Heteroaryl compounds useful as TYK2 inhibitors

Abstract

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

Description

Attorney Docket No. 2019094-0008HETEROARYL 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:N V1»2or a pharmaceutically acceptable salt thereof, wherein each of V1, V2, X1, R1, R2, and R3is as defined herein.13150943v 1 Page 1 of 319Attorney Docket No. 2019094-0008

[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. In some 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,13150943v 1 Page 2 of 319Attorney Docket No. 2019094-0008alkynyl 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 quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2Z / -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 is 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 14 K 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 in13150943v 1 Page 3 of 319Attorney Docket No. 2019094-0008which 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 examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 477-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, 3 / / -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 to13150943v 1 Page 4 of 319Attorney Docket No. 2019094-0008encompass 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; -(CH 2)0 4R0; -(CH2)o 4OR0; -0(CH2)o-4R°, -O-(CH2)O4C(O)ORO; -(CH2)O4CH(ORO)2; -(CH2)O-4SR°; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o4Q(CH2)o i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O-4N(R°)2; -(CH2)O-4N(R°)C(0)R°; -N(R°)C(S)R°; -(CH2)O-4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CI I2)o4C(O)R°; -C(S)R°; -(CH2)o4C(O)ORC; -(CH2)O^C(0)SR°; -(CH2)O ^C(O)OSiR°3; -(CH2)o4OC(O)R°; -OC(0)(CH2)O4SRO, SC(S)SR°; -(CH 2)04SC(O)R°; -(CH2)o4C(O)NRC2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2)O4OC(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)(1 4S(O)2OR°; -(CH2)0^OS(O)2R°; -S(O)2NR°2; -(CH2)O4S(O)RO; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -P(O)2R°; -P(0)RO2; -OP(O)RO2; -0P(0)(0RO)2; SiR°3; -(Ci-4straight or branched alkylene)O-N(R°)2; or -(Ci4straight 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)o13150943v 1 Page 5 of 319Attorney Docket No. 2019094-0008iPh, -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)o2OH, -(CH2)o-2OR*, -(CH2)o-2CH(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)O2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* - (Ci^i 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*. -NOR*, -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 one13150943v 1 Page 6 of 319Attorney Docket No. 2019094-0008or more halogens, and is independently C1-4 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 -R', -NR'2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf, -C(O)CH2C(O)R, -S(O)2R+, -S(O)2NRf2, -C(S)NRt2, -C(NH)NR’'2, or-N(R )S(O)2RT; wherein each R'fis independently hydrogen, C1-6 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 C1-4 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,13150943v 1 Page 7 of 319Attorney Docket No. 2019094-0008benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, 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. 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 inhibitor has 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.13150943v 1 Page 8 of 319Attorney Docket No. 2019094-0008

[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;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, or -NHRa;Rais Ci-6 aliphatic or a 5-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;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 heteroaryl13150943v 1 Page 9 of 319Attorney Docket No. 2019094-0008ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R3is substituted with 0-3 instances of Rc;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; andR 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.

[0029] 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.

[0030] 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.13150943v 1 Page 10 of 319Attorney Docket No. 2019094-0008

[0031] In some embodiments, the compound is selected from a compound of any of formulae I-a, I-b, I-c, and I-d:R3or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the compound is selected from a compound of any of formulae I-a-z, I-b-z, I-c-z, and I-d-z:R3I-d-zor a pharmaceutically acceptable salt thereof.

[0033] It will be appreciated that the embodiments described herein for formula I apply equally to any of formulae I-a, I-a-z, I-b, I-b-z, I-c, I-c-z, I-d, and I-d-z.

[0034] 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.

[0035] In some embodiments, R1is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some13150943v 1 Page 11 of 319Attorney Docket No. 2019094-0008embodiments, 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.

[0036] In some embodiments, R1is selected from

[0037]

[0038] As defined generally above, Y is -Ra, -ORa, or -NHRa. In some embodiments, Y is -Ra. In some embodiments, Y is -ORa. In some embodiments, Y is -NHRa. In someO o oXo, Rembodiments, R1is selected from', 'aY^, andNH'Ra

[0039] 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.

[0040] 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. In13150943v 1 Page 12 of 319Attorney Docket No. 2019094-0008some 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. In some embodiments, R2is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 1-3 instances of Rb. In some embodiments, R2is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 1-3 instances of Rb.

[0041] In some embodiments, R2is selected from

[0042] In some embodiments,R2isRb Rb.

[0043] 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. In some embodiments, R2is a 6-membered heteroaryl ring having 1-2 nitrogen atoms, wherein R2is substituted with 1-3 instances of Rb.

[0044] In some embodiments, R2is selected from13150943v 1 Page 13 of 319Attorney Docket No. 2019094-0008

[0046] 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*.

[0047] 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 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*.13150943v 1 Page 14 of 319Attorney Docket No. 2019094-0008

[0048] 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 or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0049] 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 0-2 instances of Rb*.

[0050] 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.

[0051] In some embodiments, R2is selected from:

[0052] 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.

[0053] 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.

[0054] In some embodiments, R2is selected from

[0055] 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 13150943v 1 Page 15 of 319Attorney Docket No. 2019094-0008with 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.

[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, 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.

[0057] 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.

[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 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.

[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 carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring formed by the cyclization of two Rb13150943v 1 Page 16 of 319Attorney Docket No. 2019094-0008groups 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.

[0060] In some embodiments, R2is selected from

[0061] As defined generally above, 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. 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.

[0062] In some embodiments, R3is halogen (e.g., fluoro or chloro).

[0063] In some embodiments, R3is -CN.

[0064] In some embodiments, R3is -OR.

[0065] In some embodiments, R3is -N(R)2.

[0066] 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 313150943v 1 Page 17 of 319Attorney Docket No. 2019094-0008instances of Rc. In some embodiments. R3is -CH3, -CH2-RC, -CH(RC)2, -C(Rc)s, -CH2CH3, or -C=C-Rf.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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 1-2 instances 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.

[0071] 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.13150943v 1 Page 18 of 319Attorney Docket No. 2019094-0008

[0072] 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 of Rc. 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.

[0073] 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.

[0074] 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.

[0075] 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 substituted13150943v 1 Page 19 of 319Attorney Docket No. 2019094-0008with 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. In some 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.

[0076] 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.

[0077] 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.13150943v 1 Page 20 of 319Attorney Docket No. 2019094-0008

[0078] 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 1-2 heteroatoms 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.

[0079] 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.

[0080] 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. In13150943v 1 Page 21 of 319Attorney Docket No. 2019094-0008some 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.

[0081] 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 0-3 instances of Rc. In some embodiments, R3is a 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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.

[0082] 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.

[0083] 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, or oxazolyl.13150943v 1 Page 22 of 319Attorney Docket No. 2019094-0008

[0084] In some embodiments, R3is selected from halogen (e g., fluoro or chloro), -CH3, -

[0085] In some embodiments, R3is selected from13150943v 1 Page 23 of 319Attorney Docket No. 2019094-0008

[0086] In some embodiments. R3is halogen (e.g., fluoro), -CH3, -CH2CH3, -C(RC)3, or(R°)o-2-p> |

[0087] As defined generally above, Rais hydrogen, 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, 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.13150943v 1 Page 24 of 319Attorney Docket No. 2019094-0008

[0088] In some embodiments, Rais hydrogen. In some embodiments, Rais Ci-6 aliphatic. In some embodiments, Rais C1-4 aliphatic. In some embodiments, Rais C1-2 aliphatic. In some embodiments, Rais -CH3, -CH2CH3, or -CH2OCH3. In some embodiments, Rais -CH3, -CD3, -CH2CH3, or -CH2OCH3.

[0089] 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.

[0090] In some embodiments, Rais phenyl.

[0091] 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.

[0092] 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. In 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, or triazolyl.

[0093] In some embodiments, Rais a 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, Rais pyridyl or pyrimidinyl.

[0094] 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 some13150943v 1 Page 25 of 319Attorney Docket No. 2019094-0008embodiments, Rais a 9-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais benzoxazolyl.

[0095] In some embodiments, Rais selected from

[0096] In some embodiments, Rais -CH3,13150943v 1 Page 26 of 319Attorney Docket No. 2019094-0008

[0100] As defined generally above, Ralis C1-6 aliphatic, In some embodiments, Ralis C1-4 aliphatic. In some embodiments, Ralis C1-2 aliphatic. In some embodiments, Ralis -CH3 or - CH2CH3.

[0101] As defined generally above, Rbis halogen, -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 heteroatoms13150943v 1 Page 27 of 319Attorney Docket No. 2019094-0008independently 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*.

[0102] In some embodiments, Rbis halogen. In some embodiments, Rbis -CN. In some embodiments, Rbis -OR (e.g., -OCH3). In some embodiments, Rbis -N(R)2.

[0103] 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, or -OR0. In some embodiments, Rbis C1-4 aliphatic optionally substituted with halogen, cyano, or-(CH2)o-40R°. In some embodiments, Rbis C1-4 aliphatic optionally substituted with halogen, cyano, or -OR°. In some embodiments, Rbis C1-2 aliphatic optionally substituted with halogen, cyano, or -(CH2)o-40R°. In some embodiments, Rbis C1-2 aliphatic optionally substituted with halogen, cyano, or -OR°.

[0104] 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, -R°, or-OR°. 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, -R°, or -OR°. 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, -R°, or -OR0. In some such embodiments, R° is a 4-membered saturated carbocyclic ring optionally substituted with halogen, or a 5- to 6-membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0105] In some embodiments, Rbis an optionally substituted 3- to 6-membered saturated carbocyclic ring. 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-13150943v 1 Page 28 of 319Attorney Docket No. 2019094-000840R°. In some embodiments, Rbis a 3-membered saturated carbocyclic ring optionally substituted with halogen, cyano, or -OR0.

[0106] 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 -(CH2)o-40R°. In some embodiments, Rbis a 4-membered saturated carbocyclic ring optionally substituted with -OR°.

[0107] In some embodiments, Rbis an optionally substituted 5-membered saturated carbocyclic ring. In some embodiments, Rbis cyclopentyl.

[0108] In some embodiments, Rbis an optionally substituted 6-membered saturated carbocyclic ring. In some embodiments, Rbis cyclohexyl.

[0109] In some embodiments, Rbis optionally substituted phenyl.

[0110] In some embodiments, Rbis an optionally substituted 3- to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 3- to 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-40R°, or -(CH2)o-4C(0)N(R°)2. In some embodiments, Rbis a 3 - to 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with halogen, cyano, oxo, -R°, -OR°, or -C(O)N(R°)2. 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).

[0111] 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-40R°, or -(CH2)o-4C(0)N(R°)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°, -OR°, or -C(O)N(R°)2. 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).13150943v 1 Page 29 of 319Attorney Docket No. 2019094-0008

[0112] 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°, 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°, -OR0, or -C(O)N(R°)2. 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 Ci-2 aliphatic optionally substituted with halogen (e.g., fluoro).

[0113] 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-40R°, or -(CH2)o-4C(0)R°. 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°, -OR°, or-C(O)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^i 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).

[0114] 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-40R°, or -(CH2)o-4C(0)R°. 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°, -OR0, or -C(O)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 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). 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-4R0, -(CH2)O-40R°, or -(CH2)o-4C(O)R°. In some embodiments, Rbis a 6-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally substituted with halogen,13150943v 1 Page 30 of 319Attorney Docket No. 2019094-0008cyano, oxo, -R°, -OR0, or -C(O)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 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). 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°, or -(CH2)o-4C(0)R°. 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, or -C(O)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 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).

[0115] In some embodiments, Rbis an optionally substituted 7- to 9-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an optionally substituted 8- to 9-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an optionally substituted 8-membered fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an optionally substituted 8-membered fused bicyclic heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis an 8-membered fused bicyclic heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more -(CH2)o-4 °. In some embodiments, Rbis an 8-membered fused bicyclic heterocyclic ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more -R°. In some such embodiments, R° is C1-6 aliphatic.

[0116] In some embodiments, Rbis an optionally substituted 7- to 9-membered bridged bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rbis a 7- to 9-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 optionally substituted 7-membered13150943v 1 Page 31 of 319Attorney Docket No. 2019094-0008bridged 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 having 1-2 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 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).

[0117] 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 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).

[0118] 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 - (CH2)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 C1-4 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).

[0119] In some embodiments, Rbis an optionally substituted 6- to 9-membered spirocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen,13150943v 1 Page 32 of 319Attorney Docket No. 2019094-0008oxygen, and sulfur. 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. 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. 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. In some embodiments, Rbis a 8-membered spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with oxo. 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.

[0120] 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.

[0121] In some embodiments, Rbis selected from13150943v 1 Page 33 of 319Attorney Docket No. 2019094-000813150943v 1 Page 34 of 319Attorney Docket No. 2019094-000813150943v 1 Page 35 of 319Attorney Docket No. 2019094-0008Page 36 of 31913150943v 1Attorney Docket No. 2019094-000813150943v 1 Page 37 of 319Attorney Docket No. 2019094-000813150943v 1 Page 38 of 319Attorney Docket No. 2019094-0008

[0123] In some embodiments, Rbis selected from

[0124] In some embodiments, Rhis selected from-F13150943v 1 Page 39 of 319Attorney Docket No. 2019094-0008

[0125] As defined generally above, 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. 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 Ci-4 aliphatic. In some embodiments, Rb* is optionally substituted C1-2 aliphatic.

[0126] In some embodiments, R2is selected from13150943v 1 Page 40 of 319Attorney Docket No. 2019094-000813150943v1 Page 41 of 319Attorney Docket No. 2019094-000813150943v1 Page 42 of 319Attorney Docket No. 2019094-000813150943v1 Page 43 of 319Attorney Docket No. 2019094-000813150943v1 Page 44 of 319Attorney Docket No. 2019094-0008(S)13150943v1 Page 45 of 319Attorney Docket No. 2019094-000813150943v1 Page 46 of 319Attorney Docket No. 2019094-000813150943v1 Page 47 of 319Attorney Docket No. 2019094-000813150943v1 Page 48 of 319Attorney Docket No. 2019094-000813150943v1 Page 49 of 319Attorney Docket No. 2019094-000813150943v1 Page 50 of 319Attorney Docket No. 2019094-000813150943v 1 Page 51 of 319Attorney Docket No. 2019094-000813150943v 1 Page 52 of 319Attorney Docket No. 2019094-000813150943v 1 Page 53 of 319Attorney Docket No. 2019094-000813150943v 1 Page 54 of 319Attorney Docket No. 2019094-000813150943v 1 Page 55 of 319Attorney Docket No. 2019094-000813150943v 1 Page 56 of 319Attorney Docket No. 2019094-0008

[0127] In some embodiments, R2is selected from13150943v 1 Page 57 of 319Attorney Docket No. 2019094-000813150943v 1 Page 58 of 319Attorney Docket No. 2019094-000813150943v 1 Page 59 of 319Attorney Docket No. 2019094-000813150943v 1 Page 60 of 319Attorney Docket No. 2019094-000813150943v 1 Page 61 of 319Attorney Docket No. 2019094-000813150943v 1 Page 62 of 319Attorney Docket No. 2019094-0008

[0128] In some embodiments, R2is selected from13150943v 1 Page 63 of 319Attorney Docket No. 2019094-000813150943v 1 Page 64 of 319Attorney Docket No. 2019094-000813150943v 1 Page 65 of 319Attorney Docket No. 2019094-000813150943v 1 Page 66 of 319Attorney Docket No. 2019094-000813150943v 1 Page 67 of 319Attorney Docket No. 2019094-000813150943v 1 Page 68 of 319Attorney Docket No. 2019094-000813150943v 1 Page 69 of 319Attorney Docket No. 2019094-000813150943v1 Page 70 of 319Attorney Docket No. 2019094-0008

[0129] As defined generally above, 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. In some embodiments, Rcis halogen (e.g., fluoro or chloro). In some embodiments, Rcis -CN. In some embodiments, Rcis -OR (e.g., -OCH3). In some embodiments, Rcis -N(R)2. In some embodiments, Rcis C1-6 aliphatic. In some embodiments, Rcis C1-4 aliphatic. In some embodiments, Rcis C1-2 aliphatic. In some embodiments, Rcis -CH3 or CH2CH3. In some embodiments, Rcis C1-6 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 or -CF3.13150943v 1 Page 71 of 319Attorney Docket No. 2019094-0008

[0130] In some embodiments, Rcis -C(O)R. In some such embodiments, Rcis -C(O)CH3.

[0131] 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.

[0132] As defined generally above, 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.

[0133] In some embodiments, R is hydrogen. In some embodiments, R is 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.

[0134] 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, -CH2CH3, or -CH(CH3)2. In some embodiments, R is -CH2F, -CHF2, or -CF3.

[0135] 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.

[0136] In some embodiments, R is an optionally substituted phenyl.

[0137] 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 saturated13150943v 1 Page 72 of 319Attorney Docket No. 2019094-0008heterocyclic 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.

[0138] 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.

[0139] In some embodiments, a compound of formula I is selected from1-713150943v 1 Page 73 of 319Attorney Docket No. 2019094-000813150943v 1 Page 74 of 319Attorney Docket No. 2019094-000813150943v 1 Page 75 of 319Attorney Docket No. 2019094-000813150943v 1 Page 76 of 319Attorney Docket No. 2019094-000813150943v 1 Page 77 of 319Attorney Docket No. 2019094-000813150943v 1 Page 78 of 319Attorney Docket No. 2019094-000813150943v 1 Page 79 of 319Attorney Docket No. 2019094-000813150943v 1 Page 80 of 319Attorney Docket No. 2019094-000813150943v 1 Page 81 of 319Attorney Docket No. 2019094-000813150943v 1 Page 82 of 319Attorney Docket No. 2019094-000813150943v 1 Page 83 of 319Attorney Docket No. 2019094-000813150943v 1 Page 84 of 319Attorney Docket No. 2019094-000813150943v 1 Page 85 of 319Attorney Docket No. 2019094-000813150943v 1 Page 86 of 319Attorney Docket No. 2019094-000813150943v 1 Page 87 of 319Attorney Docket No. 2019094-000813150943v 1 Page 88 of 319Attorney Docket No. 2019094-000813150943v 1 Page 89 of 319Attorney Docket No. 2019094-00081-223 1-22413150943v 1 Page 90 of 319Attorney Docket No. 2019094-0008or a pharmaceutically acceptable salt thereof.Pharmaceutically Acceptable C ompositions

[0140] 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.

[0141] The terms “patient” or “subject” are used interchangeably and mean an animal, preferably a mammal, and most preferably a human.

[0142] 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, poly acrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0143] 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 a13150943v 1 Page 91 of 319Attorney Docket No. 2019094-0008recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.

[0144] As used herein, the term “inhibitorily active metabolite or residue thereof’ means that a metabolite or residue thereof is also an inhibitor of TYK2.

[0145] 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.

[0146] 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 polyoxyethylated 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.

[0147] 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 also13150943v 1 Page 92 of 319Attorney Docket No. 2019094-0008typically added. For oral administration in a capsule form, useful diluents include lactose and dried 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.13150943v 1 Page 93 of 319Attorney Docket No. 2019094-0008

[0153] 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.

[0154] Most preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration.

[0155] 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.

[0156] 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.

[0157] Compounds and compositions described herein are generally useful for the inhibition of protein kinase activity of one or more enzymes.

[0158] 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 Compositions13150943v 1 Page 94 of 319Attorney Docket No. 2019094-0008

[0159] 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.

[0160] 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(1), 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(1), 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 Thl 7 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 Review s 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 the production of autoantibodies (Fernandez-Ruiz, R., & Niewold, T. B. (2022). Type I IFNs in13150943v 1 Page 95 of 319Attorney Docket No. 2019094-0008Autoimmunity. The Journal of Investigative Dermatology, 142(3 PtB), 793. https: / / doi.org / 10.1016 / JJID.2021.ll.031).

[0161] 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 (Fernandez-Ruiz & Niewold, 2022; Teng et al., 2015).

[0162] 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-FAC7F7FB61FA7MMCl. 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 (Wdss, 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 TYK2 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 but13150943v 1 Page 96 of 319Attorney Docket No. 2019094-0008increase susceptibility to intracellular pathogens (Couturier, N. et al. (2011). Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility. Brain, 734(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).

[0163] 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(17), 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).13150943v 1 Page 97 of 319Attorney Docket No. 2019094-0008

[0164] 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).

[0165] 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(\), 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 / ! 0.1056 / NEJMOA2109927 / SUPPL_FILE / NEJMOA2109927_DATA-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.

[0166] 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.

[0167] 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.

[0168] In some embodiments, a cancer is a cancer associated with TYK2 gain-of-function. Such cancers include hematological malignancies such as leukemias and lymphomas13150943v 1 Page 98 of 319Attorney Docket No. 2019094-0008(e.g., acute large cell lymphoma, T-cell acute lymphoblastic lymphoma, acute myeloid leukemia, anaplastic large cell lymphoma, etc.)

[0169] 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.

[0170] 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.

[0171] 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 or13150943v 1 Page 99 of 319Attorney Docket No. 2019094-0008comprising 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.

[0172] 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-NMDA 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-NMDA 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.13150943v 1 Page 100 of 319Attorney Docket No. 2019094-0008

[0173] In some embodiments, an autoimmune disease is aPNS 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.

[0174] 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.

[0175] 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.

[0176] 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).13150943v 1 Page 101 of 319Attorney Docket No. 2019094-0008

[0177] In some embodiments, a TYK2-mediated disease, disorder, or condition is an inflammatory disease.

[0178] In some embodiments, a TYK2 -mediated disease, disorder, or condition is a cancer.EXAMPLES

[0179] Example 1.1. KdELECT Competition Binding Assays

[0180] The KdELECT competition assays (Eurofins 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.

[0181] Binding constants (Kds) were calculated using a standard dose-response curve with the Hill equation:, Signal— Bakground

[0182] Response = Background -I -KdHtu stope \1+\. DoseHHl Slope)

[0183] The Hill Slope was set to -1. Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.

[0184] 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 of NFkB, 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). The13150943v 1 Page 102 of 319Attorney Docket No. 2019094-0008test 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.

[0185] Results are presented in Table 1.Table 1. KdELECT Competition Binding AssaysCompound # Activity Kd Compound # Activity Kd Compound # Activity Kd1-20 A 1-180 B 1-193 A1-37 A 1-181 C 1-194 A1-38 A 1-182 B 1-195 B1-46 A 1-183 B 1-196 A1-57 A 1-184 B 1-197 A1-58 B 1-185 A 1-198 A1-62 A 1-186 A 1-199 A1-67 A 1-187 A 1-200 A1-175 A 1-188 A 1-201 A1-176 A 1-189 A 1-202 A1-177 A 1-190 A 1-203 A1-178 B 1-191 A 1-204 A1-179 A 1-192 A 1-216 BActivity: A < 1 nM; 1 nM < B < 50 nM, C > 50 nM

[0186] Example 1.2. MDCK-MDR1 Assay

[0187] MDCK-MDR1 assay was used to evaluate the permeability and transport of drugs across cellular barriers.

[0188] Preparation of MDCK-MDR1 Cells13150943v 1 Page 103 of 319Attorney Docket No. 2019094-0008

[0189] 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 / mL with culture medium, and 50 pL of the cell suspension was dispensed into the filter 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.

[0190] Assessment of Cell Monolayer Integrity

[0191] 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.

[0192] Assay Procedures

[0193] 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.

[0194] 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.

[0195] 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).13150943v 1 Page 104 of 319Attorney Docket No. 2019094-0008

[0196] The plates were incubated at 37 °C for 2 hours. After incubation, 50 L 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 supernatant was then mixed with an equal volume of ultrapure water. The resulting samples were analyzed by LC-MS / MS.

[0197] Lucifer Yellow Leakage Test

[0198] 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.

[0199] Data Analysis

[0200] The apparent permeability coefficient (Papp) was calculated using the following equation:

[0201] Papp = (VA^ [drug] acceptor) '(Ar ea^ Time*[drug]Mftai, donor)where VA was the volume in the acceptor well and Area was the membrane surface area (0.143 cm2).

[0202] The efflux ratio was determined using the equation:

[0203] Efflux 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.

[0204] The recovery percentage was calculated as follows:

[0205] ReCOVery%—(VA^- [drug] acceptor^ VD* [dr Ug] donor) / (VD* [drug] initial, donor) where VA was the acceptor well volume, and VD was the donor well volume.

[0206] Lucifer Yellow leakage was calculated using the equation:

[0207] %LY leakage = 100 ILY]acceptor 0.3, flLYJdoror^ O. l- - 1 LY J acceptor 0.3)

[0208] A leakage percentage of <1% was deemed acceptable, indicating a well-qualified MDCK-MDR1 monolayer.

[0209] Results are presented in Table 2.13150943v 1 Page 105 of 319Attorney Docket No. 2019094-0008Table 2. MDCK-MDR1 AssayCompound # ER Compound # ER Compound # ER1-20 A 1-188 A 1-200 A1-37 A 1-190 A 1-204 B1-38 A 1-192 A 1-206 A1-62 A 1-194 A 1-207 A1-67 A 1-197 B 1-213 A1-176 A 1-198 A1-185 A 1-199 AEfflux ratio (ER): A < 3; B > 3

[0210] Example 1.3. Plasma Protein Binding Assay

[0211] 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 and plasma 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.

[0212] Results are presented in Table 3.Table 3. Plasma Protein Binding AssayCompound # Mouse PPB1-38 A13150943v 1 Page 106 of 319Attorney Docket No. 2019094-00081-62 A1-67 B1-176 B1-185 B1-190 A1-199 A1-205 B1-206 B1-207 B1-213 A1-218 A1-223 BMouse PPB: A< 98%; B > 98%

[0213] Example 1.4. Brain Tissue Binding Assay

[0214] 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.

[0215] Example 1.5. Brain Kpuu Measurement

[0216] A pharmacokinetic study was performed using male Sprague Dawley rat (n=3) to determine brain and plasma exposure of test compounds at a steady state. The compounds were13150943V 1 Page 107 of 319Attorney Docket No. 2019094-0008administered as IV infusion at a total dose 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% (20%HP-P-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.Table 4. Brain Kpuu MeasurementCompound # Rat steady state Kpuu1-38 A1-62 A1-185 A1-214 ARat steady state Kpuu: A > 0.1; B < 0.1

[0217] Example 1.6. IFNa-induced TYK2 phosphoSTAT5 Activity

[0218] 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 mM DMSO and serially diluted using a TECAN 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 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.13150943v 1 Page 108 of 319Attorney Docket No. 2019094-0008

[0219] 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 cellular response (IC50) as derived by non-linear regression analysis using GraphPad Prism.

[0220] Results are presented in Table 5.Table 5. IFNa-induced TYK2 phosphoSTAT5 ActivityCompound # IC50 Compound # IC50 Compound # IC501-38 A 1-204 A 1-215 A1-62 A 1-205 A 1-216 B1-67 A 1-206 A 1-217 B1-177 A 1-207 A 1-218 A1-185 A 1-208 A 1-219 B1-189 A 1-209 A 1-220 C1-196 A 1-210 B 1-221 A1-197 A 1-211 C 1-222 A1-199 A 1-212 C 1-223 A1-202 A 1-213 A 1-224 A1-203 A 1-214 AIC50: A< 100 nM; 100 nM < B < 1000 nM; C > 1000 nM

[0221] Example 1.7. JAK Cellular Functional Selectivity Assays

[0222] IL-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.

[0223] 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 AN EV0200. 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% BSA13150943v 1 Page 109 of 319Attorney Docket No. 2019094-0008blocking 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.

[0224] 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.

[0225] 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 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 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.

[0226] Results are presented in Table 6.Table 6. JAK Cellular Functional Selectivity AssaysIL-6- IL-2- IL-6- IL-2- Comp GM- Comp GM- pSTAT3 pSTAT5 pSTAT3 pSTAT5 ound # CSF- ound # CSF- IC50 IC50 IC50 IC5013150943v 1 Page 110 of 319Attorney Docket No. 2019094-0008pSTAT5 pSTAT5IC50 IC501-38 B C c 1-209 C C c 1-62 C c c 1-210 C c c 1-67 C c c 1-211 B c c 1-177 C c c 1-212 C c c 1-185 C c c 1-213 C c c 1-189 C c c 1-214 C c c 1-196 C c c 1-215 C c c 1-197 C c c 1-216 C c c 1-199 C c c 1-217 B c c 1-202 B c c 1-218 C c c 1-203 C c c 1-219 C c c 1-204 C c c 1-220 C c c 1-205 C c c 1-221 C c c 1-206 C c c 1-222 C c c 1-207 C c c 1-223 C c c 1-208 C c c 1-224 C c cIC50: A< 1 uM; 1 uM < B < lO uM; C > 10 uM

[0227] Example 2. Synthesis of Exemplary Compounds

[0228] Compounds of Formula I wherein X1=CH or N, V2=C and V1=N can be prepared according to the general scheme below:13150943v 1 Page 111 of 319Attorney Docket No. 2019094-0008wherein 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). R1, R2, R3are as defined above. LG1and LG2are suitable leaving groups (e.g., halogen such as fluoro, chloro, bromo or iodo).

[0229] Step 1: The 5-membered heteroaryl aldehyde is reacted with 2-isocyanoacetic acid ester, e.g., ethyl isocyanoacetate, in the presence of a suitable base, e.g., DBU.

[0230] Step 2: The fused 5,6-heteroaryl is reacted with a halogenating agent, e.g., N-bromosuccinimide, resulting in a halogenated derivative. The halogen can alternatively be converted further to a boronic acid or ester, e.g., bis(pinacolato)boronic ester using bis(pinacolato)diboron and a suitable palladium catalyst, e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in the presence of a suitable base, e.g., potassium acetate.

[0231] Step 3: The coupling reagent R2-G is prepared from the aryl halide by treatment with an alkyl stannane, e.g., hexamethylditin, in the presence of a palladium catalyst, e.g., tetrakis(triphenylphosphine)palladium(0). R2-Gis reacted with the halogenated intermediate in the presence of a palladium catalyst, e.g., bis(tri-tert-butylphosphine)palladium(0).

[0232] Alternatively, the boronic ester derived from the 5,6-heteroaryl is coupled with an aryl halide R2-LG2in the presence of palladium catalyst, e.g., tetrakis(triphenylphosphine)palladium(0) and a suitable base, e.g., cesium carbonate.

[0233] Step 4: The alkyl ester intermediate is next hydrolyzed to carboxylic acid using a strong base, e.g., lithium hydroxide, and further subjected to Curtius rearrangement conditions, e.g., using diphenylphosphoryl azide in the presence of a suitable base, e.g., triethylamine, in a solvent containing tert-butyl alcohol followed by hydrolysis of the resulting carbamate using a strong acid, e.g., trifluoroacetic acid.13150943v 1 Page 112 of 319Attorney Docket No. 2019094-0008

[0234] Step 5: The amino intermediate is next converted to an amide using, e.g., acyl halide or anhydride, e.g., acid anhydride, in the presence of a suitable base, e.g., tri ethylamine. Alternatively, the amino intermediate is coupled to an acid in the presence of suitable coupling agent, e.g., O-(7-azabenzotriazol-l-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate and in the presence of suitable base, e.g., N, N-diisopropylethylamine. Alternatively, the amino intermediate is derivatized to a carbamate using, e.g., alkyl chloroformate, in the presence of a suitable base, e.g., triethylamine. Alternatively, the intermediate is derivatized to a urea, i.e. using alkyl isocyanate. Alternatively, the intermediate is coupled with a heteroaromatic halide in a Buchwald-Hartwig cross coupling reaction using a palladium catalyst, e.g., EPhos Pd G4 in the presence of abase, e.g., sodium phenoxide.

[0235] Compounds of Formula I wherein X1=CH or N, V2=C and V1=N can be prepared according to the general scheme below:O HHLG1R2— LG2IR2-Gwherein: Group G is a stannane or boronate residue (e.g., G= Sn(Alk)a or alternatively G=B(OH)2 or G=B(OAlk)2). R1, R2, R3are defined above. LG1and LG2are suitable leaving groups (e.g., halogen, e.g., fluoro, chloro, bromo or iodo).

[0236] Step 1: The 5-membered heteroaryl aldehyde is reacted with 2-isocyanoacetic acid ester, e.g., ethyl isocyanoacetate, in the presence of a suitable base, e.g., DBU.

[0237] Step 2: The fused 5,6-heteroaryl is reacted with a halogenating agent, e.g., N-bromosuccinimide.

[0238] Step 3: The alkyl ester intermediate is next hydrolyzed to a carboxylic acid using strong base, e.g., lithium hydroxide, and further subjected to Curtius rearrangement conditions, e.g., diphenylphosphoryl azide in the presence of a suitable base, e.g., triethylamine, in a solvent containing tert-butyl alcohol resulting in the tert-butyloxy carbonyl protected aromatic amine.13150943v 1 Page 113 of 319Attorney Docket No. 2019094-0008

[0239] Step 4: The coupling reagent R2-G is prepared from the corresponding aryl halide by treatment with an alkyl stannane, e.g., hexamethylditin in the presence of a palladium catalyst, e.g., tetrakis(triphenylphosphine)palladium(0). R2-G is then reacted with the intermediate in the presence of a palladium catalyst, e.g., bis(tri-tert-butylphosphine)palladium(0). The tertbutyloxycarbonyl protecting group is removed by treatment with a strong acid, e.g.,tri fluoroacetic acid.

[0240] Step 5: The amino intermediate is next converted to an amide using, e.g., acyl halide or anhydride, e.g., acid anhydride, in the presence of a suitable base, e.g., tri ethylamine. Alternatively, the amino intermediate is coupled to an acid in the presence of suitable coupling agent, e.g., O-(7-azabenzotriazol-l-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate and in the presence of suitable base, e.g., N, N-diisopropylethylamine. Alternatively, the amino intermediate is derivatized to a carbamate using, e g., alkyl chloroformate in the presence of a suitable base, e.g., triethylamine. Alternatively, the intermediate is derivatized as urea, using alkyl isocyanate. Alternatively, the intermediate is coupled with a heteroaryl halide in a Buchwald-Hartwig cross coupling reaction using a palladium catalyst, e.g., EPhos Pd G4 in the presence of abase, e.g., sodium phenoxide.

[0241] Compounds of Formula I wherein X1=N, V2=N and V1=C can be prepared according to general scheme below:R2R2wherein: Group G is a stannane or boronate residue (e.g., G= Sn(Alk)a or alternatively G=B(OH)2 or G=B(OAlk)2). Ra, R2, R3are defined above. LG1and LG2are suitable leaving groups (e.g., halogen, e.g., fluoro, chloro, bromo or iodo).13150943v 1 Page 114 of 319Attorney Docket No. 2019094-0008

[0242] Step 1: The benzylic amine, e.g., (5-chloropyrazin-2-yl)methanamine is converted to an amide using, e.g., acyl halide or anhydride, e.g., acid anhydride, in the presence of a suitable base, e.g., triethylamine. Alternatively, the benzylic amine is coupled to an acid in the presence of suitable coupling agent, e.g., O-(7-azabenzotriazol-l-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate and in the presence of suitable base, e.g., N, N-diisopropylethylamine.

[0243] Step 2: The benzylic amide is cyclized to form fused 5.6 heterocycle using suitable dehydrating reagent, e.g., triflic anhydride in the presence of suitable base, e.g., pyridine.

[0244] Step 3: The fused 5,6-heteroaryl is reacted with a halogenating agent, e.g., N-bromosuccinimide.

[0245] Step 4: The coupling reagent R2-G is reacted with the 5,6-heteroaryl intermediate in the presence of a palladium catalyst, e.g., RuPhos Pd G3 and suitable base, e.g., potassium phosphate.

[0246] Step 5. The intermediate is coupled with primary amide using Buchwald-Hartwig cross coupling reaction in the presence of suitable palladium catalyst, e.g., tris(dibenzylideneacetone)dipalladium(0), suitable ligand, e.g., XPhos and suitable base, e.g., cesium carbonate.

[0247] Compounds of Formula I wherein X1=C, V2=N and V1=C 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(OH)2 or G=B(OAlk)2). Ra, R2, R3are defined above. LG1and LG2are suitable leaving groups (e.g., halogen, e.g., fluoro, chloro, bromo or iodo) and X is halogen.13150943v 1 Page 115 of 319Attorney Docket No. 2019094-0008

[0248] Step 1: 5-membered heterocyclic ester, e.g., ethyl 3 -methyl -lH-pyrrole-2-carboxylate is reacted with 2-haloacetamide in the presence of base, e.g., sodium hydride.

[0249] Step 2: The resulting amido ester is cyclized to a dione using suitable base, e.g., potassium tert-butoxide.

[0250] Step 3: The resulting dione is converted to dihalide using suitable reagent, e.g., phosphorus(V) oxychloride.

[0251] Step 4: The 5,6-heteroaryl dihalide is subjected to selective dehalogenation using, e.g., zinc in acetic acid.

[0252] Step 5: The fused 5,6-heteroaryl is activated with a halogenating agent, e.g., N-bromosuccinimide. Next, the coupling reagent R2-G is prepared from the corresponding aryl halide by treatment with an alkyl stannane, e.g., hexamethylditin in the presence of a palladium catalyst, e.g., tetrakis(triphenylphosphine)palladium(0). R2-G is then reacted with the intermediate in the presence of a palladium catalyst, e.g., bis(tri-tert-butylphosphine)palladium(O).

[0253] Alternatively, the 5,6-heteroaryl is subjected to palladium-catalyzed direct arylation without activation with the halogenating agent using aryl halide and suitable catalyst, e.g., bis(triphenylphosphine)palladium(II) chloride and suitable base, e.g., potassium acetate.

[0254] Step 6: The intermediate is further coupled with primary amide using Buchwald-Hartwig cross coupling reaction in the presence of suitable palladium catalyst, e.g., tris(dibenzylideneacetone)dipalladium(0), suitable ligand, e g., XPhos and suitable base, e.g., cesium carbonate.

[0255] Example 2.1. Synthesis of N-(5-(5-methoxy-6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)-7-methylpyrrolo [1,2-c] pyrimidin-3-yl)acetamide (1-58)13150943v 1 Page 116 of 319Attorney Docket No. 2019094-0008DBU, THF, NBS, CHCI3, RT, 16h RT, 2hOH Br2, NaOAc, AcOH,Mel, K2CO3, DMF, K2CO3, DMSO, 0 °C, RT, 3h 0 °C, RT, 2h 90 °C, 2hHexamethylditin, Pd(PPh3)4. Pd(t-Bu3p)2' Dioxane, 80 °C, 1 h DMF, 100 °C, 1 hSn

[0256] Synthesis of ethyl 7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate. 1,8-Diazabicyclo[5.4.0]undec-7-ene (23.02 g, 151.20 mmol, 1.1 equiv) was added to a stirred solution of ethyl 2-isocy anoacetate (15.55 g, 137.46 mmol, 1.0 equiv) in tetrahydrofuran (150 mL) at room temperature. The resulting solution was stirred for 15 min and 5-methyl-lH-pyrrole-2-carbaldehyde (15.00 g, 137.46 mmol, 1.0 equiv) was added and stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium13150943vl Page 117 of 319Attorney Docket No. 2019094-0008sulfate, filtered 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 (13.00 g, off white solid). MS (ES): m / z 205.1 [M+H]+.

[0257] Synthesis of ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate.To a stirred solution of ethyl 7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (13.00 g, 63.66 mmol, 1.0 equiv) in chloroform (130 mL), was added N-bromosuccinimide (11.33 g, 63.66 mmol, 1.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford the title compound (12.00 g, yellow solid). MS (ES): m / z 283.2 [M+H]+.

[0258] Synthesis of 6-bromo-2-fluoropyridin-3-ol. Bromine (17.67 g, 221.23 mmol, 1.0 equiv) was added to a stirred solution of 2-fluoropyri din-3 -ol (25.00 g, 221.23 mmol, 1.0 equiv) and sodium acetate (18.14 g, 221.23 mmol, 1.0 equiv) in acetic acid (250 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford the title compound 36.0 g, off white solid). MS (ES): m / z 189.9 [M-H]+.

[0259] 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 equiv) in N, N-dimethylformamide (260 mL), was added potassium carbonate (37.58 g, 272.33 mmol, 2.0 equiv) at room temperature. The resulting reaction mixture was cooled to 0 °C. Methyl iodide (19.32 g, 136.16 mmol, 1 equiv) 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 15% ethyl acetate in hexane) to afford the title compound (15.0 g, white solid). 'H NMR (CDC13, 400 MHz): 87.41 - 7.17 (m, 2H), 3.90 (s, 3H).13150943v 1 Page 118 of 319Attorney Docket No. 2019094-0008

[0260] Synthesis of 7-(6-bromo-3-methoxypyridin-2-yl)-4-oxa-7-azaspiro[2.5]octane.To a stirred solution of 6-bromo-2-fluoro-3-methoxypyridine (0.95 g, 4.61 mmol, 1.0 equiv) and 4-oxa-7-azaspiro[2.5]octane hydrochloride (0.62 g, 5.53 mmol, 1.2 equiv) in dimethylsulfoxide (10 mL) was added potassium carbonate (1.27 g, 9.22 mmol, 2.0 equiv) at room temperature. The resulting reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 22% ethyl acetate in hexane) to afford the title compound (0.80 g, off white solid). MS (ES): m / z 298.8 [M+H]+.

[0261] Synthesis of 7-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)-4-oxa-7-azaspiro[2.5]octane. Hexamethylditin (0.78 g, 2.40 mmol, 1.2 equiv) was added to a stirred solution of 7-(6-bromo-3-methoxypyridin-2-yl)-4-oxa-7-azaspiro[2.5]octane (0.60 g, 2.00 mmol, 1.0 equiv) in 1,4-dioxane (12 mL) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Under argon atmosphere tetrakis(triphenylphosphine)palladium(0) (0.11 g, 0.10 mmol, 0.05 equiv) was added, and the solution was again degassed for 5 min. The reaction mixture was stirred at 80 °C for 1 h and cooled to ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (0.75 g, light brown oil), which was used in the next step without further purification and characterization.

[0262] Synthesis of ethyl 5-(5-methoxy-6-(4-oxa-7-azaspiro[2.5]octan-7-yI)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (0.45 g, 1.59 mmol, 1.0 equiv) inN, N-dimethylformamide (10 mL) was added 7-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)-4-oxa-7-azaspiro[2.5]octane (0.75 g, 1.91 mmol, 1.2 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Under argon atmosphere bis(tri-t-butylphosphine)palladium(O) (80 mg, 0.15 mmol, 0.1 equiv) was added, and again the solution was degassed for 5 min. The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The13150943v 1 Page 119 of 319Attorney Docket No. 2019094-0008combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford the title compound (0.30 g, light yellow solid). MS (ES): m'z 423.1 [M+H]+.

[0263] Synthesis of 5-(5-methoxy-6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of 5-(5-methoxy-6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (0.30 g, 0.71 mmol, 1.0 equiv) in methanol (2.0 mL) and tetrahydrofuran (2.0 mL) was added lithium hydroxide monohydrate (74 mg, 1.78 mmol, 2.5 equiv) in water (2.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated under reduce pressure, diluted with cold water and acidified with 2N hydrochloric acid solution until pH ~ 4. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound (0.25 g, light yellow solid). MS (ES): m / z 395.3 [M+H]+.

[0264] Synthesis of tert-butyl (5-(5-methoxy-6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 5-(5-methoxy-6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid (0.25 g, 0.63 mmol, 1.0 equiv) in toluene (5 mL) and tert-butanol (5 mL), was added diphenylphosphoryl azide (0.34 g, 1.26 mmol, 2.0 equiv) and triethylamine (0.12 g, 1.26 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 125 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford tert-butyl title compound (0.13 g, light yellow solid). MS (ES): m / z 466.0 [M+H]1.

[0265] Synthesis of 5-(5-methoxy-6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(5-methoxy-6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.13 g, 0.27 mmol, 1.0 equiv) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 0 °C. The temperature was raised to room temperature and stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous13150943v 1 Page 120 of 319Attorney Docket No. 2019094-0008sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the title compound (0.1 g crude, light yellow solid) which was used in the next step without further purification and characterization.

[0266] Synthesis of 1-58. To a stirred solution of 5-(5-methoxy-6-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine (0.1 g, 0.27 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) were added N, N-diisopropylethylamine (0.1 g, 0.82 mmol, 3.0 equiv) and acetic anhydride (41 mg, 0.41 mmol, 1.5 equiv) in tetrahydrofuran at 0 °C. The temperature was raised to 60 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ethyl acetate and n-pentane to afford I-58 (25 mg, light yellow solid). MS (ES): m / z 408.5 [M+H]+;NMR (400 MHz, DMSO-d6): 8 10.21 (s, 1H), 8.87 (s, 1H), 8.80 (d, J= 1.5 Hz, 1H), 7.24 (d, J= 8.3 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 7.04 (s, 1H), 3.81 - 3.78 (m, 5H), 3.51 (s, 2H), 3.39 (s, 3H), 3.40 (d, J= 2.9 Hz, 2H), 2.08 (s, 3H), 0.69 (d, J= 3.3 Hz, 4H).13150943v 1 Page 121 of 319Attorney Docket No. 2019094-0008

[0267] Example 2.2. Synthesis of N-(5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide (1-38)DPPA, TEA, lifOllMer, t-BuOH, Toluene RT, 3h 125 °C, 3h. O.Hexamethylditin, OMe H HCI K2CO3, DMSO, Pd(PPh3)4, Pd(t-Bu3p)2’Dioxane, 100 °C,1h DMF, 100 °C, 1h 90 °C, 2hAc2O, DIPEA, THF, 0 °C, 1h

[0268] Synthesis of 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (12.00 g, 12.38 mmol, 1.0 equiv) in methanol (80 mL) and tetrahydrofuran (80 mL) was added lithium hydroxide monohydrate (2.54 g, 105.96 mmol, 2.5 equiv) in water (80 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated under reduce pressure, diluted with cold water and acidified with 2N hydrochloric acid solution until pH ~ 4. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound (6.00 g, yellow solid). ' H NMR (DMSO-d6, 400MHz):JH NMR (400 MHz, DMSO-d6): 5 12.95 (s, 1H), 8.96 (d, J= 1.6 Hz, 1H), 7.91 (d, J= 1.5 Hz, 1H), 6.97 (s, 1H), 2.59 (d, J = 2.9 Hz, 3H).

[0269] Synthesis of tert-butyl (5-bromo-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid (6.00 g, 23.52 mmol, 1.0 equiv) in toluene (120 mL) and tert-butanol (120 mL), was added solution of diphenylphosphoryl azide (7.77 g, 28.23 mmol, 1.2 equiv) and triethylamine (2.86 g, 28.23 mmol, 1.2 equiv). The reaction mixture was stirred at 125 °C for 3 h. The reaction mixture13150943v 1 Page 122 of 319Attorney Docket No. 2019094-0008was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford the title compound (2.00 g, light yellow solid).1H NMR (DMSO-d6, 400MHz): 89.66 (s, 1H), 8.78 (s, 1H), 7.45 (s, 1H), 6.65 (s, 1H), 1.47 (s, 9H).

[0270] Synthesis of 4-(6-bromo-3-methoxypyridin-2-yl)morpholine. To a stirred solution of 6-bromo-2-fluoro-3-methoxypyridine (5.00 g, 24.27 mmol, 1.0 equiv) and morpholine (3.17 g, 36.41 mmol, 1.5 equiv) in dimethylsulfoxide (50 mL), was added potassium carbonate (6.69 g, 48.54 mmol, 2.0 equiv) at room temperature. The resulting reaction mixture was heated at 90 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (3.50 g, off white solid). MS (ES): m,z 273.1 [M+H]+.

[0271] Synthesis of 4-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)morpholine. To a stirred solution of 4-(6-bromo-3-methoxypyridin-2-yl)morpholine (1.00 g, 3.67 mmol, 1.0 equiv) in 1,4-dioxane (20 mL) was added hexamethylditin (1.80 g, 5.514 mmol, 1.2 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Under argon atmosphere tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.18 mmol, 0.05 equiv) was added, and the solution was again degassed for 5 min. The reaction mixture was stirred at 100 °C for 1 h and cooled to ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (1.30 g, light brown oil), which was used in the next step without further purification and characterization.

[0272] Synthesis of tert-butyl (5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of tert-butyl (5-bromo-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.65 g, 1.99 mmol, 1.0 equiv) in N, N-dimethylformamide (14 mL) was added 4-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)morpholine (1.00 g, 2.99 mmol, 1.5 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Under argon atmosphere bis(tri-t-13150943v 1 Page 123 of 319Attorney Docket No. 2019094-0008butylphosphine)palladium(O) (0.14 g, 0.199 mmol, 0.1 equiv) was added and the solution was again degassed for 5 min. The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford the title compound (0.22 g, light yellow solid). MS (ES): m / z 440.3 [M+H]+.

[0273] Synthesis of 5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.22 g, 0.50 mmol, 1.0 equiv) in di chloromethane (5 mb) was added trifluoroacetic acid (2 mL) at 0 °C. The temperature was raised to room temperature and stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, 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 (0.10 g, light yellow solid). MS (ES): m z 340.2 [M+H]+.

[0274] Synthesis 1-38. To a stirred solution of 5-(5-methoxy-6-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine (0.10 g, 0.294 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) was added N, N-diisopropylamine (0.11 g, 0.88 mmol, 3.0 equiv) and acetic anhydride (45 mg, 0.44 mmol, 1.5 equiv) in tetrahydrofuran at 0 °C. The temperature was raised to 60 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ethyl acetate and n-pentane to afford 1-38 (0.025 g, light yellow solid). MS (ES): m'z 382.4 [M+H]+; 'HNMR (400 MHz, DMSO-d6): 8 10.19 (s, 1H), 8.94 (s, 1H), 8.810 (s, 1H), 7.25 (d, J= 8.0 Hz, 1H), 7.16 (d, J= 8.3 Hz, 1H), 7.05 (s, 1H), 3.79 (s, 3H), 3.76 (s, 4H), 3.44 (s, 4H), 2.51 (s, 3H), 2.08 (s, 3H).

[0275] Example 2.3. Synthesis of N-(5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide (1-37)13150943v 1 Page 124 of 319Attorney Docket No. 2019094-0008AC2O, DIPEA, THE, 60 °c, 1h

[0276] 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 equiv) in tetrahydrofuran (30 mL), was added tetrahydro-2H-pyran-4-carbonitrile (1.62 g, 14.63 mmol, 1.0 equiv) at room temperature. The resulting reaction mixture was cooled to -20 °C. To the reaction mixture was added 35% sodium bis(trimethylsilyl)amide in tetrahydrofuran (9.7 mL, 17.56 mmol, 1.2 equiv) and stirred at -20 °C for 4 h. The reaction mixture was diluted with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were 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]+.

[0277] Synthesis of 4-(6-bromo-3-methoxypyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid. To a stirred solution of 4-(6-bromo-3-methoxypyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (3.3 g, 11.14 mmol, 1.0 equiv) in ethanol (33 mL), was added 12N hydrochloric acid (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 and13150943v 1 Page 125 of 319Attorney Docket No. 2019094-0008dried under vacuum to afford the title compound (1.10 g, white solid). MS (ES): m / z 315.9 [M+H]+.

[0278] Synthesis of 6-bromo-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyridine. The solution of 4-(6-bromo-3-methoxypyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid (1.1 g, 3.49 mmol, 1.0 equiv) in di chloroethane (22 mL) was stirred at 80°C for 4 h. The reaction mixture was evaporated under reduce pressure, diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 50% ethyl acetate in hexane) to afford the title compound (0.50 g, white solid). MS (ES): m'z 1.\ [M+H]+.

[0279] Synthesis of 3-methoxy-2-(tetrahydro-2H-pyran-4-yl)-6- (trimethylstannyl)pyridine. To a stirred solution of 6-bromo-3-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyridine (0.20 g, 0.73 mmol, 1.0 equiv) in 1,4-dioxane (4 mL) was added hexamethylditin (0.38 g, 1.18 mmol, 1.6 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Under argon atmosphere tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.03 mmol, 0.05 equiv) was added, and the solution was again degassed for 5 min. The reaction mixture was stirred at 100 °C for 1 h and cooled to ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (0.35 g, light brown oil), which was used in the next step without further purification and characterization.

[0280] Synthesis of tert-butyl (5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of tert-butyl (5-bromo-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.20 g, 0.63 mmol, 1.0 equiv) inN, N-dimethylformamide (4 mL) was added 3 -methoxy -2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (0.30 g, 0.919 mmol, 1.5 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Under argon atmosphere bis(tri-t-butylphosphine)palladium(0) (31 mg, 0.613 mmol, 0.1 equiv) was added, and again degassed for 5 min. The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The13150943v 1 Page 126 of 319Attorney Docket No. 2019094-0008combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford the title compound (45 mg, light yellow solid). MS (ES): m'z 439.1 [M+H]+.

[0281] Synthesis of 5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (45 mg, 0.10 mmol, 1.0 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at 0 °C. The temperature was raised to room temperature and the solution was stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a trifluoroacetate salt, which was used in the next step without further purification.

[0282] Synthesis of I -37. To a stirred solution of 6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine trifluoroacetate salt (40 mg, 0.11 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) was added N, N-diisopropylethylamine (76 mg, 0.59 mmol, 5.0 equiv) and acetic anhydride (36.0 mg, 0.35 mmol, 3.0 equiv) in tetrahydrofuran at 0 °C. The temperature was raised to 60 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue was triturated with ethyl acetate and n-pentane to afford 1-37 (3.0 mg, light yellow solid). MS (ES): m / z 381.4 [M+H]+; 'H NMR (400 MHz, DMSO-d6): 5 10.18 (s, 1H), 8.86 (d, J= 14.3 Hz, 2H), 7.45 (d, J= 8.6 Hz, 1H), 7.36 (d, J= 8.6 Hz, 1H), 7.07 (s, 1H), 3.99 (dd, J= 10.8, 4.2 Hz, 2H), 3.82 (s, 3H), 3.49 (t, J= 11.6 Hz, 2H), 3.29 (s, 1H), 2.56 (s, 3H), 2.13 - 1.99 (m, 5H), 1.78 - 1.69 (m, 2H).

[0283] Example 2.4. Synthesis of N-(7-methyl-5-(5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolo[l,2-c]pyrimidin-3-yl)acetamide (1-46)13150943v 1 Page 127 of 319Attorney Docket No. 2019094-0008LiOH, THF, EtO^ter,125 °C, 4hAC2O, DIPEA, TFA, DCM, RT, 2h THF, 60 °C, 4h

[0284] Synthesis of 5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-amine. To a stirred solution of 2-bromo-l-(tetrahydro-2H-pyran-4-yl)propan-l-one (9.00 g, 40.71 mmol, 1.0 equiv) in ethanol (90 mL), was added thiourea (4.65 g, 61.06 mmol, 1.5 equiv) at room temperature. The reaction mixture was heated at 80 °C for 2 h. The reaction mixture was poured into ice-cold water. The precipitate was filtered, washed with saturated sodiumbicarbonate solution and water and dried under vacuum to afford the title compound (6.60 g, off white solid). MS (ES): m / z 199.2 [M+H]+.

[0285] Synthesis of 2-bromo-5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazole. To a stirred solution of 5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-amine (6.60 g, 33.29 mmol, 1.0 equiv) in acetonitrile (60 mL) was added tert-butyl nitrite (5.15 g, 49.93 mmol, 1.5 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of nitrogen for 10 min. Copper(I) bromide (5.73 g, 39.94 mmol, 1.2 equiv) was added under an argon 13150943v 1 Page 128 of 319Attorney Docket No. 2019094-0008atmosphere. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water and filtered through celite pad and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, 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 (3.0 g, pale yellow liquid). MS (ES): m z 262.0 [M+H]+.

[0286] Synthesis of ethyl 7-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (2.00 g, 7.06 mmol, 1.0equiv) and bis(pinacolato)diboron (5.38 g, 21.19 mmol, 3.0 equiv) in 1,4-dioxane (60 mL) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 10 min. [l, T-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.51 g, 0.70 mmol, 0.1 equiv) was added under an argon atmosphere and the solution was again degassed for 5 min. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated 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 (2.00 g, brown liquid). MS (ES): m / z 331.8 [M+H]+.

[0287] Synthesis of ethyl 7-methyl-5-(5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of 2-bromo-5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazole (0.50 g, 1.91 mmol, 1.0 equiv) in 1,4-dioxane (4mL) and water (1 mL) was added ethyl 7-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[l,2-c]pyrimidine-3 -carboxylate (1.26 g, 3.81 mmol, 2.0 equiv) and cesium carbonate (1.24 g, 3.81 mmol, 2.0 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.19 mmol, 0.1 equiv) was added under an argon atmosphere and the solution was again degassed for 5 min. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column13150943V 1 Page 129 of 319Attorney Docket No. 2019094-0008chromatography on silica gel (Combiflash, 100% ethyl acetate) to afford the title compound (0.30 g, light yellow solid). MS (ES): m / z 385.9 [M+H]+.

[0288] Synthesis of 7-methyl-5-(5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 7-methyl-5-(5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolo[l,2-c]pyrimidine-3 -carboxylate (0.30 g, 0.77 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) and ethanol (2 mL) was added lithium hydroxide monohydrate (82 mg, 1.95 mmol, 2.5 equiv) in water (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with cold water and acidified with 2N hydrochloric acid solution until pH ~ 6. The precipitate was filtered, washed with water, dried under vacuum, and triturated with n-pentane to afford the title compound (0.22 g, light brown solid). MS (ES): m / z 357.9 [M+H]+.

[0289] Synthesis of tert-butyl (7-methyl-5-(5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 7-methyl-5-(5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid (0.19 g, 0.54 mmol, 1.0 equiv) in toluene (4 mL) and tert-butanol (4 mL), was added solution of diphenylphosphoryl azide (0.30 g, 1.09 mmol, 2.0 equiv), triethylamine (0.11 g, 1.09 mmol, 2.0 equiv) and molecular sieves 4 A (0.20 g) at room temperature. The reaction mixture was stirred at 125 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 35% ethyl acetate in hexane) to afford the title compound (0.14 g, light brown solid). MS (ES): m / z 429.4 [M+H]+.

[0290] Synthesis of 7-methyl-5-(5-methyI-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (7-methyl-5-(5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.14 g, 0.32 mmol, 1.0 equiv) in dichloromethane (2 mL), was added trifluoroacetic acid (0.74 g, 6.53 mmol, 20 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduce pressure to afford the title compound (0.14 g, light brown solid) as a trifluoroacetate salt, which was used as such in next step without further purification MS (ES): m / z 329.3 [M+H]+.13150943v 1 Page 130 of 319Attorney Docket No. 2019094-0008

[0291] Synthesis of T-46. To a stirred solution of 7-methyl-5-(5-methyl-4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)pyrrolo[l,2-c]pyrimidin-3-amine trifluoroacetate salt (0.14 g, 0.31 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) was added N, N-diisopropylethylamine (0.20 g, 1.59 mmol, 5.0 equiv) and acetic anhydride (97 mg, 0.95 mmol, 3.0 equiv) in tetrahydrofuran at 0 °C. The temperature of the reaction mixture 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 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, 2.5% methanol in dichloromethane) to afford 1-46 (44 mg, orange solid). MS (ES): m / z 371.3 [M+H]+; 'HNMR (400 MHz, DMSO-d6): 5 10.41 (s, 1H), 8.91 (d, J= 1.5 Hz, 1H), 8.72 (s, 1H), 6.91 (d, J= 1.1 Hz, 1H), 4.97 - 3.94 (m, 2H), 3.48 (t, J= 11.2 Hz, 2H), 2.99 - 2.94 (m, 1H), 2.51 (s, 3H), 2.39 (s, 3H), 2.12 (s, 3H), 2.00 (dd, J= 12.6, 4.2 Hz, 2H), 1.60 (d, J= 12.3 Hz, 2H).13150943v 1 Page 131 of 319Attorney Docket No. 2019094-0008

[0292] Example 2.5. Synthesis of N-(7-methyl-5-(4-methyl-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyridin-2-yl)pyrrolo[l,2-c]pyrimidin-3-yl)acetamide (1-67) and N-(7-methyl-5-(4-methyl-6-((3aS,6aR)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyridin-2-yl)pyrrolo[l,2-c]pyrimidin-3-yl)acetamide (1-57)1) AD-alpha, Methanesulfonamide, NaH Water, t-BuOH, 0 °C ro RT, 16h Tosylimidazole, 2) Sodium sulfite, RT, 1 h THF, 0 °C to RT, 2hTEMPO, Phl(OAc)2’ DOM, 0 °C to RT, 10ht-sR5flA-TEfefene, 125 °C, 3hAcetic anhydride, DIPEA THF, 0 °C to 60 °c, 4h13150943v 1 Page 132 of 319Attorney Docket No. 2019094-0008

[0293] Synthesis of (3S,4S)-6-((tert-butyldimethylsilyl)oxy)hexane-l,3,4-triol. To a stirred solution of AD-mix-a (42.60 g, 54.60 mmol, 1.8 equiv), in tert-butanol (140mL) and water (140 mL) was added methanesulfonamide (2.89 g, 30.30 mmol, 1.0 equiv) followed by the addition of (E)-6-((tert-butyldimethylsilyl)oxy)hex-3-en-l-ol (7.00 g, 30.3 mmol, 1.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C and sodium sulfite (46.00 g, 364 mmol, 12 equiv) was added portion wise and allowed to stirr at room temperature for 1 h, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 95% ethyl acetate in hexane) to afford the title compound (6.80 g, off white gum).!H NMR (400 MHz, DMSO-d6): 54.32 (t, J= 5.1 Hz, 1H), 4.23 (dd, J= 5.6, 3.8 Hz, 2H), 3.71 - 3.64 (m, 2H), 3.54 - 3.45 (m, 2H), 3.38 (s, 2H), 1.58 (s, 2H), 1.45 (s, 2H), 0.86 (d, J= 2.2 Hz, 9H), 0.03 (s, 6H).

[0294] Synthesis of (2S,3S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)tetrahydrofuran-3-ol. To a stirred solution of (3S,4S)-6-((tert-butyldimethylsilyl)oxy)hexane-l,3,4-triol (6.80 g, 25.70 mmol, 1.0 equiv) in tetrahydrofuran (70 mL) was added sodium hydride (60% dispersion in oil) (1.54 g, 64.20 mmol, 2.5 equiv) at 0 °C. The reaction mixture was stirred for 30 min, followed by the addition of tosyl imidazole (5.72 g, 25.7 mmol, 1.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 45% ethyl acetate in hexane) to afford the title compound (3.3 g, off white gum).!H NMR (400 MHz, DMSO-d6): 8 4.61 (d,,7=4.8 Hz, 1H), 4.06 -4.05 (m, 1H), 3.85 - 3.75 (m, 1H), 3.73 - 3.62 (m, 2H), 3.66 -3.49 (m, 2H), 2.09 - 1.98 (m, 1H), 1.78 - 1.59 (m, 3H), 0.96 - 0.75 (m, 9H), 0.03 (s, 6H).

[0295] Synthesis of (S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)dihydrofuran-3(2H)-one. To a stirred solution of (2S,3S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)tetrahydrofuran-3-ol (2.70 g, 10.90 mmol, 1.0 equiv) in dichloromethane (54 mL), was added (2, 2,6,6-tetramethylpiperidin-l-yl)oxyl (171 mg, 1.10 mmol, 0.1 equiv) and (diacetoxyiodo)benzene (7.06 g, 21.9 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 10 h. The reaction was diluted with water and extracted with ethyl acetate. The combined organic13150943v 1 Page 133 of 319Attorney Docket No. 2019094-0008layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford the title compound (2.2 g, off white gum).1HNMR(400MHz, CDCh): 84.40 - 4.30 (m, 1H), 4.12 - 4.03 (m, 1H), 3.94- 3.63 (m, 3H), 2.75 - 2.35 (m, 2H), 2.02 - 1.88 (m, 1H), 1.87 - 1.75 (m, 1H), 0.99 (s, 9H), 0.04 (s, 6H).

[0296] Synthesis of (2S,3R)-3-(6-bromo-4-methylpyridin-2-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)tetrahydrofuran-3-ol. To a stirred solution of 2,6-dibromo-4-methyl-pyridine (1.00 g, 3.99 mmol, 1.0 equiv) in dichloromethane (20 mL) was added dropwise n-butyllithium (2.0 M in hexane) (2.39 mL, 4.78 mmol, 1.2 equiv) at -78 °C and the solution was stirred for 30 min, followed by the addition of (S)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)dihydrofuran-3(2H)-one (1.07 g, 4.38 mmol, 1.1 equiv) in dichloromethane (5 mL). The reaction mixture was allowed to warm to room temperature and it was stirred for 2 h. The reaction mixture was diluted with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 25% ethyl acetate in hexane) to afford the title compound (0.88 g, off white gum). MS (ES): m / z 416.3 [M+H]+.

[0297] Synthesis of (2S,3R)-3-(6-bromo-4-methylpyridin-2-yl)-2-(2-hydroxyethyl)tetrahydrofuran-3-ol. To a stirred solution of (2S,3R)-3-(6-bromo-4-methylpyridin-2-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)tetrahydrofuran-3-ol (0.88 g, 2.11 mmol, 1.0 equiv) in tetrahydrofuran (20 mL), was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran) (2.1 mL, 2.11 mmol, 1.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 25% ethyl acetate in hexane) to afford the title compound (0.46 g, off white gum). MS (ES): m / 'z 302.2 [M+H]+.

[0298] Synthesis of 2-bromo-4-methyl-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyridine. To a stirred solution of (2S,3R)-3-(6-bromo-4-methylpyridin-2-yl)-2-(2-hydroxyethyl)tetrahydrofuran-3-ol (0.46 g, 1.52 mmol, 1.0 equiv) in tetrahydrofuran (3 mL) was13150943v 1 Page 134 of 319Attorney Docket No. 2019094-0008added sodium hydride (60% dispersion in oil) (0.09 g, 3.81 mmol, 2.5 equiv) at 0 °C. The reaction mixture was stirred for 30 min, followed by addition of tosyl imidazole (0.33 g, 1.52 mmol, 1 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 40% ethyl acetate in hexane) to afford the title compound (0.32 g, off white gum). MS (ES): m / z 284.1 [M+H]+.

[0299] Synthesis of 4-methyI-2-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)-6-(trimethylstannyl)pyridine. To a stirred solution of 2-bromo-4-methyl-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyridine (0.25 g, 0.879 mmol, 1.0 equiv) in 1,4-dioxane (3 mL) was added hexamethylditin (0.345 g, 1.06 mmol, 1.2 equiv) at room temperature. The reaction mixture was degassed by bubbling a stream of argon for 5 min. Under argon atmosphere tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.088 mmol, 0.1 equiv) was added, and the solution was again degassed for 5 min. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound. (0.30 g, brown gum), which was used in the next step without further purification and characterization.

[0300] Synthesis ethyl 7-methyl-5-(4-methyI-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyridin-2-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (0.20 g, 0.706 mmol, 1.0 equiv) in N, N-dimethylformamide (5.0 mL) was added 4-methyl-2-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)-6-(trimethylstannyl)pyridine (0.28 g, 0.777 mmol, 1.1 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.070 mmol, 0.1 equiv) was added, and the solution again degassed for 5 min. The reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by13150943v 1 Page 135 of 319Attorney Docket No. 2019094-0008flash column chromatography on silica gel (Combiflash, 50% ethyl acetate in hexane) to afford ethyl title compound (0.20 g, yellow solid). MS (ES): m / z 408.3 [M+H]+.

[0301] Synthesis of 7-methyl-5-(4-methyl-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyridin-2-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of 7-methyl-5-(4-methyl-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyri din-2-yl)pyrrolo[l,2-c]pyrimidine-3 -carboxylate (0.20 g, 0.490 mmol, 1.0 equiv) in methanol (2 mL) and tetrahydrofuran (2 mL) was added lithium hydroxide monohydrate (29 mg, 1.23 mmol, 2.5 equiv) in water (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated under reduce 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 (0.14 g, yellow solid). MS (ES): m / z 380.3 [M+H]+.

[0302] Synthesis of tert-butyl (7-methyl-5-(4-methyl-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyridin-2-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 7-methyl-5-(4-methyl-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyridin-2-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid (0.13 g, 0.342 mmol, 1.0 equiv) in toluene (4 mL) and tert-butanol (4 mL), was added diphenylphosphoryl azide (0.19 g, 0.685 mmol, 2.0 equiv) and triethylamine (0.069 g, 0.685 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 125 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford the title compound (70 mg, light yellow solid). MS (ES): m / z 451.3 [M+H]+.

[0303] Synthesis of 7-methyl-5-(4-methyl-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyridin-2-yl)pyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (7-methyl-5-(4-methyl-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyri din-2-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate (60 mg, 0.133 mmol, 1.0 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (0.6 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was evaporated under reduced pressure, diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic13150943v 1 Page 136 of 319Attorney Docket No. 2019094-0008layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue was triturated with ethyl acetate and n-pentane to afford the title compound (50 mg, brown solid). MS (ES): m / z 351.3 [M+H]+.

[0304] Synthesis of 1-67 and 1-57. To a stirred solution of 7-methyl-5-(4-methyl-6-((3aR,6aS)-tetrahydrofuro[3,2-b]furan-3a(5H)-yl)pyridin-2-yl)pyrrolo[l,2-c]pyrimidin-3-amine (50 mg, 0.142 mmol, 1.0 equiv) in tetrahydrofuran (2.0 mL) was added N, N-diisopropylethylamine (92 mg, 0.713 mmol, 5.0 equiv) and acetic anhydride (43 mg, 0.428 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 50% ethyl acetate in hexane) to afford the title compound (28 mg, light yellow solid). MS (ES): m / z 393.6 [M+H]+.

[0305] The enentioenriched compound was purified by SFC using CHIRALPAK IB-N (250*30)mm, 5um column and mobile phase (A) 0.1% NEE in Hexane (B) 0.1% NH3 in IPA: ACN (70:30) to afford the major product 1-67 (14 mg, light yellow solid). MS (ES): m / z 393.1 [M+H]+; 'H NMR (400 MHz, DMSO-d6): 5 10.27 (s, 1H), 8.89 (d, J= 4.2 Hz, 2H), 7.34 (s, 1H), 7.14 (d, J= 17.0 Hz, 2H), 4.59 (d, J= 2.2 Hz, 1H), 4.19 - 4.16 (m, 1H), 4.08 - 3.96 (m, 3H), 2.99 (q, J= 8.7 Hz, 1H), 2.54 (s, 3H), 2.33 (s, 3H), 2.21 - 2.17 (m, 1H), 2.08 (s, 3H), 1.94 (d, J= 8.1 Hz, 2H). The minor product 1-57 (1.3 mg, light yellow solid). MS (ES): m / z 393.0 [M+H]+; 'HNMR (400 MHz, DMSO-d6): 8 10.27 (s, 1H), 8.88 (d, J= 5.0 Hz, 2H), 7.34 (s, 1H), 7.14 (d, J= 17.1 Hz, 2H), 4.59 (d, J= 3.8 Hz, 1H), 4.19 (d, J= 4.8 Hz, 1H), 4.11 - 3.94 (m, 3H), 2.99 (d, J = 11.9 Hz, 1H), 2.54 (s, 3H), 2.33 (s, 3H), 2.23 - 2.14 (m, 1H), 2.09 (s, 3H), 1.95 (s, 2H).

[0306] Example 2.6. Synthesis of N-(5-(5-methoxy-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide (1-20)13150943v 1 Page 137 of 319Attorney Docket No. 2019094-0008Isoamyl nitrite, 1 M HCI, MeOH, Pd(dppf)Cl2DCM> Hexamethylditin, Pd(PPhs)4. 60 °C, 5h Dioxane, Water 100 °c, 3h Dioxane, 100 °C, 2h80 °C, 48h

[0307] Synthesis of 3,5-dibromo-2-methoxypyrazine. To a stirred solution of 3,5-dibromopyrazin-2-amine (10.0 g, 39.54 mmol, 1.0 equiv) in methanol (100 mL) and IM hydrochloric acid (2 mL), was added isoamyl nitrite (13.90 g, 118.6 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was diluted with cold water and basified with aqueous sodium bicarbonate solution until pH ~ 8 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 4 % ethyl acetate in hexane) to afford the title compound (8.00 g, off-white solid). 'H NMR (400 MHz, CDCh): 88.15 (s, 1H), 4.05 (s, 3H).13150943v 1 Page 138 of 319Attorney Docket No. 2019094-0008

[0308] Synthesis of 5-bromo-3-(3,6-dihydro-2H-pyran-4-yl)-2-methoxypyrazine. To a stirred solution of 3,5 -dibromo-2-methoxy pyrazine (5.00 g, 18.66 mmol, 1.0 equiv) in 1,4-dioxane (40 mL) and water (10 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.70 g, 22.40 mmol, 1.2 equiv) and potassium carbonate (7.74 g, 55.99 mmol, 3.0 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 10 min. [1,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.52 g, 1.87 mmol, 0.1 equiv) was added under an argon atmosphere and the solution was again degassed for 5 min. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 30 % ethyl acetate in hexane) to afford the title compound (3.3 g, off-white solid). MS (ES): m / z 271.11 [M+H]~.

[0309] Synthesis of 3-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-5- (trimethylstannyl)pyrazine. To a stirred solution of 5-bromo-3-(3,6-dihydro-2H-pyran-4-yl)-2-m ethoxy pyrazine (1.0 g, 3.69 mmol, 1.0 equiv) in 1,4-di oxane (20 mL) was added hexamethylditin (1.93 g, 5.90 mmol, 1.6 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Bis(tri-tert-butylphosphine)palladium(O) (0.21 g, 0.18 mmol, 0.05 equiv) was added, again degassed for 5 min. The reaction mixture was stirred at 100 °C for 2 h and cooled to ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (1.45 g, crude light yellow semi solid), which was used in the next step without further purification.

[0310] Synthesis of ethyl 5-(6-(3,6-dihydro-2H-pyran-4-yl)-5-methoxypyrazin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of 3-(3,6-dihydro-2H-pyran-4-yl)-2-methoxy-5-(trimethylstannyl)pyrazine (1.40 g, 3.94 mmol, 1.0 equiv) in N. N-dimethylformamide (28 mL) was added ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (1.12 g, 3.94 mmol, 1.0 equiv) at room temperature. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Under argon atmosphere bis(tri-t-13150943v 1 Page 139 of 319Attorney Docket No. 2019094-0008butylphosphine)palladium(O) (0.20 g, 0.394 mmol, 0.1 equiv) was added, the solution was again degassed for 5 min. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford the title compound (0.56 g, light yellow solid). MS (ES): m / z 395.2 [M+H]+.

[0311] Synthesis of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-5-methoxypyrazin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 5-(6-(3,6-dihydro-2H-pyran-4-yl)-5-methoxypyrazin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (0.51 g, 1.29 mmol, 1.0 equiv) in ethanol (3.40 mL) and tetrahydrofuran (3.40 mL) was added lithium hydroxide monohydrate (0.13 g, 3.23 mmol, 2.5 equiv) in water (3.40 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated under reduce pressure, diluted with cold water and acidified with 2N hydrochloric acid solution until pH ~ 4. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound (0.36 g, light yellow solid). MS (ES): m / z 367.3 [M+H]+.

[0312] Synthesis of tert-butyl (5-(6-(3,6-dihydro-2H-pyran-4-yl)-5-methoxypyrazin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-5-methoxypyrazin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid (0.31 g, 0.846 mmol, 1.0 equiv) in toluene (6.20 mL) and tert-butanol (6.20 mL), was added diphenylphosphoryl azide (0.47 g, 1.69 mmol, 2.0 equiv) and triethylamine (0.17 g, 1.69 mmol, 2.0 equiv). The reaction mixture was stirred at 125 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 80% ethyl acetate in hexane) to afford the title compound (0.14 g, light yellow solid). MS (ES): m / z 438.4 [M+H]+.

[0313] Synthesis of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-5-methoxypyrazin-2-yl)-7-methylpyrroIo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(6-(3,6-dihydro-2H-pyran-4-yl)-5-methoxypyrazin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.12 g, 0.304 mmol, 1.0 equiv) in dichloromethane (2.40 mL) was added triethylamine (1.20 mL) at 013150943v 1 Page 140 of 319Attorney Docket No. 2019094-0008°C. The temperature was raised to room temperature and stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the title compound (0.10 g, light yellow solid). MS (ES): m / z 338.4 [M+H]+.

[0314] Synthesis of N-(5-(6-(3,6-dihydro-2H-pyran-4-yl)-5-methoxypyrazin-2-yl)-7-methylpyrroIo[l,2-c]pyrimidin-3-yl)acetamide. To a stirred solution of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-5-methoxypyrazin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine (80 mg, 0.237 mmol, 1.0 equiv) in tetrahydrofuran (0.80 mL) was added N, N-diisopropyl ethylamine (92 mg, 0.711 mmol, 3.0 equiv) and acetic anhydride (36 mg, 0.355 mmol, 1.5 equiv) in tetrahydrofuran at 0 °C. The temperature was raised to 60 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 80% ethyl acetate in hexane) to afford the title compound (50 mg, light yellow solid). MS (ES): m / z 380.2 [M+H]+.

[0315] Synthesis of 1-20. To a stirred solution of N-(5-(6-(3,6-dihydro-2H-pyran-4-yl)-5-methoxypyrazin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide (40 mg, 0.092 mmol, 1.0 equiv) in methanol (1.20 mL), was added 10% palladium on carbon (wetted, 55% water) (40 mg) at room temperature. The reaction mixture was stirred under hydrogen gas (140 psi) in autoclave at 80 °C for 48 h. After completion of the reaction, the mixture was filtered and the filter was washed with methanol (10 mL), filtrate was concentrated under reduced pressure. The crude compound was triturated with ethyl acetate and n-pentane to afford 1-20 (5.5 mg, light yellow solid). MS (ES): m / z 382.2 [M+H]+;NMR (401 MHz, DMSO-d6): 8 10.26 (s, 1H), 8.88 (d, J= 3.7 Hz, 2H), 8.34 (s, 1H), 7.16 (s, 1H), 4.00 (d, J= 10.8 Hz, 2H), 3.93 (s, 3H), 3.50 (t, J= 11.4 Hz, 2H), 3.28 - 3.19 (m, 1H), 2.67 (s, 3H), 2.10 (s, 3H), 2.05 - 1.92 (m, 2H), 1.82 (d, J= 13.4 Hz, 2H).13150943v 1 Page 141 of 319Attorney Docket No. 2019094-0008

[0316] Example 2.7. Synthesis of N-(7-methyl-5-(6-methyl-2-(tetrahydro-2H-pyran- 4-yl)pyrimidin-4-yl)pyirolo[l,2-c]pyriniidin-3-yl)acetamide (1-62)o o 3h POCI3, DMF (2) 7N Methanic Ammonia DMSOK1§S)°’C 16 h DCM, 0 " C to RT, 3 h 0 °C to RT, 3 hAC2O, DI PEA THF, 60 °C, 4 h

[0317] Synthesis of tetrahydro-2H-pyran-4-carboximidamide. To a stirred solution tetrahydro-2H-pyran-4-carboxamide (36.0 g, 278.0 mmol, 1.0 eq) in dichloromethane (700 mL) was added trimethyloxonium tetrafluoroborate (49.4 g, 334.0 mmol, 1.2 eq) at 0 °C and the reaction mixture was stirred at room temperature for 3 h under nitrogen atmosphere, followed by addition of 7 N methanolic ammonia (398 mL, 2790.0 mmol, 10.0 eq) at 0 °C. The reaction mixture was allowed to warm to room temperature and was further stirred for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the title compound (70.0 g, off white solid), which was used in the next step without further purification.

[0318] Synthesis of 6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-ol. To a stirred solution of tetrahydro-2H-pyran-4-carboximidamide (30.0 g, 234.0 mmol, 1.6 eq) in dimethyl sulfoxide (50 mL) was added methyl 3-oxobutanoate (17.0 g, 146.41 mmol, 1.0 eq) and potassium carbonate (40.4 g, 292.8 mmol, 2.0 eq). The reaction mixture was stirred at 120 °C for 16 h. Next, the reaction mixture was cooled to room temperature, diluted with water and neutralized with 1 N hydrochloric acid solution, and extracted with ethyl acetate. The combined 13150943v 1 Page 142 of 319Attorney Docket No. 2019094-0008organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was triturated with diethyl ether to afford the title compound (24.0 g, off white solid). MS (ES): nt / z' 195.2 [M+H]+.

[0319] Synthesis of 4-chloro-6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidine. To a stirred solution of 6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-ol (15.0 g, 77.23 mmol, 1.0 eq) in dichloromethane (300 mL) was added N, N-dimethylformamide (5.64 g, 77.23 mmol, 1.0 eq), followed by the addition of phosphorus(V) oxychloride (58 mL, 617.82 mmol, 8.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. Next, the reaction mixture was concentrated under reduced pressure, diluted with ice water, neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (5.0 g, brown solid). MS (ES): m / z 212.8 [M+H]+.

[0320] Synthesis of ethyl 7-methyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 7-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate (15.53 g, 47.02 mmol, 2.0 eq) in 1,4-dioxane (120 mL) and water (25 mL) was added 4-chloro-6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidine (5.0 g, 23.51 mmol, 1.0 eq) and cesium carbonate (15.32 g, 47.02 mmol, 2.0 eq). The reaction mixture was degassed by bubbling through a stream of argon for 10 min, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (2.72 g, 2.35 mmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 3 h. 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. The residue was purified by flash column chromatography on silica gel (Combiflash, 2.5% methanol in dichloromethane) to afford the title compound (4.0 g, yellow solid). MS (ES): m / z 381.2 [M+H]+.

[0321] Synthesis of 7-methyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 7-methyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3 -carboxylate (4.0 g, 10.51 mmol, 1.0 eq) in tetrahydrofuran (30 mL) and ethanol (30 mL) was added lithium hydroxide monohydrate (1.1 g, 26.29 mmol, 2.5 eq) in water (30 mL). The reaction mixture was13150943v 1 Page 143 of 319Attorney Docket No. 2019094-0008stirred for 3 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with cold water and acidified with 10% citric acid solution until pH ~ 6, and extracted with 10% methanol in dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (3.0 g, yellow solid). MS (ES): m / z 353.2 [M+H]+.

[0322] Synthesis of tert-butyl (7-methyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 7-methyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid (3.0 g, 8.51 mmol, 1.0 eq) in toluene (60 mL) and tert-butanol (60 mL), was added diphenylphosphoryl azide (4.69 g, 17.03 mmol, 2.0 eq), triethylamine (2.37 mL, 17.03 mmol, 2.0 eq) and molecular sieves, 4 A (3.0 g). The reaction mixture was stirred at 125 °C for 4 h. Next, 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, 50% ethyl acetate in hexane) to afford the title compound (1.7 g, yellow solid). MS (ES): m / z 424.4 [M+H]+.

[0323] Synthesis of 7-methyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (7-methyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate (1.7 g, 4.01 mmol, 1.0 eq) in dichloromethane (24 mL), was added trifluoroacetic acid (6.14 mL, 80.28 mmol, 20.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Next, the reaction mixture was evaporated under reduced pressure to afford 7-methyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3 -amine (1.7 g, brown liquid) as a trifluoroacetic acid salt, which was used as such in next step without further purification. MS (ES): m / z 324.2 [M+H]+.

[0324] Synthesis of 1-62 To a stirred solution of 7-methyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3 -amine trifluoroacetate salt (1.7 g, 3.90 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added N, N-diisopropylethylamine (3.4 mL, 19.48 mmol, 5.0 eq) and acetic anhydride (0.72 mL, 7.79 mmol, 2.0 eq) in tetrahydrofuran. The reaction mixture was raised to 60 °C and stirred for 4 h. Next, the reaction mixture was cooled to room temperature, diluted with water and extracted with 10% methanol in di chloromethane. The13150943v 1 Page 144 of 319Attorney Docket No. 2019094-0008combined 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, 3.5% methanol in dichloromethane) to afford 1-62 (1.1 g, light yellow solid). MS (ES): m / z 366.2 [M+H]+; ‘HNMR (400 MHz, DMSO-d6): 5 10.39 (s, 1H), 9.16 (s, 1H), 8.95 (s, 1H), 7.36 (s, 1H), 7.24 (s, 1H), 4.01 - 3.98 (m, 2H), 3.49 (td, J= 11.4, 2.4 Hz, 2H), 3.00 - 2.96 (m, 1H), 2.55 (s, 3H), 2.40 (s, 3H), 2.12 (s, 3H), 2.08 - 1.87 (m, 4H).

[0325] Example 2.8. Synthesis of N-(7-cyclopropyl-5-(4-morpholino-[l,3]dioxolo[4,5-c]pyridin-6-yl)pyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-175)13150943v 1 Page 145 of 319Attorney Docket No. 2019094-0008OHRuphos Pd G3. K3PO4’ NBS, CHCk, Toluene, Water, 100 °C, RT, 2h 4h1. LDA, THF, -78 °C, 1h 2. Trimethyl Borate, OH DIPEA, THF, -78 °C, 1h 0 °C to RT, 4h K2CO3, DMSO, 90 °C, 4h 3. 30% H2O2, RT, 2h

[0326] Synthesis of ethyl 7-cyclopropylpyirolo[l,2-c]pyrimidine-3-carboxylate). To a stirred solution of ethyl 7-bromopyrrolo[l,2-c]pyrimidine-3-carboxylate (3 g, 11.15 mmol, 1.0 eq) in toluene (24 mL) and water (6 mL) was added cyclopropylboronic acid (3.83 g, 44.59 mmol, 4.0 eq) and potassium phosphate tribasic (7.10 g, 33.45 mmol, 3.0 eq). The reaction mixture was purged under a stream of argon for 15 min before the addition of Ruphos Pd G3 (9.32 g, 11.15 mmol, 0.1 eq). 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 organic13150943v 1 Page 146 of 319Attorney Docket No. 2019094-0008layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 40% ethyl acetate in hexane) to afford the title compound (2.5 g, off white, solid). MS (ES): m / z 231.26 [M+H]+.

[0327] Synthesis of ethyl 5-bromo-7-cyclopropylpyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 7-cyclopropylpyrrolo[l,2-c]pyrimidine-3-carboxylate (1.5 g, 6.51 mmol, 1.0 eq) in chloroform (30 mb) was added N-bromosuccinimide (1.16 g, 6.51 mmol, 1.0 eq) and the reaction mixture was stirred for 2 h. Next, the reaction mixture was diluted with brine 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, 30% ethyl acetate in hexane) to afford the title compound (1.35 g, yellow solid). MS (ES): m / z 310.00 [M+H]+.

[0328] 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 the reaction mixture was stirred for 20 min. Bromomethyl methyl ether (7.81 g, 62.50 mmol, 1.2 eq) was added and the reaction mixture was stirred 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 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 (5.6 g, off white solid). MS (ES): m / z 236.1 [M+H]+.

[0329] Synthesis of 4-(6-bromo-3-(methoxymethoxy)pyridin-2-yl)morpholine. To a stirred solution of 6-bromo-2-fluoro-3-(methoxymethoxy)pyridine (10.0 g, 42.37 mmol, 1.0 eq) in dimethyl sulfoxide (100 mL) was added potassium carbonate (8.78 g, 63.55 mmol, 1.5 eq) and the reaction mixture was stirred at 90 °C 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 sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 17% ethyl acetate in hexane) to afford the title compound (9.1 g, colorless oil). MS (ES): m / z 303.4 [M+H]+.13150943v 1 Page 147 of 319Attorney Docket No. 2019094-0008

[0330] Synthesis of 6-bromo-3-(methoxymethoxy)-2-morpholinopyridin-4-ol. To a stirred solution of 4-(6-bromo-3-(methoxymethoxy)pyridin-2-yl)morpholine (9.1 g, 30.02 mmol, 1.0 eq) in tetrahydrofuran (230 mL) was added lithium diisopropylamide (37.52 mL, 75.04 mmol, 2.5 eq, 2.0 M in tetrahydrofuran) at -78 °C. The solution was stirred for 1 h, followed by the addition of trimethyl borate (7.80 g, 75.04 mmol, 2.5 eq) in tetrahydrofuran and further stirred for 1 h at -78 °C. Hydrogen peroxide (7.67 mL, 75.04 mmol, 2.5 eq, 30%) was added at -78 °C and the reaction mixture was stirred at room temperature for 2 h. 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. The residue was purified by flash column chromatography (Combiflash, 20% ethyl acetate in hexane) to afford the title compound (5.3 g, colorless oil). MS (ES): m / z 319.10 [M+H]+.

[0331] Synthesis of 6-bromo-2-morpholinopyridine-3,4-diol. To a stirred solution of 6-bromo-3-(methoxymethoxy)-2-morpholinopyridin-4-ol (5.3 g, 16.61 mmol, 1 eq) in 1,4-dioxane (20 mL) was added hydrochloric acid in (54 mL, 4M in 1,4-dioxane). The reaction mixture was stirred for 4 h. Next, the mixture was concentrated under reduced pressure, and the crude compound was triturated with diethyl ether to afford the title compound (4.5 g, off white solid). MS (ES): m / z 275.20 [M+H]+.

[0332] Synthesis of 6-bromo-4-morpholino-[l,3]dioxoIo[4,5-c]pyridine. To a stirred solution of 6-bromo-2-morpholinopyridine-3,4-diol (4.5 g, 16.36 mmol, 1.0 eq) inN, N-dimethylformamide (90 mL) was added cesium carbonate (21.4 g, 65.43 mmol, 1.5 eq) and the reaction was stirred for 10 min, followed by the addition of chloroiodomethane (8.66 g, 49.07 mmol, 1.0 eq). The reaction mixture was heated at 60 °C for 16 h. Nest, it was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Combiflash, 40% ethyl acetate in hexane) to afford the title compound (3.1 g, white solid). MS (ES): m / z 287.2 [M+H]+.

[0333] Synthesis of 4-morpholino-6-(trimethylstannyl)-[l,3]dioxolo[4,5-c]pyridine.To a stirred solution of 6-bromo-4-morpholino-[l,3]dioxolo[4,5-c]pyridine (0.600 g, 2.09 mmol, 1.0 eq) in 1,4-dioxane (6 mL) was added hexamethylditin (0.821 g, 2.51 mmol, 1.2 eq). The reaction was purged under a stream of argon for 15 min and treated with tetrakis(triphenylphosphine)palladium(0) (0.120 g, 0.104 mmol, 0.05 eq). The reaction mixture13150943v 1 Page 148 of 319Attorney Docket No. 2019094-0008was stirred at 100 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (650 mg, brown oil), which was used in next step without further purification.

[0334] Synthesis of ethyl 7-cyclopropyl-5-(4-morpholino-[l,3]dioxolo[4,5-c]pyridin-6-yl)pyrrolo[l,2-c]pyriinidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-cyclopropylpyrrolo[l,2-c]pyrimidine-3-carboxylate (0.450 g, 1.46 mmol, 1.0 eq) in N, N-dimethylformamide (4 mL) was added 4-morpholino-6-(trimethylstannyl)-[l,3]dioxolo[4,5-c]pyridine (0.648 g, 1.75 mmol, 1.2 eq). The reaction mixture was purged under a stream of argon for 10 min before the addition of bis(tri-t-butylphosphine)palladium (74 mg, 145.56 mmol, 0.1 eq). The reaction mixture was heated at 100 °C for 3 h. 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, 50% ethyl acetate in hexane) to afford the title compound (350 mg, yellow solid). MS (ES): m / z 437.06 [M+H]+.

[0335] Synthesis of 7-cyclopropyl-5-(4-morpholino-[l,3]dioxolo[4,5-c]pyridin-6-yl)pyrrolo[l,2-c]pyriinidine-3-carboxylic acid. To a stirred solution of ethyl 7-cyclopropyl-5-(4-morpholino-[l,3]dioxolo[4,5-c]pyridin-6-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate (350 mg, 0.801 mmol, 1.0 eq) in tetrahydrofuran (3 mL) and methanol (3 mL) was added aqueous a solution of lithium hydroxide (84 mg, 2.00 mmol, 5.0 eq) at 0 °C. The reaction mixture was stirred for 3 h. The reaction mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (0.250 g, orange solid). MS (ES): m / z 409.24 [M+H]+, which was used in next step without further purification.

[0336] Synthesis of tert-butyl (7-cyclopropyl-5-(4-morpholino-[l,3]dioxolo[4,5-c]pyridin-6-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 7-cyclopropyl-5-(4-morpholino-[l,3]dioxolo[4,5-c]pyridin-6-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid (0.250 g, 0.612 mmol, 1.0 eq) in toluene (4 mL) and tert-butanol (4 mL), was added solution of diphenyl phosphoryl azide (202 mg, 0.734 mmol, 1.2 eq) and triethylamine (74.33 mg, 0.734 mmol, 1.2 eq). The reaction mixture was stirred at 125 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate13150943v 1 Page 149 of 319Attorney Docket No. 2019094-0008solution, 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 (0.110 g, yellow solid). MS (ES): m / z 480.33 [M+H]+.

[0337] Synthesis of 7-cyclopropyl-5-(4-morpholino-[l,3]dioxolo[4,5-c]pyridin-6-yl)pyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (7-cyclopropyl-5-(4-morpholino-[l,3]dioxolo[4,5-c]pyridin-6-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate (90 mg, 0.187 mmol, 1.0 eq) in dichloromethane (8 mL) was added trifluoracetic acid (2 ml) at 0 °C. The temperature was raised to room temperature, and the solution was further stirred for 4 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the title compound (70 mg, light yellow solid). MS (ES): m / z 379.32 [M+H]+.

[0338] Synthesis of 1-175. To a stirred solution of 7-cyclopropyl-5-(4-morpholino-[l,3]dioxolo[4,5-c]pyridin-6-yl)pyrrolo[l,2-c]pyrimidin-3-amine (60 mg, 0.158 mmol, 1.0 eq) in dichloromethane (1 mL) was added pyridine (25.09 mg, 1.58 mmol, 10 eq) and acetic acid-d4 (10.13 mg, 0.158 mmol, 1.0 eq) in dichloromethane (0.5 mL) at 0 °C, followed by the dropwise addition of phosphorus(V) oxychloride (48.50 mg, 0.316 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred for 10 min at 0 °C. The reaction mixture was 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 preparative HPLC (0.1% formic acid in water in 100% acetonitrile) to afford 1-175 (14 mg, light yellow solid). MS (ES): m / z 425.38 [M+H]+; 'll NMR (400 MHz, DMSO-d6): 8 10.27 (s, 1H), 9.04 (s, 1H), 8.92 (s, 1H), 7.07 (s, 1H), 6.93 (s, 1H), 5.98 (s, 2H), 3.74 (d, J= 4.4 Hz, 4H), 3.61 (d, J= 4.4 Hz, 4H), 2.11 -2.10 (m, 1H), 1.00 - 0.99 (m, 2H), 0.71 - 0.70 (m, 2H).

[0339] Example 2.9. Synthesis of N-(7-cyclopropyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrim idin-4-yl)pyrrolo [1,2-c] pyrimidin-3-yl)acetamide-2,2,2-d3 (I- 176)13150943v 1 Page 150 of 319Attorney Docket No. 2019094-0008AcCI-d3’ Pyridine, 0 °C to RT

[0340] Synthesis of 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6- (trimethylstannyl)pyrimidine. To a stirred solution of 4-chloro-6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidine (600 mg, 2.82 mmol, 1.0 eq) in 1,4-dioxane (6 mL) was added hexamethylditin (1.11 g, 3.39 mmol, 1.2 eq). The reaction mixture was purged under a stream of argon for 5 min and treated with tetrakis(triphenylphosphine)palladium(0) (163 mg, 0.141 mmol, 0.05 eq). The reaction mixture was stirred at 100 °C for 3 h, cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford the title compound (794 mg, brown oil), which was used as such in next step without further purification.

[0341] Synthesis of ethyl 7-cyclopropyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-cyclopropylpyrrolo[l,2-c]pyrimidine-3-carboxylate (600 mg, 1.94 mmol, 1.0 eq) in N, N-dimethylformamide (12 mL) was added 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyrimidine (794.24 mg, 2.33 mmol, 1.2 eq). The reaction mixture was purged under a stream of argon for 10 min before the addition of bis(tri-t-butylphosphine)palladium (99 mg, 0.194 mmol, 0.1 eq). The reaction mixture was heated at 100 °C for 3 h. 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 to get crude product.13150943v 1 Page 151 of 319Attorney Docket No. 2019094-0008The residue was purified by flash column chromatography on silica gel (Combiflash, 50 % ethyl acetate in hexane) to afford the title compound (350 mg, yellow solid). MS (ES): m / z 407.43 [M+H]+.

[0342] Synthesis of 7-cyclopropyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 7-cyclopropyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate (0.350 g, 0.861 mmol, 1.0 eq) in tetrahydrofuran (3 m ): methanol (3 m ) was added aqueous solution of lithium hydroxide (0.090 g, 2.15 mmol, 2.5 eq) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (0.200 g, brown solid). MS (ES): m / z 379.23 [M+H]+.

[0343] Synthesis of tert-butyl (7-cyclopropyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 7-cyclopropyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid (200 mg, 0.528 mmol, 1.0 eq) in toluene (4 mb) and tert-butanol (4 mb), was added solution of diphenylphosphoryl azide (175 mg, 0.634 mmol, 1.2 eq) and triethylamine (64.18 mg, 0.634 mmol, 1.2 eq). The reaction mixture was stirred at 125 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford the title compound. (85 mg, yellow solid). MS (ES): m / z 450.43 [M+H]+.

[0344] Synthesis of 7-cyclopropyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3-amine trifluoroacetate. To a stirred solution of tert-butyl (7-cyclopropyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate (170 mg, 0.378 mmol, 1.0 eq) in dichloromethane (8 mb) was added trifluoroacetic acid (2 ml) at 0 °C. The temperature was raised to room temperature, and the solution was stirred for 3 h. The reaction mixture was evaporated under reduced pressure to13150943v 1 Page 152 of 319Attorney Docket No. 2019094-0008afford the title compound (150 mg, light yellow solid) as a trifluoroacetate salt. MS (ES): m / z 350.3 [M+H]+.

[0345] Synthesis of 1-176. To a stirred solution of 7-cyclopropyl-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3 -amine trifluoroacetate (130 mg, 0.372 mmol, 1.0 eq) in dichloromethane (1 mL) was added pyridine (1 mL) and 2,2,2-tri deuteri oacetyl chloride (36 mg, 0.446 mmol, 1.2 eq) in dichloromethane (1 mL) at 0 °C. The reaction mixture was stirred for 20 min. The reaction mixture was diluted with saturated sodium bicarbonate solution 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, 2.5% methanol in dichloromethane) to afford 1-176 (38 mg, light yellow solid). MS (ES): m / z 395.5 [M+H]+; 'HNMR (400 MHz, DMSO-d6): 5 10.42 (s, 1H), 9.15 (s, 2H), 7.38 (s, 1H), 7.21 (s, 1H), 3.97 (d, J= 9.6 Hz, 2H), 3.50 (t, J= 1.6 Hz, 2H), 2.97 - 2.93 (m, 1H), 2.37 (s, 3H), 2.15 -2.13 (m, 1H), 2.03 - 1.91 (m, 4H), 1.03 - 1.00 (m, 2H), 0.74- 0.73 (m, 2H).

[0346] Example 2.10. Synthesis of N-(5-(6-methyI-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidin-3-yl)acetamide (1-177)125 °C, 3hTFA, DCM, RT, 2h

[0347] Synthesis of ethyl 7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidine-3-carboxylate.To a stirred solution of ethyl 2-isocy anoacetate (2.08 g, 18.39 mmol, 1.0 eq) in tetrahydrofuran13150943v 1 Page 153 of 319Attorney Docket No. 2019094-0008(150 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (3.08 g, 20.23 mmol, 1.1 eq). The reaction mixture was stirred for 10 min, followed by the addition of 5 -(trifluoromethyl)- 1H-pyrrole-2-carbaldehyde (3 g, 18.39 mmol, 1.0 eq) in tetrahydrofuran (15 mL). The reaction mixture was stirred for 16 h. The reaction mixture was poured into 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 column chromatography on silica gel (Combiflash 12% ethyl acetate in hexane) to afford the title compound (1.3 g, light brown solid). MS (ES): tn,'z 259.2 [M+H]+.

[0348] Synthesis of ethyl 5-bromo-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidine-3-carboxylate (1.3 g, 5.03 mmol, 1.0 eq) in chloroform (13 mL) was added N-bromosuccinimide (896.14 mg, 5.03 mmol, 1.0 eq). The reaction mixture was stirred for 2 h and next it was diluted with brine 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, 30% ethyl acetate in hexane) to afford the title compound (1.3 g, light yellow). MS (ES): m / z 337.1 [M+H]+.

[0349] Synthesis of ethyl 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidine-3-carboxylate (0.700 g, 2.08 mmol, 1.0 eq) and 4-chloro-6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidine (574.13 mg, 2.70 mmol, 1.3 eq) in 1,4-dioxane (5.0 mL) was added hexamethylditin (0.884 g, 2.70 mmol, 1.3 eq). The reaction was purged under a stream of argon for 15 min and treated with bis(triphenylphosphine)palladium(II) dichloride (102 mg, 0.145 mmol, 0.07 eq). The reaction mixture was stirred at 100 °C for 16 h. 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 flash column chromatography on silica gel (40% ethyl acetate in hexane) to afford the title compound (260 mg, light yellow solid). MS (ES): m / z 435.6 [M+H]+.

[0350] Synthesis of 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid. A solution of ethyl 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidine-3-13150943v 1 Page 154 of 319Attorney Docket No. 2019094-0008carboxylate (0.210 g, 0.483 mmol, 1.0 eq) in concentrated hydrochloric acid (0.5 mL) was heated at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by preparative HPLC using (A) 0.1% formic acid in water and (B) 100% acetonitrile as a mobile phase to afford the title compound (67 mg, off white solid). MS (ES): m / z 407.2 [M+H]+.

[0351] Synthesis of tert-butyl (5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidine-3 -carboxylic acid (67 mg, 0.164 mmol, 1.0 eq) in toluene (2 mL) and tert-butanol (2 mL), was added diphenylphosphoryl azide (90 mg, 0.329 mmol, 2.0 eq), triethylamine (66 mg, 1.87 mmol, 4.0 eq) and molecular sieves 4 A (67 mg). The reaction mixture was stirred at 125 °C for 3 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, 40% Ethyl acetate in hexane) to afford the title compound (23 mg, light yellow solid). MS (ES): m 'z 478.2 [M+H]+.

[0352] Synthesis of 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidin-3-amine trifluoroacetate. To a stirred solution of tert-butyl(5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate (23 mg, 0.048 mmol, 1.0 eq) in dichloromethane (2.5 mL), was added trifluoroacetic acid (109 mg, 0.963 mmol, 20 eq) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure to afford the title compound (27 mg, light brown solid) as a trifluoroacetate salt, which was used as such in next step without further purification. MS (ES): m / z 378.3 [M+H]1.

[0353] Synthesis of compound 1-177. To a stirred solution of 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-(trifluoromethyl)pyrrolo[l,2-c]pyrimidin-3-amine trifluoroacetate (27 mg, 0.055 mmol, 1.0 eq) in tetrahydrofuran (3 mL) was added N, N-diisopropylethylamine (28 mg, 0.220 mmol, 4.0 eq) and acetic anhydride (12 mg, 0.110 mmol, 2.0 eq) in tetrahydrofuran at 0 °C. The reaction mixture was raised to 70 °C and the solution was stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with water and13150943v 1 Page 155 of 319Attorney Docket No. 2019094-0008extracted with dichloromethane. The combined organic layer was 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, 2.5% methanol in dichloromethane) to afford 1-177 (7.7 mg, yellow solid). MS (ES): m z 420.3 [M+H]+;JH NMR (400 MHz, DMSO-d6): 5 10.72 (s, 1H), 9.38 (s, 1H), 9.18 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 4.00 - 3.96 (m, 2H), 3.52 - 3.46 (m, 2H), 3.07 - 2.99 (m, 1H), 2.44 (s, 3H), 2.15 (s, 3H), 2.04 -1.94 (m, 4H).

[0354] Example 2.11. Synthesis of N-(5-(4-(difluoromethoxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyirolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-178)

[0355] Synthesis of ethyl 5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of 4-(difluoromethoxy)-2-(3,6-dihydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridine (2.20 g, 5.65 mmol, 1.0 eq) in N, N-dimethylformamide (32 mb) was added ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (1.6 g, 5.65 mmol, 1.0 eq). The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Under argon atmosphere bis(tri-tert-butylphosphine)palladium(O) (288 mg, 0.565 mmol, 0.1 eq) was added and again degassed with argon for 5 min. The reaction mixture was stirred at 100 °C for 2 h. Next, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was13150943v 1 Page 156 of 319Attorney Docket No. 2019094-0008dried over sodium sulfate and concentrated under reduced pressure to obtained crude material, which was purified by column chromatography on silica gel (Combiflash, 85% ethyl acetate in hexane) to afford the title compound (1.2 g, light yellow solid). MS (ES): m / z 430.3 [M+H]+.

[0356] Synthesis of 5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3 -carboxylate (1.1 g, 2.56 mmol, 1.0 eq) in ethanol (17 mb) and tetrahydrofuran (17 mL) was added solution of lithium hydroxide monohydrate (268.74 mg, 6.40 mmol, 2.5 eq) in water (7.0 mL) at 0 °C. The reaction mixture was then allowed to warm to room temperature and stirred for 3 h. Next, 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 (990 mg, light yellow solid). MS (ES): m / z 402.2 [M+H]+.

[0357] Synthesis of tert-butyl (5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3 -carboxylic acid (880 mg, 2.19 mmol, 1.0 eq) in toluene (18 mL) and tert-butanol (18 mL) was added solution of diphenylphosphoryl azide (1.51 g, 5.48 mmol, 2.5 eq) and tri ethylamine (554 mg, 5.48 mmol, 2.5 eq). The reaction mixture was stirred at 125 °C for 3 h. Next, the reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography on silica gel (Combiflash, 3% methanol in dichloromethane) to afford the title compound (300 mg, light yellow solid). MS (ES): m z 473.2 [M+H]1.

[0358] Synthesis of 5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (300 mg, 0.634 mmol, 1.0 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. Next, the reaction mixture was concentrated under reduced pressure, crude13150943v 1 Page 157 of 319Attorney Docket No. 2019094-0008residue was basified by aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (200 mg, light yellow solid). MS (ES): m z 373.1 [M+H]+.

[0359] Synthesis of N-(5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3. To a stirred solution of 5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine (190 mg, 0.510 mmol, 1.0 eq) in dichloromethane (2 mb) was added acetic acid-d4 (32.69 mg, 0.510 mmol, 1.0 eq) and pyridine (403.60 mg, 5.10 mmol, 10 eq) at 0 °C. To the resulting mixture phosphorus(V) oxychloride (156.47 mg, 1.02 mmol, 2.0 eq) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Next, 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 flash column chromatography on silica gel (Combiflash, 3.2% methanol in dichloromethane) affords title compound (70 mg, light yellow solid). MS (ES): m / z 418.3 [M+H]+.

[0360] Synthesis of 1-178. To a stirred solution of N-(5-(4-(difluoromethoxy)-6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (60 mg, 0.143 mmol, 1.0 eq) in ethanol (12 mb) and tetrahydrofuran (12 mb) were added ammonium formate (91 mg, 1.44 mmol, 10 eq) and palladium catalyst (15.3 mg, 10% palladium on carbon). The reaction mixture was heated at 75 °C for 2 h. Next, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, fdtered through Celite pad, and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 3.7% methanol in dichloromethane) to afford 1-178 (35 mg, light yellow solid). MS (ES): m z 420.3 [M+H]+. 'H NMR (400 MHz, DMSO-d6): 8 10.30 (s, 1H), 9.07 (s, 1H), 8.90 (s, 1H), 7.53 (s, 1H), 7.23 - 7.20 (m, 2H), 6.76 (s, 1H), 4.01 -3.99 (m, 2H), 3.48 (t, J= 8.0 Hz, 2H), 2.96 - 2.92 (m, 1H), 2.55 (s, 3H), 1.98 - 1.89 (m, 4H).

[0361] Example 2.12. Synthesis of N-(7-methyl-5-(4-morpholino-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)pyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-179)13150943v 1 Page 158 of 319Attorney Docket No. 2019094-0008Br

[0362] Synthesis of ethyl 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate. A stirred solution of ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (0.700 g, 2.47 mmol, 1.0 eq) and 4-(2-(3,6-dihydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyridin-4-yl)morpholine (1.52 g, 3.71 mmol, 1.5 eq) in N, N-dimethylformamide (15 mL) was purged under a stream of argon for 5 min and treated with bis(tri-tert-butylphosphine)palladium(0) (126.35 mg, 0.247 mmol,0.1 eq). The reaction mixture was stirred at 100 °C for 6 h. Next, the solution was cooled to ambient temperature, 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 flash column chromatography on silica gel (85 % ethyl acetate in hexane) to afford the title compound (0.800 g, light-yellow solid). MS (ES): m z[M+H]+.

[0363] Synthesis of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (0.800 g, 1.78 mmol, 1.0 eq) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added solution of lithium hydroxide (187.12 mg, 4.46 mmol, 2.5 eq) in water (5 mL) at 0 °C. The mixture was stirred at room temperature for 8 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with water and acidified with aqueous 2N hydrochloric acid13150943v 1 Page 159 of 319Attorney Docket No. 2019094-0008solution until pH ~ 4. The precipitate was filtered off, washed with water and dried under vacuum to afford the title compound (0.530 g, yellow solid). MS (ES): m / z 421.27 [M+H]+.

[0364] Synthesis of tert-butyl (5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3 -carboxylic acid (0.480 g, 1.14 mmol, 1.0 eq) in tert-butanol (5 mL) and toluene (5 mL) was added solution of diphenylphosphoryl azide (628.34 mg, 2.28 mmol,2.0 eq) and triethylamine (231.04 mg, 2.28 mmol, 2.0 eq. The reaction mixture was stirred at 125 °C for 4 h. Next, the reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 1.8% methanol in dichloromethane) to afford the title compound (0.190 g, light yellow solid). MS (ES): m / z &1A [M+H]+.

[0365] Synthesis of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.190 g, 0.386 mmol, 1.0 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) at 0 °C. The temperature was raised to room temperature and stirred for 8 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue was triturated with ethyl acetate and n-pentane to afford the title compound (0.110 g, brown solid). MS (ES): m / z 392.28 [M+H]+.

[0366] Synthesis of N-(5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yI)acetamide-2,2,2-d3. To a stirred solution of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine (0.110 g, 0.281 mmol, 1.0 eq) in dichloromethane (2 mL), were added acetic acid-d4 (18.01 mg, 0.281 mmol, 1.0 eq), pyridine (222.27 mg, 2.81 mmol, 10 eq) and phosphorus(V) oxychloride (86.17 mg, 0.561 mmol, 2.0 eq) at 0 °C. The temperature was raised to room temperature, and the solution was stirred for 1 h. Next, the reaction mixture was diluted with saturated aqueous13150943v 1 Page 160 of 319Attorney Docket No. 2019094-0008sodium bicarbonate solution 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, 2.1% methanol in dichloromethane) to afford the title compound (0.070 g, red solid). MS (ES): m / z 437.30 [M+H]+.

[0367] Synthesis of 1-179. To a stirred solution of N-(5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-morpholinopyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (0.070 g, 0.160 mmol, 1.0 eq) in ethanol (2 mL) was added ammonium formate (50.56 mg, 0.801 mmol, 5.0 eq) and palladium catalyst (43 mg, 0.400 mmol, 2.5 eq, 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 fdtered over 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 1-179 (11 mg, yellow solid). MS (ES): m / z 439.39 [M+H]+; 'H NMR (400 MHz, DMSO-d6): 8 10.20 (s, 1H), 9.02 (s, 1H), 8.85 (s, 1H), 7.20 (s, 1H), 6.93 (d, J= 2.2 Hz, 1H), 6.50 (s, 1H), 3.99 (d, J= 11.4 Hz, 2H), 3.75 (t, J = 4.8 Hz, 4H), 3.46 (td, J= 11.1, 3.3 Hz, 2H), 3.38 (s, 1H), 3.28 (s, 1H), 2.82 (s, 1H), 2.59 -2.53 (m, 1H), 2.54 (s, 3H), 2.49- 2.43 (m, 1H), 1.91 (dd, J= 13.7, 8.7 Hz, 4H).

[0368] Example 2.13. Synthesis of (R)-N-(5-(5-methoxy-6-(3-methoxypyrrolidin-l-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-180)13150943v 1 Page 161 of 319Attorney Docket No. 2019094-0008K2CO3, DMSO Hexamethylditin, Pd(PPh3)4 Bis(tri-t-butylphosphine)palladium 90 °C, 2 h Dioxane, 100 °C, 2 h DMF) 100 °C, o hDPPA, TEA, t-BuOH Toluene, 125 °C, 3 h

[0369] Synthesis of (R)-6-bromo-3-methoxy-2-(3-methoxypyrrolidin-l-yl)pyridine.To a stirred solution of 6-bromo-2-fluoro-3-methoxypyridine (1.0 g, 4.85 mmol, 1.0 eq) and (R)-3 -methoxypyrrolidine (0.801 g, 5.82 mmol, 1.2 eq) in dimethyl sulfoxide (10 mL) was added potassium carbonate (1.34 g, 9.71 mmol, 2.0 eq and the reaction mixture was stirred 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. The residue was purified by flash column chromatography on silica gel (Combiflash, 20% ethyl acetate in hexane) to afford the title compound (1.4 g, off white solid). MS (ES): m / z 287.0 [M+H]+.

[0370] Synthesis of of (R)-3-methoxy-2-(3-methoxypyrrolidin-l-yl)-6-(trimethylstannyl)pyridine. To a stirred solution of (R)-6-bromo-3-methoxy-2-(3-methoxypyrrolidin-l-yl)pyridine (1.4 g, 4.88 mmol, 1.0 eq) in 1,4-dioxane (10 mL) was added hexamethylditin (1.92 g, 5.85 mmol, 1.2 eq). The reaction mixture was purged under a stream of argon for 5 min before addition of tetrakis(triphenylphosphine)palladium(0) (0.281 mg, 0.243 mmol, 0.05 eq). The reaction mixture was heated at 100 °C for 2 h. Next, the reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced13150943vl Page 162 of 319Attorney Docket No. 2019094-0008pressure to afford the title compound (1.0 g, brown oil), which was used in the next step without further purification.

[0371] Synthesis of ethyl (R)-5-(5-methoxy-6-(3-methoxypyrrolidin-l-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (1.0 g, 3.53 mmol, 1.0 eq) inN, N-dimethylformamide (10 mL) was added (R)-3-methoxy-2-(3-methoxypyrrolidin-l-yl)-6-(trimethylstannyl)pyridine (1.14 g, 3.08 mmol, 0.87 eq. The reaction mixture was degassed with argon for 5 min before adding bis(tri-tert-butylphosphine)palladium(0) (180 mg, 0.353 mmol, 0.1 eq. The reaction mixture was stirred at 100 °C 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, 3% methanol in dichloromethane) to afford the title compound (600 mg, light yellow solid). MS (ES): m / z 411.4 [M+H]+.

[0372] Synthesis of (R)-5-(5-methoxy-6-(3-methoxypyrrolidin-l-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl (R)-5-(5-methoxy-6-(3-methoxypyrrolidin-l-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (600 mg, 1.46 mmol, 1.0 eq) in tetrahydrofuran (5 ml) and methanol (5 ml) was added solution of lithium hydroxide (87.52 mg, 3.65 mmol, 2.5 eq) in water (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with cold water and acidified with 2N hydrochloric acid solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude title compound (500 mg, off white solid), which was used in the next step without further purification.

[0373] Synthesis of tert-butyl (R)-(5-(5-methoxy-6-(3-methoxypyrrolidin-l-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of (R)-5-(5-methoxy-6-(3-methoxypyrrolidin-l-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid (470 mg, 1.23 mmol, 1.0 eq) in toluene (10 mL) and tert- butanol (10 mL), was added diphenylphosphoryl azide (676 mg, 2.46 mmol, 2.0 eq) and triethylamine (248 mg, 2.46 mmol, 2.0 eq. The reaction mixture was stirred at 125 °C for 3 h. Next, the reaction mixture was cooled to room temperature, diluted with sodium bicarbonate solution and extracted with ethyl13150943v 1 Page 163 of 319Attorney Docket No. 2019094-0008acetate. 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, 70% ethyl acetate in hexane) to afford the title compound (170 mg, off white solid). MS (ES): m / z 454.4 [M+H]+.

[0374] Synthesis of (R)-5-(5-methoxy-6-(3-methoxypyrrolidin-l-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine) trifluoroacetate. To a stirred solution of tert-butyl (R)-(5-(5-methoxy-6-(3-methoxypyrrolidin-l-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (170 mg, 0.374 mmol, 1.0 eq) in dichloromethane (1.2 mL) was added trifluoroacetic acid (1.09 mL). The reaction mixture was stirred for 2 h. Next, the reaction mixture was concentrated under reduced pressure to get crude title compound as a trifluoroacetate salt (120 mg, brown oil), which was used as such without further purification. MS (ES): m / z 354.2 [M+H]+.

[0375] Synthesis of compound 1-180. To a stirred solution of (R)-5-(5-methoxy-6-(3-methoxypyrrolidin-l-yl)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine as a trifluoroacetate salt (100 mg, 0.282 mmol, 1.0 eq) in pyridine (2 mL), was added solution of acetyl chloride-d3 (27.68 mg, 0.339 mmol, 1.2 eq) in dichloromethane at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Next, the reaction mixture was quenched 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 flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford 1-180 (26 mg, light yellow solid). MS (ES): m'z 399.4 [M+H]+; 'H NMR (400 MHz, DMSO-d6): 8 10.14 (s, 1H), 8.90 (s, 1H), 8.78 (s, 1H), 7.09 (d, J= 8.4 Hz, 1H), 7.00 (s, 1H), 6.86 (d, J= 8.0 Hz, 1H), 4.00 (s, 1H), 3.90 - 3.85 (m, 2H), 3.75 (s, 3H), 3.70 - 3.65 (m, 2H), 3.40 (s, 3H), 3.33 (s, 3H), 1.97 - 1.96 (m, 2H).

[0376] Example 2.14. Synthesis of (R)-N-(5-(5-methoxy-6-(2-(trifluoromethyl) morpholino) pyridin-2-yl)-7-methy!pyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-181) and (S)-N-(5-(5-methoxy-6-(2-(trifluoromethyl)morpholino)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-183)13150943v 1 Page 164 of 319Attorney Docket No. 2019094-0008

[0377] Synthesis of ethyl 5-(5-methoxy-6-(2-(trifluoromethyl)morpholino)pyridin-2-yl)-7-methylpyrroIo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (0.5 g, 1.77 mmol, 1.0 eq) inN, N-dimethylformamide (10 mL) was added 4-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)-2-(trifluoromethyl)morpholine (0.825 g, 1.94 mmol, 1.1 eq. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Under argon atmosphere bis(tri-t-butylphosphine)palladium(O) (0.090 g, 0.176 mmol, 0.1 eq) was added and again degassed for 5 min. The reaction mixture was stirred at 100 °C for 2 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 (Combiflash, 100% ethyl acetate in hexane) to afford the title compound (0.6 g, yellow solid). MS (ES): m / z 465.2 [M+H]+.

[0378] Synthesis of 5-(5-methoxy-6-(2-(trifluoromethyl)morpholino)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 5-(5-methoxy-6-(2-(trifluoromethyl)morpholino)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-13150943v 1 Page 165 of 319Attorney Docket No. 2019094-0008carboxylate (0.6 g, 1.29 mmol, 1.0 eq) in methanol (4.0 mb) and tetrahydrofuran (4.0 mL) was added lithium hydroxide monohydrate (0.077 g, 3.23 mmol, 2.5 eq) in water (4.0 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 off, washed with water and dried under vacuum to afford the title compound (0.400 g, light yellow solid). MS (ES): m / z 437.3 [M+H]+.

[0379] Synthesis of tert-butyl (5-(5-methoxy-6-(2-(trifluoromethyl)morpholino)pyridin-2-yl)-7-methylpyrrolo[l,2-c| pyrimidin-3-yl)carbamate. To a stirred solution of 5-(5-methoxy-6-(2-(trifluoromethyl)morpholino)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid (0.350 g, 0.802 mmol, 1.0 eq) in toluene (4.0 mL) and tert-butanol (4.0 mL), was added solution of diphenylphosphoryl azide (0.441 g, 1.60 mmol, 2.0 eq) and triethylamine (0.162 g, 1.60 mmol, 2.0 eq). The reaction mixture was stirred at 125 °C for 3 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, 70% ethyl acetate in hexane) to afford the title compound (0.180 g, light yellow solid). MS (ES): m'z 508.0 [M+H]+.

[0380] Synthesis of 5-(5-methoxy-6-(2-(trifluoromethyl)morpholino)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(5-methoxy-6-(2-(trifluoromethyl)morpholino)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.180 g, 0.354 mmol, 1.0 eq) in dichloromethane (4.0 mL) was added tri fluoroacetic acid (1.8 mL) at 0 °C. The temperature was raised to room temperature and stirred for 4 h. The reaction mixture was evaporated under reduced pressure, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (0.130 g brown solid), which was used in the next step without further purification.

[0381] Synthesis of 1-181 and 1-183. To a stirred solution of 5-(5-methoxy-6-(2-(trifluoromethyl)morpholino)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine (0.130 g, 0.319 mmol, 1.0 eq) in dichloromethane (2.0 mL), was added acetyl chloride d3 (0.026 g, 0.31913150943v 1 Page 166 of 319Attorney Docket No. 2019094-0008mmol, 1.0 eq) and pyridine (0.5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with ice cold water and neutralized with IN hydrochloric acid 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, 70% ethyl acetate in hexane) to afford racemic title compound (0.045 g, yellow solid). MS (ES): m / z 452.6 [M+H]+. The racemic compound was purified by chiral preparatory SFC method using mobile phase (A) liquid carbon dioxide (B) ammonia in isopropanol: acetonitrile (50:50) and column used CHIRALPAK IB-N (250*30)mm, 5pm to afford the title compound 1-181 (14 mg, light yellow solid). MS (ES): m'z 453.2 [M+H]+; 'H NMR (400 MHz, DMSO-d6): 5 10.22 (s, 1H), 8.87 (s, 1H), 8.82 (s, 1H), 7.30 (d, J= 8.4 Hz, 1H), 7.20 (d, J= 8.4 Hz, 1H), 7.05 (s, 1H), 4.32 (s, 1H), 4.13 -4.10 (m, 2H), 3.91 - 3.85 (m, 2H), 3.81 (s, 3H), 3.20 (t, J= 10.0 Hz, 1H), 2.94 (t, J= 10.8 Hz, 1H), 2.55 (s, 3H) and 1-183 (13 mg, light yellow solid). MS (ES): m / z 453.2 [M+H]+; 'HNMR (400 MHz, DMSO-d6): 8 10.22 (s, 1H), 8.87 (s, 1H), 8.82 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 4.32 (s, 1H), 4.13 -4.10 (m, 2H), 3.91 -3.85 (m, 2H), 3.81 (s, 3H), 3.20 (t, J= 10.0 Hz, 1H), 2.94 (t, J= 10.8 Hz, 1H), 2.55 (s, 3H).

[0382] Example 2.15. Synthesis of (R)-N-(5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yI)acetamide-2,2,2-d3 (1-182) and (S)-N-(5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-184)13150943v 1 Page 167 of 319Attorney Docket No. 2019094-0008

[0383] Synthesis of ethyl 5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (0.65 g, 2.30 mmol, 1.0 eq) inN, N-dimethylformamide (7 mL) was added 2-(difluoromethyl)-4-(3-methoxy-6-(trimethylstannyl)pyridin-2-yl)morpholine (1.12 g, 2.76 mmol, 1.2 eq. The reaction mixture was degassed by bubbling through a stream of argon for 5 min. Bis(tri-t-butylphosphine)palladium(O) (0.117 g, 0.230 mmol, 0.1 eq) was added and the solution was again degassed for 5 min. The reaction mixture was stirred at 100 °C for 2 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 (Combiflash, 2.5% methanol in dichloromethane) to afford the title compound (0.52 g, yellow solid). MS (ES): m / z 447.5 [M+H]+.

[0384] Synthesis of 5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (0.52 g, 1.16 mmol, 1.0 eq) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was13150943v 1 Page 168 of 319Attorney Docket No. 2019094-0008added lithium hydroxide monohydrate (0.122 g, 2.91 mmol, 2.5 eq) in water (5.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 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 (0.430 g, light yellow solid). MS (ES): m / z 419.2 [M+H]+.

[0385] Synthesis of tert-butyl (5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yI)carbamate. To a stirred solution of 5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3 -carboxylic acid (0.450 g, 1.08 mmol, 1.0 eq) in toluene (10.0 mL) and tertbutanol (10.0 mL), was added solution of diphenylphosphoryl azide (0.59 g, 2.15 mmol, 2.0 eq) and triethylamine (217 mg, 2.15 mmol, 2.0 eq). The reaction mixture was stirred at 125 °C for 3 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, 1.8% methanol in dichloromethane) to afford the title compound (0.20 g, light yellow solid). MS (ES): m / z 490.3 [M+H]+.

[0386] Synthesis of 5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrroIo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.20 g, 0.408 mmol, 1.0 eq) in dichloromethane (5.0 mL) was added trifluoroacetic acid (2.0 mL) at 0 °C. The temperature was raised to room temperature, and the solution was stirred for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (0.120 g brown solid), which was used in the next step without further purification.

[0387] Synthesis of 1-182 and 1-184. To a stirred solution of 5-(6-(2- (difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine (120 mg, 0.308 mmol, 1.0 eq) in dichloromethane (4 mL) was added acetic acid-d4 (19.75 mg, 0.308 mmol, 1.0 eq) and pyridine (243.76 mg, 3.08 mmol, 10 eq) at 0 °C. To the resulting mixture phosphorus(V) oxychloride (95 mg, 0.616 mmol, 2.0 eq) was added dropwise at 0 °C.13150943v 1 Page 169 of 319Attorney Docket No. 2019094-0008The reaction mixture was stirred at room temperature for 1 h. Next, 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 flash column chromatography on silica gel (Combiflash, 3.2% methanol in dichloromethane) to afford racemic title compound (50 mg, light yellow solid). MS (ES): m z 435.3 [M+H]+. The racemic compound was purified by chiral preparatory SFC method using mobile phase (A) liquid carbon dioxide (B) ammonia in isopropanol: acetonitrile (50:50) and column used CHIRALPAK IB-N (250*30)mm, 5pm to afford the title compound 1-182 (R)-N-(5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin- 3-yl)acetamide-2,2,2-d3 (14 mg, light yellow solid). MS (ES): m / z 435.0 [M+H]+; 'H NMR (400 MHz, DMSO-d6): 8 10.24 (s, 1H), 8.90 (s, 1H), 8.82 (s, 1H), 7.28 (d, J= 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H), 6.20 (s, 1H), 4.04 (d, J= 10.8 Hz, 1H), 3.90 (t, J= 12.0 Hz, 3H), 3.76 - 3.74 (m, 4H), 3.03 -2.95 (m, 2H), 2.50 (s, 3H). and 1-184 (S)-N-(5-(6-(2-(difluoromethyl)morpholino)-5-methoxypyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (12 mg, light yellow solid). MS (ES): m / z 435.0 [M+H]+; 'H NMR (400 MHz, DMSO-d6): 8 10.24 (s, 1H), 8.90 (s, 1H), 8.82 (s, 1H), 7.28 (d, J= 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H), 6.20 (s, 1H), 4.04 (d, J= 10.8 Hz, 1H), 3.90 (t, J= 12.0 Hz, 3H), 3.76 - 3.74 (m, 4H), 3.03 - 2.95 (m, 2H), 2.50 (s, 3H).

[0388] Example 2.16. Synthesis of N-(8-methyl-6-(6-methyl-2-(tetrahydro-2H-pyran- 4-yl)pyrimidin-4-yl)pyrrolo[l,2-a]pyrazin-3-yl)acetamide (1-185)13150943v 1 Page 170 of 319Attorney Docket No. 2019094-0008o NH2CS2CO3, XPhos Pd2(dba)3, DMA, 130°C, 3 h

[0389] Synthesis of ethyl l-(2-amino-2-oxoethyl)-3-methyl-lH-pyrrole-2-carboxylate. To a stirred solution of ethyl 3-methyl-lH-pyrrole-2-carboxylate (150 g, 0.979 mmol, 1.0 eq) in N, N-dimethylformamide (150 mL) was added sodium hydride (60% dispersion in mineral oil) (35.25 g, 1.47 mmol, 1.5 eq) at 0 °C and the reaction mixture was stirred for 2 h.2-Chloroacetamide (137 g, 1.47 mmol, 1.5 eq) was added and the reaction mixture was stirred at 70 °C 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, 50% ethyl acetate in hexane) to afford the title compound (48 g, colorless oil).1H NMR (400 MHz, DMSO-d6): 87.30 (s, 1H), 7.02 (s, 1H), 6.93 (d, J= 1.6 Hz, 1H), 5.95 (t, J = 2.0 Hz, 1H), 4.81 (s, 2H), 4.21 (m, 2H), 2.25 (s, 3H), 1.31 (m, 3H).

[0390] Synthesis of 8-methylpyrrolo[l,2-a]pyrazine-l,3(2H,4H)-dione. To a stirred solution of ethyl l-(2-amino-2-oxoethyl)-3-methyl-lH-pyrrole-2-carboxylate (25 g, 188.92 mmol, 1.0 eq) in ethanol (1000 mL) was added potassium tert-butoxide (297.29 mL, 297.29 mmol, 2.5 eq, IM solution in tetrahydrofuran) at room temperature. The reaction mixture was stirred at 70 °C for 16 h. After completion of reaction, the reaction mixture was cooled to 0 °C and acidified until pH ~ 6 with 2N aqueous hydrochloric acid solution. The reaction mixture was evaporated under reduce pressure, diluted with cold water and the precipitate was filtered, 13150943v 1 Page 171 of 319Attorney Docket No. 2019094-0008washed with water and dried under vacuum to afford the title compound (15 g, off white solid). MS (ES): m / z 165.0 [M+H]+.

[0391] Synthesis of l,3-dichloro-8-methylpyrrolo[l,2-a]pyrazine. To a stirred solution of 8-methylpyrrolo[l,2-a]pyrazine-l,3(2H,4H)-dione (10 g, 60.92 mmol, 1.0 eq) in phosphorus(V) oxychloride (166 mL, 1220.0 mmol, 20 eq) was added pyridine (4.91 mL, 60.92 mmol, 1.0 eq) at room temperature and the reaction mixture was stirred at 120 °C for 4 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (5.4 g, off white solid). MS (ES): m / z 201.0 [M+H]+.

[0392] Synthesis of 3-chloro-8-methylpyrrolo[l,2-a]pyrazine. To a stirred solution of l,3-dichloro-8-methylpyrrolo[l,2-a]pyrazine (3 g, 14.92 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added acetic acid (5.27 mL, 89.53 mmol, 6.0 eq) and zinc powder (3.90 g, 59.69 mmol, 4.0 eq) and the reaction mixture was stirred at 70 °C for 3 h. Next, the reaction mixture was diluted ethyl acetate and fdtered through pad of celite and washed with ethyl acetate, fdtrate was neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (2 g, off white solid), MS (ES): m / z 166.7 [M+H]+;1HNMR(400 MHz, DMSO-d6): 58.70 (s, 1H), 8.41 (s, 1H), 7.66 (d, J= 1.6 Hz, 1H), 6.78 (s, 1H), 2.40 (s, 3H).

[0393] Synthesis of 6-bromo-3-chloro-8-methylpyrrolo[l,2-a]pyrazine. To a stirred solution of 3-chloro-8-methylpyrrolo[l,2-a]pyrazine (330 mg, 1.98 mmol, 1.0 eq) in dichloromethane (4 mL) was added N-bromosuccinimide (282 mg, 1.58 mmol, 0.8 eq) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. Next, the reaction mixture was diluted with water and extracted with dichloromethane. 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 the title compound (240 mg, off white solid). MS (ES): m / z 244.9 [M+H]+.

[0394] Synthesis of 3-chloro-8-methyl-6-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-a]pyrazine. To a stirred solution of 6-bromo-3-chloro-8-methylpyrrolo[l,2-a]pyrazine (220 mg, 0.896 mmol, 1.0 eq) in N, N-dimethylformamide (5.013150943v 1 Page 172 of 319Attorney Docket No. 2019094-0008mL) was added 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyrimidine (458 mg, 1.34 mmol, 1.5 eq. The reaction mixture was degassed with argon for 5 min. Next, bis(triphenylphosphine)palladium(II) dichloride (63 mg, 0.089 mmol, 0.1 eq) was added and again the solution was degassed with argon stream for 5 min. The reaction mixture was heated at 100 °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. The residue was purified by flash column chromatography on silica gel (Combiflash, 40% ethyl acetate in hexane) to afford the title compound (90 mg, yellow solid). MS (ES): m / z 343.0 [M+H]+.

[0395] Synthesis of 1-185. To a stirred solution of 3-chloro-8-methyl-6-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-a]pyrazine (90 mg, 0.262 mmol, 1.0 eq) in N, N-dimethylacetamide (1 mL) was added acetamide (31 mg, 0.525 mmol, 2.0 eq) and cesium carbonate (171 mg, 0.525 mmol, 2.0 eq. The reaction mixture was degassed with argon for 5 min and XPhos (25 mg, 0.052 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium(0) (24 mg, O.026 mmol, 0.1 eq) were added. The solution was again degassed with argon stream for 5 min. The reaction mixture was heated at 130 °C for 3 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, 2.5% methanol in di chloromethane) to afford 1-185 (9 mg, brown solid). MS (ES): m / z 366.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6): 8 10.63 (s, 1H), 10.30 (s, 1H), 8.89 (d, J= 1.4 Hz, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 3.98 (ddd, J= 11.2, 4.3, 2.0 Hz, 2H), 3.55 - 3.44 (m, 2H), 3.17- 3.05 (m, 1H), 2.46 (s, 3H), 2.45 (s, 3H), 2.11 (s, 3H), 2.10 -2.02 (m, 2H), 1.95 (tdd, J= 13.3, 11.4, 5.6 Hz, 2H).

[0396] Example 2.17. Synthesis of N-(l-cyclopropyl-3-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrim idin-4-yl)im idazo [1,5-a] pyrazin-6-yl)acetamide (1-186)13150943v 1 Page 173 of 319Attorney Docket No. 2019094-0008ORuphos PD G3, K3PO4CS2CO3, XPhos Toluene, water, 100 °C, 2 h Pd2(dba)3. DMA, 130 °C, 2 h

[0397] Synthesis of ethyl 2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidine-4-carboxylate. To a stirred solution of ethyl 2-chloro-6-methylpyrimidine-4-carboxylate (5 g, 24.92 mmol, 1.0 eq) in N, N-dimethylformamide (40 mL), water (10 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5.24 g, 24.92 mmol, 1.0 eq) and cesium carbonate (8.12 g, 24.92 mmol, 1.0 eq. The reaction mixture was purged under a stream of argon for 5 min before the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.04 mg, 2.49 mmol, 0.1 eq) and again degassed with argon for 5 min. The reaction mixture was stirred at 110 °C for 4 h. Next, the reaction mixture was diluted with water, 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 2.3% methanol in dichloromethane) to afford the title compound (4 g, yellow solid). MS (ES): m / z 249.2 [M+H]13150943v 1 Page 174 of 319Attorney Docket No. 2019094-0008

[0398] Synthesis of ethyl 6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxylate. To a stirred solution of ethyl 2-(3,6-dihydro-2H-pyran-4-yl)-6-methylpyrimidine-4-carboxylate (3.9 mg, 15.71 mmol, 1.0 eq) in methanol (39 mL) was added palladium catalyst (1.67 g, 10% palladium on carbon, 55% water). The reaction mixture was purged with hydrogen gas for 1 h. Next, the reaction mixture was fdtered over Celite pad, the filtrate was concentrated and diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated by n-pentane to afford the title compound (2.4 g, white solid). MS (ES): m / z 250.9 [M+H]+.

[0399] Synthesis of 6-methyI-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxylic acid. To a stirred solution of ethyl 6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxylate (1 g, 4.00 mmol, 1.0 eq) in tetrahydrofuran (10 ml) and methanol (5 mL) was added lithium hydroxide monohydrate (1.91 mg, 19.98 mmol, 5.0 eq) in water (2.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was acidified with diluted hydrochloric acid solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (1 g, white solid). MS (ES): m / z.\ [M+H]+. The residue was used in the next step without further purification.

[0400] Synthesis of N-((5-chloropyrazin-2-yl)methyl)-6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide. To a stirred solution of 6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxylic acid (1.3 g, 5.85 mmol, 1.0 eq) in N, N-dimethylformamide (13 mL) was added N, N, N', N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (2.89 mg, 7.60 mmol, 1.3 eq. The reaction mixture was stirred for 10 min, followed by the addition of (5-chloropyrazin-2-yl)methanamine (839.84 mg, 5.85 mmol, 1.0 eq) in N, N-dimethylformamide and N, N-diisopropylethylamme (2.27 g, 17.55 mmol, 3.0 eq) dropwise. The reaction mixture was stirred 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. The residue was purified by flash column chromatography on silica gel (Combiflash, 3.8% methanol in dichloromethane) to afford the title compound (1.2 g, brown liquid). MS (ES): m / z 348.1 [M+H]+.13150943v 1 Page 175 of 319Attorney Docket No. 2019094-0008

[0401] Synthesis of 6-chloro-3-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)imidazo[l,5-a]pyrazine. To a stirred solution of N-((5-chloropyrazin-2-yl)methyl)-6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidine-4-carboxamide (1.1 g, 3.16 mmol, 1.0 eq) in di chloromethane (20 mL) was added pyridine (1.25 g, 9.49 mmol, 3.0 eq) at 0 °C, followed by trifluoromethanesulfonic anhydride (2.68 g, 9.49 mmol, 3.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. Next, the reaction mixture was diluted 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, 2.5% methanol in dichloromethane) to afford the title compound (500 mg, brown liquid). MS (ES): m / z 330.1 [M+H]+.

[0402] Synthesis of l-bromo-6-chloro-3-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)imidazo[l,5-a]pyrazine. To a stirred solution of 6-chloro-3-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)imidazo[l,5-a]pyrazine (450 mg, 1.36 mmol, 1.0 eq) in chloroform (8 mL) was added N-bromosuccinimide (242.86 mg, 1.36 mmol, 1.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with di chloromethane. 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, 50% ethyl acetate in hexane) to afford the title compound (400 mg, brown solid). MS (ES): m / z 408.1 [M+H]+.

[0403] Synthesis of 6-chloro-l-cyclopropyl-3-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)imidazo[l,5-a]pyrazine. To a stirred solution of l-bromo-6-chloro-3-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)imidazo[l,5-a]pyrazine (100 mg, 0.244 mmol, 1.0 eq) in toluene (0.8 mL) and water (0.2 mL) was added cyclopropylboronic acid (21.02 mg, 0.244 mmol, 1.0 eq) and potassium phosphate (156 mg, 0.734 mmol, 3.0 eq. The reaction mixture was purged under a stream of argon for 5 min before the addition of RuPhos Pd G3 (20.47 mg, 0.024 mmol, 0.1 eq) and again degassed with argon for 5 min. The reaction mixture was stirred at 100 °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. The residue was purified by flash column chromatography on silica gel (Combiflash, 50% ethyl acetate in hexane) to afford the title compound (80 mg, yellow solid). MS (ES): m / z 370.2 [M+H]+.13150943v 1 Page 176 of 319Attorney Docket No. 2019094-0008

[0404] Synthesis of 1-186. To a stirred solution of 6-chloro-l-cyclopropyl-3-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)imidazo[l,5-a]pyrazine (80 mg, 0.216 mmol, 1.0 eq) in N, N-dimethylacetamide (2.4 mL), was added acetamide (26 mg, 0.432 mmol, 2.0 eq) and cesium carbonate (176.19 mg, 0.540 mmol, 2.5 eq. The reaction mixture was degassed with argon for 5 min, followed by the addition of XPhos (20.62 mg, 0.043 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium(0) (19.81 mg, 0.021 mmol, 0.1 eq). The reaction mixture was stirred at 130 °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. The residue was purified by flash column chromatography on silica gel (Combiflash, 5% methanol in dichloromethane) to afford 1-186. (14 mg, light yellow solid). MS (ES): m / z 393.0 [M+H]+*HNMR (400 MHz, TFA D): 8 10.11 (s, 1H), 9.56 (s, 1H), 8.69 (s, 1H), 4.52 - 4.44 (m, 2H), 3.92 (t, J= 12.0 Hz, 2H), 3.75 - 3.70 (m, 1H), 3.04 (s, 1H), 3.00 (s, 3H), 2.56 - 2.45 (m, 6H), 2.28 (d, J= 13.4 Hz, 2H), 1.58 - 1.48 (m, 4H).

[0405] Example 2.18. Synthesis of N-(l-methyl-3-(6-methyl-2-(tetrahydro-2H-pyran- 4-yl)pyrimidin-4-yl)imidazo[l,5-a]pyrazin-6-yl)acetamide (1-187)o CS2CO3, XPhos, Pd2(dba)3, DMA, 130 °C, 2 h

[0406] Synthesis of 6-chloro-l-methyl-3-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)imidazo[l,5-a]pyrazine. To a stirred solution of l-bromo-6-chloro-3-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)imidazo[l,5-a]pyrazine (200 mg, 0.489 mmol, 1.0 eq) in toluene (0.8 mL) and water (0.2 mL) was added methylboronic acid (43.94 g, 0.734 mmol, 1.5 eq) and potassium phosphate (311.6 mg, 1.47 mmol, 3.0 eq. The reaction mixture was degassed with argon for 5 min and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35.81 mg, 0.048 mmol, 0.1 eq) was added and again degassed for 5 min. The reaction mixture was stirred at 100 °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 to get crude. The residue was purified by flash column chromatography on silica gel (Combiflash,13150943v 1 Page 177 of 319Attorney Docket No. 2019094-00085% methanol in dichloromethane) to afford the title compound (100 mg, yellow solid). MS (ES): m / z 344.3 [M+H]+.

[0407] Synthesis of 1-187. To a stirred solution of 6-chl oro-1 -methyl-3-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)imidazo[l,5-a]pyrazine (60 mg, 0.174 mmol, 1.0 eq) in N, N-dimethylacetamide (1 mL), was added acetamide (20.62 mg, 0.349 mmol, 2.0 eq) and cesium carbonate (142.15 mg, 0.436 mmol, 2.5 eq. The reaction mixture was degassed with argon for 5 min and XPhos (16.64 mg, 0.034 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium(0) (15.98 mg, 0.017 mmol, 0.1 eq) was added and again degassed for 5 min. The reaction mixture was stirred at 130 °C for 2 h. Next, the reaction mixture was diluted 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, 5% methanol in dichloromethane) and further purified by preparative HPLC (0.1% formic acid in water and 100% acetonitrile) to afford 1-187 (4 mg, light yellow solid). MS (ES): m / z 367.2 [M+H]+. 'll NMR (400 MHz, TFA D): 5 10.41 (s, 1H), 9.55 (s, 1H), 8.67 (s, 1H), 4.49 (dd, J= 12.4, 4.1 Hz, 2H), 3.91 (t, J= 12.1 Hz, 2H), 3.81 - 3.68 (m, 1H), 3.03 (s, 6H), 2.54 (s, 3H), 2.50 - 2.46 (m, 2H), 2.30 (t, J= 11.6 Hz, 2H).

[0408] Example 2.19. Synthesis of N-(5-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-188)13150943v 1 Page 178 of 319Attorney Docket No. 2019094-0008Hexamethylditin, Pd(PPh3)4 Bis(tri-t-butylphosphine)palladium, Dioxane, 100 °C, 2 h

[0409] Synthesis of 4-methoxy-2-(tetrahydro-2H-pyran-4-yl)-6- (trimethylstannyl)pyrimidine. To a stirred solution of 4-chloro-6-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidine (1.3 g, 5.68 mmol, 1.0 eq) in 1,4-dioxane (13 mL) wasadded hexamethylditin (2.24 mg, 6.82 mmol, 1.2 eq. The reaction was purged under a stream of argon for 5 min and tetrakis(triphenylphosphine)palladium(0) (328 mg, 0.284 mmol, 0.05 eq) was added. The reaction mixture was stirred at 100 °C for 2 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 the title compound (2 g, brown oil), which was used in next step without further purification.

[0410] Synthesis of ethyl 5-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (1.2 g, 4.240 mmol, 1.0 eq) inN, N-dimethylformamide (12 mL) was added 4-methoxy-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyrimidine (1.82 g, 5.088 mmol, 1.2 eq. The reaction mixture was degassed with argon for 5 min, after that bis(tri-tert-butylphosphine)palladium(0) (216 mg, 0.423 mmol, 0.1 eq) was added and again degassed with argon for 5 min. The reaction mixture was heated at 100 °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 evaporated13150943v 1 Page 179 of 319Attorney Docket No. 2019094-0008under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 2% methanol in di chloromethane) to afford the title compound (500 mg, yellow solid). MS (ES): m / z 397.3 [M+H]+.

[0411] Synthesis of 5-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 5-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (500 mg, 1.26 mmol, 1.0 eq) in tetrahydrofuran (5 mL) and ethanol (5 mL) was added lithium hydroxide monohydrate (132 mg, 3.150 mmol, 2.5 eq) in water (5 mL). The reaction mixture was stirred for 12 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with cold water and acidified with IN hydrochloric acid solution and filtered to afford the title compound (290 mg, yellow solid) which was used in next step without further purification.

[0412] Synthesis of tert-butyl (5-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-inethylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 5-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid (290 mg, 0.787 mmol, 1.0 eq) in toluene (6 mL) and tert-butanol (6 mL), was added diphenylphosphoryl azide (433 mg, 1.57 mmol, 2.0 eq), triethylamine (0.22 mL, 1.57 mmol, 2.0 eq) and molecular sieves 4A (300 mg). The reaction mixture was stirred at 125 °C for 4 h. Next, 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, 60% ethyl acetate in hexane) to afford the title compound (150 mg, light yellow solid).JH NMR (400 MHz, DMSO-d6): 69.73 (s, 1H), 8.93 (s, 1H), 8.87 (s, 1H), 7.22 (s, 1H), 6.84 (s, 1H), 3.99 - 3.94 (m, 3H), 3.91 (s, 3H), 3.48 (t, J = 10.4 Hz, 2H), 2.96 - 2.92 (m, 1H), 2.14 - 2.11 (m, 2H), 2.01 - 1.86 (m, 3H), 1.50 (s, 9H).

[0413] Synthesis of 5-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (150 mg, 0.341 mmol, 1.0 eq) in dichloromethane (1.5 mL, was added trifluoroacetic acid (0.5 mL, 6.83 mmol, 20 eq. The reaction mixture was stirred for 2 h. Next, the reaction mixture was evaporated under reduced pressure, basified with saturated sodium bicarbonate solution and13150943v 1 Page 180 of 319Attorney Docket No. 2019094-0008extracted 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 triturated with diethyl ether to afford the title compound (90 mg, brown solid). MS (ES): m / z 340.3 [M+H]+.

[0414] Synthesis of 1-188. To a stirred solution of 5-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine (90 mg, 0.265 mmol, 1.0 eq) and acetic acid-d4 (20 mg, 0.318 mmol, 1.2 eq) in dichloromethane (1 mb) was added pyridine (0.21 mL, 2.650 mmol, 10.0 eq) and phosphorus(V) oxychloride (60 mg, 0.397 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C at room temperature for 1 h. Next, the reaction mixture was diluted with 10% citric acid solution and extracted with dichloromethane. The combined organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 2.0% methanol in dichloromethane) to afford 1-188 (35 mg, yellow solid). MS (ES): m / z 385.4 [M+H]+; 'H NMR (400 MHz, DMSO-d6): 8 10.37 (s, 1H), 9.13 (s, 1H), 8.94 (d, J= 1.5 Hz, 1H), 7.25 (d, J= 1.1 Hz, 1H), 6.86 (s, 1H), 4.01 - 3.94 (m, 2H), 3.92 (s, 3H), 3.49 (td, J= 11.5, 2.3 Hz, 2H), 3.02 - 2.90 (m, 1H), 2.55 (s, 3H), 2.08 (d, J = 12.6 Hz, 2H), 2.02 - 1.87 (m, 2H).

[0415] Example 2.20. Synthesis of N-(5-(6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 I-189)13150943v 1 Page 181 of 319Attorney Docket No. 2019094-0008

[0416] Synthesis of 6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-ol.Sodium hydride (9.36 g, 234.06 mmol, 2.5 eq, 60 % dispersion in mineral oil) was added to ethanol (240 mL) at 0 °C, followed by ethyl 4-methoxy-3-oxobutanoate (15 g, 93.62 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 30 min and than it was treated with tetrahydro-2H-pyran-4-carboximidamide (12 g, 93.62 mmol, 1.0 eq) at 0 °C. The reaction mixture was heated at 80 °C for 16 h. Next, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash, 2.1% methanol in dichloromethane) to afford the title compound 2.4 g, off-white solid). MS (ES): m / z 225.23 [M+H]+.

[0417] Synthesis of 4-chloro-6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidine. To a stirred solution of 6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-ol (2.4 g, 17.70 mmol, 1.0 eq) in phosphorus(V) oxychloride (24 mL) was added N, N-diisopropylethylamine (12 mL) at 0 °C. The reaction mixture was heated at 100 °C for 6 h. The reaction mixture was cooled to room temperature, evaporated under reduced pressure, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography13150943v 1 Page 182 of 319Attorney Docket No. 2019094-0008on silica gel (Combiflash, 60% ethyl acetate in hexane) to afford the title compound (1.1 g, brown liquid). MS (ES): m / z 242.8 [M+H]+.

[0418] Synthesis of ethyl 5-(6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrroIo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of 4-chloro-6-(rnethoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidine (1 g, 4.12 mmol, 1.0 eq) and ethyl 7-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate (2.72 g, 8.24 mmol, 2.0 eq) in 1,4-dioxane (16 mL) and water (4 mb) was added cesium carbonate (2.68 g, 8.24 mmol, 2.0 eq. The reaction mixture was purged under a stream of argon for 15 min and tetrakis(triphenylphosphine)palladium(0) (476.12 mg, 0.412 mmol, 0.1 eq) was added. The reaction mixture was then stirred at 100 °C 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 concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Combiflash, 75% ethyl acetate in hexane) to afford the title compound (0.740 g, yellow solid). MS (ES): m / z 411.39 [M+H]+.

[0419] Synthesis of 5-(6-(methoxymethyI)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 5-(6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3 -carboxylate (0.740 g, 1.80 mmol, 1.0 eq) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added solution of lithium hydroxide (189.13 mg, 4.51 mmol, 2.5 eq) in water (5 mL) at 0 °C. The mixture was stirred at room temperature for 16 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with water and acidified with aqueous 2N hydrochloric acid solution until pH ~ 4. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound (0.410 g, brown solid). MS (ES): m / z 383.20 [M+H]+.

[0420] Synthesis of tert-butyl (5-(6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 5-(6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3 -carboxylic acid (0.360 g, 0.941 mmol, 1.0 eq) in tert-butanol (8 mL) and toluene (8 mL) was added solution of diphenyl phosphoryl azide (518.14 mg, 1.88 mmol,2.0 eq) and trimethylamine (190.52 mg, 1.88 mmol, 2.0 eq. The reaction mixture was stirred at 125 °C for 4 h. Next, the reaction mixture was cooled to room temperature, diluted with13150943v 1 Page 183 of 319Attorney Docket No. 2019094-0008saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 2.1% methanol in dichloromethane) to afford the title compound (0.180 g, light yellow solid). MS (ES): m / z [M+H]+.

[0421] Synthesis of 5-(6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.180 g, 0.396 mmol, 1.0 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) at 0 °C. The temperature was raised to room temperature, and the solution was stirred for 8 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydroussodium sulfate, fdtered, concentrated under reduced pressure. The residue was triturated with ethyl acetate and n-pentane to afford the title compound (0.150 g, brown solid). MS (ES): m / z 354.3 [M+H]+.

[0422] Synthesis of 1-189. To a stirred solution of 5-(6-(methoxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine (0.150 g, 0.424 mmol, 1.0 eq) in dichloromethane (2 mL), were added acetic acid-d4 (27.20 mg, 0.424 mmol, 1.0 eq), pyridine (335.72 mg, 4.24 mmol, 10 eq) and phosphorus(V) oxychloride (130.16 mg, 0.848 mmol, 2.0 eq) at 0 °C. The temperature was raised to room temperature, and the solution was stirred for 1 h. Next, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution 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, 2.1% methanol in dichloromethane) to afford 1-189 (28 mg, light orange solid). MS (ES): m / z 399.38 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 8 10.43 (s, 1H), 9.16 (s, 1H), 8.96 (s, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 4.43 (s, 2H), 4.00 - 3.92 (m, 2H), 3.53 - 3.39 (m, 5H), 3.02 -2.97 (m, 1H), 2.54 (s, 3H), 2.07 - 1.89 (m, 4H).

[0423] Example 2.21. Synthesis of N-(5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-190)13150943v 1 Page 184 of 319Attorney Docket No. 2019094-0008

[0424] Synthesis of ethyl pyirolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 2-isocy anoacetate (15.46 g, 136.70 mmol, 14.94 L, 1.0 eq) in tetrahydrofuran (165 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (22.89 g, 150.37 mmol, 1.1 eq. The reaction mixture was stirred for 15 min followed by addition of lH-pyrrole-2-carbaldehyde (13 g, 136.70 mmol, 1.0 eq). The reaction mixture was stirred for 16 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, 40% ethyl acetate in hexane) to afford the title compound (12 g, off white solid). MS (ES): m / z 191.14 [M+H]+.

[0425] Synthesis of ethyl 7-chloropyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl pyrrolo[l,2-c]pyrimidine-3-carboxylate (14 g, 73.61 mmol, 1.0 eq in chloroform (80 mL) was added N-chlorosuccinimide (9.83 g, 73.61 mmol, 1.0 eq) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was 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, 20% ethyl13150943v 1 Page 185 of 319Attorney Docket No. 2019094-0008acetate in hexane) to afford the title compound (8 g, off white solid). MS (ES): m / z 225.14 [M+H]+.

[0426] Synthesis of ethyl 5-bromo-7-chloropyrrolo[l,2-c]pyrimidine-3-carboxylate.To a stirred solution of ethyl 7-chloropyrrolo[l,2-c]pyrimidine-3-carboxylate (3 g, 13.35 mmol, 1.0 eq) in chloroform (60 mL) was added N-bromosuccinimide (2.38 g, 13.35 mmol, 1 eq. The reaction mixture was stirred for 2 h. The reaction mixture was diluted with brine 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, 30% ethyl acetate in hexane) to afford the title compound (2.4 g, yellow solid). MS (ES): m'z 303.00 [M+H]+.

[0427] Synthesis of ethyl 7-chloro-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 5-bromo-7-chloropyrrolo[l,2-c]pyrimidine-3-carboxylate (900 mg, 2.97 mmol, 1.0 eq) inN, N-dimethylformamide (9 mL) was added 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyrimidine (1.21 g, 3.56 mmol, 1.2 eq. The reaction mixture was purged under a stream of argon for 10 min before the addition of bis(tri-t-butylphosphine)palladium (151 mg, 0.296 mmol, 0.1 eq. The reaction mixture was heated at 100 °C for 3 h. 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, 2% methanol in dichloromethane) to afford the title compound (245 mg, yellow solid). MS (ES): m / z 401.18 [M+H]+.

[0428] Synthesis of ethyl 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate. To a stirred solution of ethyl 7-chloro-5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3 -carboxylate (650 mg, 1.62 mmol, 1.0 eq) in tetrahydrofuran (10 mL), ethanol (10 mL) and water (10 mL) was added palladium catalyst (345 mg, 10% on Carbon, 55% water) and sodium acetate (266.04 mg, 3.24 mmol, 2.0 eq. The reaction mixture was heated at 60 °C for 24 h under hydrogen (20 psi). The reaction mixture was fdtered through Celite pad, filtrate was concentrated under reduced pressure and 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,13150943v 1 Page 186 of 319Attorney Docket No. 2019094-000830% ethyl acetate in hexane) to afford the title compound (450 mg, yellow solid). MS (ES): m / z 367.20 [M+H]-.

[0429] Synthesis of 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred solution of ethyl 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylate (0.450 g, 1.23 mmol, 1.0 eq) in tetrahydrofuran(10 mL) was added aq. solution of lithium hydroxide (588 mg, 6.14 mmol, 5.0 eq) at 0 °C. The reaction mixture was stirred for 3 h. The reaction mixture was acidifying with diluted hydrochloric acid and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (0.250 g, yellow solid). MS (ES): m / z 339.20 [M+H]+.

[0430] Synthesis of tert-butyl (5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbaniate. To a stirred solution of 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidine-3-carboxylic acid (0.250 g, 0.738 mmol, 1.0 eq) in toluene (5 mL) and tert-butanol (5 mL), was added solution of diphenylphosphoryl azide (244 mg, 0.886 mmol, 1.2 eq) and tri ethylamine (89 mg, 0.886 mmol, 1.2 eq. The reaction mixture was stirred at 125 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 4.5% methanol in dichloromethane) to afford the title compound (0.120 g, yellow solid). MS (ES): m / z 410.21 [M+H]+.

[0431] Synthesis of 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tert-butyl (5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.120 g, 0.293 mmol, 1.0 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (1 ml) at 0 °C. The temperature was raised to room temperature and stirred for 4 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the title compound (80 mg, light yellow solid). MS (ES): m / z 310.39 [M+H]+.13150943v 1 Page 187 of 319Attorney Docket No. 2019094-0008

[0432] Synthesis of T-l 90. To a stirred solution of 5-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-c]pyrimidin-3 -amine (80 mg, 0.258 mmol, 1.0 eq) in pyridine (3 mL) was added 2,2,2-trideuterioacetyl chloride (21.08 mg, 0.258 mmol, 1.0 eq) in dichloromethane (0.5 mL) at 0 °C. The reaction mixture was stirred for 30 min. The reaction mixture was diluted with water 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, 3.3% methanol in di chloromethane) to afford 1-190 (20 mg, light yellow solid). MS (ES): m / z 355.21 [M+H]’; *HNMR (400 MHz, DMSO-d6): 5 10.38 (s, 1H), 9.15 - 9.13 (m, 2H), 7.63 (d, J = 2.8 Hz, 1H), 7.49 (d, J= 2.8 Hz, 1H), 7.44 (s, 1H), 3.97 (d, J= 9.6 Hz, 2H), 3.50 (t, J= 10 Hz, 2H), 3.00 - 2.95 (m, 1H), 2.40 (s, 3H), 2.04 - 1.89 (m, 4H).

[0433] Example 2.22. Synthesis of N-(6-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-a]pyrazin-3-yl)acetamide (1-191)

[0434] Synthesis of ethyl l-(2-amino-2-oxoethyl)-lH-pyrrole-2-carboxylate. To a stirred solution of ethyl lH-pyrrole-2-carboxylate (10.0 g, 71.86 mmol, 1.0 eq) inN, N-dimethylformamide (100 mL) was added 2-chloroacetamide (8.06 g, 86.24 mmol, 1.2 eq) and cesium carbonate (35.12 g, 107.80 mmol, 1.5 eq. The reaction mixture was stirred 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, 90% ethyl13150943v 1 Page 188 of 319Attorney Docket No. 2019094-0008acetate in hexane) to afford the title compound (5.4 g, off white solid). MS (ES): m / z 197.2 [M+H]+.

[0435] Synthesis of pyrrolo[l,2-a]pyrazine-l,3(2H,4H)-dione) To a stirred solution of ethyl l-(2-amino-2-oxoethyl)-lH-pyrrole-2-carboxylate (5.4 g, 27.52 mmol, 1.0 eq) in ethanol (90 mL) was added potassium tert-butoxide solution (33 mL, 2.0 eq, IM in tetrahydrofuran). The reaction mixture was stirred at 70 °C for 16 h. Next, the reaction mixture was concentrated under reduced pressure and diluted with water and acidified with IN hydrochloride solution, obtained solid was filtered under high vacuum to afford the title compound (3.0 g, off white solid), which was used in next step without further purification.

[0436] Synthesis of l,3-dichloropyrrolo[l,2-a]pyrazine. A mixture of pyrrolo[l,2-a]pyrazine-l,3(2H,4H)-dione (5.0 g, 33.30 mmol, 1.0 eq) and phosphorus(V) oxychloride (50 mL) was stirred at 100 °C for 16 h. Next, the reaction mixture was concentrated under reduced pressure. The residue was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. 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 the title compound (1.0 g, off white solid). MS (ES): m / z 187.4 [M+H]+.

[0437] Synthesis of 3-chloropyrrolo[l,2-a]pyrazine. To a stirred solution of 1,3-dichloropyrrolo[l,2-a]pyrazine (1.0 g, 5.35 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added zinc (1.36 g, 20.85 mmol, 3.9 eq) and acetic acid (1.89 g, 31.55 mmol, 5.9 eq) at 0 °C. The reaction mixture was stirred at 70 °C for 6 h. Next, the reaction mixture was filtered through Celite pad, and the filtrate was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude material was triturated with diethyl ether. The solid was dried under reduced pressure to afford the title compound (5.4 g, off white solid). MS (ES): m / z 153.1 [M+H]1.

[0438] Synthesis of 6-bromo-3-chloropyrrolo[l,2-a]pyrazine. To a stirred solution of 3-chloropyrrolo[l,2-a]pyrazine (0.350 g, 2.29 mmol, 1.0 eq) in chloroform (3 mL) was added N-bromosuccinimide (0.285 g, 1.61 mmol, 0.7 eq) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Next, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by flash column chromatography13150943v 1 Page 189 of 319Attorney Docket No. 2019094-0008on silica gel (Combiflash, 15% ethyl acetate in hexane) to afford the title compound (310 mg, light yellow solid). MS (ES): m'z 230.9 [M+H]+.

[0439] Synthesis of 3-chloro-6-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-a]pyrazine. To a stirred solution of 4-methyl-2-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)pyrimidine (0.465 g, 1.36 mmol, 1.02 eq) in N, N-dimethylformamide (3 mL) was added 6-bromo-3-chloropyrrolo[l,2-a]pyrazine (0.310 g, 1.34 mmol, 1.0 eq. The reaction mixture was degassed by argon for 5 min before addition of bis(tri-tert-butylphosphine)palladium(O) (68.44 mg, 0.133 mmol, 0.1 eq. The reaction mixture was stirred at 100 °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. The residue was purified by flash column chromatography on silica gel (Combiflash, 2.5% methanol in dichloromethane) to afford the title compound (80 mg, light yellow solid). MS (ES): m / z 329.0 [M+H]+.

[0440] Synthesis of 1-191. To a stirred solution of 3-chloro-6-(6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)pyrrolo[l,2-a]pyrazine (73 mg, 0.222 mmol, 1.0 eq) inN, N-dimethylacetamide (0.5 mL) was added acetamide (39.34 mg, 0.666 mmol, 3.0 eq) and cesium carbonate (217.02 mg, 0.666 mmol, 3.0 eq. The resulting reaction mixture was degassed with argon for 5 min and tris(dibenzylideneacetone)dipalladium (0) (20.33 mg, 0.022 mmol, 0.1 eq) and Xphos (21.17 mg, 0.044 mmol, 0.2 eq) were added. The reaction mixture was stirred at 130 °C for 2 h. Next, the reaction mixture was cooled to ambient temperature, 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 flash column chromatography on silica gel (Combiflash, 70% ethyl acetate in hexane) to afford 1-191 (4.2 mg, light yellow solid), MS (ES): m / z 352.2[M+H]+; NMR (400 MHz, DMSO-d6): 8 10.71 (s, 1H), 10.33 (s, 1H), 8.90 (s, 1H), 7.78 (d, J= 4.4 Hz, 1H), 7.74 (s, 1H), 7.02 (d, J= 4.4 Hz, 1H), 4.00 - 3.96 (m, 2H), 3.50 (td, J= 11.6, 2.3 Hz, 2H), 3.18 - 3.06 (m, 1H), 2.46 (s, 3H), 2.11 (s, 3H), 2.10-2.03 (m, 2H), 2.03 - 1.88 (m, 2H).

[0441] Example 2.23. Synthesis of (R)-N-(7-methyl-5-(4-((tetrahydro-2H-pyran-3-yl)oxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yI)pyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-192) and (S)-N-(7-methyl-5-(4-((tetrahydro-2H-pyran-3-yl)oxy)-6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)pyrrolo[l,2-c]pyrimidin-3-yl)acetamide-2,2,2-d3 (1-193)13150943v 1 Page 190 of 319Attorney Docket No. 2019094-0008

[0442] Synthesis of ethyl 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate. Ethyl 5-bromo-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (1.7 g, 6.00 mmol, 1.0 eq) and 2-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)-6-(trimethylstannyl)pyridine (3.82 g, 9.01 mmol, 1.5 eq) were dissolved in N, N-dimethylformamide (35 mL). The solution was purged under a stream of argon for 5 min and treated with bi s(tri-tert-butylphosphine)palladium(O) (306.86 mg, 0.600 mmol, 0.1 eq). The reaction mixture was then stirred at 100 °C for 6 h. Next, the reaction mixture was cooled to ambient temperature, 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, 85 % ethyl acetate in hexane) to afford the title compound (1.2 g, light yellow solid). MS (ES): m 'z 464.24 [M+H]+.

[0443] Synthesis of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid. To a stirred13150943v 1 Page 191 of 319Attorney Docket No. 2019094-0008solution of ethyl 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylate (1.2 g, 2.59 mmol, 1.0 eq) in ethanol (8 mL) and tetrahydrofuran (8 mL) was added solution of lithium hydroxide (271.59 mg, 6.47 mmol, 2.5 eq) in water (8 mL) at 0 °C. The mixture was stirred at room temperature for 8 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with water and acidified with aqueous 2N hydrochloric acid solution until pH ~ 4. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound (0.830 g, yellow solid). MS (ES): m / z 436.30 [M+H]+.

[0444] Synthesis of tert-butyl (5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate. To a stirred solution of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidine-3-carboxylic acid (0.830 g, 1.91 mmol, 1.0 eq) in tert-butanol (8 mL) and toluene (8 mL) was added solution of diphenylphosphoryl azide (1.05 g, 3.81 mmol, 2.0 eq) and triethylamine (385.73 mg, 3.81 mmol, 2.0 eq). The reaction mixture was stirred at 125 °C for 4 h. Next, the reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash, 2.1% methanol in dichloromethane) to afford the title compound (0.380 g, light yellow solid). MS (ES): m / z 507.46 [M+H]+.

[0445] Synthesis of 5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-amine. To a stirred solution of tertbutyl (5-(6-(3,6-dihydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-3-yl)oxy)pyridin-2-yl)-7-methylpyrrolo[l,2-c]pyrimidin-3-yl)carbamate (0.380 g, 0.750 mmol, 1.0 eq) in dichloromethane (4 mL) was added trifluoroacetic acid (4 mL) at 0 °C. The temperature was raised to room temperature and the solution was stirred for 8 h. Next, the reaction mixture was evaporated under reduced pressure, diluted with saturated aqueous s...

Claims

Attorney Docket No. 2019094-0008CLAIMS1. 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;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, or -NHRa;Rais Ci-6 aliphatic or a 5-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;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;Rbis halogen, -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 9-13150943v 1 Page 262 of 319Attorney Docket No. 2019094-0008membered 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; andR 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.

2. The compound according to claim 1, wherein V1is C and V2is N.

3. The compound according to claim 1, wherein V1is N and V2is C.

4. The compound according to any one of claims 1-3, wherein X1is C-H.

5. The compound according to any one of claims 1-3, wherein X1is N.13150943v 1 Page 263 of 319Attorney Docket No. 2019094-00086. The compound according to any one of claims 1-5, wherein the compound is selected from formulae I-a, I-b, I-c, and I-d:or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6, wherein R1is an optionally substituted 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

8. The compound according to claim 7, wherein R1is an optionally substituted 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

9. The compound according to any one of claims 6-8, wherein R1is selected from10. The compound according to claim 6, wherein R1is -C(O)Y.

11. The compound according to claim 10, wherein the compound is selected from formulae 1-a-z, I-b- / , I-c- / , and I-d-z:13150943v 1 Page 264 of 319Attorney Docket No. 2019094-0008R3R3I-d-ior a pharmaceutically acceptable salt thereof.

12. The compound according to claim 10, wherein Y is -ORa.

13. The compound according to claim 10, wherein Y is -NHRa.

14. The compound according to any one of claims 11-13, wherein Rais Ci-6 aliphatic.

15. The compound according to any one of claims 11-13, wherein Rais -CH3 or -CD3.

16. The compound according to claim 11, wherein Rais a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Rais substituted with 0-2 instances of Ral.

17. The compound according to claim 16, wherein R is selected from13150943v 1 Page 265 of 319Attorney Docket No. 2019094-0008>0-218. The compound according to claim 17, wherein Ralis Ci-6 aliphatic.

19. The compound according to claim 18, wherein Ralis -CH3.

20. The compound according to any one of claims 1-19, wherein R2is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 1-3 instances of Rb.

21. The compound according to claim 20, wherein R2is a 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is substituted with 1-3 instances of Rb.

22. The compound according to claim 20 or claim 21, wherein R2is selected from23. The compound according to any one of claims 1-19, wherein R2is a 6-membered heteroaryl ring having 1-2 nitrogen atoms, wherein R2is substituted with 1-3 instances of Rb.

24. The compound according to claim 23, wherein R2is selected from13150943v 1 Page 266 of 319Attorney Docket No. 2019094-000825. The compound according to any one of claims 1-19, wherein 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*.

26. The compound according to claim 25, wherein 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 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*.

27. The compound according to claim 26, wherein 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.

28. The compound according to claim 27, wherein R2is selected from:13150943v 1 Page 267 of 319Attorney Docket No. 2019094-000829. The compound according to claim 28, wherein R2is selected from30. The compound according to any one of claims 1-19, wherein 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.

31. The compound according to claim 30, wherein 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.

32. The compound according to claim 31, wherein R2is selected from13150943v 1 Page 268 of 319Attorney Docket No. 2019094-000833. The compound according to any one of claims 20-32, wherein 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-40R°, or-(CH2)o-4C(O)R°.

34. The compound according to any one of claims 20-32, wherein 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-40R°, or-(CH2)o-4C(0)R°.

35. The compound according to claim 33 or 34, wherein R° is hydrogen or Ci-4 aliphatic optionally substituted with halogen (e.g., fluoro).13150943v 1 Page 269 of 319Attorney Docket No. 2019094-000813150943v 1 Page 270 of 319Attorney Docket No. 2019094-000813150943v 1 Page 271 of 319Attorney Docket No. 2019094-000837. The compound according to claim 36, wherein Rbis selected from13150943v 1 Page 272 of 319Attorney Docket No. 2019094-000838. The compound according to any one of claims 20-28, wherein R2is selected from13150943V 1 Page 273 of 319Attorney Docket No. 2019094-000813150943v 1 Page 274 of 319Attorney Docket No. 2019094-000813150943v 1 Page 275 of 319Attorney Docket No. 2019094-000813150943v 1 Page 276 of 319Attorney Docket No. 2019094-000813150943v 1 Page 277 of 319Attorney Docket No. 2019094-000813150943v 1 Page 278 of 319Attorney Docket No. 2019094-000813150943v 1 Page 279 of 319Attorney Docket No. 2019094-000813150943v 1 Page 280 of 319Attorney Docket No. 2019094-000813150943v 1 Page 281 of 319Attorney Docket No. 2019094-000813150943v 1 Page 282 of 319Attorney Docket No. 2019094-000813150943v 1 Page 283 of 319Attorney Docket No. 2019094-000813150943v 1 Page 284 of 319Attorney Docket No. 2019094-000813150943v 1 Page 285 of 319Attorney Docket No. 2019094-000813150943v 1 Page 286 of 319Attorney Docket No. 2019094-000813150943v 1 Page 287 of 319Attorney Docket No. 2019094-000813150943v 1 Page 288 of 319Attorney Docket No. 2019094-000813150943v 1 Page 289 of 319Attorney Docket No. 2019094-000813150943v 1 Page 290 of 319Attorney Docket No. 2019094-000813150943v 1 Page 291 of 319Attorney Docket No. 2019094-000839. The compound according to claim 38, wherein R2is selected from13150943v 1 Page 292 of 319Attorney Docket No. 2019094-000813150943v 1 Page 293 of 319Attorney Docket No. 2019094-000813150943v 1 Page 294 of 319Attorney Docket No. 2019094-000813150943v 1 Page 295 of 319Attorney Docket No. 2019094-000813150943v 1 Page 296 of 319Attorney Docket No. 2019094-000813150943v 1 Page 297 of 319Attorney Docket No. 2019094-000813150943v 1 Page 298 of 319Attorney Docket No. 2019094-000840. The compound according to any one of claims 1-39, wherein R3is selected from halogen (e.g., fluoro or chloro), -CH3, -CH2CH3, -CN, -OR, -N(R)2,13150943v 1 Page 299 of 319Attorney Docket No. 2019094-000841. The compound according to claim 40, wherein Rcis halogen.

42. The compound according to claim 40 or claim 41, wherein R3is selected from13150943v 1 Page 300 of 319Attorney Docket No. 2019094-000843. The compound according to any one of claims 1-42, wherein the compound is selected from13150943v1 Page 301 of 319Attorney Docket No. 2019094-000813150943v1 Page 302 of 319Attorney Docket No. 2019094-000813150943v1 Page 303 of 319Attorney Docket No. 2019094-000813150943v1 Page 304 of 319Attorney Docket No. 2019094-00081-43 T-44 T-4513150943v1 Page 305 of 319Attorney Docket No. 2019094-000813150943v1 Page 306 of 319Attorney Docket No. 2019094-000813150943v1 Page 307 of 319Attorney Docket No. 2019094-000813150943v1 Page 308 of 319Attorney Docket No. 2019094-000813150943v1 Page 309 of 319Attorney Docket No. 2019094-000813150943v1 Page 310 of 319Attorney Docket No. 2019094-000813150943v 1 Page 311 of 319Attorney Docket No. 2019094-000813150943v 1 Page 312 of 319Attorney Docket No. 2019094-0008T-148 1-149 T-15013150943v 1 Page 313 of 319Attorney Docket No. 2019094-000813150943v 1 Page 314 of 319Attorney Docket No. 2019094-000813150943v 1 Page 315 of 319Attorney Docket No. 2019094-000813150943v 1 Page 316 of 319Attorney Docket No. 2019094-000813150943v 1 Page 317 of 319Attorney Docket No. 2019094-00081-221 1-2221-224or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition comprising a compound according to any one of claims 1- 43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

45. A method of inhibiting TYK2, the method comprising contacting a biological sample with a compound according to any one of claims 1-43.

46. 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 1-43, or a pharmaceutically acceptable salt thereof.

47. The method according to claim 46, wherein the TYK2-mediated disease, disorder, or condition is an autoimmune disorder that comprises neurological involvement.

48. The method according to claim 46, wherein the TYK2-mediated disease, disorder, or condition is systemic lupus erythematosus (SLE), rheumatoid arthritis, or psoriatic arthritis.

49. The method according to claim 46, wherein the TYK2-mediated disease, disorder, or condition is a cancer.13150943v 1 Page 318 of 319

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