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ANDROGEN RECEPTOR MODULATORS AND METHODS FOR THEIR USE

20230373934 · 2023-11-23

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to compounds of formula (ABC), (BC), (A), (B), (B-I), (C), (C-I), (D), (D-I), (E), (E-I), (F), (G), (H), (J), or (K), or any subgenera thereof, or a pharmaceutically acceptable salt, tautomer or stereoisomer. The compounds of the present disclosure are useful in modulating androgen receptor activity and for treating cancer, including prostate cancer.

    Claims

    1. A compound having the structure of formula (I-A): ##STR00404## or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: A is a 4- to 15-membered ring selected from aryl, carbocyclyl, heteroaryl, or heterocyclyl; B is a 4- to 15-membered ring selected from aryl, carbocyclyl, heteroaryl, or heterocyclyl; C is a 3- to 15-membered aryl, carbocyclyl, heteroaryl, or heterocyclyl; X is a bond, —(CR.sup.5R.sup.6).sub.t—, —O—, or —NR.sup.7; Y is a bond, —(CR.sup.8R.sup.9).sub.m—, —O—, —S—, —S(═O)—, —SO.sub.2—, —NR.sup.7—, or —N(COCH3)-; W is a bond, —(CR.sup.8aR.sup.9a).sub.m—, —C(═O)—, —NR.sup.7—, —N(R.sup.7)CO—, —CONR.sup.7—,-NSO.sub.2R.sup.7—, heteroarylene, or heterocyclene; Z is a bond, —CH.sub.2—, —C(CH.sub.3)H—, —O—,-S-, —NH—, —NCH.sub.3—, or —N(COCH.sub.3)—; V is a bond, —(CR.sup.8aR.sup.9a).sub.m—, —CR.sup.8a═CR.sup.9a-, or phenylene; L is hydrogen, halogen, —CF.sub.2R.sup.10, —CF.sub.3, —CN, —OR.sup.10, —SO.sub.2R.sup.17, —NR.sup.11R.sup.12, or —CONR.sup.11R.sup.12; R.sup.1 and R.sup.2 are each independently hydrogen, halogen, —CN,-CF.sub.3, —OH, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkoxy, optionally substituted —(C.sub.1-C.sub.6 alkyl)-(C.sub.1-C.sub.6 alkoxy), optionally substituted —(C.sub.1-C.sub.6 alkyl)-OH, oxo, —NR.sup.13R.sup.14 optionally substituted —(C.sub.1-C.sub.6 alkyl) —NR.sup.13R.sup.14, —NR.sup.14R.sup.15, optionally substituted —(C.sub.1-C.sub.6 alkyl)-NR.sup.14R.sup.15, —NR.sup.14SO.sub.2R.sup.16, optionally substituted —(C.sub.1-C.sub.6 alkyl)NR.sup.14SO.sub.2R.sup.16, —NR.sup.14COR.sup.16, optionally substituted —(C.sub.1-C.sub.6 alkyl)-NR.sup.14COR.sup.16, —CONR.sup.13R.sup.14, optionally substituted —(C.sub.1-C.sub.6 alkyl)-CONR.sup.14R.sup.15, —SO.sub.2NR.sup.14R.sup.15, optionally substituted —(C.sub.1-C.sub.6 alkyl)-SO.sub.2NR.sup.14R.sup.15, optionally substituted-SO.sub.2R.sup.16 or optionally substituted —(C.sub.1-C.sub.6 alkyl)-SO.sub.2R.sup.16; R.sup.3 is halogen, oxo, ═S, ═NR.sup.16, —CN,-CF.sub.3, —OH, —S(C.sub.1-C.sub.3 alkyl), C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, —NR.sup.13R.sup.14, —(C.sub.1-C.sub.3 alkyl)-NR.sup.13R.sup.14, —R.sup.14SO.sub.2R.sup.16, —(C.sub.1-C.sub.3 alkyl)NR.sup.14SO.sub.2R.sup.16, —NR.sup.14COR.sup.16, —(C.sub.1-C.sub.6 alkyl)-NR.sup.14COR.sup.16, —CONR.sup.14R.sup.15, —(C.sub.1-C.sub.3 alkyl)-CONR.sup.14R.sup.15, —SO.sub.2NR.sup.14R.sup.15, —(C.sub.1-C.sub.3 alkyl)-SO.sub.2NR.sup.14R.sup.15, —SO.sub.2(C.sub.1-C.sub.3 alkyl), —(C.sub.1-C.sub.6 alkyl)-SO.sub.2(C.sub.1-C3 alkyl), —N═S(═O)(C.sub.1-C.sub.3 alkyl).sub.2, ##STR00405## optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or substituted heteroaryl; R.sup.5 and R.sup.6 are each independently hydrogen, halogen, —OH, optionally substituted C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.2-C.sub.3 alkenyl, optionally substituted C.sub.2-C.sub.3 alkynyl, or C.sub.1-C.sub.3 alkoxy; or R.sup.5 and R.sup.6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl; R.sup.7 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 deuterated, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; R.sup.8 and R.sup.9 are each independently hydrogen, halogen, or C.sub.1-C.sub.3 alkyl; R.sup.8a and R.sup.9a are each independently hydrogen, —OH, halogen, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, —NR.sup.13R.sup.14, —(C.sub.1-C.sub.3 alkyl)-NR.sup.13R.sup.14, —NR.sup.14COR.sup.16, —(C.sub.1-C.sub.3 alkyl)-NR.sup.14COR.sup.16, —CONR.sup.14R.sup.15 or —(C.sub.1-C.sub.3 alkyl)-CONR.sup.14R.sup.15; or R.sup.8a and R.sup.9a taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl containing one, two, or three heteroatoms selected from N, S, or O; R.sup.10 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R.sup.11 and R.sup.12 are each independently hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R.sup.11 and R.sup.12 taken together form an optionally substituted heterocyclyl which optionally contains one or two additional heteroatoms selected from N, S, or O; R.sup.13, R.sup.14 and R.sup.15 are each independently hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, or C.sub.2-C.sub.3 alkynyl; or R.sup.14 and R.sup.15 taken together form an optionally substituted 3- to heterocyclyl; R.sup.16 is hydrogen, optionally substituted C.sub.1-C.sub.3 alkyl, optionally optionally substituted C.sub.2-C.sub.3 alkynyl, C.sub.3-C.sub.6 cycloalkyl, or phenyl; R.sup.17 is hydrogen, optionally substituted C.sub.1-C.sub.3 alkyl, optionally or optionally substituted C.sub.2-C.sub.3 alkynyl; each m is independently 0, 1, 2, or 3; n1 and n2 are each independently 0, 1, or 2; n3 is 0, 1, 2, 3, 4 or 5; and t is 0, 1 or 2.

    2. The compound of claim 1 having the structure of formula (A): ##STR00406## or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: A is a 4- to 10-membered aryl, carbocyclyl, heteroaryl, or heterocyclyl; B is a 4- to 10-membered aryl, carbocyclyl, heteroaryl, or heterocyclyl; C is a 4- to 10-membered aryl, carbocyclyl, heteroaryl, or heterocyclyl; X is-O-; Y is a bond, —CH.sub.2—, —NH—, or —O—; W is a bond, —CH.sub.2—, —CH.sub.2CH.sub.2—, —C(CH.sub.3)H—, —N(R.sup.7)CO—, —CONR.sup.7—, or heteroarylene; Z is a bond or —O—; V is a bond, —(CR.sup.8aR.sup.9a).sub.m(CR.sup.8a′R.sup.9a′)—, or —(CR.sup.8aR.sup.9a).sub.m—; L is hydrogen, halogen, —CF.sub.2R.sup.10, —CF.sub.3, —CN,-OR.sup.10, —NR.sup.11R.sup.12, or —CONR.sup.11R.sup.12; R.sup.1 and R.sup.2 are each independently halogen, oxo, —CN, or —CF.sub.3; R.sup.3 is halogen, oxo, ═S, ═NR.sup.16, —CN,-CF.sub.3, —OH, —S(C.sub.1-C.sub.3 alkyl), C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, —NR.sup.13R.sup.14, —(C.sub.1-C.sub.3 alkyl)-NR.sup.13R.sup.14, —NR.sup.14SO.sub.2R.sup.16, —(C.sub.1-C.sub.3 alkyl)NR.sup.14SO.sub.2R.sup.16, —NR.sup.14COR.sup.16, —NR.sup.14COOR.sup.16, —(C.sub.1-C.sub.6 alkyl)-NR.sup.14COR.sup.16, —CONR.sup.14R.sup.15, —(C.sub.1-C.sub.3 alkyl)-CONR.sup.14R.sup.15, —SO.sub.2NR.sup.14R.sup.15, —(C.sub.1-C.sub.3 alkyl)-SO.sub.2NR.sup.14R.sup.15, —SO.sub.2(C.sub.1-C.sub.3 alkyl), —(C.sub.1-C.sub.6 alkyl)-SO.sub.2(C.sub.1-C.sub.3 alkyl), or optionally substituted 4- to 6-membered heterocyclyl or heteroaryl; R.sup.7 is hydrogen or C.sub.1-C.sub.4 alkyl; R.sup.8a and R.sup.9a are each independently hydrogen, halogen, or C.sub.1-C.sub.3 alkyl; R.sup.8a′ and R.sup.9a′ taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl containing one, two, or three heteroatoms selected from N, S, or O; R.sup.10 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.11 and R.sup.12 are each independently hydrogen or C.sub.1-C.sub.3 alkyl; or R.sup.11 and R.sup.12 taken together form an optionally substituted heterocyclyl which optionally contains one or two additional heteroatoms selected from N, S, or O; R.sup.13, R.sup.14 and R.sup.15 are each independently hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, or C.sub.2-C.sub.3 alkynyl; or R.sup.14 and R.sup.15 taken together form an optionally substituted 3- to 6-membered heterocyclyl; R.sup.16 is hydrogen, optionally substituted C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.2-C.sub.3 alkenyl, optionally substituted C.sub.2-C.sub.3 alkynyl, optionally substituted C.sub.1-C.sub.3 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, or phenyl; m is 0, 1, 2, or 3; n1 and n2 are each independently 0, 1, or 2; and n3 is 1, 2, 3, 4 or 5.

    3. The compound of claim 2, wherein C is not quinazoline ring.

    4. (canceled)

    5. The compound of claim 2, wherein A is phenyl, pyridyl, pyrimidinyl, cyclohexyl, piperidinyl.

    6. The compound of claim 2, wherein B is phenyl.

    7. The compound of claim 2, wherein Y is a bond or -O-.

    8. The compound of claim 2, wherein W is a bond, —CH.sub.2—, —CH.sub.2CH.sub.2—, or heteroarylene.

    9. The compound of claim 2, wherein W is pyrazole, pyridine, pyrimidine, or pyrazine.

    10. The compound of claim 2, wherein C is a 4-10 membered monocyclic carbocyclyl or a bridged 5-10 membered bicyclic carbocyclyl, a 4-10 membered monocyclic heterocyclyl, a 5-10 membered monocyclic heteroaryl, or a fused 8-10 membered bicyclic heteroaryl.

    11. (canceled)

    12. The compound of claim 2, wherein C is a 6,6-fused heteroaryl or heterocycle, 5,6-fused heteroaryl or heterocycle, 6,5-fused heteroaryl or heterocycle, or 5,5-fused heteroaryl or heterocycle.

    13. The compound of claim 2, wherein C is ##STR00407## ##STR00408##

    14. The compound of claim 2, wherein at least one R.sup.3 is —CH.sub.2NHSO.sub.2CH.sub.3,-CH(CH.sub.3)NHSO.sub.2CH.sub.3,-CH.sub.2CH.sub.2NHSO.sub.2CH.sub.3,-CH.sub.2N(CH.sub.3)SO.sub.2CH.sub.3,-NHSO.sub.2CH.sub.3,-N(CH.sub.3)SO.sub.2CH.sub.3,-NHSO.sub.2CH.sub.2CH.sub.3,-NH.sub.2, —NHCH.sub.3,-SO.sub.2NH.sub.2, or -SO.sub.2CH.sub.3; and the other R.sup.3 is, if present, halogen, —CN,-CF.sub.3, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, oxo, —S(C.sub.1-C.sub.3 alkyl),-SO.sub.2(C.sub.1-C.sub.3 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.3 alkyl), —(C.sub.1-C.sub.3 alkyl)NH.sub.2,-NHSO.sub.2CH.sub.3,-NHSO.sub.2CF.sub.3,-N(CH.sub.3)SO.sub.2CH.sub.3,-NHSO.sub.2CH.sub.2CH.sub.3,-N(CH.sub.3)SO.sub.2CH.sub.2CH.sub.3,-CH.sub.2NHSO.sub.2CH.sub.3,-CH.sub.2N(CH.sub.3)SO.sub.2CH.sub.3,-SO.sub.2NH.sub.2, —CONH.sub.2, —CON(C.sub.1-C.sub.3 alkyl).sub.2, —CONH(C.sub.1-C.sub.3 alkyl), —NHCO(C.sub.1-C.sub.3 alkyl),-N(CH.sub.3)CO(C.sub.1-C.sub.3 alkyl),-NHCOCF.sub.3,-N(CH.sub.3)COCF.sub.3, —NHCOO(C.sub.1-C.sub.3 alkyl), or -N(CH.sub.3)COO(C.sub.1-C.sub.3 alkyl).

    15. The compound of claim 2, wherein: Z is —O—; V is —CH.sub.2—, —CH.sub.2CH.sub.2—, or —(CR.sup.8a′R.sup.9a′)-; R.sup.8a′ and R.sup.9a′ taken together form an optionally substituted 3- to 6-membered carbocyclyl; and L is hydrogen or halogen.

    16. The compound of claim 2, wherein-Z—V-L is-O-CH.sub.3,-O-CH.sub.2CH.sub.2Cl, —O-cyclopropyl, or —O-cyclobutyl.

    17. The compound of claim 2, wherein: Z is a bond; V is—(CR.sup.8a′R.sup.9a′)-; R.sup.8a′ and R.sup.9a′ taken together form an optionally substituted 3- to 6-membered heterocyclyl containing one, two, or three heteroatoms selected from N, S, or O; and L is hydrogen.

    18. The compound of claim 2, wherein B is phenyl and X and Z are connected at para positions of B.

    19. The compound of claim 2, wherein A is a 6-membered monocyclic ring selected from aryl, carbocyclyl, heteroaryl, or heterocyclyl; and X and Y are connected at 1 and 4 positions of A.

    20. The compound of claim 1 having the structure of formula (B-I): ##STR00409## or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: A and B are each independently a phenyl or a pyridyl ring; C is a monocyclic carbocycle, a spiral bicyclic carbocycle, a bridged bicyclic carbocycle, a monocyclic heterocycle, or a spiral bicyclic heterocycle; X is a bond, —CH.sub.2—, —C(CH.sub.3).sub.2—, —O—, or —NR.sup.7—; Y is a bond, —CH.sub.2—, —NH—, or —O—; W is —CH.sub.2—, —CH.sub.2CH.sub.2—, —C(CH.sub.3)H—, —N(R.sup.7)CO—, or —CONR.sup.7—; Z is a bond, —NH—, or —O—; V is a bond, —(CR.sup.8aR.sup.9a).sub.m(CR.sup.8a′R.sup.9a′)—, or —(CR.sup.8aR.sup.9a).sub.m—; L is hydrogen, halogen, —CF.sub.2R.sup.10, —CF.sub.3, —CN, —OR.sup.10, —NR.sup.11R.sup.12, or —CONR.sup.11R.sup.12; R.sup.1 and R.sup.2 are each independently halogen, —CN, or —CF.sub.3; at least one R.sup.3 is-CH.sub.2NHSO.sub.2CH.sub.3,-CH(CH.sub.3)NHSO.sub.2CH.sub.3,-CH.sub.2CH.sub.2NHSO.sub.2CH.sub.3, —CH.sub.2N(CH.sub.3)SO.sub.2CH.sub.3,-NHSO.sub.2CH.sub.3,-NHSO.sub.2CH.sub.2CH.sub.3,-SO.sub.2NH.sub.2,-SO.sub.2CH.sub.3, —NH.sub.2, —NH(C.sub.1-C.sub.3 alkyl),-NHCOCF.sub.3 or optionally substituted 4- to 6-membered heterocyclyl or heteroaryl; and the other R.sup.3 is, if present, halogen, —CN,-CF.sub.3, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, oxo, —S(C.sub.1-C.sub.3 alkyl), —SO.sub.2(C.sub.1-C.sub.3 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.3 alkyl), —(C.sub.1-C.sub.3 alkyl)NH.sub.2,-NHSO.sub.2CH.sub.3,-NHSO.sub.2CF.sub.3,-N(CH.sub.3)SO.sub.2CH.sub.3,-NHSO.sub.2CH.sub.2CH.sub.3,-N(CH.sub.3)SO.sub.2CH.sub.2CH.sub.3,-CH.sub.2NHSO.sub.2CH.sub.3,-CH.sub.2N(CH.sub.3)SO.sub.2CH.sub.3,-SO.sub.2NH.sub.2, —CONH.sub.2, —CON(C.sub.1-C.sub.3 alkyl).sub.2, —CONH(C.sub.1-C.sub.3 alkyl), —NHCO(C.sub.1-C.sub.3 alkyl),-N(CH.sub.3)CO(C.sub.1-C.sub.3 alkyl),-NHCOCF.sub.3,-N(CH.sub.3)COCF.sub.3, —NHCOO(C.sub.1-C.sub.3 alkyl),-N(CH.sub.3)COO(C.sub.1-C.sub.3 alkyl); or optionally substituted 4- to 6-membered heterocyclyl; R.sup.7 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 deuterated alkyl; R.sup.8a and R.sup.9a are each independently hydrogen, halogen, or C.sub.1-C.sub.3 alkyl; R.sup.8a′ and R.sup.9a′ taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl containing one, two, or three heteroatoms selected from N, S, or O; R.sup.10 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.11 and R.sup.12 are each independently hydrogen or C.sub.1-C.sub.3 alkyl; or R.sup.11 and R.sup.12 taken together form an optionally substituted heterocyclyl which optionally contains one or two additional heteroatoms selected from N, S, or O; m is 0, 1, 2, or 3; n1 and n2 are each independently 0, 1, or 2; and n3 is 1, 2, 3, 4 or 5; and wherein when C is a bridged bicyclic carbocycle,-Z—V-L is not-OCH.sub.2CH.sub.2Cl or —OCH.sub.3.

    21.-30. (canceled)

    31. The compound of claim 1 having the structure of formula (C-I): ##STR00410## or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: A is a 4- to 15-membered aryl, carbocyclyl, heteroaryl, or heterocyclyl; B is a 4- to 15-membered aryl, carbocyclyl, heteroaryl, or heterocyclyl; C is a 4- to 15-membered aryl, carbocyclyl, heteroaryl, or heterocyclyl; X is a bond, —CH.sub.2—, —C(CH.sub.3).sub.2—, —O—, or —NR.sup.7—; Y is a bond; W is a bond, heteroaryl, heterocyclyl, -heteroaryl-NH-*, or -heterocyclyl-NH-*, wherein heteroaryl or heterocyclyl of W is optionally substituted and wherein * indicates connection to ring C; Z is a bond or —O—; V is a bond, —(CR.sup.8aR.sup.9a).sub.m(CR.sup.8a′R.sup.9a′)—, or —(CR.sup.8aR.sup.9a).sub.m—; L is hydrogen, halogen, —CF.sub.2R.sup.10, —CF.sub.3, —CN, —OR.sup.10, —NR.sup.11R.sup.12, or —CONR.sup.11R.sup.12; R.sup.1 and R.sup.2 are each independently halogen, oxo, —CN, or —CF.sub.3; R.sup.3 is halogen, oxo, ═S, ═NR.sup.16, —CN,-CF.sub.3, —OH, —S(C.sub.1-C.sub.3 alkyl), C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, —NR.sup.13R.sup.14, —(C.sub.1-C.sub.3 alkyl)-NR.sup.13R.sup.14, NR.sup.14SO.sub.2R.sup.16, —(C.sub.1-C.sub.3 alkyl)NR.sup.14SO.sub.2R.sup.16, —NR.sup.14COR.sup.16, —NR.sup.14COOR.sup.16, —(C.sub.1-C.sub.6 alkyl)-NR.sup.14COR.sup.16, —CONR.sup.14R.sup.15, —(C.sub.1-C.sub.3 alkyl)-CONR.sup.14R.sup.15, —SO.sub.2NR.sup.14R.sup.15, —(C.sub.1-C.sub.3 alkyl)-SO.sub.2NR.sup.14R.sup.15, —SO.sub.2(C.sub.1-C.sub.3 alkyl), —(C.sub.1-C.sub.6 alkyl)-SO.sub.2(C.sub.1-C.sub.3 alkyl), optionally substituted 3- to 7-membered carbocycle, or optionally substituted 4- to 6-membered heterocyclyl or heteroaryl; R.sup.7 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 deuterated alkyl; R.sup.8a and R.sup.9a are each independently hydrogen, halogen, or C.sub.1-C.sub.3 alkyl; R.sup.8a′ and R.sup.9a′ taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl containing one, two, or three heteroatoms selected from N, S, or O; R.sup.10 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.11 and R.sup.12 are each independently hydrogen or C.sub.1-C.sub.3 alkyl; or R.sup.11 and R.sup.12 taken together form an optionally substituted heterocyclyl which optionally contains one or two additional heteroatoms selected from N, S, or O; R.sup.13, R.sup.14 and R.sup.15 are each independently hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, or C.sub.2-C.sub.3 alkynyl; or R.sup.14 and R.sup.15 taken together form an optionally substituted 3- to 6-membered heterocyclyl; R.sup.16 is hydrogen, optionally substituted C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.2-C.sub.3 alkenyl, optionally substituted C.sub.2-C.sub.3 alkynyl, optionally substituted C.sub.1-C.sub.3 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, or phenyl; m is 0, 1, 2, or 3; n1 and n2 are each independently 0, 1, or 2; and n3 is 1, 2, 3, 4 or 5; wherein when A is a fused or a bridged bicyclic ring; C is a 4- to 10-membered aryl, carbocyclyl, heteroaryl, or heterocyclyl; and X is a bond, —CH.sub.2—, or —C(CH.sub.3).sub.2—, then W is not a bond; and wherein when A is phenyl, and C is a fused or a bridged bicyclic ring selected from ##STR00411## and X is a bond, —CH.sub.2—, or —C(CH.sub.3).sub.2—, then W is not a bond.

    32.-45. (canceled)

    46. The compound of claim 1 having the structure of formula (D-I): ##STR00412## or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: C is pyrimidyl; X is a bond, —CH.sub.2—,-C(CH.sub.3).sub.2, —O—, or —NR.sup.7—; Z is —O— and -V-L is —(CR.sup.8aR.sup.9a).sub.m-(optionally substituted carbocycle), —(CR.sup.8aR.sup.9a).sub.m1-(optionally substituted aryl), —(CR.sup.8aR.sup.9a).sub.m-(optionally substituted heterocycle), —(CR.sup.8aR.sup.9a).sub.m-(optionally substituted heteroaryl), —CHCH.sub.2, —CHF.sub.2, —CH.sub.3, —CH.sub.2CH.sub.2CH.sub.3,-CH.sub.2CH.sub.2NHSO.sub.2CH.sub.3, or -CH.sub.2CH.sub.2CH.sub.2OC(O)NH-(optionally substituted aryl); or Z is a bond and -V-L is—(CR.sup.8aR.sup.9a).sub.m—NR.sup.11R.sup.12; or Z is a bond and -V-L is-CH.sub.2CH.sub.2OH, —CH.sub.2CH.sub.2Cl, or -CHCH.sub.2; R.sup.2 is Cl or —CN; at least one R.sup.3 is-CH.sub.2NHSO.sub.2CH.sub.3,-CH.sub.2N(CH.sub.3)SO.sub.2CH.sub.3,-CH(CH.sub.3)NHSO.sub.2CH.sub.3,-CH.sub.2CH.sub.2NHSO.sub.2CH.sub.3,-NHSO.sub.2CH.sub.3,-NHSO.sub.2CH.sub.2CH.sub.3,-SO.sub.2NH.sub.2,-SO.sub.2CH.sub.3, —NH.sub.2, —NH(C.sub.1-C.sub.3 alkyl),-NHCOCF.sub.3 or optionally substituted 4- to 6-membered heterocyclyl or heteroaryl; and the other R.sup.3 is, if present, halogen, —CN,-CF.sub.3, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 alkoxy, oxo, —S(C.sub.1-C.sub.3 alkyl),-SO.sub.2(C.sub.1-C.sub.3 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.3 alkyl), —(C.sub.1-C.sub.3 alkyl)NH.sub.2,-NHSO.sub.2CH.sub.3,-NHSO.sub.2CF.sub.3,-N(CH.sub.3)SO.sub.2CH.sub.3,-NHSO.sub.2CH.sub.2CH.sub.3,-N(CH.sub.3)SO.sub.2CH.sub.2CH.sub.3,-CH.sub.2NHSO.sub.2CH.sub.3,-CH.sub.2N(CH.sub.3)SO.sub.2CH.sub.3,-SO.sub.2NH.sub.2, —CONH.sub.2, —CON(C.sub.1-C.sub.3 alkyl).sub.2, —CONH(C.sub.1-C.sub.3 alkyl), —NHCO(C.sub.1-C.sub.3 alkyl),-N(CH.sub.3)CO(C.sub.1-C.sub.3 alkyl),-NHCOCF.sub.3,-N(CH.sub.3)COCF.sub.3, —NHCOO(C.sub.1-C.sub.3 alkyl),-N(CH.sub.3)COO(C.sub.1-C.sub.3 alkyl); or optionally substituted 4- to 6-membered heterocyclyl; R.sup.7 is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 deuterated alkyl; R.sup.11 and R.sup.12 taken together form an optionally substituted heterocyclyl which optionally contains one or two additional heteroatoms selected from N, S, or O; n3 is 1, 2, or 3; each m is independently 0, 1, 2, or 3; each m1 is independently 1, 2, or 3; and wherein when R.sup.2 is —CN,-Z—V-L is not; ##STR00413##

    47.-86. (canceled)

    87. The compound of claim 1, wherein the compound is ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419## or a pharmaceutically acceptable salt thereof.

    88. The compound of claim 1, wherein the compound is ##STR00420## ##STR00421## ##STR00422## or a pharmaceutically acceptable salt thereof.

    89. The compound of claim 1, wherein the compound is ##STR00423## ##STR00424## ##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430## or a pharmaceutically acceptable salt thereof.

    90. The compound of claim 1, wherein the compound is ##STR00431## ##STR00432## ##STR00433## ##STR00434## or a pharmaceutically acceptable salt thereof.

    91. The compound of claim 1, wherein the compound is ##STR00435## ##STR00436## ##STR00437## ##STR00438## or a pharmaceutically acceptable salt thereof.

    92.-96. (canceled)

    97. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

    98. A method for treating cancer, comprising administering the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug of the compound of claim 1, to a subject in need thereof.

    99. The method of claim 98, wherein the cancer is prostate cancer.

    100. The method of claim 99, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

    101. The method of claim 99, wherein the prostate cancer expresses full-length androgen receptor or truncated androgen receptor splice variant.

    Description

    EXAMPLES

    [1353] The disclosure now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.

    [1354] Synthetic Preparation

    [1355] The novel compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.

    [1356] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th. Ed., Wiley & Sons, 2006, as well as in Jerry March, Advanced Organic Chemistry, 4.sup.th edition, John Wiley & Sons, publisher, New York, 1992 which are incorporated herein by reference in their entirety.

    [1357] Compounds of the present invention can be prepared by the literature methods cited in the following text. The following schemes depict established, known syntheses of these scaffolds.

    [1358] The groups and/or the substituents of the compounds of the present invention can be synthesized and attached to these scaffolds by the literature methods cited in the following text. The following schemes depict the known techniques for accomplishing this joinder.

    [1359] General Synthesis

    [1360] Compounds of the present invention can be synthesized using the following methods. General reaction conditions are given, and reaction products can be purified by general known methods including crystallization, silica gel chromatography using various organic solvents such as hexane, cyclohexane, ethyl acetate, methanol and the like, preparative high pressure liquid chromatography or preparative reverse phase high pressure liquid chromatography.

    [1361] Representative Synthesis

    Example 1: Synthesis of N-((1r,3r)-3-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)cyclobutyl)methanesulfonamide (Compound A15)

    [1362] ##STR00382##

    [1363] Tert-butyl ((1r,3r)-3-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)cyclobutyl)carbamate (2): To a solution of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile (inter J) (200 mg, 0.57 mmol) and tert-butyl ((1r,3r)-3-(hydroxymethyl)cyclobutyl)carbamate (1) (230 mg, 1.14 mmol) in THE (5 mL) was added PPh.sub.3 (300 mg, 1.14 mol) and DIAD (0.2 mL, 1.14 mmol) at 0° C. under N.sub.2 atmosphere. The mixture was stirred at 20° C. for 16 hrs under N.sub.2 atmosphere. LCMS showed the reaction was completed. The resulting mixture was quenched with H.sub.2O (5 mL). The aqueous layer was extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl ((1r,3r)-3-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)cyclobutyl)carbamate (2) (270 mg, yield: 79.8%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.45 (d, J=2.4 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.08 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 4.75 (br s, 1H), 4.42 (t, J=6.2 Hz, 2H), 4.29 (br d, J=5.2 Hz, 1H), 3.98 (d, J=7.2 Hz, 2H), 3.88 (t, J=6.0 Hz, 2H), 2.72-2.56 (m, 1H), 2.40-2.26 (m, 2H), 2.13-2.06 (m, 2H), 1.64 (s, 6H), 1.45 (s, 9H).

    [1364] 5-(2-(4-(((1r,3r)-3-aminocyclobutyl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (3): A solution of tert-butyl ((1 r,3r)-3-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)cyclobutyl)carbamate (2) (270 mg, 0.48 mmol) in TFA (0.4 mL) and DCM (2 mL) was stirred at 20° C. for 1 h. LCMS showed the reaction was completed. The reaction mixture was poured into water (5 mL) and then adjusted to pH=7-8 with sat.NaHCO.sub.3 and then extracted with DCM (5 mL×3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 5-(2-(4-(((1r,3r)-3-aminocyclobutyl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (3) (184 mg, yield: 87.5%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.45 (d, J=2.0 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.25-4.94 (m, 2H), 4.42 (t, J=6.0 Hz, 2H), 3.96 (d, J=6.0 Hz, 2H), 3.89-3.80 (m, 3H), 2.85-2.80 (m, 1H), 2.40-2.34 (m, 2H), 2.30-2.25 (m, 2H), 1.64 (s, 6H).

    [1365] N-((1r,3r)-3-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)cyclobutyl)methanesulfonamide (Compound A15): To a solution of 5 (2-(4-(((1r,3 r)-3-aminocyclobutyl)methoxy)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (3) (200 mg, 0.42 mmol) and N,N-diethylethanamine (0.1 mL, 0.84 mmol) in DCM (2 mL) was added methanesulfonyl chloride (95 mg, 0.84 mmol) at 0° C. The mixture was stirred for 2 hrs at 0-25° C. LCMS showed the reaction was completed. The reaction was quenched with water (5 mL) and extracted with DCM (5 mL×3). The combined organic layers were washed with brine (5×2 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by p-HPLC(FA) to give N-((1r,3 r)-3-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)cyclobutyl)methanesulfonamide (Compound A15) (70 mg, yield: 32.6%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.45 (d, J=2.4 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 4.51 (br d, J=8.8 Hz, 1H), 4.42 (t, J=6.4 Hz, 2H), 4.24-4.10 (m, 1H), 3.99 (d, J=6.4 Hz, 2H), 3.88 (t, J=6.4 Hz, 2H), 2.95 (s, 3H), 2.71-2.68 (m, 1H), 2.48-2.41 (m, 2H), 2.29-2.17 (m, 2H), 1.65 (s, 6H). LCMS (220 nm): 100.0%. Exact Mass: 510.0; found 533.1/535.1 (M+23).

    Example 2: Synthesis of N-(6-(4-(3-chloro-4-(2-chloroethoxy)-5-cyanophenoxy)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A16)

    [1366] ##STR00383##

    [1367] 5-(4-bromophenoxy)-3-chloro-2-(2-chloroethoxy)benzonitrile (2): To a solution of (3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)boronic acid (inter S1) (3.1 g, 11.8 mmol), 4-bromophenol (1) (1.7 g, 9.83 mmol), Pyridine (1.5 g, 19.7 mmol) and 4 A M.S. (2.5 g) in DCE (60 mL) was added Cu(OAc).sub.2 (1.7 g, 9.83 mmol) at 25° C. The mixture was stirred at 70° C. under 02 for 6 hrs. LCMS showed the reaction was completed. The mixture was quenched with water (100 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by p-HPLC (FA) to give 5-(4-bromophenoxy)-3-chloro-2-(2-chloroethoxy)benzonitrile (2) (1.1 g, yield: 17.4%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.53 (d, J=8.8 Hz 2H), 7.26 (d, J=3.2 Hz, 1H), 7.08 (d, J=3.2 Hz, 1H), 6.92 (d, J=8.4 Hz 2H), 4.41 (t, J=6.0 Hz, 2H), 3.89 (t, J=6.0 Hz, 2H).

    [1368] 3-chloro-2-(2-chloroethoxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy) benzonitrile (3): To a solution of 5-(4-bromophenoxy)-3-chloro-2-(2-chloroethoxy)benzonitrile (2) (0.9 g, 1.4 mmol) and Pin.sub.2B.sub.2 (0.53 g, 2.09 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl.sub.2 (0.1 g, 0.14 mmol) and AcOK (0.41 g, 4.19 mmol) at 25° C. and the mixture was stirred at 100° C. for 3 hrs under N.sub.2 atmosphere. LCMS showed the reaction was completed. The mixture was quenched with H.sub.2O (30 mL). Then the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-(2-chloroethoxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (3) (0.6 g, yield: 89.2%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.85 (d, J=8.4 Hz 2H), 7.26 (s, 1H), 7.10 (d, J=2.8 Hz, 1H), 7.01 (d, J=8.8 Hz 2H), 4.41 (t, J=6.0 Hz, 2H), 3.89 (t, J=6.0 Hz, 2H), 1.36 (s, 12H).

    [1369] 3-chloro-2-(2-chloroethoxy)-5-(4-(2-oxo-1,2-dihydroquinoxalin-6-yl)phenoxy)benzonitrile (5): To a solution of 3-chloro-2-(2-chloroethoxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (3) (300 mg, 0.62 mmol) and 6-bromobenzo[b][1,4]azaborinin-2(1H)-one (4) (140 mg, 0.62 mmol) in 1,4-dioxane (4 mL) and H.sub.2O (1 mL) was added dipotassium;carbonate (215 mg, 1.55 mmol) and Pd(dppf)Cl.sub.2 (46 mg, 0.06 mmol) under N.sub.2 at 25° C. The mixture was stirred for 4 hrs at 100° C. under N.sub.2. LCMS showed the reaction was completed. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 3-chloro-2-(2-chloroethoxy)-5-(4-(2-oxo-1,2-dihydroquinoxalin-6-yl)phenoxy)benzonitrile (5) (360 mg, yield: 89.6%) as black solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=12.54 (s, 1H), 8.21 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.89 (dd, J=2.0, 8.4 Hz, 1H), 7.83-7.77 (m, 2H), 7.64 (d, J=2.8 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 2H), 4.42 (t, J=4.8 Hz, 2H), 3.98 (t, J=4.0 Hz, 2H).

    [1370] 3-chloro-2-(2-chloroethoxy)-5-(5-((3-fluoro-1-(methylsulfonyl)azetidin-3-yl)methoxy)-1H-indol-1-yl)benzonitrile (6): A solution of 3-chloro-2-(2-chloroethoxy)-5-(4-(2-oxo-1,2-dihydroquinoxalin-6-yl)phenoxy)benzonitrile (5) (360 mg, 0.55 mmol) in POCl.sub.3 (3 mL) and toluene (6 mL) was stirred at 110° C. for 1 h under N.sub.2 atmosphere. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure. The residue was adjusted to pH=8-9 with sat.NaHCO.sub.3. The mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-(2-chloroethoxy)-5-(5-((3-fluoro-1-(methylsulfonyl) azetidin-3-yl)methoxy)-1H-indol-1-yl)benzonitrile (6) (18 mg, yield: 68.6%) as yellow solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=9.03 (s, 1H), 8.41 (d, J=1.6 Hz, 1H), 8.28 (dd, J=2.0, 8.8 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.70 (d, J=2.8 Hz, 1H), 7.66 (d, J=2.8 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 4.43 (t, J=5.2 Hz, 2H), 3.99 (t, J=5.2 Hz, 2H).

    [1371] N-(6-(4-(3-chloro-4-(2-chloroethoxy)-5-cyanophenoxy)phenyl)quinoxalin-2-yl) methanesulfonamide (Compound A16): To a solution of 3-chloro-2-(2-chloroethoxy)-5-(5-((3-fluoro-1-(methyl sulfonyl)azetidin-3-yl)methoxy)-1H-indol-1-yl)benzonitrile (6) (130 mg, 0.27 mmol), methanesulfonamide (131 mg, 1.38 mmol) and Cs.sub.2CO.sub.3 (180 mg, 0.55 mmol) in 1,4-dioxane (3 mL) was added Pd.sub.2(dba).sub.3 (51 mg, 0.05 mmol) and Xantphos (64 mg, 0.11 mmol) at 25° C. and the mixture was stirred at 90° C. for 3 hrs under N.sub.2. LCMS showed the reaction was completed. The mixture was poured into water (5 mL) and extracted with EtOAc (3 mL×3), the combined organic layers were washed with brine (3 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by p-HPLC (FA) to give N-(6-(4-(3-chloro-4-(2-chloroethoxy)-5-cyanophenoxy)phenyl)quinoxalin-2-yl) methanesulfonamide (Compound A16) (22.3 mg, yield: 15.1%) as yellow solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=11.63 (br s, 1H), 8.61 (s, 1H), 8.25 (s, 1H), 8.12 (dd, J=2.4, 8.8 Hz, 1H), 7.94-7.92 (m, 3H), 7.68 (d, J=3.2 Hz, 1H), 7.63 (d, J=2.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 4.42 (t, J=4.8 Hz, 2H), 3.99 (t, J=5.2 Hz, 2H), 3.48 (s, 3H), LCMS (220 nm): 99.86%. Exact Mass: 528.04; found 528.9/530.9.

    Example 3: Synthesis of N-(4-((4-(2-(3-chloro-5-cyano-4-methoxyphenyl)propan-2-yl) phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (Compound A17)

    [1372] ##STR00384##

    [1373] 3-chloro-5-(2-(4-hydroxyphenyl)propan-2-yl)-2-methoxybenzonitrile (2): To a solution of 3-chloro-2-hydroxy-5-(2-(4-hydroxyphenyl)propan-2-yl)benzonitrile (1) (3.0 g, 10.4 mmol) and methanol (0.33 g, 10.4 mmol) in THF (30 mL) was added PPh.sub.3 (4.1 g, 15.6 mmol) and DIAD (3.1 mL, 15.6 mmol) at 20° C. The mixture was stirred at 25° C. for 16 hrs under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was poured into H.sub.2O (20 mL) and then extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to give 3-chloro-5-(2-(4-hydroxyphenyl)propan-2-yl)-2-methoxybenzonitrile (2) (2.7 g, yield: 85.0%) as colorless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.43 (d, J=2.4 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.10-7.02 (m, 2H), 6.85-6.68 (m, 2H), 4.94-4.78 (m, 1H), 4.05 (s, 3H), 1.64 (s, 6H).

    [1374] 3-chloro-2-methoxy-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (3): To a solution of 3-chloro-5-(2-(4-hydroxyphenyl) propan-2-yl)-2-methoxybenzonitrile (2) (500 mg, 1.66 mmol) and 4-(chloromethyl)-2-(methylthio)pyrimidine (10a) (700 mg, 3.31 mmol) in DMF (8 mL) was added Cs.sub.2CO.sub.3 (2.16 g, 6.63 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hrs. LCMS showed the reaction was completed. The reaction was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-methoxy-5-(2-(4-((2-(methylthio) pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (3) (250 mg, yield: 34.0%) as colorless oil. .sup.1H-NMR (400 MHz, CHCl.sub.3) δ=8.09 (br s, 1H), 7.82-7.67 (m, 2H), 7.38 (t, J=6.4 Hz, 2H), 6.57-6.43 (m, 2H).

    [1375] 3-chloro-2-methoxy-5-(2-(4-((2-(methylsulfonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (4): To a solution of 3-chloro-2-methoxy-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (3) (250 mg, 0.57 mmol) in THE (1.5 mL) and water (1.5 mL) was added Oxone (1.05 g, 1.70 mmol) at 25° C. and the mixture was stirred at 25° C. for 16 hrs. LCMS showed the reaction was completed. The resulting mixture was quenched with H.sub.2O (10 mL). The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers was washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-methoxy-5-(2-(4-((2-(methylsulfonyl) pyrimidin-4-yl)methoxy) phenyl) propan-2-yl)benzonitrile (4) (200 mg, yield: 74.6%) as colorless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.94 (d, J=5.2 Hz, 1H), 7.85 (d, J=5.2 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.18-7.10 (m, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.30 (s, 2H), 4.06 (s, 3H), 3.40 (s, 3H), 1.65 (s, 6H).

    [1376] N-(4-((4-(2-(3-chloro-5-cyano-4-methoxyphenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (Compound A17): To a solution of 3-chloro-2-methoxy-5-(2-(4-((2-(methyl sulfonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (4) (200 mg, 0.42 mmol) and methanesulfonamide (0.20 g, 2.12 mmol) in DMF (3 mL) was added Cs.sub.2CO.sub.3 (276 mg, 0.85 mmol) at 20° C. and the mixture was stirred at 20° C. for 16 hrs under N.sub.2 atmosphere. LCMS showed the reaction was completed. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL×3), the combined organic layers were washed with brine (3 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by p-HPLC (FA) to give N-(4-((4-(2-(3-chloro-5-cyano-4-methoxyphenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (Compound A17) (39.2 mg, yield: 18.8%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.73 (br s, 1H), 8.64 (d, J=5.2 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.29 (d, J=5.2 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 5.11 (s, 2H), 4.06 (s, 3H), 3.48 (s, 3H), 1.65 (s, 6H) LCMS (220 nm): 94.7%. Exact Mass: 486.11; found 487.0/489.0.

    Example 4: Synthesis of N-(6-(4-((3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)(2,2,2-trifluoroethyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A22)

    [1377] ##STR00385##

    [1378] 6-bromo-2-chloroquinoxaline (2): A solution of 6-bromoquinoxalin-2(1H)-one (1) (10.0 g, 44.4 mmol) in POCl.sub.3 (102 mL, 1.11 mol) and DMF (5 mL) was stirred at 100° C. for 2 hrs. LCMS showed the reaction was completed and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-bromo-2-chloroquinoxaline (2) (9.5 g, yield: 79.0%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.80 (s, 1H), 8.33 (s, 1H), 7.92 (s, 2H).

    [1379] 6-bromo-2-(methylthio)quinoxaline (3): To a solution of 6-bromo-2-chloroquinoxaline (2) (9.5 g, 35.1 mmol) in DMF (100 mL) was added NaSMe (2.9 g, 42.1 mmol) at 20° C., the mixture was stirred at 20° C. for 2 hrs. LCMS showed the reaction was completed. The mixture was quenched with H.sub.2O (100 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-bromo-2-(methylthio)quinoxaline (3) (8.4 g, yield: 84.4%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.59 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.83-7.69 (m, 2H), 2.70 (s, 3H).

    [1380] 4-(2-(methylthio)quinoxalin-6-yl)aniline (5): To a mixture of 6-bromo-2-(methylthio)quinoxaline (3) (3.0 g, 11.8 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4) (2.8 g, 12.9 mmol) in 1,4-dioxane (40 mL) and H.sub.2O (8 mL) was added disodium; carbonate (2.5 g, 23.5 mmol) and Pd(PPh.sub.3).sub.4 (2.0 g, 1.76 mmol) at 20° C. under N.sub.2 and the mixture was stirred at 80° C. for 6 h under N.sub.2. LCMS showed the reaction was completed. The mixture was quenched with H.sub.2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-(2-(methylthio)quinoxalin-6-yl)aniline (5) (3.0 g, yield: 76.3%). .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.61 (s, 1H) 8.20-8.10 (m, 1H), 7.01-8.89 (m, 2H), 7.57 (br d, J=8.4 Hz, 2H), 6.81 (br d, J=8.4 Hz, 2H), 3.83 (br s, 2H), 2.72 (s, 3H), 2.63-2.62 (m, 1H).

    [1381] 4-(2-(methylthio)quinoxalin-6-yl)-N-(2,2,2-trifluoroethyl)aniline (6): To a solution of 4-(2-(methylthio)quinoxalin-6-yl)aniline (5) (1.0 g, 2.99 mmol)) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.5 g, 15 mmol) in DMF (10 mL) was added dicesium;carbonate (2.9 g, 8.98 mmol) at 25° C. and the mixture was stirred at 80° C. for 6 hrs under N.sub.2. LCMS showed ˜30% of starting material remained and ˜35% of desired product was detected. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL×3), the combined organic layers were washed with brine (10 mL×3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-(2-(methylthio)quinoxalin-6-yl)-N-(2,2,2-trifluoroethyl)aniline (6) (180 mg, yield: 15.5%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.62 (s, 1H), 8.22 (d, J=1.2 Hz, 1H), 8.03-7.93 (m, 2H), 7.71-7.56 (m, 2H), 6.83 (d, J=8.8 Hz, 2H), 2.81-2.67 (m, 3H).

    [1382] 3-chloro-2-(2-chloroethoxy)-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (7): To a solution of 5-bromo-3-chloro-2-(2-chloroethoxy)benzonitrile (inter Q) (244 mg, 0.8 mmol), 4-(2-(methylthio)quinoxalin-6-yl)-N-(2,2,2-trifluoroethyl)aniline (6) (140 mg, 0.4 mol) and sodium; 2-methylpropan-2-olate (77 mg, 0.8 mmol) in toluene (3 mL) was added di-μ-bromobis(tri-tert-butylphosphine)dipalladium(I) (62 mg, 0.08 mmol) at 25° C. and the mixture was stirred at 100° C. for 3 hrs under N.sub.2 atmosphere. LCMS showed the reaction was completed. The mixture was poured into water (5 mL) and extracted with EtOAc (3 mL×3), the combined organic layers were washed with brine (3 mL×3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-(2-chloroethoxy)-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (6) (200 mg, yield: 79.7%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.66 (s, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.08-8.03 (m, 1H), 8.02-7.96 (m, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.19 (d, J=3.2 Hz, 1H), 7.02 (d, J=3.2 Hz, 1H), 4.40 (t, J=6.0 Hz, 2H), 4.32 (q, J=8.4 Hz, 2H), 3.89 (t, J=6.0 Hz, 2H), 2.75 (s, 3H).

    [1383] 3-chloro-2-(2-chloroethoxy)-5-((4-(2-(methylsulfonyl)quinoxalin-6-yl)phenyl) (2,2,2-trifluoroethyl)amino)benzonitrile (8): To a solution of 3-chloro-2-(2-chloroethoxy)-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (7) (150 mg, 0.24 mmol) in THF (2 mL) and H.sub.2O (2 mL) was added Oxone (368 mg, 0.6 mmol) at 25° C. The mixture was stirred for 6 hrs at 25° C. under N.sub.2. LCMS showed the reaction was completed. The reaction was quenched with Na.sub.2S03 (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 3-chloro-2-(2-chloroethoxy)-5-((4-(2-(methylsulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (8) (170 mg, yield: 95.3%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=9.54 (s, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.33-8.28 (m, 1H), 8.24-8.19 (m, 1H), 7.86-7.81 (m, 2H), 7.28 (d, J=2.8 Hz, 1H), 7.26-7.21 (m, 2H), 7.11 (d, J=2.8 Hz, 1H), 4.43 (t, J=6.0 Hz, 2H), 4.38-4.30 (m, 2H), 3.90 (t, J=6.0 Hz, 2H), 3.43 (s, 3H).

    [1384] N-(6-(44(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)(2,2,2-trifluoroethyl)amino) phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A22): To a solution of 3-chloro-2-(2-chloro ethoxy)-5-((4-(2-(methyl sulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (8) (170 mg, 0.26 mmol) in MeCN (2 mL) was added methanesulfonamide (73 mg, 0.77 mmol), dicesium;carbonate (251 mg, 0.77 mmol). The reaction was stirred at 35° C. for 6 hrs. LCMS showed the reaction was completed. The reaction was quenched with H.sub.2O (5 mL) and added HCl to adjust to pH=3-4, then the mixture was extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by p-HPLC (neutral) to give N-(6-(4-((3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)(2,2,2-trifluoroethyl) amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A22) (44 mg, yield: 36%) as yellow solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=8.51 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.09 (dd, J=2.0, 8.4 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.43 (dd, J=2.8, 12.8 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 4.77-4.73 (m, 2H), 4.38 (t, J=4.8 Hz, 2H), 3.96 (t, J=4.8 Hz, 2H), 3.38 (s, 3H). LCMS (220 nm): 100.00%. Exact Mass: 609.1; found 610.1/612.1.

    Example 5: Synthesis of N-(1-(5-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)pyrimidin-2-yl)azetidin-3-yl)methanesulfonamide (Compound A36)

    [1385] ##STR00386##

    [1386] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-(2-(methylthio)pyrimidin-5-yl)phenyl)propan-2-yl)benzonitrile (2): To a solution of 5-bromo-2-(methylthio)pyrimidine (1) (120 mg, 0.59 mmol) and 3-chloro-2-(2-chloroethoxy)-5-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)benzonitrile (Inter E) (300 mg, 0.59 mmol) in 1,4-dioxane (4 mL) and H.sub.2O (1 mL) was added dipotassium;carbonate (203 mg, 1.47 mmol) and Pd(dppf)Cl.sub.2 (43 mg, 0.06 mmol) under N.sub.2 at 25° C. The mixture was stirred at 90° C. for 4 hrs under N.sub.2 atmosphere. LCMS showed the reaction was completed. The reaction solution was filtered. The filtrate was quenched with water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-(2-chloroethoxy)-5-(2-(4-(2-(methylthio)pyrimidin-5-yl)phenyl)propan-2-yl)benzonitrile (2) (240 mg, yield: 80.3%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.76 (s, 2H), 7.52-7.48 (m, 3H), 7.37 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 4.44 (t, J=6.0 Hz, 2H), 3.89 (t, J=6.0 Hz, 2H), 2.66-2.62 (m, 3H), 1.71 (s, 6H).

    [1387] 3-chloro-2-(2-chloroethoxy)-5-(2-(4-(2-(methylsulfonyl)pyrimidin-5-yl)phenyl)propan-2-yl)benzonitrile (3): To a solution of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-(2-(methylthio)pyrimidin-5-yl)phenyl)propan-2-yl)benzonitrile (2) (230 mg, 0.45 mmol) in THE (3 mL) and H.sub.2O (3 mL) was added Oxone (694 mg, 1.13 mmol) at 25° C. The mixture was stirred at 25° C. for 12 hrs under N.sub.2. LCMS showed the reaction was completed. The reaction was quenched with sat. Na.sub.2SO.sub.3 (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 3-chloro-2-(2-chloroethoxy)-5-(2-(4-(2-(methylsulfonyl)pyrimidin-5-yl)phenyl)propan-2-yl)benzonitrile (3) (160 mg, yield: 65.0%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=9.11 (s, 2H), 7.60-7.57 (m, 2H), 7.49 (d, J=2.4 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.36 (d, J=2.4 Hz, 1H), 4.47-4.44 (m, 2H), 3.92-3.87 (m, 2H), 3.42 (s, 3H), 1.73 (s, 6H).

    [1388] tert-butyl (1-(5-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl) pyrimidin-2-yl)azetidin-3-yl)carbamate (5): To a solution of 3-chloro-2-(2-chloroethoxy)-5-(2-(4-(2-(methyl sulfonyl)pyrimidin-5-yl)phenyl)propan-2-yl)benzonitrile (3) (160 mg, 0.29 mmol) and tert-butyl azetidin-3-ylcarbamate (4) (76 mg, 0.44 mmol) in MeCN (3 mL) was added dipotassium;carbonate (122 mg, 0.88 mmol) at 25° C. under N.sub.2. The mixture was stirred at 60° C. for 4 hrs under N.sub.2. LCMS showed the reaction was completed. The reaction was quenched with water (3 mL) and extracted with EtOAc (3 mL×3). The combined organic layers were washed with brine (5 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (1-(5-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl) propan-2-yl)phenyl)pyrimidin-2-yl)azetidin-3-yl)carbamate (5) (150 mg, yield: 74.5%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.56 (s, 2H), 7.49 (d, J=2.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.37 (d, J=2.4 Hz, 1H), 7.25 (s, 2H), 5.10-4.96 (m, 1H), 4.73-4.59 (m, 1H), 4.52 (br t, J=8.0 Hz, 2H), 4.43 (t, J=6.0 Hz, 2H), 4.00 (dd, J=4.8, 9.4 Hz, 2H), 3.88 (t, J=6.0 Hz, 2H), 1.70 (s, 6H), 1.47 (s, 9H).

    [1389] 5-(2-(4-(2-(3-aminoazetidin-1-yl)pyrimidin-5-yl)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (6): To a mixture of tert-butyl (1-(5-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)pyrimidin-2-yl)azetidin-3-yl)carbamate (5) (150 mg, 0.26 mmol) in DCM (2 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL, 6.69 mmol) at 0° C. and the mixture was stirred at 25° C. for 2 hrs. LCMS showed the reaction was completed. The mixture was quenched with sat. NaHCO.sub.3 (5 mL) and extracted with DCM (5 mL×3). The Combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 5-(2-(4-(2-(3-aminoazetidin-1-yl)pyrimidin-5-yl)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (6) (150 mg, yield: 96.6%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.58-8.53 (m, 2H), 7.48 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.37-7.35 (m, 1H), 7.24 (d, J=8.4 Hz, 2H), 4.54-4.40 (m, 4H), 4.12-4.04 (m, 1H), 3.98 (br dd, J=4.8, 8.8 Hz, 2H), 3.88 (t, J=6.0 Hz, 2H), 1.71 (s, 6H).

    [1390] N-(1-(5-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)pyrimidin-2-yl)azetidin-3-yl)methanesulfonamide (Compound A36): To a solution of 5-(2-(4-(2-(3-aminoazetidin-1-yl)pyrimidin-5-yl)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy) benzonitrile (6) (150 mg, 0.28 mmol) and N,N-diethylethanamine (0.1 mL, 0.56 mmol) in DCM (3 mL) was added methanesulfonyl chloride (32 mg, 0.28 mmol) at 0° C. and stirred at 20° C. for 2 hrs. LCMS showed the reaction was completed. The mixture was quenched with water (10 mL) and extracted with DCM (5 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral) to give N-(1-(5-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)pyrimidin-2-yl)azetidin-3-yl)methanesulfonamide (Compound A36) (86 mg, yield: 54.0%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.58 (s, 2H), 7.49 (d, J=2.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.36 (d, J=1.2 Hz, 1H), 7.28 (s, 2H), 4.93 (br d, J=8.8 Hz, 1H), 4.59 (t, J=8.4 Hz, 2H), 4.54-4.47 (m, 1H), 4.44 (t, J=6.0 Hz, 2H), 4.10 (dd, J=5.2, 9.6 Hz, 2H), 3.89 (t, J=6.0 Hz, 2H), 3.03 (s, 3H), 1.70 (s, 6H). LCMS: (220 nm): 98.6%. Exact Mass: 559.1; found 560.1/562.1.

    Example 6: Synthesis of N-((1r,3r)-3-(4-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl) propan-2-yl)phenyl)-1H-pyrazol-1-yl)cyclobutyl)methanesulfonamide (Compound A44)

    [1391] ##STR00387##

    [1392] (1s,3s)-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate (2): To a solution of tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (1) (2.0 g, 10.7 mmol) in DCM (20 mL) was added pyridine (1.7 mL, 21.4 mmol), N,N-dimethylpyridin-4-amine (0.26 g, 2.14 mmol) and 4-methylbenzenesulfonyl chloride (2.6 g, 13.9 mmol) at 0° C. and the mixture was stirred for 2 hrs at 25° C. under N.sub.2 atmosphere. TLC showed the reaction was completed. The reaction was quenched with H.sub.2O (5 mL) and extracted with DCM (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by silica gel column chromatography to give (1s,3s)-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate (2) (3.0 g, yield: 74.0%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.78 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.62 (br s, 1H), 4.50 (t, J=7.2 Hz, 1H), 3.73 (br d, J=6.4 Hz, 1H), 2.77-2.63 (m, 2H), 2.46 (s, 3H), 2.08-1.92 (m, 2H), 1.41 (s, 9H).

    [1393] tert-butyl ((1r,3r)-3-(4-bromo-1H-pyrazol-1-yl)cyclobutyl)carbamate (4): To a solution of 4-bromo-1H-pyrazole (3) (0.90 g, 6.12 mmol) in DMF (10 ml) was added NaH (60.0% purity, 0.35 g, 9.19 mmol) 0° C. under N.sub.2 and the mixture was stirred at 0° C. for 15 min under N.sub.2 atmosphere, then a solution of (1s,3s)-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate (2) (2.5 g, 6.74 mmol) in DMF (20 mL) was added drop-wise at 0° C. under N.sub.2 atmosphere. The mixture was stirred 50° C. under N.sub.2 for 2 hrs. TLC showed the reaction was completed. The mixture was quenched with sat. NH.sub.4Cl (20 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 ml×3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by HPLC (neutral) to give tert-butyl ((1r,3r)-3-(4-bromo-1H-pyrazol-1-yl)cyclobutyl)carbamate (4) (0.40 g, yield: 18.6%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.48 (d, J=14.0 Hz, 2H) 4.92-4.82 (m, 1H) 4.31 (br d, J=2.4 Hz, 1H) 2.92-2.80 (m, 2H) 2.53 (br d, J=4.8 Hz, 2H) 1.46 (s, 9H).

    [1394] tert-butyl ((1r,3r)-3-(4-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl) propan-2-yl)phenyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate (5): To a mixture of tert-butyl ((1r,3r)-3-(4-bromo-1H-pyrazol-1-yl)cyclobutyl)carbamate (4) (1.0 g, 1.58 mmol) and 3-chloro-2-(2-chloroethoxy)-5-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)benzonitrile (inter E) (809 mg, 1.58 mmol) in 1,4-dioxane (10 mL) and H.sub.2O (2 mL) was added dipotassium;carbonate (546 mg, 3.95 mmol) and Pd(dppf)Cl.sub.2 (116 mg, 0.16 mmol) under N.sub.2 at 25° C. The mixture was stirred for 8 hrs at 100° C. under N.sub.2 atmosphere. LCMS showed the reaction was completed. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl ((1r,3 r)-3-(4-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate (5) (400 mg, yield: 32.9%) as colorless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.79 (s, 1H), 7.68 (s, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.36 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 4.96-4.87 (m, 2H), 4.42 (t, J=6.0 Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 2.94-2.89 (m, 2H), 2.56 (br s, 2H), 1.67 (s, 6H), 1.46 (s, 9H).

    [1395] 5-(2-(4-(1-((1r,3r)-3-aminocyclobutyl)-1H-pyrazol-4-yl)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (6): To a solution of tert-butyl ((1r,3r)-3-(4-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate (5) (200 mg, 0.32 mmol) in DCM (2 mL) was added TFA (1 mL) at 25° C. and the mixture was stirred at 25° C. for 1 h. LCMS showed the starting material was consumed and the desired product was detected. The reaction was adjusted to pH=7-8 with sat. NaHCO.sub.3, and then extracted with DCM (5 mL×3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 5-(2-(4-(1-((l r,3 r)-3-aminocyclobutyl)-1H-pyrazol-4-yl)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (6) (250 mg, yield: 92.7%) as colorless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.80 (s, 1H), 7.66 (s, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.36 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 5.06-4.97 (m, 1H), 4.43 (t, J=6.0 Hz, 2H) 3.99-3.92 (m, 1H), 3.88 (t, J=6.0 Hz, 2H), 2.93-2.81 (m, 2H), 2.39 (ddd, J=12.8, 8.4, 4.8 Hz, 2H), 1.68 (s, 6H).

    [1396] N-((1r,3r)-3-(4-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)-1H-pyrazol-1-yl)cyclobutyl)methanesulfonamide (Compound A44): To a solution of 5-(2-(4-(1-((1r,3 r)-3-aminocyclobutyl)-1H-pyrazol-4-yl)phenyl)propan-2-yl)-3-chloro-2-(2-chloroethoxy)benzonitrile (6) (250 mg, 0.48 mmol) in DCM (3 mL) was added N,N-diethylethanamine (1.0 mL, 7.17 mmol), methanesulfonyl chloride (49 mg, 0.43 mmol) at 0° C. The mixture was stirred for 1 h at 25° C. LCMS showed the reaction was completed. The reaction was quenched with water (5 mL), extracted with DCM (5 mL×3). The combined organic layers were washed with brine (2 mL×5), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by p-HPLC (FA) to give N-((1r,3r)-3-(4-(4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenyl)-1H-pyrazol-1-yl)cyclobutyl)methanesulfonamide (Compound A44) (60 mg, yield: 59%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.82 (s, 1H), 7.66 (s, 1H), 7.47 (d, J=2.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.36 (d, J=2.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 4.96-4.86 (m, 1H), 4.78 (d, J=7.2 Hz, 1H), 4.49-4.33 (m, 3H), 3.88 (t, J=6.0 Hz, 2H), 3.11-2.93 (m, 5H), 2.70-2.60 (m, 2H), 1.68 (s, 6H). LCMS (220 nm): 99.01%. Exact Mass: 546.1; found 547.1/549.1.

    Example 7: Synthesis of N-(4-amino-5-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (Compound A118)

    [1397] ##STR00388## ##STR00389##

    [1398] methyl 2-chloro-4-[(2,4-dimethoxyphenyl)methylamino]pyrimidine-5-carboxylate (2): To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (60.0 g, 290 mmol) in THF (200 mL) was added (2,4-dimethoxyphenyl)methanamine (58.2 g, 348 mmol) and DIEA (99.2 mL, 580 mmol). The mixture was stirred at 15° C. for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by column chromatography on silica gel to give methyl 2-chloro-4-[(2,4-dimethoxyphenyl)methylamino]pyrimidine-5-carboxylate (97.0 g, yield: 99.1%) as a white solid.

    [1399] [2-chloro-4-[(2,4-dimethoxyphenyl)methylamino]pyrimidin-5-yl]methanol (3): To a solution of methyl 2-chloro-4-[(2,4-dimethoxyphenyl)methylamino]pyrimidine-5-carboxylate (56 g, 14.8 mmol) in THF (1000 mL) was added LiAlH.sub.4 (0.843 g, 22.2 mmol). The mixture was stirred at −78° C. for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched with water (200 mL) and extracted with EA (800 mL). The combined organic layers were washed with brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The crude was purified by silica gel column to give [2-chloro-4-[(2,4-dimethoxyphenyl)methylamino]pyrimidin-5-yl]methanol (27 g, yield: 52.6%) as a yellow solid.

    [1400] 2-chloro-5-(chloromethyl)-N-[(2,4-dimethoxyphenyl)methyl]pyrimidin-4-amine (4): To a solution of [2-chloro-4-[(2,4-dimethoxyphenyl)methylamino]pyrimidin-5-yl]methanol (22.0 g, 71.0 mmol) in DCM (300 mL) was added 4-methylbenzenesulfonyl chloride (16.2 g, 85.2 mmol) and TEA (14.8 mL, 107 mmol). The mixture was stirred at 25° C. for 12 hours. LCMS showed the reaction was completed. The reaction mixture was quenched with water (200 mL) and extracted with EA (300 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The crude was purified by silica gel column to give 2-chloro-5-(chloromethyl)-N-[(2,4-dimethoxyphenyl)methyl]pyrimidin-4-amine (9.0 g, yield: 30.0%) as a yellow solid.

    [1401] 3-chloro-5-[1-[4-[[2-chloro-4-[(2,4-dimethoxyphenyl)methylamino]pyrimidin-5-yl]methoxy]phenyl]-1-methyl-ethyl]-2-(2-chloroethoxy)benzonitrile (6): To a solution of 2-chloro-5-(chloromethyl)-N-[(2,4-dimethoxyphenyl)methyl]pyrimidin-4-amine (9.0 g, 27.4 mmol) and 3-chloro-2-(2-chloroethoxy)-5-[1-(4-hydroxyphenyl)-1-methyl-ethyl]benzonitrile (11.5 g, 32.9 mmol) in CH.sub.3CN (200 mL) was added K.sub.2CO.sub.3 (5.68 g, 41.1 mmol) at 25° C. Then the mixture was stirred at 25° C. for 3 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to remove solvent. The reaction mixture was diluted with water (200 mL) and extracted with EA (300 mL). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The crude was purified by silica gel column to give 3-chloro-5-[1-[4-[[2-chloro-4-[(2,4-dimethoxyphenyl)methyl amino]pyrimidin-5-yl]methoxy]phenyl]-1-methyl-ethyl]-2-(2-chloroethoxy)benzonitrile (11.0 g, yield: 62.5%) as a yellow solid.

    [1402] tert-butyl N-[2-chloro-5-[[4-[1-[3-chloro-4-(2-chloroethoxy)-5-cyano-phenyl]-1-methyl-ethyl]phenoxy]methyl]pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (7): To a solution of 3-chloro-5-[1-[4-[[2-chloro-4-[(2,4-dimethoxyphenyl)methylamino]pyrimidin-5-yl]methoxy]phenyl]-1-methyl-ethyl]-2-(2-chloroethoxy)benzonitrile (11.0 g, 17.1 mmol), TEA (5.20 g, 51.4 mmol), DMAP (1.05 g, 8.57 mmol) in THE (200 mL) was added Di-tert-butyl dicarbonate (18.7 g, 85.7 mmol) at 0° C. Then the mixture was stirred at 25° C. for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude was purified by silica gel column to give tert-butyl N-[2-chloro-5-[[4-[1-[3-chloro-4-(2-chloroethoxy)-5-cyano-phenyl]-1-methyl-ethyl]phenoxy]methyl]pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (12.0 g, yield: 94.4%) as a yellow oil.

    [1403] tert-butyl N-[5-[[4-[1-[3-chloro-4-(2-chloroethoxy)-5-cyano-phenyl]-1-methyl-ethyl]phenoxy]methyl]-2-(methanesulfonamido)pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (8): To a solution of tert-butyl N-[2-chloro-5-[[4-[1-[3-chloro-4-(2-chloroethoxy)-5-cyano-phenyl]-1-methyl-ethyl]phenoxy]methyl]pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (9.0 g, 12.1 mmol) in dioxane (200.0 mL) was added methanesulfonamide (3.46 g, 36.4 mmol), Cs.sub.2CO.sub.3 (11.9 g, 36.4 mmol), Xantphos (1.05 g, 1.82 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (2.09 g, 3.64 mmol). The mixture was stirred at 100° C. for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The crude was purified by silica gel column to give tert-butyl N-[5-[[4-[l-[3-chloro-4-(2-chloroethoxy)-5-cyano-phenyl]-1-methyl-ethyl]phenoxy]methyl]-2-(methanesulfonamido)pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (7.5 g, yield: 77.2%) as a yellow oil.

    [1404] N-(4-amino-5-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (Compound A118): To a solution of tert-butyl N-[5-[[4-[1-[3-chloro-4-(2-chloroethoxy)-5-cyano-phenyl]-1-methyl-ethyl]phenoxy]methyl]-2-(methanesulfonamido)pyrimidin-4-yl]-N-[(2,4-dimethoxyphenyl)methyl]carbamate (3.0 g, 3.75 mmol) in DCM (30.0 mL) was added TFA (10.0 mL) at 25° C. Then the mixture was stirred at 40° C. for 18 hours. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure. The impure product was purified by Prep-HPLC (FA) to give N-(4-amino-5-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)methanesulfonamide (900 mg, yield: 46.3%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=7.84-7.81 (m, 1H), 7.63-7.61 (m, 1H), 7.57-7.54 (m, 1H), 7.21-7.15 (m, 2H), 6.96-6.89 (m, 2H), 4.87-4.74 (m, 2H), 4.45-4.37 (m, 2H), 3.99-3.91 (m, 2H), 3.12-2.99 (m, 3H), 1.69-1.56 (m, 6H). M+H: 550.1 (calc.); found 550.3 (LC-MS).

    Example 8: Synthesis of N-(6-(4-((3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)(cyclopropyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A80)

    [1405] ##STR00390## ##STR00391## ##STR00392##

    [1406] Synthesis of 5-bromo-3-chloro-2-(2-chloroethoxy)benzonitrile (Inter Q):

    [1407] 5-bromo-3-chloro-2-hydroxybenzaldehyde (2a): To a solution of 4-bromo-2-chloro-phenol (1a) (150 g, 0.72 mol) in TFA (1500 mL) was added Hexamethylenetetramine (203 g, 1.45 mol) at 20° C. The mixture was stirred at 100° C. for 16 h under N.sub.2 atmosphere. The reaction was quenched with water (5 L) and 50% H.sub.2SO.sub.4 (3 L) and stirred at 20° C. for 30 min. The mixture was filtered and the filter cake was concentrated under reduced pressure to give 5-bromo-3-chloro-2-hydroxybenzaldehyde (2a) (152 g, yield: 80.0%) as yellow solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=11.27-11.20 (m, 1H), 10.11 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H).

    [1408] 5-bromo-3-chloro-2-hydroxybenzonitrile (3a): To a solution of 5-bromo-3-chloro-2-hydroxybenzaldehyde (2a) (152 g, 0.65 mol) in HCOOH (1500 mL) was added HCl-NH.sub.2OH (89.7 g, 1.29 mol) and HCOONa (87.8 g, 1.29 mol) at 20° C. and stirred at 100° C. for 16 h. The resulting mixture was quenched with H.sub.2O (5000 mL) (lots of solid appeared). The suspension was filtered and the filter cake was concentrated under reduced pressure to give 5-bromo-3-chloro-2-hydroxybenzonitrile (3a) (106.5 g, yield: 63.7%) as an off-white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.71 (s, 1H), 7.61 (s, 1H).

    [1409] 5-bromo-3-chloro-2-(2-chloroethoxy)benzonitrile (inter Q): To a solution of 5-bromo-3-chloro-2-hydroxybenzonitrile (3a) (188 g, 0.81 mol) in DMF (2000 mL) was added 1-bromo-2-chloroethane (4a) (348 g, 2.43 mol) and Cs.sub.2O.sub.3 (659 g, 2.02 mol) at 20° C. and stirred at 80° C. for 16 h under N.sub.2. The mixture was quenched with water (5000 mL) and extracted with EtOAc (2000 mL×3). The combined organic layers were washed with brine (2000 mL×5), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was triturated with PE/MTBE=3/1 (500 mL) to give 5-bromo-3-chloro-2-(2-chloroethoxy)benzonitrile (inter Q) (215 g, yield: 90.6%) as an off-white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.78 (d, J=2.4 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 4.46 (t, J=6.0 Hz, 2H), 3.89 (t, J=6.0 Hz, 2H).

    [1410] Synthesis of Compound A80:

    [1411] 6-bromo-2-methylsulfanyl-quinoxaline (inter N): To a solution of 6-bromo-2-chloro-quinoxaline (8.0 g, 0.0312 mol) in DMF (100 mL) was added NaSMe (2.63 g, 0.0375 mol) at 20° C. The reaction was stirred at 20° C. for 2 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (200×2 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column to give 6-bromo-2-methylsulfanyl-quinoxaline (6.0 g, yield: 77.5%) as a white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.59 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.83-7.69 (m, 2H), 2.70 (s, 3H).

    [1412] 4-(2-(methylthio)quinoxalin-6-yl)phenol (3): To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2) (4.3 g, 17.6 mmol) and 6-bromo-2-methylsulfanyl-quinoxaline (inter N) (5 g, 17.6 mmol) in 1,4-dioxane (50 mL) and H.sub.2O (12.5 mL) was added K.sub.2CO.sub.3 (4.88 g, 35.3 mmol) and Pd(dppf)Cl.sub.2 (1.29 g, 1.76 mmol) at 25° C. under N.sub.2 and the mixture was stirred at 90° C. for 3 h under N.sub.2. The reaction was quenched with water (60 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-(2-methylsulfanylquinoxalin-6-yl)phenol (3.3 g, yield: 54.5%) as a yellow solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=9.70 (s, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 8.04 (br d, J=8.8 Hz, 1H), 7.93 (br d, J=8.4 Hz, 1H), 7.68 (br d, J=8.4 Hz, 2H), 6.91 (br d, J=8.4 Hz, 2H), 2.67 (s, 3H).

    [1413] 4-(2-(methylthio)quinoxalin-6-yl)phenyl trifluoromethanesulfonate (4): To a solution of 4-(2-(methylthio)quinoxalin-6-yl)phenol (3) (1.3 g, 2.91 mmol) and Py (460 mg, 5.81 mmol) in DCM (10 mL) was added Tf.sub.2O (1.23 g, 4.36 mmol) at 0° C. and the mixture was stirred at 20° C. for 1 h. The mixture was poured into sat. aq. NH.sub.4Cl (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give 4-(2-(methylthio)quinoxalin-6-yl)phenyl trifluoromethanesulfonate (4) (1.0 g, yield: 85.1%) as a yellow solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=8.87 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.16 (dd, J=2.4, 8.8 Hz, 1H), 8.09-8.06 (d, J=8.8 Hz, 2H, 8.05-8.01 (m, 1H), 7.65 (d, J=8.8 Hz, 2H), 2.70 (s, 3H).

    [1414] N-cyclopropyl-4-(2-(methylthio)quinoxalin-6-yl)aniline (6): To a solution of 4-(2-(methylthio)quinoxalin-6-yl)phenyl trifluoromethanesulfonate (4) (1 g, 2.5 mmol) and cyclopropanamine (5) (1.25 g, 21.9 mmol) in 1,4-dioxane (10 mL) was added Cs.sub.2CO.sub.3 (3.05 g, 9.37 mmol) and t-BuBrettPhos-Pd-G3 (213 mg, 0.25 mmol) at 20° C. under N.sub.2. The mixture was stirred at 70° C. under N.sub.2 atmosphere for 8 h. The reaction mixture was diluted with H.sub.2O (30 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-cyclopropyl-4-(2-(methylthio)quinoxalin-6-yl)aniline (6) (1.20 g, yield: 93.8%) as a yellow solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=8.78 (s, 1H), 8.11 (d, J=2.0 Hz, 1H), 8.08-8.04 (m, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 6.39 (s, 1H), 2.68 (s, 3H), 2.44-2.35 (m, 1H), 0.75-0.70 (m, 2H), 0.43-0.40 (m, 2H).

    [1415] 3-chloro-2-(2-chloroethoxy)-5-(cyclopropyl(4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino) benzonitrile (7): To a solution of N-cyclopropyl-4-(2-(methylthio)quinoxalin-6-yl)aniline (6) (300 mg, 0.976 mmol), 5-bromo-3-chloro-2-(2-chloroethoxy)benzonitrile (inter Q) (576 mg, 1.95 mmol) and t-BuONa (281 mg, 2.93 mmol) in toluene (3 mL) was added (t-Bu.sub.3PPdBr).sub.2 (152 mg, 0.2 mmol) at 25° C. and the mixture was stirred at 100° C. for 3 h under N.sub.2. The reaction mixture was diluted with H.sub.2O (10 mL). The resulting aqueous phase was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-(2-chloroethoxy)-5-(cyclopropyl(4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino)benzonitrile (7) (100 mg, yield: 17.7%) as a yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.65 (s, 1H), 8.24 (s, 1H), 8.06-7.95 (m, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.30 (d, J=3.2 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.16 (d, J=2.8 Hz, 1H), 4.37 (t, J=6.4 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 2.82-2.77 (m, 1H), 2.74 (s, 3H), 1.02-0.97 (m, 2H), 0.72-0.70 (m, 2H).

    [1416] 3-chloro-2-(2-chloroethoxy)-5-(cyclopropyl(4-(2-(methylsulfonyl)quinoxalin-6-yl) phenyl) amino)benzonitrile (8): To a solution of 3-chloro-2-(2-chloroethoxy)-5-(cyclopropyl(4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino)benzonitrile (7) (100 mg, 0.18 mmol) in THE (2 mL) and H.sub.2O (2 mL) was added Oxone (560 mg, 0.911 mmol) at 25° C. The mixture was stirred for 6 h at 35° C. The reaction was quenched with water (5 mL), extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 3-chloro-2-(2-chloroethoxy)-5-(cyclopropyl(4-(2-(methyl sulfonyl)quinoxalin-6-yl)phenyl)amino)benzonitrile (8) (100 mg, yield: 89.3%) as a yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=9.53 (s, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.33-8.26 (m, 1H), 8.26-8.19 (m, 1H), 7.81 (d, J=6.8 Hz, 2H), 7.37 (d, J=3.2 Hz, 1H), 7.30-7.25 (m, 2H), 7.21 (d, J=2.8 Hz, 1H), 4.40 (t, J=6.4 Hz, 2H), 3.91 (t, J=6.4 Hz, 2H), 3.42 (s, 3H), 2.86-2.78 (m, 1H), 1.07-0.99 (m, 2H), 0.77-0.68 (m, 2H).

    [1417] N-(6-(4-((3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)(cyclopropyl)amino)phenyl) quinoxalin-2-yl)methanesulfonamide (Compound A80): To a solution of 3-chloro-2-(2-chloroethoxy)-5-(cyclopropyl(4-(2-(methyl sulfonyl)quinoxalin-6-yl)phenyl)amino)benzonitrile (8) (100 mg, 0.16 mmol) and MsNH.sub.2 (61.9 mg, 0.65 mmol) in MeCN (3 mL) was added Cs.sub.2CO.sub.3 (159 mg, 0.49 mmol) at 20° C. under N.sub.2. The mixture was stirred for 8 h at 35° C. The mixture was quenched with water (10 mL), extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral) to give N-(6-(4-((3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)(cyclopropyl)amino)phenyl)quinoxalin-2-yl) methanesulfonamide (21.4 mg, yield: 14.4%) as a yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.45-8.40 (m, 1H), 8.18 (br s, 1H), 7.92 (br d, J=8.8 Hz, 1H), 7.70 (br d, J=8.4 Hz, 2H), 7.62-7.40 (m, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.22 (d, J=8.8 Hz, 2H), 7.15 (d, J=2.8 Hz, 1H), 4.37 (t, J=6.4 Hz, 2H), 3.89 (t, J=6.4 Hz, 2H), 3.26 (br s, 3H), 2.81-2.78 (m, 1H), 1.00-0.97 (m, 2H), 0.72-0.68 (m, 2H). LCMS (220 nm): 96.93%. Exact Mass: 567.09; found 568.0/570.0.

    Example 9: Synthesis of N-(6-(4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy) phenyl) quinoxalin-2-yl) methanesulfonamide (Compound A97)

    [1418] ##STR00393## ##STR00394##

    [1419] 4-(4-bromophenoxy)-2-chloro-1-fluorobenzene (3): To a solution of (3-chloro-4-fluorophenyl) boronic acid (1) (100 g, 0.57 mol), 4-bromophenol (2) (119 g, 0.69 mol), Pyridine (136 g, 1.72 mol) and 4 A molecular sieve (101 g) in DCE (1500 mL) was added Cu(OAc).sub.2 (156 g, 0.86 mol) at 25° C. The mixture was stirred at 70° C. under 02 ball for 6 h. The reaction was filtered by Celite and to the filtrate was added water (1000 mL) then extracted with DCM (800 mL×3). The combined organic layers were washed with brine (1000 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-(4-bromophenoxy)-2-chloro-1-fluorobenzene (3) (55.0 g, yield: 28.6%) as a yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.46 (d, J=8.8 Hz, 2H), 7.12 (t, J=8.8 Hz, 1H), 7.05 (dd, J=28.0, 6.0 Hz, 1H), 6.92-6.85 (m, 3H).

    [1420] 5-(4-bromophenoxy)-3-chloro-2-fluorobenzaldehyde (4): To a solution of 4-(4-bromophenoxy)-2-chloro-1-fluorobenzene (3) (55 g, 0.16 mol) in THE (550 mL) was added LDA (2 mol/L, 98.5 mL, 0.19 mol) drop wise at −70° C. under N.sub.2. The mixture was stirred at 70° C. for 45 min. Then DMF (24 g, 0.33 mol) was added dropwise into the reaction and the mixture was stirred for another 1 h at −70° C. under N.sub.2. The mixture was quenched with sat. NH.sub.4Cl (200 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-(4-bromophenoxy)-3-chloro-2-fluorobenzaldehyde (4) (13.0 g, yield: 21.6%) as a white solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=10.13 (s, 1H), 7.76 (dd, J=3.2, 6.0 Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.33 (dd, J=3.2, 4.8 Hz, 1H), 7.08 (d, J=8.8 Hz, 2H).

    [1421] 5-(4-bromophenoxy)-3-chloro-2-fluorobenzonitrile (inter Z): To a solution of 5-(4-bromophenoxy)-3-chloro-2-fluorobenzaldehyde (4) (13 g, 0.04 mol) in HCOOH (130 mL) was added HCOONa (5.10 g, 0.08 mol) and HCl—NH.sub.2OH (5.21 g, 0.08 mol) at 20° C. The mixture was stirred at 100° C. for 8 h under N.sub.2. The resulting mixture was quenched with H.sub.2O (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with sat. NaHCO.sub.3 (50 mL×2) and brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-(4-bromophenoxy)-3-chloro-2-fluorobenzonitrile (inter Z) (12.5 g, yield: 91.9%) as a white solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=7.79 (dd, J=3.2, 6.0 Hz, 1H), 7.73 (dd, J=3.2, 4.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H).

    [1422] 5-(4-bromophenoxy)-3-chloro-2-cyclopropoxybenzonitrile (6): To a solution of cyclopropanol (a) (1.34 g, 23.2 mmol) in DMF (100 ml) was added NaH (60.0% purity, 1.48 g, 38.6 mmol) at 0° C. under N.sub.2 and the mixture was stirred at 0° C. for 30 min, then a solution of 5-(4-bromophenoxy)-3-chloro-2-fluorobenzonitrile (inter Z) (7.0 g, 19.3 mmol) in DMF (100 mL) was added dropwise at 0° C. under N.sub.2. The mixture was stirred 20° C. under N.sub.2 for 2 h. The mixture was quenched with sat. NH.sub.4Cl (200 mL) and then extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give 5-(4-bromophenoxy)-3-chloro-2-cyclopropoxybenzonitrile (6) (4.80 g, yield: 61.4%) as a yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.53-7.50 (m, 2H), 7.25 (d, J=3.2 Hz, 1H), 7.08 (d, J=3.2 Hz, 1H), 6.91 (dd, J=2.4, 7.2 Hz, 2H), 4.46 (t d, J=3.6, 6.4 Hz, 1H), 1.03 (d, J=2.8 Hz, 2H), 0.71 (d, J=7.2 Hz, 2H).

    [1423] 3-chloro-2-cyclopropoxy-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy) benzonitrile (7): To a solution of 5-(4-bromophenoxy)-3-chloro-2-cyclopropoxybenzonitrile (6) (4.3 g, 10.6 mmol) and Pin.sub.2B.sub.2 (2.97 g, 11.7 mmol)) in 1,4-dioxane (100 mL) was added Pd(dppf)Cl.sub.2 (0.777 g, 1.06 mmol) and AcOK (2.08 g, 21.2 mmol) at 25° C. under N.sub.2. The mixture was stirred at 90° C. under N.sub.2 for 3 h. The reaction was quenched with H.sub.2O (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-cyclopropoxy-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) benzonitrile (7) (3.14 g, yield: 64.7%) as a yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.85 (d, J=8.4 Hz, 2H), 7.26 (d, J=2.8 Hz, 1H), 7.09 (d, J=2.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.45 (tt, J=2.8, 6.0 Hz, 1H), 1.36 (s, 12H), 1.09-0.99 (m, 2H), 0.73-0.65 (m, 2H).

    [1424] 3-chloro-2-cyclopropoxy-5-(4-(2-(methylthio)quinoxalin-6-yl)phenoxy)benzonitrile (8): To a solution of 3-chloro-2-cyclopropoxy-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (7) (2.6 g, 5.68 mmol) and 6-bromo-2-(methylthio)quinoxaline (inter N) (1.93 g, 6.82 mmol) in 1,4-dioxane (40 mL) and H.sub.2O (8 mL) was added K.sub.2CO.sub.3 (2.36 g, 17.1 mmol) and Pd(dppf)Cl.sub.2 (0.625 g, 0.855 mmol) under N.sub.2 at 20° C. The mixture was stirred for 6 h at 90° C. under N.sub.2. The reaction was quenched with H.sub.2O (5 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-cyclopropoxy-5-(4-(2-(methylthio)quinoxalin-6-yl)phenoxy)benzonitrile (8) (1.50 g, yield: 51.6%) as a yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.64 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.01 (d, J=8.8 Hz, 2H), 7.95 (dd, J=2.0, 8.8 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.34 (d, J=3.2 Hz, 1H), 7.17-7.13 (m, 3H), 4.47 (tt, J=2.8, 6.0 Hz, 1H), 2.74 (s, 3H), 1.09-1.02 (m, 2H), 0.72 (d, J=7.2 Hz, 2H).

    [1425] 3-chloro-2-cyclopropoxy-5-(4-(2-(methylsulfonyl)quinoxalin-6-yl)phenoxy)benzonitrile (9): To a solution of 3-chloro-2-cyclopropoxy-5-(4-(2-(methylthio) quinoxalin-6-yl) phenoxy) benzonitrile (8) (1.5 g, 2.61 mmol) in THE (15 mL) and H.sub.2O (15 mL) was added Oxone (8.02 g, 13.0 mmol) at 20° C. and the mixture was stirred at 35° C. for 8 h. The mixture was poured into saturated aq. Na.sub.2SO.sub.3 (5 mL) and then extracted with EtOAc (5 mL×3), the organic layers were washed with brine (10 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 3-chloro-2-cyclopropoxy-5-(4-(2-(methylsulfonyl)quinoxalin-6-yl)phenoxy)benzonitrile (9) (2.10 g, yield: 98.2%) as a yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=9.54 (s, 1H), 8.42 (s, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.20 (d, J=9.2 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.36 (d, J=2.4 Hz, 1H), 7.22-7.17 (m, 3H), 4.48 (tt, J=2.4, 6.4 Hz, 1H), 3.42 (s, 3H), 1.06 (br s, 2H), 0.73 (br d, J=6.4 Hz, 2H).

    [1426] N-(6-(4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenyl)quinoxalin-2-yl) methanesulfonamide (Compound A97): To a solution of 3-chloro-2-cyclopropoxy-5-(4-(2-(methyl sulfonyl)quinoxalin-6-yl)phenoxy)benzonitrile (9) (1.60 g, 2.93 mmol) and methanesulfonamide (0.835 g, 8.78 mmol) in MeCN (20 mL) was added Cs.sub.2CO.sub.3 (2.86 g, 8.78 mmol) at 25° C. and the mixture was stirred at 25° C. for 5 h. The mixture was poured into water (10 mL) and adjusted to pH=5-6 with 1M aq. HCl solution. The mixture was extracted with EtOAc (10 mL×3), the organic layers were washed with brine (10 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) give N-(6-(4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A97) (0.789 g, yield: 48.8%) as a yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.44 (s, 1H), 8.15 (s, 1H), 7.89 (br d, J=8.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.64-7.46 (m, 1H), 7.34 (d, J=3.2 Hz, 1H), 7.18-7.12 (m, 3H), 4.47 (tt, J=3.2, 6.4 Hz, 1H), 3.27 (br s, 3H), 1.09-1.03 (m, 2H), 0.72 (dd, J=0.8, 6.0 Hz, 2H). LCMS (220 nm): 98.25%. Exact Mass: 506.1; found 506.9/508.9.

    Example 10: Synthesis of N-(6-(4-((3-chloro-5-cyano-4-cyclopropoxyphenyl)(methyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A164)

    [1427] ##STR00395##

    [1428] 6-bromo-2-methylsulfanyl-quinoxaline (inter N): To a solution of 6-bromo-2-chloro-quinoxaline (8.0 g, 0.0312 mol) in DMF (100 mL) was added NaSMe (2.63 g, 0.0375 mol) at 20° C. The reaction was stirred at 20° C. for 2 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (50×2 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column to give 6-bromo-2-methylsulfanyl-quinoxaline (6.0 g, yield: 77.5%) as a white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.59 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.83-7.69 (m, 2H), 2.70 (s, 3H).

    [1429] 4-(2-(methylthio)quinoxalin-6-yl)aniline (3): To a solution of 6-bromo-2-(methylthio)quinoxaline (inter N) (1.0 g, 3.53 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2) (0.927 g, 4.23 mmol) in 1,4-dioxane (20 mL) and H.sub.2O (4 mL) was added K.sub.2CO.sub.3 (1.46 g, 10.6 mmol) and Pd(dppf)Cl.sub.2 (0.516 g, 0.706 mmol) under N.sub.2 at 20° C. The mixture was stirred for 6 h at 80° C. under N.sub.2. The reaction was quenched with H.sub.2O (10 mL), then extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-(2-(methylthio)quinoxalin-6-yl)aniline (3) (0.95 g, yield: 87.6%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.53 (s, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.86 (dd, J=1.2, 2.8 Hz, 2H), 7.49 (m, J=6.8 Hz, 2H), 6.74 (d, J=6.8 Hz, 2H), 2.64 (s, 3H).

    [1430] 3-chloro-2-fluoro-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino)benzonitrile (5): To a solution of 4-(2-(methylthio)quinoxalin-6-yl)aniline (3) (1.0 g, 3.37 mmol) and 5-bromo-3-chloro-2-fluorobenzonitrile (4) (0.947 g, 4.04 mmol) in 1,4-Dioxane (20 mL) was added Cs.sub.2CO.sub.3 (2.74 g, 8.42 mmol) and SPhos Pd G3 (0.263 g, 0.337 mmol) under N.sub.2 at 20° C. The mixture was stirred for 8 h at 90° C. under N.sub.2. The reaction was quenched with H.sub.2O (10 mL), and then extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-fluoro-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino)benzonitrile (5) (0.70 g, yield: 44.5%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.64 (s, 1H), 8.19 (s, 1H), 8.03-7.98 (m, 1H), 7.97-7.92 (m, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.35 (dd, J=2.8, 6.0 Hz, 1H), 7.22-7.13 (m, 3H), 5.96 (s, 1H), 2.73 (s, 3H).

    [1431] 3-chloro-2-fluoro-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino)benzonitrile (6): To a solution of 3-chloro-2-fluoro-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino)benzonitrile (5) (0.650 g, 1.20 mmol) and Cs.sub.2CO.sub.3 (0.805 g, 2.47 mmol) in DMF (7 mL) was added MeI (0.263 g, 1.85 mmol) at 25° C. The mixture was stirred at 25° C. for 4 h. The reaction was quenched with H.sub.2O (10 mL), and then extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-fluoro-5-((4-(2-(methylthio) quinoxalin-6-yl) phenyl) amino) benzonitrile (6) (0.290 g, yield: 43.2%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.65 (s, 1H), 8.25-8.21 (m, 1H), 8.04-8.00 (m, 1H), 7.99-7.95 (m, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.18 (dd, J=2.8, 6.0 Hz, 1H), 7.00 (dd, J=3.2, 4.0 Hz, 1H), 3.37 (s, 3H), 2.74 (s, 3H).

    [1432] 3-chloro-2-cyclopropoxy-5-(methyl(4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino) benzonitrile (8): To a solution of cyclopropanol (7) (57.7 mg, 0.993 mmol) in DMF (1 mL) was added NaH (60.0% purity, 38 mg, 0.993 mmol) at 0° C. under N.sub.2 and the mixture was stirred at 0° C. for 15 min, then 3-chloro-2-fluoro-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino)benzonitrile (6) was added at 0° C. under N.sub.2. The mixture was stirred at 25° C. under N.sub.2 for 2 h. The mixture was quenched with sat. NH.sub.4Cl (5 mL) and then extracted with EtOAc (5 mL×3), the organic layers were washed with brine (5 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-2-cyclopropoxy-5-(methyl(4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino)benzonitrile (8) (0.27 g, yield: 92.0%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.64 (s, 1H), 8.25-8.21 (m, 1H), 8.05-8.00 (m, 1H), 7.98 (dd, J=1.6, 6.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.23-7.19 (m, 3H), 7.07-7.03 (m, 1H), 4.45-4.38 (m, 1H), 3.36 (s, 3H), 2.74 (s, 3H), 1.08-1.03 (m, 2H), 0.68 (br dd, J=0.8, 6.4 Hz, 2H).

    [1433] 3-chloro-2-cyclopropoxy-5-(methyl(4-(2-(methylsulfonyl)quinoxalin-6-yl)phenyl)amino) benzonitrile (9): To a solution of 3-chloro-2-cyclopropoxy-5-(methyl(4-(2-(methylthio)quinoxalin-6-yl)phenyl)amino)benzonitrile (8) (0.260 g, 0.440 mmol) in THE (2 mL) and H.sub.2O (2 mL) was added Oxone (1.08 g, 1.76 mmol) at 20° C. and the mixture was stirred at 35° C. for 8 h. LCMS showed the reaction was completed. The mixture was poured into saturated Na.sub.2SO.sub.3 solution (5 mL) and then extracted with EtOAc (5 mL×3), the organic layers were washed with brine (10 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 3-chloro-2-cyclopropoxy-5-(methyl(4-(2-(methylsulfonyl)quinoxalin-6-yl)phenyl)amino)benzonitrile (9) (0.220 g, yield: 69.3%) as a yellow solid.

    [1434] N-(6-(4-((3-chloro-5-cyano-4-cyclopropoxyphenyl)(methyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A164): To a solution of 3-chloro-2-cyclopropoxy-5-(methyl(4-(2-(methylsulfonyl)quinoxalin-6-yl)phenyl)amino)benzonitrile (9) (220 mg, 0.349 mmol) and methanesulfonamide (99.5 mg, 1.05 mmol) in MeCN (2 mL) was added Cs.sub.2CO.sub.3 (341 mg, 1.05 mmol) at 25° C. and the mixture was stirred at 25° C. for 8 h under N.sub.2. The mixture was poured into water (3 mL) and then adjusted to pH=5-6 with 1M aq. HCl solution. The mixture was extracted with EtOAc (5 mL×3), the organic layers were washed with brine (2 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give N-(6-(4-((3-chloro-5-cyano-4-cyclopropoxyphenyl)(methyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A164) (33.5 mg, yield: 23.0%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.46-8.44 (m, 1H), 8.16 (s, 1H), 7.98-7.84 (m, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.61-7.43 (m, 1H), 7.22 (d, J=3.2 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.06 (d, J=2.8 Hz, 1H), 4.42 (tt, 6.0 Hz, 1H), 3.36 (s, 3H), 3.26 (br s, 3H), 1.08-1.03 (m, 2H), 0.72-0.65 (m, 2H). LCMS (220 nm): 97.19%. Exact Mass: 519.1; found 520.0/522.0.

    Example 11: Synthesis of N-(6-(4-((3-chloro-5-cyano-4-cyclopropoxyphenyl) (2,2,2-trifluoroethyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A186)

    [1435] ##STR00396##

    [1436] 4-(2-(methylthio)quinoxalin-6-yl)-N-(2,2,2-trifluoroethyl)aniline (3): To a solution of 4-(2-(methylthio)quinoxalin-6-yl)aniline (1) (1.20 g, 4.04 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2) (2.81 g, 12.1 mmol) in THF (10 mL) was added TEA (1.69 mL, 12.1 mmol) at 25° C. and the mixture was stirred at 80° C. for 8 h under N.sub.2. LCMS showed the 30% starting material remained and 50% desired was detected. The reaction mixture was quenched with H.sub.2O (10 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by silica gel column chromatography (petroleum either/EtOAc=10/to 1/1) to give 4-(2-(methylthio)quinoxalin-6-yl)-N-(2,2,2-trifluoroethyl)aniline (3) (700 mg, yield: 44.6%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.62 (s, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.96 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.65-7.62 (m, 2H), 6.84-6.82 (m, 2H), 4.31-3.95 (m, 2H), 2.73 (s, 3H).

    [1437] 3-chloro-2-cyclopropoxy-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (5): To a solution of 4-(2-(methylthio)quinoxalin-6-yl)-N-(2,2,2-trifluoroethyl)aniline (3) (400 mg, 1.03 mmol) and 5-bromo-3-chloro-2-cyclopropoxybenzonitrile (4) (281 mg, 1.03 mmol) in 1,4-dioxane (4 mL) was added Cs.sub.2CO.sub.3 (1.01 g, 3.09 mmol) and Ruphos Pd G3 (172 mg, 0.21 mmol) at 20° C. under N.sub.2. The mixture was stirred at 90° C. under N.sub.2 atmosphere for 8 h. LCMS showed the starting material was consumed and ˜30% desired was detected. The reaction mixture was quenched with H.sub.2O (10 mL) and extracted with EtOAc (5×3 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum either/EtOAc=3/1 to 1/1) and then further purified by p-HPLC (FA) to give 3-chloro-2-cyclopropoxy-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (5) (150 mg, yield: 24.2%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.65 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.97 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.80-7.76 (m, 2H), 7.23-7.20 (m, 3H), 7.05 (d, J=3.2 Hz, 1H), 4.47-4.42 (m, 1H), 4.32 (q, J=8.4 Hz, 2H), 2.74 (s, 3H), 1.09-1.01 (m, 2H), 0.75-0.66 (m, 2H).

    [1438] 3-chloro-2-cyclopropoxy-5-((4-(2-(methylsulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (6): To a solution of 3-chloro-2-cyclopropoxy-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (5) (150 mg, 0.25 mol) in THE (1 mL) and H.sub.2O (1 mL) was added Oxone (460 mg, 0.75 mol) at 25° C. The mixture was stirred for 8 h at 25° C. under N.sub.2. LCMS showed the reaction was completed. The reaction was quenched with H.sub.2O (2 mL) and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (5 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 3-chloro-2-cyclopropoxy-5-((4-(2-(methyl sulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (6) (150 mg, yield: 79.7%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.42 (d, J=2.0 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.21 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.82 (br d, J=8.4 Hz, 2H), 7.32 (d, J=2.8 Hz, 1H), 7.24-7.17 (m, 3H), 7.15 (d, J=2.8 Hz, 1H), 4.49-4.46 (m, 1H), 4.37-4.31 (m, 2H), 3.42 (s, 3H), 1.09-0.98 (m, 2H), 0.81-0.69 (m, 2H).

    [1439] N-(6-(4-((3-chloro-5-cyano-4-cyclopropoxyphenyl)(2,2,2-trifluoroethyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A186): To a solution of 3-chloro-2-cyclopropoxy-5-((4-(2-(methyl sulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (6) (150 mg, 0.24 mmol) in DMF (2 mL) was added MsNH.sub.2 (112 mg, 1.18 mmol), Cs.sub.2CO.sub.3 (230 mg, 0.71 mmol) at 25° C. The reaction was stirred at 25° C. for 2 h. LCMS showed the reaction was completed. The mixture was quenched with H.sub.2O (2 mL) and extracted with EtOAc (1 mL×3), then the EtOAc phases were washed with brine (2 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by p-HPLC (FA) to give N-(6-(4-((3-chloro-5-cyano-4-cyclopropoxyphenyl)(2,2,2-trifluoroethyl)amino)phenyl)quinoxalin-2-yl) methanesulfonamide (Compound A186) (85.8 mg, yield: 60.6%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.43 (br d, J=6.4 Hz, 1H), 8.16 (s, 1H), 7.90 (br d, J=8.0 Hz, 1H), 7.71 (br d, J=8.4 Hz, 2H), 7.62-7.44 (m, 1H), 7.24-7.18 (m, 3H), 7.05 (d, J=2.8 Hz, 1H), 4.46-4.43 (m, 1H), 4.35-4.28 (m, 2H), 3.27 (br s, 3H), 1.09-1.01 (m, 2H), 0.76-0.67 (m, 2H) LCMS (220 nm): 97.76%. Exact Mass: 587.10; found 588.0/590.0.

    Example 12: Synthesis of 3-chloro-2-cyclopropoxy-5-(2-(4-((2-morpholinopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound A201)

    [1440] ##STR00397##

    [1441] 3-chloro-2-fluoro-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy) phenyl)propan-2-yl)benzonitrile (2): To a solution of 3-chloro-2-fluoro-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (inter U) (2.0 g, 6.21 mmol) and (2-(methylthio)pyrimidin-4-yl)methanol (1) (1.29 g, 7.46 mmol) in THF (30 mL) was added PPh.sub.3 (2.4 g, 9.32 mmol) and DIAD (2.5 g, 12.4 mmol) at 0° C. under N.sub.2 and the mixture was stirred at 20° C. for 8 h. LCMS showed the starting material was consumed and ˜32% desired was detected. The reaction mixture was diluted with H.sub.2O (35 mL). The resulting aqueous mixture were extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=20:1 to 5:1) to give 3-chloro-2-fluoro-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (2) (2.2 g, yield: 70.3%) as colorless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.54 (d, J=5.2 Hz, 1H), 7.51-7.44 (m, 1H), 7.34 (dd, J=2.4, 5.2 Hz, 1H), 7.21 (d, J=4.8 Hz, 1H), 7.14-7.07 (m, 2H), 6.93-6.87 (m, 2H), 5.09 (s, 2H), 2.59 (s, 3H), 1.66 (s, 6H).

    [1442] 3-chloro-2-cyclopropoxy-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy) phenyl)propan-2-yl)benzonitrile (4): To a solution of cyclopropanol (3) (339 mg, 5.83 mmol) in DMF (15 mL) was added sodium hydride (79 mg, 60% purity, 7.29 mmol) at 0° C. under N.sub.2. The mixture was stirred 0° C. under N.sub.2 for 0.5 h. Then was added 3-chloro-2-fluoro-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (2) (2.6 g, 4.86 mmol) in DMF (15 mL) at 20° C. under N.sub.2. The mixture was stirred 25° C. under N.sub.2 for 2 h. LCMS showed the reaction was completed. The reaction mixture was quenched with sat.NH.sub.4Cl (45 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (3×15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=20:1 to 5:1) to give 3-chloro-2-cyclopropoxy-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy) phenyl)propan-2-yl)benzonitrile (4) (1.9 g, yield: 67.1%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.54 (d, J=5.2 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 7.15-7.09 (m, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.09 (s, 2H), 4.49-4.45 (m, 1H), 2.59 (s, 3H), 1.64 (s, 6H), 1.02 (br d, J=1.2 Hz, 2H), 0.71 (br d, J=7.2 Hz, 2H).

    [1443] 3-chloro-2-cyclopropoxy-5-(2-(4-((2-(methylsulfonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (5): To a solution of 3-chloro-2-cyclopropoxy-5-(2-(4-((2-(methylthio)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (4) (1.65 g, 3.19 mmol) in THE (20 mL) and H.sub.2O (20 mL) was added Oxone (5.88 g, 9.56 mmol) at 20° C. and the mixture was stirred at 35° C. for 8 h. LCMS showed the reaction was completed. The mixture was poured into sat.Na.sub.2SO.sub.3 (40 mL) and extracted with EtOAc (15 mL×3), the organic layers were washed with brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 3-chloro-2-cyclopropoxy-5-(2-(4-((2-(methylsulfonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (5) (1.7 g, yield: 81.4%) as colorless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.94 (d, J=5.2 Hz, 1H), 7.85 (d, J=4.8 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.91 (d, J=9.2 Hz, 2H), 5.29 (s, 2H), 4.52-4.42 (m, 1H), 3.39 (s, 3H), 1.70-1.63 (m, 6H), 1.07-0.96 (m, 2H), 0.73-0.68 (m, 2H).

    [1444] tert-butyl 3-chloro-2-cyclopropoxy-5-(2-(4-((2-morpholinopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound A201): To a solution of 3-chloro-2-cyclopropoxy-5-(2-(4-((2-(methyl sulfonyl)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (5) (100 mg, 0.19 mmol) in DMSO (1 mL) was added morpholine (6) (79 mg, 0.90 mmol) and DIEA (47 mg, 0.36 mmol) at 20° C. and stirred at 80° C. for 2 h. LCMS showed the starting material was consumed and 78% desired was detected. The reaction mixture was quenched with H.sub.2O (2 mL) and extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by p-HPLC (Neutral) to give tert-butyl 3-chloro-2-cyclopropoxy-5-(2-(4-((2-morpholinopyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (Compound A201) (44 mg, yield: 46%) as off-white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.34 (d, J=4.8 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.11 (br d, J=8.8 Hz, 2H), 6.89 (br d, J=8.8 Hz, 2H), 6.77 (d, J=4.8 Hz, 1H), 4.96 (s, 2H), 4.51-4.44 (m, 1H), 3.80 (br dd, J=4.4, 14.0 Hz, 8H), 1.64 (s, 6H), 1.07-0.98 (m, 2H), 0.76-0.67 (m, 2H). LCMS (220 nm): 98.97%. Exact Mass: 504.2, found: 505.3/506.8.

    Example 13: Synthesis of N-(6-(4-((5-cyano-6-cyclopropoxypyridin-3-yl)(2,2,2-trifluoroethyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A203)

    [1445] ##STR00398##

    [1446] 5-bromo-2-cyclopropoxynicotinonitrile (3): To a solution of cyclopropanol (2) (468 mg, 10.0 mmol) in THF (10 mL) was added sodium hydride (515 mg, 10.0 mmol) at 0° C. under N.sub.2 and the mixture was stirred at 0° C. for 30 min, then 5-bromo-2-fluoronicotinonitrile (1) (1.5 g, 10.0 mmol) in THF (5 mL) was added at 0° C. under N.sub.2. The mixture was stirred 25° C. under N.sub.2 for 2 h. LCMS showed the reaction was completed. The mixture was quenched with aq. NH.sub.4Cl (10 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=20:1 to 3:1) to give 5-bromo-2-cyclopropoxynicotinonitrile (3) (1.6 g, yield: 80.71%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.45 (d, J=2.4 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 4.45-4.33 (m, 1H), 0.89-0.84 (m, 4H).

    [1447] 2-cyclopropoxy-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)nicotinonitrile (5): To a solution of 5-bromo-2-cyclopropoxynicotinonitrile (3) (68.4 mg, 0.26 mmol), 4-(2-methylsulfanylquinoxalin-6-yl)-N-(2,2,2-trifluoroethyl)aniline (4) (100 mg, 0.26 mmol) and t-BuONa (0.4 mL) in t-Amyl-OH (2 mL) was added t-BuXphos Pd G3 (21 mg, 0.03 mmol) at 20° C. under N.sub.2 atmosphere. The mixture was stirred at 90° C. under N.sub.2 for 12 h. LCMS showed the starting material remained and ˜40% desired was detected. The reaction mixture was quenched with H.sub.2O (2 mL) and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=20:1 to 3:1) to give 2-cyclopropoxy-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)nicotinonitrile (5) (490 mg, yield: 95.1%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.63 (s, 1H), 8.30 (d, J=3.2 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H), 8.01-7.94 (m, 2H), 7.71-7.69 (m, 3H), 7.02 (d, J=8.8 Hz, 2H), 4.42-4.40 (m, 1H), 4.35-4.29 (m, 2H), 2.73 (s, 3H), 0.91-0.86 (m, 4H).

    [1448] 2-cyclopropoxy-5-((4-(2-(methylsulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)nicotinonitrile (6): To a solution of 2-cyclopropoxy-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)nicotinonitrile (5) (200 mg, 0.37 mmol) in THF (2 mL) and H.sub.2O (2 mL) was added Oxone (575 mg, 0.94 mmol) at 25° C. The mixture was stirred at 35° C. under N.sub.2 for 6 h. LCMS showed the reaction was completed. The reaction mixture was quenched with Na.sub.2SO.sub.3 (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (5 mL×3), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 2-cyclopropoxy-5-((4-(2-(methyl sulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)nicotinonitrile (6) (160 mg, yield: 63.4%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=9.52 (s, 1H), 8.38 (d, J=1.6 Hz, 1H), 8.36-8.34 (m, 1H), 8.19-8.15 (m, 2H), 7.76-7.75 (m, 2H), 7.74 (s, 1H), 7.02-6.99 (m, 2H), 4.45-4.38 (m, 1H), 4.36-4.33 (m, 2H), 3.42 (s, 3H), 0.93-0.88 (m, 4H).

    [1449] N-(6-(4-((5-cyano-6-cyclopropoxypyridin-3-yl)(2,2,2-trifluoroethyl)amino)phenyl) quinoxalin-2-yl)methanesulfonamide (Compound A203): To a solution of 2-cyclopropoxy-5-((4-(2-(methylsulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)nicotinonitrile (6) (110 mg, 0.18 mmol) and MsNH.sub.2 (53 mg, 0.55 mmol) in DMF (3 mL) was added Cs.sub.2CO.sub.3 (179 mg, 0.55 mmol) at 25° C. The mixture was stirred at 50° C. for 3 h. LCMS showed the starting material was consumed and ˜85% desired was detected. The reaction mixture was quenched with H.sub.2O (3 mL). The resulting aqueous mixture were extracted with EtOAc (1 mL×3). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Neutral) to give N-(6-(4-((5-cyano-6-cyclopropoxypyridin-3-yl)(2,2,2-trifluoroethyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A203) (68.3 mg, yield: 39.3%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.48 (s, 1H), 8.30 (d, J=2.8 Hz, 1H), 8.12 (s, 1H), 7.86 (br d, J=8.4 Hz, 1H), 7.69 (d, J=3.2 Hz, 1H), 7.63 (br d, J=8.4 Hz, 2H), 7.69-7.48 (m, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.45-4.42 (m, 1H), 4.32 (q, J=8.4, 16.8 Hz, 2H), 3.26 (br s, 3H), 0.92-0.86 (m, 4H). LCMS: (220 nm): 97.77%. Exact Mass: 554.1; found 555.0/556.0.

    Example 14: Synthesis of N-((6-(4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenyl) quinoxalin-2-yl)methyl)methanesulfonamide (Compound A207)

    [1450] ##STR00399##

    [1451] 6-bromo-2-vinylquinoxaline (2): To a solution of potassium trifluoro(vinyl)borate (a) (2.8 g, 18.5 mmol) and 6-bromo-2-chloroquinoxaline (1) (5.0 g, 18.5 mmol) in 1,4-dioxane (70 mL) was added TEA (3.8 g, 37.0 mmol) and Pd(dppf)Cl.sub.2 (1.35 g, 1.85 mmol) under N.sub.2 at 20° C. The mixture was stirred for 6 h at 90° C. under N.sub.2. LCMS showed the starting material was consumed and the product was detected. The reaction mixture was quenched with H.sub.2O (20 mL). Then the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduce pressure. The crude was purified by silica gel column chromatography (PE:EtOAc from 1:0 to 1:2) to give 6-bromo-2-vinylquinoxaline (2) (5.0 g, yield: 92.1%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.96 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.80 (dd, J=2.0, 8.8 Hz, 1H), 7.00 (dd, J=10.8, 17.6 Hz, 1H), 6.48 (d, J=17.6 Hz, 1H), 5.81 (d, J=11.2 Hz, 1H).

    [1452] 6-bromoquinoxaline-2-carboxylic acid (3): To a mixture of 6-bromo-2-vinylquinoxaline (2) (5.0 g, 19.1 mmol) in THF/H.sub.2O (80 mL, 3/1) was added NaIO.sub.4 (12.3 g, 57.4 mmol) and K.sub.2O.sub.4.2H.sub.2O (3.5 g, 9.57 mmol) at 25° C. and the mixture was stirred at 25° C. for 2 h. LCMS showed the reaction was completed. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc from 1:0 to 1:1) to give 6-bromoquinoxaline-2-carboxylic acid (3) (2.0 g, yield: 37.2%) as white solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ=9.42 (s, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.08 (dd, J=2.4, 9.2 Hz, 1H).

    [1453] Methyl 6-bromoquinoxaline-2-carboxylate (4): To a solution of 6-bromoquinoxaline-2-carboxylic acid (3) (2.0 g, 7.1 mmol) in DMF (20 mL) was added Cs.sub.2CO.sub.3 (4.6 g, 14.2 mmol) and MeI (2.0 g, 14.2 mmol) at 35° C. under N.sub.2 and the mixture was stirred at 35° C. for 8 h under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (15 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc from 1:0 to 1:2) to give methyl 6-bromoquinoxaline-2-carboxylate (4) (1.6 g, yield: 75.8%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.80 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.21 (dd, J=2.0, 9.2 Hz, 1H), 3.38 (s, 3H).

    [1454] (6-bromoquinoxalin-2-yl)methanol (5): To a solution of 6-bromoquinoxaline-2-carboxylate (4) (1.3 g, 4.87 mmol) in MeOH (10 mL) and DCM (5 mL) was added NaBH.sub.4 (0.37 g, 9.73 mmol) at 0° C. under N.sub.2. The mixture was stirred at 20° C. for 1 h. The resulting mixture was quenched with sat. NH.sub.4Cl (5 mL) and then extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc from 1:0 to 2:1) to give (6-bromoquinoxalin-2-yl)methanol (5) (0.46 g, yield: 35.6%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=9.55 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.96 (dd, J=2.0, 9.2 Hz, 1H), 4.13 (s, 2H).

    [1455] Tert-butyl ((6-bromoquinoxalin-2-yl)methyl)(methylsulfonyl)carbamate (6): To a solution of (6-bromoquinoxalin-2-yl)methanol (5) (200 mg, 0.753 mmol) and MsNHBoc (0.16 g, 0.753 mmol) in THE (2 mL) was added PPh.sub.3 (0.30 g, 1.13 mmol) and DIAD (0.30 g, 1.51 mmol) at 0° C. under N.sub.2 and the mixture was stirred at 20° C. for 8 h. LCMS showed the starting material was consumed and the product was detected. The reaction was quenched with H.sub.2O (1 mL). Then the mixture was extracted with EtOAc (1 mL×3). The combined organic layers were washed with brine (2 mL×2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduce pressure. The crude was purified by silica gel column chromatography (PE:EtOAc from 1:0 to 2:1) to give tert-butyl ((6-bromoquinoxalin-2-yl)methyl)(methylsulfonyl)carbamate (6) (0.200 g, yield: 54.2%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.81 (s, 1H), 8.32 (s, 1H), 7.86 (s, 2H), 6.35 (br s, 1H), 5.26 (s, 2H), 3.56 (s, 3H), 1.42 (s, 9H).

    [1456] Tert-butyl ((6-(4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenyl)quinoxalin-2-yl)methyl)(methylsulfonyl)carbamate (8): To a solution of 3-chloro-2-cyclopropoxy-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (7) (150 mg, 0.328 mmol) and tert-butyl ((6-bromoquinoxalin-2-yl)methyl)(methylsulfonyl)carbamate (6) (152 mg, 0.328 mmol) in 1,4-Dioxane (2.0 mL) and H.sub.2O (0.4 mL) was added K.sub.2CO.sub.3 (0.14 g, 0.984 mmol) and Pd(dppf)Cl.sub.2 (0.048 g, 0.066 mmol) at 25° C. under N.sub.2 and the mixture was stirred at 90° C. for 2 h under N.sub.2. LCMS showed the reaction was completed. The reaction was quenched with water (2 mL) and extracted with EtOAc (1 mL×3). The combined organic layers were washed with brine (1 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc from 1:0 to 1:1) to give tert-butyl ((6-(4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenyl)quinoxalin-2-yl)methyl)(methylsulfonyl)carbamate (8) (0.14 g, yield: 61.9%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.83 (d, J=11.2 Hz, 1H), 8.32 (s, 1H), 8.08-8.03 (m, 1H), 8.02-7.96 (m, 1H), 7.80-7.77 (m, 2H), 7.35 (d, J=2.8 Hz, 1H), 7.20-7.14 (m, 3H), 5.31 (d, J=4.4 Hz, 2H), 4.50-4.45 (m, 1H), 3.60 (d, J=4.4 Hz, 3H), 1.73-1.56 (m, 9H), 1.08-1.01 (m, 2H), 0.75-0.69 (m, 2H).

    [1457] N-((6-(4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenyl)quinoxalin-2-yl)methyl)methanesulfonamide (Compound A207): To a solution of tert-butyl ((6-(4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenyl)quinoxalin-2-yl)methyl) (methylsulfonyl)carbamate (8) (140 mg, 0.180 mmol) in DCM (2 mL) was added TFA (1 mL, 9.02 mmol) at 0° C. and the mixture was stirred at 20° C. for 1 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters xbridge 150*25 mm 10 um, water (NH.sub.4HCO.sub.3)-ACN from 34% to 64%) to give N-((6-(4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenyl)quinoxalin-2-yl)methyl)methanesulfonamide (Compound A207) (95.0 mg, yield: 15.0%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.89 (s, 1H), 8.33 (d, J=1.6 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.35 (d, J=3.2 Hz, 1H), 7.22-7.14 (m, 3H), 5.77 (br s, 1H), 4.76 (d, J=5.2 Hz, 2H), 4.48 (tt, J=2.8, 6.0 Hz, 1H), 3.07 (s, 3H), 1.11-1.02 (m, 2H), 0.76-0.68 (m, 2H). LCMS (220 nm): 99.5%. Exact Mass: 520.1; found Ms+18: 521.0/523.0.

    Example 15: Synthesis of N-(6-(4-((3-chloro-5-cyano-4-morpholinophenyl)(2,2,2-trifluoroethyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A224)

    [1458] ##STR00400##

    [1459] 3-chloro-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)-2-morpholinobenzonitrile (4): To a solution of 4-(2-methylsulfanylquinoxalin-6-yl)-N-(2,2,2-trifluoroethyl)aniline (400 mg, 1.14 mmol) and 5-bromo-3-chloro-2-morpholinobenzonitrile (460 mg, 1.37 mmol) in 1,4-Dioxane (6.0 mL) was added Cs.sub.2CO.sub.3 (933 mg, 2.86 mmol) and Sphos-Pd-G3 (26.8 mg, 0.34 mmol) under N.sub.2 at 20° C. The mixture was stirred for 3 h at 90° C. under N.sub.2. LCMS showed the reaction was completed. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=10:13:1) to give 3-chloro-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)-2-morpholinobenzonitrile (4) (200 mg, yield: 27.6%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.65 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.05-8.01 (m, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.15 (d, J=2.8 Hz, 1H), 7.03 (d, J=2.8 Hz, 1H), 4.31 (q, J=8.4 Hz, 2H), 3.88-3.85 (m, 4H), 3.31 (s, 4H), 2.74 (s, 3H).

    [1460] 3-chloro-5-((4-(2-(methylsulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)-2-morpholinobenzonitrile (5): To a solution of 3-chloro-5-((4-(2-(methylthio)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)-2-morpholinobenzonitrile (4) (200 mg, 0.32 mmol) in THE (2.0 mL) and H.sub.2O (2.0 mL) was added Oxone (971 mg, 1.58 mmol) at 25° C. The mixture was stirred for 8 h at 25° C. under N.sub.2. LCMS showed the reaction was completed. The reaction was quenched with sat.Na.sub.2SO.sub.3 (10 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL), dried with anhydride Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 3-chloro-5-((4-(2-(methyl sulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)-2-morpholinobenzonitrile (5) (250 mg, yield: 98.6%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=9.54 (s, 1H), 8.43 (s, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.25-7.20 (m, 3H), 7.12 (d, J=2.4 Hz, 1H), 4.38-4.30 (m, 2H), 3.90-3.86 (m, 4H), 3.43 (s, 3H), 3.34 (s, 4H).

    [1461] N-(6-(4-((3-chloro-5-cyano-4-morpholinophenyl)(2,2,2-trifluoroethyl)amino) phenyl) quinoxalin-2-yl)methanesulfonamide (Compound A224): To a solution of 3-chloro-5-((4-(2-(methyl sulfonyl)quinoxalin-6-yl)phenyl)(2,2,2-trifluoroethyl)amino)-2-morpholinobenzonitrile (5) (250 mg, 0.37 mmol) and MsNH.sub.2 (71.1 mg, 0.75 mmol) in DMF (3 mL) was added Cs.sub.2CO.sub.3 (365 mg, 1.12 mmol) at 25° C. The reaction was stirred at 25° C. for 2 h. LCMS showed the reaction was completed. The mixture was poured into water (5 mL) and extracted with EtOAc (3 mL×3), then the EtOAc phases were washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by perp-HPLC (Column: xbridge 150*25 mm 10 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN, gradient: 25%-55% B over 10 min) to give N-(6-(4-((3-chloro-5-cyano-4-morpholinophenyl)(2,2,2-trifluoroethyl)amino)phenyl)quinoxalin-2-yl)methanesulfonamide (Compound A224) (40 mg, yield: 17.3%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.44 (s, 1H), 8.17 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 2H), 7.53 (s, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.16 (s, 1H), 7.03 (s, 1H), 4.31 (q, J=7.6 Hz, 2H), 3.87 (s, 4H), 3.39-3.19 (m, 7H). LCMS: (220 nm): 97.9%. Exact Mass: 616.1, found 617.0/619.0.

    Example 16: Synthesis of N-(3-((4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanesulfonamide (Compound A228)

    [1462] ##STR00401##

    [1463] 3-chloro-2-cyclopropoxy-5-(4-hydroxyphenoxy)benzonitrile (1): To a 3-chloro-2-cyclopropoxy-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (inter Z1) (400 mg, 0.923 mmol) in THF (5 mL) and H.sub.2O (5 mL) was added Oxone (1.13 g, 1.185 mmol) at 35° C. and the mixture was stirred at 35° C. for 2 h. LCMS showed the reaction was completed. The mixture was poured into saturated Na.sub.2SO.sub.3 (5 mL) and extracted with EtOAc (mL×3), the organic layers were washed with brine (10 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 3-chloro-2-cyclopropoxy-5-(4-hydroxyphenoxy)benzonitrile (1) (0.48 g, yield: 94.8%) as yellow solid. LCMS (220 nm): 88.2%. Exact Mass: 301.0; found Mass+1: 302.0/304.0

    [1464] Tert-butyl (3-((4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (3): To a solution of 3-chloro-2-cyclopropoxy-5-(4-hydroxyphenoxy)benzonitrile (1) (200 mg, 0.597 mmol) and tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (2) (153 mg, 0.716 mmol) in Tol (2 mL) was added CMBP (280 mg, 1.19 mmol) at 25° C. and the mixture was stirred at 110° C. for 2 h under N.sub.2. LCMS showed the starting material was consumed and the desired product was detected. The reaction was quenched with H.sub.2O (2 mL), and extracted with EtOAc (1 mL×3). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE-EA from 0%-50%) to give tert-butyl (3-((4 (3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (3) (280 mg, yield: 85.0%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.18 (d, J=2.8 Hz, 1H), 7.04-6.97 (m, 1H), 6.97-6.85 (m, 4H), 4.97 (br s, 1H), 4.44-4.40 (m, 1H), 4.08 (s, 2H), 2.06 (br d, J=4.8 Hz, 6H), 1.46 (s, 9H), 1.09-0.96 (m, 2H), 0.76-0.60 (m, 2H).

    [1465] 5-(4-((3-aminobicyclo[1.1.1]pentan-1-yl)methoxy)phenoxy)-3-chloro-2-cyclopropoxybenzonitrile (4): To a mixture of tert-butyl (3-((4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (3) (280 mg, 0.507 mmol) in DCM (3 mL) was added TFA (1.5 mL, 0.507 mmol) at 0° C. Then the reaction was stirred at 20° C. for 2 h. LCMS showed the starting material was consumed and desired was detected. The mixture was quenched with sat. NaHCO.sub.3 (3 mL) and extracted with DCM (2 mL×3). The combined organic layers was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduce pressure to give 5-(4-((3-aminobicyclo[1.1.1]pentan-1-yl)methoxy)phenoxy)-3-chloro-2-cyclopropoxybenzonitrile (4) (200 mg, yield: 69.6%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.19 (d, J=2.8 Hz, 1H), 6.98 (d, J=3.2 Hz, 1H), 6.96-6.91 (m, 4H), 4.44-4.39 (m, 1H), 4.05 (s, 2H), 1.86 (s, 6H), 1.05-1.00 (m, 2H), 0.71-0.65 (m, 2H).

    [1466] N-(3-((4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenoxy)methyl) bicyclo[1.1.1.]pentan-1-yl)methanesulfonamide (Compound A228): To a solution of 5-(4-((3-aminobicyclo[1.1.1]pentan-1-yl)methoxy)phenoxy)-3-chloro-2-cyclopropoxybenzonitrile (4) (200 mg, 0.454 mmol) in DCM (3 mL) was added TEA (140 mg, 1.36 mmol) and methanesulfonyl chloride (52 mg, 0.454 mmol) at 0° C. The mixture was stirred at 20° C. for 1 h. LCMS showed the reaction was completed. The reaction was quenched with ice water (5 mL), extracted with DCM (3 mL×3). The combined organic layers were washed with brine (3 mL×2), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex luna C18 150*25 mm*10 um, water (FA)-ACN from 37% to 67%) to give N-(3-((4-(3-chloro-5-cyano-4-cyclopropoxyphenoxy)phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl) methanesulfonamide (Compound A228) (61 mg, yield: 46.2%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.19 (d, J=2.0 Hz, 1H), 6.97 (br d, J=8.4 Hz, 3H), 6.90 (d, J=8.8 Hz, 2H), 4.95 (br s, 1H), 4.47-4.39 (m, 1H), 4.09 (s, 2H), 3.02 (s, 3H), 2.15 (s, 6H), 1.03 (br s, 2H), 0.68 (q, J=2.0 Hz, 2H). LCMS (220 nm): 99.5%. Exact Mass: 474.1; found Ms+18: 492.1/494.0.

    Example 17: Synthesis of N-(3-((4-((3-chloro-5-cyano-4-cyclopropoxyphenyl)(2,2,2-trifluoroethyl)amino)phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanesulfonamide (Compound A236)

    [1467] ##STR00402##

    [1468] 5-((4-((tert-butyldimethylsilyl)oxy)phenyl)(2,2,2-trifluoroethyl)amino)-3-chloro-2-cyclopropoxybenzonitrile (4): To a solution of 4-((tert-butyldimethylsilyl)oxy)-N-(2,2,2-trifluoroethyl)aniline (2) (0.5 g, 1.64 mmol) and 5-bromo-3-chloro-2-cyclopropoxybenzonitrile (3) (0.6 g, 1.96 mmol) in 1,4-Dioxane (7 mL) was added Cs.sub.2CO.sub.3 (1.6 g, 4.91 mmol) and SPhos-Pd-G.sub.3 (0.26 g, 0.33 mmol) under N.sub.2 at 20° C. The mixture was stirred at 90° C. for 8 h under N.sub.2. LCMS showed the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=20:13:1) to give 5-((4-((tert-butyldimethylsilyl)oxy)phenyl)(2,2,2-trifluoroethyl)amino)-3-chloro-2-cyclopropoxybenzonitrile (4) (0.85 g, yield: 73.1%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.05 (d, J=8.8 Hz, 1H), 6.93-6.89 (m, 2H), 6.73 (dd, J=2.8, 6.0 Hz, 2H), 6.60 (d, J=8.4 Hz, 1H), 4.36 (tt, J=2.8, 6.0 Hz, 1H), 3.75-3.66 (m, 2H), 1.02 (s, 9H), 0.98 (s, 6H), 0.26 (s, 2H), 0.17 (s, 2H).

    [1469] 3-chloro-2-cyclopropoxy-5-((4-hydroxyphenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (5): To a solution of 5-((4-((tert-butyldimethylsilyl)oxy)phenyl)(2,2,2-trifluoroethyl)amino)-3-chloro-2-cyclopropoxybenzonitrile (4) (850 mg, 1.20 mmol) in THE (9 mL) was added TBAF (1 mol/L, 1.80 mL, 1.80 mmol) at 0° C. and the mixture was stirred at 25° C. for 1 h. LCMS showed the reaction was completed. The mixture was quenched with water (15 mL) and extracted with EtOAc (6 mL×3). The combined organic layers were washed with brine (10 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=5:11:1) to give 3-chloro-2-cyclopropoxy-5-((4-hydroxyphenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (5) (500 mg, yield: 87.3%) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.08 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.74 (d, J=8.8 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.39-4.35 (m, 1H), 3.71 (q, J=8.8 Hz, 2H), 1.04-0.98 (m, 2H), 0.69-0.61 (m, 2H).

    [1470] tert-butyl (3-((4-((3-chloro-5-cyano-4-cyclopropoxyphenyl)(2,2,2-trifluoroethyl)amino)phenoxy)methyl)bicyclo[1.1.1]pentan-l-yl)carbamate (7): To a solution of 3-chloro-2-cyclopropoxy-5-((4-hydroxyphenyl)(2,2,2-trifluoroethyl)amino)benzonitrile (5) (200 mg, 0.52 mmol) and tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (6) (111 mg, 0.52 mmol) in toluene (4.0 mL) was added CMBP (252 mg, 1.05 mmol) at 25° C. under N.sub.2 and the mixture was stirred at 110° C. for 1 h. LCMS showed the reaction was completed The mixture was quenched with H.sub.2O (10 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (5 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=10:13:1) to give tert-butyl (3-((4-((3-chloro-5-cyano-4-cyclopropoxyphenyl)(2,2,2-trifluoroethyl)amino)phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)carbamate (7) (300 mg, yield: 79.5%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.10 (d, J=8.8 Hz, 2H), 6.98-6.93 (m, 2H), 6.89 (d, J=3.2 Hz, 1H), 6.70 (d, J=3.2 Hz, 1H), 4.99 (s, 1H), 4.37-4.34 (m, 1H), 4.21-4.15 (m, 2H), 4.10 (s, 2H), 2.08 (s, 6H), 1.47 (s, 9H), 1.04-0.98 (m, 2H), 0.65-0.63 (m 2H).

    [1471] 5-((4-((3-aminobicyclo[1.1.1]pentan-1-yl)methoxy)phenyl)(2,2,2-trifluoroethyl)amino)-2-(cyclopropylamino)nicotinonitrile (8): To a solution of tert-butyl (5-((4-((3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methoxy)phenyl)(2,2,2-trifluoroethyl)amino)-3-cyanopyridin-2-yl)(cyclopropyl)carbamate (7) (250 mg, 0.39 mmol) in DCM (3 mL) was added TFA (443 mg, 3.88 mmol) at 0° C. under N.sub.2 and the mixture was stirred at 25° C. for 1 h. LCMS showed the reaction was successful. The mixture was concentrated under reduced pressure to give 5-((4-((3-aminobicyclo[1.1.1]pentan-1-yl)methoxy)phenyl)(2,2,2-trifluoroethyl)amino)-2-(cyclopropylamino)nicotinonitrile (8) (200 mg, yield: 92.9%) as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=8.15 (s, 1H), 7.30-7.27 (m, 1H), 6.91-6.86 (m, 2H), 6.86-6.81 (m, 2H), 5.26 (s, 1H), 4.19-4.12 (m, 2H), 4.03 (s, 2H), 2.82 (s, 1H), 1.95 (s, 6H), 0.87 (d, J=6.4 Hz, 2H), 0.60 (br s, 2H).

    [1472] N-(3-((4-((3-chloro-5-cyano-4-cyclopropoxyphenyl)(2,2,2-trifluoroethyl)amino)phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanesulfonamide (Compound A236): To a solution of 5-((4-((3-aminobicyclo[1.1.1]pentan-1-yl)methoxy)phenyl)(2,2,2-trifluoroethyl)amino)-2-(cyclopropylamino)nicotinonitrile (8) (200 mg, 0.42 mmol) and TEA (0.36 mL, 2.1 mmol) in DCM (4 mL) was added MsCl (43.5 mg, 0.38 mmol) at 0° C. and stirred at 20° C. for 1 h. LCMS showed the reaction was completed. The mixture was quenched with H.sub.2O (5 mL) and extracted with DCM (3 mL×3). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by perp-HPLC (Column: xbridge 150*25 mm 10 um; mobile phase: water (NH.sub.4HCO.sub.3)-ACN, gradient: 25%-55% B over 10 min) give N-(3-((4-((3-chloro-5-cyano-4-cyclopropoxyphenyl)(2,2,2-trifluoroethyl)amino)phenoxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanesulfonamide (Compound A236) (121 mg, yield: 82.1%) as white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ=7.11 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.91 (d, J=3.2 Hz, 1H), 6.69 (d, J=3.2 Hz, 1H), 4.95 (s, 1H), 4.35 (tt, J=2.8, 6.0 Hz, 1H), 4.18 (q, J=8.4 Hz, 2H), 4.12 (s, 2H), 3.02 (s, 3H), 2.16 (s, 6H), 1.05-0.98 (m, 2H), 0.62-0.67 (m, 2H). LCMS: (220 nm): purity: 98.6%. Exact Mass: 555.1, found 556.1/558.0.

    Example 18: Synthesis of Compounds of Table A

    [1473] Compounds of Table A were synthesized according to modified procedures based on the examples provided herein and/or with organic chemistry reactions known to one skilled in the art. The characterization of the synthesized compounds is provided in Table 1.

    TABLE-US-00002 TABLE 1 Characterization of Compounds of Table A (M + H by LC-MS) M + H M + H Comp ID .sup.1H-NMR (calc) (found) A1 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.81 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.55-7.49 (m, 4H), 7.36 (d, 518.1 518.0 J = 2.4 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 5.87 (s, 1H), 4.58 (d, J = 4.0 Hz, 2H), 4.45 (t, J = 6.0 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 2.99 (s, 3H), 1.72 (s, 6H). A2 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.97 (s, 1H), 8.67 (s, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 519.1 518.9 2.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 5.35 (s, 1H), 4.56 (d, J = 5.6 Hz, 2H), 4.44 (t, J = 6.0 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.01 (s, 3H), 1.72 (br s, 6H) A3 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.58 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 518.1 518.1 7.68 (d, J = 1.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 4.59 (br d, J = 8.8 Hz, 1H), 4.39-4.31 (m, 4H), 3.81 (t, J = 6.0 Hz, 2H), 2.89 (s, 3H), 1.64 (s, 6H) A4 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.97 (s, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 2.4 Hz, 1H), 519.1 518.9 7.39-7.32 (m, 3H), 5.84-5.73 (m, 1H), 4.69 (s, 2H), 4.45 (t, J = 6.4 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.04 (s, 3H), 1.73 (s, 6H) A5 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.82 (s, 2H), 8.38 (br d, J = 8.4 Hz, 2H), 7.46 (d, J = 2.0 Hz, 1H), 519.1 519.0 7.38 (d, J = 2.0 Hz, 1H), 7.32 (br d, J = 8.4 Hz, 2H), 4.77 (s, 1H), 4.43 (q, J = 6.4, 12.8 Hz, 4H), 3.88 (t, J = 6.0 Hz, 2H), 3.00 (s, 3H), 1.74-1.70 (m, 6H) A6 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.74 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 2.4, 8.0 Hz, 1H), 7.55-7.51 532.1 532.0 (m, 2H), 7.50 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.34-7.28 (m, 3H), 5.79 (t, J = 5.2 Hz, 1H), 4.45 (t, J = 6.0 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.63 (q, J = 6.0 Hz, 2H), 3.17 (t, J = 6.0 Hz, 2H), 2.97 (s, 3H), 1.72 (s, 6H) A7 .sup.1H-NMR (400 MHz, MeOD) δ = 7.37-7.31 (m, 3H), 7.20 (d, J = 2.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 484.1 484.0 2H), 4.41 (t, J = 5.6 Hz, 2H), 4.26 (q, J = 7.2, 14.4 Hz, 1H), 4.11 (br d, J = 5.2 Hz, 2H), 3.91 (t, J = 5.6 Hz, 2H), 3.55 (br s, 2H), 3.23-3.05 (m, 2H), 2.95 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H) A8 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.46 (d, J = 2.4 Hz, 1H), 7.35-7.30 (m, 3H), 7.16 (d, J = 8.0 Hz, 524.1 524.0 2H), 4.48 (br d, J = 5.2 Hz, 1H), 4.43 (t, J = 6.0 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.67 (s, 2H), 3.44 (br dd, J = 3.2, 7.2 Hz, 1H), 3.02-3.01 (m, 1H), 3.03 (br s, 1H), 2.99 (s, 3H), 2.39-2.29 (m, 2H), 2.07 (br d, J = 11.6 Hz, 2H), 1.82 (br d, J = 10.4 Hz, 2H), 1.67 (s, 6H) A9 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.37 (br d, J = 8.0 Hz, 2H), 7.28 (br s, 1H), 7.07 (d, J = 3.2 Hz, 498.1 498.3 1H), 6.98 (d, J = 8.8 Hz, 2H), 4.41 (t, J = 6.4 Hz, 2H), 4.30 (br d, J = 2.8 Hz, 1H), 3.89 (t, J = 6.0 Hz, 2H), 3.55 (br s, 2H), 3.48-3.31 (m, 1H), 3.00 (s, 3H), 2.89 (br d, J = 10.4 Hz, 2H), 2.21 (br s, 2H), 2.03 (br d, J = 11.6 Hz, 2H), 1.74-1.60 (m, 2H) A10 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.71-7.69 (m, 1H), 7.63-7.61 (m, 1H), 7.53-7.51 (m, 3H), 7.42 571.1 571.0 (s, 1H), 7.37 (s, 1H), 7.28 (br s, 1H), 7.26 (br s, 1H), 5.20 (s, 2H), 4.46-4.43 (m, 2H), 4.35 (d, J = 8.4 Hz, 2H), 4.25-4.23 (m, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.00 (s, 3H), 1.72 (s, 6H). A11 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.37 (d, J = 1.6 Hz, 1H), 7.79 (dd, J = 2.4, 8.8 Hz, 1H), 7.49 (d, 559.1 559.0 J = 2.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.46 (d, J = 8.4 Hz, 1H), 5.41 (s, 1H), 4.57-4.48 (m, 3H), 4.44 (t, J = 6.4 Hz, 2H), 4.11 (br d, J = 2.0 Hz, 2H), 3.89 (t, J = 6.4 Hz, 2H), 3.03 (s, 3H), 1.70 (s, 6H) A12 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.80 (s, 1H), 7.69 (s, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 8.4 521.1 521.0 Hz, 2H), 7.36 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 5.07 (s, 1H), 4.43 (t, J = 6.4 Hz, 2H), 4.35 (t, J = 5.2 Hz 2H), 3.88 (t, J = 6.4 Hz, 2H), 3.66 (dd, J = 6.0, 10.8 Hz, 2H), 2.94 (s, 3H), 1.69 (s, 6H) A13 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.44 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 8.4 539.2 539.1 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.42 (t, J = 6.0 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.43 (br t, J = 5.2 Hz, 2H), 3.40-3.34 (m, 4H), 3.01 (s, 3H), 2.97 (br s, 4H), 2.91 (br t, J = 5.6 Hz, 2H), 1.64 (s, 6H) A14 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.10 (br d, J = 526.1 526.4 7.6 Hz, 2H), 6.88 (br s, 2H), 4.68 (br t, J = 6.4 Hz, 1H), 4.42 (t, J = 6.0 Hz, 2H), 4.05 (br dd, J = 2.0, 11.2 Hz, 1H), 3.95-3.79 (m, 4H), 3.51-3.35 (m, 3H), 3.28-3.15 (m, 1H), 3.01 (s, 3H), 2.92-2.82 (m, 1H), 2.74-2.62 (m, 1H), 1.64 (s, 6H) A20 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.17-7.09 (m, 510.1 510.0 4H), 4.42 (t, J = 6.0 Hz, 2H), 4.22 (t, J = 5.6 Hz, 1H), 3.88 (t, J = 6.4 Hz, 2H), 3.80 (t, J = 8.4 Hz, 2H), 3.50-3.41 (m, 2H), 2.95 (s, 3H), 2.92 (d, J = 8.0 Hz, 2H), 2.77-2.71 (m, 2H), 1.65 (s, 6H) A21 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.79 (s, 1H), 7.94 (dd, J = 2.0, 8.0 Hz, 1H), 7.63-7.61 (m, 2H), 492.0 492.0 7.45 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.16-7.14 (m, 3H), 5.71 (s, 1H), 4.55 (d, J = 5.6 Hz, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.91 (t, J = 6.0 Hz, 2H), 2.99 (s, 3H). A23 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 11.64 (s, 1H), 8.64 (d, J = 1.6 Hz, 1H), 8.62 (s, 1H), 8.59 (d, 530.0 530.2 J = 2.8 Hz, 1H), 8.51 (dd, J = 1.6, 8.4 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 3.2 Hz, 1H), 7.68 (dd, J = 2.8, 8.4 Hz, 1H), 4.44 (t, J = 4.8 Hz, 2H), 3.99 (t, J = 5.6 Hz 2H), 3.47 (s, 3H) A24 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.89 (br s, 1H), 8.11 (s, 1H), 7.90 (br d, J = 9.2 Hz, 1H), 7.66 (br 529.0 528.9 d, J = 8.4 Hz, 2H), 7.34 (d, J = 2.8 Hz, 1H), 7.19 (s, 1H), 7.18-7.13 (m, 2H), 7.01 (d, J = 6.8 Hz, 1H), 4.44 (t, J = 6.0 Hz, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.16 (s, 3H) A25 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.46 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.14-7.08 (m, 525.1 525.3 2H), 6.89-6.83 (m, 2H), 4.49 (br d, J = 8.8 Hz, 1H), 4.42 (t, J = 6.0 Hz, 2H), 4.07-3.96 (m, 1H), 3.88 (t, J = 6.0 Hz, 2H), 3.80 (s, 2H), 2.96-2.92 (m, 3H), 2.62 (ddd, J = 2.8, 8.0, 10.4 Hz, 2H), 1.84 (ddd, J = 2.8, 8.0, 10.4 Hz, 2H), 1.65 (s, 6H), 1.27 (s, 3H). A26 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 8.4 529.1 529.0 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.89 (d, J = 8.8 Hz, 1H), 4.43 (t, J = 6.0 Hz, 2H), 4.27-4.16 (m, 1H), 4.05 (d, J = 12.0 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 2.97 (s, 3H), 2.95-2.82 (m, 2H), 2.53-2.41 (m, 2H), 1.65 (s, 6H) A27 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.43 (br d, J = 2.0 Hz, 1H), 8.13 (s, 1H), 7.89 (br d, J = 8.4 Hz, 528.1 528.0 1H), 7.65 (br d, J = 8.4 Hz, 2H), 7.59-7.42 (m, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.19-7.17 (m, 3H), 5.89 (s, 1H), 4.39 (t, J = 6.0 Hz, 2H), 3.90 (t, J = 6.0 Hz, 2H), 3.27 (br s, 3H). A28 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.44 (s, 1H), 8.17 (s, 1H), 7.91 (br d, J = 8.4 Hz, 1H), 7.66 (br d, 584.1 584.1 J = 8.0 Hz, 2H), 7.53 (br s, 1H), 7.19-7.17 (m, 3H), 7.00 (d, J = 2.4 Hz, 1H), 4.36 (t, J = 6.0 Hz, 2H), 3.87 (t, J = 6.0 Hz, 2H), 3.26 (br s, 3H), 1.45 (s, 9H). A29 .sup.1H-NMR (400 MHz, MeOD) δ = 7.51 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.18 (s, 4H), 538.2 538.0 4.42 (t, J = 5.6 Hz, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.31-3.25 (m, 1H), 2.99 (d, J = 12.0 Hz, 2H), 2.95 (s, 3H), 2.82-2.78 (m, 2H), 2.62-2.58 (m, 2H), 2.22 (t, J = 11.6 Hz, 2H), 1.98 (d, J = 11.2 Hz, 2H), 1.66 (s, 6H), 1.64-1.60 (m, 2H) A30 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.28 (d, J = 8.8 Hz, 2H), 7.26 (s, 1H), 7.04 (d, J = 2.8 Hz, 1H), 512.1 512.0 6.98 (d, J = 8.4 Hz, 2H), 5.12 (d, J = 2.0 Hz, 1H), 4.42 (t, J = 6.0 Hz, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.51 (br s, 1H), 3.31 (d, J = 11.6 Hz, 2H), 3.03 (s, 3H), 3.00-2.90 (m, 4H), 2.54 (t, J = 10.8 Hz, 2H), 2.16 (d, J = 11.6 Hz, 2H), 1.96 (q, J = 10.0 Hz, 2H). A31 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.4 Hz, 1H), 7.35-7.30 (m, 1H), 7.10 (br d, J = 8.4 540.1 540.0 Hz, 2H), 6.95-6.81 (m, 2H), 4.94 (br dd, J = 4.8, 6.4 Hz, 1H), 4.42 (t, J = 6.0 Hz, 2H), 4.04 (dd, J = 2.4, 11.2 Hz, 1H), 3.88 (t, J = 6.4 Hz, 2H), 3.85-3.74 (m, 2H), 3.49-3.36 (m, 3H), 3.35-3.25 (m, 1H), 2.97 (s, 3H), 2.93-2.81 (m, 1H), 2.67-2.54 (m, 1H), 1.88-1.79 (m, 2H), 1.64 (s, 6H) A32 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.46 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 566.2 566.4 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.42 (t, J = 6.4 Hz, 2H), 3.88 (t, J = 6.0 Hz, 4H), 3.61 (br d, J = 11.6 Hz, 2H), 3.19-3.12 (m, 2H), 3.08-3.01 (m, 2H), 2.99 (s, 2H), 2.81 (s, 3H), 2.23 (br d, J = 13.6 Hz, 2H), 1.72-1.66 (m, 2H), 1.64 (s, 6H) A33 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.46 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 525.1 525.0 6.4 Hz, 2H), 6.81 (d, J = 6.8 Hz, 2H), 4.42 (t, J = 6.0 Hz, 2H), 4.15 (d, J = 7.2 Hz, 1H), 4.22- 4.14 (m, 1H), 3.88 (t, J = 6.0 Hz, 2H), 3.45-3.43 (m, 1H), 3.01 (s, 3H), 2.20-2.13 (m, 4H), 1.64 (s, 6H), 1.60-1.59 (m, 2H), 1.45-1.42 (m, 2H) A34 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.46 (d, J = 2.4 Hz, 1 H), 7.34 (d, J = 2.0 Hz, 1 H), 7.27-7.24 560.1 560.0 (m, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 4.60 (d, J = 8.0 Hz, 1 H), 4.43 (t, J = 6.0 Hz, 2 H), 3.88 (t, J = 6.0 Hz, 2 H), 3.67-3.64 (m, 2 H), 3.51-3.60 (m, 1 H), 3.58-3.55 (m, 1 H), 3.23-3.17 (m, 1 H), 3.06 (s, 3 H), 2.95 (d, J = 10.8 Hz, 1 H), 2.33-2.27 (m, 1 H), 2.24 (t, J = 11.2 Hz, 1 H), 2.10-2.07 (m, 1 H), 1.84-1.82 (m, 1 H), 1.67 (s, 6 H). A35 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.36 (br d, J = 8.4 Hz, 2H), 7.28 (d, J = 2.8 Hz, 1H), 7.08 (d, J = 534.1 533.9 3.2 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 4.6 (br s, 1H), 4.41 (t, J = 6.0 Hz, 2H), 3.90 (t, J = 6.0 Hz, 2H), 3.75-3.55 (m, 3H), 3.26-3.15 (m, 1H), 3.07 (s, 3H), 2.96 (br d, J = 10.8 Hz, 1H), 2.47-2.21 (m, 2H), 2.15-2.06 (m, 1H), 1.91-1.78 (m, 1H) A37 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.50 (s, 1H), 7.90 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 560.1 560.0 7.38 (d, J = 1.6 Hz, 1H), 7.30-7.27 (m, 2H), 4.94 (d, J = 6.4 Hz, 1H), 4.55 (d, J = 5.6 Hz, 3H), 4.43 (t, J = 6.0 Hz, 2H), 4.08-4.05 (m, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.04 (s, 3H), 1.70 (s, 6H). A38 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.39 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 2.4, 8.4 Hz, 1H), 7.54- 533.1 533.0 7.51 (m, 2H), 7.30 (d, J = 2.8 Hz, 1H), 7.11 (d, J = 3.2 Hz, 1H), 7.11-7.07 (m, 2H), 6.42 (d, J = 8.8 Hz, 1H), 4.92 (d, J = 8.0 Hz, 1H), 4.49-4.47 (m, 3H), 4.41 (t, J = 6.0 Hz, 2H), 3.97-3.96 (m, 2H), 3.90 (t, J = 6.4 Hz, 2H), 3.03 (s, 3H) A39 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 529.1 529.0 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.58 (br d, J = 8.8 Hz, 1H), 4.43 (t, J = 6.0 Hz, 2H), 4.05 (d, J = 18.8 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.70 (dq, J = 3.6, 8.0 Hz, 1H), 3.00-2.93 (m, 5H), 2.49-2.36 (m, 2H), 1.65 (s, 6H) A40 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.39 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.45 (s, 560.1 560.0 1H), 7.36 (d, J = 1.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 5.2 Hz, 1H), 4.89 (d, J = 9.2 Hz, 1H), 4.61-4.57 (m, 2H), 4.45-4.42 (m, 1H), 4.43 (t, J = 6.0 Hz, 2H), 4.09 (dd, J = 4.8, 9.2 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.02 (s, 3H), 1.71 (s, 6H). A41 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.37 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.76 (s, 1H), 7.47 (d, J = 560.1 560.0 2.4 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 5.18 (br d, J = 6.4 Hz, 1H), 4.57 (t, J = 4.8 Hz, 3H), 4.44 (t, J = 6.0 Hz, 2H), 4.09 (d, J = 4.4 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.04 (s, 3H), 1.71 (s, 6H). A43 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.44 (br s, 1H), 8.15 (s, 1H), 7.89 (br d, J = 8.0 Hz, 1H), 7.70 (d, 481.1 481.0 J = 8.8 Hz, 2H), 7.54 (br d, J = 10.8 Hz, 1H), 7.34 (d, J = 3.2 Hz, 1H), 7.19-7.12 (m, 3H), 4.06 (s, 3H), 3.28 (br s, 3H). A46 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.46 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.26-7.22 (m, 560.1 560.0 2H), 7.19-7.13 (m, 2H), 5.02 (d, J = 9.6 Hz, 1H), 4.45 (t, J = 6.0 Hz, 2H), 3.90 (t, J = 6.0 Hz, 3H), 3.65 (d, J = 0.8 Hz, 2H), 3.07-3.03 (m, 1H), 2.90 (s, 3H), 2.85 (d, J = 12.0 Hz, 1H), 2.48-2.40 (m, 2H), 2.28-2.26 (m, 1H), 2.03-2.01 (m, 1H), 1.68 (s, 6H) A47 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 565.2 565.1 11.6 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.87-4.71 (br s, 1H), 4.41 (t, J = 6.0 Hz, 2H), 4.10 (br s, 1H), 3.88 (t, J = 6.0 Hz, 2H), 3.71 (q, J = 6.8, 8.4 Hz, 2H), 3.59 (td, J = 3.6, 12.4 Hz, 2H), 2.97 (t, J = 8.4 Hz, 5H), 2.83-2.75 (m, 2H), 2.20-2.12 (m, 1H), 1.78 (br dd, J = 3.2, 12.8 Hz, 2H), 1.63 (s, 6H), 1.50-1.38 (m, 2H) A48 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.46 (d, J = 2.4 Hz, 1H), 7.37-7.32 (m, 1H), 7.09 (br d, J = 8.8 565.2 565.1 Hz, 2H), 6.88 (br d, J = 8.8 Hz, 2H), 4.94-4.81 (m, 0.2H), 4.50 (br d, J = 7.2 Hz, 1H), 4.43 (t, J = 6.0 Hz, 2H), 4.16-4.03 (m, 1H), 3.89 (t, J = 6.0 Hz, 2H), 3.85-3.74 (m, 0.2H), 3.31-3.20 (m, 4H), 3.04-2.94 (m, 4H), 2.79-2.68 (m, 1H), 2.66-2.60 (m, 1H), 2.56 (br d, J = 4.4 Hz, 4H), 2.52- 2.46 (m, 1H), 2.20-2.12 (m, 2H), 1.65 (s, 6H) A50 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.20 (s, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.44-7.32 (m, 3H), 7.37 577.1 577.0 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 4.87 (d, J = 8.8 Hz, 1H), 4.56-4.54 (m, 3H), 4.43 (t, J = 6.0 Hz, 2H), 4.06 (dd, J = 5.2, 8.4 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.03 (s, 3H), 1.70 (s, 6H). A52 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.26-9.18 (m, 1H), 8.66 (d, J = 5.2 Hz, 1H), 7.41 (d, J = 2.4 Hz, 527.1 527.1 1H), 7.30-7.29 (m, 2H), 7.13 (d, J = 4.8 Hz, 2H), 6.90 (d, J = 4.8 Hz, 2H), 5.12 (s, 2H), 4.80-4.75 (m, 1H), 3.47 (s, 3H), 2.41-2.35 (m, 4H), 1.82-1.78 (m, 1H), 1.64 (s, 6H), 1.50-1.48 (m, 1H) A53 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.35 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 2.4, 8.4 Hz, 1H), 7.49 (d, 559.1 559.0 J = 2.4 Hz, 1H), 7.47-7.43 (m, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.26-7.22 (m, 2H), 6.50 (d, J = 8.8 Hz, 1H), 4.82-4.71 (m, 2H), 4.44 (t, J = 6.0 Hz, 2H), 4.28 (dd, J = 7.2, 8.4 Hz, 2H), 3.94 (dd, J = 6.0, 8.8 Hz, 2H), 3.89 (t, J = 6.4 Hz, 2H), 2.93 (s, 3H), 1.70 (s, 6H) A54 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.43 (d, J = 2.4 Hz, 1H), 7.72 (dd, J = 2.4, 8.8 Hz, 1H), 7.50 (d, 573.1 573.1 J = 2.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 8.8 Hz, 1H), 4.54 (d, J = 13.6 Hz, 1H), 4.44 (t, J = 6.0 Hz, 2H), 4.44-4.42 (m, 1H), 3.90- 3.85 (m, 3H), 3.71-3.64 (m, 1H), 3.61-3.51 (m, 2H), 3.05 (s, 3H), 2.45-2.38 (m, 1H), 2.15- 2.10 (m, 1H), 1.70 (s, 6H). A58 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.62 (d, J = 1.6 Hz, 1H), 7.85 (dd, J = 8.4, 2.4 Hz, 1H), 7.51 (d, 587.2 587.1 J = 8.4 Hz, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 4.36 (t, J = 5.2 Hz, 2H), 3.49-3.38 (m, 1H), 3.08-3.18 (m, 2H), 3.07-2.95 (m, 5H), 2.50-2.41 (m, 2H), 2.06 (d, J = 12.0 Hz, 2H), 1.71 (s, 8H). A60 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.46 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 2.4, 8.8 Hz, 1H), 7.50- 573.1 575.1 7.47 (m, 3H), 7.38 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.8 Hz, 1H), 4.44 (t, J = 6.0 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.76 (t, J = 5.2 Hz, 4H), 3.42-3.34 (t, J = 5.2, 4H), 2.83 (s, 3H), 1.70 (s, 6H) A62 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.42-9.37 (m, 1H), 8.66 (d, J = 5.2 Hz, 1H), 7.42 (d, J = 2.4 Hz, 513.1 513.3 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.12 (s, 2H), 4.50-4.45 (m, 1H), 3.47 (s, 3H), 1.65 (s, 6H), 1.02-1.01 (m, 2H), 0.73- 0.71 (m, 2H). A63 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 539.1 539.1 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.42 (t, J = 6.4 Hz, 2H), 4.13 (d, J = 7.6 Hz, 1H), 3.88 (t, J = 6.0 Hz, 2H), 3.76 (d, J = 6.0 Hz, 2H), 3.34-3.30 (m, 1H), 3.00 (s, 3H), 2.17-2.13 (m, 2H), 2.00-1.97 (m, 2H), 1.82-1.72 (m, 1H), 1.64 (s, 6H), 1.34-1.20 (m, 4H) A64 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 525.1 525.0 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.42 (t, J = 6.0 Hz, 2H), 4.19 (br t, J = 5.2 Hz, 1H), 3.98 (d, J = 6.4 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.25 (t, J = 6.4 Hz, 2H), 2.98 (s, 3H), 2.77-2.75 (m, 1H), 2.57 (td, J = 7.2, 14.4 Hz, 1H), 2.09-2.06 (m, 2H), 1.98-1.94 (m, 2H), 1.65 (s, 6H) A67 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.44 (br s, 1H), 8.16 (s, 1H), 7.90 (br d, J = 8.8 Hz, 1H), 7.71 562.1 562.0 (d, J = 8.4 Hz, 2H), 7.54-7.53 (m, 1H), 7.22 (t, J = 2.8 Hz, 2H) 7.19 (s, 1H), 7.05 (d, J = 2.8 Hz, 1H), 4.31 (q, J = 8.4 Hz, 2H), 4.04 (s, 3H), 3.27 (br s, 3H) A68 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.59 (s, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 615.1 615.0 7.15 (d, J = 2.8 Hz, 1H), 6.96 (d, J = 3.2 Hz, 1H), 4.87 (br d, J = 8.8 Hz, 1H), 4.60-4.58 (m, 2H), 4.55-4.45 (m, 1H), 4.39 (t, J = 6.4 Hz, 2H), 4.28 (q, J = 8.8 Hz, 2H), 4.11 (dd, J = 4.8, 10.0 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.04 (s, 3H). A69 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.91 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 560.1 560.1 2.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.30 (br d, J = 8.4 Hz, 2H), 6.67 (br d, J = 9.2 Hz, 1H), 5.74 (br d, J = 1.2 Hz, 1H), 4.59-4.56 (m, 3H), 4.44 (t, J = 6.0 Hz, 2H), 4.19 (br d, J = 4.0 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.03 (s, 3H), 1.71 (s, 6H) A71 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 537.1 537.1 6.4 Hz, 2H), 6.83 (d, J = 6.8 Hz, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.94 (d, J = 8.4 Hz, 4H), 3.89-3.86 (m, 4H), 2.85 (s, 3H), 2.69-2.63 (m, 1H), 2.43-2.38 (m, 2H), 2.20-2.15 (m, 2H), 1.65 (s, 6H) A72 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 523.1 523.0 6.4 Hz, 2H), 6.70 (d, J = 6.4 Hz, 2H), 4.59 (quin, J = 6.4 Hz, 1H), 4.42 (t, J = 6.0 Hz, 2H), 3.98 (s, 2H), 3.96 (s, 2H), 3.88 (t, J = 6.0 Hz, 2H), 2.86 (s, 3H), 2.78-2.72 (m, 2H), 2.42-2.37 (m, 2H), 1.64 (s, 6H) A74 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (s, 1H), 7.32 (s, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.84 (d, 525.1 525.0 J = 8.8 Hz, 2H), 4.42 (t, J = 6.0 Hz, 2H), 4.15-4.14 (m, 1H), 3.90-3.87 (m, 4H), 3.18 (t, J = 6.4 Hz, 2H), 2.97 (s, 3H), 2.80-3.65 (m, 1H), 2.55-2.45 (m, 1H), 2.28-2.25 (m, 2H), 1.71-1.68 (m, 2H), 1.64 (s, 6H) A76 NA 560.1 560.3 A78 NA 521.1 521.1 A79 NA 521.1 520.9 A87 NA 576.1 576 A100 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.67 (d, J = 5.2 Hz, 1H), 7.92 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 603.1 603.1 5.2 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.26 (s, 1H), 7.10 (d, J = 4.0 Hz, 2H), 1H), 7.09 (t, J = 1.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 5.12 (s, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 1.65 (s, 6H) A101 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 10.05 (s, 1H), 8.66 (d, J = 4.8 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 603.1 603.0 7.59 (d, J = 4.4 Hz, 1H), 7.45 (d, J = 6.0 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.06 (s, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 1.65 (s, 6H) A102 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.21 (d, J = 6.4 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 499.1 499.0 8.4 Hz, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.66 (dd, J = 4.8, 14.0 Hz, 1H), 6.33 (d, J = 6.4 Hz, 1H), 5.48 (s, 2H), 4.46-4.43 (m, 1H), 4.38 (dd, J = 2.8, 13.6 Hz, 1H), 3.22 (s, 3H), 1.69 (s, 6H) A103 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 8.37 (br s, 1H), 8.24-8.19 (m, 1H), 7.65-7.62 (m, 2H), 7.56 587.1 587.0 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.83-6.79 (m, 2H), 4.98 (s, 2H), 4.41 (t, J = 5.2 Hz, 2H), 3.95 (t, J = 5.2 Hz, 2H), 1.62 (s, 6H). A104 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.10 (s, 1H), 8.82 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.64 (d, 587.1 587.0 J = 4.8 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 9.2 Hz, 2H), 5.27 (s, 2H), 4.98 (s, 2H, 4.43 (t, J = 6.0 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 1.66 (s, 6H). A105 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.41 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.04 (d, J = 3.2 Hz, 2H), 601.1 601.0 7.45 (s, 1H), 7.32 (s, 1H), 7.23 (d, J = 5.2 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.09 (s, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.93 (s, 3H), 3.88 (t, J = 6.0 Hz, 2H), 1.65 (s, 6H). A106 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 8.93 (d, J = 5.2 Hz, 1H), 8.67 (s, 1H), 8.22 (s, 1H), 7.64 (d, 587.1 587.1 J = 5.2 Hz, 2H), 7.57 (d, J = 2.4 Hz, 1H), 7.46 (s, 2H), 7.21 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.30 (s, 2H), 4.41 (t, J = 5.2 Hz, 2H), 3.95 (t, J = 5.2 Hz, 2H), 1.64 (s, 6H). A107 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.66 (s, 1H), 8.58 (d, J = 5.2 Hz, 1H), 7.74 (s, 1H), 7.47 (s, 1H), 601.1 601.1 7.44 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.05 (s, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.88 (d, J = 6.0 Hz, 2H), 3.75 (s, 3H), 1.64 (s, 6H). A108 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.33 (s, 1H), 8.88 (d, J = 4.8 Hz, 1H), 7.73 (d, J = 5.2 Hz, 1H), 588.1 588.1 7.46 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.61 (s, 2H), 5.29 (s, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.88 (d, J = 6.0 Hz, 2H), 1.66 (s, 6H). A109 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 12.29 (s, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.79 (d, J = 3.6 Hz), 598.1 598.2 8.51 (d, J = 5.2 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.64-7.62 (m, 2H), 7.56 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 5.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 5.04 (s, 2H), 4.41 (t, J = 5.2 Hz, 2H), 3.95 (d, J = 5.2 Hz, 2H), 1.62 (s, 6H) A110 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 10.13 (s, 1H), 8.69 (d, J = 4.0 Hz, 1H), 8.56 (d, J = 5.2 Hz, 1H), 598.1 598.1 8.34 (d, J = 8.0 Hz, 1H), 7.96-7.95 (m, 1H), 7.53-7.51 (m, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.97 (s, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.88 (d, J = 6.0 Hz, 2H), 1.64 (s, 6H). A111 .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.30-8.37 (m, 1H), 8.17-8.23 (m, 1H), 7.62-7.67 (m, 1H), 564.1 564.3 7.54-7.60 (m, 1H), 7.26-7.32 (m, 1H), 7.19-7.25 (m, 1H), 7.07-7.17 (m, 1H), 6.66-6.74 (m, 1H), 5.22-5.27 (m, 2H), 4.37-4.47 (m, 2H), 3.99-4.03 (m, 2H), 3.93-3.98 (m, 2H), 2.95 (s, 3H), 1.64 (s, 6H) A112 .sup.1H NMR (400 MHz, DMSO-d6) δ = 11.19-11.67 (m, 1H), 8.60-8.68 (m, 1H), 7.61-7.67 (m, 1H), 733.2 733.1 7.53-7.60 (m, 1H), 7.23-7.30 (m, 1H), 7.14-7.19 (m, 1H), 7.08-7.13 (m, 1H), 6.93-7.00 (m, 1H), 5.11-5.19 (m, 2H), 4.38-4.49 (m, 2H), 3.92-4.01 (m, 2H), 3.53-3.60 (m, 2H), 3.36 (s, 3H), 3.23- 3.29 (m, 4H), 2.28-2.35 (m, 4H), 1.63 (s, 6H), 1.40 (s, 9H) A113 .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 5.2 Hz, 1H), 8.20-8.26 (m, 1H), 7.60-7.65 (m, 633.2 633.1 1H), 7.50-7.58 (m, 1H), 7.08-7.17 (m, 2H), 6.90-7.04 (m, 2H), 4.98-5.07 (m, 2H), 4.36-4.45 (m, 2H), 3.92-3.97 (m, 2H), 3.57 (s, 2H), 3.14 (s, 3H), 2.85-2.93 (m, 4H), 2.52-2.54 (m, 4H), 1.63 (s, 6H) A114 .sup.1H NMR (400 MHz, METHANOL) δ = 7.54-7.45 (m, 2H), 7.22-7.14 (m, 2H), 6.98-6.92 (m, 618.2 618.1 2H), 6.74-6.68 (m, 1H), 5.00 (s, 2H), 4.47-4.39 (m, 2H), 3.94-3.88 (m, 2H), 3.20 (s, 3H), 3.15- 3.09 (m, 2H), 2.73-2.63 (m, 3H), 1.89-1.82 (m, 2H), 1.71-1.67 (m, 2H), 1.67 (s, 6H) A115 .sup.1H NMR (400 MHz, DMSO-d6) δ = 11.32-11.22 (m, 1H), 7.67-7.58 (m, 1H), 7.58-7.50 (m, 718.2 718.1 1H), 7.22-7.10 (m, 3H), 7.02-6.93 (m, 2H), 5.11-5.03 (m, 2H), 4.46-4.35 (m, 2H), 4.08-3.97 (m, 2H), 3.96-3.92 (m, 2H), 3.35 (s, 3H), 2.90-2.72 (m, 3H), 1.84-1.76 (m, 2H), 1.62 (s, 6H), 1.56- 1.49 (m, 2H), 1.40 (s, 9H) A116 .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.12-8.25 (m, 1H), 7.61-7.65 (m, 1H), 7.54-7.58 (m, 1H), 619.2 619.1 7.17-7.22 (m, 2H), 6.93-7.01 (m, 2H), 6.47-6.51 (m, 1H), 4.84-4.89 (m, 2H), 4.38-4.45 (m, 2H), 3.93-3.98 (m, 2H), 3.56-3.63 (m, 4H), 3.15 (s, 3H), 2.74-2.79 (m, 4H), 1.63 (s, 6H) A117 .sup.1H NMR (400 MHz, CDCl3) δ = 9.11-9.76 (m, 1H), 7.32-7.38 (m, 1H), 7.22-7.26 (m, 1H), 719.2 719.1 7.00-7.08 (m, 2H), 6.81-6.90 (m, 2H), 6.30-6.35 (m, 1H), 4.90-5.04 (m, 2H), 4.23-4.39 (m, 2H), 3.80 (t, J = 6.4 Hz, 2H), 3.63 (br s, 4H), 3.40-3.53 (m, 4H), 3.30 (s, 3H), 1.56 (s, 6H), 1.38-1.44 (m, 9H) A119 .sup.1H NMR (400 MHz, DMSO-d6) δ = 11.36 (br s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 2.4 565.1 547.2 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.22 (br d, J = 4.8 Hz, 1H), 7.08 (dd, (M + H − H.sub.2O) J = 2.4, 8.4 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 5.14 (s, 2H), 5.05 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.47-4.37 (m, 2H), 4.00-3.91 (m, 2H), 3.35 (s, 3H), 1.63 (s, 6H) A120 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.62-7.57 (m, 2H), 7.43 (dd, J = 1.6, 8.0 Hz, 1H), 7.38 (s, 1H), 517.1 517.0 7.31 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 2.8 Hz, 1H), 7.11-7.07 (m, 2H), 4.53 (s, 2H), 4.42 (t, J = 6.0 Hz, 2H), 3.90 (t, J = 6.0 Hz, 2H), 3.62 (t, J = 6.0 Hz, 2H), 3.07 (t, J = 6.0 Hz, 2H), 2.89 (s, 3H) A121 NA 563.1 563.0 A122 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.66 (d, J = 4.8 Hz, 1H), 8.63-8.56 (m, 1H), 7.30 (d, J = 5.2 Hz, 509.0 508.7 1H), 7.23-7.21 (m, 1H), 7.04-6.96 (m, 5H), 5.12 (s, 2H), 4.39 (t, J = 6.0 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.49 (s, 3H). A123 NA 531.0 530.9 A124 NA 555.1 554.9 A125 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.48-7.41 (m, 2H), 7.31 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 8.8 Hz, 552.1 552.0 3H), 6.91 (d, J = 8.8 Hz, 2H), 5.12 (s, 2H), 4.43 (t, J = 6.0 Hz, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.50 (s, 3H), 1.65 (s, 6H). A126 NA 554.2 554.0 A128 NA 521.0 520.9 A129 NA 501.1 501.0 A130 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.61-7.54 (m, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.39-7.31 (m, 2H), 551.1 551.0 7.24-7.17 (m, 1H), 7.13 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.58 (br s, 1H), 5.13 (s, 2H), 4.43 (t, J = 6.4 Hz, 2H), 3.88 (t, J = 6.4 Hz, 2H), 3.07 (s, 3H), 1.65 (s, 6H). A131 NA 551.1 551.0 A132 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.03 (br s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 576.2 576.1 1H), 7.32-7.28 (m, 2H), 7.13 (d, J = 8.8 Hz, 2H), 6.93-6.87 (m, 2H), 5.11 (s, 2H), 3.47 (s, 3H), 3.41 (br t, J = 5.2 Hz, 4H), 2.24-2.10 (m, 4H), 1.64 (s, 6H). A133 NA 566.2 566.2 A134 NA 623.2 623.1 A135 .sup.1H-NMR (400 MHz, MeOD) δ = 8.44 (d, J = 5.6 Hz, 1H), 7.55 (s, 2H), 7.34 (d, J = 8.8 Hz, 535.1 534.7 2H), 7.15 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 6.0 Hz, 1H), 4.44 (t, J = 5.6 Hz, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.35 (s, 3H), 3.00 (s, 3H), 1.71 (s, 6H). A136 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.77 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 519.1 519.1 7.40 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 9.2 Hz, 2H), 5.13 (s, 2H), 3.78 (t, J = 7.6 Hz, 2H), 3.47 (s, 3H), 3.43 (t, J = 7.2 Hz, 2H), 1.66 (s, 6H). A137 NA 497.1 518.9 (M + Na.sup.+) A138 NA 586.1 586.1 A140 NA 530.2 530.2 A141 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.42 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.08 (d, 501.2 523.0 J = 8.8 Hz, 2H), 6.74-6.67 (m, 2H), 4.60-4.57 (m, 1H), 4.49-4.45 (m, 1H), 3.97 (d, J = 11.2 (M + Na.sup.+) Hz, 4H), 2.86 (s, 3H), 2.79-2.71 (m, 2H), 2.44-2.34 (m, 2H), 1.64 (s, 6H), 1.05-0.98 (m, 2H), 0.72-0.69 (m, 2H). A142 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.37 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.09 (d, 530.2 530.2 J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 5.09 (s, 1H), 4.07 (s, 2H), 3.85 (t, J = 4.4 Hz, 4H), 3.33 (t, J = 4.4 Hz, 4H), 3.00 (s, 3H), 2.12 (s, 6H), 1.62 (s, 6H). A143 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.41 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 501.2 523.1 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.95 (s, 1H), 4.49-4.45 (m, 1H), 4.08 (s, 2H), 3.01 (s, (M + Na.sup.+) 3H), 2.12 (s, 6H), 1.64 (s, 6H), 1.05-0.98 (m, 2H), 0.74-0.67 (m, 2H). A145 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.44 (br s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.91 (br d, J = 8.4 Hz, 545.1 545.0 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.54 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 2.8 Hz, 1H), 7.02 (d, J = 3.2 Hz, 1H), 4.37 (t, J = 6.0 Hz, 2H), 3.89 (t, J = 6.0 Hz, 2H), 3.27 (br s, 3H) A146 NA 541.2 541.1 A147 NA 527.1 527.0 A148 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.64 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 568.2 568.1 2.0 Hz, 1H), 7.30 (br s, 1H), 7.13 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.11 (s, 2H), 3.93 (t, J = 4.4 Hz, 2H), 3.47 (s, 3H), 3.43-3.38 (m, 2H), 3.28 (s, 2H), 1.64 (s, 6H), 0.91-0.85 (m, 2H), 0.72-0.63 (m, 2H). A149 NA 554.2 554.0 A150 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.45 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 537.1 536.9 8.4 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 4.57 (q, J = 6.8 Hz, 1H), 4.46-4.35 (m, 3H), 3.96-3.84 (m, 3H), 2.93 (s, 3H), 2.68-2.44 (m, 4H), 2.27-2.20 (m, 2H), 2.05 (br t, J = 9.6 Hz, 2H), 1.63 (s, 6H). A151 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.52 (s, 2H), 7.49 (br s, 1H), 7.42 (br d, J = 8.0 Hz, 2H), 7.36 588.2 588.0 (br s, 1H), 7.31-7.28 (m, 1H), 7.26-7.23 (m, 1H), 5.37 (br d, J = 6.8 Hz, 1H), 4.44 (br t, J = 6.0 Hz, 2H), 4.10-3.97 (m, 1H), 3.88 (br t, J = 6.0 Hz, 2H), 3.78 (br d, J = 12.0 Hz, 2H), 2.97 (br t, J = 10.8 Hz, 2H), 2.82 (s, 3H), 2.22 (br d, J = 10.8 Hz, 2H), 1.70 (br s, 8H). A152 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.95 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 576.2 576.1 7.32-7.28 (m, 2H), 7.13 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.11 (s, 2H), 3.56-3.49 (m, 2H), 3.47 (s, 3H), 3.29-3.24 (m, 2H), 2.12-1.95 (m, 4H), 1.64 (s, 6H). A153 NA 558.2 558.2 A154 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.46 (s, 1H), 8.16 (s, 1H), 7.90 (br d, J = 7.6 Hz, 1H), 7.71 (d, 491.1 491.0 J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.10 (dd, J = 2.8, 12.0 Hz, 1H), 7.01 (dd, J = 1.6, 2.8 Hz, 1H), 4.38 (s, 1H), 3.28 (br s, 3H), 1.03-0.96 (m, 2H), 0.76-0.68 (m, 2H). A155 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.44 (br s, 1H), 8.15 (s, 1H), 7.89 (br d, J = 8.0 Hz, 1H), 7.71 513.1 513.0 (br d, J = 8.8 Hz, 2H), 7.62-7.47 (m, 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.09 (dd, J = 2.8, 12.0 Hz, 1H), 7.02 (br s, 1H), 4.48 (t, J = 5.6 Hz, 2H), 3.86 (t, J = 6.0 Hz, 2H), 3.28 (br s, 3H). A157 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 11.15 (s, 1H), 8.23 (d, J = 10.8 Hz, 1H), 8.18 (s, 1H), 8.02 546.0 5 545.8 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 2.8 Hz, 1H), 7.62 (d, J = 2.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 4.42 (t, J = 5.2 Hz, 2H), 3.98 (t, J = 5.2 Hz, 2H), 3.52 (s, 3H). A158 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.06 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 565.1 565.0 7.18-7.12 (m, 4H), 6.89 (d, J = 8.8 Hz, 2H), 5.11 (s, 2H), 3.69 (d, J = 10.4 Hz, 6H), 3.47 (s, 3H), 2.58 (s, 4H), 1.64 (s, 6H). A160 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.05 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 599.1 599.1 7.18-7.13 (m, 4H), 6.89 (d, J = 8.8 Hz, 2H), 5.11 (s, 2H), 3.78 (s, 2H), 3.47 (s, 3H), 2.79 (t, J = 11.2 Hz, 2H), 2.56 (t, J = 4.4 Hz, 2H), 1.93-1.82 (m, 2H), 1.77-1.70 (m, 2H), 1.64 (s, 6H). A161 NA 565.1 565.0 A162 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.64 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 522.1 522.0 7.11 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 6.4 Hz, 2H), 6.90 (d, J = 2.8 Hz, 1H), 6.72 (d, J = 3.2 Hz, 1H), 5.13 (s, 2H), 4.31 (t, J = 6.4 Hz, 2H), 3.86 (t, J = 6.4 Hz, 2H), 3.49 (s, 3H), 3.24 (s, 3H) A163 NA 520.1 519.8 A165 NA 610.1 610.1 A166 NA 571.1 571.0 A167 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.63 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.17-7.14 (m, 542.2 542.0 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.10 (s, 2H), 4.77-4.72 (m, 2H), 4.35 (dd, J = 4.4, 9.6 Hz, 2H), 4.22-4.15 (m, 1H), 3.47 (s, 3H), 3.33 (s, 3H), 1.59 (s, 6H). A168 NA 576.2 576.1 A169 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.61 (d, J = 5.2 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J = 1.2 Hz, 1H), 556.2 556.0 7.26 (br s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.10 (s, 2H), 4.50-4.46 (m, 1H), 3.78 (br t, J = 6.8 Hz, 2H), 3.46 (s, 3H), 3.07 (br t, J = 6.4 Hz, 2H), 3.00 (br t, J = 7.2 Hz, 2H), 2.77 (br t, J = 8.4 Hz, 2H), 1.64 (s, 6H). A170 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.63 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 502.1 501.9 2.4 Hz, 1H), 7.28 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.12 (s, 2H), 4.28 (t, J = 4.8 Hz, 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.48 (s, 3H), 1.61 (s, 6H) A171 NA 489.1 489.0 A177 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.46 (s, 1H), 8.18 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.69 (d, 546.1 546.0 J = 8.8 Hz, 2H), 7.56 (s, 1H), 7.32 (d, J = 3.2 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 2.8 Hz, 1H), 4.44-4.39 (m, 1H), 3.28 (s, 3H), 2.82-2.77 (m, 1H), 1.07-1.03 (m, 2H), 1.01-0.95 (m, 2H), 0.72-0.66 (m, 4H). A178 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.65 (br d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.31-7.28 515.1 515.0 (m, 2H), 7.13 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.11 (s, 2H), 4.15 (t, J = 6.4 Hz, 2H), 3.47 (s, 3H), 1.94-1.84 (m, 2H), 1.64 (s, 6H), 1.09 (t, J = 7.6 Hz, 3H). A179 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.95 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 483.1 483.1 7.42 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 5.6 Hz, 1H), 7.14 (d, J = 9.2 Hz, 2H), 6.92-6.87 (m, 3H), 6.04 (d, J = 17.6 Hz, 1H), 5.78 (d, J = 11.6 Hz, 1H), 5.13 (s, 2H), 3.47 (s, 3H), 1.66 (s, 6H) A180 NA 612.2 612.0 A181 NA 565.1 565.0 A182 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.94 (br s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 7.59-7.53 (m, 2H), 563.1 563.0 7.46 (d, J = 2.0 Hz, 1H), 7.44-7.36 (m, 3H), 7.32 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.15-7.10 (m, 2H), 6.93-6.87 (m, 2H), 5.20 (s, 2H), 5.11 (s, 2H), 3.47 (s, 3H), 1.65 (s, 6H). A183 NA 594.1 594.0 A184 NA 585.2 585.0 A185 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.61 (d, J = 4.8 Hz, 1H), 8.21 (s, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 507.1 506.9 7.10 (br d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.10 (s, 2H), 4.42 (t, J = 6.0 Hz, 2H), 3.90- 3.86 (m, 4H), 3.48 (s, 3H). A187 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.44 (br s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.94-7.87 (m, 1H), 7.67 523.1 523.0 (d, J = 8.4 Hz, 2H), 7.54 (br d, J = 5.2 Hz, 1H), 7.24-7.16 (m, 3H), 7.06 (d, J = 2.8 Hz, 1H), 4.45- 4.37 (m, 1H), 3.27 (s, 3H), 1.11-1.00 (m, 2H), 0.74-0.59 (m, 2H). A188 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.54-8.30 (m, 1H), 8.15 (br s, 1H), 7.92-7.79 (m, 1H), 7.70 (br 509.1 509.0 d, J = 8.0 Hz, 2H), 7.62-7.42 (m, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.17-7.12 (m, 3H), 4.15 (t, J = 6.4 Hz, 2H), 3.26 (br s, 3H), 1.97-1.87 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H). A189 NA 563.1 562.9 A190 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.44 (s, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 1.6 Hz, 1H), 541.1 541.0 7.71 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 2.8 Hz, 1H), 7.39 (d, J = 3.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 4.65-4.62 (m, 1H), 3.27 (s, 3H), 1.03-0.94 (m, 2H), 0.88-0.81 (m, 2H). A191 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ = 11.27 (br s, 1H), 8.22 (d, J = 10.8 Hz, 1H), 8.17 (s, 1H), 524.1 524.0 8.04-7.98 (m, 1H), 7.97-7.92 (m, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 2.8 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 4.45-4.37 (m, 1H), 3.48 (br s, 3H), 0.94-0.86 (m, 2H), 0.74-0.67 (m, 2H). A192 NA 507.1 507.0 A193 .sup.1H-NMR (400 MHz, MeOD) δ = 8.22 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.88-7.82 (m, 3H), 7.71 507.1 507.1 (dd, J = 2.0, 8.4 Hz, 1H), 7.45 (d, J = 2.8 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.22-7.17 (m, 2H), 4.50-4.44 (m, 1H), 3.27 (s, 3H), 1.02-0.96 (m, 2H), 0.73-0.67 (m, 2H) A194 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.41 (s, 1H), 8.14 (s, 1H), 7.89 (dd, J = 1.6, 8.8 Hz, 1H), 7.78 429.1 429.0 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 2.8 Hz, 1H), 7.16-7.13 (m, 3H), 5.74 (s, 2H), 4.45-4.49 (m, 1H), 1.06-1.03 (m, 2H), 0.74-0.69 (m, 2H) A195 NA 521.1 521.0 A196 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.97 (s, 1H), 8.86 (s, 2H), 7.57 (br d, J = 8.8 Hz, 2H), 7.33 (d, 457.1 457.0 J = 2.8 Hz, 1H), 7.16 (br d, J = 8.0 Hz, 3H), 4.51-4.45 (m, 1H), 3.53 (s, 3H), 1.05-1.02 (m, 2H), 0.75-0.70 (m, 2H). A197 NA 483.1 483.2 A198 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.44 (br s, 1H), 8.15 (s, 1H), 7.89 (br d, J = 8.8 Hz, 1H), 7.72 498.1 498.1 (br d, J = 8.8 Hz, 2H), 7.63-7.48 (m, 1H), 7.45 (s, 2H), 7.15 (d, J = 8.8 Hz, 2H), 4.62-4.56 (m, 1H), 3.27 (br s, 3H), 1.11-1.04 (m, 2H), 0.94-0.87 (m, 2H) A199 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.45 (br s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.90 (d, J = 8.8 Hz, 572.1 572.2 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.57 (br s, 1H), 7.21 (d, J = 8.8 Hz, 2H), 6.97 (dd, J = 2.8, 12.8 Hz, 1H), 6.92-6.87 (m, 1H), 4.36-4.27 (m, 3H), 3.27 (br s, 3H), 1.01-0.95 (m, 2H), 0.73-0.67 (m, 2H). A200 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.26 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.86-7.83 (m, 1H), 7.81- 443.1 443.0 7.78 (m, 1H), 7.76-7.71 (m, 2H), 7.33 (d, J = 3.2 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 7.14-7.11 (m, 2H), 5.09 (br s, 1H), 4.49-4.44 (m, 1H), 3.18 (d, J = 5.2 Hz, 3H), 1.07-1.05 (m, 2H), 0.72- 0.70 (m, 2H). A202 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.67 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.15 (d, J = 8.8 568.1 568.2 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 3.2 Hz, 1H), 6.72 (d, J = 3.2 Hz, 1H), 5.15 (s, 2H), 4.40-4.34 (m, 1H), 4.19 (q, J = 8.4 Hz, 2H), 3.49 (s, 3H), 1.04-0.99 (m, 2H), 0.69-0.62 (m, 2H) A204 NA 499.1 499.2 A205 NA 485.1 485.0 A206 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.71 (s, 1H), 8.16 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.82 (d, 547.1 547.0 J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.34 (s, 1H), 7.19-7.12 (m, 3H), 4.47 (s, 1H), 4.39 (s, 4H), 3.20 (s, 4H), 1.07-1.05 (m, 2H), 0.73-0.71 (m, 2H). A208 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.44 (s, 1H), 8.15 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.67 (d, 504.1 504.0 J = 8.8 Hz, 2H), 7.53 (s, 1H), 7.21 (d, J = 8.8 Hz, 2H), 6.96 (dd, J = 2.8, 13.2 Hz, 1H), 6.90 (s, 1H), 4.32-4.29 (m, 1H), 3.36 (s, 3H), 3.27 (s, 3H), 1.02-0.95 (m, 2H), 0.70-0.65 (m, 2H). A209 NA 509.1 509.2 A210 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.05 (br s, 1H), 7.72-7.63 (m, 3H), 7.44 (d, J = 8.8 Hz, 1H), 509.1 509.1 7.31 (d, J = 3.2 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 7.13-7.05 (m, 2H), 6.96 (br s, 1H), 4.49-4.44 (m, 1H), 4.08 (s, 3H), 3.20 (s, 3H), 1.11-1.00 (m, 2H), 0.76-0.64 (m, 2H). A211 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.23 (d, J = 2.0 Hz, 1H), 8.05 (dd, J = 2.0, 9.2 Hz, 1H), 7.68 (d, 523.1 523.0 J = 8.4 Hz, 2H), 7.61 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.18-7.15 (m, 3H), 6.27 (s, 1H), 4.51-4.46 (m, 1H), 3.37 (s, 3H), 1.08-1.04 (m, 2H), 0.76-0.71 (m, 2H). A212 NA 470.1 470.0 A213 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.97 (s, 1H), 8.67 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 471.1 471.1 2.8 Hz, 1H), 7.17-7.13 (m, 3H), 5.38 (br s, 1H), 4.56 (d, J = 5.6 Hz, 2H), 4.51-4.45 (m, 1H), 3.02 (s, 3H), 1.09-1.02 (m, 2H), 0.75-0.70 (m, 2H). A214 NA 471.1 471.1 A215 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.26 (s, 1H), 8.11 (s, 1H), 7.91-7.84 (m, 1H), 7.78 (br d, J = 8.8 561.1 561.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 2.8 Hz, 1H), 7.17-7.11 (m, 3H), 5.03-4.80 (m, 1H), 4.53-4.37 (m, 2H), 3.33-3.14 (m, 4H), 2.64-2.53 (m, 2H), 2.38-2.22 (m, 2H), 1.11-1.01 (m, 2H), 0.77-0.67 (m, 2H) A216 NA 533.1 533.0 A217 NA 474.1 474.0 A218 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.43 (br s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.4 Hz, 483.1 483.1 1H), 7.87 (dd, J = 1.6, 8.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.59-7.49 (m, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.15-7.07 (m, 2H), 4.42-4.27 (m, 1H), 3.27 (s, 3H), 0.88-0.83 (m, 4H). A219 NA 508.1 508.0 A221 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.79 (d, J = 5.2 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 7.18-7.14 (m, 582.1 582.2 2H), 7.08-7.04 (m, 2H), 6.95 (d, J = 2.8 Hz, 1H), 6.73 (d, J = 3.2 Hz, 1H), 5.61 (br s, 1H), 5.19 (s, 2H), 4.62 (d, J = 5.2 Hz, 2H), 4.40-4.33 (m, 1H), 4.23-4.16 (m, 2H), 3.02 (s, 3H), 1.03-0.99 (m, 2H), 0.68-0.63 (m, 2H). A222 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.36 (br s, 1H), 8.08 (s, 1H), 7.82 (br d, J = 8.8 Hz, 1H), 7.62 (d, 570.1 570.0 J = 8.4 Hz, 2H), 7.47 (br s, 1H), 7.17 (d, J = 2.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 2.8 Hz, 1H), 6.09-5.79 (m, 1H), 4.38-4.35 (m, 1H), 4.05-3.99 (m, 2H), 3.27 (br s, 3H), 0.99-0.95 (m, 2H), 0.65-0.61 (m, 2H). A223 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.91 (br s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 5.2 Hz, 597.1 597.0 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 9.2 Hz, 2H), 6.89 (d, J = 3.2 Hz, 1H), 6.73 (d, J = 3.2 Hz, 1H), 5.16 (s, 2H), 4.25-4.14 (m, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.48 (s, 3H), 3.24 (s, 4H). A225 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.68 (s, 1H), 8.06 (s, 1H), 7.67 (s, 1H), 7.46 (d, J = 2.8 Hz, 1H), 510.1 510.1 7.29 (br s, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.86-6.80 (m, 2H), 5.66 (s, 2H), 4.46-4.35 (m, 1H), 3.04 (s, 3H), 1.00-0.94 (m, 2H), 0.91-0.85 (m, 2H). A226 NA 506.1 506.1 A227 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.09 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 2.8 Hz, 510.1 510.1 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 2.8 Hz, 1H), 6.85 (s, 1H), 5.64 (s, 2H), 4.45-4.37 (m, 1H), 3.05 (s, 3H), 1.00-0.95 (m, 2H), 0.92-0.87 (m, 2H). A229 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.95 (s, 1H), 7.77 (s, 1H), 7.22 (d, J = 2.8 Hz, 1H), 7.00 (s, 541.1 541.5 5H), 6.82 (s, 1H), 4.45-4.40 (m, 1H), 3.8 (t, J = 4.8 Hz 4H), 3.34-3.27 (m, 7H), 1.07-1.00 (m, 2H), 0.72-0.64 (m, 2H). A230 NA 541.1 541.1 A231 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.05 (s, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.01 (s, 5H), 6.15 (s, 500.1 500.1 1H), 4.48-4.41 (m, 1H), 4.40 (s, 2H), 4.30 (t, J = 5.6 Hz, 2H), 3.74 (t, J = 5.2 Hz, 2H), 3.05 (s, 3H), 1.06-0.99 (m, 2H), 0.71-0.66 (m, 2H) A232 NA 512.1 512.2 A233 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.43 (s, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.11 (s, 1H), 7.86 (br d, 584.2 584.1 J = 7.6 Hz, 1H), 7.64 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.51 (s, 1H), 6.96 (d, J = 8.8 Hz, 2H), 4.29 (q, J = 8.4 Hz, 2H), 3.90-3.85 (m, 4H), 3.75-3.71 (m, 4H), 3.26 (br s, 3H) A234 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 7.99 (d, J = 3.2 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H), 7.05 (d, J = 523.2 523.1 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.99 (s, 1H), 4.34-4.26 (m, 1H), 4.19 (q, J = 8.4 Hz, 2H), 4.10 (s, 2H), 3.02 (s, 3H), 2.14 (s, 6H), 0.86-0.78 (m, 4H) A235 NA 522.2 522.1 A237 NA 500.1 500.0 A238 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.28 (br s, 1H), 8.74-8.66 (m, 1H), 7.32 (br d, J = 4.8 Hz, 1H), 590.1 590.0 7.16 (d, J = 8.0 Hz, 2H), 7.06 (br d, J = 8.4 Hz, 2H), 6.93 (br s, 1H), 6.72 (br s, 1H), 5.16 (s, 2H), 4.33 (t, J = 6.0 Hz, 2H), 4.19 (q, J = 8.8 Hz, 2H), 3.86 (t, J = 6.4 Hz, 2H), 3.49 (s, 3H). A239 NA 569.2 569.1 A240 NA 498.2 498.0 A241 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 9.08 (s, 1H), 7.93 (dd, J = 2.4, 8.8 Hz, 1H), 7.85 (d, J = 1.6 Hz, 498.2 498.1 1H), 7.71-7.64 (m, 3H), 7.32 (d, J = 2.8 Hz, 1H), 7.14-7.11 (m, 3H), 4.49-4.44 (m, 1H), 4.04 (t, J = 5.2 Hz, 4H), 3.06 (t, J = 4.8 Hz, 4H), 1.09-1.02 (m, 2H), 0.75-0.68 (m, 2H) A242 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.63 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.0, 8.4 Hz, 540.2 540.2 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 3.2 Hz, 1H), 7.16-7.12 (m, 3H), 4.48-4.44 (m, 1H), 3.92-3.87 (m, 2H), 3.83 (br s, 4H), 3.71-3.65 (m, 2H), 2.19 (s, 3H), 1.09-1.01 (m, 2H), 0.75-0.68 (m, 2H). A243 NA 504.2 504.2 A244 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.34 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 546.2 546.1 2.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 5.2 Hz, 1H), 4.97 (s, 2H), 4.49-4.45 (m, 1H), 3.91-3.83 (m, 4H), 3.75-3.67 (m, 2H), 3.59-3.51 (m, 2H), 2.17 (s, 3H), 1.64 (s, 6H), 1.05-0.98 (m, 2H), 0.76-0.67 (m, 2H). A245 .sup.1H-NMR (400 MHz, CDCl.sub.3) δ = 8.38 (d, J = 5.2 Hz, 1H), 7.15-7.11 (m, 2H), 7.05-7.01 (m, 2H), 601.2 601.2 6.93 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 4.8 Hz, 1H), 6.72 (d, J = 3.2 Hz, 1H), 5.02 (s, 2H), 4.39-4.32 (m, 1H), 4.18 (q, J = 8.8 Hz, 2H), 3.92-3.85 (m, 4H), 3.73-3.68 (m, 2H), 3.58-3.52 (m, 2H), 2.17 (s, 3H), 1.03-0.97 (m, 2H), 0.67-0.62 (m, 2H).

    [1474] Biological Assays

    Example 19: Activity of Exemplary Compounds in Cellular Assays

    [1475] The PSA (6.1 kb)-luciferase reporter contains functional AREs (androgen response elements) to which AR binds in response to androgen to induce luciferase activity. LNCaP cells were transiently transfected with the PSA (6.1 kb)-luciferase reporter for 24 h, and then pretreated with vehicle (DMSO) or indicated concentration of representative compounds for one hour prior to the addition of synthetic androgen, R1881 (1 nM). After 24 h of incubation with R1881, the cells were harvested, and relative luciferase activities were determined (FIG. 1). To determine the IC.sub.50, treatments were normalized to vehicle control activity induced by R1881 (Table 2).

    [1476] Luciferase Assay A: Cells were lysed using Passive Lysis Buffer (Promega) and then collected into V-bottom 96-well tissue culture plates. Lysates were centrifuged at 4° C. for 5 minutes at 3000 rpm. To measure luminescence of LNCaP cell lysates the Firefly Luciferase Assay System (Promega) was employed, according to manufacturer's protocol. Relative luminescence units (RLU) in cell lysates were detected for 10 seconds using Promega GloMax-Multi Detection Luminometer (Promega). Values were normalized to protein content. GraphPad Prism graphing software was used to calculate IC.sub.50 values. Luciferase Assay A was run for all compounds in Table 2 unless otherwise noted below.

    [1477] Luciferase Assay B: Cells stably expressing probasin promoter (ARR2PB) or human prostate-specific antigen (PSA)-firefly luciferase reporter were plated in poly-D-lysine-coated 384-well plates. 48 h after plating, cells were pretreated with vehicle or compounds for 1 h before adding R1881 under serum-free and phenol red-free conditions and then further incubated for 24 h. R1881 was added only for LNCaP cells. Firefly luciferase activities were determined by EnVision plate reader (Perkinemer) using the Steady-Glo Luciferase Reporter Assay System (Promega). Values were normalized to protein content. GraphPad Prism graphing software was used to calculate IC.sub.50 values. Luciferase Assay B was run for Compounds A186-A219 and A221-A245 in Table 2.

    [1478] Statistical analyses were performed using GraphPad Prism (Version 6.01 for Windows; La Jolla, CA, USA). Comparisons between treatment and control groups were compared using Two-Way ANOVA with post-hoc Dunnett's and Tukey's tests. Differences were considered statistically significant at P values less than 0.05.

    [1479] Table 2 shows IC.sub.50 ranges of Compounds from Table A.

    TABLE-US-00003 TABLE 2 IC.sub.50 Ranges of Various Compounds in Androgen-Induced PSA-Luciferase Assay Compound ID PSA-Luc IC50 Range A1   ** A2   ** A3   ** A4   ** A5   ** A6   *** A7   * A8   * A9   * A10  ** A11  ** A12  ** A13  * A14  ** A15  ** A16  ** A17  ** A18  A19  A20  * A21  ** A22  ** A23  * A24  ** A25  * A26  * A27  * A28  ** A29  * A30  * A31  * A32  *** A33  * A34  * A35  * A36  *** A37  *** A38  ** A39  ** A40  * A41  * A42  ** A43  *** A44  *** A45  ** A46  * A47  * A48  * A49  ** A50  *** A51  * A52  ** A53  *** A54  *** A55  *** A56  * A57  A58  * A59  ** A60  ** A61  ** A62  ** A63  ** A64  ** A65  * A66  * A67  ** A68  *** A69  ** A70  * A71  ** A72  ** A73  A74  ** A75  ** A76  ** A77  * A78  ** A79  * A80  *** A81  *** A82  *** A83  ** A84  ** A85  ** A86  ** A87  ** A88  * A89  A90  A91  A92  A93  * A94  ** A95  ** A96  *** A97  ** A98  ** A99  ** A100 ** A101 ** A102 * A103 ** A104 * A105 ** A106 ** A107 * A108 ** A109 * A110 ** A111 * A112 ** A113 * A114 * A115 ** A116 * A117 * A118 *** A119 * A120 * A121 ** A122 * A123 * A124 ** A125 ** A126 * A127 A128 * A129 * A130 ** A131 ** A132 * A133 * A134 ** A135 ** A136 ** A137 ** A138 ** A139 ** A140 ** A141 ** A142 ** A143 ** A144 A145 ** A146 ** A147 ** A148 ** A149 ** A150 ** A151 * A152 ** A153 * A154 ** A155 ** A156 A157 ** A158 A159 * A160 * A161 * A162 ** A163 *** A164 ** A165 * A166 ** A167 * A168 * A169 * A170 * A171 * A172 A173 A174 A175 A176 A177 ** A178 *** A179 ** A180 * A181 * A182 ** A183 * A184 * A185 * A186 *** A187 ** A188 ** A189 ** A190 ** A191 ** A192 *** A193 ** A194 * A195 ** A196 ** A197 ** A198 *** A199 *** A200 * A201 ** A202 *** A203 *** A204 * A205 ** A206 ** A207 ** A208 *** A209 * A210 ** A211 * A212 ** A213 ** A214 ** A215 ** A216 * A217 * A218 ** A219 ** A220 A221 *** A222 *** A223 *** A224 *** A225 ** A226 ** A227 ** A228 * A229 * A230 *** A231 * A232 ** A233 ** A234 ** A235 * A236 *** A237 ** A238 *** A239 *** A240 * A241 * A242 ** A243 ** A244 *** A245 *** Note: *** represent IC.sub.50 < 500 nM, ** represents IC.sub.50 in the range of 500-2000 nM, * represents IC.sub.50 in the range of >2000 nM

    Example 20: Stability Assays

    [1480] Microsomal Stability Assay: Microsomal stability assay is a widely used in vitro model to characterize the metabolic conversion by phase I enzymes, such as cytochrome P450 (CYP) enzymes. Since metabolism is known to be highly variable in different species, microsomal stability assay is commonly run in multiple species. Metabolic stability of testing compound can be evaluated using human, rat, mouse, or other animal liver or intestine microsomes to predict intrinsic clearance.

    [1481] The assay was carried out in 96-well microtiter plates at 37° C. Reaction mixtures (25 μL) contained a final concentration of 1 μM test compound, 0.5 mg/mL liver microsomes protein, and 1 mM NADPH and/or 1 mM UDPGA (with alamethicin) in 100 mM potassium phosphate, pH 7.4 buffer with 3 mM MgCl.sub.2. The incubation was done with N=1, but duplicate incubation at each time point can be prepared if necessary. At each of the time points (for example, 0, 15, 30, and 60 minutes), 150 μL of quench solution (100% acetonitrile with 0.1% formic acid) with internal standard was transferred to each well. Besides the zero minute controls, mixtures containing the same components except the NADPH can also be prepared as the negative control. Verapamil was included as a positive control to verify assay performance. Plates were sealed, vortexed, and centrifuged at 4° C. for 15 minutes at 4000 rpm. The supernatant is transferred to fresh plates for LC/MS/MS analysis.

    [1482] Summarized conditions: [Compound]=1 μM, [LM]=0.5 mg/mL, [NADPH]=1 mM and/or [UDPGA]=1 mM, Buffer=100 mM Potassium Phosphate, pH 7.4 with 3 mM MgCl.sub.2, Time=0, 15, 30, and 60 min, and Temperature=37° C.

    [1483] All samples were analyzed on LC/MS/MS using an AB Sciex API 4000 instrument, coupled to a Shimadzu LC-20AD LC Pump system. Analytical samples were separated using a Waters Atlantis T3 dC18 reverse phase HPLC column (20 mm×2.1 mm) at a flow rate of 0.5 mL/min. The mobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1% formic acid in 100% acetonitrile (solvent B).

    [1484] The extent of metabolism is calculated as the disappearance of the test compound, compared to the 0-min time incubation. Initial rates are calculated for the compound concentration and used to determine half-life (t1/2).

    [1485] Liver microsome half life of representative compounds are shown in Tables 2. Compound X has the following structures:

    ##STR00403##

    TABLE-US-00004 TABLE 3 Liver Microsome Half-Life Compound Liver microsome + NADPH T½ (min) ID Human Mouse Rat Dog Monkey A1 >120 >120 61 62 >120 A11 58 >120 103 >120 28 A12 82 >120 72 >120 19 A15 >120 >120 >120 >120 >120 A16 >120 >120 >120 >120 >120 A17 >120 >120 >120 >120 >120 A22 >120 >120 >120 >120 >120 A24 >120 >120 >120 78 >120 A28 78 >120 >120 >120 >120 A36 >120 >120 66 >120 49 A37 >120 >120 >120 >120 32 A43 >120 >120 >120 >120 >120 A44 >120 >120 112 >120 117 A72 >120 >120 >120 >120 >120 A75 >120 >120 >120 >120 >120 A78 >120 >120 >120 >120 >120 A80 >120 96 >120 >120 >120 A81 >120 >120 >120 >120 >120 A82 >120 >120 >120 >120 >120 A83 >120 >120 >120 >120 >120 A84 101 >120 >120 >120 100 A94 >120 >120 >120 >120 117 A97 >120 >120 >120 >120 >120 A98 >120 >120 >120 >120 >120 A145 >120 >120 >120 >120 >120 A157 >120 >120 >120 >120 >120 A163 >120 >120 >120 >120 >120 A164 >120 >120 >120 >120 >120 A177 >120 >120 >120 >120 >120 A186 >120 >120 >120 >120 >120 A187 >120 >120 >120 >120 >120 A190 >120 >120 >120 >120 >120 A191 >120 >120 >120 >120 >120 A198 >120 >120 >120 >120 >120 A199 >120 >120 >120 >120 >120 A202 >120 >120 >120 >120 >120 A203 >120 >120 >120 >120 >120 A205 >120 >120 >120 >120 >120 A208 >120 >120 >120 >120 >120 X >120 NA NA NA NA Enzalutamide >120 >120 >120 >120 >120

    [1486] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

    [1487] While the invention has been described in connection with proposed specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.