Octahydro-1h-isoindole-heterobicyclic JAK-BTK inhibitors and methods of use thereof

Abstract

The present disclosure provides compounds useful as inhibitors of protein kinases. The present disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment of various disorders. Such compounds are of Formula (I): or a pharmaceutically acceptable salt thereof.

Description

Attorney Docket No. CENC-011 / 08WO 360899-2045OCTAHYDRO-1H-ISOINDOLE-HETEROBICYCLIC JAK-BTK INHIBITORS AND METHODS OF USE THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U. S. C. §119(e) of U. S. Provisional Application No. 63 / 779,913 filed on March 28, 2025, U. S. Provisional Application No.63 / 800,311 filed on May 5, 2025, U. S. Provisional Application No. 63 / 811,000 filed on May 23, 2025, U. S. Provisional Application No. 63 / 841,109 filed on July 9, 2025, U. S. Provisional Application No. 63 / 859,624 filed on August 7, 2025, U. S. Provisional Application No.63 / 887,995 filed on September 25, 2025, U. S. Provisional Application No. 63 / 897, 118 filed on October 10, 2025, and U. S. Provisional Application No. 63 / 985,333 filed onFebruary 18, 2026, the entirety of each of which is incorporated herein by reference.TECHNICAL FIELD OF THE INVENTION

[0002] The present disclosure relates to compounds useful as inhibitors of protein kinases. The present disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment of various disorders.BACKGROUND OF THE INVENTION

[0003] Bruton’s tyrosine kinase (BTK), a member of the TEC-kinase family, is an important signaling enzyme expressed in hematopoietic cell types. BTK plays an essential role in the B-cell signaling pathway that links cell surface B-cell receptor (BCR) stimulation to downstream responses. BTK is associated with a number of disorders such as autoimmune diseases, inflammatory diseases and cancer.

[0004] Janus kinase (JAK) is a tyrosine kinase family consisting of JAK1, JAK2, JAK3 and TYK2. JAK plays an important role in cytokine signal transduction. The downstream substrate of the kinase of the JAK family includes a signal transducer and activator of the transcriptional (STAT) protein. JAK / STAT signaling has been implicated in a number of abnormal immune responses, such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis.

[0005] There remains a need to find inhibitors of protein kinases, including more potent and more selective inhibitors, specifically BTK and JAK-3 inhibitors, and their use in the1333961159Attorney Docket No. CENC-011 / 08WO 360899-2045treatment of various diseases. The present disclosure fulfils this need and provides other related advantages.BRIEF DESCRIPTION OF FIGURES

[0006] FIGs. 1A, IB, 1C, 3A, 3B, 3C, 4A, 4B and 5 show the efficacy of Compound 1-33 in an EAE mouse model.

[0007] FIGs. 2A, 2B, 2C, 2D, and 6 show the efficacy of Compound 1-33 in an AIA rat model.

[0008] FIGs. 7A, 7B, and 7C show the efficacy of Compound 1-33 in a psoriasis model.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS1. General Description of Certain Embodiments of the Invention; Definitions

[0009] In one aspect, the present disclosure provides a compound of Formula I:Ior a pharmaceutically acceptable salt thereof, wherein:X1is CH orN;X2is C orN;X3is C or N; provided that one or two of X1, X2, and X3are N;X4is CH, C-halogen, or N;R1is a substituent comprising a warhead group;each occurrence of R2is independently a halogen, -OR, -CN, -C(O)R, -C(O)OR, -OC(O)R, - OC(O)OR, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, - NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or an optionally substituted C1-6 aliphatic;each occurrence of R3is independently halogen, -OR, -CN, -C(O)R, -C(O)OR, -OC(O)R, - OC(O)OR, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, - 2333961159Attorney Docket No. CENC-011 / 08WO 360899-2045NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, an optionally substituted Ci-6aliphatic, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rais hydrogen, halogen, -OR, -CN, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)N(R)2, - N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, an optionally substituted Ci-6aliphatic, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;-L1- is a covalent bond or a Ci-4 bivalent straight or branched hydrocarbon chain;R4is H, -C(O)R5, an optionally substituted Ci-6 aliphatic, an optionally substituted phenyl, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the phenyl or the 5-8 membered monocyclic heteroaromatic ring is substituted with p instances of R6; R5is an optionally substituted Ci-6 aliphatic, an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R6is independently halogen, -OR, -C(O)R, -C(O)OR, -OC(O)R, - OC(O)OR, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, - NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, an optionally substituted Ci-6aliphatic, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;3333961159Attorney Docket No. CENC-011 / 08WO 360899-2045each occurrence of R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, or an 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;m is 0, 1, 2, 3, 4, or 5;n is 0, 1, or 2; andp is 0, 1, 2, or 3.

[0010] As defined generally above, X1is CH or N.

[0011] In some embodiments, X1is CH. In some embodiments, X1is N.

[0012] As defined generally above, X2is C or N.

[0013] In some embodiments, X2is C. In some embodiments, X2is N.

[0014] As defined generally above, X3is C or N, provided that one or two of X1, X2, and X3are N.

[0015] In some embodiments, X3is C. In some embodiments, X3is N.

[0016] As defined generally above, X4is CH, C-halogen, or N.

[0017] In some embodiments, X4is CH. In some embodiments, X4is C-halogen. In some embodiments, X4is N. In some embodiments, X4is C-F.

[0018] In some embodiments, X1is CH, X2is C, and X3and X4are N.

[0019] In some embodiments, X1is CH, X2is N, X3is C and X4is N.333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0021] As defined generally above, R1is a substituent comprising a warhead group.

[0022] In some embodiments, the warhead group comprises an electrophilic group capable of reacting with a nucleophile under biological conditions to form a covalent bond to the nucleophile. In some embodiments, the warhead group comprises an electrophilic group capable of reacting with the thiol group of a cysteine under biological conditions to form a covalent bond to the cysteine. In some embodiments, the warhead group comprises an epoxide, a Michael acceptor (e.g., substituted or unsubstituted acrylamide, substituted or unsubstituted acrylate, substituted or unsubstituted alpha halo acetamide), an alkyl chloride, alkyl bromide, alkyl iodide, a sulfonyl halide, an alpha-halo ketone, an alpha-halo amide, an aldehyde, an aminonitrile, an N-cyanamide, a nitrile, a vinyl sulfone, a vinyl sulfonamide, or an anhydride.

[0023] In certain embodiments, R1is -L2-Y. In certain embodiments, the following combination of -L2-Y applies:-L2- is a covalent bond or a bivalent C2-8 straight or branched, hydrocarbon chain wherein one or two methylene units of -L2- are optionally and independently replaced by — NRC(O) —, — C(O)NR—, — N(R)SO2—, — SO2N(R)—, — S—, -O-, -NR-, — S(O)—, — SO2—, - C(O)-, — OC(O) —, or — C(O)O —; and additionally one methylene unit of -L2- is optionally 5333961159Attorney Docket No. CENC-011 / 08WO 360899-2045replaced by an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-10 membered bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andY is hydrogen, halogen, -COOR, -CN, -CON(R)2, -NRCN, NCh, -N(R)2, optionally substituted Ci-8 aliphatic, or an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-10 membered bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein -L2-Y comprises an alpha, beta-unsaturated carbonyl moiety, amide, cyano group, halogen, alkynyl group, sulfonyl group, or epoxide.

[0024] In certain embodiments, R1is L2-Y. In certain embodiments, the following combination of -L2-Y applies:-L2- is a covalent bond or a bivalent C2-8 straight or branched, hydrocarbon chain wherein one or two methylene units of -L2- are optionally and independently replaced by — NRC(O) —, — C(O)NR—, — N(R)SO2—, — SO2N(R)—, — S—, -O-, -NR-, — S(O)—, — SO2—, - C(O)-, — OC(O) —, or — C(O)O —; and additionally one methylene unit of -L2- is optionally replaced by an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andY is hydrogen, halogen, -COORf, -CN, -CONRf2, -NRfCN, NO2, -NRf2, C1-8 aliphatic 6333961159Attorney Docket No. CENC-011 / 08WO 360899-2045optionally substituted with halogen, NO2, or CN, or an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein -L2-Y comprises an alpha, beta-unsaturated carbonyl moiety, amide, cyano group, halogen, alkynyl group, sulfonyl group, or epoxide; and wherein each occurrence of Rfis independently H, or straight or branched C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl group optionally substituted with 1, 2 or 3 halogen atoms.

[0025] In certain embodiments, R1is -L2-Y. In certain embodiments, the following combination of -L2-Y applies:-L2- is a covalent bond or a bivalent C2-8 straight or branched, hydrocarbon chain wherein one or two methylene units of -L2- are optionally and independently replaced by — NRC(O) —, — C(O)NR—, — N(R)SO2—, — SO2N(R)—, — S—, — S(O)—, — SO2—, -C(O)-, — OC(O) —, or — C(O)O —; and additionally one methylene unit of -L2- is optionally replacedby a ring selected fromhalogen, -COORf, -CN, -CONRf2, -NRfCN, NO2, -NRf2, epoxide, C1-8 aliphatic optionallysubstituted with halogen, NO2, or CN, or a ring selected from333961159Attorney Docket No. CENC-011 / 08WO 360899-2045wherein -L2-Y comprises an alpha, beta-unsaturated carbonyl moiety, amide, cyano group, halogen, C2-6 alkynyl group, sulfonyl group, or epoxide; wherein each occurrence of Rfis independently H, or straight or branched Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl group optionally substituted with 1, 2 or 3 halogen atoms; and wherein each occurrence of Rgand Rhis independently H, halogen, or OH, or straight or branched C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl group optionally substituted with 1, 2 or 3 halogen atoms.

[0026] In certain embodiments, R1is:

[0028] In certain embodiments, R1is selected from those set forth in Table la, Table lb and Table 1c below.

[0029] In some embodiments, R1is selected from those set forth in Table la, below, wherein each wavy line indicates the point of attachment to the rest of the molecule.Table la. Exemplary Warhead Groups8333961159Attorney Docket No. CENC-011 / 08WO 360899-2045333961159Attorney Docket No. CENC-011 / 08WO 360899-2045(A89),(A94), 333961159Attorney Docket No. CENC-011 / 08WO 360899-2045333961159Attorney Docket No. CENC-011 / 08WO 360899-2045(Al 82),

[0030] In some embodiments, R1is selected from those set forth in Table lb, below, wherein each wavy line indicates the point of attachment to the rest of the molecule.Table lb. Exemplary Warhead Groups / M CNF CN

[0031] In some embodiments, R1is selected from those set forth in Table 1c, below, wherein each wavy line indicates the point of attachment to the rest of the molecule.Table 1c. Exemplary Warhead Groups12333961159Attorney Docket No. CENC-011 / 08WO 360899-2045333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0032] In some embodiments, R1is selected from those set forth in Table 1c.

[0033] In some embodiments, R1is selected from those depicted in Table 1, below.

[0034] As defined generally above, R2is selected from halogen, -OR, -CN, -C(O)R, - C(O)OR, -OC(O)R, -OC(O)OR, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, - N(R)C(O)OR, -NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or an optionally substituted Ci-6 aliphatic.

[0035] In some embodiments, R2is a halogen. In some embodiments, R2is -OR. In some embodiments, R2is -CN. In some embodiments, R2is -C(O)R. In some embodiments, R2is - C(O)OR. In some embodiments, R2is -OC(O)R. In some embodiments, R2is -OC(O)OR. In some embodiments, R2is -C(O)N(R)2. In some embodiments, R2is -N(R)C(O)R. In some embodiments, R2is -N(R)C(O)N(R)2. In some embodiments, R2is -OC(O)N(R)2. In some 14333961159Attorney Docket No. CENC-011 / 08WO 360899-2045embodiments, R2is -N(R)C(O)OR. In some embodiments, R2is -NR2. In some embodiments, R2is -SR. In some embodiments, R2is -S(O)R. In some embodiments, R2is -S(O)2R. In some embodiments, R2is -S(O)2N(R)2. In some embodiments, R2is -NRS(O)2R. In some embodiments, R2is a C1-6 aliphatic. In some embodiments, R2is a substituted C1-6 aliphatic.

[0036] In some embodiments, R2is selected from -OH, -OMe, F, and Me. In some embodiments, R2is -OH.

[0037] In some embodiments, R2is selected from those depicted in Table 1, below.

[0038] As defined generally above, R3is selected from halogen, -OR, -CN, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, an optionally substituted C1-6 aliphatic, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0039] In some embodiments, R3is a halogen. In some embodiments, R3is -OR. In some embodiments, R3is -CN. In some embodiments, R3is -C(O)R. In some embodiments, R3is -C(O)OR. In some embodiments, R3is -OC(O)R. In some embodiments, R3is -OC(O)OR. In some embodiments, R3is -C(O)N(R)2. In some embodiments, R3is -N(R)C(O)R. In some embodiments, R3is -N(R)C(O)N(R)2. In some embodiments, R3is -OC(O)N(R)2. In some embodiments, R3is -N(R)C(O)OR. In some embodiments, R3is -NR2. In some embodiments, R3is -SR. In some embodiments, R3is -S(O)R. In some embodiments, R3is -S(O)2R. In some embodiments, R3is -S(O)2N(R)2. In some embodiments, R3is -NRS(O)2R. In some embodiments, R3is a C1-6 aliphatic. In some embodiments, R3is a substituted C1-6 aliphatic. In some embodiments, R3is a phenyl. In some embodiments, R3is a substituted phenyl. In some embodiments, R3is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is a substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.15333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0040] In some embodiments, R3is selected from methyl, ethyl, isopropyl, -F, -Cl, -OMe,L '= / / N, Q N= — V,-CN, *A, A,an(i«AN

[0041] In some embodiments, R3is selected from -F, Me, -CN,, ' and N = - r•A

[0042] In some embodiments, R3is selected from those depicted in Table 1, below.

[0043] As defined generally above, Rais selected from hydrogen, halogen, -OR, -CN, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, an optionally substituted Ci-6aliphatic, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0044] In some embodiments, Rais a hydrogen. In some embodiments, Rais a halogen. In some embodiments, Rais -OR. In some embodiments, Rais -CN. In some embodiments, Rais -C(O)R. In some embodiments, Rais -C(O)OR. In some embodiments, Rais -OC(O)R. In some embodiments, Rais -OC(O)OR. In some embodiments, Rais -C(O)N(R)2. In some embodiments, Rais -N(R)C(O)R. In some embodiments, Rais -N(R)C(O)N(R)2. In some embodiments, Rais -OC(O)N(R)2. In some embodiments, Rais -N(R)C(O)OR. In some embodiments, Rais -NR2. In some embodiments, Rais -SR. In some embodiments, Rais -S(O)R. In some embodiments, Rais -S(O)2R. In some embodiments, Rais -S(O)2N(R)2. In some embodiments, Rais -NRS(O)2R. In some embodiments, Rais a Ci-6 aliphatic. In some embodiments, Rais a substituted Ci-6 aliphatic. In some embodiments, Rais a phenyl. In some embodiments, Rais a substituted phenyl. In some embodiments, Rais a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rais a substituted 5-8 membered 16333961159Attorney Docket No. CENC-011 / 08WO 360899-2045monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0045] In some embodiments, Rais selected from hydrogen, methyl, ethyl, isopropyl, -F, -Cl, -OMe, -CN, and

[0046] In some embodiments, Rais selected from hydrogen, -F, Me, -CN,and.

[0047] In some embodiments, Rais selected from those depicted in Table 1, below.

[0048] As defined generally above, -L1- is a covalent bond or a Ci-4 bivalent straight or branched hydrocarbon chain.

[0049] In some embodiments, -L1- is a covalent bond. In some embodiments, -L1- is a Ci-4 straight or branched hydrocarbon chain. In some embodiments, -L1- is a Ci straight or branched hydrocarbon chain. In some embodiments, -L1- is a C2 straight or branched hydrocarbon chain. In some embodiments, -L1- is a C3 straight or branched hydrocarbon chain. In some embodiments, -L1- is a C4 straight or branched hydrocarbon chain.

[0050] In some embodiments, -L1- is a covalent bond.

[0051] In some embodiments, -L1- is selected from those depicted in Table 1, below.

[0052] As defined generally above, R4is selected from H, -C(O)R5, an optionally substituted C1-6 aliphatic, an optionally substituted phenyl, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the phenyl or the 5-8 membered monocyclic heteroaromatic ring is substituted with p instances of R6.

[0053] In some embodiments, R4is a hydrogen. In some embodiments, R4is -C(O)R5. In some embodiments, R4is a C1-6 aliphatic. In some embodiments, R4is a substituted C1-6 aliphatic. In some embodiments, R4is a phenyl. In some embodiments, R4is a phenyl substituted with p instances of R6. In some embodiments, R4is a 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R4is a 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with p instances of R6.17333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0055] In some embodiments, R4is selected from those depicted in Table 1, below.

[0056] As defined generally above, R5is an optionally substituted Ci-6 aliphatic, an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0057] In some embodiments, R5is a Ci-6 aliphatic. In some embodiments, R5is a substituted Ci-6 aliphatic. In some embodiments, R5is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R5is a substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R5is a phenyl. In some embodiments, R5is a substituted phenyl. In some embodiments, R5is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5is a substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5is a 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R5is a substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0058] In some embodiments, R5is cyclopropyl group.

[0059] In some embodiments, R5is selected from those depicted in Table 1, below.18333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0060] As defined generally above, R6is halogen, -OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, an optionally substituted Ci-6 aliphatic, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0061] In some embodiments, R6is halogen. In some embodiments, R6is -OR. In some embodiments, R6is -C(O)R. In some embodiments, R6is -C(O)OR. In some embodiments, R6is -OC(O)R. In some embodiments, R6is -OC(O)OR. In some embodiments, R6is -C(O)N(R)2. In some embodiments, R6is -N(R)C(O)R. In some embodiments, R6is -N(R)C(O)N(R)2. In some embodiments, R6is -OC(O)N(R)2. In some embodiments, R6is -N(R)C(O)OR. In some embodiments, R6is -NR2. In some embodiments, R6is -SR. In some embodiments, R6is -S(O)R. In some embodiments, R6is -S(O)2R. In some embodiments, R6is -S(O)2N(R)2. In some embodiments, R6is -NRS(O)2R. In some embodiments, R6is a C1-6 aliphatic. In some embodiments, R6is a substituted C1-6 aliphatic. In some embodiments, R6is a phenyl. In some embodiments, R6is a substituted phenyl. In some embodiments, R6is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6is a substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6is a 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6is a substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.OH O—

[0062] In some embodiments, R6is selected from Me, Et,, and > '

[0063] In some embodiments, R6is selected from those depicted in Table 1, below.

[0064] As defined generally above, each occurrence of R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic 19333961159Attorney Docket No. CENC-011 / 08WO 360899-2045carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, or an 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0065] In some embodiments, R is hydrogen. In some embodiments, R is a Ci-6 aliphatic group. In some embodiments, R is a substituted Ci-6 aliphatic group. In some embodiments, R is a 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R is a 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, R is a substituted 3-8 membered saturated monocyclic carbocyclic ring. In some embodiments, R is a substituted 3-8 membered partially unsaturated monocyclic carbocyclic ring. In some embodiments, R is phenyl. In some embodiments, R is a substituted phenyl. In some embodiments, R is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R is a substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R is a 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 4-8 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 4-10 membered saturated or partially unsaturated bicyclic 20333961159Attorney Docket No. CENC-011 / 08WO 360899-2045carbocyclic ring. In some embodiments, R is a substituted 4-10 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R is an 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0066] In some embodiments, R is selected from those depicted in Table 1, below.

[0067] As defined generally above, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0068] In some embodiments, m is selected from those depicted in Table 1, below.

[0069] As defined generally above, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0070] In some embodiments, n is selected from those depicted in Table 1, below.

[0071] As defined generally above, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0072] In some embodiments, p is selected from those depicted in Table 1, below.

[0073] In some embodiments, the present disclosure provides a compound of Formula II:R1HIIor a pharmaceutically acceptable salt thereof, wherein:each of R1, R2, R3, Ra, R4, X1, X2, X3, X4, m and n are as defined above and described in embodiments herein, both singly and in combination.

[0074] In some embodiments, the present disclosure provides a compound of Formula III:333961159Attorney Docket No. CENC-011 / 08WO 360899-2045R1IIIor a pharmaceutically acceptable salt thereof, wherein:each of R1, R2, R3, Ra, R6, X1, X2, X3, X4, m and n are as defined above and described in embodiments herein, both singly and in combination.

[0075] In some embodiments, the present disclosure provides compounds of Formula IVa, Formula IVb, Formula IVc, Formula IVd, or Formula IVe:IVa IVbIVc IVd22333961159Attorney Docket No. CENC-011 / 08WO 360899-2045or a pharmaceutically acceptable salt thereof, wherein:each of R1, R2, and R3are as defined above and described in embodiments herein, both singly and in combination.

[0076] In some embodiments, the present disclosure provides compounds of Formula Va, Formula Vb, Formula Vc, Formula Vd, or Formula Ve:Veor a pharmaceutically acceptable salt thereof, wherein:each of R1, and R2are as defined above and described in embodiments herein, both singly and in combination.

[0077] In some embodiments, the present disclosure provides compounds of Formula VIa, Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, Formula VIg, Formula VIh, or Formula VIi:23333961159Attorney Docket No. CENC-011 / 08WO 360899-2045VIg VIhor a pharmaceutically acceptable salt thereof, wherein:333961159Attorney Docket No. CENC-011 / 08WO 360899-2045each of R1and R2are as defined above and described in embodiments herein, both singly and in combination.

[0078] In some embodiments, the present disclosure provides compounds of Formula VIIa, Formula VIIb, Formula VIIc, Formula VIId, Formula VIIe, Formula VIIf, Formula VIIg, Formula VIIh, or Formula VIIi:VllfVIIg VIIh25333961159Attorney Docket No. CENC-011 / 08WO 360899-2045VIIior a pharmaceutically acceptable salt thereof, wherein:R2is as defined above and described in embodiments herein.Table 1. Exemplary Compounds Chemical structure Compound Number I-1O'A °OHV'NL if L N—N N""^7H0 1-2_orV\ JI / ,L if C N—N N"^7H1-31-4\ J \ N— 7 X / l&1J-.,, / bN.N"^&1 / / fSH26333961159Attorney Docket No. CENC-011 / 08WO 360899-2045J? 1-5 J&1 J-.,, / ^ / ^1 / / V-Nx / N Mk ILNANA / N- H»i o 1-6 "\ / / \ | N— \I&1 >-„ / >0 V-N"x'^ *ONNA / =n-B'H0 1-7FA OH V L 'N if J / .=". N—H0 1-8 JI / / / Vkj / aT7L if L N—^N''ZXN / ^ / H0 1-9 J] / / A^L / ai'7rly^N r^NII11^N^N'Z^ / NH0 I-9aC Yl^N Y^NIIJk x-k^1N1N NH27333961159Attorney Docket No. CENC-011 / 08WO 360899-20450 1-10 JI NN" N\ Qi'7Jp=N,L if L N—HI- 10aV^N |=N,L if L N— \ / '''NZX / H0 1-11 JI / / / V N-"\Zzr-N'' 1 / / \ OHVN r^NL if L. N—H0 1-12 ^ortX\ JJ / / \si3r1 / or1 / 7~NZ'- / / \ OHr^NL if L N—N N'^7H0 1-13NZ^-"XNA^Vtlyori"HV^N f^NL if L N—N N^^7H333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-14- \f \&1\&1 )Z~N'<_y0HYS rN'< A Jl / NHI- 14a r"N^OHP < Ai J r!ZN'NH1-15^N\&1’c \&1CN'Y N Ai A r / NZ'NHI-15a °y^<NY°P N Ai J rA" NH333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-16 VN ] JoN' =\ X ' K / N^N\V ~NHI- 16a / ° A=ZN \N=\' V / ■ N^N\V ~~NH0 1-17 JI / / N"^xz^\&1 \ / 5^L / &1A VS |=NL if L N—H0 I- 17aAV'N |=NL if N—H0 1-18\&1&1 / &1N-NZ:■ / / i OHV^N r^NL if N—H1-19 \ T N— \Jorl / > / / V-Nx / N..JC A 'NANA / N-H333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-20 Z^f N^0\&i&i / &iOH VN'N r^NL if N—H0 1-21\orty£iHV^N f=HL if L N—N N^^7H1-22 <N& JLz / > f t*1JS1 / #N< A I rIN.'NHI-22a °y^<N*“S#NV N ^Ai J rL / N'NH»i o 1-23 \ I N— \1&1>-„ / / > / / Y J / =NAA / N-H333961159Attorney Docket No. CENC-011 / 08WO 360899-20450 1-24 JJrlN^N r^NL if J. N—^N^N'''^7HI-24a >=zJ o iz'e \V" \ I\ £S?P <z\ z^ z 1°\\1-25 I oJOM " / < J (=10 1-26 _ _ or1.''X JI / / VlSriAi"7zr-N'' 1 / / \ OHV^N r^NL if N—H0 1-27 y-orlXX JI / / jSjJyorl<nV^N (=NL if L N—H333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-28- \&il? / \&1d PVS / TN'< JI, NHI-28ar"NA- / Cx rV A V* 7 J rI / N> NHO 1-29V1&1 / &1^“N. OHr^N'\ L JU / N-SE NH1-30 _^N\&i> _O / . / / (&1 \\&1 >z^-rfV < i J VI, NH0 1-31Jk1 ZN^N^OH33333961159Attorney Docket No. CENC-011 / 08WO 360899-2045I-31aH1-32 0 C7 \ \ z< / f! I \ / K>I-32aA^ Z / \M C° °r S- - ) / LL I\_Z VJ / 1-33V'NL j[ J. N—H1-34 r^N^N'N-'LNt v11Z7NYS Y N A A / NH333961159Attorney Docket No. CENC-011 / 08WO 360899-2045I-34a#NN X. J rIN,'NH1-35II?<= ° 1-35aIrsr-f '1-36 °V^ / N \HO-^T\&1\& I / f-V-NL i[ L N—H333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-36a rNH0F'VN'N (=NL if J. N—N N^^5x^z7Hz >o1-37zv--.^N\\&1 / IN TX MN r^N.L if J. N— / N N^^7H1-37a rNH0\ \V L 'N if L f=NN— / / N N^^7H1-38333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-38a rNN HOy (rx f=NL if L. N—NH1-39HO-5H&1\ \&i / H'A'N |«NL if L. N—N N^^7H1-39a <N'Z'N r=NL if L. N-—H1-40 °V^HO4HS’& IV _ / / \FT NL if L N—N / XN / X / H333961159Attorney Docket No. CENC-011 / 08WO 360899-2045I-40a b v ° J zz7>=o0 1-41 IZZV-“- x\&1&1 / &1> ' Cl[ \ OHOH I 1V L 'N if L N—N N^^7H0 1-42 \AJ&1 / &1[ \OHOHV L 'N if L N—N N^^7H0 I-42a / — / tOHOHV L 'N if J r.=N. N—N^N^^7H1-43333961159Attorney Docket No. CENC-011 / 08WO 360899-2045333961159Attorney Docket No. CENC-011 / 08WO 360899-20450 1-48 CMN-NV^N r^NL if L N—Nt N"'^7H0 1-49 XI^ ) / =z=Zo / izy / 'I \fN-N \ / / 1 OHJ nV"N-Z.L if J. N N x°o— i 1N N"^7H1-50 0 1-51 A N / \ OHT N r^NL if N—N^N"^7H1-52333961159Attorney Docket No. CENC-011 / 08WO 360899-2045I-4awk / -' / O / =A HAANI-4bO / =N" NA"-- H0 1-53\ V>[l_ / )or-1"zN-N'r i£ X / N- H0 1-54V[1_ / or1N-NV r ” i[ L rx N—NH2. Compounds and Related Definitions

[0079] As described generally above, the present invention provides a compound of Formula I:333961159Attorney Docket No. CENC-011 / 08WO 360899-2045Ior a pharmaceutically acceptable salt thereof, wherein the variables are as described above. Definitions

[0080] Compounds of the present invention include those described generally herein, 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 invention, 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: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7thEdition, John Wiley & Sons: 2013; the entire contents of each of which are hereby incorporated by reference.

[0081] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or 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. 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. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0082] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated, or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “spirocyclic” refers to organic compounds that contain at least two rings with 42333961159Attorney Docket No. CENC-011 / 08WO 360899-2045one common atom, generally a quaternary carbon. Generally, the number of carbon atoms linked to the spiro atom in each ring is indicated in ascending order in brackets placed betweenthe spiro prefix and the hydrocarbon name. For example,can be represented as spiro[4.5]decane.

[0083] As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated, or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally, or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:N

[0084] Exemplary bridged bicyclics include:333961159Attorney Docket No. CENC-011 / 08WO 360899-2045H(9 G-GG 9 ©

[0085] The term “lower alkyl” refers to a C1–4straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0086] The term “lower haloalkyl” refers to a C1–4straight or branched alkyl group that is substituted with one or more halogen atoms.

[0087] 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, for example N (as in 3,4-dihydro-2J / -pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0088] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0089] As used herein, the term “bivalent C1–8(or C1–6) saturated or unsaturated, straight or branched, hydrocarbon chain,” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0090] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a 44333961159Attorney Docket No. CENC-011 / 08WO 360899-2045substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0091] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0092] The term “halogen” means F, Cl, Br, or I.

[0093] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or 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 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. 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, or tetrahydronaphthyl, and the like. The term “phenylene” refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, “phenylene” is abivalent phenyl group when it has two groups attached to it (e.g.,^); “phenylene”is a tri valent phenyl group when it has three groups attached to it (e.g.,). The term “arylene” refers to a bivalent aryl group.

[0094] 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 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-,” as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic,45333961159Attorney Docket No. CENC-011 / 08WO 360899-2045or 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, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0095] The term “heteroarylene” refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it. For example, “heteroarylene” is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it. The term “pyridinylene” refers to a multivalent pyridine radical having the appropriate number of open valences to account for groups attached to it. For example, “pyridinylene” is a bivalent pyridineradical when it has two groups attached to it (e.g.,); “pyridinylene” is a trivalentpyridine radical when it has three groups attached toit (e.g.,

[0096] 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 (as in 3,4-dihydro-2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N- substituted pyrrolidinyl).

[0097] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl,333961159Attorney Docket No. CENC-011 / 08WO 360899-2045tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, 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, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “oxo-heterocyclyl” refers to a heterocyclyl substituted by an oxo group. The term “heterocyclylene” refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it.

[0098] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0099] As described herein, compounds of the invention 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 (“optional 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 invention 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.

[0100] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–1R°; –(CH2)0–4OR°; –O(CH2)0–4R°, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted 47333961159Attorney Docket No. CENC-011 / 08WO 360899-2045with R°; -(CH2)O-40(CH2)O-I Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O-4N(R°)2; -(CH2)O-4N(R0)C(0)R°; -N(R°)C(S)R°; -(CH2)O- 4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O-4N(R0)C(0)OR°;N(R°)N(R°)C(O)R°; -N(RO)N(RO)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)o-4C(0)R°; -C(S)R°; -(CH2)O-4C(0)OR°; -(CH2)O-4C(0)SR°; –(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)o^OC(0)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; - C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)O-4SSR°; -(CH2)O-4S(0)2R°; -(CH2)O^S(0)2OR0; -(CH2)O-40S(0)2R°; -S(O)2NRO2; -(CH2)O-4S(0)R°; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2RO; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; SiR°3; –(C1–4straight or branched alkylene)O–N(R°)2; or –(C1–4straight 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, –O(CH2)0–1Ph, –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, and 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, and sulfur, which may be substituted as defined below.

[0101] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o-2OH, -(CH2)o-20R*, -(CH2)o-2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)o-2C(0)R*, -(CH2)o-2C(0)OH, -(CH2)o-2C(O)OR‘, -(CH2)O-2SR*, -(CH2)O-2SH, -(CH2)O-2NH2, -(CH2)O-2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OsiR*3, -C(O)SR* -(Ci-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.48333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0102] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R*2))2-3O- or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and 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, and sulfur.

[0103] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0104] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R’, -NR\ -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NRt2, –C(NH)NRt2, or -N(Rt)S(O)2Rt; wherein each R†is 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, and 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, and sulfur.

[0105] 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 Ci-4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5-6-49333961159Attorney Docket No. CENC-011 / 08WO 360899-2045membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0106] 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 invention include those derived from suitable inorganic and organic acids and bases.

[0107] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson etal., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference.

[0108] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1–4alkyl)4salts.

[0109] 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 invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. 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 invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.50333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0110] Compounds containing one or more stereocenters are a mixture of stereoisomers, unless otherwise stated or described (for example, with use of dashed or wedged bonds denoting stereochemistry). Generally, enhanced stereochemical representation introduces three types of identifiers that can be attached to a stereogenic center. A stereochemical group label is composed from an identifier and a group number. Each stereogenic center marked with wedge bonds belongs to one (and only one) stereochemical group. Grouping allows to specify relative relationships among stereogenic centers.

[0111] ABS denotes a stereogenic center where the absolute configuration is known. As used herein, “or” denotes a stereogenic center where the relative configuration is known, but the absolute configuration is not known. The structure represents one stereoisomer that is either the structure as drawn (R, S) or the epimer in which the stereogenic centers have the opposite configuration (S, R). One of skill in the art would understand that if a single stereogenic center is present, the designation “or” represents a single isomer for which the absolute configuration is not known. As used herein, “orl”, “or2” denote stereogenic centers where the relative configuration is known, but the absolute configuration is not known when applied to a multicenter stereogroup. The designations “and” and “&” are used interchangeably and denote a mixture of stereoisomers. It can be a pair of enantiomers or all the diastereomers.

[0112] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.

[0113] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present invention 51333961159Attorney Docket No. CENC-011 / 08WO 360899-2045can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomers are considered part of this invention.

[0114] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0115] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0116] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10 alkyl, and C1-C6alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2 -methyl- 1 -propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-m ethyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0117] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., cyclohexyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group.

[0118] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “haloalkylene” refers to a bivalent haloalkyl group.

[0119] The term “hydroxy alkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0120] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.52333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0121] The term “carbocyclylene” refers to a multivalent carbocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “carbocyclylene” is a bivalent carbocyclyl group when it has two groups attached to it; “carbocyclylene” is a trivalent carbocyclyl group when it has three groups attached to it.

[0122] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like. The term “hydroxyalkoxyl” refers to an alkoxyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkoxyl groups include -OCH2CH2OH, -OCH2C(H)(OH)CH2CH2OH, and the like. The term “alkoxylene” refers to a bivalent alkoxyl group.

[0123] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0124] The symbol “ ^vw ” indicates a point of attachment. The point of attachment can bedrawn at the end of the bond in a chemical structure, for example,Nor at the center

[0125] When a chemical structure containing a ring is depicted with a substituent having a bond that crosses a ring bond, the substituent may be attached at any available position on the Nring. For example, the chemical structureNencompassesN, andNIn the context of a polycyclic fused ring, when a chemical structure containing a polycyclic fused ring is depicted with one or more substituent(s) having a bond that crosses multiple rings, the one or more substituent(s) may be independently attached to any of the rings crossed by the bond. To illustrate, the chemical structure333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0126] When any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0127] The term “warhead” or “warhead group” as used herein refers to a functional group present on a compound wherein that functional group is capable of reversibly or irreversibly participating in a reaction with a protein. Warheads may, for example, form covalent bonds with the protein. For example, the warhead moiety can be a functional group on an inhibitor that can participate in a bond-forming reaction, wherein a new covalent bond is formed between a portion of the warhead and a donor, for example an amino acid residue of a protein. In some embodiments, the warhead is an electrophile and the “donor” is a nucleophile such as the side chain of a cysteine residue.

[0128] As used herein, the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and, most preferably, includes humans.

[0129] The term “ICso” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target. The potency of an inhibitor is usually defined by its ICso value. The lower the ICso value the greater the potency of the antagonist and the lower the concentration that is required to inhibit the maximum biological response. In certain embodiments, an inhibitor has an ICso and / or binding constant of less than about 100 pM, less than 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.

[0130] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits the target with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner. In some embodiments, the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at54333961159Attorney Docket No. CENC-011 / 08WO 360899-2045least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.

[0131] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change or inhibition in target activity between a sample comprising a compound of the present invention, or composition thereof an equivalent sample comprising target, in the absence of said compound, or composition thereof.

[0132] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.

[0133] As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[0134] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0135] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15thEd., MackPubl. Co., Easton, PA

[1975] ,333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0136] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0137] In addition, when a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (z.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0138] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0139] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.3. Methods of Use

[0140] It has now been found that the compounds and compositions of the disclosure can modulate BTK, JAK1, JAK2, JAK3, or a combination thereof, and are useful in treating associated disorders.

[0141] In one aspect, the present disclosure provides a method of modulating the activity of BTK in vitro or in vivo, comprising contacting BTK with a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the present disclosure provides a method of modulating the activity of BTK in a subject, comprising administering to the subject a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0143] In one aspect, the present disclosure provides a method of modulating the activity of JAK3 in vitro or in vivo, comprising contacting JAK3 with a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.56333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0144] In some embodiments, the present disclosure provides a method of modulating the activity of JAK3 in a subject, comprising administering to the subject a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0145] In one aspect, the present disclosure provides a method of modulating the activity of JAK3 in vitro or in vivo, while not significantly modulating the activity of JAK1 or JAK2, comprising contacting JAK3 with a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the present disclosure provides a method of modulating the activity of JAK3 in a subject, while not significantly modulating the activity of JAK1 or JAK2, comprising administering to the subject a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0147] In one aspect, the present disclosure provides a method of modulating the activity of JAK1 in vitro or in vivo, comprising contacting JAK1 with a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the present disclosure provides a method of modulating the activity of JAK1 in a subject, comprising administering to the subject a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0149] In one aspect, the present disclosure provides a method of modulating the activity of JAK2 in vitro or in vivo, comprising contacting JAK2 with a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the present disclosure provides a method of modulating the activity of JAK2 in a subject, comprising administering to the subject a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0151] In one aspect, the present disclosure provides a method of modulating the activity of BTK and JAK3 in vitro or in vivo, comprising contacting BTK and JAK3 with a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the present disclosure provides a method of modulating the activity of BTK and JAK3 in a subject, comprising administering to the subject a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0153] In one aspect, the present disclosure provides a method of modulating the activity of BTK and JAK3 in vitro or in vivo, while not significantly modulating the activity of JAK1 or JAK2, comprising contacting BTK and JAK3 with a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.57333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0154] In some embodiments, the present disclosure provides a method of modulating the activity of BTK and JAK3 in a subject, while not significantly modulating the activity of JAK1 or JAK2, comprising administering to the subject a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0155] In one aspect, the present disclosure provides a method of treating a BTK, JAK1, JAK2, or JAK3 associated disorder or disease, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0156] In one aspect, the present disclosure provides a method of treating a BTK associated disorder or disease, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0157] In one aspect, the present disclosure provides a method of treating a JAK3 associated disorder or disease, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0158] In one aspect, the present disclosure provides a method of treating a BTK and JAK3 associated disorder or disease, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0159] In one aspect, the present disclosure provides a method of treating a BTK associated disorder or disease, wherein the BTK associated disorder or disease is associated with systemic BTK activity, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the systemic distribution of the compound.

[0160] In one aspect, the present disclosure provides a method of treating a JAK3 associated disorder or disease, wherein the JAK3 associated disorder or disease is associated with systemic JAK3 activity, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the systemic distribution of the compound.

[0161] In one aspect, the present disclosure provides a method of treating a BTK and JAK3 associated disorder or disease, wherein the BTK and JAK3 associated disorder or disease is associated with systemic BTK and JAK3 activity, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically 58333961159Attorney Docket No. CENC-011 / 08WO 360899-2045acceptable salt thereof, wherein the administration results in the systemic distribution of the compound.

[0162] In one aspect, the present disclosure provides a method of treating a BTK associated disorder or disease, wherein the BTK associated disorder or disease is associated with BTK activity in the gastrointestinal tract, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the distribution of the compound in the gastrointestinal tract.

[0163] In one aspect, the present disclosure provides a method of treating a JAK3 associated disorder or disease, wherein the JAK3 associated disorder or disease is associated with JAK3 activity in the gastrointestinal tract, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the distribution of the compound in the gastrointestinal tract.

[0164] In one aspect, the present disclosure provides a method of treating a BTK and JAK3 associated disorder or disease, wherein the BTK and JAK3 associated disorder or disease is associated with BTK and JAK3 activity in the gastrointestinal tract, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the distribution of the compound in the gastrointestinal tract.

[0165] In one aspect, the present disclosure provides a method of treating a BTK associated disorder or disease, wherein the BTK associated disorder or disease is associated with BTK activity in the brain, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the distribution of the compound into the brain.

[0166] In one aspect, the present disclosure provides a method of treating a BTK associated disorder or disease, wherein the JAK3 associated disorder or disease is associated with JAK3 activity in the brain, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the distribution of the compound into the brain.

[0167] In one aspect, the present disclosure provides a method of treating a BTK and JAK3 associated disorder or disease, wherein the BTK and JAK3 associated disorder or disease is associated with BTK and JAK3 activity in the brain, comprising administering to a subject in59333961159Attorney Docket No. CENC-011 / 08WO 360899-2045need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the distribution of the compound into the brain.

[0168] In one aspect, the present disclosure provides a method of treating a BTK associated disorder or disease, wherein the BTK associated disorder or disease is associated with BTK activity in the skin (e.g., dermis and / or epidermis), comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the distribution of the compound into the skin.

[0169] In one aspect, the present disclosure provides a method of treating a BTK associated disorder or disease, wherein the JAK3 associated disorder or disease is associated with JAK3 activity in the skin (e.g., dermis and / or epidermis), comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the distribution of the compound into the skin.

[0170] In one aspect, the present disclosure provides a method of treating a BTK and JAK3 associated disorder or disease, wherein the BTK and JAK3 associated disorder or disease is associated with BTK and JAK3 activity in the skin (e.g., dermis and / or epidermis), comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the administration results in the distribution of the compound into the skin.

[0171] In one aspect, the present disclosure provides a method of treating a BTK, JAK3, or BTK and JAK3 associated disorder or disease, while minimizing any off-target effects associated with inhibition of JAK1 or JAK2, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof.

[0172] In one aspect, the present disclosure provides a method of treating a BTK, JAK1, JAK2, or JAK3 associated disorder or disease, comprising administering to a subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a second agent.

[0173] In one aspect, the present disclosure provides a method of treating a BTK, or JAK3 associated disorder or disease, comprising administering to a subject in need thereof a60333961159Attorney Docket No. CENC-011 / 08WO 360899-2045compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a second agent.

[0174] In one aspect, the present disclosure provides a method of treating a BTK or JAK3 associated disorder or disease, while minimizing any off-target effects associated with inhibition of JAK1 or JAK2, comprising administering to a subject in need thereof a compound or composition thereof disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a second agent.

[0175] In some embodiments, compounds are inhibitors of BTK and are thus useful for treating one or more disorders associated with the activity of BTK. Thus, in some embodiments, the disclosure provides a method of treating a BTK-mediated disorder comprising administering a compound of the disclosure, or a pharmaceutically acceptable composition thereof, to a patient in need thereof.

[0176] In some embodiments, the disclosure provides a method of treating or alleviating the severity of one or more diseases and conditions associated with BTK. In some embodiments, the disease or condition is an autoimmune disease, such as inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, childhood arthritis, diabetes mellitus, Type 1 diabetes, Type 2 diabetes, IgG4 related diseases, Graft versus Host Disease (GVHD), myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Grave's disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, Crohn's disease, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, ocular shin syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hepatitis, autoimmune gastritis, malignant anemia, celiac disease, Goodpasture syndrome, chronic myelogenous leukemia, chronic biliary cirrhosis, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, cold autoimmune hemolytic anemia, granulomatosis with polyangiitis, psoriasis, autonomic dysfunction, glomerulonephritic nephropathy, endometriosis, interstitial cystitis, pemphigus pemphigoid, blister-like pemphigus, neuromuscular plexus, scleroderma, or vulva. In some embodiments, the disease or condition is an hyperproliferative disorder or immunologically mediated disorder, including rejection of the transplanted organ or tissue and acquired immunodeficiency syndrome (AIDS, also known as HIV).

[0177] In some embodiments, the disclosure provides a method of treating or alleviating the severity of one or more diseases and conditions associated with BTK, said disease or 61333961159Attorney Docket No. CENC-011 / 08WO 360899-2045condition being selected from the group consisting of inflammatory diseases such as asthma, appendicitis, atopic dermatitis, asthma, chronic inflammatory bowel disease, colitis, conjunctivitis, Crohn's disease, cystitis, lacrimal gland, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, biliary cirrhosis, bronchitis, bursitis, cervicitis, inflammatory bowel disease, laryngitis, mastitis, meningitis, myelitis, myositis, myositis, myelodysplastic syndromes, gastrointestinal inflammation, gastroenteritis, epididymitis, fasciitis, fibrosis, gastritis, nephritis, osteomyelitis, testicular inflammation, osteitis, diverticulitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, peritonitis, phlebitis, pulmonary enteritis, pneumonia, multiple myositis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvar saliva.

[0178] In some embodiments, the disclosure provides a method of treating or alleviating the severity of one or more diseases and conditions associated with BTK, wherein the disease or condition is selected from cancer. In one embodiment, the cancer is selected from the group consisting of B-cell proliferative disorders such as diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B cell lymphocytic leukemia, (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, lymphoid plasma lymphoma, Waldenstrom macroglobulinemia, peripheral zone lymphoma of the spleen, multiple myeloma leukemia, peripheral lymphoma, or granulomatous lymphoma. In some embodiments, the cancer is cancer of the breast, prostate, or mast cell (eg, mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mastocytosis). In certain embodiments, the cancer is colorectal cancer or pancreatic cancer.

[0179] In some embodiments, the disclosure provides a method of treating a condition selected from the group consisting of rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and lighter disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, food allergies and methods of treating or alleviating the severity of one or more diseases or conditions associated with BTK, including bone and joint diseases.

[0180] In some embodiments, the disclosure provides methods of treating or alleviating the severity of one or more diseases and conditions associated with BTK, including infectious and non-infectious inflammatory events and autoimmune and other inflammatory diseases. Such autoimmune and inflammatory diseases, disorders and syndromes include inflammatory pelvic diseases, urethritis, skin burns, sinusitis, pulmonary enteritis, encephalitis, meningitis,62333961159Attorney Docket No. CENC-011 / 08WO 360899-2045myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, inflammatory bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease (COPD), autoimmune polyclonal disease (also known as autoimmune polyclinic syndrome), autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, Gudd's Passer syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom giant globulinemia, myasthenia gravis, Hashimoto thyroiditis, atopic dermatitis, degenerative joint disease, acute respiratory distress syndrome, and Grave's disease, as well as other diseases, such as, for example, immunosuppressive hypogonadism, Guillain-Barre syndrome, Behcet's disease, and scleroderma.

[0181] In some embodiments, the disclosure provides methods of treating or alleviating the severity of one or more diseases and conditions associated with BTK, including skin diseases. Such skin diseases include hidradenitis suppurativa, cutaneous lupus, chronic spontaneous urticaria, chronic idiopathic urticaria, acne inversa, atopic dermatitis, prurigo nodularis, vitiligo, acne conglobata, and dermatomyositis.

[0182] In some embodiments, compounds are inhibitors of JAK3 and are thus useful for treating one or more disorders associated with the activity ofJAK3. Thus, in some embodiments, the disclosure provides a method of treating a JAK3-mediated disorder comprising administering a compound of the disclosure, or a pharmaceutically acceptable composition thereof, to a patient in need thereof.

[0183] In some embodiments, the disclosure provides a method of treating or alleviating the severity of one or more diseases and conditions associated with JAK3. In some embodiments, the disease or condition comprises an autoimmune disorder, a chronic inflammatory disorder, an acute inflammatory disorder, an autoinflammatory disorder, a fibrosis disorder, a metabolic disorder, a neoplasia, a cardiovascular disorder or a cerebrovascular disorder.

[0184] In some embodiments, the JAK3 mediated disease or disorder is selected from the group consisting of a skin disorder, itch, a hair defect disorder, cancer, neoplasm, Alzheimer’s disease, an inflammatory condition, connective tissue disease, and an autoimmune condition.63333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0185] In certain embodiments, the JAK3 mediated disease or disorder is a neoplasm, malignancy, myeloproliferative disorder, hematopoietic tissue neoplasm, spinal cord neoplasm, lymphoid tissue neoplasm, and myelodysplastic syndrome.

[0186] It should be appreciated that BTK mediated diseases or disorders and JAK3 mediated diseases or disorders are not mutually exclusive. Thus, any and all of the diseases or disorders listed under BTK mediated diseases or disorders and any and all of the diseases or disorders listed under JAK3 mediated diseases or disorders recited herein can be treated by targeting BTK, targeting JAK3, or targeting BTK and JAK3.4. Compositions

[0187] The present disclosure also provides compositions that comprise or deliver a compound as provided herein. In some embodiments, the present disclosure provides compositions comprising a compound provided herein with one or more other components.

[0188] In some embodiments, provided compositions comprise and / or deliver a compound described herein. In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a compound provided herein and further comprises a pharmaceutically acceptable carrier.

[0189] Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more carriers or excipients (e.g., fillers, disintegrants, lubricants, glidants, anti -adherents, and / or anti-statics, etc.). Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and / or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions.

[0190] Provided pharmaceutical compositions can be prepared with any appropriate available technologies.

[0191] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total 64333961159Attorney Docket No. CENC-011 / 08WO 360899-2045single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0192] Provided compositions may be administered in accordance with a dosing regimen (i.e., that includes a single dose or multiple doses separated from one another in time, administered via a particular route of administration) that is (e.g., has been demonstrated to be) effective for treating (e.g., delaying onset of and / or decreasing incidence and / or intensity of) a disease or disorder, for example as described herein.

[0193] The present disclosure also provides methods of preparing pharmaceutical compositions provided herein. In some embodiments, provided methods comprise (i) providing a provided compound or a pharmaceutically acceptable salt thereof; and (ii) formulating the compound with suitable excipients to give a pharmaceutical composition.5. General Methods of Providing the Present Compounds

[0194] The compounds of this invention may be prepared or isolated in general by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.

[0195] In the schemes and chemical reactions depicted in the detailed description, and Examples, where a particular protecting group (“PG”), leaving group (“LG”), or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7thEdition, John Wiley & Sons, 2013, Comprehensive Organic Transformations, R. C. Larock, 3rdEdition, John Wiley & Sons, 2018, and Protective Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014, the entirety of each of which is hereby incorporated herein by reference.

[0196] As used herein, the phrase “leaving group” (LG) includes, but is not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.65333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0197] As used herein, the phrase “oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include 66 yridin, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, tri ethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxy carbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyl oxy methyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-di chlorobenzyl, p -cyanobenzyl, and 2- and 4-picolyl.

[0198] Amino protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyl oxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, di chloroacetyl, tri chloroacetyl, phenyl acetyl, trifluoroacetyl, benzoyl, and the like.66333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0199] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See, for example, March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith, and J. March, 7thEdition, John Wiley & Sons, 2013, Comprehensive Organic Transformations, R. C. Larock, 3rdEdition, John Wiley & Sons, 2018, the entirety of each of which is incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below.

[0200] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. Such groups and transformations are described in detail in March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7thEdition, John Wiley & Sons, 2013, Comprehensive Organic Transformations, R. C. Larock, 3rdEdition, John Wiley & Sons, 2018, and Protective Groups in Organic Synthesis, P. G. M. Wuts, 5thedition, John Wiley & Sons, 2014, the entirety of each of which is hereby incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below in the Exemplification.EXEMPLIFICATION

[0201] As depicted in the Examples below, exemplary compounds are prepared according to the following general procedures and used in biological assays and other procedures described generally herein. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein. Similarly, assays and other analyses can be adapted according to the knowledge of one of ordinary skilled in the art.67333961159Attorney Docket No. CENC-011 / 08WO 360899-2045Example 1: Synthesis of CompoundsGeneral synthetic schemes

[0202] The compounds of Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and transformations that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared by routine methods known in the art, such as those methods disclosed in standard reference books. Preferred methods include, but are not limited to, those described below.

[0203] During any of the following synthetic sequences it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.

[0204] Compounds of Formula I, or their pharmaceutically acceptable salts, can be prepared according to the reaction Schemes discussed herein below. Unless otherwise indicated, the substituents in the Schemes are defined as above. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.

[0205] It will be understood by one skilled in the art that the various symbols, superscripts and subscripts used in the schemes, methods and examples are used for convenience of representation and / or to reflect the order in which they are introduced in the schemes and are not intended to necessarily correspond to the symbols, superscripts or subscripts in the appended claims. Additionally, one skilled in the art will recognize that in many cases, these compounds will be mixtures and enantiomers that may be separated at various stages of the synthetic schemes using conventional techniques, such as, but not limited to, crystallization, normal phase chromatography, reversed phase chromatography and chiral chromatography, to afford single enantiomers. The schemes are representative of methods useful in synthesizing the compounds of the present invention. They are not to constrain the scope of the invention in any way.Scheme 168333961159Attorney Docket No. CENC-011 / 08WO 360899-2045-R2Ia, R2= PgIb, R2= H( Ic, R2= C(O)CH=CH2

[0206] Scheme 1 illustrates a method for preparing compounds of Formula I (la, lb, and Ic). A compound of Formula B, in which X is a displaceable leaving group (such as bromide, iodide, methanesulfonate, or p-toluenesulfonate, for example) is treated with a compound of Formula A (in which atom Ai may be carbon or nitrogen) to furnish a product of Formula la. The displaceable leaving group X may also be part of an epoxide ring. The reaction is typically carried out in the presence of a suitable base for effecting the reaction class generally known as bimolecular nucleophilic substitution, such as cesium carbonate or potassium carbonate in a solvent or solvent mixture, such as THF or N, N-dimethylformamide. The compounds of Formulas A and B may be obtained from commercial vendors, or prepared by methods reported in the chemical literature, or as described within this specification. The substituent Ri may be an appropriately substituted amine, or it may be a halide such as chloride, that is subsequently converted into an appropriately substituted amine. The substituent R2 is typically a removable amine protecting group (“Pg”) known in the art, with the tertbutoxycarbonyl group (“Boc”) being particularly suitable. Further transformations are performed on the compound of Formula la as shown in the scheme. For example, the removable amine protecting group (“Pg”) is removed to afford a compound of Formula lb, in which the substituent Riis H. Subsequently, acylation of the compound of Formula lb with acrylic acid or an acrylic acid derivative, for example acryloyl chloride, affords a compound of Formula Ic. It will be appreciated by one skilled in the art that various further substituents may be included in, introduced to, or further transformed upon the compounds of Formulas A, B, la, lb, and Ic. Further, one skilled in the art will recognize the potential for the formation and isolation of diastereomers and enantiomers depending on the relative configurations of the various bonds.Scheme 269333961159Attorney Docket No. CENC-011 / 08WO 360899-2045R2 / — <^hrR2AI-NH r-N \ )1Ri < la, R2= Pgz lb, R2= H< Ic, R2= C(O)CH=CH2

[0207] Scheme 2 illustrates another method for preparing compounds of Formula I (la, lb, and Ic), in which the substituents Ai, Ri, R2 are as previously defined. A compound of Formula A is treated with a compound of Formula B to furnish a product of Formula la. The reaction is typically carried out in the presence of a suitable reagent or reagent mixture for effecting the reaction class generally known as Mitsunobu reactions, in a reaction compatible solvent or solvent mixture, such as toluene, THF orN, N-dimethylformamide. Further transformations are performed on the compound of Formula la as shown in the scheme and as previously described to provide a compound of Formula Ic. It will be appreciated by one skilled in the art that various further substituents may be included in, introduced to, or further transformed upon the compounds of Formulas A, B, la, lb, and Ic. Further, one skilled in the art will recognize the potential for the formation and isolation of diastereomers and enantiomers depending on the relative configurations of the various bonds.Scheme 3

[0208] Scheme 3 illustrates another method for preparing compounds of Formula I (la, lb, and Ic), in which the substituents Ri and R2 are as previously defined. The substituents X and X2 are halide substituents, typically bromide or iodide. A compound of Formula A is treated with a compound of Formula B to furnish a product of Formula la. The reaction is typically carried out in the presence of suitable reagents for effecting the reaction class generally known as nickel-catalyzed cross-electrophile coupling reactions, in a reaction compatible solvent or solvent mixture, such as N, N-dimethylacetamide. Further transformations are performed on the compound of Formula la as shown in the scheme and as previously described to provide a 70333961159Attorney Docket No. CENC-011 / 08WO 360899-2045compound of Formula Ic. It will be appreciated by one skilled in the art that various further substituents may be included in, introduced to, or further transformed upon the compounds of Formulas A, B, la, lb, and Ic. Further, one skilled in the art will recognize the potential for the formation and isolation of diastereomers and enantiomers depending on the relative configurations of the various bonds.Scheme 4

[0209] Scheme 4 illustrates another method for preparing compounds of Formula I (la, lb, and Ic), in which the substituents Ri and R2 are as previously defined. The substituents X and X2 are non-identical halide substituents. Typically, X will be bromide or iodide, as these halides readily undergo oxidative addition by palladium, while typically X2 will be chloride or fluoride, as these halides readily undergo nucleophilic aromatic substitution. A compound of Formula A is treated with a compound of Formula B to furnish a product of Formula Ila. The reaction is typically carried out in the presence of suitable reagents, typically bases such as triethylamine or potassium carbonate, for example, for effecting the reaction class generally known as nucleophilic aromatic substitution, in a reaction compatible solvent or solvent mixture, such as THF or ethanol. The compound of Formula Ila is then converted to a compound of Formula lib by treatment with a suitable terminal alkyne of the formula HC(triplebond)CR3, which has a carbon or silicon substituent R3 using reagents known to effect the reaction class known as the Sonogashira reaction, frequently mixtures containing a palladium phosphine complex, copper(I) iodide, and a tertiary amine such as tri ethylamine. The compound of Formula lib is then converted to a compound of Formula la by treatment with reagents known to affect the pericyclic ring cyclization reaction to close the five - membered ring, with one such reagent 71333961159Attorney Docket No. CENC-011 / 08WO 360899-2045being tetra-n-butylammonium fluoride. Further transformations are performed on the compound of Formula la as shown in the scheme and as previously described to provide a compound of Formula Ic. It will be appreciated by one skilled in the art that various further substituents may be included in, introduced to, or further transformed upon the compounds of Formulas A, B, Ila, lib, la, lb, and Ic. Further, one skilled in the art will recognize the potential for the formation and isolation of diastereomers and enantiomers depending on the relative configurations of the various bonds.Experimental Procedures and Working Examples

[0210] The following procedures illustrate the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art.

[0211] It will be understood that the intermediate compounds of the invention depicted above are not limited to the particular enantiomer shown but also include all stereoisomers and mixtures thereof.Experimental Procedures

[0212] Experiments were carried out with continuous stirring under inert atmosphere (nitrogen or argon). Commercial solvents and reagents were generally used without further purification, including anhydrous solvents where appropriate. Unless noted otherwise, all reactants were obtained commercially. All concentrations were conducted under reduced pressure using techniques well known to one skilled in the art. Solvent mixtures used for chromatography are expressed as volume ratios; for example, petroleum ether / ethyl acetate (3:1) means three volumes of petroleum ether were mixed with one volume of ethyl acetate to prepare the eluting solvent. Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing.

[0213] Mass spectrometry data is reported from either liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI) or gas chromatography-mass spectrometry (GCMS) instrumentation. Nuclear magnetic resonance (NMR) data were recorded on Bruker 300 MHz or 400 MHz instruments internally referenced to a tetramethylsilane (TMS) signal. Chemical shifts (5) and coupling constants (J) are expressed in parts per million and hertz, respectively.72333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0214] Methods used for LCMS include the following:Method-A: Column: ZORBAX SB-Aq, 4.6*50 mm, 1.8 um, Mobile Phase: A: Water / 0.05% TFA; B: Acetonitrile / 0.05% TFA, Flow Rate: 1.5 mL / min. Temperature: 40 C, Gradient program (B%): 0.01 / 5, 2.00 / 95, 2.80 / 95, 2.81 / 5.Method-B: Column: SB-Aq 4.6*50 mm 1.8 um, Mobile Phase A: Water / 0.02% formic acid; Mobile Phase B: Acetonitrile / 0.02% formic acid, Flow Rate: 1.50 mL / min. Temperature: 40 C, Gradient program (B%): 0.00 / 5.0, 2.00 / 95.0, 2.90 / 95.0, 2.91 / 5.0.Method-C: Column: YMC-Triart C18, 3.0*50 mm, 3um, Mobile Phase: A: Water / 0.05% ammonia; B: Acetonitrile, Flow Rate: 1.2 mL / min. Temperature: 40 C, Gradient program (B%): 0.01 / 5, 2.00 / 95, 2.80 / 95, 2.81 / 5.Method-D: Column: SB-Aq 4.6*50mm 1.8um, Mobile Phase: A: Water / 0.05% TFA; B: Acetonitrile, Flow Rate: 1.5 mL / min. Temperature: 40 C, Gradient program (B%): 0.00 / 5, 2.00 / 95, 2.70 / 95, 2.71 / 5.Method-E: Column: L-column3 C18, 3.0*30 mm, 3um, Mobile Phase: A: Water / 0.05% ammonium bicarbonate; B: Acetonitrile, Flow Rate: 1.5 mL / min. Temperature: 40 C, Gradient program (B%): 0.01 / 5, 2.00 / 95, 2.80 / 95, 2.81 / 5.Method-F: Column: HPH-C18, 3.0*50 mm, 2.7 um, Mobile Phase: A: Water / 0.05% ammonia; B: Acetonitrile, Flow Rate: 1.2 mL / min. Temperature: 40 C, Gradient program (B%): 0.01 / 5, 2.00 / 95, 2.80 / 95, 2.81 / 5.Method-G: Column: L-column3 C18 3.0*30mm 3um, Mobile Phase: A: 5 mM ammonium bicarbonate in water; B: Acetonitrile, Flow Rate: 1.2 mL / min. Temperature: 40 C, Gradient program (B%): 0.00 / 10.0, 0.30 / 40, 1.80 / 70, 2.20 / 95, 2.90 / 95, 2.91 / 10.Method-H: Column: SB-Aq 4.6*50 mm 1.8 um, Mobile Phase: A: Water / 0.05% TFA; B: Acetonitrile, Flow Rate: 1.5 mL / min. Temperature: 40 C, Gradient program (B%): 0.00 / 5, 0.40 / 40, 3.20 / 70, 4.10 / 95, 4.80 / 95, 4.81 / 5.

[0215] Methods used for supercritical fluid chromatography include the following:Method-A: Column: (R, R)-WHELK-01 4.6*50mm 3.5um; Co-Solvent: MeOH / DCM (1 / 1, containing 20 mM NH₃); Gradient (B): 10% to 50% in 2 min, hold 1 min at 50%. Flow rate: 3.0 ml / min; Column Temperature: 35 C.Method-B: Column: CHIRALPAK IH-3, 3.0*50mm, 3um; Co-Solvent: MeOH / DCM (1 / 1, containing 20 mM NH3); Gradient (B): 10% to 50% in 2.0 min, hold 1.0 min at 50%. Flow rate: 3.0 ml / min; Column Temperature: 35 C.73333961159Attorney Docket No. CENC-011 / 08WO 360899-2045Method-C: Column: CHIRALPAK IG-U, 50*3.0mm, 1.6um; Co-Solvent: MeOH / DCM=1 / 1 (20 mM NH₃); Gradient (B): 10% to 50% in 2.0 min, hold 1.0 min at 50%. Flow rate: 3.0 ml / min; Column Temperature: 35 C.Method-D: Column: CHIRALPAK IA-3 4.6*100mm 3.0um; Co-Solvent: MeOH (containing 10 mM NH3); Start Conc. of Pump B: 10.0%. Flow rate: 3.0 ml / min; Column Temperature: 50 C.Method-V: Column: Amylose-C Neo 4.6*100mm 3.0um; Co-Solvent: EtOH (containing 20mM NH3); Gradient (B): 2.50 / 50, 3.70 / 50, 3.71 / 10; Flow rate: 3.0 ml / min; Column Temperature: 50 C.

[0216] Methods used for chiral stationary phase HPLC include the following:Method-A: CHIRALPAK IF-3, 4.6*50mm, 3um IF30CB-CP002; Mobile Phase: A: n-Hexane / DCM (5 / 1); Mobile Phase B: 2-Propanol (containing 0.1% diethylamine); Conc. of Pump B: 30.0%; Flow rate: 1.0 ml / min; Column Temperature: 25 C.Method-B: Column: CHIRALPAK IH-3, 4.6* 100mm, 3um IH30CC-BT002; Mobile Phase A: n-Hexane / THF (4 / 1), Mobile Phase B: MeOH, Conc. of Pump B: 2.0%; Flow rate: 1.0 ml / min; Oven Temperature: 25 C.Method-C: Column: CHIRALPAK IH-3, 4.6*50mm, 3um 30CC-WH004; Mobile Phase A: n-Hexane / THF (4 / 1), Mobile Phase B: MeOH (containing 0.5% formic acid), Conc. of Pump B: 5.0%; Flow rate: 1.0 ml / min; Oven Temperature: 25 C.Method-D: Column: (R, R)-WHELK-O1 4.6*100mm, 3.5um 71749; Mobile Phase A: n-Hexane / DCM (3 / 1), Mobile Phase B: EtOH (containing 0.1% diethylamine), Conc. of Pump B: 20.0%; Flow rate: 1.0 ml / min; Oven Temperature: 25 C.

[0217] For syntheses referencing procedures in other Examples or Methods, reaction conditions (length of reaction and temperature) may vary. In general, reactions were followed by thin layer chromatography and / or liquid chromatography-mass spectrometry and subjected to work-up when appropriate. It will be recognized by one skilled in the art that purifications may vary between experiments: in general, sorbents, solvents and the solvent ratios used for eluants / gradients were chosen to provide appropriate Rfs or retention times. It will also be recognized by one skilled in the art that HPLC purifications may be effected in a variety of ways, including the use of normal stationary phases, reverse stationary phases, chiral stationary phases, and supercritical eluants. The appropriate choices of conditions for chromatographic and HPLC purifications will be discerned by one skilled in the art.74333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0218] The following Preparations describe the preparation of certain intermediates used in the Methods and Examples that follow. The following Preparations, Methods and Examples are intended to illustrate particular embodiments of the invention and preparations thereto and are not intended to limit the specification, including the claims, in any manner.AbbreviationsUnless indicated otherwise, the following abbreviations have the indicated meanings:°C degrees CelsiusAPCI atmospheric pressure chemical ionizationbr. broad peaksd doublet peakdd double doublet peakdt double triplet peakEquiv. equivalents to limiting reagentg gram(s)h hour(s)H (e.g., 1 H, 2 H) hydrogen(s)L liter(s)LC liquid chromatographym multipletM molar, molaritymg milligram(s)MHz megahertzmin minute(s)mL milliliter(s)mmol millimole(s)Mol mole(s)mp melting pointMS mass spectrumNMR nuclear magnetic resonancenm nanometerspH negative logarithm of hydronium ion concentrationprep preparativepsi pounds per square inchq quartet peakRT retention times singlet peakSFC supercritical fluid chromatographyt triplet peaktd triple doublet peakTLC thin layer chromatographyv / v volume to volume ratioμL microliter75333961159Attorney Docket No. CENC-011 / 08WO 360899-2045The following chemical formulas and abbreviations represent the indicated meanings: Boc tert-(butoxy)carbonylBrine saturated solution of sodium chloride in waterBz BenzoylCaCl₂ calcium chlorideCs₂CO₃ cesium carbonateCMBP (tributylphosphoranylidene)acetonitrile, CAS 157141-27-0 DCM dichloromethaneDIEA N,N-diisopropylethylamineDMA N,N-dimethylacetamideDMF N,N-dimethylformamideDMSO dimethylsulfoxideTHF tetrahydrofuranEt3N triethylamineEtOAc ethyl acetateEtOH ethanolHCl hydrogen chlorideHPLC high performance liquid chromatographyK3PO4 potassium triphosphateLiHMDS lithium hexamethyldisilazidem-CPBA meta-chloroperbenzoic acidMeCN acetonitrileMeI iodomethaneMeOH methanolNa2SO3sodium sulfiteMsCl methanesulfonyl chlorideMTBE methyl tert-butyl etherNa2SO4sodium sulfate anhydrousNaBH₄ sodium borohydrideNaH sodium hydride, typically containing 40% mineral oil by weight NaHCO₃ sodium bicarbonate, typically a saturated aqueous solution Nal sodium iodideLiOH lithium hydroxiden-BuOH 1-butanolNH₄Cl ammonium chlorideNH4OH ammonium hydroxide, a solution of ammonia in water Pd(OAc)2palladium (II) acetatePPh3triphenylphosphineSEMCl 2-(trimethylsilyl)ethoxymethyl chlorideTBS tert-butyldimethyl silylSEM 2-(trimethylsilyl)ethoxymethylSFC supercritical fluid chromatographyTBAF tetra-n-butylammonium fluorideTFA trifluoroacetic acid76333961159Attorney Docket No. CENC-011 / 08WO 360899-2045l-[bis(dimethylamino)methylene]-U / -l,2,3-triazolo[4,5-Z>]pyridinium 3- HATUoxide hexafluorophosphate, CAS 148893-10-1NH4HCO3 ammonium bicarbonatePd(PPh3)4tetrakis(triphenylphosphine)palladium(0)Preparations

[0219] Preparation 1: Synthesis of N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (A-1)N-NHA-l

[0220] To a mixture of 6-chloro-U / -pyrazolo[3,4-d] pyrimidine (200 g, 1.30 mol) and 1-methylpyrazol-4-amine (189 g, 1.94 mol, 1.50 equiv.) in w-BuOH (3.00 L) was added 4 MHC1 solution in 1,4-dioxane (520 mL) slowly at about 25 °C. The mixture was then heated to 120 °C and stirred for about 1 h. The resulting precipitate was filtered and dissolved in MTBE (3 L). The mixture was neutralized to about pH 7 to 8 with saturated aqueous NaHCCh. The MTBE phase was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by trituration with a mixture of petroleum ether and ethyl acetate (5 / 1, v / v). The solid matter was filtered and dried under reduced pressure to provide the title compound A-l (209 g, 75% yield).¹H NMR (300 MHz, DMSO-d₆): 5 13.16 (s, 1H), 9.59 (s, 1H), 8.91 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 3.83 (s, 3H).LCMS: Calculated for C21H27N7O2: 215.1; Observed: 216.1 [M+H]+.

[0221] Preparation 2: Synthesis of N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (B-1)B-l

[0222] To a stirred solution of 2-chloro-7J / -pyrrolo[2,3- ]pyrimidine (CAS 335654-06-3, 1.2 kg, 7.81 mol) and l-methylpyrazol-4-amine (0.83 kg, 8.60 mol, 1.10 equiv.) in n-BuOH 77333961159Attorney Docket No. CENC-011 / 08WO 360899-2045(15 L) was added HC1 (12 M, 1.04 L, 12.5 mol, 1.60 equiv.). The mixture was then heated to about 100 °C and heating was continued for about 48 h. After cooling to about 25 °C, the mixture was diluted with water and adjusted to about pH 8 with K3PO4 solution. The precipitate was filtered and dried, then purified by trituration with petroleum ether (5 L).to afford the title compound B-l (1.28 kg, 76% yield).

[0223] ¹H NMR (400 MHz, DMSO-d₆): 5 11.35 (s, 1H), 9.00 (s, 1H), 8.60 (s, 1H), 7.92(s, 1H), 7.50 (s, 1H), 7.09 (m, 1H), 6.34 (d, J= 2.0 Hz, 1H), 3.80 (s, 3H).LCMS Calculated for CioHioNe: 214.1; Observed: 215.1 [M+H]+.

[0224] Preparation 3: Synthesis of 7-bromo-N-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (C1-A)BrCl-A

[0225] A mixture of 7-bromo-2-chloropyrrolo[2,l- / |[l,2,4]triazine (5.00 g, 21.5 mmol), CS2CO3 (21 g, 64.5 mmol, 3.00 equiv.) and l-methylpyrazol-4-amine (3.1 g, 32.2 mmol, 1.50 equiv.) in DMF (100 mL) was stirred at about 25 °C overnight. The reaction was diluted with 500 mL of ice water and extracted with ethyl acetate (3 x 100 mL). The combined EtOAc extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by reversed-phase flash chromatography on Cl 8 silica gel eluting with a gradient of MeCN in water (containing 0.1% v / v concentrated NH4OH), using a 10% to 50% gradient of MeCN in 10 min. to provide the title compound Cl-A (2.40 g, 38% yield).

[0226] ’H NMR (300 MHz, DMSO-tL): 59.59 (s, 1H), 8.84 (s, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 6.95 - 6.81 (m, 2H), 3.85 (s, 3H).LCMS Calculated for C₁₀H₉BrN₆: 292.1 (79Br isotope); Observed: 293.2 [M+H]+, (79Br isotope).

[0227] Preparation 4: Synthesis of 7-bromo-N-(1-methyl-1H-pyrazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (C1-B)78333961159Attorney Docket No. CENC-011 / 08WO 360899-2045BrSEMCl-B

[0228] Sodium hydride (60% in oil, 4.37 g, 0.11 mol, 1.6 equiv.) was added to a solution of compound Cl-A (20.0 g, 68.2 mmol) in DMF (300 mL) at about 0 °C. After about 30 min., 2-(trimethylsilyl)ethoxymethyl chloride (11.9 g, 71.6 mmol, 1.05 equiv.) was added and the mixture was allowed to warm to about 10 °C and stirred for about 1 h. The reaction mixture was poured into 1.5 L of water and extracted with EtOAc (5 x 200 mL). The combined EtOAc extracts were washed with brine (3 x 300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (3:1) to afford the title compound Cl-B (26.0 g, 90% yield).

[0229] ¹H NMR (300 MHz, DMSO-d₆): 58.93 (s, 1H), 8.01 (s, 1H), 7.70 (s, 1H), 6.99 (d, J = 4.8 Hz, 1H), 6.94 (d, J = 4.8 Hz, 1H), 5.42 (s, 2H), 3.85 (s, 3H), 3.61 (d, J = 8.1 Hz 2H), 0.90 (d, J = 8.1 Hz, 2H), -0.08 (s, 9H).LCMS Calculated for C₁₆H₂₃BrN₆OSi: 422.1 (79Br isotope); Observed: 423.1 [M+H]+(79Br isotope).1-23rac-1-((3aR,5S,7aS)-5-(6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)octahydro-2H-isoindol-2-yl)prop-2-en-1-one

[0230] Step 1: tert-butyl 5-(methanesulfonyloxy)-octahydroisoindole-2-carboxylate (A3-A3-2

[0231] A mixture of tert-butyl 5-hydroxy-octahydroisoindole-2-carboxylate (CAS 203661-67-0, 500 mg, 2.07 mmol, 1.00 equiv.) and EtsN (629 mg, 6.21 mmol, 3.00 equiv.) in THF (10 mL) was treated with MsCl (338 mg, 3.10 mmol, 1.50 equiv.) dropwise at about 0 °C. Once the addition was complete, the mixture was kept at about 25 °C for about 1 h, then diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with water (30 mL), dried (Na2SO4), filtered and concentrated to afford the title compound A3-2 (500 mg) which was used without further purification.79333961159Attorney Docket No. CENC-011 / 08WO 360899-2045LCMS Calculated for C14H25NO5S: 319.2; Observed: 320.2 [M+H]+.

[0232] Step 2. tert-butyl 5-{6-[(l-methylpyrazol-4-yl)amino]pyrazolo[3,4-d]pyrimidin-l-yl}-octahydroisoindole-2-carboxylate (A3-3)

[0233] To a solution of compound A-l (500 mg, 2.32 mmol, 1.00 equiv.) and compound A3-2 (890 mg, 2.78 mmol, 1.20 equiv.) in DMF (15.0 mL) was added CS2CO3 (1.51 g, 4.64 mmol, 2.00 equiv.). The reaction mixture was heated at about 100 °C overnight before being cooled to about 25 °C and subsequently diluted with water (50 mL). After extraction with EtOAc (3 x 30 mL), the combined EtOAc extracts were washed with water (50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford a product that was purified further by preparative HPLC with the following conditions (Column: XSelect CSH -C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 35mL / min mL / min; Gradient: isocratic 38%-85% 9min; Wavelength: 254nm / 220nm nm; RTl(min): 8.3) to afford the title compound A3-3 (110 mg, 11% yield). LCMS Calculated for C22H30N8O2: 438.3; Observed: 439.3 [M+H]+.

[0234] Step 3: l-methyl-N-[l-(octahydro-lH-isoindol-5-yl)pyrazolo[3,4-d]pyrimidin-6-yl]pyrazol-4-amine (A3-4)

[0235] A solution of compound A3-3 (100 mg, 0.22 mmol, 1.00 equiv.) in DCM (0.5 mL) and HC1 (4.0 M in 1,4-dioxane, 0.5 mL, 2.0 mmol, 9.1 equiv.) was stirred at about 250C for 80333961159Attorney Docket No. CENC-011 / 08WO 360899-2045about 1 h, then was concentrated to dryness to give the title product A3-4 hydrochloride (70 mg) which was used without further purification.LCMS Calculated for C17H22N8: 338.2; Observed: 339.2 [M+H]+.

[0236] Step 4. rac'-l-((3a / ,5 7aA')-5-(6-((l-rnethyl-IT / -pyrazol-4-yl)arnino)-l7 / -pyrazolo[3,4- t ]pyrimidin- 1 -yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one (1-23)

[0237] To a stirred mixture of compound A3-4 (70 mg, 0.20 mmol, 1.00 equiv.) and DIEA (134 mg, 1.03 mmol, 5.00 equiv.) in DMA (3.0 mL) was added acryloyl chloride (19 mg, 0.20 mmol, 1.00 equiv.) at about 0 °C. The reaction was subsequently quenched with MeOH (0.5 mL) after warming to about 25 °C. The product was isolated by prep-HPLC with the following conditions (Column: Ultimate - XB-C18 Column, 30*150 mm, 10pm; Mobile Phase A: Water(0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 90 mL / min; Gradient: isocratic 10%-50% llmin; Wavelength: 254nm / 220nm; RT l(min): 10.5) to afford the title product I-23 1 -(5 - { 6- [( 1 -methylpyrazol-4-yl)amino]pyrazolo[3,4-d]pyrimidin- 1 -yl } -octahy droi so-indol-2-yl)prop-2-en-l-one (40 mg, 49% yield).

[0238] ¹H NMR (300 MHz, DMSO-d₆) 59.81 (s, 1H), 8.90 (s, 1H), 8.18 - 7.96 (m, 2H), 7.56 (s, 1H), 6.79 - 6.51 (m, 1H), 6.28 - 6.06 (m, 1H), 5.84 - 5.56 (m, 1H), 4.87 (s, 1H), 3.87 (d, J= 8.7 Hz, 3H), 3.76 (d, J= 9.1 Hz, 1H), 3.71 - 3.59 (m, 1H), 3.53 - 3.45 (m, 1H), 3.40 (d, J= 4.5 Hz, 1H), 2.77 - 2.59 (m, 1H), 2.38 - 1.78 (m, 6H), 1.55 (s, 1H).

[0239] LCMS Calculated for C20H24N8O: 392.21; Observed: 393.4 [M+H]+.Purity (Method-B): 99.59% atRT 1.454 min.1-4rac-l-((3a7?,57?,7a5)-5-(6-((l-methyl-U / -pyrazol-4-yl)amino)-U / -pyrazolo[3,4- ]pyrimidin- 1 -yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one81333961159Attorney Docket No. CENC-011 / 08WO 360899-2045Step 1: rac-tert-butyl (3aR,5R,7aS)-5-(6-((l-methyl-lH-pyrazol-4-yl)amino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)octahydro-2H-isoindole-2-carboxylate (A3-1)A3-1

[0240] Amixture of compound E31 (570 mg, 1.81 mmol, 1.00 equiv.), compound Al (391 mg, 1.81 mmol, 1.00 equiv.), and CS2CO3 (1.18 g, 3.63 mmol, 2.00 equiv.) was prepared at about 25 °C then heated at about 80 °C for about 8 h. After cooling to about 25 °C, water (10 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were washed with brine (1 x 50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to afford the title compound A3-1 (330 mg, 41% yield).LCMS Calculated for C22H30N8O2: 438.3; Observed: 439.3 [M+H]+.

[0241] Step 2. rac-N-(l-methyl-lH-pyrazol-4-yl)-l-((3aR,5R,7aS)-octahydro-lH-isoindol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-6-amine (A3-2)HA3-2

[0242] A solution of compound A3-1 (330 mg, 0.753 mmol, 1.00 equiv.) in DCM (20 mL) was treated with HC1 (4.0 M in 1,4-dioxane, 0.75 mL, 4.00 equiv.) at about 0 °C for about 3 h, then brought to about 25 °C and concentrated to afford the title compound A3-2 hydrochloride (80 mg), which was used without further purification.LCMS Calculated for C17H22N8: 338.2; Observed: 339.2 [M+H]+.82333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0243] Step 3. racM-((3a / ,5A>,7ari)-5-(6-((l-methyl-l / / -pyrazol-4-yl)arnino)-l / / -pyrazolo[3,4- t / ]pyri midi n- 1 -yl )octahydro-2 / / -i soindol -2-yl )prop-2-en- 1 -one (1-4)1-4

[0244] A solution of compound A3-2 hydrochloride (80 mg, 0.24 mmol, 1.00 equiv.) and EtsN (71.7 mg, 0.71 mmol, 3.00 equiv.) in DCM (10 mL) was treated with acryloyl chloride (21 mg, 0.24 mmol, 1.00 equiv.) at about 25 C°. The resulting mixture was stirred at about 25 C° for about 30 min, then water (1 mL) was added, and the mixture was extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were washed with brine (1 x 20 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by prep-HPLC with the following conditions (Column: Xbridge -C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (containing 0.05% NH4OH), Mobile Phase B: MeCN; Flow rate: 35 mL / min mL / min; Gradient (B%): isocratic 15%-35% 10 min; wavelength: 254 nm / 220 nm; RT l(min): 10) to afford the title product 1-4 rac-l-((3a7?,5A,7a5)-5-(6-((l-methyl-U / -pyrazol-4-yl)amino)-UT-pyrazolo[3,4- ]pyrimidin-l-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-on (13 mg, 14% yield).

[0245] 1H NMR (300 MHz, DMSO-t / e) 58.79 (d, J= 2.7 Hz, 1H), 7.89 (d, J= 4.9 Hz, 1H), 7.80 (d, J= 7.1 Hz, 1H), 7.71 (d, J= 7.2 Hz, 1H), 7.29 (d, J = 2.5 Hz, 2H), 6.53 - 6.34 (m, 2H), 5.71 (d, J= 10.8 Hz, 1H), 4.66 (s, 1H), 3.96 (d, J = 3.6Hz, 3H), 3.77- 3.56 (m, 4H), 2.51 (s, 1H), 2.05 - 1.96 (m, 6H).

[0246] LCMS Calculated for C20H24N8O: 392.2; Observed: 393.1 [M+H]+.Purity (Method-A): 99.0% at RT 0.808 min.1-53 and 1-54rel-l-((3aR,5R,7aS)-5-(6-((l-methyl-lH-pyrazol-4-yl)amino)-lH-pyrazolo[3,4-d]pyrimidin- 1 -yl)octahydro-2H-isoindol-2-yl)prop-2-en- 1 -one rel-l-((3aS,5S,7aR)-5-(6-((l-methyl-lH-pyrazol-4-yl)amino)-lH-pyrazolo[3,4-d]pyrimidin- 1 -yl)octahydro-2H-isoindol-2-yl)prop-2-en- 1 -oneStep 1: Separation of compound 1-53 by preparative chiral HPLC83333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-53 1-54

[0247] Compound 1-4 rac-l-((3aR,5R,7aS)-5-(6-((l-methyl-lH-pyrazol-4-yl)amino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)octahydro-2H-isoindol-2-yl)prop-2-en-l-one (6.0 g, 15.3 mmol, 1.00 equiv) was separated by SFC, eluted with Column: XA-CHIRALPAK IK, 3*25cm 5um; Mobile Phase A: CO2, Mobile Phase B: absolute methanol: dichloromethane =2: l(0.1%MSA); Flow rate: 80 mL / min; Gradient (B%): isocratic 50% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 10.51; RT2(min): 17.74; Sample Solvent: absolute methanol: dichloromethane =1: 1; Injection Volume: 1 mL to afford fraction pKl, pK2. Adjust the pH to 8-9 respectively using 4M ammonia-methanol solution and concentrated in vacuum to give the 2 desired crude product. The crude product was diluted with water (50 mL) and extracted with DCM (50 mLx3). The combined organic phase was washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford rel-l-[(3aR,5R,7aS)-5-{6-[(l-methylpyrazol-4-yl)amino]pyrazolo[3,4-d]pyrimidin-l-yl}-octahydroisoindol-2-yl]prop-2-en-1-one (1-53) (1.0 g, 16.6%yield, 98.6%purity) as a yellow solid. The same procedure was used to afford rel-l-[(3aS,5S,7aR)-5-{6-[(l-methylpyrazol-4-yl)amino]pyrazolo[3,4-d]pyrimidin-l-yl}-octahydroisoindol-2-yl]prop-2-en-l-one (1-54) (1.0 g, 16.67%yield, 99.2%purity) as a yellow solid.Data for 1-53

[0248] ’H NMR (300 MHz, CDCh): 5 8.79 (s, 1H), 7.95 - 7.87 (m, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.71 (d, J= 6.7 Hz, 1H), 7.31 - 7.25 (m, 1H), 6.58 - 6.34 (m, 2H), 5.76 - 5.63 (m, 1H), 4.71 - 4.61 (m, 1H), 3.99 - 3.92 (m, 3H), 3.84 - 3.41 (m, 4H), 2.70 - 2.41 (m, 2H), 2.28 - 2.08 (m, 2H), 2.08 - 1.93 (m, 4H).

[0249] LCMS Calculated for C20H24N8O: 392.2; Observed: 393.1 [M+H]+.Chiral purity (Method-A): 100% at RT 2.43 min.Data for 1-54333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0250] XH NMR (300 MHz, CDCh): 5 8.79 (s, 1H), 7.94 - 7.87 (m, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.71 (d, J= 6.9 Hz, 1H), 7.36 - 7.31 (m, 1H), 6.57 - 6.36 (m, 2H), 5.76 - 5.63 (m, 1H), 4.71 - 4.61 (m, 1H), 3.99 - 3.92 (m, 3H), 3.83 - 3.40 (m, 4H), 2.69 - 2.41 (m, 2H), 2.28 - 2.07 (m, 2H), 2.06 - 1.92 (m, 4H).

[0251] LCMS Calculated for C20H24N8O: 392.2; Observed: 393.2 [M+H]+.Chiral purity (Method-A): 99.95% at RT 2.60 min.1-6rac- 1 -((3 a7?,5A,7a5)-5-(2-(( 1 -methyl- U / -pyrazol-4-yl)amino)pyrrolo[2, 1 -f\ [ 1,2,4]triazin-7- yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-oneStep 1. rac-tert-butyl (3aR,7aS)-5-iodooctahydro-2H-isoindole-2-carboxylate (E42)f J N-BocE42

[0252] A mixture of rac-tert-butyl (3aR,7aS)-5-hydroxyoctahydro-2H-isoindole-2-carboxylate (CAS 318502-89-5, 600 mg, 2.48 mmol, 1.00 equiv.), PPI13 (1.30 g, 4.97 mmol, 2.00 equiv.), imidazole (508 mg, 7.45 mmol, 3.00 equiv.) and iodine (947 mg, 3.72 mmol, 1.50 equiv.) in toluene (10 mL) was heated at about 110 °C for about 2 h, then cooled to about 25 °C and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (5: 1) to afford the title compound E42 (300 mg, 34% yield). LCMS Calculated for C13H22INO2: 351.1; Observed: 352.2 [M+H]+.

[0253] Step 2. rac-tert-butyl (3aR,5R,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (C4-2A) & rac-tert-butyl (3aR,5S,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (C4-2B)

[0254] A solution of compound E42 (233 mg, 0.66 mmol, 1.50 equiv.), nickel(II) chloride (115 mg, 0.88 mmol, 2.00 equiv.) and pyridine-2-carboximidamide hydrochloride (CAS 85333961159Attorney Docket No. CENC-011 / 08WO 360899-204551285-26-8, 70 mg, 0.44 mmol, 1.00 equiv.) in DMA (6.0 mL) was heated at about 40 °C for about 4 h. After cooling to about 25 °C, zinc (87 mg, 1.32 mmol, 3.00 equiv.) and compound Cl-A (130 mg, 0.44 mmol, 1.00 equiv.) were added and the mixture was heated at about 40 °C overnight. After cooling to about 25 °C, the mixture was purified by reversed phase flash chromatography under the following conditions (Column, Cl 8 silica gel; mobile phase, MeCN in water (containing 0.1% NH4OH), 30% to 70% gradient in 12 min; detector, 254 nm. This provided the compound C4-2A rac-tert-butyl (3aR,5R,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (45 mg, 23%yield) and the compound C4-2B rac-tert-butyl (3aR,5S,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2, l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (55 mg, 28% yield).LCMS Calculated for C23H31N7O2: 437.3; Observed: 438.4 [M+H]+.

[0255] Step 3. Rac-N-(l-methyl-lH-pyrazol-4-yl)-7-((3aR,5R,7aS)-octahydro-lH-isoindol-5-yl)pyrrolo[2,l-f][l,2,4]triazin-2-amine (C4-3A)C4-3A

[0256] A solution of compound C4-2A (45 mg, 0.10 mmol, 1.00 equiv.) in DCM (2.0 mL) was treated with HC1 (4.0 M in 1,4-dioxane, 2.00 mL, 8.0 mmol) at about 25 °C. After about 2 h, the mixture was concentrated to provide the title compound hydrochloride C4-3A (25 mg), which was used without further purification.LCMS Calculated for C18H23N7: 337.2; Observed: 338.3 [M+H]+.

[0257] Step 4. Rac-l-((3aR,5R,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f] [ 1,2,4]triazin-7-yl)octahy dro-2H-i soindol -2-yl)prop-2-en- 1 -one (1-6)86333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-6

[0258] Compound C4-3A (25 mg, 0.07 mmol, 1.00 equiv.) and DIEA (48 mg, 0.37 mmol, 5.00 equiv.) were dissolved in DMA (3.0 mL) at about 25 °C and cooled to about 0 °C. Acryloyl chloride (6 mg, 0.06 mmol, 0.90 equiv.) was added and stirring at about 0 °C was continued for about 30 min. After dilution with MeOH, the mixture was purified by reversed phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (containing 0.1% NH4OH), 10% to 65% gradient in 13 min; detector, 254 nm to provide the title product 1-6 Rac-l-((3aR,5R,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2, 1 -f] [ 1,2,4]triazin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en- 1 -one (5 mg, 17% yield).1-5Rac-l-((3aR,5S,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7- yl)octahy dro-2H-i soindol-2-yl)prop-2-en- 1 -oneStep 1. rac-N-(l-methyl-lH-pyrazol-4-yl)-7-((3aR,5S,7aS)-octahydro-lH-isoindol-5-yl)pyrrolo[2, 1 -f] [ 1,2,4]triazin-2-amine (C4-3B)

[0259] Compound C4-2B (45 mg, 0.10 mmol, 1.00 equiv.) was dissolved in HC1 (4 M in 1,4-dioxane, 2.0 mL) and DCM (2.0 mL) at about 25 °C and the reaction mixture was stirred for about 2 h, then concentrated to give the title compound C4-3B hydrochloride (25 mg), which was used without further purification.87333961159Attorney Docket No. CENC-011 / 08WO 360899-2045LCMS Calculated for C18H23N7: 337.2; Observed: 338.2 [M+H]+.

[0260] Step 2. rac-l-((3a7?,55,7aS)-5-(2-((l-methyl-l / 7-pyrazol-4-yl)amino)pyrrolo[2,l-f\ [ 1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one (1-5)1-5

[0261] Compound C4-3B (25.0 mg, 0.074 mmol, 1.00 equiv.) andDIEA (48 mg, 0.37 mmol, 5.00 equiv.) were dissolved in DMA (4.0 mL) and the mixture was cooled to about 0 °C, after which acryloyl chloride (6 mg, 0.07 mmol, 0.900 equiv.) was added. The reaction mixture was kept at about 0 °C for about 30 min, then MeOH was added and the mixture was purified by reversed-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, MeCN in water (containing 0.1% NH4OH), 15% to 65% gradient in 12 min; detector, UV 254 nm) to give the title product 1-5 rac-l-((3aR,5S,7aS)-5-(2-((l- methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindol-2- yl)prop-2-en-l-one (5 mg, 17% yield).

[0262] ¹H NMR (300 MHz, DMSO-d₆) 59.32 - 9.23 (m, 1H), 8.78 (s, 1H), 7.94 - 7.81 (m, 1H), 7.61 - 7.41 (m, 1H), 6.80 - 6.52 (m, 3H), 6.17 - 6.05 (m, 1H)„ 5.68 (dt, J= 10.0, 2.7 Hz, 1H), 3.97 - 3.83 (m, 3H), 3.82 - 3.37 (m, 5H), 2.74 - 2.56 (m, 1H), 2.35 - 2.13 (m, 2H), 2.07 - 1.93 (m, 1H), 1.86 - 1.35 (m, 4H).

[0263] LCMS Calculated for C21H25N7O: 391.2; Observed (Method A): 392.4 [M+H]+. Purity (Method A): 99.72% at RT 1.676 min.1-31-19Rel-l-( 3aR, 5R, 7aS)-5-(2-( ( 1 -methyl- lH-pyrazol-4-yl)amino)pyrrolo[ 2, l-f][ 1, 2, 4 Jtriazin- 7- yl)octahydro-2H-isoindol-2-yl)prop-2-en-l-one rel-\- l-((3aS,5S,7aR)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7- yl)octahy dro-2H-i soindol-2-yl)prop-2-en- 1 -one88333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0264] Step 1. Separation of compound 1-6 by preparative chiral HPLC1-3 1-19

[0265] Compound 1-6 rac-l-((3aR,5R,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2, 1 -f] [ 1,2,4]triazin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en- 1 -one (11 mg) was separated by preparative chiral HPLC under the following conditions (Instrument: Shimadzu LC-20AD; Column: Chiralpak IH30CC-WH004, 50*4.6mm, 3um; Mobile Phase: A: hexane / DCM (3 / 1), B: ethanol (containing 0.1% N-isopropylmethylamine); Flow Rate: 1.0000 mL / min; Conc. of Pump B: 5.0%; Temperature: 25 °C) to afford the title products 1-3 rel- l-((3aR, 5R,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l, 2, 4]tri azin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en-l-one (2.6 mg, 36% yield) and 1-19 rel-\-((3 aS, 5 S,7aR)-5-(2-(( 1 -methyl- 1 / / -pyrazol -4-yl )ami no)pyrrol o[2, 1 -f\ [ 1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (3.5 mg, 36% yield).

[0266] Data for 1-3:

[0267] XH NMR (300 MHz, DMSO-t / e): 5 9.28 (s, 1H), 8.75 (s, 1H), 7.85 (d, J= 2.3 Hz, 1H), 7.52 (d, J= 2.3 Hz, 1H), 6.71 (d, J= 4.5 Hz, 1H), 6.66 - 6.47 (m, 2H), 6.17 - 6.05 (m, 1H), 5.63 (ddd, J= 9.99, 7.2, 2.5 Hz, 1H), 3.82 (s, 3H), 3.68 - 3.36 (m, 4H), 3.23 - 3.09 (m, 1H), 2.62 - 2.50 (m, 1H), 2.43 - 2.34 (m, 1H), 2.02 - 1.85 (m, 4H), 1.62 - 1.51 (m, 1H), 1.44 - 1.26 (m, 1H).

[0268] LCMS Calculated for C21H25N7O: 391.2; Observed: 392.3 [M+H]+.

[0269] Achiral purity (Method A): 99.43% at RT 1.652 min.

[0270] Chiral purity (Method-A): 100% at RT 2.319 min.

[0271] Data for 1-19:

[0272] ’H NMR (300 MHz, DMSO-t / e): 5 9.27 (s, 1H), 8.76 (s, 1H), 7.85 (d, J= 2.3 Hz, 1H), 7.52 (d, J= 2.3 Hz, 1H), 6.71 (d, J= 4.6 Hz, 1H), 6.65 - 6.47 (m, 2H), 6.17 - 6.05 (m, 1H), 5.63 (ddd, J= 9.99, 7.2, 2.5 Hz, 1H), 3.82 (s, 3H), 3.69 - 3.41 (m, 3H), 3.37 (t, J= 5.3333961159Attorney Docket No. CENC-011 / 08WO 360899-2045Hz, 1H), 3.23 - 3.09 (m, 1H), 2.66 - 2.53 (m, 1H), 2.44 - 2.30 (m, 1H), 2.03 - 1.85 (m, 4H), 1.66 - 1.46 (m, 1H), 1.44 - 1.23 (m, 1H).

[0273] LCMS Calculated for C20H25N7O: 391.2; Observed: 392.4 [M+H]+.

[0274] Achiral purity (Method A): 99.66% at RT 1.653 min.

[0275] Chiral purity (Method-A): 99.75% at RT 2.958 min.1-21-27re / -l-((3a7?,5A,7a5)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- ]pyrimidin-7- yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one re / -l-((3aS,5S,7aR)-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7- yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one

[0276] Step 1. Chiral Separation of 1-8 by preparative chiral HPLC1-27

[0277] Compound 1-8 rac-l-((3aR,5R,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en-l-one was separated by prep-chiral SFC under the following conditions (Column: Cellulose-SB 100*4.6mm 3.0 um; Mobile Phase A: CO2, Mobile Phase B: MeOH / DCM containing 20mM NH3; Flow rate: 3 mL / min; Gradient: isocratic 10.0% B; Column Temperature 35 °C; Back Pressure (bar): 15; Wavelength: 254 nm; RT l(min): 2; RT 2(min): 2.2; Sample injection solvent: MeOH; Injection volume: 8 mL) to afford the title products 1-2 re / -l-((3a7?,5A,7a5)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (53 mg, 27% yield) and 1-27 re / -l-((3aS,5S,7aR)-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (102 mg, 51% yield).

[0278] Data for 1-2:90333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0279] XH NMR (300 MHz, CDCh) 58.57 (s, 1H), 7.76 (d, J= 4.0 Hz, 1H), 7.69 (s, 1H), 7.03 (s, 1H), 6.94 (d, J= 3.5 Hz, 1H), 6.52 - 6.35 (m, 3H), 5.77 - 5.64 (m, 1H), 4.58 (s, 1H), 3.91 (d, J= 2.0 Hz, 3H), 3.74 - 3.56 (m, 3H), 3.42 (d, J= 10.2 Hz, 1H), 2.52 (s, 2H), 2.12 -1.66 (m, 6H).

[0280] LCMS Calculated for C21H25N7O: 391.2; Observed: 392.2 [M+H] +.

[0281] Achiral purity (Method-A): 92.6 % at RT 1.212 min.

[0282] Chiral purity (Method-D): 100% at RT 2.046 min.Data for 1-27:

[0283] 1H NMR (300 MHz, CDCh) 58.57 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 4.1 Hz, 1H), 7.68 (s, 1H), 7.02 (s, 1H), 6.95 (s, 1H), 6.53 - 6.36 (m, 3H), 5.77 - 5.64 (m, 1H), 4.57 (s, 1H), 3.91 (d, J= 1.9 Hz, 3H), 3.72 - 3.55 (m, 3H), 3.42 (d, J= 10.1 Hz, 1H), 2.53 (d, J= 11.5 Hz, 2H), 2.01 (s, 3H), 1.84 (s, 2H), 1.74 - 1.62 (m, 1H).

[0284] LCMS Calculated for C21H25N7O: 391.2; Observed: 392.2 [M+H]+.

[0285] Achiral purity (Method-A): 93.3 % atRT 1.213 min.

[0286] Chiral purity (Method-D): 99.3% atRT 2.293 min.1-331 -((3a7?,4A, 5S, 7a5)-4-hydroxy-5-(2-((l -methyl- U / -pyrazol-4-yl)amino)pyrrolo[2, 1 - f\ [ 1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one l-((3aS',4S,57?,7aZ?)-4-hydroxy-5-(2-((l-methyl-l / / -pyrazol-4-yl)amino)pyrrolo[2,l- f\ [ 1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one

[0287] Step 1. Separation of 1-7 by preparative chiral HPLC

[0288] 1-7 rac-l-[(3aS,4S,5R,7aR)-4-hydroxy-5-{2-[(l-methylpyrazol-4-yl)amino]pyrrolo-[2, 1 -f] [ 1,2,4]triazin-7-yl } -octahydroisoindol-2-yl]prop-2-en- 1 -one (3.0 g)333961159Attorney Docket No. CENC-011 / 08WO 360899-2045was separated by chiral-SFC under the following conditions (Column: CHIRALPAK IF-3 50x3. Omm 3.0pm Co Solvent: MeOH / DCM (2:1) containing NFb) to afford 1-1 1- ((3a7?,4A,55,7a5)-4-hydroxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)pyrrolo-[2,l- / |[l,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (885 mg, 42% yield) and I- 33 l-((3a5,45,5A,7a7?)-4-hydroxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)pyrrolo-[2,l- / |[l,2,4]triazin-7-yl)octahydro-2Z7-isoindol-2-yl)prop-2-en-l-one (970 mg, 45% yield).

[0289] Data for 1-1:

[0290] 1H NMR (300 MHz, DMSO-d6) δ 9.19 (d, J= 2.5 Hz, 1H), 8.73 (s, 1H), 7.87 (d, J = 5.1 Hz, 1H), 7.55 (d, J= 7.3 Hz, 1H), 6.73 (d, J= 4.6 Hz, 1H), 6.69 - 6.51 (m, 2H), 6.23 - 6.06 (m, 1H), 5.73 - 5.58 (m, 1H), 4.91 - 4.77 (m, 1H), 3.95 - 3.71 (m, 4H), 3.68 - 3.44 (m, 3H), 3.29 - 3.16 (m, 2H), 2.69 - 2.56 (s, 1H), 2.24 - 2.04 (m, 1H), 1.99 - 1.72 (m, 3H), 1.69 - 1.49 (m, 1H).

[0291] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.3 [M+H] +.

[0292] Purity (Method-A): 98.7% at RT 0.679 min.

[0293] Chiral purity (Method-A): 99.3% at RT 2.68 min.

[0294] Optical rotation: [aD] = -47.8°, C = 0.094, MeOH

[0295] Data for 1-33:

[0296] 1H NMR (300 MHz, DMSO-d6) δ 9.19 (d, J= 2.5 Hz, 1H), 8.73 (s, 1H), 7.87 (d, J = 5.1 Hz, 1H), 7.55 (d, J= 7.3 Hz, 1H), 6.73 (d, J= 4.6 Hz, 1H), 6.69 - 6.51 (m, 2H), 6.23 - 6.06 (m, 1H), 5.73 - 5.58 (m, 1H), 4.91 - 4.77 (m, 1H), 3.95 - 3.71 (m, 4H), 3.68 - 3.44 (m, 3H), 3.29 - 3.16 (m, 2H), 2.69 - 2.56 (s, 1H), 2.24 - 2.04 (m, 1H), 1.99 - 1.72 (m, 3H), 1.69 - 1.49 (m, 1H).

[0297] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.3 [M+H]+.

[0298] Purity (Method-A): 99.2% at RT 1.096 min.

[0299] Chiral purity (Method-A): 100% at RT 2.090 min.

[0300] Optical rotation: [aD] = +40.7°, C = 0.094, MeOHAlternate synthesis (i) of 1-33

[0301] Compound 1-33 was also synthesized according to the scheme shown below. Intermediate C2-3 was reacted with acryloyl chloride to convert to intermediate 1-7 which was then separated by preparative chiral HPLC to afford 1-33 and 1-1.92333961159Attorney Docket No. CENC-011 / 08WO 360899-2045PhSO3HAlternate synthesis (ii) of 1-33

[0302] Compound 1-33 was also synthesized according to the scheme shown below.20 % NICI2DME 5 equiv. Zn DMA, 1h, rt 30.4 %yield1) 3:1 TFA / water, DCM, 20°C 2) HCI, EtOAc, rt, 12 h 94.7% yieldLarge scale synthesis of 1-3393333961159Attorney Docket No. CENC-011 / 08WO 360899-2045 NaH, SEMCI, DMF O°C~rt, 2 h H SEMPhN(Tf)2_ LiHMDS PPh3, Pd(OAc)2THF, -78°C, 2 h TfCT ^i'"7TEA, FA, THF E23-2 m-CPBA DCME23-3Br NiCl2.DME, ligand, Zn DMAC0~25°C, 1 h THF, H2OI-3394333961159Attorney Docket No. CENC-011 / 08WO 360899-2045SEMCl-B

[0303] N-{7-bromopyrrolo[2,l-f] [1,2,4] triazin-2-yl}-l-methylpyrazol-4-amine (1.90 kg, 1.0 equiv) and DMF (19.0 L) were combined in a 50 L reactor at 20 ± 5°C. Agitation of the reaction mixture was initiated. 60% NaH (520.5 g, 2.0 equiv) was added in portions at 0°C and stirred for 1 h. SEMC1 (1.30 kg, 1.2 equiv) was added dropwise at 0°C. The inner temperature was allowed to warm up to rt and stirred for an additional 2 h. The mixture was added to ice water 38.0 L (20 V) dropwise at 0 ± 5 °C. MTBE / EA (1:1, 10.0 L) was added and the mixture was separated. The aqueous phase was extracted with MTBE / EA (1:1, 6.0 L). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by silica gel column chromatography, eluted with PE / EA (15-30%) to afford the title product Cl-B N-{7-bromopyrrolo[2,l-f][l,2,4]triazin-2-yl}-l-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-amine (2.10 kg, 76.5% yield) as light brown oil.LCMS-PDM-CLL-SPC-2025-01-13: (ES, m / z): 423 [M+H]+I I N-BocE23-2

[0304] Rac-tert-butyl (3aR,7aS)-5-oxo-hexahydro-lH-isoindole-2-carboxylate (2.0 kg, 1.0 equiv) and THF (14.0 L) were combined into a 50 L reactor at 20 ± 5°C. Agitation of the reaction mixture was initiated. IMLiHMDS (12.50 L, 1.5 equiv) was added dropwise at -78°C. The mixture was stirred for 2 h at -78°C. A solution of 1,1,1 -trifhioro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (3.58 kg, 1.2 equiv) in THF (6.0 L) was added dropwise. The inner temperature was allowed to warm up to rt. The temperature was cooled to -10 ± 5°C. The mixture was quenched with saturated aqueous ammonium chloride(10.0 L). The aqueous phase was extracted with EA (10.0 L). The organic phases were combined and concentrated to remove solvent. The residue was diluted with EA (10.0 L) and washed with brine (10.0 L). This operation was repeated 3 times. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to afford the crude title product E23-2 rac-tert-butyl (3aR,7aR)-5-(trifluoromethanesulfonyloxy)- 95333961159Attorney Docket No. CENC-011 / 08WO 360899-2045l,3,3a,6,7,7a-hexahydroisoindole-2-carboxylate (13.30 kg, crude product) as a brown oil which was used in next step without purification. GCMS-PDM-CLL-SPC-2025-01-5: (ES, m / z): 316 [M-56]+.| I N-BocE23-3

[0305] Rac-tert-butyl (3aR,7aR)-5-(tri fluoromethanesulfonyloxy)- 1,3, 3 a, 6, 7, 7a-hexahydroisoindole-2-carboxylate (4.50 kg, 1.0 equiv) and THF (45.0 L) were combined into a 100 L reactor at 20 ± 5°C. Agitation of the reaction mixture was initiated. PPhs (320.0 g, 0.10 equiv) and Pd(OAc)2 (266.7 g, 0.10 equiv) were added at rt, followed by triethylamine (2.76 kg, 2.25 equiv) and formic acid (1.23 kg, 2.2 equiv) dropwise at rt. The reaction mixture was purged with N2. The inner temperature was warmed up to 60°C, stirring for 2 h, then cooled to rt. The residue was filtered and the filter cake was washed with EA (9.0 L). The filtrate was concentrated to remove solvent. The resulting residue was diluted with EA (22.0 L) and washed with brine (22.0 L). This operation was repeated 2 times. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by silica gel column chromatography, eluted with PE / EA (0-20%) to afford the title product E23-3 rac-tert-butyl (3aR,7aS)-l,3,3a,6,7,7a-hexahydroisoindole-2-carboxylate (7.0 kg, 81.3% yield) as a yellow oil. GCMS-PDM-CLL-SPC-2025-01-6: (ES, m / z): 167 [M-56]+.E23 mixture

[0306] E23-3 (3.50 kg, 1.0 equiv) and DCM (35.0 L) were combined into a 100 L reactor at 20 ± 5°C. Agitation of the reaction mixture was initiated. m-CPBA (4.77 kg, 1.5 equiv, 85 wt%) was added in portions at 0°C. The inner temperature was allowed to warm up to rt, stirring for 16 h, then cooled down to 0°C. The mixture was added to saturated aqueous NaiSCh (10.0 L) dropwise at 5 ± 5°C. The aqueous phase was extracted with DCM (10.0 L). The organic phase was washed with saturated NaHCOs (10.0 L) and brine (10.0 L). This operation was repeated. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by silica gel column chromatography, eluted with PE / EA (15-30%) to afford the title product E23 mixture (6.50 kg, 87.9% yield) as a brown oil. GCMS-PDM-CLL-SPC-2025-01-7: (ES, m / z): 239 [M]+.96333961159Attorney Docket No. CENC-011 / 08WO 360899-2045OHE24

[0307] E23 mixture (3.50 kg, 1.0 equiv) and MeCN (35.0 L) were combined into a 50 L reactor at 20 ± 5°C. Agitation of the reaction mixture was initiated. Nal (6.58 kg, 3.0 equiv) and Cerium (III) chloride heptahydrate (6.54 kg, 1.20 equiv) were added in portions at 0°C. The inner temperature was allowed to warm up to rt, stirring for 1 h, then cooled down to 0°C. The residue was filtered and the filter cake was washed with ACN (3.30 L). The organic phases were combined and concentrated to remove solvent. The residue was diluted with EA (8.25 L) and washed with H2O (8.25 L). This operation was repeated one time. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by silica gel column chromatography, eluted with THF / EA (15-20% ) to afford the title product E24 rac-tert-butyl (3aR,4R,5R,7aS)-4-hydroxy-5-iodooctahydro-2H-isoindole-2-carboxylate (3.0 kg, 33.5% yield) as an off-white solid. LCMS-PDM-CLL-SPC-2025-01-8: (ES, m / z): 353 [M-56+MeCN]+.OHF2

[0308] Rac-tert-butyl (3aR,4R,5R,7aS)-4-hydroxy-5-iodooctahydro-2H-isoindole-2-carboxylate (3.0 kg, 1.0 equiv, 95%) was purified by SFC using the following conditions: Column: XA-CHIRALPAK AY-H, 5*25cm lOum; Mobile Phase A: CO2, Mobile Phase B: IPA: ACN=1: 1; Flow rate: 170 mL / min; Gradient (B%) 40% B; Column Temperature (°C): 35; Back Pressure (bar): 100; Wave Length: 220 nm; RTl(min): 2.6; RT2(min): 3.8; Sample Solvent: IPA: ACN=1: 1; Injection Volume: 19.80 mL to afford the title product F2 tert-butyl (3aS,4S,5S,7aR)-4-hydroxy-5-iodooctahydro-2H-isoindole-2-carboxylate (1.15 kg, 40.3% yield) as a yellow oil.97333961159Attorney Docket No. CENC-011 / 08WO 360899-2045F3

[0309] Into a 2 L reactor were added N-{7-bromopyrrolo[2,l-f][l,2,4]triazin-2-yl}-l-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}pyrazol-4-amine (100.0 g, 1.0 equiv), tert-butyl (3aS,4S,5S,7aR)-4-hydroxy-5-iodooctahydro-2H-isoindole-2-carboxylate (86.75 g, 1.0 equiv), Ligand (pyridine-2-carboximidamide hydrochloride) (14.9 g, 0.4 equiv) and NiCl2(DME) (10.4 g, 0.2 equiv) at 25°C. The reaction mixture was purged with Nitrogen. DMAc (1.0 L) was added to the reactor and the reactor was again purged with nitrogen. Zn (77.21 g, 5.0 equiv) was added to the solution and the reactor was again purged with nitrogen. The resulting solution was stirred for Ih at 25°C. The reaction was quenched by the addition of saturated ammonium chloride (1.0 L) at 0°C. Ethyl acetate (1.0 L) was added to the reaction mixture and the resulting mixture was filtered over diatomite, the filter cake was then washed with ethyl acetate (2 x 500 mL). The filtrate was separated and the aqueous layer was extracted with Ethyl acetate (1.0 L). The organic phases were combined and concentrated under reduced pressure. This operation was repeated 10 times. The residue was purified by silica gel column chromatography, eluted with THF / PE (30-45%) to afford the title product F3 tert-butyl (3aS,4S,5R,7aR)-4-hydroxy-5-(2-((l-methyl-lH-pyrazol-4-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (483.0 g, 30.4% yield) as a yellow oil. LCMS-PDM-CLL-SPC-2025-01-10: (ES, m / z): 584 [M+H]+.

[0310] tert-butyl (3aS,4S,5R,7aR)-4-hydroxy-5-(2-((l-methyl-lH-pyrazol-4-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (20.0 g, 1.0 equiv) and dichloromethane (40.0 mL) were combined in a reactor at 20 ± 5°C. Agitation of the reaction mixture was initiated. Trifluoroacetic acid (58.59 g, 15.0 equiv) and water (3.09 g, 5.0 equiv) were added in portions at rt. The inner temperature of the reaction mixture was allowed to warm up to rt, stirring for 18 h. The reaction was concentrated under vacuum to afford (3aR,4R,5S,7aS)-5-{2-[(l-methylpyrazol-4-yl) amino] pyrrolo[2,l-f] [1,2,4] triazin-7-yl}-octahydro-lH-isoindol-4-ol (20.0 g, TFA salt,98333961159Attorney Docket No. CENC-011 / 08WO 360899-2045crude). Crude (3aR,4R,5S,7aS)-5-{2-[(l-methylpyrazol-4-yl) amino] pyrrolo[2,l-f] [1,2,4] triazin-7-yl}-octahydro-lH-isoindol-4-ol (TFA salt) and ethyl acetate (200.0 mL) were combined into a reactor at 20 ± 5°C. Agitation of the reaction mixture was initiated. HC1 (4 M in EA, 40.0 mL) was added in portions at rt and stirred for 12 h. The reaction was concentrated under vacuum to afford crude product. This operation was repeated 23 times. The crude product was slurried with MTBE to afford the title product F4 (3aS,4S,5R,7aR)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-lH-isoindol-4-ol (277.0 g, 94.7% yield) (HC1 salt) as a light brown solid. LCMS-PDM-CLL-SPC-2025-01-11: (ES, m / z): 354 [M+H]+.1-33

[0311] (3aR,4R,5S,7aS)-5-{2-[(l-methylpyrazol-4-yl)amino]pyrrolo[2,l-f][l,2,4]triazin-7-yl}-octahydro-lH-isoindol-4-ol (HC1 salt) (20.0 g, 1.0 equiv), THF (120.0 mL) and H2O (120.0 mL) into reactor at 20 ± 5°C, start agitation. CS2CO3 (83.57 g, 5.0 equiv) was added in portions at 0°C. Acryloyl chloride (6.96 g, 1.5 equiv) was added in portions at 0°C. The inner temperature of the reaction mixture was allowed to warm up to rt, stirring for 2 h. This operation was repeated 13 times. The reaction mixtures were combined with brine (1.5 L) and the phases were separated. The aqueous phase was extracted with tetrahydrofuran (2 x 1.40 L). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and purified by silica gel column chromatography, eluted with MeOH / DCM (0~6%), then freezing to afford the title product 1-33 1-((3aS,4S,5R,7aR)-4-hydroxy-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en-l-one (155.0 g, 53.5% yield) as a yellow solid. LCMS-PDM-CLL-SPC-2025-01-0: (ES, m / z): 408 [M+H]+.1-17rac-l-((3a7?,55',6A,7a5)-5-fluoro-6-(2-((l-methyl-17 / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one99333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0312] Step 1. tert-butyl (3aS,5S,6S,7aR)-5-hydroxy-6-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B4-1)B4-1

[0313] A solution of rac-tert-butyl (laR,2aR,5aS,6aS)-octahydro-4ELoxireno[2,3-f]isoindole-4-carboxylate (CAS 2640571-95-3, 500 mg, 2.09 mmol, 1.00 equiv.) and compound Bl (537 mg, 2.51 mmol, 1.20 equiv.) in DMSO (5.0 mL) was treated with NaH (60%, 167 mg, 4.2 mmol, 2.0 equiv.), added in portions at about 25 °C. The mixture was then heated at about 120 °C overnight. After cooling to about 25 °C, water (50 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined EtOAc extracts were washed with brine (1 x 30 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc to afford the title compound B4-1 (270 mg, 28%). LCMS Calculated for C23H31N7O3: 453.3; Observed: 454.3 [M+H]+.

[0314] Step 2. rac-tert-butyl (3aR,5S,6R,7aS)-5-fluoro-6-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B4-2)

[0315] A solution of compound B4-1 (270 mg, 0.60 mmol, 1.00 equiv.) in DCM (5.0 mL) was treated with (diethylaminosulfur)trifluoride (CAS 38078-09-0, 384 mg, 2.38 mmol, 4.00 equiv.) at about -78 °C for about 2 h. The reaction was subsequently allowed to warm to about 25 °C and quenched with NaHCOs at that temperature. After phase separation and further extraction with DCM (3 x 10 mL), the combined DCM extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by prep-TLC eluting with petroleum ether / tetrahydrofuran (3:1) to afford the title compound B4-2 (60 mg, 22% yield).100333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0316] LCMS Calculated for C23H30FN7O2: 455.2; Observed: 456.3 [M+H]+.

[0317] Step 3. rac-7-((3aR,5S,6R,7aS)-6-fluorooctahydro-lH-isoindol-5-yl)-N-(l-methyl-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (B4-3)

[0318] A solution of compound B4-2 (60.0 mg, 0.13 mmol, 1.00 equiv.) and benzenesulfonic acid (25 mg, 0.16 mmol, 1.20 equiv.) in DCM (1.0 mL) was stirred at about 40 °C for about 2 h. After completion of reaction, the resulting mixture was concentrated to afford the title compound B4-3 containing residual benzenesulfonic acid (58 mg). The compound was used in the next step directly without further purification.LCMS Calculated for C18H22FN7: 355.2; Observed: 356.2 [M+H]+.

[0319] Step 4. rac-l-((3a7?,55,6A,7a5)-5-fluoro-6-(2-((l-methyl-lJ / -pyrazol-4-yl)amino)- 7J / -pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (1-17)1-17

[0320] A solution of the compound B4-3 prepared above (58.0 mg, 0.13 mmol, 1.00 equiv.) in DCM (1.0 mL) was treated with DIEA (63 mg, 0.49 mmol, 3.00 equiv.) at about 25 °C for about 10 min. After cooling to about 0 °C, acryloyl chloride (10 mg, 0.11 mmol, 0.70 equiv.) was added, then the mixture was brough to about 25 °C for about 15 min, then concentrated. The residue was dissolved in DMF (0.5 mL). The product was isolated by prep-HPLC with the following conditions (Column: XBridge Prep RP C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 35 mL / min;101333961159Attorney Docket No. CENC-011 / 08WO 360899-2045Gradient: isocratic 38%-68% 12min; Wavelength: 254nm / 220nm; RTl(min): 6) to afford the title product 1-17 rac-l-((3a7?, 5S,6R, 7a5)-5-fluoro-6-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7 / / -pyrrolo[2,3-t / ]pyrimidin-7-yl)octahydro-2 / / -isoindol-2-yl)prop-2-en-l-one (4 mg, 6% yield).

[0321] 'H NMR (400 MHz, DMSO-t / e) 5 9.20 (s, 1H), 8.62 (s, 1H), 7.93 (s, 1H), 7.52 (s, 1H), 7.30 - 7.22 (m, 1H), 6.65 - 6.52 (m, 1H), 6.38 (d, J= 3.7 Hz, 1H), 6.17 - 5.97 (m, 2H), 5.72 - 5.62 (m, 1H), 5.18-5.00 (m, 1H), 4.93 - 4.76 (m, 1H), 3.84 - 3.69 (m, 3H), 3.69 - 3.61 (m, 1H), 3.57 - 3.41 (m, 2H), 2.74 - 2.54 (m, 2H), 2.35 - 2.02 (m, 3H), 1.89 - 1.76 (m, 1H).

[0322] LCMS Calculated for C21H24F4N7O: 409.2; Observed: 410.2 [M+H]+.

[0323] Purity (Method-A): 96.66% at RT 0.829 min.1-7rac- 1 -((3a5, 45, 5A,7a7?)-4-hydroxy-5-(2-((l -methyl- U / -pyrazol-4-yl)amino)pyrrolo[2, 1 - f\ [ 1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one

[0324] Step 1. rac-tert-butyl (3aR,4R,5R,7aS)-4-hydroxy-5-iodooctahydro-2H-isoindole-2-carboxylate (E24)OHE24

[0325] A solution of mixture E23 (80.0 g, 334 mmol, 1.00 equiv.) in MeCN (800 mL) was treated with Nal (150 g, 1.00 mol, 3.00 equiv.) at about 25 °C followed by the addition of cerium(III) chloride heptahydrate (149 g, 401 mmol, 1.20 equiv.) in portions. The reaction mixture was then heated to about 40 °C for 1 h, then cooled to about 25 °C and diluted with water (500 mL). The mixture was filtered, and the filter cake was washed with ethyl acetate (2 x 200 mL). The combined filtrates were concentrated and extracted with EtOAc (2 x 500 mL). The combined EtOAc extracts were washed with brine (2 x 500 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound E24 (55 g, 44% yield).

[0326] ’H NMR (300 MHz, DMSO-t / e): 55.49 (s, 1H), 4.05 (qd, J= 8.4, 7.3, 4.0 Hz, 1H), 3.58 - 3.00 (m, 5H), 2.34 - 2.10 (m, 2H), 1.97 - 1.86 (m, 2H), 1.72 - 1.55 (m, 2H), 1.40 (s, 9H).102333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0327] Step 2. rac-tert-butyl (3aS,4S,5R,7aR)-4-hydroxy-5-(2-[(l-methylpyrazol-4-yl)(([2-(trimethylsilyl)ethoxy]methyl)amino]pyrrolo[2,l-f][l,2,4]triazin-7-yl-octahydroisoindole-2-carboxylate (C2-2) and rac-tert-butyl (3aS,4R,5S,7aR)-4-hydroxy-5-(2-((1 -methyl- lH-pyrazol-4-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (C2-2A)C2-2A

[0328] To a stirred solution of compound Cl-B (26.0 g, 61.4 mmol, 1.00 equiv.) and compound E24 (22.6 g, 61.4 mmol, 1.00 equiv.) in DMA (260 mL) were added pyridine-2,6-dicarboximidamide dihydrochloride (2.90 g, 12.3 mmol, 0.20 equiv.), zinc (12.0 g, 184 mmol, 3.00 equiv.) and nickel (II) chloride ethylene glycol dimethyl ether complex (13.5 g, 61.4 mmol, 1.00 equiv.) at about 25 °C. The mixture was then heated at about 50 °C for about 1 h before being cooled to about 25 °C, diluted with water (500 mL), and filtered. The filtrate was extracted with ethyl acetate (2 x 300 mL). The filter cake was washed with EtOAc (2 x 200 mL). The combined EtOAc extracts and washes were washed with brine (2 x 300 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to afford the title compounds C2-2 (9.72 g, 27% yield) and C2-2A (3.8 g, 11% yield). LCMS Calculated for C29H45N7O4Si: 583.3; Observed: 584.4 [M+H]+.

[0329] Step 3. rac-(3aR,4R,5S,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f] [ 1,2,4]triazin-7-yl)octahy dro- 1 H-i soindol -4-ol (C2-3)C2-3103333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0330] A solution of compound C2-2 (9.00 g, 15.4 mmol, 1.00 equiv.) in TFA (180 mL) was stirred at about 25 °C for about 3 h, then concentrated to dryness to afford the title compound C2-3 trifluoroacetate containing residual TFA (14.0 g). LCMS Calculated for C18H23N7O: 353.2; Observed: 354.2 [M +H]+.

[0331] Step 4. rac-l-((3a7?,4A,55,7a5)-4-hydroxy-5-(2-((l-methyl-lJ / -pyrazol-4- yl)amino)pyrrolo[2, 1 -f\ [ 1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one (1-7)1-7

[0332] A solution of compound C2-3 (14.0 g, 15.4 mmol, 1.00 equiv.) in DCM (900 mL) and EtsN (12.0 g, 119 mmol, 7.7 equiv.) was kept at about 25 °C for about 20 min before being cooled to about -50 °C. Acryloyl chloride (1.61 g, 17.8 mmol, 1.15 equiv.) was added dropwise with continued cooling and the mixture was stirred at about -50 °C for about 40 min before the addition of water (80 mL). After the reaction mixture had returned to about 25 °C, the phases were separated and the DCM phase was washed with water (2 x 100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (10:1) to afford the title compound 1-7 rac-1- ((3a7?,4A,55,7a5)-4-hydroxy-5-(2-((l-methyl-lJ / -pyrazol-4-yl)amino)pyrrolo[2,l- / |[l,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (3.0 g, 62% yield).

[0333] 1HNMR (300 MHz, CDCh) 58.58 - 8.51 (m, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 6.78 - 6.70 (m, 1H), 6.62 - 6.50 (m, 2H), 6.50 - 6.35 (m, 2H), 5.74 - 5.63 (m, 1H), 4.15 - 3.95 (m, 1H), 3.95 - 3.81 (m, 3H), 3.78 - 3.58 (m, 3H), 3.58 - 3.30 (m, 3H), 2.86 - 2.60 (m, 2H), 2.33 -2.19 (m, 1H), 1.99 - 1.77 (m, 3H).

[0334] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.3 [M+H]+.

[0335] Purity (Method- A): 97.8% at RT 1.124min.1-20104333961159Attorney Docket No. CENC-011 / 08WO 360899-2045rac-1 -((3a7?, 45,57?, 7a5)-4-hydroxy-5-(2-((l -methyl-1 J7-pyrazol-4-yl)amino)pyrrolo[2,l-f\ [ 1, 2,4] tri azi n-7-yl )octahydro-27 / -i soi ndol -2-yl )prop-2-en- 1 -oneStep 1. rac-l-((3aR,4S,5R,7aS)-4-hydroxy-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo- [2, 1 -f] [ 1,2,4]triazin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en- 1 -one (1-20)O1-20

[0336] A solution of compound C2-2A (61 mg, 0.13 mmol, 1.00 equiv.) in DCM (1.0 mL) was treated with benzenesulfonic acid (32 mg, 0.20 mmol, 1.50 equiv.) at about 25 °C for about 1 h. After cooling to about 0 °C, EtsN (52 mg, 0.52 mmol, 6.00 equiv.) was added. After about 15 min, acryloyl chloride (2.3 mg, 0.03 mmol, 0.300 equiv.) was added. After stirring at about 0 °C for about 30 min, water (0.20 mL) was added at about 25 °C and the mixture was concentrated. The residue was purified by reversed-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, acetonitrile in water (containing 0.1% NTLOH), 30% to 60% gradient in 15 min; detector, UV 254 nm) to give the title product 1-20 rac-l-[(3aR,4S,5R,7aS)-4-hydroxy-5-{2-[(l-methylpyrazol-4-yl)amino]pyrrolo[2,l- f][l,2,4]-triazin-7-yl}-octahydroisoindol-2-yl]prop-2-en-l-one (2.1 mg, 6% yield).

[0337] ’H NMR (300 MHz, Chloroform-^) 3 8.63 - 8.53 (m, 1H), 7.98 - 7.66 (m, 1H), 7.62 - 7.37 (m, 1H), 6.78 - 6.71 (m, 1H), 6.69 - 6.60 (m, 1H), 6.60 - 6.52 (m, 1H), 6.52 - 6.36 (m, 2H), 5.77 - 5.67 (m, 1H), 4.27 - 4.05 (m, 3H), 4.01 - 3.78 (m, 3H), 3.76 - 3.60 (m, 2H), 3.60 - 3.46 (m, 2H), 2.98 - 2.84 (m, 1H), 2.47 - 2.26 (m, 1H), 1.94- 1.71 (m, 3H), 1.47- 1.35 (m, 1H).

[0338] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.3 [M+H]+.

[0339] Purity (Method-A): 96.8% at RT 1.169 min.1-411-42105333961159Attorney Docket No. CENC-011 / 08WO 360899-2045rac-l-((3a7?,4A,5A,7a5)-4,5-dihydroxy-5-(2-((l-methyl-17 / -pyrazol-4-yl)amino)pyrrolo[2,l- f\ [ 1,2,4]triazin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en- 1 -one rac- 1 -((3a7?,45',55',7a5)-4,5-dihydroxy-5-(2-((l -methyl- 1 J / -pyrazol-4-yl)amino)pyrrolo[2, 1 - f\ [ 1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one

[0340] Step 1. rac-tert-butyl (3aR,7aS)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,3a,4,5,7a-hexahydro-2H-isoindole-2-carboxylate (E48)

[0341] A mixture of compound E23-2 (30.0 g, 80.8 mmol, 1.00 equiv.), bis(pinacolato)diboron (24.6 g, 96.9 mmol, 1.20 equiv.), potassium acetate (23.8 g, 242 mmol, 3.00 equiv.) and [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS 72287-26-4, 5.91 g, 8.08 mmol, 0.100 equiv.) in 1,4-dioxane (500 mL) was heated at about 80 °C for about 3 h. After cooling to about 25 °C, the mixture was concentrated and the residue was taken up in water (300 mL) and extracted with EtOAc (3 x 200 mL). The combined EtOAc extracts were washed with brine (1 x 200 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (5:1) to afford the title compound E48 (26 g, 92% yield).LCMS Calculated for C19H32BNO4: 349.2; Observed: 350.3 [M+H]+.

[0342] Step 2. rac-tert-butyl (3aR,7aS)-5-{2-[(l-methylpyrazol-4-yl)amino]pyrrolo[2,l-f][l,2,4]triazin-7-yl}-l,3,3a,6,7,7a-hexahydroisoindole-2-carboxylate (C10-1)C10-1

[0343] A mixture of compound E48 (46.0 g, 132 mmol, 1.00 equiv.), compound Cl-A (38.6 g, 132 mmol, 1.00 equiv.), K2CO3 (54.6 g, 395 mmol, 3.00 equiv.), and water (92.0 mL) in in dioxane (920 mL) was treated with [1,1’-106333961159Attorney Docket No. CENC-011 / 08WO 360899-2045bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS 72287-26-4, 4.82 g, 6.59 mmol, 0.050 equiv.) at about 25 °C, then heated at about 80 °C for about 2 h. The reaction was cooled to about 25 °C, diluted with water (2 L), and extracted with a dichloromethane / methanol mixture (3:1, v / v, 3 x 800 mL). The combined extracts were washed with brine (1 x 1 L), dried (Na2SO4), filtered and concentrated. The residue was purified by trituration with a mixture of dichloromethane / petroleum ether (1:5, v / v) to give the title compound C10-1 (41.9 g, 73% yield).LCMS Calculated for C23H29N7O2: 435.2; Observed: 436.3 [M+H]+.

[0344] Step 3. tert-butyl (3aRS,4RS&,5RS&,7aSR)-4,5-dihydroxy-5-{2-[(l-methylpyrazol-4-yl)amino]pyrrolo[2, 1 -f] [ 1,2,4]triazin-7-yl J -hexahydro- lH-isoindole-2-carb oxy late (Cl 0-2)C10-2

[0345] A solution of compound C10-1 (1.00 g, 2.25 mmol, 1.00 equiv.), potassium osmate(VI) dihydrate (829 mg, 2.25 mmol, 1.00 equiv.) and N-methylmorpholine-N-oxide (790 mg, 6.75 mmol, 3.00 equiv.) in acetone (180 mL) and water (18.0 mL) was heated at about 50 °C for 2 days. The reaction mixture was diluted with water (1 L) and extracted with EtOAc (5 x 200 mL). The combined EtOAc extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (20:1) to afford the title compound C10-2 (475 mg, 45% yield).LCMS Calculated for C23H31N7O4: 469.2; Observed: 470.4 [M+H]+.

[0346] Step 4. (3aRS,4RS&,5RS&,7aSR)-5-{2-[(l-methylpyrazol-4-yl)amino]pyrrolo[2,l-f][l,2,4]triazin-7-yl}-octahydroisoindole-4,5-diol (C10-3)333961159Attorney Docket No. CENC-011 / 08WO 360899-2045C10-3

[0347] To a solution of compound C10-2 (200 mg, 0.43 mmol, 1.00 equiv.) in DCM (3.0 mL) was added TFA (1.00 mL) at about 20 °C. After about 1 h, the mixture was concentrated to dryness to give the title compound C10-3 trifluoroacetate (130 mg), which was used without further purification.LCMS Calculated for C18H23N7O2: 369.2; Observed: 370.3 [M+H]+.

[0348] Step 5. ((3aRS,4RS,5RS,7aSR)-4,5-dihydroxy-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en-l-one (C10- 4)

[0349] To a stirred solution of compound C10-3 (120 mg, 0.325 mmol, 1.00 equiv.) and EtiN (0.23 mL, 1.66 mmol, 5.09 equiv.) in DMF (3 mL) was added acryloyl chloride (29 mg, 0.33 mmol, 1.00 equiv.) at about 0 °C. After about 1 h, water (0.3 mL) was added at about 0 °C and the mixture was purified by prep-HPLC under the following conditions Column: Column: Xbridge -Phenyl Column, 30*150 mm, 5pm; Mobile Phase A: Water (containing 0.05% NH4OH), Mobile Phase B: MeCN; Flow rate: 35 mL / min mL / min; Gradient (B%): isocratic 11% - 41% 14 min; Wavelength: 254nm / 220nm nm; RT l(min): 8.23) to afford the title compound C10-4 (15 mg, 11% yield).LCMS Calculated for C21H25N7O3: 423.2; Observed: 424.3 [M+H]+.

[0350] Step 6. rac-l-((3a7?,4A,5A,7a5)-4,5-dihydroxy-5-(2-((l-methyl-17 / -pyrazol-4-yl)amino)pyrrolo[2,l- / |[l,2,4]triazin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en-l-one (1-41) and rac-l-((3a7?,45,55,7a5)-4,5-dihydroxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)pyrrolo[2, 1 -f\ [ 1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one (1-42)108333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0351] Compound C10-4 (15 mg, 0.035 mmol) was separated by achiral-SFC under the following conditions: Column Name: Column: XA-DCpak P4VP, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH / DCM (2: 1 v / v, containing 0.1% 2M NH3 in MeOH); Flow rate: 80 mL / min; Gradient (B%): isocratic 40% B; Column Temperature (°C): 35; Back Pressure (bar): 100; Wavelength: 220 nm; RT l(min): 3.65; RT 2(min): 4.46; Sample Solvent: MeOH / DCM (v / v); Injection Volume: 1 mL; Number Of Runs: 9 to afford the title products 1-41 rac-l-((3a7?,4A,5A,7a5)-4,5-dihydroxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)pyrrolo[2, 1 -f\ [ 1,2,4]triazin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en- 1 -one (6 mg, 40% yield) and 1-42 rac-l-((3aR, 45,55, 7a5)-4,5-dihydroxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)-pyrrolo[2, 1 -f\ [ 1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one (7 mg, 47% yield).

[0352] Data for 1-41:

[0353] ¹H NMR (300 MHz, DMSO-d₆): 3 9.02 - 8.97 (m, 1H), 8.76 (d, J= 3.6 Hz, 1H), 7.93 - 7.27 (m, 3H), 6.72 (d, J= 1.8 Hz, 2H), 6.57 (m, 1H), 6.20 - 6.04 (m, 1H), 5.71 - 5.57 (m, 1H), 5.55 - 5.34 (m, 1H), 4.82 - 4.62 (m, 1H), 3.91 - 3.43 (m, 7H), 3.30 - 3.19 (m, 1H), 2.36 -2.33 (m, 1H), 2.18 - 1.45 (m, 4H).

[0354] LCMS Calculated for C21H25N7O3: 423.2; Observed: 424.3 [M+H]+.

[0355] Purity (Method-A): 83.0% at RT 0.827 min.

[0356] Chiral SFC: 100% at RT 2.022 min.

[0357] Data for 1-42

[0358] 1H NMR (300 MHz, DMSO-d6): 39.21 (s, 1H), 8.78 (s, 1H), 7.82 (d, J= 12.3 Hz, 1H), 7.57 (d, J= 3.6 Hz, 1H), 6.75 - 6.72 (m, 2H), 6.63 - 6.49 (m, 1H), 6.17 - 6.10 (m, 1H), 5.66 (td, J= 9.9, 2.7 Hz, 1H), 5.37 (d, J = 11.1 Hz, 1H), 5.00 - 4.69 (m, 2H), 4.34 - 3.97 (m, 1H), 3.83 (s, 3H), 3.76 - 3.39 (m, 3H), 2.86 - 2.54 (m, 2H), 2.46 - 2.32 (m, 1H), 1.80 - 1.61 (m, 2H), 1.55 - 1.42 (s, 1H).

[0359] LCMS Calculated for C21H25N7O3: 423.2; Observed: 424.3 [M+H]+.109333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0360] Purity (Method-A): 95.3% atRT 1.161 min.

[0361] Chiral-SFC: 98.7% at RT 2.216 min.1-32rac-l-((3a7?,5A,7a5)-5-(6-amino-7-fluoro-lJ / -pyrrolo[3,2-c]pyridin-l-yl)octahydro-2JT- isoindol-2-yl)prop-2-en-l-one

[0362] Step 1. rac-tert-butyl (3aR,5R,7aS)-5-(6-chloro-7-fluoro-lH-pyrrolo[3,2-c]pyridin- 1 -yl)octahydro-2H-isoindole-2-carboxylate (D35-3)

[0363] A mixture of 6-chloro-7-fluoro-lH-pyrrolo[3,2-c]pyridine (CAS 2703771-38-2, 1.80 g, 10.6 mmol, 1.00 equiv.), compound E31 (5.06 g, 15.8 mmol, 1.50 equiv.), and CS2CO3 (10.31 g, 31.7 mmol, 3.00 equiv.) in acetonitrile (18 mL) was heated at about 80 °C for about 16 h, then cooled and filtered. The filter cake was washed with MeCN (2 x 10 mL), and the combined filtrates were concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to afford the title compound D35-3 (1.50 g, 36% yield).LCMS Calculated for C20H25CIFN3O2: 393.2; Observed: 394.1 [M+H]+.

[0364] Step 2. rac-tert-butyl (3aR,5R,7aS)-5-(6-((diphenylmethylene)amino)-7-fluoro-lH-pyrrolo[3,2-c]pyridin-l-yl)octahydro-2H-isoindole-2-carboxylate (D35-4)

[0365] To a solution of compound D35-3 (1.50 g, 3.81 mmol, 1.00 equiv) and benzophenone imine (2.07 g, 11.4 mmol, 3.00 equiv.) in toluene (15 mL) were added sodium 110333961159Attorney Docket No. CENC-011 / 08WO 360899-2045ter -butoxide (1.10 g, 11.4 mmol, 3.00 equiv.) and tris(dibenzylideneacetone)dipalladium(0) (CAS 51364-51-3, 0.35 g, 0.381 mmol, 0.10 equiv.) and the mixture was heated at about 110 °C for about 16 h. After cooling, the mixture was filtered, and the filter cake was washed with EtOAc (2 x 20 mL). The combined filtrates were concentrated and the residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (containing 0.05% NH4OH), 40% to 80% gradient in 20 min; detector, UV 254 nm to provide the title compound D35-4 (540 mg, 26% yield).LCMS Calculated for C33H35FN4O2: 538.3; Observed: 539.1 [M+H]+.

[0366] Step 3. rac-7-fluoro-l-((3aR,5R,7aS)-octahydro-lH-isoindol-5-yl)-lH-pyrrolo[3,2-c]pyridin-6-amine (D35-5)D35-5

[0367] Compound D35-4 (300 mg, 0.56 mmol, 1.00 equiv.) was dissolved in HC1 (4 M in 1,4-di oxane, 3 mL) at about 0 °C and kept for about 30 min, then concentrated to dryness to give the title compound D35-5 hydrochloride (120 mg), which was used without further purification.LCMS Calculated for C15H19FN4: 274.2; Observed: 275.1 [M+H]+.

[0368] Step 4. rac-l-((3a7?,5A,7a5)-5-(6-amino-7-fluoro-lJ / -pyrrolo[3,2-c]pyridin-l-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (1-32)

[0369] A solution of compound D35-5 (120 mg, 0.44 mmol, 1.00 equiv.) and Et3N (133 mg, 1.31 mmol, 3.00 equiv.) in DMF (1.5 mL) was treated with acryloyl chloride (40 mg, 0.44111333961159Attorney Docket No. CENC-011 / 08WO 360899-2045mmol, 1.00 equiv.) at about 0 °C. After about 1 h at about 0 °C, water (0.5 mL) was added and the mixture was purified by prep-HPLC under the following conditions (column: XBridge Prep Phenyl Column, 19*250 mm, 5pm; Mobile Phase A: water (containing 0.1% NH4OH), Mobile Phase B: MeCN; Flow rate: 35 mL / min; Gradient (B%): isocratic 27% - 39% 14 min; Wavelength: 254nm / 220nm nm; RT l(min): 6.73) to give the title product 1-32 rac-1-((3a7?,5A,7a5)-5-(6-amino-7-fluoro-U / -pyrrolo[3,2-c]pyridin-l-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (14 mg, 10% yield).

[0370] 1H NMR (300 MHz, DMSO-d6) 58.05 (d, J= 1.5 Hz, 1H), 7.35 (d, J= 3.4 Hz, 1H), 6.67 - 6.48 (m, 1H), 6.40 (d, J= 3.0 Hz, 1H), 6.21 - 6.08 (m, 1H), 5.66 (td, J= 10.1, 2.5 Hz, 1H), 5.41 (s, 2H), 4.47 - 4.29 (m, 1H), 3.70 - 3.36 (m, 3H), 2.45 - 2.23 (m, 2H), 1.99 - 1.76 (m, 6H), 1.74 - 1.58 (m, 1H).

[0371] LCMS Calculated for C18H21FN4O: 328.2; Observed: 329.1 [M+H]+.

[0372] Purity (Method-C): 95.2% at RT 1.169 min.1-8rac-l-((3a7?,5A,7a5)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- ]pyrimidin-7- yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one

[0373] Step 1. rac-tert-butyl (3aR,5S,7aS)-5-((methylsulfonyl)oxy)octahydro-2H-isoindole-2-carboxylate (E31)I&1 I N-BocE31

[0374] A solution of rac-tert-butyl (3aR,5S,7aS)-5-hydroxyoctahydro-2H-isoindole-2-carboxylate (CAS 2007919-65-3, 500 mg, 2.07 mmol, 1.00 equiv.) in DCM (20 mL) was treated at about 25 °C with EtsN (419 mg, 4.14 mmol, 2.00 equiv.), followed after about 5 min by the addition of MsCl (225 mg, 2.07 mmol, 1.00 equiv.) in portions at about 0 °C. After a further 1 h at about 0 °C, the mixture was allowed to warm to about 25 °C and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to afford the title compound E31 (570 mg) which was used in the next step directly without further purification.112333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0375] Step 2. rac-tert-butyl (3aA, 5R, 7aA')-5-(2-((l-methyl-l / / -pyrazol-4-yl)amino)-7 / / -pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-27 / -isoindole-2-carboxylate (B8-1)B8-1

[0376] A mixture of compound E31 (582 mg, 1.82 mmol, 1.50 equiv.), compound Bl (260 mg, 1.21 mmol, 1.00 equiv) and CS2CO3 (790 mg, 2.43 mmol, 2.00 equiv.) in DMF (6.0 mL) was heated at about 80 °C for about 3 h, then cooled to about 25 °C and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with water (3 x 50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound B8-1 (400 mg, 75% yield).LCMS Calculated for C18H23N7: 437.3; Observed: 438.3 [M+H]+

[0377] Step 3. rac'-A-(l-methyl-l / / -pyrazol-4-yl)-7-((3aA>, 5R, 7a5)-octahydro-17T-isoindol-5-yl)-77 / -pyrrolo[2,3-d]pyrimidin-2-amine (B8-2)B8-2

[0378] Compound B8-1 (400 mg, 0.91 mmol, 1.00 equiv.) was dissolved in DCM (4.0 mL) and treated with TFA (312 mg, 2.74 mmol, 3.00 equiv.) at about 25 °C. After the reaction was deemed to be complete, the mixture was concentrated to provide the title compound B8-2 trifluoroacetate, which was used without further purification.LCMS Calculated for C18H23N7: 337.2; Observed: 338.2 [M+H]+.

[0379] Step 4. rac-l-((3aA,5A,7a5)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7JT-pyrrolo[2,3-t / ]pyrimidin-7-yl)octahydro-2 / / -isoindol-2-yl)prop-2-en- l-one (1-8)113333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0380] A solution of compound B8-2 trifluoroacetate (310 mg, 0.92 mmol, 1.00 equiv.) and EtsN (105 mg, 2.76 mmol, 3.00 equiv.) in DCM (3.50 mL) was cooled to about 0 °C and acryloyl chloride (59 mg, 0.64 mmol, 0.700 equiv.) was added. The mixture was kept at about 0 °C for about 20 min, then concentrated. The residue was purified by prep-HPLC with the following conditions (Column: Ultimate - XB-C18 Column, 30*150 mm, 10pm; Mobile Phase A: Water (containing 0.05% NH4OH), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: isocratic 30%-80% 11 min; Wavelength: 254 nm / 220 nm; RT1 (min): 10.5) to afford the title product 1-8 rac-l-((3a7?,5A,7a5)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7JT-pyrrolo[2,3-t ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (300 mg, 84% yield).¹H NMR (300 MHz, CDCl₃) 58.53 (s, 1H), 7.81 - 7.72 (m, 1H), 7.03 (d, J= 3.8 Hz, 1H), 6.44 (dd, J= 10.2, 4.9 Hz, 3H), 5.72 (td, J= 8.3, 7.1, 4.5 Hz, 1H), 5.44 - 5.28 (m, 2H), 4.65 - 4.53 (m, 1H), 3.93 (s, 2H), 3.74 - 3.44 (m, 3H), 2.53 (s, 2H), 2.24 (t, J = 7.6 Hz, 3H), 2.04 - 2.02 (m, 3H), 1.68 - 1.64 (m, 2H).

[0381] LCMS Calculated for C21H25N7O: 391.21; Observed: 392.3 [M+H]+.

[0382] Purity (Method-A): 96.3 % atRT 0.735 min.1-24rac-1 -((3a7?, 5A,6A,7a5)-5-hydroxy-6-(2-((l -methyl- U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2, 3- J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one

[0383] Step 1. rac-tert-butyl (3aR,5R,6S,7aS)-5,6-dihydroxyoctahydro-2H-isoindole-2-carboxylate (E41-1)E41-1114333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0384] To a stirred solution of rac-tert-butyl (3aR,7aS)-l,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate (CAS 474925-37-6, 2.30 g, 10.3 mmol, 1.00 equiv.) and N-methylmorpholine-N-oxide (1.81 g, 15.5 mmol, 1.50 equiv.) in acetone (30 mL) and water (6.0 mL) was added potassium osmate(VI) dihydrate (0.19 g, 0.52 mmol, 0.05 equiv.). The mixture was stirred at about 25 °C overnight, then quenched with saturated aqueous Na2SCh and extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were washed with saturated aqueous Na2SCh (2 x 50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound E41-1 (2.00 g, 75%).LCMS Calculated for C13H23NO4: 257.2; Observed: 258.2 [M+H]+.

[0385] Step 2. rac-tert-butyl (3aR,5R,6S,7aS)-5-((tert-butyldimethylsilyl)oxy)-6-hydroxyoctahydro-2H-isoindole-2-carboxylate (E41)J&l J N-BOCE41

[0386] A solution of compound E41-1 (2.00 g, 7.77 mmol, 1 equiv.), imidazole (1.06 g, 15 mmol, 2.00 equiv.) and tert-butylchlorodimethylsilane (1.17 g, 7.77 mmol, 1.00 equiv.) in DCM (30 mL) was stirred at about 25 °C for about 2 h before being diluted with saturated aqueous Na2SO3 and extracted with DCM (3 x 50 mL). The combined DCM extracts were washed with brine (2 x 40 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (3:1) to afford the title compound E41 (1.10 g, 38%).LCMS Calculated for C19H37NO4Si: 371.2; Observed: 372.3 [M+H]+.

[0387] Step 3. rac-tert-butyl (3aR,5R,6R,7aS)-5-[(tert-butyldimethylsilyl)oxy]-6-{2-chloropyrrolo[2,3-d]pyrimidin-7-yl}-octahydroisoindole-2-carboxylate (B7-1)333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0388] A solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS 335654-06-3, 800 mg, 5.21 mmol, 1.00 equiv.) and compound E41 (2.32 g, 6.25 mmol, 1.20 equiv.) in toluene (15.0 mL) was treated with CMBP (3.15 g, 13.0 mmol, 2.50 equiv.) at about 25 °C. The solution was heated at about 100 °C for about 5 h, then cooled to about 25 °C and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound B7-1 (410 mg, 16% yield).LCMS Calculated for C25H39ClN4O3Si: 506.3; Observed: 507.3 [M+H]+.

[0389] Step 4. rac-tert-butyl (3aR,5R,6R,7aS)-5-((tert-butyldimethylsilyl)oxy)-6-(2-((l-methyl- IH-pyra zol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B7-2)

[0390] A mixture of compound B7-1 (400 mg, 0.79 mmol, 1.00 equiv.), 1-methylpyrazol-4-amine (84 mg, 0.87 mmol, 1.10 equiv.), and Cs2CO3(514 mg, 1.57 mmol, 2.00 equiv.) in 1,4-dioxane (5.0 mL) was treated with DPPF Pd G3 (CAS 1445086-28-1, 147 mg, 0.16 mmol, 0.20 equiv.) at about 25 °C, then heated at about 100 °C overnight. The mixture was concentrated after cooling to about 25 °C. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2: 1) to afford the title compound B7-2 (200 mg, 45% yield).LCMS Calculated for C29H45N7O3Si: 567.3; Observed: 568.4 [M+H]+.

[0391] Step 5. rac-tert-butyl (3aR,5R,6R,7aS)-5-hydroxy-6-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B7-3)116333961159Attorney Docket No. CENC-011 / 08WO 360899-2045B7-3

[0392] A solution of compound B7-2 (200 mg, 0.35 mmol, 1.00 equiv.) in THF (3.0 mL) was treated with TBAF (1 M in THF, 0.70 mL, 0.70 mmol, 2.00 equiv.) with cooling to about 0 °C, then stirred at about 25 °C for about 2 h before being concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford compound B7-3 (130 mg, 81% yield).LCMS Calculated for C23H31N7O3: 453.3; Observed: 454.3 [M+H]+.

[0393] Step 6. rac-(3aR,5R,6R,7aS)-6-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-lH-isoindol-5-ol (B7-4)HB7-4

[0394] A solution of compound B7-3 (130 mg, 0.29 mmol, 1.00 equiv.) in DCM (1.0 mL) was treated with TFA (1.0 mL) at 25 °C and kept for 1 h before being concentrated to afford the title compound B7-4 trifluoroacetate (132 mg), which was used without further purification. LCMS Calculated for C18H23N7O: 353.2; Observed: 354.2 [M+H]+.

[0395] Step 7. rac-l-((3a7?,5A,6A,7a5)-5-hydroxy-6-(2-((l-methyl-17 / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (I- 24)

[0396] A solution of compound B7-4 (132 mg, 0.28 mmol, 1.00 equiv.) and DIEA (73 mg, 0.57 mmol, 2.00 equiv.) in DCM (2.0 mL) was treated with acryloyl chloride (21 mg, 0.23 mmol, 0.800 equiv.) at about 25 °C and kept for about 1 h before being concentrated to dryness.117333961159Attorney Docket No. CENC-011 / 08WO 360899-2045The residue was purified by reversed-phase flash chromatography with the following conditions: Column, C18 silica gel; mobile phase, MeCN in water (containing 0.1% formic acid), 30% to 70% gradient in 10 min; detector, UV 254 nm to provide the title product 1-24 rac-1 -((3a7?,5A,6A,7a5)-5-hydroxy-6-(2-((l -methyl- lJ / -pyrazol-4-yl)arnino)-7J / -pyrrolo[2, 3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (25 mg, 22% yield).

[0397] XH NMR (300 MHz, DMSO-t / e) 5 9.62 (s, 1H), 8.66 (s, 1H), 7.94 (d, J = 6.7 Hz, 1H), 7.61 (d, J= 10.4 Hz, 2H), 6.68 - 6.43 (m, 2H), 6.14 (d, = 16.9 Hz, 1H), 5.67 (t, = 12.0 Hz, 1H), 4.37 (s, 2H), 4.19 (s, 2H), 3.90 - 3.80 (m, 3H), 3.79 - 3.57 (m, 3H), 3.50 - 3.27 (m, 2H), 2.60 - 2.50 (m, 2H), 2.21 - 2.05 (m, 1H), 1.92 - 1.64 (m, 3H).LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.2 [M+H]+.Purity (Method-A): 97.32% at RT 0.790 min.1-31rac-N-(l-((3a7?,57?,7a5)-2-acryloyloctahydro-U / -isoindol-5-yl)-U / -pyrrolo[3,2-c]pyridin-6- yl)cyclopropanecarboxamide

[0398] Step 1. rac-tert-butyl (3aR,5R,7aS)-5-(6-chloro-lH-pyrrolo[3,2-c]pyridin-l-yl)octahydro-2H-isoindole-2-carboxylate (D36-1)

[0399] A solution of rac-tert-butyl (3aR,5S,7aS)-5-hydroxyoctahydro-2H-isoindole-2-carboxylate (CAS 2007919-65-3, 1.80 g, 7.45 mmol, 1.00 equiv.), 6-chloro-lH-pyrrolo[3,2-c]pyridine (1.37 g, 8.95 mmol, 1.2 equiv.), and CMBP (2.70 g, 11.2 mmol, 1.5 equiv.) in toluene (10 mL) was heated at 100 °C for about 16 h, then cooled and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (5:1) to afford the title compound D36-1 (246 mg, 9% yield).LCMS Calculated for C20H26CIN3O2: 375.2 (35C1 isotope); Observed: 376.2 [M+H]+(35C1 isotope).118333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0400] Step 2. rac-tert-butyl (3aR,5R,7aS)-5-(6-(cyclopropanecarboxamido)-lH-pyrrolo[3,2-c]pyridin-l-yl)octahydro-2H-isoindole-2-carboxylate (D36-2)

[0401] A mixture of compound D36-1 (236 mg, 0.628 mmol, 1.00 equiv.), cyclopropanecarboxamide (80 mg, 0.94 mmol, 1.50 equiv.), XPhos (60 mg, 0.13 mmol, 0.2 equiv.), Pd(OAc)2 (28 mg, 0.13 mmol, 0.2 equiv.), CS2CO3 (409 mg, 1.25 mmol, 2.00 equiv.) in 1,4-dioxane (3 mL) was heated at about 130 °C for about 16 h then cooled to about 25 °C. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined EtOAc extracts were washed with water (2 x 10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to afford the title compound D36-2 (100 mg, 38% yield). LCMS Calculated for C24H32N4O3: 424.3; Observed: 425.3 [M+H]+.

[0402] Step 3. rac-N-(l-((3aR,5R,7aS)-octahydro-lH-isoindol-5-yl)-lH-pyrrolo[3,2-c]pyridin-6-yl)cyclopropanecarboxamide (D36-3)D36-3

[0403] A solution of compound D36-2 (90 mg, 0.21 mmol, 1.00 equiv.) and TFA (0.5 mL) in DCM (2 mL) was stirred at about 25 °C for about 3 h, then concentrated to dryness to give the title compound D36-3 trifluoroacetate (121 mg), which was used without further purification.LCMS Calculated for C19H24N4O: 324.2; Observed: 325.2 [M+H]+.119333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0404] Step 4. rac-N-(l-((3aA,5A,7aA')-2-acryloyloctahydro-l / / -isoindol-5-yl)-l / / -pyrrolo[3,2-c]pyridin-6-yl)cyclopropanecarboxamide (1-31)1-31

[0405] A solution of compound D36-3 (121 mg, 0.28 mmol, 1.00 equiv.) in DCM (1.0 mL) was treated with EtsN (84 mg, 0.83 mmol, 3.00 equiv.), followed by the addition of acryloyl chloride (30 mg, 0.33 mmol, 1.20 equiv.) at about 25 °C and was stirred at about 25 °C for about 1 h, then concentrated. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (containing 0.1% NH4OH and 10 mM NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to give the title product 1-31 rac-N-(l-((3aA,5A,7a5)-2-acryloyloctahydro-l / Z-isoindol-5-yl)-17 / -pyrrolo[3,2-c]pyridin-6-yl)cyclopropanecarboxamide (4 mg, 4% yield).

[0406] 'H NMR (400 MHz, DMSO ) 5 10.59 (s, 1H), 8.53 (s, 1H), 8.19 (d, J = 7.5 Hz, 1H), 7.59 (dd, J= 7.2, 3.4 Hz, 1H), 6.75 - 6.46 (m, 2H), 6.13 (m, 1H), 5.65 (ddd, J= 14.8, 10.3, 2.5 Hz, 1H), 4.25 (t, J= 10.6 Hz, 1H), 3.76 - 3.39 (m, 3H), 3.37 (d, J= 3.4 Hz, 1H), 2.45 -2.30 (m, 1H), 2.09 - 1.60 (m, 7H), 1.24 (s, 1H), 0.87 - 0.73 (m, 4H).

[0407] LCMS Calculated for C22H26N4O2: 378.2; Observed: 379.2 [M+H]+.

[0408] Purity (Method-G): 97.7% at RT 1.249 min.1-9rac-l-( 63aR, 5R, 7aS)-5-( 6-(pyridazin-4-ylamino)-lH-pyrrolo[ 3, 2-c ]pyridin-l-yl)octahydro- 2H-isoindol-2-yl)prop-2-en-l-one

[0409] Step 1. rac-tert-butyl (3aR,5R,7aS)-5-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (D38-1)333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0410] A solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS 335654-06-3, 500 mg, 3.26 mmol, 1.00 equiv.) and rac-tert-butyl (3aR,5S,7aS)-5-hydroxy-octahydroisoindole-2-carboxylate (CAS 2007919-65-3, 1.18 g, 4.88 mmol, 1.50 equiv.) in toluene (5.00 mL) was treated with CMBP (2.36 g, 9.77 mmol, 3.00 equiv.) and the mixture was heated at about 100 °C for about 2 h. After cooling to about 25 °C, the mixture was concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound D38-1 (750 mg, 61% yield).LCMS Calculated for C19H25CIN4O2: 376.2 (35C1 isotope); Observed: 377.1 [M+H]+(35C1 isotope).

[0411] Step 2. rac-tert-butyl (3aR,5R,7aS)-5-(2-(pyridazin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (D38-2)D38-2

[0412] A mixture of compound D38-1 (400 mg, 1.06 mmol, 1.00 equiv.), 4-pyridazinamine (CAS 20744-39-2, 151 mg, 1.59 mmol, 1.50 equiv.) CS2CO3 (1.03 g, 3.18 mmol, 3.00 equiv.), and BrettPhos Pd G3 (CAS 1470372-59-8, 96 mg, 0.11 mmol, 0.100 equiv.) in toluene (4 mL) was heated at about 100 °C for about 16 h. After cooling to about 25 °C, the mixture was filtered, and the filter cake was washed with EtOAc (2 x 10 mL). The combined filtrates were concentrated, and the residue was purified by reversed-phase flash chromatography under the following conditions (Column, Cl 8 silica gel; mobile phase, acetonitrile in water (containing 0.05% NH4OH), 30% to 80% gradient in 20 min; detector, UV 254 nm) to give the title compound D38-2 (300 mg, 65% yield).LCMS Calculated for C23H29N7O2: 435.2; Observed: 436.1 [M+H]+.

[0413] Step 3. rac-7-((3aR,5R,7aS)-octahydro-lH-isoindol-5-yl)-N-(pyridazin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (D38-3)121333961159Attorney Docket No. CENC-011 / 08WO 360899-2045D38-3

[0414] Compound D38-2 (150 mg, 0.344 mmol, 1.00 equiv) was dissolved in HC1 (4.0 M in 1,4-dioxane, 1.50 mL) and stirred at about 0 °C for about 30 min, then concentrated to dryness to give the title compound D38-3 hydrochloride (130 mg), which was used without further purification.LCMS Calculated for C18H21N7: 335.2; Observed: 336.1 [M+H]+.

[0415] Step 4. rac-l-((3aR,5R,7aS)-5-(2-(pyridazin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en-l-one (1-9)1-9

[0416] A solution of compound D38-3 (130 mg, 0.31 mmol, 1.00 equiv.) and EtsN (94 mg, 0.93 mmol, 3.00 equiv.) in DMF (1.50 mL) was treated with acryloyl chloride (14 mg, 0.16 mmol, 0.500 equiv.) at about 0 °C, then stirred at about 25 °C for about 1 h. After the addition of water (0.2 mL), the mixture was purified by prep-HPLC under the following conditions (Column: Xbridge Cl 8 19*250mm, 5um; Mobile Phase A: Water (containing 0.05% NELOH), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient (B%): isocratic 15% - 35% 9 min; Wavelength: 254nm / 220nm nm; RT l(min): 7.48) to give the title product 1-9 rac-1-((3aR,5R,7aS)-5-(2-(pyridazin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en-l-one (18 mg, 14% yield).

[0417] ’H NMR (400 MHz, DMSO-t / e) 5 10.22 (s, 1H), 9.43 (dd, J= 18.7, 2.8 Hz, 1H), 8.91 (dd, J= 8.2, 6.0 Hz, 1H), 8.83 (s, 1H), 8.24 (ddd, J= 14.2, 6.1, 2.8 Hz, 1H), 7.64 (d, J = 3.6 Hz, 1H), 6.67 - 6.50 (m, 2H), 6.14 (dd, J= 16.8, 2.6 Hz, 1H), 5.71 - 5.61 (m, 1H), 4.69 -122333961159Attorney Docket No. CENC-011 / 08WO 360899-20454.52 (m, 1H), 3.77 - 3.43 (m, 3H), 3.42 - 3.35 (m, 2H), 2.46 - 2.36 (m, 1H), 2.13 - 2.00 (m, 1H), 1.99 - 1.72 (m, 5H)

[0418] LCMS Calculated for C21H23N7O: 389.2; Observed: 390.2 [M+H]+.

[0419] Purity (Method-A): 97.9% at RT 1.139 min.1-10rac-7-((3a7?,57?,7a5)-2-acryloyloctahydro-U / -isoindol-5-yl)-2-((l-methyl-U / -pyrazol-4- yl)amino)-7J / -pyrrolo[2,3- ]pyrimidine-6-carbonitrile

[0420] Step 1. 2-Chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (D21-1)D21-1

[0421] N, N’ -Carbonyldiimidazole (984 mg, 6.07 mmol, 1.20 equiv.) was added to a solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (CAS 1503461-20-8, 1.00 g, 5.06 mmol, 1.00 equiv.) in THF (12 mL) at about 0 °C. After about 1 h at about 0 °C, NH4OH (20 mL) was added dropwise over 5 min and stirring at about 0 °C was continued for about 1 h. The mixture was concentrated and the residue was purified by trituration with MeCN (80 mL) to afford the title compound D21-1 (720 mg, 72% yield).LCMS Calculated for: C7H5CIN4O: 196.0; Observed: 197.1 [M+H]+.

[0422] Step 2. rac-tert-butyl (3aR,5R,7aS)-5-(6-carbamoyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (D21-2)

[0423] A mixture of compound D21-1 (500 mg, 2.54 mmol, 1.00 equiv.), rac-tert-butyl (3aR,5S,7aS)-5-hydroxyoctahydro-2H-isoindole-2-carboxylate (CAS 2007919-65-3, 1.84 g, 7.63 mmol, 3.00 equiv.) and CMBP (CAS 157141-27-0, 920 mg, 3.82 mmol, 1.50 equiv.) in 123333961159Attorney Docket No. CENC-011 / 08WO 360899-2045toluene (5 mL) was heated for about 2 h at about 100 °C, then cooled to about 0 °C and diluted with water (50 mL). The mixture was extracted with EtOAc (3 x 30 mL) and the combined EtOAc extracts were washed with brine (60 mL), dried (Na2SO4), filtered and concentrated to provide the title compound D21-2 (1.00 g), which was used without further purification. LCMS Calculated for: C20H26CIN5O3: 419.2. Observed: 420.1 [M+H]+.

[0424] Step 3. rac-tert-butyl (3aR,5R,7aS)-5-(2-chloro-6-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (D21-3)

[0425] A solution of compound D21-2 (1.00 g) and EtiN (0.96 g, 9.52 mmol, 4.00 equiv.) in DCM (10 mL) was treated with trifluoroacetic anhydride (1.00 g, 4.76 mmol, 2.00 equiv.) at about 0 °C, then stirred for about 30 min at about 25 °C. After concentration, the residue was purified by silica gel column chromatography eluted with a gradient of ethyl acetate in petroleum ether (30% to 50%) to afford the title compound D21-3 (320 mg, 33% yield).LCMS Calculated for: C20H24CIN5O2: 401.2. Observed: 402.2 [M+H]+.

[0426] Step 4. rac-tert-butyl (3aR,5R,7aS)-5-(6-cyano-2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (D21-4)D21-4

[0427] A mixture of compound D21-3 (100 mg, 0.25 mmol, 1.00 equiv.), 1-methylpyrazol-4-amine (48 mg, 0.50 mmol, 2.00 equiv.), CS2CO3 (243 mg, 0.75 mmol, 3.00 equiv.), BrettPhos Pd G3 (CAS 1470372-59-8, 22 mg, 0.025 mmol, 0.10 equiv.) in DMF (1 mL) was heated for about 2 h at about 100 °C. After cooling, water (10 mL) was added, and the mixture was 124333961159Attorney Docket No. CENC-011 / 08WO 360899-2045extracted with EtOAc (3 x 5 mL). The combined EtOAc extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography eluted with a gradient of ethyl acetate in petroleum ether (30% to 60%) to afford the title compound D21-4 (105 mg, 91% yield).LCMS Calculated for C24H30N8O2: 462.3. Observed: 463.2 [M+H]+.

[0428] Step 5. rac-2-((l-methyl-lH-pyrazol-4-yl)amino)-7-((3aR,5R,7aS)-octahydro-lH-isoindol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (D21-5)D21-5

[0429] Compound D21-4 (100 mg, 0.22 mmol, 1.00 equiv.) was added to a mixture of DCM and TFA (5:1 v / v, 1.5 mL) at about 25 °C. The mixture was stirred for about 1 h, then concentrated to dryness to afford the title compound D21-5 trifluoroacetate (70 mg), which was used without further purification.LCMS Calculated for: C19H22N8: 362.2. Observed: 363.2 [M+H]+.

[0430] Step 6. rac-7-((3a / ,5 / ,7aA')-2-acryloyloctahydro-l7 / -isoindol-5-yl)-2-((l-methyl-lJ / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidine-6-carbonitrile (1-10)

[0431] A solution of compound D21-5 (70 mg) and EtiN (58 mg, 0.58 mmol, 3.00 equiv.) in DMF (2 mL) was cooled to about 0 °C and treated with acryloyl chloride (17 mg, 0.19 mmol, 1.00 equiv.). The mixture was stirred for about 1 h at about 0 °C, then purified by prep-HPLC under the following conditions (Column: YMC-Actus Triart Cl 8, 50*250 mm,125333961159Attorney Docket No. CENC-011 / 08WO 360899-20455pm; Mobile Phase A: Water (containing lOmM NH4HCO3), Mobile Phase B: MeCN; Flow rate: 90mL / min; Gradient: 45% B to 75% B in 16 min; Wavelength: 254nm / 220nm; RT l(min): 10) to afford the title product 1-10 rac-7-((3a / ,5 / ,7aA')-2-acryloyloctahydro-l7 / -isoindol-5-yl)-2-((l -methyl- U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidine-6-carbonitrile (23 mg, 28% yield).

[0432] XHNMR (400 MHz, DMSO-t / e) 59.75 - 9.71 (m, 1H), 8.82 (s, 1H), 7.92- 7.82 (m, 1H), 7.71 - 7.43 (m, 2H), 6.67 - 6.49 (m, 1H), 6.18 - 6.08 (m, 1H), 5.72 - 5.61 (m, 1H), 4.66 - 4.62 (m, 1H), 3.88 - 3.81 (m, 3H), 3.76 - 3.52 (m, 2H), 3.49 - 3.36 (m, 2H), 2.45 - 2.33 (m, 3H), 2.11 - 1.77 (m, 5H).

[0433] LCMS Calculated for C22H24N8O: 416.2. Observed: 417.2 [M+H]+.

[0434] Purity (Method-B): 98.90% at RT 1.273 min.1-18rac- 1 -((3 a7?,4A, 57?,7a5)-4-hydroxy-5-(6-(( 1 -methyl- 177-pyrazol -4-yl )ami no)- 1H- pyrazolo[3,4- t / ]pyri mi di n- 1 -yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one

[0435] Step 1. rac-tert-butyl (3aR,4R,5R,7aS)-4-hydroxy-5-(6-((l-methyl-lH-pyrazol-4-yl)amino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)octahydro-2H-isoindole-2-carboxylate (A8-1)

[0436] A mixture of compound E23 (99 mg, 0.41 mmol, 1.00 equiv.), compound Al (63 mg, 0.29 mmol, 0.70 equiv.), and CS2CO3 (408 mg, 1.25 mmol, 3.00 equiv.) in DMF (2 mL) was heated at about 100 °C for about 2 h, then cooled to about 25 °C. Water (10 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined EtOAc extracts were washed with brine (1 x 10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (containing 0.1% NH4 OH), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound A8-1 (55 mg, 29% yield).LCMS Calculated for C22H30N8O3: 454.24; Observed: 455.3 [M+H]+.126333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0437] Step 2. rac-(3aR,4R,5R,7aS)-5-(6-((l-methyl-lH-pyrazol-4-yl)amino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)octahydro-lH-isoindol-4-ol (A8-2)A8-2

[0438] Compound A8-1 (50 mg, 0.11 mmol, 1.00 equiv.) was dissolved in a solution of HC1 (4.0 M in 1,4-dioxane, 1 mL) at about 0 °C for about 30 min before being concentrated to dryness to provide compound A8-2 hydrochloride (60 mg), which was used without further purification.LCMS Calculated for C17H22N8O: 354.2; Observed: 355.2 [M+H]+.

[0439] Step 3. rac-l-((3a / ,4 / ,5 / ,7ak)-4-hydroxy-5-(6-((l-methyl-l / / -pyrazol-4-yl)amino)- l / / -pyrazolo[3,4-t / ]pyrimidin- l-yl)octahydro-2 / / -isoindol-2-yl)prop-2-en-l-one (I-18)1-18

[0440] A solution of compound A8-2 (60 mg, 0.10 mmol, 1.00 equiv.) and EtsN (72 mg, 0.71 mmol, 6.00 equiv.) in DMF (1 mL) was cooled to about 0 °C for about 30 min, after which acryloyl chloride (13 mg, 0.14 mmol, 1.20 equiv.) was added. The reaction mixture was kept at 0 °C for about 30 min, brought to about 25 °C and treated with water (0.1 mL). The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (containing 0.1% formic acid), 10% to 50% gradient in 10 min; detector, UV 254 nm to provide the title product rac-l-((3a7?,47?,57?,7a5)-4-hydroxy-5-(6-(( 1 -methyl- 1 / / -pyrazol -4-yl )ami no)- 1 / / -pyrazol o[3,4-t ]pyrimidin- 1 -yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (7.2 mg, 17% yield).127333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0441] 1HNMR(300MHz, DMSO-£Z6)<59.79-9.56 (m, 1H), 8.87 (s, 1H), 8.06- 7.82 (m, 2H), 7.68 - 7.49 (m, 1H), 6.75 - 6.51 (m, 1H), 6.22 - 6.04 (m, 1H), 5.75 - 5.61 (m, 1H), 5.06 - 4.86 (m, 1H), 4.52 - 4.37 (m, 1H), 3.89 - 3.80 (m, 4H), 3.79 - 3.62 (m, 2H), 3.62 - 3.44 (m, 2H), 3.28 - 3.19 (m, 1H), 2.30 - 2.11 (m, 2H), 2.01 - 1.63 (m, 3H).

[0442] LCMS Calculated for C20H24N8O2: 408.2; Observed: 409.2 [M+H]+.

[0443] Purity (Method-A): 99.2% at RT 0.668 min.1-16rac-1 -((3a7?, 4A,5A,7a5)-4-methoxy-5-(2-((l -methyl- 17 / -pyrazol-4-yl)amino)-7J / -pyrrolo[2, 3- J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one

[0444] Step 1. rac-tert-butyl (3aR,4R,5R,7aS)-4-methoxy-5-(2-((l-methyl-lH-pyrazol-4-yl)((2-(trimethy lsilyl)ethoxy) methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B9-1)SEMB9-1

[0445] A solution of compound B5-1 (500 mg, 1.10 mmol, 1.00 equiv.) in THF (6.0 mL) was treated with sodium hydride (60%, 132 mg, 3.31 mmol, 3.00 equiv) at about 0 °C for about 30 min, after which 2-(trimethylsilyl)ethoxymethyl chloride (202 mg, 1.21 mmol, 1.10 equiv.) was added. The reaction mixture was stirred at about 0 °C for about 2 h, then iodomethane (469 mg, 3.31 mmol, 3.00 equiv.) was added. Stirring at about 0 °C was continued for about 2 h further prior to the addition of saturated aqueous NH4Q solution (10 mL) with continued cooling. The mixture was extracted with EtOAc (3 x 15 mL) and the combined EtOAc extracts were washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:2) to afford the title compound B9-1 (160 mg, 24% yield).LCMS Calculated for C30H47N7O4Si: 597.4; Observed: 598.5 [M+H]+

[0446] Step 2. rac-7-((3aR,4R,5R,7aS)-4-methoxyoctahydro-lH-isoindol-5-yl)-N-(l-methyl-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (B9-2)128333961159Attorney Docket No. CENC-011 / 08WO 360899-2045B9-2

[0447] To a solution of compound B9-1 (160 mg, 0.27 mmol, 1.00 equiv.) in DCM (3.0 mL) was added TFA (1.00 mL) at about 25 °C and the mixture was kept for about 2 h before being concentrated to dryness to afford the title product B9-2 trifluoroacetate (200 mg), which was used without further purification.LCMS Calculated for C19H25N7O: 367.2; Observed: 368.3 [M+H]+.

[0448] Step 3. rac-l-((3a7?,4A,5A,7a5)-4-methoxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (I-16)A solution of compound B9-2 trifluoroacetate (51.0 mg, 0.14 mmol, 1.00 equiv.) in DMF (1.0 mL) was treated with EtsN (42 mg, 0.42 mmol, 3.00 equiv.) at about 0 °C for about 5 min prior to the addition of acryloyl chloride (15 mg, 0.17 mmol, 1.20 equiv.). The reaction mixture was stirred at about 0 °C for about 1 h prior to the addition of water (0.2 mL) at about 25 °C. The mixture was purified by reverse phase flash chromatography under the following conditions: Column: Xbridge -phenyl Column, 30*150 mm, 5pm; Mobile Phase A: Water (containing 0.05% NH4OH), Mobile Phase B: MeOH; Flow rate: 35 mL / min; Gradient (B%): isocratic 30% - 90% 10 min; Wavelength: 254nm / 220nm nm; RT l(min): 7.6 to provide the title product 1-16 rac-1 -((3a7?,4A,5A, 7a5)-4-methoxy-5-(2-((l -methyl- UT-pyrazol -4-yl)amino)-7JT-pyrrolo[2,3-t ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (9.0 mg, 15% yield).

[0449] 1H NMR (400 MHz, DMSO-t / e) 59.16 - 9.11 (m, 1H), 8.60 (s, 1H), 7.93 - 7.85 (m, 1H), 7.79 - 7.31 (m, 2H), 6.70 - 6.52 (m, 1H), 6.42 (t, J = 3.9 Hz, 1H), 6.21 - 6.11 (m, 1H), 5.74 - 5.62 (m, 1H), 4.55 - 4.45 (m, 1H), 3.85 - 3.80 (m, 3H), 3.73 - 3.53 (m, 3H), 3.53 - 3.39 (m, 2H), 2.72 (s, 3H), 2.59 -2.51 (m, 1H), 2.45 - 1.92 (m, 2H), 1.92 - 1.65 (m, 3H).LCMS Calculated for C22H27N7O2: 421.2; Observed 422.2 [M+H]+.Purity (Method- A): 81.6% at RT 1.492 min.129333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-11rac-l-((3a / ,4 / ,5 / ,7aA')-4-hydroxy-5-(2-((l -methyl- / / / -pyrazol -4-yl )amino)-7 / / -pyrrolo[2, 3- t / ]pyrimidin-7-yl)octahydro-2 / / -isoindol-2-yl)prop-2-en-l-one

[0450] Stepl. rac-tert-butyl (3aR,7aR)-6-(((trifluoromethyl)sulfonyl)oxy)-l,3,3a,4,5,7a-hexahydro-2H-isoindole-2-carboxylate (E23-2)J N-BocE23-2

[0451] A solution of rac-tert-butyl (3aR,7aS)-5-oxo-hexahydro-lH-isoindole-2-carboxylate (CAS 1858251-59-8, 161 g, 673 mmol, 1.00 equiv.) in THF (1.6 L) was cooled to about -78 °C, and then LiHMDS (1.0 M in hexanes, 1.01 L, 1.01 mol, 1.50 equiv.) was added dropwise with continued cooling to about -78 °C. The mixture was stirred at about -78 °C for about 1 h prior to the addition of N-phenyl-bis(trifluoromethanesulfonimide) (CAS 37595-74-7, 288 g, 807 mmol, 1.20 equiv.) in portions over about 10 min with continued cooling at about -78 °C. The resulting mixture was then warmed to about 25 °C and stirred for about 3 h further. After cooling to about 0 °C, saturated aqueous NH4Q was added, then the mixture was diluted with water (3 L) and extracted with EtOAc (3 x I L). The combined extracts were washed with brine (1 x 500 mL), dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (10:1) to afford the title compound E23-2 (191 g, 76% yield).LCMS Calculated for C14H20NO5S: 371.10; Observed: 372.1 [M+H]+

[0452] Step 2. rac-tert-butyl (3aR,7aS)-l,3,3a,4,5,7a-hexahydro-2H-isoindole-2-carboxylate (E23-3)I N-Bocsi’"7E23-3

[0453] To a solution of E23-2 (180 g, 485 mmol, 1.00 equiv.) in THF (2.5 L) were added EtsN (110 g, 1.09 mol, 2.25 equiv.), formic acid (49.1 g, 1.07 mol, 2.20 equiv.), PPI13 (12.7 g, 48.5 mmol, 0.10 equiv.) and Pd(OAc)2 (3.26 g, 14.5 mmol, 0.03 equiv.) at about 25 C°. The mixture was heated to about 60 °C and kept for about 2 hours before being cooled to about 25 °C and concentrated. The residue was diluted with water (1000 mL) and extracted with EtOAc 130333961159Attorney Docket No. CENC-011 / 08WO 360899-2045(3 x 500 mL). The combined EtOAc extracts were washed with brine (1000 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography, eluted with petroleum ether / ethyl acetate (3:1) to afford the title compound E23-3 (95.0 g, 87% yield).LCMS Calculated for C13H21NO2: 223.2; Observed: 224.2 [M+H]+

[0454] Step 3. Mixture of rac-tert-butyl (laR,3aR,6aS,6bS)-octahydro-5H-oxireno[2,3-e]isoindole-5-carboxylate and rac-tert-butyl (laR,3aS,6aR,6bS)-octahydro-5H-oxireno[2,3-e]isoindole-5-carboxylate (E23)E23 mixture

[0455] A solution of E23-3 (95.0 g, 425 mmol, 1.00 equiv.) in DCM (1.00 L) was cooled to about 0 °C and m-CPBA (85%, 130 g, 638 mmol, 1.50 equiv.) was added in portions with continued cooling at about 0 °C, after which the reaction was continued for about 16 h at about 25 °C. A saturated aqueous sodium sulfite solution (1000 mL) was added and the mixture was extracted with DCM (3 x 500 mL). The combined DCM extracts were washed with NaHCCh (800 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (3:1) to afford the title compound mixture E23 (80 g, 78% yield).LCMS Calculated for C13H21NO3: 239.2; Observed: 240.2 [M+H]+

[0456] Step 4. rac-tert-butyl (3aR,4R,5R,7aS)-4-hydroxy-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B5-1)B5-1

[0457] Compound mixture E23 (200 mg, 0.84 mmol, 1.00 equiv.), compound Bl (125 mg, 0.59 mmol, 0.70 equiv.) and CS2CO3 (817 mg, 2.51 mmol, 3.00 equiv.) were combined in DMF 131333961159Attorney Docket No. CENC-011 / 08WO 360899-2045(5.0 mL) and heated at about 100 °C for about 4 h. After cooling to about 20 °C, water (15 mL) was added, followed by extraction with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with brine (1 x 20 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in Water (0.1% Ammonium Hydroxide), 10% to 80% gradient in 30 min; detector, UV 254 nm the title compound B5-1 (100 mg, 26% yield). LCMS Calculated for C23H31N7O3: 453.3; Observed: 454.3 [M+H]+.

[0458] Step 5. rac-(3aR,4R,5R,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-lH-isoindol-4-ol hydrochloride (B5-2)B5-2

[0459] Compound B5-1 (100 mg, 0.22 mmol, 1 equiv.) was dissolved in HC1 (4 M in 1,4-dioxane, 2.0 mL, 36 equiv.). The solution was stirred at about 25 °C for about 1 h, then concentrated to afford the title product B5-2 hydrochloride (5 mg).LCMS Calculated for C18H23N7O: 353.2; Observed: 354.3 [M+H]+.

[0460] Step 6. rac-l-((3a7?,4A,5A,7a5)-4-hydroxy-5-(2-((l-methyl-7J / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (I-OH1-11

[0461] A solution of compound B5-2 hydrochloride (90 mg, 0.26 mmol, 1.00 equiv.) in DMF (1.0 mL) was treated with EtiN (7 mg, 0.76 mmol, 3.00 equiv.) at about 0 °C for about 5 min, after which acryloyl chloride (28 mg, 0.31 mmol, 1.20 equiv.) was added. The reaction 132333961159Attorney Docket No. CENC-011 / 08WO 360899-2045mixture was stirred at about 0 °C for about 1 h, then diluted with water (0.20 mL) at about 25 °C. The product was isolated by prep-HPLC with the following conditions (Column: Ultimate - XT-C18 Column, 30*150 mm, 10pm; Mobile Phase A: Water (lOmmol / L Ammonium hydrogen carbonate), Mobile Phase B: Acetonitrile; Flow rate: 35 mL / min; Gradient (B%): isocratic 5%-60% 10 min; Wavelength: 254nm / 220nm; RT l(min): 8.2) to afford the title product 1-11 rac-l-((3a7?,4A,5A,7aS)-4-hydroxy-5-(2-((l-methyl-7J / -pyrazol-4-yl)amino)-777-pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-277-isoindol-2-yl)prop-2-en-l-one (42 mg, 40% yield).

[0462] ’H NMR (300 MHz, DMSO ) 59.05 (d, J= 3.3 Hz, 1H), 8.56 (s, 1H), 7.94-7.85 (m, 1H), 7.59-7.46 (m, 1H), 7.36 (t, J= 3.6 Hz, 1H), 6.69-6.53 (m, 1H), 6.35 (dd, J= 3.6, 2.1 Hz, 1H), 6.22-6.08 (m, 1H), 5.72-5.61 (m, 1H), 5.03-4.90 (m, 1H), 4.41 - 4.35 (m, 1H), 3.90 - 3.78 (m, 4H), 3.76 - 3.45 (m, 3H), 3.44 - 3.34 (m, 1H), 2.67 - 2.61 (m, 1H), 2.30 - 2.02 (m, 2H), 1.94 - 1.64 (m, 3H).

[0463] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.2 [M+H]+.

[0464] Purity (Method-A): 89.3% at RT 1.076 min.

[0465] Chiral purity (Method- V): 47.4% at RT 2.342 min, 47.0% at RT 3.214 min.1-211-13re / -7-((3a7?,57?,7a5)-2-acryloyloctahydro-177-isoindol-5-yl)-2-((l-methyl-177-pyrazol-4- yl)amino)-777-pyrrolo[2,3-J]pyrimidine-6-carbonitrile re / -7-((3a5',55',7a7?)-2-acryloyloctahydro-177-isoindol-5-yl)-2-((l-methyl-177-pyrazol-4- yl)amino)-777-pyrrolo[2,3-J]pyrimidine-6-carbonitrile

[0466] Step 1. Chiral Separation of 1-10 by preparative chiral HPLC

[0467] Compound 1-10 rac-7-((3aR,5R,7aS)-2-acryloyloctahydro-lH-isoindol-5-yl)-2- ((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (60 mg) was 133333961159Attorney Docket No. CENC-011 / 08WO 360899-2045separated under the following conditions: Column, XA-CHIRALPAK IH, 3*25 cm, 5 pm; Mobile Phase A: Hexane / DCM (5: 1 v / v), Mobile Phase B: MeOH / EtOH (1: 1 v / v); Flow rate: 35 mL / min; Gradient: isocratic 5; Wavelength: 254 nm; RT l(min): 8.3; RT 2(min): 9.8; Sample Solvent: hexane / EtOH (1: 1, v / v); Injection Volume: 0.5 mL; Number of runs: 26) to afford re / -7-((3a7?,5A,7a5)-2-acryloyloctahydro-U / -isoindol-5-yl)-2-((l-methyl-l / 7-pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidine-6-carbonitrile (1-13) (20 mg, 33% yield) and rel-1-((3a5',55',7a7?)-2-acryloyloctahydro-U / -isoindol-5-yl)-2-((l-methyl-U / -pyrazol-4-yl)amino)-7Z7-pyrrolo[2,3- ]pyrimidine-6-carbonitrile (1-21) (20 mg, 33% yield).

[0468] Data for 1-21

[0469] XH NMR (400 MHz, DMSO ) 59.84 - 9.66 (m, IH), 8.88 - 8.72 (m, IH), 7.96 -7.78 (m, IH), 7.73 - 7.42 (m, 2H), 6.68 - 6.46 (m, IH), 6.18 - 6.07 (m, IH), 5.73 - 5.57 (m, IH), 4.72 - 4.58 (m, IH), 3.89 - 3.80 (m, 3H), 3.76 - 3.53 (m, 2H), 3.49 - 3.36 (m, 2H), 2.47 -2.35 (m, 3H), 2.13 - 1.73 (m, 5H).

[0470] LCMS Calculated for: C22H24NsO: 416.2. Observed: 417.2 [M+H]+.

[0471] Purity (Method-F): 98.83% at RT 0.992 min.

[0472] Chiral purity (Method-A): 99.60% atRT 1.71 min.

[0473] Optical rotation: [a]D = +132, (c=0.1, MeOH, T=25oC).

[0474] Data for 1-13

[0475] XH NMR (400 MHz, DMSO-t / e) 59.83 - 9.64 (m, IH), 8.82 (s, IH), 7.94 - 7.81 (m, IH), 7.77 - 7.43 (m, 2H), 6.69 - 6.45 (m, IH), 6.19 - 6.04 (m, IH), 5.74 - 5.60 (m, IH), 4.74 -4.56 (m, IH), 3.91 - 3.81 (m, 3H), 3.75 - 3.53 (m, 2H), 3.51 - 3.36 (m, 2H), 2.47 - 2.37 (m, 3H), 2.11 - 1.92 (m, 2H), 1.91 - 1.75 (m, 3H).

[0476] LCMS Calculated for: C22H24N8O: 416.2. Observed: 417.2 [M+H]+.

[0477] Purity (Method-F): 98.92% at RT 0.986 min.

[0478] Chiral purity (Method-A): 100% at RT 1.58 min.

[0479] Optical rotation: [a]D= -148 (c = 0.1, MeOH, T=25 °C).1-261-121-29rel-\ -( 3aR, 4A,5A,7a5)-4-hydroxy-5-(2-((l -methyl- U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2, 3- J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one134333961159Attorney Docket No. CENC-011 / 08WO 360899-2045 / 'c7-l-((3ak,4k,5k,7a / )-4-hydroxy-5-(2-((l-methyl-l / / -pyrazol-4-yl)amino)-77 / -pyrrolo[2,3- t / ]pyrimidin-7-yl)octahydro-2 / / -isoindol-2-yl)prop-2-en-l-one racM-((3a / ,4k,5k,7ak)-4-hydroxy-5-(2-((l-methyl-l / / -pyrazol-4-yl)arnino)-7 / / -pyrrolo[2,3- t / ]pyrimidin-7-yl)octahydro-2 / / -isoindol-2-yl)prop-2-en-l-one

[0480] Step 1. Separation of 1-11 by preparative chiral chromatography1-26 1-12 1-29

[0481] Compound 1-11 (42 mg) was separated by chiral-SFC using the following conditions: Column: XA-CHIRALPAK ID, 2*25 cm, 5 pm; Mobile Phase A: MTBE, Mobile Phase B: Methanol (containing 0.5% 2M NHa in Methanol); Flow rate: 25mL / min; Gradient (B%): isocratic 20; Wavelength: 254 nm; RTl(min): 5.8; RT2 (min): 10.3; Sample Solvent: Ethanol / Dichloromethane (1; 1); Injection Volume: 2 mL; Number of runs: 4 to afford 1-12 re / -l-((3a5',45',55',7a7?)-4-hydroxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (20 mg, 48% yield) and a sample of impure rel-l-((3aR,4R,5R,7aS)-4-hydroxy-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindol-2-yl)prop-2-en-l-one (20 mg, 48% yield). This latter sample was further separated by chiral-SFC under the following conditions: Column: XA CHIRAL ART Amylose-C NEO, 3*25 cm, 5 pm; Mobile Phase A: Carbon Dioxide, Mobile Phase B: Methanol (containing 0.1% 2M NH3 in Methanol); Flow rate: 80 mL / min; Gradient (B%): isocratic 50% B; Column Temperature: 35 °C; Back Pressure(bar): 100; Wavelength: 220 nm; RTl(min): 3.51; RT2(min): 5.60; Sample Solvent: Methanol; Injection Volume: 4.5 mL to afford 1-26 re / -l-((3a7?,4A,5A,7a5)-4-hydroxy-5-(2-((1 -methyl- lJ / -pyrazol-4-yl)amino)-7J / -pyrrolo[2, 3-t / ]pyrimi din-7-yl)octahy dro-277-isoindol-2-yl)prop-2-en-l-one (15 mg, 35% yield) and 1-29 rac-l-((3a7?,45',55',7a5)-4-hydroxy-5-(2-((1 -methyl- lJ / -pyrazol-4-yl)amino)-7J / -pyrrolo[2, 3-t / ]pyrimi din-7-yl)octahy dro-277-isoindol-2-yl)prop-2-en-l-one (2.8 mg, 6.7% yield).

[0482] Data for 1-26135333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0483] XHNMR (400 MHz, DMSO ) 59.06 (d, J= 4.4 Hz, 1H), 8.56 (s, 1H), 7.94-7.84 (m, 1H), 7.58-7.48 (m, 1H), 7.37 (t, J = 4.4 Hz, 1H), 6.68-6.54 (m, 1H), 6.35 (t, J= 3.2 Hz, 1H), 6.20-6.11 (m, 1H), 5.71-5.64 (m, 1H), 5.01 - 4.93 (m, 1H), 4.40 - 4.32 (m, 1H), 3.89 -3.79 (m, 4H), 3.72 - 3.52 (m, 3H), 3.49-3.32 (m, 1H), 2.71 - 2.52 (m, 1H), 2.27 - 2.02 (m, 2H), 1.93 - 1.79 (m, 2H), 1.77 - 1.67 (m, 1H).

[0484] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.2 [M+H]+.

[0485] Purity (Method-B): 99.7% at RT 1.367 min.

[0486] Chiral purity (Method- V): 100.0% at RT 2.341 min.

[0487] Optical rotation: [aD] = +113° (c=0.106, MeOH, T = 25 °C).

[0488] Data for 1-12

[0489] ’H NMR (400 MHz, DMS0 ) 59.06 (d, J= 4.4 Hz, 1H), 8.57 (s, 1H), 7.93-7.85 (m, 1H), 7.57-7.49 (m, 1H), 7.37 (t, J = 4.4 Hz, 1H), 6.67-6.55 (m, 1H), 6.35 (t, J= 3.2 Hz, 1H), 6.20-6.11 (m, 1H), 5.72-5.63 (m, 1H), 5.02-4.92 (m, 1H), 4.43 -4.33 (m, 1H), 3.89-3.53 (m, 7H), 3.47-3.36 (m, 1H), 2.71 - 2.53 (m, 1H), 2.26 - 2.09 (m, 2H), 1.93 - 1.64 (m, 3H).

[0490] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.3 [M+H]+.

[0491] Purity (Method-B): 95.3% at RT 0.412 min.

[0492] Chiral purity (Method- V): 100.0% at RT 3.191 min,

[0493] Optical rotation: [aD] = -105° (c=0.110, MeOH, T = 25 °C).

[0494] Data for 1-29

[0495] XH NMR (400 MHz, DMSO-t / e) 59.10 (d, 8.8 Hz, 1H), 8.57 (s, 1H), 7.96 (d, J = 5.6 Hz, 1H), 7.56-7.47 (m, 1H), 7.26 (t, J= 3.6 Hz, 1H), 6.72-6.54 (m, 1H), 6.37 (d, J= 3.6 Hz, 1H), 6.21-6.11 (m, 1H), 5.74-5.63 (m, 1H), 5.01 -4.93 (m, 1H), 4.64 -4.54 (m, 1H), 4.46 - 4.32 (m, 1H), 3.82 (d, J= 9.2 Hz, 3H), 3.76-3.71 (m, 1H), 3.70 - 3.45 (m, 2H), 3.44 - 3.35 (m, 1H), 2.97 - 2.61 (m, 1H), 2.47 - 2.23 (m, 1H), 2.10 - 2.06 (m, 1H), 1.91 - 1.58 (m, 2H), 1.47 - 1.33 (m, 1H).

[0496] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.3 [M+H]+.

[0497] Purity (Method B): 99.3% at RT 0.561 min.

[0498] Chiral purity (Method- V): 99.3% at RT 2.839 min.1-34136333961159Attorney Docket No. CENC-011 / 08WO 360899-2045rac-1 -((3a7?,5A,7a5)-5-(6-(l -methyl- \H- 1,2, 3-tri azol-4-yl)-2-((l -methyl- UT-pyrazol-4- yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one

[0499] Step 1. rac-tert-butyl (3aR,5R,7aS)-5-{6-bromo-2-chloropyrrolo[2,3-d]pyrimidin-7-yl}-octahydroisoindole-2-carboxylate (D37-1)

[0500] A solution of rac-tert-butyl (3aR,5S,7aS)-5-hydroxy-octahydroisoindole-2-carboxylate (CAS 2007919-65-3, 500 mg, 2.07 mmol, 2.50 equiv.), 6-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS 1638763-34-4, 192 mg, 0.829 mmol, 1.00 equiv.), and CMBP (400 mg, 1.66 mmol, 2.00 equiv.) in toluene (30 mL) was heated at about 110 °C for about 1 h, then to about 25 °C. Water (1 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were washed with brine (1 x 30 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to afford the title compound D37-1 (350 mg), which was used without further purification.

[0501] LCMS Calculated for Ci9H24BrClN4O2: 454.1 (35C1,79Br isotopes); Observed: 455.1 [M+H]+(35C1,79Br isotopes).

[0502] Step 2. rac-tert-butyl (3aR,5R,7aS)-5-[2-chloro-6-(l-methyl-l,2,3-triazol-4-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-octahydroisoindole-2-carboxylate (D37-2)137333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0503] A solution of 4-bromo-l-methyl-l,2,3-triazole (CAS 13273-53-5, 43 mg, 0.26 mmol, 1.20 equiv.), hexamethyldistannane (79 mg, 0.24 mmol, 1.10 equiv.) and Pd(PPh3)4 (25 mg, 0.02 mmol, 0.10 equiv.) in toluene (20 mL) was heated at about 100 °C for about 2 h. The mixture was cooled to about 25 °C and compound D37-1 (100 mg, 0.22 mmol, 1.00 equiv.) and additional Pd(PPh3)4 (25 mg, 0.02 mmol, 0.10 equiv.) were added and the mixture was heated at 100 °C for about 1 h. After cooling to about 25 °C, water (1 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were washed with brine (1 x 40 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2:1) to afford the title compound D37-2 (40 mg), which was used without further purification.LCMS Calculated for C22H28CIN7O2: 457.2 (35C1 isotope); Observed: 458.2 [M+H]+(35C1 isotope).

[0504] Step 3. rac-tert-butyl (3aR,5R,7aS)-5-[6-(l-methyl-l,2,3-triazol-4-yl)-2-[(l-methylpyrazol-4-yl)amino]pyrrolo[2,3-d]pyrimidin-7-yl]-octahydroisoindole-2-carboxylate (D37-3)

[0505] A mixture of compound D37-2 (30 mg, 0.07 mmol, 1.00 equiv.) and 1-methylpyrazol-4-amine (19 mg, 0.2 mmol, 3.00 equiv.), CS2CO3 (64 mg, 0.2 mmol, 3.00 equiv.), and BINAP Pd G2 (CAS 1445085-60-8, 12 mg, 0.013 mmol, 0.20 equiv.) in 1,4-di oxane (10 mL) was heated at about 80 °C for about 2 h, then cooled to about 25 °C and water (0.1 mL) at about 25 °C. The mixture was extracted with EtOAc (3 x 10 mL), and the combined EtOAc extracts were washed with brine (1 x 10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol (10:1) to afford the title compound D37-3 (14 mg, 41% yield).LCMS Calculated for C26H34N10O2: 518.6; Observed: 519.6 [M+H]+.138333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0506] Step 4. rac-N-{7-[(3aR,5R,7aS)-octahydro-lH-isoindol-5-yl]-6-(l-methyl-l,2,3-triazol-4-yl)pyrrolo[2,3-d]pyrimidin-2-yl}-l-methylpyrazol-4-amine (D37-4)

[0507] A solution of compound D37-3 (10 mg, 0.02 mmol, 1.00 equiv.) and TFA (1 mL) in DCM (3 mL) was stirred at about 25 °C for about 1 h, then concentrated to dryness. The title compound D37-4 trifluoroacetate so obtained was used without further purification.LCMS Calculated for C21H26N10: 418.2; Observed: 419.2 [M+H]+.

[0508] Step 5. rac-l-((3a / ,5 / ,7aA')-5-(6-(l-methyl-l7 / -l,2,3-triazol-4-yl)-2-((l-methyl- IT / -pyrazol-4-yl)amino)-77 / -pyrrolo[2,3-t / ]pyrimidin-7-yl)octahydro-27 / -isoindol-2-yl)prop-2-en-l-one (1-34)1-34

[0509] A solution of compound D37-4 (8 mg, 0.02 mmol, 1.00 equiv.) in DCM (5 mL) was treated with Et₃N (4 mg, 0.04 mmol, 2.00 equiv.), followed by acryloyl chloride (2 mg, 0.02 mmol, 1.00 equiv.) at about 0 °C, then stirred at about 0 °C for about 30 min. Water (0.1 mL) was added and the mixture was concentrated. The residue was purified by prep-HPLC under the following conditions (Column: SunFirePrep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (containing 0.1% formic acid), Mobile Phase B: MeCN; Flow rate: 35 mL / min; Gradient (B%): isocratic 5% - 30% 10 min; Wavelength: 254nm / 220nm nm; RT l(min): 8.5) to afford the title product 1-34 rac-l-((3a7?,57?,7a5)-5-(6-(l-methyl-l / 7-l,2,3-triazol-4-yl)-2- 139333961159Attorney Docket No. CENC-011 / 08WO 360899-2045((l-methyl-l / / -pyrazol-4-yl)amino)-7 / / -pyrrolo[2,3-t / ]pyrimidin-7-yl)octahydro-2 / / -isoindol-2-yl)prop-2-en-l-one (3.5 mg, 39% yield).

[0510] 1H NMR (300 MHz, DMSO-6) 5 9.18 (s, 1H), 8.65 (d, J = 1.1 Hz, 1H), 8.46 (s, 1H), 7.88 - 7.44 (m, 2H), 6.68 - 6.47 (m, 2H), 6.11 (t, J = 2.8 Hz, 1H), 5.65 (m, 1H), 4.74 (d, J= 11.1 Hz, 1H), 4.13 (d, J = 2.9Hz, 3H), 3.85 (d, J = 10.9 Hz, 3H), 3.66 (d, J= 10.0 Hz, 2H), 3.43 - 3.21 (m, 2H), 2.90 (d, J = 13.4 Hz, 1H), 2.39 - 2.22 (m, 3H), 1.93 (d, J = 14.3 Hz, 1H), 1.83-1.65 (m, 3H).

[0511] LCMS Calculated for C24H28N10O: 472.2; Observed: 473.4 [M+H]+.

[0512] Purity (Method-A): 99.5% at RT 0.442 min.1-22rac-l-((3a / ,5 / ,7ak)-5-(2-((l-methyl-l / / -pyrazol-4-yl)amino)-6-(oxetan-3-yl)-7 / / - pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one

[0513] Step 1. rac-tert-butyl (3aR,5R,7aS)-5-[2-chloro-6-(oxetan-3-yl)pyrrolo[2,3-d]pyrimidin-7-yl]-octahydroisoindole-2-carboxylate (D39-1)D39-1

[0514] A mixture of compound D37-1 (100 mg, 0.219 mmol, 1.00 equiv), 3-bromooxetane (30 mg, 0.22 mmol, 1.00 equiv.), nickel(II) chloride ethylene glycol dimethyl ether complex (6 mg, 0.04 mmol, 0.20 equiv.), zinc (86 mg, 1.31 mmol, 6.00 equiv.), and pyridine-2-carboximidamide hydrochloride (7 mg, 0.04 mmol, 0.20 equiv.) in DMA (3.0 mL) was heated at about 60 °C for about 2 h, then cooled to about 25 °C diluted with water (10 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the combined EtOAc extracts were washed with brine (2 x 20 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound D39-1 (30 mg, 31% yield).LCMS Calculated for C22H29CIN4O3: 432.2 (35C1 isotope); Observed: 433.9 [M+H]+(35C1 isotope).140333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0515] Step 2. rac-tert-butyl (3aR,5R,7aS)-5-{2-[(l-methylpyrazol-4-yl)amino]-6- (oxetan-3-yl)pyrrolo[2,3-d]pyrimidin-7-yl}-octahydroisoindole-2-carboxylate (D39-2)D39-2

[0516] A mixture of compound D39-1 (28.0 mg, 0.065 mmol, 1.00 equiv.), 1-methylpyrazol-4-amine (13 mg, 0.13 mmol, 2.00 equiv.), CS2CO3 (63 mg, 0.2 mmol, 3.00 equiv.), and BINAP Pd G2 (12.0 mg, 0.013 mmol, 0.20 equiv.) in 1,4-dioxane (15 mL) was heated at about 80 °C for about 3 h, then cooled and water (30 mL) was added. The mixture was extracted with EtOAc (3 x 20 mL) and the combined EtOAc extracts were washed with brine (1 x 10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with di chloromethane / methanol (10:1) to afford the title compound D39-2 (18 mg, 56% yield).LCMS Calculated for C26H35N7O3: 493.3; Observed: 494.3 [M+H]+.

[0517] Step 3. rac-N-{7-[(3aR,5R,7aS)-octahydro-lH-isoindol-5-yl]-6-(oxetan-3-yl)pyrrolo[2,3-d]pyrimidin-2-yl}-l-methylpyrazol-4-amine (D39-3)

[0518] Compound D39-2 (16 mg, 0.03 mmol, 1.00 equiv.) was dissolved in DCM (3.0 mL) and treated with TFA (1.0 mL). The mixture was stirred at about 25 °C for about 1 h, then141333961159Attorney Docket No. CENC-011 / 08WO 360899-2045concentrated to dryness to give the title compound D39-3 trifluoroacetate (8 mg), which was used without further purification.LCMS Calculated for C21H27N7O: 393.3; Observed: 394.3 [M+H]+.

[0519] Step 4. rac-l-[(3aR,5R,7aS)-5-{2-[(l-methylpyrazol-4-yl)amino]-6-(oxetan-3-yl)pyrrolo[2,3-d]pyrimidin-7-yl}-octahydroisoindol-2-yl]prop-2-en-l-one (1-22)1-22

[0520] A solution of compound D39-3 (8 mg, 0.02 mmol, 1.00 equiv.) in DCM (2.0 mL) was treated with Et₃N (4 mg, 0.04 mmol, 2.00 equiv.), followed by the addition of acryloyl chloride (2 mg, 0.02 mmol, 1.00 equiv.) at about 0 °C and for about 30 min. Water (0.2 mL) was added and the mixture was concentrated. The residue was purified by prep-HPLC under the following conditions (Column: SunFirePrep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (containing 0.1% formic acid), Mobile Phase B: MeCN; Flow rate: 35 mL / min; Gradient (B%): isocratic 5% - 30% lOmin; Wavelength: 254nm / 220nm; RT l(min): 8.8) to afford the title product 1-22 (0.7 mg, 8% yield).

[0521] ’H NMR (300 MHz, DMSO-t / e) 59.19 (s, 1H), 8.57 (d, = 1.6 Hz, 1H), 7.86-7.41 (m, 2H), 6.69 - 6.45 (m, 2H), 6.10 (t, J = 2.5 Hz, 1H), 5.65 (t, J= 10.8, 1H), 5.00 - 4.90 (m, 2H), 4.74 - 4.65 (m, 2H), 4.59 (d, J= 8.1 Hz, 2H), 3.89 - 3.77 (m, 3H), 3.42 - 3.20 (m, 1H), 3.13 - 3.01 (m, 1H), 2.35 (d, J= 16.0 Hz, 1H), 2.19 - 2.04 (m, 1H), 2.00 - 1.87 (m, 2H), 1.68 - 1.52 (m, 3H), 1.24 - 1.12 (m, 3H).

[0522] LCMS Calculated for C24H29N7O2: 447.2; Observed: 448.3 [M+H]+.

[0523] Purity (Method-A): 96.7% at RT 0.522 min.1-25rac-l-((3a7?,45',5A,7a5)-4-hydroxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one142333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0524] Step 1. rac-tert-butyl (3aR,4S,5R,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((4-nitrobenzoyl)oxy)octahydro-2H-isoindole-2-carboxylate (B12-1)B12-1

[0525] A solution of compound B5-1 (1.20 g, 2.65 mmol, 1.00 equiv.) in THF (24 mL) was treated with 4-nitrobenzoic acid (0.440 g, 2.65 mmol, 1.00 equiv.) and PPh3(2.08 g, 7.94 mmol, 3.00 equiv.) at about 0 °C for about 30 min, followed by the addition of di -tert-butyl azodi carb oxy late (1.22 g, 5.29 mmol, 2.00 equiv.) with continued cooling to about 0 °C over about 30 min before being stirred at about 25 °C for 14 h. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 40 mL). The combined EtOAc extracts were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (containing 0.1% NH4OH), 30% - 60% gradient in 10 min; detector, 254 nm to provide the title compound B12-1 (1.00 g, 63% yield).LCMS Calculated for C30H34N8O6: 602.3; Observed: 603.3 [M+H]+.

[0526] Step 2. rac-tert-butyl (3aR,4S,5R,7aS)-4-hydroxy-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B12-2)

[0527] A solution of compound B12-1 (900 mg, 1.49 mmol, 1.00 equiv.) in THF (20 mL) and water (7 mL) was treated with LiOH monohydrate (250 mg, 6.0 mmol, 4.00 equiv.) at 143333961159Attorney Docket No. CENC-011 / 08WO 360899-2045about 25 °C for about 36 h. After dilution with water (100 mL), the mixture was extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated to afford the title compound B12-2 (650 mg, 96% yield). LCMS Calculated for C23H31N7O3: 453.3; Observed: 454.3 [M+H]+.

[0528] Step 3. rac-(3aR,4S,5R,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-lH-isoindol-4-ol (B12-3)B12-3

[0529] A solution of compound B12-2 (70 mg, 0.154 mmol, 1.00 equiv.) in DCM (2.0 mL) was treated with TFA (0.70 mL) at about 25 °C for about 30 min, then concentrated to dryness to give the title compound B12-3 trifluoroacetate (100 mg), which was used without further purification, a yellow oil.LCMS Calculated for C18H23N7O: 353.2; Observed: 354.2 [M+H]+.

[0530] Step 4. rac-l-((3a7?,45,5A,7a5)-4-hydroxy-5-(2-((l-methyl-lJ / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (I- 25)1-25

[0531] A solution of compound B12-3 trifluoroacetate (92 mg, 0.14 mmol, 1.00 equiv.) and Et3N (112 mg, 1.11 mmol, 8.00 equiv.) in DMF (2.0 mL) was treated with acryloyl chloride (15 mg, 0.17 mmol, 1.20 equiv.) at about 0 °C for about 30 min. After warming to about 25 °C, water (0.2 mL) was added and the mixture was purified by reversed-phase flash 144333961159Attorney Docket No. CENC-011 / 08WO 360899-2045chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (containing 0.1% formic acid), 10% - 40% gradient in 10 min; detector, 254 nm to give the title product 1-25 rac-l-((3a7?,45',5A,7a5)-4-hydroxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7Z7-pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2Z7-isoindol-2-yl)prop-2-en-l-one (35 mg, 61% yield).

[0532] 1H NMR (300 MHz, CDCl₃) d 10.75 - 10.08 (m, 1H), 8.40 - 8.30 (m, 1H), 7.92 -7.79 (m, 1H), 7.68 - 7.60 (m, 1H), 7.47 - 7.30 (m, 1H), 6.50 - 6.05 (m, 3H), 5.64 - 5.54 (m, 1H), 4.67 - 4.51 (m, 1H), 4.28 - 4.14 (m, 1H), 3.90 (s, 3H), 3.82 - 3.63 (m, 2H), 3.62 - 3.50 (m, 2H), 2.67 - 2.47 (m, 2H), 2.45 - 2.34 (m, 1H), 2.08 - 1.89 (m, 2H), 1.76 - 1.55 (m, 2H).

[0533] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.3 [M+H]+.

[0534] Purity (Method-A): 97.6% at RT 1.307 min.1-28rac- 1 -((3a7?,5A,7a5)-5-(2-((l -(oxetan-3-yl)- 17 / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3 - J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one

[0535] Step 1. rac-tert-butyl (3a7?,5A,7a5)-5-(2-((l-(oxetan-3-yl)-17 / -pyrazol-4-yl)amino)-7Z7-pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2Z7-isoindole-2-carboxylate (Bll-1)rac-fert-butyl (3aR,5R,7aS)-5-(2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)-7f / - pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylateBll-1

[0536] A mixture of compound B3-1 (200 mg, 0.531 mmol, 1.00 equiv.), l-(oxetan-3-yl)pyrazol-4-amine (CAS 1338719-26-8, 88 mg, 0.64 mmol, 1.20 equiv.) and CS2CO3 (518 mg, 1.59 mmol, 3.00 equiv.) in DMF (2.0 mL) was treated with BrettPhos Pd G4 (CAS 1599466-83-7, 48 mg, 0.05 mmol, 0.100 equiv.) and heated at about 100 °C for about 4 h, then cooled to about 25 °C and diluted with water (2.0 mL). The mixture was extracted with EtOAc (2 x 3.0 mL). The combined EtOAc extracts were washed with brine (2 x 3 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column 145333961159Attorney Docket No. CENC-011 / 08WO 360899-2045chromatography, eluted with petroleum ether / ethyl acetate (5: 1) to afford the title compound Bll-1 (160 mg, 63%yield).LCMS Calculated for C25H33N7O3: 479.3; Observed: 480.3 [M+H]+.

[0537] Step 2. rac-7-((3aR,5R,7aS)-octahydro-lH-isoindol-5-yl)-N-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Bl 1-2)

[0538] A solution of compound Bll-1 (150 mg, 0.31 mmol, 1.00 equiv.) and TFA (0.50 mL) in DCM (1.5 mL) was stirred at about 25 °C for 1 h, then concentrated to dryness to provide the title compound Bl 1-2 trifluoroacetate (200 mg), which was used without further purification.LCMS Calculated for C20H25N7O: 379.2; Observed: 380.2 [M+H]+.

[0539] Step 3. rac- 1 -[(3 aR, 5R,7aS)-5-(2-{ [ 1 -(oxetan-3 -yl)pyrazol-4-yl]amino}pyrrolo[2,3-d]pyrimidin-7-yl)-octahydroisoindol-2-yl]prop-2-en-l-one (1-28)

[0540] A solution of Bl 1-2 trifluoroacetate (40 mg, 0.10 mmol, 1.00 equiv.), Et₃N (32 mg, 0.32 mmol, 3.00 equiv.) in DCM (1.0 mL) was treated with acryloyl chloride (11 mg, 0.13 mmol, 1.20 equiv.) at about 0 °C, then stirred at about 25 °C for 1 h. The reaction mixture was 146333961159Attorney Docket No. CENC-011 / 08WO 360899-2045purified by prep-HPLC under the following conditions: Column, XBridge Prep Cl 8 OBD 19*150mm 5um; mobile phase, A: water containing 0.05% NH4OH; B: MeCN; Gradient: 30 -60% B in 7.9 min; Flow rate: 20 mL / min; Detector, 254 nm to provide the title product 1-28 rac-l-((3a7?,57?,7a5)-5-(2-((l-(oxetan-3-yl)-177-pyrazol-4-yl)amino)-777-pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-277-isoindol-2-yl)prop-2-en-l-one (17 mg, 37% yield).

[0541] ¹H NMR (400 MHz, DMSO-d₆): 5 9.27 (s, 1H), 8.61 (s, 1H), 8.15 (d, J = 6.2 Hz, 1H), 7.71 (d, J= 9.3 Hz, 1H), 7.40 (t, J= 3.8 Hz, 1H), 6.61 - 6.49 (m, 1H), 6.38 (t, J= 3.5 Hz, 1H), 6.14 (ddd, J= 16.8, 4.3, 2.5 Hz, 1H), 5.66 (ddd, J= 15.0, 10.3, 2.5 Hz, 1H), 5.61 - 5.50 (m, 1H), 4.99 - 4.83 (m, 4H), 4.56 (s, 1H), 3.77 - 3.41 (m, 3H), 3.39 (d, J= 4.3 Hz, 1H), 2.42 (s, 1H), 2.04 - 1.64 (m, 7H).LCMS Calculated for C23H27N7O2: 433.2; Observed: 434.3 [M+H]+.Purity (Method-B): 99.7% atRT 0.549 min.1-14rac-l-((3a7?, 57?, 7a5)-5-(2-((l -(2 -hydroxy ethyl)- 177-pyrazol-4-yl)amino)-777-pyrrolo[2, 3- ]pyrimidin-7-yl)octahydro-277-isoindol-2-yl)prop-2-en-l-one

[0542] Step 1. rac-tert-butyl (3aR,5R,7aS)-5-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B3-1)Boc^N\B3-1

[0543] A mixture of tert-butyl (3aR,5S,7aS)-5-hydroxyoctahydro-2H-isoindole-2-carboxylate (CAS 2007919-65-3, 1.50 g, 6.21 mmol, 1.00 equiv.), 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS 335654-06-3, 956 mg, 6.23 mmol, 1.00 equiv.) and CMBP (6.00 g, 24.9 mmol, 4.00 equiv.) in toluene (20 mL) was heated at about 90 °C for about 3 h, then cooled to about 20 °C, diluted with water (20 mL), and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methanol gradient (50: 1 to 20: 1) to afford the title compound B3-1 (1.1 g, 46% yield).147333961159Attorney Docket No. CENC-011 / 08WO 360899-2045LCMS Calculated for C19H25CIN4O2: 376.2; Observed: 377.2 [M+H]+.

[0544] Step 2. rac-tert-butyl (3aR,5R,7aS)-5-(2-((l-(2-hydroxyethyl)-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B3-2)B3-2

[0545] A mixture of compound B3-1 (250 mg, 0.663 mmol, 1.00 equiv.), 2-(4-amino-lH-pyrazol-l-yl)ethan-l-ol (CAS 948571-47-9, 127 mg, 0.999 mmol, 1.51 equiv.), cesium carbonate (648 mg, 1.99 mmol, 3.00 equiv.) and BINAP Pd G2 (CAS 1445085-60-8, 62 mg, 0.066 mmol, 0.10 equiv.) in 1,4-dioxane (8.0 mL) was heated at about 80°C for about 8 h, then cooled to about 25 °C, filtered, and the filter cake was washed with ethyl acetate (3 x 10 mL). The filtrates were combined, washed with brine, and concentrated. The residue was purified by silica gel column chromatography, eluted with di chloromethane / methanol (20: 1) to afford the title compound B3-2 (217 mg, 70% yield).LCMS Calculated for C24H33N7O3: 467.3; Observed: 468.3 [M+H]+.

[0546] Step 3. rac-2-(4-((7-((3aR,5R,7aS)-octahydro-lH-isoindol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)- IH-pyrazol- 1 -yl)ethan- 1 -ol (B3-3)

[0547] To a solution of compound B3-2 (80 mg, 0.17 mmol, 1.00 equiv.) inDCM (2.0 mL) was added TFA (0.5 mL) at about 20 °C. After about 2 h about 20 °C, the mixture was 148333961159Attorney Docket No. CENC-011 / 08WO 360899-2045concentrated to afford the title compound B3-3 trifluoroacetate (70 mg) which was used without further purification.

[0548] LCMS Calculated for C19H25N7O: 367.2; Observed: 368.3 [M+H]+.

[0549] Step 4. rac-l-((3a7?,5A,7a5)-5-(2-((l-(2-hydroxyethyl)-U / -pyrazol-4-yl)amino)- 7J / -pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (1-14)1-14

[0550] A solution of compound B3-3 (61 mg, 0.17 mmol, 1.00 equiv.) in DMF (1.5 mL) was treated with Et₃N (0.12 mL, 0.83 mmol, 5.00 equiv.) at about 20 °C for about 30 min, after which acryloyl chloride (15 mg, 0.17 mmol, 1.00 equiv.) was added at about 0 °C. The reaction was subsequently diluted with water (0.2 mL) at 0 °C. The product was isolated by prep-HPLC with the following conditions Column: SunFire Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water(0.1% formic acid), Mobile Phase B: MeCN; Flow rate: 35 mL / min; Gradient (B%): isocratic 5%-40% lOmin; Wavelength: 254nm / 220nm; RT l(min): 9.3 to afford the title product 1-14 rac-l-((3a7?,5A,7a5)-5-(2-((l-(2-hydroxyethyl)-U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (18 mg, 26% yield).

[0551] 1HNMR(300 MHz, CDCh) 3 10.31 (s, 1H), 8.38 (s, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.81 (s, 1H), 7.11 (s, 1H), 6.60 - 6.30 (m, 3H), 5.80 - 5.59 (m, 1H), 4.55 (d, J= 12.6 Hz, 1H), 4.25 (d, J= 5.2 Hz, 2H), 4.04 (s, 2H), 3.80 - 3.64 (m, 2H), 3.64 - 3.47 (m, 2H), 3.43 (d, J = 10.2 Hz, 1H), 2.64 -2.54 (m, 2H), 2.03 - 1.86 (m, 4H), 1.85 - 1.66 (m, 1H).

[0552] LCMS Calculated for C22H27N7O2: 421.2; Observed 422.3 [M+H]+.

[0553] Purity (Method-A): 97.6% at RT 1.558 min.1-15149333961159Attorney Docket No. CENC-011 / 08WO 360899-2045rac-l-((3aA, 5R, 7a5)-5-(2-((l -(2 -methoxy ethyl)- IT / -pyrazol-4-yl)amino)-77 / -pyrrolo[2, 3- t / ]pyrimidin-7-yl)octahydro-27 / -isoindol-2-yl)prop-2-en-l-one

[0554] Step 1. rac-tert-butyl (3aR,5R,7aS)-5-(2-((l-(2-methoxyethyl)-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (D40-1)D40-1

[0555] A mixture of compound D38-1 (200 mg, 0.53 mmol, 1.00 equiv.), l-(2-methoxyethyl)pyrazol-4-amine CAS 948570-74-9, 112 mg, 0.80 mmol, 1.50 equiv.), CS2CO3 (519 mg, 1.59 mmol, 3.00 equiv.) and BINAP Pd G2 (CAS 1445085-60-8, 50 mg, 0.05 mmol, 0.100 equiv.) in 1,4-dioxane (5.0 mL) was heated at about 80 °C for about 8 h, then cooled and filtered. The filter cake was washed with EtOAc (3 x 10 mL) and the combined filtrates were concentrated. The residue was purified by silica gel column chromatography, eluted with DCM / methanol (20:1) to afford the title compound D40-1 (225 mg, 88% yield).LCMS Calculated for C25H35N7O3: 481.3; Observed: 482.4 [M+H]+.

[0556] Step 2. rac-N-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)-7-((3aR,5R,7aS)-octahydro-lH-isoindol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (D40-2)D40-2

[0557] A solution of compound D40-1 (85 mg, 0.18 mmol, 1.00 equiv.) and TFA (0.5 mL) in DCM (2.0 mL) was stirred at about 20 °C for about 2 h, then concentrated to dryness to150333961159Attorney Docket No. CENC-011 / 08WO 360899-2045afford the title compound D40-2 trifluoroacetate (70 mg), which was used without further purification.LCMS Calculated for C20H27N7O: 381.2; Observed: 382.3 [M+H]+.

[0558] Step 3. rac-l-((3a7?,5A,7a5)-5-(2-((l-(2-methoxyethyl)-U / -pyrazol-4-yl)amino)- 7J / -pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (1-15)

[0559] A solution of compound D40-2 (66 mg, 0.16 mmol, 1 equiv.) in DMF (1.0 mL) was treated with Et3N (0.07 mL, 0.48 mmol, 3.00 equiv.) at about 20 °C for 30 min, followed by the addition of acryloyl chloride (14 mg, 0.16 mmol, 1.00 equiv.) at about 0 °C. After about 30 min at about 0 °C, water (0.2 mL) was added and the mixture was purified by prep-HPLC under the following conditions (Column: Xbridge -Phenyl Column, 30*150 mm, 5pm; Mobile Phase A: Water (containing 10 mM NH4HCO3), Mobile Phase B: MeCN; Flow rate: 35 mL / min; Gradient (B%): isocratic 18% - 48% 14 min; Wavelength: 254nm / 220nm; RT l(min): 8.87) to afford the title product 1-15 rac-l-((3a7?,5A,7a5)-5-(2-((l-(2-methoxyethyl)-U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (11 mg).

[0560] ’H NMR (300 MHz, DMSO-t / e) 5 9.16 (s, 1H), 8.59 (s, 1H), 7.98 (d, J = 5.5 Hz, 1H), 7.57 (d, J= 6.7 Hz, 1H), 7.38 (t, J= 3.4 Hz, 1H), 6.67-6.50 (m, 1H), 6.37 (t, J= 3.0 Hz, 1H), 6.21 - 6.05 (m, 1H), 5.66 (td, J= 10.7, 2.5 Hz, 1H), 4.53 (t, J= 6.0 Hz, 1H), 4.22 (s, 2H), 3.74-3.60 (m, 4H), 3.55-3.39 (m, 2H), 3.25 (s, 3H), 2.47-2.35(m, 2H), 2.09 - 1.57 (m, 6H).

[0561] LCMS Calculated for C23H29N7O2: 435.2; Observed: 436.2 [M+H]+.

[0562] Purity (Method-D): 91.3% purity at RT 0.968 min.1-30151333961159Attorney Docket No. CENC-011 / 08WO 360899-2045rac-l-((3a7?,45',5A,7a5)-4-methoxy-5-(2-((l-methyl-17 / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- t / ]pyrimidin-7-yl)octahydro-27 / -isoindol-2-yl)prop-2-en-l-one

[0563] Step 1. rac-tert-butyl (3aR,4S,5R,7aS)-4-methoxy-5-(2-((l-methyl-lH-pyrazol-4-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B10-1)SEMB10-1

[0564] A solution of compound B12-2 (100 mg, 0.22 mmol, 1.00 equiv.) in DMF (2.0 mL) was treated with NaH (60%, 27 mg, 0.66 mmol, 3.00 equiv.) at about 0 °C for about 30 min, after which 2-(trimethylsilyl)ethoxymethyl chloride (40 mg, 0.24 mmol, 1.10 equiv.) was added. Stirring at about 0 °C was continued for about 1 h, then iodomethane (94 mg, 0.66 mmol, 3.00 equiv.) was added. After stirring at about 0 °C for about 1 h further, saturated aqueous NH4CI (5.0 mL) was added and the mixture was extracted with EtOAc (3 x 5 mL). The combined EtOAc extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:2) to afford the title compound B10-1 (80 mg, 61% yield). LCMS Calculated for C30H47N7O4Si: 597.4; Observed: 598.4 [M+H]+.

[0565] Step 2. rac-7-((3aR,4S,5R,7aS)-4-methoxyoctahydro-lH-isoindol-5-yl)-N-(l-methyl-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (B10-2)B10-2

[0566] A solution of compound B10-1 (70 mg, 0.12 mmol, 1.00 equiv.) in DCM (1.5 mL) was treated with TFA (0.5 mL) at about 25 °C for about 1 h then concentrated to dryness to152333961159Attorney Docket No. CENC-011 / 08WO 360899-2045afford the title product B10-2 trifluoroacetate (100 mg), which was used without further purification.LCMS Calculated for C19H25N7O: 367.2; Observed: 368.3 [M+H]+.

[0567] Step 3. rac-l-((3a7?,45',5A,7a5)-4-methoxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (I- 30)1-30

[0568] A solution of compound B10-2 trifluoroacetate (43 mg, 0.12 mmol, 1.00 equiv.) in DMF (1.0 mL) was treated with EtsN (36 mg, 0.35 mmol, 3.00 equiv.) at about 0 °C for about 5 min, after which acryloyl chloride (13 mg, 0.14 mmol, 1.20 equiv.) was added. After about 1 h at about 0 °C, water (0.20 mL) was added at about 25 °C. The mixture was purified by reverse phase flash chromatography under the following conditions: Column: SunFire Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (containing 0.1% formic acid), Mobile Phase B: MeCN; Flow rate: 35 mL / min; Gradient (B%): isocratic 5% - 35% 10 min; Wavelength: 254nm / 220nm; RT l(min): 9.2 to provide the title compound 1-30 rac-1-((3a7?,45',5A,7a5)-4-methoxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (10 mg, 20% yield).

[0569] 'H NMR (400 MHz, DMSO-t / e) 5 10.20 (s, 1H), 8.81 (d, J= 1.8 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J= 3.8 Hz, 1H), 6.66 - 6.59 (m, 1H), 6.59 - 6.51 (m, 1H), 6.16 - 6.06 (m, 1H), 5.68 - 5.59 (m, 1H), 4.70 - 4.61 (m, 1H), 3.87 (s, 3H), 3.76 - 3.56 (m, 3H), 3.51 - 3.19 (m, 2H), 2.82 (d, J= 5.1 Hz, 3H), 2.57 - 2.52 (m, 1H), 2.49 - 2.27 (m, 2H), 2.05 - 1.84 (m, 2H), 1.67 - 1.60 (m, 1H).

[0570] LCMS Calculated for C22H27N7O2: 421.2; Observed: 422.3 [M+H]+.

[0571] Purity (Method-A): 95.4% at RT 1.295 min.1-45153333961159Attorney Docket No. CENC-011 / 08WO 360899-2045rac-l-((3a7?,45',55',7a5)-4-hydroxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)pyrrolo[2,l- f\ [ 1,2,4]tri azi n-7-yl )octahydro-2 / / -i soi ndol -2-yl )prop-2-en- 1 -one

[0572] Step 1. rac-tert-butyl (3aR,4R,5S,7aS)-4-hydroxy-5-(2-[(l-methylpyrazol-4-yl)amino]pyrrolo[2,l-f][l,2,4]triazin-7-yl-octahydroisoindole-2-carboxylate (Cll-1)Cll-1

[0573] To a solution of compound E24 (10.0 g, 27.2 mmol, 1.00 equiv.) and compound Cl-A (7.98 g, 27.2 mmol, 1.00 equiv.) in DMA (200 mL) were added pyridine-2,6-dicarboximidamide dihydrochloride (1.29 g, 5.45 mmol, 0.200 equiv.), zinc dust (5.34 g, 81.7 mmol, 3.00 equiv.) and nickel (II) chloride ethylene glycol dimethyl ether complex (5.98 g, 27.2 mmol, 1.00 equiv.) at about 25 °C, after which the mixture was heated at about 50 °C for about 1 h. After cooling to about 25 °C, water (500 mL) was added and the mixture was filtered. The filtrate was extracted with EtOAc (2 x 200 mL). The filter cake was washed with EtOAc (2 x 200 mL). The combined EtOAc extracts and EtOAc filtrates were washed with brine (2 x 200 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound Cll-1 (1.6 g, 13% yield).LCMS Calculated for C23H31N7O3: 453.2; Observed: 454.3 [M+H]+.

[0574] Step 2. rac-tert-butyl (3aR,4R,5S,7aS)-4-(((chloromethyl)sulfonyl)oxy)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (Cl 1-2)154333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0575] A solution of compound Cll-1 (250 mg, 0.551 mmol, 1.00 equiv.) and 2,6-lutidine (354 mg, 3.31 mmol, 6.00 equiv.) in DCM (5.0 mL) was treated with chloromethanesulfonyl chloride (205 mg, 1.38 mmol, 2.50 equiv.) at about 0 °C, then stirred at about 25 °C for about 3 h. Water (5.0 mL) was added and the mixture was extracted with DCM (3 x 5.0 mL). The combined DCM extracts were washed with 1 M HC1 (1 x 10 mL), saturated aqueous NaHCCh (1 x 10 mL), brine (1 x 10 mL), dried (Na2SO4), filtered and concentrated to afford the title compound Cl 1-2 (280 mg, 90% yield), which was used without further purification.LCMS Calculated for C24H32ClN7O5S: 565.2 (35Cl isotope); Observed: 566.4 [M+H]+, (35Cl isotope).

[0576] Step 3. rac-tert-butyl (3aR,4S,5S,7aS)-4-acetoxy-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (Cll-3)

[0577] A mixture of compound Cll-2 (280 mg, 0.495 mmol, 1.00 equiv.), cesium acetate (285 mg, 1.49 mmol, 3.00 equiv.) and 18-crown-6 (65 mg, 0.25 mmol, 0.50 equiv.) in toluene (6.0 mL) was heated at about 80 °C for about 4 h, then cooled to about 25 °C and filtered. The filter cake was washed with EtOAc (3 x 5.0 mL) and the combined filtrates were concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:5) to afford the title compound Cll-3 (136 mg, 55% yield).LCMS Calculated for C25H33N7O4: 495.3; Observed: 496.4 [M+H]+.

[0578] Step 4. rac-tert-butyl (3aR,4S,5S,7aS)-4-hydroxy-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (Cll-4)333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0579] Compound Cll-3 (136 mg, 0.27 mmol, 1.00 equiv.) and K2CO3 (114 mg, 0.82 mmol, 3.00 equiv.) were heated in methanol (3.0 mL) at about 60 °C for about 1 h, then cooled to about 25 °C and filtered. The filter cake was washed with DCM (3 x3.0 mL). The combined filtrates were concentrated and the residue was purified by silica gel column chromatography, eluted with petroleum ether / THF (1: 1) to afford the title compound Cll-4 (44 mg, 35% yield).

[0580] 'H NMR (400 MHz, DMSO-t / e) 5 9.25 (s, 1H), 8.76 (s, 1H), 7.84 (s, 1H), 7.52 (s, 1H), 6.77 (d, J= 4.5 Hz, 1H), 6.64 - 6.58 (m, 1H), 4.69 - 4.60 (m, 1H), 4.29 - 3.98 (m, 1H), 3.83 (s, 3H), 3.56 - 3.45 (m, 1H), 3.20 - 2.91 (m, 3H), 2.32 - 2.15 (m, 1H), 2.04 - 1.93 (m, 1H), 1.78 - 1.64 (m, 1H), 1.56 - 1.34 (m, 3H), 1.34 - 1.25 (m, 9H), 1.25 - 1.20 (m, 1H).

[0581] LCMS Calculated for C23H31N7O3: 453.3; Observed: 454.4 [M+H]+.

[0582] Step 5. rac-(3aR,4S,5S,7aS)-5-(2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-lH-isoindol-4-ol 2,2,2-trifluoroacetate (Cl 1-5)Cll-5

[0583] A solution of compound Cll-4 (40.0 mg, 0.088 mmol, 1 equiv.) in DCM (1.5 mL) was treated with TFA (0.5 mL) at 25 °C for about 1 h, then concentrated to dryness to provide the title compound Cll-5 trifluoroacetate (35 mg), which was used without further purification.LCMS Calculated for C18H23N7O: 353.2; Observed: 354.3 [M+H]+.156333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0584] Step 6. rac-l-((3a7?, 45,55, 7aA')-4-hydroxy-5-(2-((l-methyl-l / / -pyrazol-4- yl)amino)pyrrolo[2, 1 -f\ [ 1,2,4]tri azi n-7-yl )octahydro-2 / / -i soindol -2-yl )prop-2-en- 1 -one (1-45)

[0585] A solution of acrylic acid (11 mg, 0.149 mmol, 1.50 equiv.) and DIEA (77 mg, 0.594 mmol, 6.00 equiv.) inDMF (1.0 mL) was treated with HATU (57 mg, 0.149 mmol, 1.50 equiv.) at about 0 °C for about 10 min after which compound Cll-5 (35 mg, 0.099 mmol, 1.00 equiv.) was added. After about 1 h at about 0 °C, water (0.2 mL) was added and the mixture was purified by prep-HPLC under the following conditions (Column: Prep Shield RP18, 30*150 mm, 5pm; Mobile Phase A: Water (containing 0.05% NH4OH), Mobile Phase B: acetonitrile; Flow rate: 35 mL / min; Gradient (B%): isocratic 8% - 38% 14min; Wavelength: 254nm / 220nm nm; RT l(min): 8.47) to afford the title product 1-45 rac-l-((3a7?,45,55,7a5)-4- hydroxy-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)pyrrolo[2,l- / |[l,2,4]triazin-7-yl)octahydro- 2J / -isoindol-2-yl)prop-2-en-l-one (7 mg, 17%).

[0586] XH NMR (300 MHz, DMSO ) 58.67 (s, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.58 (dd, J= 1.5, 0.8 Hz, 1H), 6.90 -6.64 (m, 2H), 6.57 - 6.25 (m, 1H), 6.18 - 6.04 (m, 1H), 5.59 - 5.42 (m, 1H), 4.52 - 4.25 (m, 1H), 3.88 (d, J= 1.4 Hz, 3H), 3.81 - 3.68 (m, 2H), 3.67 - 3.11 (m, 4H), 3.07 - 2.90 (m, 1H), 2.60 - 2.35 (m, 1H), 2.23 -2.11 (m, 1H), 1.96 - 1.75 (m, 1H), 1.70 - 1.42 (m, 2H).

[0587] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.1 [M+H]+.

[0588] Purity (Method-A): 99.6% at RT 0.812 min.1-36rac-1 -((3 a / , 4R, 5S, 7a5)-5-(5-fhroro-2-((l -methyl- 177-pyrazol-4-yl)amino)pyrrolo[2,l-f\ [ 1,2,4]triazin-7-yl)-4-hydroxyoctahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one

[0589] Step 1. ethyl l-amino-3-fluoropyrrole-2-carboxylate (D54-1)157333961159Attorney Docket No. CENC-011 / 08WO 360899-2045NH2D54-1

[0590] A mixture of ethyl 3-fluoro-lH-pyrrole-2-carboxylate (15.0 g, 95.5 mmol, 1.00 equiv.) and O-(2,4-dinitrophenyl) hydroxylamine (22.8 g, 115 mmol, 1.2 equiv.) inMeCN (150 mL) was treated with potassium trimethylsilanolate (18.4 g, 143 mmol, 1.50 equiv.) at about 25 °C and the reaction mixture was stirred at about 25 °C for about 3 h before being diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined EtOAc extracts were washed with brine (1 x 200 mL), dried (Na2SO4), filtered and concentrated to give the title compound D54-1 (13.5 g), which was used without further purification.LCMS Calculated for C7H9FN2O2: 172.1; Observed: 173.1 [M+H]+.

[0591] Step 2. ethyl l-(3-benzoylthioureido)-3-fluoro-lH-pyrrole-2-carboxylate (D54-2)° FHNS<^NHBzD54-2

[0592] A mixture of compound D54-1 (13.5 g, 78.4 mmol, 1.00 equiv.) and benzoyl isothiocyanate (15.4 g, 94.1 mmol, 1.20 equiv.) in MeCN (140 mL) was stirred at about 25 °C for about 2 h, then concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to afford the title compound D54-2 (12.0 g, 46% yield).LCMS Calculated for C15H14FN3O3S: 335.1; Observed: 336.1 [M+H]+.

[0593] Step 3. 5-fhioro-2-sulfanylidene-lH,3H-pyrrolo[2,l f][l,2,4]triazin-4-one (D54-3)D54-3

[0594] To a solution of sodium hydroxide (2.15 g, 53.7 mmol, 1.50 equiv.) in water (150 mL) was added compound D54-2 (12.0 g, 35.8 mmol, 1.00 equiv) at about 25 °C, then the158333961159Attorney Docket No. CENC-011 / 08WO 360899-2045reaction mixture was heated at about 80 °C overnight. The mixture was cooled and acidified to about pH 5 with concentrated hydrochloric acid. The precipitate was filtered, washed with water (3 x 200 mL) and dried to give the title compound D54-3 (14 g), which was used without further purification.LCMS Calculated for C6H4FN3OS: 185.0; Observed: 186.0 [M+H]+.

[0595] Step 4. 5-fluoro-2-(methylsulfanyl)-3H-pyrrolo[2,l-f][l,2,4]triazin-4-one (D54-4)D54-4

[0596] A solution of compound D54-3 (14.0 g, 75.6 mmol, 1.00 equiv.) in THF (140 mL) was treated with iodomethane (10.7 g, 75.6 mmol, 1.00 equiv.) at about 0° C, then kept at about 25 °C for about 2 h before being concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2: 1) to afford the title compound D54-4 (6.5 g, 43% yield).LCMS Calculated for C7H5FN3OS: 199.02; Observed: 200.1 [M+H]+.

[0597] Step 5. 4-chloro-5-fluoro-2-(methylsulfanyl)pyrrolo[2,l-f][l,2,4]triazine (D54-5)D54-5

[0598] A mixture of compound D54-4 (6.50 g, 32.6 mmol, 1.00 equiv.) and phosphorus oxychloride (70 mL) was heated at about 90 °C overnight. After cooling to about 25 °C, the mixture was concentrated, diluted with water (100 mL) and extracted with EtOAc (3 x 80 mL). The combined EtOAc extracts were washed with brine (1 x 150 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2: 1) to afford the title compound D54-5 (5.50 g, 77% yield). LCMS Calculated for C7H5ClFN3S: 217.0 (35Cl isotope); Observed: 218.1 [M+H]+(35Cl isotope).159333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0599] Step 6. 7-bromo-4-chloro-5-fluoro-2-(methylsulfanyl)pyrrolo[2,l-f][l,2,4]triazine (D54-6)ND54-6

[0600] N-Bromosuccinimide (4.95 g, 27.8 mmol, 1.10 equiv.) was added to a solution of compound D54-5 (5.50 g, 25.3 mmol, 1.00 equiv.) in MeCN (60.0 mL) in portions at about 25 °C and the mixture was stirred at about 25 °C for about 3 h, then concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2:1) to afford the title compound D54-6 (4.50 g, 60% yield).

[0601] LCMS Calculated for C7H4BrClFN3S: 297.0 (35Cl,79Br isotopes); Observed: 298.1 [M+H]+(35Cl,79Br isotopes).

[0602] Step 7. 7-bromo-5-fluoro-2-(methylsulfanyl)pyrrolo[2,l-f][l,2,4]triazine (D54-7)NND54-7

[0603] Sodium borohydride (2.87 g, 75.9 mmol, 5.00 equiv.) was added in portions to a solution of compound D54-6 (4.50 g, 15.2 mmol, 1.00 equiv.) in 2-propanol (50.0 mL) at about 25 °C. After stirring overnight, the mixture was concentrated. The residue was dissolved in DCM (50 mL) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (3.44 g, 15.2 mmol, 1.00 equiv.) was added in portions over about 10 min at about 25 °C. After about 2 h further, the mixture was concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2: 1) to afford the title compound D54-7 (4.00 g).LCMS Calculated for C7H5BrFN3S: 260.9 (79Br isotope); Observed: 262.1 [M+H]+(79Br isotope).

[0604] Step 8. 7-bromo-5-fluoro-2-(methylsulfinyl)pyrrolo[2,l-f][l,2,4]triazine (D54-8)160333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0605] A solution of compound D54-7 (2.50 g, 9.54 mmol, 1.00 equiv.) in DCM (40 mL) was treated with m-CPBA (1.65 g, 9.54 mmol, 1.00 equiv.) at about 25 °C and for about 1 h. Saturated aqueous NaHCOs (10.0 mL) was added and the DCM was separated and concentrated to give the title compound D54-8 (2.5 g), which was used without further purification.LCMS Calculated for C7H5BrFN3OS: 276.9 (79Br isotope); Observed: 278.0 [M+H]+(79Br isotope).

[0606] Step 9. 7-bromo-5-fluoro-N-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l-f][l,2,4]triazin-2-amine (D54-9)

[0607] To a solution of compound D54-8 (2.50 g, 8.99 mmol, 1.00 equiv.) and DIEA (5.81 g, 45.0 mmol, 5.00 equiv.) in DMSO (40 mL) was added l-methylpyrazol-4-amine (4.37 g, 45.0 mmol, 5.00 equiv.) and the mixture was heated at about 100 °C overnight. After cooling, the mixture was diluted with water and extracted with EtOAc (3 x 80 mL). The combined EtOAc extracts were washed with brine (1 x 200 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to afford the title compound D59-4 (1.2 g, 43% yield). LCMS Calculated for CioHsBrFNe: 310.0 (79Br isotope); Observed: 311.0 [M+H]+(79Br isotope).

[0608] Step 10. 7-bromo-5-fluoro-N-(l-methyl-lH-pyrazol-4-yl)-N-((2- (trimethylsilyl)ethoxy)methyl)pyrrolo[2,l-f][l,2,4]triazin-2-amine (D54-10)161333961159Attorney Docket No. CENC-011 / 08WO 360899-2045D54-10

[0609] Sodium hydride (0.280 g, 11.6 mmol, 3.00 equiv.) was added in portions to a solution of compound D54-9 (1.20 g, 3.86 mmol, 1.00 equiv. ) in DMF (20 mL) at about 0°C, and the mixture was stirred at about 0 °C for about 30 min, after which 2-(trimethylsilyl)ethoxymethyl chloride (0.710 g, 4.24 mmol, 1.10 equiv.) was added. Stirring at about 25 °C was continued for about 1 h, then water (100 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were washed with brine (1 x 100 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound D54-10 (950 mg, 56%yield).LCMS Calculated for C16H22BrFN6OSi: 440.1 (79Br isotope); Observed: 441.0 [M+H]+(79Br isotope).

[0610] Step 11. rac-tert-butyl (3aR,4R,5S,7aS)-5-(5-fluoro-2-((l-methyl-lH-pyrazol-4-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)-4-hydroxyoctahydro-2H-isoindole-2-carboxylate (D54-11)D54-11

[0611] To a mixture of compound D54-10 7 (950 mg, 2.15 mmol, 1.00 equiv.) and compound E24 (1.58 g, 4.30 mmol, 2.00 equiv) in DMF (15.0 mL) were added zinc dust (422 mg, 6.46 mmol, 3.00 equiv.), nickel(II) chloride ethylene glycol dimethyl ether complex (335 mg, 1.53 mmol, 0.500 equiv.), and pyridine-2,6-dicarboximidamide dihydrochloride (102 mg, 0.430 mmol, 0.200 equiv.) and the mixture was heated at about 50 °C for about 1 h, then cooled.162333961159Attorney Docket No. CENC-011 / 08WO 360899-2045The mixture was purified by reversed-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, MeCN in water (containing 0.1% formic acid), 30% to 70% gradient in 10 min; detector, UV 254 nm.) to provide the title compound D54-11 (300 mg, 23% yield).LCMS Calculated for C29H44FN7O4Si: 601.3; Observed: 602.3 [M+H]+.

[0612] Step 12. rac-(3aR,4R,5S,7aS)-5-(5-fluoro-2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-lH-isoindol-4-ol (D54-12)

[0613] Compound D54-11 (300 mg, 0.50 mmol, 1.00 equiv.) was dissolved in HC1 (4.0 M in 1,4-dioxane, 5.0 mL) at about 25 °C. After about 1 h, the mixture was concentrated to afford the title compound D54-12 hydrochloride (150 mg), which was used without further purification.LCMS Calculated for C18H22FN7O: 371.2; Observed: 372.2 [M+H]+.

[0614] Step 13. rac-l-((3aR,4R,5S,7aS)-5-(5-fluoro-2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)-4-hydroxyoctahydro-2H-isoindol-2-yl)prop-2-en-l-one (1-36)163333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0615] To a solution of compound D54-12 (150 mg, 0.41 mmol, 1.00 equiv.) and EtsN (123 mg, 1.22 mmol, 3.00 equiv.) in DCM (2.00 mL) was added acryloyl chloride (37 mg, 0.41 mmol, 1.00 equiv.) at about -30 °C. After about 2 h at about 2 h, the mixture was concentrated. The residue was purified by reversed-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, MeCN in water (containing 0.1% formic acid), 30% to 70% gradient in 10 min; detector, UV 254 nm) to give the title product 1-36 rac-1 -((3 aR,4R, 5S,7aS)-5-(5 -fluoro-2-(( 1 -methyl - 1 H-pyrazol-4-yl)amino)pyrrolo- [2,1-f][l,2,4]triazin-7-yl)-4-hydroxyoctahydro-2H-isoindol-2-yl)prop-2-en-l-one (30 mg, 17% yield).

[0616] XHNMR (400 MHz, DMSO-t / e): 59.29 (d, J = 2.5 Hz, 1H), 8.81 (s, 1H), 7.84 (d, J = 5.7 Hz, 1H), 7.54 (dd, J = 8.7, 0.7 Hz, 1H), 6.66 - 6.53 (m, 1H), 6.48 (d, J = 8.5 Hz, 1H), 6.20 - 6.07 (m, 1H), 5.75 - 5.62 (m, 1H), 4.89 (dd, J= 15.0, 6.6 Hz, 1H), 3.91 - 3.76 (m, 4H), 3.62 -3.45 (m, 3H), 3.29-3.13 (m, 2H), 2.74 - 2.60 (m, 1H), 2.20 - 2.04 (m, 1H), 1.91 - 1.67 (m, 3H), 1.67 - 1.52 (m, 1H).

[0617] LCMS Calculated for C21H24FN7O2: 425.2; Observed: 426.4 [M+H]+.

[0618] Purity (Method-A): 99.31% at RT 0.789 min.1-37rac- 1 -((3a7?,4A, 5S, 7a5)-5-(2-((l -ethyl- U / -pyrazol-4-yl)amino)pyrrolo[2, 1 -f\[ 1,2, 4]tri azin-7- yl)-4-hydroxyoctahydro-2J / -isoindol-2-yl)prop-2-en-l-one

[0619] Step 1. 7-bromo-N-(l-ethyl-lH-pyrazol-4-yl)pyrrolo[2,l-f][l,2,4]triazin-2-amine (C13-1)BrC13-1

[0620] A mixture of 7-bromo-2-chloropyrrolo[2,l-f][l,2,4]triazine (CAS 1233186-50-9, 900 mg, 3.87 mmol, 1.00 equiv) and l-ethylpyrazol-4-amine (CAS 876343-24-7, 645 mg, 5.81 mmol, 1.50 equiv.) in DMSO (10.0 mL) was heated for about 2 h at about 100 °C. After cooling to about 25 °C, water (80 mL) was added and the mixture was extracted with EtOAc (2 x 50 mL). The combined EtOAc extracts were washed with brine (100 mL), dried (Na2SO4), filtered164333961159Attorney Docket No. CENC-011 / 08WO 360899-2045and concentrated. The residue was purified by silica gel chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to afford the title compound C13-1 (550 mg, 46% yield). LCMS Calculated for C11H11BrN6: 306.0 (79Br isotope). Observed: 307.1 [M+H]+(79Br isotope).

[0621] Step 2. rac-tert-butyl (3aR,4R,5S,7aS)-5-(2-((l-ethyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)-4-hydroxyoctahydro-2H-isoindole-2-carboxylate (C13-2)N-BOC% I] NC13-2

[0622] Compound C13-1 (500 mg, 1.63 mmol, 1.00 equiv.), compound E24 (1.57 g, 4.88 mmol, 3.00 equiv.), and nickel (II) chloride ethylene glycol dimethyl ether complex (357 mg, 1.63 mmol, 1.00 equiv.) were added to DMA (6.0 mL) at about 25 °C. Zinc dust (319 mg, 4.88 mmol, 3.00 equiv.) and 4,4'-di-tert-butyl-2,2'-bipyridine (87 mg, 0.33 mmol, 0.200 equiv.) were added and the mixture was heated at about 50 °C for about 1 h. After cooling to about 25 °C, water (80 mL) was added and the mixture was extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were washed with brine (1 x 50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography, eluted with ethyl acetate to afford the title compound C13-2 (98 mg, 13% yield).LCMS Calculated for C24H33N7O3: 467.3. Observed: 468.2 [M+H]+.

[0623] Step 3. rac-(3aR,4R,5S,7aS)-5-(2-((l-ethyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-lH-isoindol-4-ol (C13-3)C13-3165333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0624] Compound 13-2 (88 mg, 0.19 mmol, 1.00 equiv.) was dissolved in a mixture of DCM and TFA (5:1 v / v, 1.5 mL) at about 25 °C. After about 1 h, the mixture was concentrated to dryness to afford compound C13-3 trifluoroacetate (65 mg), which was used without further purification.LCMS Calculated for C19H25N7O: 367.2. Observed: 368.2 [M+H]+.

[0625] Step 4. rac-l-((3a7?,47?,55,7aS)-5-(2-((l-ethyl-l / 7-pyrazol-4-yl)amino)pyrrolo[2,l-f\ [ 1,2,4]triazin-7-yl)-4-hydroxyoctahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one (1-37)

[0626] A solution of compound C13-3 (65 mg, 0.18 mmol, 1.00 equiv.) and EtsN (54 mg, 0.53 mmol, 3.00 equiv.) was cooled to about 0 °C for about 10 min, after which acryloyl chloride (16 mg, 0.18 mmol, 1.00 equiv.) was added. After about 1 h at about 0 °C, the mixture was purified by prep-HPLC under the following conditions (Column: YMC-Actus Triart C18 Column, 50*250 mm, 5pm; Mobile Phase A: Water (containing lOmmol / L NH-iHCOs), Mobile Phase B: MeCN; Flow rate: 90mL / min; Gradient: 45% B to 75% B in 16 min; Wavelength: 254nm / 220nm; RT l(min): 10) to provide the title product 1-37 rac-l-((3a7?,4A,55,7a5)-5-(2- ((1 -ethyl- 177-pyrazol -4-yl )ami no)pyrrol o[2, 1 -f\ [ 1,2,4]triazin-7-yl)-4-hydroxyoctahydro-2JT- isoindol-2-yl)prop-2-en-l-one (29 mg, 39% yield).

[0627] 1HNMR (300 MHz, DMSO-t / e) 59.19 (d, 2.8 Hz, 1H), 8.73 (s, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.56 (d, J= 7.1 Hz, 1H), 6.76 - 6.69 (m, 1H), 6.69 - 6.54 (m, 2H), 6.22 - 6.08 (m, 1H), 5.72 - 5.62 (m, 1H), 4.91 - 4.78 (m, 1H), 4.19 - 4.05 (m, 2H), 3.95 - 3.82 (m, 1H), 3.67 - 3.49 (m, 3H), 3.25 (d, J= 11.7 Hz, 1H), 2.77 - 2.50 (m, 2H), 2.22 - 2.04 (m, 1H), 1.99 - 1.74 (m, 3H), 1.66 - 1.55 (m, 1H), 1.40 (t, J= 7.3 Hz, 3H).

[0628] LCMS Calculated for C22H27N7O2: 421.2. Observed: 422.3 [M+H]+.

[0629] Purity (Method-C): 99.09% at RT 1.625 min.1-43166333961159Attorney Docket No. CENC-011 / 08WO 360899-2045rac-l-((3a7?,4A,5A,7a5)-4-hydroxy-5-(5-methyl-2-((l-rnethyl-lJ / -pyrazol-4- yl)amino)pyrrolo[2, 1 -f\ [ 1,2,4]tri azi n-7-yl )octahydro-2 / / -i soindol -2-yl )prop-2-en- 1 -one

[0630] Step 1. rac-tert-butyl (3aR,4R,5S,7aS)-5-(5-bromo-2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)-4-hydroxyoctahydro-2H-isoindole-2-carboxylate (C12-1)C12-1

[0631] A solution of compound Cll-1 (300 mg, 0.66 mmol, 1.00 equiv.) and N-bromosuccinimide (129 mg, 0.73 mmol, 1.10 equiv.) in DMF (6.0 mL) was stirred at about 25 °C for about 1 h, then diluted with saturated NaHCCh solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with brine (1 x 40 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:3) to afford the title compound C12-1 (230 mg, 65% yield).LCMS Calculated for C23H3oBrN?03: 531.2 (79Br isotope); Observed: 532.3 [M+H]+(79Br isotope).

[0632] Step 2. rac-tert-butyl (3aR,4R,5S,7aS)-4-hydroxy-5-(5-methyl-2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo[2,l-f][l,2,4]triazin-7-yl)octahydro-2H-isoindole-2-carboxylate (C12-2)333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0633] A mixture of compound C12-1 (230 mg, 0.43 mmol, 1.00 equiv.), K3PO4 (275 mg, 1.30 mmol, 3.00 equiv.) and methylboronic acid (33 mg, 0.56 mmol, 1.30 equiv.) in dioxane (5.0 mL) and water (1.0 mL) was treated with XPhos Pd G2 (CAS 1310584-14-5, 17.0 mg, 0.022 mmol, 0.050 equiv.) at about 20 °C, then heated at about 100 °C for about 1 h. After cooling to about 25 DC, water (10 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined EtOAc extracts were washed with brine (1 x 20 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:2) to afford compound C12-2 (163 mg, 81% yield).

[0634] XHNMR (400 MHz, DMSO-t / e) 59.10 (s, 1H), 8.73 (s, 1H), 7.85 (s, 1H), 7.52 (d, J = 4.8 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 4.80 (s, 1H), 3.82 (s, 3H), 3.66 - 3.47 (m, 2H), 3.40 - 3.08 (m, 3H), 2.60 - 2.52 (m, 1H), 2.32 (s, 3H), 2.10 - 2.02 (m, 1H), 1.92 - 1.66 (m, 4H), 1.59 - 1.49 (m, 1H), 1.42 (s, 9H).LCMS Calculated for C24H33N7O3: 467.3; Observed: 468.3 [M+H] +.

[0635] Step 3. rac-(3aR,4R,5S,7aS)-5-(5-methyl-2-((l-methyl-lH-pyrazol-4-yl)amino)pyrrolo-[2,l-f][l,2,4]triazin-7-yl)octahydro-lH-isoindol-4-ol (C12-3)

[0636] To a solution of compound C12-2 (150 mg, 0.32 mmol, 1.00 equiv.) in DCM (3.0 mL) was added TFA (1.00 mL) at about 25 °C. After about 1 h, the mixture was concentrated to dryness to give the title compound C12-3 trifluoroacetate (130 mg), which was used without further purification.LCMS Calculated for C19H25N7O: 367.2; Observed: 368.3 [M +H]+.

[0637] Step 4. rac-l-((3a7?,4A,55',7a5)-4-hydroxy-5-(5-methyl-2-((l-methyl-U / -pyrazol-4-yl)amino)pyrrolo[2, 1 -f\ [ 1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en- 1 -one (I-43)168333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-43

[0638] A solution of acrylic acid (38 mg, 0.53 mmol, 1.50 equiv.) andDIEA(274 mg, 2.12 mmol, 6.00 equiv.) in DMF (3.0 mL) HATU (202 mg, 0.53 mmol, 1.50 equiv.) at about 0 °C for about 10 min, followed by the addition of compound C12-3 (130 mg, 0.35 mmol, 1.00 equiv.). After about 1 h, water (0.2 mL) was added and the mixture was purified by prep-HPLC under the following conditions (Column: Prep Shield RP18, 30*150 mm, 5pm; Mobile Phase A: Water (containing 0.05% NH4OH), Mobile Phase B: MeCN; Flow rate: 35 mL / min; Gradient (B%): isocratic 15% - 45% 15min; Wavelength: 254nm / 220nm nm; RT l(min): 11.07) to afford the title product 1-43 rac-l-((3a7?,4A,55,7a5)-4-hydroxy-5-(5-methyl-2-((l-methyl- U / -pyrazol-4-yl)amino)pyrrolo[2, 1 -f\ [1,2,4]triazin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (10 mg, 7% yield).

[0639] 'H NMR (400 MHz, DMSO-t / e) 59.10 (d, J= 4.2 Hz, 1H), 8.73 (s, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.53 (d, J = 10.0 Hz, 1H), 6.66 - 6.55 (m, 1H), 6.44 (s, 1H), 6.20 - 6.11 (m, 1H), 5.71 - 5.63 (m, 1H), 4.86 - 4.76 (m, 1H), 3.91 - 3.77 (m, 4H), 3.67 - 3.44 (m, 3H), 3.31 - 3.09 (m, 2H), 2.75 - 2.55 (m, 1H), 2.31 (s, 3H), 2.22 - 2.04 (m, 1H), 1.93 - 1.69 (m, 3H), 1.66 - 1.48 (m, 1H).

[0640] LCMS Calculated for C22H27N7O2: 421.2; Observed: 422.4 [M+H]+.

[0641] Purity (Method-A): 92.5% at RT 0.469 min.1-39 / Y / c-l-((3a / ,4 / ,5 / ,7aA')-4-hydroxy-5-(6-methyl-2-((l-methyl-l / / -pyrazol-4-yl)amino)-7 / / - pyrrolo[2,3-t / ]pyrimidin-7-yl)octahydro-2 / / -isoindol-2-yl)prop-2-en-l-one

[0642] Step 1. rac-tert-butyl (3aR,4R,5R,7aS)-5-amino-4-hydroxyoctahydro-2H-isoindole-2-carboxylate (B50-1)169333961159Attorney Docket No. CENC-011 / 08WO 360899-2045Boc^N\H2N'B50-1

[0643] A solution of compound E23 (1.60 g, 6.67 mmol, 1.00 equiv.) and NH4OH in 1,4-di oxane (10 mL) was heated at about 60 °C for about 16 h, then cooled to about 25 °C and concentrated to afford the title compound B50-1 (1.50 g), which was used without further purification.LCMS Calculated for C13H24N2O3: 256.2; Observed: 257.3 [M+H]+.

[0644] Step 2. rac-tert-butyl (3aR,4R,5R,7aS)-5-((2-chloro-5-iodopyrimidin-4-yl)amino)-4-hydroxyoctahydro-2H-isoindole-2-carboxylate (B50-2)BocB50-2

[0645] 2,4 -Dichloro-5-iodopyrimidine (2.41 g, 8.78 mmol, 1.50 equiv.) was added to a solution of compound B50-1 (1.50 g, 5.85 mmol, 1.00 equiv.) and DIEA (2.27 g, 17.6 mmol, 3.00 equiv.) in THF (20 mL) at about 0 °C and stirred for about 1 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (3: 1) to afford the title compound B50-2 (2.00 g, 69% yield). LCMS Calculated for C17H24CIIN4O3: 494.1 (35C1 isotope); Observed: 495.2 [M+H]+(35C1 isotope).

[0646] Step 3. rac-tert-butyl (3aR,4R,5R,7aS)-5-((2-chloro-5-(prop-l-yn-l-yl)pyrimidin-4-yl)amino)-4-hydroxyoctahydro-2H-isoindole-2-carboxylate (B50-3)170333961159Attorney Docket No. CENC-011 / 08WO 360899-2045BocB50-3

[0647] A solution of compound B50-2 (2.00 g, 4.04 mmol, 1.00 equiv), 1-(trimethylsilyl)propyne (CAS 6224-91-5, 1.36 g, 12.1 mmol, 3.00 equiv) and EtsN (1.23 g, 12.1 mmol, 3.00 equiv.) in THF (20 mL) was treated with TBAF (1.0 M, 8.08 mL, 8.08 mmol, 2.00 equiv.), copper(I) iodide (0.08 g, 0.404 mmol, 0.100 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (0.28 g, 0.404 mmol, 0.100 equiv.) at about 20 °C. The reaction was continued for about 4 h at about 20 °C, then concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to afford the title compound B50-3 (1.60 g, 97% yield).LCMS Calculated for C20H27ClN4O3: 406.2; Observed: 407.3 [M+H]+.

[0648] Step 4. rac-tert-butyl (3aR,4R,5R,7aS)-5-(2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-hydroxyoctahydro-2H-isoindole-2-carboxylate (B50-4)BocB50-4

[0649] Compound B50-3 (1.6 g, 3.93 mmol, 1.00 equiv.) was dissolved in TBAF (1.0 M in tetrahydrofuran, 20 mL) and heated at about 70 °C for about 4 h, then cooled and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 1) to give the title compound B50-4 (1.10 g, 69% yield). LCMS Calculated for C20H27ClN4O3: 406.2; Observed: 407.3 [M+H]+.171333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0650] Step 5. rac-tert-butyl (3aR,4R,5R,7aS)-4-hydroxy-5-(6-methyl-2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B50-5)

[0651] To a solution of compound B50-4 (1.10 g, 2.7 mmol, 1.00 equiv.) in 1,4-dioxane (20 mL) were added 1-methylpyrazol-4-amine (0.39 g, 4.05 mmol, 1.50 equiv.), Cs2CO3 (2.64 g, 8.11 mmol, 3.00 equiv.) and BINAP-Pd-G2 (CAS CAS: 1445085-60-8, 0.25 g, 0.27 mmol, 0.100 equiv.) and the reaction mixture was heated at about 100 °C for about 16 h. After cooling to about 25 °C, the mixture was filtered, and the filter cake was washed with EtOAc (2 x 20 mL). The combined filtrates were concentrated, and the residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (10:1) to afford the title compound B50-5 (600 mg, 48% yield).LCMS Calculated for C24H33N7O3: 467.3; Observed: 468.4 [M+H]+.

[0652] Step 6. rac-(3aR,4R,5R,7aS)-5-(6-methyl-2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-lH-isoindol-4-ol (B50-6)

[0653] Compound B50-5 (250 mg, 0.54 mmol, 1.00 equiv.) was dissolved in DCM (4.0 mL) and TFA (2.00 mL) was added at about 20 °C. After about 2 h, the mixture was172333961159Attorney Docket No. CENC-011 / 08WO 360899-2045concentrated to dryness to give the title compound B50-6 trifluoroacetate (200 mg), which was used without further purification.LCMS Calculated for C19H25N7O: 367.2; Observed: 368.3 [M+H]+.

[0654] Step 7. rac-l-((3a7?,4A,5A,7a5)-4-hydroxy-5-(6-methyl-2-((l-methyl-U / -pyrazol- 4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (1-39)1-39

[0655] To a solution of acrylic acid (59 mg, 0.82 mmol, 1.50 equiv.) and DIEA (422 mg, 3.26 mmol, 6.00 equiv.) in DMF (2.0 mL) were added HATU (CAS 148893-10-1, 310 mg, 0.816 mmol, 1.50 equiv), followed by a solution of compound B50-6 (200 mg, 0.54 mmol, 1.00 equiv.) in DMF (2.0 mL). The mixture was stirred at about 20 °C for about 2 h, then purified by prep-HPLC under the following conditions (Column: Prep Shield RP18, 30*150 mm, 5pm; Mobile Phase A: Water (containing 0.05% NH4OH), Mobile Phase B: MeCN; Flow rate: 35 mL / min; Gradient (B%): isocratic 18% - 38% 14min; Wavelength: 254nm / 220nm nm; RT l(min): 9.65) to afford the title product 1-39 rac-l-((3a7?,4A,5A,7a5)-4-hydroxy-5-(6-methyl-2-((l-methyl-17 / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (30 mg, 13% yield).

[0656] ’H NMR (300 MHz, DMSO ) d 9.05 - 8.68 (m, 1H), 8.41 (d, J= 3.3 Hz, 1H), 7.95 - 7.29 (m, 2H), 7.95 - 7.29 (m, 1H), 6.22 - 6.01 (m, 2H), 5.72 - 5.58 (m, 1H), 5.20 - 4.76 (m, 1H), 4.12 - 3.98 (m, 1H), 3.93 - 3.75 (m, 4H), 3.74 - 3.40 (m, 3H), 3.28 - 3.05 (m, 1H), 2.76 - 2.57 (m, 1H), 2.45 (s, 1H), 2.34 (s, 3H), 2.22 - 2.00 (m, 1H), 1.97 - 1.80 (m, 2H), 1.78 - 1.68 (m, 1H).

[0657] LCMS Calculated for C22H27N7O2: 421.2; Observed: 422.1 [M+H]+.

[0658] Purity (Method-A): 96.9% at RT 0.916 min.173333961159Attorney Docket No. CENC-011 / 08WO 360899-20451-44rac-l-((3a / ,5A',6 / ,7aA')-5-hydroxy-6-(2-((l -methyl-IT / -pyrazol-4-yl)amino)-77 / -pyrrolo[2,3- t / ]pyrimidin-7-yl)octahydro-27 / -isoindol-2-yl)prop-2-en-l-one

[0659] Step 1. rac-tert-butyl (3aR,5R,6R,7aS)-5-hydroxy-6-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B52-1)B52-1

[0660] Sodium hydride (60%, 401 mg, 10.0 mmol, 2.00 equiv.) was added to a solution of rac-tert-butyl (laR,2aR,5aS,6aS)-octahydrooxireno[2,3-f]isoindole-4-carboxylate (CAS 2640571-95-3, 1.80 g, 7.52 mmol, 1.50 equiv.) and compound Bl (1.07 g, 5.01 mmol, 1.00 equiv.) in DMSO (20 mL) in portions at about 25 °C, then the solution was heated at about 120 °C for about 3 h. After cooling to about 25 °C, water (20 ml) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined EtOAc extracts were washed with brine (3 x 20 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1:1) to afford the title compound B52-1 (960 mg, 42% yield).LCMS Calculated for C23H31N7O3, 453.2; Observed: 454.3 [M+H]+.

[0661] Step 2. rac-tert-butyl (3aR,5R,6R,7aS)-5-(((chloromethyl)sulfonyl)oxy)-6-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B52-2)174333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0662] A solution of compound B52-1 (960 mg, 2.11 mmol, 1.00 equiv), 2,6-lutidine (1.36 g, 12.7 mmol, 6.00 equiv.) in DCM (2.0 mL) was treated with chloromethanesulfonyl chloride (788 mg, 5.29 mmol, 2.50 equiv.) added in portions at about 0 °C. After about 1 h at about 25 °C, water (20 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined EtOAc were washed with brine (3 x 10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (5:1) to afford compound B52-2 (820 mg, 68% yield).LCMS Calculated for C24H32ClN7O5S, 565.2; Observed: 566.3 [M+H]+.

[0663] Step 3. rac-tert-butyl (3aR,5S,6R,7aS)-5-acetoxy-6-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B52-3)HB52-3

[0664] A mixture of compound B52-2 (820 mg, 1.45 mmol, 1.00 equiv.), cesium acetate (834 mg, 4.35 mmol, 3.00 equiv) and 18-crown-6 (191 mg, 0.72 mmol, 0.500 equiv.) in toluene (2.0 mL) was stirred at about 25 °C for about 2 h, then extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with brine (3 x 20 mL), dried (Na2SO4), filtered and concentrated to give the title compound B52-3 (715 mg, 48% yield), which was used without further purification.LCMS Calculated for C25H33N7O4, 495.3; Observed: 496.3 [M+H]+.

[0665] Step 4. rac-tert-butyl (3aR,5S,6R,7aS)-5-hydroxy-6-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-2H-isoindole-2-carboxylate (B52-4)333961159Attorney Docket No. CENC-011 / 08WO 360899-2045B52-4

[0666] A mixture of compound B52-3 (715 mg, 1.58 mmol, 1.00 equiv.) and K2CO3 (598 mg, 4.32 mmol, 2.70 equiv.) in MeOH (10 mL) was stirred at about 25 °C for about 2 h, then diluted water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined EtOAc extracts were washed with brine (3 x 10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1: 10) to afford the title compound B52-4 (150 mg, 27% yield).LCMS Calculated for C23H31N7O3, 453.3; Observed: 454.3 [M+H]+.

[0667] Step 5. rac-(3aR,5S,6R,7aS)-6-(2-((l-methyl-lH-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)octahydro-lH-isoindol-5-ol (B52-5)

[0668] A solution of compound B52-4 (150 mg, 0.27 mmol, 1.00 equiv.) inDCM (1.5 mL) was treated with TFA (0.5 mL) at about 0 °C. After about 1 h at about 25 °C, the mixture was concentrated to dryness to give the title compound B52-5 trifluoroacetate (64 mg), which was used without further purification.LCMS Calculated for C18H23N7O, 353.2; Observed: 353.3 [M+H]+.

[0669] Step 6. rac-l-((3a7?,55',6A,7a5)-5-hydroxy-6-(2-((l-methyl-17 / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (I-1-44176333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0670] A solution of compound B52-5 (64.0 mg, 0.181 mmol, 1.00 equiv.) in DCM (1.00 mL) was treated with DIEA (70.2 mg, 0.54 mmol, 3.00 equiv), followed by the addition of acryloyl chloride (16 mg, 0.18 mmol, 1.00 equiv.) at about 0 °C. After about 2 h, the mixture was concentrated and the residue was purified by prep-HPLC under the following conditions (Column: Prep Shield RP18, 30*150 mm, 5 um; Mobile Phase A: Water (containing lOmM ammonium bicarbonate), Mobile Phase B: MeCN; Flow rate: 35 mL / min; Gradient (B%): isocratic 13% - 43% 14 min; Wavelength: 254nm / 220nm nm; RT l(min): 9.22) to afford the title product 1-44 rac-l-((3a7?,55',6A,7a5)-5-hydroxy-6-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7J / -pyrrolo[2,3-J]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one (5.7 mg, 7% yield).

[0671] XHNMR (400 MHz, DMSO-t / e) 5 9.14 (s, 1H), 8.59 (s, 1H), 7.92 (s, 1H), 7.52 (s, 1H), 7.25 (dd, J= 3.7, 2.7 Hz, 1H), 6.63 - 6.52 (m, 1H), 6.38 - 6.29 (m, 1H), 6.20 - 6.09 (m, 1H), 5.70 - 5.62 (m, 1H), 5.10 (t, J= 5.9 Hz, 1H), 4.66 (d, J= 12.7 Hz, 1H), 4.15 (s, 1H), 4.06 (t, J= 10.4 Hz, 1H), 3.81 (s, 3H), 3.69 (t, J= 8.6 Hz, 1H), 3.59 - 3.47 (m, 1H), 3.44 (d, J= 3.3 Hz, 1H), 2.37 (s, 1H), 2.32 - 2.16 (m, 1H), 2.05 - 1.95 (m, 2H), 1.70 - 1.62 (m, 1H), 1.24 (s, 1H).

[0672] LCMS Calculated for C21H25N7O2: 407.2; Observed: 408.3 [M+H]+.

[0673] Purity (Method A): 93.8% at RT 10.179 min.1-52rac-l-((3a7?,4A,5A,7a5)-4-hydroxy-3a-methyl-5-(2-((l-methyl-U / -pyrazol-4-yl)amino)-7JT-pyrrolo[2,3- ]pyrimidin-7-yl)octahydro-2J / -isoindol-2-yl)prop-2-en-l-one

[0674] Step 1. rac-(3a7?, 7a5)-2-benzyl-3a-methyl-hexahydroisoindol-4-one (E72-1)Bn / ^N\E72-1

[0675] 2-Methylcyclohex-2-en-l-one (10.0 g, 90.8 mmol, 1.00 equiv.) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (43.1 g, 182 mmol, 2.00 equiv.) were dissolved in THF (100 mL) and cooled to about 0 °C, then TFA (1.04 g, 9.078 mmol, 0.10 equiv.) was added dropwise. The reaction mixture was stirred at about 25 °C for about 16 h,177333961159Attorney Docket No. CENC-011 / 08WO 360899-2045then diluted with cold water and extracted with EtOAc. The combined EtOAc extracts were washed with saturated aqueous NaHCCh, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (100:1) to afford the title compound E72-1 (8 g, 36% yield).LCMS Calculated for C16H21NO: 243.2; Observed: 244.2 [M+H]+.

[0676] Step 2. (3aRS,4RS&,7aSR)-2-benzyl-3a-methyl-hexahydro-lH-isoindol-4-ol (E72-2)Bn / ^N\E72-2

[0677] Compound E72-1 (8.00 g, 32.9 mmol, 1.00 equiv.) was dissolved in THF (80 mL) and lithium aluminum hydride (1.87 g, 49.3 mmol, 1.50 equiv.) was added in portions over about 20 min at about 0 °C. The reaction mixture was stirred at about 25 °C for about 30 min longer before being cooled to about 0° C, after which sodium sulfate decahydrate (15.89 g, 49.311 mmol, 1.50 equiv.) was added. After filtration, the filtrate was concentrated to afford the title compound E72-2 (5.0 g, 62% yield), which was used without further purification.LCMS Calculated for C16H23NO: 245.2; Observed: 246.2 [M+H]+.

[0678] Step 3. tert-butyl (3aRS,4RS&,7aSR)-4-hydroxy-3a-methyl-hexahydro-lH-isoindole-2-carboxylate (E72-3)E72-3

[0679] To a solution of compound E72-2 (5.00 g, 20.4 mmol, 1.00 equiv.), EtsN (3.09 g, 30.6 mmol, 1.50 equiv.) and di-tert-butyl decarbonate (5.34 g, 24.5 mmol, 1.20 equiv.) in MeOH (50 mL) was added a 10% palladium on carbon catalyst (0.22 g). The mixture was hydrogenated at about 25 °C under about 10 atmospheres of hydrogen pressure for about 16 h, then filtered through diatomaceous earth. The filtrate was concentrated and the residue was 178333961159Attorney Docket No. CENC-011 / 08WO 360899-2045purified by silica gel column chromatography, eluted with diethyl ether / ethyl acetate (100:1) to afford the title compound E72-3 (2.00 g, 38% yield).LCMS Calculated for C14H25NO3: 255.2; Observed: 256.3 [M+H]+.

[0680] Step 4. rac-tert-butyl (3aA, 7a5)-3a-methyl-3,6,7,7a-tetrahydro-l / / -isoindole-2-carboxylate (E72-4)Boc^N\E72-4

[0681] Methanesulfonyl chloride (2.06 g, 18.0 mmol, 2.30 equiv.) was added dropwise to a solution of compound E72-3 (1.50 g, 5.87 mmol, 1.00 equiv.) and EtiN (1.98 g, 19.6 mmol, 2.50 equiv.) in DCM (30 mL) at about 0 °C. The mixture was kept for about 40 min. at about 0 °C, after which saturated aqueous NaHCOs solution (50 mL) was added and the mixture was extracted with DCM (3 x 30 mL). The combined DCM extracts were washed with brine (1 x 100 mL), dried (Na2SO4), filtered and concentrated. The residue was dissolved in DMF (20 mL) and lithium bromide (3.40 g, 39.2 mmol, 5.00 equiv.) was added. The mixture was heated at about 120 °C for about 6 h, then cooled, diluted with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were washed with brine (1 x 50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with diethyl ether / ethyl acetate (100:1) to afford the title compound E72-4 (1.0 g, 54% yield).LCMS Calculated for C14H23NO2: 237.2; Observed: 238.3 [M+H]+.

[0682] Step 5. tert-butyl (laRS,3aRS&,6aSR&,6bSR)-6a-methyl-hexahydro-laH-oxireno[2,3-e]isoindole-5-carboxylate (E72)Boc^N\E72179333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0683] A solution of compound E72-4 (1.0 g, 4.21 mmol, 1.00 equiv.) in DCM (10.0 mL) was treated with m-CPBA (1.09 g, 6.32 mmol, 1.50 equiv.) at about 25 °C and the reaction mixture was stirred at about 25 °C for about 4 h. Saturated aqueous NaHCOs solution (30 mL) was added and the mixture was extracted with DCM (5 x 30 mL). The combined DCM extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with diethyl ether / ethyl acetate (100:1) to afford the title compound E72 (0.5 g, 47% yield).LCMS Calculated for C14H23NO3: 253.2; Observed: 198.2 [M-C4H8]+(fragment ion).

[0684] Step 6. terLbutyl (3aRS,4RS&,5RS&,7aSR)-4-hydroxy-3a-methyl-5-{2-[(l-methylpyrazol-4-yl)amino]pyrrolo[2,3-d]pyrimidin-7-yl}-hexahydro-lJ / -isoindole-2-carboxylate (B56-1)&2B56-1

[0685] A mixture of compound E72 (0.500 g, 1.97 mmol, 1.00 equiv.) compound Bl (0.300 g, 1.38 mmol, 0.70 equiv.) and CS2CO3 (1.29 g, 3.95 mmol, 2.00 equiv.) in DMF ( 4.0 mL) was heated at about 100 °C for about 6 h. After cooling and dilution with water (30 mL), the mixture was extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were washed with brine (1 x 30 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by reversed-phase flash chromatography under the following conditions (column, C18 silica gel; Mobile phase A: water (containing 0.05% NH4OH), Mobile Phase B: MeCN, isocratic 0% - 100% 20 min; detector, UV 254 nm) to give the title compound B56-1 (0.320 g, 35% yield).LCMS Calculated for C24H33N7O3: 467.3; Observed: 468.1 [M+H]+.

[0686] Step 7. (3aRS,4RS&,5RS&,7aSR)-3a-methyl-5-{2-[(l-methylpyrazol-4-yl)amino]pyrrolo[2,3-d]pyrimidin-7-yl}-octahydroisoindol-4-ol (B56-2)180333961159Attorney Docket No. CENC-011 / 08WO 360899-2045B56-2

[0687] Compound B56-1 (0.320 g, 0.68 mmol, 1.00 equiv.) in DCM (4.0 mL) was treated with TFA (0.80 mL) at about 0 °C, then the reaction was kept at about 25 °C until it was judged to be complete. The mixture was then concentrated to give the title compound B56-2 trifluoroacetate (0.252 g), which was used without further purification.LCMS Calculated for C19H25N7O: 367.2; Observed: 368.3 [M+H]+.

[0688] Step 8. rac-l-((3a / ,4 / ,5 / ,7ak)-4-hydroxy-3a-methyl-5-(2-((l-methyl-IT / -pyrazol-4-yl)amino)-77 / -pyrrolo[2,3-t / ]pyrimidin-7-yl)octahydro-27 / -isoindol-2-yl)prop-2-en-l-one (1-52)1-52

[0689] To a stirred solution of compound B56-2 (0.252 g, 0.54 mmol, 1.00 equiv.) and EtsN (0.17 g, 1.63 mmol, 3.00 equiv.) in DMF (4.0 mL) was added acryloyl chloride (0.05 g, 0.54 mmol, 1.00 equiv.) at about 0 °C and the mixture was stirred at about 0 °C for about 30 min. After concentration, the residue was purified by prep-HPLC under the following conditions (Column: Xbridge -Prep C18, 30*150 mm, 5pm; Mobile Phase A: Water (containing 0.05% NH4OH), Mobile Phase B: MeCN; Flow rate: 35 mL / min; Gradient (B%): isocratic 16% - 46% 14 min; wavelength: 254nm / 220nm; RT l(min): 8.85) to give the title product 1-52 (52 mg, 23% yield).181333961159Attorney Docket No. CENC-011 / 08WO 360899-2045

[0690] 1H NMR (300 MHz, DMSO-d6): 59.09 (dd, J = 14.2, 4.9 Hz, 1H), 8.56 (d, J= 6.5 Hz, 1H), 8.02 - 7.91 (m, 1H), 7.52 (d, J= 9.6 Hz, 1H), 7.46 - 7.23 (m, 1H), 6.71 - 6.50 (m, 1H), 6.40 - 6.31 (m, 1H), 6.15 (dt, J= 16.9, 3.2 Hz, 1H), 5.67 (dd, J= 8.1, 2.6 Hz, 1H), 4.87 (d, J= 13.8 Hz, 1H), 4.62 (d, J= 13.3 Hz, 1H), 3.99 - 3.85 (m, 1H), 3.84 - 3.78 (m, 3H), 3.77 - 3.67 (m, 1H), 3.66 - 3.52 (m, 1H), 3.43 (dd, J= 18.4, 11.4 Hz, 1H), 3.28 - 3.12 (m, 1H), 2.43-2.15 (m, 2H), 1.94 (d, J = 14.9 Hz, 1H), 1.74 (s, 2H), 1.20 (dd, J = 5.2, 3.5 Hz, 3H).

[0691] LCMS Calculated for C22H27N7O2: 421.2; Observed: 422.2 [M+H]+.

[0692] Purity (Method-A): 95.0% at RT 0.651 min and 0.859 min.

[0693] Chiral purity (Method-A): 97.8% at RT 4.447 min and 4.607 min.Example 2: Biological AssaysJAK3 and BTK biochemical activity assays at ImM ATP

[0694] Activity of human Janus Kinase 3 (JAK3) and Bruton’ s tyrosine kinase (BTK) was determined using a HTRF KinEASE-TK and LanthaScreen TR-FRET assay, respectively, to monitor phosphorylation of a synthetic peptide by the kinase domain of the recombinant human protein. Test compounds were solubilized in dimethyl sulfoxide (DMSO) at 10 or 30 mM. Compound plates were made containing test compounds serially diluted in DMSO to create a 10-point half-log dilution series. An aliquot of 10 nL of compound from this plate was then transferred to a 384-well assay ...

Claims

1. Attorney Docket No. CENC-011 / 08WO 360899-2045CLAIMS1. A compound of Formula I:HIor a pharmaceutically acceptable salt thereof, wherein:X1is CH orN;X2is C orN;X3is C or N; provided that one or two of X1, X2, and X3are N;X4is CH, C-halogen, or N;R1is a substituent comprising a warhead group;each occurrence of R2is independently a halogen, -OR, -CN, -C(O)R, -C(O)OR, -OC(O)R, - OC(O)OR, -C(0)N(R)2, -N(R)C(O)R, -N(R)C(0)N(R)2, -0C(0)N(R)2, -N(R)C(O)OR, - NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, or an optionally substituted C1-6aliphatic;each occurrence of R3is independently halogen, -OR, -CN, -C(O)R, -C(O)OR, -OC(O)R, - OC(O)OR, -C(0)N(R)2, -N(R)C(O)R, -N(R)C(0)N(R)2, -0C(0)N(R)2, -N(R)C(O)OR, - NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, an optionally substituted Ci-6aliphatic, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Rais hydrogen, halogen, -OR, -CN, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)N(R)2, - N(R)C(O)R, -N(R)C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, an optionally substituted C1-6aliphatic, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from 210333961159Attorney Docket No. CENC-011 / 08WO 360899-2045nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;-L1- is a covalent bond or a Ci-4 bivalent straight or branched hydrocarbon chain;R4is H, -C(O)R5, an optionally substituted Ci-6 aliphatic, an optionally substituted phenyl, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the phenyl or the 5-8 membered monocyclic heteroaromatic ring is substituted with p instances of R6; R5is an optionally substituted Ci-6 aliphatic, an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R6is independently halogen, -OR, -C(O)R, -C(O)OR, -OC(O)R, - OC(O)OR, -C(0)N(R)2, -N(R)C(O)R, -N(R)C(0)N(R)2, -0C(0)N(R)2, -N(R)C(O)OR, - NR2, -SR, -S(O)R, -S(O)2R, -S(O)2N(R)2, -NRS(O)2R, an optionally substituted Ci-6aliphatic, an optionally substituted phenyl, an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-8 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each occurrence of R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, or an 8-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;211333961159Attorney Docket No. CENC-011 / 08WO 360899-2045m is 0, 1, 2, 3, 4, or 5;n is 0, 1, or 2; andp is 0, 1, 2, or 3.

2. The compound of claim 1, wherein R1is -L2-Y, wherein-L2- is a covalent bond or a bivalent C2-8 straight or branched, hydrocarbon chain wherein one or two methylene units of -L2- are optionally and independently replaced by — NRC(O) —, — C(O)NR—, — N(R)SO2—, — SO2N(R)—, — S—, -O-, -NR-, — S(O)—, — SO2—, - C(O)-, — OC(O) —, or — C(O)O —; and additionally one methylene unit of -L2- is optionally replaced by an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-10 membered bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andY is hydrogen, halogen, -COOR, -CN, -CON(R)2, -NRCN, NO2, -N(R)2, optionally substituted C1-8 aliphatic, or an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 4-10 membered bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein -L2-Y comprises an alpha, beta-unsaturated carbonyl moiety, amide, cyano group, halogen, alkynyl group, sulfonyl group, or epoxide.

3. The compound of claim 1 or 2, wherein R1is -L2-Y, wherein212333961159Attorney Docket No. CENC-011 / 08WO 360899-2045-L2- is a covalent bond or a bivalent C2-8 straight or branched, hydrocarbon chain wherein one or two methylene units of -L2- are optionally and independently replaced by — NRC(O) —, — C(O)NR—, — N(R)SO2—, — SO2N(R)—, — S—, -O-, -NR-, — S(O)—, — SO2—, - C(O)-, — OC(O) —, or — C(O)O —; and additionally one methylene unit of -L2- is optionally replaced by an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andY is hydrogen, halogen, -COORf, -CN, -CONRf2, -NRfCN, NO2, -NRf2, C1-8 aliphatic optionally substituted with halogen, NO2, or CN, or an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- 10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein -L2-Y comprises an alpha, beta-unsaturated carbonyl moiety, amide, cyano group, halogen, alkynyl group, sulfonyl group, or epoxide; and wherein each occurrence of Rfis independently H, or straight or branched C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl group optionally substituted with 1, 2 or 3 halogen atoms.

4. The compound of any one of claims 1 to 3, wherein R1is -L2-Y, wherein-L2- is a covalent bond or a bivalent C2-s straight or branched, hydrocarbon chain wherein one or two methylene units of -L2- are optionally and independently replaced by — NRC(O) —, — C(O)NR—, — N(R)SO2—, — SO2N(R)—, — S—, — S(O)—, — SO2—, -C(O)-, — OC(O)—, or — C(O)O —; and additionally one methylene unit of -L2- is optionally replaced by a ring', and; and Y is hydrogen, halogen, -COORf, -CN, -CONRf2, - NRfCN, NO2, -NRf2, epoxide, C1-8 aliphatic optionally substituted with halogen, NO2, or CN,213333961159Attorney Docket No. CENC-011 / 08WO 360899-2045, and Rg; wherein -L2-Y comprises an alpha, beta-unsaturated carbonyl moiety, amide, cyano group, halogen, C2-6 alkynyl group, sulfonyl group, or epoxide; wherein each occurrence of Rfis independently H, or straight or branched C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl group optionally substituted with 1, 2 or 3 halogen atoms; and wherein each occurrence of Rgand Rhis independently H, halogen, or OH, or straight or branched C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl group optionally substituted with 1, 2 or 3 halogen atoms.

5. The compound of any one of claims 1 to 4, wherein R1is selected from Table la, Table lb or Table 1c.o6. The compound of any one of claims 1 to 5, wherein R1is7. The compound of any one of claims 1 to 6, wherein X1is CH orN.

8. The compound of any one of claims 1 to 7, wherein X2is C or N.

9. The compound of any one of claims 1 to 8, wherein X3is C or N.

10. The compound of any one of claims 1 to 9, wherein X4is CH, C-F, orN.214333961159Attorney Docket No. CENC-011 / 08WO 360899-204511. The compound of any one of claims 1 to 10, wherein R2is selected from -OH, -OMe, F, and Me.

12. The compound of any one of claims 1 to 11, wherein R3is selected from methyl, ethyl,isopropyl, -F, -Cl, -OMe, -CN,13. The compound of any one of claims 1 to 12, wherein Rais selected from hydrogen,methyl, ethyl, isopropyl, -F, -Cl, -OMe, -CN,14. The compound of any one of claims 1 to 13, wherein R4is selected from H, \,15. The compound of any one of claims 1 to 14, wherein R6is selected from Me, Et,16. The compound of any one of claims 1 to 15, wherein the compound is of Formula II:215333961159Attorney Docket No. CENC-011 / 08WO 360899-2045or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1 to 15, wherein the compound is of Formula III:R1IIIor a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 1 to 15, wherein the compound is of Formula IVa, Formula IVb, Formula IVc, Formula IVd, or Formula IVe:IVa IVb216333961159Attorney Docket No. CENC-011 / 08WO 360899-2045or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 1 to 15, wherein the compound is of Formula Va, Formula Vb, Formula Vc, Formula Vd, or Formula Ve:Vc Vd217333961159Attorney Docket No. CENC-011 / 08WO 360899-2045Veor a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1 to 15, wherein the compound is of Formula VIa, Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, Formula VIg, Formula VIh, or Formula VIi:VIa VIbVIe VIf218333961159Attorney Docket No. CENC-011 / 08WO 360899-2045VIior a pharmaceutically acceptable salt thereof.

21. The compound of any one of claims 1 to 15, wherein the compound is of Formula VIIa, Formula VIIb, Formula VIIc, Formula VIId, Formula VIIe, Formula VIIf, Formula VIIg, Formula VIIh, or Formula VIIi:219333961159Attorney Docket No. CENC-011 / 08WO 360899-2045VIIe VIIfVIIg VIIhVIIior a pharmaceutically acceptable salt thereof.

22. A compound selected from one of those shown in Table 1 or Example 1, or a pharmaceutically acceptable salt thereof.

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

24. A method of treating a disorder or disease associated with JAK3 or BTK, comprising administering to a subject in need thereof the compound or composition of any one of preceding claims, or a pharmaceutically acceptable salt thereof.220333961159

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