398 g, 1.116 mmol, 2.0 eq) were subjected to the conditions described in General Procedure Cl. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford compound 1-288 (0.110 g, lightyellow solid). MS (ES): m / z 382.1 [M+H]+; 'H NMR (DMSO-d6, 400 MHz): 8 10.88 (s, 1H), 8.50 (s, 1H), 8.32 (dd, J= 8.7, 2.8 Hz, 1H), 8.04 (s, 1H), 7.58 (dd, J= 8.9, 2.8 Hz, 1H), 4.01 (dd, J= 11.0, 4.3 Hz, 2H), 3.98 (s, 3H), 3.54 - 3.48 (m, 2H), 3.45 - 3.35 (m, 1H), 2.49 (s, 3H), 2.10 (s, 3H), 2.04- 1.94 (m, 2H), 1.80 - 1.77 (m, 2H).

[0459] Example 2.15. Synthesis of N-(7-methyl-5-(4-(tetrahydro-2H-pyran-4-yl)- [1,3] dioxolo [4,5-c] pyridin-6-yl)imidazo [l,2-c]pyrimidin-2-yl)acetamide (1-290)

[0460] Synthesis of 6-bromo-2-fluoro-3-(methoxymethoxy)pyridine. To a stirred solution of 6-bromo-2-fluoropyridin-3-ol (10 g, 52.09 mmol, 1.0 eq) in tetrahydrofuran (100 mL) was added N, N-diisopropylethylamine (20.20 g, 156.26 mmol, 3.0 eq) at 0 °C and thereaction mixture was stirred for 20 min. Next, bromo(methoxy)methane (7.81 g, 62.50 mmol, 1.2 eq) was added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford title compound (5.6 g, off white solid). MS (ES): m / z 236.1 [M+H]+.

[0461] Synthesis of methyl 4-(6-bromo-3-(methoxymethoxy)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxylate. To a stirred solution of 6-bromo-2-fluoro-3- (methoxymethoxy)pyridine (2.6 g, 11.02 mmol, 1.0 eq) and methyl tetrahydro-2H-pyran-4-carboxylate (1.91 g, 13.22 mmol, 1.2 eq) in tetrahydrofuran was added sodium bis(trimethylsilyl)amide (35% in tetrahydrofuran) (3.03 g, 16.52 mmol, 1.5 eq) at 0 °C. The reaction mixture was allowed to stir at room temperature for 4 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 40% ethyl acetate in hexane) to afford title compound (2.3 g, colorless oil). MS (ES): m / z 359.9 [M+H]+.

[0462] Synthesis of 4-(6-bromo-3-(methoxymethoxy)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid To a stirred solution of 4-(6-bromo-3-(methoxymethoxy)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxylate (2.3 g, 6.39 mmol, 1.0 eq) in methanol (23 mL) was added 25% aqueous sodium hydroxide (23 mL). The reaction mixture was then stirred at 100 °C for 4 h. After completion, the reaction mixture was concentrated, acidified with IN hydrochloric acid and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, concentrated under reduced pressure to afford title compound (1.6 g, off white solid). MS (ES): m / z 346.2 [M+H]+.

[0463] Synthesis of 6-bromo-3-(methoxymethoxy)-2-(tetrahydro-2H-pyran-4-yl)pyridine. 4-(6-Bromo-3-(methoxymethoxy)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid (1.5 g, 4.33 mmol, 1 eq) was subjected to the conditions described in General Procedure A with the reaction time extended to 32 h. The residue was purified by flash columnchromatography on silica gel (Combiflash, 30% ethyl acetate in hexane) to afford title compound (1.1 g, off white solid). MS (ES): m / z 301.8 [M+H]+.

[0464] Synthesis of 6-bromo-3-(methoxymethoxy)-2-(tetrahydro-2H-pyran-4-yl)pyridin-4-ol To a stirred solution of 6-bromo-3-(methoxymethoxy)-2-(tetrahydro-2H-pyran-4-yl)pyridine (700 mg, 2.32 mmol, 1 eq) in tetrahydrofuran (14 mL) was added lithium diisopropylamide solution (2.0 M in tetrahydrofuran) (0.65 mL, 5.79 mmol, 2.5 eq) at -78 °C and the solution was stirred for 1 h. To the resulting mixture, trimethyl borate (601 mg, 5.79 mmol, 2.5 eq) in tetrahydrofuran was added at same temperature and the solution was stirred for 3 h at -78 °C. To this solution hydrogen peroxide (30% w / w in water) (0.23 mL, 2.32 mmol, 1.0 eq) was added at -78 °C. The reaction mixture was then allowed to stir at room temperature for 4 h. Next, the reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate, the organic layer was dried over sodium sulfate concentrated under reduced pressure and the crude compound was purified by flash column chromatography on silica gel (Combiflash, 50% ethyl acetate in hexane) to afford title compound (550 mg, off white solid). MS (ES): m / z 318.1 [M+H]+.

[0465] Synthesis of 6-bromo-2-(tetrahydro-2H-pyran-4-yl)pyridine-3,4-diol. To a stirred solution of 6-bromo-3-(methoxymethoxy)-2-(tetrahydro-2H-pyran-4-yl)pyridin-4-ol (0.5 g, 1.57 mmol, 1.0 eq) in 1,4-dioxane (20 mL) was added 4M hydrochloric acid in 1,4-dioxane (5 mL) and the solution was stirred for 4 h. Next, the reaction mixture was concentrated under reduced pressure, and the crude compound was triturated with diethyl ether to afford title compound (0.37 g, off white solid). MS (ES): m / z 274.1 [M+H]+.

[0466] Synthesis of 6-bromo-4-(tetrahydro-2H-pyran-4-yl)-[l,3]dioxolo[4,5-cjpyridine. To a stirred solution of 6-bromo-2-(tetrahydro-2H-pyran-4-yl)pyridine-3,4-diol (0.37 g, 1.35 mmol, 1.0 eq) in N, N-dimethylformamide (10 mL), caesium carbonate (0.66 g, 2.02 mmol, 1.5 eq) was added and the suspension was stirred for 10 minutes. To this suspension, chloroiodomethane (0.24 g, 1.35 mmol, 1 eq) was added and the reaction mixture was heated at 60 °C for 8 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, concentrated under reduced pressure to afford crude compound, which was purified by flash column chromatography on silica gel (Combiflash, 40% ethyl acetate in hexane) to afford title compound (0.28 g, off white solid). MS (ES): m / z 286.2 [M+H]+.

[0467] Synthesis of 4-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)- [1.3]dioxolo[4,5-c]pyridine. 6-Bromo-4-(tetrahydro-2H-pyran-4-yl)-[l,3]dioxolo[4,5-c]pyridine (280 mg, 0.978 mmol, 1.0 eq) was subjected to the conditions described in General Procedure B with the reaction time shortened to 1 h to afford title compound (350 mg, black oil) which was used for next step without further purification.

[0468] Synthesis of ethyl 7-methyl-5-(4-(tetrahydro-2H-pyran-4-yl)-[l,3]dioxolo[4,5-c]pyridin-6-yl)imidazo[l,2-c]pyrimidine-2-carboxylate. 5-Chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (150 mg, 0.625 mmol, 1.0 eq) and 4-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)-[l,3]dioxolo[4,5-c]pyridine (347.40 mg, 0.938 mmol, 1.5 eq) was subjected to the conditions described in General Procedure Cl with the reaction time shortened to 1 h. The crude material was purified by flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford title compound. MS (ES): m / z 411.3 [M+H]+. (170 mg, light yellow solid).

[0469] Synthesis of 7-methyl-5-(4-(tetrahydro-2H-pyran-4-yl)-[l,3]dioxolo[4,5-c]pyridin-6-yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid. 7-Methyl-5-(4-(tetrahydro-2H-pyran-4-yl)-[l,3]dioxolo[4,5-c]pyridin-6-yl)imidazo[l,2-c]pyrimidine-2-carboxylate (170 mg, 0.414 mmol, 1 eq) was subjected to the conditions described in General Procedure D to afford title compound (130 mg, light yellow solid). MS (ES): m / z 383.3 [M+H]+.

[0470] Synthesis of tert-butyl (7-methyl-5-(4-(tetrahydro-2H-pyran-4-yl)- [1.3]dioxolo[4,5-c]pyridin-6-yl)imidazo[l,2-c]pyrimidin-2-yl)carbamate. 7-Methyl-5-(4-(tetrahydro-2H-pyran-4-yl)-[l,3]dioxolo[4,5-c]pyridin-6-yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid (130 mg, 0.339 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E with reaction time shortened to 2 h. The crude material was purified by flash column chromatography on silica gel (Combiflash, 80 % ethyl acetate in hexane) to afford title compound (50 mg, light yellow solid). MS (ES): m / z 454.2 [M+H]+.

[0471] Synthesis of 7-methyl-5-(4-(tetrahydro-2H-pyran-4-yl)-[l,3]dioxolo[4,5-c]pyridin-6-yl)imidazo[l,2-c]pyrimidin-2-aniine. Tert-butyl (7-methyl-5-(4-(tetrahydro-2H-pyran-4-yl)-[l, 3]dioxolo[4,5-c]pyridin-6-yl)imidazo[l,2-c]pyrimi din-2 -yl)carbamate (50 mg, 0.110 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F to afford 7-methyl-5-(4-(tetrahydro-2H-pyran-4-yl)-[l,3]dioxolo[4,5-c]pyridin-6-yl)imidazo[l,2-c]pyrimidin-2-amine (40 mg, crude light-yellow solid) which was used without further purification. MS (ES): m / z 354.3 [M+H]+.

[0472] Synthesis of 1-290. 7-Methyl-5-(4-(tetrahydro-2H-pyran-4-yl)-[l,3]dioxolo[4,5-c]pyridin-6-yl)imidazo[l,2-c]pyrimidin-2-amine (40 mg, 0.113 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G with the reaction time shortened to 2 h. The crude residue was purified by flash column chromatography on silica gel (Combiflash, 80% ethyl acetate in hexane) to afford 1-290 (10.3 mg, light yellow solid). MS (ES): m / z 396.3 [M+H]+;NMR (400 MHz, DMSO-d6): 8 10.78 (s, 1H), 9.37 (s, 1H), 7.90 (s, 1H), 7.36 (s, 1H), 6.28 (s, 2H), 4.00 (dt, J= 10.6, 3.4 Hz, 2H), 3.53 - 3.47 (m, 2H), 3.17 - 3.16 (m, 1H), 2.52 (s, 3H), 2.09 (s, 3H), 2.05 (d, J= 3.6 Hz, 1H), 2.05 - 1.96 (m, 1H), 1.89 - 1.86 (m, 2H).

[0473] Example 2.16. Synthesis of N-(5-(4-(difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)acetamide (1-289)

[0474] Synthesis of 2,6-dibromo-4-(difluoromethoxy)pyridine. To a stirred solution of 2,6-dibromopyridin-4-ol (5.00 g, 19.77 mmol, 1 eq) in N, N-dimethylformamide (100 mL) were added ethyl bromodifluoroacetate (4.82 g, 23.73 mmol, 1.2 eq) and potassium carbonate (5.47 g, 39.54 mmol, 2.0 eq). The reaction mixture was then stirred at 50 °C for 16 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, concentrated under reduced pressure to obtain crude material which was purified by column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford title compound (2.8 g, colorless oil). 'H NMR (400 MHz, CDCh): 57.26 - 7.23 (m, 2H), 6.64 (s, 1H).

[0475] Synthesis of 4-(6-bromo-4-(difluoromethoxy)pyridin-2-yl)tetrahydro-2H-pyran-4-ol. To a stirred solution of 2, 6-dibromo-4-(difluorom ethoxy )pyri dine (2.7 g, 8.91 mmol, 1 eq) in dichloromethane (92.46 mL) was added n-butyllithium solution (2.5M in tetrahydrofuran) (7.13 mL, 17.83 mmol, 2.0 eq) at -78 °C. The reaction mixture was stirred at the same temperature for 10 minutes and tetrahydro-4H-pyran-4-one (1.34 g, 13.37 mmol, 1.5 eq) in tetrahydrofuran was added and the solution was stirred at -78 °C for 1 h. Next, the reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by column chromatography on silica gel (Combiflash, 40% ethyl acetate in hexane) to afford title compound (1.6 g, colorless oil). MS (ES): m / z 324.1 [M+H]L

[0476] Synthesis of 2-bromo-4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridine.4-(6-Bromo-4-(difluoromethoxy)pyridin-2-yl)tetrahydro-2H-pyran-4-ol (1.6 g, 4.94 mmol, 1.0 e<?) was dissolved in sulfuric acid (9.6 mL) and the solution was stirred at 60 °C for 1 h. Next, the reaction mixture was neutralized with aqueous solution of sodium hydroxide and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, concentrated under reduced pressure to obtain crude material, which was purified by column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford title compound (0.4 g, colorless oil). MS (ES): m / z 306.1 [M+H]+.

[0477] Synthesis of 4-(difluoromethoxy)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine.2-Bromo-4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridine (410 mg, 1.34 mmol, 1.0 eq) was subjected to the conditions described in GeneralProcedure B with the reaction time shortened to 1 h to afford title compound (480 mg, black oil), which was used into the next step without further purification.

[0478] Synthesis of ethyl 5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[1,2-c]pyrimidine-2-carboxylate. Ethyl 5-chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (200 mg, 0.834 mmol, 1.0 eq) and (4-(difluoromethoxy)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine) (488.21 mg, 1.25 mmol, 1.5 eq) were subjected to the conditions described in General Procedure Cl with the reaction time shortened to 1 h. The crude material was purified by column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford title compound (240 mg, light yellow solid). MS (ES): m / z 431.6 [M+H]+.

[0479] Synthesis of ethyl 5-(4-(difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate. To a stirred solution of ethyl 5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (200 mg, 0.464 mmol, 1.0 eq) in ethanol (0.65mL), ammonium formate (146.50 mg, 2.32 mmol, 5 eq) and palladium (0.1 g, 10% on carbon) were added. The reaction mixture was stirred at 75 °C for 2 h. Next, the reaction mixture was filtered through celite pad and washed with ethanol. The filtrate was concentrated under reduced pressure and diluted with water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, concentrated under reduced pressure to afford title compound (180 mg, light yellow solid). MS (ES): m / z 433.4 [M+H]+.

[0480] Synthesis of 5-(4-(difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid. Ethyl 5-(4-(difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (180 mg, 0.416 mmol, 1.0 eq) was subjected to the conditions described in General Procedure D to afford title compound (140 mg, light yellow solid). MS (ES): m / z 405.1 [M+H]+.

[0481] Synthesis of tert-butyl (5-(4-(difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methyliinidazo[l,2-c]pyrimidin-2-yl)carbamate. 5-(4-(Difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid (140 mg, 0.346 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E obtain crude compound which was purified by column chromatography on silica gel(Combiflash, 80 % ethyl acetate in hexane) to afford title compound (30 mg, light yellow solid). MS (ES): m / z 476.1 [M+H]+.

[0482] Synthesis of 5-(4-(difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine. Tert-butyl (5-(4-(difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate (30 mg, 0.063 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F to afford 5-(4-(difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine (23 mg, light yellow solid). MS (ES): m / z 376.0 [M+H]+.

[0483] Synthesis of 1-289. 5-(4-(Difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine (23 mg, 0.061 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G with reaction time shortened to 2 h. The crude material was purified by column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford 1-289 (6 mg, light yellow solid). MS (ES): m / z 417.8 [M+H]+;rH NMR (400 MHz, DMSO-d6): 8 10.83 (s, 1H), 9.36 (s, 1H), 8.02 (s, 1H), 7.63 (s, 1H), 7.45 (s, 1H), 7.39 (s, 1H), 4.02 (d, J = 11.5 Hz, 2H), 3.52 (s, 2H), 3.13 (s, 1H), 2.66 (s, 3H), 2.09 (s, 3H), 1.93 (s, 4H).

[0484] Example 2.17. Synthesis of N-(5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-(pyrrolidin-l-yl)imidazo[l,2-c]pyrimidin-2-yl)acetamide (1-78)

[0485] Synthesis of ethyl 7-chloro-5-hydroxyimidazo[l,2-c]pyrimidine-2-carboxylate. To a stirred solution of 4-amino-2,6-dichloropyrimidine (25 g, 152.45 mmol, 1.0 eq) in acetic acid (500 mL) was added ethyl bromopyruvate (74.32 g, 381.13 mmol, 2.5 eq) at room temperature. The reaction mixture was heated at 120 °C for 2 h. Next, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The reside was dissolved in diethyl ether and resulted solid were filtered, washed with diethyl ether and dried to afford title compound (40 g, light brown solid) which was used without further purification.

[0486] Synthesis of ethyl 5,7-dichloroimidazo[l,2-c]pyrimidine-2-carboxylate To a stirred solution of ethyl 7-chloro-5-hydroxyimidazo[l,2-c]pyrimidine-2-carboxylate (15 g, 62.08 mmol, 1.0 eq) in phosphorus(V) oxychloride (150 mL) was added N, N-diisopropylethylamine (70 mL) at 0 °C. The reaction mixture was heated at 100 °C for 2 h. Next, the reaction mixture was cooled to room temperature, evaporated under reduced pressure, diluted with saturated aqueous 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 residue was purified by flash column chromatography on silica gel (Combiflash,60% ethyl acetate in hexane) to afford title compound (5.5 g, off white, solid) MS (ES): m / z 260.0 [M+H]+.

[0487] Synthesis of ethyl 7-chloro-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylate. Ethyl 5,7-dichloroimidazo[l,2-c]pyrimidine-2-carboxylate (1 g, 3.85 mmol, 1 eq) and 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (1.57 g, 4.61 mmol, 1.2 eq) were subjected to the conditions described in General Procedure Cl with reaction time shortened to 2 h. The residue was purified by flash column chromatography on silica gel (Combiflash, 45% ethyl acetate in hexane) to afford title compound (0.20 g, light yellow solid). MS (ES): m z 401.3 [M+H]+.

[0488] Synthesis of ethyl 5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-(pyrrolidin-l-yl)imidazo[l,2-c]pyrimidine-2-carboxylate. To a stirred solution of ethyl 7-chloro-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidine-2-carboxylate (50 mg, 0.124 mmol, 1 eq) and pyrrolidine (10.65 mg, 0.149 mmol, 1.2 eq) in N, N-dimethylformamide (1 m ). The resulting reaction mixture was stirred at 40 °C for 30 minutes. Next, the reaction mixture was cooled to ambient temperature, diluted with 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 obtain crude material. A total of 12 batches of 50 mg each were carried out and combined at work up stage. After combining all the batches, the crude material was purified by flash column chromatography on silica gel (Combiflash, 50% ethyl acetate in hexane) to afford title compound (0.4 g, off white solid). MS (ES): m / z 436.6 [M+H]+.

[0489] Synthesis of 5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-(pyrrolidin-l-yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid. Ethyl 5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-(pyrrolidin-l-yl)imidazo[l,2-c]pyrimidine-2-carboxylate (0.4 g, 0.918 mmol, 1 eq) was subjected to the conditions described in General Procedure D to afford title compound (0.28 g, light yellow solid). MS (ES): m / z 408.6 [M+H]+.

[0490] Synthesis of tert-butyl (5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-(pyrrolidin-l-yl)imidazo[l,2-c]pyrimidin-2-yl)carbamate. 5-(4-Methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-(pyrrolidin-l-yl)imidazo[l,2-c]pyrimidine-2-carboxylic acid (0.28 g, 0.687 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E with reaction time shortened to 3 h. The residue was purified by flash column chromatography onsilica gel (Combiflash, 4.5% methanol in dichloromethane) to afford title compound (0.12 g, yellow solid). MS (ES): m / z 479.0 [M+H]+.

[0491] Synthesis of 5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-(pyrrolidin-l-yl)imidazo[l,2-c]pyrimidin-2-amine. Tert-butyl (5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-(pyrrolidin-l-yl)imidazo[l,2-c]pyrimidin-2-yl)carbamate (0.12 g, 0.25 mmol, 1.0 eq) was subjected to General Procedure F to obtain the title compound (0.1 g, tri fluoroacetic acid salt, dark brown solid) which was used in the next step without further purification. MS (ES): m / z 379.5 [M+H]+.

[0492] Synthesis of 1-78. 5-(4-Methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-(pyrrolidin-l-yl)imidazo[l,2-c]pyrimidin-2-amine (trifluoroacetic acid salt) (0.1 g, 0.203 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G with reaction time shortened to 2 h. The residue was triturated by ethyl acetate and n-pentane to afford 1-78 (18 mg, light yellow solid). MS (ES): m'z 421.7 [M+H]+;1HNMR(400 MHz, DMSO-d6): 8 10.52 (s, 1H), 9.02 (s, 1H), 8.08 (s, 1H), 7.37 (s, 1H), 6.17 (s, 1H), 4.00 (d, J= 11.1 Hz, 2H), 3.49 (s, 6H), 3.04 (s, 1H), 2.44 (s, 3H), 2.05 (d, J= 2.8 Hz, 3H), 2.02 - 1.90 (m, 7H).

[0493] Example 2.18. Synthesis of 2-methoxy-N-(7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidin-2-yl)acetamide (1-71)

[0494] Synthesis of 1-71. To a stirred solution of 7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidin-2-amine (90 mg, 0.278 mmol, 1 eq) in dichloromethane (2.0 mL) were added N-ethyldiisopropylamine (107.90 mg, 0.834 mmol, 3.0 eq) and methoxyacetyl chloride (60.40 mg, 0.556 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash, 75% ethyl acetate in hexane) to afford 1-71 (4.5 mg, light yellow solid). MS (ES): m / z 396.3 [M+H]+; H NMR (400 MHz, DMSO-d6): 8 10.52 (s, 1H), 9.41 (s, 1H),8.13 (s, 1H), 7.42 (s, 2H), 4.09 (s, 2H), 4.02 -3.99 (m, 2H), 3.55 - 3.48 (m, 2H), 3.37 (s, 3H), 3.12 - 3.08 (m, 1H), 2.55 (s, 3H), 2.47 (m, 3H) 1.98 - 1.92 (m, 4H).

[0495] Example 2.19. Synthesis of N-(7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidin-2-yl)furan-2-carboxamide (1-16)

[0496] Synthesis of 1-16. To a stirred solution of 7-methyl-5-(4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyri din-2 -yl)imidazo[l,2-c]pyrimidin-2-amine (80 mg, 0.247 mmol, 1.0 eq) in pyridine (1.0 mL) was added 2-furoyl chloride (38.75 mg, 0.296 mmol, 1.2 eq) at 0 °C. The reaction mixture was stirred for 30 minutes at room temperature. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash, 75% ethyl acetate in hexane) to afford 1-16. (27 mg, light yellow solid). MS (ES): m / z 418.36 [M+H]+; 'H NMR (400 MHz, DMSO-d6): 8 10.20 (s, 1H), 9.47 (s, 1H), 8.13 (s, 1H), 7.94 (s, 1H), 7.61 - 7.60 (m, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 6.70 - 6.69 (m, 1H), 4.04-4.01 (m, 2H), 3.56 - 3.51 (m, 2H), 3.12- 3.08 (m, 1H), 2.61 (s, 3H), 2.46 (s, 3H), 1.99 - 1.91 (m, 4H).

[0497] Example 2.20. Synthesis of (S)-N-(7-methyl-5-(4-((tetrahydro-2H-pyran-3-yl)oxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidin-2-yl)acetamide (1-18) and (R)-N-(7-methyl-5-(4-((tetrahydro-2H-pyran-3-yl)oxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyriniidin-2-yl)acetamide (1-102)

[0498] Synthesis of 2,6-dibromo-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridine. To a stirred solution of 3-hydroxytetrahydropyran (3.62 g, 35.47 mmol, 1.0 eq) in tetrahydrofuran (100 ml) was added sodium hydride (60% dispersion in mineral oil) (0.93 g, 39.02 mmol, 1.1 eq) at 0 °C and the reaction mixture was stirred for 15 minutes. To the resulting mixture, 2,6-dibromo-4-nitropyridine (10.0 g, 35.47 mmol, 1.0 eq) was added and the reaction mixture was stirred at 50 °C for 1 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 30% ethyl acetate in hexane) to afford title compound (10.6 g, colorless, liquid). MS (ES): m / z 336.1 [M+H]+.

[0499] Synthesis of 4-(6-bromo-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)tetrahydro-2H-pyran-4-oI. To a stirred solution of 2,6-dibromo-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridine (10.6 g, 31.45 mmol, 1.0 eq) in dichloromethane (170 mL) was added dropwise n-butyllithium solution (2.5 M in hexanes) (18.87 mL, 47.18 mmol, 1.5 eq) at -78 °C and the reaction mixture was stirred for 30 minutes. To the resulting mixture, a solution of tetrahydro-4H-pyran-4-one (4.72 g, 47.18 mmol, 1.5 eq) in dichloromethane (30 mL) was added at same temperature and the reaction mixture was stirred at room temperature for 1 h. Next, the reaction mixture was diluted with saturated ammonium chloride and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash, 8% ethyl acetate in hexane) to afford title compound (6.3 g, colorless, liquid). MS (ES): m / z 358.2 [M+H]+.

[0500] Synthesis of 2-bromo-6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridine. 4-(6-Bromo-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)tetrahydro-2H-pyran-4-ol (9.2 g, 25.68 mmol, 1.0 eq) was dissolved in sulfuric acid (46 mL) at 0 °C and the reaction mixture was stirred at room temperature for 3 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 15% ethyl acetate in hexane) to afford title compound (3.8 g, colorless, liquid). MS (ES): m z 339.9 [M+H]+.

[0501] Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)-6-(trimethylstannyI)pyridine. 2-Bromo-6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridine (3.0 g, 8.82 mmol, 1.0 eq) was subjected to the conditions described in General Procedure B with reaction time shortened to 2 h to afford title compound (3.40 g, brown oil), which was used in next step without further purification.

[0502] Synthesis of ethyl 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate. Ethyl 5-chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (1.8 g, 7.51 mmol, 1.0 eq) and2-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)-6-(trimethylstannyl)pyridine (3.34 g, 7.89 mmol, 1.05 eq) were subjected to the conditions described in General Procedure Cl withreaction time shortened to 3 h. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford title compound (2.3 g, yellow solid). MS (ES): m / z 465.4 [M+H]+.

[0503] Synthesis of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid. Ethyl 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (2.3 g, 4.95 mmol, 1.0 eq) was subjected to the conditions described in General Procedure D with reaction time extended to 8 h to afford title compound (1.4 g, light orange solid). MS (ES): m / z 437.2 [M+H]+, which was used in the next step without further purification.

[0504] Synthesis of tert-butyl (5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbaniate. 5-(6-(3,6-Dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid (1.2 g, 2.75 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E. The residue was purified by flash column chromatography on silica gel (Combiflash, 95% ethyl acetate in hexane) to afford title compound (0.510 g, yellow solid). MS (ES): m / z 508.4 [M+H]+.

[0505] Synthesis of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine (trifluoracetic acid salt). Tert-butyl (5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate (0.510 g, 1.00 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F to afford title compound (0.35 g, light yellow solid). MS (ES): m / z 408.4 [M+H]+, which was used in the next step without work up and further purification.

[0506] Synthesis of N-(5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)acetamide. 5-(6-(3,6-Dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine as a trifluoracetic acid salt (0.35 g, 0.858 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G with reaction time shortened to 1 h. The residue was purified by flash column chromatography on silica gel (Combiflash, 80% ethyl acetate in hexane) to afford title compound (0.28 g, light yellow solid). MS (ES): m / z 450.4 [M+H]+.

[0507] Synthesis of 1-18 and 1-102. To a stirred solution of N-(5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)acetamide (0.220 g, 0.489 mmol, 1.0 eq) in methanol (8 mL), was added palladium (10% on carbon, 50% water). The reaction mixture was stirred under hydrogen (15 psi) in autoclave at 80 °C for 16 h. Next, the reaction mixture was filtered through small pad of celite, the pad was washed with methanol (10 mL) and the filtrate was concentrated under reduced pressure. The crude compound was triturated with ethyl acetate and n-pentane to afford N-(7-methyl-5-(4-((tetrahydro-2H-pyran-3-yl)oxy)-6-(tetrahydro-2H-pyran-4-yl)pyri din-2 -yl)imidazo[ 1,2-c]pyrimidin-2-yl)acetamide (0.140 g, orange solid). MS (ES): m / z 451.9 [M+H]+.

[0508] The racemic compound was separated by SFC using CHIRALPAK IC (250*30) mm, 5pm as a column and (A) liquid carbon dioxide and (B) 0.1% ammonia in 2-propanol: acetonitrile (50%:50%) as a mobile phase to afford 1-18. (0.027 g, light yellow solid). MS (ES): m / z 452.3 [M+H]+; 'HNMR (400 MHz, DMSO-d6): 8 10.78 (s, 1H), 9.29 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.39 (s, 1H), 7.17 (d, 7 = 2.3 Hz, 1H), 4.70 (s, 1H), 4.01 (d, J= 11.3 Hz, 2H), 3.87 (d, J= 9.6 Hz, 1H), 3.67 - 3.58 (m, 3H), 3.56 - 3.45 (m, 2H), 3.07 (p, J= 8.2 Hz, 1H), 2.55 (s, 3H), 2.11 (s, 4H), 1.94 (dd, J= 8.4, 3.3 Hz, 4H), 1.82 (s, 2H), 1.59 (s, 1H) and 1-102. (0.022 g, light yellow solid). MS (ES): m / z 452.3 [M+H]+; 'H NMR (400 MHz, DMSO-d6): 6 10.78 (s, 1H), 9.29 (s, 1H), 7.75 (d, J= 2.3 Hz, 1H), 7.39 (s, 1H), 7.17 (d, J= 2.3 Hz, 1H), 4.69 (s, 1H), 4.01 (d, J= 11.3 Hz, 2H), 3.85 (d, J= 9.6 Hz, 1H), 3.67 - 3.58 (m, 3H), 3.56 -3.45 (m, 2H), 3.07 (p,.7= 8.2 Hz, 1H), 2.55 (s, 3H), 2.10 (s, 4H), 1.94 (dd,.7= 8.4, 3.3 Hz, 4H), 1.82 (s, 2H), 1.59 (s, 1H).

[0509] Example 2.21. Synthesis of N-(5-(4-(3,3-difluorocyclobutoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methyIimidazo[l,2-c]pyrimidin-2-yl)acetamide (1-31)

[0510] Synthesis of 2,6-dibromo-4-(3,3-difluorocyclobutoxy)pyridine. To a stirred solution of 2,6-dibromopyridin-4-ol (3.8 g, 15.03 mmol, 1.0 eq) and 3,3-difluorocyclobutan-l-ol (1.95 g, 18.03 mmol, 1.2 eq) in toluene (76 m ), triphenylphosphine (5.91 g, 22.54 mmol, 1.5 eq) was added. The reaction mixture was heated at 80 °C for 15 minutes. Next, diisopropyl azodicarboxylate (4.56 g, 22.54 mmol, 1.5 eq) was added dropwise at 80 °C. The reaction mixture was then stirred at the same temperature for 5 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford title compound (3.0 g, colorless, liquid). MS (ES): m / z 341.9 [M+H]+.

[0511] Synthesis of 4-(6-bromo-4-(3,3-difluorocyclobutoxy)pyridin-2-yl)tetrahydro-2H-pyran-4-ol. To a stirred solution of 2,6-dibromo-4-(3,3-difluorocyclobutoxy)pyridine (3.2 g, 9.33 mmol, 1.0 eq) in dichloromethane (64 mL) was added dropwise n-butyllithium solution (2.5 M in hexanes) (5.6 mL, 14.00 mmol, 1.5 eq) at -78 °C. The reaction mixture was stirred for 2 minutes at -78 °C. Next, tetrahydro-4H-pyran-4-one (1.0 g, 10.26 mmol, 1.1 eq) was added at same temperature. The reaction mixture was stirred at room temperature for 1 h. Next, the reaction mixture was quenched with IN hydrochloric acid solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash, 30% ethyl acetate in hexane) to afford title compound (2.7 g, colorless, liquid). MS (ES): m / z 364.2 [M+H]+.

[0512] Synthesis of 2-bromo-4-(3,3-difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridine.4-(6-Bromo-4-(3,3-difluorocyclobutoxy)pyridin-2-yl)tetrahydro-2H-pyran-4-ol (2.5 g, 6.86 mmol, 1.0 eq) was dissolved in sulfuric acid (25 mL) at room temperature. The reaction mixture was heated at 80 °C for 15 minutes. Next, the reaction mixture was quenched with 10% sodium hydroxide solution and extracted with ethyl acetate. The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 30% ethyl acetate in hexane) to afford title compound (0.80 g, colorless, liquid). MS (ES): m / z 346.3 [M+H]+.

[0513] Synthesis of 4-(3,3-difluorocyclobutoxy)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine.2-Bromo-4-(3,3-difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridine (0.75 g, 2.17 mmol, 1.0 eq) was subjected to the conditions described in General Procedure B with reaction time shortened to 1 h to afford title compound (900 mg, brown oil), which was used in next step without further purification.

[0514] Synthesis of ethyl 5-(4-(3,3-difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate. Ethyl 5-chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (0.45 g, 1.88 mmol, 1.0 eq) and 4-(3,3-difluorocyclobutoxy)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (0.88 g, 2.07 mmol, 1.1 eq) were subjected to the conditions described in General Procedure Cl with reaction time shortened to 2 h. The residue was purified by flash column chromatography on silica gel(Combiflash, 40% ethyl acetate in hexane) to afford title compound (0.30 g, yellow solid). MS (ES): m / z 471.0 [M+H]+.

[0515] Synthesis of 5-(4-(3,3-difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methyliniidazo[l,2-c]pyrimidine-2-carboxylic acid. Ethyl 5-(4-(3,3-difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (0.3 g, 0.63 mmol, 1.0 eq) was subjected to the conditions described in General Procedure D to afford title compound (0.23 g, yellow solid), which was used in next step without further purification. MS (ES): m / z 443.3 [M+H]+.

[0516] Synthesis of tert-butyl (5-(4-(3,3-difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate. 5-(4-(3,3-Difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid (0.23 g, 0.519 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E. The residue was purified by flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford title compound (0.080 g, yellow solid). MS (ES): m / z 514.1 [M+H]+.

[0517] Synthesis of 5-(4-(3,3-difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine (trifluoracetic acid salt). Tertbutyl (5-(4-(3,3-difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate (0.080 g, 0.155 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F afford title compound (0.080 g, yellow solid), which was used in next step without further purification.

[0518] Synthesis of N-(5-(4-(3,3-difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)acetaniide. 5-(4-(3,3-Difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine (trifluoracetic acid salt) (0.080 g, 0.151 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford title compound (0.028 g, light yellow solid). MS (ES): m / z 456.4 [M+H]+.

[0519] Synthesis of I-31. To a stirred solution of N-(5-(4-(3,3-difluorocyclobutoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)acetamide (0.028 g, 0.061 mmol, 1.0 eq) and ammonium formate (0.019 g, 0.307 mmol, 5.0 eq), in ethanol(1 mL), was added palladium (0.013 g, 10% on carbon, 50% water). The reaction mixture was heated at 75 °C for 2 h. Next, the reaction mixture was filtered and washed with ethyl acetate, the filtrate was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was trituration with diethyl ether and n-pentane to afford 1-31 (7 mg, light yellow solid). MS (ES): m / z 458.4 [M+H]+; ‘HNMR (400 MHz, DMSO-d6): 5 10.79 (s, 1H), 9.29 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.40 (s, 1H), 7.11 (d, J= 2.4 Hz, 1H), 5.03 (s, 1H), 4.01 (dt, J= 11.3, 3.3 Hz, 2H), 3.56 - 3.49 (m, 2H), 3.08 (s, 1H), 2.89 - 2.75 (m, 2H), 2.55 (s, 3H), 2.49 (s, 2H), 2.11 (s, 3H), 2.03 - 1.91 (m, 4H).

[0520] Example 2.22. Synthesis of N-(7-methyl-5-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)imidazo[l,2-c]pyrimidin-2-yl)acetamide (1-33)

[0521] Synthesis of 4-(2,6-dibromopyridin-4-yl)morpholine. To a stirred solution of 2,6-dibromo-4-nitropyridine (10 g, 35.47 mmol, 1.0 eq) in N, N-dimethylformamide (200 mL)was added potassium carbonate (14.71 g, 106.42 mmol, 3.0 eq) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 15 minutes, followed by addition of morpholine (3.09 g, 35.47 mmol, 1.0 eq) and it was further stirred at room temperature for 16 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 15% ethyl acetate in hexane) to afford title compound (4.5 g, off white solid). MS (ES): m / z 321.1 [M+H]+.

[0522] Synthesis of 4-(6-bromo-4-morpholinopyridin-2-yl)tetrahydro-2H-pyran-4-ol. To a stirred solution of 4-(2,6-dibromopyridin-4-yl)morpholine (4.5 g, 13.98 mmol,1.0 eq) in dichloromethane (100 mL), were added n-butyllithium solution (2.5M in hexane) (13.98 mL, 34.94 mmol, 2.5 eq) and tetrahydro-4H-pyran-4-one (3.50 g, 34.94 mmol, 2.5 eq) at -78 °C. The reaction mixture was allowed to stirred at room temperature for 6 h. Next, the reaction was diluted with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash, 15% ethyl acetate in hexane) to afford title compound (2.4 g, light yellow solid). MS (ES): m / z 343.0 [M+H]+.

[0523] Synthesis of 4-(2-bromo-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-4-yl)morpholine.4-(6-Bromo-4-morpholinopyridin-2-yl)tetrahydro-2H-pyran-4-ol (2.4 g, 6.99 mmol, 1.0 eq) was dissolved in sulfuric acid (12 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. Next, the reaction mixture was cooled to room temperature, diluted with ice-cold water, neutralized with sodium hydroxide solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 55% ethyl acetate in hexane) to afford title compound (1.2 g, light-yellow solid). MS (ES): m / z 324.7 [M+H]+.

[0524] Synthesis of 4-(2-(3,6-dihydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridin-4-yl)morpholine.4-(2-Bromo-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-4-yl)morpholine (1 g, 3.08 mmol, 1.0 eq) was subjected to the conditions described in General Procedure B with reaction time shortened to 3 h to afford title compound (2.5 g, black oil) which was used in the next step without further purification.

[0525] Synthesis of ethyl 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate. Ethyl 5-chloro-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (0.80 g, 3.34 mmol, 1.0 eq) and 4-(2-(3,6-dihydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridin-4-yl)morpholine (2.73 g, 6.68 mmol, 2.0 eq) were subjected to the conditions described in General Procedure Cl with reaction time shortened to 2 h. The residue was purified by column chromatography on silica gel (85 % ethyl acetate in hexane) to afford title compound (0.650 g, light-yellow solid). MS (ES): m / z 450.4 [M+H]+.

[0526] Synthesis of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid. Ethyl 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylate (0.650 g, 1.45 mmol, 1.0 eq) was subjected to the conditions described in General Procedure D with reaction time shortened to 2 h to afford title compound (0.18 g, off white solid). MS (ES):[M+H]+.

[0527] Synthesis of tert-butyl (5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate. 5-(6-(3,6-Dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidine-2-carboxylic acid (0.180 g, 0.427 mmol, 1.0 eq) was subjected to the conditions described in General Procedure E. The residue was purified by flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford title compound (0.120 g, light yellow solid). MS (ES): m / z 493.4 [M+H]+.

[0528] Synthesis of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine. Tert-butyl (5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)carbamate (0.120 g, 0.243 mmol, 1.0 eq) was subjected to the conditions described in General Procedure F to afford title compound (0.080 g, light-yellow solid). MS (ES): m / z 393.4 [M+H]+.

[0529] Synthesis of N-(5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)acetamide. 5-(6-(3,6-Dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-amine (0.080 g, 0.203 mmol, 1.0 eq) was subjected to the conditions described in General Procedure G. The residue was triturated with ethyl acetate and n-pentane to afford title compound (0.070 g, light-yellow solid). MS (ES): m / z 435.4 [M+H]+.

[0530] Synthesis of I-33. To a stirred solution of N-(5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylimidazo[l,2-c]pyrimidin-2-yl)acetamide (0.070 g, 0.161 mmol, 1.0 eq) in ethanol (2 mL) was added ammonium formate (50.79 mg, 0.805 mmol, 5.0 eq) and palladium (42.86 mg, 10% on carbon). The temperature was raised to 75 °C and stirred for 16 h. Next, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered over through celite pad. The filtrate was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 75% ethyl acetate in hexane) to afford 1-33 (0.017 g, yellow solid). MS (ES): m / z 437.4 [M+H]+; 'HNMR (401 MHz, DMSO-d6): 5 10.76 (s, 1H), 9.20 (s, 1H), 7.63 (d, J= 2.4 Hz, 1H), 7.37 (s, 1H), 7.00 (d, J= 2.4 Hz, 1H), 4.03 -3.95 (m, 2H), 3.76 (t, J= 4.9 Hz, 4H), 3.53 - 3.43 (m, 2H), 3.47 - 3.36 (m, 4H), 3.03 - 2.90 (m, 1H), 2.50 (s, 3H), 2.09 (s, 3H), 1.99 - 1.86 (m, 4H).

[0531] Example 2.23. Synthesis of N-(4-(5-methoxy-6-morpholinopyridin-2-yl)-6-methylpyrazolo[l,5-a]pyrazin-2-yl)acetamide (1-285)

[0532] Synthesis of ethyl 3-nitro-l-(2-oxopropyl)-lH-pyrazole-5-carboxylate. To a stirred solution of ethyl 3-nitro-lH-pyrazole-5-carboxylate (15 g, 81.02 mmol, 1.0 eq) in acetone (150 mL) was added potassium carbonate (12.32 g, 89.12 mmol, 1.1 eq). The resulting reaction mixture was cooled to 0 °C. To the reaction was added chloroacetone (7.50 g, 81.02 mmol, 1.0 eq) and the suspension was further stirred at room temperature for 6 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash,30% ethyl acetate in hexane) to afford title compound (15 g, white solid). MS (ES): m / z 242.1 [M+H]+.

[0533] Synthesis of 6-methyl-2-nitropyrazolo[l,5-a]pyrazin-4(5H)-one. To a stirred solution of ethyl 3-nitro-l-(2-oxopropyl)-lH-pyrazole-5-carboxylate (15 g, 62.19 mmol, 1.0 eq) in acetic acid (360 mL), was added ammonium acetate (95.87 g, 1243.8 mmol, 20.0 eq) at 0 °C. The reaction mixture was stirred at 120 °C for 48 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with cold water, the precipitate was fdtered off, washed with water and dried under vacuum to afford title compound (9.0 g, white solid). MS (ES): m / z 193.1 [M-H]+.

[0534] Synthesis of 4-chloro-6-methyl-2-nitropyrazolo[l,5-a]pyrazine. To a stirred solution of 6-methyl-2-nitropyrazolo[l,5-a]pyrazin-4(5H)-one (9.0 g, 46.36 mmol, 1.0 eq) in phosphorus(V) oxychloride (180 mL) was added N, N-diisopropyl ethylamine (90 mL) at 0 °C. The reaction mixture was heated at 100 °C for 16 h. Next, the reaction mixture was cooled to room temperature, evaporated under reduced pressure, diluted with saturated aqueous sodium bicarbonate solution, and extracted with et...

Claims

CLAIMS1. A compound of Formula I:I’or a pharmaceutically acceptable salt thereof, wherein:V1is N and V2is C, or V2is N and V1is C;X1is C-H orN;Ring A is a 6-membered heteroaryl ring having 0-2 nitrogen atoms in addition to V1or V2; R1is -C(O)Y or an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Y is -Ra, -ORa, -NHRa, or -C(O)NHRa;R2is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 0-3 instances of Rb;R3is halogen, -CN, -OR, -N(R)2, C1-6aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 5- to 8-membered bridged bicyclic carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc;Rais hydrogen, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 - to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral;Ralis Ci-6 aliphatic, halogen, or -OR;Rxb ¥ yR is halogen, -CN, -OR",, - or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 6- to 8-membered bridged bicyclic carbocyclic ring, a 3- to 8-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered fused bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 11 -membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:two instances of Rb, together with the atoms to which they are attached, may cyclize to form a 5- to 6-membered saturated carbocyclic ring, a 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rbgroups is substituted by 0-3 instances of Rb*;Rb* is halogen, -OR, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7- to 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein two instances of Rb* attached to the same carbon atom may cyclize to form a 3- to 6- membered saturated carbocyclic ring or a 3- to 6-membered heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur;Rcis halogen, oxo, -CN, -OR, -N(R)2, Ci-6 aliphatic optionally substituted with 1-3 halogen, - C(O)R, -CO2R, or a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rwis hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 6- to 8-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rxis hydrogen or Ci-6 aliphatic;Ryis hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9- membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 8-membered fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 8- membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R is hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andn is 0-2.

2. A compound of F ormul a II:IIor a pharmaceutically acceptable salt thereof, wherein:V1is N and V2is C, or V2is N and V1is C;X1is C-H orN;Ring A is a 6-membered heteroaryl ring having 0-2 nitrogen atoms in addition to V1or V2;R2is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 0-3 instances of Rb;R3is halogen, -CN, -OR, -N(R)2, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc;Rais hydrogen, Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6- membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 - to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral;Ralis Ci -6 aliphatic or -OR;Rbis -CN, -OR, -N(R)2, an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6- membered saturated carbocyclic ring, a 3 - to 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9- membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9- membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rcis halogen, -CN, -OR, -N(R)2, Ci-6 aliphatic, -C(O)R, or a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R is hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, phenyl, a 3- to 6-membered saturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andn is 0-2.

3. The compound according to claim 1, wherein R1is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

4. The compound according to claim 3, wherein R1is a an optionally substituted 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

5. The compound according to claim 4, wherein R1is selected from6. The compound according to claim 1, wherein R1is -C(O)Y.

7. The compound according to claim 6, wherein Y is -Ra.

8. The compound according to claim 7, wherein Rais C1-6 aliphatic substituted with 0-2 instances of Ral.

9. The compound according to claim 8, wherein Ralis -OR.

10. The compound according to claim 9, wherein Rais -CH3, -CH2CH3, or -CH2OR.

11. The compound according to claim 10, wherein the R group of Ralis C1-6 aliphatic.

12. The compound according to claim 11, wherein the R group of Ralis -CH3.

13. The compound according to claim 7, wherein Rais a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral.

14. The compound according to claim 13, wherein Rais a 5- to 6-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral.

15. The compound according to claim 13, wherein Rais a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais Ci-6 aliphatic substituted with 0-2 instances of Ral.

16. The compound according to claim 14, wherein Ralis Ci-6 aliphatic.

17. The compound according to claim 16, wherein Ralis -CH3.

18. The compound according to claim 13, wherein Rais a 6-membered heteroaryl ring having 1-2 nitrogen atoms, wherein Rais substituted with 0-2 instances of Ral.

19. The compound according to any one of claims 15-18, wherein Rais selected from20. The compound according to claim 7, wherein Rais phenyl substituted with 0-2 instances ofRal.

21. The compound according to claim 7, wherein Rais a 9- to 10-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral.

22. The compound according to claim 21, wherein Rais a 9-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral.

23. The compound according to claim 22, wherein24. The compound according to claim 7, wherein Rais a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral.

25. The compound according to claim 24, wherein Rais a 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral.

26. The compound according to claim 25, wherein Rais27. The compound according to claim 7, wherein Rais a 3- to 6-membered saturated carbocyclic ring substituted with 0-2 instances of Ral.

28. The compound according to claim 7, wherein Rais a 3-membered saturated carbocyclic ring substituted with 0-2 instances of Ral.

29. The compound according to claim 6, wherein Y is -ORa.

30. The compound according to claim 29, wherein Rais -CH3.

31. The compound according to claim 6, wherein Y is -NHRa.

32. The compound according to claim 31, wherein Rais hydrogen.

33. The compound according to claim 31, wherein Rais -CH3.

34. The compound according to claim 6, wherein Y is -C(O)NHRa.

35. The compound according to any one of claims 1-34, wherein R3is halogen (e.g., chloro) or -CN.

36. The compound according to any one of claims 1-34, wherein R3is -OR or -N(R)2.

37. The compound according to claim 36, wherein the R group of R3is optionally substituted C1-6 aliphatic or an optionally substituted 3- to 6-membered saturated carbocyclic ring.

38. The compound according to claim 37, wherein the R group of R3is -CH3, -CHF2, or39. The compound according to claim 38, wherein R3is40. The compound according to any one of claims 1-33, wherein R3is C1-6 aliphatic, wherein R3is substituted with 0-3 instances of Rc.

41. The compound according to claim 40, wherein R3is C1-2 aliphatic, wherein R3is substituted with 0-3 instances of Rc.

42. The compound according to claim 41, wherein Rcis halogen, -OR, -N(R)2, -C(O)R, or a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

43. The compound according to claim 42, wherein the R group of Rcis optionally substituted C1-6 aliphatic.

44. The compound according to claim 43, wherein R3is -CH3, -CH2CH3,45. The compound according to any one of claims 1-33, wherein R3is a 3- to 6-membered saturated carbocyclic ring substituted with 0-3 instances of Rc.

46. The compound according to claim 45, wherein R3is a 3- to 4-membered saturated carbocyclic ring, wherein R3is substituted with 0-3 instances of Rc.

47. The compound according to claim 46, wherein Rcis halogen or -CN.The compound according to claim 47, wherein49. The compound according to any one of claims 1-33, wherein R3is phenyl substituted with 0-3 instances of Rc.

50. The compound according to any one of claims 1-33, wherein R3is a 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc.

51. The compound according to claim 50, wherein R3is a 4- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc.

52. The compound according to claim 51, wherein Rcis halogen, Ci-6 aliphatic, -OR, or -C(O)R.

53. The compound according to claim 51 or claim 52, wherein R3is54. The compound according to any one of claims 1-33, wherein R3is a 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc.

55. The compound according to claim 54, wherein R3is an 8-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

56. The compound according to claim 55, wherein57. The compound according to any one of claims 1-33, wherein R3is a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc.

58. The compound according to claim 57, wherein R3is a 7-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

59. The compound according to claim 58, wherein60. The compound according to any one of claims 1-33, wherein R3is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

61. The compound according to claim 60, wherein R3is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc.

62. The compound according to claim 61, wherein Rcis Ci-6 aliphatic.

63. The compound according to claim 62, wherein R3is64. The compound according to any one of claims 1-63, wherein R2is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 0-3 instances of Rb.

65. The compound according to claim 64, wherein R2is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 0-3 instances of Rb.

66. The compound according to claim 64, wherein R2is a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 0-3 instances of Rb.

67. The compound according to any one of claims 64-66, wherein Rbis -CN.

68. The compound according to any one of claims 64-66, wherein Rbis -OR or -N(R)2.

69. The compound according to any one of claims 64-66, wherein Rbis an optionally substituted group selected from Ci-6 aliphatic, a 3- to 6-membered saturated carbocyclic ring, a 3- to 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7- to 9-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur, a 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

70. The compound according to claim 69, wherein Rbis optionally substituted Ci-6 aliphatic.

71. The compound according to claim 70, wherein Rbis -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CHF2, or -CF3.

72. The compound according to claim 69, wherein Rbis an optionally substituted 3- to 6-membered saturated carbocyclic ring.

73. The compound according to claim 72, wherein Rbis an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring.

74. The compound according to claim 69, wherein Rbis an optionally substituted 3- to 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

75. The compound according to claim 74, wherein Rbis an optionally substituted 3- to 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur.

76. The compound according to claim 74, wherein Rbis an optionally substituted 5- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

77. The compound according to claim 75 or 76, wherein Rbis an optionally substituted azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, oxepanyl, or 1,4-oxazepanyl ring.

78. The compound according to claim 69, wherein Rbis an optionally substituted 7- to 9-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

79. The compound according to claim 78, wherein Rbis an optionally substituted 7-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

80. The compound according to claim 78, wherein Rbis an optionally substituted 8-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

81. The compound according to claim 69, wherein Rbis an optionally substituted 6- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

82. The compound according to claim 81, wherein Rbis an optionally substituted 6-membered bridged bicyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur.

83. The compound according to claim 81, wherein Rbis an optionally substituted 7-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

84. The compound according to claim 81, wherein Rbis an optionally substituted 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

85. The compound according to claim 81, wherein Rbis an optionally substituted 9-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

86. The compound according to claim 69, wherein Rbis an optionally substituted 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

87. The compound according to claim 69, wherein Rbis an optionally substituted 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

88. The compound according to claim 87, wherein Rbis an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

89. The compound according to claim 87, wherein Rbis an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms.

90. The compound according to claim 1, wherein the compound is selected from any of formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h:I-k-ior a pharmaceutically acceptable salt thereof.

91. A compound selected from any of the compounds in Table A.or a pharmaceutically acceptable salt thereof.

92. A pharmaceutical composition comprising a compound according to any one of claims 1-91, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

93. A method of inhibiting TYK2, the method comprising contacting a biological sample with a compound according to any one of claims 1-91.

94. A method of treating a TYK2-mediated disease, disorder, or condition, the method comprising administering to a subject a compound according to any one of claims 1-91, or a pharmaceutically acceptable salt thereof.

95. The method according to claim 94, wherein the TYK2-mediated disease, disorder, or condition is an autoimmune disorder that comprises neurological involvement.

96. The method according to claim 95, wherein the TYK2-mediated disease, disorder, or condition is systemic lupus erythematosus (SLE), rheumatoid arthritis, or psoriatic arthritis.

97. The method according to claim 94, wherein the TYK2-mediated disease, disorder, or condition is a cancer.

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